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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Melarsoprol


Melarsoprol2DCSD.svg

Melarsoprol

MelarsoprolCAS Registry Number: 494-79-1 
CAS Name: 2-[4-[(4,6-Diamino-1,3,5-triazin-2-yl)amino]phenyl]-1,3,2-dithiarsolane-4-methanolAdditional Names:p-[(4,6-diamino-s-triazin-2-yl)amino]dithiobenzenearsonous acid 3-hydroxypropylene ester; 2-p-(4,6-diamino-s-triazin-2-ylamino)phenyl-4-hydroxymethyl-1,3,2-dithiarsoline; 2-(4-melamin-2-ylphenyl)-4-hydroxymethyl-1,3-dithia-2-arsolaneTrademarks: Mel B; Arsobal (Specia) 
Molecular Formula: C12H15AsN6OS2Molecular Weight: 398.34 
Percent Composition: C 36.18%, H 3.80%, As 18.81%, N 21.10%, O 4.02%, S 16.10%Literature References: Prepn: Friedheim, US2659723 (1953); US2772303 (1956).Properties: Practically insol in water, cold ethanol, methanol. Sol in propylene glycol. 
Therap-Cat: Antiprotozoal (Trypanosoma).Keywords: Antiprotozoal (Trypanosoma).

Melarsoprol is a medication used for the treatment of sleeping sickness (African trypanosomiasis).[1] It is specifically used for second-stage disease caused by Trypanosoma brucei rhodesiense when the central nervous system is involved.[1] For Trypanosoma brucei gambienseeflornithine or fexinidazole is usually preferred.[1] It is effective in about 95% of people.[3] It is given by injection into a vein.[2]

Melarsoprol has a high number of side effects.[4] Common side effects include brain dysfunction, numbness, rashes, and kidney and liver problems.[2] About 1-5% of people die during treatment.[3] In those with glucose-6-phosphate dehydrogenase (G6PD) deficiencyred blood cell breakdown may occur.[2] It has not been studied in pregnancy.[2] It works by blocking pyruvate kinase, an enzyme required for aerobic metabolism by the parasite.[2]

Melarsoprol has been used medically since 1949.[1] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[5] In regions of the world where the disease is common, melarsoprol is provided for free by the World Health Organization.[4] It is not commercially available in Canada or the United States.[2] In the United States, it may be obtained from the Centers for Disease Control and Prevention, while in Canada it is available from Health Canada.[1][2]

Medical uses

People diagnosed with trypanosome-caused disease should be treated with an anti-trypanosomal. Treatment is based on stage, 1 or 2, and parasite,T. b. rhodesiense or T. b. gambiense. In stage 1 disease, trypanosomes are present only in the peripheral circulation. In stage 2 disease, trypanosomes have crossed the blood-brain barrier and are present in the central nervous system.[6]

The following are considerable treatment options:[6]

Melarsoprol is a treatment used during the second stage of the disease. So far, it is the only treatment available for late-stage T. b. rhodesiense.[7]

Due to high toxicity, melarsoprol is reserved only for the most dangerous cases. Other agents associated with lower toxicity levels are used during stage 1 of the disease.[8] The approval of the nifurtimox-eflornithine combination therapy (NECT) in 2009 for the treatment of T. b. gambiense limited the use of melarsoprol to the treatment of second-stage T. b. rhodesiense.[9]

Failure rates of 27% in certain African countries have been reported.[10] This was caused by both drug resistance and additional mechanisms that have not yet been elucidated. Resistance is likely due to transport problems associated with the P2 transporter, an adenine-adenosine transporter. Resistance can occur with point mutations within this transporter.[11] Resistance has been present since the 1970s.[12]

Mechanism of action

Melarsoprol is a prodrug, which is metabolized to melarsen oxide (Mel Ox) as its active form. Mel Ox is an phenylarsonous acid derivative that irreversibly binds to sulfhydryl groups on pyruvate kinase, which disrupts energy production in the parasite. The inability to distinguish between host and parasite PK renders this drug highly toxic with many side effects.

Mel Ox also reacts with trypanothione (a spermidine-glutathione adduct that replaces glutathione in trypanosomes). It forms a melarsen oxide-trypanothione adduct (Mel T) that competitively inhibits trypanothione reductase, effectively killing the protist.[11]

Pharmacokinetics

The half-life of melarsoprol is less than one hour, but bioassays indicate a 35-hour half-life. This is commonly associated with pharmacologic agents that have active metabolites. One such metabolite, Mel Ox, reaches maximum plasma levels about 15 minutes after melarsoprol injection. Melarsoprol clearance is 21.5 ml/min/kg and the Mel Ox half-life is approximately 3.9 hours.[13]

Dosage

Two arsenic-containing stereoisomers exist in a 3:1 molar ratio. Since melarsoprol is insoluble in water, dosage occurs via a 3.6% propylene glycol intravenous injection.[11] To avoid the risk of injection site reactions, melarsoprol must be given slowly.[citation needed]

Melarsoprol used for the treatment of African trypanosomiasis with CNS involvement is given under a complicated dosing schedule. The dosing schedule for children and adults is 2–3.6 mg/kg/day intravenously for three days, then repeated every seven days for a total of three series.[6] To monitor for relapse, follow-up is recommended every six months for at least two years.[3]

Side effects

Although melarsoprol cures about 96% of people with late stage disease, its toxicity limits its use.[7] About 1-5% of people die during treatment.[3] As a toxic organic compound of arsenic, melarsoprol is a dangerous treatment that is typically only administered by injection under the supervision of a licensed physician. Notable side effects are similar to arsenic poisoning. Among clinicians, it is colloquially referred to as “arsenic in antifreeze”.[14] Severe and life-threatening adverse reactions are associated with melarsoprol. It is known to cause a range of side effects including convulsions, fever, loss of consciousness, rashes, bloody stools, nausea and vomiting. In approximately 5-10% of cases, it causes encephalopathy. Of those, about 50% die due to encephalopathy-related adverse reactions.[6] Additional potentially serious side effects of melarsoprol include damage to the heart, presence of albumin in the urine that could be associated with kidney damage, and an increase in blood pressure.[3]

Cautions

Numerous warnings must be examined before melarsoprol treatment can be initiated. Prior to initiation, the following must be noted: glucose-6-phosphate dehydrogenase deficiency, kidney or liver disease, cardiac problems (high blood pressure, irregular beating of the heart or arrhythmias, any damage to the heart muscles and potential signs of heart failure), preexisting nervous system disorders, and any signs of leprosy.

Routine laboratory testing is needed before and after melarsoprol initiation. Laboratory parameters for both therapeutic effects and toxic effects need to be evaluated.

Blood analysis is used to detect the presence of trypanosomes. An evaluation of the cerebrospinal fluid via a lumbar puncture is also used to determine an individual’s white blood count and level of protein. These are diagnostic criteria such that the presence of trypanosomes, an elevated white blood count greater than five per microliter, or a protein content greater than 40 mg are considered abnormal and initiation should be considered. Continuous cerebrospinal fluid evaluation should be repeated every six months for at least three years in individuals that have undergone melarsoprol treatment.

To assess potential concerns related to toxicity, the following should be completed: a complete blood count, an assessment of electrolyte levels, liver and kidney function tests, and a urinalysis to detect the appearance, concentration and content of the urine.

Melarsoprol should be given using glass syringes (if they can be reliably sterilised). The propylene glycol it contains is capable of dissolving plastic.[15]

Pregnancy and breastfeeding

Currently, melarsoprol is not recommended for use in pregnant women. The World Health Organization suggests that treatment be deferred until immediately after delivery since the effects of the medication on the developing fetus have not yet been established.[3]

Lactation guidelines associated with melarsoprol have not yet been established.

Society and culture

Melarsoprol is produced by Sanofi-Aventis and under an agreement with the WHO, they donate melarsoprol to countries where the disease is common.[medical citation needed]

Melarsoprol was used to treat a patient with African trypanosomiasis on season 1 episode 7 “Fidelity” of the medical drama House MD.[16]

PAPER

Journal of Organometallic Chemistry (2006), 691(5), 1081-1084.

https://www.sciencedirect.com/science/article/abs/pii/S0022328X05009344

Graphical abstract

(2-Phenyl-[1,3,2]dithiarsolan-4-yl)-methanol derivatives were tested on K562 and U937 human leukemia cell lines. Their systemic toxicity was estimated by the corresponding LD50 on mice. The cytotoxic activity of each derivative was significantly better than that of arsenic trioxide and the therapeutic index (T.I. = LD50/IC50) was improved.

References

  1. Jump up to:a b c d e f “Our Formulary Infectious Diseases Laboratories CDC”http://www.cdc.gov. 22 September 2016. Archived from the original on 16 December 2016. Retrieved 7 December 2016.
  2. Jump up to:a b c d e f g h “Melarsoprol Drug Information, Professional”http://www.drugs.com. 20 December 1994. Archived from the original on 30 December 2016. Retrieved 7 December 2016.
  3. Jump up to:a b c d e f “WHO Model Prescribing Information: Drugs Used in Parasitic Diseases – Second Edition: Protozoa: African trypanosomiasis: Melarsoprol”WHO. 1995. Archived from the original on 2016-11-10. Retrieved 2016-11-09.
  4. Jump up to:a b “Trypanosomiasis, human African (sleeping sickness)”World Health Organization. February 2016. Archived from the original on 4 December 2016. Retrieved 7 December 2016.
  5. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  6. Jump up to:a b c d CDC (2013). “Disease Control and Prevention: Parasites – African Trypanosomiasis”Archived from the original on 2017-06-19.
  7. Jump up to:a b “Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense (African Trypanosomiasis) – Infectious Disease and Antimicrobial Agents”http://www.antimicrobe.orgArchived from the original on 2016-11-28. Retrieved 2016-11-17.
  8. ^ Bisser S, N’Siesi FX, Lejon V, et al. (2007). “Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei rhodesiense sleeping sickness”J. Infect. Dis195 (3): 322–9. doi:10.1086/510534PMID 17205469.
  9. ^ Farrar J (2014). “Manson’s Tropical Diseases: Expert Consult-Online”. 23: 616.
  10. ^ Kioy, D.; Jannin, J.; Mattock, N. (March 2004). “Human African trypanosomiasis”Nature Reviews Microbiology2 (3): 186–187. doi:10.1038/nrmicro848PMID 15751187S2CID 36525641.
  11. Jump up to:a b c Brunton L (2011). “Goodman & Gillman’s The Pharmacological Basis of Therapeutics”. McGraw Hill Medical: 1427–28.
  12. ^ Brun, Reto; Schumacher, Reto; Schmid, Cecile; Kunz, Christina; Burri, Christian (November 2001). “The phenomenon of treatment failures in Human African Trypanosomiasis”. Tropical Medicine and International Health6 (11): 906–914. doi:10.1046/j.1365-3156.2001.00775.xPMID 11703845S2CID 21542129.
  13. ^ Keiser J.; Ericsson O; Burri C (2000). “Investigations of the metabolites of the trypanocidal drug melarsoprol”. Clinical Pharmacology67 (5): 478–88. doi:10.1067/mcp.2000.105990PMID 10824626S2CID 24326873.
  14. ^ Hollingham R (2005). “Curing diseases modern medicine has left behind”New Scientist2005 (2482): 40–41. Archived from the original on 2015-05-11.
  15. ^ “MELARSOPROL injectable – Essential drugs”medicalguidelines.msf.org. Retrieved 6 December 2019.
  16. ^ Holtz, Andrew (2006). The Medical Science of House, M.D.Penguin. p. 272. ISBN 1440628734. Retrieved 25 March 2020.

External links

Clinical data
Trade namesArsobal[1]
Other namesMel B, Melarsen Oxide-BAL[2]
AHFS/Drugs.comMicromedex Detailed Consumer Information
Routes of
administration
IV
ATC codeP01CD01 (WHOQP51AD04 (WHO)
Pharmacokinetic data
Elimination half-life35 hours
ExcretionKidney
Identifiers
showIUPAC name
CAS Number494-79-1 
PubChem CID10311
ChemSpider9889 
UNIIZF3786Q2E8
KEGGD00832 
ChEMBLChEMBL166 
CompTox Dashboard (EPA)DTXSID90862033 
ECHA InfoCard100.007.086 
Chemical and physical data
FormulaC12H15AsN6OS2
Molar mass398.33 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
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Isotretinoin


Isotretinoin structure.svg

Isotretinoin

Title: Isotretinoin

CAS Registry Number: 4759-48-2
CAS Name: 13-cis-Retinoic acid

Additional Names: 2-cis-vitamin A acid; neovitamin A acid

Manufacturers’ Codes: Ro-4-3780Trademarks: Accutane (Roche); Isotrex (Stiefel); Oratane (Douglas); Roaccutane (Roche)
Molecular Formula: C20H28O2Molecular Weight: 300.44Percent Composition: C 79.95%, H 9.39%, O 10.65%
Literature References: Naturally occurring metabolite of vitamin A, q.v.; inhibits sebum production. Prepn: C. D. Robeson et al.,J. Am. Chem. Soc.77, 4111 (1955). Stereoselective process: R. Lucci, EP111325idem,US4556518 (1984, 1985 both to Hoffmann-La Roche). Toxicology and teratogenicity study: J. J. Kamm, J. Am. Acad. Dermatol.6, 652 (1982). Identification as endogenous metabolite of all-trans-retinoic acid: M. E. Cullum, M. H. Zile, J. Biol. Chem.260, 10590 (1985). HPLC determn in serum: G. Tang, R. M. Russell, J. Lipid Res.31, 175 (1990). Review of pharmacology and clinical efficacy in acne: A. R. Shalita et al.,Cutis42, Suppl. 6A, 1-19 (1988). Symposium on clinical experience: Dermatology195, Suppl. 1, 1-37 (1997).
Properties: Reddish-orange plates from isopropyl alcohol, mp 174-175°. uv max: 354 nm (e 39800). LD50 (20 day) in mice, rats (mg/kg): 904, 901 i.p.; 3389, >4000 orally (Kamm).

Melting point: mp 174-175°Absorption maximum: uv max: 354 nm (e 39800)Toxicity data: LD50 (20 day) in mice, rats (mg/kg): 904, 901 i.p.; 3389, >4000 orally (Kamm)Therap-Cat: Antiacne.Keywords: Antiacne.

Isotretinoin, also known as 13-cis-retinoic acid and sold under the brand name Accutane among others, is a medication primarily used to treat severe acne. It is also used to prevent certain skin cancers (squamous-cell carcinoma), and in the treatment of other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body. Its isomertretinoin, is also an acne drug.

The most common adverse effects are a transient worsening of acne (lasting 1–4 months), dry lips (cheilitis), dry and fragile skin, and an increased susceptibility to sunburn. Uncommon and rare side effects include muscle aches and pains (myalgias), and headaches. Isotretinoin is known to cause birth defects due to in-utero exposure because of the molecule’s close resemblance to retinoic acid, a natural vitamin A derivative which controls normal embryonic development. It is also associated with psychiatric side effects, most commonly depression but also, more rarely, psychosis and unusual behaviours. Other rare side effects include hyperostosis, and premature epiphyseal closure, have been reported to be persistent.

In the United States, a special procedure is required to obtain the pharmaceutical. In most other countries, a consent form is required which explains these risks. In other countries, such as Israel, it is prescribed like any other medicine from a dermatologist (after proper blood tests).

Women taking isotretinoin must not get pregnant during and for one month after the discontinuation of isotretinoin therapy. Sexual abstinence or effective contraception is mandatory during this period. Barrier methods by themselves (e.g., condoms) are not considered adequate due to the unacceptable failure rates of approximately 3%. Women who become pregnant while taking isotretinoin therapy are generally counseled to have an abortion.

It was patented in 1969 and approved for medical use in 1982.[2] It sold well, but in 2009, Roche decided to discontinue manufacturing due to diminishing market share due to the availability of the many generic versions and the settling of multiple lawsuits over side effects. It continues to be manufactured as of 2019 by Absorica, Amnesteem, Claravis, Myorisan, Sotret, and Zenatane.[3]

Medical uses

Isotretinoin is used primarily for severe cystic acne and acne that has not responded to other treatments.[4][5][6][7] Many dermatologists also support its use for treatment of lesser degrees of acne that prove resistant to other treatments, or that produce physical or psychological scarring.[8] Isotretinoin is not indicated for treatment of prepubertal acne and is not recommended in children less than 12 years of age.[9]

It is also somewhat effective for hidradenitis suppurativa and some cases of severe rosacea.[10] It can also be used to help treat harlequin ichthyosis, lamellar ichthyosis and is used in xeroderma pigmentosum cases to relieve keratoses. Isotretinoin has been used to treat the extremely rare condition fibrodysplasia ossificans progressiva. It is also used for treatment of neuroblastoma, a form of nerve cancer.

Isotretinoin therapy has furthermore proven effective against genital warts in experimental use, but is rarely used for this indication as there are more effective treatments. Isotretinoin may represent an efficacious and safe alternative systemic form of therapy for recalcitrant condylomata acuminata (RCA) of the cervix. In most countries this therapy is currently unapproved and only used if other therapies failed.[11][12]

Prescribing restrictions

Isotretinoin is a teratogen; there is about a 20–35% risk for congenital defects in infants exposed to the drug in utero, and about 30–60% of children exposed to isotretinoin prenatally have been reported to show neurocognitive impairment.[13] Because of this, there are strict controls on prescribing isotretinoin to women who may become pregnant and women who become pregnant while taking isotretinoin are strongly advised to terminate their pregnancies.[13]

In most countries, isotretinoin can only be prescribed by dermatologists or specialist physicians; some countries also allow limited prescription by general practitioners and family doctors. In the United Kingdom[14] and Australia,[15][16] isotretinoin may be prescribed only by or under the supervision of a consultant dermatologist. Because severe cystic acne has the potential to cause permanent scarring over a short period, restrictions on its more immediate availability have proved contentious.[17] In New Zealand, isotretinoin can be prescribed by any doctor but subsidised only when prescribed by a vocationally-registered general practitioner, dermatologist or nurse practitioner.[18]

In the United States, since March 2006 the dispensing of isotretinoin is run through a website called iPLEDGE. The FDA required the companies marketing the drug in the US, which at the time that iPLEDGE was launched were Roche, Mylan, Barr, and Ranbaxy, to put this website in place as a risk evaluation and mitigation strategy. These companies formed a group called the Isotretinoin Products Manufacturing Group, and it hired Covance to run the website.[19][20] Prescribers, pharmacists, and all people to whom the drug is prescribed need to register on the site and log information into it. Women with child-bearing potential must commit to using two forms of effective contraception simultaneously for the duration of isotretinoin therapy and for a month immediately preceding and a month immediately following therapy. Additionally they must have two negative pregnancy tests 30 days apart and have negative pregnancy tests before each prescription is written.[21][22]

History[edit]

The compound 13-cis retinoic acid was first studied in the 1960s at Roche Laboratories in Switzerland by Werner Bollag as a treatment for skin cancer. Experiments completed in 1971 showed that the compound was likely to be ineffective for cancer and, surprisingly, that it could be useful to treat acne. However, they also showed that the compound was likely to cause birth defects, so in light of the events around thalidomide, Roche abandoned the product. In 1975, Gary Peck and Frank Yoder independently rediscovered the drug’s use as a treatment of cystic acne while studying it as a treatment for lamellar ichthyosis, and published that work. Roche resumed work on the drug. In clinical trials, subjects were carefully screened to avoid including women who were or might become pregnant. Roche’s New Drug Application for isotretinoin for the treatment of acne included data showing that the drug caused birth defects in rabbits. The FDA approved the application in 1982.

Scientists involved in the clinical trials published articles warning of birth defects at the same time the drug was launched in the US, but nonetheless isotretinoin was taken up quickly and widely, both among dermatologists and general practitioners. Cases of birth defects showed up in the first year, leading the FDA to begin publishing case reports and to Roche sending warning letters to doctors and placing warning stickers on drug bottles, and including stronger warnings on the label. Lawsuits against Roche started to be filed. In 1983 the FDA’s advisory committee was convened and recommended stronger measures, which the FDA took and were that time unprecedented: warning blood banks not to accept blood from people taking the drug, and adding a warning to the label advising women to start taking contraceptives a month before starting the drug. However use of the drug continued to grow, as did the number of babies born with birth defects. In 1985 the label was updated to include a boxed warning. In early 1988 the FDA called for another advisory committee, and FDA employees prepared an internal memo estimating that around 1,000 babies had been born with birth defects due to isotretinoin, that up to around 1,000 miscarriages had been caused, and that between 5,000 and 7,000 women had had abortions due to isotretinoin. The memo was leaked to the New York Times[77] a few days before the meeting, leading to a storm of media attention. In the committee meeting, dermatologists and Roche each argued to keep the drug on the market but to increase education efforts; pediatricians and the CDC argued to withdraw the drug from the market. The committee recommended to restrict physicians who could prescribe the drug and to require a second opinion before it could be prescribed. The FDA, believing it did not have authority under the law to restrict who had the right to prescribe the drug, kept the drug on the market but took further unprecedented measures: it required to Roche to make warnings yet more visible and graphic, provide doctors with informed consent forms to be used when prescribing the drug, and to conduct follow up studies to test whether the measures were reducing exposure of pregnant women to the drug. Roche implemented those measures, and offered to pay for contraception counseling and pregnancy testing for women prescribed the drug; the program was called the “Pregnancy Prevention Program”.

A CDC report published in 2000[78] showed problems with the Pregnancy Prevention Program and showed that the increase in prescriptions was from off-label use, and prompted Roche to revamp its program, renaming it the “Targeted Pregnancy Prevention Program” and adding label changes like requirements for two pregnancy tests, two kinds of contraception, and for doctors to provide pharmacists with prescriptions directly; providing additional educational materials, and providing free pregnancy tests. The FDA had another advisory meeting in late 2000 that again debated how to prevent pregnant women from being exposed to the drug; dermatologists testified about the remarkable efficacy of the drug, the psychological impact of acne, and demanded autonomy to prescribe the drug; others argued that the drug be withdrawn or much stricter measures be taken. In 2001 the FDA announced a new regulatory scheme called SMART (the System to Manage Accutane Related Teratogenicity) that required Roche to provide defined training materials to doctors, and for doctors to sign and return a letter to Roche acknowledging that they had reviewed the training materials, for Roche to then send stickers to doctors, which doctors would have to place on prescriptions they give people after they have confirmed a negative pregnancy test; prescriptions could only be written for 30 days and could not be renewed, thus requiring a new pregnancy test for each prescription.[citation needed]

In February 2002, Roche’s patents for isotretinoin expired, and there are now many other companies selling cheaper generic versions of the drug. On June 29, 2009, Roche Pharmaceuticals, the original creator and distributor of isotretinoin, officially discontinued both the manufacture and distribution of their Accutane brand in the United States due to what the company described as business reasons related to low market share (below 5%), coupled with the high cost of defending personal-injury lawsuits brought by some people who took the drug.[79] Generic isotretinoin will remain available in the United States through various manufacturers. Roche USA continues to defend Accutane and claims to have treated over 13 million people since its introduction in 1982. F. Hoffmann-La Roche Ltd. apparently will continue to manufacture and distribute Roaccutane outside of the United States.[80]

Among others, actor James Marshall sued Roche over allegedly Accutane-related disease that resulted in removal of his colon.[81] The jury, however, decided that James Marshall had a pre-existing bowel disease.[82]

Several trials over inflammatory bowel disease claims have been held in the United States thus far, with many of them resulting in multimillion-dollar judgments against the makers of isotretinoin.[83]

Society and culture

Brands

As of 2017 isotretinoin was marketed under many brand names worldwide: A-Cnotren, Absorica, Accuran, Accutane, Accutin, Acne Free, Acnecutan, Acnegen, Acnemin, Acneone, Acneral, Acnestar, Acnetane, Acnetin A, Acnetrait, Acnetrex, Acnogen, Acnotin, Acnotren, Acretin, Actaven, Acugen, Acutret, Acutrex, Ai Si Jie, Aisoskin, Aknal, Aknefug Iso, Aknenormin, Aknesil, Aknetrent, Amnesteem, Atlacne, Atretin, Axotret, Casius, Ciscutan, Claravis, Contracné, Curacne, Curacné, Curakne, Curatane, Cuticilin, Decutan, Dercutane, Effederm, Epuris, Eudyna, Farmacne, Flexresan, Flitrion, I-Ret, Inerta, Inflader, Inotrin, Isac, Isdiben, Isoacne, Isobest, Isocural, Isoderm, Isoface, IsoGalen, Isogeril, Isolve, Isoprotil, Isoriac, Isosupra, Isosupra Lidose, Isotane, Isotina, Isotinon, Isotren, Isotret, Isotretinoin, Isotretinoina, Isotretinoína, Isotretinoine, Isotretinoïne, Isotrétinoïne, Isotretinoinum, Isotrex, Isotrin, Isotroin, Izotek, Izotziaja, Lisacne, Locatret, Mayesta, Myorisan, Neotrex, Netlook, Nimegen, Noitron, Noroseptan, Novacne, Oralne, Oraret, Oratane, Piplex, Policano, Procuta, Reducar, Retin A, Roaccutan, Roaccutane, Roacnetan, Roacta, Roacutan, Rocne, Rocta, Sotret, Stiefotrex, Tai Er Si, Teweisi, Tretin, Tretinac, Tretinex, Tretiva, Tufacne, Zenatane, Zerocutan, Zonatian ME, and Zoretanin.[1]

As of 2017 it was marketed as a topical combination drug with erythromycin under the brand names Isotrex Eritromicina, Isotrexin, and Munderm.[1]

Research

While excessive bone growth has been raised a possible side effect, a 2006 review found little evidence for this.[84]

syn

File:Isotretinoin synthesis.svg

C. D. Robeson et al., J. Am. Chem. Soc. 77, 4111 (1955). Stereoselective process: R. Lucci, EP 111325; idem, US 4556518 (1984, 1985 both to Hoffmann-La Roche). doi:10.1021/jo00349a001.

syn

J Chem Soc 1968,(16),1982-83

The reaction of vinyl-beta-ionol (I) with triphenylphosphonium bromide (II) in ethanol gives the corresponding phosphonium salt (III), which is condensed through a Wittig reaction with cis-beta-formylcrotonic acid (IV) by means of sodium ethoxide in ethanol to afford a mixture of cis-2-cis-4-vitamin A acid (V) and the desired product. Finally, compound (V) is isomerized bv irradiation with diffuse light in ether in the presence of iodine.

syn

Tetrahedron 2000,56(37),7211

The formylation of the beta-ionone (I) with methyl formate and NaOMe gives the enol (II), which by reaction with methanol and H2SO4 yields the dimethylacetal (III). The reaction of (III) with methylenetriphenylphosphorane (IV) affords the methylene compound (V), which is treated with formic acid to provide the aldehyde (VI). The condensation of (VI) with isopropylidenemalonic acid dimethyl ester (VII) by means of NaOH gives the polyenic malonic acid (VIII) as a mixture of isomers that is separated by crystallization in ethyl ether to yield the desired all-trans-isomer (IX). Finally, this malonic acid is selectively monodecarboxylated by means of refluxing 2,6-dimethylpyridine to afford the target (E,E,E,Z)-isomer.

References

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  59. ^ Nelson AM, Cong Z, Gilliland KL, Thiboutot DM (September 2011). “TRAIL contributes to the apoptotic effect of 13-cis retinoic acid in human sebaceous gland cells”The British Journal of Dermatology165 (3): 526–33. doi:10.1111/j.1365-2133.2011.10392.xPMC 3166444PMID 21564055.
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External links

Clinical data
PronunciationSee note at tretinoin
Trade namesAccutane, Roaccutane, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa681043
License dataUS FDAIsotretinoin
Pregnancy
category
AU: X (High risk)US: X (Contraindicated)
Routes of
administration
By mouthtopical
ATC codeD10AD04 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)CA℞-onlyUK: POM (Prescription only)US: ℞-onlyIn general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityVariable
Protein binding99.9%
MetabolismLiver
Elimination half-life10–20 hours
ExcretionKidney and fecal
Identifiers
IUPAC name[show]
CAS Number4759-48-2 
PubChem CID5282379
IUPHAR/BPS7600
DrugBankDB00982 
ChemSpider4445539 
UNIIEH28UP18IF
KEGGD00348 
ChEBICHEBI:6067 
ChEMBLChEMBL547 
CompTox Dashboard (EPA)DTXSID4023177 
ECHA InfoCard100.022.996 
Chemical and physical data
FormulaC20H28O2
Molar mass300.442 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]O=C(O)\C=C(/C=C/C=C(/C=C/C1=C(/CCCC1(C)C)C)C)C
InChI[hide]InChI=1S/C20H28O2/c1-15(8-6-9-16(2)14-19(21)22)11-12-18-17(3)10-7-13-20(18,4)5/h6,8-9,11-12,14H,7,10,13H2,1-5H3,(H,21,22)/b9-6+,12-11+,15-8+,16-14- Key:SHGAZHPCJJPHSC-XFYACQKRSA-N 

////////////Antiacne, 13-cis-Retinoic acid, 2-cis-vitamin A acid,  neovitamin A acid, Isotretinoin

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Samidorphan


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Samidorphan

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FormulaC21H26N2O4
CAS852626-89-2
Mol weight370.4421

FDA  APPROVED 5/28/2021 Lybalvi

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ChemSpider 2D Image | Samidorphan L-malate | C25H32N2O9

UNII0AJQ5N56E0

CAS Number1204592-75-5

WeightAverage: 504.536
Monoisotopic: 504.210780618

Chemical FormulaC25H32N2O9

INGREDIENTUNIICASINCHI KEY
Samidorphan L-malate0AJQ5N56E01204592-75-5RARHXUAUPNYAJF-QSYGGRRVSA-N

IUPAC Name(1R,9R,10S)-17-(cyclopropylmethyl)-3,10-dihydroxy-13-oxo-17-azatetracyclo[7.5.3.0^{1,10}.0^{2,7}]heptadeca-2,4,6-triene-4-carboxamide; (2S)-2-hydroxybutanedioic acid

MOA:mu-Opioid antagonist; delta-Opioid partial agonist; kappa-Opioid partial agonistsIndication:Alcohol dependence

New Drug Application (NDA): 213378
Company: ALKERMES INChttps://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213378s000lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/213378Orig1s000,%20Orig2s000ltr.pdf

To treat schizophrenia in adults and certain aspects of bipolar I disorder in adults

LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan (as samidorphan L-malate), an opioid antagonist.

Olanzapine is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine. The molecular formula of olanzapine is: C17H20N4S and the molecular weight is 312.44 g/mol. It is a yellow crystalline powder and has pKa values of 7.80 and 5.44. The chemical structure is:

Olanzapine Structural Formula - Illustration

Samidorphan L-malate is morphinan-3-carboxamide, 17-(cyclopropylmethyl)-4, 14-dihydroxy-6-oxo-, (2S)-2-hydroxybutanedioate. The molecular formula of samidorphan L-malate is C21H26N2O4 • C4H6O5 and the molecular weight is 504.54 g/mol. It is a white to off-white crystalline powder and has pKa values of 8.3 (amine) and 10.1 (phenol). The chemical structure is:

Samidorphan Structural Formula - Illustration

LYBALVI is intended for oral administration and is available as film-coated, bilayer tablets in the following strengths: 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, and 20 mg/10 mg of olanzapine and samidorphan (equivalent to 13.6 mg of samidorphan L-malate).

Inactive ingredients include colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The film coating ingredients include hypromellose, titanium dioxide, triacetin, and color additives [iron oxide yellow (5 mg/10 mg); iron oxide yellow and iron oxide red (10 mg/10 mg); FD&C Blue No. 2/ indigo carmine aluminum lake (15 mg/10 mg); iron oxide red (20 mg/10 mg)].

  • to treat schizophrenia
  • alone for short-term (acute) or maintenance treatment of manic or mixed episodes that happen with bipolar I disorder
  • in combination with valproate or lithium to treat manic or mixed episodes that happen with bipolar I disorder

Olanzapine is an effective atypical antipsychotic that, like other antipsychotics, is associated with weight gain, metabolic dysfunction, and increased risk of type II diabetes.5,6 Samidorphan is a novel opioid antagonist structurally related to naltrexone, with a higher affinity for opioid receptors, more potent μ-opioid receptor antagonism, higher oral bioavailability, and a longer half-life, making it an attractive candidate for oral dosing.1,5,11 Although antipsychotic-induced weight gain is incompletely understood, it is thought that the opioid system plays a key role in feeding and metabolism, such that opioid antagonism may be expected to ameliorate these negative effects. Samidorphan has been shown in animal models and clinical trials to ameliorate olanzapine-induced weight gain and metabolic dysfunction.5,6

Samidorphan was first approved as a variety of fixed-dose combination tablets with olanzapine by the FDA on May 28, 2021, and is currently marketed under the trademark LYBALVI™ by Alkermes Inc.11

Samidorphan (INNUSAN) (developmental code names ALKS-33RDC-0313), also known as 3-carboxamido-4-hydroxynaltrexone,[2] is an opioid antagonist that preferentially acts as an antagonist of the μ-opioid receptor (MOR). It is under development by Alkermes for the treatment of major depressive disorder and possibly other psychiatric conditions.[3]

Development

Samidorphan has been investigated for the treatment of alcoholism and cocaine addiction by its developer, Alkermes,[4][5] showing similar efficacy to naltrexone but possibly with reduced side effects.

However, it has attracted much more attention as part of the combination product ALKS-5461 (buprenorphine/samidorphan), where samidorphan is combined with the mixed MOR weak partial agonist and κ-opioid receptor (KOR) antagonist buprenorphine, as an antidepressant. Buprenorphine has shown antidepressant effects in some human studies, thought to be because of its antagonist effects at the KOR, but has not been further developed for this application because of its MOR agonist effects and consequent abuse potential. By combining buprenorphine with samidorphan to block the MOR agonist effects, the combination acts more like a selective KOR antagonist, and produces only antidepressant effects, without typical MOR effects such as euphoria or substance dependence being evident.[6][7]

Samidorphan is also being studied in combination with olanzapine, as ALKS-3831 (olanzapine/samidorphan), for use in schizophrenia.[8] A Phase 3 study found that the addition of samidorphan to olanzapine significantly reduced weight gain compared to olanzapine alone.[9] The combination is now under review for approval by the US Food and Drug Administration.[10]

Pharmacology

Pharmacodynamics

The known activity profile of samidorphan at the opioid receptors is as follows:[11][12]

As such, samidorphan is primarily an antagonist, or extremely weak partial agonist of the MOR.[11][12] In accordance with its in vitro profile, samidorphan has been observed to produce some side effects that are potentially consistent with activation of the KOR such as somnolencesedationdizziness, and hallucinations in some patients in clinical trials at the doses tested.[13]

SYNPATENT

WO2006052710A1.

https://patents.google.com/patent/WO2006052710A1/enExample 1 -Synthesis of 3-Carboxyamido-4-hvdroxy-naltrexone derivative 3

Figure imgf000020_0001

(A) Synthesis of 3-Carboxyamido-naltrexone 2[029] The triflate 11 of naltrexone was prepared according to the method of Wentland et al. (Bioorg. Med. Chem. Lett. 9, 183-187 (2000)), and the carboxamide 2 was prepared by the method described by Wentland et al. [(Bioorg. Med. Chem. Lett. ϋ, 623-626 (2001); and Bioorg. Med. Chem. Lett. 11, 1717-1721 (2001)] involving Pd-catalyzed carbonylation of the triflate 11 in the presence of ammonia and the Pd(O) ligand, DPPF ([l,l’-bis(diphenylρhosphino)ferrocene]) and DMSO.(B) Synthesis of 3-Carboxyamido-4-hydroxy-naltrexone derivative 3[030] Zinc dust (26 mg, 0.40 mmol) was added in portions to a solution of 2 (50 mg, 0.14 mmol) in HCl (37%, 0.2 mL) and AcOH (2 mL) at reflux. After heating at reflux for a further 15 min, the reaction was cooled by the addition of ice/water (10 mL) and basified (pH=9) with NH3/H2O, and the solution was extracted with EtOAc (3×10 mL). The organic extracts were washed with brine, dried, and concentrated. The residue was purified by column chromatography (SiO2, CH2Cl2, CH3OH : NH3/H2O = 15:1:0.01) to give compound 3 as a foam (25 mg, 50%). 1H NMR (CDC13) δl3.28(s, IH, 4-OH), 7.15(d, IH, J=8.1, H-2), 6.47(d, IH, J=8.4, H- 1), 6.10(br, IH, N-H), 4.35(br, IH, N-H), 4.04(dd,lH, J=I.8, 13.5, H-5), 3.11( d, IH, J=6), 2.99( d, IH, J=5.7), 2.94( s, IH), 2.86( d, IH, J= 6), 2.84-2.75(m, 2H), 2.65-2.61(m, 2H), 2.17-2.05(m, IH), 1.89-1.84(m, 2H), 0.85(m, IH), 0.56-0.50(m, 2H), 0.13-0.09(m, 2H). [α]D25= -98.4° (c=0.6, CH2Cl2). MS m/z (ESI) 371(MH+).

Paper

 Bioorg. Med. Chem. Lett. 200010, 183-187.

https://www.sciencedirect.com/science/article/abs/pii/S0960894X99006708

Abstract

Opioid binding affinities were assessed for a series of cyclazocine analogues where the prototypic 8-OH substituent of cyclazocine was replaced by amino and substituted-amino groups. For μ and κ opioid receptorssecondary amine derivatives having the (2R,6R,11R)-configuration had the highest affinity. Most targets were efficiently synthesized from the triflate of cyclazocine or its enantiomers using Pd-catalyzed amination procedures.

PAPER

Bioorg. Med. Chem. Lett. 200111, 1717-1721.

https://www.sciencedirect.com/science/article/abs/pii/S0960894X01002785

Abstract

In response to the unexpectedly high affinity for opioid receptors observed in a novel series of cyclazocine analogues where the prototypic 8-OH was replaced by a carboxamido group, we have prepared the corresponding 3-CONH2 analogues of morphine and naltrexone. High affinity (Ki=34 and 1.7 nM) for μ opioid receptors was seen, however, the new targets were 39- and 11-fold less potent than morphine and naltrexone, respectively.

Abstract

High-affinity binding to μ opioid receptors has been identified in a series of novel 3-carboxamido analogues of morphine and naltrexone.

References

  1. ^ Turncliff R, DiPetrillo L, Silverman B, Ehrich E (February 2015). “Single- and multiple-dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers”. Clinical Therapeutics37 (2): 338–48. doi:10.1016/j.clinthera.2014.10.001PMID 25456560.
  2. ^ Wentland MP, Lu Q, Lou R, Bu Y, Knapp BI, Bidlack, JM (April 2005). “Synthesis and opioid receptor binding properties of a highly potent 4-hydroxy analogue of naltrexone”. Bioorganic & Medicinal Chemistry Letters15 (8): 2107–10. doi:10.1016/j.bmcl.2005.02.032PMID 15808478.
  3. ^ “Samidorphan”Adis Insight. Springer Nature Switzerland AG.
  4. ^ Hillemacher T, Heberlein A, Muschler MA, Bleich S, Frieling H (August 2011). “Opioid modulators for alcohol dependence”. Expert Opinion on Investigational Drugs20 (8): 1073–86. doi:10.1517/13543784.2011.592139PMID 21651459.
  5. ^ Clinical trial number NCT01366001 for “ALK33BUP-101: Safety and Pharmacodynamic Effects of ALKS 33-BUP Administered Alone and When Co-administered With Cocaine” at ClinicalTrials.gov
  6. ^ “ALKS 5461 drug found to reduce depressive symptoms in Phase 1/2 study”.
  7. ^ “Investigational ALKS 5461 Channels ‘Opium Cure’ for Depression”.
  8. ^ LaMattina J (15 January 2013). “Will Alkermes’ Antipsychotic ALKS-3831 Become Another Tredaptive?”Forbes.
  9. ^ Correll, Christoph U.; Newcomer, John W.; Silverman, Bernard; DiPetrillo, Lauren; Graham, Christine; Jiang, Ying; Du, Yangchun; Simmons, Adam; Hopkinson, Craig; McDonnell, David; Kahn, René S. (2020-08-14). “Effects of Olanzapine Combined With Samidorphan on Weight Gain in Schizophrenia: A 24-Week Phase 3 Study”American Journal of Psychiatry177 (12): 1168–1178. doi:10.1176/appi.ajp.2020.19121279ISSN 0002-953X.
  10. ^ “FDA Panel: Some Risk OK for Olanzapine Combo With Less Weight Gain”http://www.medpagetoday.com. 2020-10-09. Retrieved 2021-01-23.
  11. Jump up to:a b Linda P. Dwoskin (29 January 2014). Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Elsevier Science. pp. 398–399, 402–403. ISBN 978-0-12-420177-4.
  12. Jump up to:a b Wentland MP, Lou R, Lu Q, Bu Y, Denhardt C, Jin J, et al. (April 2009). “Syntheses of novel high affinity ligands for opioid receptors”Bioorganic & Medicinal Chemistry Letters19 (8): 2289–94. doi:10.1016/j.bmcl.2009.02.078PMC 2791460PMID 19282177.
  13. ^ McElroy SL, Guerdjikova AI, Blom TJ, Crow SJ, Memisoglu A, Silverman BL, Ehrich EW (April 2013). “A placebo-controlled pilot study of the novel opioid receptor antagonist ALKS-33 in binge eating disorder”The International Journal of Eating Disorders46(3): 239–45. doi:10.1002/eat.22114PMID 23381803.

External links

 
Clinical data
Other namesALKS-33, RDC-0313; 3-Carboxamido-4-hydroxynaltrexone
Routes of
administration
Oral
Pharmacokinetic data
Elimination half-life7–9 hours[1]
Identifiers
showIUPAC name
CAS Number852626-89-2 
PubChem CID11667832
ChemSpider23259667
UNII7W2581Z5L8
KEGGD10162 
Chemical and physical data
FormulaC21H26N2O4
Molar mass370.449 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

/////////samidorphan, サミドルファン, ALKS 33, ALKS-33, RDC-0313, RDC-0313-00, APPROVALS 2021, FDA 2021, Lybalvi

SMILESO[C@@H](CC(O)=O)C(O)=O.NC(=O)C1=CC=C2C[C@H]3N(CC4CC4)CC[C@@]4(CC(=O)CC[C@@]34O)C2=C1O

wdt-11

NEW DRUG APPROVALS

one time

$10.00

Amivantamab


(A chain)
QVQLVESGGG VVQPGRSLRL SCAASGFTFS TYGMHWVRQA PGKGLEWVAV IWDDGSYKYY
GDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARDG ITMVRGVMKD YFDYWGQGTL
VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA
VLQSSGLYSL SSVVTVPSSS LGTQTYICNV NHKPSNTKVD KRVEPKSCDK THTCPPCPAP
ELLGGPSVFL FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR
EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP
PSREEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG SFLLYSKLTV
DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPGK
(B chain)
QVQLVQSGAE VKKPGASVKV SCETSGYTFT SYGISWVRQA PGHGLEWMGW ISAYNGYTNY
AQKLQGRVTM TTDTSTSTAY MELRSLRSDD TAVYYCARDL RGTNYFDYWG QGTLVTVSSA
STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG
LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPELLGGP
SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS
TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSREEM
TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS RLTVDKSRWQ
QGNVFSCSVM HEALHNHYTQ KSLSLSPGK
(C chain)
AIQLTQSPSS LSASVGDRVT ITCRASQDIS SALVWYQQKP GKAPKLLIYD ASSLESGVPS
RFSGSESGTD FTLTISSLQP EDFATYYCQQ FNSYPLTFGG GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(D chain)
DIQMTQSPSS VSASVGDRVT ITCRASQGIS NWLAWFQHKP GKAPKLLIYA ASSLLSGVPS
RFSGSGSGTD FTLTISSLQP EDFATYYCQQ ANSFPITFGQ GTRLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: A22-A96, A152-A208, A228-C214, A234-B228, A237-B231, A269-A329, A375-A433, B22-B96, B146-B202, B222-D214, B263-B323, B369-B427, C23-C88, C134-C194, D23-D88, D134-D194)

Amivantamab

FDA APPR 2021/5/21 Rybrevant

アミバンタマブ (遺伝子組換え)

FormulaC6472H10014N1730O2023S46
CAS2171511-58-1
Mol weight145900.1288
  • CNTO-4424
  • JNJ 61186372
  • JNJ-611
  • JNJ-61186372
EfficacyDiseaseAntineoplastic
 Non-small cell lung cancer (EGFR exon 20 insertion)
CommentMonoclonal antibody

FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-amivantamab-vmjw-metastatic-non-small-cell-lung-cancer

On May 21, 2021, the Food and Drug Administration granted accelerated approval to amivantamab-vmjw (Rybrevant, Janssen Biotech, Inc.), a bispecific antibody directed against epidermal growth factor (EGF) and MET receptors, for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

FDA also approved the Guardant360® CDx (Guardant Health, Inc.) as a companion diagnostic for amivantamab-vmjw.

Approval was based on CHRYSALIS, a multicenter, non-randomized, open label, multicohort clinical trial (NCT02609776) which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Efficacy was evaluated in 81 patients with advanced NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Patients received amivantamab-vmjw once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity.

The main efficacy outcome measures were overall response rate (ORR) according to RECIST 1.1 as evaluated by blinded independent central review (BICR) and response duration. The ORR was 40% (95% CI: 29%, 51%) with a median response duration of 11.1 months (95% CI: 6.9, not evaluable).

The most common adverse reactions (≥ 20%) were rash, infusion-related reactions, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting.

The recommended dose of amivantamab-vmjw is 1050 mg for patients with baseline body weight < 80 kg, and 1400 mg for those with body weight ≥ 80 kg, administered weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity.

View full prescribing information for Rybrevant.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Brazilian Health Regulatory Agency (ANVISA) and United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA). The application reviews are ongoing at the other regulatory agencies.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 2 months ahead of the FDA goal date.

This product was granted breakthrough therapy designation for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Amivantamab, sold under the brand name Rybrevant, is a monoclonal antibody medication used to treat non-small cell lung cancer.[1][2][3]

The most common side effects include rash, infusion-related reactions, skin infections around the fingernails or toenails, muscle and joint pain, shortness of breath, nausea, fatigue, swelling in the lower legs or hands or face, sores in the mouth, cough, constipation, vomiting and changes in certain blood tests.[2][3]

Amivantamab is a bispecific epidermal growth factor (EGF) receptor-directed and mesenchymal–epithelial transition (MET) receptor-directed antibody. It is the first treatment for adults with non-small cell lung cancer whose tumors have specific types of genetic mutations: epidermal growth factor receptor (EGFR) exon 20 insertion mutations.[2]

Amivantamab was approved for medical use in the United States in May 2021.[2][3][4][5]

Amivantamab, also known as JNJ-61186372, is an anti-EGFR-MET bispecific antibody, derived from Chinese hamster ovary cells, approved for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.1,9 Patients with NSCLC often develop resistance to drugs that target EGFR and MET individually, so amivantamab was developed to attack both targets, reducing the chance of resistance developing.1,2 Amivantamab was found to be more effective than the EGFR inhibitor erlotinib or the MET inhibitor crizotinib in vivo.1,3 Patients with NSCLC with exon 20 insertion mutations in EGFR do not respond to tyrosine kinase inhibitors, and were generally treated with platinum-based therapy.5

Amivantamab was granted FDA approval on 21 May 2021.9

Medical uses

Amivantamab is indicated for the treatment of adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.[3]

History

The U.S. Food and Drug Administration (FDA) approved amivantamab based on CHRYSALIS, a multicenter, non-randomized, open label, multicohort clinical trial (NCT02609776) which included participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations.[3] Efficacy was evaluated in 81 participants with advanced NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy.[3]

The FDA collaborated on the review of amivantamab with the Brazilian Health Regulatory Agency (ANVISA) and the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA).[3] The application reviews are ongoing at the other regulatory agencies.[3]

Society and culture

Legal status

Amivantamab was approved for medical use in the United States in May 2021.[2][3][4][5] A marketing authorization application is pending in the EU.[6][7]

Names

Amivantamab is the recommended international nonproprietary name (INN).[8]

Research

Amivantamab is being investigated in combination with lazertinib versus osimertinib; and in combination with carboplatin-pemetrexed chemotherapy compared to carboplatin-pemetrexed.[9][10]

PAPER

https://www.jbc.org/article/S0021-9258(21)00427-0/fulltext#secsectitle0085

Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET

Open AccessDOI:https://doi.org/10.1016/j.jbc.2021.10064

Experimental procedures

 Preparation of BsAb panel

The generation of parental antibodies followed expression and purification protocols as described (30

,40

). The MET parental mAbs had the F405L mutation and the EGFR parental mAbs had the K409R mutation. The IgG1 b12 arm served as isotype control and null arm to preserve the BsAb architecture. The low fucose parental mAbs were generated using proprietary cell lines. The quality of the BsAb were confirmed as being monodisperse and monomeric via size exclusion chromatography and being pure via SDS-PAGE.

 Flow cytometric binding assay

Binding to cells expressing EGFR and MET (A549 [ATCC CCL-185], NCI-H1975 [ATCC, CRL-5908], and NCI-H441 [ATCC HTB-174] cells) was evaluated using flow cytometry (fluorescence-activated cell sorting [FACS]). All BsAbs and controls were diluted in FACS buffer (PBS supplemented with 1% bovine serum albumin and 0.2% sodium azide). After 1 h incubation, unbound antibodies were removed by a FACS buffer wash. The cells were then incubated with goat anti-human IgG-PE (Jackson) for FACS detection (BD FACS Canto). The mean fluorescence intensity of the cells in the live gate was plotted against antibody concentration, and the EC50 was determined by nonlinear regression fitting. Anti-EGFR zalutumumab and anti-MET 5D5 (onartuzumab) were positive controls and anti-CD20 7D8 (Genmab) was the negative control.

 MET phosphorylation assay

A549 cells were incubated with 30 μg/ml of test antibody for 15 min and tested for MET phosphorylation using rabbit anti-phospho MET (Tyr1234–1235) (Cell Signaling 3129) and total MET protein using mouse anti-human MET antibody (Cell Signaling 3127). A score of 1 to 4 was given, where 1 = no visible band, 2 = slightly visible band, 3 = phosphorylation comparable with weak agonist (MET B IgG1), and 4 = phosphorylation level similar to positive controls (MET A and MET 5D5 IgG1 mAbs).

 Proliferation assays

Test molecules were added to H1975, KP4 (Riken Cell bank, RCB1005), or NCI-H441 cells plated at 5000 or 10,000 (KP4) cells/well in 96-well plates. After 6 (KP4) or 7 (H1975 and NCI-H441) days of incubation at 37 °C and 5% CO2, the number of viable cells was determined using an AlamarBlue assay (Biosource DAL1100). A615 values were measured and plotted in a bar diagram.

 EGFR phosphorylation assay

Approximately 106 A549 or SNU-5 cells/well were grown overnight in six-well plates and incubated for 15 min with 30 μg/ml of antibody in the absence or presence of 40 ng/ml EGF. After cell lysis, Western blots determined EGFR phosphorylation status with phospho-EGFR (Tyr1068) antibody (Cell Signaling 2234) and total EGFR protein using an anti-EGFR antibody (Cell Signaling 2232).

 Expression and purification of proteins for crystallization

Human MET Sema-PSI region (residues 39–564) containing a C-terminal 8xHis tag was expressed in Tni PRO insect cells infected with recombinant baculovirus. The culture was harvested 72 h post infection, and the MET Sema-PSI protein was purified by affinity and size exclusion chromatography. Briefly, MET was captured with a Ni-NTA resin (Novagen) equilibrated in TBS, 10 mM imidazole, pH 7.4 and eluted from the column with 250 mM imidazole, TBS, pH 7.4. Fractions containing MET were identified by SDS-PAGE and loaded into a Superdex 200 column (GE Healthcare) equilibrated in 20 mM Tris, 50 mM NaCl, pH 7. The final protein concentration was determined by absorbance at 280 nm.The anti-MET Fab of amivantamab was transiently expressed in Expi293F cells. Briefly, the cells were cotransfected with separate plasmids encoding the Fab heavy and light chains at 3:1 (light:heavy chain) molar ratio following transfection kit instructions (Life Technologies). The culture was harvested 5 days post transfection, and the Fab was purified by affinity and cation exchange chromatography. Briefly, the Fab was captured with a HiTrap resin (GE Healthcare) equilibrated in PBS pH 7.2 and eluted from the column with a gradient of 30 to 300 mM imidazole in PBS pH 7.2. The eluate was buffer exchanged into 25 mM NaCl, 20 mM MES pH 6.0, bound to a Source 15S column (GE Healthcare), and eluted with a NaCl gradient in 20 mM MES pH 6.0.

 Crystallization and structure determination

The amivantamab anti-MET Fab–MET Sema-PSI complex was prepared by overnight mixing of MET and Fab at a molar ratio of 1:1.3 (excess Fab) at 4 °C, while buffer exchanging to 20 mM Hepes pH 7.0. The complex was captured with a monoS 5/50 column (GE Healthcare) equilibrated in 20 mM Hepes pH 7.0 and eluted from the column with a gradient of NaCl. The complex was concentrated to 4.8 mg/ml.Crystallization trials for the Fab–MET complex were carried out with a Mosquito LCP robot (TTP LabTech) for the setup of sitting drops on 96-well plates (Corning 3550) and a Rock Imager 54 (Formulatrix) for plate storage at 20 °C and automated imaging of drops. Small crystals were initially obtained from 2 M NH4(SO4)2, 0.1 M MES pH 6.5, and they were used as seeds in next rounds of optimization. Crystals suitable for X-ray diffraction were obtained from 2.5 M sodium formate, 5% PEG 400 Da, 0.1 M Tris pH 8.5 after multiple rounds of seeding. The crystals were soaked for a few seconds in a cryoprotectant solution containing mother liquor supplemented with 20% glycerol and then flash frozen in liquid nitrogen. X-ray diffraction data were collected with a Pilatus 6M detector on beamline 17-ID at the Advanced Photon Source (Argonne National Laboratory), and the diffraction data were processed with the program HKL2000. The crystal structure of the Fab–MET complex was solved by molecular replacement with PHASER using previously solved MET Sema-PSI (PDB code 1SHY) and anti-HER3 Fab RG7116 (PDB code 4LEO) structures as search models. The structure was refined with PHENIX, and model adjustments were performed using COOT. His tags (at C-terminal of heavy chain and PSI), Fab interchain disulfide bond, heavy chain residues 133 to 139, Sema residues 303 to 309, 407, and glycan linked to N399 are disordered and not included in the structure. The Fab was numbered sequentially and Sema-PSI numbering starts at the N terminus of the signal peptide.

Epitope and paratope residues were assigned within a 4-Å contact distance cutoff using the CCP4 program CONTACT. The epitope area was calculated with the CCP4 program AREA. The buried surface area of binding residues was calculated with the program MOE (47

). Structural overlays of equivalent Cα atoms in the Sema domain (residues 40–515; PDB codes 1SHY, 4K3J, 2UZX, and 2UZY) were performed with COOT. Molecular graphics were generated with PyMol (PyMOL Molecular Graphics System, Version 1.4.1, Schrödinger, LLC) and MOE. The atomic coordinates and structure factors for the amivantamab anti-MET Fab–MET Sema-PSI complex were deposited in the RCSB PDB (accession code 6WVZ).

 HCC827-HGF xenograft model

Female SCID Beige mice CB17.B6-Prkdcscid Lystbg/Crl (Charles River) bearing established subcutaneous HCC827-HGF tumors were randomized 13 days post inoculation (day 1). Individual tumor volumes ranged from 144 to 221 mm3; mean tumor volume ranged from 180 to 184 mm3. PBS and amivantamab (10 mg/kg) were dosed i.p. biweekly for 3 weeks. Crizotinib (30 mg/kg), erlotinib (25 mg/kg), crizotinib (30 mg/kg) and erlotinib (25 mg/kg), and vehicle controls (0.5% carboxymethyl cellulose in sterile water and 1% carboxymethyl cellulose in 0.1% Tween 80) were dosed daily p.o. for 3 weeks. Subcutaneous tumors were measured twice weekly as the mean tumor volume (mm3 ± standard error of the mean [SEM]). To calculate the percent tumor growth inhibition (%TGI) for group A versus group B, the tumor volumes were log transformed, where A = treated and B = control. The difference between these transformed values was taken at day 1 versus the designated day. Means were taken and converted by anti-log to numerical scale. Percentage TGIs were then calculated as (1 − A/B) × 100%. In vivo experiment was reviewed and approved by the Charles River Laboratories Institutional Animal Care and Use Committee and was done in accordance with the Guide for Care and Use of Laboratory Animals.

References

  1. Jump up to:a b “Rybrevant- amivantamab injection”DailyMed. Janssen Pharmaceutical Companies. Retrieved 25 May 2021.
  2. Jump up to:a b c d e f “FDA Approves First Targeted Therapy for Subset of Non-Small Cell Lung Cancer”U.S. Food and Drug Administration (FDA) (Press release). 21 May 2021. Retrieved 21 May 2021.  This article incorporates text from this source, which is in the public domain.
  3. Jump up to:a b c d e f g h i j “FDA grants accelerated approval to amivantamab-vmjw for mNSCLC”U.S. Food and Drug Administration (FDA). 21 May 2021. Retrieved 21 May 2021.  This article incorporates text from this source, which is in the public domain.
  4. Jump up to:a b “Rybrevant (amivantamab-vmjw) Receives FDA Approval as the First Targeted Treatment for Patients with Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations” (Press release). Janssen Pharmaceutical Companies. 21 May 2021. Retrieved 21 May 2021 – via PR Newswire.
  5. Jump up to:a b “Genmab Announces that Janssen has been Granted U.S. FDA” (Press release). Genmab A/S. 21 May 2021. Retrieved 21 May 2021 – via GlobeNewswire.
  6. ^ “Amivantamab”SPS – Specialist Pharmacy Service. 25 February 2021. Retrieved 23 May 2021.
  7. ^ “Janssen Submits European Marketing Authorisation Application for Amivantamab for the Treatment of Patients with Metastatic Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations” (Press release). Janssen Pharmaceutical Companies. 28 December 2020. Retrieved 23 May 2021 – via Business Wire.
  8. ^ World Health Organization (2020). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83” (PDF). WHO Drug Information34 (1).
  9. ^ Kaplon H, Reichert JM (2021). “Antibodies to watch in 2021”mAbs13 (1): 1860476. doi:10.1080/19420862.2020.1860476PMC 7833761PMID 33459118.
  10. ^ “Updated Amivantamab and Lazertinib Combination Data Demonstrate Durable Responses and Clinical Activity for Osimertinib-Relapsed Patients with EGFR-Mutated Non-Small Cell Lung Cancer” (Press release). Janssen Pharmaceutical Companies. 20 May 2021. Retrieved 23 May 2021 – via Business Wire.

Further reading

External links

  • “Amivantamab”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02609776 for “Study of Amivantamab, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer (CHRYSALIS)” at ClinicalTrials.gov
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetEpidermal growth factor receptor (EGFR) and Mesenchymal–epithelial transition (MET)
Clinical data
Trade namesRybrevant
Other namesJNJ-61186372, amivantamab-vmjw
License dataUS DailyMedAmivantamab
Routes of
administration
Intravenous infusion
Drug classAntineoplastic
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2][3]
Identifiers
CAS Number2171511-58-1
DrugBankDB16695
UNII0JSR7Z0NB6
KEGGD11894
Chemical and physical data
FormulaC6472H10014N1730O2023S46
Molar mass145902.15 g·mol−1
NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
RybrevantInjection350 mg/1IntravenousJanssen Biotech, Inc.2021-05-21Not applicableUS flag 

/////////Amivantamab, FDA 2021, APPROVALS 2021, PEPTIDE, Rybrevant, アミバンタマブ (遺伝子組換え), CNTO-4424, JNJ 61186372, JNJ-611, JNJ-61186372, breakthrough therapy designation, Janssen Biotech

wdt-8

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OCID 5090, Enmetazobactam


2D chemical structure of 1001404-83-6
Unii-80vun7L00C.png

OCID 5090

Enmetazobactam

Beta-lactamase inhibitor.

AAI-101
RN: 1001404-83-6
UNII: 80VUN7L00C

Molecular Formula, C11-H14-N4-O5-S, Molecular Weight, 314.3206

(2S,3S,5R)-3-Methyl-3-((3-methyltriazol-3-ium-1-yl)methyl)-4,4,7-trioxo-4^6-thia-1-azabicyclo(3.2.0)heptane-2-carboxylate

  • 1H-1,2,3-Triazolium, 3-(((2S,3S,5R)-2-carboxy-3-methyl-4,4-dioxido-7-oxo-4-thia-1-azabicyclo(3.2.0)hept-3-yl)methyl)-1-methyl-, inner salt
  • Enmetazobactam

The Board of directors of Orchid Pharma Ltd has announced that the company had developed a new molecule known as OCID-5090, which was licensed to a company named Allecra Therapeutics, this molecule was undergoing the clinical trials and the company is happy to announce that the molecule has cleared the Phase 3 clinical trials.

Allecra Therapeutics would now either directly or through out license file for NDA of this molecule. Allecra has already out licensed the product to Haini Pharmaceuticals, China for the Chinese Territory at a value of $78mn plus royalties.

As per the IP Agreement between Orchid Pharma Limited and Allecra Therapeutics, Orchid is entitled to receive a Royalty of 6-8% on the worldwide sales of the product. Therefore, once the molecule is commercialised, Orchid can expect a regular stream of Royalty from Allecra. Further, the rights to develop and commercialise the molecule in India (which is under patent protection) remain with Orchid Pharma Limited, and the company is evaluating the various options to commercialise the product.

Orchid had developed a new molecule known as OCID-5090, which was licensed to a company named Allecra Therapeutics, this molecule was undergoing the clinical trials and the molecule has cleared the Phase 3 clinical trials.

Allecra Therapeutics would now either directly or through out license file for NDA of this molecule. Allecra has already out licensed the product to Haini Pharmaceuticals, China for the Chinese Territory at a value of $78mn plus royalties.

As per the IP Agreement between Orchid Pharma Limited and Allecra Therapeutics, Orchid is entitled to receive a Royalty of 6-8% on the worldwide sales of the product. Therefore, once the molecule is commercialised, Orchid can expect a regular stream of Royalty from Allecra. Further, the rights to develop and commercialise the molecule in India (which is under patent protection) remain with Orchid Pharma Limited, and the company is evaluating the various options to commercialise the product.

INVENTOR

senthil

Senthilkumar U P

ORCHID

Summary of Profile of Dr. U. P. Senthilkumar, R&D Centre, Orchid Pharma Ltd.
Dr. U. P. Senthilkumar Ph.D., the principal inventor of novel beta-lactamase inhibitor, OCID5090, is currently serving as the senior vice-president at Orchid’s Research and Development Centre, Chennai.
With illustrious credentials — top ranks in B.Sc. and M.Sc. degrees, first rank in the Graduate Aptitude Test in Engineering (GATE), UGC-CSIR Junior Research Fellowship (JRF) and the prestigious Dr. K.S. Krishnan Fellowship from the Department of Atomic Energy (DAE) and publication of M.Sc. project work in the Indian Journal of Chemistry in 1987 — Mr. Senthilkumar chose to pursue his doctoral research in synthetic organic chemistry with his mentor Prof.
Ramasubbu Jeyaraman at Bharathidasan University, Tiruchirapalli. His research focus on the conformational preferences of sterically challenged novel N-Nitroso heterocycles and their conformation dependent anti-cancer properties, led to the publication of 9 articles in reputed peer-reviewed international journals – a commendable accomplishment in the 90s.
After a brief post-doctoral stint on fluorescent dicyclopentapyridines, Dr. U. P. Senthilkumar joined Torrent Research Centre at Ahmedabad and started his new endeavor of drug discovery on ACE inhibitors. At the process research and development laboratory, he was actively involved in asymmetric and stereo-selective synthesis of Active Pharmaceutical Ingredients (APIs), and exploited the full potential of chiral prep-HPLC to realize the target molecules.
After joining Orchid Pharma Ltd., Chennai, Dr. Senthilkumar led the efforts in the development of differentiated and patentable manufacturing processes for APIs related to both non-antibiotics and beta-lactam antibiotics. He played a significant role in successfully implementing the manufacturing processes overcoming several challenging problems. In addition, his scientific insights and breath of understanding on the patent landscape were invaluable and impactful in
creating significant value to the organization and growth of the company in realizing the mission to become a leader in the pharmaceutical generic business.
One finds more than 100 articles/patents/publications to his credit, which include inventions on new drugs, drug-intermediates, products, processes, new synthetic routes, rearrangements and novel polymorphs. As a Leadership Persona of the IP management team, he had exhibited a thoroughness of the science/invention and meticulously executed the task of prosecution of few hundred patents in many countries from both New Drug Discovery and Process Chemistry space.
All the successful effort earned Orchid Pharma Ltd the National Intellectual Property Award from the Department of Industrial Policy and Promotion, Ministry of Commerce and Industry,Government of India.
Through his executive and decision-making skills combined with scientific rationale and clarity, Dr. Senthilkumar played significant role in the selection of products and creation of generic product portfolio for Orchid, with unique IP strategies, analysis of patents, patent mapping, designing & developing invalidation/non-infringing positions, and early launch opportunity, including first-to-file (FTF) positioning. His appearance in the US courts, for deposition in couple of patent litigations, and successful accomplishment of the same are testimony to his depth, thoroughness of science and the ability to defend the invention with grit and professionalism.
Additionally, his effectual role in the first-to-launch of one of the large volume sterile penicillins with regulatory exclusivity, achieved successfully by overcoming the citizen petition process in the regulatory pathway, is another shining example of his leadership and scientific strength.
To support in-house projects as well as multinational pharma majors, Dr. Senthilkumar has taken up CRAMS (Contract Research and Manufacturing Services) and CMC (Chemistry, Manufacturing and Control) for new chemical entities. Besides, he passionately focused on novel beta-lactamase inhibitors and their antibiotic combinations that were envisaged by him to exhibit potent activity against multi-drug resistant bacteria. His dedicated effort brought a novel extended spectrum beta-lactamase inhibitor, OCID5090, which was out-licensed to Allecra Inc. OCID5090/cefepime combination has completed successfully the Phase III clinical trials for treating complicated urinary-track-infections (cUTI), including acute pyelonephritis (AP), and rightfully, OCID5090 has gotten the US FDA fast track designation as a Qualified Infectious Disease product (QIDP) that provides a five-year additional market exclusivity and priority review.
His never-ending passion for research is infectious and roped him with academic institutions to explore novel technologies including electron-beam irradiated heterogeneous catalysis. His commendable knowledge on intellectual property is being utilized by the IP Cells of various institutions as well as the Tamil Nadu State Technology Development and Promotion Centre.
A sincere student he is, Dr. Senthilkumar is also a founder-member of Prof. Ramasubbu Jeyaraman Science Foundation (RJSF). Since 2011, he has been playing a significant role in rganizing several academic events (seminars, work-shops, invited lectures, state-level proficiency tests, and research-orientation programs) for post-graduate chemistry students to create passion for research. His concern and help for poor and rural students show his human face.

SYN

PATENT

US 20080015156

https://patents.google.com/patent/US20080015156A1/en

  • [0050]
  • [0051]To a suspension of (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo-[3.2.0]heptane-2-carboxylic acid 4,4-dioxide (25 g) in acetone (100 mL) at 25-30° C. was added slowly N,O-bis(silylacetamide) (18.6 g) with stirring. The reaction mixture was stirred at this temperature (25-30° C.) for 15-20 min. To the clear solution obtained, methyl iodide (100 mL) was added over a period of 15 min. and stirred at 25-30 min. for 24 h. The precipitated solid was separated by filtration and washed with acetone (25 mL). Wet weight of the solid obtained was 30 g.
  • [0052]The above wet solid was stirred with purified water (300 mL) at 10-15° C. for 2.5 h. To the resulted reaction mixture was added sodium thiosulfate (0.1 g) and stirred at 10-15° C. for 10-15 min. To the reaction mixture, dichloromethane (300 mL) was added, stirred and the organic layer separated. The aqueous layer was washed with a solution of Amberlite LA-2 resin (5% solution in dichloromethane twice, followed by dichloromethane twice. To the aqueous solution, activated carbon (1 g) was added, stirred for 15 min, filtered and washed with purified water (25 mL). The solution was filtered and lyophilized to get the title compound in pure form (10 g). 1H NMR (400 MHz, DMSO) δ ppm: 1.39 (s, 3H), 3.14 (dd, J=16.0, 1.3 Hz, 1H), 3.55 (dd, J=16.0, 4.2 Hz, 1H), 3.97 (s, 1H), 4.34 (s, 3H), 5.05 (dd, J=4.2, 1.3 Hz, 1H), 5.29 (d, J=14.7 Hz, 1H), 5.42 (d, J=14.7 Hz, 1H), 8.91 (d, J=1.3 Hz, 1H), 8.99 (d, J=1.3 Hz, 1H). Mass m/z: M+1 peak at 315. Alternatively the solution could be subjected to spray-drying to yield the title compound.

PATENT

WO 2012070071

IN 2010CH03555

US 20140057888

PATENT

 WO 2015173378

Scheme 1

Examples

Synthesis of (2535.5R)-3-methyl-3-((3-methyl-lH-1.2 -triazol-3-ium-l-yl)methvn-7-oxo-4-thia-l-azabicyclor3.2.01heptane-2-carboxylate 4,4-dioxide (4),

Compound (4) was prepared according to Scheme 2.

Scheme 2

i) Ν,Ο-bis-trimethylsilylacetamide, CH2CI2; ii) CH3OTf; iii) Na 2-ethylhexanoate

In a round bottom flask under nitrogen flow 100 g of Tazobactam acid (1) and 500 mL of Dichloromethane are loaded. The temperature is adjusted to +30/35°C then 37 g of Ν,Ο-Bis(trimethylsilyl) acetamide are loaded in 15-20 minutes maintaining the temperature to +35/42°C. The mixture is heated to reflux (+40/42°C) for 60 minutes. If the solution is not clear, N,0-Bis(trimethylsilyl) acetamide is loaded in small portions (0,5-1.0 g each) waiting 15 minutes every time till a clear solution containing intermediate (2) is obtained. 0.55 moles of N,0-Bis(trimethylsilyl) acetamide is used, with further 0.1-0.2 equivalents being added if the reaction is not complete.

Then the temperature is cooled down to 0/+5°C and 70 g of Methyl trifluoromethanesulfonate are loaded in 60-90 minutes maintaining the temperature at 0/+5°C. After 30 minutes the reaction is monitored by HPLC to control the disappearance of intermediate (2) and formation of intermediate (3). The reaction is monitored every 30 minutes until completion.

In a round bottom flask, under nitrogen, are loaded 500 mL of Ethanol and 55 g of Sodium 2-Ethylhexanoate and the temperature is adjusted to +20/25°C, then the reaction solution containing intermediate (3) is added in 60-90 minutes maintaining the temperature of +20/25 °C under vigorous stirring. The suspension is stirred for 30 minutes then is filtered and washed with 300 mL of Ethanol followed by 500 mL of Dichloromethane under nitrogen. The crude product (4) is dried under nitrogen flow till constant weight (150 g) is obtained. The crude product compound (4) was isolated as a solid product (HPLC assay = 70%, yield = 80%).

Purification of (2tS’,3^5^)-3-methyl-3-((3-methyl-lH-l,2,3-triazol-3-ium-l-yl)methyl)-7-oxo-4-thia-l-azabicyclor3.2.01heptane-2-carboxylate 4,4-dioxide (4)

In a round bottom flask 800 mL of Dimethylformamide are loaded, the temperature is adjusted to +20/25°C then crude Compound 4 (150g) obtained above is loaded using 100 mL of Dimethylformamide to facilitate the transfer. The mixture is stirred for 5 minutes and a solution is obtained, then and after a few minutes crystallization takes place. The suspension is stirred for about 3 hours, then is cooled to 0/+5°C and stirred for another 3 hours.

The solid is filtered and washed with 300 mL of Dimethylformamide pre-cooled to 0/+5°C. Compound 4 is then suspended in 700 mL of Ethyl acetate and the temperature is adjusted to +40/45°C. The suspension is stirred for 30 minutes then the solid is filtered and washed with 150 mL of Ethyl acetate pre-heated to +40/45°C. The suspension with

Ethyl acetate is repeated twice. Finally Compound 4 is dried under vacuum at +40°C till constant weight is achieved (66 g, HPLC assay = 99%, yield = 76%).

Compound 4 Sterile filtration and recrystallization Procedure

In a round bottom flask 350 mL of Methanol are loaded, the temperature is adjusted to +30/35°C then 100 g of Compound 4 are loaded and finally the flask is washed with 60 mL of Methanol. After 5-10 minutes a solution is obtained. The solution is diluted with 330 mL of acetone adjusting the temperature to +20/+25°C. The obtained solution is treated with 2,2 g of charcoal for 20 minutes then filtered using a 0.22microM filter and the filter is washed with a mixture of 13 mL of Methanol and 110 mL of Acetone. The temperature of the solution is adjusted to +30/35°C and under vigorous stirring 830 mL of Acetone are loaded in about 15-20 minutes. After stirring for 60 minutes at temperature of +30/35°C 1170 mL of Acetone are loaded in 45-60 minutes. Then the temperature is adjusted to +20/25 °C in about 30-60 minutes and maintained for 30 minutes. The obtained crystalline solid is filtered and washed with 430 mL of Acetone. Finally the product is dried under vacuum at +40°C till constant weight is achieved (83 g of Compound 4) are obtained with an HPLC assay = 98-99%, yield =t 80%).

Mr. Ram Gopal Agarwal

Chairman and Non-Executive Director

  • Mr. Ram Gopal Agarwal is Founder Chairman of Dhanuka Group.
  • He is a decisive and action oriented visionary who took over a sick pesticide Company named Northern Mineral Pvt. Ltd. in 1980 and transformed it today into a Rs 1000 Crore organization called Dhanuka Agritech Ltd.
  • His deep commitment and inspiring leadership in initial turbulent days is an example worth inculcating and his passion to contribute to Indian Agriculture is commendable.
  • His ability to prioritize and deal effectively with a number of tasks simultaneously reinforced with the skills to make effective decisions, has metamorphosed the business venture into one of the fastest growing Agrochemical Company in India which has thrice been rated as ‘Best under a Billion Company’ by Forbes Magazine.
  • In order to achieve his aspiration of “Transforming India through Agriculture” he has dedicated himself to bring changes in Agrochemicals Industry and the farming community. His contribution for adopting newer farming techniques at the grass root level, judicious use of agro chemicals in farming and imparting knowledge through his nationwide network of distributors and Dhanuka Doctors in field has resulted in the overall prosperity of farmers.
  • Mr. Ram Gopal Agarwal has been the past Chairman of CCFI, (Crop Care Federation of India) the apex Chamber of all Indian Agrochemical majors. He is also Chairman of Advisory Committee of AGRO Chemicals Federation of India.
  • Mr. Ram Gopal Agarwal, Group Chairman, has been bestowed with many Awards for his tremendous contribution in Agro Industry like “Life Time Achievement Award” by Agri Business Summit and Agri Awards 2019, “Distinguished Contribution to Indian Agrochemicals Industry” during India Chem 2016 International Conference organised by FICCI etc.

Mr. Manish Dhanuka

Managing Director

  • Mr. Manish Dhanuka is the Director of Orchid Pharma Limited; he has the vision to rejuvenate Orchid Pharma Ltd. and take it on a fruitful path. His wide-ranging experience of handling operations, commercial, marketing and finance in the manufacturing industry provides for his analytical and decision-making skills facilitating the restoration of the company to its glorious past and to achieve even greater heights.
  • He excels in creating economical Pharmaceutical technologies and accelerated evaluation process for improving healthcare. Experience of 25 years in research, evaluation, and teaching in the pharmaceutical industry equips him with the expertise in innovative pharmaceutical technologies…
  • He holds a B.Tech in Chemical Engineering from IIT, New Delhi, and M.S in Chemical Engineering from the University of Akron, USA.
  • Before establishing Dhanuka Laboratories Ltd. in 1993, he began his career at Ranbaxy Labs Ltd. in New Delhi and worked there for 5 years. His vision and strategy to grow the Pharmaceutical industry in the Indian sub-continent, have helped the Dhanuka Group of companies enhance its Bulk Drugs manufacturing arm exponentially. He spearheaded the acquisition of Synmedic Laboratories in the year 2013 which is involved in pharmaceutical formulations. This entrepreneurial vigor enabled him to take over the operations of Orchid Pharma Ltd. in March 2020.
  • Outside of work, he likes to travel for wildlife adventures.

Mr. Mridul Dhanuka

Whole-Time Director

He is associated with Dhanuka Group Ltd. since 2005. He was responsible in successfully realigning the entire supply chain vertical from procurement to sales. At Orchid, he hopes to replicate the Group’s success and put another feather in Dhanuka cap.

CLIP

image

Orchid Chemicals & Pharmaceuticals, or Orchid Pharma since its recent name change in 2015, was established in 1992 in Chennai to manufacture antibiotics, and entered drug discovery in 2001 with projects in the areas of anti-infectives and treatments for pain.32197 In 2002, the company engaged in a joint venture to develop US-based firm Bexel Biotechnology’s BLX-1002, an oral, non-PPAR AMPK activator for the treatment of diabetes,198 later repositioned for NASH (2012), but no further progress has been reported recently.197 In 2008, Orchid invested in Diakron Pharmaceuticals, a US-based company that had an exclusive license to MSD′s investigational oral anticoagulant drug, a direct thrombin inhibitor later known as DPOC-4088 (or DP-4088),199 which reached Phase 1 clinical studies in Europe in 2012 (Supporting Information Table 6b, entries 5–6).200 The company’s own internal discovery efforts had a broad therapeutic focus, covering infectious diseases, inflammation, pain, oncology, metabolic disorders, and CNS diseases. OCID-2987,197201 a PDE4 inhibitor for the treatment of inflammatory disorders such as COPD, completed successfully Phase 1 studies in Europe in 2012, and OCID-4681 29,202203 a histone deacetylase (HDAC) inhibitor for cancer had received approval in 2011 for Phase 1 studies for solid tumors in India, but we assume both have been abandoned, as cancer and inflammation are not mentioned in the company’s latest annual reports.197 Two additional compounds were abandoned at the preclinical stage: OCID-5005, a STAT-3/IL-6 inhibitor for oncology, and a unnamed Th1/Th2 cytokine synthesis inhibitor for inflammation (Supporting Information Table 2a, entries 134–138).197 Financial issues led Orchid, as of 2009, to sell parts of its business to Hospira (now part of Pfizer). As a consequence, no progress has been reported on its discovery programs since 2010, and no further NCE patent application has been published since 2012. However, in 2013 Orchid licensed its broad-spectrum β-lactamase inhibitor OCID-5090, a zwitterionic N-methylated tazobactam derivative, to the German Allecra Therapeutics for a 20 % stake in the company, for use in combination with antibiotics to treat multidrug-resistant gram negative bacteria.204207 Allecra’s lead compound AAI202, a combination of cefepime and AAI101/OCID-5090 30, is currently in Phase 1 studies in France.208209

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Dr. B. Gopalan - PredOmix TechnologiesPredOmix Technologies

Dr. B. Gopalan

Scientific Advisor

Dr. Gopalan is a synthetic organic chemist with extensive experience in the field of drug discovery and development. After completing his PhD from University of Madras, he went to Harvard University where he worked with the Nobel Laureate, Prof. E.J. Corey, as a post-doctoral fellow. Subsequent to this he joined Syntex Research Inc. in California to work on the synthesis of unnatural amino acids. After a year, he moved to Bristol-Meyers Squibb, Princeton, New Jersey, to contribute to their program on novel antibiotics and ACE inhibitors. Dr. Gopalan then moved back to India in 1982 to join the Drug Discovery Research Division of Boots Pharmaceuticals (India) Ltd. in Mumbai. Over his decade long stint there he contributed extensively to their drug discovery program, and one of the product candidates that he developed went up to Phase-2 clinical trials in both USA and UK. He then moved to Sun Pharma Advanced Research Center as Vice-President and, after a year, took up the position as General Manager at Glaxo (India) Ltd. in 1993. Here, he worked in a broad range of areas that included process development, synthesis of impurities of APIs, and generation of small molecule libraries to support drug discovery efforts to Glaxo, France. In 1999 he took over as Senior Vice President of the Drug Discovery Chemistry Division of Glenmark Pharmaceuticals Ltd. where he was involved in the design and development of inhibitors for PDE IV and DPP IV, as well as agonists for CB2. After a 6-year stint at Glenmark, Dr. Gopalan joined Matrix Laboratories Ltd. as CSO and Executive Vice-President, where he successfully helped to develop novel and selective inhibitors for PDE4 and DPP4. Five years later he became CSO and Executive Director of Orchid Pharmaceuticals Ltd in Chennai. He served in this capacity for close to a decade, contributing extensively to drug design and development in the broad segments of oncology, anti-infectives, and anti-inflammatory & metabolic disorders. Since 2017, Dr. Gopalan has been associated with CSIR-Indian Institute of Chemical Technology as a Scientific Advisor.

Dr. Gopalan’s illustrious career is endowed with numerous successes. He has been inventor, or co-inventor, of several drugs or candidate drugs. These include the novel potassium channel blockers BTS-67582 (BTI-2927) for tpe-2 diabetes, the PDE IV inhibitors Oglemilast (COPD) and Revamilast (RA); DPP IV inhibitor Melogliptin; a selective Cannaboid-2 agonist Tedalinib (Neuropathic pain); a Beta lactamase inhibitor Enmetazobactum (OCID-5090); OCID-18034 (an inhibitor of KPC enzyme); and OCID-18174 (an inhibitor of P. arugenosa). Most of these compounds were out-licensed to major international pharmaceutical companies such as Forest Laboratories Inc. USA, Teijin of Japan, Merck KGaA of Germany, Allecra of Switzerland, and Merck & Co. USA. Dr.Gopalan has 34 publications in National and International Journals, has contributed a Chapter,Co-authored with Professor K.K.Balasubramanian (IITM) on Applications of Click Chemistry in Drug Discovery and Development in a Book on Click reaction in Organic Synthesis, published by Wiley-VCH VERLAG GmbH &Co,KGaA, Weinheim,Germany,Chapter 2, p 25-70,2016, edited by Prof. S. Chandrasekharan (IISc,Bangalore) & 51 Patents.

Commensurate with his achievements, Dr. Gopalan has also received many awards. The more prominent of these include Inventor’s award by Glenmark (2004), Ranbaxy Science Foundation Award in Pharmaceutical Sciences (2005), and the Lifetime Achievement Award in the Field of Chemistry from Vels University (2011).

//////////OCID 5090, AAI-101, AAI 101,  Enmetazobactam, ORCHID, Allecra Therapeutics, PHASE 3

C[n+]1ccn(C[C@@]2(C)[C@@H](N3[C@@H](CC3=O)S2(=O)=O)C(=O)[O-])n1

Pabinafusp alfa


(Heavy chain)
EVQLVQSGAE VKKPGESLKI SCKGSGYSFT NYWLGWVRQM PGKGLEWMGD IYPGGDYPTY
SEKFKVQVTI SADKSISTAY LQWSSLKASD TAMYYCARSG NYDEVAYWGQ GTLVTVSSAS
TKGPSVFPLA PSSKSTSGGT AALGCLVKDY FPEPVTVSWN SGALTSGVHT FPAVLQSSGL
YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS
VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST
YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY TLPPSRDELT
KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSK LTVDKSRWQQ
GNVFSCSVMH EALHNHYTQK SLSLSPGKGS SETQANSTTD ALNVLLIIVD DLRPSLGCYG
DKLVRSPNID QLASHSLLFQ NAFAQQAVCA PSRVSFLTGR RPDTTRLYDF NSYWRVHAGN
FSTIPQYFKE NGYVTMSVGK VFHPGISSNH TDDSPYSWSF PPYHPSSEKY ENTKTCRGPD
GELHANLLCP VDVLDVPEGT LPDKQSTEQA IQLLEKMKTS ASPFFLAVGY HKPHIPFRYP
KEFQKLYPLE NITLAPDPEV PDGLPPVAYN PWMDIRQRED VQALNISVPY GPIPVDFQRK
IRQSYFASVS YLDTQVGRLL SALDDLQLAN STIIAFTSDH GWALGEHGEW AKYSNFDVAT
HVPLIFYVPG RTASLPEAGE KLFPYLDPFD SASQLMEPGR QSMDLVELVS LFPTLAGLAG
LQVPPRCPVP SFHVELCREG KNLLKHFRFR DLEEDPYLPG NPRELIAYSQ YPRPSDIPQW
NSDKPSLKDI KIMGYSIRTI DYRYTVWVGF NPDEFLANFS DIHAGELYFV DSDPLQDHNM
YNDSQGGDLF QLLMP
(Light chain)
DIVMTQTPLS LSVTPGQPAS ISCRSSQSLV HSNGNTYLHW YLQKPGQSPQ LLIYKVSNRF
SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCSQSTHVP WTFGQGTKVE IKRTVAAPSV
FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL
SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC
(Disulfide bridge: H22-H96, H145-H201, H221-L219, H227-H’227, H230-H’230, H262-H322, H368-H426, H596-H609, H847-H857, H’22-H’96, H’145-H’201, H’221-L’219, H’262-H’322, H’368-H’426, H’596-H’609, H’847-H’857, L23-L93, L139-L199, L’23-L’93, L’139-L’199)

Pabinafusp alfa

CAS 2140211-48-7

PMDA 2021/3/23, JAPAN 

Pabinafusp alfa (genetical recombination) (JAN)

Pabinafusp alfa (INN)

2140211-48-7, UNII: TRF8S0U6ON

Immunoglobulin G1, anti-(human transferrin receptor) (human-mus musculus monoclonal JR-141 gamma1-chain) fusion protein with peptide (synthetic 2-amino acid linker) fusion protein with human iduronate-2-sulfatase, disulfide with human-mus musculus mono

Immunoglobulin G1-kappa, anti-(human transferrin receptor 1, tfr1) humanized monoclonal antibody, fused with human iduronate-2-sulfatase, glycoform alfa:

Pabinafusp alfa is under investigation in clinical trial NCT03568175 (A Study of JR-141 in Patients With Mucopolysaccharidosis II).

JR-141

wdt-3

NEW DRUG APPROVALS

ONE TIME

$10.00

JCR Pharmaceuticals Announces Approval of IZCARGO® (Pabinafusp Alfa) for Treatment of MPS II (Hunter Syndrome) in Japan

– First Approved Enzyme Replacement Therapy for MPS II to Penetrate Blood-Brain Barrier via Intravenous Administration, Validating JCR’s J-Brain Cargo® Technology –March 23, 2021 07:30 AM Eastern Daylight Time

HYOGO, Japan–(BUSINESS WIRE)–JCR Pharmaceuticals Co., Ltd. (TSE 4552; “JCR”) today announced that the Ministry of Health, Labour and Welfare (MHLW) in Japan has approved IZCARGO® (pabinafusp alfa 10 mL, intravenous drip infusion) for the treatment of mucopolysaccharidosis type II (MPS II, or Hunter syndrome). IZCARGO® (formerly known as JR-141) is a recombinant iduronate-2-sulfatase enzyme replacement therapy (ERT) that relies on J-Brain Cargo®, a proprietary technology developed by JCR, to deliver therapeutics across the blood-brain barrier (BBB). It is the first-ever approved ERT that penetrates the BBB via intravenous administration, a potentially life-changing benefit for individuals with lysosomal storage disorders (LSDs) such as MPS II.

“Subsequent to this approval in Japan, I look forward to further accumulation of clinical evidence for pabinafusp alfa in Brazil, the US and EU”Tweet this

Many patients with MPS II show complications not only in somatic symptoms but also in the central nervous system (CNS), which are often severe, with significant effects on patients’ neurocognitive development, independence, and quality of life. By delivering the enzyme to both the body and the brain, IZCARGO® treats the neurological complications of Hunter syndrome that other available therapies have been unable or inadequate to address so far.

“Approval of IZCARGO® in Japan under SAKIGAKE designation is a key milestone in JCR Pharmaceuticals’ global expansion. It comes on the heels of Fast Track designation from the US FDA, orphan designation from the European Medicines Agency, and the FDA’s acceptance of the JR-141 Investigational New Drug application, enabling JCR to begin our Phase 3 trial in the US,” said Shin Ashida, chairman and president of JCR Pharmaceuticals. “These critical regulatory milestones in Japan, where we have such a strong record of success, and those in the US and Europe, provide important validation of the value of our J-Brain Cargo® technology to deliver therapies across the blood-brain barrier, which we believe is essential to addressing the central nervous system complications of lysosomal storage disorders. We will continue our uncompromising effort to take on the challenge of providing new treatment options for patients with lysosomal storage disorders around the world as soon as possible.”

The MHLW’s approval of IZCARGO® is based on totality of evidence from non-clinical and clinical studies1-4. In a phase 2/3 clinical trial conducted in Japan, all 28 patients experienced significant reductions in heparan sulfate (HS) concentrations in the cerebrospinal fluid (CSF) – a biomarker for effectiveness against CNS symptoms of MPS II – after 52 weeks of treatment, thus meeting the trial’s primary endpoint. IZCARGO® maintained somatic disease control in patients who switched from standard ERT to IZCARGO®. The study also confirmed an improvement in somatic symptoms in participants who had not previously received standard ERT prior to the start of the trial. Additionally, a neurocognitive development assessment demonstrated maintenance or improvement of age-equivalent function in 21 of the 28 patients. There were no reports of serious treatment-related adverse events in the trial, suggestive of a favorable safety and tolerability profile for IZCARGO®.4

“Subsequent to this approval in Japan, I look forward to further accumulation of clinical evidence for pabinafusp alfa in Brazil, the US and EU,” said Dr. Paul Harmatz of University of California – San Francisco (UCSF) Benioff Children’s Hospital Oakland, Oakland, CA, United States. “The availability of an enzyme replacement therapy that crosses the blood-brain barrier is expected to treat both CNS and somatic symptoms associated with this devastating and life-threatening disorder, including developmental and cognitive delays, bone deformities, and abnormal behavior, which have, historically, been unaddressed.”

JCR recently filed an application with the Brazilian Health Surveillance Agency (Agência Nacional de Vigilância Sanitária [ANVISA]) for marketing approval of IZCARGO® for the treatment of patients with MPS II. JCR is also preparing to launch a Phase 3 trial of IZCARGO® in the US, Brazil, the UK, Germany, and France.

About pabinafusp alfa

Pabinafusp alfa (10 mL, intravenous drip infusion) is a recombinant fusion protein of an antibody against the human transferrin receptor and idursulfase, the enzyme that is missing or malfunctioning in subjects with Hunter syndrome. It incorporates J-Brain Cargo®, JCR’s proprietary BBB-penetrating technology, to cross the BBB through transferrin receptor-mediated transcytosis, and its uptake into cells is mediated through the mannose-6-phosphate receptor. This novel mechanism of action is expected to make pabinafusp alfa effective against the CNS symptoms of Hunter syndrome.

In pre-clinical trials, JCR has confirmed both high-affinity binding of pabinafusp alfa to transferrin receptors, and passage across the BBB into neuronal cells, as evidenced by electron microscopy. In addition, JCR has confirmed enzyme uptake in various brain tissues. The company has also confirmed a reduction of substrate accumulation in the CNS and peripheral organs in an animal model of Hunter syndrome.1

In several clinical trials of pabinafusp alfa, JCR obtained evidence of reduced HS concentrations in the CSF, a biomarker for assessing effectiveness against CNS symptoms. The results were consistent with those obtained in pre-clinical studies. Clinical studies have also demonstrated positive effects of pabinafusp alfa on CNS symptoms.2

About J-Brain Cargo® Technology

JCR’s first-in-class proprietary technology, J-Brain Cargo®, enables the development of therapies that cross the BBB and penetrate the CNS. The CNS complications of diseases are often severe, resulting in developmental delays, an impact on cognition and, above all, poor prognosis, which affect patients’ independence as well as the quality of life of patients and their caregivers. With J-Brain Cargo®, JCR seeks to address the unresolved clinical challenges of LSDs by delivering the enzyme to both the body and the brain.

About Mucopolysaccharidosis II (Hunter Syndrome)

Mucopolysaccharidosis II (Hunter syndrome) is an X-linked recessive LSD caused by a deficiency of iduronate-2-sulfatase, an enzyme that breaks down complex carbohydrates called glycosaminoglycans (GAGs, also known as mucopolysaccharides) in the body. Hunter syndrome, which affects an estimated 7,800 individuals worldwide (according to JCR research), gives rise to a wide range of somatic and neurological symptoms. The current standard of care for Hunter syndrome is ERT. CNS symptoms related MPS II have been unmet medical needs so far.

About JCR Pharmaceuticals Co., Ltd.

JCR Pharmaceuticals Co., Ltd. (TSE 4552) is a global specialty pharmaceuticals company that is redefining expectations and expanding possibilities for people with rare and genetic diseases worldwide. We continue to build upon our 45-year legacy in Japan while expanding our global footprint into the US, Europe, and Latin America. We improve patients’ lives by applying our scientific expertise and unique technologies to research, develop, and deliver next-generation therapies. Our approved products in Japan include therapies for the treatment of growth disorder, Fabry disease, acute graft-versus host disease, and renal anemia. Our investigational products in development worldwide are aimed at treating rare diseases including MPS I (Hurler syndrome, Hurler-Scheie, and Scheie syndrome), MPS II (Hunter syndrome), Pompe disease, and more. JCR strives to expand the possibilities for patients while accelerating medical advancement at a global level. Our core values – reliability, confidence, and persistence – benefit all our stakeholders, including employees, partners, and patients. Together we soar. For more information, please visit https://www.jcrpharm.co.jp/en/site/en/.

1 Sonoda H, Morimoto H, Yoden E, et al. A blood-brain-barrier-penetrating anti-human transferrin receptor antibody fusion protein for neuronopathic mucopolysaccharidosis II. Molecular Therapy. 2018;26(5):1366-1374.

2 Morimoto H, Kida K, Yoden E, et al. Clearance of heparan sulfate in the brain prevents neurodegeneration and neurocognitive impairment in MPS II mice. Molecular Therapy. 2021;S1525-0016(21)00027-7.

3 Okuyama T, Eto Y, Sakai N, et al. Iduronate-2-sulfatase with anti-human transferrin receptor antibody for neuropathic mucopolysaccharidosis II: a phase 1/2 trial. Molecular Therapy. 2019;27(2):456-464.

Okuyama T, Eto Y, Sakai N, et al. A phase 2/3 trial of pabinafusp alfa, IDS fused with anti-human transferrin receptor antibody, targeting neurodegeneration in MPS-II. Molecular Therapy. 2021;29(2):671-679.

//////////Pabinafusp alfa, JR-141, JR 141,APPROVALS 21, JAPAN 2021

#Pabinafusp alfa, #JR-141, #JR 141, #APPROVALS 21, #JAPAN 2021

DASATINIB


Dasatinib.svg
2D chemical structure of 863127-77-9

DASATINIB

ダサチニブ水和物

BMS 354825

863127-77-9 HYDRATE, USAN, BAN INN, JAN
UNII: RBZ1571X5H

302962-49-8 FREE FORM Dasatinib anhydrous USAN, INN

Molecular Formula, C22-H26-Cl-N7-O2-S.H2-O, Molecular Weight, 506.0282T6N DNTJ A2Q D- DT6N CNJ B1 FM- BT5N CSJ DVMR BG F1[WLN]X78UG0A0RNдазатиниб [Russian] [INN]دازاتينيب [Arabic] [INN]达沙替尼 [Chinese] [INN]1132093-70-9[RN]302962-49-8[RN]5-Thiazolecarboxamide, N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-87129966762[Beilstein]

A pyrimidine and thiazole derived ANTINEOPLASTIC AGENT and PROTEIN KINASE INHIBITOR of BCR-ABL KINASE. It is used in the treatment of patients with CHRONIC MYELOID LEUKEMIA who are resistant or intolerant to IMATINIB.

An orally bioavailable synthetic small molecule-inhibitor of SRC-family protein-tyrosine kinases. Dasatinib binds to and inhibits the growth-promoting activities of these kinases. Apparently because of its less stringent binding affinity for the BCR-ABL kinase, dasatinib has been shown to overcome the resistance to imatinib of chronic myeloid leukemia (CML) cells harboring BCR-ABL kinase domain point mutations. SRC-family protein-tyrosine kinases interact with a variety of cell-surface receptors and participate in intracellular signal transduction pathways; tumorigenic forms can occur through altered regulation or expression of the endogenous protein and by way of virally-encoded kinase genes. (NCI Thesaurus)

5-Thiazolecarboxamide, N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)-1-piperazinyl)-2-methyl-4-pyrimidinyl)amino)-, monohydrate

Synthesis ReferenceUS6596746

DASATINIB ANHYDROUS

  • KIN 001-5
  • NSC 759877
  • Sprycel
  • 302962-49-8 Dasatinib anhydrous
  • 5-THIAZOLECARBOXAMIDE, N-(2-CHLORO-6-METHYLPHENYL)-2-((6-(4-(2-HYDROXYETHYL)-1-PIPERAZINYL)-2-METHYL-4-PYRIMIDINYL)AMINO)-
  • BMS-354825
  • DASATINIB [INN]
  • DASATINIB [MI]
  • DASATINIB [WHO-DD]
  • DASATINIB ANHYDROUS
No.NDA No.Major Technical ClassificationPatent No.Estimated Expiry DateDrug Substance ClaimDrug Product ClaimPatent Use Code
All list
1N021986Formula65967462020-06-28YYU – 748
2N021986Formula65967462020-06-28YYU – 780
3N021986Uses(Indication)71258752020-04-13  U – 779
4N021986Uses(Indication)71258752020-04-13  U – 780
5N021986Uses(Indication)71538562020-04-28  U – 780
6N021986Crystal74917252026-03-28YY 
7N021986Formulation86801032025-02-04 Y

SPRYCEL (dasatinib) is an inhibitor of multiple tyrosine kinases.

The chemical name for dasatinib is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2- methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. The molecular formula is C22H26ClN7O2S • H2O, which corresponds to a formula weight of 506.02 (monohydrate).

The anhydrous free base has a molecular weight of 488.01. Dasatinib has the following chemical structure: Dasatinib is a white to off-white powder and has a melting point of 280°–286° C.

The drug substance is insoluble in water and slightly soluble in ethanol and methanol. SPRYCEL tablets are white to off-white, biconvex, film-coated tablets containing dasatinib, with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol

DASATINIBDASATINIB (DASATINIB) | ANDA #202103 | TABLET;ORAL | Discontinued | APOTEX INC
SPRYCELSPRYCEL (DASATINIB) | NDA #021986 | TABLET;ORAL | Prescription | BRISTOL MYERS SQUIBBSPRYCEL (DASATINIB) | NDA #022072 | TABLET; ORAL | Prescription | BRISTOL MYERS SQUIBB

Clip

https://www.pharmainbrief.com/files/2017/09/A-106-17-20170918-Reasons.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/202103Orig1s000ltr.pdfU.S. Patent Number Expiration Date 6,596,746 (the ‘746 patent) June 28, 20207,125,875 (the ‘875 patent) April 13, 20207,153,856 (the ‘856 patent) April 28, 20207,491,725 (the ‘725 patent) March 28, 20268,680,103 (the ‘103 patent) February 4, 2025

Drug Name:Dasatinib HydrateResearch Code:BMS-354825Trade Name:Sprycel®MOA:Kinase inhibitorIndication:Acute lymphoblastic leukaemia (ALL); Chronic myeloid leukemia (CML )Status:ApprovedCompany:Bristol-Myers Squibb (Originator)Sales:$1,620 Million (Y2015); 
$1,493 Million (Y2014);
$1,280 Million (Y2013);
$1,019 Million (Y2012);
$803 Million (Y2011);ATC Code:L01XE06Approved Countries or Area

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2006-06-28Marketing approvalSprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet, Film coatedEq. 20 mg/50 mg/70 mg/80 mg/100 mg/140 mg DasatinibBristol-Myers SquibbPriority; Orphan
2006-06-28Additional approvalSprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet, Film coated70 mgBristol-Myers SquibbPriority

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2006-11-20Marketing approvalSprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet, Film coated20 mg/50 mg/70 mg/80 mg/100 mg/140 mgBristol-Myers SquibbOrphan

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2011-06-16Modified indicationSprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet, Film coated20 mg/50 mgBristol-Myers Squibb, Otsuka 
2009-01-21Marketing approvalSprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet, Film coated20 mg/50 mgBristol-Myers Squibb, Otsuka 

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2013-09-17Marketing approval Acute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet20 mg南京正大天晴制药 
2013-09-17Marketing approval Acute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet50 mg南京正大天晴制药 
2013-09-17Marketing approval Acute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet70 mg南京正大天晴制药 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet50 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet50 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet50 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet20 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet20 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet20 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet70 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet70 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet70 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet100 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet100 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet100 mgBristol-Myers Squibb 

SPRYCEL (dasatinib) is a kinase inhibitor. The chemical name for dasatinib is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. The molecular formula is C22H26ClN7O2S • H2O, which corresponds to a formula weight of 506.02 (monohydrate). The anhydrous free base has a molecular weight of 488.01. Dasatinib has the following chemical structure:

SPRYCEL (dasatinib) tablets, for oral use Structural Formula - Illustration

Dasatinib is a white to off-white powder. The drug substance is insoluble in water and slightly soluble in ethanol and methanol.

SPRYCEL tablets are white to off-white, biconvex, film-coated tablets containing dasatinib, with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol.

Dasatinib hydrate was first approved by the U.S. Food and Drug Administration (FDA) on June 28, 2006, then approved by European Medicine Agency (EMA) on Nov 20, 2006, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Jan 21, 2009. It was developed and marketed as Sprycel® by Bristol Myers Squibb in the US.

Dasatinibhydrate is a kinase inhibitor.It is indicated for the treatment ofchronic myeloid leukemia and acutelymphoblastic leukemia.

Sprycel® is available as film-coatedtabletfor oral use, containing 20, 50, 70, 80, 100 or 140 mg offreeDasatinib. The recommended dose is 100 mg once daily forchronic myeloid leukemia. Another dose is 140 mg once daily for accelerated phase chronic myeloid leukemia, myeloid or lymphoid blast phase chronic myeloid leukemia, or Ph+ acutelymphoblastic leukemia.

Dasatinib, also known as BMS-354825, is an orally bioavailable synthetic small molecule-inhibitor of SRC-family protein-tyrosine kinases. Dasatinib binds to and inhibits the growth-promoting activities of these kinases. Apparently because of its less stringent binding affinity for the BCR-ABL kinase, dasatinib has been shown to overcome the resistance to imatinib of chronic myeloid leukemia (CML) cells harboring BCR-ABL kinase domain point mutations.

Dasatinib, sold under the brand name Sprycel among others, is a targeted therapy medication used to treat certain cases of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL).[3] Specifically it is used to treat cases that are Philadelphia chromosome-positive (Ph+).[3] It is taken by mouth.[3]

Common adverse effects include low white blood cellslow blood plateletsanemiaswelling, rash, and diarrhea.[3] Severe adverse effects may include bleeding, pulmonary edemaheart failure, and prolonged QT syndrome.[3] Use during pregnancy may result in harm to the baby.[3] It is a tyrosine-kinase inhibitor and works by blocking a number of tyrosine kinases such as Bcr-Abl and the Src kinase family.[3]

Dasatinib was approved for medical use in the United States and in the European Union in 2006.[3][2] It is on the World Health Organization’s List of Essential Medicines.

Medical uses

Dasatinib is used to treat people with chronic myeloid leukemia and people with acute lymphoblastic leukemia who are positive for the Philadelphia chromosome.[5]

In the EU dasatinib is indicated for children with

  • newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukaemia in chronic phase (Ph+ CML CP) or Ph+ CML CP resistant or intolerant to prior therapy including imatinib.[2]
  • newly diagnosed Ph+ acute lymphoblastic leukaemia (ALL) in combination with chemotherapy.[2]
  • newly diagnosed Ph+ CML in chronic phase (Ph+ CML-CP) or Ph+ CML-CP resistant or intolerant to prior therapy including imatinib.[2]

and adults with

  • newly diagnosed Philadelphia-chromosome-positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase;[2]
  • chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib mesilate;[2]
  • Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy.[2]

Adverse effects

The most common side effects are infectionsuppression of the bone marrow (decreasing numbers of leukocyteserythrocytes, and thrombocytes),[6] headache, hemorrhage (bleeding), pleural effusion (fluid around the lungs), dyspnea (difficulty breathing), diarrheavomitingnausea (feeling sick), abdominal pain (belly ache), skin rashmusculoskeletal paintirednessswelling in the legs and arms and in the facefever.[2] Neutropenia and myelosuppression were common toxic effects. Fifteen people (of 84, i.e. 18%) in the above-mentioned study developed pleural effusions, which was a suspected side effect of dasatinib. Some of these people required thoracentesis or pleurodesis to treat the effusions. Other adverse events included mild to moderate diarrhea, peripheral edema, and headache. A small number of people developed abnormal liver function tests which returned to normal without dose adjustments. Mild hypocalcemia was also noted, but did not appear to cause any significant problems. Several cases of pulmonary arterial hypertension (PAH) were found in people treated with dasatinib,[7] possibly due to pulmonary endothelial cell damage.[8]

On October 11, 2011, the U.S. Food and Drug Administration (FDA) announced that dasatinib may increase the risk of a rare but serious condition in which there is abnormally high blood pressure in the arteries of the lungs (pulmonary hypertension, PAH).[9] Symptoms of PAH may include shortness of breath, fatigue, and swelling of the body (such as the ankles and legs).[9] In reported cases, people developed PAH after starting dasatinib, including after more than one year of treatment.[9] Information about the risk was added to the Warnings and Precautions section of the Sprycel drug label.[9]

Pharmacology

Crystal structure[10] (PDB 2GQG) of Abl kinase domain (blue) in complex with dasatinib (red).

Dasatinib is an ATP-competitive protein tyrosine kinase inhibitor. The main targets of dasatinib are BCR/Abl (the “Philadelphia chromosome”), Srcc-Kitephrin receptors, and several other tyrosine kinases.[11] Strong inhibition of the activated BCR-ABL kinase distinguishes dasatinib from other CML treatments, such as imatinib and nilotinib.[11][12] Although dasatinib only has a plasma half-life of three to five hours, the strong binding to BCR-ABL1 results in a longer duration of action.[12]

History

See also: Discovery and development of Bcr-Abl tyrosine kinase inhibitors

Dasatinib was developed by collaboration of Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd,[13][14][15] and named for Bristol-Myers Squibb research fellow Jagabandhu Das, whose program leader says that the drug would not have come into existence had he not challenged some of the medicinal chemists‘ underlying assumptions at a time when progress in the development of the molecule had stalled.[16]

Society and culture

Legal status

Dasatinib was approved for used in the United States in June 2006 and in the European Union in November 2006[17][2]

In October 2010, dasatinib was approved in the United States for the treatment of newly diagnosed adults with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (CP-CML).[18]

In November 2017, dasatinib was approved in the United States for the treatment of children with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase.[19]

Approval was based on data from 97 pediatric participants with chronic phase CML evaluated in two trials—a Phase I, open-label, non-randomized, dose-ranging trial and a Phase II, open-label, non-randomized trial.[19] Fifty-one participants exclusively from the Phase II trial were newly diagnosed with chronic phase CML and 46 participants (17 from the Phase I trial and 29 from the Phase II trial) were resistant or intolerant to previous treatment with imatinib.[19] The majority of participants were treated with dasatinib tablets 60 mg/m2 body surface area once daily.[19] Participants were treated until disease progression or unacceptable toxicity.[19]

Economics

The Union for Affordable Cancer Treatment objected to the price of dasatinib, in a letter to the U.S. trade representative. The average wholesale price in the U.S. is $367 per day, twice the price in other high income countries. The price in India, where the average annual per capita income is $1,570, and where most people pay out of pocket, is Rs6627 ($108) a day. Indian manufacturers offered to supply generic versions for $4 a day, but, under pressure from the U.S., the Indian Department of Industrial Policy and Promotion refused to issue a compulsory license.[20]

Bristol-Myers Squibb justified the high prices of cancer drugs with the high R&D costs, but the Union of Affordable Cancer Treatment said that most of the R&D costs came from the U.S. government, including National Institutes of Health funded research and clinical trials, and a 50% tax credit. In England and Wales, the National Institute for Health and Care Excellence recommended against dasatinib because of the high cost-benefit ratio.[20]

The Union for Affordable Cancer Treatment said that “the dasatinib dispute illustrates the shortcomings of US trade policy and its impact on cancer patients”[20]

Brand names

In Bangladesh dasatinib is available under the trade name Dasanix by Beacon Pharmaceuticals.In India, It is marketed by brand name NEXTKI by EMCURE PHARMACEUTICALS[medical citation needed]

Research

Dasatinib has been shown to eliminate senescent cells in cultured adipocyte progenitor cells.[21] Dasatinib has been shown to induce apoptosis in senescent cells by inhibiting Src kinase, whereas quercetin inhibits the anti-apoptotic protein Bcl-xL.[21] Administration of dasatinib along with quercetin to mice improved cardiovascular function and eliminated senescent cells.[22] Aged mice given dasatinib with quercetin showed improved health and survival.[22]

Giving dasatinib and quercetin to mice eliminated senescent cells and caused a long-term resolution of frailty.[23] A study of fourteen human patients suffering from idiopathic pulmonary fibrosis (a disease characterized by increased numbers of senescent cells) given dasatinib and quercetin showed improved physical function and evidence of reduced senescent cells.[21]Route 1

Reference:1. WO2005077945A2 / US2012302750A1.Route 2

Reference:1. WO0062778A1 / US6596746B1.Route 3

Reference:1. J. Med. Chem. 200447, 6658-6661.

2. J. Med. Chem. 200649, 6819-6832.Route 4

Reference:1. CN104292223A.Route 5

Reference:1. CN103420999A.

Syn 1

Reference

Balaji, N.; Sultana, Sayeeda. Trace level determination and quantification of potential genotoxic impurities in dasatinib drug substance by UHPLC/infinity LC. International Journal of Pharmacy and Pharmaceutical Sciences. Department of Chemistry. St. Peter’s University. Tamil Nadu, India 600054. Volume 8. Issue 10. Pages 209-216. 2016

SYN 2

Reference

Zhang, Shaoning; Wei, Hongtao; Ji, Min. Synthesis of dasatinib. Zhongguo Yiyao Gongye Zazhi. Dept. of Pharmaceutical Engineering, School of Chemistry & Chemical Engineering. Southeast University. Nanjing, Jiangsu Province, Peop. Rep. China 210096. Volume 41. Issue 3. Pages 161-163. 2010

SYN 3

Reference

Suresh, Garbapu; Nadh, Ratnakaram Venkata; Srinivasu, Navuluri; Yennity, Durgaprasad. A convenient new and efficient commercial synthetic route for dasatinib (Sprycel). Synthetic Communications. Division of Chemistry, Department of Science and Humanities. Vignan’s Foundation for Science Technology and Research University. Guntur, India. Volume 47. Issue 17. Pages 1610-1621. 2017

SYN 4

Reference

Chen, Bang-Chi; Zhao, Rulin; Wang, Bei; Droghini, Roberto; Lajeunesse, Jean; Sirard, Pierre; Endo, Masaki; Balasubramanian, Balu; Barrish, Joel C. A new and efficient preparation of 2-aminothiazole-5-carbamides: applications to the synthesis of the anticancer drug dasatinib. ARKIVOC (Gainesville, FL, United States). Discovery Chemistry. Bristol-Myers Squibb Research and Development. Princeton, USA 08543. Issue 6.Pages 32-38. 2010

SYN 5

Reference

An, Kang; Guan, Jianning; Yang, Hao; Hou, Wen; Wan, Rong. Improvement on the synthesis of Dasatinib. Jingxi Huagong Zhongjianti. College of Science. Nanjing University of Technology. Nanjing, Jiangsu Province, Peop. Rep. China 211816. Volume 41. Issue 2. Pages 42-44. 2011

PATENT

https://patents.google.com/patent/US7491725B2/en

EXAMPLESExample 1Preparation of Intermediate:

(S)-1-sec-Butylthiourea

Figure US07491725-20090217-C00048

To a solution of S— sec-butyl-amine (7.31 g, 0.1 mol) in chloroform (80 mL) at 0° C. was slowly added benzoyl isothiocyanate (13.44 mL, 0.1 mol). The mixture was allowed to warm to 10° C. and stirred for 10 min. The solvent was then removed under reduced pressure, and the residue was dissolved in MeOH (80 mL). An aqueous solution (10 mL) of NaOH (4 g, 0.1 mol) was added to this solution, and the mixture was stirred at 60° C. for another 2 h. The MeOH was then removed under reduced pressure, and the residue was stirred in water (50 mL). The precipitate was collected by vacuum filtration and dried to provide S-1-sec-butyl-thiourea (12.2 g, 92% yield). mp 133-134° C.; 1H NMR (500 MHz, DMSO-D6) δ 7.40 (s, 1H), 7.20 (br s, 1H), 6.76 (s, 1H), 4.04 (s, 1H), 1.41 (m, 2H), 1.03 (d, J=6.1 Hz, 3H), 0.81 (d, J=7.7 Hz, 3H); 13C NMR (125 MHz, DMSO-D6) δ 182.5, 50.8, 28.8, 19.9, 10.3; LRMS m/z 133.2 (M+H); Anal. Calcd for C5H12N2S: C, 45.41; H, 9.14; N, 21.18; S, 24.25. Found: C, 45.49; H, 8.88; N, 21.32; S, 24.27.

Example 2Preparation of Intermediate:

(R)-1-sec-Butylthiourea

Figure US07491725-20090217-C00049

(R)-1-sec-Butylthiourea was prepared in 92% yield according to the general method outlined for Example 1. mp 133-134° C.; 1H NMR(500 MHz, DMSO) δ 0.80(m, 3H, J=7.7), 1.02(d, 3H, J=6.1), 1.41(m, 2H), (3.40, 4.04)(s, 1H), 6.76(s, 1H), 7.20(s, br, 1H), 7.39(d, 1H, J=7.2); 13C NMR (500 MHz, DMSO) δ: 10.00, 19.56, 28.50, 50.20, 182.00; m/z 133.23 (M+H); Anal. Calcd for C5H12N2S: C, 45.41; H, 9.14; N, 21.18; S, 24.25. Found: C, 45.32; H, 9.15; N, 21.14; S, 24.38.

Example 3Preparation of:

Figure US07491725-20090217-C00050

To a solution of 3-amino-N-methyl-4-methylbenzamide hydrochloride (1.0 g, 5 mmol) in acetone (10 mL) at 0° C. was added pyridine (1.2 mL, 15 mmol) dropwise via syringe. 3-Methoxyacryloyl chloride (0.72 mL. 6.5 mmol) was added and the reaction stirred at room temperature for 1 h. The solution was cooled again to 0° C. and 1N HCl (1.5 mL) was added dropwise via pipet. The reaction mixture was stirred for 5 min, then water (8.5 mL) was added via an addition funnel. The acetone was removed in vacuo and the resulting solution stirred for 4h. Crystallization began within 15 min. After stirring for 4 h, the vessel was cooled in an ice bath for 30 min, filtered, and rinsed with ice cold water (2×3 mL) to give compound 3A (0.99 g, 78% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.12 (br s, 1H), 7.76 (s, 1H), 7.29 (m, 2H), 7.05 (d, J=7.9 Hz, 1H), 5.47 (d, J=12.3 Hz, 1H), 3.48 (s, 3H), 2.54 (d, J=4.7 Hz, 3H), 2.03 (s, 3H); HPLC rt 2.28 min (Condition A).

3B. Example 3To a 50 mL RBF containing the above compound 3A (0.5 g, 2.0 mmol) was added THF (2.5 mL) and water (2 mL), followed by NBS (0.40 g, 2.22 mmol), and the solution was stirred for 90 min. R-sec-butylthiourea (Ex. 2) (267 mg), was added, and the solution was heated to 75° C. for 8 h. Conc. NH4OH was added to adjust the pH to 10 followed by the addition of EtOH (15 mL). Water (15 mL) was added and the slurry stirred for 16 h, filtered, and washed with water to give Example 3 as a light brown solid (0.48 g, 69% yield, 98% purity). MS 347.1; HPLC 2.59.

Example 4Preparation of:

Figure US07491725-20090217-C00051

Example 4 is prepared following the methods of Example 3 but using the appropriate acryl benzamide and Example 1.

Example 5Preparation of:

N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (The Compound of Formula (IV))

Figure US07491725-20090217-C00052

5A. 1-(6-Chloro-2-methylpyrimidin-4-yl)thiourea

Figure US07491725-20090217-C00053

To a stirring slurry of 4-amino-5-chloro-2-methylpyrimidine (6.13 g, 42.7 mmol) in THF (24 mL) was added ethyl isothiocyanatoformate (7.5 mL, 63.6 mmol), and the mixture heated to reflux. After 5h, another portion of ethyl isothiocyanato formate (1.0 mL, 8.5 mmol) was added and after 10h, a final portion (1.5 mL, 12.7 mmol) was added and the mixture stirred 6h more. The slurry was evaporated under vacuum to remove most of the solvent and heptane (6 mL) added to the residue. The solid was collected by vacuum filtration and washed with heptane (2×5 mL) giving 8.01 g (68% yield) of the intermediate ethyl 6-chloro-2-methylpyrimidin-4-ylcarbamothioylcarbamate.A solution of ethyl 6-chloro-2-methylpyrimidin-4-ylcarbamothioylcarbamate (275 mg, 1.0 mmol) and 1N sodium hydroxide (3.5 eq) was heated and stirred at 50° C. for 2h. The resulting slurry was cooled to 20-22° C. The solid was collected by vacuum filtration, washed with water, and dried to give 185 mg of 1-(6-chloro-2-methylpyrimidin-4-yl)thiourea (91% yield). 1H NMR (400 MHz, DMSO-d6): δ2.51 (S, 3H), 7.05 (s, 1H), 9.35 (s,1H), 10.07 (s, 1H), 10.91 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ: 25.25, 104.56, 159.19, 159.33, 167.36, 180.91.

5B. (E)-N-(2-Chloro-6-methylphenyl)-3-ethoxyacrylamide

Figure US07491725-20090217-C00054

To a cold stirring solution of 2-chloro-6-methylaniline (59.5 g 0.42 mol) and pyridine (68 ml, 0.63 mol) in THF (600 mL) was added 3-ethoxyacryloyl chloride (84.7 g, 0.63 mol) slowly keeping the temp at 0-5° C. The mixture was then warmed and stirred for 2 h. at 20° C. Hydrochloric acid (1N, 115 mL) was added at 0-10° C. The mixture was diluted with water (310 mL) and the resulting solution was concentrated under vacuum to a thick slurry. The slurry was diluted with toluene (275 mL) and stirred for 15 min. at 20-22° C. then 1 h. at 0° C. The solid was collected by vacuum filtration, washed with water (2×75 mL) and dried to give 74.1 g (73.6% yield) of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide). 1H NMR (400 Hz, DMSO-d6) δ 1.26 (t, 3H, J=7 Hz), 2.15 (s, 3H), 3.94 (q, 2H, J=7 Hz), 5.58 (d, 1H, J=12.4 Hz), 7.10-7.27 (m, 2H, J=7.5 Hz), 7.27-7.37 (d, 1H, J=7.5 Hz), 7.45(d, 1H, J=12.4 Hz), 9.28 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 14.57, 18.96, 67.17, 97.99, 126.80, 127.44, 129.07, 131.32, 132.89, 138.25, 161.09, 165.36.

5C. 2-Amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

Figure US07491725-20090217-C00055

To a mixture of compound 5B (5.00 g, 20.86 mmol) in 1,4-dioxane (27 mL) and water (27 mL) was added NBS (4.08 g, 22.9 mmol) at −10 to 0° C. The slurry was warmed and stirred at 20-22° C. for 3h. Thiourea (1.60 g, 21 mmol) was added and the mixture heated to 80° C. After 2h, the resulting solution was cooled to 20-22° and conc. ammonium hydroxide (4.2 mL) was added dropwise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0-5° C. The solid was collected by vacuum filtration, washed with cold water (10 mL), and dried to give 5.3 g (94.9% yield) of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ δ 2.19 (s, 3H), 7.09-7.29 (m, 2H, J=7.5), 7.29-7.43 (d, 1H, J=7.5), 7.61 (s, 2H), 7.85 (s, 1H), 9.63 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ: 18.18, 120.63, 126.84, 127.90, 128.86, 132.41, 133.63, 138.76, 142.88, 159.45, 172.02.

5D. 2-(6-Chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

Figure US07491725-20090217-C00056

To a stirring solution of compound 5C (5.00 g, 18.67 mmol) and 4,6-dichloro-2-methylpyrimidine (3.65 g 22.4/mmol) in THF (65 mL) was added a 30% wt. solution of sodium t-butoxide in THF (21.1 g, 65.36 mmol) slowly with cooling to keep the temperature at 10-20° C. The mixture was stirred at room temperature for 1.5 h and cooled to 0-5° C. Hydrochloric acid, 2N (21.5 mL) was added slowly and the mixture stirred 1.75 h at 0-5° C. The solid was collected by vacuum filtration, washed with water (15 mL) and dried to give 6.63 g (86.4% yield) of compound 5D. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.58 (s, 3H), 6.94 (s, 1H), 7.18-7.34, (m, 2H, J=7.5), 7.34-7.46 (d, 1H, J=7.5), 8.31 (s, 1H), 10.02 (s, 1H), 12.25 (s, 1H).

5E. Example 5To a mixture of compound 5D (4.00 g, 10.14 mmol) and hydroxyethylpiperazine (6.60 g, 50.69 mmol) in n-butanol (40 mL) was added DIPEA (3.53 mL, 20.26 mmol). The slurry was heated at 118° C. for 4.5 h, then cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with n-butanol (5 mL), and dried. The product (5.11 g) was dissolved in hot 80% EtOH—H2O (80 mL), and the solution was clarified by filtration. The hot solution was slowly diluted with water (15 mL) and cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with 50% ethanol-water (5 mL) and dried affording 4.27 g (83.2% yield) of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide as monohydrate. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.40 (s, 3H), 2.42 (t, 2H, J=6), 2.48 (t, 4H, J=6.3), 3.50 (m, 4H), 3.53 (q, 2H, J=6), 4.45 (t, 1H, J=5.3), 6.04 (s, 1H), 7.25 (t, 1H, J=7.6), 7.27 (dd, 1H, J=7.6, 1.7), 7.40 (dd, 1H, J=7.6, 1.7), 8.21 (s, 1H), 9.87 (s, 1H), 11.47.

Example 6Preparation of:

N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide

Figure US07491725-20090217-C00057

To a slurry of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide 5B (120 mg, 0.50 mmol) in THF (0.75 ml) and water (0.5 mL) was added NBS (98 mg, 0.55 mmol) at 0° C. The mixture was warmed and stirred at 20-22° C. for 3h. To this was added 1-(6-chloro-2-methylpyrimidin-4-yl)thiourea 5A (100 mg, 0.49 mmol), and the slurry heated and stirred at reflux for 2h. The slurry was cooled to 20-22° C. and the solid collected by vacuum filtration giving 140 mg (71% yield) of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide 5D. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.58 (s, 3H), 6.94 (s, 1H), 7.18-7.34, (m, 2H, J=7.5), 7.34-7.46 (d, 1H, J=7.5), 8.31 (s, 1H), 10.02 (s, 1H), 12.25 (s, 1H).Compound 5D was elaborated to N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide, following Step 5E.

Example 7Preparation of:

N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide7A. 2-[4-(6-Chloro-2-methyl-pyrimidin-4-yl)-piperazin-1-yl]-ethanol

Figure US07491725-20090217-C00058

2-piperazin-1-yl-ethanol (8.2 g, 63.1 mmol) was added to a solution of 4,6-dichloro-2-methylpyrimidine (5.2 g, 31.9 mmol) in dichloromethane (80 ml) at rt. The mixture was stirred for two hours and triethylamine (0.9 ml) was added. The mixture was stirred at rt for 20h. The resultant solid was filtered. The cake was washed with dichloromethane (20 ml). The filtrate was concentrated to give an oil. This oil was dried under high vacuum for 20h to give a solid. This solid was stirred with heptane (50 ml) at rt for 5h. Filtration gave 7C (8.13 g) as a white solid

7B. Example 7

Figure US07491725-20090217-C00059


To a 250 ml of round bottom flask were charged compound 5C (1.9 g, 7.1 mmol), compound 7C (1.5 g, 5.9 mmol), K2CO(16 g, 115.7 mmol), Pd (OAc)(52 mg, 0.23 mmol) and BINAP (291 mg, 0.46 mmol). The flask was placed under vacuum and flushed with nitrogen. Toluene was added (60 ml). The suspension was heated to 100-110° C. and stirred at this temperature for 20h. After cooling to room temperature, the mixture was applied to a silica gel column. The column was first eluted with EtOAC, and then with 10% of MeOH in EtOAC. Finally, the column was washed with 10% 2M ammonia solution in MeOH/90% EtOAC. The fractions which contained the desired product were collected and concentrated to give compound IV as a yellow solid (2.3 g).

Analytical MethodsSolid State Nuclear Magnetic Resonance (SSNMR)All solid-state C-13 NMR measurements were made with a Bruker DSX-400, 400 MHz NMR spectrometer. High resolution spectra were obtained using high-power proton decoupling and the TPPM pulse sequence and ramp amplitude cross-polarization (RAMP-CP) with magic-angle spinning (MAS) at approximately 12 kHz (A. E. Bennett et al, J. Chem. Phys., 1995, 103, 6951), (G. Metz, X. Wu and S. O. Smith, J. Magn. Reson. A., 1994, 110, 219-227). Approximately 70 mg of sample, packed into a canister-design zirconia rotor was used for each experiment. Chemical shifts (δ) were referenced to external adamantane with the high frequency resonance being set to 38.56 ppm (W. L. Earl and D. L. VanderHart, J. Magn. Reson., 1982, 48, 35-54).X-Ray Powder DiffractionOne of ordinary skill in the art will appreciate that an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed. In particular, it is generally known that intensities in a X-ray diffraction pattern may fluctuate depending upon measurement conditions employed. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account. Additionally, a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about 5% or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles. Consequently, it is to be understood that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein. Any crystal forms that provide X-ray diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present invention. The ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art.X-Ray powder diffraction data for the crystalline forms of Compound (IV) were obtained using a Bruker GADDS (BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison, Wis. 53711 USA) (General Area Detector Diffraction System) manual chi platform goniometer. Powder samples were placed in thin walled glass capillaries of 1 mm or less in diameter; the capillary was rotated during data collection. The sample-detector distance was 17 cm. The radiation was Cu Kα (45 kV 111 mA, λ=1.5418 Å). Data were collected for 3<2θ<35° with a sample exposure time of at least 300 seconds.Single Crystal X-RayAll single crystal data were collected on a Bruker-Nonius (BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison, Wis. 53711 USA) Kappa CCD 2000 system using Cu Kα radiation (λ=1.5418 Å) and were corrected only for the Lorentz-polarization factors. Indexing and processing of the measured intensity data were carried out with the HKL2000 software package (Otwinowski, Z. & Minor, W. (1997) in Macromolecular Crystallography, eds. Carter, W. C. Jr & Sweet, R. M. (Academic, NY), Vol. 276, pp. 307-326) in the Collect program suite (Data collection and processing user interface: Collect: Data collection software, R. Hooft, Nonius B. V., 1998).The structures were solved by direct methods and refined on the basis of observed reflections using either the SDP (SDP, Structure Determination Package, Enraf-Nonius, Bohemia NY 11716 Scattering factors, including f′ and f″, in the SDP software were taken from the “International Tables for Crystallography”, Kynoch Press, Birmingham, England, 1974; Vol IV, Tables 2.2A and 2.3.1) software package with minor local modifications or the crystallographic package, MAXUS (maXus solution and refinement software suite: S. Mackay, C. J. Gilmore, C. Edwards, M. Tremayne, N. Stewart, K. Shankland. maXus: a computer program for the solution and refinement of crystal structures from diffraction data).The derived atomic parameters (coordinates and temperature factors) were refined through full matrix least-squares. The function minimized in the refinements was Σw(|Fo|−|Fc|)2. R is defined as Σ∥Fo|−|Fc∥/Σ|Fo| while Rw=[Σw(|Fo|−|Fc|)2w|Fo|2]1/2 where w is an appropriate weighting function based on errors in the observed intensities. Difference maps were examined at all stages of refinement. Hydrogens were introduced in idealized positions with isotropic temperature factors, but no hydrogen parameters were varied.The derived atomic parameters (coordinates and temperature factors) were refined through full matrix least-squares. The function minimized in the refinements was Σw(|Fo|−|Fc|)2. R is defined as Σ∥Fo|−|Fc∥/Σ|Fo| while Rw=[Σw(|Fo|−|Fc|)2w|Fo|2]1/2 where w is an appropriate weighting function based on errors in the observed intensities. Difference maps were examined at all stages of refinement. Hydrogens were introduced in idealized positions with isotropic temperature factors, but no hydrogen parameters were variedDifferential Scanning CalorimetryThe DSC instrument used to test the crystalline forms was a TA Instruments® model Q1000. The DSC cell/sample chamber was purged with 100 ml/min of ultra-high purity nitrogen gas. The instrument was calibrated with high purity indium. The accuracy of the measured sample temperature with this method is within about +/−1° C., and the heat of fusion can be measured within a relative error of about +/−5%. The sample was placed into an open aluminum DSC pan and measured against an empty reference pan. At least 2 mg of sample powder was placed into the bottom of the pan and lightly tapped down to ensure good contact with the pan. The weight of the sample was measured accurately and recorded to a hundredth of a milligram. The instrument was programmed to heat at 10° C. per minute in the temperature range between 25 and 350° C.The heat flow, which was normalized by a sample weight, was plotted versus the measured sample temperature. The data were reported in units of watts/gram (“W/g”). The plot was made with the endothermic peaks pointing down. The endothermic melt peak was evaluated for extrapolated onset temperature, peak temperature, and heat of fusion in this analysis.Thermogravimetric Analysis (TGA)The TGA instrument used to test the crystalline forms was a TAInstruments® model Q500. Samples of at least 10 milligrams were analyzed at a heating rate of 10° C. per minute in the temperature range between 25° C. and about 350° C.

Example 8Preparation of:

crystalline monohydrate of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV)An example of the crystallization procedure to obtain the crystalline monohydrate form is shown here:

  • Charge 48 g of the compound of formula (IV).
  • Charge approximately 1056 mL (22 mL/g) of ethyl alcohol, or other suitable alcohol.
  • Charge approximately 144 mL of water.
  • Dissolve the suspension by heating to approximately 75° C.
  • Optional: Polish filter by transfer the compound of formula (IV) solution at 75° C. through the preheated filter and into the receiver.
  • Rinse the dissolution reactor and transfer lines with a mixture of 43 mL of ethanol and 5 mL of water.

Heat the contents in the receiver to 75-80° C. and maintain 75-80° C. to achieve complete dissolution.Charge approximately 384 mL of water at a rate such that the batch temperature is maintained between 75-80° C.Cool to 75° C., and, optionally, charge monohydrate seed crystals. Seed crystals are not essential to obtaining monohydrate, but provide better control of the crystallization.

  • Cool to 70° C. and maintain 70° C. for ca. 1 h.
  • Cool from 70 to 5 C over 2 h, and maintain the temperature between 0 at 5° C. for at least 2 h.
  • Filter the crystal slurry.
  • Wash the filter cake with a mixture of 96 mL of ethanol and 96 mL of water.
  • Dry the material at ≦50° C. under reduced pressure until the water content is 3.4 to 4.1% by KF to afford 41 g (85 M %).
    Alternately, the monohydrate can be obtained by:
    • 1) An aqueous solution of the acetate salt of compound IV was seeded with monohydrate and heated at 80° C. to give bulk monohydrate.
    • 2) An aqueous solution of the acetate salt of compound IV was seeded with monohydrate. On standing several days at room temperature, bulk monohydrate had formed.
    • 3) An aqueous suspension of compound IV was seeded with monohydrate and heated at 70° C. for 4 hours to give bulk monohydrate. In the absence of seeding, an aqueous slurry of compound IV was unchanged after 82 days at room temperature.
    • 4) A solution of compound IV in a solvent such as NMP or DMA was treated with water until the solution became cloudy and was held at 75-85° C. for several hours. Monohydrate was isolated after cooling and filtering.
    • 5) A solution of compound IV in ethanol, butanol, and water was heated. Seeds of monohydrate were added to the hot solution and then cooled. Monohydrate was isolated upon cooling and filtration.

One of ordinary skill in the art will appreciate that the monohydrate of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 1 or by a representative sampling of peaks as shown in Table 1.Representative peaks taken from the XRPD of the monohydrate of the compound of formula (IV) are shown in Table 1.TABLE 1 2-Theta d(Å) Height 17.994 4.9257 915 18.440 4.8075 338 19.153 4.6301 644 19.599 4.5258 361 21.252 4.1774 148 24.462 3.6359 250 25.901 3.4371 133 28.052 3.1782 153The XRPD is also characterized by the following list comprising 2θ values selected from the group consisting of: 4.6±0.2, 11.2±0.2, 13.8±0.2, 15.2±0.2, 17.9±0.2, 19.1±0.2, 19.6±0.2, 23.2±0.2, 23.6±0.2. The XRPD is also characterized by the list of 2θ values selected from the group consisting of: 18.0±0.2, 18.4±0.2, 19.2±0.2, 19.6±0.2, 21.2±0.2, 24.5±0.2, 25.9±0.2, and 28.0±0.2.Single crystal x-ray data was obtained at room temperature (+25° C.). The molecular structure was confirmed as a monohydrate form of the compound of Formula (IV).The following unit cell parameters were obtained for the monohydrate of the compound of formula (IV) from the x-ray analysis at 25° C.:a(Å)=13.8632(7); b(Å)=9.3307(3); c(Å)=38.390(2);V(Å3) 4965.9(4); Z′=1; Vm=621Space group PbcaMolecules/unit cell 8Density (calculated) (g/cm3) 1.354Wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).Single crystal x-ray data was also obtained at −50° C. The monohydrate form of the compound of Formula (IV) is characterized by unit cell parameters approximately equal to the following:Cell dimensions:

  • a(Å)=13.862(1);
  • b(Å)=9.286(1);
  • c(Å)=38.143(2);

Volume=4910(1) Å3Space group PbcaMolecules/unit cell 8Density (calculated) (g/cm3) 1.369wherein the compound is at a temperature of about −50° C.The simulated XRPD was calculated from the refined atomic parameters at room temperature.The monohydrate of the compound of formula (IV) is represented by the DSC as shown in FIG. 2. The DSC is characterized by a broad peak between approximately 95° C. and 130° C. This peak is broad and variable and corresponds to the loss of one water of hydration as seen in the TGA graph. The DSC also has a characteristic peak at approximately 287° C. which corresponds to the melt of the dehydrated form of the compound of formula (IV).The TGA for the monohydrate of the compound of Formula (IV) is shown in FIG. 2 along with the DSC. The TGA shows a 3.48% weight loss from 50° C. to 175° C. The weight loss corresponds to a loss of one water of hydration from the compound of Formula (IV).The monohydrate may also be prepared by crystallizing from alcoholic solvents, such as methanol, ethanol, propanol, i-propanol, butanol, pentanol, and water.

Example 9Preparation of:

crystalline n-butanol solvate of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV)The crystalline butanol solvate of the compound of formula (IV) is prepared by dissolving compound (IV) in 1-butanol at reflux (116-118° C.) at a concentration of approximately 1 g/25 mL of solvent. Upon cooling, the butanol solvate crystallizes out of solution. Filter, wash with butanol, and dry.The following unit cell parameters were obtained from the x-ray analysis for the crystalline butanol solvate, obtained at room temperature:a(Å)=22.8102(6); b(Å)=8.4691(3); c(Å)=15.1436(5); β=95.794(2);V(Å3) 2910.5(2); Z′=1; Vm=728Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.283Wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the butanol solvate of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 3 or by a representative sampling of peaks. Representative peaks for the crystalline butanol solvate are 2θ values of: 5.9±0.2, 12.0±0.2, 13.0±0.2, 17.7±0.2, 24.1±0.2, and 24.6±0.2.

Example 10Preparation of:

crystalline ethanol solvate of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV)

Figure US07491725-20090217-C00060

To a 100-mL round bottom flask was charged 4.00 g (10.1 mmol) of 5D (contained 2.3 Area % 5C) 6.60 g (50.7 mmol) of 7B, 80 mL of n-butanol and 2.61 g (20.2 mmol) of DIPEA. The resulting slurry was heated to 120° C. and maintained at 120° C. for 4.5 h whereby HPLC analysis showed 0.19 relative Area % of residual 5D to compound IV. The homogeneous mixture was cooled to 20° C. and left stirring overnight. The resulting crystals were filtered. The wet cake was washed twice with 10-mL portions of n-butanol to afford a white crystalline product. HPLC analysis showed this material to contain 99.7 Area % compound IV and 0.3 Area % 5C.The resulting wet cake was returned to the 100-mL reactor, and charged with 56 mL (12 mL/g) of 200 proof ethanol. At 80° C. an additional 25 mL of ethanol was added. To this mixture was added 10 mL of water resulting in rapid dissolution. Heat was removed and crystallization was observed at 75-77° C. The crystal slurry was further cooled to 20° C. and filtered. The wet cake was washed once with 10 mL of 1:1 ethanol: water and once with 10 mL of n-heptane. The wet cake contained 1.0% water by KF and 8.10% volatiles by LOD. The material was dried at 60° C./30 in Hg for 17 h to afford 3.55 g (70 M %) of material containing only 0.19% water by KF, 99.87 Area % by HPLC. The 1H NMR spectrum, however revealed that the ethanol solvate had been formed.The following unit cell parameters were obtained from the x-ray analysis for the crystalline ethanol solvate (di-ethanolate, E2-1), obtained at −40° C.:a(Å)=22.076(1); b(Å)=8.9612(2); c(Å)=16.8764(3); β=114.783(1);V(Å3) 3031.1(1); Z′=1; Vm=758Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.271Wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the ethanol solvate (E2-1) of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 4 or by a representative sampling of peaks. Representative peaks for the crystalline ethanol solvate are 2θ values of: 5.8±0.2, 11.3±0.2, 15.8±0.2, 17.2±0.2, 19.5±0.2, 24.1±0.2, 25.3±0.2, and 26.2±0.2.In addition, during the process to form the ethanolate (diethanolate) the formation of another ethanol solvate (½ ethanolate, T1E2-1) has been observed. To date this additional ethaonol solvate is known strictly as a partial desolvation product of the original diethanolate form E2-1, and has only been observed on occasion during crystallization of E2-1The following unit cell parameters were obtained from the x-ray analysis for the crystalline ½ ethanol solvate T1E2-1, obtained at −10° C.:a(Å)=22.03(2); b(Å)=9.20(1); c(Å)=12.31(1);β=93.49(6)V(Å3) 2491(4)); Z′=1; Vm=623;Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.363Wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the ethanol solvate (T1E2-1) of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 7 or by a representative sampling of peaks. Representative peaks for the crystalline ethanol solvate are 2θ values of: 7.20±0.2, 12.01±0.2, 12.81±0.2, 18.06±0.2, 19.30±0.2, and 25.24±0.2.

Example 11Preparation of:

crystalline N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV) (Neat form N-6)To a mixture of compound 5D (175.45 g, 0.445 mol) and hydroxyethylpiperazine (289.67 g, 2.225 mol) in NMP (1168 mL) was added DIPEA (155 mL, 0.89 mol). The suspension was heated at 110° C. (solution obtained) for 25 min., then cooled to about 90° C. The resulting hot solution was added dropwise into hot (80° C.) water (8010) mL, keeping the temperature at about 80° C. The resulting suspension was stirred 15 min at 80° C. then cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with water (2×1600 mL) and dried in vacuo at 55-60° C. affording 192.45 g (88.7% yield) of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide. 1H NMR (400 MHz, DMSO-d6): δ 2.24 (s, 3H), 2.41 (s, 3H), 2.43 (t, 2H, J=6), 2.49 (t, 4H, J=6.3), 3.51 (m, 4H), 3.54 (q, 2H, J=6), 4.46 (t, 1H, J=5.3), 6.05 (s, 1H), 7.26 (t, 1H, J=7.6), 7.28 (dd, 1H, J=7.6, 1.7), 7.41 (dd, 1H, J=7.6, 1.7), 8.23 (s, 1H), 9.89 (s, 1H), 11.48. KF0.84; DSC: 285.25° C. (onset), 286.28° C. (max).The following unit cell parameters were obtained from the x-ray analysis for the neat crystalline compound IV, obtained at 23° C.:a(Å)=22.957(1); b(Å)=8.5830(5); c(Å)=13.803(3); β=112.039(6);V(Å3)=2521.0(5); Z′=1; Vm=630Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.286Wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the crystalline form of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 5 or by a representative sampling of peaks. Representative peaks for the crystalline neat form (N-6) are 2θ values of: 6.8±0.2, 11.1±0.2, 12.3±0.2, 13.2±0.2, 13.7±0.2, 16.7±0.2, 21.0±0.2, 24.3±0.2, and 24.8±0.2.

Example 12Preparation of:

crystalline N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV) (neatform T1H1-7)The title neat form may be prepared by heating the monohydrate form of the compound of formula (IV) above the dehydration temperature.The following unit cell parameters were obtained from the x-ray analysis for the neat crystalline (T1H1-7) compound IV, obtained at 25° C.:a(Å)=13.4916; b(Å)=9.3992(2); c(Å)=38.817(1);V(Å3)=4922.4(3); Z′=1; Vm=615Space group PbcaDensity (calculated) (g/cm3) 1.317Wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the neat crystalline form (T1H1-7) of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 6 or by a representative sampling of peaks. Representative peaks for the crystalline neat form (T1H1-7)) are 2θ values of: 8.0±0.2, 9.7±0.2, 11.2±0.2, 13.3±0.2, 17.5±0.2, 18.9±0.2, 21.0±0.2, 22.0±0.2.Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.PATENThttps://patents.google.com/patent/US8680103B2/enAminothiazole-aromatic amides of formula I

Figure US08680103-20140325-C00002


wherein Ar is aryl or heteroaryl, L is an optional alkylene linker, and R2, R3, R4, and R5, are as defined in the specification herein, are useful as kinase inhibitors, in particular, inhibitors of protein tyrosine kinase and p38 kinase. They are expected to be useful in the treatment of protein tyrosine kinase-associated disorders such as immunologic and oncological disorders [see, U.S. Pat. No. 6,596,746 (the ‘746 patent), assigned to the present assignee and incorporated herein by reference], and p38 kinase-associated conditions such as inflammatory and immune conditions, as described in U.S. patent application Ser. No. 10/773,790, filed Feb. 6, 2004, claiming priority to U.S. Provisional application Ser. No. 60/445,410, filed Feb. 6, 2003 (hereinafter the ‘410 application), both of which are also assigned to the present assignee and incorporated herein by reference.The compound of formula (IV), ′N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, is an inhibitor of SRC/ABL and is useful in the treatment of oncological diseases.

Figure US08680103-20140325-C00003

Other approaches to preparing 2-aminothiazole-5-carboxamides are described in the ‘746 patent and in the ‘410 application. The ‘746 patent describes a process involving treatment of chlorothiazole with n-BuLi followed by reaction with phenyl isocyanates to give chlorothiazole-benzamides, which are further elaborated to aminothiazole-benzamide final products after protection, chloro-to-amino substitution, and deprotection, e.g.,

Figure US08680103-20140325-C00004

The ‘410 application describes a multi-step process involving first, converting N-unsubstituted aminothiazole carboxylic acid methyl or ethyl esters to bromothiazole carboxylic acid esters via diazotization with tert-butyl nitrite and subsequent CuBrtreatment, e.g.,

Figure US08680103-20140325-C00005


then, hydrolyzing the resulting bromothiazole esters to the corresponding carboxylic acids and converting the acids to the corresponding acyl chlorides, e.g.,

Figure US08680103-20140325-C00006


then finally, coupling the acyl chlorides with anilines to afford bromothiazole-benzamide intermediates which were further elaborated to aminothiazole-benzamide final products, e.g.,

Figure US08680103-20140325-C00007

Other approaches for making 2-aminothiazole-5-carboxamides include coupling of 2-aminothiazole-5-carboxylic acids with amines using various coupling conditions such as DCC [Roberts et al, J. Med. Chem. (1972), 15, at p. 1310], and DPPA [Marsham et al., J. Med. Chem. (1991), 34, at p. 1594)].The above methods present drawbacks with respect to the production of side products, the use of expensive coupling reagents, less than desirable yields, and the need for multiple reaction steps to achieve the 2-aminothiazole-5-carboxamide compounds.Reaction of N,N-dimethyl-N′-(aminothiocarbonyl)-formamidines with α-haloketones and esters to give 5-carbonyl-2-aminothiazoles has been reported. See Lin, Y. et al, J. Heterocycl. Chem. (1979), 16, at 1377; Hartmann, H. et al, J. Chem. Soc. Perkin Trans. (2000), 1, at 4316; Noack, A. et al; Tetrahedron (2002), 58, at 2137; Noack, A.; et al. Angew. Chem. (2001), 113, at 3097; and Kantlehner, W. et al., J. Prakt. Chem./Chem.-Ztg. (1996), 338, at 403. Reaction of β-ethoxy acrylates and thioureas to prepare 2-aminothiazole-5-carboxylates also has been reported. See Zhao, R., et al., Tetrahedron Lett. (2001), 42, at 2101. However, electrophilic bromination of acrylanilide and crotonanilide has been known to undergo both aromatic bromination and addition to the α,β-unsaturated carbon-carbon double bonds. See Autenrieth, Chem. Ber. (1905), 38, at 2550; Eremeev et al., Chem. Heterocycl. Compd. Engl. Transl. (1984), 20, at 1102.New and efficient processes for preparing 2-aminothiazole-5-carboxamides are desired.

SUMMARY OF THE INVENTION

This invention is related to processes for the preparation of 2-aminothiazole-5-aromatic amides having the formula (I),

Figure US08680103-20140325-C00008


wherein L, Ar, R2, R3, R4, R5, and m are as defined below, comprising reacting a compound having the formula (II),

Figure US08680103-20140325-C00009


wherein Q is the group —O—P*, wherein P* is selected so that, when considered together with the oxygen atom to which P* is attached, Q is a leaving group, and Ar, L, R2, R3, and m are as defined below,
with a halogenating reagent in the presence of water followed by a thiourea compound having the formula (III),

Figure US08680103-20140325-C00010


wherein, Rand Rare as defined below,
to provide the compound of formula (I),

Figure US08680103-20140325-C00011


wherein,Ar is the same in formulae (I) and (II) and is aryl or heteroaryl;L is the same in formulae (I) and (II) and is optionally-substituted alkylene;Ris the same in formulae (I) and (II), and is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclo;Ris the same in formulae (I) and (II), and is selected from hydrogen, halogen, cyano, haloalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclo;Ris (i) the same in each of formulae (I) and (III), and (ii) is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclo, or alternatively, Ris taken together with R5, to form heteroaryl or heterocyclo;Ris (i) the same in each of formulae (I) and (III), and (ii) is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclo, or alternatively, Ris taken together with R4, to form heteroaryl or heterocyclo; andm is 0 or 1.Applicants have surprisingly discovered said process for converting β-(P*)oxy acryl aromatic amides and thioureas to 2-aminothiazole derivatives, wherein the aromatic amides are not subject to further halogenation producing other side products. Aminothiazole-aromatic amides, particularly, 2-aminothiazole-5-benzamides, can thus be efficiently prepared with this process in high yield.In another aspect, the present invention is directed to crystalline forms of the compound of formula (IV).

EXAMPLESExample 1Preparation of Intermediate:

(S)-1-sec-Butylthiourea

Figure US08680103-20140325-C00049

To a solution of S-sec-butyl-amine (7.31 g, 0.1 mol) in chloroform (80 mL) at 0° C. was slowly added benzoyl isothiocyanate (13.44 mL, 0.1 mol). The mixture was allowed to warm to 10° C. and stirred for 10 min. The solvent was then removed under reduced pressure, and the residue was dissolved in MeOH (80 mL). An aqueous solution (10 mL) of NaOH (4 g, 0.1 mol) was added to this solution, and the mixture was stirred at 60° C. for another 2 h. The MeOH was then removed under reduced pressure, and the residue was stirred in water (50 mL). The precipitate was collected by vacuum filtration and dried to provide S-1-sec-butyl-thiourea (12.2 g, 92% yield). mp 133-134° C.; 1H NMR (500 MHz, DMSO-D6) δ 7.40 (s, 1H), 7.20 (br s, 1H), 6.76 (s, 1H), 4.04 (s, 1H), 1.41 (m, 2H), 1.03 (d, J=6.1 Hz, 3H), 0.81 (d, J=7.7 Hz, 3H); 13C NMR (125 MHz, DMSO-D6) δ 182.5, 50.8, 28.8, 19.9, 10.3; LRMS m/z 133.2 (M+H); Anal. Calcd for C5H12N2S: C, 45.41; H, 9.14; N, 21.18; S, 24.25. Found: C, 45.49; H, 8.88; N, 21.32; S, 24.27.

Example 2Preparation of Intermediate:

(R)-1-sec-Butylthiourea

Figure US08680103-20140325-C00050

(R)-1-sec-Butylthiourea was prepared in 92% yield according to the general method outlined for Example 1. mp 133-134° C.; 1H NMR (500 MHz, DMSO) δ 0.80 (m, 3H, J=7.7), 1.02 (d, 3H, J=6.1), 1.41 (m, 2H), (3.40, 4.04) (s, 1H), 6.76 (s, 1H), 7.20 (s, br, 1H), 7.39 (d, 1H, J=7.2); 13C NMR (500 MHz, DMSO) δ: 10.00, 19.56, 28.50, 50.20, 182.00; m/z 133.23 (M+H); Anal. Calcd for C5H12N2S: C, 45.41; H, 9.14; N, 21.18; S, 24.25. Found: C, 45.32; H, 9.15; N, 21.14; S, 24.38.

Example 3Preparation of:

Figure US08680103-20140325-C00051

To a solution of 3-amino-N-methyl-4-methylbenzamide hydrochloride (1.0 g, 5 mmol) in acetone (10 mL) at 0° C. was added pyridine (1.2 mL, 15 mmol) dropwise via syringe. 3-Methoxyacryloyl chloride (0.72 mL 6.5 mmol) was added and the reaction stirred at room temperature for 1 h. The solution was cooled again to 0° C. and 1N HCl (1.5 mL) was added dropwise via pipette. The reaction mixture was stirred for 5 min, then water (8.5 mL) was added via an addition funnel. The acetone was removed in vacuo and the resulting solution stirred for 4 h. Crystallization began within 15 min. After stirring for 4 h, the vessel was cooled in an ice bath for 30 min, filtered, and rinsed with ice cold water (2×3 mL) to give compound 3A (0.99 g, 78% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.12 (br s, 1H), 7.76 (s, 1H), 7.29 (m, 2H), 7.05 (d, J=7.9 Hz, 1H), 5.47 (d, J=12.3 Hz, 1H), 3.48 (s, 3H), 2.54 (d, J=4.7 Hz, 3H), 2.03 (s, 3H); HPLC rt 2.28 min (Condition A).

3B. Example 3To a 50 mL RBF containing the above compound 3A (0.5 g, 2.0 mmol) was added THF (2.5 mL) and water (2 mL), followed by NBS (0.40 g, 2.22 mmol), and the solution was stirred for 90 min. R-sec-butylthiourea (Ex. 2) (267 mg), was added, and the solution was heated to 75° C. for 8 h. Conc. NH4OH was added to adjust the pH to 10 followed by the addition of EtOH (15 mL). Water (15 mL) was added and the slurry stirred for 16 h, filtered, and washed with water to give Example 3 as a light brown solid (0.48 g, 69% yield, 98% purity). MS 347.1; HPLC 2.59.

Example 4Preparation of:

Figure US08680103-20140325-C00052

Example 4 is prepared following the methods of Example 3 but using the appropriate acryl benzamide and Example 1.

Example 5Preparation of:

N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (The compound of Formula (IV))

Figure US08680103-20140325-C00053

5A. 1-(6-Chloro-2-methylpyrimidin-4-yl)thiourea

Figure US08680103-20140325-C00054

To a stirring slurry of 4-amino-5-chloro-2-methylpyrimidine (6.13 g, 42.7 mmol) in THF (24 mL) was added ethyl isothiocyanatoformate (7.5 mL, 63.6 mmol), and the mixture heated to reflux. After 5 h, another portion of ethyl isothiocyanato formate (1.0 mL, 8.5 mmol) was added and after 10 h, a final portion (1.5 mL, 12.7 mmol) was added and the mixture stirred 6 h more. The slurry was evaporated under vacuum to remove most of the solvent and heptane (6 mL) added to the residue. The solid was collected by vacuum filtration and washed with heptane (2×5 mL) giving 8.01 g (68% yield) of the intermediate ethyl 6-chloro-2-methylpyrimidin-4-ylcarbamothioylcarbamate.A solution of ethyl 6-chloro-2-methylpyrimidin-4-ylcarbamothioylcarbamate (275 mg, 1.0 mmol) and 1N sodium hydroxide (3.5 eq) was heated and stirred at 50° C. for 2 h. The resulting slurry was cooled to 20-22° C. The solid was collected by vacuum filtration, washed with water, and dried to give 185 mg of 1-(6-chloro-2-methylpyrimidin-4-yl)thiourea (91% yield). 1H NMR (400 MHz, DMSO-d6): δ2.51 (S, 3H), 7.05 (s, 1H), 9.35 (s, 1H), 10.07 (s, 1H), 10.91 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ: 25.25, 104.56, 159.19, 159.33, 167.36, 180.91.

5B. (E)-N-(2-Chloro-6-methylphenyl)-3-ethoxyacrylamide

Figure US08680103-20140325-C00055

To a cold stirring solution of 2-chloro-6-methylaniline (59.5 g 0.42 mol) and pyridine (68 ml, 0.63 mol) in THF (600 mL) was added 3-ethoxyacryloyl chloride (84.7 g, 0.63 mol) slowly keeping the temp at 0-5° C. The mixture was then warmed and stirred for 2 h. at 20° C. Hydrochloric acid (1N, 115 mL) was added at 0-10° C. The mixture was diluted with water (310 mL) and the resulting solution was concentrated under vacuum to a thick slurry. The slurry was diluted with toluene (275 mL) and stirred for 15 min. at 20-22° C. then 1 h. at 0° C. The solid was collected by vacuum filtration, washed with water (2×75 mL) and dried to give 74.1 g (73.6% yield) of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide). 1H NMR (400 Hz, DMSO-d6) δ 1.26 (t, 3H, J=7 Hz), 2.15 (s, 3H), 3.94 (q, 2H, J=7 Hz), 5.58 (d, 1H, J=12.4 Hz), 7.10-7.27 (m, 2H, J=7.5 Hz), 7.27-7.37 (d, 1H, J=7.5 Hz), 7.45 (d, 1H, J=12.4 Hz), 9.28 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 14.57, 18.96, 67.17, 97.99, 126.80, 127.44, 129.07, 131.32, 132.89, 138.25, 161.09, 165.36.

5C. 2-Amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

Figure US08680103-20140325-C00056

To a mixture of compound 5B (5.00 g, 20.86 mmol) in 1,4-dioxane (27 mL) and water (27 mL) was added NBS (4.08 g, 22.9 mmol) at −10 to 0° C. The slurry was warmed and stirred at 20-22° C. for 3 h. Thiourea (1.60 g, 21 mmol) was added and the mixture heated to 80° C. After 2 h, the resulting solution was cooled to 20-22° and conc. ammonium hydroxide (4.2 mL) was added dropwise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0-5° C. The solid was collected by vacuum filtration, washed with cold water (10 mL), and dried to give 5.3 g (94.9% yield) of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ δ 2.19 (s, 3H), 7.09-7.29 (m, 2H, J=7.5), 7.29-7.43 (d, 1H, J=7.5), 7.61 (s, 2H), 7.85 (s, 1H), 9.63 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ: 18.18, 120.63, 126.84, 127.90, 128.86, 132.41, 133.63, 138.76, 142.88, 159.45, 172.02.

5D. 2-(6-Chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

Figure US08680103-20140325-C00057

To a stirring solution of compound 5C (5.00 g, 18.67 mmol) and 4,6-dichloro-2-methylpyrimidine (3.65 g 22.4/mmol) in THF (65 mL) was added a 30% wt. solution of sodium t-butoxide in THF (21.1 g, 65.36 mmol) slowly with cooling to keep the temperature at 10-20° C. The mixture was stirred at room temperature for 1.5 h and cooled to 0-5° C. Hydrochloric acid, 2N (21.5 mL) was added slowly and the mixture stirred 1.75 h at 0-5° C. The solid was collected by vacuum filtration, washed with water (15 mL) and dried to give 6.63 g (86.4% yield) of compound 5D. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.58 (s, 3H), 6.94 (s, 1H), 7.18-7.34, (m, 2H, J=7.5), 7.34-7.46 (d, 1H, J=7.5), 8.31 (s, 1H), 10.02 (s, 1H), 12.25 (s, 1H).

5E. Example 5To a mixture of compound 5D (4.00 g, 10.14 mmol) and hydroxyethylpiperazine (6.60 g, 50.69 mmol) in n-butanol (40 mL) was added DIPEA (3.53 mL, 20.26 mmol). The slurry was heated at 118° C. for 4.5 h, then cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with n-butanol (5 mL), and dried. The product (5.11 g) was dissolved in hot 80% EtOH—H2O (80 mL), and the solution was clarified by filtration. The hot solution was slowly diluted with water (15 mL) and cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with 50% ethanol-water (5 mL) and dried affording 4.27 g (83.2% yield) of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide as monohydrate. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.40 (s, 3H), 2.42 (t, 2H, J=6), 2.48 (t, 4H, J=6.3), 3.50 (m, 4H), 3.53 (q, 2H, J=6), 4.45 (t, 1H, J=5.3), 6.04 (s, 1H), 7.25 (t, 1H, J=7.6), 7.27 (dd, 1H, J=7.6, 1.7), 7.40 (dd, 1H, J=7.6, 1.7), 8.21 (s, 1H), 9.87 (s, 1H), 11.47.

Example 6Preparation of:

N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide

Figure US08680103-20140325-C00058

To a slurry of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide 5B (120 mg, 0.50 mmol) in THF (0.75 ml) and water (0.5 mL) was added NBS (98 mg, 0.55 mmol) at 0° C. The mixture was warmed and stirred at 20-22° C. for 3 h. To this was added 1-(6-chloro-2-methylpyrimidin-4-yl)thiourea 5A (100 mg, 0.49 mmol), and the slurry heated and stirred at reflux for 2 h. The slurry was cooled to 20-22° C. and the solid collected by vacuum filtration giving 140 mg (71% yield) of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide 5D. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.58 (s, 3H), 6.94 (s, 1H), 7.18-7.34, (m, 2H, J=7.5), 7.34-7.46 (d, 1H, J=7.5), 8.31 (s, 1H), 10.02 (s, 1H), 12.25 (s, 1H).Compound 5D was elaborated to N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide, following Step 5E.

Example 7Preparation of:

N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide7A. 2-[4-(6-Chloro-2-methyl-pyrimidin-4-yl)-piperazin-1-yl]-ethanol

Figure US08680103-20140325-C00059

2-Piperazin-1-yl-ethanol (8.2 g, 63.1 mmol) was added to a solution of 4,6-dichloro-2-methylpyrimidine (5.2 g, 31.9 mmol) in dichloromethane (80 ml) at rt. The mixture was stirred for two hours and triethylamine (0.9 ml) was added. The mixture was stirred at rt for 20 h. The resultant solid was filtered. The cake was washed with dichloromethane (20 ml). The filtrate was concentrated to give an oil. This oil was dried under high vacuum for 20 h to give a solid. This solid was stirred with heptane (50 ml) at rt for 5 h. Filtration gave 7C (8.13 g) as a white solid

7B. Example 7

Figure US08680103-20140325-C00060

To a 250 ml of round bottom flask were charged compound 5C (1.9 g, 7.1 mmol), compound 7C (1.5 g, 5.9 mmol), K2CO(16 g, 115.7 mmol), Pd (OAc)(52 mg, 0.23 mmol) and BINAP (291 mg, 0.46 mmol). The flask was placed under vacuum and flushed with nitrogen. Toluene was added (60 ml). The suspension was heated to 100-110° C. and stirred at this temperature for 20 h. After cooling to room temperature, the mixture was applied to a silica gel column. The column was first eluted with EtOAC, and then with 10% of MeOH in EtOAC. Finally, the column was washed with 10% 2M ammonia solution in MeOH/90% EtOAC. The fractions which contained the desired product were collected and concentrated to give compound IV as a yellow solid (2.3 g).

Analytical MethodsSolid State Nuclear Magnetic Resonance (SSNMR)All solid-state C-13 NMR measurements were made with a Bruker DSX-400, 400 MHz NMR spectrometer. High resolution spectra were obtained using high-power proton decoupling and the TPPM pulse sequence and ramp amplitude cross-polarization (RAMP-CP) with magic-angle spinning (MAS) at approximately 12 kHz (A. E. Bennett et al, J. Chem. Phys., 1995, 103, 6951), (G. Metz, X. Wu and S. O, Smith, J. Magn. Reson. A, 1994, 110, 219-227). Approximately 70 mg of sample, packed into a canister-design zirconia rotor was used for each experiment. Chemical shifts (6) were referenced to external adamantane with the high frequency resonance being set to 38.56 ppm (W. L. Earl and D. L. VanderHart, J. Magn. Reson., 1982, 48, 35-54).X-Ray Powder DiffractionOne of ordinary skill in the art will appreciate that an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed. In particular, it is generally known that intensities in a X-ray diffraction pattern may fluctuate depending upon measurement conditions employed. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account. Additionally, a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about 5% or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles. Consequently, it is to be understood that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein. Any crystal forms that provide X-ray diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present invention. The ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art.X-Ray powder diffraction data for the crystalline forms of Compound (IV) were obtained using a Bruker GADDS (BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison, Wis. 53711 USA) (General Area Detector Diffraction System) manual chi platform goniometer. Powder samples were placed in thin walled glass capillaries of 1 mm or less in diameter; the capillary was rotated during data collection. The sample-detector distance was 17 cm. The radiation was Cu Kα (45 kV 111 mA, λ=1.5418 Å). Data were collected for 3<2θ<35° with a sample exposure time of at least 300 seconds.Single Crystal X-RayAll single crystal data were collected on a Bruker-Nonius (BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison, Wis. 53711 USA) Kappa CCD 2000 system using Cu Kα radiation (λ=1.5418 Å) and were corrected only for the Lorentz-polarization factors. Indexing and processing of the measured intensity data were carried out with the HKL2000 software package (Otwinowski, Z. & Minor, W. (1997) in Macromolecular Crystallography, eds. Carter, W. C. Jr. & Sweet, R. M. (Academic, NY), Vol. 276, pp. 307-326) in the Collect program suite (Data collection and processing user interface: Collect: Data collection software, R. Hooft, Nonius B. V., 1998).The structures were solved by direct methods and refined on the basis of observed reflections using either the SDP (SDP, Structure Determination Package, Enraf-Nonius, Bohemia N.Y. 11716 Scattering factors, including f′ and f″, in the SDP software were taken from the “International Tables for Crystallography”, Kynoch Press, Birmingham, England, 1974; Vol IV, Tables 2.2A and 2.3.1) software package with minor local modifications or the crystallographic package, MAXUS (maXus solution and refinement software suite: S. Mackay, C. J. Gilmore, C. Edwards, M. Tremayne, N. Stewart, K. Shankland. maXus: a computer program for the solution and refinement of crystal structures from diffraction data).The derived atomic parameters (coordinates and temperature factors) were refined through full matrix least-squares. The function minimized in the refinements was Σw(|Fo|−|Fc|)2. R is defined as Σ∥Fo|−|Fc∥/Σ|Fo| while Rw=[Σw(|Fo|−|Fc|)2w|Fo|2]1/2 where w is an appropriate weighting function based on errors in the observed intensities. Difference maps were examined at all stages of refinement. Hydrogens were introduced in idealized positions with isotropic temperature factors, but no hydrogen parameters were varied.The derived atomic parameters (coordinates and temperature factors) were refined through full matrix least-squares. The function minimized in the refinements was Σw(|Fo|−|Fc|)2. R is defined as Σ∥Fo|−|Fc∥/Σ|Fo| while Rw=[Σw(|Fo|−|Fc|)2w|Fo|2]1/2 where w is an appropriate weighting function based on errors in the observed intensities. Difference maps were examined at all stages of refinement. Hydrogens were introduced in idealized positions with isotropic temperature factors, but no hydrogen parameters were variedDifferential Scanning CalorimetryThe DSC instrument used to test the crystalline forms was a TA INSTRUMENTS° model Q1000. The DSC cell/sample chamber was purged with 100 ml/min of ultra-high purity nitrogen gas. The instrument was calibrated with high purity indium. The accuracy of the measured sample temperature with this method is within about +/−1° C., and the heat of fusion can be measured within a relative error of about +/−5%. The sample was placed into an open aluminum DSC pan and measured against an empty reference pan. At least 2 mg of sample powder was placed into the bottom of the pan and lightly tapped down to ensure good contact with the pan. The weight of the sample was measured accurately and recorded to a hundredth of a milligram. The instrument was programmed to heat at 10° C. per minute in the temperature range between 25 and 350° C.The heat flow, which was normalized by a sample weight, was plotted versus the measured sample temperature. The data were reported in units of watts/gram (“W/g”). The plot was made with the endothermic peaks pointing down. The endothermic melt peak was evaluated for extrapolated onset temperature, peak temperature, and heat of fusion in this analysis.Thermogravimetric Analysis (TGA)The TGA instrument used to test the crystalline forms was a TA INSTRUMENTS® model Q500. Samples of at least 10 milligrams were analyzed at a heating rate of 10° C. per minute in the temperature range between 25° C. and about 350° C.

Example 8Preparation of:

Crystalline monohydrate of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV)An example of the crystallization procedure to obtain the crystalline monohydrate form is shown here:Charge 48 g of the compound of formula (IV).Charge approximately 1056 mL (22 mL/g) of ethyl alcohol, or other suitable alcohol.Charge approximately 144 mL of water.Dissolve the suspension by heating to approximately 75° C.Optional: Polish filter by transfer the compound of formula (IV) solution at 75° C. through the preheated filter and into the receiver.Rinse the dissolution reactor and transfer lines with a mixture of 43 mL of ethanol and 5 mL of water.Heat the contents in the receiver to 75-80° C. and maintain 75-80° C. to achieve complete dissolution.Charge approximately 384 mL of water at a rate such that the batch temperature is maintained between 75-80° C.Cool to 75° C., and, optionally, charge monohydrate seed crystals. Seed crystals are not essential to obtaining monohydrate, but provide better control of the crystallization.Cool to 70° C. and maintain 70° C. for ca. 1 h.Cool from 70 to 5 C over 2 h, and maintain the temperature between 0 at 5° C. for at least 2 h.Filter the crystal slurry.Wash the filter cake with a mixture of 96 mL of ethanol and 96 mL of water.Dry the material at ≦50° C. under reduced pressure until the water content is 3.4 to 4.1% by KF to afford 41 g (85 M %).Alternately, the monohydrate can be obtained by:1) An aqueous solution of the acetate salt of compound IV was seeded with monohydrate and heated at 80° C. to give bulk monohydrate.2) An aqueous solution of the acetate salt of compound IV was seeded with monohydrate. On standing several days at room temperature, bulk monohydrate had formed.3) An aqueous suspension of compound IV was seeded with monohydrate and heated at 70° C. for 4 hours to give bulk monohydrate. In the absence of seeding, an aqueous slurry of compound IV was unchanged after 82 days at room temperature.4) A solution of compound IV in a solvent such as NMP or DMA was treated with water until the solution became cloudy and was held at 75-85° C. for several hours. Monohydrate was isolated after cooling and filtering.5) A solution of compound IV in ethanol, butanol, and water was heated. Seeds of monohydrate were added to the hot solution and then cooled. Monohydrate was isolated upon cooling and filtration.One of ordinary skill in the art will appreciate that the monohydrate of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 1 or by a representative sampling of peaks as shown in Table 1.Representative peaks taken from the XRPD of the monohydrate of the compound of formula (IV) are shown in Table 1.TABLE 1 2-Theta d(Å) Height 17.994 4.9257 915 18.440 4.8075 338 19.153 4.6301 644 19.599 4.5258 361 21.252 4.1774 148 24.462 3.6359 250 25.901 3.4371 133 28.052 3.1782 153The XRPD is also characterized by the following list comprising 2θ values selected from the group consisting of: 4.6±0.2, 11.2±0.2, 13.8±0.2, 15.2±0.2, 17.9±0.2, 19.1±0.2, 19.6±0.2, 23.2±0.2, 23.6±0.2. The XRPD is also characterized by the list of 2θ values selected from the group consisting of: 18.0±0.2, 18.4±0.2, 19.2±0.2, 19.6±0.2, 21.2±0.2, 24.5±0.2, 25.9±0.2, and 28.0±0.2.Single crystal x-ray data was obtained at room temperature (+25° C.). The molecular structure was confirmed as a monohydrate form of the compound of Formula (IV).The following unit cell parameters were obtained for the monohydrate of the compound of formula (IV) from the x-ray analysis at 25° C.:a(Å)=13.8632(7); b(Å)=9.3307(3); c(Å)=38.390(2);V(Å3) 4965.9(4); Z′=1; Vm=621Space group PbcaMolecules/unit cell 8Density (calculated) (g/cm3) 1.354wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).Single crystal x-ray data was also obtained at −50° C. The monohydrate form of the compound of Formula (IV) is characterized by unit cell parameters approximately equal to the following:Cell dimensions: a(Å)=13.862(1);

  • b(Å)=9.286(1);
  • c(Å)=38.143(2);

Volume=4910(1) Å3Space group PbcaMolecules/unit cell 8Density (calculated) (g/cm3) 1.369wherein the compound is at a temperature of about −50° C.The simulated XRPD was calculated from the refined atomic parameters at room temperature.The monohydrate of the compound of formula (IV) is represented by the DSC as shown in FIG. 2. The DSC is characterized by a broad peak between approximately 95° C. and 130° C. This peak is broad and variable and corresponds to the loss of one water of hydration as seen in the TGA graph. The DSC also has a characteristic peak at approximately 287° C. which corresponds to the melt of the dehydrated form of the compound of formula (IV).The TGA for the monohydrate of the compound of Formula (IV) is shown in FIG. 2 along with the DSC. The TGA shows a 3.48% weight loss from 50° C. to 175° C. The weight loss corresponds to a loss of one water of hydration from the compound of Formula (IV).The monohydrate may also be prepared by crystallizing from alcoholic solvents, such as methanol, ethanol, propanol, i-propanol, butanol, pentanol, and water.

Example 9Preparation of:

Crystalline n-butanol solvate of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV)The crystalline butanol solvate of the compound of formula (IV) is prepared by dissolving compound (IV) in 1-butanol at reflux (116-118° C.) at a concentration of approximately 1 g/25 mL of solvent. Upon cooling, the butanol solvate crystallizes out of solution. Filter, wash with butanol, and dry.The following unit cell parameters were obtained from the x-ray analysis for the crystalline butanol solvate, obtained at room temperature:a(Å)=22.8102(6); b(Å)=8.4691(3); c(Å)=15.1436(5); β=95.794(2);V(Å3) 2910.5(2); Z′=1; Vm=728Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.283wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the butanol solvate of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 3 or by a representative sampling of peaks. Representative peaks for the crystalline butanol solvate are 2θ values of: 5.9±0.2, 12.0±0.2, 13.0±0.2, 17.7±0.2, 24.1±0.2, and 24.6±0.2.

Example 10Preparation of:

Crystalline ethanol solvate of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV)

Figure US08680103-20140325-C00061

To a 100-mL round bottom flask was charged 4.00 g (10.1 mmol) of 5D (contained 2.3 Area % 5C) 6.60 g (50.7 mmol) of 7B, 80 mL of n-butanol and 2.61 g (20.2 mmol) of DIPEA. The resulting slurry was heated to 120° C. and maintained at 120° C. for 4.5 h whereby HPLC analysis showed 0.19 relative Area % of residual 5D to compound IV. The homogeneous mixture was cooled to 20° C. and left stirring overnight. The resulting crystals were filtered. The wet cake was washed twice with 10-mL portions of n-butanol to afford a white crystalline product. HPLC analysis showed this material to contain 99.7 Area % compound IV and 0.3 Area % 5C.The resulting wet cake was returned to the 100-mL reactor, and charged with 56 mL (12 mL/g) of 200 proof ethanol. At 80° C. an additional 25 mL of ethanol was added. To this mixture was added 10 mL of water resulting in rapid dissolution. Heat was removed and crystallization was observed at 75-77° C. The crystal slurry was further cooled to 20° C. and filtered. The wet cake was washed once with 10 mL of 1:1 ethanol:water and once with 10 mL of n-heptane. The wet cake contained 1.0% water by KF and 8.10% volatiles by LOD. The material was dried at 60° C./30 in Hg for 17 h to afford 3.55 g (70 M %) of material containing only 0.19% water by KF, 99.87 Area % by HPLC. The 1H NMR spectrum, however revealed that the ethanol solvate had been formed.The following unit cell parameters were obtained from the x-ray analysis for the crystalline ethanol solvate (di-ethanolate, E2-1), obtained at −40° C.:a(Å)=22.076(1); b(Å)=8.9612(2); c(Å)=16.8764(3); β=114.783(1);V(Å3) 3031.1(1); Z′=1; Vm=758Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.271wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the ethanol solvate (E2-1) of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 4 or by a representative sampling of peaks. Representative peaks for the crystalline ethanol solvate are 2θ values of: 5.8±0.2, 11.3±0.2, 15.8±0.2, 17.2±0.2, 19.5±0.2, 24.1±0.2, 25.3±0.2, and 26.2±0.2.In addition, during the process to form the ethanolate (diethanolate) the formation of another ethanol solvate (½ ethanolate, T1E2-1) has been observed. To date this additional ethanol solvate is known strictly as a partial desolvation product of the original diethanolate form E2-1, and has only been observed on occasion during crystallization of E2-1The following unit cell parameters were obtained from the x-ray analysis for the crystalline ½ ethanol solvate T1E2-1, obtained at −10° C.:a(Å)=22.03(2); b(Å)=9.20(1); c(Å)=12.31(1);β=93.49(6)V(Å3) 2491(4)); Z′=1; Vm=623;Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.363wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the ethanol solvate (T1E2-1) of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 7 or by a representative sampling of peaks. Representative peaks for the crystalline ethanol solvate are 2θ values of: 7.20±0.2, 12.01±0.2, 12.81±0.2, 18.06±0.2, 19.30±0.2, and 25.24±0.2.

Example 11Preparation of:

Crystalline N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV) (Neat form N-6)To a mixture of compound 5D (175.45 g, 0.445 mol) and hydroxyethylpiperazine (289.67 g, 2.225 mol) in NMP (1168 mL) was added DIPEA (155 mL, 0.89 mol). The suspension was heated at 110° C. (solution obtained) for 25 min., then cooled to about 90° C. The resulting hot solution was added dropwise into hot (80° C.) water (8010) mL, keeping the temperature at about 80° C. The resulting suspension was stirred 15 min at 80° C. then cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with water (2×1600 mL) and dried in vacuo at 55-60° C. affording 192.45 g (88.7% yield) of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide. 1H NMR (400 MHz, DMSO-d6): δ 2.24 (s, 3H), 2.41 (s, 3H), 2.43 (t, 2H, J=6), 2.49 (t, 4H, J=6.3), 3.51 (m, 4H), 3.54 (q, 2H, J=6), 4.46 (t, 1H, J=5.3), 6.05 (s, 1H), 7.26 (t, 1H, J=7.6), 7.28 (dd, 1H, J=7.6, 1.7), 7.41 (dd, 1H, J=7.6, 1.7), 8.23 (s, 1H), 9.89 (s, 1H), 11.48. KF0.84; DSC: 285.25° C. (onset), 286.28° C. (max).The following unit cell parameters were obtained from the x-ray analysis for the neat crystalline compound IV, obtained at 23° C.:a(Å)=22.957(1); b(Å)=8.5830(5); c(Å)=13.803(3); β=112.039(6);V(Å3)=2521.0(5); Z′=1; Vm=630Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.286wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the crystalline form of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 5 or by a representative sampling of peaks. Representative peaks for the crystalline neat form (N-6) are 2θ values of: 6.8±0.2, 11.1±0.2, 12.3±0.2, 13.2±0.2, 13.7±0.2, 16.7±0.2, 21.0±0.2, 24.3±0.2, and 24.8±0.2.

Example 12Preparation of:

Crystalline N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV) (neat form T1H1-7)The title neat form may be prepared by heating the monohydrate form of the compound of formula (IV) above the dehydration temperature.The following unit cell parameters were obtained from the x-ray analysis for the neat crystalline (T1H1-7) compound IV, obtained at 25° C.:a(Å)=13.4916; b(Å)=9.3992(2); c(Å)=38.817(1);V(Å3)=4922.4(3); Z′=1; Vm=615Space group PbcaDensity (calculated) (g/cm3) 1.317wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the neat crystalline form (T1H1-7) of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 6 or by a representative sampling of peaks. Representative peaks for the crystalline neat form (T1H1-7)) are 2θ values of: 8.0±0.2, 9.7±0.2, 11.2±0.2, 13.3±0.2, 17.5±0.2, 18.9±0.2, 21.0±0.2, 22.0±0.2.Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein. 
 PAPERhttps://pubs.acs.org/doi/abs/10.1021/jm060727j

2-Aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure−activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 ∼ 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFα production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.

Abstract Image

PATENT

https://patents.google.com/patent/WO2019209908A1/enDasatinib (DAS), having the chemical designation N-(2-chloro-6-methylphenyl)-2- [[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5- thiazolecarboxamide, monohydrate, is an orally bioavailable inhibitor of the receptor tyrosine kinase (RTK) epidermal growth factor receptor (ErbB; EGFR) family, with antineoplastic activity. Dasatinib has the following structure:

Figure imgf000002_0001

Dasatinib is commercially marketed under the name SPRY CEL® and is indicated for the treatment of patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase, for the treatment of patients chronic, accelerated, or myeloid or lymphoid blast phase Philadelphia chromosome-positive chronic myeloid leukemia with resistance or intolerance to prior therapy and for the treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy.Solid forms of dasatinib are described in U.S. Patent Nos. 7491725 (butanol solvate, monohydrate, diethanolate, hemi-ethanolate, anhydrous), 8680103 (butanol solvate, monohydrate, diethanolate, hemi-ethanolate, anhydrous), 7973045 (anhydrous), 8067423 (isopropyl alcohol solvate), 8242270 (butanol solvate, monohydrate, diethanolate, hemi- ethanolate, anhydrous), 8884013 (monohydrates), 9249134 (amorphous), 9456992 (solid dispersion nanoparticles), 9556164 (saccharin salt crystal) and 9884857 (saccharinate, glutarate, nicotinate); in U.S. Publication Nos. 20160250153 (solid dispersion nanoparticles), 20160264565 (Form-SDI), 20160361313 (solid dispersion nanoparticles), 20170183334 (salts) and 20140031352 (anti-oxidative acid); in International Publication Nos.W02010067374 (solvated forms and Form I), W02010139980, W02010139981,W02013065063 (anhydrous), W02017103057, W02017108605 (solid dispersion),WO2017134617 (amorphous), WO2014086326 (NMP, isoamyl-OH, 1, 3-propanediol process), WO2015107545, WO2015181573, WO2017134615 (PG solvate), W02010062715 (isosorbide dimethyl ether, N,N’-dimethylethylene urea, N,N’-dimethyl-N,N’-propylene urea), WO2010139979 (DCM, DMSP, monohydrate), WO2011095588 (anhydrate, hydrochloride, hemi-ethanol), W02012014149 (N-methylformamide) and W02017002131 (propandiol, monohydrate); and in Chinese Patent Nos. CN102643275, CN103059013, CN103819469, CN104341410. None of the references describe an ethyl formate solvate of dasatinib.Dasatinib co-crystals are described in U.S. Patent No. 9,340,536 (co-crystals selected from methyl-4-hydroxybenzoate, nicotinamide, ethyl gallate, methyl gallate, propyl gallate, ethyl maltol, vanillin, menthol, and (lR,2S,5R)-(-)-menthol) and International Publication No. W02016001025 (co-crystal selected from menthol or vanillin). None of the references describe dasatinib co-crystal comprising dasatinib and a second compound, as a co-crystal former, wherein the second compound is selected from butyl paraben, propyl paraben and ethyl vanillin.Dasatinib (DAS), having the chemical designation N-(2-chloro-6-methylphenyl)-2- [[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5- thiazolecarboxamide, monohydrate, is an orally bioavailable inhibitor of the receptor tyrosine kinase (RTK) epidermal growth factor receptor (ErbB; EGFR) family, with antineoplastic activity. Dasatinib has the following structure:

Figure imgf000002_0001

Dasatinib is commercially marketed under the name SPRY CEL® and is indicated for the treatment of patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase, for the treatment of patients chronic, accelerated, or myeloid or lymphoid blast phase Philadelphia chromosome-positive chronic myeloid leukemia with resistance or intolerance to prior therapy and for the treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy.Solid forms of dasatinib are described in U.S. Patent Nos. 7491725 (butanol solvate, monohydrate, diethanolate, hemi-ethanolate, anhydrous), 8680103 (butanol solvate, monohydrate, diethanolate, hemi-ethanolate, anhydrous), 7973045 (anhydrous), 8067423 (isopropyl alcohol solvate), 8242270 (butanol solvate, monohydrate, diethanolate, hemi- ethanolate, anhydrous), 8884013 (monohydrates), 9249134 (amorphous), 9456992 (solid dispersion nanoparticles), 9556164 (saccharin salt crystal) and 9884857 (saccharinate, glutarate, nicotinate); in U.S. Publication Nos. 20160250153 (solid dispersion nanoparticles), 20160264565 (Form-SDI), 20160361313 (solid dispersion nanoparticles), 20170183334 (salts) and 20140031352 (anti-oxidative acid); in International Publication Nos.W02010067374 (solvated forms and Form I), W02010139980, W02010139981,W02013065063 (anhydrous), W02017103057, W02017108605 (solid dispersion),WO2017134617 (amorphous), WO2014086326 (NMP, isoamyl-OH, 1, 3-propanediol process), WO2015107545, WO2015181573, WO2017134615 (PG solvate), W02010062715 (isosorbide dimethyl ether, N,N’-dimethylethylene urea, N,N’-dimethyl-N,N’-propylene urea), WO2010139979 (DCM, DMSP, monohydrate), WO2011095588 (anhydrate, hydrochloride, hemi-ethanol), W02012014149 (N-methylformamide) and W02017002131 (propandiol, monohydrate); and in Chinese Patent Nos. CN102643275, CN103059013, CN103819469, CN104341410. None of the references describe an ethyl formate solvate of dasatinib.Dasatinib co-crystals are described in U.S. Patent No. 9,340,536 (co-crystals selected from methyl-4-hydroxybenzoate, nicotinamide, ethyl gallate, methyl gallate, propyl gallate, ethyl maltol, vanillin, menthol, and (lR,2S,5R)-(-)-menthol) and International Publication No. W02016001025 (co-crystal selected from menthol or vanillin). None of the references describe dasatinib co-crystal comprising dasatinib and a second compound, as a co-crystal former, wherein the second compound is selected from butyl paraben, propyl paraben and ethyl vanillin. hereafter. ClaimsHide Dependent  What is claimed is:1. A dasatinib co-crystal comprising dasatinib and a second compound, wherein the second compound is selected from butyl paraben, propyl paraben and ethyl vanillin.2. The dasatinib co-crystal according to claim 1, wherein a molar ratio of the dasatinib to the second compound is about 1: 1.3. The dasatinib co-crystal according to claim 1, wherein the second compound is butyl paraben.4. The dasatinib co-crystal according to claim 3, wherein a molar ratio of the dasatinib to the butyl paraben is about 1 : 1.5. The dasatinib co-crystal according to claim 1, which is Form I co-crystal of dasatinib and butyl paraben.6. The dasatinib co-crystal according to claim 5, characterized by having at least 2 or more X-ray powder diffraction peaks selected from about 4.9, 9.8, 11.3, 14.9, 17.5, 20.8, 21.6, 22.6 and 25.4° 2Q degrees.7. The dasatinib co-crystal according to claim 5, characterized by a thermal event at about 287.3 °C, as measured by differential scanning calorimetry.8. The dasatinib co-crystal according to claim 5, characterized by a weight loss of 8.1% from about 70 °C through about 165 °C, as measured by thermal gravimetric analysis.9. The dasatinib co-crystal of claim 5 monoclinic, P2i/C.10. The dasatinib co-crystal d of claim 5 which has single crystal parametersa = 18.630 (2) Ab = 8.725 (1) Ac = 22.331 (2) Aa = g = 90°, b = 104.575 (8)°.11. The dasatinib co-crystal of claim 5 which has a cell volume is about 3512.9 A3.12. The dasatinib co-crystal according to claim 1, wherein the second compound is ethyl vanillin.13. The dasatinib co-crystal according to claim 9, wherein a molar ratio of the dasatinib to the ethyl vanillin is about 1 : 1.14. The dasatinib co-crystal according to claim 1, which is Form II co-crystal of dasatinib and ethyl vanillin.15. The dasatinib co-crystal according to claim 14, characterized by having at least 2 or more X-ray powder diffraction peaks selected from about 5.7, 10.9, 13.5, 17.1, 18.4, 19.4, 23.7 and 26.3° 2Q degrees.16. The dasatinib co-crystal according to claim 14, characterized by one or more thermal events selected from about 140 °C, about 181 °C, and about 293 °C, as measured by differential scanning calorimetry.17. The dasatinib co-crystal according to claim 14, characterized by a weight loss of 24.3% from about 120 through 250 °C, as measured by thermal gravimetric analysis.18. The dasatinib co-crystal of claim 14 monoclinic, P2i/n.19. The dasatinib co-crystal d of claim 14 which has single crystal parametersa = 18.452 (1) Ab = 9.441 (6) Ac = 19.377 (1) Aa = g = 90°, b = 108.78 (1)°.20. The dasatinib co-crystal of claim 5 which has a cell volume is about 3195.71 A3.21. The dasatinib co-crystal according to claim 1, wherein the second compound is propyl paraben.22. The dasatinib co-crystal according to claim 21, wherein a molar ratio of the dasatinib to the propyl paraben is about 1 : 1.23. The dasatinib co-crystal according to claim 1, which is Form III co-crystal ofdasatinib and propyl paraben.24. The dasatinib co-crystal according to claim 23, characterized by having at least 2 or more X-ray powder diffraction peaks selected from about 4.8, 9.6, 11.9, 14.8, 18.4, 22.2, 23.9 and 26.1° 2Q degrees.25. The dasatinib co-crystal of claim 23 monoclinic, P2i/n.26. The dasatinib co-crystal of claim 23 which has single crystal parametersa = 18.859 (9) Ab = 8.131 (6) Ac = 22.473 (1) Aa = g = 90°, b = 103.87(1)°.27. The dasatinib co-crystal of claim 23 which has a cell volume is about 3345.51 A3.28. An ethyl formate solvate of dasatinib.29. The ethyl formate solvate of dasatinib according to claim 28, wherein a molar ratio of the dasatinib to the ethyl formate is about 1 : 1.30. The ethyl formate solvate of dasatinib according to claim 1, which is Form I of ethyl formate solvate of dasatinib.31. The ethyl formate solvate of dasatinib according to claim 30, characterized by having at least 2 or more X-ray powder diffraction peaks selected from about 6.0, 12.1, 15.1, 18.0, 23.8 and 24.8° 2Q degrees.32. The ethyl formate solvate of dasatinib according to claim 30, characterized by athermal event at about 287.3 °C, as measured by differential scanning calorimetry.33. The ethyl formate solvate of dasatinib according to claim 30, characterized by aweight loss of 8.1% from about 70 °C through about 165 °C, as measured by thermal gravimetric analysis.34. The ethyl formate solvate of dasatinib of claim 23 orthorhombic, P2i/c.35. The ethyl formate solvate of dasatinib of claim 23 which has single crystal parameters a = 14.8928 (5) Ab = 8.3299 (3) Ac = 22.18990 (6) Aa = g =b = 90°.36. The ethyl formate solvate of dasatinib of claim 23 which has a cell volume is about 2731.9 A3.37. A pharmaceutical composition comprising a pharmaceutically effective amount of the dasatinib co-crystal according to claim 1 and pharmaceutically acceptable excipient.38. A method of treating disease in a patient comprising administering a pharmaceutical formulation according to claim 37 to the patient in need thereof.39. A method of treating disease according to claim 38, wherein the disease ismyelogenous leukemia.40. A method of treating disease according to claim 38, wherein the disease isPhiladelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.41. A method of treating disease according to claim 38, wherein the disease Ph+ acute lymphoblastic leukemia (Ph+ ALL).42. A method of making the dasatinib co-crystal according to claim 1, comprisingdissolving dasatinib and a second compound, wherein the second compound is selected from the group consisting of butyl paraben, propyl paraben and ethyl vanillin, in heated methanol (-10: 1 – wt(mg)DAs:v(mL)MeOH and molD,\s:mohnci compound is 1 : 1.1) to form a clear solution, heating the solution under vacuum for about l8-20h to yield the dasatinib co-crystal.43. A process for the preparation Form II co-crystal of dasatinib and ethyl vanillin,according to claim 14, comprising: (g) dissolving Form I of ethyl formate solvate of dasatinib and ethyl vanillin in N-methyl-2-pyrrolidone to form a solution;(h) adding water to the solution;(i) stirring the solution for about 12-24 hours to form a slurry;(j) filtering the slurry to yield a precipitate;(k) washing the precipitate with water; and(l) drying the precipitate under vacuum with warming to yield Form II co crystal of dasatinib and ethyl vanillin.44. A process for the preparation of Form I of ethyl formate solvate of dasatinib,according to claim 30, comprising:(d) dissolving dasatinib in ethyl formate to form a solution;(e) stirring the solution for about 12-24 hours form a slurry;(f) filtering the slurry to yield Form I of ethyl formate solvate of dasatinib.45. A process for the preparation of Form I of ethyl formate solvate of dasatinib,according to claim 30, comprising:(g) dissolving dasatinib in N-Methyl-2-pyrrolidone to form a solution;(h) adding ethyl formate to the solution to form a slurry;(i) adding additional ethyl formate to the slurry;(j) stirring the slurry for about 2 hours;(k) filtering the slurry to yield a precipitate; and(l) washing the precipitate with ethyl formate to yield Form I of ethyl formate solvate of dasatinib. 

ATENThttps://patents.google.com/patent/WO2013065063A1/en
 Dasatinib, N-(2-chloro-6-methylphenyl)-2- [(6-[4-(2-hydroxyl)- 1 -piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5- thiazolecarboxamide compound having the following chemical structure of Formula (I)

Figure imgf000002_0001

Formula IAlso known as BMS-354825, it is a drug produced by Bristol Myers Squibb and sold under the trade name Sprycel. Dasatinib is an oral dual BCR/ABL and SRC family tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after Imatinib treatment has failed and Philadelphia chromosome- positive acute lymphoblastic leukemia (Ph + ALL). It is also being assessed for use in metastatic melanoma.A preparation of Dasatinib is described in US patent No. 6596746 (B l ), where the process is done by reacting compound of the following formula III with N-(2- hydroxyethyl) piperazine at 80° C.

Figure imgf000002_0002

Formula IIIThe compound of Formula (I) and its preparation is described in US Patent No. 6596746, US patent application No. 2005/0176965 Al , and US patent application No. 2006/0004067 Al .l Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and /or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and / or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, 1R etc. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR). Solvent medium and mode of crystallization play very important role in obtaining a crystalline form.The discovery of new polymorphic forms is a continuing goal of formulators. The new polymorphs may be advantageous for dosage form development and enhancing bioavailability owing to the altered physiochemical properties. Some form may turn out to be more efficacious. Discovering novel processes to prepare known polymorphic forms is also a primary goal of the pharmaceutical development scientists. New processes can provide novel intermediates or synthetic pathways that result in product with increased chemical and polymorphic purity in addition to providing cost and other advantages. There is thus a need to provide novel synthetic routes and intermediates that can realize these goals.Several crystalline forms of Dasatinib are described in the literature; these are designated as HI -7, BU-2, E2-1 , N-6, T1 H1 -7 and TIE2-1. Crystalline Dasatinib monohydrate (H I -7) and butanol solvate (BU-2) along with the processes for their preparation are described in WO 2005077945. In addition US 2006/0004067, which is continuation of US 2005215795 also describe two ethanol solvates (E2-1 ; TIE2-1) and two anhydrous forms (N-6 and T1 H1 -7).WO 2009053854 discloses various Dasatinib solvates including their crystalline form, amorphous form and anhydrous form.US patent No. 7973045 discloses the anhydrous form of Dasatinib and process for preparation thereof. The anhydrous form disclosed therein have typical characteristic XRD peaks at about 7.2, 1 1.9, 14.4, 16.5, 17.3, 19.1 , 20.8, 22.4, 23.8, 25.3 and 29.1 on the 2- theta value. WO 2010062715 discloses isosorbide dimethyl ether solvate, Ν,Ν’- dimethylethylene urea solvate and N,N’-dimethyl-N,N’-propylene urea solvate of Dasatinib.WO 2010067374 discloses novel crystalline form I, solvates of DMF, DMSO, toluene, isopropyl acetate and processes for their preparation.WO 2010139979 discloses MDC solvate and process of preparation, for use in the manufacture of pure Dasatinib.WO 2010139980 discloses a process for the preparation of crystalline Dasatinib monohydrate.The present invention is a step forward in this direction and provides a novel anhydrous form and process for its preparation, which can be used for the preparation of pure Dasatinib, in particularly Dasatinib monohydrate.The process for preparing Dasatinib monohydrate is described in US 2006/0004067. Further studies by the inventors have shown that the preparation of Dasatinib by using the method, which is disclosed in US 2006/0004067 yields the monohydrate with ~ 90% purity. Therefore the present invention provides a novel anhydrous form which can be used to get Dasatinib monohydrate with high yield and purity.Preparing API with increased purity is always an aim of the pharmaceutical development team. The inventors of the present invention have found that preparingDasatinib monohydrate using the novel anhydrous form of the present invention resulted in a highly pure product with a good yield.Scheme 1 shows a general process for the preparation of Dasatinib as disclosed in US 2006/0004067. Intermediate 3 and N-(2-hydroxyethyl) piperazine are heated together in a solvent system comprising n-butanol as a solvent and diisopropyl ethylamine (DIPEA) as a base. On cooling of the reaction mixture, Dasatinib precipitates out which is isolated by filtration.

Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0003

DasatinibScheme 1Example – 1In a reaction vessel, N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4- pyrimidinyl) amino] -5-thiazolecarboxamide (1 gm, 2.54 mmol) and N-(2- hydroxyethyl) piperazine (5.3 gm, 40.70 mmol) was added under stirring. The reaction mixture was heated at 80 °C for 2H. Acetonitrile was added into reaction mixture at 80 °C and stirred for 30 min. Cooled the suspension to room temperature and stirred for 30 min. Filtered, washed with acetonitrile and dried at 60 °C under vacuum to get 950 mg anhydrous N-(2-chloro-6-methylphenyl)-2-[(6-[4-(2-hydroxy 1)- 1 -piperaziny l]-2- methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide (76.73 % Yield).HPLC Purity 99.90 %M/C by KF 0.12 %DSC 278.17 °CTGA 2.05 %XRD as provided in Fig. 2

Patent

Publication numberPriority datePublication dateAssigneeTitleUS7491725B22004-02-062009-02-17Bristol-Myers Squibb CompanyProcess for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitorsWO2009147238A12008-06-062009-12-10Boehringer Ingelheim International GmbhSolid pharmaceutical formulations comprising bibw 2992WO2010062715A22008-11-032010-06-03Teva Pharmaceutical Industries Ltd.Polymorphs of dasatinib and process for preparation thereofWO2010067374A22008-12-082010-06-17Hetero Research FoundationPolymorphs of dasatinibWO2010139980A12009-06-032010-12-09Generics [Uk] LimitedProcess for preparing crystalline dasatinib monohydrateWO2010139979A22009-06-032010-12-09Generics [Uk] LimitedProcesses for preparing crystalline formsWO2010139981A22009-06-032010-12-09Generics [Uk] LimitedProcesses for preparing crystalline formsWO2011003853A22009-07-062011-01-13Boehringer Ingelheim International GmbhProcess for drying of bibw2992, of its salts and of solid pharmaceutical formulations comprising this active ingredientUS7973045B22007-10-232011-07-05Teva Pharmaceutical Industries Ltd.Anhydrous form of dasatinib and process for preparation thereofWO2011095588A12010-02-042011-08-11Ratiopharm GmbhPharmaceutical composition comprising n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamidWO2012014149A12010-07-302012-02-02Ranbaxy Laboratories LimitedN-methylformamide solvate of dasatinibCN102643275A2011-02-212012-08-22江苏先声药物研究有限公司A new preparation method for Dasatinib N-6 crystal formCN103059013A2011-10-182013-04-24北京本草天源药物研究院New crystal of Dasatinib monohydrate and preparation method thereofWO2013065063A12011-11-032013-05-10Cadila Healthcare LimitedAnhydrous form of dasatinib, process for its preparation and its useUS20140031352A12012-07-242014-01-30Laurus Labs Private LimitedSolid forms of tyrosine kinase inhibitors, process for the preparation and their pharmaceutical composition thereofCN103819469A2012-11-162014-05-28重庆医药工业研究院有限责任公司Crystal form of dasatinib and preparation method for crystal form of dasatinibWO2014086326A12012-12-062014-06-12Zentiva, K.S.A method for the preparation and purification of new and known polymorphs and solvates of dasatinibUS8884013B22010-02-082014-11-11Nan Jing Cavendish Bio-Engineering Technology Co., Ltd.Polymorphs of Dasatinib, preparation methods and pharmaceutical compositions thereofCN104341410A2013-08-092015-02-11上海科胜药物研发有限公司New Dasatinib crystal form and preparation method thereofWO2015107545A12013-12-182015-07-23Dharmesh Mahendrabhai ShahWater soluble salts of dasatinib hydrateWO2015181573A12014-05-262015-12-03Egis Gyógyszergyár Zrt.Dasatinib saltsWO2016001025A12014-06-302016-01-07Basf SeMulticomponent crystals of dasatinib with menthol or vanillinUS9249134B22013-03-262016-02-02Cadila Healthcare LimitedProcess for preparation of amorphous form of dasatinibUS9340536B22012-06-152016-05-17Basf SeMulticomponent crystals comprising dasatinib and selected co-crystal formersUS20160250153A12012-01-132016-09-01Xspray Microparticles AbNovel methodsUS20160264565A12013-11-082016-09-15Shilpa Medicare LimitedCrystalline dasatinib processWO2017002131A12015-06-292017-01-05Msn Laboratories Private LimitedCrystalline forms of n-(2-chloro-6-methy]phenvn-2-[f6-[4-(2-hvdroxvethvl)-l- piperazinvil-2-methvl-4-pvrimidinvllaminol-5-thiazolecarboxamide and their process thereofUS9556164B22013-07-252017-01-31Basf SeSalts of Dasatinib in crystalline formWO2017103057A12015-12-162017-06-22Synthon B.V.Pharmaceutical composition comprising anhydrous dasatinibWO2017108605A12015-12-222017-06-29Synthon B.V.Pharmaceutical composition comprising amorphous dasatinibWO2017134615A12016-02-032017-08-10Dr. Reddy’s Laboratories LimitedSolid state forms of dasatinib and processes for their preparationWO2017134617A12016-02-032017-08-10Dr. Reddy’s Laboratories LimitedProcess for the preparation of amorphous dasatinibUS9884857B22013-07-252018-02-06Basf SeSalts of dasatinib in amorphous form

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dasatinibUS20120309968A1 *2010-02-082012-12-06Nan Jing Cavendish Bio-Engineering Technology Co., Ltd.Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereofUS8530492B22009-04-172013-09-10Nektar TherapeuticsOligomer-protein tyrosine kinase inhibitor conjugatesUS8680103B22004-02-062014-03-25Bristol-Myers Squibb CompanyProcess for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitorsWO2014102759A22012-12-312014-07-03Ranbaxy Laboratories LimitedProcess for the preparation of dasatinib and its intermediatesUS8816077B22009-04-172014-08-26Nektar TherapeuticsOligomer-protein tyrosine kinase inhibitor conjugatesUS20150057446A1 *2012-04-202015-02-26Shilpa Medicare LimitedProcess for preparing dasatinib monohydrateWO2016001025A12014-06-302016-01-07Basf SeMulticomponent crystals of dasatinib with menthol or vanillinUS9340536B22012-06-152016-05-17Basf SeMulticomponent crystals comprising dasatinib and selected co-crystal formersUS9556164B22013-07-252017-01-31Basf SeSalts of Dasatinib in crystalline formUS9884857B22013-07-252018-02-06Basf SeSalts of dasatinib in amorphous formWO2018078392A12016-10-292018-05-03Cipla LimitedPolymorphs of dasatinibWO2018100585A12016-12-012018-06-07Natco Pharma LimitedAn improved process for the preparation of dasatinib polymorphWO2018134189A12017-01-202018-07-26Cerbios-Pharma SaCo-crystal of an antitumoral compoundWO2018134190A12017-01-202018-07-26Cerbios-Pharma SaCo-crystals of an antitumoral compoundUS10174018B22016-12-132019-01-08Princeton Drug Discovery IncProtein kinase inhibitorsWO2019209908A12018-04-252019-10-31Johnson Matthey Public Limited CompanyCrystalline forms of dasatinibUS10722484B22016-03-092020-07-28K-Gen, Inc.Methods of cancer treatmentUS10799459B12019-05-172020-10-13Xspray Microparticles AbRapidly disintegrating solid oral dosage forms containing dasatinibFamily To Family CitationsUS7396935B22003-05-012008-07-08Bristol-Myers Squibb CompanyAryl-substituted pyrazole-amide compounds useful as kinase inhibitorsUS7652146B2 *2004-02-062010-01-26Bristol-Myers Squibb CompanyProcess for preparing 2-aminothiazole-5-carboxamides useful as kinase inhibitorsTW200600513A *2004-06-302006-01-01Squibb Bristol Myers CoA method for preparing pyrrolotriazine compoundsPE20061394A1 *2005-03-152006-12-15Squibb Bristol Myers CoMetabolites of n- (2-chloro-6-methylphenyl) -2 – [[6- [4- (2-hydroxyethyl) -1-piperazinyl] -2-methyl-4-pyrimidinyl] amino] -5-thiazolecarboxamidesUS20060235006A1 *2005-04-132006-10-19Lee Francis YCombinations, methods and compositions for treating cancerPL1885339T32005-05-052015-12-31Bristol Myers Squibb Holdings IrelandFormulations of a src/abl inhibitorWO2008076883A22006-12-152008-06-26Abraxis Bioscience, Inc.Triazine derivatives and their therapeutical applicationsWO2010139979A22009-06-032010-12-09Generics [Uk] LimitedProcesses for preparing crystalline formsWO2010139980A1 *2009-06-032010-12-09Generics [Uk] LimitedProcess for preparing crystalline dasatinib monohydrateEP2359813A12010-02-042011-08-24Ratiopharm GmbHPharmaceutical composition comprising N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamidCN102250084A *2010-02-082011-11-23南京卡文迪许生物工程技术有限公司Dasatinib polymorphic substance as well as preparation method and pharmaceutical composition thereofCN102643275B *2011-02-212016-04-20江苏先声药物研究有限公司The preparation method that a kind of Dasatinib N-6 crystal formation is newWO2013065063A12011-11-032013-05-10Cadila Healthcare LimitedAnhydrous form of dasatinib, process for its preparation and its useUS20150087687A12012-03-232015-03-26Dennis BrownCompositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigoSG10201610869TA2012-06-262017-02-27Del Mar PharmaceuticalsMethods for treating tyrosine-kinase-inhibitor-resistant malignancies in patients with genetic polymorphisms or ahi1 dysregulations or mutations employing dianhydrogalactitol, diacetyldianhydrogalactiCN103664929B *2012-08-302016-08-03石药集团中奇制药技术(石家庄)有限公司Dasatinib polycrystalline form medicament and preparation methodCN102838595B *2012-09-132014-09-24江苏奥赛康药业股份有限公司Preparation method of high-purity dasatinib and by-product of dasatinibCN103819469A *2012-11-162014-05-28重庆医药工业研究院有限责任公司Crystal form of dasatinib and preparation method for crystal form of dasatinibCZ306598B62012-12-062017-03-22Zentiva, K.S.A method of preparation and purification of new and known polymorphs and dasatinib solvatesCN105764502A2013-07-262016-07-13现代化制药公司Combinatorial methods to improve the therapeutic benefit of bisantrene and analogs and derivatives thereofCN103408542B *2013-08-132016-06-29南京优科生物医药研究有限公司A kind of preparation method of highly purified Dasatinib anhydrideWO2015049645A2 *2013-10-042015-04-09Alembic Pharmaceuticals LimitedAn improved process for the preparation of dasatinibCZ306732B62013-12-192017-05-31Zentiva, K.S.A method of preparation of the anhydrous polymorphic form of N-6 DasatinibCN104788445B *2015-04-102017-06-23山东新时代药业有限公司A kind of synthetic method of Dasatinib intermediateCN106668022B *2015-11-052020-09-15武汉应内药业有限公司Application of aminothiazole MyD88 specific inhibitor TJM2010-5* Cited by examiner, † Cited by third party, ‡ Family to family citation 

References[edit]

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  21. Jump up to:a b c Kirkland JL, Tchkonia T (2020). “Senolytic drugs: from discovery to translation”Journal of Internal Medicine288 (5): 518–536. doi:10.1111/joim.13141PMC 7405395PMID 32686219.
  22. Jump up to:a b Paez-Ribes M, González-Gualda E, Doherty GJ, Muñoz-Espín D (2019). “Targeting senescent cells in translational medicine”EMBO Molecular Medicine11 (12): e10234. doi:10.15252/emmm.201810234PMC 6895604PMID 31746100.
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Further reading[edit]

  • Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, et al. (December 2004). “Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays”. Journal of Medicinal Chemistry47 (27): 6658–61. doi:10.1021/jm049486aPMID 15615512.

External links[edit]

  • “Dasatinib”Drug Information Portal. U.S. National Library of Medicine.
Clinical data
Trade namesSprycel, Dasanix
AHFS/Drugs.comMonograph
MedlinePlusa607063
License dataEU EMAby INNUS DailyMedDasatinibUS FDADasatinib
Pregnancy
category
AU: D
Routes of
administration
By mouth (tablets)
ATC codeL01EA02 (WHO)
Legal status
Legal statusAU: S4 (Prescription only) [1]US: ℞-onlyEU: Rx-only [2]In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding96%
MetabolismLiver
Elimination half-life1.3 to 5 hours
ExcretionFecal (85%), kidney (4%)
Identifiers
showIUPAC name
CAS Number302962-49-8 
PubChem CID3062316
IUPHAR/BPS5678
DrugBankDB01254 
ChemSpider2323020 
UNIIX78UG0A0RN
KEGGD03658 
ChEBICHEBI:49375 
ChEMBLChEMBL1421 
CompTox Dashboard (EPA)DTXSID4040979 
ECHA InfoCard100.228.321 
Chemical and physical data
FormulaC22H26ClN7O2S
Molar mass488.01 g·mol−1
3D model (JSmol)Interactive image
hideSMILESCc1cccc(c1NC(=O)c2cnc(s2)Nc3cc(nc(n3)C)N4CCN(CC4)CCO)Cl
hideInChIInChI=1S/C22H26ClN7O2S/c1-14-4-3-5-16(23)20(14)28-21(32)17-13-24-22(33-17)27-18-12-19(26-15(2)25-18)30-8-6-29(7-9-30)10-11-31/h3-5,12-13,31H,6-11H2,1-2H3,(H,28,32)(H,24,25,26,27) Key:ZBNZXTGUTAYRHI-UHFFFAOYSA-N 

/////////////DASATINIB, BMS 35482503, KIN 001-5, NSC 759877, Sprycel, BMS, APOTEX, ダサチニブ水和物 , X78UG0A0RN, дазатиниб , دازاتينيب , 达沙替尼 , 

#DASATINIB, #BMS 35482503, #KIN 001-5, #NSC 759877, #Sprycel, #BMS, #APOTEX, #ダサチニブ水和物 , #X78UG0A0RN, #дазатиниб , #دازاتينيب , #达沙替尼 , 

O.Cc1nc(Nc2ncc(s2)C(=O)Nc3c(C)cccc3Cl)cc(n1)N4CCN(CCO)CC4

PATENT

https://patents.google.com/patent/US8884013B2/enDasatinib, with the trade name SPRYCEL™, is a oral tyrosine kinase inhibitor and developed by BMS Company. It is used to cure adult chronic myelogenous leukemia (CML), acute lymphatic leukemia (ALL) with positive Philadelphia chromosome, etc. Its chemical name is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidyl]amino]-5-thiazolformamide and its chemical structure is as following:

Figure US08884013-20141111-C00001

Five polymorphs of Dasatinib and the preparation methods thereof were described by Bristol-Myers Squibb in the Chinese Patent Application No. CN200580011916.6 (publication date is 13 Jun. 2007). The preparation methods instructed in this document are:Monohydrate: Dasatinib (48 g) was added into ethanol (1056 mL 22 ml/g) and water (144 mL), and dissolved by heating to 75° C.; the mixture was purified, filtrated and transferred to the receiver. The solution reactor and transferring pipes were washed with the mixture of ethanol (43 mL) and water (5 mL). The solution was heated to 75˜80° C. to be soluble completely and water (384 mL) was heated and the temperature of the solution was kept between 75° C. and 80° C. The seed crystal of monohydrate (preferable) was added when cooling to 75° C., and keep the temperature at 70° C. for 1 h; cooling to 5° C. within 2 h and keeping the temperature at 0˜5° C. for 2 h. The slurry was filtrated and the filter cake was washed by the mixture of ethanol (96 mL) and water (96 mL); after being dried under vacuum≦50° C. 41 g of solid was obtained.Butanol solvate: under refluxing (116° C.˜118° C.), Dasatinib was dissolved in 1-butanol (about 1 g/25 mL) to yield crystalline butanol solvate of Dasatinib. When cooling, this butanol solvate was recrystallized from solution. The mixture was filtrated and the filter cake was dried after being washed with butanol.Ethanol solvate: 5D (4 g, 10.1 mmol), 7B (6.6 g, 50.7 mmol), n-bubanol (80 mL) and DIPEA (2.61 g, 20.2 mmol)) were added into a 100 ml round flask. The obtained slurry was heated to 120° C. and kept the temperature for 4.5 h, and then cooled to 20° C. and stirred over night. The mixture was filtrate, and the wet filter cake was washed with n-butanol (2×10 mL) to yield white crystal product. The obtained wet filter cake was put back to the 100 ml reactor and 56 mL (12 mL/g) of 200 proof ethanol was added. Then additional ethanol (25 mL) was added at 80° C., and water (10 mL) was added into the mixture to make it dissolved rapidly. Heat was removed and crystallization was observed at 75° C.˜77° C. The crystal slurry was further cooled to 20° C. and filtrated. The wet filter cake was washed with ethanol:water (1:1, 10 mL) once and then washed with n-heptane (10 mL) once. After that it was dried under the condition of 60° C./30 in Hg for 17 h to yield 3.55 g of substance only containing 0.19% water.Neat form of N-6: DIPEA (155 mL, 0.89 mmol) was added into the mixture of compound 5D (175.45 g, 0.445 mol) and hydroxyethylpiperazine (289.67 g, 2.225 mol) in NMP (1168 mL). The suspension was heated at 110° C. for 25 min to be solution, which was then cooled down to about 90° C. The obtained solution was added dropwise into hot water (80° C., 8010 mL), and the mixture was stirred at 80° C. with heat preservation for 15 min and cooled to room temperature slowly. The solid was filtrated under vacuum and collected, washed by water (2×1600 mL) and dried under vacuum at 55° C.˜60° C. to give 192.45 of compound.Neat form of T1H1-7 (neat form and pharmaceutically acceptable carrier): monohydrate of Dasatinib was heated over dehydrate temperature to yield.Because Dasatinib is practically insoluble in water or organic solvent (e.g. methanol, ethanol, propanol, isopropanol, butanol, pentanol, etc.), even in the condition of heating, a large amount (over 100 times) of solvent is needed, which is disadvantageous in industrial production; in addition, with the method described in the Patent document of CN200580011916.6, the related substances in products can not be lowed effectively during the process of crystal preparation to improve the products quality.In terms of polymorphs of drug, each polymorph has different chemical and physical characteristics, including melting point, chemical stability, apparent solubility, rate of dissolution, optical and mechanical properties, vapor pressure as well as density. Such characteristics can directly influence the work-up or manufacture of bulk drug and formulation, and also affect the stability, solubility and bioavailability of formulation. Consequently, polymorph of drug is of great importance to quality, safety and efficacy of pharmaceutical preparation. When it comes to Dasatinib, there are still needs in the art for new polymorphs suitable for industrial production and with excellent physical and chemical properties as well.Example 1Preparation of the Polymorph IA. Dasatinib (10 g) and DMSO (40 ml) were added into a flask and heated up to 60˜70° C. by stirring, after dissolving, the mixture (120 mL) of water and acetone (1:1) was added under heat preservation. When crystal was precipitated, cooled it down to 0° C. to grow the grains for 10 minutes. Filtrate it and the cake was washed by water and then by the mixture of water and acetone (1:1). After that it was dried under −0.095 MPa at about 50° C. using phosphorus pentoxide as drying aid to give 7.7 g of white solid. Yield was 77%.Contrasts Index of raw material Items before transformation Index of Polymorph I Appearance off-white powder White crystal powder Related substance 0.85% 0.07% KF moisture 0.67% 3.59% 70~150 0.72% 3.63% TGA weight loss
The following items of products prepared by Method A were detected: microscope-crystal form (See. FIG. 1); XRPD Test (See. FIG. 2), IR Test (See. FIG. 3), DSC-TGA Test (See. FIG. 4-1, 42), 13C Solid-state NMR Test (See. FIG. 5).B. Dasatinib (10 g) and DMSO (40 ml) were added into a flask and heated slowly up to 60˜70° C. by stirring, after dissolving, the mixture (160 mL) of ethanol and water (1:1) was added under heat preservation. When crystal was precipitated, cooled it down to 0° C. to grow the grains for 10 minutes. Filtrate it and the cake was washed by the mixture of ethanol and water (1:1) and dried under −0.095 MPa at about 50° C. using phosphorus pentoxide as drying aid to give 7.7 g of white solid. Yield was 87%.Contrasts Index of raw material Items before transformation Index of Polymorph I Appearance off-white powder White crystal powder Related substance 0.85% 0.08% KF moisture 0.67% 3.58% 70~150 0.72% 3.67% TGA weight lossHPLC.Related Substances DeterminationHPLC conditions and system applicability: octadecylsilane bonded silica as the filler; 0.05 mol/L of potassium dihydrogen phosphate (adjusted to pH 2.5 by phosphoric acid, 0.2% triethylamine)-methanol (45:55) as the mobile phase; detection wavelength was 230 nm; the number of theoretical plates should be not less than 2000, calculated according to the peak of Dasatinib. The resolution of the peak of Dasatinib from the peaks of adjacent impurities should meet requirements.Determination method: sample was dissolved in mobile phase to be the solution containing 0.5 mg per milliliter. 20 μL of such solution was injected into liquid chromatograph, and chromatogram was recorded until the sixfold retention time of major component peak. If there were impurities peaks in the chromatogram of sample solution, total impurities and any single impurity were calculated by normalization method on the basis of peak area.Stability of Polymorph in the FormulationsThe XRPD patterns of capsules and tablets respectively prepared in the Example 3 and Example 4 have been tested, and compared with XRPD characteristic peaks of Polymorph I of Dasatinib prepared by the Method A in the Example 1 in the present invention, as listed in the following table:Bulk Drug Capsules 1 Capsules 2 Tablets 2 (Polymorph (Polymorph (Polymorph Tablets 1 (Polymorph I) I) I) (Polymorph I) I) 2θ 2θ 2θ 2θ 2θ 9.060 9.080 9.070 9.060 9.070 11.100 11.120 11.110 11.100 11.110 13.640 13.670 13.650 13.640 13.650 15.100 15.120 15.110 15.100 15.110 17.820 17.840 17.830 17.820 17.820 19.380 19.400 19.390 19.380 19.390 22.940 22.970 22.950 22.950 22.950The results in the above-mentioned comparative table have shown that the crystal form had substantially no change after Polymorph I of Dasatinib in the invention were prepared into capsules or tablets by the formulation process.In addition, The relative substances of capsules and tablets respectively prepared in the Example 3 and Example 4 have been tested, and compared with those of Polymorph I of Dasatinib prepared by the Method A in the Example 1 in the present invention, as listed in the following table:Bulk Drug (Polymorph I) Capsules 1 Capsules 2 Tablets 1 Tablets 2 0.07% 0.08% 0.08% 0.07% 0.08%The results in the above-mentioned comparative table have shown that the Polymorph I of Dasatinib was stable, and there were no significantly changes in respect to the relative substances, after Polymorph I of Dasatinib in the invention were prepared into capsules or tablets by the formulation process.INDUSTRIAL APPLICATIONThe present invention provides novel polymorphs of Dasatinib, preparing methods, and pharmaceutical composition comprising them. These polymorphs have better physicochemical properties, are more stable and are more suitable for industrial scale production, furthermore, are suitable for long-term storage, and are advantageous to meet the requirements of formulation process and long-term storage of formulations. The preparation technique of this invention was simple, quite easy for operation and convenient for industrial production, and the quality of the products was controllable with paralleled yields. In addition, by the methods of polymorph preparation in this invention, the amount of organic solvent used in crystal transformation could be reduced greatly, which led to reduced cost of products; organic solvents in Class III with low toxicity could be used selectively to prepare the polymorphs of this invention, reducing the toxic effects of the organic solvents potentially on human body to some extent.PATENThttps://patents.google.com/patent/WO2010067374A2/enDasatinib are antineoplastic agents, which were disclosed in WO Patent Publication No. 00/62778 and U.S. Patent No. 6,596,746. Dasatinib, chemically N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4- pyrimidinyl]amino]-5-thiazolecarboxamide, is represented by the following structure:

Figure imgf000002_0001

Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and /or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and / or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other. Dasatinib can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.U.S. Patent Application No. 2005/0215795 A1 (herein after referred to as the 795 patent application) described five crystalline forms of dasatinib (monohydrate, butanol solvate, ethanol solvate, neat form (N-6) and neat form (T1H1-7)), characterized by powder X-ray diffraction (P-XRD) pattern.According to the ‘795 patent application, dasatinib monohydrate is characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 18.0, 18.4, 19.2, 19.6, 21.2, 24.5, 25.9 and 28.0 ± 0.2 degrees. As per the process exemplified in the ‘795 patent application, dasatinb monohydrate can be obtained in dasatinib, by heating and dissolving the dasatinib in an ethanol and water mixture. Crystallizing the monohydrate from the ethanol and water mixture and cooled to get dasatinib monohydrate.According to the ‘795 patent application, dasatinib crystalline butanol solvate is characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 5.9, 12.0, 13.0, 17.7, 24.1 and 24.6 ± 0.2 degrees.According to the 795 patent application, dasatinib crystalline ethanol solvate is characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 5.8, 11.3, 15.8, 17.2, 19.5, 24.1, 25.3 and 26.2 ± 0.2 degrees.According to the 795 patent application, dasatinib crystalline neat form (N-6) is characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 6.8, 11.1, 12.3, 13.2, 13.7, 16.7, 21.0, 24.3 and 24.8 ± 0.2 degrees.According to the 795 patent application, dasatinib crystalline neat form (T1H1-7) is characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 8.0, 9.7, 11.2, 13.3, 17.5, 18.9, 21.0 and 22.0 ± 0.2 degrees.U.S. Patent application No. 2006/0094728 disclosed ethanolate form (T1E2-1) of dasatinib, characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 7.2, 12.0, 12.8, 18.0, 19.3 and 25.2 ± 0.2 degrees. We have discovered novel crystalline form of dasatinib, dasatinib dimethylformamide solvate, dasatinib dimethyl sulfoxide solvate, dasatinib toluene solvate and dasatinib isopropyl acetate solvate.Another object of the present invention is to provide process for preparing the novel crystalline form of dasatinib, dasatinib dimethylformamide solvate, dasatinib dimethyl sulfoxide solvate, dasatinib toluene solvate, dasatinib isopropyl acetate solvate and known crystalline dasatinib monohydrate.Still another object of the present invention is to provide pharmaceutical compositions containing the novel crystalline form of dasatinib.Reference Example2-(6-Cholro-2-methylpyrimidin-4-yl-amino)-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide (15 gm) was added to 1-(2-hydroxyethyl)piperazine at 250C and heated to 850C, stirred for 2 hours 30 minutes at 850C. To the solution was added water (500 ml) at 800C and slowly cooled to 250C, stirred for 1 hour at 250C. The solid was collected by filtration and the solid was washed with water (50 ml), and then dried the solid at 550C under vacuum to obtain 15 gm of dasatinib.Example 1Dasatinib (5 gm) obtained according to reference example was dissolved in ethyl acetate (300 ml) at 250C and heated to reflux temperature. To the solution was added methanol (100 ml) and stirred for 30 minutes at reflux temperature to form clear solution. The solution was slowly cooled to room temperature and then cooled to O0C, stirred for 1 hour at O0C. The solid was collected by filtration and the solid was washed with mixture of ethyl acetate and methanol (20 ml, 3:1), and then dried the solid at 500C under vacuum to obtain 3.5 gm of crystalline dasatinib form I.Example 2Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in acetone (100 ml) and methanol (250 ml) and heated to reflux temperature, stirred for 30 minutes at reflux temperature to form clear solution. The solution was cooled to room temperature and then cooled to 200C, stirred for 1 hour at 200C. The solid was collected by filtration and the solid was washed with mixture of acetone (10 ml) and methanol (25 ml), and then dried the solid at 500C under vacuum to obtain 4 gm of crystalline dasatinib form I (HPLC purity: 99.85%).Example 3Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in dimethylformamide (25 ml) at 250C and heated to 650C to form clear solution. To the solution was slowly added acetone (50 ml) at 650C and stirred for 1 hour at 650C. The solution was slowly cooled to 250C and stirred for 1 hour at 250C. The contents are filtered and the solid obtained was washed with mixture of dimethylformamide and acetone (15 ml, 1:2), and then dried the solid at 500C under vacuum to obtain 4 gm of dasatinib dimethylformamide solvate (HPLC purity: 99.94%).Example 4Dasatinib (5 gm) was dissolved in dimethylformamide (25 ml) at 250C and heated to 650C to form clear solution. Ethyl acetate (50 ml) was added slowly to the solution at 650C and stirred for 1 hour at 650C. The solution was slowly cooled to 250C, stirred for 1 hour at 250C and filtered. The solid obtained was washed with mixture of dimethylformamide and ethyl acetate (30 ml, 1:2), and then dried the solid at 500C under vacuum to obtain 4 gm of dasatinib dimethylformamide solvate.Example 5Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in dimethylformamide (25 ml) and heated to 650C to form a clear solution. The solution was cooled to 250C and then cooled to 50C, stirred for 4 hour at 50C. The solid was collected by filtration and the solid was washed with chilled dimethylformamide (10 ml), and then dried the solid at 500C under vacuum to obtain 4 gm of dasatinib dimethylformamide solvate (HPLC purity: 99.9%).Example 6Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in dimethylformamide (25 ml) and heated to 650C to form a clear solution. Water (50 ml) was added slowly to the solution at 650C and stirred for 1 hour at 650C. The solution was cooled to 250C and stirred for 30 minutes at 250C. The solid was collected by filtration and the solid was washed with mixture of dimethylformamide and water (15 ml, 1 :2), and then dried the solid at 500C under vacuum to obtain 4.7 gm of dasatinib dimethylformamide solvate (HPLC purity: 99.93%).Example 7Dasatinib dimethylformamide solvate (4.7 gm) obtained as in example 6 was dissolved in water (50 ml) and heated to 750C, stirred for 4 hours at 750C. The solution was cooled to 250C, stirred for 30 minutes at 250C and filtered. The solid obtained was washed with water (15 ml), and then dried at 500C under vacuum to obtain 4.7 gm of dasatinib monohydrate.Example 8Dasatinib (20 gm) was dissolved in dimethyl sulfoxide (100 ml) at 250C and heated to 650C to form clear solution. To the solution was slowly added water (200 ml) at 650C and stirred for 1 hour at 650C. The solution was slowly cooled to 250C and stirred for 30 minutes at 250C. The solid was collected by filtration and the solid was washed with mixture of dimethyl sulfoxide and water (30 ml, 1 :2), and then dried the solid at 500C under vacuum to obtain 19.5 gm of dasatinib monohydrate.Example 9Dasatinib (5 gm) was dissolved in isopropyl acetate (65 ml) and heated to 800C, stirred for 1 hour at 800C to form a clear solution. The solution was cooled to 250C, stirred for 1 hour at 250C and filtered. The solid obtained was washed with isopropyl acetate (15 ml) to obtain 5 gm of dasatinib isopropyl acetate solvate.Example 10Dasatinib (6 gm) was dissolved in toluene (100 ml) and heated to reflux temperature, stirred for 2 hours at reflux temperature to form a clear solution. The solution was slowly cooled to 250C. The contents are filtered and the solid obtained was washed with toluene (20 ml) to obtain 5.5 gm of dasatinib toluene solvate.Example 11Dasatinib (5 gm) was dissolved in dimethyl sulfoxide (20 ml) at 250C and heated to 650C. To the solution was slowly added ethyl acetate (200 ml) at 650C and the solution was slowly cooled to O0C, stirred for 2 hours at O0C. The solid was collected by filtration and the solid was washed with mixture of dimethyl sulfoxide and ethyl acetate (55 ml, 1 :10), and then dried the solid at 500C under vacuum to obtain 4 gm of dasatinib dimethyl sulfoxide solvate.
PATENThttps://patents.google.com/patent/WO2014086326A1/enDasatinib, N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)- 1 -piperazinyl]-2- methyl-4-pyrimidmyl]amino]-5-thiazole carboxamide of formula I, also known as BMS- 354825, is a cancer treatment drug developed by Bristol-Myers Squibb and sold under the trade name Sprycel®. Dasatinib is a multi- BCR/ABL and Src family tyrosine kinase inhibitor and it is used for treatment of chronic myelogenous leukaemia (CML) as a secondary drug after primary treatment with imatinib (Gleevec®). It is also used for treatment of acute lymphoblastic leukaemia caused by mutation/translocation of chromosomes and development of the so-called Philadelphia chromosome (Ph+ ALL). However, its potential is so wide that the possibility of using it for treatment of other types of cancer, including advanced stages of prostate cancer, is still being investigated.

Figure imgf000002_0001

(I)In accordance with the basic patent WO2000062778A1, dasatinib is prepared by reaction of the key intermediate of formula II with l-(2-hydroxyethyl)piperazine in the presence of a base and a suitable solvent (Scheme 1). A similar preparation method was later used in a number of other process patents, only varying the corresponding base or solvent. Through the selection of a suitable solvent or procedure a great number of solvates or polymorphs can be prepared. Polymorphs have been one of the most frequently studied physical characteristics of active pharmaceutical substances (API) recently. Thus, different polymorphs of one API may have entirely different physical-chemical properties such as solubility, melting point, mechanical resistance of crystals but they may also influence the chemical and physical stability. Then, these properties may have an impact on further processes such as handling of the particular API, grinding or formulation method. These various physical-chemical characteristics of polymorphs influence the resulting bioavailability of the solid dosage form. Therefore, looking for new polymorphs and solvates is becoming an important tool for obtaining a polymorph form with the desired physical-chemical characteristics.

Figure imgf000003_0001

The process patent WO2005077945A2 describes preparation of the following solvates of dasatinib: monohydrate, butanol solvate, as well as two anhydrous forms (N-6 and T1H1- 7). A related patent also mentions two ethanol solvates, the hemi-ethanol and diethanol solvates (US 8 242 270 B2). Salts, various combinations of salts and their solvates have been described in detail in the patent application WO2007035874A1.Another process patent, WO2009053854A2, dealt with the preparation of a number of solvates or mixed solvates out of which especially the isopropanol and mixed isopropanol/dimethyl sulfoxide solvates, as well as a new solid form B, another anhydrous polymorph of dasatinib, are worth mentioning. Other patent applications have also dealt with the preparation of other solvates/mixed solvates (WO2010067374A2), or processes for the preparation and purification of the monohydrate/anhydrous form (WO2010139981A2) and its polymorphs (WO2011095059 Al).API solvates or salts are used in drug formulations in many cases. In the case of solvates the limits for individual solvents, their contents or maximum daily doses have to be strictly observed. Then, these limits can dramatically restrict their effective use. Thus, the clearly most convenient option is the use of sufficiently stable polymorphs of API that do not contain any solvents bound in the crystalline structure.Some of the above mentioned patent documents describe preparation of a stable anhydrous form of dasatinib (N-6). In accordance with individual patent documents the main disadvantages of the preparation of N-6 is the necessity of desolvation of the solvated form of the API at high temperatures (WO2009053854A2), or application of an increased temperature (50°C and more) and vacuum for a relatively long time (8-12h; WO2010139981A2 and WO2005077945A2). These procedures are very demanding from the point of view of general technology, energy and time, to say nothing of the necessity to work under an inert atmosphere to prevent possible oxidation-degradation reactions of the API. This is because dasatinib may be oxidized by atmospheric oxygen to the corresponding N-oxide (oxidation occurs in the piperazine ring), which may undergo the Cope elimination at increased temperatures. This secondary reaction may subsequently impair the purity of the prepared API.With a view to the above mentioned facts it is obvious that completely new methods and processes have to be developed even for polymorphs or solvates that are already well- known. Generally, the development of technologically and economically more efficient procedures is the main decisive parameter in their industrial utilization for the preparation of the API.Dasatinib of formula I is prepared by a reaction of the intermediate of formula II with l-(2- hydroxyethyl)piperazine in the presence of diisopropylethylamine (DIPEA) in an organic solvent from the group of dipolar aprotic solvents, higher alcohols or diols.If a dipolar aprotic solvent from the group of N-methyl-2-pyrrolidone (NMP), N^iV-dimethyl formamide (DMF), AyV-dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), formamide (FA), N,N -dimethyl propylene urea (DMPU) and l,3-dimethyl-2-imidazolidinone (DMI) is used, the reaction is carried out at 50-110°C under an inert atmosphere for 1/2-6 hours. In a preferable embodiment, NMP, DMSO, DMPU or DMI is used and the reaction is carried out at 90°C for 1-3 hours. The result of the reaction is crude dasatinib in the form of a solution in the corresponding solvent.If an alcohol from the group of isoamyl alcohol or 1,3-propanediol is used as a solvent for preparation of the crude dasatinib, the reaction mixture is heated at 120-160°C for 2-12 hours, in a preferable embodiment at 135°C for 3-6 hours.If dipolar aprotic solvents (NMP, DMF, DMA, DMSO, FA, DMPU and DMI) are used, in step a) a precipitant is added to the hot solution (90°C) under continuous stirring in an inert atmosphere in a 2- 15 fold, most preferably 4-10fold (by volume) amount with respect to the dipolar aprotic solvent. Suitable precipitants comprise especially acetonitrile, propionitrile, most preferably acetonitrile.After addition of the precipitant the obtained solution is withdrawn from the heating bath and is slowly left to cool down to 22°C under continuous stirring in an inert atmosphere. Crystallization occurs within 1-120 minutes (depending on the volume, until complete cooling). After having cooled down to 22°C (laboratory temperature), the suspension is stirred for another hour. The corresponding solvate of dasatinib is aspirated by well-known techniques in an inert atmosphere at 10-35 °C, most preferably at 22°C, and washed with the respective co-solvent.The solvate of dasatinib obtained this way can be directly used in the next step – recrystallization, without the necessity of drying. If necessary, the product may be dried at 10- 35°C, most preferably at 25°C, and at the pressure of 10-200 kPa, most preferably 50 kPa, for 6-24 hours, most preferably 12 hours.If NMP is used as the solvent in step a), the corresponding NMP solvate is isolated. The obtained dried crystalline NMP solvate (NM) of dasatinib has a characteristic XRPD pattern, which is presented in Figure no. 1. The NMP solvate (NM) has the following characteristic peaks: 5.88; 6.73; 10.73; 11.92; 13.39; 14.97; 16.72; 18.95; 20.17; 21.46; 22.81; 24.65; 25.18; 26.02 and 28.06 ± 0.2° 2-theta.If isoamyl alcohol or 1,3-propanediol are used as the solvents in step a), the reaction mixture is left to cool down to 22°C after expiration of the reaction time (3-6 h). Crystallization generally begins when the inner temperature of the reaction mixture drops to 100°C. After cooling down to 22°C (laboratory temperature), the suspension is further stirred for another 1 hour. Crystalline dasatinib is aspirated by well-known techniques in an inert atmosphere at 10-35°C, most preferably at 22°C, and washed with the corresponding solvent.The obtained product is dried at 10-35°C, most preferably at 25°C, and at the pressure of 10-200 kPa, most preferably 50 kPa, for 6-24 hours, most preferably 12 hours.The obtained crystalline isoamyl alcohol solvate (SI) of dasatinib has a characteristic XRPD pattern, which is shown in Figure no. 2. The solvate (SI) has the following characteristic peaks: 5.72; 10.35; 11.42; 12.61; 13.14; 14.27; 15.33; 17.18; 17.44; 17.97; 19.12; 19.95; 20.38; 22.05; 22.42; 23.01; 23.46; 23.68; 25.26; 26.20; 26.45; 26.62 and 27.78 ± 0.2° 2-theta.The obtained crystalline 1,3-propanediol solvate (SP) of dasatinib has a characteristic XRPD pattern, which is shown in Figure no. 3. The solvate (SP) has the following characteristic peaks: 6.04; 12.01; 15.10; 17.95; 18.35; 18.77; 21.25; 21.51; 22.96; 24.08; 24.62; 25.80; 26.16; 28.16 and 33.6578 ± 0.2° 2-theta.These solvates (or polymorph forms) are then easily converted to the desired anhydrous polymorph N-6 or another solvate in steps b) and c). All the forms prepared this way are sufficiently stable and can easily be isolated in the chemical purities of 99% and higher (in accordance with HPLC).The anhydrous polymorph form N-6 is prepared in the following way: any solvate or another polymorph is dissolved under an inert atmosphere at 90°C (reflux) in a 10-30 times, most preferably 20 times, the (weight) amount of the crystallization solvent. Suitable crystallization solvents include especially methanol, ethanol, isopropanol, most preferably methanol.A co-solvent is added in 0.1-10 times, most preferably ½-l times, the volume of the crystallization solvent used in an inert atmosphere at 90°C. The co-solvent can be, e.g., acetonitrile, propionitrile and their mixtures, most preferably acetonitrile. After addition of the co-solvent the obtained solution is withdrawn from the heating bath and is slowly left to cool down to 22°C under continuous stirring in an inert atmosphere. Crystallization occurs during 1-120 minutes (depending on the volume, until complete cooling). After having cooled down to 22°C (laboratory temperature), the suspension is stirred for another hour. Crystalline dasatinib is aspirated by well-known techniques in an inert atmosphere at 10-35°C, most preferably at 22°C, and washed with the corresponding co-solvent. The chemical purity of the obtained product is 99% (in accordance with HPLC); it is the polymorph form N-6 and its XRPD pattern is shown in Figure no. 4. The polymorph form N-6 has the following characteristic peaks: 6.77; 12.31; 13.16; 13.75; 16.70; 17.20; 18.54; 19.34; 20.25; 20.95; 21.94; 24.28; 24.82; and 27.80 ± 0.2° 2-theta.Brief Description of Drawings:Figure 1: shows an X-ray powder diffraction pattern of the crystalline solvate NM. Individual axes: independently variable: reflection angle 2Θ, dependently variable: intensity of detected radiation.Figure 2: shows an X-ray powder diffraction pattern of the isoamyl alcohol crystalline solvate SI. Individual axes: independently variable: reflection angle 2Θ, dependently variable: intensity of detected radiation. Figure 3: shows an X-ray powder diffraction pattern of the 1,3 propanediol crystalline solvate SP. Individual axes: independently variable: reflection angle 2Θ, dependently variable: intensity of detected radiation.Figure 4: shows an X-ray powder diffraction pattern of the crystalline anhydrous form N-6. Individual axes: independently variable: reflection angle 2Θ, dependently variable: intensity of detected radiation.Examples: The following working examples illustrate methods for the preparation of dasatinib of formula I, its polymorph form N-6 and its solvates NM, SI, SP.The polymorph forms and solvates of dasatinib were characterized with X-ray powder diffraction using the following methods:The diffraction patterns were measured using an X’PERT PRO MPD PANalytical diffractometer with a graphite monochromator, radiation used CuKa (λ=1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 – 40° 2Θ, increment: 0.01° 2Θ. The measurement was carried out using a flat powder sample that was placed on a Si plate. For the primary optic setting programmable divergence diaphragms with the irradiated sample area of 10 mm, Soller diaphragms 0.02 rad and an anti-dispersion diaphragm ¼ were used. For the secondary optic setting an X’Celerator detector with the maximum opening of the detection slot, Soller diaphragms 0.02 rad and an anti-dispersion diaphragm 5.0 mm were used. HPLC method:Stock solution of samples: dissolve 5.0 mg of the sample in 10.0 ml of 50% acetonitrile R with water.Dimensions of the chromatographic HPLC column: / = 0.10 m, d= 3 mm- stationary phase: Zorbax Eclipse Plus Phenyl-Hexyl RRHD 1.8 μιη; temperature: 35 °C. Mobile phase: A: phosphate buffer (0.01 M sodium dihydrogen phosphate, pH treated by addition of sodium hydroxide to 7.00 ± 0.05); B: acetonitrile R.Gradient (A/B; flow 0.6 ml/min): 0 min 80/20; 10 min 50/50; 11 min 50/50; 12 min 80/20. Detection at the wavelength of 220 nm.Feed: 2 μΐ of the sample stock solution Example 1.Preparation of the NMP solvate (NM) of dasatinib:The intermediate of formula II (1.00 g; 2.54 mmol) and l-(2-hydroxyethyl)piperazine (1.66 g; 12.77 mmol) were dissolved in N-methylpyrrolidone (5 ml) under an inert atmosphere and diisopropylethylamine (0.9 ml, 5.18 mmol) was added to the reaction mixture. The reaction mixture was stirred and heated up to 90°C for 70 minutes and then acetonitrile (30 ml) was added to the reaction. The mixture was withdrawn from the heating bath and stirred intensively. Crystallization started after 5 minutes, the suspension was left to cool down under continuous stirring. After achieving the laboratory temperature it was stirred for another 2 hours. The crystalline substance was aspirated on frit S3, washed with acetonitrile (5 ml) and dried by suctioning under an inert nitrogen atmosphere for 15 minutes. The XRPD pattern of the sample obtained this way corresponds to the NMP solvate (NM) and can be used in the subsequent steps without the necessity of drying. Drying after 6 hours in an exsiccator at the laboratory temperature in vacuo (50 kPa) provided 1.2 g of crystalline dasatinib; 80% of the theoretical yield. HPLC purity 99.12%. The 1H NMR and 13C NMR spectra correspond to the data known from the literature. The XRPD pattern of the dried product corresponds to the NMP solvate (NM). The NM solvate is characterized by the reflections presented in Table 1 :Table 1 – NM forminterplanarpos. distance[°2Th.] [nm] rel. int. [%]5.88 1.5024 81.86.73 1.3131 100.010.73 0.8236 10.611.92 0.7420 59.213.39 0.6606 19.614.97 0.5915 38.416.72 0.5298 45.018.95 0.4679 10.920.17 0.4399 13.921.46 0.4138 13.422.81 0.3895 21.024.65 0.3608 13.325.18 0.3534 14.426.02 0.3422 11.928.06 0.3177 5.8 

Norepinephrine bitartrate


Thumb
(+-)-Norepinephrine bitartrate.png
2D chemical structure of 3414-63-9

Norepinephrine bitartrate

Arterenol bitartrate
RN: 3414-63-9

FREE FORM 138-65-8

UNIIIFY5PE3ZRW

R FORM CAS Number108341-18-0,

  • 1,2-Benzenediol, 4-(2-amino-1-hydroxyethyl)-, (R)-, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (salt), monohydrate
  • 1,2-Benzenediol, 4-[(1R)-2-amino-1-hydroxyethyl]-, (2R,3R)-2,3-dihydroxybutanedioate (1:1) (salt), monohydrate (9CI)
  • Arterenol, tartrate, monohydrate (6CI)
  • L-Noradrenaline bitartrate monohydrate
  • Levarterenol bitartrate monohydrate

WeightAverage: 337.281
Chemical FormulaC12H19NO10

(+-)-Arterenol bitartrate

(+-)-Noradrenaline bitartrate

(+-)-Norepinephrine bitartrate

(2R,3R)-2,3-dihydroxybutanedioic acid 4-[(1R)-2-amino-1-hydroxyethyl]benzene-1,2-diol hydrate

ORD +41.3 °, water, 4% ; Wavlen: 589.3 nm; Temp: 25 °C, AND MP 163-165 °C, GB 747768 1956 NorepinephrineCAS Registry Number: 51-41-2CAS Name: 4-[(1R)-2-Amino-1-hydroxyethyl]-1,2-benzenediolAdditional Names: (-)-a-(aminomethyl)-3,4-dihydroxybenzyl alcohol; l-3,4-dihydroxyphenylethanolamine; noradrenaline; levarterenolTrademarks: Adrenor; Levophed (Winthrop)Molecular Formula: C8H11NO3Molecular Weight: 169.18Percent Composition: C 56.79%, H 6.55%, N 8.28%, O 28.37%Literature References: Demethylated precursor of epinephrine, q.v. Occurs in animals and man, and is a sympathomimetic hormone of both adrenal origin and adrenergic orthosympathetic postganglionic origin in man. Physiologic review: Malmejac, Physiol. Rev.44, 186 (1964). It has also been found in plants, e.g., Portulaca olerocea L., Portulacaceae: Fing et al.,Nature191, 1108 (1961). Synthesis of dl-form: Payne, Ind. Chem.37, 523 (1961). Historic review of synthesis: Loewe, Arzneim.-Forsch.4, 583 (1954). Resolution of dl-form: Tullar, J. Am. Chem. Soc.70, 2067 (1948); idem,US2774789 (1956 to Sterling Drug). Configuration: Pratesi et al.,J. Chem. Soc.1959, 4062. Comprehensive description: C. F. Schwender, Anal. Profiles Drug Subs.1, 149-173 (1972); T. D. Wilson, ibid.11, 555-586 (1982).Properties: Microcrystals, dec 216.5-218°. [a]D25 -37.3° (c = 5 in water with 1 equiv HCl).Optical Rotation: [a]D25 -37.3° (c = 5 in water with 1 equiv HCl) 
Derivative Type: HydrochlorideCAS Registry Number: 329-56-6Trademarks: Arterenol (HMR)Molecular Formula: C8H11NO3.HClMolecular Weight: 205.64Percent Composition: C 46.73%, H 5.88%, N 6.81%, O 23.34%, Cl 17.24%Properties: Crystals, mp 145.2-146.4°. [a]D25 -40° (c = 6). Freely sol in water. Solns slowly oxidize under the influence of light and oxygen in a manner comparable to epinephrine hydrochloride.Melting point: mp 145.2-146.4°Optical Rotation: [a]D25 -40° (c = 6) 
Derivative Type:d-BitartrateCAS Registry Number: 69815-49-2Additional Names: Levarterenol bitartrateTrademarks: Aktamin; BinodrenalMolecular Formula: C8H11NO3.C4H6O6Molecular Weight: 319.26Percent Composition: C 45.14%, H 5.37%, N 4.39%, O 45.10%Properties: Obtained as the monohydrate, crystals, mp 102-104°. [a]D25 -10.7° (c = 1.6 in H2O). When anhydr, mp 158-159° (some decompn). Freely sol in water.Melting point: mp 102-104°; mp 158-159° (some decompn)Optical Rotation: [a]D25 -10.7° (c = 1.6 in H2O) 
Derivative Type:dl-FormProperties: Crystals, dec 191°. Sparingly sol in water; very slightly sol in alc, ether; readily sol in dilute acids, caustic. 
Therap-Cat: Adrenergic (vasopressor); antihypotensive.Therap-Cat-Vet: Sympathomimetic; vasopressor in shock.Keywords: a-Adrenergic Agonist; Antihypotensive.

Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic.

Norepinephrine (sometimes referred to as l-arterenol/Levarterenol or l-norepinephrine) is a sympathomimetic amine which differs from epinephrine by the absence of a methyl group on the nitrogen atom.

Norepinephrine Bitartrate is (-)-α-(aminomethyl)-3,4-dihydroxybenzyl alcohol tartrate (1:1) (salt) monohydrate and has the following structural formula:

Levophed™ (norepinephrine bitartrate) Structural Formula Illustration

LEVOPHED is supplied in sterile aqueous solution in the form of the bitartrate salt to be administered by intravenous infusion following dilution. Norepinephrine is sparingly soluble in water, very slightly soluble in alcohol and ether, and readily soluble in acids. Each mL contains the equivalent of 1 mg base of norepinephrine, sodium chloride for isotonicity, and not more than 2 mg of sodium metabisulfite as an antioxidant. It has a pH of 3 to 4.5. The air in the ampuls has been displaced by nitrogen gas.

Norepinephrine, also known as noradrenaline, is a medication used to treat people with very low blood pressure.[2] It is the typical medication used in sepsis if low blood pressure does not improve following intravenous fluids.[3] It is the same molecule as the hormone and neurotransmitter norepinephrine.[2] It is given by slow injection into a vein.[2]

Common side effects include headache, slow heart rate, and anxiety.[2] Other side effects include an irregular heartbeat.[2] If it leaks out of the vein at the site it is being given, norepinephrine can result in limb ischemia.[2] If leakage occurs the use of phentolamine in the area affected may improve outcomes.[2] Norepinephrine works by binding and activating alpha adrenergic receptors.[2]

Norepinephrine was discovered in 1946 and was approved for medical use in the United States in 1950.[2][4] It is available as a generic medication.[2]

Medical uses

Norepinephrine is used mainly as a sympathomimetic drug to treat people in vasodilatory shock states such as septic shock and neurogenic shock, while showing fewer adverse side-effects compared to dopamine treatment.[5][6]

Mechanism of action

It stimulates α1 and α2 adrenergic receptors to cause blood vessel contraction, thus increases peripheral vascular resistance and resulted in increased blood pressure. This effect also reduces the blood supply to gastrointestinal tract and kidneys. Norepinephrine acts on beta-1 adrenergic receptors, causing increase in heart rate and cardiac output.[7] However, the elevation in heart rate is only transient, as baroreceptor response to the rise in blood pressure as well as enhanced vagal tone ultimately result in a sustained decrease in heart rate.[8] Norepinephrine acts more on alpha receptors than the beta receptors.[9]

Names

Norepinephrine is the INN while noradrenaline is the BAN.

SYN

Chemical Synthesis

Norepinephrine, L-1-(3,4-dihydroxyphenyl)-2-aminoethanol (11.1.4), is synthesized by two methods starting from 3,4-dihydroxybenzaldehyde. According to the first method, the indicated aldehyde is transformed into the cyanohydrin (11.1.3) by reaction with hydrogen cyanide, which is then reduced into norepinephrine (11.1.5).

The second method consists of the condensation of diacetate of the same aldehyde with nitromethane, which forms (3,4-diacetoxyphenyl)-2-nitroethanol (11.1.5). Then the nitro group is reduced and the product (11.1.6) is hydrolyzed into the desired norepinephrine (11.1.4) [4,9,13,14].

Purification Methods

Recrystallise adrenor from EtOH and store it in the dark under N2. [pKa, Lewis Brit J Pharmacol Chemother 9 488 1954, UV: Bergstr.m et al. Acta Physiol Scand 20 101 1950, Fluorescence: Bowman et al. Science NY 122 32 1955, Tullar J Am Chem Soc 70 2067 1948.] The L-tartrate salt monohydrate has m 102-104.5o, [] D -11o (c 1.6, H2O), after recrystallisation from H2O or EtOH. [Beilstein 13 III 2382.]

PATENT

https://patents.google.com/patent/WO2013008247A1/en4-[(lR)-2-amino-l-hydroxyethyl]benzene-l,2-diol, commonly known as (R)-(-)- norepinephrine or noradrenaline is a catecholamine with multiple roles including as a hormone and a neurotransmitter. As a stress hormone, norepinephrine affects parts of the brain where attention and responding actions are controlled. Along with epinephrine, norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. Norepinephrine also has a neurotransmitter role when released diffusely in the brain as an antiinflammatory agent.When norepinephrine acts as a drug it increases blood pressure by increasing vascular tone through a-adrenergic receptor activation. The resulting increase in vascular resistance triggers a compensatory reflex that overcomes its direct stimulatory effects on the heart, called the baroreceptor reflex, which results in a drop in heart rate called reflex bradycardia.(R)-(-)-Norepinephrine has a following structure:

Figure imgf000002_0001

(R)-(-)-Norepinephrine was first time disclosed in the US patent US2774789, where it was obtained by resolution of dl-norepinephrine, with optically active acids such as d- tartaric acid, 1-malic acid or N-benzoyl-l-threonine. The patent does not disclose the preparation of dl-norepinephrine. The patent GB747768 describes reduction of amino ketones where 3,4-dihydroxy-a- aminoacetophenone hydrochloride was converted into its d-tartrate salt; followed by reduction of the d-tartrate salt. This process leads to formation of excessive amount of d- adrenaline d-tartrate (which is a bi-product) as it crystallized first; whereas the desired 1- adrenaline d-tartrate crystallizes after 2 days and in smaller yield. Also the patent does not disclose the source of 3,4-dihydroxy-a-aminoacetophenone hydrochloride.It has been unsuccessfully tried to treat dihydroxy-a-chloroacetophenone with hexamethylenetetramine (commonly known as hexamine) and to treat the reaction product with an acid to obtain arterenone (see Mannich, Hahn B., Berichte der deutschen chemischen Gesellschaft, volume 44, issue 2, Pages 1542 – 1552 (1911)). Mannich found that the treatment of this and similar halogen ketones with hexamine did not produce an addition compound but resulted in splitting of halogen acid which made the process impossible. Mannich also found that an addition compound of the halogen ketone and hexamine is formed only when the two phenolic hydroxyl groups are closed i.e. protected by acylation or etherification. Hence according to Mannich, the reaction is not at all possible for the compounds containing two unprotected phenolic hydroxyl groups. The US patent US 1680055 discloses the preparation of monohydroxy-a-substituted- aminoacetophenones either by reacting monohydroxy-a-bromoacetophenones with a substituted amine or by reacting protected monohydroxy-a-bromoacetophenones with a substituted amine followed by deprotection. The patent does not disclose the preparation of dihydroxy-a-aminoacetophenones (where amino group is unsubstituted).It is disclosed in the US patent US2786871 that when chloroaceto pyrocatechol is treated with ammonia, arterenone is obtained in 50% yield. However when the reaction is carried out in basic medium, darkening of the reaction mass takes place which results in coloured product. The patent also discloses preparation of amino-methyl-(monohydroxyphenyl)- ketones by reacting halogen ketone with hexamine. It is also disclosed in the patent that the process is applicable only to the halogenomethyl-monohydroxyphenyl-ketones.Following are some of the methods for preparation of 3,4-dihydroxy-a- aminoacetophenone, reported in the literature. J. Am. Pharm. Association (1946) 35, 306 – 309 discloses preparation of 3,4-dihydroxy- a-aminoacetophenone by reacting 3,4-dihydroxy-a-chloroacetophenone with dibenzyl amine followed by hydrogenation of resulting dibenzylamino ketone. The main disadvantage of this reaction is formation of derivatives of dibenzyl amines, which remain in the final product in the form of impurities.Acta Chimica Academiae Scientiarum Hungaricae (1951), 1, 395-402, discloses preparation of 3,4-dihydroxy-a-aminoacetophenone from 3,4-dihydroxyphenyloxo acetaldehyde and benzyl amine followed by reduction of benzylamino ketone intermediate. The main disadvantage of this method is that the starting acetaldehyde derivative is very expensive and not easily available.It is disclosed in Recueil des Travaux Chimiques des Pays-Bas et de la Belgique (1952), 71, 933-44, that 3,4-dihydroxy-a-aminoacetophenone hydrochloride is formed by demethylation of 3,4-dimethoxy-a-aminoacetophenone hydrochloride using 48% HBr. The reaction results in less than 10% yield of the aminoacetophenone.Monatshefte fuer Chemie (1953), 84 1021-32, discloses preparation of 3,4-dihydroxy-a- aminoacetophenone by reacting 3,4-dihydroxy-a-chloroacetophenone with sodium azide followed by hydrogenation of azide intermediate using 4% palladium on carbon as a catalyst. In the hydrogenation step, 1.6 gm of azide intermediate requires 1.4 gm of catalyst, which is not economical and industrially feasible.

Preparation of 3,4-dihydroxy-a-aminoacetophenones hydrochloride is disclosed in J. Am. Chem. Soc, 1955, volume 77, issue 10, pages 2896 – 2897. The following scheme is disclosed in the article:

Figure imgf000004_0001
Figure imgf000004_0002

It is clear from the above scheme that the process requires additional steps of protection and deprotection of hydroxyl and amino groups, and use of potassium phthalimide requires anhydrous reaction conditions. Therefore the process is time consuming and not economical.Chinese patent CN101798271A describes reduction of 3,4-dihydroxy-a- aminoacetophenone hydrochloride in water as solvent followed by neutralization with aqueous ammonia. Since dl-norepinephrine has partial solubility in aqueous basic medium result in to loss of product. Also it is necessary to maintain low volume of solvent throughout the process for better yields making the process stringent.European patent EP1930313 discloses preparation of a-amino ketones. The preparation is carried out by reacting an organic sulfide in a polar solvent with a compound containing a leaving group attached to a primary or secondary carbon atom to form a sulfonium salt, which is reacted with a ketone in presence of a base and a polar solvent. Oxiranes obtained are further converted into the corresponding aminoketone, by aminolysis followed by selective oxidation. The following scheme is disclosed in the patent.

Figure imgf000005_0001

It is clear from the above scheme that the process requires many steps and hence is time consuming. The patent does not exemplify the synthesis of dihydroxy-a- aminoacetophenones.Thus, the search for a suitable manufacturing process for (R)-norepinephrine intermediates remains undoubtedly of interest. We were surprised to find that hardly any literature discloses the process for preparation of dihydroxy-a-aminoacetophenones acid addition salts. We have found that the reaction of dihydroxy-a-haloacetophenone with hexamine is feasible and results in high yield of product although both the hydroxyl groups on the phenyl ring of acetophenone are unprotected. Object of the invention:It is therefore an object of the invention is to overcome or ameliorate at least one disadvantage of the prior art or to provide a useful alternative.Another object of the invention is to provide a novel, safe, efficient, concise, ecological, high yielding, industrially feasible and simpler process for preparation of (R)-(-)- norepinephrine intermediates.Another object of the invention is to provide a process for synthesis of 3,4-dihydroxy-a- aminoacetophenone salt, which is feasible without protecting both the hydroxyl group on the phenyl ring of acetophenone.Yet another object of the invention is to provide an improved process for hydrogenation of 3,4-dihydroxy-a-aminoacetophenone salt to prepare (dl)-norepinephrine salt.Summary of the invention:In accordance with the above objectives, the present invention provides a process for preparation of (dl)-norepinephrine intermediate of formula (III) comprising reacting 3,4- dihydroxy-a-haloacetophenone of formula (I) with hexamine to provide a quaternary ammonium salt of formula (II); followed by hydrolyzing the quaternary ammonium salt of formula (II) with an acid.In a second aspect, the present invention provides a novel quaternary ammonium salt of formula (II) and its preparation.In a third aspect, the present invention provides a novel process for hydrogenation of 3,4- dihydroxy-a-aminoacetophenone acid salt to provide (dl)-norepinephrine acid addition salt.Example 1Preparation of quaternary ammonium saltA 5000 ml four neck round bottom flask with water condenser and calcium chloride tube was charged with Hexamine (210.28 gm), chloroform (1200 ml), 3,4-dihydroxy-a- chloroacetophenone (250 gm) and isopropanol (1000 ml) at room temperature. The reaction mass was gently heated at 63°C for 4 hours. The reaction was monitored by TLC. The reaction mass was cooled to room temperature and filtered to get solid. The solid was washed with acetone and dried at 50°C for 4 hours to obtain quaternary ammonium salt which was used in the next step without purification.Yield – 410 gm (93.65%)Nature – off white solidm.p. – 180 to l82°CNMR (DMSO-d6): – δ =4.51 – 4.75 (m, 8H), 5.39 (s, 6H), 6.92 (d, 1H, J= 7.5 Hz), 7.37 – 7.42 (m, 2H), 9.67 (s, br, 1H), 10.44 (s, br, 1H)Example 2Preparation of 3,4-dihydroxy-a-aminoacetophenone hydrochlorideA 2000 ml four neck round bottom flask with water condenser and calcium chloride tube was charged with the quaternary ammonium salt obtained in the example 1 (120 gm), methanol (862.5 ml) and cone, hydrochloric acid (194.4 ml). The reaction mixture was heated to 60 to 65°C and aged at same temperature for 3 to 4 hours. The reaction was monitored by TLC. The reaction mass was cooled and neutralized using base to give 3,4- dihydroxy-a-aminoacetophenone. The solid was filtered, washed with water and dried at 50°C. This base was further converted in to its hydrochloride salt with IPA-HC1 mixture. Yield – 72 gm (96.3%)Nature – off white solidHPLC – 99.7%1H NMR(CD30D) – 5 = 3.62(s, 1H), 6.80 (d, J = 8 Hz, 1H), 7.38 (d, J = 1.3 Hz, 1H), 7.63 (d, J = 8 Hz, 1H).Example 3Preparation of (dl)-norepinephrine hydrochlorideA 500 ml hydrogenation flask was charged with 3,4-dihydroxy-a-aminoacetophenone hydrochloride obtained in the example 2 (55 gm), 10% palladium on carbon (5 gm) and methanol (300 ml). The reaction mixture was heated to 45°C with hydrogen gas pressure of 4 to 5 kg m2. The reaction mixture was stirred at 45°C for 5 hours. The catalyst was removed by filtration. The filtrate was cooled to 5 to 10 °C and ammonia gas was passed through the solvent for 2 h till the pH of the solution was around 9. The solid obtained was filtered, washed with methanol and dried in air to obtain (dl)-norepinephrine. Yield – 43.5 gm (96.7%)Nature white crystalline solidHPLC 99.6%Example 4Preparation of (dl)-norepinephrine hydrochlorideA 500 ml hydrogenation flask was charged with 3,4-dihydroxy-a-aminoacetophenone hydrochloride obtained from process similar to example 2 (55 gm), 10% palladium on carbon (5 gm) and methanol (300 ml). The reaction mixture was aged at 25 °C with hydrogen gas pressure of 4 to 3 kg/m2. The reaction mixture was stirred at 25°C for 15 hours. The reaction was monitored by TLC. The catalyst was removed by filtration. The filtrate was cooled to 5 to 10 °C and ammonia solution was added to the reaction mixture till the pH of the solution around 9. The solid obtained was filtered, washed with methanol and dried in air to obtain (dl)-norepinephrine.Yield – 41.5 gm (92.2%)Nature – white crystalline solidHPLC – 99.5% 
PATENTUS-10865180https://patentscope.wipo.int/search/en/detail.jsf?docId=US283323778&_cid=P11-KMEC1N-93277-1

Norepinephrine Bitartrate (Arterenol Bitartrate) is chemically known as (−)-α-(aminomethyl)-3, 4-dihydroxybenzyl alcohol tartrate (1:1) (salt) monohydrate is a catecholamine family that functions in the brain and body as a hormone and neurotransmitter. As a stress hormone, Norepinephrine affects parts of the brain where attention and responding actions are controlled. Along with epinephrine, Norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. Norepinephrine also has a neurotransmitter role when released diffusely in the brain as an anti-inflammatory agent.
      LEVOPHED® (l-Norepinephrine) is supplied in sterile aqueous solution in the form of the bitartrate salt to be administered by intravenous infusion following dilution. Norepinephrine is sparingly soluble in water, very slightly soluble in alcohol and ether, and readily soluble in acids. Each ml contains the equivalent of 1 mg base of Norepinephrine, sodium chloride for isotonicity, and not more than 2 mg of sodium metabisulfite as an antioxidant.
      Norepinephrine Bitartrate is (−)-α-(amino methyl)-3,4-dihydroxybenzyl alcohol tartrate (1:1) (salt) monohydrate and has the following structural formula:

 (MOL) (CDX)
      (l)-Norepinephrine was first disclosed in 1947 by Sterling Drugs. U.S. Pat. No. 2,774,789 discloses the resolution of dl-Norepinephrine with optically active acids such as d-tartaric acid, 1-malic acid or N-benzoyl-l-threonine. The patent does not disclose the basic synthesis of dl-Norepinephrine.
       Journal of the American Chemical Society, Volume 70 (6), 1948 describes the resolution of dl-Norepinephrine in to d-arterenol-d-bitartrate and l-arterenol-d-bitartrate in water and aqueous methanol. Further it also describes isolation of d-arterenol and l-arterenol form above tartrate salts.
      U.S. Pat. No. 2,786,871 discloses the process for the preparation of arterenol wherein chloroacetopyrocatechol is treated with ammonia and arterenol is obtained in 50% yield.
       J. Am. Pharm. Association (1946) 35, 306-309 discloses preparation of 3,4-dihydroxyaminoacetophenone by reacting 3,4-dihydroxy-α-chloroacetophenone with dibenzyl amine, followed by hydrogenation of the resulting dibenzylamino ketone. The main disadvantage of this reaction is the formation of derivatives of dibenzyl amines, which carried over to final product in the form of impurities.
       Acta Chimica Academiae Scientiarum Hungaricae (1951), 1, 395-402 discloses preparation of 3, 4-dihydroxy-α-aminoacetophenone from 3,4-dihydroxyphenyloxo acetaldehyde and benzyl amine followed by reduction of the benzylamino ketone intermediate. The main disadvantage of this method is that the starting acetaldehyde derivative is very expensive and not easily available.
      CN101798271A describes reduction of 3,4-dihydroxy-α-aminoacetophenone hydrochloride in water as solvent followed by neutralization with aqueous ammonia. Since dl-Norepinephrine has partial solubility in aqueous basic medium, this process results in a loss of product. Also, it is necessary to maintain low volume of solvent throughout the process for better yields making the process stringent.
      WO2009004593 describes the process for the preparation of Epinephrine wherein (−) epinephrine is obtained by chiral separation of dl-epinephrine using the chiral acid such as L-tartaric acid with an optical purity of 95.24%.
      WO2013008247 discloses a process for preparation of (dl)-norepinephrine hydrochloride salt by reacting 3,4-dihydroxy-a-haloacetophenone with hexamethylenetetramine to provide hexamine salt; followed by hydrolysis and hydrogenation. However, this process fails to teach the resolution of (dl)-norepinephrine hydrochloride and preparation of l-Norepinephrine Bitartrate monohydrate.
      WO2016038422 discloses a process for the preparation of optically enriched adrenaline or adrenaline tartrate comprising the steps of: (a) reacting a mixture of (−)-adrenaline and (+)-adrenaline with L(+)-tartaric acid to form adrenaline tartrate; (b) contacting the adrenaline tartrate with less than 1 equivalent of ammonium hydroxide. However, the product achieved is with purity of only 98%.
      CN107298646 describes the process for the preparation of Norepinephrine wherein L-Norepinephrine tartrate is obtained by chiral separation of dl-Norepinephrine using the chiral acid such as L-tartaric acid. The chiral separation step using L-tartaric acid is repeated once to obtain pure Norepinephrine. However, there is no information on bitartrate salt and its optical purity.
      In light of the above, there remains a need in the art for highly pure l-Norepinephrine Bitartrate having high enantiomeric purity i.e. greater than 99.0% so as to provide enhanced therapeutic efficacy and safety when administered. Surprisingly the present inventors have found out a process for the preparation of (l)-Norepinephrine Bitartrate having enantiomeric purity greater than 99.5%, for which protection is sought.

Reference Example-1(U.S. Pat. No. 2,774,789, Example-A)

Preparation of l-Norepinephrine Bitartrate

      To a four necked 100 ml flask charged racemic Norepinephrine base (20 gm), d-(−) tartaric acid (18.34 gm), and water (35 ml) at room temperature. The reaction mass was stirred to obtain clear solution, cooled to 0-5° C. After 5 hours slight turbidity was observed. Turbidity increases slowly to get thick white slurry after 6 hours, reaction mass becomes very thick which was difficult to filter, washed solid wet cake by 4.0 ml water followed by two 12 ml portions of 95% ethanol. Suck dried the solid completely, dried at 45° C. to get l-Norepinephrine Bitartrate (28 gm) which is in crude form.
      Crude l-Norepinephrine Bitartrate (20 gm) dissolved in 14 ml of water at 50° C. Clear solution was obtained. Activated charcoal was added to this solution and stirred the reaction mass for more for 30 min. Filtered through Hyflo and cooled to 0-5° C. After 2 hours, clear solution obtained gets converted to thick solid mass. Filtered and washed the solid with 1.5 ml of chilled water followed 14 ml of 95% ethanol.
      This dry solid 8 gm (after 1 st purification) was then dissolved in 8 ml of water at 50° C. to get clear solution. This reaction mass was then cooled to 0-5° C. After 1 hour, a clear solution gets converted to a thick solid mass. Maintained the reaction mass for more than 2 hours at the same conditions. Filtered the thick solid and washed with 95% ethanol. Dried the solid at 45° C. to obtain l-Norepinephrine Bitartrate.
      Chiral Purity by HPLC: l-Norepinephrine Bitartrate=68.45%, and d-isomer=31.55%
      Specific Optical Rotation: −6.33°

Reference Example-2 (JAGS, 1948, Page-2067-68, Example-a)

      To a four necked flask charged racemic Norepinephrine base (20 gm), d-(−) tartaric acid (18.34 gm), and water (35.20 ml) at room temperature. After 5 minutes reaction mass becomes clear liquid. Cooled the reaction mass to 2-3° C. After 30 minutes, reaction mass was observed to be turbid and further the reaction mass becomes very thick. This mass was, stirred for 2 hours at 0-5° C. Then filtered reaction mass at same temperature and washed solid wet cake with 3.5 ml water followed by two 11.8 ml portions of 95% ethanol. Dried the solid at air oven at 45° C. to get crude tartrate salt (15 gm).
      Crude tartrate salt (15 gm) was dissolved in 5 ml of water at 50° C. to get clear solution. Cooled to 2-3° C. After 30 minutes, a clear solution gets converted to a thick solid mass. Filtered the solid and washed with 1.5 ml of chilled water and then 15 ml of 95% ethanol. Dried the solid at 45° C. to obtain semi pure l-Norepinephrine Bitartrate (8 gm).
      This semi pure l-Norepinephrine Bitartrate (8 gm) was dissolved in 8 ml of water at 50° C. to get clear solution. Cooled the mass to 2-3° C. After 30 minutes clear solution gets converted to thick solid mass. Filtered the solid and washed with 8 ml of 95% ethanol. Dried the solid at 45° C. to obtain pure l-Norepinephrine Bitartrate (3 gm).
      Chiral Purity: l-Norepinephrine Bitartrate=77.14%, d-isomer=22.86%
      Specific Optical Rotation: −10.4°

Example-1: Preparation of 2-Chloro-1-(3, 4-Dihydroxyacetophenone)

      In round bottom flask, charged Methylene Chloride (1000 ml), Aluminium chloride (300 gm) and cooled to 0-5° C. Pyrocatechol (100 gm) was added lot wise. Chloroacetyl chloride (108 gm) was added drop wise at 0-5° C. Then stirred the reaction mass at 25-30° C. for 20-24 hours. After completion of the reaction, reaction mass was quenched in aq. HCl, filtered the reaction mass and wet cake was charged in water containing acetic acid. Filtered the reaction mass and cooled to 15-20° C., filtered solid and washed with water.
      Yield: 110 gm.
      HPLC Purity: 99.5%

Example-2: Preparation of Hexamine Salt

      In a round bottom flask charged 2-chloro-1-(3, 4-dihydroxyacetophenone) (100 gm), Hexamine (87 gm), IPA (500 ml), Chloroform (400 ml). Stirred the reaction mass at reflux temperature for 6 hours. After completion of the reaction, cooled to 25-30° C., filtered and washed the wet cake with IPA and Methanol.
      Yield: 160 gm.
      HPLC Purity: 99.3%

Example-3: Preparation of 2-Amino-1-(3,4-Dihydroxyphenyl)Ethanone Hydrochloride

      In a round bottom flask charged Hexamine salt (100 gm), Methanol (600 ml), aqueous HCl and heated the reaction mass to 55-60° C. After completion of the reaction, the mass was dissolved in water, by adjusting pH with liquor ammonia. Filtered the solid and washed with water, dried the material at 45-50° C.
      This free base was charged in 900 ml methanol and pH was adjusted to 1-1.5 by IPA.HCl and distilled off methanol completely to get white solid which was isolated by filtration.
      Yield: 37 gm
      HPLC Purity: 99.5%

Example-4: Preparation of [4-(2-Amino-1-Hydroxyethyl) Benzene-1, 2-Diol] (Racemic Norepinephrine Base)

      Charged 2-amino-1-(3, 4-dihydroxyphenyl) ethanone hydrochloride (100 gm), 10% Pd/C(10 gm), methanol (700 ml) and water (300 ml) mixture in autoclave. Stirred the reaction mass at 40-45° C. After completion of reaction, Pd/C was removed by filtration. Collected filtrate and distilled off methanol. pH was adjusted by liquor ammonia. Isolated the solid by filtration and washed with water followed by methanol. Dried the solid at 40-45° C.
      Yield: 67 gm
      Purity: 99.2%

Example-5: Preparation of l-Norepinephrine Base

      Charged racemic Norepinephrine base (100 gm), D-(−)-Tartaric acid (142 gm), water (100 ml) in a round bottom flask. The reaction mass was stirred to get clear solution. After some time, solid started to crystallize. Reaction mass was diluted with methanol (900 ml). Maintained the reaction mass under stirring for 24 hours at 25-30° C. Filtered and washed the wet cake with methanol to obtain Crude l-Norepinephrine tartrate salt.
      Yield: 85 gm
      The crude l-Norepinephrine tartrate salt was converted into its free base by dissolving this crude tartrate salt in water (500 ml) and adjusted pH to 8-8.5 by liquor ammonia and isolated the solid by filtration. Dried the material at 40-45° C. to obtain pure l-Norepinephrine free base (43 gm).
      Yield: 43 gm (l-Norepinephrine pure base).
      HPLC Purity: 99.7%
      Chiral Purity: 98.0%

Example-6: Preparation of Pure l-Norepinephrine Base

      Charged l-Norepinephrine base (100 gm) obtained from Example-5, D-(−)-Tartaric acid (142 gm), water (100 ml) in a round bottom flask. The reaction mass was stirred to get clear solution. After some time, a solid started to crystallize. Reaction mass was diluted with methanol (900 ml). Maintained the reaction mass under stirring for 24 hours at 25-30° C. Filtered and washed the wet cake with methanol to obtain l-Norepinephrine tartrate salt.
      Yield: 88 gm
      The l-Norepinephrine tartrate salt was converted into its free base by dissolving this crude tartrate salt in water (500 ml) and adjusted the pH to 8-8.5 by liquor ammonia and isolated the solid by filtration. Dried the material at 40-45° C. to obtain pure l-Norepinephrine free base (44 gm).
      Yield: 44 gm (l-Norepinephrine pure base).
      HPLC Purity: 99.7%
      Chiral Purity: 99.1%

Example-7: Preparation of Highly Pure Norepinephrine Bitartrate Monohydrate

      Charged Norepinephrine pure base (100 gm), L-(+) tartaric acid (100 gm), water (100 ml) and methanol (900 ml), Stirred the reaction mass to get clear solution. After some time, a solid started to crystallize then the reaction mass was diluted with methanol (900 ml). Maintained the reaction mass under stirring at 25-30° C. for 24 hours. Filtered and washed the wet cake with methanol to obtain Norepinephrine Bitartrate Monohydrate (90 gm).
      HPLC Purity: 99.8%
      Chiral Purity: 99.4%

Example-8: Purification of l-Norepinephrine Bitartrate Monohydrate

      Charged 100 gm tartrate salt obtained from example-6, purified water (100 ml) and heated the reaction mass to 40-45° C. to obtain clear solution, cooled to 0-5° C. Charged IPA (100 ml) slowly and the mass was stirred for one hour. The solid was isolated by filtration and washed with IPA. Dried the material at 40-45° C. to obtain l-Norepinephrine Bitartrate Monohydrate (82 gm) having high enantiomeric purity.
      HPLC Purity: 99.85%
      Chiral Purity: 99.87%
      Specific Optical rotation: −11.0°

Example-9

      The following table sets forth the high purity of the l-Norepinephrine Bitartrate monohydrate of the invention as compared with prior art references.
[TABLE-US-00001]   Referencel-Norepinephrine  Example-2Bitartrate U.S. Pat. No.(JACS, 1948,monohydrate 2,774,789Page-2067-68,of the presentPurity CriteriaExample-AExample-a)invention  Optical purity of l-68.45%77.14%99.87%NorepinephrineBitartratemonohydrateSpecific Optical−6.33°−10.4°−11.0°rotation(Limit: −10°to −12°) 
      It is evident from the above table that the compound of the present invention has substantially improved optical purity.

PATENTCN-102525895

Publication numberPriority datePublication dateAssigneeTitleCN101053557A *2006-04-132007-10-17邵长青Noradrenaline bitartrate medicine composition frozen dried powder injectionCN102335123A *2010-07-162012-02-01上海禾丰制药有限公司Noradrenaline bitartrate injection and preparation technology thereofPublication numberPriority datePublication dateAssigneeTitleEP3110399B12014-02-272018-01-10Sintetica S.A.Process for producing a stable low concentration, injectable solution of noradrenalineFamily To Family CitationsCN109394683A *2018-12-072019-03-01远大医药(中国)有限公司A kind of preparation method of noradrenaline bitartrate injection

References

  1. ^ Andersen, A. M. (1975). “Structural Studies of Metabolic Products of Dopamine. IV. Crystal and Molecular Structure of (−)-Noradrenaline”Acta Chem. Scand. 29b: 871–876. doi:10.3891/acta.chem.scand.29b-0871.
  2. Jump up to:a b c d e f g h i j “Norepinephrine Bitartrate”. The American Society of Health-System Pharmacists. Archived from the original on 26 March 2017. Retrieved 26 March 2017.
  3. ^ Latifi, Rifat (2016). Surgical Decision Making: Beyond the Evidence Based Surgery. Springer. p. 67. ISBN 9783319298245Archived from the original on 2017-03-27.
  4. ^ Encyclopedia of the Neurological Sciences. Academic Press. 2014. p. 224. ISBN 9780123851581Archived from the original on 2017-03-27.
  5. ^ Rhodes, Andrew; Evans, Laura E (March 2017). “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2016” (PDF). Critical Care Medicine45 (3): 486–552. doi:10.1097/CCM.0000000000002255hdl:10281/267577PMID 28098591S2CID 52827184We recommend norepinephrine as the first-choice vasopressor (strong recommendation, moderate quality of evidence).
  6. ^ De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, Brasseur A, Defrance P, Gottignies P, Vincent JL (March 2010). “Comparison of dopamine and norepinephrine in the treatment of shock”. The New England Journal of Medicine362 (9): 779–89. doi:10.1056/nejmoa0907118PMID 20200382.
  7. ^ I Moore, Joanne (6 December 2012). Pharmacology (3 ed.). Springer Science and Business Media. p. 39. ISBN 9781468405248. Retrieved 19 November 2017.
  8. ^ “CV Physiology | Circulating Catecholamines”cvphysiology.com. Retrieved 2019-02-27.
  9. ^ Sacha, Pollard; Stephenie, B Edwin; Cesar, Alaniz (July 2015). “Vasopressor and Inotropic Management Of Patients With Septic Shock”Physical Therapy40 (7): 449–450. PMC 4495871PMID 26185405.

External links

Skeletal formula of noradrenaline
Ball-and-stick model of the zwitterionic form of noradrenaline found in the crystal structure[1]
Clinical data
Trade namesLevarterenol, Levophed, Norepin, other
Other namesNoradrenaline
(R)-(–)-Norepinephrine
l-1-(3,4-Dihydroxyphenyl)-2-aminoethanol
AHFS/Drugs.comMonograph
License dataUS DailyMedNorepinephrineUS FDANorepinephrine
Pregnancy
category
AU: B3
Routes of
administration
Intravenous
ATC codeC01CA03 (WHO)
Physiological data
Source tissuesLocus coeruleussympathetic nervous systemadrenal medulla
Target tissuesSystem-wide
Receptorsα1α2β1β3
AgonistsSympathomimetic drugsclonidineisoprenaline
AntagonistsTricyclic antidepressantsBeta blockersantipsychotics
MetabolismMAO-ACOMT
Legal status
Legal statusAU: S4 (Prescription only)CA℞-onlyUK: POM (Prescription only)US: ℞-only
Pharmacokinetic data
MetabolismMAO-ACOMT
ExcretionUrine (84–96%)
Identifiers
showIUPAC name
CAS Number51-41-2 
PubChem CID439260
IUPHAR/BPS505
DrugBankDB00368 
ChemSpider388394 
UNIIX4W3ENH1CV
KEGGD00076 as salt: D05206 
ChEBICHEBI:18357 
ChEMBLChEMBL1437 
Chemical and physical data
FormulaC8H11NO3
Molar mass169.180 g·mol−1
3D model (JSmol)Interactive image
Density1.397±0.06 g/cm3
Melting point217 °C (423 °F) (decomposes)
Boiling point442.6 °C (828.7 °F) ±40.0°C
hideSMILESOc1ccc(cc1O)[C@@H](O)CN
hideInChIInChI=1S/C8H11NO3/c9-4-8(12)5-1-2-6(10)7(11)3-5/h1-3,8,10-12H,4,9H2/t8-/m0/s1 Key:SFLSHLFXELFNJZ-QMMMGPOBSA-N 

////////Norepinephrine bitartrate, ARTERELOL, a-Adrenergic Agonist, Antihypotensive,  levarterenol, Adrenor,  Levophed,

#Norepinephrine bitartrate, #ARTERELOL, #a-Adrenergic Agonist, #Antihypotensive, #levarterenol, #Adrenor,  #Levophed,

O.O[C@H]([C@@H](O)C(O)=O)C(O)=O.NC[C@H](O)C1=CC(O)=C(O)C=C1

Pyridostigmine


Pyridostigmine.svg
ChemSpider 2D Image | Pyridostigmine | C9H13N2O2

Pyridostigmine 

  • Molecular FormulaC9H13N2O2
  • Average mass181.211 Da

155-97-5[RN]3-[(Dimethylcarbamoyl)oxy]-1-methylpyridinium
3-Dimethylcarbamoyloxy-1-methyl-pyridinium5-21-02-00078 (Beilstein Handbook Reference)[Beilstein]

Pyridostigmine Bromide

 Pyridostigmine BromideCAS Registry Number: 101-26-8CAS Name: 3-[[(Dimethylamino)carbonyl]oxy]-1-methylpyridinium bromideAdditional Names: 3-hydroxy-1-methylpyridinium bromide dimethylcarbamate; 1-methyl-3-hydroxypyridinium bromide dimethylcarbamate; 3-(dimethylcarbamyloxy)-1-methylpyridinium bromideManufacturers’ Codes: Ro-1-5130Trademarks: Kalymin (Temmler); Mestinon (Roche); Regonol (Organon)Molecular Formula: C9H13BrN2O2Molecular Weight: 261.12Percent Composition: C 41.40%, H 5.02%, Br 30.60%, N 10.73%, O 12.25%Literature References: Reversible inhibitor of acetylcholinesterase. 
Prepn: Urban, US2572579 (1951 to Hoffmann-La Roche). Mechanism of protective effect in soman poisoning: X. Deyi et al.,Fundam. Appl. Toxicol.1, 217 (1981). Evaluation of effect on neuromuscular function: M. Glikson et al.,ibid.16, 288 (1991). Evaluation of side effects profile under desert conditions: J. E. Cook et al.,Mil. Med.157, 250 (1992). Review of prophylactic effect in nerve agent poisoning: R. M. Dawson, J. Appl. Toxicol.14, 317 (1994).Properties: Shiny, hygroscopic crystals from abs ethanol, mp 152-154°. Freely sol in water, alcohol. Practically insol in ether, acetone, benzene. Aq solns may be sterilized by autoclaving with steam.Melting point: mp 152-154°Therap-Cat: Cholinergic; in treatment of myasthenia gravis. Pre-exposure antidote to chemical warfare agents.Keywords: Cholinergic.

Pyridostigmine is a medication used to treat myasthenia gravis.[1] It is also used together with atropine to end the effects of neuromuscular blocking medication of the non-depolarizing type.[2] It is typically given by mouth but can also be used by injection.[2] The effects generally begin within 45 minutes and last up to 6 hours.[2]

Common side effects include nausea, diarrhea, frequent urination, and abdominal pain.[2] More severe side effects include low blood pressure, weakness, and allergic reactions.[2] It is unclear if use in pregnancy is safe for the fetus.[2] Pyridostigmine is an acetylcholinesterase inhibitor in the cholinergic family of medications.[2] It works by blocking the action of acetylcholinesterase and therefore increases the levels of acetylcholine.[2]

Pyridostigmine was patented in 1945 and came into medical use in 1955.[3] It is on the World Health Organization’s List of Essential Medicines.[4] Pyridostigmine is available as a generic medication.[2]

Medical uses

Pyridostigmine is used to treat muscle weakness in people with myasthenia gravis or forms of congenital myasthenic syndrome and to combat the effects of curariform drug toxicity. Pyridostigmine bromide has been FDA approved for military use during combat situations as an agent to be given prior to exposure to the nerve agent Soman in order to increase survival. Used in particular during the first Gulf War, pyridostigmine bromide has been implicated as a causal factor in Gulf War syndrome.[5]

Pyridostigmine sometimes is used to treat orthostatic hypotension.[6] It may also be of benefit in chronic axonal polyneuropathy.[7]

It is also being prescribed ‘off-label’ for the postural tachycardia syndrome as well as complications resulting from Ehlers–Danlos syndrome.[7][8]

Contraindications

Pyridostigmine bromide is contraindicated in cases of mechanical intestinal or urinary obstruction and should be used with caution in patients with bronchial asthma.[9][10]

Side effects

Common side effects include:[9]

  • Sweating
  • Diarrhea
  • Nausea
  • Vomiting
  • Abdominal cramps
  • Increased salivation
  • Tearing
  • Increased bronchial secretions
  • Constricted pupils
  • Facial flushing due to vasodilation
  • Erectile dysfunction

Additional side effects include:[9]

  • Muscle twitching
  • Muscle cramps and weakness

Mechanism of action

Pyridostigmine inhibits acetylcholinesterase in the synaptic cleft, thus slowing down the hydrolysis of acetylcholine. It is a quaternary carbamate inhibitor of cholinesterase that does not cross the blood–brain barrier which carbamylates about 30% of peripheral cholinesterase enzyme. The carbamylated enzyme eventually regenerates by natural hydrolysis and excess ACh levels revert to normal.

The ACh diffuses across the synaptic cleft and binds to receptors on the post synaptic membrane, causing an influx of Na+, resulting in depolarization. If large enough, this depolarization results in an action potential. To prevent constant stimulation once the ACh is released, an enzyme called acetylcholinesterase is present in the endplate membrane close to the receptors on the post synaptic membrane, and quickly hydrolyses ACh.

Names

Pyridostigmine bromide is available under the trade names Mestinon (Valeant Pharmaceuticals), Regonol and Gravitor (SUN Pharma).

Chemistry

Pyridostigmine, 3-[(dimethylaminocarbonyl)oxy]-1-methyl pyridinium bromide, is synthesized from 3-hydroxypyridine, which is reacted with dimethylaminocarbamoyl chloride, which gives 3-(dimethylaminocarbamoyl)pyridine. The last is reacted with methylbromide, giving pyridostigmine.

Syn

youtube

SYN

Method of synthesis

i. 3-hydroxypiridine is reacted with dimethylaminocarbamoyl chloride to give 3-(dimethylaminocarbamoyl)pyridine.

ii. The above formed compound is reacted with methylbromide to produce pyridostigmine. [2]

File:Synthese von Pyridostigmin.svg - Wikimedia Commons

CLIP

Paper

Journal of Biological Chemistry (1961), 236, 1498-500.

 Zeitschrift fuer Klinische Medizin (1985) (1986), 41(7), 495-8

Zhonghua Yaoxue Zazhi (1993), 45(6), 601-14.

Trends in Organic Chemistry (2011), 15, 25-31.

PATENT

WO 9822458

PATENT

WO 2008074816

https://patents.google.com/patent/WO2008074816A1/en

References

  1. ^ World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 429. hdl:10665/44053ISBN 9789241547659.
  2. Jump up to:a b c d e f g h i “Neostigmine Bromide”. The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  3. ^ Fischer, Janos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 540. ISBN 9783527607495Archived from the original on 2016-12-20.
  4. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. ^ Golomb BA (March 2008). “Acetylcholinesterase inhibitors and Gulf War illnesses”Proceedings of the National Academy of Sciences of the United States of America105 (11): 4295–300. Bibcode:2008PNAS..105.4295Gdoi:10.1073/pnas.0711986105JSTOR 25461411PMC 2393741PMID 18332428Lay summary – Reuters (March 10, 2008).
  6. ^ Gales BJ, Gales MA (2007). “Pyridostigmine in the treatment of orthostatic intolerance”. Annals of Pharmacotherapy41 (2): 314–8. doi:10.1345/aph.1H458PMID 17284509S2CID 22855759.
  7. Jump up to:a b Gales BJ, Gales MA (February 2007). “Pyridostigmine in the treatment of orthostatic intolerance”. The Annals of Pharmacotherapy41 (2): 314–8. doi:10.1345/aph.1H458PMID 17284509S2CID 22855759.
  8. ^ Kanjwal K, Karabin B, Sheikh M, et al. (June 2011). “Pyridostigmine in the treatment of postural orthostatic tachycardia: a single-center experience”. Pacing and Clinical Electrophysiology34 (6): 750–5. doi:10.1111/j.1540-8159.2011.03047.xPMID 21410722S2CID 20405336.
  9. Jump up to:a b c Mestinon | Home Archived 2008-05-13 at the Wayback Machine
  10. ^ Mestinon Official FDA information, side effects and uses Archived 2008-05-24 at the Wayback Machine

External links[

Clinical data
Trade namesMestinon, others
AHFS/Drugs.comMonograph
MedlinePlusa682229
Pregnancy
category
AU: C
Routes of
administration
by mouth, intravenous
ATC codeN07AA02 (WHO)
Legal status
Legal statusUK: POM (Prescription only)US: ℞-only
Pharmacokinetic data
Bioavailability7.6 +/- 2.4%
Elimination half-life1.78 +/- 0.24hrs
Excretionkidney
Identifiers
showIUPAC name
CAS Number155-97-5 
PubChem CID4991
DrugBankDB00545 
ChemSpider4817 
UNII19QM69HH21
KEGGD00487 
ChEMBLChEMBL1115 
CompTox Dashboard (EPA)DTXSID20165786 
Chemical and physical data
FormulaC9H13N2O2
Molar mass181.215 g·mol−1
3D model (JSmol)Interactive image
hideSMILESO=C(Oc1ccc[n+](c1)C)N(C)C
hideInChIInChI=1S/C9H13N2O2/c1-10(2)9(12)13-8-5-4-6-11(3)7-8/h4-7H,1-3H3/q+1 Key:RVOLLAQWKVFTGE-UHFFFAOYSA-N 

/////////////Pyridostigmine,

Buspirone


Buspirone 200.svg
Buspirone

Buspirone

  • Molecular FormulaC21H31N5O2
  • Average mass385.503 Da
  • буспиронبوسبيرون丁螺酮

251-489-4[EINECS]253-072-2[EINECS]36505-84-7[RN]8-[4-(4-Pyrimidin-2-yl-piperazin-1-yl)-butyl]-8-aza-spiro[4.5]decane-7,9-dione8-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione

  • 8-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione
  • Buspin
  • Buspirone
  • Spitomin

BuspironeCAS Registry Number: 36505-84-7CAS Name: 8-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dioneMolecular Formula: C21H31N5O2Molecular Weight: 385.50Percent Composition: C 65.43%, H 8.11%, N 18.17%, O 8.30%Literature References: Non-benzodiazepine anxiolytic; 5-hydroxytryptamine (5-HT1) receptor agonist. Prepn: Y. H. Wu et al.,J. Med. Chem.15, 477 (1972); Y. H. Wu, J. W. Rayburn, DE2057845 (1971 to Bristol-Myers); eidem,US3717634 (1973 to Mead-Johnson). Pharmacology: L. E. Allen et al.,Arzneim.-Forsch.24, 917 (1974). Comparison with diazepam in treatment of anxiety: H. L. Goldberg, R. J. Finnerty, Am. J. Psychiatry136, 1184 (1979); A. F. Jacobson et al.,Pharmacotherapy5, 290 (1985). Nonsynergistic effect with alcohol: T. Seppala et al.,Clin. Pharmacol. Ther.32, 201 (1982). Disposition and metabolism: S. Caccia et al.,Xenobiotica13, 147 (1983). Series of articles on chemistry, pharmacology, addictive potential, and clinical trials: J. Clin. Psychiatry43, pp 1-116 (1982); on pharmacology, safety and clinical comparison with clorazepate: Am. J. Med.80, Suppl. 3B, 1-51 (1986). Review of pharmacology and therapeutic efficacy: K. L. Goa, A. Ward, Drugs32, 114-129 (1986). Review: M. W. Jann, Pharmacotherapy8, 100-116 (1988); D. P. Taylor, FASEB J.2, 2445-2452 (1988). 
Derivative Type: HydrochlorideCAS Registry Number: 33386-08-2Trademarks: Ansial (Vita); Ansiced (Abello); Axoren (Glaxo Wellcome); Bespar (BMS); Buspar (BMS); Buspimen (Menarini); Buspinol (Zdravlje); Buspisal (Lesvi); Narol (Almirall)Molecular Formula: C21H31N5O2.HClMolecular Weight: 421.96Percent Composition: C 59.77%, H 7.64%, N 16.60%, O 7.58%, Cl 8.40%Properties: Crystals from abs ethanol, mp 201.5-202.5°. LD50 i.p. in rats: 136 mg/kg (Allen).Melting point: mp 201.5-202.5°Toxicity data: LD50 i.p. in rats: 136 mg/kg (Allen) 
Therap-Cat: Anxiolytic.Keywords: Anxiolytic; Arylpiperazines; Serotonin Receptor Agonist.

Buspirone, sold under the brand name Buspar, among others, is a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder.[9][10] Benefits support its short term use.[11] It has not been found to be effective in treating psychosis.[9] It is taken by mouth, and it may take up to four weeks to have an effect.[9][10]

Common side effects of buspirone include nausea, headaches, dizziness, and difficulty concentrating.[9][11] Serious side effects may include hallucinationsserotonin syndrome, and seizures.[11] Its use in pregnancy appears to be safe but has not been well studied, while use during breastfeeding is not recommended.[11][12] It is a serotonin 5-HT1A receptor agonist.[2]

Buspirone was first made in 1968 and approved for medical use in the United States in 1986.[9][10] It is available as a generic medication.[11] In 2018, it was the 92nd most-commonly prescribed medication in the United States, with more than 8 million prescriptions.[13][14]

Medical uses

Anxiety

Buspirone is used for the short-term treatment of anxiety disorders or symptoms of anxiety.[15][16][17][18][19] It is generally less preferred than selective serotonin reuptake inhibitors (SSRIs).[10]

Buspirone has no immediate anxiolytic effects, and hence has a delayed onset of action; its full clinical effectiveness may require 2–4 weeks to manifest itself.[20] The drug has been shown to be similarly effective in the treatment of generalized anxiety disorder (GAD) to benzodiazepines including diazepamalprazolamlorazepam, and clorazepate.[2] Buspirone is not known to be effective in the treatment of other anxiety disorders besides GAD,[21] although there is some limited evidence that it may be useful in the treatment of social phobia as an adjunct to selective serotonin reuptake inhibitors (SSRIs).[2][22]

Other uses

Sexual dysfunction

There is some evidence that buspirone on its own may be useful in the treatment of hypoactive sexual desire disorder (HSDD) in women.[23]

Miscellaneous

Buspirone is not effective as a treatment for benzodiazepine withdrawalbarbiturate withdrawal, or alcohol withdrawal/delirium tremens.[24]

SSRI and SNRI antidepressants such as paroxetine and venlafaxine may cause jaw pain/jaw spasm reversible syndrome (although it is not common), and buspirone appears to be successful in treating bruxism on SSRI/SNRI-induced jaw clenching.[25][26]

Contraindications

Buspirone has these contraindications:[27][28]

Side effects

Main article: List of side effects of buspirone

Known side effects associated with buspirone include dizzinessheadachesnauseanervousness, and paresthesia.[2] Buspirone is relatively well tolerated, and is not associated with sedationcognitive and psychomotor impairmentmuscle relaxationphysical dependence, or anticonvulsant effects.[2] In addition, buspirone does not produce euphoria[20] and is not a drug of abuse.[16]

It is unclear if there is a risk of tardive dyskinesia or other movement disorders with buspirone.[9]

Overdose

Buspirone appears to be relatively benign in cases of single-drug overdose, although no definitive data on this subject appear to be available.[29] In one clinical trial, buspirone was administered to healthy male volunteers at a dosage of 375 mg/day, and produced side effects including nauseavomitingdizzinessdrowsinessmiosis, and gastric distress.[15][16][18] In early clinical trials, buspirone was given at dosages even as high as 2,400 mg/day, with akathisiatremor, and muscle rigidity observed.[30] Deliberate overdoses with 250 mg and up to 300 mg buspirone have resulted in drowsiness in about 50% of individuals.[30] One death has been reported in association with 450 mg buspirone together with alprazolamdiltiazemalcoholcocaine.[30]

Interactions

Buspirone has been shown in vitro to be metabolized by the enzyme CYP3A4.[8] This finding is consistent with the in vivo interactions observed between buspirone and these inhibitors or inducers of cytochrome P450 3A4 (CYP3A4), among others:[27]

Elevated blood pressure has been reported when buspirone has been administered to patients taking monoamine oxidase inhibitors (MAOIs).[27]

Pharmacology

Pharmacodynamics

SiteKi (nM)SpeciesRef
5-HT1A3.98–214
21 (median)
Human[33][34]
5-HT1B>100,000Rat[35]
5-HT1D22,000–42,700Human[36][37]
5-HT2A138
759–1,300
Human
Rat
[38]
[35][38]
5-HT2B214Human[38]
5-HT2C490
1,100–6,026
Human
Rat/pig
[38]
[35][38]
5-HT3>10,000Rat[39][40]
5-HT4>10,000Rat[40]
5-HT6398Mouse[41]
5-HT7375–381Rat[42][43]
α11,000Rat[35]
α26,000Rat[44]
α2A7.3 (1-PP)Human[35]
β8,800Rat[35]
D133,000Rat[35]
D2484
240
Human
Rat
[45]
[35]
D398Human[45]
D429Human[45]
mACh38,000Rat[35]
GABAA
(BDZ)
>100,000Rat[35]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Buspirone acts as an agonist of the serotonin 5-HT1A receptor with high affinity.[2][35] It is a partial agonist of both presynaptic 5-HT1A receptors, which are inhibitory autoreceptors, and postsynaptic 5-HT1A receptors.[2] It is thought that the main effects of buspirone are mediated via its interaction with the presynaptic 5-HT1A receptor, thus reducing the firing of serotonin-producing neurons.[2] Buspirone also has lower affinities for the serotonin 5-HT2A5-HT2B5-HT2C5-HT6, and 5-HT7 receptors.[33]

In addition to binding to serotonin receptors, buspirone is an antagonist of the dopamine D2 receptor with weak affinity.[2][35] It preferentially blocks inhibitory presynaptic D2 autoreceptors, and antagonizes postsynaptic D2 receptors only at higher doses.[2] In accordance, buspirone has been found to increase dopaminergic neurotransmission in the nigrostriatal pathway at low doses, whereas at higher doses, postsynaptic D2 receptors are blocked and antidopaminergic effects such as hypoactivity and reduced stereotypy, though notably not catalepsy, are observed in animals.[2] Buspirone has also been found to bind with much higher affinity to the dopamine D3 and D4 receptors, where it is similarly an antagonist.[45]

A major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP), occurs at higher circulating levels than buspirone itself and is known to act as a potent α2-adrenergic receptor antagonist.[44][46][47] This metabolite may be responsible for the increased noradrenergic and dopaminergic activity observed with buspirone in animals.[46][48] In addition, 1-PP may play an important role in the antidepressant effects of buspirone.[48] Buspirone also has very weak and probably clinically unimportant affinity for the α1-adrenergic receptor.[35][49] However, buspirone has been reported to have shown “significant and selective intrinsic efficacy” at the α1-adrenergic receptor expressed in a “tissue- and species-dependent manner”.[49]

Unlike benzodiazepines, buspirone does not interact with the GABAA receptor complex.[2][50]

Pharmacokinetics

Buspirone has a low oral bioavailability of 3.9% relative to intravenous injection due to extensive first-pass metabolism.[2] The time to peak plasma levels following ingestion is 0.9 to 1.5 hours.[2] It is reported to have an elimination half-life of 2.8 hours,[2] although a review of 14 studies found that the mean terminal half-life ranged between 2 and 11 hours, and one study even reported a terminal half-life of 33 hours.[4] Buspirone is metabolized primarily by CYP3A4, and prominent drug interactions with inhibitors and inducers of this enzyme have been observed.[7][8] Major metabolites of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP.[4][5][6] 6-Hydroxybuspirone has been identified as the predominant hepatic metabolite of buspirone, with plasma levels that are 40-fold greater than those of buspirone after oral administration of buspirone to humans.[5] The metabolite is a high-affinity partial agonist of the 5-HT1A receptor (Ki = 25 nM) similarly to buspirone, and has demonstrated occupancy of the 5-HT1A receptor in vivo.[5] As such, it is likely to play an important role in the therapeutic effects of buspirone.[5] 1-PP has also been found to circulate at higher levels than those of buspirone itself and may similarly play a significant role in the clinical effects of buspirone.[46][48]

Phase I Metabolism of buspirone in humans[51][52][8]

History

Buspirone was first synthesized, by a team at Mead Johnson, in 1968,[21] but was not patented until 1975.[54][55] It was initially developed as an antipsychotic drug acting on the D2 receptor, but was found to be ineffective in the treatment of psychosis; it was then used as an anxiolytic instead.[2] In 1986, Bristol-Myers Squibb gained FDA approval for buspirone in the treatment of GAD.[21][56] The patent placed on buspirone expired in 2001 and it is now available as a generic drug.

Society and culture

Buspar (buspirone) 10-mg tablets

Generic names

Buspirone is the INNBANDCF, and DCIT of buspirone, while buspirone hydrochloride is its USANBANM, and JAN.[1][57][58][59]

Brand name

Buspirone was primarily sold under the brand name Buspar.[57][59] Buspar is currently listed as discontinued by the US Federal Drug Administration.[60] In 2010, in response to a citizen petition, the US FDA determined that Buspar was not withdrawn for sale because of reasons of safety or effectiveness.[61]

2019 shortage

Due to interrupted production at a Mylan Pharmaceuticals plant in Morgantown, West Virginia, the United States experienced a shortage of buspirone in 2019.[62]

Research

Some tentative research supports other uses such as the treatment of depression and behavioral problems following brain damage.[2]

Chemistry

Buspirone is a member of the azapirone chemical class, and consists of azaspirodecanedione and pyrimidinylpiperazine components linked together by a butyl chain.

Analogues

Structural analogues of buspirone include other azapirones like gepironeipsapironeperospirone, and tandospirone.[53]

Synthesis

Buspirone synthesis:[54] DE 2057845 U.S. Patent 3,717,634 U.S. Patent 3,907,801 U.S. Patent 3,976,776

Alkylation of 1-(2-pyrimidyl)piperazine (1) with 3-chloro-1-cyanopropane (2, 4-chlorobutyronitrile) gives 3, which is reduced either by hydrogenation over Raney nickel catalyst, or with LAH. The resulting 1° amine (4) from the previous step is then reacted with 3,3-tetramethyleneglutaric anhydride (5, 8-Oxaspiro[4.5]decane-7,9-dione) in order to yield buspirone (6).

PAPERS

  1. Koziol, Anna E.; Acta Crystallographica, Section E: Structure Reports Online 2006, V62(12), Po5616-o5618 
  2. Mou, Jie; Organic Preparations and Procedures International 2008, V40(4), P391-394 
  3. Kairisalo, Pekka Juhani; FI 72975 B 1987 
  4. Journal of medicinal chemistry (1983), 26(2), 194-203
  5. Journal of medicinal chemistry (1986), 29(8), 1476-82.
  6. Medicinal research reviews (1990), 10(3), 283-326.
  7. Heterocycles (1993), 36(7), 1463-9
  8. Journal of medicinal chemistry (1996), 39(5), 1125-9.
  9. Journal of medicinal chemistry (1996), 39(16), 3195-202.
  10. Nature Catalysis, 3(10), 843-850; 2020

PAPER

https://pubs.rsc.org/en/content/articlelanding/2019/GC/C8GC03328E#!divAbstract

  1. Green Chemistry, 21(1), 59-63; 2019

Abstract

A continuous flow method for the direct conversion of alcohols to amines via a hydrogen borrowing approach is reported. The method utilises a low loading (0.5%) of a commercial catalyst system ([Ru(p-cymene)Cl2]2 and DPEPhos), reagent grade solvent and is selective for primary alcohols. Successful methylation of amines using methanol and the direct dimethylamination of alcohols using commercial dimethylamine solution are reported. The synthesis of two pharmaceutical agents Piribedil (5) and Buspirone (25) were accomplished in good yields employing these new methods.

Graphical abstract: Fast continuous alcohol amination employing a hydrogen borrowing protocol

http://www.rsc.org/suppdata/c8/gc/c8gc03328e/c8gc03328e2.pdf
8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-7,9-dione (23): A solution of 3,3-tetramethyleneglutaric anhydride (0.25 mol/L in THF) was combined in a tee piece with a solution of 4-amino-1-butanol (0.25 mol/L in THF) and reacted in a 20 mL reactor coil (stainless steel, 20 min residence time) heated at 250 °C. The output was concentrated in vacuo and the residue purified by column chromatography on silica gel to afford the product in 84% yield (Rf = 0.31, 63% DCM/AcOEt). 1H NMR (400 MHz, CDCl3) δ = 3.78 (t, J = 7.2 Hz, 2H), 3.65 (t, J = 6.0 Hz, 2H), 2.58 (s, 4H), 1.77 – 1.64 (m, 4H), 1.64 – 1.53 (m, 4H), 1.53 – 1.43 (m, 4H). 13C NMR (100 MHz, CDCl3) δ = 172.33, 62.28, 44.87, 39.47, 39.14, 37.54, 29.81, 24.35, 24.17. HRMS for [C13H22NO3] + calculated 240.1594 found 240.1605. 

8-(4-(4-(pyrimidin-2-yl)piperazin-1-yl)butyl)-8-azaspiro[4.5]decane-7,9-dione (Buspirone, 25): The flow system was flushed with THF, the back-pressure regulator was set to 50 bar, and the coil reactor heated to 250 °C. Then a solution (10 mL overall volume) containing 1-(2-pyrimidyl)piperazine (2 mmol), 8-(4-hydroxybutyl)- 8-azaspiro[4.5]decane-7,9-dione (23) (2 mmol), dichloro(p-cymene)ruthenium(II) dimer (0.08 mmol) and bis[(2- diphenylphosphino)phenyl] ether (DPEPhos, 0.17 mmol) was pumped at 0.8 ml/min through a heated coil (8 mL, Phoenix reactor). The output solution obtained in steady state (monitored using the FlowUV) was concentrated in vacuo and purified by column chromatography on silica gel to afford the desired product in 76% yield (Rf = 0.29, 5% MeOH/DCM). 1H NMR (400 MHz, CDCl3) δ = 8.31 (d, J = 4.7 Hz, 2H), 6.48 (t, J = 4.7 Hz, 1H), 3.84 (t, J = 5.1 Hz, 4H), 3.79 (t, J = 6.8 Hz, 2H), 2.60 (s, 4H), 2.50 (t, J = 5.1 Hz, 4H), 2.40 (t, J = 6.8 Hz, 2H), 1.79 – 1.65 (m, 4H), 1.65 – 1.42 (m, 8H). 13C NMR (100 MHz, CDCl3) δ = 172.19, 161.63, 157.68, 109.77, 58.31, 53.06, 44.92, 43.60, 39.48, 39.35, 37.56, 26.04, 24.19, 24.19. HRMS for [C21H32N5O2] + calculated 386.2551 found 386.2570.

PAPER

Organic Preparations and Procedures International, 40(4), 391-394; 2008

https://www.tandfonline.com/doi/abs/10.1080/00304940809458099

PATENTS

US 3907801

ES 526304

EP 395192

EP 565274

EP 634411

EP 680961

US 5521313

Indian Pat. Appl., 2011MU01860,

PATENTS

WO 2014152737

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014152737

Syn

J Med Chem 1972,15(5),477-479

DE 2057845; FR 2073406; GB 1332194; US 3717634

The condensation of 1-(2-pyrimidinyl)piperazine (I) with 3-chloro-1-cyanopropane (II) by means of Na2CO3 in n-butanol gives 4-(2-pyrimidinyl)-1-(3-cyanopropyl)piperazine (III). This product is reduced with LiAlH4 or with H2 and Raney-Ni yielding 4-(2-pyrimidinyl)-1-(4-aminobutyl)piperazine (IV), which is finally condensed with 8-oxaspiro[4.5]decane-7,9-dione-(3,3-tetramethylene-glutaric anhydride) (V) in pyridine.

CLIP

Anxiolytics (Tranquilizers)

R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006

Buspirone

Buspirone, 8-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-8-azaspiro [4,5] decan-7,9-dione (5.2.6), is synthesized by the reaction of 1-(2-pyrimidyl)-4-(4-aminobutyl)piperazine (5.2.4) with 8-oxaspiro[4,5]decan-7,9-dione (5.2.5). In turn, 1-(2-pyrimidyl)-4-(4-aminobutyl)piperazine (5.2.4) is synthesized by the reaction of 1-(2-pyrimidyl)piperazine with 4-chlorobutyronitrile, giving 4-(2-pyrimidyl)-1-(3-cyanopropyl)piperazine (5.2.3), which is hydrogenated with Raney nickel into buspirone (5.2.4) [51–55].

Buspirone is an extremely specific drug that could possibly represent a new chemical class of anxiolytics—azaspirones. As an anxiolytic, its activity is equal to that of benzodiazepines; however, it is devoid of anticonvulsant and muscle relaxant properties, which are characteristic of benzodiazepines. It does not cause dependence or addiction. The mechanism of its action is not conclusively known. It does not act on the GABA receptors, which occurs in benzodiazepine use; however, it has a high affinity for seratonin (5-HT) receptors and a moderate affinity for dopamine (D2) receptors. Buspirone is effective as an anxiolytic. A few side effects of buspirone include dizziness, drowsiness, headaches, nervousness, fatigue, and weakness. This drug is intended for treatment of conditions of anxiety in which stress, muscle pain, rapid heart rate, dizziness, fear, etc. are observed; in other words, conditions of anxiety not associated with somewhat common, usual, and everyday stress. Synonyms for buspirone are anizal, axoren, buspar, buspimen, buspinol, narol, travin, and others.

CLIP

Applications of Biocatalysis for Pharmaceuticals and Chemicals

Ramesh N. Patel, in Organic Synthesis Using Biocatalysis, 2016

5.2 Enzymatic Preparation of 6-Hydroxybuspirone

Buspirone (Buspar®59, Figure 11.17) is a drug used for the treatment of anxiety and depression, thought to produce its effects by binding to the serotonin 5HT1A receptor [114–116]. Mainly as a result of hydroxylation reactions, it is extensively converted to various metabolites and blood concentrations return to low levels a few hours after dosing [117]. A major metabolite, 6-hydroxybuspirone, produced by the action of liver cytochrome P450 CYP3A4, was present at much higher concentrations in human blood than buspirone itself. For development of 6-hydroxybuspirone as a potential antianxiety drug, preparation and testing of the two enantiomers as well as the racemate was of interest. An enantioselective microbial reduction process was developed for the reduction of 6-oxobuspirone 60 to (R)-6-hydroxybuspirone 61a or (S)-6-hydroxybuspitone 61b. About 150 microbial cultures were screened for the enantioselective reduction of 60Rhizopus stolonifer SC 13898, Neurospora crassa SC 13816, Mucor racemosus SC 16198, and Pseudomonas putida SC 13817 gave >50% reaction yields and >95% ee of (S)-6-hydroxybuspirone 61a. The yeast strains Hansenula polymorpha SC 13845 and Candida maltosa SC 16112 gave (R)-6-hydroxybuspirone in >60% reaction yield and >97% ee [118]. The NADPH-dependent (R)-reductase (RHBR) from H. polymorpha SC 13845 was purified to homogeneity, its N-terminal and internal amino acid sequences were determined and the corresponding gene was cloned and expressed in E. coli. To regenerate the NADPH required for reduction, glucose-6-phosphate dehydrogenase gene from Saccharomyces cerevisiae was cloned and coexpressed in the same E. coli strain. Recombinant cultures coexpressing (R)-reductase (RHBR) and glucose 6-phosphate dehydrogenase catalyzed the reduction of 6-ketobuspirone to (R)-6-hydroxybuspirone 61a in 99% yield and 99.9% ee at 50 g/L substrate input [119].

The NADH-dependent (S)-reductase (SHBR) from P. putida SC 16269 was also purified to homogeneity, its N-terminal and internal amino acid sequences were determined and the corresponding gene was cloned and expressed in E. coli. To regenerate the NADH required for reduction, the NAD+ dependent formate dehydrogenase gene from Pichia pastoris was also cloned and co-expressed in the same E. coli strain. Recombinant E. coli coexpressing (S)-reductase and formate dehydrogenase was used to catalyze the reduction of 6-ketobuspirone to (S)-6-hydroxybuspirone 61b, in >98% yield and >99.8% ee at 50 g/L substrate input [119].

PATENT

https://patents.google.com/patent/US6686361

The present invention relates to methods of treating anxiety and depression using R-6-hydroxy-buspirone and pharmaceutical compositions containing R-6-hydroxy-buspirone.

Buspirone, chemically: 8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-8-azaspiro(4,5)-decane-7,9-dione, is approved for the treatment of anxiety disorders and depression by the United States Food and Drug Administration. It is available under the trade name BUSPAR® from Bristol-Myers Squibb Company.

Studies have shown that buspirone is extensively metabolized in the body. (See, for example, Mayol, et al., Clin. Pharmacol. Ther., 37, p. 210, 1985). One of the metabolites is 6-hydroxy-8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-8-azaspiro(4,5)-decane-7,9-dione having Formula I. This metabolite is also known as BMS 28674, BMS 442608, or

Figure US06686361-20040203-C00001

as 6-hydroxy-buspirone. This compound is believed to be the active metabolite of buspirone and its use in treating anxiety disorders and depression is disclosed in U.S. Pat. No. 6,150,365. The specific stereochemistry of 6-hydroxy-buspirone has not been described previously. Neither racemic 6-hydroxy-buspirone nor its enantiomers are commercially available at the present time.

Preclinical studies demonstrate that 6-hydroxy-buspirone, like buspirone, demonstrates a strong affinity for the human 5-HT1A receptor. In functional testing, 6-hydroxy-buspirone produced a dose-dependent anxiolytic response in the rat pup ultrasonic vocalization test, a sensitive method for assessment of anxiolytic and anxiogenic effects (Winslow and Insel, 1991, Psychopharmacology, 105:513-520).

Clinical studies in volunteers orally dosed with buspirone demonstrate that 6-hydroxy-buspirone blood plasma levels were not only 30 to 40 times higher but were sustained compared to buspirone blood plasma levels. The time course of 6-hydroxy-buspirone blood plasma levels, unlike buspirone blood plasma levels, correlate more closely with the sustained anxiolytic effect seen following once or twice a day oral dosing with buspirone.

Although buspirone is an effective treatment for anxiety disorders and depression symptomatology in a significant number of patients treated, about a third of patients get little to no relief from their anxiety and responders often require a week or more of buspirone treatment before experiencing relief from their anxiety symptomatology. Further, certain adverse effects are reported across the patient population. The most commonly observed adverse effects associated with the use of buspirone include dizziness, nausea, headache, nervousness, lightheadedness, and excitement. Also, since buspirone can bind to central dopamine receptors, concern has been raised about its potential to cause unwanted changes in dopamine-mediated neurological functions and a syndrome of restlessness, appearing shortly after initiation of oral buspirone treatment, has been reported in small numbers of patients. While buspirone lacks the prominent sedative effects seen in more typical anxiolytics such as the benzodiazepines, patients are nonetheless advised against operating potentially dangerous machinery until they experience how they are affected by buspirone.

It can be seen that it is desirable to find a medicament with buspirone’s advantages but which demonstrates more robust anxiolytic potency with a lack of the above described adverse effects.

Formation of 6-hydroxy-buspirone occurs in the liver by action of enzymes of the P450 system, specifically CYP3A4. Many substances such as grapefruit juice and certain other drugs; e.g. erythromycin, ketoconazole, cimetidine, etc., are inhibitors of the CYP3A4 isozyme and may interfere with the formation of this active metabolite from buspirone. For this reason it would be desirable to find a compound with the advantages of buspirone but without the drug—drug interactions when coadministered with agents affecting the activity level of the CYP3A4 isozyme.

EXAMPLE 3One-Step Synthesis of 6-Hydroxy-buspirone (I)

Buspirone (19.3 g, 50 mmole) was dissolved in dry THF (400 mL) and the resulting solution was cooled to −78° C. A solution of KN(SiMe3)in toluene (100 mL, 1 M) was added slowly. After the reaction mixture was stirred at −78° C. for 1 h, a solution of 2-(phenylsulfonyl)-3-phenyloxaziridine (Davis reagent, prepared according to literature method: F. A. Davis, et al., Org. Synth., 1988, 66, 203) (17.0 g, 65 mmole) in dry THF (150 mL, precooled to −78° C.) was added quickly via a cannular. After stirred for 30 mins at −78° C., the reaction was quenched with 1 N HCl solution (500 mL). It was extracted with EtOAc (3×500 mL). The aqueous layer was separated, neutralized with saturated sodium bicarbonate solution, and extracted with EtOAc (3×500 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a white solid residue which was subjected to column chromatography using CH2Cl2/MeOH/NH4OH (200:10:1) as the eluent to give pure 6-hydroxy-buspirone (I, 7.2 g) and a mixture of buspirone and 6-hydroxy-buspirone (I). The mixture was purified by above column chromatography to afford another 3.3 g of pure 6-hydroxy-buspirone (I).

1H NMR (CDCl3) δ8.30 (d, J=4.7 Hz, 2H), 6.48 (t, J=4.7 Hz, 1H), 4.20 (s, 1H), 3.83-3.72 (m, 5H), 3.55 (s, 1H), 2.80 (d, J=17.5 Hz, 1H), 2.55-2.40 (m, 7H), 2.09-2.03 (m, 1H), 1.76-1.54 (m, 10 H), 1.41-1.36 (m, 1H), 1.23-1.20 (m, 1H).

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External links

  •  Media related to Buspirone at Wikimedia Commons
  • “Buspirone”Drug Information Portal. U.S. National Library of Medicine.
Clinical data
Pronunciation/ˈbjuːspɪroʊn/ (BEW-spi-rohn)
Trade namesBuspar, Namanspin
Other namesMJ 9022-1[1]
AHFS/Drugs.comMonograph
MedlinePlusa688005
Pregnancy
category
AU: B1
Routes of
administration
By mouth
ATC codeN05BE01 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)CA℞-onlyUK: POM (Prescription only)US: ℞-only
Pharmacokinetic data
Bioavailability3.9%[2]
Protein binding86–95%[3]
MetabolismLiver (via CYP3A4)[7][8]
Metabolites5-OH-Buspirone; 6-OH-Buspirone; 8-OH-Buspirone; 1-PP[4][5][6]
Elimination half-life2.5 hours[7]
ExcretionUrine: 29–63%[3]
Feces: 18–38%[3]
Identifiers
showIUPAC name
CAS Number36505-84-7 
33386-08-2 (hydrochloride)
PubChem CID2477
IUPHAR/BPS36
DrugBankDB00490 
ChemSpider2383 
UNIITK65WKS8HL
KEGGD07593 
ChEBICHEBI:3223 
ChEMBLChEMBL49 
CompTox Dashboard (EPA)DTXSID2022707 
ECHA InfoCard100.048.232 
Chemical and physical data
FormulaC21H31N5O2
Molar mass385.512 g·mol−1
3D model (JSmol)Interactive image
hideSMILESO=C1N(CCCCN2CCN(CC2)C3=NC=CC=N3)C(CC4(CCCC4)C1)=O
hideInChIInChI=1S/C21H31N5O2/c27-18-16-21(6-1-2-7-21)17-19(28)26(18)11-4-3-10-24-12-14-25(15-13-24)20-22-8-5-9-23-20/h5,8-9H,1-4,6-7,10-17H2 Key:QWCRAEMEVRGPNT-UHFFFAOYSA-N 

////////////Buspirone, буспирон , بوسبيرون , 丁螺酮 , Anxiolytic,Arylpiperazines,  Serotonin Receptor Agonist, Ansial, Vita,  Ansiced,  Abello,  Axoren, Glaxo Wellcome,  Bespar, BMS,  Buspar, Buspimen, Menarini,  Buspinol, Zdravlje,  Buspisal, Lesvi,  Narol, Almirall,

#Buspirone, #буспирон , #بوسبيرون , #丁螺酮 , #Anxiolytic, #Arylpiperazines,  #Serotonin Receptor Agonist, #Ansial, #Vita,  #Ansiced,  #Abello,  #Axoren, #Glaxo Wellcome,  #Bespar, #BMS,  #Buspar, #Buspimen, Menarini,  Buspinol, Zdravlje,  Buspisal, Lesvi,  Narol, Almirall,

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