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EP0190224A1 - VERFAHREN ZUR HERSTELLUNG VON CIS, ENDO-OCTAHYDROCYCLOPENTA[b]PYRROL-2-CARBOXYLATEN - Google Patents

VERFAHREN ZUR HERSTELLUNG VON CIS, ENDO-OCTAHYDROCYCLOPENTA[b]PYRROL-2-CARBOXYLATEN

Info

Publication number
EP0190224A1
EP0190224A1 EP85903779A EP85903779A EP0190224A1 EP 0190224 A1 EP0190224 A1 EP 0190224A1 EP 85903779 A EP85903779 A EP 85903779A EP 85903779 A EP85903779 A EP 85903779A EP 0190224 A1 EP0190224 A1 EP 0190224A1
Authority
EP
European Patent Office
Prior art keywords
substituted
lower alkyl
cis
pyrrole
compound
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP85903779A
Other languages
English (en)
French (fr)
Inventor
Elijah Herman Gold
Bernard Ray Neustadt
Elizabeth Melva Smith
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Original Assignee
Schering Corp
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 Corp filed Critical Schering Corp
Publication of EP0190224A1 publication Critical patent/EP0190224A1/de
Ceased legal-status Critical Current

Links

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°.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pyrrole Compounds (AREA)
EP85903779A 1984-07-30 1985-07-26 VERFAHREN ZUR HERSTELLUNG VON CIS, ENDO-OCTAHYDROCYCLOPENTA[b]PYRROL-2-CARBOXYLATEN Ceased EP0190224A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US635390 1984-07-30
US06/635,390 US4587258A (en) 1980-10-23 1984-07-30 Angiotensin-converting enzyme inhibitors

Publications (1)

Publication Number Publication Date
EP0190224A1 true EP0190224A1 (de) 1986-08-13

Family

ID=24547612

Family Applications (1)

Application Number Title Priority Date Filing Date
EP85903779A Ceased EP0190224A1 (de) 1984-07-30 1985-07-26 VERFAHREN ZUR HERSTELLUNG VON CIS, ENDO-OCTAHYDROCYCLOPENTA[b]PYRROL-2-CARBOXYLATEN

Country Status (7)

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

Families Citing this family (23)

* 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
DE3431541A1 (de) * 1984-08-28 1986-03-06 Hoechst Ag, 6230 Frankfurt Cis,endo-2-azabicycloalkan-3-carbonsaeure-derivate, verfahren zu deren herstellung, deren verwendung sowie zwischenprodukte bei deren herstellung
DE3518514A1 (de) * 1985-05-23 1986-11-27 Hoechst Ag, 6230 Frankfurt Neue derivate bicyclischer aminosaeuren, verfahren zu ihrer herstellung, diese enthaltende mittel und deren verwendung
DE3722007A1 (de) * 1987-07-03 1989-01-12 Hoechst Ag Verfahren zur herstellung bicyclischer aminocarbonsaeuren, zwischenprodukte dieses verfahrens und deren verwendung
DE3839127A1 (de) * 1988-11-19 1990-05-23 Hoechst Ag Pyrrolidon-2-carbonsaeure-derivate mit psychotroper wirkung
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
GB9716657D0 (en) 1997-08-07 1997-10-15 Zeneca Ltd Chemical compounds
GB9803226D0 (en) 1998-02-17 1998-04-08 Zeneca Ltd Chemical compounds
GB9902461D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902455D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902452D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902453D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902459D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB0000625D0 (en) 2000-01-13 2000-03-01 Zeneca Ltd Chemical compounds
AU2003290401A1 (en) * 2003-11-24 2005-06-08 Potluri Ramesh Babu A process for industrially viable preparation of (s,s,s) phenylmethyl-2-azabicyclo-(3.3.0)-octane-3-carboxylate tosylate
KR20060128976A (ko) 2003-12-29 2006-12-14 세프라코 아이엔시. 피롤 및 피라졸 디에이에이오 억제제
CA2636324C (en) 2006-01-06 2012-03-20 Sepracor Inc. Cycloalkylamines as monoamine reuptake inhibitors
US8053603B2 (en) 2006-01-06 2011-11-08 Sunovion Pharmaceuticals Inc. Tetralone-based monoamine reuptake inhibitors
CA2648121C (en) 2006-03-31 2013-08-06 Sepracor Inc. Preparation of chiral amides and amines
JP2010516697A (ja) 2007-01-18 2010-05-20 セプラコール インク． Ｄ−アミノ酸オキシダーゼ阻害剤
US7902252B2 (en) 2007-01-18 2011-03-08 Sepracor, Inc. Inhibitors of D-amino acid oxidase
KR101581289B1 (ko) 2007-05-31 2015-12-31 세프라코 아이엔시. 모노아민 재흡수 억제제로서 페닐 치환된 시클로알킬아민

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3174844D1 (en) * 1980-10-23 1986-07-24 Schering Corp Carboxyalkyl dipeptides, processes for their production and pharmaceutical compositions containing them
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
IE55867B1 (en) * 1981-12-29 1991-02-14 Hoechst Ag New derivatives of bicyclic aminoacids,processes for their preparation,agents containing these compounds and their use,and new bicyclic aminoacids as intermediates and processes for their preparation
IE54551B1 (en) * 1982-01-22 1989-11-22 Ici Plc Amide derivatives
DE3211676A1 (de) * 1982-03-30 1983-10-06 Hoechst Ag Neue derivate von cycloalka (c) pyrrol-carbonsaeuren, verfahren zu ihrer herstellung, diese enthaltende mittel und deren verwendung sowie neue cycloalka (c) pyrrol-carbonsaeuren als zwischenstufen und verfahren zu deren herstellung
DE3302125A1 (de) * 1983-01-22 1984-07-26 Boehringer Ingelheim KG, 6507 Ingelheim Aminosaeure-derivate, verfahren zu ihrer herstellung und verwendung
HU191120B (en) * 1983-01-31 1987-01-28 Hoechts Ag,De Process for raceme separation of optically active byciclic imino-alpha-carbonic acid esthers
DE3315464A1 (de) * 1983-04-28 1984-10-31 Hoechst Ag, 6230 Frankfurt Verfahren zur herstellung von n-alkylierten dipeptiden und deren estern
FR2546886B2 (fr) * 1983-06-06 1986-05-16 Adir Derives d'acides isoindoledicarboxyliques, leur preparation et compositions pharmaceutiques les contenant
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Non-Patent Citations (1)

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Also Published As

Publication number Publication date
DK140886D0 (da) 1986-03-26
WO1986000896A1 (en) 1986-02-13
AU4671885A (en) 1986-02-25
AU581919B2 (en) 1989-03-09
DK140886A (da) 1986-03-26
JPS61502818A (ja) 1986-12-04
CA1244041A (en) 1988-11-01
ZA855659B (en) 1987-03-25

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