Peptides having tachykinin antagonist activity, a process for preparation thereof and pharmaceutical compositions comprising the same

摘要

Amino acid derivs. of formula (I) and their pharmaceutically acceptable salts are new. R1 = vinyl, aryl, heteroaryl, aralkyl, heteroaralkyl, arylvinyl, heteroarylvinyl, aryloxyalkyl, arylalkyloxy, 3-8C cycloalkyl, 3-8C cycloalkyl-alkyl, opt. mono-, di- or tri-Me substd. bicycloheptyl or bicycloheptyl alkyl, etc. In R1, aryl = naphthyl or Ph (this last opt. mono, di or tri-substd. by halogen, trihalo-methyl, alkoxy, alkyl, OH, NO2, alkylcarbonyl or CN); heteroaryl = indolyl (opt. substd. at position 1 with alkyl or benzyl), pyridyl, etc. A1 = Ala, Val, Leu, Ile, Ser, Thr, allo-Thr, Cys, Met, Phe, Trp (opt. N-formyl protected), Tyr, Pro, DPro (e.g. D(3,4)-Pro), Pro(OH) (e.g. Pro(3OH) or Pro(4OH)), A2t, Tpr, Pro(NH2) (e.g. Pro(nH2) or Pro(4NH2)), pGlu, Aib, 2,3-diamino-propionic acid, 2,4-diaminobutyric acid, etc. B = A2NR2R3 or R5; A2 = a lipophilic alpha-amino acid contg. an opt. mono-, di- or tri-substd. Ph, or heteroaryl, cyclohexyl, cyclopentyl, naphthyl or mono- or di(1-3C) alkyl amino, etc. In A2 the substits on Ph = halogen, alkoxy, alkyl, CN or 1-pyrrolidinyl; the chain members in the 1-8 membered chain are CHR4, CO, O, S and/or NR4, etc. R4 = H, alkyl, aryl or aralkyl. In R4, aryl = naphthyl or Ph (this last opt. mono-, di- or tri-substd. with halogen, etc.); R2, R3 = alkyl, arylalkyl, heteroaryl, etc. In R2 and R3, aryl = naphthyl or Ph (this last opt. mono-, di- or tri-substd. by halogen, trihalomethyl, etc.); R5 = a gp. of formula (a) or (b); R6 = aralkyl, diarylalkyl (aryl = Ph or naphthyl and alkyl contains 1-5C), heteroaryl (1-5C)alkyl (heteroaryl - 2-, 3- or 4-pyridyl or 2- or 3-thienyl), etc.; R7 = H or 1-5C alkyl; X = O or H2; Y, Z = H, 1-5C alkyl, 1-5C alkyloxy, benzyloxy (the Ph gp. being opt mono-, di- or tri-substd. with 1-5C alkyl, esp. mono-, di- or tri-substd. with 1-5C alkyl, esp. Me, 1-5C alkoxy, esp. MeO, NMe2, halogen, C3, CN or OCF3) OCF3, halogen, CF3, CN, etc. t = u = 0, t = 1 and u = 0; t = u = 1; t = 2 and u = 0; and if t = 1 and u = 0, R5 can also be a gp. of formula (c); R8 = H and R9 = OH, 1-5C alkoxy, phenyl-(1-5C) alkyloxy, naphthyl (1-5C)alkyloxy or 1-4C alkylcarbonyl; or R8 + R9 together form O or OCH2CH2O; the chirality on C is R or S.