Patent DE-19919218-A1 (DE)
Title: New peptide compounds, e.g. aza-heterocyclic substituted beta-alanine derivatives, are integrin receptor antagonists useful e.g. for treating atherosclerosis, cancer, osteoporosis, hypertension or inflammation
Inventor: KLING ANDREAS
IPC: C07D409/12
Filed: 1999-04-28
Abstract: Peptide compounds (I) are new.  Peptide derivatives of formula A-E-G-L (I) and their salts, prodrugs, enantiomers, diastereomers and tautomers are new. L  = -N(R4)-CHR3-(CHR2)a-T;  a  = 0 or 1; T  = COOH or group hydrolyzable to COOH;  R2  = H, NHSO2R21, NHCOR21 or NHCOOR22;  R21  = 1-6C alkyl, 3-6C cycloalkyl, (1-4C) alkyl-(3-6C) cycloalkyl, 5-12C bicycloalkyl or 6-18C tricycloalkyl (all optionally substituted (os)); or aryl, aralkyl, alkylheteroaryl or 3-6 membered (un)saturated or aromatic heterocycle (all os by 1-3 groups, two of which may together form a fused (un)saturated or aromatic heterocycle, itself os and optionally carrying a fused os (un)saturated or aromatic ring);  R22  = alkyl, aryl, or alkylaryl (all os);  R3  = H or -(CH2)b-(X)c-R31;  b  = 0-3;  c  = 0 or 1;  X = SO2, S, O, CO, NHSO2, OCO, COO, NHCO, CONH, CON(R31), N(R31)CO, SO2NH, SO2N(R31) or N(R31)SO2;  R31  = H or OH; 1-6C alkyl, alkoxy, arylalkoxy or aryloxy (all os); primary and optionally secondary or tertiary substituted amino; 2-6C alkenyl or 2-6C alkynyl (both os by 1-4C alkyl or aryl); 5-12C bicycloalkyl or 6-18C tricycloalkyl; or 3-6 membered (un)saturated heterocycle, 3-8C cycloalkyl, aryl or heteroaryl (all os by 1-3 groups, two of which may together form a fused (un)saturated or aromatic carbocycle or heterocycle, itself os and optionally carrying a fused os (un)saturated or aromatic ring); R4  = 1-4C alkyl, 3-6C alkenyl, 3-6C alkynyl or 3-6C cycloalkyl (all os);  G  = -N(R6)-CH((CH2)dR5)-CO-;  d  = 0-2;l  R5  = as R31; or the side-chain of a natural aminoacid;  R6  = H or as R4;  E  = -(NH)g-(CH2)t-Q-(CH2)e-CO-;  e  = 0-2;  f, g  = 0 or 1;  Q  = os heteroarylene (where two substituents may together form a fused (un)saturated or aromatic carbocycle or heterocycle, itself os and optionally carrying a fused os (un)saturated or aromatic ring);  A  = R10R11N-C(O)-, R10R11N-C(S)-, R10R11N-C(O)-, R12OC(O)- or R14N-C(=NR13)-; 2-pyridinyl, 2-pyrimidinyl or 4-pyrimidinyl, all substituted by R16 and R17; a diaza-heterocyclic group of formula (A1); a fused imidazole group of formula (A2); 3,4-dihydro-5H-1,3-thiazin-2-yl; uracil-6-yl; 1-aza-cyclopent-1-en-2-yl; 1-aza-cyclohex-1-en-2-yl; 1-aza-cyclohept-1-en-2-yl; or 5-oxo-4,5-dihydro-imidazol-2-yl;  R10, R11  = H or -(CH2)h(X)i-R101;  or NR10R11  = 3-8 membered os (un)saturated or aromatic heterocycle (optionally containing two further O, N or heteroatoms);  h  = 0-3;  i  = 0 or 1;  R101  = as R31 but not H;  R12  = alkyl, alkylaryl, 3-6C cycloalkyl, (1-4C) alkyl-(3-6C) cycloalkyl or aryl (all os);  R13  = H, OH, CN or CONH2; or 1-4C alkyl, 1-4C alkoxy, -OCO-(1-4C) alkyl, alkylaryl, -O-alkylaryl, -OCO-aryl, -OCO-alkylaryl or -OCO-allyl (all os);  R14 = H or (all os) 1-4C alkyl, -COO-(1-4C) alkyl, alkylaryl, -COO-alkylaryl, -COO-allyl, -CO-(1-4C) alkyl, -CO-alkylaryl or -CO-allyl;  R15  = H or (all os) 1-4C alkyl, aryl or alkylaryl;  R16, R17  = NH2, halo or (all os) 1-4C alkyl, 1-4C alkoxy or aryl;  V  = CH2CH2, CH=CH, 1,2-cyclohexylene, 1,2-cyclohex-1-enylene, (CH2)3 or CH2C(Me)2CH2;  Z1-Z4  = CH, C(Me), C(Cl) or N; heterocycles contain 1-3 of O, S and/or N.