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Osanetant , SR-142,801

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Osanetant (SR-142,801)

160492-56-8 CAS

: MW 605.257582985
Chemical Formula C35H41Cl2N3O2

(R)-(+)-N-[[3-[1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1-yl]-4-phenylpiperidin-4-yl]-N-methylacetamide

Osanetant (SR-142,801) was a neurokinin 3 receptor antagonist developed by Sanofi-Synthélabo, which was being researched for the treatment of schizophrenia, but was discontinued.[1][2] It was the first non-peptide NK3 antagonist developed in the mid-1990s,[3][4] Other potential applications for osanetant is in the treatment of drug addiction, as it has been found to block the effects ofcocaine in animal models.[5][6]

Developed by Sanofi-Aventis (formerly Sanofi-Synthelabo), osanetant (SR-142801) is an NK3 receptor antagonist which was under development for the treatment of schizophrenia and other Central Nervous System (CNS) disorders. In a review of its R&D portfolio, the company announced in August 2005 that it would cease any further development ofosanetant. This follows an earlier decision to discontinue development of eplivanserin for schizophrenia

(R)-(+)-N-[[3-[1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1-yl]-4-phenylpiperidin-4-yl]-N-methylacetamide and to a process for their preparation. (R)-(+)-N-[[3-[1-Benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1-yl]-4-phenylpiperidin-4-yl]-N-methylacetamide, hereinafter denoted by its International Non-proprietary Name “osanetant”, is the first antagonist of the NK-3 receptor described in the literature, the preparation of which, in particular in the hydrochloride form, is illustrated in EP-A-673 928.
Osanetant.png
According to this document, osanetant is prepared by reacting N-methyl-N-(4-phenylpiperidin-4-yl)acetamide with 1-benzoyl-3-(3,4-dichlorophenyl)-3-(methanesulfonyloxyprop-1-yl)piperidine and by converting the osanetant thus obtained to its hydrochloride. It has been found that osanetant hydrochloride is isolated in the form of an amorphous solid which is difficult to purify. This product comprises impurities originating from the preceding synthetic stages.
Preparative chromatography starting from osanetant base can be used to obtain osenetant in the pure form.
Osanetant is a neurokinin (NK3) receptor antagonist under development by Sanofi-Synthélabo (formerly Sanofi) as a potential treatment for schizophrenia . Sanofi was originally investigating its potential use as a treatment for psychosis and anxiety . Following phase IIa clinical trials , osanetant entered phase IIb development in February 2001 . Osanetant was the first potent and selective non-peptide antagonist described for the NK3 tachykinin receptor . It has a higher affinity for human and guinea pig NK3 receptors than for rat NK3 receptors . In October 1999, Lehman Brothers predicted that the probability of the product reaching the market was 10%, with a possible launch in 2003 and potential peak sales of US $200 million in 2011 .
Sanofi-Aventis CEO, Chris Vihebacher,
PATENT
EP 0673928; FR 2717477; FR 2717478; FR 2719311; JP 1996048669; US 5741910; US 5942523; US 6124316
N-Benzyl-4-hydroxy-4-phenylpiperidine (II) was prepared by addition of phenyllithium to N-benzyl-4-piperidone (I). Carbinol (II) was then converted to acetamide (III) by acid-catalyzed Ritter reaction with acetonitrile. Replacement of the acetamido for an N-Boc group in (III) was effected by acidic hydrolysis of amide (III) to give (IV), followed by treatment with di-tert-butyl dicarbonate. The resultant 1-benzyl-4-(Boc-amino)-4-phenylpiperidine (V) was subjected to catalytic hydrogenolysis in the presence of Pd/C, and the N-debenzylated piperidine (VI) was reprotected as the N-trityl derivative (VII) by treatment with triphenylmethyl chloride and triethylamine. Reduction of the N-Boc group of (VII) by LiAlH4, yielded the N-methyl amine (VIII). After acylation of (VIII) with acetyl chloride to acetamide (IX), its N-trityl group was cleaved by treatment with hot aqueous formic acid to produce the intermediate piperidine (X).
Michael addition of methyl acrylate (XII) to (3,4-dichlorophenyl)acetonitrile (XI) produced the cyano diester adduct (XIII). Catalytic hydrogenation of the cyano group of (XIII) over Raney nickel with concomitant intramolecular cyclization gave rise to the piperidinone (XIV). After basic hydrolysis of the methyl ester function of (XIV), the resultant piperidone propionic acid (XV) was reduced to piperidino alcohol (XVI) by means of borane in THF. Resolution of the racemic piperidine (XVI) employing (+)-camphorsulfonic acid provided the dextro enantiomer (XVII). After N-protection of (XVII) as the Boc derivative (XVIII), its primary alcohol was activated as the corresponding mesylate (XIX) with methanesulfonyl chloride and Et3N. Condensation between mesylate (XIX) and intermediate piperidine (X) in acetonitrile at 60 C, produced (XX). The title benzamido derivative was then obtained by acid-promoted Boc group cleavage in (XX), followed by acylation with benzoyl chloride.
WO 9805640
Bioorg Med Chem Lett 1996,6(19),2307
In a related synthesis, (3,4-dichlorophenyl)acetonitrile (XI) was alkylated with bromide (XXII) –prepared by protection of 3-bromopropanol (XXI) with dihydropyran– to afford (XXIII). Subsequent Michael addition of methyl acrylate (XII) to (XXIII) in the presence of Triton B?gave the cyanoacid (XXIV). This was cyclized to the glutarimide (XXV) by refluxing in HOAc in the presence of H2SO4. Reduction of (XXV) using borane-dimethylsulfide complex produced the already reported racemic piperidinoalcohol (XVI). After acylation of the amine group of (XVI) with benzoyl chloride to yield (XXVI), its hydroxyl group was converted into the target mesylate precursor (XXVII) with methanesulfonyl chloride and Et3N.
An alternative preparation of the precursor 4-(N-methyl-N-acetyl)amino-4-phenylpiperidine (XXXIX) has been reported. The N-benzyl protecting group of piperidine (III) was replaced with an N-Boc group by catalytic hydrogenolysis to (XXXVI), followed by treatment with Boc2O to yield (XXXVII). Amide (XXXVII) alkylation with iodomethane under phase-transfer conditions gave the N-methyl derivative (XXXVIII). Subsequent N-Boc group cleavage in (XXXVIII) was accomplished by using zinc chloride in CH2Cl2 to afford the piperidine-ZnCl2 complex (XXXIX). This was then alkylated with mesylate (XXVII), and the title compound was finally isolated from the racemic mixture by means of preparative chiral HPLC.
In a further method, aminopiperidine (IV) was converted to the formamide (XL) by heating in ethyl formate. Formyl group reduction in (XL) with LiAlH4 provided the N-metyl amine (XLI). The N-benzyl group of (XLI) was then removed by catalytic hydrogenation over Pd/C. Alkylation of the resultant piperidine (XLII) with mesylate (XXVII) gave adduct (XLIII). After acetylation of (XLIII) in neat Ac2O, the racemic mixture was separated by chiral HPLC.
In a further procedure, nitrile (XXIII) was alkylated with ethyl 3-bromopropionate (XXVIII) to give cyano ester (XXIX). Catalytic hydrogenation of the cyano group of (XXIX) gave rise to the piperidinone (XXX), which was further reduced to piperidine (XXXI) with LiAlH4 in THF. Acid deprotection of the tetrahydropyranyl group of (XXXI), followed by resolution with (+)-camphorsulfonic acid, furnished the desired (S)-piperidinoalcohol camphorsulfonate salt (XXXII). Treatment of piperidine (XXXII) with benzoyl chloride in the presence of DIEA yielded benzamide (XXXIII). Conversion of the primary alcohol of (XXXIII) into the desired alkyl iodide (XXXV) was achieved via formation of the mesylate ester (XXXIV), followed by displacement of the mesylate group with KI in refluxing acetone.
Bioorg Med Chem Lett 1997,7(5),555
A new method has been reported. Formamide (XL) was prepared form carbinol (II) by a modified Ritter reaction with cyanotrimethylsilane. Subsequent reduction of (XL) with LiAlH4 gave the N-methyl amine (XLI), which was converted to acetamide (XLIV) by treatment with acetyl chloride. Benzyl group hydrogenolysis in (XLIV) afforded the piperidine (X). Finally, alkylation of piperidine (X) with the chiral alkyl iodide (XXXV) provided the title compound.
Cited Patent Filing date Publication date Applicant Title
US5741910 * Feb 29, 1996 Apr 21, 1998 Sanofi Compounds which are selective antagonists of the human NK3 receptor and their use as medicinal products and diagnostic tools
US5942523 * Feb 29, 1996 Aug 24, 1999 Sanofi Compounds which are selective antagonists of the human NK3 receptor and their use as medicinal products and diagnostic tools
US6040316 * Sep 2, 1997 Mar 21, 2000 Warner-Lambert Company 3-alkyl-3-phenyl-piperidines
US6124316 * May 7, 1999 Sep 26, 2000 Sanofi Compounds which are specific antagonists of the human NK3 receptor and their use as medicinal products and diagnostic tools
Citing Patent Filing date Publication date Applicant Title
US7648992 Jul 4, 2005 Jan 19, 2010 Astrazeneca Ab Hydantoin derivatives for the treatment of obstructive airway diseases
US7655664 Dec 14, 2005 Feb 2, 2010 Astrazeneca Ab Hydantoin derivatives as metalloproteinase inhibitors
US7662845 Aug 7, 2006 Feb 16, 2010 Astrazeneca Ab 2,5-Dioxoimidazolidin-4-yl acetamides and analogues as inhibitors of metalloproteinase MMP12
US7666892 May 5, 2008 Feb 23, 2010 Astrazeneca Ab Metalloproteinase inhibitors
US7700604 Dec 14, 2005 Apr 20, 2010 Astrazeneca Ab Hydantoin derivatives as metalloproteinase inhibitors
US7754750 Jul 13, 2010 Astrazeneca Ab Metalloproteinase inhibitors
US7989620 Aug 2, 2011 Astrazeneca Ab Hydantoin derivatives for the treatment of obstructive airway diseases
US8153673 Jan 26, 2010 Apr 10, 2012 Astrazeneca Ab Metalloproteinase inhibitors
US8183251 Nov 28, 2007 May 22, 2012 Astrazeneca Ab Hydantoin compounds and pharmaceutical compositions thereof
US20080032997 * Dec 14, 2005 Feb 7, 2008 Astrazeneca Ab Novel Hydantoin Derivatives as Metalloproteinase Inhibitors
US20080064710 * Jul 4, 2005 Mar 13, 2008 Astrazeneca Ab Novel Hydantoin Derivatives for the Treatment of Obstructive Airway Diseases
US20080221139 * Nov 28, 2007 Sep 11, 2008 David Chapman Novel Compounds
US20080262045 * May 5, 2008 Oct 23, 2008 Anders Eriksson Metalloproteinase Inhibitors
US20080293743 * Dec 14, 2005 Nov 27, 2008 Astrazeneca Ab Novel Hydantoin Derivatives as Metalloproteinase Inhibitors
US20080306065 * May 6, 2008 Dec 11, 2008 Anders Eriksson Metalloproteinase Inhibitors
US20100144771 * Dec 2, 2009 Jun 10, 2010 Balint Gabos Novel Hydantoin Derivatives for the Treatment of Obstructive Airway Diseases
WO2007106022A2 * Mar 15, 2007 Sep 20, 2007 Astrazeneca Ab A new crystalline form g of (5s) -5- [4- (5-chloro-pyridin-2- yloxy) -piperidine-1-sulfonylmethyl] – 5 -methyl -imidazolidine – 2,4-dione (i) and intermediates thereof.
WO2007106022A3 * Mar 15, 2007 Nov 1, 2007 Astrazeneca Ab A new crystalline form g of (5s) -5- [4- (5-chloro-pyridin-2- yloxy) -piperidine-1-sulfonylmethyl] – 5 -methyl -imidazolidine – 2,4-dione (i) and intermediates thereof.

References

  1.  “osanetant Sanofi-Aventis discontinued, France.”. Highbeam.
  2. Kamali, F (July 2001). “Osanetant Sanofi-Synthélabo”. Current opinion in investigational drugs (London, England : 2000). 2 (7): 950–6.PMID 11757797.
  3.  Emonds-Alt, X; Bichon, D; Ducoux, JP; Heaulme, M; Miloux, B; Poncelet, M; Proietto, V; Van Broeck, D; et al. (1995). “SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor”. Life Sciences. 56 (1): PL27–32. doi:10.1016/0024-3205(94)00413-M.PMID 7830490.
  4.  Quartara L, Altamura M (August 2006). “Tachykinin receptors antagonists: from research to clinic”. Current Drug Targets. 7 (8): 975–92.doi:10.2174/138945006778019381. PMID 16918326. Retrieved 2011-04-14.
  5.  Desouzasilva, M; Mellojr, E; Muller, C; Jocham, G; Maior, R; Huston, J; Tomaz, C; Barros, M (May 2006). “The tachykinin NK3 receptor antagonist SR142801 blocks the behavioral effects of cocaine in marmoset monkeys”. European Journal of Pharmacology. 536 (3): 269–78.doi:10.1016/j.ejphar.2006.03.010. PMID 16603151.
  6.  Jocham, Gerhard; Lezoch, Katharina; Müller, Christian P.; Kart-Teke, Emriye; Huston, Joseph P.; De Souza Silva, M. AngéLica (September 2006). “Neurokinin receptor antagonism attenuates cocaine’s behavioural activating effects yet potentiates its dopamine-enhancing action in the nucleus accumbens core”. European Journal of Neuroscience. 24 (6): 1721–32. doi:10.1111/j.1460-9568.2006.05041.x.PMID 17004936.
X Emonds-Alt et al. SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor. Life Sci. 1995, 56(1), PL27-32.
F Kamali. Osanetant Sanofi-Synthélabo. Curr. Opin. Invest. Drugs. 2001, 2(7), 950-956.
L Quartara and M Altamura. Tachykinin receptors antagonists: from research to clinic. Curr. Drug Targets. 2006, 7(8), 975-992.
MA De Souza Silva et al. The tachykinin NK3 receptor antagonist SR142801 blocks the behavioral effects of cocaine in marmoset monkeys. Eur. J. Pharmacol. 2006, 536(3), 269-278.
G Jocham et al. Neurokinin receptor antagonism attenuates cocaine’s behavioural activating effects yet potentiates its dopamine-enhancing action in the nucleus accumbens core. Eur. J. Neurosci. 2006, 24(6), 1721-1732.
Osanetant
Osanetant.png
Systematic (IUPAC) name
N-(1-{3-[(3R)-1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]propyl}-4-phenylpiperidin-4-yl]-N-methylacetamide
Identifiers
CAS Number 160492-56-8 Yes
ATC code none
PubChem CID 219077
IUPHAR/BPS 2110
ChemSpider 189901 
UNII K7G81N94DT Yes
ChEMBL CHEMBL346178 
Chemical data
Formula C35H41Cl2N3O2
Molar mass 606.625 g/mol

///////Osanetant , SR-142,801, 

CC(=O)N(C)C1(CCN(CC1)CCC[C@@]2(CCCN(C2)C(=O)C3=CC=CC=C3)C4=CC(=C(C=C4)Cl)Cl)C5=CC=CC=C5

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DR ANTHONY CRASTO

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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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