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US 4,748,160 AGranted
Angiotensin converting enzyme inhibitors and their formulation and use as pharmaceuticals
AssigneeFisons Limited
InventorsColin Bennion, David P. Marriott, Anthony R. Cook, David H. Robinson
Life of this patent
Estimating the term…
Abstract
There are described compounds of formula I, ZCHRCON(--N.dbd.CR.sub.4 R.sub.5)CHR.sub.6 (CH.sub.2).sub.n COY I where the substituents are defined in the disclosure. There are also described methods for making the compounds, formulations containing them and their use, e.g. as antihypertensives.
Claims11
A compound of formula I,
- ZCHRCON(--N.dbd.CR.sub.4 R.sub.5)CHR.sub.6 (CH.sub.2).sub.n COY
- in which
- Z is R.sub.2 CH(COOH)NH--, R.sub.1 SCH.sub.2 -- or Ph(CH.sub.2).sub.p PO(OH)--,
- Ph is phenyl,
- p is an integer from 1 to 6,
- R.sub.1 is hydrogen or R.sub.8 CO--,
- R.sub.8 is alkyl C1 to 10 or phenyl,
- R is hydrogen or alkyl C1 to 10,
- R.sub.2 is alkyl C1 to 10 or phenylalkyl C7 to 12,
- R.sub.4 and R.sub.5, which may be the same or different, are each hydrogen, phenyl, naphthyl;
- a heterocyclic group selected from thiophenyl, furyl, pyrrolyl, imidazol, oxazolyl, thiazolyl, pyrimidinyl and pyridyl, each of which is optionally fused to a benzene ring;
- a 5 or 6 membered alicyclic ring fused to a benzene ring;
- cycloalkyl containing 3 to 7 carbon atoms, or alkyl C1 to 10 optionally substituted by phenyl, naphthyl or a heterocyclic group selected from thiophenyl, furyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrimidinyl and pyridyl, each of which is optionally fused to a benzene ring,
- when R.sub.4 or R.sub.5 are phenyl, naphthyl, a 5 or 6 membered alicyclic ring or a heterocyclic group as defined above, said phenyl, naphthyl, alicyclic ring or heterocyclic group can be optionally substituted by one or more alkyl C1 to 10 alkoxy C1 to 10, halogen, phenylalkyl C7 to 12, phenylalkoxy C7 to 12, phenyl, hydroxy, .dbd.O, fluoroalkyl C1 to 10, cyano, nitro, phenylsulphonamido, dialkyl (C1 to 10)-amino-alkoxy (C1 to 10), alkylthio C1 to 10, or dialkyl (C1 to 10)-amino,
- or R.sub.4 and R.sub.5 together form a --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, ##STR4## R.sub.6 is hydrogen or alkyl C1 to 10, q is 2 or 3,
- n is 0 or 1,
- Y is hydroxy or --NHSO.sub.2 R.sub.g, and
- R.sub.9 is alkyl C1 to 10,
- and pharaceutically acceptable salts, alkyl C1 to 6 and benzyl esters thereof.
16 more elements
A compound selected from
- (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-2-(phenylmethylene)-1-hydrazinoacet ic acid,
- Ethyl(S)-1-(3-acetylthio-2-methyl-1-oxopropyl)-2-(phenylmethylene)hydrazino acetate,
- (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-2-(1-naphthylmethylene)-1-hydrazino acetic acid,
- (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-2-(2-naphthylmethylene)-1-hydrazino acetic acid,
- (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-2-(3,4-dihydronaphthylidene)-1-hydr azinoacetic acid,
- 2-[(2,6-Dichlorophenyl)methylene]-1-(3-mercapto-1-oxopropyl)-1-hydrazinoace tic acid,
- (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-2-(1-phenylethylidene)-1-hydrazinoa cetic acid,
- (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-2-(diphenylmethylidine)-1-hydrazino acetic acid,
- (S)-2-[(4-Cyanophenyl)methylene]-1-(3-mercapto-2-methyl-1-oxopropyl)-1-hydr azinoacetic acid,
- (S)-2-[((4-Phenylsulphonamido)phenyl)methylene]-1-(3-mercapto-2-methyl-1-ox opropyl)-1-hydrazinoacetic acid,
- (S)-2-Cyclohexylmethylene-1-(3-mercapto-2-methyl-1-oxopropyl)-1-hydrazinoac etic acid,
- 2-Cyclohexyl-hexahydro-6-(S)-methyl-5-oxo-[1,3,4-thiadiazepinyl]-4-acetic acid,
- (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-2-(2-methyl propylidene)-1-hydrazinoacetic acid,
- Hexahydro-6-methyl-2-(1-methyl-ethyl)-5-oxo-[1,3,4-thiadiazepinyl]-4-acetic acid,
- (S)-2-Adamantylidene-1-(3-mercapto-2-methyl-1-oxopropyl)1-hydrazinoacetic acid,
- Hexahydro-6-(S)-methyl-5-oxo-spiro[1,3,4-thiadiazepine-2,2'-tricyclo-[3,3,1 ,1.sup.3,7 ]decane]-4-acetic acid,
- (S)-2-Adamantylidene-1-(3-mercapto-2-methyl-1-oxopropyl)-1-hydrazinoacetic acid,
- Hexahydro-6-(S)-methyl-5-oxo-spiro[1,3,4-thiadiazepine-2,2'-tricyclo-[3,3,1 ,1.sup.3,7 ]decane]-4-acetic acid,
- (S)-2-[(1,1'-Biphenyl)-4-ylmethylene]-1-(3-mercapto-2-methyl-1-oxopropyl)-1 -hydrazinoacetic acid,
- (S)-2-Cyclohexylidene-1-(3-mercapto-2-methyl-1-oxopropyl)-1-hydrazinoacetic acid,
- (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-2-(2,2-dimethylpropylidene)-1-hydro azinoacetic acid,
- (S)-2-(4-Chlorophenylmethylene)-1-(3-mercapto-2-methyl-1-oxopropyl)-1-hydra zinoacetic acid,
- Ethyl (S)-1-(3-acetylthio-2-methyl-1-oxopropyl)-2-(4-chlorophenylmethylene)-1-hy drazinoacetate,
- (S)-2-[(2,6-Dichlorophenyl)methylene]-1-(3-mercapto-2-methyl-1-oxopropyl)-1 -hydrazinoacetic acid,
- (S)-2-[(2-Chlorophenyl)methylene]-1-(3-mercapto-2-methyl-1-oxopropyl)-1-hyd razinoacetic acid,
- (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-2[(3-pyridyl)methylene]-1-hydrazino acetic acid,
- (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-2[(2-pyridyl)methylene]-1-hydrazino acetic acid,
- (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-2[(2-thienyl)methylene]-1-hydrazino acetic acid,
- (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-2-[(4-methoxyphenyl)methylene]-1-hy drazinoacetic acid,
- (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-2-[(4-methylthiazol-2-yl)methylene) -1-hydrazinoacetic acid,
- (S)-2-[(1,1'-biphenyl)-2-ylmethylene]-1-(3-mercapto-2-methyl-1-oxopropyl)-1 -hydrazinoacetic acid,
- (S)-2-[(4-Butylphenyl)methylene]-1-(3-mercapto-2-methyl-1-oxopropyl-1-hydra zinoacetic acid,
- (S)-2-[(2-Hydroxyphenyl)methylene]-1-(3-mercapto-2-methyl-1-oxopropyl)-1-hy drazinoacetic acid,
- (S)-N-(3-Mercapto-2-methyl-1-oxopropyl)-N-(1,2-dihydro-2-oxo-3-indolylimino )glycine,
- 1-[N-(1-(S)-Carboxy-3-phenylpropyl)-L-alanyl]-2-(phenylmethylene)-1-hydrazi noacetic acid,
- t-Butyl 1-[N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-2-(phenylmethylene)-1 -hydrazinoacetate,
- 1-[N-(1-(S)-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-2-(phenylmethylene)-1- hydrazinoacetic acid,
- 1-(N-(1-(S)-Carboxy-3-phenylpropyl)-L-alanyl]-2-(cyclohexylmethylene)-1-hyd razinoacetic acid,
- t-Butyl 2-(cyclohexylmethylene)-1-[N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alany l]-1-hydrazinoacetate,
- 2-(Cyclohexylmethylene)-1-[N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl ]-1-hydrazinoacetic acid,
- (S)-1-(3-Benzoylthio-2-methyl-1-oxopropyl)-2-cyclohexylmethylene-1-hydrazin oacetic acid,
- t-Butyl (S)-1-(3-benzoylthio-2-methyl-1-oxopropyl)-2-cyclohexylmethylene-1-hydrazi noacetate,
- 2-[1-(3-Benzoylthio-1-oxopropyl)-2-(phenylmethylene)-1-hydrazino]propanoic acid,
- t-Butyl 2-[1-(3-benzoylthio-1-oxopropyl)-2-(phenylmethylene)-1-hydrazino]-propanoa te,
- and pharmaceutically acceptable salts of any one thereof.
42 more elements
Dependencies are inferred from the claim text.