NOVEL SULPHUR DERIVATIVES COMPRISING AN AMIDE BOND, METHOD FOR PREPARING SAME, USE THEREOF AS DRUGS, AND PHARMACEUTICAL COMPOSITIONS CONTAINING SUCH DERIVATIVES

摘要

The use of N-((mercapto) (aryl) alkanoyl)-aminoacid or -amine derivatives of formula HS(CH2)nC*H(CH2R1)C(O)NHC*H(R2)A (I), with the exception of thiorphan, is claimed for the preparation of a medicament for treating disorders requiring inhibition of endothelin converting enzyme (ECE). (I) are in any possible racemic, enantiomeric or diastereomeric form, and include addition salts with mineral or organic acids or bases. * = chiral centre; n = 0 or 1; R1 = phenyl or biphenyl (both optionally substituted by one or more of halo, OH (optionally protected), 1-4C alkoxy, OPh, CN, COOH (optionally salified, esterified or amidated), benzyloxy and dioxole); R2 = H; or methyl substituted by phenyl, phenylthio or indolyl and optionally by a second phenyl (where the phenyl, phenylthio and indolyl are optionally substituted by one or more of halo, OH (optionally protected), 1-4C alkoxy, CN, COOH (optionally salified, esterified or amidated), benzyloxy, thienyl, naphthyl or phenyl, the last 3 groups being themselves optionally substituted by one or more of halo, OH (optionally protected), 1-4C alkoxy, CN and COOH (optionally salified, esterified or amidated)); A = COOH (optionally salified, esterified or amidated) or tetrazolyl (optionally salified); or 1-10C alkyl substituted by OH (optionally protected), 1-4C alkoxy, COOH (optionally salified, esterified or amidated), phenoxy, phenyl, thienyl, naphthyl, indolyl or pyridyl, themselves optionally substituted by one or more of halo, OH (optionally protected), 1-4C alkoxy, CN and COOH (optionally salified, esterified or amidated). The following compounds (I) (including isomers and salts as described above) are new: N-(3-(3-bromophenyl)-2-(mercaptomethyl)-1-oxopropyl)-L-tryptophan (Ia); N-(3-((1,1'-biphenyl)-3-yl)-2-(mercaptomethyl)-1-oxopropyl)-L-tryptophan; (R,S)-N-(3-(4-bromophenyl)-2-(mercaptomethyl)-1-oxopropyl)-L-tryptophan; (R,S)-N-(3-((1,1'-biphenyl)-4-yl)-2-(mercaptomethyl)-1-oxopropyl)-L-tryptophan; (S)-N-(2-(mercaptomethyl)-1-oxo-3-phenylpropyl)-4-(2-thienyl)-L-phenylalanine; (S)-N-(2-(mercaptomethyl)-1-oxo-3-phenylpropyl)-4-(1-naphthyl)-L-phenylalanine; (S)-N-(2-(mercaptomethyl)-1-oxo-3-phenylpropyl)-L-tryptophan; (S)-4-phenyl-N-(2-(mercaptomethyl)-1-oxo-3-phenylpropyl)-L-phenylalanine; (S,S)-N-(2-((1,1'-biphenyl)-4-yl)-1-(1H-tetrazol-5-yl)-ethyl)-alpha -(mercaptomethyl)-benzene-propanamide; (R) and (S)-N-(3-(3-bromophenyl)-2-(mercaptomethyl)-1-oxo-propyl)-4-(2-thienyl)-L-phenylalanine (isomers A and B); and N-(3-(3-bromophenyl)-2-(mercaptomethyl)-1-oxopropyl)-7-(phenylmethoxy)-L-tryptophan. Also claimed are (i) methods for preparation of (I) for use as above; (ii) pharmaceutical compositions containing the new compounds (I) as active agents; and (iii) the use of compounds of formulae WC(O)SCH2CH(CH2R1')C(O)NHCH(R2')A' (IX) and WC(O)SCH(CH2R1')C(O)NHCH(R2')A' (XIV) for the preparation of an ECE inhibitor.