Patent DE-19858029-A1 (DE)
Title: New substituted (hetero)aryl-alkanes, used as thrombin inhibitors, serine protease inhibitors, antithrombotic agents and intermediates
Inventor: PRIEPKE HENNING
IPC: C07D213/50
Filed: 1998-12-16
Abstract: Substituted (hetero)aryl alkanes (I) are new.  Substituted (hetero)aryl alkanes of formula Ar-A-CHR1-X-Y (I) and their tautomers, stereoisomers, mixtures and salts are new.  A  = ethynylene; or ethylene or vinylene (both optionally substituted (os) by T, -Tc, Cl, Br or I);  R1  = H, T or -Tc;  Ar  = phenyl or Het, both substituted by R2-R4;  R2  = (i) 1-6C alkyl or -T-Cy (both os in the alkyl part by COOH, Ph, N(T')2, N(T')-Tc, NH-Cy, N(T')Ph, N(1-4C alkanoyl)-phenylamino, N(T')-Het, N(Tc)Ph or N(Tc)Het; (ii) carboxyalkyl, substituted in the alkyl by NTT', pyrrolidino, piperidino or hexamethyleneimino or having one CH2 of alkyl replaced by 3-6C cycloalkylidene; (iii) Ph, OPh or SO2Ph (all os by halo, T, Tc or COOT); (iv) mono- or dialkylamino, NHTc, N(alkyl)-Tc, NH-Cy, N(Tc)-Cy, N(T')-Ph, N(Tc)-Ph, N(T')-Het or N(Tc)-Het; (v) N(T')CO-alkyl, N(T')CO-Cy, N(T')CO-aryl, N(T')CO-Het, N(T')SO2-alkyl, N(T')SO2-aryl or N(T')SO2-Het (where N-(T) moieties are os by COOH, CON(T')-Tc or (other than on the  alpha -C) OH, OTc, NH2 or N(T')-Tc); (vi) 5-7 membered cycloalkyleneimino; (vii) NH2, NH-alkyl, NH-aryl, NH-T-aryl, NH-Het or NH-T-Het (all os on N by COT, COTc, CONH-Tc, 2-oxo-pyrrolidinocarbonyl or piperazinocarbonyl; where NH2 groups monosubstituted by COT, COTc or CONHTc may be additionally substituted by 5-7 membered cycloalkyleneimino or dialkylamino; and COT moieties are os in T by COOH, NH2, OH, COOH, OTc, CON(T')-Tc or NHCO-T-NH2); (viii) carbimino, N-substituted by OTc, N(T')2 or N(T')-Tc and C-substituted by alkyl, Ph (os by T or OT) or Het (os by T); (ix) Het or -T-Het (both os in the ring by Ph or Het or by Ph or Het plus -Tc or -T-COOT); (x) 5-oxo-4,5-dihydropyrazolyl or 6-oxo-4,5-dihydropyridazinyl (both os by 1-3 T, Tc or T-COOT); or (xi) -CO-Q;  Q  = (i) H, OH, alkoxy or -T-piperazino; (ii) O-Cy, alkyl or Cy (both os by COOH); (iii) Ph (os by halo, T, Tc, OT or COOH); (iv) NH2, NH-alkyl, NH-Tc, NH-Cy, NH-Ph or NH-Het (all os on N by alkyl, Cy, -T-Ph, -Tc, (CH2)2N(T)2, (CH2)3-N(T)2, N(T)2, (CH2)2N(T)-Tc, (CH2)3-N(T)-Tc, N(T)-Tc, Ph, pyridyl, pyrrolidinyl or piperidinyl); (v) pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl (all os by 1 or 2 T and optionally fused to a benzene ring); (vi) 5-8C bicycloalkyleneimino, morpholino, piperazino, dihydropyrazolo, tetrahydropyrazolo, tetrahydroisoxazolo, tetrahydropyrazinyl or tetrahydropyridazinyl (all os by T or -Tc); or (vii) 3-6C cycloalkyleneimino (os by T, Tc, OH, -T-OH, NH2, COOH, -T-OTc, -T-NHTc or -T-CONH-Tc);  R3  = H, halo, CHO, CF3, N(T)2, -N(T')-(1-4C alkanoyl), T (os by OH, OT, COOH, OTc, N(T')Tc or CONHTc), 2-3C alkenyl (os by COOH or CONHTc) or N-(OTc or NHCONH2)-carbimino (os on C by T); or R2 + R3  = COOCH2 or COOCH2CH2;  R4  = H, halo, T, Cy, CF3 or OT;  X  = O, S, C(T')2, CO, SO, SO2, NH, N(T) (os in the 2- or 3-position of T by N(T')2, or N(T')-(1-4C) alkanoyl) or N(Tc);  Y  = amino-substituted cyclohexyl, R5-substituted Ph (os by halo, T or OT) or R5-substituted Het (os by T);  R5  = H or CN; or NH2, -T-NH2, amidino, guanidino or -T-guanidino (all os by an in vivo cleavable group);  Het  = heteroaryl, i. e. (i) 5-membered heteroaryl (os by 1 or 2 T; and containing one N(T'), O or S and optionally 1 or 2 further N) or its partially hydrogenated (specifically dihydro) derivative, (ii) 6-membered heteroaryl containing 1-3 N or (iii) a group (i) or (ii) fused to a benzene ring;  T  = 1-3C alkyl;  T'  = H or T;  Tc  = 1-3C carboxyalkyl;  Cy  = 3-7C cycloalkyl;  unless specified otherwise alkyl moieties have 1-5C; all COOH groups are optionally replaced by tetrazolyl or groups convertible into COOH in vivo; all imino or amino groups are optionally substituted by groups cleavable in vivo.  An Independent claim is included for the preparation of (I).