WO1986000896A1 - PROCEDE ORIGINAL POUR LA PREPARATION DE CIS, ENDO-OCTAHYDROCYCLOPENTA ADb BDPYRROLE-2-CARBOXYLATE - Google Patents

PROCEDE ORIGINAL POUR LA PREPARATION DE CIS, ENDO-OCTAHYDROCYCLOPENTA ADb BDPYRROLE-2-CARBOXYLATE Download PDF

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Publication number
WO1986000896A1
WO1986000896A1 PCT/US1985/001406 US8501406W WO8600896A1 WO 1986000896 A1 WO1986000896 A1 WO 1986000896A1 US 8501406 W US8501406 W US 8501406W WO 8600896 A1 WO8600896 A1 WO 8600896A1
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WO
WIPO (PCT)
Prior art keywords
substituted
lower alkyl
cis
compound
pyrrole
Prior art date
Application number
PCT/US1985/001406
Other languages
English (en)
Inventor
Elijah Herman Gold
Bernard Ray Neustadt
Elizabeth Melva Smith
Original Assignee
Schering Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US06/635,390 external-priority patent/US4587258A/en
Application filed by Schering Corporation filed Critical Schering Corporation
Publication of WO1986000896A1 publication Critical patent/WO1986000896A1/fr
Priority to DK140886A priority Critical patent/DK140886A/da

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
    • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered

Definitions

  • Inhibitors of angiotensin-converting enzymes are useful in the treatment of cardiovascular disorders especially as antihypertensive agents and also in the treatment of congestive heart failure and of glaucoma.
  • Such ACE-inhibitors have, for example, been described in the published European patent applications Nos. 50800 and 79022.
  • ACE-inhibitors are compounds of the general formula (I)
  • R and R 6 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, diloweralkyl- amino lower alkoxy (e.g. dimethylaminoethoxy), acylamino lower alkoxy (e.g. acetylaminoethoxy), acyloxy lower alkoxy (e.g. pivaloyloxyethoxy), aryloxy (e.g. phenoxy), arylloweralkoxy (e.g. benzyloxy), amino, lower alkylamino, diloweralkylamino, hydroxyamino, aryllower alkylamino (e.g. benzylamino), or substituted aryloxy or substituted arylloweralkoxy wherein the substituent is methyl, halo or methoxy;
  • R 1 is hydrogen, alkyl of from 1 to 10 carbon atoms, including branched and cyclic and unsaturated (e.g. allyl) alkyl groups, substituted lower alkyl wherein the substituent is hydroxy, lower alkoxy, aryloxy (e.g. phenoxy), substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, lower alkylamino, diloweralkylamino, acylamino, arylamino, substituted arylamino, guanidino, imidazolyl, indolyl, lower alkylthio, arylthio (e.g.
  • phenylthio substituted arylthio, carboxy, carbamoyl, lower alkoxycarbonyl, aryl (e.g. phenyl or naphthyl), substituted aryl, aralkyloxy, substituted aralkyloxy, aralkylthio, or substituted aralkylthio, wherein the aryl or heteroaryl portion of said substituted aryloxy, heteroaryloxy, arylamino, arylthio, aryl, aralkyloxy or aralkylthio groups is substituted with a group selected from halo, loweralkyl, hydroxy, lower alkoxy, amino, aminomethyl, carboxyl, cyano and sulfamoyl; and
  • R 3 is hydrogen, lower alkyl, phenyl lower alkyl, aminomethylphenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, acylamino lower alkyl (e.g. benzoylamino lower alkyl or acetylamino lower alkyl), amino lower alkyl, dimethylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, or lower alkylthio lower alkyl.
  • acylamino lower alkyl e.g. benzoylamino lower alkyl or acetylamino lower alkyl
  • acyl includes J wherein
  • R 12 is lower alkyl, lower alkenyl or aryl.
  • the lower alkyl or lower alktnyl groups except where noted otherwise are represented by any of the variables including straight and branched chain hydrocarbon radicals from one to six carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, hexyl or vinyl, allyl, butenyl and the like.
  • Cycloalkyl groups include bridged and non-bridged groups.
  • the aralkyl groups represented by any of the above variables have from one to four carbon atoms in the alkyl portion thereof and include for example, benzyl, p-methoxybenzyl and the like.
  • Halo means chloro, bromo, iodo or fluoro.
  • Aryl where it appears in any of the radicals, except where noted, represents phenyl or naphthyl.
  • Heteroaryl groups where they appear include for example pyridyl, thienyl, furyl, indolyl,benzothienyl, imidazolyl and thiazolyl.
  • the R 1 and R 3 substituted lower alkyl moieties are exemplified by groups such as
  • Preferred compounds of formula I are those in which R is hydroxy or lower alkoxy, R 1 is lower alkyl or substituted lower alkyl wherein the substituent is aryl, R 3 is lower alkyl or aminoloweralkyl and R 6 is hydroxy.
  • stereoisoaers are the cis,endooctahydrocyclopenta [b] pyrrole-2(S)-carboxylic acids, wherein preferably the absolute configuration at the carbon atoms marked by /_double asterisk in the above formula I is most similar to that of natural L-amino acids, which usually are assigned the S-configuration.
  • Particularly preferred compounds are l-[N-(1(S)-carboxy-3 phenylpropyl)-(S)- alanyl]-cis,endo-octahydrocyclopenta [b]-pyrrole-2(S)- carboxylic acid, 1-[N-(1(S)- carboethoxy-3-
  • a most preferred compound is 1-[N-(1(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]cis,endo-octahydrocyclopenta[b]pyrrole-2-(S)-carboxylic acid and its hydrochloride salt.
  • R 6 is as defined above.
  • Compounds of formula III consist of eight stereoisomers composed of four racemic pairs; the two cis epimers. IIIa and IlIb, and the two trans epimers, IIIc and IIId:
  • formulae IIIa, IIIb, IIIc and IIId are meant to comprise the relevant racemic pair of optical isomers.
  • the compounds of formula III can be prepared by known methods, such as disclosed in the publications mentioned above, followed, if desirer, by isolation of the racemic pairs of isomers or their individual component enantiomers according to resolution methods well described in the art.
  • the present invention provides a novel process for the preparation of the compounds of the general formula IIIa. This process comprises catalytic reduction of compound II
  • R 6 is as defined above, followed, if desired by the resolution of the racemic mixture to obtain the individual enantiomer.
  • Compound II can be prepared by the reaction of a halopyruvate ester (V)
  • R 6 is as defined above and Hal stands for halogen, with benzyliminocyclopentane.
  • the process for preparing the novel compounds II (1-benzy1-1,4,5,6-tetrahydrocyclopentane[b]pyrrole- 2-carboxylic acid or its esters) preferably uses a lower alkyl ester of bromo pyruvate (e.g. R 6 is ethoxy, methoxy or t-butoxy).
  • R 6 is ethoxy, methoxy or t-butoxy
  • eguimolar amounts of reactants are used.
  • the reaction is carried out in an inert solvent such as, for example, an alcohol (e.g. ethanol), acetonitrile or dimethylformamide in the presence of a base such as, for example, triethyl- amine.
  • the reaction may be carried out at from 0-100°C for 2-8 hours, but is preferably carried out at low temperatures (e.g. 0-5°C) for approximately 2 hours, then at reflux (temperature depends on solvent) for 2 hours.
  • the catalytic reduction of compound II to saturate the ring and remove the benzyl group is carried out in a solvent such as an alcohol (e.g. ethanol) in the presence of hydrogen gas and a catalyst such as Pd(OH) 2 on carbon, Pd on carbon or other appropriate catalysts.
  • a solvent such as an alcohol (e.g. ethanol)
  • a catalyst such as Pd(OH) 2 on carbon, Pd on carbon or other appropriate catalysts.
  • the resultant product may be isolated by methods well known to those skilled in the art, e.g. by treating with an acid such as HC1 to prepare the salt, followed by removal of the salt (e.g. by basifying with sodium hydroxide) to obtain the compound of formula Ilia, followed, if desired by the isolation of the individual enantiomers.
  • the group R being other than hydrogen can be hydrogenolyzed to some extent. Consequently, an additional esterification step may be required to obtain the desired compound.
  • the individual enantiomers can be obtained by conventional resolution methods well described in the art, such as fractional crystallization of appropriate diastereomeric salts, for example the fractional crystallization of compounds IIIa wherein R° is benzyloxy or its benzyloxycarbonyl-L-phenylalanine salt.
  • the compounds of formulae IIIa (cis,endo- form) can be converted to the corresponding compounds having the cis,exo-form (IIIb).
  • Such epimerizations are most conveniently carried out on the free base ester forms of these compounds, in the absence or presence of additional basic catalysts such as potassium t-butoxide, triethylamine and the like.
  • Method I Add a 20% HC1 in dioxane solution (100 ml) to 5 g. of cis,endo- octahydrocyclopenta[b]pyrrole-2-carboxylic acid. Stir the resulting mixture at room temperature for 30 min. and then concentrate it in vacuo. Wash the white residue with anhydrous ether and dry in vacuo to obtain the title compound of Part A as a white solid, m.p. 209-211°.

Abstract

Procédé original pour la préparation de cis,endo-octahydrocyclopenta AD BDpyrrole-2-carboxylate (IIIa) où R6 est hydroxyle, alkoxyle inférieur, alkenoxyle inférieur, alkoxyle inférieur alkylamino bisinférieur, alkoxyle inférieur acylamino, alloxyle inférieur, acyloxyle, aryloxyle, arylalkoxyle inférieur, amino, alcoylamino inférieur, alcoylamino bisinférieur, hydroxyamino, alcoylamino aryle inférieur ou aryloxyle substitué ou l'alkoxyle aryle inférieur substitué où le substituant est le méthyle, halo ou méthoxy. Ce procédé comprend une réduction catalytique du composé (II) et, de plus, peut comporter la préparation du composé de formule (II) par la réaction d'un ester halopyruvate (V) avec du benzyliminocyclopentane. Les composés (IIIa) sont des intermédiaires utiles pour la préparation de certains inhibiteurs d'enzymes de transportation d'angiotensine (ACE).
PCT/US1985/001406 1984-07-30 1985-07-26 PROCEDE ORIGINAL POUR LA PREPARATION DE CIS, ENDO-OCTAHYDROCYCLOPENTA ADb BDPYRROLE-2-CARBOXYLATE WO1986000896A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DK140886A DK140886A (da) 1984-07-30 1986-03-26 Fremgangsmaade til fremstilling af cis,endo-octahydrocyclo-penta(b)pyrrol-2-carboxylater

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US06/635,390 US4587258A (en) 1980-10-23 1984-07-30 Angiotensin-converting enzyme inhibitors
US635,390 1984-07-30

Publications (1)

Publication Number Publication Date
WO1986000896A1 true WO1986000896A1 (fr) 1986-02-13

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1985/001406 WO1986000896A1 (fr) 1984-07-30 1985-07-26 PROCEDE ORIGINAL POUR LA PREPARATION DE CIS, ENDO-OCTAHYDROCYCLOPENTA ADb BDPYRROLE-2-CARBOXYLATE

Country Status (7)

Country Link
EP (1) EP0190224A1 (fr)
JP (1) JPS61502818A (fr)
AU (1) AU581919B2 (fr)
CA (1) CA1244041A (fr)
DK (1) DK140886A (fr)
WO (1) WO1986000896A1 (fr)
ZA (1) ZA855659B (fr)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0203450A2 (fr) * 1985-05-23 1986-12-03 Hoechst Aktiengesellschaft Dérivés d'amino-acides bicycliques, leur procédé de préparation, les agents les contenant et leur emploi
EP0297620A2 (fr) * 1987-07-03 1989-01-04 Hoechst Aktiengesellschaft Procédé pour la préparation d'acides aminocarboxyliques bicycliques, intermédiaires pour ce procédé et leur utilisation
EP0370378A2 (fr) * 1988-11-19 1990-05-30 Hoechst Aktiengesellschaft Dérivés de l'acide pyrrolidine-2-carboxylique à acitivité psychotrope
EP0173199B1 (fr) * 1984-08-28 1994-07-13 Hoechst Aktiengesellschaft Dérivés de l'acide cis, endo-aza-2 bicycloalcane carboxylique-3, procédés pour leur préparation et les produits intermédiaires lors de leur préparation
US5629345A (en) * 1993-07-23 1997-05-13 Vide Pharmaceuticals Methods and compositions for ATP-sensitive K+ channel inhibition for lowering intraocular pressure
US5965620A (en) * 1993-07-23 1999-10-12 Vide Pharmaceuticals Methods and compositions for ATP-sensitive K+ channel inhibition for lowering intraocular pressure
US6291507B1 (en) 1998-02-17 2001-09-18 Astrazeneca Uk Limited Chemical compounds
US6441004B1 (en) 1997-08-07 2002-08-27 Zeneca Limited Monocyte chemoattractant protein-1 inhibitor compounds
US6569888B1 (en) 1999-02-05 2003-05-27 Astrazeneca Ab Anti-inflammatory indole derivatives
US6613760B1 (en) 1999-02-05 2003-09-02 Astrazeneca Ab Indole derivatives and their use as MCP-1 receptor antagonists
US6737435B1 (en) 1999-02-05 2004-05-18 Astrazeneca Ab Indole derivatives and their use as MCP-1 antagonist
US6833387B1 (en) 1999-02-05 2004-12-21 Astrazeneca Ab Chemical compounds
WO2005049568A1 (fr) * 2003-11-24 2005-06-02 Potluri Ramesh Babu Procede de preparation industriellement viable de (s,s,s) phenylmethyl-2-azabicyclo-[3.3.0]-octane-3-carboxylate tosylate
US6911465B1 (en) 1999-02-05 2005-06-28 Astrazeneca Ab Anti-inflammatory indole derivatives
US6984657B1 (en) 2000-01-13 2006-01-10 Astrazeneca Ab Indole derivatives as MCP-1 receptor antagonists
WO2008089453A2 (fr) 2007-01-18 2008-07-24 Sepracor Inc. Inhibiteurs de la d-amino acide oxydase
US7893098B2 (en) 2003-12-29 2011-02-22 Sepracor Inc. Pyrrole and pyrazole DAAO inhibitors
US7902252B2 (en) 2007-01-18 2011-03-08 Sepracor, Inc. Inhibitors of D-amino acid oxidase
US8053603B2 (en) 2006-01-06 2011-11-08 Sunovion Pharmaceuticals Inc. Tetralone-based monoamine reuptake inhibitors
US8097760B2 (en) 2006-03-31 2012-01-17 Sunovion Pharmacuticals Inc. Preparation of chiral amides and amines
US8669291B2 (en) 2007-05-31 2014-03-11 Sunovion Pharmaceuticals Inc. Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors
US8877975B2 (en) 2006-01-06 2014-11-04 Sunovion Pharmaceuticals Inc. Cycloalkylamines as monoamine reuptake inhibitors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3226768A1 (de) * 1981-11-05 1983-05-26 Hoechst Ag, 6230 Frankfurt Derivate der cis, endo-2-azabicyclo-(3.3.0)-octan-3-carbonsaeure, verfahren zu ihrer herstellung, diese enthaltende mittel und deren verwendung

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EP0050800A1 (fr) * 1980-10-23 1982-05-05 Schering Corporation Dipeptides carboxyalcoyliques, procédés pour les préparer et compositions pharmaceutiques les contenant
EP0079022A2 (fr) * 1981-11-05 1983-05-18 Hoechst Aktiengesellschaft Dérivés de l'acide cis, endo-2-azabicyclo-(3.3.0)-octane-3-carboxylique, procédé pour leur préparation, medicaments les contenant et leur application
EP0084164A2 (fr) * 1981-12-29 1983-07-27 Hoechst Aktiengesellschaft Dérivés d'amino-acides bicycliques, procédé pour leur préparation, agents les contenant et leur utilisation ainsi que des amino-acides bicycliques comme intermédiaires et procédé pour leur préparation
EP0084941A1 (fr) * 1982-01-22 1983-08-03 Imperial Chemical Industries Plc Dérivés d'amides
EP0090362A2 (fr) * 1982-03-30 1983-10-05 Hoechst Aktiengesellschaft Dérivés des acides cycloalka(c)pyrrol carboxyliques, leur procédé de préparation, les agents les contenant, leur emploi, les acides cycloalka(c)pyrrol carboxyliques comme intermédiaires et leur procédé de préparation
EP0115345A1 (fr) * 1983-01-31 1984-08-08 Hoechst Aktiengesellschaft Procédé de dédoublement d'esters d'acides imino-alpha-carboxyliques bicycliques optiquement actifs et utilisation des composés ainsi productibles pour la synthèse de carboxyalkyldipeptides
EP0116842A2 (fr) * 1983-01-22 1984-08-29 Boehringer Ingelheim Kg Dérivés d'amino-acides, leur procédé de préparation et leur emploi
EP0126986A1 (fr) * 1983-04-28 1984-12-05 Hoechst Aktiengesellschaft Procédé de préparation de dipeptides N-alcoylés et leurs esters
EP0135181A2 (fr) * 1983-09-16 1985-03-27 Hoechst Aktiengesellschaft Procédé de production de peptides N-alcoylés et de leurs esters

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FR2546886B2 (fr) * 1983-06-06 1986-05-16 Adir Derives d'acides isoindoledicarboxyliques, leur preparation et compositions pharmaceutiques les contenant
US4514391A (en) * 1983-07-21 1985-04-30 E. R. Squibb & Sons, Inc. Hydroxy substituted peptide compounds

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0050800A1 (fr) * 1980-10-23 1982-05-05 Schering Corporation Dipeptides carboxyalcoyliques, procédés pour les préparer et compositions pharmaceutiques les contenant
EP0079022A2 (fr) * 1981-11-05 1983-05-18 Hoechst Aktiengesellschaft Dérivés de l'acide cis, endo-2-azabicyclo-(3.3.0)-octane-3-carboxylique, procédé pour leur préparation, medicaments les contenant et leur application
EP0084164A2 (fr) * 1981-12-29 1983-07-27 Hoechst Aktiengesellschaft Dérivés d'amino-acides bicycliques, procédé pour leur préparation, agents les contenant et leur utilisation ainsi que des amino-acides bicycliques comme intermédiaires et procédé pour leur préparation
EP0084941A1 (fr) * 1982-01-22 1983-08-03 Imperial Chemical Industries Plc Dérivés d'amides
EP0090362A2 (fr) * 1982-03-30 1983-10-05 Hoechst Aktiengesellschaft Dérivés des acides cycloalka(c)pyrrol carboxyliques, leur procédé de préparation, les agents les contenant, leur emploi, les acides cycloalka(c)pyrrol carboxyliques comme intermédiaires et leur procédé de préparation
EP0116842A2 (fr) * 1983-01-22 1984-08-29 Boehringer Ingelheim Kg Dérivés d'amino-acides, leur procédé de préparation et leur emploi
EP0115345A1 (fr) * 1983-01-31 1984-08-08 Hoechst Aktiengesellschaft Procédé de dédoublement d'esters d'acides imino-alpha-carboxyliques bicycliques optiquement actifs et utilisation des composés ainsi productibles pour la synthèse de carboxyalkyldipeptides
EP0126986A1 (fr) * 1983-04-28 1984-12-05 Hoechst Aktiengesellschaft Procédé de préparation de dipeptides N-alcoylés et leurs esters
EP0135181A2 (fr) * 1983-09-16 1985-03-27 Hoechst Aktiengesellschaft Procédé de production de peptides N-alcoylés et de leurs esters

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0173199B1 (fr) * 1984-08-28 1994-07-13 Hoechst Aktiengesellschaft Dérivés de l'acide cis, endo-aza-2 bicycloalcane carboxylique-3, procédés pour leur préparation et les produits intermédiaires lors de leur préparation
EP0203450A2 (fr) * 1985-05-23 1986-12-03 Hoechst Aktiengesellschaft Dérivés d'amino-acides bicycliques, leur procédé de préparation, les agents les contenant et leur emploi
EP0203450A3 (en) * 1985-05-23 1989-07-26 Hoechst Aktiengesellschaft Derivatives of bicyclic amino acids process for their preparation, agents containing them and their use
US4920144A (en) * 1985-05-23 1990-04-24 Hoechst Aktiengesellschaft Derivatives of bicyclic amino acids, agents containing them and their use as hypotensives
EP0297620A2 (fr) * 1987-07-03 1989-01-04 Hoechst Aktiengesellschaft Procédé pour la préparation d'acides aminocarboxyliques bicycliques, intermédiaires pour ce procédé et leur utilisation
EP0297620A3 (fr) * 1987-07-03 1991-06-05 Hoechst Aktiengesellschaft Procédé pour la préparation d'acides aminocarboxyliques bicycliques, intermédiaires pour ce procédé et leur utilisation
EP0370378A3 (fr) * 1988-11-19 1991-11-27 Hoechst Aktiengesellschaft Dérivés de l'acide pyrrolidine-2-carboxylique à acitivité psychotrope
EP0370378A2 (fr) * 1988-11-19 1990-05-30 Hoechst Aktiengesellschaft Dérivés de l'acide pyrrolidine-2-carboxylique à acitivité psychotrope
US5629345A (en) * 1993-07-23 1997-05-13 Vide Pharmaceuticals Methods and compositions for ATP-sensitive K+ channel inhibition for lowering intraocular pressure
US5965620A (en) * 1993-07-23 1999-10-12 Vide Pharmaceuticals Methods and compositions for ATP-sensitive K+ channel inhibition for lowering intraocular pressure
US6441004B1 (en) 1997-08-07 2002-08-27 Zeneca Limited Monocyte chemoattractant protein-1 inhibitor compounds
US6953809B2 (en) 1997-08-07 2005-10-11 Zeneca Limited Monocyte chemoattractant protein-1 inhibitor compounds
US6291507B1 (en) 1998-02-17 2001-09-18 Astrazeneca Uk Limited Chemical compounds
US6737435B1 (en) 1999-02-05 2004-05-18 Astrazeneca Ab Indole derivatives and their use as MCP-1 antagonist
US6833387B1 (en) 1999-02-05 2004-12-21 Astrazeneca Ab Chemical compounds
US6911465B1 (en) 1999-02-05 2005-06-28 Astrazeneca Ab Anti-inflammatory indole derivatives
US6569888B1 (en) 1999-02-05 2003-05-27 Astrazeneca Ab Anti-inflammatory indole derivatives
US6613760B1 (en) 1999-02-05 2003-09-02 Astrazeneca Ab Indole derivatives and their use as MCP-1 receptor antagonists
US6984657B1 (en) 2000-01-13 2006-01-10 Astrazeneca Ab Indole derivatives as MCP-1 receptor antagonists
WO2005049568A1 (fr) * 2003-11-24 2005-06-02 Potluri Ramesh Babu Procede de preparation industriellement viable de (s,s,s) phenylmethyl-2-azabicyclo-[3.3.0]-octane-3-carboxylate tosylate
US7893098B2 (en) 2003-12-29 2011-02-22 Sepracor Inc. Pyrrole and pyrazole DAAO inhibitors
US8877975B2 (en) 2006-01-06 2014-11-04 Sunovion Pharmaceuticals Inc. Cycloalkylamines as monoamine reuptake inhibitors
US8053603B2 (en) 2006-01-06 2011-11-08 Sunovion Pharmaceuticals Inc. Tetralone-based monoamine reuptake inhibitors
US9868718B2 (en) 2006-01-06 2018-01-16 Sunovion Pharmaceuticals Inc. Cycloalkylamines as monoamine reuptake inhibitors
US10562878B2 (en) 2006-01-06 2020-02-18 Sunovion Pharamceuticals Inc. Cycloalkylamines as monoamine reuptake inhibitors
US8097760B2 (en) 2006-03-31 2012-01-17 Sunovion Pharmacuticals Inc. Preparation of chiral amides and amines
US7902252B2 (en) 2007-01-18 2011-03-08 Sepracor, Inc. Inhibitors of D-amino acid oxidase
WO2008089453A2 (fr) 2007-01-18 2008-07-24 Sepracor Inc. Inhibiteurs de la d-amino acide oxydase
US8669291B2 (en) 2007-05-31 2014-03-11 Sunovion Pharmaceuticals Inc. Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors
US9586888B2 (en) 2007-05-31 2017-03-07 Sunovion Pharmaceuticals Inc. Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors

Also Published As

Publication number Publication date
EP0190224A1 (fr) 1986-08-13
DK140886D0 (da) 1986-03-26
DK140886A (da) 1986-03-26
AU4671885A (en) 1986-02-25
CA1244041A (fr) 1988-11-01
JPS61502818A (ja) 1986-12-04
AU581919B2 (en) 1989-03-09
ZA855659B (en) 1987-03-25

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