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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

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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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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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FDA approves new treatment Hemlibra (emicizumab-kxwh) to prevent bleeding in certain patients with hemophilia A


FDA approves new treatment to prevent bleeding in certain patients with hemophilia A

The U.S. Food and Drug Administration today approved Hemlibra (emicizumab-kxwh) to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors.Continue reading.

 

 

November 16, 2017

Summary

FDA approves new treatment to prevent or reduce frequency of bleeding episodes in patients with hemophilia A who have Factor VIII inhibitors.

Release

The U.S. Food and Drug Administration today approved Hemlibra (emicizumab-kxwh) to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors.

“Reducing the frequency or preventing bleeding episodes is an important part of disease management for patients with hemophilia. Today’s approval provides a new preventative treatment that has been shown to significantly reduce the number of bleeding episodes in patients with hemophilia A with Factor VIII inhibitors,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “In addition, patients treated with Hemlibra reported an improvement in their physical functioning.”

Hemophilia A is an inherited blood-clotting disorder that primarily affects males. According to the National Institutes of Health, hemophilia affects one in every 5,000 males born in the United States, approximately 80 percent of whom have hemophilia A. Patients with hemophilia A are missing a gene which produces Factor VIII, a protein that enables blood to clot. Patients may experience repeated episodes of serious bleeding, primarily into their joints, which can be severely damaged as a result. Some patients develop an immune response known as a FVIII inhibitor or antibody. The antibody interferes with the effectiveness of currently available treatments for hemophilia.

Hemlibra is a first-in-class therapy that works by bridging other Factors in the blood to restore blood clotting for these patients. Hemlibra is a preventative (prophylactic) treatment given weekly via injection under the skin (subcutaneous).

The safety and efficacy of Hemlibra was based on data from two clinical trials. The first was a trial that included 109 males aged 12 and older with hemophilia A with FVIII inhibitors. The randomized portion of the trial compared Hemlibra to no prophylactic treatment in 53 patients who were previously treated with on-demand therapy with a bypassing agent before enrolling in the trial. Patients taking Hemlibra experienced approximately 2.9 treated bleeding episodes per year compared to approximately 23.3 treated bleeding episodes per year for patients who did not receive prophylactic treatment. This represents an 87 percent reduction in the rate of treated bleeds. The trial also included patient-reported Quality of Life metrics on physical health. Patients treated with Hemlibra reported an improvement in hemophilia-related symptoms (painful swellings and joint pain) and physical functioning (pain with movement and difficulty walking) compared to patients who did not receive prophylactic treatment.

The second trial was a single arm trial of 23 males under the age of 12 with hemophilia A with FVIII inhibitors. During the trial, 87 percent of the patients taking Hemlibra did not experience a bleeding episode that required treatment.

Common side effects of Hemlibra include injection site reactions, headache, and joint pain (arthralgia).

The labeling for Hemlibra contains a boxed warning to alert healthcare professionals and patients that severe blood clots (thrombotic microangiopathy and thromboembolism) have been observed in patients who were also given a rescue treatment (activated prothrombin complex concentrate) to treat bleeds for 24 hours or more while taking Hemlibra.

The FDA granted this application Priority Review and Breakthrough Therapydesignations. Hemlibra also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Hemlibra to Genentech, Inc.

///////Hemlibra, emicizumab-kxwh, FDA 2017, hemophilia A, Priority Review and Breakthrough Therapy designation,  Orphan Drug designation

 

 

“NEW DRUG APPROVALS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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TAFAMIDIS


Tafamidis skeletal.svgChemSpider 2D Image | Tafamidis | C14H7Cl2NO3

Tafamidis

  • Molecular Formula C14H7Cl2NO3
  • Average mass 308.116 Da

TAFAMIDIS, Fx-1006A
PF-06291826

2-(3,5-Dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid
594839-88-0 [RN]
6-Benzoxazolecarboxylic acid, 2-(3,5-dichlorophenyl)-
Vyndaqel
Tafamidis meglumine
Familial amyloid polyneuropathy LAUNCHED PFIZER 2011 EU
ApprovedJapanese Pharmaceuticals and Medical Devices Agency in September 2013
PHASE 3, at  FDA, Amyloidosis, PFIZER
Image result for Vyndaqel tafamidis meglumine
Molecular Formula: C21H24Cl2N2O8
Molecular Weight: 503.329 g/mol

CAS 951395-08-7

Image result for Vyndaqel tafamidis meglumine

D-Glucitol, 1-deoxy-1-(methylamino)-, 2-(3,5-dichlorophenyl)-6-benzoxazolecarboxylate

Tafamidis (INN, or Fx-1006A,[1] trade name Vyndaqel) is a drug for the amelioration of transthyretin-related hereditary amyloidosis(also familial amyloid polyneuropathy, or FAP), a rare but deadly neurodegenerative disease.[2][3] The drug was approved by the European Medicines Agency in November 2011 and by the Japanese Pharmaceuticals and Medical Devices Agency in September 2013.[4]

In 2011 and 2012, orphan drug designation was assigned in Japan and the U.S., respectively, for the treatment of transthyretin amyloid polyneuropathy. This designation was assigned in the E.U. in 2012 for the treatment of senile systemic amyloidosis. In 2017, fast drug designation was assigned in the U.S. for the treatment of transthyretin cardiomyopathy.

Tafamidis is a novel specific transthyretin (TTR) stabilizer or dissociation inhibitor. TTR is a tetramer that is responsible in transporting the retinol-binding protein-vitamin A complex and minimally transporting thyroxine in the blood. In TTR-related disorders such as transthyretin familial amyloid polyneuropathy (TTR-FAP), tetramer dissociation is accelerated that results in unregulated amyloidogenesis and amyloid fibril formation. Eventually the failure of autonomic and peripheral nervous system is induced. Tafamidiswas approved by the European Medicines Agency (EMA) in 2011 under the market name Vyndaqel for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adult patients with early-stage symptomatic polyneuropathy to delay peripheral neurologic impairment. Tafamidis is an investigational drug under the FDA and in June 2017, Pfizer received FDA Fast Track Designation for tafamidis

Image result for TAFAMIDIS

The marketed drug, a meglumine salt, has completed an 18 month placebo controlled phase II/III clinical trial,[5][6] and an 12 month extension study[7] which provides evidence that tafamidis slows progression of Familial amyloid polyneuropathy.[8] Tafamidis (20 mg once daily) is used in adult patients with an early stage (stage 1) of familial amyloidotic polyneuropathy.[9][10]

Tafamidis was discovered in the Jeffery W. Kelly Laboratory at The Scripps Research Institute[11] using a structure-based drug design strategy[12] and was developed at FoldRx pharmaceuticals, a biotechnology company Kelly co-founded with Susan Lindquist. FoldRx was led by Richard Labaudiniere when it was acquired by Pfizer in 2010.

Tafamidis functions by kinetic stabilization of the correctly folded tetrameric form of the transthyretin (TTR) protein.[13] In patients with FAP, this protein dissociates in a process that is rate limiting for aggregation including amyloid fibril formation, causing failure of the autonomic nervous system and/or the peripheral nervous system (neurodegeneration) initially and later failure of the heart. Kinetic Stabilization of tetrameric transthyretin in familial amyloid polyneuropathy patients provides the first pharmacologic evidence that the process of amyloid fibril formation causes this disease, as treatment with tafamidis dramatically slows the process of amyloid fibril formation and the degeneration of post-mitotic tissue. Sixty % of the patients enrolled in the initial clinical trial have the same or an improved neurologic impairment score after six years of taking tafamidis, whereas 30% of the patients progress at a rate ≤ 1/5 of that predicted by the natural history. Importantly, all of the V30M FAP patients remain stage 1 patients after 6 years on tafamidis out of four stages of disease progression. [Data presented orally by Professor Coelho in Brazil in 2013][7]

The process of wild type transthyretin amyloidogenesis also appears to cause wild-type transthyretin amyloidosis (WTTA), also known as senile systemic amyloidosis (SSA), leading to cardiomyopathy as the prominent phenotype.[14] Some mutants of transthyretin — including V122I, which is primarily found in individuals of African descent — are destabilizing, enabling heterotetramer dissociation, monomer misfolding, and subsequent misassembly of transthyretin into a variety of aggregate structures [15] including amyloid fibrils[16]leading to familial amyloid cardiomyopathy.[17] While there is clinical evidence from a small number of patients that tafamidis slows the progression of the transthyretin cardiomyopathies,[18] this has yet to be demonstrated in a placebo-controlled clinical trial. Pfizer has enrolled a placebo-controlled clinical trial to evaluate the ability of tafamidis to slow the progression of both familial amyloid cardiomyopathy and senile systemic amyloidosis (ClinicalTrials.gov identifier: NCT01994889).

Regulatory Process

Tafamidis was approved for use in the European Union by the European Medicines Agency in November 2011, specifically for the treatment of early stage transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP (all mutations). In September 2013 Tafamidis was approved for use in Japan by the Pharmaceuticals and Medical Devices Agency, specifically for the treatment of transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP (all mutations). Tafamidis is also approved for use in Brazil, Argentina, Mexico and Israel by the relevant authorities.[19] It is currently being considered for approval by the United States Food and Drug Administration (FDA) for the treatment of early stage transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP.

In June 2012, the FDA Peripheral and Central Nervous System Drugs Advisory Committee voted “yes” (13-4 favorable vote) when asked if the findings of the pivotal clinical study with tafamidis were “sufficiently robust to provide substantial evidence of efficacy for a surrogate endpoint that is reasonably likely to predict a clinical benefit”. The Advisory Committee voted “no” 4-13 to reject the drug–in spite of the fact that both primary endpoints were met in the efficacy evaluable population (n=87) and were just missed in the intent to treat population (n=125), apparently because more patients than expected in the intent to treat population were selected for liver transplantation during the course of the trial, not owing to treatment failure, but because their name rose to the top of the transplant list. However, these patients were classified as treatment failures in the conservative analysis used.

Pfizer (following its acquisition of FoldRx ), under license from Scripps Research Institute , has developed and launched tafamidis, a small-molecule transthyretin stabilizer, useful for treating familial amyloid polyneuropathy.

SYN

 European Journal of Medicinal Chemistry, 121, 823-840; 2016

SYN 2

INNOVATORS

THE SCRIPPS RESEARCH INSTITUTE [US/US]; 10550 N Torrey Pines Road, La Jolla, CA 92037 (US)

KELLY, Jeffrey, W.; (US).
SEKIJIMA, Yoshiki; (US)

Image result for The Scripps Research Institute

Dr. Jeffery W. Kelly

Lita Annenberg Hazen Professor of Chemistry

Co-Chairman, Department of Molecular Medicine

Click here to download a concise version of Dr. Jeffery Kelly’s curriculum vitae.

Image result for The Scripps Research Institute

PATENT

WO2004056315

Example 5: Benzoxazoles as Transthyretin Amyloid Fibril Inhibitors
Transthyretin’s two thyroxine binding sites are created by its quaternary structural interface. The tetramer can be stabilized by small molecule binding to these sites, potentially providing a means to treat TTR amyloid disease with small molecule drugs. Many families of compounds have been discovered whose binding stabilizes the tetrameric ground state to a degree proportional to the small molecule dissociation constants Km and Ka2. This also effectively increases the dissociative activation barrier and inhibits amyloidosis by kinetic stabilization. Such inhibitors are typically composed of two aromatic rings, with one ring bearing halogen substituents and the other bearing hydrophilic substituents. Benzoxazoles substituted with a carboxylic acid at C(4)-C(7) and a halogenated phenyl ring at C(2) also appeared to complement the TTR thyroxine binding site. A small library of these compounds was therefore prepared by dehydrocyclization of N-acyl amino-hydroxybenzoic acids as illustrated in Scheme 1.

Scheme 1: General Synthesis of Benzoxazoles
Reagents: (a) ArCOCl, THF, pyridine (Ar = Phenyl, 3,5-Difluorophenyl, 2,6-Difluorophenyl, 3,5-Dichlorophenyl, 2,6-Dichlorophenyl, 2-(Trifluoromethyl)phenyl, and 3-(Trifluoromethyl)phenyl); (b) TsOH*H2O, refluxing xylenes; (c) TMSCHN2, benzene, MeOH; (d) LiOH, THF, MeOH, H2O (8-27% yield over 4 steps).

The benzoxazoles were evaluated using a series of analyses of increasing stringency. WT TTR (3.6 μM) was incubated for 30 min (pH 7, 37 °C) with a test compound (7.2 μM). Since at least one molecule ofthe test compound must bind to each molecule of TTR tetramer to be able to stabilize it, a test compound concentration of 7.2 μM is only twice the minimum effective concentration. The pH was then adjusted to 4.4, the optimal pH for fibrilization. The amount of amyloid formed after 72 h (37 °C) in the presence ofthe test compound was determined by turbidity at 400 nm and is expressed as % fibril formation (ff), 100%) being the amount formed by TTR alone. Ofthe 28 compounds tested, 11 reduced fibril formation to negligible levels (jf< 10%; FIG. 7).
The 11 most active compounds were then evaluated for their ability to bind selectively to TTR over, all other proteins in blood. Human blood plasma (TTR cone. 3.6 -5.4 μM) was incubated for 24 h with the test compound (10.8 μM) at 37 °C. The TTR and any bound inhibitor were immunoprecipitated using a sepharose-bound polyclonal TTR antibody. The TTR with or without inhibitor bound was liberated from the resin at high pH, and the inhibitor: TTR stoichiometry was ascertained by HPLC analysis (FIG. 8). Benzoxazoles with carboxylic acids in the 5- or 6-position, and 2,6-dichlorophenyl (13, 20) or 2-trifluoromethylphenyl (11, 18) substituents at the 2-position displayed the highest binding stoichiometries. In particular, 20 exhibited excellent inhibitory activity and binding selectivity. Hence, its mechanism of action was characterized further.
To confirm that 20 inhibits TTR fibril formation by binding strongly to the tetramer, isothermal titration calorimetry (ITC) and sedimentation velocity experiments were conducted with wt TTR. ITC showed that two equivalents of 20 bind with average dissociation constants of Kdi = Kd2 = 55 (± 10) nM under physiological conditions. These are comparable to the dissociation constants of many other highly efficacious TTR
amyloidogenesis inhibitors. For the sedimentation velocity experiments, TTR (3.6 μM) was incubated with 20 (3.6 μM, 7.2 μM, 36 μM) under optimal fibrilization conditions (72 h, pH 4.4, 37 °C). The tetramer (55 kDa) was the only detectable species in solution with 20 at 7.2 or 36 μM. Some large aggregates formed with 20 at 3.6 μM, but the TTR remaining in solution was tetrameric.
T119M subunit inclusion and small molecule binding both prevent TTR amyloid formation by raising the activation barrier for tetramer dissociation. An inhibitor’s ability to do this is most rigorously tested by measuring its efficacy at slowing tetramer dissociation in 6 M urea, a severe denaturation stress. Thus, the rates of TTR tetramer dissociation in 6 M urea in the presence and absence of 20, 21 or 27 were compared (FIG. 9). TTR (1.8 μM) was completely denatured after 168 h in 6 M urea. In contrast, 20 at 3.6 μM prevented tetramer dissociation for at least 168 h (> 3 the half-life of TTR in human plasma). With an equimolar amount of 20, only 27% of TTR denatured in 168 h. Compound 27 (3.6 μM) was much less able to prevent tetramer dissociation (90% unfolding after 168 h), even though it was active in the fibril formation assay. Compound 21 did not hinder the dissociation of TTR at all. These results show that inhibitor binding to TTR is necessary but not sufficient to kinetically stabilize the TTR tetramer under strongly denaturing conditions; it is also important that the dissociation constants be very low (or that the off rates be very slow). Also, the display of functional groups on 20 is apparently optimal for stabilizing the TTR tetramer; moving the carboxylic acid from C(6) to C(7), as in 27, or removing the chlorines, as in 21, severely diminishes its activity.

The role ofthe substituents in 20 is evident from its co-crystal stracture with TTR (FIG. 10). Compound 20 orients its two chlorine atoms near halogen binding pockets 2 and 2′ (so-called because they are occupied by iodines when thyroxine binds to TTR). The 2,6 substitution pattern on the phenyl ring forces the benzoxazole and phenyl rings out of planarity, optimally positioning the carboxylic acid on the benzoxazole to hydrogen bond to the ε-NH3+ groups of Lys 15/15′. Hydrophobic interactions between the aromatic rings of 20 and the side chains of Leu 17, Leu 110, Ser 117, and Val 121 contribute additional binding energy.

PAPER

ChemMedChem (2013), 8(10), 1617-1619.

Nature Reviews Drug Discovery (2012), 11(3), 185-186

PAPER

Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV
J Med Chem 2011, 54(2): 510

PATENT

WO-2017190682

Novel crystalline forms of tafamidis methylglucamine (designated as Form E), processes for their preparation and compositions comprising them are claimed. Also claimed is their use for treating familial amyloid neuropathy. Represents first PCT filing from Crystal Pharmatech and the inventors on this API.

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=2C2DC88BD4DC90B179C38EC5283D0941.wapp2nA?docId=WO2017190682&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

CLIP

http://pubs.rsc.org/en/content/articlelanding/2016/ob/c5ob02496j/unauth#!divAbstract

Image result for TAFAMIDIS

2-(3, 5-Dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis)

m.p. = 200.4–202.7 °C; Rf = 0.37 (petroleum ether/ethyl acetate/acetic acid = 6:1:0.01).

IR (cm-1 , KBr): 3383, 1685, 1608, 1224, 769;

1H NMR (DMSO-d6, 400 MHz) (ppm) 8.27 (s, 1H), 8.18 (d, J = 6.8 Hz, 1H), 8.04–8.02 (m, 1H), 7.94 (s, 1H), 7.88 (d, J = 1.6 Hz, 1H), 7.67 (dd, J = 6.8 Hz, 5.2 Hz, 1H);

13C NMR (DMSOd6, 100 MHz) (ppm) 167.2, 162.1, 150.1, 145.0, 137.8, 133.7, 131.4, 128.6, 126.8, 124.3, 120.5, 112.6.

Data was consistent with that reported in the literature. [27]Yamamoto, T.; Muto, K.; Komiyama, M.; Canivet, J.; Yamaguchi, J.; Itami, K. Chem. Eur. J. 2011, 17, 10113.

Clip

http://synth.chem.nagoya-u.ac.jp/wordpress/publication/nicatalystscopemechanism?lang=en

Image result for TAFAMIDIS

CLIP

Proc Natl Acad Sci U S A. 2012 Jun 12; 109(24): 9629–9634.
Published online 2012 May 29. doi:  10.1073/pnas.1121005109

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386102/

str1

The transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or cardiomyopathy. ATTR are caused by aggregation of transthyretin (TTR), a natively tetrameric protein involved in the transport of thyroxine and the vitamin A–retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation. One such compound, tafamidis meglumine (Fx-1006A), has recently completed Phase II/III trials for the treatment of Transthyretin Type Familial Amyloid Polyneuropathy (TTR-FAP) and demonstrated a slowing of disease progression in patients heterozygous for the V30M TTR mutation. Herein we describe the molecular and structural basis of TTR tetramer stabilization by tafamidis. Tafamidis binds selectively and with negative cooperativity (Kds ∼2 nM and ∼200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by tafamidis binding. The crystal structure of tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis.

4-Amino-3-hydroxybenzoic acid (AHBA) is reacted with HCl (3 to 6 M equivalents) in methanol (8 to 9 L/kg). Methyl t-butyl ether (TBME) (9 to 11 L/kg) is then added to the reaction mixture. The product, methyl 4-amino-3-hydroxybenzoate hydrochloride salt, is isolated by filtration and then reacted with 3,5-dichlorobenzoyl chloride (0.95 to 1.05 M equivalents) in the presence of pyridine (2.0 to 2.5 M equivalents) in dichloromethane (DCM), (8 to 9 L/kg) as a solvent. After the distillation of DCM, acetone and water are added to the reaction mixture, producing methyl 4-(3,5-dichlorobenzoylamino)-3- hydroxy-benzoate. This is recovered by filtration and reacted with p-toluenesulfonic acid monohydrate (0.149 to 0.151 M equivalents) in toluene (12 to 18 L/kg) at reflux with water trap. Treatment with charcoal is then performed. After the distillation of toluene, acetone (4-6 L/kg) is added. The product, methyl 2-(3,5-dichlorophenyl)-benzoxazole-6- carboxylate, is isolated by filtration and then reacted with LiOH (1.25 to 1.29 M equivalents) in the presence of tetrahydrofuran (THF) (7.8 to 8.2 L/kg) and water (7.8 to 8.2 L/kg) at between 40 and 45 °C. The pH of the reaction mixture is adjusted with aqueous HCl to yield 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid, the free acid of tafamidis. This is converted to the meglumine salt by reacting with N-methyl-Dglucamine (0.95 to 1.05 M equivalents) in a mixture of water (4.95 to 5.05 L/kg)/isopropyl alcohol (19.75 to 20.25 L/kg) at 65-70 °C. Tafamidis meglumine (dglucitol, 1-deoxy-1-(methylamino)-,2-(3,5-dichlorophenyl)-6-benzoxazole carboxylate) is then isolated by filtration.

2 The following fragments were identified from electrospray ionization mass spectra acquired in positive-ion mode: meglumine M+ (C7H18NO5+, m/z = 196.13), M (carboxylate form) +2H (C14H6Cl2NO3, m/z = 308.13), M (salt) + H (C21H24Cl2N2O8, m/z = 504.26). 1 H-nuclear magnetic resonance spectra were acquired on a 700 MHz Bruker AVANCE II spectrometer in acetone:D2O (~8:2). Data were reported as chemical shift in ppm (δ), multiplicity (s = singlet, dd = double of doublets, m = multiplet), coupling constant (J Hz), relative integral and assignment: δ = 8.14 (m, JH2-H5 = 0.6 and JH2-H6 = 1.5, 1H, H2), 8.02 (dd, JH9-H11 = 1.9 and JH13-H11 = 1.9, 2H, H9 and H13), 7.97 (dd, JH6-H5 = 8.25, 1H, H6), 7.67 (dd, JH5-H2 = 0.6 and JH5-H6 = 8.25, 1H, H5), 7.58 (m, JH11-H9 = 1.9 and JH11-H13 = 1.9, 1H, H11), 4.08 (m, JH16-H17 = 4.9, 1H, H16), 3.79 (dd, JH17-H18 = 2.2, 1H, H17), 3.73 (dd, JH19-H20 = 3.2, 1H, H20), 3.69 (m, JH19-H20 = 3.2, 1H, H19), 3.61 (m, JH18-H19 = 12.25, 1H, H18), 3.58 (m, JH19-H20′ = 5.8 and JH20-H20′ = 11.7, 1H, H20′ ), 3.19 (m, JH15-H15′ = 12.9 and JH15′-H16 = 9.25 and JH15-H16 = 3.5, 2H, H15).

CLIP

http://onlinelibrary.wiley.com/store/10.1002/chem.201101091/asset/supinfo/chem_201101091_sm_miscellaneous_information.pdf?v=1&s=7badb204a12057710743c1711a744253eccd636a

Concise Synthesis of Tafamidis (Scheme 8)

4-(6-Benzoxazoyl)morpholine (8)

str1

A mixture of 4-amino-3-hydroxybenzoic acid (1.53 g, 10 mmol) and trimethyl orthofomate (3 mL) was heated at 100 ºC for 5 h. After cooling to room temperature, trimethyl orthofomate was removed under reduced pressure. To a solution of benzoxazole 6-carboxylic acid in CH2Cl2 (10 mL) were added DMF (0.1 mL) and oxalyl chloride (1.8 mL, 20 mmol) and the resultant mixture was stirred at room temperature for 12 h. After cooling to room temperature, DMF and oxalyl chloride were removed under reduced pressure to yield the corresponding acid chloride as a solid. Thus-generated acid chloride and morpholine (2.2 mL) were stirred at room temperature for 3 h. After removing solvents under reduced pressure, the mixture was treated with saturated aqueous sodium bicarbonate (20 mL) and ethyl acetate (20 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with brine (20 mL), dried with anhydrous magnesium sulfate, and the solvent removed under reduced pressure. Purification of the resulting oil by flash column chromatography on silica (5% methanol in CHCl3 as eluent) afforded heteroarene 8 (1.30 g, 56%) as a white solid. Rf = 0.47 (MeOH/CHCl3 = 1:20). 1 H NMR (600 MHz, CDCl3) δ 8.23 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.71 (s, 1H) 7.44 (d, J = 7.6 Hz, 1H), 4.00–3.25 (br, 8H). 13C NMR (150 MHz, CDCl3) δ 169.52, 153.87, 149.67, 141.24, 132.90, 123.79, 120.76, 110.48, 66.81. HRMS (DART) m/z calcd for C12H13N2O3 [MH]+ : 233.0926, found 233.0926.

4-(3,5-Dichlorophenyl 6-benzoxazoyl)morpholine

To a 20-mL glass vessel equipped with J. Young® O-ring tap containing a magnetic stirring bar were added Ni(cod)2 (13.9 mg, 0.05 mmol), 2,2’-bipyridyl (7.8 mg, 0.05 mmol), LiOt-Bu (60 mg, 0.75 mmol), 8 (174.2 mg, 0.5 mmol), 3,5-dichloroiodobenzene (9: 203.9 mg, 0.75 mmol), followed by dry 1,2-dimethoxyethane (2.0 mL). The vessel was sealed with an O-ring tap and then heated at 100 °C in an 8-well reaction block with stirring for 24 h. After cooling the reaction mixture to room temperature, the mixture was passed through a short silica gel pad (EtOAc). The filtrate was concentrated and the residue was subjected to preparative thin-layer chromatography (5% methanol in CHCl3 as eluent) to afford SI-2 (139.6 mg, 74 %) as a white foam. Rf = 0.70 (MeOH/CHCl3 = 1:20). 1 H NMR (600 MHz, CDCl3) δ 8.16 (d, J = 2.0 Hz, 2H), 7.82 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 4.00–3.25 (br, 8H). 13C NMR (150 MHz, CDCl3) δ 169.38, 161.78, 150.40, 142.90, 135.82, 132.95, 131.61, 129.26, 125.91, 124.23, 120.41, 110.26, 66.77. HRMS (DART) m/z calcd for C18H15Cl2N2O3 [MH]+ : 377.0460 found 377.0465.

Tafamidis[19  ] Razavi, H.; Palaninathan, S. K.; Powers, E. T.; Wiseman, R. L.; Purkey, H. E.; Mohamedmohaideen, N. N.; Deechongkit, S.; Chiang, K. P.; Dendle, M. T. A.; Sacchettini, J. C.; Kelly, J. W. Angew. Chem. Int. Ed. 2003, 42, 2758.]

HF·pyridine (0.5 mL) was added to a stirred solution of SI-2 (32 mg, 0.09 mmol) in THF (0.5 mL) at 70 ºC for 12 h. After cooling the reaction mixture to room temperature, the mixuture was diluted with EtOAc and washed sequentially with sat.NaHCO3, 2N HCl and brine. The organic layer was concentrated and the residue was subjected to preparative thin-layer chromatography (1% acetic acid, 5% methanol in CHCl3 as eluent) to afford tafamidis (24.7 mg, 94%) as a white foam.

1 H NMR (600 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.08 (d, J = 1.4 Hz, 2H), 8.00 (d, J = 8.3 Hz, 1H), 7.88 (m, 2H).

13C NMR (150 MHz, DMSO-d6) δ 166.6, 162.0, 150.0, 144.6, 135.1, 131.7, 129.1, 128.7, 126.5, 125.8, 120.0, 112.2.

HRMS (DART) m/z calcd for C14H8Cl2NO3 [MH]+ : 307.9881, found 307.9881.

References

  1. Jump up^ Bulawa, C.E.; Connelly, S.; DeVit, M.; Wang, L. Weigel, C.;Fleming, J. Packman, J.; Powers, E.T.; Wiseman, R.L.; Foss, T.R.; Wilson, I.A.; Kelly, J.W.; Labaudiniere, R. “Tafamidis, A Potent and Selective Transthyretin Kinetic Stabilizer That Inhibits the Amyloid Cascade”. Proc. Natl. Acad. Sci., 2012 109, 9629-9634.
  2. Jump up^ Ando, Y., and Suhr, O.B. (1998). Autonomic dysfunction in familial amyloidotic polyneuropathy (FAP). Amyloid, 5, 288-300.
  3. Jump up^ Benson, M.D. (1989). “Familial Amyloidotic polyneuropathy”. Trends in Neurosciences, 12.3, 88-92, PMID 2469222doi:10.1016/0166-2236(89)90162-8.
  4. Jump up^ http://www.businesswire.com/news/home/20111117005505/en/Pfizer%E2%80%99s-Vyndaqel%C2%AE-tafamidis-Therapy-Approved-European-Union
  5. Jump up^ Clinical trial number NCT00409175 for “Safety and Efficacy Study of Fx-1006A in Patients With Familial Amyloidosis” at ClinicalTrials.gov
  6. Jump up^ Coelho, T.; Maia, L.F.; Martins da Silva, A.; Cruz, M.W.; Planté-Bordeneuve, V.; Lozeron, P.; Suhr, O.B.; Campistol, J.M.; Conceiçao, I.; Schmidt, H.; Trigo, P. Kelly, J.W.; Labaudiniere, R.; Chan, J., Packman, J.; Wilson, A.; Grogan, D.R. “Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial”. Neurology, 2012, 79, 785-792.
  7. Jump up to:a b Coelho, T.; Maia, L.F.; Martins da Silva, A.; Cruz, M.W.; Planté-Bordeneuve, V.; Suhr, O.B.; Conceiçao, I.; Schmidt, H. H. J.; Trigo, P. Kelly, J.W.; Labaudiniere, R.; Chan, J., Packman, J.; Grogan, D.R. “Long-term Effects of Tafamidis for the Treatment of Transthyretin Familial Amyloid Polyneuropathy”. J. Neurology, 2013 260, 2802-2814.
  8. Jump up^ Ando, Y.; Sekijima, Y.; Obayashi, K.; Yamashita, T.; Ueda, M.; Misumi, Y.; Morita, H.; Machii, K; Ohta, M.; Takata, A; Ikeda, S-I. “Effects of tafamidis treatment on transthyretin (TTR) stabilization, efficacy, and safety in Japanese patients with familial amyloid polyneuropathy (TTR-FAP) with Val30Met and non-Varl30Met: A phase III, open-label study”. J. Neur. Sci., 2016 362, 266-271, doi:10.1016/j.jns.2016.01.046.
  9. Jump up^ Andrade, C. (1952). “A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves”. Brain: a Journal of Neurology, 75, 408-427.
  10. Jump up^ Coelho, T. (1996). “Familial amyloid polyneuropathy: new developments in genetics and treatment”. Current Opinion in Neurology, 9, 355-359.
  11. Jump up^ Razavi, H.; Palaninathan, S.K. Powers, E.T.; Wiseman, R.L.; Purkey, H.E.; Mohamadmohaideen, N.N.; Deechongkit, S.; Chiang, K.P.; Dendle, M.T.A.; Sacchettini, J.C.; Kelly, J.W. “Benzoxazoles as Transthyretin Amyloid Fibril Inhibitors: Synthesis, Evaluation and Mechanism of Action”. Angew. Chem. Int. Ed., 2003, 42, 2758-2761.
  12. Jump up^ Connelly, S., Choi, S., Johnson, S.M., Kelly, J.W., and Wilson, I.A. (2010). “Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses”. Current Opinion in Structural Biology, 20, 54-62.
  13. Jump up^ Hammarstrom, P.; Wiseman, R. L.; Powers, E.T.; Kelly, J.W. “Prevention of Transthyretin Amyloid Disease by Changing Protein Misfolding Energetics”. Science, 2003, 299, 713-716
  14. Jump up^ Westermark, P., Sletten, K., Johansson, B., and Cornwell, G.G., 3rd (1990). “Fibril in senile systemic amyloidosis is derived from normal transthyretin”. Proc Natl Acad Sci U S A, 87, 2843-2845.
  15. Jump up^ Sousa, M.M., Cardoso, I., Fernandes, R., Guimaraes, A., and Saraiva, M.J. (2001). “Deposition of transthyretin in early stages of familial amyloidotic polyneuropathy: evidence for toxicity of nonfibrillar aggregates”. The American Journal of Pathology, 159, 1993-2000.
  16. Jump up^ Colon, W., and Kelly, J.W. (1992). “Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro”. Biochemistry 31, 8654-8660.
  17. Jump up^ Jacobson, D.R., Pastore, R.D., Yaghoubian, R., Kane, I., Gallo, G., Buck, F.S., and Buxbaum, J.N. (1997). “Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans”. The New England Journal of Medicine, 336, 466-473.
  18. Jump up^ Maurer, M.S.; Grogan, D.R.; Judge, D.P.; Mundayat, R.; Lombardo, I.; Quyyumi, A.A.; Aarts, J.; Falk, R.H. “Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes.” Circ. Heart. Fail. 2015 8, 519-526.
  19. Jump up^http://www.pfizer.com/sites/default/files/news/Brazil%20Approval%20Press%20Statement%2011-7-16_0.pdf
Patent ID

Patent Title

Submitted Date

Granted Date

US2016185739 Solid Forms Of A Transthyretin Dissociation Inhibitor
2015-12-22
2016-06-30
US2017196985 SULFUR(VI) FLUORIDE COMPOUNDS AND METHODS FOR THE PREPARATION THEREOF
2015-06-05
US9770441 Crystalline solid forms of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole
2015-08-31
2017-09-26
Patent ID

Patent Title

Submitted Date

Granted Date

US9771321 Small Molecules That Covalently Modify Transthyretin
2014-04-14
2014-11-13
US9610270 NEW THERAPY FOR TRANSTHYRETIN-ASSOCIATED AMYLOIDOSIS
2012-10-23
2014-10-02
US2015057320 TRANSTHYRETIN LIGANDS CAPABLE OF INHIBITING RETINOL-DEPENDENT RBP4-TTR INTERACTION FOR TREATMENT OF AGE-RELATED MACULAR DEGENERATION, STARGARDT DISEASE, AND OTHER RETINAL DISEASE CHARACTERIZED BY EXCESSIVE LIPOFUSCIN ACCUMULATION
2014-10-31
2015-02-26
US9249112 SOLID FORMS OF A TRANSTHYRETIN DISSOCIATION INHIBITOR
2012-09-12
2015-01-29
US9499527 COMPOSITIONS AND METHODS FOR THE TREATMENT OF FAMILIAL AMYLOID POLYNEUROPATHY
2013-02-27
2015-05-07
Patent ID

Patent Title

Submitted Date

Granted Date

US9150489 1-(2-FLUOROBIPHENYL-4-YL)-ALKYL CARBOXYLIC ACID DERIVATIVES FOR THE THERAPY OF TRANSTHYRETIN AMYLOIDOSIS
2011-10-27
US2014134753 METHODS FOR TREATING TRANSTHYRETIN AMYLOID DISEASES
2014-01-15
2014-05-15
US8703815 Small molecules that covalently modify transthyretin
2010-10-14
2014-04-22
US8653119 Methods for treating transthyretin amyloid diseases
2011-11-22
2014-02-18
US2008131907 ASSAYS FOR DETECTING NATIVE-STATE PROTEINS AND IDENTIFYING COMPOUNDS THAT MODULATE THE STABILITY OF NATIVE-STATE PROTEINS
2007-09-14
2008-06-05
Patent ID

Patent Title

Submitted Date

Granted Date

US7214695 Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
2004-08-05
2007-05-08
US7214696 Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
2006-03-16
2007-05-08
US7560488 Methods for treating transthyretin amyloid diseases
2007-04-05
2009-07-14
US8168663 Pharmaceutically acceptable salt of 6-carboxy-2-(3, 5 dichlorophenyl)-benzoxazole, and a pharmaceutical composition comprising the salt thereof
2010-05-13
2012-05-01
US8236984 COMPOUND AND USE THEREOF IN THE TREATMENT OF AMYLOIDOSIS
2010-09-30
2012-08-07
Tafamidis
Tafamidis skeletal.svg
Clinical data
Trade names Vyndaqel
License data
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
Formula C14H7Cl2NO3
Molar mass 308.116 g/mol
3D model (JSmol)

//////////////TTAFAMIDIS, Fx-1006A, PF-06291826, Orphan Drug, SCRIPP, PFIZER

C1=CC2=C(C=C1C(=O)O)OC(=N2)C3=CC(=CC(=C3)Cl)Cl

CNC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.c1cc2c(cc1C(=O)O)oc(n2)c3cc(cc(c3)Cl)Cl

 

“NEW DRUG APPROVALS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

FDA approves Mepsevii (vestronidase alfa-vjbk) for treatment for rare genetic enzyme disorder


FDA approves treatment for rare genetic enzyme disorder

The U.S. Food and Drug Administration today approved Mepsevii (vestronidase alfa-vjbk) to treat pediatric and adult patients with an inherited metabolic condition called mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome. MPS VII is an extremely rare, progressive condition that affects most tissues and organs. Continue reading.

 

 

November 15, 2017

Summary

First FDA approved treatment for pediatric and adult patients with MPS VII

Release

The U.S. Food and Drug Administration today approved Mepsevii (vestronidase alfa-vjbk) to treat pediatric and adult patients with an inherited metabolic condition called mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome. MPS VII is an extremely rare, progressive condition that affects most tissues and organs.

“This approval underscores the agency’s commitment to making treatments available to patients with rare diseases,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research (CDER). “Prior to today’s approval, patients with this rare, inherited condition had no approved treatment options.”

MPS VII is an inherited, rare genetic condition and impacts less than 150 patients worldwide. The features of MPS VII vary widely from patient to patient, but most patients have various skeletal abnormalities that become more pronounced with age, including short stature. Affected individuals can also develop heart valve abnormalities, enlarged liver and spleen, and narrowed airways which can lead to lung infections and trouble breathing. The life expectancy of individuals with MPS VII depends on the severity of symptoms. Some affected individuals do not survive infancy, while others may live into adolescence or adulthood. Heart disease and airway obstruction are major causes of death in people with MPS VII. Affected individuals may have developmental delay and progressive intellectual disability.

MPS VII is a lysosomal storage disorder caused by deficiency of an enzyme called beta-glucuronidase, which causes an abnormal buildup of toxic materials in the body’s cells. Mepsevii is an enzyme replacement therapy that works by replacing the missing enzyme.

The safety and efficacy of Mepsevii were established in clinical trial and expanded access protocols enrolling a total of 23 patients ranging from 5 months to 25 years of age. Patients received treatment with Mepsevii at doses up to 4 mg/kg once every two weeks for up to 164 weeks. Efficacy was primarily assessed via the six-minute walk test in ten patients who could perform the test. After 24 weeks of treatment, the mean difference in distance walked relative to placebo was 18 meters. Additional follow-up for up to 120 weeks suggested continued improvement in three patients and stabilization in the others. Two patients in the Mepsevii development program experienced marked improvement in pulmonary function. Overall, the results observed would not have been anticipated in the absence of treatment. The effect of Mepsevii on the central nervous system manifestations of MPS VII has not been determined.

The most common side effects after treatment with Mepsevii include infusion site reactions, diarrhea, rash and anaphylaxis.

The FDA granted this application Fast Track designation, which seeks to expedite the development and review of drugs that are intended to treat serious conditions where initial evidence showed the potential to address an unmet medical need. Mepsevii also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is receiving a Rare Pediatric Disease Priority Review Voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive Priority Review of a subsequent marketing application for a different product. This is the twelfth rare pediatric disease priority review voucher issued by the FDA since the program began.

The FDA is requiring the manufacturer to conduct a post-marketing study to evaluate the long-term safety of the product.

The FDA granted approval of Mepsevii to Ultragenyx Pharmaceutical, Inc.

/////////Mepsevii, vestronidase alfa-vjbk, fda 2017

Pracinostat


Pracinostat.svg

ChemSpider 2D Image | Pracinostat | C20H30N4O2

Pracinostat.png

2D chemical structure of 929016-96-6

Pracinostat

  • Molecular Formula C20H30N4O2
  • Average mass 358.478 Da
2-Propenamide, 3-[2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl]-N-hydroxy-, (2E)-
929016-96-6 [RN]
SB939
(2E)-3-{2-butyl-1-[2-(diethylamino)ethyl]-1,3-benzodiazol-5-yl}-N-hydroxyprop-2-enamide
N-hydroxy-1-[(4-methoxyphenyl)methyl]-1H-indole-6-carboxamide
PCI 34051,  UNII: GPO2JN4UON
929016-98-8 DI HCl salt, C20 H30 N4 O2 . 2 Cl H, 431.4
929016-96-6 (free base)
929016-97-7 (trifluoroacetate)
S*BIO (Originator)
Leukemia, acute myeloid, phase 3, helsinn
Image result for S*BIO
str1
CAS 929016-98-8 DI HCl salt, C20 H30 N4 O2 . 2 Cl H, 431.4
E)-3-[2-Butyl-1-(2-diethylaminoethyl)-1H-benzimidazol-5-yl]-N-hydroxyacrylamide Dihydrochloride Salt

Pracinostat (SB939) is an orally bioavailable, small-molecule histone deacetylase (HDAC) inhibitor based on hydroxamic acid with potential anti-tumor activity characterized by favorable physicochemical, pharmaceutical, and pharmacokinetic properties.

WO-2017192451  describes Novel polymorphic crystalline forms of pracinostat (designated as Form 3) and their hydrates, processes for their preparation and compositions and combination comprising them are claimed. Also claimed is their use for inhibiting histone deacetylase and treating cancer, such as myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), breast cancer, colon cancer, prostate cancer, pancreas cancer, leukemia, lymphoma, ovary cancer, melanoma and neuroblastoma.

See WO2014070948 ,  Helsinn , under sub-license from MEI Pharma (under license from S*Bio), is developing pracinostat, an oral HDAC inhibitor, for treating hematological tumors, including AML, MDS and myelofibrosis.

The oncolytic agent pracinostat hydrochloride is an antagonist of histone deacetylase 1 (HDAC1) and 2 (HDAC2) that was discovered by the Singapore-based company S*BIO. Helsinn obtained the exlusive development and commercialization rights in July 2016, and is conducting phase III clinical trials in combination with azacitidine in adults with newly diagnosed acute myeloid leukemia. Phase II trials are also under way for the treatment of previously untreated intermediate-2 or high risk myelodysplastic syndrome patients and for the treatment of primary or post essential thrombocythemia/polycythemia vera) in combination with ruxolitinib.In North America, S*BIO had been conducting phase II clinical trials of pracinostat hydrochloride in patients with solid tumors and for the treatment of myeloproliferative diseases and phase I clinical trials in patients with leukemia; however, recent progress reports are not available at present. The University of Queensland had been evaluating the compound in preclinical studies for malaria.

Image result for University of Queensland

University of Queensland

Image result for MEI Pharma

MEI Pharma

The Canadian Cancer Society Research Institute (the research branch of the Canadian Cancer Society upon its integration with the National Cancer Institute of Canada to form the new Canadian Cancer Society) is conducting phase II clinical trials in Canada for the treatment of recurrent or metastatic prostate cancer.

Image result for Canadian Cancer Society Research Institute

Canadian Cancer Society Research Institute

In 2012, the product was licensed to MEI Pharma by S*BIO on a worldwide basis. In 2016, MEI Pharma and Helsinn entered into a licensing, development and commercialization agreement by which Helsinn obtained exclusive worldwide rights (including manufacturing and commercialization rights).

Image result for HELSINN

HELSINN

In 2014, the FDA assigned an orphan drug designation to MEI Pharma for the treatment of acute myeloid leukemia. In 2016, the product received breakthrough therapy designation in the U.S. in combination with azacitidine for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) who are older than 75 years of age or unfit for intensive chemotherapy.

Pracinostat is an orally available, small-molecule histone deacetylase (HDAC) inhibitor with potential antineoplastic activity. Pracinostat inhibits HDACs, which may result in the accumulation of highly acetylated histones, followed by the induction of chromatin remodeling; the selective transcription of tumor suppressor genes; the tumor suppressor protein-mediated inhibition of tumor cell division; and, finally, the induction of tumor cell apoptosis. This agent may possess improved metabolic, pharmacokinetic and pharmacological properties compared to other HDAC inhibitors.

Pracinostat is a novel HDAC inhibitor with improved in vivo properties compared to other HDAC inhibitors currently in clinical trials, allowing oral dosing. Data demonstrate that Pracinostat is a potent and effective anti-tumor drug with potential as an oral therapy for a variety of human hematological and solid tumors

SYNTHESIS

Figure

Clinically tested HDAC inhibitors.

Activity

Pracinostat selectively inhibits HDAC class I,II,IV without class III and HDAC6 in class IV,[1] but has no effect on other Zn-binding enzymes, receptors, and ion channels. It accumulates in tumor cells and exerts a continuous inhibition to histone deacetylase,resulting in acetylated histones accumulation, chromatin remodeling, tumor suppressor genes transcription, and ultimately, apoptosis of tumor cells.[2]

Clinical medication

Clinical studies suggests that pracinostat has potential best pharmacokinetic properties when compared to other oral HDAC inhibitors.[3]In March 2014, pracinostat has granted Orphan Drug for acute myelocytic leukemia (AML) and for the treatment of T-cell lymphoma by the Food and Drug Administration.

Clinical Trials

CTID Title Phase Status Date
NCT03151304 A Safety and Efficacy Study of Pracinostat and Azacitidine in Patients With High Risk Myelodysplastic Syndromes 2 Recruiting
2017-10-27
NCT03151408 An Efficacy and Safety Study Of Pracinostat In Combination With Azacitidine In Adults With Acute Myeloid Leukemia 3 Recruiting
2017-10-17
NCT02267278 Ruxolitinib and Pracinostat Combination Therapy for Patients With Myelofibrosis (MF) 2 Active, not recruiting
2017-04-27
NCT01873703 Phase 2 Study of Pracinostat With Azacitidine in Patients With Previously Untreated Myelodysplastic Syndrome 2 Active, not recruiting
2017-04-21
NCT02118909 Evaluate the Effects of Itraconazole and Ciprofloxacin on Single-Dose PK of Pracinostat in Healthy Nonsmoking Subjects 1 Completed
2017-02-22
NCT02058784 Study to Evaluate the Food Effect of Single-dose Bioavailability of Pracinostat in Healthy Adult Subjects 1 Completed
2017-02-22
NCT01993641 Phase 2 Study Adding Pracinostat to a Hypomethylating Agent (HMA) in Patients With MDS Who Failed to Respond to Single Agent HMA 2 Completed
2017-02-22
NCT01112384 A Study of SB939 in Patients With Translocation-Associated Recurrent/Metastatic Sarcomas 2 Completed
2016-11-25
NCT01184274 A Phase I Study of SB939 in Pediatric Patients With Refractory Solid Tumours and Leukemia 1 Completed
2014-01-16
NCT01200498 Study of SB939 in Subjects With Myelofibrosis 2 Completed
2013-12-13

PATENT

WO2005028447

Inventors Dizhong ChenWeiping DengKanda SangthongpitagHong Yan SongEric T. SunNiefang YuYong Zou
Applicant S*Bio Pte Ltd

Scheme I

Figure imgf000041_0001

Scheme II

Figure imgf000042_0001Scheme III

Figure imgf000043_0001Scheme IV

Figure imgf000044_0001 Scheme V

Figure imgf000045_0001

PAPER

Discovery of (2E)-3-{2-Butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an Orally Active Histone Deacetylase Inhibitor with a Superior Preclinical Profile

Chemistry Discovery, Biology Discovery, and §Pre-Clinical Development, S*BIO Pte Ltd., 1 Science Park Road, No. 05-09 The Capricorn, Singapore Science Park II, Singapore 117528, Singapore
J. Med. Chem.201154 (13), pp 4694–4720
DOI: 10.1021/jm2003552
Phone: +65-68275019. Fax: +65-68275005. E-mail: haishan_wang@sbio.com.

Abstract

Abstract Image

A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC50), liver microsomal stability (t1/2), cytochrome P450 inhibitory (3A4 IC50), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.

(E)-3-[2-Butyl-1-(2-diethylaminoethyl)-1H-benzimidazol-5-yl]-N-hydroxyacrylamide Dihydrochloride Salt (3)

The freebase of 3 was prepared according to procedure D. The hydroxamic acid moiety was identified by 1H–15N HSQC (DMSO-d6) with δN = 169.0 ppm (CONHOH). Other nitrogens in 3were identified by 1H–15N HMBC (DMSO-d6) with δN of 241.4 ppm for N3 of the benzimidazole ring, 152.3 ppm for N1, and 41.3 ppm for the diethylamino group (reference to nitromethane δN = 380.0 ppm in CDCl3). The dihydrochloride salt of 3 was prepared according to procedure D as white or off-white solid or powder in ∼60% yield from 9 in two steps. LC–MS m/z 359.2 ([M + H]+).
1H NMR (DMSO-d6) δ 11.79 (brs, 1H, NH or OH), 10.92 (very br s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.97 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 15.8 Hz, 1H), 6.65 (d, J = 15.8 Hz, 1H), 5.01 (t-like, J = 7.7 Hz, 2H), 3.48 (m, 2H), 3.30–3.19 (m, 6H), 1.87 (quintet, J = 7.8 Hz, 2H), 1.47 (sextet, J = 7.5 Hz, 2H), 1.29 (t, J = 7.2 Hz, 6H), 0.97 (t, J = 7.3 Hz, 3H);
13C NMR (DMSO-d6) δ 162.3, 156.0, 137.3 (CH), 132.8, 132.3, 132.0 (br, identified by HMBC), 124.7 (CH), 120.2 (CH), 113.1 (2 × CH), 48.2, 46.3, 39.0, 28.1, 25.0, 21.7, 13.6, 8.3.
Anal. (C20H30N4O2·2HCl·0.265H2O) C, H, N, Cl. Water content = 1.09% (Karl Fisher method). HRMS (ESI) m/z [M + H]+ calcd for C20H31N4O2, 359.2442; found, 359.2449.

PATENT

WO 2007030080

http://google.com/patents/WO2007030080A1?cl=en

 
Inventors Dizhong ChenWeiping DengKen Chi Lik LeePek Ling LyeEric T. SunHaishan WangNiefang Yu
Applicant S*Bio Pte Ltd

SEE

WO 2008108741

WO 2014070948

Patent

WO-2017192451

References

  1. Jump up^ “In vitro enzyme activity of SB939 and SAHA”. 22 Aug 2014.
  2. Jump up^ “The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML”. Blood Cancer Journaldoi:10.1038/bcj.2012.14.
  3. Jump up^ Veronica Novotny-Diermayr; et al. (March 9, 2010). “SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer”Mol Cancer Therdoi:10.1158/1535-7163.MCT-09-0689.
PATENT 
Cited Patent Filing date Publication date Applicant Title
WO2005028447A1 * Sep 21, 2004 Mar 31, 2005 S*Bio Pte Ltd Benzimidazole derivates: preparation and pharmaceutical applications
US20050137234 * Dec 14, 2004 Jun 23, 2005 Syrrx, Inc. Histone deacetylase inhibitors
Reference
1 None
2 See also references of EP1937650A1
Citing Patent Filing date Publication date Applicant Title
WO2009084544A1 * Dec 24, 2008 Jul 9, 2009 Idemitsu Kosan Co., Ltd. Nitrogen-containing heterocyclic derivative and organic electroluminescent device using the same
WO2010043953A2 * Oct 14, 2009 Apr 22, 2010 Orchid Research Laboratories Ltd. Novel bridged cyclic compounds as histone deacetylase inhibitors
WO2010043953A3 * Oct 14, 2009 Mar 24, 2011 Orchid Research Laboratories Ltd. Novel bridged cyclic compounds as histone deacetylase inhibitors
WO2017030938A1 * Aug 12, 2016 Feb 23, 2017 Incyte Corporation Heterocyclic compounds and uses thereof
DE102007037579A1 Aug 9, 2007 Feb 19, 2009 Emc Microcollections Gmbh Neue Benzimidazol-2-yl-alkylamine und ihre Anwendung als mikrobizide Wirkstoffe
US8865912 Jan 27, 2014 Oct 21, 2014 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9024029 Sep 3, 2013 May 5, 2015 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US9062003 Sep 9, 2014 Jun 23, 2015 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9156797 May 15, 2015 Oct 13, 2015 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9402829 Feb 20, 2015 Aug 2, 2016 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
US9717713 Jun 10, 2016 Aug 1, 2017 Mei Pharma, Inc. Benzimidazole derivatives: preparation and pharmaceutical applications
Patent ID

Patent Title

Submitted Date

Granted Date

US2016158186 USE OF DIANHYDROGALACTITOL AND ANALOGS AND DERIVATIVES THEREOF TO TREAT RECURRENT MALIGNANT GLIOMA OR PROGRESSIVE SECONDARY BRAIN TUMOR
2015-04-09
2016-06-09
US2015051288 Methods and Compositions for Treatment of Autism
2014-10-10
2015-02-19
US2017128534 TREATING ROTATOR CUFF CONDITIONS
2015-07-09
Patent ID

Patent Title

Submitted Date

Granted Date

US2014235649 USE OF PHOSPHATASE INHIBITORS OR HISTONE DEACETYLASE INHIBITORS TO TREAT DISEASES CHARACTERIZED BY LOSS OF PROTEIN FUNCTION
2012-05-24
2014-08-21
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2012-06-01
2014-11-27
US2017100354 COMPOSITIONS AND METHODS FOR TREATING KABUKI SYNDROME AND RELATED DISORDERS
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Patent ID

Patent Title

Submitted Date

Granted Date

US9387263 RbAp48 TRANSGENIC MICE FOR DRUG DISCOVERY IN AGE-RELATED MEMORY DECLINE
2012-08-02
2014-10-02
US2014051716 COMPOUNDS AND METHODS FOR IMPROVING IMPAIRED ENDOGENOUS FIBRINOLYSIS USING HISTONE DEACETYLASE INHIBITORS
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US2016069887 BIOMARKERS FOR PROGNOSIS
2014-04-08
2016-03-10
US8937050 Methods and compositions for treatment of autism
2012-10-31
2015-01-20
Patent ID

Patent Title

Submitted Date

Granted Date

US2017049784 METHOD OF TREATING ACUTE MYELOID LEUKEMIA AND/OR ACUTE LYMPHOBLASTIC LEUKEMIA USING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2015-05-01
US2017095484 METHOD OF TREATING RESISTANT NON-HODGKIN LYMPHOMA, MEDULLOBLASTOMA, AND/OR ALK+NON-SMALL CELL LUNG CANCER USING THIENOTRIAZOLODIAZEPINE COMPOUNDS
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US2015182490 METHODS FOR TREATING TYROSINE-KINASE-INHIBITOR-RESISTANT MALIGNANCIES IN PATIENTS WITH GENETIC POLYMORPHISMS OR AHI1 DYSREGULATIONS OR MUTATIONS EMPLOYING DIANHYDROGALACTITOL, DIACETYLDIANHYDROGALACTITOL, DIBROMODULCITOL, OR ANALOGS OR DERIVATIVES THEREOF
2013-06-24
2015-07-02
Patent ID

Patent Title

Submitted Date

Granted Date

US8143282 Heterocyclic Compounds
2009-02-19
2012-03-27
US2017020874 COMPOUNDS AND METHODS FOR IMPROVING IMPAIRED ENDOGENOUS FIBRINOLYSIS USING HISTONE DEACETYLASE INHIBITORS
2015-12-01
US2017231931 PRODUCTS FOR THE TREATMENT AND PREVENTION OF NEUROLOGICAL DISORDERS COURSING WITH A COGNITION DEFICIT OR IMPAIRMENT, AND OF NEURODEGENERATIVE DISEASES
2015-08-25
US2017273988 METHODS OF TREATING LYMPHOMA USING THIENOTRIAZOLODIAZEPINE COMPOUNDS
2015-08-19
US2017095436 METHODS FOR TREATING MENDELIAN DISORDERS OF THE EPIGENETIC MACHINERY
2015-05-29
Pracinostat
Pracinostat.svg
Names
IUPAC name

(E)-3-(2-Butyl-1-(2-(diethylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide
Other names

Pracinostat
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
Properties
C20H30N4O2
Molar mass 358.49 g·mol−1
Density 1.1±0.1 g/cm3
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

//////////////Pracinostat, PCI 34051, SB939, orphan drug designation, Leukemia, acute myeloid, phase 3, helsinn

CCCCC1=NC2=C(N1CCN(CC)CC)C=CC(=C2)C=CC(=O)NO

 

“NEW DRUG APPROVALS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

Nefopam Hydrochloride, Нефопама Гидрохлорид, 塩酸ネホパム


Nefopam2DACS.svg

Nefopam

  • Molecular Formula C17H19NO
  • Average mass 253.339 Da
Cas 13669-70-0 [RN]
1H-2,5-Benzoxazocine, 3,4,5,6-tetrahydro-5-methyl-1-phenyl-
237-148-2 [EINECS]
3,4,5,6-Tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxazocine
SCX-001
Image result for Nefopam Hydrochloride, Fenazoxine
Derivative Type: Hydrochloride
CAS Registry Number: 23327-57-3
Additional Names: Fenazoxine
SCX-001,  R-738
Non-Opioid Analgesics
Wound-Healing Agents
Biocodex, 1983 pain
Нефопама Гидрохлорид
塩酸ネホパム

Nefopam, sold under the brand names Acupan among others, is a painkilling medication. It is primarily used to treat moderate, acuteor chronic pain[3]

It is believed to work in the brain and spinal cord to relieve pain. There it is believed to work via rather unique mechanisms. Firstly it increases the activity of the serotoninnorepinephrine and dopamineneurotransmitters involved in, among other things, pain signaling. Secondly, it modulates sodium and calcium channels, thereby inhibiting the release of glutamate, a key neurotransmitter involved in pain processing.[4

Medical uses

Nefopam has additional action in the prevention of shivering, which may be a side effect of other drugs used in surgery.[5] Nefopam was significantly more effective than aspirin as an analgesic in one clinical trial,[6] although with a greater incidence of side effects such as sweating, dizziness and nausea, especially at higher doses.[7][8] Nefopam is around a third to half the potency and slightly less effective as an analgesic compared to morphine,[9][10][11] or oxycodone,[12] but tends to produce fewer side effects, does not produce respiratory depression,[13] and has much less abuse potential, and so is useful either as an alternative to opioids, or as an adjunctive treatment for use alongside opioid(s) or other analgesics.[11][14] Nefopam is also used to treat severe hiccups.[15]

Contraindications

Nefopam is contraindicated in people with convulsive disorders, those that have received treatment with irreversible monoamine oxidase inhibitors such as phenelzinetranylcypromine or isocarboxazid within the past 30 days and those with myocardial infarctionpain, mostly due to a lack of safety data in these conditions.[16]

Side effects

Common side effects include nausea, nervousness, dry mouth, light-headedness and urinary retention.[16] Less common side effects include vomiting, blurred vision, drowsiness, sweating, insomnia, headache, confusion, hallucinations, tachycardia, aggravation of angina and rarely a temporary and benign pink discolouration of the skin or erythema multiforme.[16]

Overdose

Overdose and death have been reported with nefopam,[17] although these events are less common with nefopam than with opioid analgesics.[18] Overdose usually manifests with convulsionshallucinationstachycardia, and hyperdynamic circulation.[16] Treatment is usually supportive, managing cardiovascular complications with beta blockers and limiting absorption with activated charcoal.[16]

Interactions

It has additive anticholinergic and sympathomimetic effects with other agents with these properties.[16] Its use should be avoided in people receiving some types of antidepressants (tricyclic antidepressants or monoamine oxidase inhibitors) as there is the potential for serotonin syndrome or hypertensive crises to result.[16]

Pharmacology

Nefopam[19][20]
Site Ki (nM)
SERT 29
NET 33
DAT 531
5-HT2A 1,685
5-HT2B 330
5-HT2C 56

The mechanism of action of nefopam and its analgesic effects are not well understood, although inhibition of the reuptake of serotoninnorepinephrine, and to a lesser extent dopamine (that is, acting as an SNDRI) is thought to be involved.[21][4] It also reduces glutamate signaling via modulating sodium and calcium channels.[22][4]

Pharmacokinetics

The absolute bioavailability of nefopam is low.[1] It is reported to achieve therapeutic plasma concentrations between 49 and 183 nM.[20] The drug is approximately 73% protein-bound across a plasma range of 7 to 226 ng/mL (28–892 nM).[1] The metabolism of nefopam is hepatic, by Ndemethylation and via other routes.[1] Its terminal half-life is 3 to 8 hours, while that of its active metabolite, desmethylnefopam, is 10 to 15 hours.[1] It is eliminated mostly in urine, and to a lesser extent in feces.[1]

Chemistry

Nefopam is a cyclized analogue of orphenadrinediphenhydramine, and tofenacin, with each of these compounds different from one another only by the presence of one or two carbons.[23][24][25] The ring system of nefopam is a benzoxazocine system.[23][26]

Society and culture

Recreational use

Recreational use of nefopam has been reported,[17] although this is less common than with opioid analgesics.[18]

SYNTHESIS

Image result for Nefopam synthesis

PATENT

ES 8605495

The reaction of 2-benzoylbenzoic acid (I) with SOCl2 in CHCl3, benzene or DMF gives the corresponding acyl chloride (II), which is condensed with ethanolamine (III) by means of TEA in CHCl3 to yield the amide (IV). The reduction of (IV) with LiAlH4 in THF affords the diol (V), which is cyclized by means of Ts-OH in refluxing benzene to provide 1-phenyl-3,4,5,6-tetrahydro-1H-2,5-benzoxazocine (VI). Finally, this compound is methylated by means of dimethyl sulfate in refluxing benzene, or by means of formaldehyde in hot dioxane/water. Alternatively, the cyclization of N-[2-[1-[2-(chloromethyl)phenyl]-1-phenylmethoxy]ethyl]-N-methylamine (VII) by means of pyridine in refluxing acetonitrile gives also the target benzoxazocine

PATENT

KE 8201564

PATENT

ES 8104800

The reaction of 3-phenylphthalide (I) with N-methylethanolamine (II) in refluxing benzene gives N-(2-hydroxyethyl)-2-(1-hydroxy-1-phenylmethyl)-N-methylbenzamide (III), which is cyclized by means of Ts-OH in refluxing toluene to yield 5-methyl-1-phenyl-3,4,5,6-tetrahydro-1H-2,5-benzoxazocin-6-one (IV). Finally this compound is reduced with LiAlH4 in refluxing THF to afford the target benzoxazocine. In an alternative method, the reduction of 2-benzoyl-N-(2-hydroxyethyl)-N-methylbenzamide (V) by means of sodium bis(2-methoxyethoxy)aluminum hydride in refluxing toluene gives the diol (VI), which is then cyclized by means of Ts-OH in refluxing toluene, or by means of aq. 48% HBr in hot chloroform to afford the target benzoxazocine

The reaction of 2-benzoylbenzoic acid (I) with refluxing SOCl2 gives the corresponding acyl chloride (II), which is condensed with 2-(methylamino)acetic acid (III) in benzene to yield the N-(2-benzoylbenzoyl)-N-methylglycine (IV). The reduction of (IV) by means of LiAlH4 in refluxing THF affords the diol (V), which is finally cyclized by means of PPA at 80 C to provide the target benzoxazocine.

PATENT

US 4208349

PATENT

https://www.google.com/patents/EP0033585A1?cl=enFigure imgb0001

This compound is useful as an intermediate in producing the pharmacologically valuable 3,4,5,6-tetrahydro-5-methyl-l-phenyl-lH-2,5-benzoxazocine- hydrochloride, or nefopam, which is used, e.g. as a muscle relaxant, an analgesic or antidepressant drug.

Processes for producing the compound of formula I are already known. For instance, according to German Patent 1,620,198, phthalic aldehyde is used as a starting material. According to the German Patent, the phthalic aldehyde is reacted with a Grignard reagent, phenylmagnesiumbromide, and an N-substituted aminoalcohol is coupled to the reaction mixture, to produce a product of formula:

Figure imgb0002

This product is catalytically hydrogenated with the aid of Pd/C, Pt or Raney-Ni, and a product of formula I is obtained.

In another method, according to the German Patent 1,620,198, o-benzoylbenzoic acid is used as a starting material, which is converted by means of thionylchloride into an acid chloride. To this acid chloride is then coupled methylethanolamine, and N-(2-hydroxyethyl)-N-methyl-o-benzoylbenzamide is obtained as an intermediate, which is reduced using LiAlH4 and an end-product of formula I is produced.

According to United States Patent 3,487,153 o-benzoylbenzoic acid amide is used as starting material to produce the intermediate. With the aid of thionylchloride the corresponding acid chloride is formed, which is allowed to react with N-methyl-2-aminoethanol. The so-produced N-(2-hydroxyethyl)-N-methyl-o-benzoylbenzamide is reduced with LiAlH4 to 2{[N-(2-hydroxyethyl)-N-methyl)amino}-methylbenzhydrol.

According to German Offenlegungschrift 2,834,312 o-benzoylbenzoic acid is used as a starting material, which is allowed to react with phosphorus trichloride in dichloroethane. The acid chloride formed is allowed to react with triethylamine and N-methyl-2-hydroxyethyl- amine, after which N-(2-hydroxyethyl)-N-methyl-o-benzoylbenzamide is formed. This compound is treated with phosphorus trichloride (at pH=7.0) and N-(2-chloroethyl)-N-methyl-o-benzoylbenzoic amide is obtained, which is then reduced with NaBH4 in acetic acid. By these means 2-{[N-(2-hydroxyethyl)-N-methyl]-amino?-methylbenzhydrol is obtained.

According to Finnish Patent No. 54793, which corresponds to Canadian Patent 982,608, a compound of formula III is used as starting material, which is reduced with NaBH4 to a corresponding benzhydrol derivative of formula IV, which is then allowed to react with an alkylamine to an a-substituted 2-aminomethyl- benzylalcohol of formula V. The abovementioned Patent does not concern either the preparation of nefopam or its intermediates

Figure imgb0003

When reviewing the abovementioned Patents, i.e. German Patent 1,620,198 and United States Patent 3,487,153, one can observe the disadvantage that catalytic hydrogenation with palladium on charcoal, platinum or Raney-Ni, or lithium aluminium hydride are to be used to reduce the starting materials. This latter reagent is expensive and reacts with water very intensely, so that even a little humidity in the working surroundings or in the solvents can cause a fire. Explosive hydrogen is also produced by the reaction. Grignard reactions and catalytic hydrogenations are technically difficult to perform on a large scale. Moreover, the price of o-phthalic aldehyde is high.

According to the method described in German Offenlegungschrift 2,834,312 the reducing of the amide- carbonyl group with sodium borohydride in acetic acid requires, however, great additional amounts or about 2-3 equivalents of sodium borohydride. The yield of the reaction is quite poor (about 50-55%) and the reaction time is long, so the production costs become high. Moreover, the number of synthetic reaction steps is high and the use of phosphorus trichloride especially on a production scale is difficult.

In the method according to the Finnish Patent 54793, which corresponds to the Canadian Patent 982,608, a benzophenone derivative (of formula III) is reduced with NaBH4 to the corresponding benzhydrol derivative (formula IV). This compound is, however, unstable because of the methylene halogen group in o-position, especially when R1 = H in formula IV. On storing for only a short time hydrogenchloride gas is released and a very stable 5-ring ether is formed, which is useless. The use of this method on a large scale is therefore almost impossible, because the intermediate is impossible to isolate fast enough to obtain at least a reasonable amount of the end product.

The present invention provides a process for the preparation of 2-{[N-(2-hydroxyethyl)-N-methyl]-amino}-methylbenzhydrol (as such or as an acid addition salt) which comprises reacting 2-chloromethylbenzophenone with 2-methylaminoethanol to give 2-J[N-(2-hydroxyethyl)-N-methyl]-amino}-methylbenzophenone (as such or as a salt), and reducing the latter with sodium borohydride to give 2-{[N-2-(hydroxyethyl)-N-methyl)-aminol}-methylbenzhydrol (as such or as an acid addition salt). The 2-chlorobenzophenone (of formula VI) is brought to react with methylethanolamine in the presence of e.g. sodium carbonate, and 2-{[N-(2-hydroxyethyl)-N-methyl]-amino}- methylbenzophenone (of formula VII) is formed. This substance is theoreduced with sodium borohydride to 2-{(N-(hydroxyethyl)-N-methyl]-amino}-methylbenzhydrol (of formula VIII), as shown below:

Figure imgb0004

Figure imgb0005

The starting material, 2-chloromethyl benzophenone, can be produced in known manner by halogenating the corresponding 2-methylbenzophenone (Monatshefte far Chemie 99, 1990-2003, 1968) or 2-hydroxymethylbenzophenone, of which the former is commercially available and the latter can be produced in known manner from the phthalide (see British Patent 1,526,331). The compound of formula VII is new, and as such a feature of the invention.

The following Examples illustrate the invention.

EXAMPLE 1

8.50 g (0.037 mol) 2-chloromethylbenzophenone is dissolved in 40 ml ethylalcohol, and 4.0 g sodium carbonate and 2.80 g (0.037 mol) 2-methylaminoethanol are added, The mixture is boiled for 3 hours and the salts formed are filtered off from the cooled solution. A pure reaction product is obtained when the ethanol is evaporated from the solution and the product is crystallized as a hydrochloride salt from a mixture of diethylether and alcohol. The yield is 10.7 g (95 %) of 2{(N-(2-hydroxyethyl)-N-methyl]-amino}- methylbenzophenone as a crystalline powder, m.p. 135-136 C.

This compound, as the free base, shows the following N M R spectrum (in cDC13 using T M S as internal reference): 7.8 – 7.1 (aromatic), 3.5 (singlet), 3.4 (triplet), about 2.6 (singlet), 2.3 (triplet),1.9 (singlet). Its infra-red spectrum shows maxima at the following frequencies (cm-1): 680, 720, 760, 910, 1010, 1060, 1140, 1230, 1260, 1300, 1430, 1560,1580, 1640, 2760, 2920, 3030 and 3400.

EXAMPLE 2

10.0 g (0.033 mol) of the hydrochloride salt prepared in Example 1 are dissolved in a mixture comprising 15 ml water, 60 ml methanol and 3.5 g sodium hydroxide. To the mixture is added 0.65 g sodium borohydride and the solution is mixed for half an hour at room temperature.

The solution is acidified with concentrated hydrochloric acid and the methanol is evaporated in vacum. 40 ml of water is added, the pH of the water solution is adjusted with diluted sodium hydroxide solution to an alkaline reaction and the product is extracted into chloroform. The chloroform extracts are washed well with water, dried over sodium sulphate and evaporated to dryness. The product is separated by precipitating as a hydrochloride salt from a mixture of diethylether and ethylalcohol. The yield is 9.8 g (96 %) of 2-{(N-(2-hydroxyethyl)-N-methyl]-amino}- methylbenzhydrol as a crystalline powder, m.p. 128-133 C.

PATENT CITATIONS
Cited Patent Filing date Publication date Applicant Title
DE2834312A1 * Aug 4, 1978 Feb 15, 1979 Riker Laboratories Inc Verfahren zur herstellung von 2 eckige klammer auf n-(2-hydroxyaethyl)- n-niederalkylaminomethyl eckige klammer zu -benzhydrolen
ES485471A * Title not available
Reference
1 * CHEMICAL ABSTRACTS Vol. 94, No. 11, 16 March 1981 Columbus, Ohio, USA FARMA-LEPORI “2-(n-2-Hydroxyethylmethylaminomethyl)benzhydrol” page 690, column 2, Abstract No. 83757s & ES – A – 485 471.
Citing Patent Filing date Publication date Applicant Title
CN102363610A * Nov 1, 2011 Feb 29, 2012 安徽万和制药有限公司 New method for synthesizing nefopam hydrochloride
CN102924320A * Nov 15, 2012 Feb 13, 2013 南京海陵中药制药工艺技术研究有限公司 Method for preparing nefopam intermediate I
CN102924320B * Nov 15, 2012 Jan 14, 2015 南京海陵中药制药工艺技术研究有限公司 Method for preparing nefopam intermediate I

PATENT

CN 102363610

https://www.google.com/patents/CN102363610A?cl=en

Example 1:

[0043] o-benzoyl benzoate 120g, phosphorus trichloride 30g, 220g of the mixture placed in a reaction flask dichloroethane, Mh was stirred at room temperature, the supernatant was separated to give acid chloride solution A;

[0044] A solution of this acid chlorine solution to 5 ° C and at a pre-filled with N- methyl ethanolamine 44g, triethylamine 64g, 200g dichloroethane reaction flask, stirred at room temperature drop after 10h, get amine solution B;

[0045] B in the amine solution and then dropping phosphorus trichloride 33g, reaction at 65 ° C 2h, washed with water cooling, the solution was washed with a dilute solution of sodium hydroxide, to sub-alkaline layer chloride solution C.

[0046] In the reaction flask was added a certain amount of potassium borohydride; potassium borohydride to mass, and then the mixture was added 15% acetic acid and dichloroethane (solvent of acetic acid mass ratio of 1: 1); to potassium borohydride mass, and then added dropwise to obtain 45% of the chlorination reaction chloride solution C, stirring the reaction was heated to reflux for 2h, pre-reduction; with potassium borohydride mass, further addition of 10% acetic acid and dichloroacetyl alkane mixture (mass ratio of acetic acid to solvent is 1: 1), the reaction was stirred Ih; in reducing mass, and finally the mixture was added dropwise 45% obtained by chlorinating liquid the chlorination reaction C with acetic acid (chloride quality liquid C and acetic acid ratio of 1: 1), the reaction was stirred tank for the final reduction. Plus 40% hydrolyzed sodium hydroxide solution, the organic layer was separated D

[0047] The separated organic layer D was cooled to room temperature and added slowly to 65 ° C hydrobromide reaction 6h, the reaction is completed, cooled to 0 ° C, and filtered to give the cyclization product E.

[0048] The cyclization to give the reaction product E was added sodium hydroxide solution and then dropwise addition of concentrated hydrochloric acid, to obtain Nefopam.

[0049] Example 2:

[0050] o-benzoyl benzoate 120g, phosphorus trichloride 30g, 220g of the mixture placed in a reaction flask dichloroethane, Mh was stirred at room temperature, the supernatant was separated to give acid chloride solution A;

[0051] A solution of this acid chlorine solution to 5 ° C and at a pre-filled with N- methyl ethanolamine 44g, triethylamine 64g, 200g dichloroethane reaction flask, stirred at room temperature drop after 10h, get amine solution B;

[0052] B in the amine solution and then dropping phosphorus trichloride 33g, reaction at 65 ° C 2h, washed with water cooling, the solution was washed with a dilute solution of sodium hydroxide, to sub-alkaline layer chloride solution C.

[0053] In the reaction flask was added a certain amount of potassium borohydride; potassium borohydride to mass, and then the mixture was added 25% acetic acid and dichloroethane (solvent of acetic acid mass ratio of 1: 1); to potassium borohydride mass, then dropping to 50% of the chlorination reaction chloride solution C, stirring heated to reflux for 2h, pre-reduction; potassium borohydride mass, then add 20% acetic acid and dichloroethane alkane mixture (mass ratio of acetic acid to solvent is 1: 1), the reaction was stirred Ih; in reducing mass, and finally the mixture was added dropwise a 50% solution chlorination reaction C and obtained by chlorinating acetic acid (chloride quality liquid C and acetic acid ratio of 1: 1), the reaction was stirred tank for the final reduction. Plus 40% hydrolyzed sodium hydroxide solution, the organic layer was separated D

[0054] The separated organic layer D was cooled to room temperature and added slowly with stirring at 65 ° C the reaction hydrobromide 8h, the reaction is completed, cooled to 0 ° C, and filtered to give the cyclization product E.

[0055] The cyclization to give the reaction product E was added sodium hydroxide solution and then dropwise addition of concentrated hydrochloric acid, to obtain Nefopam.

[0056] The applicant stated the above embodiments of the present invention will be described in detail the process equipment and process of the present invention, but the invention is not limited to the above detailed process equipment and process, that does not mean that the present invention must rely on such details process equipment and processes to be implemented. Skill in the art should be appreciated that any improvement in the present invention, the present invention is the product of the raw materials equivalents and adding auxiliary components, choice of specific ways, and fall within the scope of the public of the scope of the present invention.

Figure CN102363610AD00051

Figure CN102363610AD00052

Figure CN102363610AD00053

PATENT CITATIONS
Cited Patent Filing date Publication date Applicant Title
EP0033585A1 * Jan 9, 1981 Aug 12, 1981 Farmos-Yhtyma Oy A process for the preparation of a benzhydrol derivative and a novel intermediate for use therein
US3978085 * Mar 7, 1975 Aug 31, 1976 Riker Laboratories, Inc. Process for benz[f]-2,5-oxazocines
US4208349 * Mar 5, 1979 Jun 17, 1980 Riker Laboratories, Inc. Process for the preparation of 2-[N-(2-hydroxyethyl)-N-lower alkylaminomethyl]benzhydrols
Reference
1 * 胡颂凯: “镇痛药盐酸苯并噁唑辛的合成“, 《医药工业》, no. 8, 28 August 1984 (1984-08-28)
Citing Patent Filing date Publication date Applicant Title
CN102924320A * Nov 15, 2012 Feb 13, 2013 南京海陵中药制药工艺技术研究有限公司 Method for preparing nefopam intermediate I

CLIP

1H NMR (400 MHz, D2O, δ/ppm): 7.36–7.25 (m, 6H, arom H), 7.21–7.18 (m, 2H, arom H), 7.12–7.10 (m, 1H, arom H), 5.89 (s, 1H, Aryl–CH–Aryl), 5.45 (d, 1H, Aryl–CH(H)–N–, J = 12.8 Hz), 4.34–4.27 (m, 1H, –CH(H)–O–), 4.21 (d, 1H, Aryl–CH(H)–N–, J = 13.2 Hz), 4.05–4.00 [m (dt), 1H, –CH(H)–O–, J = 6.8 Hz and J = 3.6 Hz], 3.30-3.23 (m, 1H, –CH(H)– N–), 3.08–3.02 [m (dt), 1H, –CH(H)–N–, J = 7.2 Hz and J = 3.6 Hz), 2.87 (s, 3H, –CH3).

13C NMR (100 MHz, D2O, δ/ppm): 142.4, 141.1, 134.3, 130.5, 129.1, 129.0 (2C), 128.7, 128.4, 127.7 (2C), 125.3, 85.3, 64.9, 58.3, 50.5, 41.6

Powder XRD spectra and data of pure API (1). ABOVE

EXPANDED VIEW

5-Methyl-1-phenyl-3,4,5,6-tetrahydro-1H-2,5-benzoxazocine Hydrochloride (1

White crystalline solid, mp 248–251 °C, [α]D20 = −0.016 (c 1.0, H2O).
1H NMR (400 MHz, D2O, δ/ppm): 7.36–7.25 (m, 6H, arom H), 7.21–7.18 (m, 2H, arom H), 7.12–7.10 (m, 1H, arom H), 5.89 (s, 1H, Aryl–CH–Aryl), 5.45 (d, 1H, Aryl–CH(H)–N–, J = 12.8 Hz), 4.34–4.27 (m, 1H, −CH(H)–O−), 4.21 (d, 1H, Aryl–CH(H)–N–, J = 13.2 Hz), 4.05–4.00 (m (dt), 1H, −CH(H)–O–, J = 6.8 Hz and J = 3.6 Hz), 3.30–3.23 (m, 1H, −CH(H)–N−), 3.08–3.02 (m (dt), 1H, −CH(H)–N–, J = 7.2 Hz and J = 3.6 Hz), 2.87 (s, 3H, −CH3).
13C NMR (100 MHz, D2O, δ/ppm): 142.4, 141.1, 134.3, 130.5, 129.1, 129.0 (2C), 128.7, 128.4, 127.7 (2C), 125.3, 85.3, 64.9, 58.3, 50.5, 41.6.
ESI-MS (m/z): 254.20 (M + H)+. CHN analysis data (wt %): Anal. Calcd for C17H19NO·HCl or C1

PAPER

Old is Gold? Nefopam Hydrochloride, a Non-opioid and Non-steroidal Analgesic Drug and Its Practical One-Pot Synthesis in a Single Solvent for Large-Scale Production

Mohan Reddy Bodireddy, Kiran Krishnaiah, Prashanth Kumar Babu, Chaithanya Bitra, Madhusudana Rao Gajula*, and Pramod Kumar*
Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, Fourth Phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore-560 105, Karnataka, India
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00228

*Tel.: 0811 0415647, ext. 245; + 91 9008448247 (mobile). E-mail: pramodkumar@microlabs.in., *E-mail: gmadhusudanrao@yahoo.com.

 Abstract Image

Nefopam hydrochloride is extensively used in most of the European countries until today as an analgesic because of its non-opiate (non-narcotic) and non-steroidal action with fewer side effects compared with opioid and other analgesics, which cause more troublesome side effects. A multikilogram synthesis of nefopam hydrochloride has been achieved in one pot using a single solvent (toluene). A ≥99.9% purity of the active pharmaceutical ingredient (API) was achieved in excellent overall yield (≥79%). The one-pot, five-step synthetic process involves formation of an acid chloride (3) from benzoylbenzoic acid (2) followed by amidation (4), reduction (5), cyclization (6), and formation of the hydrochloride salt (1). The major advantages include (i) use of a single solvent, (ii) >90% conversion in each step, (iii) a cost-effective and operationally friendly process, (iv) averting the formation of genotoxic impurities, and (v) improved overall yield (≥79%) provided by the one-pot operation. For the first time, we report the characterization data of API 1, intermediates 34, and 5, and also a possible impurity (5a).

CLIP

Nefopam

Title: Nefopam
CAS Registry Number: 13669-70-0
CAS Name: 3,4,5,6-Tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxazocine
Additional Names: 5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine
Molecular Formula: C17H19NO
Molecular Weight: 253.34
Percent Composition: C 80.60%, H 7.56%, N 5.53%, O 6.32%
Literature References: A cyclized analog of orphenadrine and diphenhydramine, q.q.v.; representative of a new class of centrally acting skeletal muscle relaxants, the benzoxazocines. Prepn: NL 6606390 (1966 to Rexall); M. W. Klohs et al., US 3830803 (1974 to Riker). Pharmacology: Bassett et al., Br. J. Pharmacol. 37, 69 (1969); Klohs et al., Arzneim.-Forsch. 22, 132 (1972). Review of pharmacology and therapeutic efficacy: R. C. Heel et al., Drugs 19, 249-267 (1980).
Derivative Type: Hydrochloride
CAS Registry Number: 23327-57-3
Additional Names: Fenazoxine
Manufacturers’ Codes: R-738
Trademarks: Acupan (3M); Ajan (3M)
Molecular Formula: C17H19NO.HCl
Molecular Weight: 289.80
Percent Composition: C 70.46%, H 6.96%, N 4.83%, O 5.52%, Cl 12.23%
Properties: mp 238-242°. LD50 in mice, rats (mg/kg): 119, 178 orally; 44.5, 28 i.v. (Baltes).
Melting point: mp 238-242°
Toxicity data: LD50 in mice, rats (mg/kg): 119, 178 orally; 44.5, 28 i.v. (Baltes)
Therap-Cat: Analgesic; antidepressant.
Keywords: Analgesic (Non-Narcotic); Antidepressant; Bicyclics.

References

  1. Jump up to:a b c d e f g h i j k l m Sanga M, Banach J, Ledvina A, Modi NB, Mittur A (2016). “Pharmacokinetics, metabolism, and excretion of nefopam, a dual reuptake inhibitor in healthy male volunteers”. Xenobiotica46 (11): 1001–16. PMID 26796604doi:10.3109/00498254.2015.1136989.
  2. Jump up^ G. Seyffart (6 December 2012). Drug Dosage in Renal Insufficiency. Springer Science & Business Media. pp. 407–. ISBN 978-94-011-3804-8.
  3. Jump up^ Brayfield, A, ed. (27 October 2016). “Nefopam hydrochloride”MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 4 September 2017.
  4. Jump up to:a b c Girard, P; Chauvin, M; Verleye, M (January 2016). “Nefopam analgesia and its role in multimodal analgesia: A review of preclinical and clinical studies.”. Clinical and Experimental Pharmacology & Physiology43 (1): 3–12. PMID 26475417doi:10.1111/1440-1681.12506.
  5. Jump up^ Alfonsi P, Adam F, Passard A, Guignard B, Sessler DI, Chauvin M (January 2004). “Nefopam, a Non-sedative Benzoxazocine Analgesic, Selectively Reduces the Shivering Threshold”Anesthesiology100 (1): 37–43. PMC 1283107Freely accessiblePMID 14695722doi:10.1097/00000542-200401000-00010.
  6. Jump up^ Cohen A, Hernandez CM (1976). “Nefopam hydrochloride: new analgesic agent”. Journal of International Medical Research4 (2): 138–43. PMID 799984.
  7. Jump up^ Wang RI, Waite EM (July 1979). “The clinical analgesic efficacy of oral nefopam hydrochloride”. Journal of Clinical Pharmacology19 (7): 395–402. PMID 479385doi:10.1002/j.1552-4604.1979.tb02498.x.
  8. Jump up^ Pillans PI, Woods DJ (September 1995). “Adverse reactions associated with nefopam”. New Zealand Medical Journal108 (1008): 382–4. PMID 7566787.
  9. Jump up^ Sunshine A, Laska E (November 1975). “Nefopam and morphine in man”. Clinical Pharmacology and Therapeutics18 (5 Pt 1): 530–4. PMID 1102231.
  10. Jump up^ Phillips G, Vickers MD (October 1979). “Nefopam in postoperative pain”. British Journal of Anaesthesia51 (10): 961–5. PMID 391253doi:10.1093/bja/51.10.961.
  11. Jump up to:a b Heel RC, Brogden RN, Pakes GE, Speight TM, Avery GS (1980). “Nefopam: a review of its pharmacological properties and therapeutic efficacy”. Drugs19 (4): 249–67. PMID 6991238doi:10.2165/00003495-198019040-00001.
  12. Jump up^ Tigerstedt I, Tammisto T, Leander P (December 1979). “Comparison of the analgesic dose-effect relationships of nefopam and oxycodone in postoperative pain”. Acta Anaesthesiologica Scandinavica23 (6): 555–60. PMID 397711doi:10.1111/j.1399-6576.1979.tb01486.x.
  13. Jump up^ Gasser JC, Bellville JW (August 1975). “Respiratory effects of nefopam”. Clinical Pharmacology and Therapeutics18 (2): 175–9. PMID 1097153.
  14. Jump up^ Kapfer B, Alfonsi P, Guignard B, Sessler DI, Chauvin M (January 2005). “Nefopam and Ketamine Comparably Enhance Postoperative Analgesia”Anesthesia and Analgesia100 (1): 169–74. PMC 1283103Freely accessiblePMID 15616073doi:10.1213/01.ANE.0000138037.19757.ED.
  15. Jump up^ Bilotta, F; Rosa, G (December 2000). “Nefopam for severe hiccups.”. The New England Journal of Medicine343 (26): 1973–4. PMID 11186682doi:10.1056/nejm200012283432619.
  16. Jump up to:a b c d e f g “Data Sheet ACUPAN™ Nefopam hydrochloride 30 mg tablets 20 mg intramuscular injection” (PDF). Medsafe New Zealand. iNova Pharmaceuticals (New Zealand) Limited. 3 September 2007. Retrieved 10 March 2014.
  17. Jump up to:a b Bismuth, C; Fournier, PE; Bavoux, E; Husson, O; Lafon, D (September 1987). “[Chronic abuse of the analgesic nefopam (Acupan)].”. Journal de Toxicologie Clinique et Experimentale (in French). 7 (5): 343–6. PMID 3448182.
  18. Jump up to:a b Tracqui, A; Berthelon, L; Ludes, B (May 2002). “Fatal overdosage with nefopam (Acupan).” (PDF). Journal of Analytical Toxicology26 (4): 239–43. PMID 12054367doi:10.1093/jat/26.4.239.
  19. Jump up^ Roth, BL; Driscol, J. “PDSP Ki Database”Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  20. Jump up to:a b Gregori-Puigjané, E.; Setola, V; Hert, J; Crews, BA; Irwin, JJ; Lounkine, E; Marnett, L; Roth, BL; Shoichet, BK (18 June 2012). “Identifying mechanism-of-action targets for drugs and probes” (PDF). Proceedings of the National Academy of Sciences109 (28): 11178–11183. PMC 3396511Freely accessiblePMID 22711801doi:10.1073/pnas.1204524109.
  21. Jump up^ Bausch & Lomb (NZ) Ltd (17 May 2017). “NEW ZEALAND DATA SHEET ACUPAN(TM)” (PDF). Medsafe. New Zealand The Ministry of Health. Retrieved 4 September 2017.
  22. Jump up^ Kim, KH; Abdi, S (April 2014). “Rediscovery of nefopam for the treatment of neuropathic pain.”The Korean Journal of Pain27 (2): 103–11. PMC 3990817Freely accessiblePMID 24748937doi:10.3344/kjp.2014.27.2.103.
  23. Jump up to:a b Camille Georges Wermuth; David Aldous; Pierre Raboisson; Didier Rognan (1 July 2015). The Practice of Medicinal Chemistry. Elsevier Science. pp. 250–251. ISBN 978-0-12-417213-5.
  24. Jump up^ Walter Sneader (23 June 2005). Drug Discovery: A History. John Wiley & Sons. pp. 405–. ISBN 978-0-471-89979-2.
  25. Jump up^ Hugo Kubinyi; Gerhard MÃ1⁄4ller (6 March 2006). Chemogenomics in Drug Discovery: A Medicinal Chemistry Perspective. John Wiley & Sons. pp. 54–. ISBN 978-3-527-60402-9.
  26. Jump up^ Amy Cruz (2014). Therapeutic Hypothermia. CRC Press. pp. 176–. GGKEY:R0AP2X4GZYF.
Nefopam
Nefopam2DACS.svg
Nefopam ball-and-stick model.png
Clinical data
Trade names Acupan
AHFS/Drugs.com International Drug Names
Routes of
administration
Oralintramuscularintravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability Low[1]
Protein binding 70–75% (mean 73%)[1][2]
Metabolism Liver (Ndemethylation, others)[1]
Metabolites Desmethylnefopam, others[1]
Biological half-life Nefopam: 3–8 hours[1]
Desmethylnefopam: 10–15 hours[1]
Excretion Urine: 79.3%[1]
Feces: 13.4%[1]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ECHA InfoCard 100.033.757
Chemical and physical data
Formula C17H19NO
Molar mass 253.34 g/mol
3D model (JSmol)

////////////Nefopam Hydrochloride, Fenazoxine, Нефопама Гидрохлорид, 塩酸ネホパム

CN1CCOC(C2=CC=CC=C2C1)C3=CC=CC=C3

DISCLAIMER

“DRUG APPROVALS INT” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

Ubrogepant, MK-1602


imgUbrogepant.pngImage result for UbrogepantImage result for Ubrogepant

Ubrogepant, MK-1602

(S)-N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide

(3’S)-N-[(3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl]-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide
(6S)-N-[(3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-3-piperidinyl]-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide
Spiro[6H-cyclopenta[b]pyridine-6,3′-[3H]pyrrolo[2,3-b]pyridine]-3-carboxamide, 1′,2′,5,7-tetrahydro-N-[(3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-3-piperidinyl]-2′-oxo-, (6S)-

CAS: 1374248-77-7
Chemical Formula: C29H26F3N5O3

Molecular Weight: 549.5542

UNII-AD0O8X2QJR

CAS TRIHYDRATE 1488325-95-6

CAS MONOHYDRATE 1488327-13-4

  • Originator Merck & Co
  • Class Amides; Antimigraines; Fluorine compounds; Small molecules; Spiro compounds
  • Mechanism of Action Calcitonin gene-related peptide receptor antagonists
  • Phase III Migraine, Allergan

Most Recent Events

  • 01 Sep 2016 Allergan initiates a phase III extension trial for Migraine in USA (PO, Tablet) (NCT02873221)
  • 12 Aug 2016 Allergan plans a phase III trial for Migraine in USA (PO) (NCT02867709)
  • 01 Aug 2016 Allergan initiates a phase III trial for Migraine in USA (PO) (NCT02867709)

Image result for Ubrogepant

Image result for Ubrogepant

Process for making piperidinone carboxamide indane and azainane derivatives, which are CGRP receptor antagonists useful for the treatment of migraine. This class of compounds is described in U.S. Patent Application Nos. 13/293,166 filed November 10, 2011 , 13/293, 177 filed November 10, 2011 and 13/293,186 filed November 10, 2011, and PCT International Application Nos. PCT/US11/60081 filed November 10, 2011 and PCT/US 11/60083 filed November 10, 2011.

CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messehger RNA and is widely distributed in the central and peripheral nervous system. CGRP is localized predominantly in sensory afferent and central neurons and mediates several biological actions, including vasodilation. CGRP is expressed in alpha- and beta-forms that vary by one and three amino acids in the rat and human, respectively. CGRP-alpha and CGRP-beta display similar biological properties. When released from the cell, CGRP initiates its biological responses by binding to specific cell surface receptors that are predominantly coupled to the activation of adenylyl cyclase. CGRP receptors have been identified and pharmacologically evaluated in several tissues and cells, including those of brain, cardiovascular, endothelial, and smooth muscle origin.

Based on pharmacological properties, these receptors are divided into at least two subtypes, denoted CGRPi and CGRP2. Human oc-CGRP-(8-37), a fragment of CGRP that lacks seven N-terminal amino acid residues, is a selective antagonist of CGRP l, whereas the linear analogue of CGRP, diacetoamido methyl cysteine CGRP ([Cys(ACM)2,7]CGRP), is a selective agonist of CGRP2. CGRP is a potent neuromodulator that has been implicated in the pathology of cerebrovascular disorders such as migraine and cluster headache. In clinical studies, elevated levels of CGRP in the jugular vein were found to occur during migraine attacks (Goadsby et al., Ann. Neurol., 1990, 28, 183-187), salivary levels of CGRP are elevated in migraine subjects between attacks (Bellamy et al., Headache, 2006, 46, 24-33), and CGRP itself has been shown to trigger migrainous headache (Lassen et al., Cephalalgia, 2002, 22, 54-61). In clinical trials, the CGRP antagonist BIBN4096BS has been shown to be effective in treating acute attacks of migraine (Olesen et al., New Engl. J. Med., 2004, 350, 1104-1110) and was able to prevent headache induced by CGRP infusion in a control group (Petersen et al., Clin. Pharmacol. Ther., 2005, 77, 202-213).

CGRP-mediated activation of the trigeminovascular system may play a key role in migraine pathogenesis. Additionally, CGRP activates receptors on the smooth muscle of intracranial vessels, leading to increased vasodilation, which is thought to contribute to headache pain during migraine attacks (Lance, Headache Pathogenesis: Monoamines, Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers, 1997, 3-9). The middle meningeal artery, the principle artery in the dura mater, is innervated by sensory fibers from the trigeminal ganglion which contain several neuropeptides, including CGRP. Trigeminal ganglion stimulation in the cat resulted in increased levels of CGRP, and in humans, activation of the trigeminal system caused facial flushing and increased levels of CGRP in the external jugular vein (Goadsby et al, Ann. Neurol., 1988, 23, 193-196). Electrical stimulation of the dura mater in rats increased the diameter of the middle meningeal artery, an effect that was blocked by prior administration of CGRP(8-37), a peptide CGRP antagonist (Williamson et al., Cephalalgia, 1997, 17, 525-531). Trigeminal ganglion stimulation increased facial blood flow in the rat, which was inhibited by CGRP(8-37) (Escott et al., Brain Res. 1995, 669, 93-99). Electrical stimulation of the trigeminal ganglion in marmoset produced an increase in facial blood flow that could be blocked by the non-peptide CGRP antagonist BIBN4096BS (Doods et al., Br. J.Pharmacol., 2000, 129, 420-423). Thus the vascular effects of CGRP may be attenuated, prevented or reversed by a CGRP antagonist.

CGRP-mediated vasodilation of rat middle meningeal artery was shown to sensitize neurons of the trigeminal nucleus caudalis (Williamson et al., The CGRP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, and Adrenomedullin, Landes Bioscience, 2000, 245-247). Similarly, distention of dural blood vessels during migraine headache may sensitize trigeminal neurons. Some of the associated symptoms of migraine, including extracranial pain and facial allodynia, may be the result of sensitized trigeminal neurons (Burstein et al., Ann. Neurol. 2000, 47, 614-624). A CGRP antagonist may be beneficial in attenuating, preventing or reversing the effects of neuronal sensitization.

The ability of the compounds to act as CGRP antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans. Such disorders include migraine and cluster headache (Doods, Curr Opin Inves Drugs, 2001, 2 (9), 1261-1268; Edvinsson et al., Cephalalgia, 1994, 14, 320-327); chronic tension type headache (Ashina et al., Neurology, 2000, 14, 1335-1340); pain (Yu et al., Eur. J. Pharm., 1998, 347, 275-282); chronic pain (Hulsebosch et al., Pain, 2000, 86, 163-175);neurogenic inflammation and inflammatory pain (Holzer, Neurosci., 1988, 24, 739-768; Delay-Goyet et al., Acta Physiol. Scanda. 1992, 146, 537-538; Salmon et al., Nature Neurosci., 2001, 4(4), 357-358); eye pain (May et al. Cephalalgia, 2002, 22, 195-196), tooth pain (Awawdeh et al., Int. Endocrin. J., 2002, 35, 30-36), non-insulin dependent diabetes mellitus (Molina et al., Diabetes, 1990, 39, 260-265); vascular disorders; inflammation (Zhang et al, Pain, 2001, 89, 265), arthritis, bronchial hyperreactivity, asthma, (Foster et al., Ann. NY Acad. Sci., 1992, 657, 397-404; Schini et al., Am. J. Physiol., 1994, 267, H2483-H2490; Zheng et al., J. Virol., 1993, 67, 5786-5791); shock, sepsis (Beer et al., Crit. Care Med., 2002, 30 (8), 1794-1798); opiate withdrawal syndrome (Salmon et al., Nature Neurosci., 2001, 4(4), 357-358); morphine tolerance (Menard et al., J. Neurosci., 1996, 16 (7), 2342-2351); hot flashes in men and women (Chen et al., Lancet, 1993, 342, 49; Spetz et al., J. Urology, 2001, 166, 1720-1723); allergic dermatitis (Wallengren, Contact Dermatitis, 2000, 43 (3), 137-143); psoriasis; encephalitis, brain trauma, ischaemia, stroke, epilepsy, and neurodegenerative diseases (Rohrenbeck et al., Neurobiol. of Disease 1999, 6, 15-34); skin diseases (Geppetti and Holzer, Eds., Neurogenic Inflammation, 1996, CRC Press, Boca Raton, FL), neurogenic cutaneous redness, skin rosaceousness and erythema; tinnitus (Herzog et al., J. Membrane Biology, 2002, 189(3), 225); inflammatory bowel disease, irritable bowel syndrome, (Hoffman et al. Scandinavian Journal of Gastroenterology,2002, 37(4) 414-422) and cystitis. Of particular importance is the acute or prophylactic treatment of headache, including migraine and cluster headache.

Ubrogepant (MK-1602), an oral calcitonin gene-related peptide (CGRP) antagonist, is in phase III clinical development at Allergan for the acute treatment of migraine attacks.

In August 2015, the product was licensed to Allergan by Merck, for the development and marketing worldwide for the treatment of migraine.

Synthesis

WO 2013138418

CONTD………..

CONTD……….

Inventors Ian M. BellMark E. FraleySteven N. GallicchioAnthony GinnettiHelen J. MitchellDaniel V. PaoneDonnette D. StaasHeather E. StevensonCheng WangC. Blair Zartman
Applicant Merck Sharp & Dohme Corp.

Ian Bell

Ian Bell

Principal Scientist at Merck
Merck
Mark Fraley

Mark Fraley

Principal Scientist, Merck
Steven Gallicchio

Steven Gallicchio

Patent

 WO 2012064910

EXAMPLE 1

Figure imgf000072_0002

(65yN-[(3£5£ )-6-Methyl-2-oxo-5-pheny

i’,2′,5 J-tetrahvdrospiro[cyclopenta|^lpyridine-6,3′-pyrroloj2,3-¾lpyridine1-3-carboxamide (Benzotriazol- 1 -yloxy)tr/i,(dimethylamino)phosphonium hexafluorophosphate (1.89 g, 4.28 mmol) was added to a solution of (6S -2′-oxo- ,2,,5,7- tetrahydrospiro[cyclopenta[&]pyridine-6,3′-pyrrolo[2,3-&]pyridine]-3-carboxylic acid (described in Intermediate 1) (1.10 g, 3.92 mmol), (3JS’,55′,6J?)-3-amino-6-methyl~5~phenyl-l-(2,2,2- trifluoroethyl)piperidin-2-one hydrochloride (described in Intermediate 4) (1.15 g, 3.56 mmol), and NjiV-diisopropylethylamine (3.1 1 m.L, 17.8 mmol) in DMF (40 mL), and the resulting mixture was stirred at 23 °C for 3 h. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate solution (200 mL) and ethyl actetate (3 χ 200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with hexanes initially, then grading to 100% EtOAc before stepping to 5% MeOH in EtOAc to afford the title compound as an amorphous solid, which was further purified by the following crystallization procedure. A solution of the amorphous product in a minimal amount of methanol required for dissolution was diluted with 10 volumes water, and the resulting slurry was seeded with crystalline product and stirred at 23 °C for 4 h. The solids were filtered, washed with water, and dried under a stream of nitrogen to give the title compound as a crystalline solid. HRMS: m/z = 550.2068, calculated m/z – 550.2061 for C29H27F3N503. lH NMR (500 MHz, CDC13) δ 8.91 (s, 1H), 8.70 (s, 1H), 8.17 (dd, 1H, J- 5.4, 1.5 Hz), 8.04 (s5 1H), 7.37 (m, 3H), 7.29 (t, 1H, J= 7.3 Hz), 7.21 (d, 2H, J= 7.3 Hz), 7.13 (dd, 1H, J = 7.3, 1.2 Hz), 6.89 (dd, 1H, J = 7.3, 5.4 Hz), 4.99- 4.90 (m, 1H), 4.53 (dt, 1H, J= 10.7, 6.6 Hz), 3.94 (p, 1H, J = 5.9 Hz), 3.78 (d, 1H, J = 17.1 Hz), 3.67 (d, 1H, J- 16.4 Hz), 3.65 (m, 1H), 3.34-3.26 (m, 1H), 3.28 (d, 1H, J- 17.1 Hz), 3.17 (d, 1H, J = 16.6 Hz), 2.79 (m, 1H), 2.58 (q, 1H, J – 12.7 Hz), 1.07 (d, 3H, J= 6.6 Hz).

PATENT

WO 2013169348

(5)-N-((3^,5^,6i?)-6-Methyl-2-oxo-5-phenyl 2,2,2-trifluoroethyl)piperidine-3-yl)-2*-oxo- l\2 5,7-tetrahydrospiro[cyclopenta[¾]pyridine-6,3′-pyrrolo[2,3-¾]pyridine]-3-carboxam trihydrate (15)

Figure imgf000054_0001

To a suspension of 11 (465 g, 96% wt, 0.99 mol) in iPAc (4.6 L) was added 5% aqueous K3PO4 (4.6 L). The mixture was stirred for 5 min. The organic layer was separated and washed with 5%> aqueous K3PO4 (4.6 L) twice and concentrated in vacuo and dissolved in acetonitrile (1.8 L).

To another flask was added 14 (303 g, 91.4 wt%>), acetonitrile (1.8 L) and water (1.8 L) followed by 10 N NaOH (99 mL). The resulting solution was stirred for 5 min at room temperature and the chiral amine solution made above was charged to the mixture and the container was rinsed with acetonitrile (900 mL). HOBT hydrate (164 g) was charged followed by EDC hydrochloride (283 g). The mixture was agitated at room temperature for 2.5 h. To the mixture was added iPAc (4.6 L) and organic layer was separated, washed with 5%> aqueous NaHC03 (2.3 L) followed by a mixture of 15%> aqueous citric acid (3.2 L) and saturated aqueous NaCl (1.2 L). The resulting organic layer was finally washed with 5%> aqueous NaHC03 (2.3 L). The organic solution was concentrated below 50 °C and dissolved in methanol (2.3 L). The solution was slowly added to a mixture of water (6 L) and methanol (600 mL) with ~ 2 g of seed crystal. And the resulting suspension was stirred overnight at room temperature. Crystals were filtered, rinsed with water/methanol (4 L, 10 : 1), and dried under nitrogen flow at room temperature to provide 15 (576 g, 97 % yield) as trihydrate.

Ή NMR (500 MHz, CDCI3): δ 10.15 (br s, 1 H), 8.91 (br s, 1 H), 8.21 (d, J= 6.0 Hz, 1 H), 8.16 (dd, J= 5.3, 1.5 Hz, 1 H), 8.01 (br s, 1 H), 7.39-7.33 (m, 2 H), 7.31-7.25 (m, 1 H), 7.22-7.20 (m, 2 H), 7.17 (dd, J= 7.4, 1.6 Hz, 1 H), 6.88 (dd, J= 7.4, 5.3 Hz, 1 H), 4.94 (dq, J= 9.3, 7.6 Hz, 1 H), 4.45-4.37 (m, 1 H), 3.94-3.87 (m, 1 H), 3.72 (d, J= 17.2 Hz, 1 H), 3.63-3.56 (m, 2 H), 3.38-3.26 (m, 1 H), 3.24 (d, J= 17.3 Hz, 1 H), 3.13 (d, J= 16.5 Hz, 1 H), 2.78 (q, J= 12.5 Hz, 1 H), 2.62-2.56 (m, 1 H), 1.11 (d, J= 6.5 Hz, 3 H); 13C NMR (126 MHz, CD3CN): δ 181.42, 170.63, 166.73, 166.63, 156.90, 148.55, 148.08, 141.74, 135.77, 132.08, 131.09, 130.08, 129.66, 129.56, 128.78, 128.07, 126.25 (q, J= 280.1 Hz), 119.41, 60.14, 53.07, 52.00, 46.41 (q, J= 33.3 Hz), 45.18, 42.80, 41.72, 27.79, 13.46; HRMS m/z: calcd for C29H26F3N503 550.2061 (M+H): found 550.2059.

Alternative procedure for 15:

Figure imgf000055_0001

13

To a suspension of 13 (10 g, 98 wt%, 23.2 mmol) in MTBE (70 mL) was added 0.6 N HCI (42 mL). The organic layer was separated and extracted with another 0.6 N HCI (8 mL). The combined aqueous solution was washed with MTBE (10 mL x3). To the resulting aqueous solution was added acetonitrile (35 mL) and 14 (6.66 g, 99 wt%). To the resulting suspension was neutralized with 29 % NaOH solution to pH 6. HOPO (0.26 g) was added followed by EDC hydrochloride (5.34 g). The mixture was stirred at room temperature for 6-12 h until the conversion was complete (>99%). Ethanol (30 ml) was added and the mixture was heated to 35 °C. The resulting solution was added over 2 h to another three neck flask containing ethanol (10 mL), water (30 mL) and 15 seeds (0.4 g). Simultaneously, water (70 mL) was also added to the mixture. The suspension was then cooled to 5 °C over 30 min and filtered. The cake was washed with a mixture of ethanol/water (1 :3, 40 mL). The cake was dried in a vacuum oven at 40 °C to give 15 trihydrate (13.7 g, 95%) as crystals.

PATENT

WO 2013138418

PATENT

US 9174989

CLIP

Practical Asymmetric Synthesis of a Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist Ubrogepant

 Department of Process Chemistry, MRL, 126 East Lincoln Avenues, Rahway, New Jersey 07065, United States
 Department of Process Chemistry, MSD Research Laboratories, Hertford Road, Hoddesdon, Hertford, Hertfordshire EN11 9BU, United Kingdom
§ Department of Process Chemistry, MRL, 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States
 Codexis, Inc., 200 Penobscot Drive, Redwood City, California 94063, United States
 Shanghai SynTheAll Pharmaceutical Co. Ltd., 9 Yuegong Road, Jinshan District, Shanghai, 201507, China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00293

Abstract

Abstract Image

The development of a scalable asymmetric route to a new calcitonin gene-related peptide (CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the intermediates were accessed through novel chemistry. Chiral lactam 2 was prepared by an enzyme mediated dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted in an optimized transaminase providing the desired configuration in >60:1 syn/anti. The final chiral center was set via a crystallization induced diastereomeric transformation. The asymmetric spirocyclization to form the second fragment, chiral spiro acid intermediate 3, was catalyzed by a novel doubly quaternized phase transfer catalyst and provided optically pure material on isolation. With the two fragments in hand, development of their final union by amide bond formation and subsequent direct isolation is described. The described chemistry has been used to deliver over 100 kg of our desired target, ubrogepant.

(S)-N-((3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide Trihydrate (1)

………..of white solids as 1 trihydrate (95%).
1H NMR (500 MHz, CDCl3): δ 10.15 (br s, 1H); 8.91 (br s, 1H); 8.21 (d, J = 6.0 Hz, 1H); 8.16 (dd, J = 5.3, 1.5 Hz, 1H); 8.01 (br s, 1H); 7.39–7.33 (m, 2H); 7.31–7.25 (m, 1H); 7.22–7.20 (m, 2H); 7.17 (dd, J = 7.4, 1.6 Hz, 1H); 6.88 (dd, J = 7.4, 5.3 Hz, 1H); 4.94 (dq, J = 9.3, 7.6 Hz, 1H); 4.45–4.37 (m, 1H); 3.94–3.87 (m, 1H); 3.72 (d, J = 17.2 Hz, 1H); 3.63–3.56 (m, 2H); 3.38–3.26 (m, 1H); 3.24 (d, J = 17.3 Hz, 1H); 3.13 (d, J = 16.5 Hz, 1H); 2.78 (q, J = 12.5 Hz, 1H); 2.62–2.56 (m, 1H); 1.11 (d, J = 6.5 Hz, 3H);
13C NMR (126 MHz, CDCl3): δ 181.4, 170.6, 166.7, 166.6, 156.9, 148.6, 148.1, 141.7, 135.8, 132.1, 131.1, 130.1, 129.7, 129.6, 128.8, 128.1, 126.3 (q, J = 280.1 Hz), 119.4, 60.1, 53.1, 52.0, 46.4 (q, J = 33.3 Hz), 45.2, 42.8, 41.7, 27.8, 13.5;
HRMS m/z: calcd for C29H27F3N5O3: 550.2061 (M + H); found: 550.2059.

US7390798 * Feb 9, 2005 Jun 24, 2008 Merck & Co., Inc. Carboxamide spirolactam CGRP receptor antagonists
US20090054408 * Sep 6, 2005 Feb 26, 2009 Bell Ian M Monocyclic anilide spirolactam cgrp receptor antagonists
US20100160334 * Mar 5, 2010 Jun 24, 2010 Bell Ian M Tricyclic anilide spirolactam cgrp receptor antagonists
US20100179166 * Jun 2, 2008 Jul 15, 2010 Ian Bell Carboxamide heterocyclic cgrp receptor antagonists
US20120122899 * Nov 10, 2011 May 17, 2012 Merck Sharp & Dohme Corp. Piperidinone carboxamide azaindane cgrp receptor antagonists
US20120122900 * Nov 10, 2011 May 17, 2012 Merck Sharp & Dohme Corp. Piperidinone carboxamide azaindane cgrp receptor antagonists
US20120122911 * Nov 10, 2011 May 17, 2012 Merck Sharp & Dohme Corp. Piperidinone carboxamide azaindane cgrp receptor antagonists
Reference
1 * See also references of EP2849568A4
Citing Patent Filing date Publication date Applicant Title
CN105037210A * May 27, 2015 Nov 11, 2015 江苏大学 Alpha,beta-dehydrogenated-alpha-amino acid synthesis method
US9688660 Oct 28, 2016 Jun 27, 2017 Heptares Therapeutics Limited CGRP receptor antagonists
Patent ID

Patent Title

Submitted Date

Granted Date

US2016346198 NOVEL DISINTEGRATION SYSTEMS FOR PHARMACEUTICAL DOSAGE FORMS
2015-02-04
US2016346214 TABLET FORMULATION FOR CGRP ACTIVE COMPOUNDS
2015-01-30
Patent ID

Patent Title

Submitted Date

Granted Date

US2015112067 PROCESS FOR MAKING CGRP RECEPTOR ANTAGONISTS
2013-03-13
2015-04-23
US9174989 Process for making CGRP receptor antagonists
2013-03-12
2015-11-03
US2016220552 FORMULATIONS FOR CGRP RECEPTOR ANTAGONISTS
2014-09-11
2016-08-04
US2016130273 Process for Making CGRP Receptor Antagonists
2015-09-15
2016-05-12
US2017027925 PIPERIDINONE CARBOXAMIDE AZAINDANE CGRP RECEPTOR ANTAGONISTS
2016-10-14
Patent ID

Patent Title

Submitted Date

Granted Date

US8754096 Piperidinone carboxamide azaindane CGRP receptor antagonists
2011-11-10
2014-06-17
US8912210 Piperidinone carboxamide azaindane CGRP receptor antagonists
2011-11-10
2014-12-16
US8481556 Piperidinone carboxamide azaindane CGRP receptor antagonists
2011-11-10
2013-07-09
US9499545 PIPERIDINONE CARBOXAMIDE AZAINDANE CGRP RECEPTOR ANTAGONISTS
2014-09-12
2015-01-01
US9487523 PROCESS FOR MAKING CGRP RECEPTOR ANTAGONISTS
2013-09-19
2015-02-05

REFERENCES

1: Voss T, Lipton RB, Dodick DW, Dupre N, Ge JY, Bachman R, Assaid C, Aurora SK, Michelson D. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia. 2016 Aug;36(9):887-98. doi: 10.1177/0333102416653233. PubMed PMID: 27269043.

/////////////ubrogepant, MK-1602, Phase III,  Migraine

 O=C(C1=CN=C2C(C[C@@]3(C4=CC=CN=C4NC3=O)C2)=C1)N[C@@H]5C(N(CC(F)(F)F)[C@H](C)[C@H](C6=CC=CC=C6)C5)=O

FDA approves first treatment Zelboraf (vemurafenib)for certain patients with Erdheim-Chester Disease, a rare blood cancer


FDA approves first treatment for certain patients with Erdheim-Chester Disease, a rare blood cancer

The U.S. Food and Drug Administration today expanded the approval of Zelboraf (vemurafenib) to include the treatment of certain adult patients with Erdheim-Chester Disease (ECD), a rare cancer of the blood. Zelboraf is indicated to treat patients whose cancer cells have a specific genetic mutation known as BRAF V600. This is the first FDA-approved treatment for ECD. Continue reading.

//////Zelboraf, vemurafenib, fda 2017, Erdheim-Chester Disease,

 

Vemurafenib
Vemurafenib structure.svg
Vemurafenib ball-and-stick model.png
Clinical data
Pronunciation /ˌvɛməˈræfənɪb/ VEM-ə-RAF-ə-nib
Trade names Zelboraf
Synonyms PLX4032, RG7204, RO5185426
AHFS/Drugs.com Monograph
MedlinePlus a612009
License data
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Routes of
administration
By mouth (tablets)
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
ECHA InfoCard 100.226.540
Chemical and physical data
Formula C23H18ClF2N3O3S
Molar mass 489.92 g/mol
3D model (JSmol)

Vemurafenib (INN, marketed as Zelboraf) is a B-Raf enzyme inhibitor developed by Plexxikon (now part of Daiichi-Sankyo) and Genentech for the treatment of late-stage melanoma.[1] The name “vemurafenib” comes from V600E mutated BRAF inhibition.

Approvals

Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011,[2] making it the first drug designed using fragment-based lead discovery to gain regulatory approval.[3]

Vemurafenib later received Health Canada approval on February 15, 2012.[4]

On February 20, 2012, the European Commission approved vemurafenib as a monotherapy for the treatment of adult patients with BRAF V600E mutation positive unresectable or metastatic melanoma, the most aggressive form of skin cancer.[5]

Mechanism of action

Vemurafenib causes programmed cell death in melanoma cell lines.[6] Vemurafenib interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway − if the B-Raf has the common V600E mutation.

Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid).[7] About 60% of melanomas have this mutation. It also has efficacy against the rarer BRAF V600K mutation. Melanoma cells without these mutations are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases.[8][9]

Resistance

Three mechanisms of resistance to vemurafenib (covering 40% of cases) have been discovered:

Clinical trials

In a phase I clinical study, vemurafenib (then known as PLX4032) was able to reduce numbers of cancer cells in over half of a group of 16 patients with advanced melanoma. The treated group had a median increased survival time of 6 months over the control group.[13][14][15][16]

A second phase I study, in patients with a V600E mutation in B-Raf, ~80% showed partial to complete regression. The regression lasted from 2 to 18 months.[17]

In early 2010 a Phase I trial[18] for solid tumors (including colorectal cancer), and a phase II study (for metastatic melanoma) were ongoing.[19]

A phase III trial (vs dacarbazine) in patients with previously untreated metastatic melanoma showed an improved rates of overall and progression-free survival.[20]

In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study.[21] The BRIM3 trial reported good updated results in 2012.[22]

Further trials are planned including a trial of vemurafenib co-administered with GDC-0973 (cobimetinib), a MEK-inhibitor.[21] After good results in 2014 the combination was submitted to the EC and FDA for marketing approval.[23]

In January 2015 trial results compared vemurafenib with the combination of dabrafenib and trametinib for metastatic melanoma.[24]

Side effects

At the maximum tolerated dose (MTD) of 960 mg twice a day 31% of patients get skin lesions that may need surgical removal.[1] The BRIM-2 trial investigated 132 patients; the most common adverse events were arthralgia in 58% of patients, skin rash in 52%, and photosensitivity in 52%. In order to better manage side effects some form of dose modification was necessary in 45% of patients. The median daily dose was 1750 mg, 91% of the MTD.[25]

A trial combining vemurafenib and ipilimumab was stopped in April 2013 because of signs of liver toxicity.[26]

References

  1. Jump up to:a b c PDB3OG7​; Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G, et al. (September 2010). “Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma”Nature467 (7315): 596–599. doi:10.1038/nature09454PMC 2948082Freely accessiblePMID 20823850.
  2. Jump up^ “FDA Approves Zelboraf (Vemurafenib) and Companion Diagnostic for BRAF Mutation-Positive Metastatic Melanoma, a Deadly Form of Skin Cancer” (Press release). Genentech. Retrieved 2011-08-17.
  3. Jump up^ Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, Hirth P (November 2012). “Vemurafenib: the first drug approved for BRAF-mutant cancer”. Nat Rev Drug Discov11 (11): 873–86. doi:10.1038/nrd3847PMID 23060265.
  4. Jump up^ Notice of Decision for ZELBORAF
  5. Jump up^ Hofland P (February 20, 2012). “First Personalized Cancer Medicine Allows Patients with Deadly Form of Metastatic Melanoma to Live Significantly Longer”Onco’Zine. The International Cancer Network.
  6. Jump up^ Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C (May 2008). “BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells”. Mol. Cancer Res6 (5): 751–9. doi:10.1158/1541-7786.MCR-07-2001PMID 18458053.
  7. Jump up^ Maverakis E, Cornelius LA, Bowen GM, Phan T, Patel FB, Fitzmaurice S, He Y, Burrall B, Duong C, Kloxin AM, Sultani H, Wilken R, Martinez SR, Patel F (2015). “Metastatic melanoma – a review of current and future treatment options”. Acta Derm Venereol95 (5): 516–524. doi:10.2340/00015555-2035PMID 25520039.
  8. Jump up^ Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, Morales T, Aliagas I, Liu B, Sideris S, Hoeflich KP, Jaiswal BS, Seshagiri S, Koeppen H, Belvin M, Friedman LS, Malek S (February 2010). “RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth”. Nature464 (7287): 431–5. doi:10.1038/nature08833PMID 20130576.
  9. Jump up^ Halaban R, Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S, Krauthammer M, McCusker JP, Kluger Y, Sznol M (February 2010). “PLX4032, a Selective BRAF(V600E) Kinase Inhibitor, Activates the ERK Pathway and Enhances Cell Migration and Proliferation of BRAF(WT) Melanoma Cells”Pigment Cell Melanoma Res23(2): 190–200. doi:10.1111/j.1755-148X.2010.00685.xPMC 2848976Freely accessiblePMID 20149136.
  10. Jump up^ Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS (November 2010). “Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation”Nature468 (7326): 973–977. doi:10.1038/nature09626PMC 3143360Freely accessiblePMID 21107323Lay summary – Genetic Engineering & Biotechnology News.
  11. Jump up^ Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB, Ribas A, Lo RS, Flaherty KT, Ogino S, Wargo JA, Golub TR (July 2012). “Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion”Nature487 (7408): 500–4. doi:10.1038/nature11183PMC 3711467Freely accessiblePMID 22763439.
  12. Jump up^ Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, Peng J, Lin E, Wang Y, Sosman J, Ribas A, Li J, Moffat J, Sutherlin DP, Koeppen H, Merchant M, Neve R, Settleman J (July 2012). “Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors”Nature487 (7408): 505–9. doi:10.1038/nature11249PMC 3724525Freely accessiblePMID 22763448.
  13. Jump up^ “Drug hope for advanced melanoma”. BBC News. 2009-06-02. Retrieved 2009-06-07.
  14. Jump up^ Harmon, Amy (2010-02-21). “A Roller Coaster Chase for a Cure”The New York Times.
  15. Jump up^ Garber K (December 2009). “Melanoma drug vindicates targeted approach”. Science326 (5960): 1619. doi:10.1126/science.326.5960.1619PMID 20019269.
  16. Jump up^ Flaherty K. “Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer”2009 ASCO Annual Meeting Abstract, J Clin Oncol 27:15s, 2009 (suppl; abstr 9000).
  17. Jump up^ Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (August 2010). “Inhibition of mutated, activated BRAF in metastatic melanoma”. N. Engl. J. Med363 (9): 809–19. doi:10.1056/NEJMoa1002011PMID 20818844Lay summary – Corante: In the Pipeline.
  18. Jump up^ “Safety Study of PLX4032 in Patients With Solid Tumors”. ClinicalTrials.gov.
  19. Jump up^ “A Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma”. ClinicalTrials.gov. 2010-02-15.
  20. Jump up^ “Plexxikon Announces First Patient Dosed in Phase 3 Trial of PLX4032 (RG7204) for Metastatic Melanoma” (Press release). Plexxikon. 2010-01-08.
  21. Jump up to:a b “Plexxikon and Roche Report Positive Data from Phase III BRAF Mutation Melanoma Study”. 6 June 2011.
  22. Jump up^ “Vemurafenib Improves Overall Survival in Patients with Metastatic Melanoma”.
  23. Jump up^ Cobimetinib at exelixis.com
  24. Jump up^ “MEK/BRAF Inhibitor Combo Reduces Death by One-Third in Melanoma”. 2015.
  25. Jump up^ “BRIM-2 Upholds Benefits Emerging with Vemurafenib in Melanoma”Oncology & Biotech News5 (7). July 2011.
  26. Jump up^ “Getting close and personal”The Economist. January 4, 2014. ISSN 0013-0613. Retrieved 2016-04-15.

Secnidazole, секнидазол , سيكنيدازول , 塞克硝唑 ,


Secnidazole.svg ChemSpider 2D Image | Secnidazole | C7H11N3O3

Secnidazole

  • Molecular FormulaC7H11N3O3
  • Average mass185.180 Da
1-(2-Methyl-5-nitroimidazol-1-yl)-2-propanol
1H-Imidazole-1-ethanol, α,2-dimethyl-5-nitro- [ACD/Index Name]
222-134-0 [EINECS]
3366-95-8 [RN]
a,2-Dimethyl-5-nitro-1H-imidazole-1-ethanol
UNII:R3459K699K
секнидазол [Russian] [INN]
سيكنيدازول [Arabic] [INN]
塞克硝唑 [Chinese] [INN]
RP-14539, PM-185184, Flagentyl

Solosec (secnidazole) ; Symbiomix Therapeutics; For the treatment of bacterial vaginosis , Approved September 2017

Company: Symbiomix Therapeutics

Approval Status: Approved FDA September 2017

Specific Treatments: bacterial vaginosis

Therapeutic Areas Obstetrics/Gynecology (Women’s Health)

Infections and Infectious Diseases

 

Secnidazole is a second-generation 5-nitroimidazole antimicrobial that is structurally related to other 5-nitroimidazoles including Metronidazole and Tinidazole, but displays improved oral absorption and longer terminal elimination half-life than antimicrobial agents in this class [1]. Secnidazole is selective against many anaerobic Gram-positive and Gram-negative bacteria and protozoa. In September 2017, FDA granted approval to secnidazole under the market name Solosec as a single-dose oral treatment for bacterial vaginosis, which is a common vaginal infection in women aged 15 to 44 years. The antimicrobial therapy is only intended to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria [FDA Label].

Title: Secnidazole
CAS Registry Number: 3366-95-8
CAS Name: a,2-Dimethyl-5-nitro-1H-imidazole-1-ethanol
Additional Names: 1-(2-hydroxypropyl)-2-methyl-5-nitroimidazole; 1-(2-methyl-5-nitroimidazol-1-yl)-2-propanol
Manufacturers’ Codes: PM-185184; RP-14539
Trademarks: Flagentyl (Rh>e-Poulenc)
Molecular Formula: C7H11N3O3
Molecular Weight: 185.18
Percent Composition: C 45.40%, H 5.99%, N 22.69%, O 25.92%
Literature References: Analog of metronidazole, q.v. Prepn: FR M3270 (1965 to Rhône-Poulenc), C.A. 63, 11571d (1965); C. Cosar et al., Arzneim.-Forsch. 16, 23 (1966). Anti-amebic and trichomonacidal activities: F. Benazet, L. Guillaume, Bull. Soc. Pathol. Exot. Ses Fil. 69, 309 (1976), C.A. 90, 145922v (1979). Serum half-life: J. Symonds, J. Antimicrob. Chemother. 5, 484 (1979). Therapeutic use: D. Videau et al., Br. J. Vener. Dis. 54, 77 (1978).
Properties: Cryst from toluene, mp 76° (Cosar).
Melting point: mp 76° (Cosar)
Therap-Cat: Antiamebic. Antiprotozoal (Trichomonas).
Keywords: Antiamebic; Antiprotozoal (Trichomonas).

Secnidazole (trade names FlagentylSindoseSecnil) is a nitroimidazole anti-infective. Effectiveness in the treatment of dientamoebiasis has been reported.[1] It has also been tested against Atopobium vaginae.[2]

Mechanism of Action

Solosec (secnidazole) is a 5-nitroimidazole antimicrobial. 5-nitroimidazoles enter the bacterial cell as an inactive prodrug where the nitro group is reduced by bacterial enzymes to radical anions. It is believed that these radical anions interfere with bacterial DNA synthesis of susceptible isolates.

DE 2107405; FR 2079880; GB 1278757; JP 49080066

The condensation of (I) with propylene oxide (A) in ethanol at 20 C gives 1-(2-hydroxypropyl)-2-methylimidazole (III), which is acetylated with acetyl chloride in refluxing acetonitrile yielding the corresponding acetate (IV). The nitration of (IV) by means of HNO3 and P2O5 affords 1-(2-acetoxypropyl)-2-methyl-4-nitroimidazole (V), which is finally hydrolyzed with 4N HCl at 90 C

CH 513177; DE 2107423; FR 2079879; GB 1278758; NL 7101641

The reaction of (I) with chloroacetone (C) by means of K2CO3 in refluxing acetone gives (2-methylimidazol-1-yl)acetone (VI), which is nitrated with HNO3 and P2O5 affording the corresponding nitro compound (VII). Finally, this product is reduced with NaBH4 in methanol at room temperature.

Drugs Fut 1979,4(4),280, Arzneim-Forsch Drug Res 1966,16(1),23-29

The nitration of (I) with HNO3 and H2SO4 gives 2-methyl-4(5)-nitroimidazole (II), which is then condensed with refluxing 1-chloroisopropanol (B) or with propylene oxide in 85% formic acid (A).

References

  1. Jump up^ Girginkardeşler, N.; Coşkun, S.; Cüneyt Balcioğlu, I.; Ertan, P.; Ok, U. Z. (2003). “Dientamoeba fragilis, a neglected cause of diarrhea, successfully treated with secnidazole”. Clinical Microbiology and Infection9 (2): 110–113. PMID 12588330doi:10.1046/j.1469-0691.2003.00504.x.
  2. Jump up^ De Backer, E.; Dubreuil, L.; Brauman, M.; Acar, J.; Vaneechoutte, M. (2009). “In vitro activity of secnidazole against Atopobium vaginae, an anaerobic pathogen involved in bacterial vaginosis”. Clinical Microbiology and Infection16 (5): 470–472. PMID 19548924doi:10.1111/j.1469-0691.2009.02852.x.

External links

  • Gillis, J. C.; Wiseman, L. R. (1996). “Secnidazole. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic use in the management of protozoal infections and bacterial vaginosis”. Drugs51 (4): 621–38. PMID 8706597doi:10.2165/00003495-199651040-00007.
Secnidazole
Secnidazole.svg
Clinical data
Synonyms PM 185184, RP 14539
AHFS/Drugs.com International Drug Names
Routes of
administration
Oral
ATC code
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.020.123
Chemical and physical data
Formula C7H11N3O3
Molar mass 185.180 g/mol
3D model (JSmol)

////////////Secnidazole, секнидазол سيكنيدازول 塞克硝唑 , FDA 2017, RP-14539, PM-185184, Flagentyl

CC1=NC=C(N1CC(C)O)[N+](=O)[O-]

DISCLAIMER

“NEW DRUG APPROVALS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

FDA approves new treatment for adults with mantle cell lymphoma


FDA approves new treatment for adults with mantle cell lymphoma

The U.S. Food and Drug Administration today granted accelerated approval to Calquence (acalabrutinib) for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy.

“Mantle cell lymphoma is a particularly aggressive cancer,” 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. “For patients who have not responded to treatment or have relapsed, Calquence provides a new treatment option that has shown high rates of response for some patients in initial studies.” Continue reading.

Enclomiphene citrate, New patent, WO 2017182097, F.I.S. – FABBRICA ITALIANA SINTETICI S.P.A


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Enclomiphene citrate, New patent, WO 2017182097, F.I.S. – FABBRICA ITALIANA SINTETICI S.P.A

WO-2017182097

F.I.S. – FABBRICA ITALIANA SINTETICI S.P.A

CARUANA, Lorenzo; (IT).
PADOVAN, Pierluigi; (IT).
DAL SANTO, Claudio; (IT)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017182097&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

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Enclomiphene citrate is an active pharmaceutical ingredient currently under evaluation in clinical phase III for the treatment of secondary hypergonadism. Moreover, it also could be potentially used for an adjuvant therapy in hypogonadal men with Type 2 diabetes.

Enclomiphene citrate of formula (I):

has chemical name of Ethanamine, 2-[4-[(1 )-2-chloro-1 ,2-diphenyl ethenyl]phenoxy]-/V,/V-diethyl-, 2-hydroxy-1 ,2,3-propanetricarboxylate (1 : 1 ); has CAS RN. 7599-79-3, and it is also named trans-Clomiphene monocitrate, E-Clomiphene citrate or Enclomiphene monocitrate.

Enclomiphene is component of Clomiphene, an active pharmaceutical ingredient, having chemical name Ethanamine, 2-[4-(2-chloro-1 ,2- diphenylethenyl)phenoxy]-N,N-diethyl, since Clomiphene is a mixture of the geometric isomers trans-Clomiphene (i.e. Enclomiphene) and cis- Clomiphene.

The US patent 3,848,030, in examples 31 and 32, discloses a process for the resolution of the geometric isomers of Clomiphene through the preparation of salts with racemic binaphthyl-phosphoric acid.

In the later publication Acta Cryst. (1976), B32, pag. 291 -293, the actual geometric isomery has been definitely established by single crystal X-Ray diffraction.

Finally, in the publication “Analytical profiles of drug substances and excipients”, vol. 25, (1998), pag. 85-121 , in particular at pag. 99, it is stated that prior to 1976 the cis stereochemistry was wrongly assigned to the trans-isomer of Clomiphene (E-Chlomiphene or Enclomiphene), and only after the above publication on Acta Cryst. the correct geometric isomery has been definitively assigned.

These observations in the prior art have been confirmed by our experimentation. In particular, repeating the experiment 31 of US patent 3,848,030, the trans-Clomiphene salt with racemic binaphthyl-phosphoric acid was isolated and not the salt with cis-Clomiphene as stated in said patent, as confirmed by 2D H-NMR analysis (NOESY experiment). Thus, Example 31 of US3,848,030, provides, at the end, Enclomiphene citrate, crystallized from a mixture of ethyl ether and ethanol, having a m.p. of 133-135°C. Example 32, instead provided Cis-Clomiphene citrate, crystallized from a mixture of ethyl ether and ethanol, having a m.p. of 120-126°C.

Thus, with the aim of preparing Enclomiphene citrate, whole experiment 31 of US3,848,030 has been reworked also carrying out the crystallization of the product form a mixture of ethyl ether and ethanol, hence providing a not crystalline solid with two DSC peaks respectively at 1 14°C and 188°C, although the starting material used for the reworking example was quite a pure substance (HPLC Analysis (A A%) is 98.95% of Enclomiphene), and having a substantially the same chemical purity of that used in the prior art experiment (m.p. of our Enclomiphene BPA salt was 218°C versus 220- 222°C of the prior art Enclomiphene BPA salt of Example 31 ).

The patent US2,914,563, in example 3, discloses a process for the preparation of trans-Clomiphene citrate, containing from 30% to 50% of cis-Clomiphene, as citrate, by reaction of 1 -ρ-(β- diethylaminoethoxy)phenyl]-1 ,2-diphenylethylene hydrochloride with N- chlorosuccinimmide in dry chloroform under reflux.

Khimiko-Farmatsevticheskii Zhurnal (1984), 18(1 1 ), 1318-24 English translation in the review Pharmaceutical Chemistry Journal November 1984, Volume 18, Issue 1 1 , pag. 758-764 (Title: Synthesis and biological study of the cis- and trans-isomers of Clomiphene citrate and some intermediates of its synthesis) discloses the trans-isomer of Clomiphene citrate, i.e. Enclomiphene citrate, characterized by:

1 H-NMR (MeOD) d 7.4-6.7 (m, 14H); 4.27 (t, 2H, -OCH2); 3.51 (t, 2H, CH2- N); 3.28 (q, 4H, 2xN-CH2)); 2.73 (2H); 2.78 (2H); 1.31 (t, 6H, 2xN-C-CHs)) Melting point: 138-139°C (98% purity by GLC);

IR spectrum, v cm-1 (suspension in mineral oil): 3640, 3430, 1720, 1710

(citrate), 1600-1555 (broad band, stilbene system); 750.

UV spectrum: λ max = 243 nm, ε 21 ,800 and λ max 300 nm, ε 1 1 ,400.

These prior art methods for the preparation of Enclomiphene citrate do not allow the preparation of Enclomiphene citrate having needle shaped crystal habit, indeed the crystallization by means of a mixture of ethyl ether and ethanol does not provide a crystalline solid having needle crystals.

Moreover, Enclomiphene citrate was described in literature with different melting points, in particular, 133-135°C and 138-139°C. Said solid forms of Enclomiphene citrate fail to comply with stabilities studies and furthermore show relatively poor solubility in water either in neutral or acid pH.

Furthermore, the prior art methods have the drawbacks related to the poor reproducibility of the process and of the solid form thus obtained.

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EXPERIMENTAL SECTION

The starting material Clomiphene citrate can be prepared according to well-known prior art methods, or for example, as described in the example 1 of PCT/EP2015/074746 or can be purchased on the market.

[00190] Example 1 : Preparation of salt of Enclomiphene with racemic binaphthyl- phosphoric acid, starting from Clomiphene citrate.

Clomiphene citrate

[00191] A round bottom flask was charged 100 gr of Clomiphene Citrate (HPLC analysis (A/A%): 65.21 % Enclomiphene, 34.06% Z-Clomiphene) and 1000 mL of methanol. The suspension was stirred at 30°C up the complete

dissolution. Then a solution of racemic binaphthyl-phosphoric acid (abbreviated BPA) 30 gr (0.515 eq) in 30 ml_ of DMF was added. At the end of addition the mixture was stirred for 1 h at 30°C. The obtained suspension was filtered and the solid was washed with 100 ml_ of methanol.

[00192] 50.4 gr of Enclomiphene BPA salt (III) were obtained.

[00193] HPLC Analysis (A/A%): 97.04% Enchlomiphene, 2.5% Z-Clomiphene.

[00194] Example 1 b: Preparation of salt of Enclomiphene with racemic binaphthyl- phosphoric acid, starting from Clomiphene citrate.

[00195] A round bottom flask was charged 50 gr of Clomiphene Citrate and 500 ml_ of methanol. The suspension was heated at 40-45°C and stirred up to the complete dissolution. Then a solution of BPA 15 gr (0.515 eq) in 300 ml_ of methanol was added. At the end of addition the mixture was stirred for 1 h at 20°C. The obtained suspension was filtered and the solid was washed with 100 ml_ of methanol.

24.1 gr of Enclomiphene BPA salt were obtained.

HPLC Analysis (A/A%): 98.96% Enchlomiphene, 0.69% Z-Clomiphene.

[00196] Example 1 c: Preparation of salt of Enclomiphene with racemic binaphthyl- phosphoric acid, starting from Clomiphene citrate.

[00197] In a round bottom flask was charged 100 gr of Clomiphene Citrate and 1000 ml_ of methanol. The suspension was heated at 40-45°C and stirred up the complete dissolution. Then a solution of BPA 30 gr (0.515 eq) in 1000 ml_ of methanol was added. At the end of addition the mixture was stirred for 1 h at 20°C. the obtained suspension was filtered and the solid was wash with 100 ml_ of methanol.

47.9 gr of Enclomiphene BPA salt were obtained.

HPLC Analysis (A/A%): 98.81 % Enclomiphene, 0.79% Z-Clomiphene.

[00198] Example 1d: Preparation of salt of Enclomiphene with racemic binaphthyl- phosphoric, starting from Clomiphene citrate.

[00199] In a round bottom flask was charged 150 gr of Clomiphene citrate and 1500 mL of methanol. The suspension was heater at 40-45°C and stirred up the complete dissolution. Then a solution of BPA 45 gr (0.515 eq) in 900 mL of methanol was added. At the end of addition the mixture was

stirred for 1 h at 20°C. the obtained suspension was filtered and the solid was wash with 100 ml_ of methanol.

76.4 gr of E-Clomiphene BPA salt were obtained.

HPLC Analysis (A/A%): 98.82% Enchlomiphene, 0.80% Z-Clomiphene.

[00200] Example 2: Recrystallization of Enclomiphene BPA salt of formula (III) (the step A).

(Ill)

[00201] Into a proper 0.5 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene BPA salt (III) (50 g) and having Z-isomer of 1.64 % was suspended in DMF (2.1 L/Kg of Enclomiphene BPA (III)) and methanol (1.4 L/Kg of Enclomiphene BPA salt (III)). The suspension was heated to reflux (~ 76-79°C). Further DMF (0.1 L/Kg of Enclomiphene BPA (III)) might be required to improve the solubility of the starting material. Once the starting material was completely dissolved, methanol was added as anti-solvent (3.5 L/Kg of Enclomiphene BPA (III)). The temperature was decreased to 60°C and the mixture was stirred for 2 – 3 h. Then, the temperature was further decreased to 20 °C and filtered. The wet cake was washed twice with methanol (1.5 L/Kg of Enclomiphene BPA salt (III)). The product was dried under vacuum at 60 – 70 °C for 12 – 24 h. Time of drying could be prolonged until residual DMF is < 2500 ppm.

[00202] Analysis of quality of the final product of the above mentioned example and of the same product, obtained from repetition following the same process, it is shown in the following table:

Enclomiphene BPA (III) salt Enclomiphene BPA (III) salt rixx (Starting product) (finale product)

Z-isomer = 1.64 A/A% Z-isomer = 0.07 A/A%

Z-isomer = 0.79 A/A% Z- isomer = 0.03 A/A%

[00203] Example 3: Preparation of Enclomiphene citrate of formula (I), having needle shaped crystal habit, starting from Enclomiphene BPA salt formula (III).

(II)

[00204] Into a proper 4 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene BPA salt of formula (III) (400 g, assay 99.8 wt% 0.528 mol, 1 equiv.) was suspended in methyl-tert-butyl ether (MTBE, 2 L), isopropanol (IPA, 0.5 L) and water (2 L). The mixture was stirred for 15 minutes, then 0.48 L of ammonia solution 30 wt% was added and the mixture was further stirred for one hour. The aqueous phase was separated and the organic layer was washed with a solution of ammonia solution 30 wt% (0.12 L) and water (0.6 L). The aqueous phase was separated and the organic layer was finally washed with water (0.6 L). The organic solution was evaporated to residue under vacuum at 60-65°C. The residue was dissolved in 1.36 L of absolute ethanol. The assay of the solution was determined at this stage through a potentiometric titration and results in 15.125 wt% as Enclomiphene of formula (II) (0.466 mol). Then 0.24 L of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (100.8 g, 0.475 mol, 1.02 equiv.) was dissolved in absolute ethanol (1.7 L) and water (0.3 L), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30- 40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle- shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 0.4 L of absolute ethanol. The product was dried under vacuum at 65°C. At the end of drying, 269 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 91.8% molar yield.

[00205] HPLC Analysis (A/A%): 99.79% Enchlomiphene, 0.04% Z-Clomiphene (i.e. Z-isomer).

[00206] Example 4: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit, with a mixture of ethanol and water, wherein the amount of water is 15%.

(I)

[00207] Into a proper 1 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (15,0 g, assay 99.9 wt% 0.0369 mol, 1 equiv.) was dissolved in absolute ethanol (102 ml_, 6.8 mL/g of free base), then 18 ml_ (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (7.92 g, 0.0377 mol, 1.02 equiv.) was dissolved in absolute ethanol (127 ml_) and water (23 ml_), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30-40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle-shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 ml_ of absolute ethanol. The product was dried under

vacuum at 65°C. At the end of drying, 20.2 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 91.4% molar yield.

[00208] HPLC Analysis (A/A%): 99.86% Enchlomiphene, 0.03% Z-Clomiphene.

[00209] Example 4a: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit, with a mixture of isopropanol and water, wherein the amount of water is 15%.

[00210] Into a proper 1 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (40,0 g, assay 99.9 wt% 0.0985 mol, 1 equiv.) was dissolved in isopropanol (272 ml_, 6.8 mL/g of free base), then 48 ml_ (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (21.10 g, 0.100 mol, 1.02 equiv.) was dissolved in isopropanol (340 ml_, 8.5 mL/g of free base) and water (60 mL, 1.5 mL/g of free base), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30- 40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle- shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 mL of isopropanol. The product was dried under vacuum at 65°C. At the end of drying, 56.5 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 95.9% molar yield.

[0021 1] Example 4b: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit, with a mixture of n-propanol and water, wherein the amount of water is 15%.

[00212] Into a proper 0.5 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (9,0 g, assay 99.9 wt% 0.0985 mol, 1 equiv.) was dissolved in 7-propanol (61 mL, 6.8 mL/g of free base), then 1 1 ml_ (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (4.70 g, 0.0224 mol, 1.02 equiv.) was dissolved in 7-propanol (77 ml_, 8.5 mL/g of free base) and water (14 ml_, 1.5 mL/g of free base), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30- 40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle- shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 mL of 7-propanol I. The product was dried under vacuum at 65°C. At the end of drying, 1 1.7 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 88.1 % molar yield

[00213] Example 4c: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit, with a mixture of n-butanol and water, wherein the amount of water is 15%.

[00214] Into a proper 0.5 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (9,0 g, assay 99.9 wt% 0.0985 mol, 1 equiv.) was dissolved in 7-butanol (61 mL, 6.8 mL/g of free base), then 1 1 mL (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (4.70 g, 0.0224 mol, 1.02 equiv.) was dissolved in 7-butanol (77 mL, 8.5 mL/g of free base) and water (14 mL, 1.5 mL/g of free base), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30- 40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle- shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 ml_ of 7-butanol. The product was dried under vacuum at 65°C. At the end of drying, 1 1.6 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 87.4% molar yield.

[00215] Example 4d: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit, with a mixture of tert-butanol and water, wherein the amount of water is 15%.

[00216] Into a proper 0.5 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (9,0 g, assay 99.9 wt% 0.0985 mol, 1 equiv.) was dissolved in te T-butanol (61 ml_, 6.8 mL/g of free base), then 1 1 ml_ (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (4.70 g, 0.0224 mol, 1.02 equiv.) was dissolved in te T-butanol (77 ml_, 8.5 mL/g of free base) and water (14 mL, 1.5 mL/g of free base), the solution was heated to 65°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 65°C. The dosage takes place in 30- 40 minutes. The inner temperature was decreased very slowly to 60°C over 80 minutes, then it was further decrease to 55°C over 40 minutes. When the inner temperature was in the range 60-55°C (typically at 58°C), the crystallization mixture was seeded with Enclomiphene citrate needle- shaped and a white product began to precipitate. Once reached 55°C the temperature was further decreased to 30°C over 30 minutes, then to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 mL of te T-butanol. The product was dried under vacuum at 65°C. At the end of drying, 1 1.2 g of Enclomiphene citrate of formula (I) as needle crystal were isolated, corresponding to 84.4% molar yield.

[00217] Example 5: Preparation of Enclomiphene citrate of formula (I), having a needle shaped crystal habit. Preparation of the seed crystal.

[00218] Into a proper 1 L reactor, equipped with propeller, temperature probes, condenser; Enclomiphene of fomula (II) (15,0 g, assay 99.9 wt% 0.0369 mol, 1 equiv.) was dissolved in absolute ethanol (102 ml_, 6.8 mL/g of free base), then 18 ml_ (1.2 mL/g of free base) of water were added and the solution was heated to 65°C. Meanwhile, citric acid monohydrate (7.92 g,

0.0377 mol, 1.02 equiv.) was dissolved in absolute ethanol (127 ml_, 8.5 mL/g of free base) and water (23 mL 1.5 mL/g of free base), the solution was heated to 50°C. The solution of citric acid was dropped into the solution of Enclomiphene (II), while maintaining 50°C. The dosage takes place in 30-40 minutes. At the end of the dosage, the stirring was turned off and the mixture was allowed to cool down to room temperature without stirring. The product began to crystallize at 40-30°C. Once reached 20- 25°C the stirring was turned on and the temperature was further decreased to 0°C over 30 minutes. The slurry was stirred at 0°C for at least two hours, then it was filtered and the wet cake was washed with 30 mL of absolute ethanol. The product was dried under vacuum at 65°C. At the end of drying, 13.9 g of Enclomiphene citrate of formula (I) were isolated, corresponding to 62.3% molar yield

[00219] Example 6: Preparation of Enclomiphene citrate of formula (I), having a non-needle shaped crystals, with a mixture of acetone and water, wherein the amount of water is 15%.

Comparative example (see Fig. 8) and evidence example of the invention. Following the same process described in the example 4, substituting ethanol solvent with acetone solvent. Starting from 15,0 g of Enclomiphene of formula (II), following the above mentioned process, 22.3 g of Enclomiphene citrate of formula (I) were isolated, corresponding to 94.2% molar yield product. For the morphology of the crystal see fig. 8.

[00220] Indeed, the microscopy analysis provides a better further evidence of the crystal habit of Enclomiphene citrate (I) of the example 6 (see Fig.8) which has a form more different than/to Enclomiphene citrate (I) having a needle shaped crystal habit, obtained according to above described examples,

1. e. 4, 4a, 4b, 4c, 4d (see Fig. 5, 6 and 7).

[00221] HPLC Analysis (A/A%): 99.63% Enchlomiphene, 0.20% Z-Clomiphene.

[00222] Example 7: Analytical method to identify and quantify Z-Clomiphene of formula (IV) into Enclomiphene of formula (II) or Enclomiphene citrate of formula (I) or Enclomiphene BPA salt of formula (III) and for determining the chemical purity.

[00223] Chromatographic conditions:

Dim. Column: 250 mm x 4.6 mm , 5 pm

Stationaly phase: Butyl sylane (USP phase L26, Vydac 4C is suggested) Temp. Column: room temperature

Mobile Phase: Methanol / water / triethylamine 55 : 45 : 0.3 v/v

Adjust at pH 2.5 with phosphoric acid

Flow: 1.0 mL/min

Detector UV a 233 nm,

Injection Volume: 10 μΙ_

Sample diluent: mobile phase.

Applying the conditions described above the expected retention times are as indicated below:

/////////////////Enclomiphene citrate, New patent, WO 2017182097, F.I.S. – FABBRICA ITALIANA SINTETICI S.P.A

File:Enclomiphene.png

Enclomiphene

Synonyms: Chloramiphene Citrate; Citrato de cloramifeno; Clomifencitrat; Clomifène, citrate de; Clomifeni Citras; Clomifeno, citrato de; Clomiphene Citrate; Klomifeenisitraatti; Klomifen Sitrat; Klomifen-citrát; Klomifén-citrát; Klomifencitrat; Klomifeno citratas; MER-41; MRL-41; NSC-35770; クロミフェンクエン酸塩
BAN: Clomifene Citrate [BANM]
USAN: Clomiphene Citrate
INN: Clomifene Citrate [rINNM (en)]
INN: Citrato de clomifeno [rINNM (es)]
INN: Clomifène, Citrate de [rINNM (fr)]
INN: Clomifeni Citras [rINNM (la)]
INN: Кломифена Цитрат [rINNM (ru)]
Chemical name: A mixture of the E and isomers of 2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethylethanamine dihydrogen citrate
Molecular formula: C26H28ClNO,C6H8O7 =598.1
CAS: 911-45-5 (clomifene);15690-57-0((E)-clomifene ); 15690-55-8 ((Z)-clomifene); 50-41-9 (clomifene citrate); 7599-79-3 ((E)-clomifene
citrate); 7619-53-6 ((Z)-clomifene citrate)
ATC code: G03GB02
ATC code (veterinary): QG03GB02
UNII code: 1B8447E7YI (clomifene citrate); UY5X264QZV ((Z)-clomifene citrate)

Chemical Structure of ClomifeneChemical Structure of Clomifene

NOTE:

Clomifene may be separated into its Z-and E-isomers, zuclomifene and enclomifene
.

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