New Drug Approvals

Home » Uncategorized

Category Archives: Uncategorized

Advertisements
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 2,302,015 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,308 other followers

Follow New Drug Approvals on WordPress.com

Categories

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,308 other followers

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 PHARMACEUTICALS 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 year tenure till date Dec 2017, 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, 50 Lakh plus views on dozen plus blogs, 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 19 lakh plus views on New Drug Approvals Blog in 216 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

Personal Links

Verified Services

View Full Profile →

Categories

Flag Counter
Advertisements

Eflornithine, эфлорнитин , إيفلورنيثين , 依氟鸟氨酸 , エフロルニチン


Figure

Eflornithine.svg

ChemSpider 2D Image | Eflornithine | C6H12F2N2O2

Eflornithine

DFMO, RMI-71782ATC:P01CX03, BRN 2250529 / HSDB 7923 / MDL 71782 / RFI 7178 / RMI 71782

Ornithine, 2-(difluoromethyl)-
UNII:ZQN1G5V6SR
ZQN1G5V6SR
эфлорнитин [Russian] [INN]
إيفلورنيثين [Arabic] [INN]
依氟鸟氨酸 [Chinese] [INN]
エフロルニチン
5551
67037-37-0 [RN]
70052-12-9 CAS
a-Difluoromethylornithine
(RS)-2,5-diamino-2-(difluoromethyl)pentanoic acid
  • Use:hirsutism treatment inhibitor of ornithine decarboxylase
  • Chemical name:2-(difluoromethyl)-dl-ornithine
  • Formula:C6H12F2N2O2, MW:182.17 g/mol
  • CAS-RN:67037-37-0
  • LD50:>3000 mg/kg (M, i.p.); >5000 mg/kg (M, p.o.);
    1364 μg/kg (R, intracerebral)

Eflornithine, also known as α-difluoromethylornithine (DFMO), is an Active Pharmaceutical Ingredient (API) on the World Health Organization’s list of essential medicines. DFMO is used to treat the second stage of African trypanosomiasis (sleeping sickness). In addition, DFMO is also used to treat opportunistic infections with Pneumocystis carinii pneumonia, a form of pneumonia found in people with a weak immune system suffering from conditions such as acquired immunodeficiency syndrome (AIDS) It has also been explored as chemopreventive agent in cancer therapy with minor success. Today, its main use is to treat excessive facial hair growth on women (hirsutism). The topical cream (Vaniqa) significantly reduces the psychological burden of those affected.\

Eflornithine is a prescription drug indicated in the treatment of facial hirsutism (excessive hair growth). Eflornithine hydrochloride cream for topical application is intended for use in women suffering from facial hirsutism and is sold by Allergan, Inc. under the brand name Vaniqa. Besides being a non-mechanical and non-cosmetic treatment, eflornithine is the only non-hormonal and non-systemic prescription option available for women who suffer from facial hirsutism. Eflornithine for injection against sleeping sickness was manufactured by Sanofi Aventis and sold under the brand name Ornidyl in the USA. It is now discontinued. Eflornithine is on the World Health Organization’s List of Essential Medicines.

Derivatives

Monohydrochloride

  • Formula:C6H12F2N2O2 • HCl
  • MW:218.63 g/mol
  • CAS-RN:68278-23-9
  • EINECS:269-532-0

Monohydrochloride monohydrate

  • Formula:C6H12F2N2O2 • HCl • H2O
  • MW:236.65 g/mol
  • CAS-RN:96020-91-6

Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis (sleeping sickness) and excessive hair growth on the face in women.[1][2] Specifically it is used for the 2nd stage of sleeping sickness caused by T. b. gambiense and may be used with nifurtimox.[1][3] It is used by injection or applied to the skin.[1][2]

Common side effects when applied as a cream include rash, redness, and burning.[2] Side effects of the injectable form include bone marrow suppression, vomiting, and seizures.[3] It is unclear if it is safe to use during pregnancy or breastfeeding.[3] It is recommended typically for children over the age of 12.[3]

Eflornithine was developed in the 1970s and came into medical use in 1990.[4] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] There is no generic version as of 2015 in the United States.[6] In the United States the injectable form can be obtained from the Centers for Disease Control and Prevention.[3] In the 1990s the cost of a course of treatment in Africa was 210 USD.[7] In regions of the world where the disease is common eflornithine is provided for free by the World Health Organization.[8]

https://www.google.com/patents/US4330559

Medical uses

Sleeping sickness

Sleeping sickness, or trypanosomiasis, is treated with pentamidine or suramin (depending on subspecies of parasite) delivered by intramuscular injection in the first phase of the disease, and with melarsoprol and eflornithine intravenous injection in the second phase of the disease. Efornithine is commonly given in combination with nifurtimox, which reduces the treatment time to 7 days of eflornithine infusions plus 10 days of oral nifurtimox tablets.[9]

Eflornithine is also effective in combination with other drugs, such as melarsoprol and nifurtimox. A study in 2005 compared the safety of eflornithine alone to melarsoprol and found eflornithine to be more effective and safe in treating second-stage sleeping sickness Trypanosoma brucei gambiense.[10] Eflornithine is not effective in the treatment of Trypanosoma brucei rhodesiense due to the parasite’s low sensitivity to the drug. Instead, melarsoprol is used to treat Trypanosoma brucei rhodesiense.[11] Another randomized control trial in Uganda compared the efficacy of various combinations of these drugs and found that the nifurtimox-eflornithine combination was the most promising first-line theory regimen.[12]

A randomized control trial was conducted in Congo, Côte d’Ivoire, the Democratic Republic of the Congo, and Uganda to determine if a 7-day intravenous regimen was as efficient as the standard 14-day regimen for new and relapsing cases. The results showed that the shortened regimen was efficacious in relapse cases, but was inferior to the standard regimen for new cases of the disease.[13]

Nifurtimox-eflornithine combination treatment (NECT) is an effective regimen for the treatment of second stage gambiense African trypanosomiasis.[14][15]

Trypanosome resistance

After its introduction to the market in the 1980s, eflornithine has replaced melarsoprol as the first line medication against Human African trypanosomiasis (HAT) due to its reduced toxicity to the host.[13] Trypanosoma brucei resistant to eflornithine has been reported as early as the mid-1980s.[13]

The gene TbAAT6, conserved in the genome of Trypanosomes, is believed to be responsible for the transmembrane transporter that brings eflornithine into the cell.[16] The loss of this gene due to specific mutations causes resistance to eflornithine in several trypanosomes.[17] If eflornithine is prescribed to a patient with Human African trypanosomiasis caused by a trypanosome that contains a mutated or ineffective TbAAT6 gene, then the medication will be ineffective against the disease. Resistance to eflornithine has increased the use of melarsoprol despite its toxicity, which has been linked to the deaths of 5% of recipient HAT patients.[13]

Excess facial hair in women

The topical cream is indicated for treatment of facial hirsutism in women.[18] It is the only topical prescription treatment that slows the growth of facial hair.[19] It is applied in a thin layer twice daily, a minimum of eight hours between applications. In clinical studies with Vaniqa, 81% percent of women showed clinical improvement after twelve months of treatment.[20] Positive results were seen after eight weeks.[21] However, discontinuation of the cream caused regrowth of hair back to baseline levels within 8 weeks.[22]

Vaniqa treatment significantly reduces the psychological burden of facial hirsutism.[23]

Chemo preventative therapy

It has been noted that ornithine decarboxylase (ODC) exhibits high activity in tumor cells, promoting cell growth and division, while absence of ODC activity leads to depletion of putrescine, causing impairment of RNA and DNA synthesis. Typically, drugs that inhibit cell growth are considered candidates for cancer therapy, so eflornithine was naturally believed to have potential utility as an anti-cancer agent. By inhibiting ODC, eflornithine inhibits cell growth and division of both cancerous and noncancerous cells.

However, several clinical trials demonstrated minor results.[24] It was found that inhibition of ODC by eflornithine does not kill proliferating cells, making eflornithine ineffective as a chemotherapeutic agent. The inhibition of the formation of polyamines by ODC activity can be ameliorated by dietary and bacterial means because high concentrations are found in cheese, red meat, and some intestinal bacteria, providing reserves if ODC is inhibited.[25] Although the role of polyamines in carcinogenesis is still unclear, polyamine synthesis has been supported to be more of a causative agent rather than an associative effect in cancer.[24]

Other studies have suggested that eflornithine can still aid in some chemoprevention by lowering polyamine levels in colorectal mucosa, with additional strong preclinical evidence available for application of eflornithine in colorectal and skin carcinogenesis.[24][25] This has made eflornithine a supported chemopreventive therapy specifically for colon cancer in combination with other medications. Several additional studies have found that eflornithine in combination with other compounds decreases the carcinogen concentrations of ethylnitrosourea, dimethylhydrazine, azoxymethane, methylnitrosourea, and hydroxybutylnitrosamine in the brain, spinal cord, intestine, mammary gland, and urinary bladder.[25]

Contraindications

Topical

Topical use is contraindicated in people hypersensitive to eflornithine or to any of the excipients.[26]

Throughout clinical trials, data from a limited number of exposed pregnancies indicate that there is no clinical evidence that treatment with Vaniqa adversely affects pregnant women or fetuses.[26]

By mouth

When taken by mouth the risk-benefit should be assessed in people with impaired renal function or pre-existing hematologic abnormalities, as well as those with eighth-cranial-nerve impairment.[27] Adequate and well-controlled studies with eflornithine have not been performed regarding pregnancy in humans. Eflornithine should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus. However, since African trypanosomiasis has a high mortality rate if left untreated, treatment with eflornithine may justify any potential risk to the fetus.[27]

Side effects

Eflornithine is not genotoxic; no tumour-inducing effects have been observed in carcinogenicity studies, including one photocarcinogenicity study.[28] No teratogenic effects have been detected.[29]

Topical

The topical form of elflornithine is sold under the brand name Vaniqa . The most frequently reported side effect is acne (7–14%). Other side effects commonly (> 1%) reported are skin problems, such as skin reactions from in-growing hair, hair loss, burning, stinging or tingling sensations, dry skin, itching, redness or rash.[30]

Intravenous

The intravenous dosage form of eflornithine is sold under the brand name Ornidyl. Most side effects related to systemic use through injection are transient and reversible by discontinuing the drug or decreasing the dose. Hematologic abnormalities occur frequently, ranging from 10–55%. These abnormalities are dose-related and are usually reversible. Thrombocytopenia is thought to be due to a production defect rather than to peripheral destruction. Seizures were seen in approximately 8% of patients, but may be related to the disease state rather than the drug. Reversible hearing loss has occurred in 30–70% of patients receiving long-term therapy (more than 4–8 weeks of therapy or a total dose of >300 grams); high-frequency hearing is lost first, followed by middle- and low-frequency hearing. Because treatment for African trypanosomiasis is short-term, patients are unlikely to experience hearing loss.[30]

Interactions

Topical

No interaction studies with the topical form have been performed.[26]

Mechanism of action

Figure 1
(A) 3D structure of L-Ornithine
(B) 3D structure of Eflornithine. This molecule is similar to the structure of L-Ornithine, but its alpha-difluoromethyl group allows interaction with Cys-360 in the active site

Eflornithine ODC Reaction Mechanism

Description

Eflornithine is a “suicide inhibitor,” irreversibly binding to ornithine decarboxylase (ODC) and preventing the natural substrate ornithine from accessing the active site (Figure 1). Within the active site of ODC, eflornithine undergoes decarboxylation with the aid of cofactor pyridoxal 5’-phosphate (PLP). Because of its additional difluoromethyl group in comparison to ornithine, eflornithine is able to bind to a neighboring Cys-360 residue, permanently remaining fixated within the active site.[29]

During the reaction, eflornithine’s decarboxylation mechanism is analogous to that of ornithine in the active site, where transamination occurs with PLP followed by decarboxylation. During the event of decarboxylation, the fluoride atoms attached to the additional methyl group pull the resulting negative charge from the release of carbon dioxide, causing a fluoride ion to be released. In the natural substrate of ODC, the ring of PLP accepts the electrons that result from the release of CO2.

The remaining fluoride atom that resides attached to the additional methyl group creates an electrophilic carbon that is attacked by the nearby thiol group of Cys-360, allowing eflornithine to remain permanently attached to the enzyme following the release of the second fluoride atom and transimination.

Evidence

Figure 2
Experimental Evidence for Eflornithine End Product[31]

The reaction mechanism of Trypanosoma brucei‘s ODC with ornithine was characterized by UV-VIS spectroscopy in order to identify unique intermediates that occurred during the reaction. The specific method of multiwavelength stopped-flow spectroscopy utilized monochromatic light and fluorescence to identify five specific intermediates due to changes in absorbance measurements.[32] The steady-state turnover number, kcat, of ODC was calculated to be 0.5 s-1 at 4 °C.[32] From this characterization, the rate-limiting step was determined to be the release of the product putrescine from ODC’s reaction with ornithine. In studying the hypothetical reaction mechanism for eflornithine, information collected from radioactive peptide and eflornithine mapping, high pressure liquid chromatography, and gas phase peptide sequencing suggested that Lys-69 and Cys-360 are covalently bound to eflornithine in T. brucei ODC’s active site.[31] Utilizing fast-atom bombardment mass spectrometry (FAB-MS), the structural conformation of eflornithine following its interaction with ODC was determined to be S-((2-(1-pyrroline-methyl) cysteine, a cyclic imine adduct. Presence of this particular product was supported by the possibility to further reduce the end product to S-((2-pyrrole) methyl) cysteine in the presence of NaBH4 and oxidize the end product to S-((2-pyrrolidine) methyl) cysteine (Figure 2).[31]

Active site

Figure 3
Active Site of ODC Formed by Homodimerization (Green and White Surface Structures)
(A) Ornithine in the Active Site of ODC, Cys-360 highlighted in yellow
(B) Product of Eflornithine Decarboxylation bound to Cys 360 (highlighted in yellow). The pyrroline ring blocks ornithine from entering the active site
Derived from Grishin, Nick V., et al. “X-ray structure of ornithine decarboxylase from Trypanosoma brucei: the native structure and the structure in complex with α-difluoromethylornithine.” Biochemistry 38.46 (1999): 15174-15184. PDB ID: 2TOD

Eflornithine’s suicide inhibition of ODC physically blocks the natural substrate ornithine from accessing the active site of the enzyme (Figure 3).[29] There are two distinct active sites formed by the homodimerization of ornithine decarboxylase. The size of the opening to the active site is approximately 13.6 Å. When these openings to the active site are blocked, there are no other ways through which ornithine can enter the active site. During the intermediate stage of eflornithine with PLP, its position near Cys-360 allows an interaction to occur. As the phosphate of PLP is stabilized by Arg 277 and a Gly-rich loop (235-237), the difluoromethyl group of eflornithine is able to interact and remain fixated to both Cys-360 and PLP prior to transimination. As shown in the figure, the pyrroline ring interferes with ornithine’s entry (Figure 4). Eflornithine will remain permanently bound in this position to Cys-360. As ODC has two active sites, two eflornithine molecules are required to completely inhibit ODC from ornithine decarboxylation.

History

Eflornithine was initially developed for cancer treatment at Merrell Dow Research Institute in the late 1970s, but was found to be ineffective in treating malignancies. However, it was discovered to be highly effective in reducing hair growth,[33] as well as in the treatment of African trypanosomiasis (sleeping sickness),[34] especially the West African form (Trypanosoma brucei gambiense).

Hirsutism[]

In the 1980s, Gillette was awarded a patent for the discovery that topical application of eflornithine HCl cream inhibits hair growth. In the 1990s, Gillette conducted dose-ranging studies with eflornithine in hirsute women that demonstrated that the drug slows the rate of facial hair growth. Gillette then filed a patent for the formulation of eflornithine cream. In July 2000, the U.S. Food and Drug Administration (FDA) granted a New Drug Application for Vaniqa. The following year, the European Commission issued its Marketing Authorisation.

Sleeping sickness treatment

The drug was registered for the treatment of gambiense sleeping sickness on November 28, 1990.[35] However, in 1995 Aventis (now Sanofi-Aventis) stopped producing the drug, whose main market was African countries, because it did not make a profit.[36]

In 2001, Aventis and the WHO formed a five-year partnership, during which more than 320,000 vials of pentamidine, over 420,000 vials of melarsoprol, and over 200,000 bottles of eflornithine were produced by Aventis, to be given to the WHO and distributed by the association Médecins sans Frontières (also known as Doctors Without Borders)[37][38] in countries where sleeping sickness is endemic.

According to Médecins sans Frontières, this only happened after “years of international pressure,” and coinciding with the period when media attention was generated because of the launch of another eflornithine-based product (Vaniqa, for the prevention of facial-hair in women),[36]while its life-saving formulation (for sleeping sickness) was not being produced.

From 2001 (when production was restarted) through 2006, 14 million diagnoses were made. This greatly contributed to stemming the spread of sleeping sickness, and to saving nearly 110,000 lives.

Society and culture

Available forms

Vaniqa is a cream, which is white to off-white in colour. It is supplied in tubes of 30 g and 60 g in Europe.[30] Vaniqa contains 15% w/w eflornithine hydrochloride monohydrate, corresponding to 11.5% w/w anhydrous eflornithine (EU), respectively 13.9% w/w anhydrous eflornithine hydrochloride (U.S.), in a cream for topical administration.

Ornidyl, intended for injection, was supplied in the strength of 200 mg eflornithine hydrochloride per ml.[39]

Cost

In 2000, the cost for the 14-day regimen was US $500; a price that many in countries where the disease is common cannot afford.[13]

Market

Vaniqa, granted marketing approval by the US FDA, as well as by the European Commission[40] among others, is currently the only topical prescription treatment that slows the growth of facial hair.[19] Besides being a non-mechanical and non-cosmetic treatment, it is the only non-hormonal and non-systemic prescription option available for women who suffer from facial hirsutism.[18] Vaniqa is marketed by Almirall in Europe, SkinMedica in the USA, Triton in Canada, Medison in Israel, and Menarini in Australia.[40]

Ornidyl, the injectable form of eflornithine hydrochloride, is licensed by Sanofi-Aventis, but is currently discontinued in the US.[41]

Clip

Scalable Continuous Flow Process for the Synthesis of Eflornithine Using Fluoroform as Difluoromethyl Source

 Center for Continuous Flow Synthesis and Processing (CC FLOW)Research Center Pharmaceutical Engineering GmbH (RCPE)Inffeldgasse 13, 8010 Graz, Austria
 Institute of ChemistryUniversity of Graz, NAWI GrazHeinrichstrasse 28, A-8010 Graz, Austria
§ Microreactor Technology, Lonza AG, CH-3930 Visp, Switzerland
 Institute of Inorganic ChemistryGraz University of TechnologyStremayrgasse 9, 8010 Graz, Austria
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00318
Abstract Image

The development of a scalable telescoped continuous flow procedure for difluoromethylation of a protected amino acid with fluoroform (CHF3, R-23) gas and subsequent high temperature deprotection to provide eflornithine, an important Active Pharmaceutical Ingredient (API), is described. Eflornithine is used for the treatment of sleeping sickness and hirsutism, and it is on the World Health Organization’s list of essential medicines. Fluoroform is produced in large quantities as a side product in the manufacture of polytetrafluoroethylene (PTFE, Teflon). Fluoroform is an ozone-benign and nontoxic gas, but its release into the environment is forbidden under the Kyoto protocol owing to its high global warming potential. The existing manufacturing route to eflornithine uses chlorodifluoromethane (CHClF2, R-22) which will be phased out under the Montreal protocol; therefore, the use of the fluoroform presents a viable cost-effective and more sustainable alternative. The process parameters and equipment setup were optimized on laboratory scale for the two reaction steps to improve product yield and scalability. The telescoped flow process utilizing fluoroform gas was operated for 4 h to afford the target molecule in 86% isolated yield over two steps with a throughput of 24 mmol/h.

1hydrochloride monohydrate as colorless powder. (17.05 g, 72.3 mmol, 86% yield). Mp. 228 °C;

1H NMR (300.36 MHz, D2O): δ = 6.46 (t, 2JHF = 52.8 Hz, 1H), 3.05 (t,3JHH = 7.6 Hz, 2H), 2.25–1.97 (m, 2H), 1.96–1.79 (m, 1H), 1.76–1.59 (m, 1H) ppm.

13C NMR (75 MHz, D2O): δ = 167.8 (d, 3JCF = 6.4 Hz), 114.0 (dd, 1JCF = 249.7 Hz, 1JCF = 247.0 Hz), 64.5 (dd, 2JCF = 20.4 Hz, 2JCF = 18.7 Hz), 38.8 (d, 3JCF = 7.3 Hz), 31.6 (d, 4JCF = 3.2 Hz), 20.8 ppm.

19F NMR (282 MHz, D2O): δ = −126.28 (dd, 2JFF = 283.5 Hz, 2JHF = 52.4 Hz), – 131.76 (dd, 2JFF = 283.5 Hz, 2JHF = 52.4 Hz) ppm.

str1 str2 str3

References

  1. Jump up to:a b c “19th WHO Model List of Essential Medicines (April 2015)” (PDF). WHO. April 2015. Archived (PDF) from the original on May 13, 2015. Retrieved May 10, 2015.
  2. Jump up to:a b c “Eflornithine”. The American Society of Health-System Pharmacists. Archivedfrom the original on 20 December 2016. Retrieved 28 November 2016.
  3. Jump up to:a b c d e “CDC – African Trypanosomiasis – Resources for Health Professionals”http://www.cdc.gov. 10 August 2016. Archived from the original on 28 November 2016. Retrieved 6 December 2016.
  4. Jump up^ Marcondes, Carlos Brisola (2016). Arthropod Borne Diseases. Springer. p. 292. ISBN 9783319138848Archived from the original on 2017-09-10.
  5. Jump up^ “WHO Model List of Essential Medicines (19th List)” (PDF)World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
  6. Jump up^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 192. ISBN 9781284057560.
  7. Jump up^ Grayson, M. Lindsay; Crowe, Suzanne M.; McCarthy, James S.; Mills, John; Mouton, Johan W.; Norrby, S. Ragnar; Paterson, David L.; Pfaller, Michael A. (2010). Kucers’ The Use of Antibiotics Sixth Edition: A Clinical Review of Antibacterial, Antifungal and Antiviral Drugs. CRC Press. p. 2194. ISBN 9781444147520Archived from the original on 2017-09-10.
  8. Jump up^ “Trypanosomiasis, human African (sleeping sickness)”World Health Organization. February 2016. Archived from the original on 4 December 2016. Retrieved 7 December2016.
  9. Jump up^ Babokhov P; et al. (2013). “A current analysis of chemotherapy strategies for the treatment of human African trypanosomiasis”Pathog Glob Health107 (5): 242–52. doi:10.1179/2047773213Y.0000000105PMC 4001453PMID 23916333.
  10. Jump up^ Priotto, Gerardo; et al. (December 2006). “Three drug combinations for late-stageTrypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Uganda”PLoS Clinical Trials1 (8): e39. doi:10.1371/journal.pctr.0010039PMC 1687208PMID 17160135.
  11. Jump up^ Lutje, Vittoria; Seixas, Jorge; Kennedy, Adrian (2013-06-28). “Cochrane Database of Systematic Reviews”. Cochrane Database of Systematic Reviews (6): CD006201. doi:10.1002/14651858.cd006201.pub3PMID 23807762.
  12. Jump up^ Chappuis F, et al. (2005). “Eflornithine is safer than melarsoprol for the treatment of second-stage Trypanosoma brucei gambiense human African trypanosomiasis”. Clinical Infectious Diseases41 (5): 748–751. doi:10.1086/432576PMID 16080099.
  13. Jump up to:a b c d e Vincent, Isabel M.; et al. (November 2010). “A molecular mechanism for eflornithine resistance in African trypanosomes”PLoS Pathogens6 (11): e1001204. doi:10.1371/journal.ppat.1001204PMC 2991269PMID 21124824.
  14. Jump up^ “Nifurtimox-eflornithine combination treatment for sleeping sickness (human African trypanosomiasis): WHO wraps up training of key health care personnel”. World Health Organization. March 23, 2010.
  15. Jump up^ Franco, Jose; Pere, Simarro; Diarra; Ruiz-Postigo; Samo; Jannin (2012). “Monitoring the use of nifurtimox-eflornithine combination therapy (NECT) in the treatment of second stage gambiense human African trypanosomiasis” (PDF)Research and Reports in Tropical Medicine3: 93–101. doi:10.2147/RRTM.S34399PMC 6067772PMID 30100776.
  16. Jump up^ Sayé M, et al. (2014). “Proline Modulates the Trypanosoma cruzi Resistance to Reactive Oxygen Species and Drugs through a Novel D, L-Proline Transporter”PLoS ONE9 (3): e92028. Bibcode:2014PLoSO…992028Sdoi:10.1371/journal.pone.0092028PMC 3956872PMID 24637744.
  17. Jump up^ Barrett, M. P., et al. “Human African trypanosomiasis: pharmacological re‐engagement with a neglected disease.” British Journal of Pharmacology 152.8 (2007): 1155-1171.
  18. Jump up to:a b “NHS and UKMi New Medicines Profile” (PDF). Archived from the original (PDF)on 2010-02-15.
  19. Jump up to:a b Balfour JA, McClellan K (June 2001). “Topical Eflornithine”. Am J Clin Dermatol2 (3): 197–201. doi:10.2165/00128071-200102030-00009PMID 11705097.
  20. Jump up^ Schrode K; Huber F; Staszak J; Altman DJ. “Evaluation of the long-term safety of eflornithine 15% cream in the treatment of women with excessive facial hair. Presented at 58th Annual Meeting of the Academy of Dermatology 2000, 10–15 March, San Francisco; USA, Poster 294”. the Eflornithine Study Group.
  21. Jump up^ Schrode K, Huber F; Staszak, J; Altman DJ, Shander D & Morton J, the Eflornithine Study Group. “Randomized, double-blind, vehicle-controlled safety and efficacy evaluation of eflornithine 15% cream in the treatment of women with excessive facial hair. Presented at 58th Annual Meeting of the Academy of Dermatology 2000, 10–15 March, San Francisco; USA, Poster 291”.
  22. Jump up^ Wolf, John E.; Shander, Douglas; Huber, Ferdinand; Jackson, Joseph; Lin, Chen-Sheng; Mathes, Barbara M.; Schrode, Kathy; the Eflornithine HCl Study Group (2007-01-01). “Randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine HCl 13.9% cream in the treatment of women with facial hair”. International Journal of Dermatology46 (1): 94–98. doi:10.1111/j.1365-4632.2006.03079.xISSN 1365-4632PMID 17214730.
  23. Jump up^ Jackson J, Caro JJ; Caro G, Garfield F; Huber F, Zhou W; Lin CS, Shander D & Schrode K. “The effect of eflornithine 13.9% cream on the bother and discomfort due to hirsutism. Int J Derm 2007; 46: 976-981”. the Eflornithine HCl Study Group.
  24. Jump up to:a b c Paul, F. “Revival of 2-(difluoromethyl) ornithine (DFMO), an inhibitor of polyamine biosynthesis, as a cancer chemopreventive agent.” Biochemical Society Transactions 35.Pt 2 (2007): 353-355.
  25. Jump up to:a b c Gerner EW, Meyskens FL (2004). “Polyamines and cancer: old molecules, new understanding” (Submitted manuscript)Nature Reviews Cancer4 (10): 781–792. doi:10.1038/nrc1454PMID 15510159.
  26. Jump up to:a b c “Vaniqa Summary of Product Characteristics 2008”. Archived from the original on 2009-12-05.
  27. Jump up to:a b “Ornidyl Drug Information”. Archived from the original on 2011-06-07.
  28. Jump up^ Malhotra B, Noveck R, Behr D, Palmisano M (September 2001). “Percutaneous absorption and pharmacokinetics of Eflornithine HCI 13.9% cream in women with unwanted facial hair”J Clin Pharmacol41 (9): 972–978. doi:10.1177/009127000104100907(inactive 2018-09-12). PMID 11549102Archived from the original on 2016-11-12.
  29. Jump up to:a b c “Vaniqa Product Monograph”.
  30. Jump up to:a b c “Vaniqa US Patient Information Leaflet” (PDF)Archived (PDF) from the original on 2010-02-15.
  31. Jump up to:a b c Poulin, R; Lu, L; Ackermann, B; Bey, P; Pegg, AE (Jan 5, 1992). “Mechanism of the irreversible inactivation of mouse ornithine decarboxylase by alpha-difluoromethylornithine. Characterization of sequences at the inhibitor and coenzyme binding sites”. The Journal of Biological Chemistry267 (1): 150–8. PMID 1730582.
  32. Jump up to:a b Brooks, HB; Phillips, MA (Dec 9, 1997). “Characterization of the reaction mechanism for Trypanosoma brucei ornithine decarboxylase by multiwavelength stopped-flow spectroscopy”. Biochemistry36 (49): 15147–55. doi:10.1021/bi971652bPMID 9398243.
  33. Jump up^ Wolf JE; Shander D; Huber F; Jackson J; Lin CS; Mathes BM; Schrode K; the Eflornithine Study Group. (January 2007). “Randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine HCI 13.9% cream in the treatment of women with facial hair”. Int J Dermatol46 (1): 94–8. doi:10.1111/j.1365-4632.2006.03079.xPMID 17214730.
  34. Jump up^ Pepin J, Milord F, Guern C, Schechter PJ (1987). “Difluoromethylornithine for arseno-resistant Trypanosoma brucei gambiense sleeping sickness”Lancet2 (8573): 1431–3. doi:10.1016/S0140-6736(87)91131-7PMID 2891995.
  35. Jump up^ “New lease of life for resurrection drug”.[permanent dead link]
  36. Jump up to:a b “Supply of sleeping sickness drugs confirmed”Archived from the original on 2015-09-21.
  37. Jump up^ “Sanofi-Aventis Access to Medicines Brochure” (PDF)Archived (PDF) from the original on 2008-11-14.
  38. Jump up^ “IFPMA Health Initiatives: Sleeping Sickness”. Archived from the original on 2006-08-29.
  39. Jump up^ “Ornidyl facts”Archived from the original on 2011-07-20.
  40. Jump up to:a b “Vaniqa Training Programme Module 5”.
  41. Jump up^ “Drugs@FDA: FDA Approved Drug Products”http://www.accessdata.fda.govArchivedfrom the original on 2014-09-05. Retrieved 2016-11-17.

External links

References

    • Bey, P. et al.: J. Org. Chem. (JOCEAH) 44, 2732 (1979).
    • Metcalf, B.W. et al.: J. Am. Chem. Soc. (JACSAT) 100, 2551 (1978).
    • US 4 413 141 (Merrell-Toraude; 1.11.1983; appl. 17.9.1982; prior. 11.7.1977, 2.7.1979).
    • US 4 330 559 (Merrell-Toraude; 18.5.1982; appl. 3.2.1981; prior. 11.7.1977, 10.4.1979).
  • synthesis of (–)-isomer:

    • EP 357 029 (Merrell Dow; appl. 30.8.1989; USA-prior. 31.8.1988).
  • pharmaceutical composition:

    • BE 881 209 (Merrell-Toraude; appl. 16.5.1980; USA-prior. 10.4.1979).
  • combination with interferon:

    • US 4 499 072 (Merrell Dow; 12.2.1985; appl. 24.1.1983; prior. 29.11.1982).
Eflornithine
Eflornithine.svg
Eflornithine-3D-vdW.png
Clinical data
Trade names Vaniqa, others
Synonyms α-difluoromethylornithine or DFMO
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • C
Routes of
administration
intravenous, topical
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100% (Intravenous)
Negligible (Dermal)
Metabolism Not metabolised
Elimination half-life hours
Excretion Kidneys
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C6H12F2N2O2
Molar mass 182.17 g·mol−1
3D model (JSmol)

/////////////ZQN1G5V6SR, эфлорнитин إيفلورنيثين 依氟鸟氨酸 , Eflornithine, エフロルニチン

Advertisements

FDA permits marketing of two devices that detect parathyroid tissue in real-time during surgery


DRUG REGULATORY AFFAIRS INTERNATIONAL

FDA permits marketing of two devices that detect parathyroid tissue in real-time during surgery
Today, the U.S. Food and Drug Administration permitted marketing of two devices that provide real-time location of parathyroid tissue during surgical procedures such as thyroidectomy (surgery to remove all or part of the thyroid) and parathyroidectomy (surgery to remove one or more parathyroid glands).
“For some patients with parathyroid disease, treatment may mean a surgical procedure,” said Binita Ashar, M.D., director of the Division of Surgical Devices in the FDA’s Center for Devices and Radiological Health.  “Real-time identification of parathyroid tissue during surgery can provide surgeons… Continue reading.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624982.htm?utm_campaign=11022018_PR_FDA%20authorizes%20devices%20to%20detect%20parathyroid%20tissue%20in%20during%20surgery&utm_medium=email&utm_source=Eloqua

November 2, 2018

Release

Today, the U.S. Food and Drug Administration permitted marketing of two devices that provide real-time location of parathyroid tissue during surgical procedures such as thyroidectomy (surgery to remove all or part of the thyroid) and parathyroidectomy (surgery to remove one or…

View original post 556 more words

Statement from FDA Commissioner Scott Gottlieb, M.D., on findings from the romaine lettuce E. coli O157:H7 outbreak investigation and FDA’s efforts to prevent future outbreaks


DRUG REGULATORY AFFAIRS INTERNATIONAL

tatement from FDA Commissioner Scott Gottlieb, M.D., on findings from the romaine lettuce E. coli O157:H7 outbreak investigation and FDA’s efforts to prevent future outbreaks

Earlier this year, we experienced the largest E. coli O157:H7 outbreak the country has seen in the last decade, leaving hundreds sick and claiming the lives of five people who consumed contaminated romaine lettuce.
We’re committed to taking necessary actions to prevent future outbreaks like this and to improving the safety of leafy greens available in the marketplace. Since the next romaine growing season for the Yuma region is underway, it’s critical for all of us to understand what happened so we can identify the changes that can prevent future outbreaks and reduce the scope of any problems that could arise.
Since the first signs of the outbreak appeared…Continue reading

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624867.htm?utm_campaign=11012018_Statement_findings%20from%20the%20romaine%20lettuce%20E.%20coli%20O157%3AH7&utm_medium=email&utm_source=Eloqua

November 1, 2018

Statement

Earlier this year, we experienced the largest E. coli

View original post 1,168 more words

FDA warns patients and doctors about risk of inaccurate results from home-use device to monitor blood thinner warfarin


DRUG REGULATORY AFFAIRS INTERNATIONAL

FDA warns patients and doctors about risk of inaccurate results from home-use device to monitor blood thinner warfarin

The U.S. Food and Drug Administration today is warning patients and doctors, who use at-home or in-the-office medical devices to monitor levels of the blood thinner, warfarin, that certain test strips used with the devices may provide inaccurate results and should not be relied upon to adjust the drug dosage. Roche Diagnostics issued a voluntary recall of certain test strip lots used with its CoaguChek test meter devices. The recall involves more than 1.1 million packages of CoaguChek XS PT Test Strips that were distributed nationwide from Jan. 12, 2018 to Oct. 29, 2018. Today, the FDA announced this action as…Continue reading 

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624904.htm?utm_campaign=11012018_PR_FDA%20warns%20of%20inaccurate%20test%20results%20for%20device%20to%20monitor%20warfarin&utm_medium=email&utm_source=Eloqua

November 1, 2018

Release

The U.S. Food and Drug Administration today is warning patients and doctors, who use at-home or in-the-office medical devices to monitor levels of…

View original post 768 more words

Pirlindole


Pirlindole structure.svg

Pirlindole

  • Molecular FormulaC15H18N2
  • Average mass226.317 Da
1H-Pyrazino[3,2,1-jk]carbazole, 2,3,3a,4,5,6-hexahydro-8-methyl-
2,3,3a,4,5,6-hexahydro-8-methyl-1h-pyrazino[3,2,1-jk]carbazole
4615
60762-57-4 [RN] FREE FORM, 16154-78-2 (hydrochloride)
12-methyl-1,4-diazatetracyclo[7.6.1.0⁵,¹⁶.0¹⁰,¹⁵]hexadeca-9(16),10,12,14-tetraene
8-Methyl-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole
UNII:V39YPH45FZ
V39YPH45FZ
INNOVATOR Russian Academy of Medical Sciences
For the treatment of major depression.
Pirlindole is a reversible inhibitor of monoamine oxidase A (RIMA) which was developed and is currently used in Russia as an antidepressant. It is structurally and pharmacologically related to metralindole. Pirlindole is a selective, reversible inhibitor of monoamine oxidase (MAO) subtype A (MAO-A) that is approved in several European and non-European countries for the treatment of major depression. The antidepressant efficacy and safety of pirlindole have been demonstrated in numerous studies and, supported by many years of clinical experience in the treatment of depression. Pirlindole’s efficacy and safety have also been shown in the treatment of fibromyalgia.

Pirlindole (LifrilPyrazidol) is a reversible inhibitor of monoamine oxidase A (RIMA) which was developed and is used in Russia as an antidepressant.[1]:337 It is structurally and pharmacologically related to metralindole.

Biovista is investigating BVA-201, a repurposed oral formulation of pirlindole mesylate, for the potential treatment of multiple sclerosis

SYN 1

SYN 2

PAPER

Khimiko-Farmatsevticheskii Zhurnal (1986), 20(3), 300-3.

PATENT

U.S.S.R. (1986), SU 276060

PAPER

Sudebno-meditsinskaia ekspertiza (1989), 32(4), 49-50

PAPER

Journal of Pharmaceutical and Biomedical Analysis

Volume 18, Issues 4–5, 1 December 1998, Pages 605-614

https://www.sciencedirect.com/science/article/abs/pii/S0731708598002131

PATENT

WO2015171003 ,

claiming method for resolving racemic mixture of pirlindole hydrochloride into enantiomerically pure (S)-pirlindole and/or (R)-pirlindole,

Pirlindole, 2, 3, 3a, 4, 5, 6-hexahydro-lH-8-methyl-pyrazine

[3, 2, 1-j , k] carbazole, is a tetracyclic compound of the formula I

(I)

Pirlindole is a reversible monoamine oxidase A inhibitor being up to date useful as a medicament in the treatment of depression.

Pirlindole has an asymmetric carbon atom which implies that there are two enantiomers, (S) -pirlindole and (R) -pirlindole .

The state of the art teaches several methods for the enantiomeric separation of pirlindole. For example, The Journal of Pharmaceutical and Biomedical Analysis, 18(1998) 605- 614, “Enantiomeric separation of pirlindole by liquid chromatography using different types of chiral stationary phases”, Ceccato et al, discloses the enantiomeric separation of pirlindole by liquid chromatography (LC) using three different chiral stationary phases.

Further, The Journal of Pharmaceutical and Biomedical Analysis 27(2002) 447-455, “Automated determination of pirlindole enantiomers in plasma by on-line coupling of a pre-column packed with restricted access material to a chiral liquid chromatographic column”, Chiap et al., discloses the use of a pre-column packed with restricted access material for sample clean up coupled to a column containing a cellulose based chiral stationary phase for separation and quantitative analysis of the enantiomers .

According to the prior art, Chirality 11:261-266 (1999) all attempts to obtain the enantiomers of pirlindole by selective crystallization with optically active acids failed, and it was only possible to obtain at laboratory scale (few grams) as hydrochloride salt, using derivatization technique in conjunction with preparative chromatography.

The characteristics of the process disclosed in the state of the art limit in a definitive way, its implementation on an industrial or semi-industrial scale due to the necessity to use a separation by chromatography on a large scale which makes the process very costly, difficult to implement and with poor reproducibility. .

EXAMPLE 7

(R) -Pirlindole mesylate

Starting from 10 g of (R) -pirlindole (S) -mandelate obtained in Example 1 and following the procedure described in Example 5 using methanesulfonic acid as pharmaceutical acceptable acid, ,

7.4 g (0.023 mole) of (R) -pirlindole mesylate were obtained (yield = 85.2% ). Chiral HPLC (enantiomeric purity = 98.0%).

XAMPLE 9

(S) -pirlindole mesylate

Starting from 10 g of (S) -pirlindole (R) -mandelate obtained in Example 2 and following the procedure described in Example 6 using methanesulfonic acid as pharmaceutical acceptable acid, 6.8 g (0.021 mole) of (S) -pirlindole mesylate were obtained (yield = 77.8%). Chiral HPLC (enantiomeric purity = 98.0%).

PATENT

WO-2018193415

Process for the preparation of pirlindole .  useful for treating depression.

Pirlindole (8-methyl-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole) of formula I

Compound Formula I

also described as Pyrazidole™ represents a new class of original tetracyclic antidepressants, the pyrazinocarbazole derivatives. The drug was synthesized and characterized at the end of the 1960s and was marketed as an anti-depressant in 1975. Current clinical trials have demonstrated to be a highly effective short-acting and safe drug.

[0003] Pirlindole is a selective, reversible inhibitor of MAO-A. In-vitro evidence suggest the catalytic oxidation of Pirlindole into dehydro-pirlindole by MAO-A. Dehydro-pirlindole may be a more potent slowly reversible inhibitor of MAO-A and this might explain the persistence of MAO-A inhibition in-vivo (MAO-The mother of all amine oxidases, John P.M. Finberg et al. 1998, Springer).

[0004] Pirlindole chemical structure is composed of one stereogenic centre which indicates the existence of two enantiomers, the ( ?)-Pirlindole and the (S)-Pirlindole.

[0005] Although Pirlindole pharmacological data and the clinical use were performed on the racemate, recently there have been increasing interest in the pharmacological profile of each enantiomer (WO 2015/171005 Al).

[0006] International patent publication WO 2015/171003A1 filed 9th May 2014 discloses a resolution of racemic pirlindole into optically active pirlindole. The Resolution-Racemization-Recycle (RRR) synthesis described involves derivatization by preparation of pairs of diastereomers in the form of salts from an optically active organic acid. These diastereomers can be separated by conventional techniques such as crystallisation. Although it is a very efficient procedure to prepare laboratorial scale or pre-clinical batch of (/?)- or (S)-Pirlindole, it is not economically convenient at an industrial scale because the process relies on Pirlindole racemate as the starting material.

[0007] Andreeva et al. (Pharmaceutical Chemistry 1992, 26., 365-369) discloses the first isolation of Pirlindole enantiomers in isolated form. ( ?)-Pirlindole of formula II

was isolated as an hydrochloride salt from a racemic base by the fractional crystallization of racemic pirlindole salt with (+)-camphor-10-sulfonic acid. (S)-Pirlindole formula III

was also isolated as an hydrochloride salt although via asymmetric synthesis from the 6-methyl-2,3,4,9-tetrahydro-lH-carbazol-l-one IV

[0008] Compound of formula IV was reacted with chiral auxiliary (S)-(-)-a-methylbenzylamine to afford asymmetric (S)-6-methyl-N-(l-phenylethyl)-2,3,4,9-tetrahydro-lH-carbazol-l-imine V

[0009] Compound of formula V was subjected to stereoselective reduction with sodium borohydride in ethanol. According to Andreeva et al. the reaction might occur through directed intramolecular hydride transfer after formation of a complex between compound of formula V and reducing agent to afford (S)-6-methyl-N-((S)-l-phenylethyl)-2,3,4,9-tetrahydro-lH-carbazol-l-amine VI

[0010] Compound of formula VI is reacted with ethylene glycol ditosylate by ethylene bridge formation under alkaline conditions to yield (S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole VII.

[0011] Alkaline agent is sodium hydride (NaH), in the presence of dimethyl sulfoxide (DMSO) or dimethylformamide (DMF).

[0012] The ratio between alkaline agent, compound of formula VI and ethylene glycol ditosylate is 1.2:1:1.

[0013] The cyclization reaction occurs at room temperature for a period of 4.5 hours. [0014] Compound of formula VII was subjected to catalytic hydrogenolysis conditions to afford the desired hydrochloride salt of compound of formula III.

[0015] The hydrogenolysis reaction was catalysed by Palladium on charcoal (Pd content 0.1 g, 9 mol%) and was conducted in methanol. The conversion of compound of formula VII into compound of formula III was performed under a hydrogen pressure of 1.8-2.0 MPa at 22 °C for a period of 17h.

[0016] The work-up conditions for the hydrogenolysis reaction involved neutralization with ammonia solution followed by benzene recrystallization. The hydrochloride salt of compound of formula III was formed from addition of hydrochloric acid to a solution of free base in ethanol.

[0017] The process yielded (S)-Pirlindole hydrochloride with a final yield of 10% with respect to the intermediate VI.

[0018] The mixture of sodium hydride with DMSO generates dimsyl anion. This anion is very often used in laboratory scale, but because it is unstable its use on large scale should be under specific precautions. Dimsyl anion decomposition is exotermic. It is reported that dimsyl anion decomposition starts even at 20 °C, and above 40 °C it decomposes at an appreciable rate (Lyness, W. I. et ai, U.S. 3,288,860 1966, CI. 260-607).

[0019] The mixture of DMF and sodium hydride is reported in ‘Sax & Lewis’s Dangerous Properties of Industrial Materials’ to give a violent reaction with ignition above 50 °C. Buckey, J. et ai, Chem. Eng. News 1982, 60(28), 5, describes the thermal runaway of a pilot plant reactor containing sodium hydride and DMF from 50 °C. Accelerated Rate Calorimetry (ARC) tests showed exothermic activity as low as 26 °C. Similar behaviour was also seen with DMA. De Wall, G. et ai, Chem. Eng. News 1982, 60(37), 5, reports a similar incident, wherein runaway started at 40 °C, and rose 100 °C in less than 10 minutes, boiling off most of the DMF.

[0020] There exists a need for safe, industrial- and eco-friendly processes for the preparation of Pirlindole enantiomers. These facts are disclosed in order to illustrate the technical problem addressed by the present disclosure.

[0068] In an embodiment, the preparation of (S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole, compound of formula VII was carried out as follow.

[0069] In an embodiment, in a 2 L three necked round bottomed flask equipped with magnetic stirrer, ethylene glycol ditosylate (73 g, 197 mmol) and DMI (240 mL) were loaded. To the resulting clear solution, NaH (60% suspension in mineral oil, 15.8 g, 394 mmol) was added carefully. To the resulting suspension a solution of VI ((S)-6-methyl-N-((S)-l-phenylethyl)-2,3,4,9-tetrahydro-lH-carbazol-l-amine) (30 g, 98.5 mmol) in DMI (60 mL) was added dropwise at 60 °C. The mixture was stirred for 1 h at 60 °C. The mixture was cooled down to room temperature, then MeOH was added slowly with ice-water cooling. A white precipitation appeared, and the resulting suspension was stirred and then filtered. The filtered product was washed with water-MeOH. The product was dried under vacuum to give 24.9 g of compound of formula VII (75.2 mmol, yield: 76%). Purity >99.9area% (HPLC).

[0070] In an embodiment, the preparation of hydrochloride salt of (S)-Pirlindole, compound of formula III, was performed as follow.

[0071] In an embodiment, the free amine VII ((S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole) (8,32 g, 25 mmol) was dissolved in DCM (42 mL) and excess of HCI in MeOH (42 mL) was added. The solvents were evaporated under reduced pressure to dryness to give a yellow oil. The residue was dissolved in MeOH (120 mL) and was added to the dispersion of Pd/C (1,74 g, -50% water) in MeOH (20 mL). The reaction mixture was stirred at 50 °C under a 750 KPa (7.5 bar) pressure of hydrogen for 5h. After completion (HPLC) the suspension was filtered through a celite pad, and the filter cake was washed with MeOH. The pH of the resulting solution was checked (<3) and it was evaporated to give the crude hydrochloride salt of compound of formula III. To the crude material iPrOH was added and the suspension was allowed to stir at reflux. The suspensions were filtered, and the product was dried under vacuum to give the hydrochloride salt of (S)-Pirlindole, compound of formula III (5.11 g, 19.5 mmol, yield: 77%). Purity > 99.5% (HPLC). Enantiomeric purity 99.5% (Chiral HPLC). MS (ESI): m/z 227.2 (M+H)+.

PATENT

WO-2018193414

Process for the preparation of piperazine ring for the synthesis of pyrazinocarbazole derivatives, such as the antidepressant pirlindole .

Pirlindole hydrochloride is the compound represented in formula I

[0003] It is the common name of 8-methyl-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole hydrochloride which is an active pharmaceutical ingredient marketed with the name Pyrazidol™. The compound is effective as an anti-depressant agent.

[0004] Pirlindole chemical structure belongs to the pyrazinocarbazole group. It is composed of one stereogenic centre which anticipate the existence of two enantiomers, the ( ?)-Pirlindole of formula II and the (S)-Pirlindole of formula III.

[0005] Although Pirlindole pharmacological data and the clinical use were performed on the racemate, recently there have been increasing interest in the pharmacological profile of each enantiomer (WO 2015/171005 Al).

[0006] The document WO 2015/171003Al(Tecnimede group) filed 9th May 2014 discloses a resolution of racemic pirlindole into optically active pirlindole. The Resolution-Racemization-Recycle (RRR) synthesis described involves derivatization by preparation of pairs of diastereomers in the form of salts from an optically active organic acid. These diastereomers can be separated by conventional techniques such as crystallisation. Although it is a very efficient procedure to prepare laboratorial scale or pre-clinical batch of (/?)- or (S)-Pirlindole, it is not economically convenient at an industrial scale because the process relies on Pirlindole racemate as the starting material.

[0007] Processes to prepare Pirlindole involve the formation of a piperazine ring. The state of the art discloses different processes for piperazine ring formation but they are generally a multistep approach, and they are hampered by low yields, expensive reagents, or are reported as unsuccessful (Roderick et al. Journal of Medicinal Chemistry 1966, 9, 181-185).

[0008] The first asymmetric synthesis of Pirlindole enantiomers described by Andreeva et al. (Pharmaceutical Chemistry 1992, 26, 365-369) discloses a one-step process to prepare pyrazinocarbazole piperazine ring system from a tetrahydrocarbazole-amine. The process discloses a very low yield (23.8 %) and employs the use of sodium hydride (NaH) in the presence of dimethyl sulfoxide (DMSO) or dimethyl formamide (DMF), both conditions described as generating exothermic decomposition that can cause reaction ignition or reaction thermal runaway.

[0009] The mixture of sodium hydride with DMSO generates dimsyl anion. This anion is very often used in laboratory scale, but because it is unstable its use on large scale should be under specific precautions. The dimsyl anion decomposition is exothermic. It is reported that dimsyl anion decomposition starts even at 20 °C, and above 40 °C it decomposes at an appreciable rate (Lyness et al. US 3288860).

[0010] The mixture of DMF and sodium hydride is reported in Sax & Lewis’s Dangerous Properties of Industrial Materials to give a violent reaction with ignition above 50 °C. Buckey et al., (Chemical & Engineering News, 1982, 60(28), 5) describes the thermal runaway of a pilot plant reactor containing sodium hydride and DMF from 50 °C. Accelerated Rate Calorimetry (ARC) tests showed exothermic activity as low as 26 °C.

Similar behaviour was also seen with DMA. De Wall et al. (Chem. Eng. News, 1982, 60(37), 5) reports a similar incident, wherein runaway started at 40 °C, and rose 100 °C in less than 10 minutes, boiling off most of the DMF.

[0011] An alternative process for the preparation of a piperazine ring system of a pyrazinocarbazole derivative can involve the formation of a lactam ring in a three steps approach:

1. N-acylation reaction;

2. intramolecular indole acetamide cyclisation to afford a lactam ring;

3. lactam reduction.

[0012] Intramolecular indole chloroacetamide cyclization to yield a lactam ring has been described by Bokanov et al. (Pharmaceutical Chemistry Journal 1988, 23, 12, 1311-1315) particularly in the non-enantioselective synthesis of pyrazinocarbazolone derivatives. Bokanov et al. did not describe the lactam reduction into a piperazine ring.

[0013] Intramolecular indole chloroacetamide cyclization to yield a lactam ring has also been described both by Rubiralta et al. (Journal of Organic Chemistry 54, 23, 5591-5597) and Bennasar, et al. (Journal of Organic Chemistry 1996., 61, 4, 1239-1251), as an unexpected outcome of a photocyclization reaction. The lactam conversion was low (<11% yield).

[0014] Lactam reduction of a pyrazinone into piperazine ring systems is disclosed both by Aubry et al. (Biorganic Medicinal Chemistry Letters 2007, 17, 2598-2602) and Saito et al. (Tetrahedron 1995, 51, 30, 8213-8230) in the total synthesis of alkaloid natural products.

[0015] There exists the need for improved processes for the preparation of piperazine ring derivatives in particular enantioselective processes for the preparation of pyrazinocarbazole intermediates precursors of Pirlindole enantiomers compounds of formula II and III.

Example 1 – Preparation of (S)-8-methyl-3-((S)-l-phenylethyl)-3a,4,5,6-tetrahydro-lH-pyrazino[3,2,l-jk]carbazol-2(3H)-one – Formula IV

[00106] In an embodiment, the preparation of (S)-8-methyl-3-((S)-l-phenylethyl)-3a,4,5,6-tetrahydro-lH-pyrazino[3,2,l-jk]carbazol-2(3H)-one (Formula IV) was carried out as follows. To the solution of VI (S)-6-methyl-N-((S)-l-phenylethyl)-2,3,4,9-tetrahydro-lH-carbazol-l-amine (30 g, 98.5 mmol) in toluene (300 mL), 50 % (w/v) aqueous NaOH (79 g) was added dropwise at 0-5 °C, then the solution of chloroacetyl

chloride (12 mL, 148 mmol, 1.5 equiv.) in toluene (15 mL) was added dropwise at 0-5 °C. The mixture was stirred at 0-5 °C for approximately 2.5 h, and additional chloroacetyl chloride (12 mL, 148 mmol, 1.5 equiv.) in toluene (15 mL) was added dropwise at 0-5 °C. The mixture was stirred at 0-5 °C for approximately 1.5 h. Water was added to the reaction mixture keeping the temperature below 5 °C. The phases were separated, and the aqueous phase was extracted with toluene. The organic phase was treated with 2M aqueous HCI. The resulting suspension was filtered. The filtered solid was identified as the HCI salt of VI, which can be liberated and driven back to the chloroacetylation step. The phases of the mother liquor were separated, and the aqueous phase was extracted with toluene. The organic phase was dried over Na2S04, filtered and concentrated under reduced pressure to about 350 mL as a solution in toluene. The toluene solution of the crude product compound of formula X was reacted in the next step.

[00107] In an embodiment, in the same reaction vessel to the toluene solution of crude intermediate obtained in previous step were added TBAB (0.394 g, 1.22 mmol, 1 w/w% for the theoretical yield of prev. step) and 50 % (w/v) aqueous NaOH (8.1 g, 10 equiv.). The reaction mixture was stirred for 1 h at 65 °C, while the reaction was complete. Water was added to the mixture at 0 °C, and the phases were separated, the organic phase was washed with aqueous HCI, and with water, then dried over Na2S04, filtered and evaporated to give 32.87 g of compound IV (S)-8-methyl-3-((S)-l-phenylethyl)-3a,4,5,6-tetrahydro-lH-pyrazino[3,2,l-jk]carbazol-2(3H)-one (yield: 97% for the two steps) as a brown solid. The crude product was reacted in the next step without further purification.

Example 2 – Preparation of (S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole _ Formula V

[00108] In an embodiment, the preparation of (S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole (Formula V) was performed as follows. To the stirred solution of 32.87 g of IV, (S)-8-methyl-3-((S)-l-phenylethyl)-3a,4,5,6-tetrahydro-lH-pyrazino[3,2,l-jk]carbazol-2(3H)-one (95.4 mmol) in dry THF (170 mL) 66 mL solution of sodium bis(2-methoxyethoxy)aluminium hydride in toluene (70 w/w%, 237 mmol, 2.5 equiv.) was added dropwise. The reaction mixture was warmed to 40 °C, and the end of the addition the mixture was stirred at 50 °C until the total consumption of the starting material. Additional 22 mL of sodium bis(2-methoxyethoxy)aluminium hydride solution (70 w/w%, 79 mmol, 0.8 equiv.) was added dropwise. After completion the mixture was cooled to room temperature and 5% aqueous NaOH was added carefully. Water and DCM were added to the mixture, the phases were separated, and the aqueous phase was extracted with DCM. The organic phase was dried over Na2S04, filtered and the solvent was evaporated to get a brown solid (28.8 g). This crude product was dissolved in DCM and MeOH was added. White solid precipitated. The solid was filtered and washed with MeOH to give V (S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a,4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole 14.6 g (yield: 46%) as an off-white cotton-like solid.

Example 3 – Preparation of (S)-Pirlindole Hydrochloride – Formula III

[00109] In an embodiment, the preparation of (S)-Pirlindole hydrochloride III was carried out as follows. The free amine V ((S)-8-methyl-3-((S)-l-phenylethyl)-2,3,3a, 4,5,6-hexahydro-lH-pyrazino[3,2,l-jk]carbazole) (8.32 g, 25 mmol) was dissolved in DCM (42 mL) and excess of HCI in MeOH (42 mL) was added. The solvents were evaporated under reduced pressure to dryness to give a yellow oil. The residue was dissolved in MeOH (120 mL) and was added to the dispersion of Pd/C (1.74 g, -50% water) in MeOH (20 mL). The reaction mixture was stirred at 50 °C under 750 KPa (7.5 bar) pressure of hydrogen for 5h. After completion (HPLC) the suspension was filtered through a celite pad, and the filter cake was washed with MeOH. The pH of the resulting solution was checked (<3) and it was evaporated to give the crude hydrochloride salt of compound of formula III. To the crude material iPrOH was added and the suspension was allowed to stir at reflux. The suspensions were filtered, and the product was dried under vacuum to give the hydrochloride salt of (S)-Pirlindole, compound of formula III (5.11 g, 19.5 mmol, yield: 77%). Purity > 99.5% (HPLC). Enantiomeric purity 99.5% (Chiral HPLC). MS (ESI): m/z 227.2 (M+H)+.

[00110] Table 1. Comparative yields

Synthesis Reference

http://www.biomedsearch.com/nih/Pirlindole-in-treatment-depression-meta/21053988.html

General References

  1. Branco JC, Tome AM, Cruz MR, Filipe A: Pirlindole in the treatment of depression and fibromyalgia syndrome. Clin Drug Investig. 2011 Oct 1;31(10):675-89. doi: 10.2165/11595410-000000000-00000. [PubMed:21877764]
  2. Bruhwyler J, Liegeois JF, Geczy J: Pirlindole: a selective reversible inhibitor of monoamine oxidase A. A review of its preclinical properties. Pharmacol Res. 1997 Jul;36(1):23-33. doi: 10.1006/phrs.1997.0196. [PubMed:9368911]
  3. Psychiatry: The State of the Art Volume 3 Pharmacopsychiatry [Link]
  4. Chemistry Dashboard- Pirlindole [Link]
  5. Pirlindole in the Treatment of Depression and Fibromyalgia Syndrome [Link]
  6. Hypertensive effect and cheese [Link]
  7. Monamine oxide inhibitors [Link]

References

  1. Jump up^ Medvedev AE, et al. The influence of the antidepressant pirlindole and its dehydro-derivative on the activity of monoamine oxidase A and GABAA receptor binding. Chapter 36 in MAO – The Mother of all Amine Oxidases (Journal of Neural Transmission. Supplementa). Eds Finberg JPM, Youdim MBH, Riederer P, Tipton KF. Special edition of Journal of Neural Transmission, Suppl. 52 1st ed. 1998 ISBN 978-3211830376
Pirlindole
Pirlindole structure.svg
Clinical data
Trade names Pirazidol
Routes of
administration
Oral
ATC code
  • none
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 20–30%
Protein binding 95%
Metabolism hepatic
Onset of action 2 to 8 hours
Elimination half-life 185 hours
Excretion urine (50–70%), feces (25–45%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C15H18N2
Molar mass 226.32 g/mol
3D model (JSmol)

//////////////PirlindoleLifrilPyrazidol, 60762-57-4, DEPRESSION

CC1=CC2=C(C=C1)N3CCNC4C3=C2CCC4

A call to (green) arms: a rallying cry for green chemistry and engineering for CO2 capture, utilisation and storage


Green Chemistry International

Graphical abstract: A call to (green) arms: a rallying cry for green chemistry and engineering for CO2 capture, utilisation and storage

A call to (green) arms: a rallying cry for green chemistry and engineering for CO2 capture, utilisation and storage

 Author affiliations

Abstract

Chemists, engineers, scientists, lend us your ears… Carbon capture, utilisation, and storage (CCUS) is among the largest challenges on the horizon and we need your help. In this perspective, we focus on identifying the critical research needs to make CCUS a reality, with an emphasis on how the principles of green chemistry (GC) and green engineering can be used to help address this challenge. We identify areas where GC principles can readily improve the energy or atom efficiency of processes or reduce the environmental impact. Conversely, we also identify dilemmas where the…

View original post 115 more words

Technetium (99mTc) tetrofosmin, テトロホスミンテクネチウム (99mTc)


99mTc-tetrofosmin structure.svg

Thumb

Technetium Tc-99m tetrofosmin.png

Technetium (99mTc) tetrofosmin, 99mTc-Tetrofosmin

テトロホスミンテクネチウム (99mTc)

Formula C36H80O10P4Tc
Molar mass 895.813 g/mol
CAS Number

UNII42FOP1YX93

2-[bis(2-ethoxyethyl)phosphanyl]ethyl-bis(2-ethoxyethyl)phosphane;technetium-98;dihydrate

Technetium Tc 99m tetrofosmin; Technetium Tc-99m tetrofosmin; TECHNETIUM TC-99M TETROFOSMIN KIT; Tc-99m tetrofosmin; Technetium-99 tetrofosmin; Technetium (99mTc) tetrofosmin

Title: Tetrofosmin
CAS Registry Number: 127502-06-1
CAS Name: 6,9-Bis(2-ethoxyethyl)-3,12-dioxa-6,9-diphosphatetradecane
Additional Names: ethylenebis[bis(2-ethoxyethyl)phosphine]
Manufacturers’ Codes: P53
Molecular Formula: C18H40O4P2
Molecular Weight: 382.46
Percent Composition: C 56.53%, H 10.54%, O 16.73%, P 16.20%
Literature References: Prepn: J. D. Kelly et al., EP 337654eidem, US 5045302 (1989, 1991 both to Amersham). Pharmacology and determn of radiochemical purity: idem et al., J. Nucl. Med. 34, 222 (1993). Clinical biodistribution: B. Higley et al., ibid. 30. Clinical trial as a myocardial perfusion imaging agent: B. L. Zaret et al., Circulation 91, 313 (1995).
Derivative Type: 99mTc-Complex
CAS Registry Number: 127455-27-0
Additional Names: 99mTc tetrofosmin; [99mTc(tetrofosmin)2O2]+
Manufacturers’ Codes: PPN1011
Trademarks: Myoview (GE Healthcare)
Molecular Formula: C36H80O10P499mTc

Technetium Tc-99m Tetrofosmin is a radiopharmaceutical consisting of tetrofosmin, composed of two bidentate diphosphine ligands chelating the metastable radioisotope technetium Tc-99 (99mTc), with potential imaging activity upon SPECT (single photon emission computed tomography). Upon administration, technetium Tc 99m tetrofosmin is preferentially taken up by, and accumulates in, myocardial cells. Upon imaging, myocardial cells can be visualized and changes in ischemia and/or perfusion can be detected.

Technetium Tc-99m tetrofosmin is a drug used in nuclear myocardial perfusion imaging. The radioisotope, technetium-99m, is chelated by two 1,2-bis[di-(2-ethoxyethyl)phosphino]ethane ligands which belong to the group of diphosphines and which are referred to as tetrofosmin. It is a lipophilic technetium phosphine dioxo cation that was formulated into a freeze-dried kit which yields an injection.[A31592] Technetium Tc-99m tetrofosmin was developed by GE Healthcare and FDA approved on February 9, 1996.

Technetium Tc-99m tetrofosmin is a drug used in nuclear myocardial perfusion imaging. The radioisotope, technetium-99m, is chelated by two 1,2-bis[di-(2-ethoxyethyl)phosphino]ethane ligands which belong to the group of diphosphines and which are referred to as tetrofosmin. It is a lipophilic technetium phosphine dioxo cation that was formulated into a freeze-dried kit which yields an injection.[1] Technetium Tc-99m tetrofosmin was developed by GE Healthcare and FDA approved on February 9, 1996.

Technetium (99mTc) tetrofosmin is a drug used in nuclear medicine cardiac imaging. It is sold under the brand name Myoview (GE Healthcare). The radioisotopetechnetium-99m, is chelated by two 1,2-bis[di-(2-ethoxyethyl)phosphino]ethane ligands which belong to the group of diphosphines and which are referred to as tetrofosmin.[1][2]

Image result for Technetium (99mTc) tetrofosmin synthesis

Tc-99m tetrofosmin is rapidly taken up by myocardial tissue and reaches its maximum level in approximately 5 minutes. About 66% of the total injected dose is excreted within 48 hours after injection (40% urine, 26% feces). Tc-99m tetrofosmin is indicated for use in scintigraphic imaging of the myocardium under stress and rest conditions. It is used to determine areas of reversible ischemia and infarcted tissue in the heart. It is also indicated to detect changes in perfusion induced by pharmacologic stress (adenosinelexiscandobutamine or persantine) in patients with coronary artery disease. Its third indication is to assess left ventricular function (ejection fraction) in patients thought to have heart disease. No contraindications are known for use of Tc-99m tetrofosmin, but care should be taken to constantly monitor the cardiac function in patients with known or suspected coronary artery disease. Patients should be encouraged to void their bladders as soon as the images are gathered, and as often as possible after the tests to decrease their radiation doses, since the majority of elimination is renal. The recommended dose of Tc-99m tetrofosmin is between 5 and 33 millicuries (185-1221 megabecquerels). For a two-dose stress/rest dosing, the typical dose is normally a 10 mCi dose, followed one to four hours later by a dose of 30 mCi. Imaging normally begins 15 minutes following injection.[3]

Image result for Technetium (99mTc) tetrofosmin synthesis

Amersham (formerly Nycomed Amersham , now GE Healthcare ) has developed and launched 99mTc-tetrofosmin (Myoview) as an injectable nuclear imaging agent for ischemic heart disease in several major territories and for use in detecting breast tumors

Technetium (99mTc) tetrofosmin is a drug used in nuclear medicine cardiac imaging. It is sold under the brand name Myoview (GE Healthcare). The radioisotope, technetium-99m, is chelated by two 1, 2-bis-[bis-(2-ethoxyethyl)phosphino] ethane ligands, which belong to the group of diphosphines and which are referred to as tetrofosmin and has the structural Formula 1 :

Formula 1

99mTc -based radiopharmaceuticals are commonly used in diagnostic nuclear medicine, especially for in vivo imaging (e.g. via immunoscintigraphy or radiolabeling). Usually cold kits are manufactured in advance in accordance with strict requirements of Good Manufacturing Practice (GMP) Guidelines, containing the chemical ingredients (e.g. 99mTc -coordinating ligands, preservatives) in lyophilized form. The radioactive isotope 99mTc (ti/2 = 6h) is added to those kits shortly before application to the patient via intravenous or subcutaneous injection.

Tc-99m tetrofosmin is rapidly taken up by myocardial tissue and reaches its maximum level in approximately 5 minutes. About 66% of the total injected dose is excreted within 48 hours after injection (40% urine, 26% feces). Tc-99m tetrofosmin is indicated for use in scintigraphic imaging of the myocardium under stress and rest conditions. It is used to determine areas of reversible ischemia and infarcted tissue in the heart. It is also indicated to detect changes in perfusion induced by pharmacologic stress (adenosine, lexiscan, dobutamine or persantine) in patients with coronary artery disease. Its third indication is to assess left ventricular function (ejection fraction) in patients thought to have heart disease. No contraindications are known for use of Tc-99m tetrofosmin, but care should be taken to constantly monitor the cardiac function in patients with known or suspected coronary artery disease. Patients should be encouraged to void their bladders as soon as the images are gathered, and as often as possible after the tests to decrease their radiation doses, since the majority of elimination is renal. The recommended dose of Tc-99m tetrofosmin is between 5 and 33 millicuries (185-1221 megabecquerels). For a two-dose stress/rest dosing, the typical dose is normally a 10 mCi dose, followed one to four hours later by a dose of 30 mCi. Imaging normally begins 15 minutes following injection.

99mTc -Tetrofosmin is also described to be useful for tumor diagnostics, in particular of breast cancer and parathyroid gland cancer, and for multidrug resistance (MDR) research.

US5045302 discloses 99mTc-coordinating diphosphine ligands (L), wherein one preferred example thereof is the ether functionalized diphosphine ligand l,2-bis[bis(2-ethoxy- ethyl)phosphino]ethane according to Formula 1, called tetrofosmin (“P53”), that forms a dimeric cationic technetium (V) dioxo phosphine complex, [TCO2L2] with 99mTc, useful as myocardial imaging agent. Example 1 of said patent described the process for preparing tetrofosmin by reacting ethyl vinyl ether, bis(diphosphino)ethane in the presence of a-azo-isobutyronitrile (AIBN) in a fischer pressure-bottle equipped with a teflon stirring bar followed by removal of volatile materials and non-distillable material obtained, as per below mentioned Scheme 1.

Scheme 1

Formula 2 Formula 3 Formula 1

CN 1184225 C discloses tetrofosmin salts containing chloride or bromide or aryl sulfonates as negatively charged counter ions, which can be used for the preparation of a 99mTc- Tetrofosmin radiopharmaceutical composition. According to this patent tetrofosmin hydrochloride is a viscous liquid. Own experiments of the inventors of the present invention revealed that the halide salts of tetrofosmin are hygroscopic oils, which are complicated to handle, e.g. when weighed. The oily and hygrospcopic

properties of tetrofosmin hydrochloride hampers its use in pharmaceutical preparations. Attempts to synthesize the subsalicylate salt of tetrofosmin failed because the starting material sulfosalicylic acid was not soluble in ether in the concentration specified in the patent (3.4 g in 15 ml).

WO2006/064175A1 discloses tetrofosmin was converted to tetrofosmin subsalicylate by reaction with 2.3 to 2.5 molar equivalents of 5-sulfosalicyclic acid at room temperature in ethanol, followed by recrystallisation from ethanol/ether.

WO2015/114002A1 relates to tetrafluoroborate salt of tetrafosmin and its process for the preparation thereof. Further this application also discloses one-vial and two vial kit formulation with tetrafluoroborate salt of tetrafosmin.

The article Proceedings of the International Symposium, 7th, Dresden, Germany, June 18-22, 2000 by Amersham Pharmacia Biotech UK Limited titled “The synthesis of [14C]tetrofosmin, a compound vital to the development of Myoview, Synthesis and Applications of Isotopically Labelled Compounds” disclosed a process for the preparation of tetrofosmin as per below mentioned Scheme 2:

Scheme 2

Formula 1A Formula 7

The starting material was bis(2- ethoxyethyl)benzylphosphine of Formula 4 . This was prepared from benzyl phosphonate, PhCH2P(0)(OEt)2 by reduction with lithium aluminium hydride to give the intermediate benzylphosphine, PhCH2PH2, followed by a photolysis reaction in the presence of ethyl vinyl ether to give compound of Formula 4. The compound of Formula 4 in acetonitrile was treated with dibromo[U-14C]ethane to give compound of Formula 6, further it was treated with excess of 30% aqueous sodium hydroxide in ethanol. The mixture was stirred at room temperature for 24 hours. The solvent was removed and the residue was treated with excess concentrated hydrochloric acid at 0°C. Aqueous work up gave compound of Formula 7. Then compound of Formula 7 in dry benzene was treated with hexachlorodisilane and hydrolysed with excess 30% aqueous sodium hydroxide at 0°C. Aqueous work up followed by flash column chromatography on silica gave [bisphosphinoethane- 1,2-14C]tetrofosmin of formula 1A.

The article Polyhedron (1995), 14(8), 1057-65, titled “Synthesis and characterization of Group 10 metal complexes with a new trifunctional ether phosphine. The X-ray crystal structures of bis[bis(2-ethoxyethyl)benzylphosphine]dichloronickel(II) and bis[bis(2-ethoxyethyl)benzylphosphine]chlorophenylnickel(II)” disclosed the process for the preparation of bis(2-ethoxyethyl)benzylphosphine as per below mentioned Scheme 3:

Scheme 3

Formula 8 Formula 9 Formula 4

The compound bis(2-ethoxyethyl)benzylphosphine of Formula 4 was prepared by first reduction of diethylbenzylphosphonate of Formula 8 using lithium aluminium hydride to obtain benzyl phosphine of Formula 9 followed by radical catalysed coupling reaction with ethyl vinyl ether carried out by using UV photolysis.

Tetrofosmin is extremely sensitive to atmospheric oxygen, which makes synthesis of the substance, as well as manufacturing and handling of the kit complicated as the substance has constantly to be handled in an oxygen free atmosphere.

High purity and stability under dry and controlled conditions are pivotal requirements for chemical compounds used as active ingredients in pharmaceuticals.

The processes disclosed in prior art for the preparation of compound of Formula 4 involves that coupling reaction of benzyl phosphine of Formula 9 with ethyl vinyl ether carried out by using photolytic conditions. Such technology is expensive as it requires separate instruments including isolated facility (to avoid the UV radiation exposure etc.), also it is not suitable for commercial scale production.

PATENT

WO-2018162964

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018162964&tab=PCTDESCRIPTION&maxRec=1000

Example 1

Preparation of benzyl phosphine:

A mixture of lithium aluminium hydride (25 g) in methyl tertiary butyl ether (MTBE) (800 ml) was cooled to 0 to 5°C and added a solution of diethylbenzylphosphonate in methyl tertiary butyl ether (100 g in 200ml). The temperature of reaction mixture was raised to 25 to 30 °C and stirred for 14 to 16 hour. After completion of the reaction, the reaction mixture was cooled to 0 to 5°C and 6N hydrochloric acid was added slowly. Further raised the temperature of reaction mixture to 25 to 30 °C and stirred for 30-45 minutes. The layers were separated, the aqueous layer was extracted with MTBE (250ml) and the combined organic layer was washed with deoxygenated water. The organic layer was dried over sodium sulfate and concentrated to obtain the title compound as non-distillable liquid.

Example 2

Preparation of benzylbis(2-ethoxyethyl)phosphane:

To a mixture of benzyl phosphine (obtained from example 1) and vinyl ethyl ether (250 ml) in pressure RB flask was added a-azo-isobutyronitrile (AIBN) (1.5g). The resulting reaction mixture was maintained at 80 to 90°C for 14 to 16 hours. The mixture was cooled to 20 to 30°C and AIBN (0.5g) added, then continued to heat the reaction mixture at 80 to 90°C for 6 to 7 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature and distilled under vacuum to obtain title compound as an oil (107 g).

Example 3

Preparation of Ethane- 1,2-diylbis (benzylbis(2-ethoxyethyl) phosphonium) bromide:

To a mixture of benzylbis(2-ethoxyethyl)phosphane 107.g) in acetonitrile (100ml) in pressure bottle was added 1, 2-dibromoethane (30.5 g). The reaction mixture was maintained at 80 to 90°C for 20 to 25 hours. After completion of the reaction, the reaction mass was cooled to room temperature and stirred for 45 to 60 minutes to obtain the solid. To the solid obtained was added methyl tertiary butyl ether (MTBE) (500ml) and stirred at room temperature for 2 to 3 hour. The reaction mass was filtered, washed with MTBE and suck dried. Further the filtered solid was heated in acetone (400ml) at 50 to 55°C for 2 to 3 hour. Then cooled the reaction mixture to room temperature, stirred, filtered and washed with acetone to obtain the title compound as white solid. (85g)

Example 4

Preparation of Ethane- 1, 2-diylbis (bis (2-ethoxy ethyl) phosphine oxide):

To a mixture of Ethane- 1,2-diylbis (benzylbis(2-ethoxyethyl) phosphonium) bromide (80g) in ethanol (480 ml) was added an aq. solution of sodium hydroxide ( 48g in 160 ml water) at room temperature. The reaction mass was maintained at 25 to 35°C for 10 to 12 hour. After completion of the reaction, the reaction mass was cone, under vacuum to obtained the residue. The residue was dissolved in deoxygenated water (400 ml) and washed with MTBE (400 ml x 2). The layers were separated, the aqueous layer was cooled to 10 to 20°C and 6N hydrochloric acid (200 ml) was added slowly. Then extracted the aqueous layer with dichloromethane (2000 ml), washed the organic layer with deoxygenated water (160 ml), dried the organic layer using sodium sulfate, filtered, and distilled under vacuum to obtain the residue. Further MTBE (160 ml x 2) was added to the residue and continued distillation under vacuum, degassed to obtain the solid. To the obtained solid, MTBE (400 ml) was added and heated at 45 to 50°C for 1-2 hour, further slowly cooled the reaction mass to 25 to 30°C, filtered the solid product. Again MTBE (400 ml) was added to the solid product and heated at 45 to 50°C for 1-2 hour, further slowly cooled the reaction mass to 25 to 30°C, filtered, washed with MTBE and dried under vacuum to obtain the title compound as white solid (32g).

Example 5

Preparation of tetrofosmin free base:

To a mixture of ethane- 1, 2-diylbis (bis (2-ethoxyethyl) phosphine oxide (18g) in toluene (180ml) in pressure RB flask argon/nitrogen gas was purged for 5 minute and hexachlorodisilane (30g) was added. The reaction mixture was heated to 80 to 90°C, stirred for 10 to 12 hour, further slowly cooled to -5 to 0°C and slowly added 30% aqueous sodium hydroxide solution (45g sodium hydroxide in 150 ml deoxygenated water) the temperature of reaction mixture was raised to 25 to 30°C and stirred for 1 to 2 hour. The layers were separated and the aq. layer was extracted with Toluene (180 ml). The combined organic layer was washed with deoxygenated water (180 ml). Further dried the organic layer using sodium sulfate, distilled under vacuum to obtain the residue of tetrofosmin free base (15.5g).

Example 6

Preparation of tetrofosmin disulfosalicylate salt:

To the residue of tetrofosmin free base (15.5g) was added an aq. solution of 5-sulfosalicylic acid dihydrate (21.6g in 75ml deoxygenated water) and stirred at 25 to 30°C for 25 to 30 minutes. Further heated the reaction mass to 55 to 60°C, stirred for 15 to 30 minute, slowly cooled the reaction mass to 10 to 15°C and stirred for 1-2 hour. Filtered, washed with chilled deoxygenated water, and dried under vacuum to obtain the title compound as white solid. (30g).

Example 7

Preparation of Form J of tetrofosmin disulfosalicylate salt:

An aq. solution of 5-sulfosalicylic acid dihydrate (21.6g in 75ml deoxygenated water) was added slowly into tetrofosmin free base (15.5g) and stirred at room temperature for 30 to 40 minutes. The temperature of reaction mixture was further raised to 50 to 60°C, stirred for 20 to 30 minute, cooled the reaction mass to 10 to 15°C and stirred for 1-2 hour. Filtered, washed with chilled deoxygenated water, and dried under vacuum to obtain the title compound.

PATENT

EP337654 ,

PATENT

US9549999

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 1 (FDA Orange Book Patent ID)
Patent 9549999
Expiration Mar 10, 2030
Applicant GE HEALTHCARE
Drug Application
  1. N020372 (Prescription Drug: MYOVIEW 30ML. Ingredients: TECHNETIUM TC-99M TETROFOSMIN KIT)
  2. N020372 (Prescription Drug: MYOVIEW. Ingredients: TECHNETIUM TC-99M TETROFOSMIN KIT)

References

  1. Jump up^ Kelly JD, Alan M. Forster AM, Higley B, et al. (February 1993). “Technetium-99m-Tetrofosmin as a new radiopharmaceutical for myocardial perfusion imaging”Journal of Nuclear Medicine34 (2): 222–227. PMID 8429340.
  2. Jump up^ Elhendy A, Schinkel AF, et al. (December 2005). “Risk stratification of patients with angina pectoris by stress 99mTc-tetrofosmin myocardial perfusion imaging”Journal of Nuclear Medicine46 (12): 2003–2008. PMID 16330563.
  3. Jump up^ Myoview package insert. Arlington Heights, IL: GE Healthcare, 2006, Aug.
Technetium (99mTc) tetrofosmin
99mTc-tetrofosmin structure.svg
Clinical data
Routes of
administration
Intravenous
ATC code
Pharmacokinetic data
Bioavailability N/A
Identifiers
CAS Number
Chemical and physical data
Formula C36H80O10P4Tc
Molar mass 895.813 g/mol
Patent ID

Title

Submitted Date

Granted Date

US9549999 RADIOPHARMACEUTICAL COMPOSITION
2010-09-23

External links

Myoview Prescribing Information Page

//////////99mTc-Tetrofosmin, Technetium (99mTc) tetrofosmin, テトロホスミンテクネチウム (99mTc)

CCOCCP(CCOCC)CCP(CCOCC)CCOCC.CCOCCP(CCOCC)CCP(CCOCC)CCOCC.O.O.[Tc]

Diazoxide choline


Diazoxide choline.png

Image result for Diazoxide choline

Diazoxide choline,

RN: 1098065-76-9
UNII: 2U8NRZ7P8L

Diazoxide choline; UNII-2U8NRZ7P8L; 2U8NRZ7P8L; YLLWQNAEYILHLV-UHFFFAOYSA-N

Molecular Formula: C13H20ClN3O3S
Molecular Weight: 333.831 g/mol

Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, compd. with 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine dioxide (1:1)

7-Chloro-3-methyl-2H-1,2,4-benzothiadiazine dioxide compd. with 2-hydroxy-N,N,N-trimethylethanaminium (1:1)

7-chloro-3-methyl-1$l^{6},2,4-benzothiadiazin-2-ide 1,1-dioxide;2-hydroxyethyl(trimethyl)azanium

DiazoxideDiazoxide

CAS: 364-98-7 FREE FORM

2H-1,2,4-Benzothiadiazine, 7-chloro-3-methyl-, 1,1-dioxide

  • 4H-1,2,4-Benzothiadiazine, 7-chloro-3-methyl-, 1,1-dioxide (7CI)
  • 3-Methyl-7-chloro-1,2,4-benzothiadiazine 1,1-dioxide
  • 7-Chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide
  • Diazoxide
  • Dizoxide
  • Eudemine injection
  • Hyperstat
  • Hypertonalum
  • Mutabase
  • NSC 64198
  • NSC 76130
  • Proglicem
  • Proglycem
  • SRG 95213
  • Sch 6783
Diazoxide
CAS Registry Number: 364-98-7
CAS Name: 7-Chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide
Additional Names: 3-methyl-7-chloro-1,2,4-benzothiadiazine 1,1-dioxide
Manufacturers’ Codes: SRG-95213
Trademarks: Eudemine Injection (Schering); Proglicem (Essex); Hyperstat (Schering); Hypertonalum (Essex); Mutabase (Schering); Proglycem (Schering)
Molecular Formula: C8H7ClN2O2S
Molecular Weight: 230.67
Percent Composition: C 41.66%, H 3.06%, Cl 15.37%, N 12.14%, O 13.87%, S 13.90%
Literature References: Hypotensive agent that inhibits secretion of insulin from pancreatic beta cells. Prepn: A. A. Rubin et al.,Science 133, 2067 (1961); J. G. Topliss et al., US 2986573eidem, US 3345365 (1961, 1967 both to Schering); Raffa, Monzani, Farmaco Ed. Sci. 17, 244 (1962). Crystal and molecular structure: G. Bandoli, M. Nicolini, J. Cryst. Mol. Struct. 7, 229 (1978). Review of effect on insulin secretion: Nutr. Rev. 30, 194-198 (1972); of pharmacology and efficacy in hypertension: J. Koch-Weser, N. Engl. J. Med. 294, 1271-1274 (1976).
Properties: Crystals from dil alc, mp 330-331°. uv max (methanol): 268 nm (e 11300). Sol in alcohol and alkaline solns. Insol in water.
Melting point: mp 330-331°
Absorption maximum: uv max (methanol): 268 nm (e 11300)
Therap-Cat: Antihypoglycemic; antihypertensive.
Keywords: Antihypertensive; Thiazides and Analogs; Antihypoglycemic.

Diazoxide (INN; brand name Proglycem[1]) is a potassium channel activator, which causes local relaxation in smooth muscle by increasing membrane permeability to potassium ions. This switches off voltage-gated calcium ion channels, preventing calcium flux across the sarcolemma and activation of the contractile apparatus.

In the United States, this agent is only available in the oral form and is typically given in hospital settings.[2]

Medical uses

Diazoxide is used as a vasodilator in the treatment of acute hypertension or malignant hypertension.[3]

Diazoxide also inhibits the secretion of insulin by opening ATP-sensitive potassium channel of beta cells of the pancreas, thus it is used to counter hypoglycemia in disease states such as insulinoma (a tumor producing insulin)[4] or congenital hyperinsulinism.

Diazoxide acts as a positive allosteric modulator of the AMPA and kainate receptors, suggesting potential application as a cognitive enhancer.[5]

Side effects

The Food and Drug Administration published a Safety Announcement in July 2015 highlighting the potential for development of pulmonary hypertension in newborns and infants treated with this drug.[2]Diazoxide interferes with insulin release through its action on potassium channels.[6] Diazoxide is one of the most potent openers of the K+ ATP channels present on the insulin producing beta cells of the pancreas. Opening these channels leads to hyperpolarization of cell membrane, a decrease in calcium influx, and a subsequently reduced release of insulin.[7] This mechanism of action is the mirror opposite of that of sulfonylureas, a class of medications used to increase insulin release in Type 2 Diabetics. Therefore, this medicine is not given to non-insulin dependent diabetic patients.

SYN

Medicinal Chemistry Research, 12(9), 457-470; 2004

PATENT

WO 2009006483

https://patents.google.com/patent/WO2009006483A1/enIt

PATENT

US 20120238554

PATENT

WO 2013130411

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013130411&recNum=95&docAn=US2013027676&queryString=Telmisartan%20OR%20Hydrochlorothiazide&maxRec=4800

able 16. Characterization of Forms A and B of Diazoxide Choline Salt In

Screening Study

Experiment Form A Form B

*Maj or peaks (2-Θ):

Form A (9.8, 10.5, 14.9, 17.8, 17.9, 18.5, 19.5, 22.1, 22.6, 26.2, 29.6, 31.2);

Form B (8.9, 10.3, 12.0, 18.3, 20.6, 24.1, 24.5, 26.3, 27.1, 28.9).

** Unique FTIR (ATR) absorbances (cm 1):

Form A (2926, 2654, 1592, 1449, 1248);

Form B (3256, 2174, 2890, 1605, 1463, 1235).

6.1.5.1. Solubility Screen in organic solvents.

[00725] Diazoxide choline, prepared in MEK using choline hydroxide as 50 wt % solution in water (see above) displayed some solubility in the following solvents:

acetonitrile, acetone, ethanol, IPA, MEK, DMF, and methanol. These solvents were chosen due to differences in functionality, polarity, and boiling points and their ability to dissolve diazoxide. Other solvents which showed poor ability to dissolve salts were used as antisolvents and in slurry experiments where some solubility was observed: dioxane, MTBE, EtOAc, IP Ac, THF, water, cyclohexane, heptane, CH2C12, and toluene.

[00726] Solvents for crystallizations during screening were chosen based on the solubility screen summarized in Table 17. Crystallizations of diazoxide choline from all conditions afforded a total of two forms, A and B. Forms A and B were found to be anhydrous polymorphs of diazoxide choline. Form B was observed to be generated from most solvents used. It was difficult to isolate pure Form A on large scales (>50 mg) as conditions observed to produce Form A on a smaller scale (approximately 50 mg or less) were found to result in Form B or mixtures of both forms on larger scales. Based on room-temperature slurry experiments, anhydrous Form B was found to be the most thermodynamically stable form in this study. Form A readily converted to Form B in all slurry solvents utilized.

Table 17. Solubility Screen for Diazoxide Choline Salt

Solvent Cmpd Solvent Cone. Temp. Soluble

(mg) (mL) (mg/niL) (°C)

CH2CI2 1.3 5.00 0.26 55 Partially

Toluene 1.4 5.00 0.28 55 No

.1.5.2. Single-Solvent Crystallizations

[00727] Fast cooling procedure: Diazoxide (approximately 20 mg) was weighed out into vials and enough solvent (starting with 0.25 mL) was added until the material completely dissolved at elevated temperature. After hot filtration the vials were placed in a refrigerator (4 °C) for 16 hours. After the cooling-process the samples were observed for precipitates which were isolated by filtration. Vials not demonstrating precipitates were evaporated down to dryness using a gentle stream of nitrogen. All solids were dried in vacuo at ambient temperature and 30 in. Hg.

[00728] Slow cooling procedure: Diazoxide (approximately 30 mg of choline salt) was weighed out into vials and enough solvent was added until the material went into solution at elevated temperature. After hot filtration the vials were then slowly cooled to room temperature at the rate of 20 °C/h and stirred at room temperature for 1-2 hours. All solids were dried in vacuo at ambient temperature and 30 in. Hg.

[00729] Based on the initial solubility study, seven solvents were selected for the fast-cooling crystallization: acetonitrile, acetone, ethanol, IPA, MEK, DMF, and methanol. Table 18 shows a list of the solvents that were used and the amount of solvent needed to dissolve the material. After the cooling-process precipitates were noticed in samples # 2, 3, 5, and 6, the solids were isolated by filtration. The other samples (# 1, 4, and 7) were evaporated down to dryness using a gentle stream of nitrogen. The diazoxide choline salts were found to be consistent with Form A by XRPD analysis for all solids with the exception of sample #2 (consistent with the freeform) and sample #5 (consistent with Form B with preferred orientation observed).

Table 18. Single- Solvent Crystallization of Diazoxide Choline Salt Using Fast- Cooling Procedure

[00730] In accordance with the data obtained from fast-cooling experiments, four solvents which showed precipitation of solids were chosen for the slow-cooling experiments: MeOH, EtOH, MeCN, and IPA (Table 19). All obtained analyzable solids of the choline salt were found to be consistent with Form B by XRPD with the exception of Entry #1 which was consistent with diazoxide freeform and Entry #2 which was not analyzable. Mother liquor of Entry #2 was concentrated to dryness and the residual solids were analyzed by XRPD and found to be Form B material. As a result of obtaining freeform material from the single- solvent crystallizations in methanol, three more alcohols were tested for the single- solvent crystallizations using fast- and slow-cooling procedures. Tables 20 and 21 provide a list of the solvents that were used and the amount of solvent needed to dissolve the material. XRPD patterns of the fast-cooling procedure showed freeform of diazoxide from isobutanol, Form B from isoamyl alcohol, and Form A from tert-amyl alcohol compared to the slow-cooling procedure, which afforded Form B material from all three solvents.

Table 19. Single-Solvent Crystallization of Diazoxide Choline Salt Using Slow- Cooling Procedure

Table 20. Single- Solvent Crystallization of Diazoxide Choline Salt Using Fast- Cooling Procedure

Table 21. Single-Solvent Crystallization of Diazoxide Choline Salt Using Slow- Cooling Procedure

[00731] The results of the choline salt single- solvent fast- and slow-cooling crystallizations (see Tables 19 to 21) indicated that Form A was more likely to be isolated with fast-cooling profiles and Form B with slow-cooling profiles.

6.1.5.3. Binary Solvent Crystallizations

[00732] Binary- solvent crystallizations of the choline salt were performed using four primary solvents (MeOH, EtOH, IPA, and MeCN) and nine cosolvents (MTBE, EtOAc, IPAc, THF, c-hexane, heptane, toluene, CH2CI2, and dioxane) with a fast-cooling profile (supra). XRPD patterns showed that Form B was obtained from mixtures of MeOH with MTBE, EtOAc, IPAc, toluene, and dioxane. As shown in Table 22, Form A was obtained from mixtures of MeOH with THF and with CH2CI2 after evaporating the solvent to dryness. The mixtures of MeOH with cyclohexane and heptane provided the freeform of diazoxide. All solids obtained from fast-cooling procedures with EtOH, IPA, and MeCN as primary solvents provided Form B material.

Table 22. Binary-Solvent Crystallizations of Choline Salt of Diazoxide Using Fast- Cooling Procedure and MeOH as a Primary Solvent

* Solids were dissolved at 62 °C.

** Freeform of diazoxide.

[00733] Binary- solvent recrystallizations of the choline salt with the slow-cooling procedure were performed using two primary solvents (IPA and MeCN) and nine cosolvents (MTBE, EtOAc, IPAc, THF, c-hexane, heptane, toluene, CH2C12, and dioxane). All solids obtained from a slow-cooling procedure with IPA and MeCN as primary solvents provided Form B material based on XRPD analysis. The results of

binary- solvent crystallizations indicated that Form B was the most thermodynamic ally stable form of diazoxide choline.

6.1.5.4. Binary Solvent Crystallizations Using Water as a Cosolvent

[00734] In an attempt to investigate the formation of hydrates of the choline salt, experiments was performed using fast- and slow-cooling procedures and water as a cosolvent.

[00735] The fast cooling procedure (supra) was used with the exception of using different primary solvents which were miscible with water: acetone, acetonitrile, DMF, IPA, i-BuOH, i-AmOH, and t-AmOH. Water was utilized in these crystallizations as a cosolvent. All solids obtained from the fast-cooling procedure with water as the cosolvent provided diazoxide freeform material by XRPD analysis.

[00736] To compare the results obtained from the fast-cooling procedure a set of experiments was performed using a slow-cooling procedure and water as a cosolvent. All obtained solids were analyzed by XRPD and afforded patterns consistent with diazoxide freeform. Without wishing to be bound by theory, these results suggest that the conditions used for crystallization caused dissociation of the choline salt. A small amount of a second crop was obtained in each sample, but only two samples were analyzable by XRPD and indicated that the samples were freeform material. All mother liquors were evaporated to dryness and the residual solids were also analyzed by XRPD to afford patterns consistent with Form B of the choline salt.

6.1.5.5. Metastable Zone Width Estimation

[00737] Form B: To produce a robust process, an understanding of the solubility profiles of the various solid forms under consideration is required. From a practical standpoint, this involves the measurement of the metastable zone width (MSZW) of pure forms, whereby the saturation and supersaturation curves of the different forms are generated over a well defined concentration and temperature range. This knowledge can then be used to design a crystallization protocol that should ideally favor a selective crystal growth of the desired form.

[00738] Form B of diazoxide choline salt showed moderate solubility in a solvent mixture made of MeCN/MeOH/MtBE (10: 1: 12, volume ratios). The wide width of the metastable zone as shown in Table 23 gives many seeding options. During the MSZW measurement, aliquots from the crystallizing material were withdrawn and analyzed by XRPD to ensure that no form conversion occurred during the experiment. Indeed, the material remained unchanged during the test.

Table 23. Meta-Stable Zone Width For Form B Diazoxide Choline Salt in

MeCN/MeOH/MtBE (10:1:12) (v/v).

[00739] Form A: The metastable zone width for Form could not be estimated because this polymorphic form converted during the experiment to Form B.

6.1.5.6. Crystallization of Form A of Diazoxide Choline Salt

[00740] The choline salt of diazoxide (160.3 mg) was dissolved in 1 mL of IPA at 55 °C which was then passed through a Millipore 0.45 μΜ filter into a clean vial. This vial was placed in freezer a -20 °C overnight. Solids were not noticed and the flask was scratched with a micro- spatula. The vial was placed back in the freezer and nucleation was noticed after ten minutes. The solids were collected by vacuum filtration and washed with 1 mL of MtBE. The solids were dried in vacuo at 40 °C and 30 in. Hg to afford 70 mg (43.6% recovery) of Form A as determined by XRPD.

6.1.5.7. 500-mg Scale Crystallization of Form B of Diazoxide Choline Salt

[00741] The choline salt of diazoxide (524.3 mg) was dissolved in 3 mL of IPA at 78 °C and this solution was then cooled to 55 °C for the addition of MtBE. The MtBE (4 mL) was added until nucleation was observed. After nucleation the batch was allowed to cool to room temperature at a rate of 20 °C /h. The solids were collected by vacuum filtration and washed with 1 mL of MtBE. The solids were dried in vacuo at 40 °C and 30 in. of Hg to afford 426.7 mg (81.3% recovery) of Form B as determined by XRPD.

6.1.5.8. 2-g Scale Crystallization of Form B of Diazoxide Choline Salt

[00742] The choline salt of diazoxide (2.0015 g) was dissolved in 5.5 mL of IPA at 78 °C to afford a clear solution. This solution was passed through a Millipore Millex FH 0.45 μΜ filter. This solution was then cooled to 55 °C. MtBE was added in 1 mL portions, with a two minute interval between portions. Nucleation was noted after the second addition of MtBE. This suspension was allowed to cool to room temperature at a rate of 20 °C /h and stirred at this temperature for 16 hours. The solids were collected by vacuum filtration and washed with 1 mL of MtBE. The solids were dried in vacuo at 40 °C and 30 in. of Hg to afford 1.6091 g (80.4% recovery) of Form B as determined by XRPD.

6.1.5.9. Detection of Form Impurities

[00743] Mixtures of diazoxide choline Forms A and B were prepared by adding a minor amount of Form A to Form B. Samples were lightly ground by hands with a mortar and pestle for approximately one minute. Samples were then analyzed by XRPD analysis. XRPD analysis was found to be suitable for detecting 5% of Form A in Form B.

References

  1. Jump up^ Diazoxide, drugs.com
  2. Jump up to:a b “FDA Drug Safety Communication: FDA warns about a serious lung condition in infants and newborns treated with Proglycem (diazoxide)” (Press release). Food and Drug Administration. July 16, 2015. Retrieved 2015-07-19.
  3. Jump up^ van Hamersvelt HW, Kloke HJ, de Jong DJ, Koene RA, Huysmans FT (August 1996). “Oedema formation with the vasodilators nifedipine and diazoxide: direct local effect or sodium retention?”. Journal of Hypertension14 (8): 1041–5. doi:10.1097/00004872-199608000-00016PMID 8884561.closed access publication – behind paywall
  4. Jump up^ Huang Q, Bu S, Yu Y, et al. (January 2007). “Diazoxide prevents diabetes through inhibiting pancreatic beta-cells from apoptosis via Bcl-2/Bax rate and p38-beta mitogen-activated protein kinase”Endocrinology148 (1): 81–91. doi:10.1210/en.2006-0738PMID 17053028.open access publication – free to read
  5. Jump up^ Randle, John C.R.; Biton, Catherine; Lepagnol, Jean M. (15 November 1993). “Allosteric potentiation by diazoxide of AMPA receptor currents and synaptic potentials”. European Journal of Pharmacology247 (3): 257–65. doi:10.1016/0922-4106(93)90193-DPMID 8307099.closed access publication – behind paywall
  6. Jump up^ Panten, Uwe; Burgfeld, Johanna; Goerke, Frank; Rennicke, Michael; Schwanstecher, Mathias; Wallasch, Andreas; Zünkler, Bernd J.; Lenzen, Sigurd (1989-04-15). “Control of insulin secretion by sulfonylureas, meglitinide and diazoxide in relation to their binding to the sulfonylurea receptor in pancreatic islets”Biochemical Pharmacology38 (8): 1217–1229. doi:10.1016/0006-2952(89)90327-4.
  7. Jump up^ Doyle, Máire E.; Egan, Josephine M. (2003-03-01). “Pharmacological Agents That Directly Modulate Insulin Secretion”Pharmacological Reviews55 (1): 105–131. doi:10.1124/pr.55.1.7ISSN 1521-0081PMID 12615955.
Patent ID

Title

Submitted Date

Granted Date

US2013309301 SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF
2012-11-07
2013-11-21
US2013040942 SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF
2012-07-06
2013-02-14
US2010028429 SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF
2010-02-04
US9381202 SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF
2013-03-18
2013-08-29
US2010256360 SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF
2010-10-07
Patent ID

Title

Submitted Date

Granted Date

US2012238554 SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF
2012-02-27
2012-09-20
US7799777 SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF
2007-08-16
2010-09-21
US2009062264 SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF
2009-03-05
US9765043 SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF
2014-08-22
2014-12-11
US7572789 SALTS OF POTASSIUM ATP CHANNEL OPENERS AND USES THEREOF
2009-06-11
2009-08-11

//////////////Diazoxide choline

CC1=NC2=C(C=C(C=C2)Cl)S(=O)(=O)[N-]1.C[N+](C)(C)CCO

CC1=NC2=C(C=C(C=C2)Cl)S(=O)(=O)[N-]1.C[N+](C)(C)CCO

Zoledronic acid


 Thumb

Zoledronic acid

    • CGP-42446, ZOL-446
    • ATC:M05BA08
  • Use:antineoplastic, bone resorption inhibitor, biphosphonate
  • Chemical name:[1-hydroxy-2-(1H-imidazol-1-yl)ethylidene]bis[phosphonic acid]
  • Formula:C5H10N2O7P2
  • MW:272.09 g/mol
  • CAS-RN:118072-93-8

Derivatives

Zoledronate disodium.png

Disodium salt tetrahydrate

  • Formula:C5H8N2Na2O7P2 • 4H2O
  • MW:388.11 g/mol
  • CAS-RN:165800-07-7

Trisodium salt hydrate

  • Formula:C5H7N2Na3O7P2 • 2/5H2O
  • MW:1726.21 g/mol
  • CAS-RN:165800-08-8
Zoledronic Acid
CAS Registry Number: 118072-93-8; 165800-06-6 (monohydrate)
CAS Name: [1-Hydroxy-2-(1H-imidazol-1-yl)ethylidene]bisphosphonic acid
Additional Names: 2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid
Manufacturers’ Codes: CGP-42446
Trademarks: Zometa (Novartis)
Molecular Formula: C5H10N2O7P2
Molecular Weight: 272.09
Percent Composition: C 22.07%, H 3.70%, N 10.30%, O 41.16%, P 22.77%
Literature References: Bisphosphonate antiresorptive agent. Prepn: JPKokai 88 150291; K. A. Jaeggi, L. Wilder, US4939130(1988, 1990 both to Ciba-Geigy). Effect on bone metabolism: J. R. Green et al.,J. Bone Miner. Res.9, 745 (1994). Determn in plasma by enzyme inhibition assay: F. Risser et al.,J. Pharm. Biomed. Anal.15, 1877 (1997). Series of articles on pharmacology and clinical experience: Br. J. Clin. Pract. Suppl.87, 15-22 (1996). Clinical trial in tumor-induced hypercalcemia: J. J. Body, Cancer80, 1699 (1997); of i.v. infusion in osteoporosis: I. R. Reid et al., N. Engl. J. Med.346, 653 (2002); in bone metastases of prostate cancer: F. Saad et al., J. Natl. Cancer Inst.94, 1458 (2002). Review of pharmacology and therapeutic use: J.-J. Body, Expert Opin. Pharmacother.4, 567-580 (2003).
Properties: Crystals from water, mp 239° (dec).
Melting point: mp 239° (dec)
Zoledronate disodium.png
disodium;hydroxy-[1-hydroxy-1-[hydroxy(oxido)phosphoryl]-2-imidazol-1-ylethyl]phosphinate;tetrahydrate
cas 165800-07-7
Derivative Type: Disodium salt tetrahydrate
CAS Registry Number: 165800-07-7
Additional Names: Zoledronate disodium
Manufacturers’ Codes: CGP-42446A
Molecular Formula: C5H8N2Na2O7P2.4H2O
Molecular Weight: 388.11
Percent Composition: C 15.47%, H 4.16%, N 7.22%, Na 11.85%, O 45.35%, P 15.96%
Derivative Type: Trisodium salt hydrate
CAS Registry Number: 165800-08-8
Additional Names: Zoledronate trisodium
Manufacturers’ Codes: CGP-42446B
Molecular Formula: (C5H7N2Na3O7P2)5.2H2O
Molecular Weight: 1726.21
Percent Composition: C 17.39%, H 2.28%, N 8.11%, Na 19.98%, O 34.29%, P 17.94%
Therap-Cat: Bone resorption inhibitor.
Keywords: Antiosteoporotic; Antipagetic; Bone Resorption Inhibitor.
INGREDIENT UNII CAS INCHI KEY
Zoledronate disodium 7D7GS1SA24 165800-07-7 IEJZOPBVBXAOBH-UHFFFAOYSA-L
Zoledronate trisodium ARL915IH66 165800-08-8 Not applicable
Zoledronic acid hemipentahydrate 1K9U67HDID Not Available AZZILOGHCMYHQY-UHFFFAOYSA-N
Zoledronic acid monohydrate 6XC1PAD3KF 165800-06-6 FUXFIVRTGHOMSO-UHFFFAOYSA-N

Zoledronate (zoledronic acid, marketed by Novartis under the trade names Zometa and Reclast) is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer. It can also be used to treat hypercalcemia of malignancy and can be helpful for treating pain from bone metastases.

An annual dose of Zoledronate may also prevent recurring fractures in patients with a previous hip fracture.

Zoledronate is a single 5 mg infusion for the treatment of Paget’s disease of bone. In 2007, the FDA also approved Reclast for the treatment of postmenopausal osteoporosis.

Zoledronic acid, also known as zoledronate, is a medication used to treat a number of bone diseases.[1] This include osteoporosishigh blood calcium due to cancerbone breakdown due to cancer, and Paget’s disease of bone.[1] It is given by injection into a vein.[1]

Common side effects include feverjoint painhigh blood pressure, diarrhea, and feeling tired.[1] Serious side effects may include kidney problemslow blood calcium, and osteonecrosis of the jaw.[1] Use during pregnancy may result in harm to the baby.[1] It is in the bisphosphonate family of medications.[1] It works by blocking the activity of osteoclast cells and thus decreases the breakdown of bone.[1]

Zoledronic acid was approved for medical use in the United States in 2001.[1] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[3] The wholesale cost in the developing world is between 5.73 USD and 26.80 USD per vial.[4] In the United Kingdom, as of 2015, a dose costs the NHS about 220 pounds.[5]

Medical uses

Bone complications of cancer

Zoledronic acid is used to prevent skeletalfractures in patients with cancers such as multiple myeloma and prostate cancer, as well as for treating osteoporosis.[6] It can also be used to treat hypercalcemia of malignancy and can be helpful for treating pain from bone metastases.[7]

It can be given at home rather than in hospital. Such use has shown safety and quality-of-life benefits in people with breast cancer and bone metastases.[8]

Osteoporosis

Zoledronic acid may be given as a 5 mg infusion once per year for treatment of osteoporosis in men and post-menopausal women at increased risk of fracture.[9]

In 2007, the U.S. Food and Drug Administration (FDA) also approved it for the treatment of postmenopausal osteoporosis.[10][11]

Paget’s disease

A single 5 mg dose of zoledronic acid is used for the treatment of Paget’s disease.[medical citation needed][12]

Contraindications

Side effects

Side effects can include fatigueanemiamuscle achesfever, and/or swelling in the feet or legs. Flu-like symptoms are common after the first infusion, although not subsequent infusions, and are thought to occur because of its potential to activate human γδ T cells(gamma/delta T cells).

Kidneys

There is a risk of severe renal impairment. Appropriate hydration is important prior to administration, as is adequate calcium and vitamin D intake prior to Aclasta therapy in patients with preexisting hypocalcaemia, and for ten days following Aclasta in patients with Paget’s disease of the bone. Monitoring for other mineral metabolism disorders and the avoidance of invasive dental procedures for those who develop osteonecrosis of the jaw is recommended.[14]

Zoledronate is rapidly processed via the kidneys; consequently its administration is not recommended for patients with reduced renal function or kidney disease.[15] Some cases of acute renal failure either requiring dialysis or having a fatal outcome following Reclast use have been reported to the U.S. Food and Drug Administration (FDA).[16] This assessment was confirmed by the European Medicines Agency (EMA), whose Committee for Medicinal Products for Human Use (CHMP) specified new contraindications for the medication on 15 December 2011, which include hypocalcaemia and severe renal impairment with a creatinine clearance of less than 35 ml/min.[17]

Bone

A rare complication that has been recently observed in cancer patients being treated with bisphosphonates is osteonecrosis of the jaw. This has mainly been seen in patients with multiple myeloma treated with zoledronate who have had dental extractions.[18]

Atypical fractures : After approving the drug on 8 July 2009, the European Medicines Agency conducted a class review of all bisphosphonates, including Zoledronate, after several cases of atypical fractures were reported.[19] In 2008, the EMA’s Pharmacovigilance Working Party (PhVWP) noted that alendronic acid was associated with an increased risk of atypical fracture of the femur that developed with low or no trauma. In April 2010, the PhVWP noted that further data from both the published literature and post-marketing reports were now available which suggested that atypical stress fractures of the femur may be a class effect. The European Medicines Agency then reviewed all case reports of stress fractures in patients treated with bisphosphonates, relevant data from the published literature, and data provided by the companies which market bisphosphonates. The Agency recommended that doctors who prescribe bisphosphonate-containing medicines should be aware that atypical fractures may occur rarely in the femur, especially after long-term use, and that doctors who are prescribing these medicines for the prevention or treatment of osteoporosis should regularly review the need for continued treatment, especially after five or more years of use.[19]

Mechanism of action

Zoledronic acid slows down bone resorption, allowing the bone-forming cells time to rebuild normal bone and allowing bone remodeling.[20]

Research

Zoledronic acid has been found to have a direct antitumor effect and to synergistically augment the effects of other antitumor agents in osteosarcoma cells.[21]

Zoledronate has shown significant benefits versus placebo over three years, with a reduced number of vertebral fractures and improved markers of bone density.[22][11] An annual dose of zoledronic acid may also prevent recurring fractures in patients with a previous hip fracture.[9]

Zoledronate also attenuates accumulation of DNA damage in mesenchymal stem cells and protects their function.[23] Given this characteristic, its potential to affect conditions arising from stem-cell dysfunction makes it a promising medicine for a range of age-related diseases[24]

With hormone therapy for breast cancer

An increase in disease-free survival (DFS) was found in the ABCSG-12 trial, in which 1,803 premenopausal women with endocrine-responsive early breast cancer received anastrozole with zoledronic acid.[25] A retrospective analysis of the AZURE trial data revealed a DFS survival advantage, particularly where estrogen had been reduced.[26]

In a meta-analysis of trials where upfront zoledronic acid was given to prevent aromatase inhibitor-associated bone loss, active cancer recurrence appeared to be reduced.[27]

As of 2010 “The results of clinical studies of adjuvant treatment on early-stage hormone-receptor-positive breast-cancer patients under hormonal treatment – especially with the bisphosphonate zoledronic acid – caused excitement because they demonstrated an additive effect on decreasing disease relapses at bone or other sites. A number of clinical and in vitro and in vivo preclinical studies, which are either ongoing or have just ended, are investigating the mechanism of action and antitumoral activity of bisphosphonates.”[28]

A 2010 review concluded that “adding zoledronic acid 4 mg intravenously every 6 months to endocrine therapy in premenopausal women with hormone receptor-positive early breast cancer … is cost-effective from a US health care system perspective”.[29]

Synthesis

PAPER

J Med Chem 2002,45(17),3721

https://pubs.acs.org/doi/10.1021/jm020819i

Highly Potent Geminal Bisphosphonates. From Pamidronate Disodium (Aredia) to Zoledronic Acid (Zometa)

Novartis Pharma Research, Arthritis and Bone Metabolism Therapeutic Area, CH-4002 Basel, Switzerland
J. Med. Chem.200245 (17), pp 3721–3738
DOI: 10.1021/jm020819i
Abstract Image

Bisphosphonates (BPs) are pyrophosphate analogues in which the oxygen in P−O−P has been replaced by a carbon, resulting in a metabolically stable P−C−P structure. Pamidronate (1b, Novartis), a second-generation BP, was the starting point for extensive SAR studies. Small changes of the structure of pamidronate lead to marked improvements of the inhibition of osteoclastic resorption potency. Alendronate (1c, MSD), with an extra methylene group in the N-alkyl chain, and olpadronate (1h, Gador), the N,N-dimethyl analogue, are about 10 times more potent than pamidronate. Extending one of the N-methyl groups of olpadronate to a pentyl substituent leads to ibandronate (1k, Roche, Boehringer-Mannheim), which is the most potent close analogue of pamidronate. Even slightly better antiresorptive potency is achieved with derivatives having a phenyl group linked via a short aliphatic tether of three to four atoms to nitrogen, the second substituent being preferentially a methyl group (e.g., 4g4j5d, or 5r). The most potent BPs are found in the series containing a heteroaromatic moiety (with at least one nitrogen atom), which is linked via a single methylene group to the geminal bisphosphonate unit. Zoledronic acid (6i), the most potent derivative, has an ED50 of 0.07 mg/kg in the TPTX in vivo assay after sc administration. It not only shows by far the highest therapeutic ratio when comparing resorption inhibition with undesired inhibition of bone mineralization but also exhibits superior renal tolerability. Zoledronic acid (6i) has thus been selected for clinical development under the registered trade name Zometa. The results of the clinical trials indicate that low doses are both efficacious and safe for the treatment of tumor-induced hypercalcemia, Paget’s disease of bone, osteolytic metastases, and postmenopausal osteoporosis.

SYN 1

AU 8781453; EP 0275821; JP 1988150291; US 4939130

Zoledronate sodium can be prepared by reaction of 2-(1-imidazolyl)acetic acid hydrochloride (I) with PCl3, with optional presence of phosphoric acid, in refluxing chlorobenzene, followed by hydrolysis with refluxing 9N hydrochloric acid and final formation of the sodium salt by treatment with aqueous NaOH.

SYN

PAPER

https://www.sciencedirect.com/science/article/pii/S0969804311006385

Image result for zoledronic acid synthesis

Clip

https://link.springer.com/article/10.1007/s11094-015-1205-0

A One-Pot and Efficient Synthesis of Zoledronic Acid Starting from Tert-butyl Imidazol-1-yl Acetate

A one-pot synthesis of zoledronic acid in high yield is described. The procedure involves a non-aqueous ester cleavage of the tert-butyl imidazol-1-yl acetate under dry conditions in the presence of methanesulfonic acid as solubilizer and chlorobenzene as solvent to afford in situthe corresponding imidazolium methanesulfonate salt which yields zoledronic acid upon reaction with phosphoric acid and phosphorus oxychloride. A possible chemical mechanism for the synthesis of this acid is described.

Image result for zoledronic acid synthesis

Paper

https://www.beilstein-journals.org/bjoc/articles/4/42

str1 str2

Preparation of imidazol-1-yl-acetic acid tert-butyl ester (2)

To a solution of imidazole (10.0 g, 0.15 mol) in ethyl acetate (160 mL) was added powdered K2CO3 (29.0 g, 0.21 mol) followed by tert-butyl chloroacetate (25.7 mL, 0.18 mol) at room temperature and the mixture was refluxed for 10.0 h. After completion of the reaction as indicated by TLC (10% MeOH/CHCl3, I2 active), the reaction mass was quenched with cold water (80 mL) and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (2 × 80 mL) and the combined ethyl acetate layers were washed with brine, dried with anhydrous sodium sulfate and then concentrated under vacuum. The resulting solid was stirred with hexane (50 mL) at RT, filtered and washed with hexane (2 × 20 mL) to afford the title compound as an off-white solid (20.0 g, 75%). mp: 111.3–113.2 °C (Lit [10]: 111–113 °C). IR (cm−1): 3458, 3132, 3115, 2999, 2981, 2884, 1740, 1508, 1380, 1288, 1236, 1154, 1079, 908, 855, 819, 745, 662, 583; 1H NMR (300 MHz, CDCl3) δ 1.47 (s, 9H), 4.58 (s, 2H), 6.94 (s, 1H), 7.09 (s, 1H), 7.49 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 27.7, 48.6, 82.9, 119.8, 129.2, 137.7, 166.3; MS (m/z) 183.0 [M+1, 100%], 127.0.

Preparation of imidazol-1-yl-acetic acid hydrochloride (6)

To a solution of imidazol-1-yl-acetic acid tert-butyl ester (2) (10.0 g, 0.05 mol) in dichloromethane (100 mL) was added titanium tetrachloride (8.0 mL, 0.07 mol) dropwise slowly at −15 to −10 °C over 1 h and the mixture was stirred at −5 to 0 °C for 2 h. Isopropyl alcohol (25 mL) was added at 0 to −10 °C over 0.5 h and the reaction mass was stirred at room temperature for 0.5 h. Additional isopropyl alcohol (125 mL) was added dropwise at room temperature over 0.5 h and the mixture was stirred for 1 h. Dichloromethane was distilled out under a low vacuum and the resulting crystalline solid precipitated was filtered to afford the title compound as an off-white crystalline solid (7.4 g, 83%). mp 200.3–202.3 °C; IR (cm−1): 3175, 3125, 3064, 2945, 2869, 2524, 2510, 1732, 1581, 1547, 1403, 1223, 1193, 1081, 780, 650; 1H NMR (300 MHz, D2O + 3-(trimethylsilyl)propionic acid sodium salt) δ 5.1 (s, 3H, -CH2– + HCl), 7.5 (br s, 2H), 8.7 (s, 1H); 13C NMR (75 MHz, D2O + 3-(trimethylsilyl)propionic acid sodium salt) 52.7, 122.4, 125.9, 138.8, 172.8; MS (m/z) 127.0 [M+1, 100%]; HCl-content: found 21.8% (along with 3.25% moisture), calcd 22.43% for C5H6N2O2·HCl.

Preparation of zoledronic acid (7)

To a suspension of imidazol-1-yl-acetic acid hydrochloride (6) (7.0 g, 0.043 mol) and phosphorous acid (9.5 g, 0.116 mol) in chlorobenzene (50 mL) was added phosphorous oxychloride (9.6 ml, 0.103 mol) at 80–85 °C over a period of 2 h then heated to 90–95 °C for 2.5 h. The reaction mass was cooled to 60–65 °C and water (100 mL) was added at the same temperature. The aqueous layer was separated, collected and refluxed for 18 h. It was then cooled to room temperature and diluted with methanol (140 mL). The mixture was cooled to 0–5 °C and stirred for 3 h. The precipitated solid was filtered, washed with cold water followed by methanol and then dried under vacuum at 60 °C for 12 h to afford the title compound (6.6 g, 57% yield) as a white solid; mp 237–239 °C (lit [1] 239 °C with decomposition).

PATENT

https://patents.google.com/patent/CN104610357A/en

Sodium Zoledronic (Zoledronate sodium, I), chemical name [1-yl light -2- (lH- imidazol-1-yl) ethylidene] bisphosphonic acid monosodium salt monohydrate, is by the Novartis (Novartis) developed imidazole heterocyclic bisphosphonates, belongs to the third generation of bisphosphonates bisphosphonate drugs, in October 2000, first marketed in Canada. Subsequently approved in the European Union, the United States more than 80 countries or regions, trade name Zometa, for the treatment of hypercalcemia of malignancy (HCM) and multiple myeloma and bone metastases of solid tumors. The drug is effective in treating cancer caused by HCM, advanced bone metastases and Paget’s disease, reduce the incidence of skeletal related events, relieve symptoms and improve quality of life, is also expected to be used to treat osteoporosis. Compared with other similar drugs, high efficacy, dosage, ease of administration, better security, etc., is currently the only FDA-approved for metastatic bone tumor effective bisphosphonate drugs.Currently bisphosphonate drugs in our country is still in the initial stages of clinical applications, but in recent years has made rapid progress, broad market prospect.

[0003] The prior art synthesis reaction conditions zoledronate sodium harsh, toxicity and use methanol, chloroform and chlorobenzene, easily exceeding the amount of residual organic solvents, low yield, low product purity, contamination environment, does not meet the medical criteria, is not conducive to industrial production. Environmental pollution has attracted increasing attention around the world today, the development of new green efficient synthesis of a pharmaceutical drug synthesis is an important issue facing the Institute. In recent years, room temperature ionic liquids as a reaction medium is environmentally friendly, has been widely used in a variety of organic synthesis reactions. Compared with traditional organic solvents, ionic liquids have very low vapor pressure, non-flammable, good thermal stability, both as a reaction medium underway catalysis, can be recycled and many other advantages.

Image result for zoledronic acid synthesis

Example 1 of zoledronic alendronate

Figure CN104610357AD00061

(1) Synthesis of imidazol-1-yl acetate were added successively imidazole (13.62g, 0.2mol) and [bmim] BF4 (IOOmL) a three-necked flask, heated with stirring warmed to 60 ° C, incubated under reflux was slowly added dropwise chlorination ethyl acetate (24. 51g, 0. 2mol), dropwise addition time is about 2h, dropwise, with stirring maintained at reflux for 16 h, the reaction monitored by TLC showed no starting material end point, completion of the reaction, cooled to room temperature, to give imidazole -1 – ethyl crude, about 24g, crude without purification, was used directly in the next reaction.

[0014] (2) Synthesis of imidazol-1-yl acetate hydrochloride A solution of 24g 1-yl imidazole prepared above was added crude ethyl necked flask, concentrated hydrochloric acid (34 mL), exotherm to 85 ° C, warmed to reflux heating was continued, the reaction was stirred at reflux for 10H, the reaction was completed, the solvent was evaporated under reduced pressure, 20ml of absolute ethanol was added to the residue, vigorously stirred for 2h, filtered off with suction, the filter cake finally at 80 ° C blast pressure and dried to give a white solid imidazol-1-yl acetate hydrochloride about 25. 65g, 79.4% overall yield.

[0015] (3) Synthesis of zoledronic acid monohydrate were added imidazol-1-yl acetate hydrochloride (17. 26g, 0. 137mol) a three-necked flask, in an ionic liquid with stirring – n-butyl-3- methylimidazolium tetrafluoroborate [bmim] BF4 (40mL) and concentration of 85% phosphoric acid solution (16mL), heating to 60 ° C was added dropwise phosphorus trichloride (30mL) , about 4h dropwise, reaction was continued under reflux for 4h at 65 ° C, the reaction was complete, cooled to 40 ° C, filtered off with suction, the filter cake was added to a molar concentration in 80mL 9mol / L hydrochloric acid, heated with stirring state the reaction was refluxed for 6h, the reaction was completed, filtered hot, the filter cake was added to a molar concentration in 80mL 9mol / L hydrochloric acid, the above-described operation is repeated to continue the combined filtrate was evaporated to dryness under reduced pressure to give a yellow oily residue was slowly added to the residue volume ratio of 1: 1 acetone – ethanol mixture 240 mL, was stirred, and the precipitated solid was 15min, filtered off with suction, the filter cake was recrystallized in 30mL of deionized water, suction filtered to give a white solid that is zoledronic acid monohydrate , about 35. 8g, yield 90.1%, determined by HPLC, purity> 98.5%.

After [0016] (4) Synthesis of zoledronic sodium phosphinate obtained above azole zoledronic acid monohydrate (46.4g, 0. 16mol) washed with water (450 mL of) was dissolved, was added sodium hydroxide (5. 6g, 0. IOmol), were refluxed for 30min, cooling and crystallization, filtration, to obtain a crude product zoledronate sodium, crude mother liquor was concentrated and then half with distilled water (410 mL), isopropanol (60 mL), heated to dissolve the combined, activated carbon bleaching, charcoal filtered off, cooling and crystallization, filtration, washed with water, dried at 40-60 ° C to about crystallization water containing one to give zoledronate sodium (42. 4g, 85%), total yield of more than 60% by HPLC assay, purity 99. 8%, mp239 ° C. IR: 711011 ^ 671 (^ 1 is the stretching vibration peak of the PC, 1643〇 ^ 1 = 0 (: stretching vibration peak, 3011〇 ^ 1 = (: – stretching vibration peak 11 ^ 1 is CN 1406〇 the stretching vibration, 1643CHT1 is C = N stretching vibration peak of 3447 (3485 ^^ (^ 1 is the stretching vibration peak of OH, 1459CHT1 symmetrical bending vibration of CH, 2830CHT1 stretching vibration of CH, 1324CHT1 is P = O the stretching vibration, 1094CHT1 stretching vibration peak of .1HNMR PO (400MHz, D20), S: 8.68 (lH, s), 7.48 (lH, s), 7.34 (lH, s), 4.67 (2H, t).

Effects [0017] Example 2 was added dropwise phosphorus trichloride fixed time on the yield other conditions remain unchanged, only the changes of phosphorus trichloride dropwise addition, dropping zoledronic Table 1 Effect of Sodium yield Experimental results show that excessive phosphorus trichloride was added dropwise, and instantly generate a large amount of gas, the reaction is very intense, the liquid splashing, a rapid rise in temperature, resulting in the low yield, if slowly added dropwise, the reaction rate is too slow, consumption too long, and therefore is the best 4h dropping time.

Figure CN104610357AD00071

Zoledronic fixed effect of sodium yield other conditions remain unchanged, imidazol-1-yl acetic acid hydrochloride with phosphorus trichloride and phosphoric acid condensation reaction temperature is zoledronic acid monohydrate embodiment the reaction temperature Example 3 Effect yield (Table 2). The results show that, with increasing temperature, increasing the yield, but at higher temperatures to reflux, shows a decreasing trend in yield, due to decomposition sake phosphorus trichloride, resulting in reduction reaction. Further, when the temperature is too high, solvent evaporation and solvent leakage losses will increase, the reflux temperature is low, the reaction rate is slow, the reaction is insufficient, therefore the yield is low, and therefore the optimum reaction temperature is about 65 ° C.

Figure CN104610357AD00072

Example 4

Figure CN104610357AD00081

Effect of the ionic liquid frequency reuse sodium zoledronic yield of the reaction medium can be recovered and reused important concern is “green chemistry” used in the present embodiment examines the sodium ionic liquid used in the synthesis of zoledronic repeated use, the experiment results shown in Table 3. Seen from Table 3, the ionic liquid after 5 subsequent to use, product yield began to decrease, the ionic liquid may be recovered and reused effectively, and repeated five times using good performance, and therefore is an ionic liquid in this reaction green solvents may be recycled.

Figure CN104610357AD00082

Example 5 different ionic liquids zoledronic same impact conditions were examined yield sodium 1-butyl-3-methylimidazolium tetrafluoroborate ionic liquids ([bmim] BF4), N- ethyl pyridinium tetrafluoroborate ([EPy] BF4), l- butyl-3-methylimidazolium hexafluorophosphate ([bmim] PF6), 1- hydroxyethyl-2,3-dimethyl imidazolium chloride (LOH), 1- propyl-3-carbonitrile methylimidazolium chloride (the LCN) and 1-carboxyethyl-3-methyl imidazolium chloride (LOOH) Effects of sodium zoledronic yield the results are shown in Table 4, the test results show little effect on the synthesis of ionic liquids yield.

Figure CN104610357AD00083

Clip

Mar 5, 2013 –

Dr. Reddy’s Laboratories  announced today that it has launched Zoledronic Acid Injection (4 mg/5 mL), a bioequivalent generic version of Zometa® (zoledronic acid) 4 mg/5 mL Injection in the US market on March 4, 2013, following the approval by the United States Food & Drug Administration (USFDA) of Dr. Reddy’s ANDA for Zoledronic Acid Injection (4 mg/5 mL).

Dr. Reddy’s Zoledronic Acid Injection 4 mg/5mL is available in a single use vial of concentrate.

Zoledronic acid (INN) or zoledronate (marketed by Novartis under the trade names ZometaZomeraAclasta and Reclast) is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer, as well as for treating osteoporosis.It can also be used to treat hypercalcemia of malignancy and can be helpful for treating pain from bone metastases.

An annual dose of zoledronic acid may also prevent recurring fractures in patients with a previous hip fracture.

Reclast is a single 5 mg infusion for the treatment of Paget’s disease of bone. In 2007, the U.S. Food and Drug Administration (FDA) also approved Reclast for the treatment of postmenopausal osteoporosis.

About Dr. Reddy’s Laboratories Ltd.

Dr. Reddy’s Laboratories Ltd. (NYSE: RDY) is an integrated global pharmaceutical company, committed to providing affordable and innovative medicines for healthier lives. Through its three businesses – Pharmaceutical Services and Active Ingredients, Global Generics and Proprietary Products – Dr. Reddy’s offers a portfolio of products and services including APIs, custom pharmaceutical services, generics, biosimilars, differentiated formulations and NCEs. Therapeutic focus is on gastro-intestinal, cardiovascular, diabetology, oncology, pain management, anti-infective and pediatrics. Major markets include India, USA, Russia and CIS, Germany, UK, Venezuela, S. Africa, Romania, and New Zealand. For more information, log on to: http://www.drreddys.com

Zometa® is a registered trademark of Novartis AG

References

    • US 4 939 130 (Ciba-Geigy; 3.7.1990; CH-prior. 21.11.1986).
  • transdermal formulation:

    • EP 407 344 (Ciba-Geigy; appl. 28.6.1990; CH-prior. 7.7.1989).
  • treatment of angiogenesis:

    • WO 2 000 071 104 (Novartis AG; appl. 19.5.2000; GB-prior. 21.5.1999).

PATENT

ApplicationPriority dateFiling dateTitle
CN 2015100011672015-01-052015-01-05Preparation method for sodium zoledronic acid

ApplicationFiling dateTitle
CN 2015100011672015-01-05Preparation method for sodium zoledronic acid

References

  1. Jump up to:a b c d e f g h i j k “Zoledronic Acid”. The American Society of Health-System Pharmacists. Retrieved 8 December 2017.
  2. Jump up^ Drugs.com International trade names for zoledronic acid Page accessed Jan 14, 2015
  3. Jump up^ “WHO Model List of Essential Medicines (20th List)” (PDF). World Health Organization. March 2017. Retrieved 29 June 2017.
  4. Jump up^ “Single Drug Information”International Medical Products Price Guide. Retrieved 9 December 2017.
  5. Jump up^ British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 528. ISBN 9780857111562.
  6. Jump up^ National Prescribing Service (2009). “Zoledronic Acid for Osteoporosis”. Medicines Update, Available at “Archived copy”. Archived from the original on April 23, 2010. Retrieved January 20, 2010.
  7. Jump up^ http://www.health.gov.il/units/pharmacy/trufot/alonim/533.pdf Zomera prescribing information
  8. Jump up^ Wardley, A; Davidson, N; Barrett-Lee, P; et al. (May 2005). “Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration”Br. J. Cancer92 (10): 1869–76. doi:10.1038/sj.bjc.6602551PMC 2361764Freely accessiblePMID 15870721.
  9. Jump up to:a b Lyles K, et al. (2007). “Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture”N. Engl. J. Med357 (18): 1799–809. doi:10.1056/NEJMoa074941PMC 2324066Freely accessiblePMID 17878149.
  10. Jump up^ “Biotech PRESS RELEASE: Novartis’s Reclast Receives FDA Approval FOR Women With Postmenopausal Osteoporosis”, FierceBiotech, A Division of Questex A FierceMarkets Publication Aug 20, 2007. Retrieved 2018-03-27
  11. Jump up to:a b Black; et al. (2007). “Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis”NEJM356 (18): 1809–1822. doi:10.1056/nejmoa067312PMID 17476007.
  12. Jump up^ “Paget’s Disease of Bone”http://www.rheumatology.org. Retrieved 2015-07-09.
  13. Jump up^ Vondracek, S. F. (2010). “Managing osteoporosis in postmenopausal women”. American Journal of Health-System Pharmacy67 (7 Suppl 3): S9–19. doi:10.2146/ajhp100076PMID 20332498.
  14. Jump up^ http://www.nps.org.au/__data/assets/pdf_file/0006/60945/nvcaclin.pdf
  15. Jump up^ “Zometa 4mg/5ml Concentrate for Solution for Infusion”medicines.org.uk.
  16. Jump up^ “FDA Alert: Reclast (zoledronic acid): Drug Safety Communication – New Contraindication and Updated Warning on Kidney Impairment”drugs.com.
  17. Jump up^ “European Medicines Agency – Human medicines”europa.eu.
  18. Jump up^ Durie BG, Katz M, Crowley J (2005). “Osteonecrosis of the jaw and bisphosphonates”. N. Engl. J. Med353 (1): 99–102; discussion 99–102. doi:10.1056/NEJM200507073530120PMID 16000365.
  19. Jump up to:a b “European Medicines Agency – Human medicines”europa.eu.
  20. Jump up^ Aclasta label- Australia
  21. Jump up^ Koto K, Murata H, Kimura S, et al. (July 2010). “Zoledronic acid inhibits proliferation of human fibrosarcoma cells with induction of apoptosis, and shows combined effects with other anticancer agents”. Oncol. Rep24 (1): 233–9. doi:10.3892/or_00000851PMID 20514467.
  22. Jump up^ Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, Widmer A, Devogelaer JP, Kaufman JM, Jaeger P, Body JJ, Brandi ML, Broell J, Di Micco R, Genazzani AR, Felsenberg D, Happ J, Hooper MJ, Ittner J, Leb G, Mallmin H, Murray T, Ortolani S, Rubinacci A, Saaf M, Samsioe G, Verbruggen L, Meunier PJ (2002). “Intravenous zoledronic acid in postmenopausal women with low bone mineral density”. N. Engl. J. Med346 (9): 653–61. doi:10.1056/NEJMoa011807PMID 11870242.
  23. Jump up^ Juhi Misra, Sindhu T. Mohanty, Sanjeev Madan, James A. Fernandes, F. Hal Ebetino, R. Graham, G. Russell, Ilaria Bellantuono. (December 2015). Zoledronate attenuates accumulation of DNA damage in mesenchymal stem cells and protects their function. Stem Cells, doi:10.1002/stem.2255
  24. Jump up^ “Bone drug protects stem cells from aging.” ScienceDaily. 17 December 2015
  25. Jump up^ PMID 19213681 Gnant, Mlineritsch. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360:679-691 February 12, 2009 Full Free Text [1]
  26. Jump up^ Coleman RE, Winter MC, Cameron D, et al. (March 2010). “The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer”Br. J. Cancer102 (7): 1099–105. doi:10.1038/sj.bjc.6605604PMC 2853093Freely accessiblePMID 20234364.
  27. Jump up^ Brufsky A, Bundred N, Coleman R, et al. (May 2008). “Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole”. Oncologist13 (5): 503–14. doi:10.1634/theoncologist.2007-0206PMID 18515735.
  28. Jump up^ Tonyali O, Arslan C, Altundag K (November 2010). “The role of zoledronic acid in the adjuvant treatment of breast cancer: current perspectives”. Expert Opin Pharmacother11(16): 2715–25. doi:10.1517/14656566.2010.523699PMID 20977404.
  29. Jump up^ Delea TE, Taneja C, Sofrygin O, Kaura S, Gnant M (August 2010). “Cost-effectiveness of zoledronic acid plus endocrine therapy in premenopausal women with hormone-responsive early breast cancer”. Clin. Breast Cancer10 (4): 267–74. doi:10.3816/CBC.2010.n.034PMID 20705558.
Zoledronic acid
Zoledronic acid.svg
Zoledronic-acid-from-xtal-2003-3D-balls.png
Clinical data
Trade names Reclast, Zometa, others[2]
AHFS/Drugs.com Monograph
MedlinePlus a605023
License data
Pregnancy
category
Routes of
administration
Intravenous
Drug class Bisphosphonate[1]
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 22%
Metabolism Nil
Elimination half-life 146 hours
Excretion Kidney (partial)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
Chemical and physical data
Formula C5H10N2O7P2
Molar mass 272.09 g/mol
3D model (JSmol)

Judith Aronhime, Revital Lifshitz-Liron, “Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation.” U.S. Patent US20050054616, issued March 10, 2005., US20050054616

/////////////////disodium zoledronate tetrahydrate, zoledronic acid, ZOMETA, CGP-42446, CGP-42446A

OC(CN1C=CN=C1)(P(O)(O)=O)P(O)(O)=O

Bepotastine Besilate, ベポタスチンベシル酸塩


ChemSpider 2D Image | Bepotastine Besilate | C27H31ClN2O6SBepotastine besilate.png

Bepotastine Besilate

ベポタスチンベシル酸塩

  • Molecular FormulaC27H31ClN2O6S
  • Average mass547.063 Da
UNII:6W18MO1QR3
(+)-(S)-4-(4-((4-Chlorophenyl)(2-pyridyl)methoxy)piperidino)butyric acid monobenzenesulfonate
(S)-4-(4-((4-chlorophenyl)(pyridin-2-yl)methoxy)piperidin-1-yl)butanoic acid compound with benzenesulfonic acid (1:1)
190786-44-8 [RN]
125602-71-3 FREE FORM,
UNII: 6W18MO1QR3
1-Piperidinebutanoic acid, 4-[(S)-(4-chlorophenyl)-2-pyridinylmethoxy]-, benzenesulfonate (1:1) [ACD/Index Name]
4-{4-[(S)-(4-Chlorophenyl)(2-pyridinyl)methoxy]-1-piperidinyl}butanoic acid benzenesulfonate (1:1)
Talion [Trade name]
tau284
TAU-284DS, TAU-284
DA-5206
HL-151
SNJ-1773
    • Use:antiallergic, antihistaminic
For the symptomatic treatment of itchy eyes (caused by IgE-induced mast cell degranulation) due to allergic conjunctivitis.
10 mg Tablets  For the treatment of allergic rhinitis  27.03.2017 CDSCO

APPROVED 

USFDA

NDA 22-288 Bepotastine Besilate 1.5% Ophthalmic Solution ISTA Pharmaceuticals, Inc.

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/02228s000_ChemR.pdf

str1

Drug Substance Bepotastine besilate is manufactured by Ube Industries and the information for the NDA is submitted through DMF #19966. Bepotastine besilate is a white crystalline powder with no odor and bitter taste. It is very soluble in but sparingly soluble in . It is stable when exposed to light, and optically active. The S-isomer is the active drug and is controlled as an impurity through synthesis. The distribution coefficient in 1-octanol is higher than in aqueous buffer in the pH 5-9 range. There are 10 potential impurities but only one impurity is above 0.1%. Two potential genotoxic impurities are controlled below . Residual is controlled below Bepotastine besilate is stable under long term storage conditions for (25ºC/60% RH) over 5 years

Bepotastine besilate was originally developed as an oral tablet dosage form and got approval in Japan in 2000 for allergic rhinitis. It is a non-sedating anti-allergic drug. The proposed NDA is an ophthalmic solution indicated for allergic conjunctivitis. Bepotastine besilate ophthalmic solution 1.5% is a sterile solution. It is an aqueous solution to be administered as drops at or near physiological pH range of tears. The formulation contains sodium chloride, monobasic sodium phosphate as dihydrate, benzalkonium chloride, sodium hydroxide and purified water; typically these components are used for , preservative action, pH adjustment,

INTRO

Bepotastine is a non-sedating, selective antagonist of the histamine 1 (H1) receptor. Bepotastine was approved in Japan for use in the treatment of allergic rhinitis and uriticaria/puritus in July 2000 and January 2002, respectively, and is marketed by Tanabe Seiyaku Co., Ltd. under the brand name Talion. It is available in oral and opthalmic dosage forms in Japan. The opthalmic solution is FDA approved since Sept 8, 2009 and is under the brand name Bepreve.

Tae Hee Ha, Chang Hee Park, Won Jeoung Kim, Soohwa Cho, Han Kyong Kim, Kwee Hyun Suh, “PROCESS FOR PREPARING BEPOTASTINE AND INTERMEDIATES USED THEREIN.” U.S. Patent US20100168433, issued July 01, 2010., US20100168433

BEPREVE® (bepotastine besilate ophthalmic solution) 1.5% is a sterile, topically administered drug for ophthalmic use. Each mL of BEPREVE contains 15 mg bepotastine besilate.

Bepotastine besilate is designated chemically as (+) -4-[[(S)-p-chloro-alpha -2pyridylbenzyl] oxy]-1-piperidine butyric acid monobenzenesulfonate. The chemical structure for bepotastine besilate is:

BEPREVE® (bepotastine besilate) Structural Formula Illustration

Bepotastine besilate is a white or pale yellowish crystalline powder. The molecular weight of bepotastine besilate is 547.06 daltons. BEPREVE ophthalmic solution is supplied as a sterile, aqueous 1.5% solution, with a pH of 6.8.

The osmolality of BEPREVE (bepotastine besilate ophthalmic solution) 1.5% is approximately 290 mOsm/kg.

ベポタスチンベシル酸塩 JP17
Bepotastine Besilate

C21H25ClN2O3▪C6H6O3S : 547.07
[190786-44-8]

Title: Bepotastine
CAS Registry Number: 190786-43-7
CAS Name: 4-[(S)-(4-Chlorophenyl)-2-pyridinylmethoxy]-1-piperidinebutanoic acid
Additional Names: betotastine
Molecular Formula: C21H25ClN2O3
Molecular Weight: 388.89
Percent Composition: C 64.86%, H 6.48%, Cl 9.12%, N 7.20%, O 12.34%
Literature References: Histamine H1-receptor antagonist. Prepn (stereochem. unspec.): A. Koda et al., EP 335586eidem, US4929618 (1989, 1990 both to Ube). Prepn of optically active salts: J. Kita et al., EP 949260 (1999 to Ube; Tanabe Seiyaku). Pharmacology: M. Kato et al., Arzneim.-Forsch. 47, 1116 (1997). Suppression of IL-5 production: O. Kaminuma et al., Biol. Pharm. Bull. 21, 411 (1998). Antiallergic activity in animal models: M. Ueno et al., Pharmacology 57, 206 (1998).
Derivative Type: Benzenesulfonate salt
CAS Registry Number: 190786-44-8
Additional Names: Bepotastine besilate
Manufacturers’ Codes: TAU-284
Trademarks: Talion (Tanabe)
Molecular Formula: C21H25ClN2O3.C6H6O3S
Molecular Weight: 547.06
Percent Composition: C 59.28%, H 5.71%, Cl 6.48%, N 5.12%, O 17.55%, S 5.86%
Properties: Pale grey prisms from acetonitrile, mp 161-163°. [a]D20 +6.0° (c = 5 in methanol).
Melting point: mp 161-163°
Optical Rotation: [a]D20 +6.0° (c = 5 in methanol)
Therap-Cat: Antihistaminic.
Keywords: Antihistaminic.

Bepotastine (TalionBepreve) is a 2nd generation antihistamine.[1] It was approved in Japan for use in the treatment of allergic rhinitisand urticaria/pruritus in July 2000 and January 2002, respectively. It is currently marketed in the United States under the brand-name Bepreve, by ISTA Pharmaceuticals.

Bepotastine besilate is a second-generation antihistamine that was launched in a tablet formulation under a collaboration between Tanabe Seiyaku and Ube in 2000 and in 2002 for the treatment of allergic rhinitis including sneeze, mucus discharge and solidified mucus, and for the treatment of urticaria, respectively. An orally disintegrating tablet was made available in Japan in 2006, while a dry syrup formulation for the treatment of allergic rhinitis was studied in clinical trials at Tanabe Seiyaku for the treatment of allergic rhinitis

Originally developed at Ube, bepotastine besilate was later licensed to Tanabe Seiyaku as part of a collaboration agreement. In 2010, rights were licensed to Dong-A and Mitsubishi Tanabe Pharma in Korea for the treatment of eye disorders.

Pharmacology

Bepotastine is available as an ophthalmic solution and oral tablet. It is a direct H1-receptor antagonist that inhibits the release of histamine from mast cells.[2] The ophthalmic formulation has shown minimal systemic absorption, between 1 and 1.5% in healthy adults.[3] Common side effects are eye irritation, headache, unpleasant taste, and nasopharyngitis.[3] The main route of elimination is urinary excretion, 75-90% excreted unchanged.[3]

Marketing history

It is marketed in Japan by Tanabe Seiyaku under the brand name Talion. Talion was co-developed by Tanabe Seiyaku and Ube Industries, the latter of which discovered bepotastine. In 2001, Tanabe Seiyaku granted Senju, now owned by Allergan, exclusive worldwide rights, with the exception of certain Asian countries, to develop, manufacture and market bepotastine for ophthalmic use. Senju, in turn, has granted the United States rights for the ophthalmic preparation to ISTA Pharmaceuticals.

Sales and patents

In 2011, ISTA pharmaceuticals experienced a 2.4% increase in net revenues from 2010, which was driven by the sales of Bepreve. Their net revenue for 2011 was $160.3 million.[4] ISTA Pharmaceuticals was acquired by Bausch & Lomb in March 2012 for $500 million.[5] Bausch & Lomb hold the patent for bepotastine besilate (https://www.accessdata.fda.gov/scripts/cder/ob/docs/temptn.cfm. On November 26, 2014, Bausch & Lomb sue Micro Labs USA for patent infringement.[6] Bausch & Lomb was recently bought out by Valeant Pharmaceuticals in May 2013 for $8.57 billion, Valeant’s largest acquisition to date, causing the company’s stock to rise 25% when the deal was announced.[7]

Clinical trials

A Phase III clinical trial was carried out in 2010 to evaluate the effectiveness of bepotastine besilate ophthalmic solutions 1.0% and 1.5%.[8] These solutions were compared to a placebo and evaluated for their ability to reduce ocular itchiness. The study was carried out with 130 individuals and evaluated after 15 minutes, 8 hours, or 16 hours. There was a reduction in itchiness at all-time points for both ophthalmic solutions. The study concluded that bepotastine besilate ophthalmic formulations reduced ocular itchiness for at least 8 hours after dosing compared to placebo. Phase I and II trials were carried out in Japan.

Studies have been performed in animals and bepotastine besilate was not found to be teratogenic in rats during fetal development, even at 3,300 times more that typical use in humans.[3] Evidence of infertility was seen in rats at 33,000 times the typical ocular does in humans.[3] The safety and efficacy has not been established in patients under 2 years of age and has been extrapolated from adults for patients under 10 years of age.[3]

SYN

EP 0335586; JP 1989242574; JP 1990025465; JP 1993294929; US 4929618

The reaction of 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (I) with ethyl 4-bromobutyrate (II) by means of K2CO3 in refluxing acetone gives the corresponding condensation product (III), which is then hydrolyzed with NaOH in ethanol/water yielding compound (IV).

SYN 2

JP 1998237070; JP 2000198784; WO 9829409

A new synthesis of betotastine has been developed: The racemic 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (I) is submitted to optical resolution with N-acyl amino acids such as N-acetyl-L-phenylalanine (preferred), N-acetyl-L-leucine, N-(benzyloxycarbonyl)-L-phenylalanine, N-(benzyloxycarbonyl)-L-valine, N-(benzyloxycarbonyl)-L-threonine, N-(benzyloxycarbonyl)-L-serine or with (2R,3R)-3-(5-chloro-2-nitrophenylsulfanyl)-2-hydroxy-3-(4-methoxyphenyl)propionic acid (preferred) or (2R,3R)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylsulfanyl)propionic acid as chiral intermediates, yielding the (S)-isomer (II). The condensation of (II) with ethyl 4-bromobutyrate (III) by means of a base such as Na2CO3, NaHCO3, K2CO3 or KHCO3 gives the expected 4-(1-piperidinyl)butyric acid ester (IV), which is finally hydrolyzed with NaOH or KOH in aqueous ethanol or methanol.

SYN 3

A new synthesis of betotastine has been developed: The racemic 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (I) is submitted to optical resolution with N-acyl amino acids such as N-acetyl-L-phenylalanine (preferred), N-acetyl-L-leucine, N-(benzyloxycarbonyl)-L-phenylalanine, N-(benzyloxycarbonyl)-L-valine, N-(benzyloxycarbonyl)-L-threonine, N-(benzyloxycarbonyl)-L-serine or with (2R,3R)-3-(5-chloro-2-nitrophenylsulfanyl)-2-hydroxy-3-(4-methoxyphenyl)propionic acid (preferred) or (2R,3R)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylsulfanyl)propionic acid as chiral intermediates, yielding the (S)-isomer (II). The condensation of (II) with ethyl 4-bromobutyrate (III) by means of a base such as Na2CO3, NaHCO3, K2CO3 or KHCO3 gives the expected 4-(1-piperidinyl)butyric acid ester (IV), which is finally hydrolyzed with NaOH or KOH in aqueous ethanol or methanol.

CLIP

A Novel Synthetic Method for Bepotastine, a Histamine H1 Receptor …

journal.kcsnet.or.kr

A Novel Synthetic Method for Bepotastine, a Histamine H1 Receptor Antagonist

file:///C:/Users/91200291/Downloads/B130241_549.pdf

Scheme 1. Synthesis of bepotastine l-menthyl ester N-benzyloxycarbonyl-L-aspartic acid complex (3), bepotastine besilate (4) and bepotastine calcium (5). Reagents and conditions; i) 4-bromobutanoic acid l-menthyl ester, K2CO3, acetone, reflux, 7 h, 95-99%; ii) N-benzyloxycarbonyl-L-aspartic acid (NCbzLAA), ethyl acetate, rt, 12 h, 71-73%; iii) Ethyl acetate/H2O, NaHCO3, 97-99%; iv) EtOH:H2O = 1:1, NaOH, rt, 12 h, 3.0 N-HCl Neutralization, 92- 95%; v) AcOH, reflux, 12 h, racemization 97-100%; vi) Bezensulfonic acid, acetonitrile, rt, 12 h, 64-67%; vii) NaOH, H2O, CaCl2, rt, 12 h, 86-89%.

Synthesis of (S)-Bepotastine Besilate (4). Bepotastine (50 g, 0.13 mol) was dissolved in 500 mL of acetonitrile, and benzenesulfonic acid monohydrate (20 g, 0.11 mol) was added to the reaction mixture. Bepotastine besilate (0.5 g, 1.28 mmol) was seeded in the reaction mixture and stirred at rt for 12 h. The solid precipitate was filtered and dried. The product was obtained 38 g (yield: 64%, optical purity: 99.5% ee) as a pale white crystalline powder. Melting point: 161- 163 o C. Water: 0.2% (Karl-Fischer water determination). MS: m/z 389.1 [M+H]; 1 H-NMR (300 MHz, DMSO-d6) δ 9.2 (br s, 1H), 8.5 (d, J = 4.1 Hz, 1H), 7.8 (t, J = 7.7 Hz, 1H), 7.6 (m, 3H), 7.4 (m, 4H), 7.3 (m, 4H), 5.7 (s, 1H), 3.7 (br s, 2H), 3.3 (br s, 3H), 3.1 (br s, 2H), 2.3 (t, J = 14.1 Hz, 2H), 2.2 (m, 1H), 2.0 (m, 1H), 1.8 (m, 3H), 1.7 (m, 1H); IR (KBr, cm−1 ): 3422, 2996, 2909, 2735, 2690, 2628, 1719, 1592, 1572, 1488, 1470, 1436, 1411, 1320, 1274, 1221, 1160, 1123, 1066, 1031, 1014, 996, 849, 830, 771, 759, 727, 693, 612, 564

Synthesis

Patent ID

Title

Submitted Date

Granted Date

US9849121 AQUEOUS LIQUID PREPARATIONS AND LIGHT-STABILIZED AQUEOUS LIQUID PREPARATIONS
2014-10-10
2015-01-29
US2012225905 BEPOTASTINE COMPOSITIONS
2012-05-02
2012-09-06
US8883825 Aqueous liquid preparations and light-stabilized aqueous liquid preparations
2012-08-30
2014-11-11
Patent ID

Title

Submitted Date

Granted Date

US6638534 Preparation capable of releasing drug at target site in intestine
2001-01-29
2003-10-28
US2010168433 PROCESS FOR PREPARING BEPOTASTINE AND INTERMEDIATES USED THEREIN
2010-07-01
US7282589 Acid addition salt of optically active piperidine compound and process for preparing the same
2004-11-04
2007-10-16
US6307052 Acid-addition salts of optically active piperidine compound and process for producing the same
2001-10-23
EP0949260 ACID-ADDITION SALTS OF OPTICALLY ACTIVE PIPERIDINE COMPOUND AND PROCESS FOR PRODUCING THE SAME
1999-10-13
2002-05-22
Patent ID

Title

Submitted Date

Granted Date

US9446055 DISINTEGRATING PARTICLE COMPOSITION AND ORALLY RAPIDLY DISINTEGRATING TABLET
2010-08-11
2012-06-21
US2011257628 INSTRUMENT FOR ALLEVIATING ADDICTIVE DRUG CRAVING, METHOD FOR USING SAME AND METHOD FOR TREATING ADDICTIVE DRUG DEPENDENCE
2009-12-02
2011-10-20
US2013046240 BEPOTASTINE COMPOSITIONS
2011-10-06
2013-02-21
US2012328675 FILM PREPARATION CONTAINING MEDICAMENT WITH UNPLEASANT TASTE
2011-03-03
2012-12-27
US8771724 Percutaneous absorption enhancer and transdermal preparation using the same
2009-06-22
2014-07-08
Patent ID

Title

Submitted Date

Granted Date

US6780877 Acid addition salt of optically active piperidine compound and process for preparing the same
2002-02-28
2004-08-24
US8877168 Aqueous liquid preparations and light-stabilized aqueous liquid preparations
2014-06-25
2014-11-04
US8784789 Aqueous liquid preparations and light-stabilized aqueous liquid preparations
2003-07-30
2014-07-22
US2010137367 NOVEL CRYSTALLINE BEPOTASTINE METAL SALT HYDRATE, METHOD FOR PREPARING SAME, AND PHARMACEUTICAL COMPOSITION COMPRISING SAME
2010-06-03
US8900602 Disintegrating particle composition and orally rapidly disintegrating tablet
2010-08-11
2014-12-02
Bepotastine
Bepotastine.svg
Clinical data
Trade names Bepreve
AHFS/Drugs.com International Drug Names
MedlinePlus a610012
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
Oral, topical (eye drops)
ATC code
  • none
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability High (oral)
Minimal (topical)
Protein binding ~55%
Excretion Renal (75–90%)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C21H25ClN2O3
Molar mass 388.88 g/mol
3D model (JSmol)

References

    • EP 335 586 (Ube Ind.; appl. 22.3.1989; J-prior. 25.3.1988).
    • EP 485 984 (Ube Ind.; appl. 13.11.1991; J-prior. 15.11.1990).
    • WO 9 829 409 (Ube Ind.; appl. 25.12.1997; J-prior. 26.12.1996).
  • racemization :

    • JP 10 237 069 (Ube Ind.; appl. 21.2.1997).

References

  1. Jump up^ H. Takahashi; A. Ishida-Yamamoto; H. Iizuka (September 2004). “Effects of bepotastine, cetirizine, fexofenadine, and olopatadine on histamine-induced wheal-and flare-response, sedation, and psychomotor performance”Clinical and Experimental Dermatology29: 526–532. doi:10.1111/j.1365-2230.2004.01618.x.
  2. Jump up^ “Bepotastine Monograph”LexiComp.
  3. Jump up to:a b c d e f “Bepreve prescribing Information” (PDF).
  4. Jump up^ [phx.corporate-ir.net/External.File?item…t=1 “2011 Net Revenues Increase to $160.3 Million On an Adjusted Cash Net Income Basis, ISTA Posts Second Year of Profitability Company Reaffirms 2012 Financial Guidance”] Check |url= value (help).
  5. Jump up^ “Bausch & Lomb to Buy ISTA Pharmaceuticals for $500 Million”DealBook. Retrieved 2015-12-05.
  6. Jump up^ “Bausch & Lomb Inc. et al. v. Micro Labs USA, Inc. et al.”
  7. Jump up^ “Valenant pharmaceuticals eyes China with Bausch deal”.
  8. Jump up^ Macejko, Thomas T.; Bergmann, Mark T.; Williams, Jon I.; Gow, James A.; Gomes, Paul J.; McNamara, Timothy R.; Abelson, Mark B. (2010-07-01). “Multicenter Clinical Evaluation of Bepotastine Besilate Ophthalmic Solutions 1.0% and 1.5% to Treat Allergic Conjunctivitis”American Journal of Ophthalmology150 (1): 122–127.e5. doi:10.1016/j.ajo.2010.02.007.

////////////Bepotastine Besilate, ベポタスチンベシル酸塩  ,Talion , tau284, TAU-284DS, TAU-284, DA-5206
HL-151 , SNJ-1773

C1CN(CCC1OC(C2=CC=C(C=C2)Cl)C3=CC=CC=N3)CCCC(=O)O.C1=CC=C(C=C1)S(=O)(=O)O

%d bloggers like this: