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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK 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

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Lofexidine, лофексидин , لوفيكسيدين , 洛非西定 ,


Lofexidine.svgLofexidine.png

Lofexidine

  • Molecular FormulaC11H12Cl2N2O
  • Average mass259.132 Da
  • (±)-2-[1-(2,6-Dichlorophenoxy)ethyl]-2-imidazoline
UNII:UI82K0T627
лофексидин [Russian] [INN]
لوفيكسيدين [Arabic] [INN]
洛非西定 [Chinese] [INN]
1H-Imidazole, 2-(1-(2,6-dichlorophenoxy)ethyl)-4,5-dihydro- (9CI)
2-{1-[(2,6-dichlorophenyl)oxy]ethyl}-4,5-dihydro-1H-imidazole
CAS 31036-80-3 [RN]
Lofetensin, Loxacor
Synthesis Reference ZA 6800850eidem, US 3966757 (1968, 1976 both to Nordmark)
DE 1935479, Jan 21, 1971
U.S. Patent 3,966,757.

FDA Approved May 2018

Lofexidine was developed by US Woldmeds LLC and it got approved by the FDA on May 16, 2018

File:Lofexidine synthesis.svg

Experimental Properties

PROPERTY VALUE SOURCE
melting point (°C) 221-223 U.S. Patent 3,966,757.
boiling point (°C) 421.5 ºC at 760 mm Hg ‘MSDS’
water solubility Soluble ‘MSDS’
logP 5.37 FDA Advisory Committee Briefing Document.
pKa 9.43 FDA Advisory Committee Briefing Document.

SYN

Organic Process Research & Development, 13(3), 415-419; 2009

Title: Lofexidine
CAS Registry Number: 31036-80-3
CAS Name: 2-[1-(2,6-Dichlorophenoxy)ethyl]-4,5-dihydro-1H-imidazole
Additional Names: 2-[1-(2,6-dichlorophenoxy)ethyl]-2-imidazoline
Molecular Formula: C11H12Cl2N2O
Molecular Weight: 259.13
Percent Composition: C 50.99%, H 4.67%, Cl 27.36%, N 10.81%, O 6.17%
Literature References: a2-Adrenoceptor agonist related structurally to clonidine, q.v. Prepn of the HCl salt: H. Baganz, H. J. May, ZA 6800850eidem, US 3966757 (1968, 1976 both to Nordmark); of the free base: eidem, DE 1935479 (1971 to Nordmark), C.A.74, 87979 (1971). Pharmacological studies: J. Velly, J. Pharmacol. 8, 351 (1977); B. Jarrot et al., Biochem. Pharmacol. 28, 141 (1979). NMR data and cardiovascular effects: P. B. M. Timmermans, P. A. Van Zwieten, Eur. J. Med. Chem. 15, 323 (1980). Hypotensive and sedative properties: P. Birch et al., Br. J. Pharmacol. 68, 107 (1980). Effects in hypertension: N. D. Vlachakis et al., Fed. Proc. 39, 4844 (1980). Series of articles on pharmacology, toxicology, clinical studies: Arzneim.-Forsch. 32, 915-993 (1982). Toxicity studies: T. H. Tsai et al., ibid. 955. Review of clinical trials in treatment of opiate withdrawal: J. Strang et al., Am. J. Addict. 8, 337-348 (1999).
Properties: Crystals, mp 126-128°.
Melting point: mp 126-128°
Derivative Type: Hydrochloride
CAS Registry Number: 21498-08-8
Manufacturers’ Codes: MDL-14042A; Ba-168
Trademarks: BritLofex (Britannia); Lofetensin (Nattermann)
Molecular Formula: C11H12Cl2N2O.HCl
Molecular Weight: 295.59
Percent Composition: C 44.70%, H 4.43%, Cl 35.98%, N 9.48%, O 5.41%
Properties: Crystals from ethanol/ether or 2-propanol, mp 221-223° (U.S. patent); also reported as mp 230-232° (Ger. patent). Very sol in water, ethanol. Slightly sol in 2-propanol. Practically insol in ether. LD50 in mice, rats, dogs (mg/kg): between 74-147 orally (all species); between 8-18 i.v. (all species) (Tsai).
Melting point: mp 221-223° (U.S. patent); mp 230-232° (Ger. patent)
Toxicity data: LD50 in mice, rats, dogs (mg/kg): between 74-147 orally (all species); between 8-18 i.v. (all species) (Tsai)
Therap-Cat: In treatment of opioid withdrawal symptoms; antihypertensive.
Keywords: Antihypertensive; Imidazole Derivatives.

Image result for lofexidine synthesis

LOFEXIDINE HYDROCHLORIDE

Cas No. 21498-08-8

Lofexidine, sold under the brand name Lucemyra among others,[1] is a medication historically used to treat high blood pressure, but more commonly used to help with the physical symptoms of opioid withdrawal.[2] It is taken by mouth.[3] It is an α2A adrenergic receptoragonist.[3] It was approved for use by the Food and Drug Administration in the United States in 2018.[3]

Medical uses

In the United States, the brand name Lucemyra (lofexidine HCl) is approved for the “mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults,” for a treatment duration of 14 days.[1] In the United Kingdom, lofexidine is commonly used in conjunction with the opioid receptor antagonist naltrexone in rapid detoxification cases. When these two drugs are paired, naltrexone is administered to induce an opioid-receptor blockade sending the subject into immediate withdrawal and accelerating the detoxificationprocess, while lofexidine is given to relieve the symptoms associated with the withdrawal including chills, sweating, stomach cramps, muscle pain, and runny nose.[citation needed]

Opioid withdrawal

The United Kingdom’s National Institute for Health and Care Excellence (NICE) guidelines recommend the use of methadone or buprenorphine as first-line agents in the management of opioid use disorder. However, lofexidine is considered an acceptable alternative for people with mild or uncertain opioid dependence in need of short-term detoxification.[4]

Lofexidine is not an opioid.[3] It does not eliminate the symptoms of opioid withdrawal but reduces them.[3] Indeed, one suggested use for lofexidine is to ease withdrawal symptoms of methadone dependence. Its use is approved in the United States for up to 14 days.[3]

Other clinical uses

The possibility of using lofexidine to treat alcohol withdrawal symptoms has been investigated, and has not yet been shown to be an effective treatment.[5] It is also used in treatment of cases suffering from postmenopausal hot flashes.

Special populations

Lofexidine’s safety in pregnancy or in the setting of breastfeeding are unknown.[6] Caution is warranted if chronic kidney impairment is present.[6]

Adverse effects

Adverse effects that have occurred after taking lofexidine include the following:[6]

In addition, people may experience a sudden jump in blood pressure after stopping lofexidine.[1]

Overdose

The LD50 of lofexidine is above 77 mg/kg in animals. Studies of high-dose, single administrations of lofexidine proved tolerable for animals, but repeat administration induced symptoms consistent with toxicity. In studies on mice, rats, and dogs, these included ataxiasomnolence, and tremors. It is expected that an overdose of lofexidine would result in symptoms akin to its pharmacological side effects in humans, such as bradycardia and hypotension.[7]

Interactions

Many drug-drug interactions with lofexidine are possible.[8]

QT prolongation

Lofexidine prolongs the QT interval, which can result in a severe interaction (torsade de pointes) when combined with other drugs that also prolong the QT interval. Patient-specific characteristics that increase the risk for a clinically-significant drug-drug interaction include:[8]

As a result, there are many QT-prolonging drugs that may interact with lofexidine. These include medications such as amiodaronecitalopram, and fluconazole. Other medications may increase the risk for a low level of potassium in the blood, thereby indirectly increasing the risk for QT prolongation. For example, dexamethasonehydrochlorothiazide, and theophylline can lower the level of potassium in the blood.[8]

CNS depression

Lofexidine can depress the central nervous system (CNS), which, in combination with other CNS depressants, may reduce a person’s ability to perform tasks that require skills and attention. For example, clobazamgabapentin, and levetiracetam all can depress the CNS.[8]

Hypotension

The risk of hypotension (low blood pressure) is increased when lofexidine is combined with other drugs that lower blood pressure. These may include losartanmetoprolol, and pramipexole.[8]

Pharmacology

Lofexidine is an agonist at the α-2A, 2B, and 2C adrenergic receptor subtypes, with the highest activity at the alpha-2A receptor.[9]

Ki for lofexidine[9]
Adrenergic receptor Ki (nM)
α-2A 4
α-2B 67
α-2C 69

Ki represents the dissociation constant[10] for lofexidine’s binding to a specific subtype of alpha-2 receptor. The smaller the Ki value, the stronger the drug binds to the receptor to exert its activity.

Lofexidine inhibits the release of norepinephrine in the central and peripheral nervous system, thereby reducing some of the symptoms of opioid withdrawal, but it has no documented effect on drug craving and endogenous opioid levels.[2]

Pharmacokinetics

Lofexidine’s oral bioavailability is about 90%, with extensive oral absorption. Peak plasma concentrations occur at 3 hours after a single administration, with a half-life of 11 hours. Lofexidine is extensively metabolized by the liver, and primarily cleared by the kidney. It is 80-90% plasma protein bound.[7]

Chemistry

Lofexidine exists as a solid at room temperature, with a melting point of 127 degrees C.[7] The pair of ortho chlorine (Cl) atoms on the phenyl ring are necessary for lofexidine’s agonism at the α2a adrenergic receptor subtype; removal of either chlorine atom results in antagonism at the receptor.[9]

Comparison to clonidine

Structure of clonidine and lofexidine

Lofexidine is structurally analogous to clonidine, another α2 adrenergic receptor agonist used for treatment of opioid withdrawal symptoms. A comparison of the two structures is shown at right. Both contain an imidazoline ring and a 2,6-dichlorinated phenyl ring. The differences in structure are shown in red, while the similarities are in black. In addition to the structural differences, administration of lofexidine to people who abuse opioids has been shown to be more effective for a longer duration, with fewer withdrawal symptoms than clonidine even after one day.[11] However, clonidine is often preferred as it is substantially cheaper than lofexidine when purchased with a private (non-NHS) prescription. This factor is exacerbated by the considerable number of and quantities of medications prescribed to alleviate the constellation of withdrawal signs and symptoms. Additionally, clonidine has been shown to significantly lower blood pressure. Therefore, although similar to lofexidine, clonidine is most frequently prescribed to treat high blood pressure.[citation needed]

Society and culture

Britannia Pharmaceuticals has licensed lofexidine to be sold by US WorldMeds for sale in North America.[12] In the United Kingdom, the hydrochloride form, lofexidine HCl, has been licensed and sold since 1992 for opioid withdrawal relief in tablet form as BritLofex by Britannia Pharmaceuticals.[2] BritLofex is only available by prescription. Lofexidine was first approved by the US FDA on May 16, 2018 under the brand name Lucemyra, produced by US WorldMeds.[13] It was noted as the first, non-opioid drug approved in the US for the treatment of opioid withdrawal.[1]

Heroin has been reported to be the most prominent illicit drug of abuse among admissions at public!} -funded substance abuse treatment facilities in the US. At some time in their lives, about 2.4 million people have used heroin; in 1997, there were 81 ,000 new heroin users of whom 87% were less than 26 years of age. In spite of efforts to decrease illicit drug abuse, the problem escalates and the abusing population is increasingly younger. Hospital emergency room episodes from 21 metropolitan areas show that 14% of drug-related emergency room episodes involved heroin, and such episodes increased more than 2-fold from 1991 to 1996. Additionally, prescription opioid abuse escalates; the number of people addicted to prescription pain relievers is 3 -fold higher than those addicted to heroin. For example, from 1999 to 2001, the non-medical use of OxyContin®increased 4-fold, and its use continues to escalate.

[0003] Generally, opioid addiction has been associated with high morbidity and mortality, with a 15-20 fold increase in risk of death for intravenous drug users compared with their same age peers. Clearly, the medical and social importance of the development of effective treatments for opioid addiction is well recognized. Surprisingly, few treatment options for opioid addiction are available.

[0004] Withdrawal, maintenance and relapse are considered the progressive stages for treatment of opioid addiction. There are two predominant management strategies for the treatment of opioid addiction, detoxification and substitution therapy, which are typically combined with medical, social and psychological support. A majority of individuals may benefit from remaining in the maintenance phase for an indefinite period of time, while others may be able to directly undergo medically-supervised detoxification and/or relapse therapy, without the need for maintenance therapy. Methadone and buprenorphine constitute the most commonly used pharmacotherapies. Although patients continue to be successfully treated with methadone, a mμ opioid receptor agonist, several disadvantages of methadone treatment include the length of time for withdrawal, the difficulty of obtaining complete abstinence, and liability for its abuse. Due to the abuse liability of methadone and its consequent Schedule II classification by the Drug Enforcement Administration (DEA), methadone has additional disadvantages with respect to its prescription requirements, the carefully controlled conditions under which it is dispensed, and the annoyance experienced by patients who must frequently visit the dispensing unit to obtain their methadone dosages.

[0005] BritLofex™ (Lofexidine hydrochloride 0.2 mg tablet), an α2-adrenergic agonist, is used as a non-opioid medication for opioid detoxification in the United Kingdom (UK). There is no non-opioid medication approved by the Food and Drug Administration (FDA) for this indication in the US. The only medications currently approved by the FDA for opioid detoxification are methadone and buprenorphine, both opioid receptor agonists and both associated with abuse liability. Clonidine, an 012-adrenergic agonist, is often used “off-label” for this indication in the U.S. However, clonidine has not been approved by the FDA for this indication. However, the use of clonidine is limited by its side-effect profile, i.e., significant hypotension at doses effective in alleviating opioid withdrawal symptoms.

[0006] In contrast, Lofexidine HCl is the only non-opiate, non-addictive treatment approved for use in the UK to manage withdrawal symptoms in patients undergoing opiate detoxification. Lofexidine has been found to be effective in reducing the symptoms associated with heroin withdrawal such as chills, vomiting, sweating, stomach cramps, diarrhea, muscle pain, and runny nose and eyes. In the UK, the treatment is responsible for approximately 20,000 detoxifications per year. The drug’s proven level of safety permits its use in an outpatient situation. This is of great importance to patients in the US who are located in parts of the country where treatment clinics are not readily available.

[0007] Although naltrexone, methadone and more recently buprenorphine are FDA approved in the treatment of opioid addiction, these opioid treatments are associated with high relapse rates. Furthermore, there is currently insufficient availability of methadone and buprenorphine treatment for patients who abuse opioids. A significant number of these patients are undergoing detoxification treatments. However, the great risk of abuse and several other existing restrictions, such as medical prescribing and pharmaceutical dispensing, limit the use of methadone and buprenorphine for outpatient detoxification. In addition, the unapproved status of clonidine, its side effects, such as the lowering of blood pressure, and moderate efficacy limit its use. A substantial amount of research is ongoing to understand the mechanisms that may underline the high rates of relapse associated with opioid addiction. There is growing evidence that chronic drug use results in neuroadaptive changes in brain stress and reward circuits that may be associated with increased drug craving and risk of relapse particularly in the face of environmental triggers such as stressful life events and drug cues.

PATENT

https://patents.google.com/patent/EP2334297A1/en

The lofexidine hydrochloride tablets available in the UK market (BritLofex™) contain the racemic mixture of the drug. However, since lofexidine enantiomers exhibit different affinities for central the nervous system neurotransmitter receptors involved in (±)-lofexidine’s action as a medication for opioid detoxification, each of these enantiomers may have therapeutic benefits in the treatment of opioid addiction.

Experimental

[0028] 1) Resolution of (-)-lofexidine and (+)-lofexidine enantiomers found in the racemic mixture using chiral stationary phases by HPLC method:

[0029] A chiral chromatographic matrix was used to separate a racemic mixture of lofexidine into its component enantiomers by a process of HPLC to obtain optically pure (-)- lofexidine and optically pure (+)-lofexidine. The separation was performed using a chiral stationary phase consisted of D-glucose cyclodextran complex (Cyclobond HP-RSP) from Astec

Company (Whippany, NJ, USA) using a mobile phase consisted of 1OmM ammonium acetate

(88%), acetonitrile (8%), and methanol (8%) at 0.85 ml/min flow rate. Analysis was performed using Agilent series 1100 HPLC system comprising a solvent degasser unit, quaternary pump, autosampler, and DAD detector. Using such chiral stationary phase in a preparative scale enables the yield of gram quantities of desired enantiomers.

[0030] Resolution of (-)-lofexidine and (+)-lofexidine enantiomers found in the racemic mixture using a chiral acid, not only diastereomeric salt formation but also preferential crystallization: [0031] Optical resolution of (±)-lofexidine hydrochloride by using the classical methods of salt formation with a chiral acid such as, [( Di-p-toluoyl-D-tartaric acid [D]D20 +142° (c=l, CH3OH)] as shown in Figure 1, yielded (-)-lofexidine hydrochloride and (+)-lofexidine hydrochloride enantiomers (yield = 87%). The method comprised the following steps: [0032] A racemic form of lofexidine (10 mmol) was placed in ethanol (100 mL), and the chiral acid (+)-Di-p-toluoyl-D-tartaric acid was added in order to form a mixture of the (+)(-) and (+)(+) diastereomeric lofexidine salts. The diastereomeric salts i.e.: (+)(-) lofexidine Di-p- toluoyl-D-tartarate salt was separated from the (+)(+) lofexidine Di-p-toluoyl-D-tartarate salt by a process of fractional crystallization. 10 mL methanol and 1 ml water was added and the mixture was heated for 1 hour at 55-65 0C. After the mixture became clear it was left to cool down at room temperature. The crystals were isolated after two days, dried under vacuum. Recrystallization was performed using ethanol (20 volumes). Final yield was 87%. [0033] Chiral purity of the resulting crystals was tested by the chiral HPLC method. The

(+)(-) lofexidine Di-p-toluoyl-D-tartarate salt or the(+)(+) lofexidine Di-p-toluoyl-D-tartarate salt obtained was treated with a base such as 0.1 N sodium carbonate to liberate (-)-lofexidine and (+)-lofexidine. The resulting enantiomerically pure free base of (-)-lofexidine and (+)-lofexidine was converted to lofexidine hydrochloride salt.

PAPER

A Scalable, Enantioselective Synthesis of the α2-Adrenergic Agonist, Lofexidine

Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, Kentucky 40536, U.S.A.
Org. Process Res. Dev.200913 (3), pp 415–419
DOI: 10.1021/op8002689

https://pubs.acs.org/doi/abs/10.1021/op8002689

* Author to whom correspondence may be sent. Tel: 859-257-1718. Fax: 859-257-7585. E-mail: pcrooks@email.uky.edu.
Abstract Image

A scalable and high-yielding synthetic route toward pure enantiomers of the α2-adrenergic agonist, lofexidine hydrochloride, is presented. Salient features include a rapid one-pot amide alkylation-imidazoline formation sequence on the carboxamide function of α-(2,6-dichlorophenoxy)propionamide, while preserving the sensitive configuration about the α-carbon of the resulting product. A means to accelerate the sluggish O-alkylation of the carboxamide function of α-(2,6-dichlorophenoxy)propionamide by Me3O+BF4 is also described, which may be of general applicability.

PATENTS

US8101779B2 *2008-10-062012-01-24University Of Kentucky Research FoundationEnantioselective synthesis of (+) and (–)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene

DE3149009A1 *1981-12-101983-06-23Nattermann A & Cie(-) – 2- (1- (2,6-dichlorophenoxy) ethyl) -1,3-diazacyclopent-2-ene, its preparation and its use in pharmaceutical preparations
DE3149010A1 *1981-12-101983-07-07Nattermann A & Cie(+) – 2- (1- (2,6-dichlorophenoxy) ethyl) -1,3-diazacyclopent-2-ene, its preparation and its use in preparations pharamazeutischen
EP1762239B1 *2005-09-082010-05-26Texcontor EtablissementLofexidine for intraspinal administration

References

  1. Jump up to:a b c d “Press Announcements – FDA approves the first non-opioid treatment for management of opioid withdrawal symptoms in adults”http://www.fda.gov. U.S. Food and Drug Administration. Retrieved 16 May 2018.
  2. Jump up to:a b c Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. p. 330. ISBN 978-0-85711-084-8.
  3. Jump up to:a b c d e f “Press Announcements – FDA approves the first non-opioid treatment for management of opioid withdrawal symptoms in adults”http://www.fda.gov. Retrieved 18 May2018.
  4. Jump up^ “Pharmacological interventions in opioid detoxification for drug misuse in people over 16”pathways.nice.org.uk. NICE. Retrieved 16 May 2018.
  5. Jump up^ Keaney F, Strang J, Gossop M, Marshall EJ, Farrell M, Welch S, Hahn B, Gonzalez A. A double-blind randomized placebo-controlled trial of lofexidine in alcohol withdrawal: lofexidine is not a useful adjunct to chlordiazepoxide. Alcohol Alcohol (2001) 36:426–30.
  6. Jump up to:a b c “LOFEXIDINE HYDROCHLORIDE”bnf.nice.org.uk. NICE. Retrieved 16 May2018.
  7. Jump up to:a b c “Lofexidine”pubchem.ncbi.nlm.nih.gov. National Center for Biotechnology Information. Retrieved 16 May 2018.
  8. Jump up to:a b c d e “Lofexidine | Interactions | BNF”bnf.nice.org.uk. NICE. Retrieved 16 May 2018.
  9. Jump up to:a b c Fulton, Brian (2014). Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies. John Wiley & Sons. p. 151. ISBN 0470614161.
  10. Jump up^ Neubig, R. R. (1 December 2003). “International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology”. Pharmacological Reviews55 (4): 597–606. doi:10.1124/pr.55.4.4.
  11. Jump up^ G. Gerra, et al., Lofexidine versus clonidine in rapid opioid detoxification, Journal of Substance Abuse TreatmentVolume 21, Issue 1, , July 2001, Pages 11-17.
  12. Jump up^ Britannia Pharmaceuticals Limited
  13. Jump up^ “Lucemyra (lofexidine hydrochloride) FDA Approval History – Drugs.com”Drugs.com. Retrieved 16 May 2018.
Lofexidine
Lofexidine.svg
Clinical data
Trade names BritLofex, Lucemyra, Kai Er Ding, others
AHFS/Drugs.com International Drug Names
Routes of
administration
By mouth (tablets)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability >90%
Protein binding 80–90%
Metabolism Liver (glucuronidation)
Elimination half-life 11 hours
Excretion Kidney
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C11H12Cl2N2O
Molar mass 259.131 g/mol
3D model (JSmol)
Chirality Racemic mixture

/////////////lofexidine, FDA 2018, лофексидин لوفيكسيدين 洛非西定 , Lofetensin, Loxacor

CC(C1=NCCN1)OC2=C(C=CC=C2Cl)Cl

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FDA approves new treatment Xeljanz (tofacitinib) for moderately to severely active ulcerative colitis


The U.S. Food and Drug Administration today expanded the approval of Xeljanz (tofacitinib) to include adults with moderately to severely active ulcerative colitis. Xeljanz is the first oral medication approved for chronic use in this indication. Other FDA-approved treatments for the chronic treatment of moderately to severely active ulcerative colitis must be administered through an intravenous infusion or subcutaneous injection.

May 30, 2018

Release

The U.S. Food and Drug Administration today expanded the approval of Xeljanz (tofacitinib) to include adults with moderately to severely active ulcerative colitis. Xeljanz is the first oral medication approved for chronic use in this indication. Other FDA-approved treatments for the chronic treatment of moderately to severely active ulcerative colitis must be administered through an intravenous infusion or subcutaneous injection.

“New treatments are needed for patients with moderately to severely active ulcerative colitis,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research. “Today’s approval provides an alternative therapy for a debilitating disease with limited treatment options.”

Ulcerative colitis is a chronic, inflammatory bowel disease affecting the colon. Patients experience recurrent flares of abdominal pain and bloody diarrhea. Other symptoms include fatigue, weight loss and fever. More than 900,000 patients are affected in the U.S., many of them experiencing moderately to severely active ulcerative colitis, and there is currently no cure.

The efficacy of Xeljanz for the treatment of moderately to severely active ulcerative colitis was demonstrated in three controlled clinical trials. This included two 8-week placebo-controlled trials that demonstrated that 10 mg of Xeljanz given twice daily induces remission in 17 to 18 percent of patients by week eight. In a placebo-controlled trial among patients who achieved a clinical response by week eight, Xeljanz, at a 5 mg or 10 mg dose given twice daily, was effective in inducing remission by week 52 in 34 percent and 41 percent of patients, respectively. Among patients who achieved remission after 8 weeks of treatment, 35 percent and 47 percent achieved sustained corticosteroid-free remission when treated with 5 mg and 10 mg, respectively.

The safety of chronic use of Xeljanz for ulcerative colitis was studied in the 52-week placebo- controlled trial. Additional supportive safety information was collected from patients who received treatment in an open-label long-term study.

The most common adverse events associated with Xeljanz treatment for ulcerative colitis were diarrhea, elevated cholesterol levels, headache, herpes zoster (shingles), increased blood creatine phosphokinase, nasopharyngitis (common cold), rash and upper respiratory tract infection.

Less common serious adverse events included malignancy and serious infections such as opportunistic infections. Xeljanz has a boxed warning for serious infections and malignancy. Patients treated with Xeljanz are at increased risk for developing serious infections that may lead to hospitalization or death. Lymphoma and other malignancies have been observed in patients treated with Xeljanz.

Use of Xeljanz in combination with biological therapies for ulcerative colitis or with potent immunosuppressants, such as azathioprine and cyclosporine, is not recommended.

Xeljanz, made by Pfizer Labs, was previously approved in 2012 for rheumatoid arthritis and in 2017 for psoriatic arthritis.

/////////////Xeljanz, tofacitinib, pfizer, fda 2017, psoriatic arthritis, ulcerative colitis

Selonsertib, GS-4997, GS-4977


Selonsertib.png

GS-4997, GS-4977, Selonsertib

Selonsertib; 1448428-04-3; GS-4997; UNII-NS3988A2TC; NS3988A2TC; 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]benzamide

  • 5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-[6-[4-(1-methylethyl)-4H-1,2,4-triazol-3-yl]-2-pyridinyl]benzamide
  • 5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}benzamide
Molecular Formula: C24H24FN7O
Molecular Weight: 445.502 g/mol
      • NMR  https://file.medchemexpress.com/batch_PDF/HY-18938/Selonsertib-HNMR-25028-MedChemExpress.pdf

str1

Selonsertib is an orally bioavailable inhibitor of apoptosis signal-regulating kinase 1 (ASK1; IC50 = 3.2 nM), which is involved in a variety of conditions, including fibrosis, oxidative stress, and inflammation, among others.1 A formulation containing selonsertib showed antifibrotic activity in a Phase II clinical trial. Clinical trials are ongoing for other conditions, including severe alcoholic hepatitis and nonalcoholic steatohepatitis.

Synonyms
  • GS-4997
  • GS-4977
  • Originator Gilead Sciences
  • Class Benzamides; Cardiovascular therapies; Imidazoles; Pyridines; Triazoles
  • Mechanism of Action MAP kinase kinase kinase 5 inhibitors

Highest Development Phases

  • Phase III Non-alcoholic steatohepatitis
  • Phase II Alcoholic hepatitis; Diabetic nephropathies; Non-alcoholic fatty liver disease; Pulmonary arterial hypertension

Most Recent Events

  • 13 Apr 2018 Efficacy data from a phase II trial in Non-alcoholic fatty liver disease presented at the The International Liver Congress™ 2018 of the European Association for the Study of the Liver (EASL-2018)
  • 13 Apr 2018 Gilead completes enrolment in the STELLAR 3 phase III trial for Non-alcoholic steatohepatitis in US, Argentina, Australia, Austria, Belgium, Brazil, Canada, France, Germany, Hong Kong, India, Israel, Italy, Japan, South Korea, Malaysia, Mexico, Netherlands, New Zealand, Poland, Portugal, Puerto Rico, Singapore, Spain, Switzerland, Taiwan, Turkey, and United Kingdom (NCT03053050)
  • 13 Apr 2018 Gilead completes enrolment in the STELLAR 4 phase III trial for Non-alcoholic steatohepatitis in the US, Australia, Austria, Belgium, Canada, France, Germany, Hong Kong, India, Israel, Italy, Japan, South Korea, Mexico, New Zealand, Poland, Puerto Rico, Singapore, Spain, Switzerland, Taiwan, and United Kingdom ( NCT03053063)

Apoptosis signal -regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase (“MAP3K”) family that activates the c-Jun N-terminal protein kinase (“JNK”) and p38 MAP kinase (Ichijo, H., Nishida, E., e, K., Dijke, P. T., Saitoh, M., Moriguchi, T., Matsumoto, K., Miyazono, K., and Gotoh, Y. (1997) Science, 275, 90-94).

ASK1 is activated by a variety of stimuli including oxidative stress, reactive oxygen species (ROS), LPS, TNF-a, FasL, ER stress, and increased intracellular calcium concentrations (Hattori, K., Naguro, I., Runchel, C, and Ichijo, H. (2009) Cell Comm. Signal. 7: 1-10; Takeda, K., Noguchi, T., Naguro, I., and Ichijo, H. (2007) Annu. Rev. Pharmacol. Toxicol. 48: 1-8.27; Nagai, H., Noguchi, T., Takeda, K., and Ichijo, I. (2007) J. Biochem. Mol. Biol. 40: 1-6).

Phosphorylation of ASK1 protein can lead to apoptosis or other cellular responses depending on the cell type. ASK1 activation and signaling have been reported to play an important role in a broad range of diseases including neurodegenerative, cardiovascular, inflammatory,

autoimmune, and metabolic disorders. In addition, ASK1 has been implicated in mediating organ damage following ischemia and reperfasion of the heart, brain, and kidney (Watanabe et al. (2005) BBRC 333, 562-567; Zhang et al, (2003) Life Sci 74-37-43; Terada et al. (2007) BBRC 364: 1043-49).

ROS are reported be associated with increases of inflammatory cytokine production, fibrosis, apoptosis, and necrosis in the kidney. (Singh DK, Winocour P, Farrington K. Oxidative stress in early diabetic nephropathy: fueling the fire. Nat Rev Endocrinol 201 1 Mar;7(3): 176- 184; Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001 Dec 13; 414(6865):813-820; Mimura I, Nangaku M. The suffocating kidney:

tubulointerstitial hypoxia in end-stage renal disease. Nat Rev Nephrol 2010 Nov; 6(1 1):667- 678).

Moreover, oxidative stress facilitates the formation of advanced glycation end-products (AGEs) that cause further renal injury and production of ROS. (Hung KY, et al. N- acetylcysteine-mediated antioxidation prevents hyperglycemia-induced apoptosis and collagen synthesis in rat mesangial cells. Am J Nephrol 2009;29(3): 192-202).

Tubulointerstitial fibrosis in the kidney is a strong predictor of progression to renal failure in patients with chronic kidney diseases (Schainuck LI, et al. Structural-functional correlations in renal disease. Part II: The correlations. Hum Pathol 1970; 1 : 631-641.).

Unilateral ureteral obstruction (UUO) in rats is a widely used model of tubulointerstitial fibrosis. UUO causes tubulointerstital inflammation, increased expression of transforming growth factor beta (TGF-β), and accumulation of myofibroblasts, which secrete matrix proteins such as collagen and fibronectin. The UUO model can be used to test for a drug’s potential to treat chronic kidney disease by inhibiting renal fibrosis (Chevalier et al., Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy, Kidney International (2009) 75, 1 145-1152.

Thus, therapeutic agents that function as inhibitors of ASK1 signaling have the potential to remedy or improve the lives of patients in need of treatment for diseases or conditions such as neurodegenerative, cardiovascular, inflammatory, autoimmune, and metabolic disorders. In particular, ASK1 inhibitors have the potential to treat cardio-renal diseases, including kidney disease, diabetic kidney disease, chronic kidney disease, fibrotic diseases (including lung and kidney fibrosis), respiratory diseases (including chronic obstructive pulmonary disease (COPD) and acute lung injury), acute and chronic liver diseases.

U.S. Publication No. 2007/0276050 describes methods for identifying AS 1 inhibitors useful for preventing and/or treating cardiovascular disease and methods for preventing and/or treating cardiovascular disease in an animal.

WO2009027283 discloses triazolopyridine compounds, methods for preparation thereof and methods for treating autoimmune disorders, inflammatory diseases, cardiovascular diseases and neurodegenerative diseases.

U.S. Patent Publication No. 2001/00095410A1, published January 13, 201 1, discloses compounds useful as ASK-1 inhibitors. U.S. Patent Publication No. 2001/00095410A1 relates to compounds of Formula (I):

Figure imgf000004_0001
SYN
WO  2016106384

PRODUCT PATENT

WO 2013112741

https://patents.google.com/patent/WO2013112741A1/en

InventorGregory Notte Original AssigneeGilead Sciences, Inc. Priority date 2012-01-27

SCHEME 1

Figure imgf000013_0001

SCHEME 2

 Figure imgf000015_0001

COUPLING

Figure imgf000014_0001Figure imgf000015_0003

GIVES

Figure imgf000015_0002

The name of the compound of the present invention as generated using ChemBioDraw Ultra 11.

Figure imgf000012_0001
is 5-(4-cyclopropyl- 1 H-imidazol- 1 -yl)-N-(6-(4-isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)-2- fluoro-4-methylbenzamide also known as 5-((4-cyclopropyl-lH-imdazol-l-yl)-2-fluoro-N-(6-(4- isopropyl-4H- 1 ,2,4-triazole-3 -yl)pyridine-2-yl)-4-methylbenzamide.

One method of preparing compounds of formula (I) is shown in Reaction Schemes 1 and 2 below.

Scheme 1

Figure imgf000013_0001

Preparation of Compound A

To a solution of methyl 6-aminopicolinate (432 g, 2.84 mol) in MeOH (5 L) was added NH2NH2.H2O (284 g, 5.68 mol, 2.0 eq.). The reaction mixture was heated under reflux for 3 hr and then cooled to room temperature. The precipitate formed in the mixture was collected by filtration, washed with EA (2 L><2) and then dried in vacuo to give compound A (405 g, 94% yield) as white solid.

Preparation of compound B

A mixture of compound A (405 g, 2.66 mol) in dimethylformamide-dimethylacetal (DMF-DMA) (3.54 L) was heated under reflux for 18 hr, cooled to room temperature and then concentrated under reduced pressure. The residue was taken up in EA (700 mL) and heated at 50°C for 20 min. After being cooled to room temperature, the solid was collected by filtration and dried in vacuo to give compound B (572 g, 82% yield) as white solid.

Preparation of C

To a solution of compound B (572 g, 2.18 mol) in a mixture of CH3CN-AcOH (3.6 L, 4:1) was added propan-2-amine (646 g, 5.0 eq.). The resulting mixture was heated under reflux for 24 hr and then cooled to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved in water (2.8 L) and 1 N aqueous NaOH was added to a pH of 8.0 H. The precipitate was collected by filtration and the filtrate was extracted with EA (500 mLx3). The combined organic layers were dried over anhydrous Na2S04, and then concentrated to a volume of 150 mL. To this mixture at 0°C was slowly added PE (400 mL) and the resulting suspension was filtered. The combined solid was re-crystallized from EA-PE to give compound C (253 g, 57% yield) as off-white solid.

1H- MR (400 MHz, CDC13): δ 8.24 (s, 1 H), 7.52 (m, 2 H), 6.51 (dd, J = 1.6, 7.2 Hz, 1 H), 5.55 (m, 1 H), 4.46 (bs, 2 H), 1.45 (d, J = 6.8 Hz, 6 H). MS (ESI+) m/z: 204 (M+l)+.

Compound C is a key intermediate for the synthesis of the compound of formula (I). Thus, an object of the present invention is also the provision of the intermediate compound C,

Figure imgf000014_0001

its salts or protected forms thereof, for the preparation of the compound of formula (I). An example of a salt of the compound C is the HC1 addition salt. An example of a protected form of compound C is the carbamate compound such as obtained with Cbz-Cl. Protective groups, their preparation and uses are taught in Peter G.M. Wuts and Theodora W. Greene, Protective Groups in Organic Chemistry, 2nd edition, 1991, Wiley and Sons, Publishers. Scheme 2

Preparation of the Compound of formula (I) continued:

Figure imgf000015_0001
Figure imgf000015_0002

Formula (I)

Compound 6 is a key intermediate for the synthesis of the compound of formula (I). Thus an object of the present invention is also the provision of intermediate compound 6,

Figure imgf000015_0003

6

salts or protected forms thereof, for the preparation of the compound of formula (I). An example of a salt of the compound 6 is the HC1 addition salt. An example of a protected form of the compound 6 is an ester (e.g. methyl, ethyl or benzyl esters) or the carbamate compound such as obtained with Cbz-Cl. Protective groups, their preparations and uses are taught in Peter G.M. Wuts and Theodora W. Greene, Protective Groups in Organic Chemistry, 2nd edition, 1991, Wiley and Sons, Publishers. Step 1 – Preparation of 5-amino-2-fluoro-4-methylbenzonitrile – Compound (2)

The starting 5-bromo-4-fluoro-2-methylaniline (1) (20g, 98 mmol) was dissolved in anhydrous 1-methylpyrrolidinone (100 mL), and copper (I) cyanide (17.6g, 196 mmol) was added. The reaction was heated to 180°C for 3 hours, cooled to room temperature, and water (300 mL) and concentrated ammonium hydroxide (300 mL) added. The mixture was stirred for 30 minutes and extracted with EA (3 x 200 mL). The combined extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure. The oily residue was washed with hexanes (2 x 100 mL), and the solid dissolved in dichloromethane and loaded onto a silica gel column. Eluting with 0 to 25% EA in hexanes gradient provided 5-amino-2-fluoro- 4-methylbenzonitrile (10.06g, 67.1 mmol). LC/MS (m/z:151 M+1).

Step 2 – Preparation of 5-(2-cvclopropyl-2-oxoethylamino)-2-fluoro-4-methylbenzonitrile – Compound (3)

5-Amino-2-fluoro-4-methylbenzonitrile (12g, 80mmol) was dissolved in anhydrous N,N- dimethylformamide (160 mL) under nitrogen, and potassium carbonate (13.27g, 96 mmol) and potassium iodide (14.61g , 88mmol) were added as solids with stirring. The reaction was stirred for 5 minutes at room temperature and then bromomethyl cyclopropylketone (20.24 mL, 180 mmol) was added. The reaction mixture was heated to 60°C for 3 hours, and then the solvents removed under reduced pressure. The residue was dissolved in EA (400 mL) and washed with 400 mL of water. The organic layer was dried over magnesium sulfate, and solvent was removed under reduced pressure. The residue was re-dissolved in a minimum amount of EA, and hexanes were added to bring the solution to 3: 1 hexanes: EA by volume. The product precipitated out of solution and was collected by filtration to provide 5-(2-cyclopropyl-2- oxoethylamino)-2-fluoro-4-methylbenzonitrile (14.19g, 61.2 mmol). LC/MS (m/z : 233, M+1)

Step 3 – Preparation of 5-(4-cvclopropyl-2-mercapto-lH-imidazol-l -yl)-2-fluoro-4- methylbenzonitrile – Compound (4)

5-(2-Cyclopropyl-2-oxoethylamino)-2-fluoro-4-methylbenzonitrile (14.19g, 61.2mmol) was dissolved in glacial acetic acid (300 mL). Potassium thiocyanate (11.9g, 122.4mmol) was added as a solid with stirring. The reaction mixture was heated to 110°C for 4 hours at which time the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (200 mL) and washed with 200 mL water. The aqueous extract was extracted with (2 x 200 mL) additional dichloromethane, the organic extracts combined and dried over magnesium sulfate. The solvent was removed under reduced pressure and the oily residue was re-dissolved in EA (50 mL) and 150 mL hexanes was added. A dark layer formed and a stir bar was added to the flask. Vigorous stirring caused the product to precipitate as a peach colored solid. The product was collected by filtration, to yield 5-(4-cyclopropyl-2-mercapto-lH- imidazol-l-yl)-2-fluoro-4-methylbenzonitrile, (14.26g, 52.23 mmol). Anal. LC/MS (m/z : 274, M+1)

Step 4 – Preparation of 5-(4-cyclopropyl-lH-imidazol -yl)-2-fluoro-4-methylbenzonitrile – Compound (5)

In a 500 mL three neck round bottom flask was placed acetic acid (96 mL), water (19 mL) and hydrogen peroxide (30%, 7.47 mL, 65.88 mmol). The mixture was heated to 45°C with stirring under nitrogen while monitoring the internal temperature. 5-(4-Cyclopropyl-2- mercapto-lH-imidazol-l-yl)-2-fluoro-4-methylbenzonitrile (6.00g, 21.96 mmol) was then added as a solid in small portions over 30 minutes while maintaining an internal temperature below 55°C. When addition of the thioimidazole was complete the reaction was stirred for 30 minutes at a temperature of 45 C, and then cooled to room temperature, and a solution of 20% wt/wt sodium sulfite in water (6 mL) was slowly added. The mixture was stirred for 30 minutes and solvents were removed under reduced pressure. The residue was suspended in 250 mL of water and 4N aqueous ammonium hydroxide was added to bring the pH to ~10. The mixture was extracted with dichloromethane (3 x 200ml), the organics combined, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in 20 mL EA, and 80 mL of hexanes were added with stirring. The solvents were decanted off and an oily residue was left behind. This process was repeated and the product, 5-(4-cyclopropyl-lH- imidazol-l-yl)-2-fluoro-4-methylbenzonitrile was obtained as a viscous oil (5.14 g, 21.33 mmol) Anal. LC/MS (m/z: 242, M+1)

Step 5 – Preparation of 5-(4-cvclopropyl-lH-imidazol-l-yl)-2-fluoro-4-methylbenzoic acid hydrochloride (6)

5-(4-Cyclopropyl-lH-imidazol-l-yl)-2-fluoro-4-methylbenzonitrile (1 1.21g, 46.50mmol) was placed in a round bottom flask fitted with a reflux condenser, and suspended in 38% hydrochloric acid (200 mL). The mixture was heated to 100°C for 4.5 hours, and then cooled to room temperature. Solvent was removed under reduced pressure to give a pink solid, to which was added 100ml of EA. The solid product was collected by filtration and washed with 3 xlOO mL EA. To the solid product was added 100 mL 10% methanol in dichloromethane, the mixture stirred, and the filtrate collected. This was repeated with 2 more 100ml portions of 10% methanol in dichloromethane. The filtrates were combined and solvent was removed under reduced pressure, to provide crude 5-(4-cyclopropyl-lH-imidazol-l -yl)-2-fluoro-4- methylbenzoic acid hydrochloride. No further purification was carried out (1 1.13g, 37.54mmol). Anal. LC/MS (m/z: 261 , M+1)

Step 6 – Preparation of 5-(4-cvclopropyl- 1 H-imidazol- 1 -yl)-2-fluoro-N-(6-(4-isopropyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide – formula (I)

5-(4-Cyclopropyl- 1 H-imidazol- 1 -yl)-2-fluoro-4-methylbenzoic acid hydrochloride (1.5g,

5.07mmol) was suspended in anhydrous 1 ,2-dichlorom ethane (25 mL) at room temperature. Oxalyl chloride (0.575ml, 6.59mmol) was added with stirring under nitrogen, followed by N,N- dimethylformamide (0.044ml, 0.507mmol). The ; mixture was stirred for 4 hr at room temperature, and then the solvent was removed under reduced pressure. The residue was dissolved in 25 mL anhydrous dichloromethane. 6-(4-isopropyl-4H-l ,2,4-triazol-3-yl)pyridin-2- amine (1.13g, 5.58mmol) (compound C) and 4-dimethylaminopyridine (0.62g, 5.07 mmol) were rapidly added with stirring under nitrogen. The reaction was stirred for 2 hours at room temperature and aqueous saturated NaHC03 (15 mL) was added. The mixture was stirred for 10 minutes, and the layers were separated, and the aqueous layer was washed 1 x 20 mL dichloromethane. The combined organics were dried (MgS04), filtered and concentrated. The residue was dissolved in a minimum amount of CH3CN and water was slowly added until solids precipitated from the mixture. The solid was collected by filtration and dried to give 5-(4- cyclopropyl-lH-imidazol-l -yl)-2-fluoro-N-(6-(4-isopropyl-4H-l ,2,4-triazol-3-yl)pyridin-2-yl)- 4-methylbenzamide in -96% purity (1.28g, 2.88 mmol). Anal. LC/MS (m/z: 446, M+1). The material was further purified by RP-HPLC (reverse phase HPLC) to obtain an analytically pure sample as the HC1 salt.

Figure imgf000018_0001

C24H24FN7O-HCI. 446.2 (M+1). 1H-NMR (DMSO): δ 1 1.12 (s, 1H), 9.41 (s, 1H), 9.32 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.07 (t, J = 8.4 Hz, 1 H), 7.95 (d, J = 6.4 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.59 (d, J = 10.4 Hz, 1H), 5.72 (sept, J = 6.8 Hz, 1H), 2.29 (s, 3H), 2.00-2.05 (m, 1H), 1.44 (d, J = 6.8 Hz, 6H), 1.01-1.06 (m, 2H), 0.85-0.89 (m, 2H).

PATENT

US 9067933

US 20150342943

WO 2016187393

WO 2016025474

WO 2016112305

WO 2017205684

WO 2017210526

WO 2018013936

PAPER

Bioorganic & Medicinal Chemistry Letters (2018), 28(3), 400-404

https://www.sciencedirect.com/science/article/pii/S0960894X17311861?via%3Dihub

https://ars.els-cdn.com/content/image/1-s2.0-S0960894X17311861-mmc1.pdf

PAPER

ACS Medicinal Chemistry Letters (2017), 8(3), 316-320

https://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00481

https://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.6b00481/suppl_file/ml6b00481_si_001.pdf

Abstract Image

Apoptosis signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury.

PATENT

FORM I TO IX POLYMORPHS

WO 2016105453

https://patents.google.com/patent/WO2016105453A1/zh-CN

Compound I is known to exhibit ASK1 inhibitory activity and is described in, for example, U.S. Patent No. 8,742,126, which is hereby incorporated by reference in its entirety. Compound I has the formula:

Compound I

Compound I can be synthesized according to the methods described in U.S. Patent No. 8,742,126 or U.S. Provisional Application No. 62/096,391, U.S. Provisional Application No. 62/269,064 and PCT Application PCT/US2015/067511 (filed on even date herewith and titled “Processes for Preparing ASK1 Inhibitors”), all of which are incorporated by reference in their entirety.

The present disclosure provides forms of Compound I and salts, co-crystals, hydrates, and solvates thereof. Also described herein are processes for making the forms of Compound I, pharmaceutical compositions comprising crystalline forms of Compound I and methods for using such forms and pharmaceutical compositions in the treatment of diseases mediated by ASK1 disregulation.

Thus, one embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I Form I) characterized by an X-ray powder diffractogram comprising the following peaks: 16.7, 21.3, and 22.8 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Kct radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I Form II) characterized by an X-ray powder diffractogram comprising the following peaks: 11.2, 16.6, and 17.4 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I Form III) characterized by an X-ray powder diffractogram comprising the following peaks: 5.1, 10.2, and 25.3 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Κ radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormIV) characterized by an X-ray powder diffractogram comprising the following peaks: 7.2, 12.6, and 19.3 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormV) characterized by an X-ray powder diffractogram comprising the following peaks: 9.7, 13.3, and 16.4 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormVI) characterized by an X-ray powder diffractogram comprising the following peaks: 8.8, 23.2, and 23.5 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormVII) characterized by an X-ray powder diffractogram comprising the following peaks: 8.2, 14.2, and 22.9 °2Θ ± 0.2 °2Θ as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormVIII) characterized by an X-ray powder diffractogram comprising the following peaks: 8.4, 19.3, and 24.3 °2Θ ± 0.2 °2Θ as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyI-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormIX) characterized by an X-ray powder diffractogram comprising the following peaks: 6.9, 14.3, 23.7, and 24.8 °2Θ ± 0.2 °2Θ as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is amorphous 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide.

Some embodiments provided herein relate to crystalline forms of salts or co-crystals of Compound I.

The compound, 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (also known as 5-((4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(4-isopropyl-4H-l,2,4-triazole-3-yl)pyridine-2-yl)-4-methylbenzamide)) designated herein as Compound I, has the formula:

Compound I exhibits an EC50 value of about 2 nanomolar in an ASK1 293 cell-based assay. The experimental protocol for this assay is known in the art and is described in U.S. Patent No. 8,742,126, which is hereby incorporated by reference in its entirety.

The present disclosure relates to various crystalline forms of Compound I, and processes for making the crystalline forms. Compound I also provides forms further described herein as “Compound I Form I,” “Compound I Form II,” “Compound I Form III,” “Compound I Form TV,” “Compound I Form V,” “Compound I Form VI,” “Compound I Form VII,” “Compound I Form VIII,” “Compound I Form IX,” and “amorphous Compound I.” In some embodiments, such forms of Compound I may be a solvate or a hydrate.

Additional crystalline forms of Compound I are also further described herein. In some embodiments, crystalline forms of Compound I may include salts or co-crystals of Compound I. Salts or co-crystals of Compound I may have the following formula:

 X

PATENT

WO 2016106384

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016106384&recNum=31&docAn=US2015067511&queryString=EN_ALL:nmr%20AND%20PA:(gilead%20sciences)&maxRec=1065

As described generally above, the disclosure provides in some embodiments processes for making a compound of formula (A).

Scheme 1 represents an exemplary synthesis of a compound of formula (A) and can be carried out according to the embodiments described herein. It is contemplated that the exemplary synthesis shown in Scheme 1 may be particularly advantageous. For example, the synthesis employs less toxic starting materials (i.e., using Compound (H) in place of its corresponding analog having bromide at the tosylate position), avoids toxic reagents (i.e., CuCN), and employs less toxic solvents (i.e., using dichloromethane instead of dichloroethane), including at the final step of the synthesis. The synthesis also can utilize milder reaction conditions (i.e., avoids high temperatures needed for cyanation, etc.), can avoid the use of heavy metals, and can require less purification steps (e.g. avoid column chromatography). The particular reaction conditions and reagents employed in Scheme 1 are discussed below.

Scheme 1


Compound (B)

Scheme 2

Compound (A)

Scheme 3

Compound (E) Compound (A)

EXAMPLES

The compounds of the disclosure may be prepared using methods disclosed herein and routine modifications thereof which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of compounds described herein, may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g. from Sigma Aldrich or other chemical suppliers. Unless otherwise noted, the starting materials for the following reactions may be obtained from commercial sources.

Example 1: Synthesis of Compound (A)

Compound (C)


MeCN Toluene, /Pr2EtN

Compound (J) Compound (H)

ompound F

(COCI)2, DMF 

Compound (D-a)

Compound (B) J Compound (A) Hydroxytosylation of Compound (J) to form Compound (H)

Compound (J) Compound (H)

Koser’s reagent, PhI(OH)OTs, (1.0 eq.) and acetonitrile (5 vols) are charged to a flask. Cyclopropylmethyl ketone (Compound (J), 1.2 eq.) is charged and the mixture is heated to about 70 °C to about 75 °C. Once the reaction is complete, the contents are cooled and concentrated. The residue is diluted in dichloromethane (about 2.5 vols) and washed with water (2 x about 1 to 2 volumes). The organic phase is concentrated to approximately 1.5 vols and the product is triturated with hexanes (about 1.5 to 2 vols) and concentrated to remove dichloromethane and the distilled volume is replaced with hexanes. The slurry is agitated for about two hours, filtered and washed with hexanes. The solids are dried under vacuum at about 40 °C to afford Compound (H). 1H MR (400 MHz, DMSO-d6): δ 7.82 (d, 2H, J= 8.0 Hz), 7.49 (d, 2H, J= 8.0 Hz), 4.98 (s, 2H), 2.42 (s, 3H), 2.02-2.08 (m, 1H), 0.95-0.91 (m, 2H), 0.89-0.82 (m, 2H). 13C MR (100 MHz, DMSO-de): 202.39, 145.60, 132.76, 130.57, 128.12, 72.98, 21.52, 17.41, 11.39.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of Koser’s reagent, alternative reagents may include, but are not limited to, (diacetoxyiodo)benzene organosulfonic acid, (diacetoxyiodo)benzene and p-toluenesulfonic acid, iodosylbenzene/p-toluenesulfonic acid, m-chloroperbenzoic acid/p-toluenesulfonic acid, poly(4-hydroxy tosyloxyiodo)styrenes, N-methyl-O-tosylhydroxylamine, Dess-Martin periodinane/p-toluenesulfonic acid, HlCVp-toluenesulfonic acid, and o-iodoxybenzoic acid/p-toluenesulfonic acid. Various solvents, such as toluene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and chloroform, may be employed. The reaction may take place at temperatures that range from about 20 °C to about 100 °C.

Alkylation of Compound (H) with Compound (I) to form Compound (G)

Co

To a mixture of Compound (I) (1.0 equiv) and Compound (H) (1.1 equiv) in toluene (5 vols) is charged iPr2 Et (2.1 equiv). The mixture is heated to about 90 to about 100 °C and aged for about less than 10 hours. Upon completion, the mixture is cooled and diluted with water (about 5 to about 6 vols). The biphasic mixture is separated and the organic solution is washed sequentially with aq. H4C1 (about 27 wt%, about 2 to about 3 vols), aq. NaHC03 (about 9 wt%, about 2 to about 3 vols), and aq. NaCl (about 15 wt%, about 1 vols). The organic solution is dried over Na2S04, filtered, and washed with toluene (about 2 to about 3 vols). The solution is concentrated under vacuum at about 45 °C and the residue is crystallized by the addition of hexane at about 20 °C to about 25 °C and at about 10 °C to about 15 °C. The slurry is filtered, washed with cooled isopropanol (about 1 vol) and dried under vacuum at about 37 °C to about 43 °C to afford Compound (G). 1H NMR(400 MHz, DMSO-d6): δ 7.05 (d, 1H, J= 12.0 Hz), 6.51 (d, lH, J= 8.0 Hz), 5.27 (t, 1H, J= 4.0 Hz), 4.17 (d, 2H, J= 4.0 Hz), 2.21-2.14 (m, 1H), 2.10 (s, 3H), 0.96-0.86 (m, 4H). 13NMR (100 MHz, DMSO-d6): 208.17, 151.63, 149.32, 143.99, 143.97, 123.81, 123.74, 118.13, 117.90, 112.87, 105.09, 104.88, 53.72, 18.33, 17.43, 17.42, 10.85.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative bases, including but not limited to organic bases (e.g., DBU and DMAP), alkali metal bases (e.g., NaH), hexamethyldisilazane bases (e.g, sodium, potassium and lithium hexamethyldisilazide), carbonate bases (e.g., Cs2C03, Na2C03), and potassium tert-butoxide. Various solvents, such as THF, MTBE, 2-MeTHF, acetonitrile, dioxane, benzene, DMF, DMAc, NMP, may be employed. The reaction may take place at temperatures that range from about -78 °C to about 100 °C.

Formylation of Compound (G) to form Compound (F)

Acetic anhydride (4 equiv) is added to aqueous formic acid (about 3 to about 4 vols) at about 0 °C to about 5 °C and the mixture is agitated. Compound (G) (1.0 equiv) in DCM (about 3 vols) is charged. The reaction is aged at about 0 to about 5 °C until it is deemed complete. Upon reaction completion, water (about 4 vols) is charged and the mixture is adjusted to about pH 8-9 by the addition of 40-50% aqueous NaOH with the content temperature maintained between about 0 °C to about 15 °C. The biphasic mixture is separated and the aqueous solution is extracted with dichloromethane (about 6 vols). The organic solution is washed with saturated aqueous NaCl (about 4 vols), dried over Na2S04, and filtered. Compound (F) is carried forward to the next step as a solution in dichloromethane without further purification. 1H MR (400 MHz, DMSO-de): δ (mixture of amide rotamers) 8.17 (s, 1H), 8.14 (s, 1H), 7.61 (d, 1H, J= 8.0 Hz), 7.45 (d, 1H, J= 8.0 Hz), 7.42 (d, 1H, J= 12.0 Hz), 7.33 (d, 1H, J= 12.0 Hz), 4.87 (s, 2H), 4.68 (s, 2H), 2.25 (s, 3H), 2.16 (s, 3H), 2.12-2.03 (m, 1H), 0.98-0.85 (m, 4H). 13C MR (100 MHz, DMSO-de): 206.68 (204.85), 163.71 (163.22), 158.95 (158.69), 156.51 (156.35), 139.09 (139.02), 138.61 (138.53), 137.58 (137.55), 133.35 (133.34), 132.45, 119.02 (118.79), 118.58 (118.36), 105.35 (105.03), 104.77 (104.55), 58.68, 55.40, 17.84 (17.77).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of acetic anhydride and formic acid, acetic acid monoanhydride with carbonic acid or trifluoroacetic anhydride with formic acid may be used. Various solvents, such as chloroform, acetonitrile, isopropyl acetate, or THF, may be employed. The reaction may take place at temperatures that range from about -10 °C to about 40 °C.

Imidazole Cyclization to Form Compound (E)

To a solution of Compound (F) (1.0 equiv) in DCM is charged acetic acid (about 5 vols). The solution is concentrated under vacuum at about 35 °C to remove the bulk of DCM and ammonium acetate (3.9 equiv) is added. The mixture is heated to about 110 °C to about 115 °C and agitated until the reaction is deemed complete. The reaction is cooled, diluted with water (about 10 vols) and iPrOAc (about 6 vols). The mixture is adjusted to about pH 8-9 by the addition of 40-50% aqueous NaOH. The biphasic mixture is separated. Sodium chloride (about 0.3 wt equiv wrt Compound (F)) is charged to the aqueous layer and the aqueous layer is extracted with iPrOAc (about 2 vols). The organic solution is washed with water (about 5 vols) and aq. NaCl (about 10 wt%, about 4 to about 5 vols). The solution is concentrated under vacuum and solvent exchanged to about 2-3 vols Ν,Ν-di methyl acetamide (DMAc). Water (about 5 to about 6 vols) is charged to afford Compound (E) as a slurry. The slurry is filtered and washed sequentially with DMAc/water, water, and hexanes. The resulting solids are dried under vacuum at about 55 °C to afford Compound (E). 1H NMR (400 MHz, DMSO-d6): δ 7.68 (d, 1H, J= 4.0 Hz), 7.64 (d, 1H, J= 1.0 Hz), 7.46 (d, 1H, J= 12.0 Hz), 7.12 (d, 1H, J= 1.0 Hz), 2.12 (s, 3H), 1.85-1.79 (m, 1H), 0.81-0.76 (m, 2H), 0.70-0.66 (2H). 13NMR (100 MHz, DMSO-d6): 159.11, 156.67, 156.67, 143.94, 137.36, 136.19, 136.11, 134.44, 134.41, 131.21, 131.20, 119.05, 118.82, 116.21, 105.56, 105.34, 17.72, 17.71, 9.26, 7.44.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of ammonium acetate, alternative sources of ammonia may be used, including but not limited to ammonium formate and ammonium hydroxide. Various solvents, such as toluene, benzene, and isopropanol, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 120 °C.

Carboxylation o Compound (E) to form Compound (D)

Compound (E) then 15 10 25 c Compound (D)

A mixture of Compound (E) (1.0 equiv) in THF (about 15 vols) was cooled to about -10 to about 0 °C and a solution of iPrMgCl (2.0 M in THF, 1.2 equiv) was charged slowly to maintain the internal temperature below about 5 °C. The mixture was stirred for about 1 hour at about -5 to about 5 °C after which C02 was bubbled slowly into the mixture (exothermic). The addition is continued until the exotherm subsides and the internal temperature typically increases to about 15 to about 25 °C after the addition. Upon reaction completion, the mixture is concentrated under vacuum to approximately 3 vols and water (about 6 to about 7 vols) is added, followed by about 1 vol 6M HC1. MTBE (about 10 vols) is added and the biphasic mixture is separated. A solution of 6 M HC1 is added slowly to the aqueous layer to adjust the pH (initially at > 10) to approximately 4.8. The mixture is seeded with Compound (D) (if necessary), which was formed according to the procedure outlined above, and the resultant slurry is cooled slowly to about 0 °C to about 5 °C and aged. The slurry is filtered, washed with water (about 4 vols), isopropanol (about 4 vols), followed by n-heptane (about 6 vols). The solids are dried under vacuum at about 40 °C to afford Compound (D). 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, 1H, J= 2.0 Hz), 7.67 (d, 1H, J= 8.0 Hz), 7.40 (d, 1H, J= 8.0 Hz), 7.15 (d, 1H, J= 2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m, 2H). 13NMR (100 MHz, DMSO-d6): 164.52, 164.48, 161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative bases, including but not limited to organolithium bases (e.g., MeLi, «-BuLi, t-BuLi, and sec- uLi) and Grignard bases (e.g., MeMgCl, «-BuMgCl, and PhMgCl). Various solvents, such as 2-MeTHF, dioxane, MTBE, and Et20, may be employed. The reaction may initially take place at temperatures that range from about -20 °C to about 40 °C and then continue at temperature that range from about -10 °C to about 50 °C.

Conversion o Compound (D) to form Compound (D-a)

Compound (D) Compound (D-a)

To a mixture of Compound (D) (1.0 equiv) in methanol (about 4 vols) at about 15 °C to about 25 °C is charged concentrated HC1 (1.1 equiv relative to Compound (D)). The mixture is aged until most of the Compound (D) is dissolved, seeded with Compound (D-a) (0.005 equiv), which was formed according to the procedure outlined above, and MTBE (about 3 vols relative to the amount of seed) is charged slowly. The slurry is aged, filtered, and rinsed with MTBE (5 vols) and the solids are dried under vacuum at about 40 °C to afford Compound (D-a). 1H MR (400 MHz, DMSO-de): δ 9.34 (s, 1H), 8.00 (d, 1H, J= 8.0 Hz), 7.76 (d, 1H, J= 2.0 Hz), 7.54 (d, 1H, J= 12.0 Hz), 2.25 (s, 3H), 2.08-2.01 (m, 1H), 1.05-1.00 (m, 2H), 0.92-0.88 (m, 2H). 13C MR QOO MHz, DMSO-d6): 164.08, 164.05, 162.73, 160.14, 142.11, 142.01, 137.11, 135.91, 131.14, 131.11, 130.73, 120.19, 119.96, 118.78, 118.39, 118.27, 17.71, 8.24, 6.13.

Carboxylation o Compound (E) to form Compound (D) Hydrate

Compound (E) then 15 10 25 °c Compound (D) Hydrate

A mixture of Compound (E) (1.0 equiv) in THF (about 15 vols) was cooled to about -10 to about 0 °C and a solution of iPrMgCl (2.0 M in THF, 1.2 equiv) was charged slowly to maintain the internal temperature below about 5 °C. The mixture was stirred for about 1 hour at about -5 to about 5 °C after which C02 was bubbled slowly into the mixture (exothermic). The addition is continued until the exotherm subsides and the internal temperature typically increases to about 15 to about 25 °C after the addition. Upon reaction completion, the mixture is concentrated under vacuum to approximately 3 vols and water (about 6 to about 7 vols) is added, followed by about 1 vol 6 M HC1. MTBE (about 10 vols) is added and the biphasic mixture is separated. A solution of 6 M HC1 is added slowly to the aqueous layer to adjust the pH (initially at > 10) to approximately 4.8. The mixture is seeded with Compound (D) (if necessary), which was formed according to the procedure outlined above, and the resultant slurry is cooled slowly to about 0 °C to about 5 °C and aged. The slurry is filtered and washed with water (about 4 vols). The solids are dried under vacuum at about 40 °C to afford Compound (D) hydrate. 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, 1H, J= 2.0 Hz), 7.67 (d, 1H, J= 8.0 Hz), 7.40 (d, 1H, J = 8.0 Hz), 7.15 (d, 1H, J= 2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m, 2H). 13NMR (100 MHz, DMSO-d6): 164.52, 164.48, 161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative bases, including but not limited to organolithium bases (e.g., MeLi, «-BuLi, t-BuLi, and sec- uLi) and Grignard bases (e.g., MeMgCl, «-BuMgCl, and PhMgCl). Various solvents, such as 2-MeTHF, dioxane, MTBE, and Et20, may be employed. The reaction may initially take place at temperatures that range from about -20 °C to about 40 °C and then continue at temperature that range from about -10 °C to about 50 °C.

Acid Chloride Formation Using Compound (D-a) to Form Compound (B)

Compound (B)

To a mixture of Compound (D-a) (1.0 equiv), DCM (about 10 vols) and DMF (0.1 equiv), a solution of oxalyl chloride (about 1.7 equiv) was slowly charged to maintain the internal temperature below about 30 °C. The mixture was stirred for about 1 hour at about 20 °C after which time the mixture is distilled to about about 4 vols total volume. DCM (about 5 vols) is repeatedly charged and the mixture distilled to about 4 vols total volume. DCM is then charged to bring the total volume to about 12 vols of Compound (B). The solution is carried forward to the next step without further purification.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of Compound (D-a), compound (D) may be used. Additionally, in lieu of oxalyl chloride and DMF, thionyl chloride, PC15, and PCI3 may be used. Various

solvents, such as MeCN, THF, and MTBE, may be employed. In some embodiments, additives may be used, including but not limited to trimhetylsilyl chloride, water, HC1, or tetrabutyl ammonium chloride. The reaction may take place at temperatures that range from about -20 °C to about 40 °C.

Acid Chloride Formation Using Compound (D) Hydrate to Form Compound (B)

To a mixture of Compound (D) hydrate (1.0 equiv), DCM (about 10 vols) and DMF (0.1 equiv), a solution of oxalyl chloride (1.2 equiv) was slowly charged to maintain the internal temperature below about 30 °C. The mixture was stirred for about 1 hour at about 20 °C after which time the mixture is distilled to about about 4 vols total volume. DCM (about 5 vols) is repeatedly charged and the mixture distilled to about 4 vols total volume. DCM is then charged to bring the total volume to about 12 vols of Compound (B). The solution is carried forward to the next step without further purification.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of Compound (D) hydrate, compound (D) may be used.

Additionally, in lieu of oxalyl chloride and DMF, thionyl chloride, PC15, and PCI3 may be used. Various solvents, such as MeCN, THF, and MTBE, may be employed. In some embodiments, additives may be used, including but not limited to trimhetylsilyl chloride, water, HC1, or tetrabutyl ammonium chloride. The reaction may take place at temperatures that range from about -20 °C to about 40 °C.

mide Bond Formation to form Compound (A)

Compound (C) 15 to 25 °C Compound (A)

Compound (C) was synthesized as described in U.S. Patent No. 8,742, 126, which is hereby incorporated by reference in its entirety.

To a solution of Compound (B) (about 1 equiv in about 12 vols DCM) was charged diisopropylethyl amine (1.0 equiv) followed by Compound (C) (1.05 equiv). Upon reaction completion, 5% aqueous sodium hydroxide (about 5 vols) is added and the layers of the biphasic mixture are separated. A solution of 10% aqueous citric acid (about 2 vols) is charged to the organic layer and the layers of the biphasic mixture are separated. Water (about 5 vols) is charged to the organic layer and the layers of the biphasic mixture are separated. The organic solution is filtered, and the solution is solvent swapped to about 15% DCM in EtOH under vacumm at about 45 °C. The mixture is seeded with about 0.001 equiv of Compound (A), which was synthesized as described by U.S. Patent No. 8,742,126, and the resultant slurry is aged at about 45 °C. An additional 2-3 vols solvent is distilled in vacuo and then heptane (about 10 vols) is charged slowly and the slurry is aged, cooled to about 20 °C, filtered and washed with 1 :2 EtOH:heptane (about 3 vols). The solids are dried under vacuum at about 40 °C to afford Compound (A). Characterization data for Compound (A) matches that disclosed in U.S. Patent No. 8,742,126.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative bases may be used, including but not limited to Et3N, pyridine, and DMAP. Various solvents, such as 2-MeTHF, toluene, MTBE, and chloroform, may be employed. The reaction may take place at temperatures that range from about 0 °C to about 40 °C.

In lieu of Compound (B), Compound (D) or activated esters thereof may be employed.

Coupling reagents may also be employed; non-limiting examples of such reagents include

propane phosphonic acid anhydride (T3P®), Ι, -carbonyldiimidazole, EDC/HOBt or other imide coupling reagents, isobutylchloroformate (to generate an isobutyl ester), and pivoyl chloride (to generate a pivalate ester).

Example 2: Alternative Synthesis of Compound (D)


ompound (K) Compound (L)

Compound (D)

Coupling of Compound (K) and Compound (L-a) to provide Compound (D)

Compound (K) Compound (L-a) Compound (D)

Compound 2-1 Compound 2-2

Compound (L-a) (1.0 eq), Compound (K) (1.5 eq), potassium phosphate (5.0 eq), copper

(I) oxide (0.05 eq), and 8-hydroxyquinoline, Compound 2-2 (0.2 eq) were combined with degassed DMSO (about 6 vols). The reaction mixture was heated to about 95 °C to about 105 °C and stirred for about 22 h. Upon reaction completion, the mixture was cooled to ambient temperature and diluted with water (about 6 vols) and isopropyl acetate (about 5 vols). The aqueous layer was washed with isopropyl acetate (about 5 vols), and the pH was adjusted to about 6 by the addition of 8 M HC1. The solution was seeded with about about 0.003 equiv of Compound (D) seed, which was synthesized as described in U.S. Patent No. 8,742, 126, and the pH was further adjusted to pH about 4.8. The resultant slurry was cooled to about 0 °C for about 2 h, filtered, and washed with cold dilute HC1 (pH about 4.8, about 2 vols) and cold isopropyl alcohol (about 2 vols) to provide Compound (D). 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d,

1H, J= 2.0 Hz), 7.67 (d, 1H, J= 8.0 Hz), 7.40 (d, 1H, J= 8.0 Hz), 7.15 (d, 1H, J= 2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m, 2H). 13C MR (100 MHz, DMSO-d6): 164.52, 164.48, 161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative bases may be used, including but not limited to carbonate bases (such as CS2CO3, K2C03, and Na2C03). In lieu of Cu20, alternative catalysts may be used, such as CuOAc, Cul, CuBr, and [(CuOTf)2-benzene complex]. Non-limiting examples of alternative ligands include phenanthroline ligands (such as 4,7-dimethoxy-l, 10-phenanthroline (Compound 2-1) and 1,10-phenanthroline), aminoarenethiols (such as 2-((dimethylamino)methyl)benzenethiol), oxime-phospine oxides, phosphoramidites, 2-aminopyrimidine diols (such as 2-aminopyrimidine-4,6-diol), and oxime-phosphine oxides (such as 2-hydroxybenzaldehyde oxime). In some embodiments, additives may be used, including but not limited to polyethyleneglycol and/or water, Et4NHC03, and cetryltrimethylammonium bromide.

In lieu of Compound (L-a), alternative starting material can be used, including but not limited to 5-bromo-2-fluoro-4-methylbenzoic acid, 2-fluoro-4-methyl-5-(((trifluoromethyl)sulfonyl)oxy)benzoic acid, and 2-fluoro-4-methyl-5-(tosyloxy)benzoic acid. Additionally, in lieu of the free base of Compound (K), various salts of Compound (K) may be used, such as the besylate salt.

Various solvents may be used, including but not limited to DMF, DMAc, DMSO, butyronitrile, xylenes, EtCN, dioxane, and toluene. The reaction may take place at temperatures that range from about 80 °C to about 150 °C.

Coupling of Compound (L-b) with Compound (K) to provide Compound (D)

Compound (L-b) Compound (K) Compound (D)

Compound (L-b) (1 equiv), Compound (K) (1.2 equiv), and Cu(OAc)2 (1 equiv) was added methanol (about 20 vols) followed by pyridine (2.2 equiv). The mixture was then stirred at about 23 °C for about 16 h, then at about 45 °C for about 4 h.The reaction mixture was diluted with methanol (about 60 vols), filtered though a pad of celite and concentrated in vacuo to afford Compound (D) . 1H MR (400 MHz, DMSO-d6): δ 7.69 (d, 1H, J= 2.0 Hz), 7.67 (d, 1H, J= 8.0 Hz), 7.40 (d, 1H, J= 8.0 Hz), 7.15 (d, 1H, J= 2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m, 2H). 13C MR (100 MHz, DMSO-d6): 164.52, 164.48, 161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of Compound (L-b), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid may be used. In lieu of Compound (K), the besylate salt of Compound (K) may be used.

Various copper reagents can be employed, such as Cu(OTf)2, Cu20, and CuBr.

Alternative bases include but are not limited to triethylamine and N,N-diisopropylethylamine. Various solvents, such as DCM and DMF, may be employed. The reaction may take place at temperatures that range from about 23 °C to about 100 °C and under an atmosphere of oxygen or nitrogen.

Example 3: Alternative Synthesis of Compound (C)

C


Compound (C)

Coupling of Compound (O) with Compound (N-a) to form Compound (M)

Compound (O) Compound (N-a)

Compound (M)

To a mixture of Compound (O) (1.0 equiv), Compound (N-a) (1.6 equiv), PdCl2(PPh3)2 (65 mol%), Cs2C03 (2.0 equiv), and Cul (4.7 mol%) was charged dioxane (10 mL). The mixture

was degassed and then heated to about 95 °C to about 105 °C. After a period of about 20 hours, the mixture was cooled to ambient temperature. The reaction mixture was diluted with EtOAc (about 10 vols), washed with water (about 10 vols) and the layers of the biphasic mixture were separated. The organic layer was dried over MgS04 and concentrated in vacuo. The crude residue was purified by silica gel chromatography to afford Compound (M). 1H NMR (400

MHz, DMSO-de): δ 8.95 (s, 1H), 8.16-8.04 (m, 2H), 7.67 (d, 1H, J= 8.4 Hz), 5.34 (sep, 1H, J = 6.6 Hz), 1.50 (d, 6H, 6.6 Hz). 13NMR (100 MHz, DMSO-d6): 149.90, 149.58, 148.36, 144.11, 141.62, 125.27, 122.92, 48.91, 23.42.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative catalysts may be other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, including but not limited to: Pd(PPh3)4, Pd2dba3/PPh3, Pd(OAc)2/dppf, Pd2dba3/dppp, Pd(OAc)2/PPh3, Pd(OAc)2/dppe, Pd2dba3/dppf. Various bases may be used, such as a carbonate base (e.g. K2C03 or Na2C03). Various solvents, such as DMF, DMAc, DMSO, butyronitrile, and NMP, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 150 °C.

Conversion of Compound (M) to form Compound (C)

Compound (M) Compound (C)

To a mixture of Compound (M) (1.0 equiv), Pd(OAc)2 (2.0 mol%), rac-BINAP (3.0 mol%), and Cs2C03 (1.4 equiv), was charged dioxane (about 9 vols) followed by benzophenone imine (2.0 equiv). The mixture was degassed, sealed and then heated to about 75 °C to about 85 °C under nitrogen. After a period of about 20 hours, the mixture was cooled to ambient temperature, and HC1 (6 M, about 8 vols) was charged until the pH of the reaction mixture was about 1 to about 2. The solution was maintained at ambient temperature for about 15 minutes, then NaOH (30 wt.%, about 1 to about 2 vols) was charged until the pH of the reaction mixture was about 8-9. The reaction mixture was concentrated in vacuo, slurried in MeOH (about 22 vols), and filtered to remove gross solids, which were washed with MeOH (2 x about 3 vols). The resulting solution was concentrated in vacuo, adsorbed onto celite and purified by silica gel chromatography to provide compound (C). LRMS [M+H]+: 204.08.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative catalysts may be other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, including but not limited to: Pd(PPh3)4, Pd2dba3/PPh3, Pd(OAc)2/dppf, Pd2dba3/dppp, Pd(OAc)2/PPh3, Pd(OAc)2/dppe, Pd2dba3/dppf,

Pd2dba3/CyJohnPhos, Pd2dba3/P(t-Bu)3. Various ammonia sources may be used such as

LiHMDS or ammonium hydroxide. Various carbonate bases (e.g. K2C03 or Na2C03) or phosphate bases such as K3P04 may be used. Various solvents, such as THF, DMAc, DMSO, and NMP, may be employed. The reaction may take place at temperatures that range from about 75 °C to about 150 °C and pressures ranging from about 15 to about 50 psig.

Example 4: Alternative Synthesis of Compound (C)

Co 
mpound (O)

Compound (C)

Coupling of Compound (O) with Compound (P-a) to form Compound (C)

C


)

To a mixture of Compound (O) (1.0 equiv), Compound (P-a) (1.0 equiv), PdCl2(PPh3)2 (10 mol%), Cs2C03 (2.0 equiv), and Cul (4.7 mol%) was charged dioxane (about 20 vols). The mixture was degassed and then heated to about 95 °C to about 105 °C. After a period of about 20 to about 40 hours, the mixture was cooled to ambient temperature. The reaction mixture was diluted with EtOAc (about 40 vols) and the organic layer was washed with water (about 40 vols) The layers of the biphasic mixture were separated and the aqueous phase was extracted with

EtOAc (about 40 vols). The combined organic phases were concentrated in vacuo. To the residue was charged IPA (about 20 vols), and the resulting suspension was stirred at about 40 °C to about 50 °C for about 1 h and then stirred at ambient temperature for about 16 h. The suspension was cooled to about 5 °C, filtered and washed with cold IPA (about 4 vols). The resulting solids were dried at about 40 °C to afford Compound (C). 1H NMR (400 MHz, DMSO-d6): δ 8.77 (s, 1H), 7.51 (t, 1H, J= 8.0 Hz), 7.18 (d, 1H, J= 4.0 Hz), 6.53 (d, 1H, J= 8.0 Hz), 6.17 (s, 1H), 5.53 (sep, 1H, J= 8.0 Hz), 1.42 (d, 6H, J= 8.0 Hz). 13NMR (100 MHz, DMSO-d6): 159.59, 151.18, 146.25, 142.97, 138.41, 111.90, 108.88, 48.12, 23.55.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative catalysts may be other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, including but not limited to: Pd(PPh3)4, Pd2dba3/PPh3, Pd(OAc)2/dppf, Pd2dba3/dppp; Pd(OAc)2/PPh3; Pd(OAc)2/dppe; Pd2dba3/dppf, Pd(OAc) 2/(m-tolyl)3P, Pd(OAc)2/JohnPhos; PdCl2dppf, Pd(OAc)2/(o-tolyl)3P; PdCl2(AmPhos)2; Pd(OAc) 2/(cyclohexanlyl)3P. Various bases may be used, such as a carbonate base (e.g. K2C03 or Na2C03). Various solvents, such as DMF, DMAc, DMSO, butyronitrile, and NMP, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 150 °C.

Coupling of Compound (O) with Compound (P-b) to form Compound (C)

Co


)

A solution of Compound (O) (1.0 equiv) in THF (about 20 vols) was degassed with nitrogen. The solution was cooled to about -55 °C to about -70 °C and a solution of n-BuLi (1.6 M solution in hexane, 1.0 equiv) was added over about 15 to about 20 minutes. The suspension was stirred for about 15 to about 25 minutes at about -55 °C to about -60 °C, followed by the slow addition of ZnCl2 (0.5 M solution in THF, 1 equiv). The suspension was stirred for about 30 minutes and warmed to ambient temperature. To a separate flask was charged Compound (P-b) (1.0 equiv) and Pd(PPh3)4 (231 mg, 4.4 mol%) in dioxane (about 20 vols). The mixture was degassed and transferred to the flask containing the organozinc intermediate. The mixture was sealed and heated to about 115 °C to about 125 °C for about 15 hours then cooled to ambient temperatureThe reaction mixture was concentrated in vacuo at ambient temperature and triturated with MTBE (about 10 mL) to afford Compound (C). 1H NMR (400 MHz, DMSO-d6): δ 8.77 (s, 1H), 7.51 (t, 1H, J= 8.0 Hz), 7.18 (d, 1H, J= 4.0 Hz), 6.53 (d, 1H, J= 8.0 Hz), 6.17 (s, 1H), 5.53 (sep, 1H, 7= 8.0 Hz), 1.42 (d, 6H, 7= 8.0 Hz). 13NMR (100 MHz, DMSO-d6): 159.59, 151.18, 146.25, 142.97, 138.41, 111.90, 108.88, 48.12, 23.55.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, for the metallation, in lieu of n-BuLi, other organolithium reagents (such as t-BuLi, MeLi, and s-BuLi) or Grignard reagents (such as iPrMgCl and PhMgCl) may be used. In lieu of 1 equivalent of ZnCl2, 0.5 equivalent of ZnCl2 or ZnCl2 with LiCl, ZnBr2, or Znl2 can be used. Alternative solvents to THF can include 2-MeTHF, MTBE, or Et20, and this reaction may take place at temperatures that range from about -78 °C to about -40 °C.

Additionally, during the coupling reaction, alternative catalysts may be other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, such as Pd(PPh3)4.

Various solvents, such as NMP, THF, butyronitrile, and toluene, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 140 °C.

Example 5: Alternative Synthesis for Compound (D) 

Compound (E) Compound (Q) Compound (D)

Carboalkoxylation to form Compound (Q)

CO (1 atm)

Compound (E)

Compound (Q)

To a reaction flask was added 1-butanol (7 volumes). Compound (E) (1 equiv) was added followed by K2C03 (1.5 equiv) and Pd(dppf)Cl2 (0.02 equiv) and the reaction was placed under a CO atmostphere. The reaction mixture was heated at about 90 °C until reaction completion. The reaction contents were cooled to ambient temperature, the reaction mixture was filtered through a pad of Celite to remove solids, and then rinsed forward with EtOAc. The mother liquor was washed with water and brine, and dried over Na2S04, filtered, and concentrated to afford Compound (Q). Purification by flash chromatography afforded Compound (Q): 1H MR (400 MHz, CDC13) δ 7.77 (d, J = 6.7 Hz, 1H), 7.39 (s, 1H), 7.08 (d, J= 10.8 Hz, 1H), 6.74 (s, 1H), 4.31 (t, J= 6.6 Hz, 2H), 2.20 (s, 3H), 1.87 (m, 1H), 1.73 (tt, J= 6.7, 6.6 Hz, 3H), 1.43 (tq, J= 7.3, 7.4 Hz), 0.94 (t, J= 7.4 Hz, 3H), 0.88 (m, 2H), 0.79 (m, 2H); Exact mass for Ci8H22N202F [M+H], 317.2. Found [M+H], 317.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative catalysts may be used. Non-limiting examples include other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, such as

PdCl2(dppf) or Pd(OAc)2 with PPh3, xantphos, tBu3P-HBF4, dppe, dppb, dpcb, tBu-dppf, and (Ad)2P(nBu). Alternative bases can be used, such as other carbonate bases (such as Cs2C03, and Na2C03), NaOAc, KOAc, or organic bases such as TMEDA, Et3N, and iPr2NEt. Various solvents may be employed, such as 1-butanol with other co-solvents (e.g. DMF). The reaction may take place at temperatures that range from about 70 °C to about 115 °C and at CO pressures of about 5 to about 50 psig.

Hydrolysis of Compound (Q) to Compound (D)

Compound (Q) Compound (D)

To a reaction flask was added Compound (Q) (1.0 equiv) and MeOH (7 volumes). A 25% NaOH solution (5 equiv) was then added dropwise. Consumption of Compound (D) was observed after about 1.5 hours at which point the pH of the solution was carefully adjusted to about 1 by the addition of 6 N HC1. Methanol was removed under vacuum to afford a solid which was isolated by filtration. The crude product was first triturated in THF and then filtered. This solid was then triturated in CH2Cl2/MeOH (9: 1) and filtered. Concentration of the mother liquor afforded Compound (D). 1H MR (400 MHz, CD3OD) δ 8.87 (s, 1H), 7.94 (d, J = 6.6 Hz, 1H), 7.43 (s, 1H), 7.31 (d, J= 1 1.5 Hz, lH), 2.21 (s, 3H), 1.96 (m, 1H), 1.04 (m, 2H), 0.81 (m, 2H); LRMS: Calculated mass for C14H14N2O2F [M+H], 261.1. Found [M+H], 261.

Alternative reagents and reaction conditions to those disclosed above may also be employed.

For example, an alternative hydroxide base, including but not limited to KOH, LiOH, and CsOH, may be used in lieu of NaOH. Various solvents may be employed, such as THF, EtOH, and 2-propanol. The reaction may take place at temperatures that range from about 0 °C to about 50 °C.

Example 6: Alternative Synthesis of Compound (A)

Com ound C

(A)

Compound (E) (1 equiv.), Compound (C) (1 equiv.), DMF (about 16 vols), Et3N (1.5 equiv.), Pd(OAc)2 (0.02 equiv.), and Ad2P(«-Bu) (0.04 equiv.) were combined and the contents were purged with N2 followed by CO and then pressurized with CO (20 psi). The reaction mixture was heated to about 95 °C to about 105 °C. After about 24 hours, the reaction was allowed to cool to about 20 °C to about 30 °C to afford Compound (A).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative catalysts may be used. Non-limiting examples include other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, such as

PdCl2(PPh3)2, PdCl2(A-Phos)2 or Pd(OAc)2 with PPh3. Alternative bases can be used, including but not limited to other organic bases (such as iPr2NEt and TMEDA) and inorganic bases (such as NaOAc, KOAc, Na2C03, and Cs2C03). Various solvents, NMP, dioxane, and toluene, may be employed. The reaction may take place at temperatures that range from about 90 °C to about 120 °C and at CO pressures of about 20 psig to about 60 psig.

Example 7: Alternative Synthesis of Compound (A)

Compound (A)

Compound (D) (1.0 equiv), Compound (C) (1.05 equiv), 4-(dimethylamino)pyridine (1.0 equiv), ethyl acetate (about 4 V) and diisopropylethylamine (1.2 equiv) were combined and the resulting slurry was charged T3P® as a 50 wt% solution in ethyl acetate (2.0 equiv) over about 3 min at about 20 °C. During the addition, a small exotherm was observed. The mixture was stirred at about 20 °C for about 24 h. After reaction completion, 0.5 M aqueous hydrochloric acid (about 5 vols was added, and the mixture was stirred for about 15 min. Stirring was then stopped, and the phases were allowed to separate. Then, the aqueous phase was reintroduced to the reactor. The pH of the aqueous solution was then adjusted to about 7 with a 5 wt% solution of aqueous sodium hydroxide (about 12 vols). The resulting slurry was stirred for about 12 h at about 20 °C and then filtered, and the reactor was rinsed forward with water (about 3 vols). The filter cake was washed with isopropanol (2 vols), and the resulting solids were dried under vacuum at about 45 °C to provide Compound (A).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of T3P®, other coupling reagents may be used, including but not limited to Ι, Γ-carbonyldiimidazole, isobutyl chloroformate, pivoyl chloride, EDC-HCl/HOBt, thionyl chloride, and 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride. Alternative bases may be used, including but not limited organic amines (such as trialkyl amine bases (for example, triethylamine), N-methyl morpholine, and the like) and carbonates (such as lithium carbonates, sodium carbonates, cesium carbonates, and the like). Various solvents, such as DCM, THF, DMF, ethyl acetate, MTBE, toluene, MP, DMAc, acetonitrile, dichloroethane,

2-MeTHF, and cyclopentyl methyl ether, may be employed. The reaction may take place at temperatures that range from about -10 °C to about 60 °C or from about 0 °C to about 30 °C.

Example 8: Alternative Synthesis of Compound (C)

Compound (8-b)

The mixture of Compound (8-a) and Compound (8-b) is dissolved in about 10 volumes of process water. The solution is heated to about 80 °C, and the solution is allowed to age for about 6 hours. Upon reaction completion, the solution is cooled to about 60 °C. The reaction mixture is seeded with 0.001 equiv of Compound (C), which was obtained by suitable means, and cooled to about 0 °C. Compound (C) is filtered from the cold aqueous solution to yield the product.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, instead of the mixture of Compuond (8-a) and (8-b), the reaction may be carried out with Compound (8-a) or Compound (8-b). Additionally, other organic acids may be used, including but not limited to acetic acid and trifluoroacetic acid. Various solvents, such as toluene, dimethylacetamide, MP, and 2-MeTHF, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 110 °C or about 100 °C.

rnative Synthesis of Compound (C)

Compound (9-c)

Compound (C) may be synthesized as described in U.S. Patent No. 8,742, 126, which is hereby incorporated by reference in its entirety. Additionally, when starting with Compound (9-a), it was found that Compound (C) may be formed through two additional intermediates, Compound (9-b) and Compound (9-c). LRMS for Compound (9-b): Calculated mass, C14H14N2O2F [M+H], 235.1; Found [M+H], 235.9. LRMS for Compound (9-c): Calculated mass, C14H14N2O2F [M+H], 207.1; Found [M+H], 208.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of acetic acid, other organic acids may be used, including but not limited to trifluoroacetic acid. Various solvents, such as toluene, dimethylacetamide, NMP, 2-MeTHF, acetic acid, and water, may be employed. The reaction may take place at

temperatures that range from about 80 °C to about 110 °C or about 100 °C.

Example 10: Alternative Synthesis of Compou

Compound (10-a) Compound (C)

Compound (10-a) (1 equiv), toluene (about 20 vols), N-isopropylformamide (3.00 equiv), isopropylamine (3.00 equiv) and trifluoroacetic acid (2.50 equiv) were sequentially

combined. The vial was sealed and heated to about 100 °C. After about 22 h, the vial was cooled to room temperature and the contents were analyzed by HPLC. Compound (C) was observed by HPLC.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, other organic acids may be used, including but not limited to acetic acid. Various solvents, such as dimethylacetamide, MP, and acetic acid, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 110 °C or about 100 °C.

Example 11: Alternative Synthesis of Compound (C)

Compound (10-a) Compound (11 -b) Compound (C)

Compound (10-a) (1.0 equiv), toluene (about 12 volumes), 79 wt% 

dimethylformimidamide (3.0 equiv), isopropylamine (3.0 equiv) and trifluoroacetic acid 2.5 equiv) were combined and heated to about 100 °C. After about 22 h, the reaction mixture was cooled to room temperature. The mixture was seeded with Compound (C), which was obtained by suitable means, and cooled to about 0 °C. After about 30 min, the heterogeneous mixture was filtered and the vial was rinsed forward with toluene (about 25 vols). The solid was collected and dried under vacuum at about 40 °C to provide Compound (C).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, organic acids may be used, including but not limited to acetic acid. Various solvents, such as acetic acid, dimethylacetamide, and NMP, may be employed.

Alternative organic amines may also be added. The reaction may take place at temperatures that range from about 80 °C to about 110 °C or about 90 °C to about 100 °C.

Example 12: Alternative Synthesis of Compound (C)

Compound (10-a) Compound (C)

A suitable reactor fitted with a reflux condenser was charged with acyl hydrazide (1 equiv), toluene (6 volumes), isopropylamine (7.20 equiv) andN.N-dimethylformamide dipropyl acetal (2.70 equiv). To the resulting slurry was charged acetic acid (1.50 equiv) over about 2 min at about 20 °C. During the addition, an exotherm was observed. The mixture was heated to about 95 °C for about 20 h. After reaction completion, the mixture was concentrated under vacuum at about 80 °C. The mixture was diluted with water (10 volumes), and the resulting biphasic solution was concentrated under vacuum at about 80 °C. Water was added (3 volumes), and the solution is heated to about 85 °C. The resulting solution was cooled to about 60 °C and seeded with Compound (C), which was obtained by suitable means. The resulting slurry was aged for about 30 min and then cooled to about 20 °C over about 1 h and aged for about 15 h. The resulting slurry was cooled to about 5 °C and aged for about 3 h. The cold slurry is filtered and the reactor is rinsed forward with cold water (15 mL). The resulting solids were dried under vacuum at about 40 °C to give Compound (C).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative formamide reagents may be used, such as dimethyl formamide diethyl acetal, dimethyl formamide diisopropyl acetal, dimethyl formamide disec-butyl acetal, dimethyl formamide diisobutyl acetal, and the like. Other organic acids may be used, including but not limited to trifluoroacetic acid, chloroacetic acid, and methanesulfonic acid. Various solvents, such as acetic acid, dimethylacetamide, 2-MeTHF, NMP, isobutyl acetate, isobu

Phase 2 Data for Selonsertib in Nonalcoholic Steatohepatitis (NASH) Presented at The Liver Meeting® 2016

— Results Demonstrate Improvement in Fibrosis Stage among NASH Patients with Moderate to Severe Fibrosis —

BOSTON–(BUSINESS WIRE)–Nov. 14, 2016– Gilead Sciences (Nasdaq:GILD) today announced detailed results from an open-label Phase 2 trial evaluating the investigational apoptosis signal-regulating kinase 1 (ASK1) inhibitor selonsertib (formerly GS-4997) alone or in combination with the monoclonal antibody simtuzumab (SIM) in patients with nonalcoholic steatohepatitis (NASH) and moderate to severe liver fibrosis (fibrosis stages F2 or F3). The data demonstrate regression in fibrosis that was, in parallel, associated with reductions in other measures of liver injury in patients treated with selonsertib for 24 weeks. These data were presented in a late-breaking abstract session at The Liver Meeting® 2016 in Boston (#LB-3).

Patients receiving selonsertib demonstrated improvements in several measures of liver disease severity, including fibrosis stage, progression to cirrhosis, liver stiffness (measured by magnetic resonance elastography, MRE) and liver fat content (measured by magnetic resonance imaging (MRI)-proton density fat fraction, PDFF). Data for these efficacy endpoints are summarized in the table below. As no differences were observed between combination and monotherapy, results are presented for selonsertib (18 mg and 6 mg) with/without SIM and for SIM alone. Additionally, patients with fibrosis improvement demonstrated reductions in hepatic collagen content, liver biochemistry (e.g., serum ALT) and the apoptosis marker, cytokeratin-18, supporting the biological activity of selonsertib.

Endpoint (Week 24) Selonsertib

18 mg ± SIM

Selonsertib 
6 mg ± SIM

SIM
Fibrosis Improvement ≥1 Stage from Baseline* 43% (n=13/30) 30% (n=8/27) 20% (n=2/10)
Progression to Cirrhosis 3% (n=1/30) 7% (n=2/27) 20% (n=2/10)
≥15% Reduction in Liver Stiffness by MRE 20% (n=5/25) 32% (n=7/22) 0% (n=0/7)
≥30% Reduction in Liver Fat by MRI-PDFF 26% (n=8/31) 13% (n=3/24) 10% (n=1/10)

*Fibrosis staged according to the NASH Clinical Research Network (CRN) classification by a central pathologist blinded to treatment group.

Selonsertib demonstrated no dose-related increases in treatment-emergent adverse events or serious adverse events. Headache, nausea and sinusitis were the most common adverse events in patients receiving selonsertib.

“Currently, no approved treatments exists for NASH, and patients with advanced fibrosis would potentially benefit from new options to halt and/or reverse the progression of their disease,” said Rohit Loomba, MD, MHSc, lead study author and Director, NAFLD Research Center, Director of Hepatology, Professor of Medicine, Vice Chief, Division of Gastroenterology, University of California San Diego School of Medicine. “After only 24 weeks of therapy, selonsertib exhibited promising anti-fibrotic activity in this study, which was the first known multi-center NASH clinical trial to use centrally-assessed MRE, MRI-PDFF, in addition to liver biopsy as endpoints. Based on these data, selonsertib represents an important investigational drug candidate for further clinical trials in patients with NASH and significant fibrosis.”

Other Gilead NASH data being presented at The Liver Meeting include results from Phase 1 studies evaluating the investigational selective, non-steroidal Farnesoid X receptor (FXR) agonist GS-9674. Data from a Phase 1 study demonstrated the biological activity and safety profile of GS-9674 in healthy volunteers and support the evaluation of this compound in patients with NASH and cholestatic liver disorders (#1077 and #1140). Phase 2 studies with GS-9674 are ongoing in patients with NASH, primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).

Additionally, preclinical data for the combination of selonsertib and GS-9674 in a rodent model of advanced fibrosis suggested that the combination of selonsertib and GS-9674 resulted in greater anti-fibrotic activity than either agent alone (#1588). These preclinical data support clinical evaluation of combination approaches with selonsertib and GS-9674 in patients with NASH and advanced fibrosis.

Selonsertib, GS-9674 and simtuzumab have not been determined to be safe or efficacious.

About Selonsertib and the Study

Selonsertib is an investigational small molecule inhibitor of ASK1, a protein that promotes inflammation, apoptosis (cell death) and fibrosis in settings of oxidative stress. Oxidative stress can be increased in many pathological conditions including liver diseases such as NASH.

This Phase 2, randomized, open-label trial evaluated the safety, tolerability and efficacy of selonsertib alone or in combination with SIM in 72 patients with NASH and fibrosis stages F2 (n=25) or F3 (n=47). Eligible patients were randomized (2:2:1:1:1) to receive selonsertib 6 mg (n=20), selonsertib 18 mg (n=22), selonsertib 6 mg plus SIM 125 mg (n=10), selonsertib 18 mg plus SIM 125 mg (n=10) or SIM 125 mg alone (n=10) for 24 weeks. Selonsertib was administered orally once daily and SIM was administered via weekly subcutaneous injection.

About Gilead’s Clinical Programs in NASH

Gilead is advancing a pipeline of novel investigational therapies for the treatment of NASH with advanced fibrosis. Gilead is currently planning or conducting Phase 2 and Phase 3 clinical trials evaluating single-agent and combination therapy approaches against multiple core pathways associated with NASH – metabolic dysfunction, inflammation and fibrosis. Compounds in development include the ASK1 inhibitor, selonsertib; the FXR agonist, GS-9674; and an inhibitor of acetyl-coA carboxylase (ACC), GS-0976, currently being evaluated in a Phase 2 study in patients with NASH.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

 

Patent ID

Patent Title

Submitted Date

Granted Date

US2016166556 METHODS OF TREATING PULMONARY HYPERTENSION
2015-08-11
2016-06-16
US2015342943 METHODS OF TREATING LIVER DISEASE
2015-05-29
2015-12-03
US9771328 Processes for preparing ASK1 inhibitors
2017-01-23
2017-09-26
US9586933 Processes for preparing ASK1 inhibitors
2015-12-22
2016-08-25
US8742126 Apoptosis signal-regulating kinase inhibitor
2013-01-24
2014-06-03
Patent ID

Patent Title

Submitted Date

Granted Date

US9643956 SOLID FORMS OF AN ASK1 INHIBITOR
2015-12-22
2016-09-29
US9750730 APOPTOSIS SIGNAL-REGULATING KINASE INHIBITOR
2016-04-27
2016-08-18
US2017273952 METHODS OF TREATING LIVER DISEASE
2015-09-22
US9333197 APOPTOSIS SIGNAL-REGULATING KINASE INHIBITOR
2014-04-16
2014-08-14
US8552196 Apoptosis signal-regulating kinase inhibitors
2012-09-13
2013-10-08

/////////Selonsertib,  GS-4997, PHASE 3, GILEAD, GS-4997, GS-4977

CC1=C(C=C(C(=C1)F)C(=O)NC2=CC=CC(=N2)C3=NN=CN3C(C)C)N4C=C(N=C4)C5CC5

GFT 505, Elafibranor, элафибранор , إيلافيبرانور , 依非兰诺 


Image result for Elafibranor

ChemSpider 2D Image | (E)-Elafibranor | C22H24O4SElafibranor.pngChemSpider 2D Image | Elafibranor | C22H24O4S

(E)-Elafibranor

  • Molecular FormulaC22H24O4S
  • Average mass384.489 Da

Elafibranor

CAS 824932-88-9  E Z MIXTURE USAN

CAS 923978-27-2 E ISOMER INN

2-(2,6-Dimethyl-4-{3-[4-(methylsulfanyl)phenyl]-3-oxo-1-propen-1-yl}phenoxy)-2-methylpropanoic acid

Elafibranor(GFT505)
GFT505;GFT-505;GFT 505
UNII:2J3H5C81A5
(E)-Elafibranor
2-(2,6-Dimethyl-4-{(1E)-3-[4-(methylsulfanyl)phenyl]-3-oxo-1-propen-1-yl}phenoxy)-2-methylpropanoic acid
2-(2,6-Dimethyl-4-{(1E)-3-[4-(methylsulfanyl)phenyl]-3-oxo-1-propen-1-yl}phenoxy)-2-methylpropansäure
2J3H5C81A5
CAS 923978-27-2 E ISOMER INN
Acide 2-(2,6-diméthyl-4-{(1E)-3-[4-(méthylsulfanyl)phényl]-3-oxo-1-propén-1-yl}phénoxy)-2-méthylpropanoïque[French] [ACD/IUPAC Name]
GFT505
Propanoic acid, 2-[2,6-dimethyl-4-[(1E)-3-[4-(methylthio)phenyl]-3-oxo-1-propen-1-yl]phenoxy]-2-methyl-
UNII-2J3H5C81A5
(E)-2-(2,6-Dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid
элафибранор[Russian][INN]
إيلافيبرانور[Arabic][INN]
依非兰诺[Chinese][INN]
UNII-2J3H5C81A5
Treatment of Non-Alcoholic Steato-Hepatitis, Reducing Cardiometabolic Risk Factors in Patients with Diabetes and Pre-Diabetes
InventorJean DelhomelKarine Caumont-Bertrand Current Assignee Genfit
Priority date 2002-07-08  EXPIRY 2032 JULY
OTHERS
US7385082
US8058308
CN 106674069
WO 2016127019
WO 2018060373
WO 2018060372
INNOVATOR Genfit SA
Image result for Genfit SA
FAST TRACK FDA
Fibrosis; Primary biliary cirrhosis; Cholangitis; Obesity; Non-alcoholic steatohepatitis; Lipid metabolism disorder; Cancer; Non-insulin dependent diabetes; Crohns disease
Genfit is developing elafibranor (GFT-505; structure shown), a PPAR alpha and delta agonist with antioxidant properties and an anti-inflammatory action, for the potential oral treatment of non-alcoholic steatohepatitis (NASH) dyslipidemia, type 2 diabetes, atherogenic dyslipidemia, abdominal obesity and primary biliary cholangitis (PBC)

REGULATORY

In November 2016, the EMA approved elafibranor’s Pediatric Investigation Plan (PIP) . In February 2017, the company expected to obtain conditional marketing authorization for elafibranor in NASH during the course of the second half of 2019 or first half of 2020 .

In February 2014, the FDA granted Fast Track designation for GFT-505 for the treatment of NASH

PHASE III

In March 2015, the company was planning to begin a late stage phase III trial in patients with seriously Ill NASH (expected n = 2,000)

EUROPE

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/pips/EMEA-001857-PIP01-15/pip_001493.jsp&mid=WC0b01ac058001d129

Active substance Elafibranor
Decision number P/0237/2016
PIP number EMEA-001857-PIP01-15
Pharmaceutical form(s) Capsule, hard; Coated tablet
Condition(s)/indication(s) Treatment of non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH)
Route(s) of administration Oral use
PIP applicant Genfit SA
France
Tel.+33 320164000
Fax +33 320164001
Email: contact@genfit.com
Decision type P: decision agreeing on a investigation plan, with or without partial waiver(s) and or deferral(s)
Doubts on drug substance
  • Elafibranor
  • GFT 505
  • GFT-505
  • UNII-2J3H5C81A5

scifinder refers to CAS Registry Number 923978-27-2 as E isomer

  • 2-[2,6-Dimethyl-4-[(1E)-3-[4-(methylthio)phenyl]-3-oxo-1-propen-1-yl]phenoxy]-2-methylpropanoic acid
  • GFT 505

SYNTHESIS

6 STEPS

WO 2005005369, WO 2004005233

SYN 2

CN106674069

Solubility (25°C)

In vitro DMSO 76 mg/mL (197.66 mM)
Ethanol 76 mg/mL (197.66 mM)
Water Insoluble

Biological Activity

Description Elafibranor is an agonist of the peroxisome proliferator-activated receptor-α(PPAR-alpha) and peroxisome proliferator-activated receptor-δ(PPAR-δ). It improves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation.
Targets
PPARα [1]
()
PPARδ [1]
()
In vitro GFT505 is a novel PPAR modulator that shows a preferential activity on PPAR-α and concomitant activity on PPAR-δ[2].
In vivo Elafibranor (GFT505) is a dual PPARα/δ agonist that has demonstrated efficacy in disease models of nonalcoholic fatty liver disease (NAFLD)/NASH and liver fibrosis. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. Elafibranor confers liver protection by acting on several pathways involved in NASH pathogenesis, reducing steatosis, inflammation, and fibrosis. GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin-1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression[1].

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Elafibranor (code name GFT505) is a multimodal and pluripotent medication for treatment of atherogenic dyslipidemia for an overweight patient with or without diabetes. It is an oral treatment that acts on the 3 sub-types of PPAR (PPARa, PPARg, PPARd) with a preferential action on PPARa. As of February 2016, elafibranor has completed 8 clinical trials and a phase III is in progress.

Elafibranor (INN,[2] code name GFT505) is an experimental medication that is being studied and developed by Genfit for the treatment of cardiometabolic diseases including diabetesinsulin resistancedyslipidemia, and non-alcoholic fatty liver disease (NAFLD).[3][4][5]

Elafibranor is a dual PPARα/δ agonist.[6][7]

Elafibranor is an agonist of the peroxisome proliferator-activated receptor-α(PPAR-alpha) and peroxisome proliferator-activated receptor-δ(PPAR-δ). It improves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation

FT505 is an oral treatment that acts on the 3 sub-types of PPAR (PPARa, PPARg, PPARd) with a preferential action on PPARa. It has a sophisticated mechanism of action. It is able to differentially recruit cofactors to the nuclear receptor, which subsequently lead to differential regulation of genes and biological effect. Therefore, the ability to identify and profile the activity of selective nuclear receptor modulator (SNuRMs) is a powerful approach to select innovative drug candidates with improved efficacy and diminished side effects. These pluripotent and multimodal molecules have significant positive effects on obesity, insulin-resistance and diabetes, atherosclerosis, inflammation, and the lipid triad (increasing of HDL cholesterol, lowering of triglycerides and LDL cholesterol).

Clinical studies

Administered to over 800 patients and healthy volunteers to date, elafibranor has demonstrated:

  • beneficial properties for non-alcoholic steatohepatitis (NASH)[8]
  • improvement of insulin sensitivity and glucose homeostasis[9]

Phase 2b (GOLDEN) results were published online in Gastroenterology in February 2016[10] and will be fully available in the paper version in May 2016.

As of February 2016, elafibranor has completed 8 clinical trials and a phase III is in progress.[11]

Pre-clinical studies

Efficacy on histological NASH parameters (steatosis, inflammation, fibrosis) in animal disease models — anti-fibrotic activities.[12]

The absence of safety concern has been confirmed in a full toxicological package up to 2-year carcinogenicity studies and cardiac studies (in mice).[13]

PATENT

20060142611 or 20050176808

Patent

US20070032543

https://patents.google.com/patent/US20070032543A1/en

    Compound 29: 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-en-1-one

  • Figure US20070032543A1-20070208-C00178
  • This compound was synthesized from 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-isopropyloxycarbonyldimethylmethyloxyphenyl]prop-2-en-1-one (compound 28) according to general method 5 described earlier.
  • Purification was made by chromatography on silica gel (elution: dichloromethane/methanol 98:2).
  • 1H NMR DMSO-dδppm: 1.39 (s, 6H), 2.22 (s, 6H), 2.57 (s, 3H), 7.40 (d, J=8.55 Hz, 2H), 7.57 (s, 2H), 7.62 (d, J=15.5 Hz, 1H), 7.83 (d, J=15.5 Hz, 1H), 8.1 (d, J=8.55 Hz, 2H), 12.97 (s, 1H).
  • MS (ES-MS): 383.3 (M−1).

PATENT

WO 2016127019

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=FD673C8170C27624DC7C0E0C9420AD23.wapp2nB?docId=WO2016127019&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PATENT

CN 106674069

https://patents.google.com/patent/CN106674069A/enhttps://patents.google.com/patent/CN106674069A/en

The liver is one of the most important organs of the body, is one of the highest organ of risk. Many factors can lead to liver disease. For example, drinking too much can lead to cirrhosis, excessive medication can lead to liver damage and even obesity can lead to fatty liver. Thus, the pharmaceutical treatment of fatty liver diseases has become a hot spot of bio-pharmaceutical development.

French Genf biopharmaceutical company said recently that the US Food and Drug Administration has agreed to continue the development of peroxisome proliferator-activated receptor α / δ dual agonist GFT505, and begin Phase IIb study in the United States. GFT 505 is expected to rule early diagnosis of fatty liver, heart disease and its complications, prevention and treatment of diabetes-related lipid hyperlipidemia. French Food and Drug Administration approval to a detailed in-depth far for preclinical and clinical data were analyzed based. Experts expressed the Authority, GFT505 to ensure safe operation and research and can lead to liver cancer or liver cirrhosis related biomarkers all favorable. GFT505 structure as shown in formula III.

Figure CN106674069AD00061

GFT505 Intermediate I is a key intermediate GFT505III, the existing technology (e.g., Patent Document 1 ^ 1 ^ 20060142611 or 20050176808) are synthesized by the method of 4-methylthio-acetophenone and 3,5 dimethyl-4-hydroxybenzaldehyde GFT505 condensation of intermediate IV, with 2-bromo-iso-butyric acid tert-butyl ester obtained. Process GFT505 Intermediate I Z double bond configuration is a type, but the 4-methylthio-acetophenone and 3,5_-dimethyl-4-hydroxybenzaldehyde condensation process, the formation of a double bond, it is difficult GFT505 avoid intermediate IV of formula Z, E mixtures of formula, and then 2-bromo-iso-butyric acid tert-butyl ester to give GFT505 intermediate II, R is also of formula Z, E mixtures of formula. E-isomer and Z-type polarity very close to the crystallization purification difficult, very precise product by column chromatography is not suitable for industrial production.

Figure CN106674069AD00062

 Accordingly, a need to find an efficient synthesis, reducing the content of Z-isomer impurities to improve the purity and yield of the products, and to avoid use of column chromatography purification process difficult industrialization.

The present invention provides a method for the preparation of intermediate I GFT505, comprising the steps of: an organic solvent, a compound II with an alkali metal t-butoxide isomerization reaction to give intermediate I GFT505; the said compound II is a double bond in Z / E mixtures, according GFT505 intermediate I is a compound of formula E; the double bonds in Z / E mixtures of formula Z refers to the product from 0.1% to 99.0% of the total mass of the mixture (including 0.1%, comprising 99.0%); the compound of formula E E means that the content of the compound of formula more than 99.0% (including 99.0%);

Figure CN106674069AD00071

 In reaction I of the preparation of intermediates GFT505, the organic solvent is preferably a protic solvent, a polar aprotic organic solvent non-polar solvent, more preferably a non-polar solvent. The protic solvent is preferably & ~ (: 4 alcoholic solvent; the & ~ (: t-butanol 4 alcoholic solvent preferably the polar aprotic organic solvent is preferably C 1-C4 nitrile solvents, &. ~ C6 ketone solvents, C1-C4 one or more 4 sulfone amide solvents and C1-C solvent. C1-C4 of the nitrile solvents preferably acetonitrile. the C 1-C6 ketone solvent preferably acetone and / or methyl isobutyl ketone. C1-C4 of the amide-based solvent is preferably N, N- dimethylformamide. C 1-C4 of the sulfone solvent is preferably dimethylsulfoxide. the said nonpolar solvent is preferably aromatic hydrocarbon solvent; the aromatic hydrocarbon solvent preferably toluene.

Example 1: Preparation of intermediate IV GFT505 (refer to Patent W02011 / 144579)

Figure CN106674069AD00091

 A mixture of 4-mercapto-acetophenone (50g, 0.30 Imo 1), 3,5- dimethyl-4-hydroxybenzaldehyde (45g, 0.30 Imo 1) was added to a methanol solution of hydrogen chloride in 200ml (4moI / L) , 20 ~ 30 ° C for 3 hours, cooled to 0 ~ 10 ° C, stirred for 1 hour, filtered and dried to give 83g GFT505 intermediate (IV) as a yellow solid in 93% yield.

Example 2: Preparation of intermediate IV GFT505 (refer to Patent W02011 / 144579)

A mixture of 4-mercapto-acetophenone (I 9Kg, 114mo 1), 3,5- dimethyl-4-hydroxybenzaldehyde (I 7.1Kg, 114mo 1) was added to a methanol solution of hydrogen chloride in 76L (4mol / L ), 20 ~ 30 ° C for 3 hours, cooled to 0 ~ 10 ° C, stirred for 1 hour, centrifuged, 40 ° C and dried under vacuum for 12 hours to obtain 31.6Kg GFT505 intermediate (IV) as a yellow solid, yield 93% . LCMS: m / z = 299 (M + H) +.

Example 3: GFT505 intermediate II preparation (Ref US2006 / 142611)

Figure CN106674069AD00092

 The GFT505 Intermediate IV (78.8g, 0.263mol) was added to the reaction flask was added acetonitrile (480 ml of), potassium carbonate (54.5g, 0.395mol), tert-butyl 2-bromo-isobutyrate (39.3 g, 0.176mol), heated to 75 ~ 85 ° C for 10 hours, additional potassium carbonate (54.5g, 0.395mol), 2_ tert-butyl bromoisobutyrate (39.3g, 0.176mol) 10 hours, refed with potassium carbonate (54 · 5g, 0 · 395mol), 2- tert-butyl bromoisobutyrate (39 · 3g, 0 · 176mol) for 10 hours, until completion of the reaction compound, and concentrated under reduced pressure to dryness, was added 800g 400g of dichloromethane and water, layers were separated, washed with water, the organic phase dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated to dryness, ethyl acetate and petroleum ether to give a solid compound II 81. Ig, yield 70% 〇

Example 4: GFT505 intermediate II preparation (Ref US2006 / 142611)

The GFT505 Intermediate IV (30Kg, 100mol) was added to acetonitrile (183L) was added potassium carbonate (21Kg, 152mol), 2- tert-butyl bromoisobutyrate (14 · 9Kg, 66 · 8mol), was heated to 75 ~ 85 ° C for 10 hours, additional potassium carbonate (21Kg, 152mol), 2- tert-butyl bromoisobutyrate (14.9Kg, 66.8mol) for 10 hours, refed with potassium carbonate (21Kg, 152mol), 2- tert-butyl bromoisobutyrate (14.9Kg, 66.8mol) for 10 hours, until the reaction was complete compound, 45 ~ 55 ° C was slowly concentrated under reduced pressure to distilled off, water was added and 300Kg 160Kg dichloromethane , the organic layer was separated out, IOOKg IOOKg water and washed with 10% concentration of aqueous sodium chloride solution (the mass concentration refers to the percentage by mass of the total mass of sodium chloride aqueous solution), 15 to 25 ° C was slowly distilled off under reduced pressure to concentrate. Ethyl acetate was added IOOKg was heated to 75 ~ 85 ° C a clear solution was added heptane 180Kg, cooled to stirred 15 ~ 25 ° C for 2-3 hours. Centrifugation, washed with n-heptane 40Kg, 40 ~ 50 ° C was dried in vacuo for 12 hours to obtain 31.6Kg GFT505 intermediate II, R a yield of 71.6%. LC-MS: m / z = 441 (M + H) + square

Example 5: Preparation of Intermediate I GFT505

Figure CN106674069AD00101

Compound II (81 · lg, 0.184mol) was added to 400g of toluene, cooled to 10 ~ 20 ° C, was added sodium tert-butoxide (26.8g, 0.279mol), heated to 50 ~ 60 ° C for 2 hours , 400g of water was added, layers were separated, washed with water, the organic phase concentrated to dryness under reduced pressure, methanol was added to 200ml, cooled to 0-10 ° C, stirred for 1 hour, filtered, 40 ~ 50 ° C (-0 · 08MPa ~ -0 · IMPa ) was dried in vacuo for 12 hours to give a yellow solid 78.8g GFT505 intermediate I, a yield of 97.0% APLC: 99.23% (in terms of E-form, Z configurational isomers accounted for 0.085%, largest other single impurity 0.41%).

Intermediate I the preparation of GFT505: 6 cases of  Embodiment

Figure CN106674069AD00102

Compound II (31Kg, 70.5mol) was added to 153Kg of toluene, cooled to 10 ~ 20 ° C, was added sodium tert-butoxide (10 · 3Kg, 107mol), warmed to 50 ~ 60 ° C for 2 hours, 160Kg of water, layered, and water IOOKg IOOKg mass concentration of the aqueous solution was washed with 10% sodium chloride (the concentration refers to the percentage by mass of the total mass of sodium chloride aqueous solution), 40 ~ 50 ° C Save concentrated under pressure to slowly distilled off, methanol was added to 60Kg, cooled to 0 ~ 10 ° C, stirred for 1 hour, centrifuged, washed with methanol 20Kg, 40 ~ 50 ° C (-0.08MPa ~ -0.1 MPa) was dried under vacuum for 12 hours to give 30.4 Kg GFT505 yellow solid intermediate I, 1.0 yield 98%. LC-MS: m / z = 441 (M + H) +; HPLC: 99 · 50% E configuration similar terms, Z configurational isomers accounted for 0.082%, largest other single impurity of 0.32%.

7  Example: Preparation of Intermediate I GFT505

 The compound II (8.0g, 0.018mol) was added to 64g tert-butanol, cooled to 10 ~ 20 ° C, was added potassium tert-butoxide (6.05g, 0.054mol), heated to 70 ~ 80 ° C Reaction 4 to 5 hours, was added 200g of water, 60g extracted twice with isopropyl acetate, and the organic phase concentrated to dryness under reduced pressure, methanol was added 20ml, cooled to 0-10 ° C, stirred for 1 hour, filtered, 40 ~ 50 ° C (_ 0.08MPa ~ -0.1 MPa) was dried in vacuo for 12 hours to give 7.62g yellow solid GFT505 intermediate I, a yield of 95.2% dHPLC: 99.36% (in terms of E-form, Z configurational isomers accounted for 0.079%, single largest other 0.42% impurities).

Example 8: Preparation of Intermediate I GFT505

Compound II (8.Og, 0.018mo 1) was added to 16g N, N- dimethylformamide, cooled to 10 ~ 20 ° C, was added sodium tert-butoxide (2.17g, 0.023mol), heated to the reaction 90 ~ 100 ° C for 1-2 hours, was added 100g of water, 60g extracted twice with isopropyl acetate, the organic phase concentrated to dryness under reduced pressure, methanol was added 20ml, cooled to O-HTC, stirred for 1 hour, filtered, 40 ~ 50 ° C (-0.08MPa ~ -0 IMPa.) was dried in vacuo for 12 hours to give 7.34g yellow solid GFT505 intermediate I, a yield of 91.7% APLC: 99.21% E configuration similar terms, Z configurational isomers accounted 0.097%, the largest single other impurities 0.48%).

9  Example: Preparation of Intermediate I GFT505

The compound II (8.0g, 0.018mol) was added to 160g of acetonitrile, cooled to 10 ~ 20 ° C, was added lithium t (7.21g, 0.090mol) butanol, warmed to 40 ~ 50 ° C the reaction 9-10 hours, was added 160g of water, 90g extracted twice with isopropyl acetate, and the organic phase concentrated to dryness under reduced pressure, methanol was added 20ml, cooled to 0-10 ° C, stirred for 1 hour, filtered, 40 ~ 50 ° C (_ 0.08MPa ~ -0.1 MPa) was dried in vacuo for 12 hours to give 7.29g yellow solid GFT505 intermediate I, a yield of 91.1% dHPLC: 99.16% (in terms of E-form, Z configurational isomers accounted for 0.089%, largest other single impurity 0.49 %).

10  Example: Preparation of Intermediate I GFT505

The compound II (8.0g, 0.018mol) was added to 28g of dimethyl sulfoxide, cooled to 10 ~ 20 ° C, was added potassium t-butoxide (5.04g, 0.045mol), heated to 60 ~ 70 ° C the reaction 3 to 4 hours, was added 100g of water, 60g extracted twice with isopropyl acetate, and the organic phase concentrated to dryness under reduced pressure, methanol was added 20ml, cooled to O-UTC, stirred for 1 hour, filtered, 40 ~ 50 ° C (_ 0.08 MPa ~ -0.1 MPa) was dried in vacuo for 12 hours to give 7.33g yellow solid GFT505 intermediate I, a yield of 91.6% dHPLC: 99.46% (in terms of E-form, Z configurational isomers accounted for 0.077%, largest single impurity other 0.27%).

Preparation of GFT505III: 11 cases of Embodiment

Figure CN106674069AD00111

 The GFT505 Intermediate I (77.9g, 0.177mol, may be prepared as described in Example 10) was added to the reaction flask was added 790g of dichloromethane was added trifluoroacetic acid (209.7g, 1.84mol), 20 ~ 30 ° C the reaction for 5-6 hours, concentrated to dryness, was added 600ml ethyl acetate and 600ml of water, layers were separated, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated to a small volume the organic phase, 10-20 ° C for 2 hours crystallization, filtration, under -0.08MPa ~ -0.1 MPa, 40 ° C ~ 50 ° C was dried in vacuo 12 hours to give 60.1 g as a yellow solid. 25〇1 yellow solid was recrystallized from ethyl acetate to give 52.98 ^ as a yellow solid 6? 505 (111), a yield of 77.8%.

 LC-MS: m / z = 385 (M + H) +; HPLC: 99 · 86%, largest single impurity 0.5 06%.

GFT505III prepared: Example 12 Embodiment

The GFT505 Intermediate I (30Kg, 68.2mol, may be prepared as described in Example 9) was added to 307Kg dichloromethane was added trifluoroacetic acid (80.8Kg, 709mol), 20-30 ° C the reaction 5-6 h, concentrated to dryness, ethyl acetate and water 197Kg 231Kg, layered, and water IOOKg IOOKg concentration of 10 mass% aqueous sodium chloride concentration (which refers to the quality of the aqueous solution of sodium chloride percentage of total mass) washing, 40 ~ 50 ° C to about 80Kg concentrated under reduced pressure, cooled to IO ~ 20 ° C for 2 hours crystallization, centrifugation was washed with ethyl acetate 20Kg, at -0.08MPa ~ -O.IMPa, 40 ~ 50 ° C was dried in vacuo for 12 hours to give a yellow solid was 23.2Kg. As a yellow solid was obtained as a yellow solid GFT505III 20.9Kg 82Kg recrystallized from ethyl acetate, 5.8 79% yield. LCMS: m / z = 385 (M + H) +; HPLC: 99 · 95%, largest single impurity 0.5 03%.

Patent ID

Patent Title

Submitted Date

Granted Date

US9221751 USE OF 1, 3-DIPHENYLPROP-2-EN-1-ONE DERIVATIVES FOR TREATING LIVER DISORDERS
2014-10-24
2015-02-19
US8058308 SUBSTITUTED 1, 3-DIPHENYLPROP-2-EN-1-ONE DERIVATIVES, PREPARATION AND USES THEREOF
2011-08-04
2011-11-15
US8106097 COMPOSITION BASED ON SUBSTITUTED 1, 3-DIPHENYLPROP-2-EN-1-ONE DERIVATIVES, PREPARATION AND USES THEREOF
2010-05-13
2012-01-31
US7566737 Combinations of substituted 1, 3-diphenylprop-2-EN-1-one derivatives with other therapeutically active ingredients
2007-02-08
2009-07-28
US7943661 Substituted 1, 3-diphenylprop-2-en-1-one derivatives and preparation and uses thereof
2005-08-11
2011-05-17

References

  1. Jump up^ Cariou, B.; Zair, Y.; Staels, B.; Bruckert, E. (2011). “Effects of the New Dual PPAR / Agonist GFT505 on Lipid and Glucose Homeostasis in Abdominally Obese Patients with Combined Dyslipidemia or Impaired Glucose Metabolism”Diabetes Care34 (9): 2008–2014. doi:10.2337/dc11-0093PMC 3161281Freely accessiblePMID 21816979.
  2. Jump up^ “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 74” (PDF). World Health Organization. p. 10. Retrieved 9 November 2016.
  3. Jump up^ “Advanced Compound Status” (Press release). Genfit.
  4. Jump up^ “GFT505 Broadens Its Therapeutic Potential” (PDF) (Press release). Retrieved 31 Mar 2013.
  5. Jump up^ Cariou, Bertrand; Staels, Bart (2014-10-01). “GFT505 for the treatment of nonalcoholic steatohepatitis and type 2 diabetes”. Expert Opinion on Investigational Drugs23 (10): 1441–1448. doi:10.1517/13543784.2014.954034ISSN 1744-7658PMID 25164277.
  6. Jump up^ US Patent No. 7655641 “96 dpi image of original patent USPTO 7655641” (PDF). Retrieved 31 Mar 2013.
  7. Jump up^ “GFT-505” (PDF). Drugs of the Future37 (8): 555–559. 2012.[permanent dead link]
  8. Jump up^ Staels, Bart; Rubenstrunk, Anne; Noel, Benoit; Rigou, Géraldine; Delataille, Philippe; Millatt, Lesley J.; Baron, Morgane; Lucas, Anthony; Tailleux, Anne (2013-12-01). “Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis”Hepatology58 (6): 1941–1952. doi:10.1002/hep.26461ISSN 1527-3350.
  9. Jump up^ Cariou, Bertrand; Hanf, Rémy; Lambert-Porcheron, Stéphanie; Zaïr, Yassine; Sauvinet, Valérie; Noël, Benoit; Flet, Laurent; Vidal, Hubert; Staels, Bart (2013-05-28). “Dual Peroxisome Proliferator–Activated Receptor α/δ Agonist GFT505 Improves Hepatic and Peripheral Insulin Sensitivity in Abdominally Obese Subjects”Diabetes Care36: DC_122012. doi:10.2337/dc12-2012ISSN 0149-5992PMC 3781493Freely accessiblePMID 23715754.
  10. Jump up^ “Elafibranor, an Agonist of the Peroxisome Proliferator-activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening – Gastroenterology”http://www.gastrojournal.org. Retrieved 2016-03-08.
  11. Jump up^ clinical trials involving GFT505
  12. Jump up^ Quintero, Pablo; Arrese, Marco (2013-12-01). “Nuclear control of inflammation and fibrosis in nonalcoholic steatohepatitis: therapeutic potential of dual peroxisome proliferator-activated receptor alpha/delta agonism”. Hepatology58 (6): 1881–1884. doi:10.1002/hep.26582ISSN 1527-3350PMID 23787705.
  13. Jump up^ Hanf, Rémy; Millatt, Lesley J.; Cariou, Bertrand; Noel, Benoit; Rigou, Géraldine; Delataille, Philippe; Daix, Valérie; Hum, Dean W.; Staels, Bart (2014-11-01). “The dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 exerts anti-diabetic effects in db/db mice without peroxisome proliferator-activated receptor gamma-associated adverse cardiac effects”. Diabetes & Vascular Disease Research11 (6): 440–447. doi:10.1177/1479164114548027ISSN 1752-8984PMID 25212694.

External links

Elafibranor
Elafibranor.svg
Clinical data
Synonyms GFT505, SureCN815512
ATC code
  • None
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
Formula C22H24O4S
Molar mass 384.489 g/mol
3D model (JSmol)

/////////////////Elafibranor, E Elafibranor,  923978-27-2,  GFT-505,  UNII-2J3H5C81A5, GFT505, GFT 505, элафибранор إيلافيبرانور 依非兰诺 , PHASE 3, FAST TRACK 

CC1=CC(=CC(=C1OC(C)(C)C(=O)O)C)C=CC(=O)C2=CC=C(C=C2)SC

Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite


STR4

SR1

SR2

Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.8b00565

Pronay Das†ab, Palak Babbar†c, Nipun Malhotra†c, Manmohan Sharmac , Goraknath R. Jachakab , Rajesh G. Gonnadebd, Dhanasekaran Shanmugambe, Karl Harlosf , Manickam Yogavelc , Amit Sharmac *, and D. Srinivasa Reddyab* †All three have contributed equally to this work.
aOrganic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
b Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
cMolecular Medicine Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi 110067, India dCenter for Material Characterization, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
e Biochemical Sciences Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
fDivision of Structural Biology, Welcome Trust Centre for Human Genetics, The Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
J. Med. Chem., Just Accepted Manuscript
DOI: 10.1021/acs.jmedchem.8b00565
Publication Date (Web): May 21, 2018
Copyright © 2018 American Chemical Society
The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral centre anti-malarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme- and structure-based assays.
We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency where changes at C3 are sensed by rotameric flipping of Glutamate332.
Given that scores of anti-malarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of anti-microbial drug development.
Cladosporin (12) displays exquisite selectivity for the parasite lysyl-tRNA synthetase over human enzyme. This species specific selectivity of cladosporin has been previously described through comprehensive sequence alignment, where the residues val329 and ser346 seem to be sterically crucial for accommodating the methyl moiety of THP ring10. The structural features of compound 12 clearly indicate the presence of three stereocenters, and therefore 2n (n=3) i.e., eight stereoisomers are possible (Fig.1). Till date, only one asymmetric total synthesis of cladosporin13 has been achieved which was followed by another report of formal syntheses14. Here, we have developed a general chemical synthesis route to synthetically access all the eight possible stereoisomers of compound 12.
cladosporin (compound 12) (0.052 g) as a white solid with a yield of 54 %. Melting point: 171-173 °C; [α]25 D = -15.75 (c = 0.6, EtOH); IR υmax(film): cm-1 3416, 3022, 1656, 1218; 1H NMR (400 MHz, CDCl3): δ 11.06 (s, 1H), 7.47 (br. s., 1H), 6.29 (s, 1H), 6.16 (s, 1H), 4.68 (t, J = 9.8 Hz, 1H), 4.12 (s, 1H), 4.01 (s, 1H), 2.89 – 2.75 (m, 2H), 2.00 – 1.94 (m, 1H), 1.87 – 1.81 (m, 1H), 1.70 – 1.63 (m, 4H), 1.35 (d, J = 6.1 Hz, 2H), 1.23 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 169.9, 164.3, 163.1, 141.8, 106.7, 102.0, 101.5, 76.3, 68.0, 66.6, 39.3, 33.6, 30.9, 18.9, 18.1; HRMS calculated for C16H21O5 [M + H]+ 293.1384, observed 293.1379.
STR1

STR2

Dr. D. Srinivasa Reddy has been appointed as an editor of Bioorganic & Medicinl Chemistry Letters, Elsevier Publications. Congratulation Sir !

Click here for details. https://www.journals.elsevier.com/bioorganic-and-medicinal-chemistry-letters

The research interests of his group lie in issues related to application of oriented organic synthesis, in particular total synthesis of biologically active natural products, medicinal chemistry and crop protection. This team has been credited with having accomplished total synthesis of more than 25 natural products with impressive biological activities. “Some of our recent achievements include identification of potential leads, like antibiotic compound based on hunanamycin natural product for treating food infections, anti-diabetic molecule in collaboration with an industry partner and  anti-TB compound using a strategy called ‘re-purposing of a drug scaffold’,” said Reddy.

A total of two awardees out of four were from CSIR institutes. In addition to Reddy, Rajan Shankarnarayanan, CSIR – CCMB, Hyderabad (basic sciences), also was conferred with the award. Vikram Mathews, CMC, Vellore (medical research) and Prof Ashish Suri, AIIMS, New Delhi (clinical research), were the others to receive the awards.

With more than 80 scientific publications and 35 patents, Reddy is one of the most prominent scientists in the city and has already been honoured with the Shanti Swarup Bhatnagar prize in chemical sciences. Reddy is also a nominated member of the scientific body of Indian Pharmacopoeia, government of India and was  elected as a fellow of the Telangana and Maharashtra Academies of Sciences in addition to the National Academy of Sciences, India (NASI).

//////////CLADOSPORIN, NCL, CSIR, SRINIVASA REDDY, PUNE, MALARIA

PF-04965842


PF-04965842, >=98% (HPLC).png

img

2D chemical structure of 1622902-68-4

PF-04965842

UNII: 73SM5SF3OR

CAS Number 1622902-68-4, Empirical Formula  C14H21N5O2S, Molecular Weight 323.41

N-[cis-3-(Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclobutyl]-1-propanesulfonamide,

N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide

1-Propanesulfonamide, N-(cis-3-(methyl-7H-pyrrolo(2,3-d)pyrimidin-4-ylamino)cyclobutyl)-

N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide

PHASE 3, for the potential oral treatment of moderate-to-severe atopic dermatitis (AD)

Jak1 tyrosine kinase inhibitor

THE US

In February 2018, the FDA granted Breakthrough Therapy designation for the treatment of patients with moderate-to-severe AD

PHASEIII

In December 2017, a randomized, double-blind, placebo-controlled, parallel-group, phase III trial (NCT03349060; JADE Mono-1; JADE; B7451012; 2017-003651-29) of PF-04965842 began in patients aged 12 years and older (expected n = 375) with moderate-to-severe AD

PRODUCT PATENT

Pub. No.: WO/2014/128591 International Application No.: PCT/IB2014/058889
Publication Date: 28.08.2014 International Filing Date: 11.02.2014

EXPIRY  Roughly 2034

form powder
color white to beige
solubility DMSO: 10 mg/mL, clear
storage temp. room temp
    Biochem/physiol Actions
    • PF-04965842 is a Janus Kinase (JAK) inhibitor selective for JAK1 with an IC50value of 29 nM for JAK1 compared to 803 nM for JAK2, >10000 nM for JAK3 and 1250 nM for Tyk2. JAKs mediate cytokine signaling, and are involved in cell proliferation and differentiation. PF-04965842 has been investigated as a possible treatment for psoriasis.
  • Originator Pfizer
  • Class Skin disorder therapies; Small molecules
  • Mechanism of Action Janus kinase 1 inhibitors

Highest Development Phases

  • Phase IIIAtopic dermatitis
  • DiscontinuedLupus vulgaris; Plaque psoriasis

Most Recent Events

  • 08 Mar 2018Phase-III clinical trials in Atopic dermatitis (In children, In adults, In adolescents) in USA (PO) (NCT03422822)
  • 14 Feb 2018PF 4965842 receives Breakthrough Therapy status for Atopic dermatitis in USA
  • 06 Feb 2018Pfizer plans the phase III JADE EXTEND trial for Atopic Dermatitis (In children, In adults, In adolescents) in March 2018 (PO) (NCT03422822)

This compound was developed by Pfizer for Kinase Phosphatase Biology research. To learn more about Sigma′s partnership with Pfizer and view other authentic, high-quality Pfizer compounds,

Image result for PF-04965842

PF-04965842 is an oral Janus Kinase 1 inhibitor being investigated for treatment of plaque psoriasis.

Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity, arising from mutation, over-expression, or inappropriate regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines has been i mplicated in many diseases, including but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune d iseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer’s disease. Inappropriate kinase activity triggers a variety of biological cellular responses relating to cell growth, cell differentiation , survival, apoptosis, mitogenesis, cell cycle control, and cel l mobility implicated in the aforementioned and related diseases.

Thus, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) play a central role in cytoki ne signaling (Kisseleva et al., Gene, 2002, 285 , 1; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molecules, notably, members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression. Numerous cytokines are known to activate the JAK family. These cytokines include, the IFN family (IFN-alpha, IFN-beta, IFN-omega, Limitin, IFN-gamma, IL- 10, IL- 19, IL-20, IL-22), the gp 130 family (IL-6, IL- 11, OSM, LIF, CNTF, NNT- 1//SF-3, G-CSF, CT- 1, Leptin, IL- 12 , I L-23), gamma C family (IL-2 , I L-7, TSLP, IL-9, IL- 15 , IL-21, IL-4, I L- 13), IL-3 family (IL-3 , IL-5 , GM-CSF), single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF- 1, HGF), and G-protein coupled receptors (ATI).

There remains a need for new compounds that effectively and selectively inhibit specific JAK enzymes, and JAK1 in particular, vs. JAK2. JAK1 is a member of the Janus family of protein kinases composed of JAK1, JAK2, JAK3 and TYK2. JAK1 is expressed to various levels in all tissues. Many cytokine receptors signal through pairs of JAK kinases in the following combinations: JAK1/JAK2, JAK1/JAK3, JAK1/TYK2 , JAK2/TYK2 or JAK2/JAK2. JAK1 is the most broadly

paired JAK kinase in this context and is required for signaling by γ-common (IL-2Rγ) cytokine receptors, IL—6 receptor family, Type I, II and III receptor families and IL- 10 receptor family. Animal studies have shown that JAK1 is required for the development, function and homeostasis of the immune system. Modulation of immune activity through inhibition of JAK1 kinase activity can prove useful in the treatment of various immune disorders (Murray, P.J.

J. Immunol., 178, 2623-2629 (2007); Kisseleva, T., et al., Gene, 285 , 1-24 (2002); O’Shea, J . J., et al., Ceil , 109, (suppl .) S121-S131 (2002)) while avoiding JAK2 dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling (Neubauer H., et al., Cell, 93(3), 397-409 (1998);

Parganas E., et al., Cell, 93(3), 385-95 (1998)).

Figure

Tofacitinib (1), baricitinib (2), and ruxolitinib (3)

SYNTHESIS 5+1 =6 steps

Main synthesis

Journal of Medicinal Chemistry, 61(3), 1130-1152; 2018

 

 

INTERMEDIATE

CN 105732637

ONE STEP

CAS 479633-63-1,  7H-Pyrrolo[2,3-d]pyrimidine, 4-chloro-7-[(4- methylphenyl)sulfonyl]-

Image result for PF-04965842

Pfizer Receives Breakthrough Therapy Designation from FDA for PF-04965842, an oral JAK1 Inhibitor, for the Treatment of Patients with Moderate-to-Severe Atopic Dermatitis

Wednesday, February 14, 2018 8:30 am EST

Dateline:

NEW YORK

Public Company Information:

NYSE:
PFE
US7170811035
“We look forward to working closely with the FDA throughout our ongoing Phase 3 development program with the hope of ultimately bringing this important new treatment option to these patients.”

NEW YORK–(BUSINESS WIRE)–Pfizer Inc. (NYSE:PFE) today announced its once-daily oral Janus kinase 1 (JAK1) inhibitor PF-04965842 received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with moderate-to-severe atopic dermatitis (AD). The Phase 3 program for PF-04965842 initiated in December and is the first trial in the J AK1 A topic D ermatitis E fficacy and Safety (JADE) global development program.

“Achieving Breakthrough Therapy Designation is an important milestone not only for Pfizer but also for patients living with the often devastating impact of moderate-to-severe atopic dermatitis, their providers and caregivers,” said Michael Corbo, Chief Development Officer, Inflammation & Immunology, Pfizer Global Product Development. “We look forward to working closely with the FDA throughout our ongoing Phase 3 development program with the hope of ultimately bringing this important new treatment option to these patients.”

Breakthrough Therapy Designation was initiated as part of the Food and Drug Administration Safety and Innovation Act (FDASIA) signed in 2012. As defined by the FDA, a breakthrough therapy is a drug intended to be used alone or in combination with one or more other drugs to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. If a drug is designated as a breakthrough therapy, the FDA will expedite the development and review of such drug.1

About PF-04965842 and Pfizer’s Kinase Inhibitor Leadership

PF-04965842 is an oral small molecule that selectively inhibits Janus kinase (JAK) 1. Inhibition of JAK1 is thought to modulate multiple cytokines involved in pathophysiology of AD including interleukin (IL)-4, IL-13, IL-31 and interferon gamma.

Pfizer has established a leading kinase research capability with multiple unique kinase inhibitor therapies in development. As a pioneer in JAK science, the Company is advancing several investigational programs with novel selectivity profiles, which, if successful, could potentially deliver transformative therapies for patients. Pfizer has three additional kinase inhibitors in Phase 2 development across multiple indications:

  • PF-06651600: A JAK3 inhibitor under investigation for the treatment of rheumatoid arthritis, ulcerative colitis and alopecia areata
  • PF-06700841: A tyrosine kinase 2 (TYK2)/JAK1 inhibitor under investigation for the treatment of psoriasis, ulcerative colitis and alopecia areata
  • PF-06650833: An interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor under investigation for the treatment of rheumatoid arthritis

Working together for a healthier world®

At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world’s best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.pfizer.com. In addition, to learn more, please visit us on www.pfizer.com and follow us on Twitter at @Pfizer and @Pfizer_NewsLinkedInYouTube and like us on Facebook at Facebook.com/Pfizer.

DISCLOSURE NOTICE: The information contained in this release is as of February 14, 2018. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.

This release contains forward-looking information about PF-04965842 and Pfizer’s ongoing investigational programs in kinase inhibitor therapies, including their potential benefits, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical trial commencement and completion dates and regulatory submission dates, as well as the possibility of unfavorable clinical trial results, including unfavorable new clinical data and additional analyses of existing data; risks associated with preliminary data; the risk that clinical trial data are subject to differing interpretations, and, even when we view data as sufficient to support the safety and/or effectiveness of a product candidate, regulatory authorities may not share our views and may require additional data or may deny approval altogether; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when drug applications may be filed in any jurisdictions for any potential indication for PF-04965842 or any other investigational kinase inhibitor therapies; whether and when any such applications may be approved by regulatory authorities, which will depend on the assessment by such regulatory authorities of the benefit-risk profile suggested by the totality of the efficacy and safety information submitted, and, if approved, whether PF-04965842 or any such other investigational kinase inhibitor therapies will be commercially successful; decisions by regulatory authorities regarding labeling, safety and other matters that could affect the availability or commercial potential of PF-04965842 or any other investigational kinase inhibitor therapies; and competitive developments.

A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2016 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at www.sec.gov  and www.pfizer.com .

Image result for PF-04965842

# # # # #

1 Food and Drug Administration Fact Sheet Breakthrough Therapies at https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDASIA/ucm329491.htmaccessed on January 25, 2018

PATENT

CA 2899888

PATENT

WO 2014128591

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=6767BBB5964A985E88C9251B6DF3182B.wapp2nB?docId=WO2014128591&recNum=233&maxRec=8235&office=&prevFilter=&sortOption=&queryString=EN_ALL%3Anmr+AND+PA%3Apfizer&tab=PCTDescription

PFIZER INC. [US/US]; 235 East 42nd Street New York, New York 10017 (US)

BROWN, Matthew Frank; (US).
FENWICK, Ashley Edward; (US).
FLANAGAN, Mark Edward; (US).
GONZALES, Andrea; (US).
JOHNSON, Timothy Allan; (US).
KAILA, Neelu; (US).
MITTON-FRY, Mark J.; (US).
STROHBACH, Joseph Walter; (US).
TENBRINK, Ruth E.; (US).
TRZUPEK, John David; (US).
UNWALLA, Rayomand Jal; (US).
VAZQUEZ, Michael L.; (US).
PARIKH, Mihir, D.; (US)

COMPD 2

str1

Example 2 : N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane- l -sulƒonamide

This compound was prepared using 1-propanesulfonyl chloride. The crude compound was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (93 : 7) to afford the title compound as a tan sol id (78% yield). 1NMR (400 MHz, DMSO-d6): δ 11.60 (br s, 1 H), 8.08 (s, 1 H), 7.46 (d, 1 H), 7.12 (d, 1 H), 6.61 (d, 1 H), 4.81-4.94 (m, 1 H), 3.47-3.62 (m, 1 H), 3.23 (s, 3 H), 2.87-2.96 (m, 2 H), 2.52-2.63 (m, 2 H), 2.14-2.27 (m, 2 H) 1.60- 1.73 (m, 2 H) 0.96 (t, 3 H). LC/MS (exact mass) calculated for C14H21N5O2S;

323.142, found (M + H+); 324.1.

PAPER

 Journal of Medicinal Chemistry (2018), 61(3), 1130-1152.

Abstract Image

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.7b01598

N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (25)

Compound 48a·2HBr …………..was collected by filtration, washed with 2:1 EtOH/H2O (100 mL), and again dried overnight in a vacuum oven at 40 °C.
1H NMR (400 MHz, DMSO-d6): 11.64 (br s, 1H), 8.12 (s, 1 H), 7.50 (d, J = 9.4 Hz, 1H), 7.10–7.22 (m, 1H), 6.65 (dd, J= 1.8, 3.3 Hz, 1H), 4.87–4.96 (m, 1H), 3.53–3.64 (m, 1H), 3.27 (s, 3H), 2.93–2.97 (m, 2H), 2.57–2.64 (m, 2H), 2.20–2.28 (m, 2H), 1.65–1.74 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).
LC/MS m/z (M + H+) calcd for C14H22N5O2S: 324. Found: 324. Anal. Calcd for C14H21N5O2S: C, 51.99; H, 6.54; N, 21.65; O, 9.89; S, 9.91. Found: C, 52.06; H, 6.60; N, 21.48; O, 10.08; S, 9.97.

SchmiederG.DraelosZ.PariserD.BanfieldC.CoxL.HodgeM.KierasE.Parsons-RichD.MenonS.SalganikM.PageK.PeevaE. Efficacy and safety of the Janus Kinase 1 inhibitor PF-04965842 in patients with moderate to severe psoriasis: phase 2, randomized, double-blind, placebo-controlled study Br. J. Dermatol. 2017DOI: 10.1111/bjd.16004

Compound 25N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide is available through MilliporeSigma (cat. no. PZ0304).

REFERENCES

1: Schmieder GJ, Draelos ZD, Pariser DM, Banfield C, Cox L, Hodge M, Kieras E, Parsons-Rich D, Menon S, Salganik M, Page K, Peeva E. Efficacy and safety of the Janus Kinase 1 inhibitor PF-04965842 in patients with moderate to severe psoriasis: phase 2, randomized, double-blind, placebo-controlled study. Br J Dermatol. 2017 Sep 26. doi: 10.1111/bjd.16004. [Epub ahead of print] PubMed PMID: 28949012

 2 Journal of Medicinal Chemistry (2018), 61(3), 1130-1152.

/////////////////PF-04965842, PF 04965842, PF04965842, PF 4965842, Phase 3, Atopic dermatitis, PFIZER, Breakthrough Therapy Designation

CCCS(=O)(N[C@H]1C[C@@H](N(C)C2=C3C(NC=C3)=NC=N2)C1)=O

CCCS(=O)(=O)N[C@@H]1C[C@@H](C1)N(C)c2ncnc3[nH]ccc23

LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus


Sreeni Labs Private Limited

SREENI LABS CONTRIBUTION
Customer requested Sreeni Labs to make BL001 first on  few mg scale. Sreeni labs synthesized and supplied in a short time with full characterization data. Later, customer requested us to make it on several gram scale and we synthesized and delivered as custom synthesis project.

LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus

NATURE COMMUNICATIONS | (2018) 9:1488 |DOI: 10.1038/s41467-018-03943-0 | http://www.nature.com/naturecommunications

Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by
immune cells. Current therapies focused on repressing the immune attack or stimulating beta
cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative
targets to dampen the immune process, while promoting beta cell survival and function. Liver
receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive
organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small
LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation
of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic
patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1
agonism favors a dialogue between immune and islet cells, which could be druggable to
protect against diabetes mellitus.

 

//////////////SREENI LABS

FDA approves new drug Doptelet (avatrombopag) for patients with chronic liver disease who have low blood platelets and are undergoing a medical procedure


Avatrombopag.png

Avatrombopag

https://newdrugapprovals.org/2015/08/24/avatrombopag/

FDA approves new drug for patients with chronic liver disease who have low blood platelets and are undergoing a medical procedure

The U.S. Food and Drug Administration today approved Doptelet (avatrombopag) tablets to treat low blood platelet count (thrombocytopenia) in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure. This is the first drug approved by the FDA for this use.Continue reading.

May 21, 2018

Release

The U.S. Food and Drug Administration today approved Doptelet (avatrombopag) tablets to treat low blood platelet count (thrombocytopenia) in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure. This is the first drug approved by the FDA for this use.

“Patients with chronic liver disease who have low platelet counts and require a procedure are at increased risk of bleeding,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Doptelet was demonstrated to safely increase the platelet count. This drug may decrease or eliminate the need for platelet transfusions, which are associated with risk of infection and other adverse reactions.”

Platelets (thrombocytes) are colorless cells produced in the bone marrow that help form blood clots in the vascular system and prevent bleeding. Thrombocytopenia is a condition in which there is a lower-than-normal number of circulating platelets in the blood. When patients have moderately to severely reduced platelet counts, serious or life-threatening bleeding can occur, especially during invasive procedures. Patients with significant thrombocytopenia typically receive platelet transfusions immediately prior to a procedure to increase the platelet count.

The safety and efficacy of Doptelet was studied in two trials (ADAPT-1 and ADAPT-2) involving 435 patients with chronic liver disease and severe thrombocytopenia who were scheduled to undergo a procedure that would typically require platelet transfusion. The trials investigated two dose levels of Doptelet administered orally over five days as compared to placebo (no treatment). The trial results showed that for both dose levels of Doptelet, a higher proportion of patients had increased platelet counts and did not require platelet transfusion or any rescue therapy on the day of the procedure and up to seven days following the procedure as compared to those treated with placebo.

The most common side effects reported by clinical trial participants who received Doptelet were fever, stomach (abdominal) pain, nausea, headache, fatigue and swelling in the hands or feet (edema). People with chronic liver disease and people with certain blood clotting conditions may have an increased risk of developing blood clots when taking Doptelet.

This product was granted Priority Review, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

The FDA granted this approval to AkaRx Inc.

 

//////////////Doptelet, avatrombopag, fda 2018, akarx, priority review,

FDA Approves Tavalisse (fostamatinib disodium hexahydrate) for Chronic Immune Thrombocytopenia — Med-Chemist


Rigel Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) approved Tavalisse (fostamatinib disodium hexahydrate) for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. Tavalisse is an oral spleen tyrosine kinase (SYK) inhibitor that targets the underlying autoimmune cause of the…

via FDA Approves Tavalisse (fostamatinib disodium hexahydrate) for Chronic Immune Thrombocytopenia — Med-Chemist

Mibefradil, a new class of compound to study TRPM7 channel function — Sussex Drug Discovery Centre


Transient receptor potential (TRPM) is a family of non-selective cation channels that are widely expressed in mammalian cells. TRP channels are composed of six transmembrane domains and the family consists of eight different channels, TRPM1–TRPM8. TRPM7 is compromised of an ion channel moiety essential for the ion channel function, which serves to increase intracellular calcium […]

via Mibefradil, a new class of compound to study TRPM7 channel function — Sussex Drug Discovery Centre

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