Patent DE-10124867-A1 (DE)
Title: New substituted (hetero)aryl-alkenes or -alkynes, used as thrombin inhibitors, serine protease inhibitors, antithrombotic agents and intermediates
Inventor: PRIEPKE HENNING
IPC: C07C311/37
Filed: 2001-05-22
Abstract: (Hetero)aryl-substituted 1-(phenyl or pyridyl)-alk-1-ene or alk-1-yne derivatives (I) are new.  Substituted (hetero)aryl alkenes or alkynes of formula (I) and their tautomers, stereoisomers, mixtures and salts are new. A = ethynylene or ethylene; R1 = H, T, G, Ph, -T-Ph, Het, -T-Het, -T-CONTT' or -T-(4-7C cyclalkyleneiminocarbonyl); Ar = phenyl or pyridyl, both substituted by R2-R4; R2 = 1-6C alkyl or -T-Cy (both optionally substituted in the alkyl part by COOH, N(T')2, N(T')-G, NH-Cy, pyrrolidino, piperidino or hexamethyleneimino) carboxyalkyl (substituted in the alkyl by NTT', pyrrolidino, piperidino or hexamethyleneimino or having one CH2 of alkyl replaced by 3-6C cycloalkylidene), Ph or Het (both optionally substituted by halo, CF3, T, G, OT, SO2T or SO2NT'2), mono- or dialkylamino, NHG, N(alkyl)-G, NH-Cy, N(G)-Cy, NHCOCy, N(T'')-alkylcarbonylamino or N(T'')-cycloalkylcarbonylamino, 5-7 membered cycloalkyleneimino, NH2, NH-alkyl or NH-Cy (all optionally substituted on N by CO-alkyl, COG or CONHG, the alkyl parts of CO-alkyl or COG being optionally substituted by NH2, OH, OG, CONHG, NT'G, or -NHCO-T-NH2), or -CO-Q; Q = alkyl or Cy (both optionally substituted by COOH), Ph (optionally substituted by halo, T, G, OT, COOH, SO2T or SO2NT'2), NH2, NH-alkyl, NH-G or NH-Cy (all optionally substituted on N by alkyl, Cy, G, -(1-4C) alkyl-NHT', (CH2)2N(T)2, (CH2)3-N(T)2, Ph, pyridyl, pyrrolidinyl, piperidinyl, 2,5-dihydro-1H-pyrrolyl or 1,2,5,6-tetrahydropyridinyl), pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl (all optionally substituted by 1-2 T and optionally fused to a benzene ring), or 3-6C cycloalkyleneimino (optionally substituted by T, G, OH, -T-OH, NH2, COOH, -T-OG, -T-NHG or -T-CONH-G, provided that OH or NH2 groups are not in the 2-position); R3 = H, halo, CHO, CF3, mono- or di-(1-2C alkyl)-amino or (1-2C) alkanoylamino; or T, 2-4C alkenyl, 2-4C alkynyl or 3-4C cycloalkyl (all optionally substituted by OT', COOH, OG or CONHG); R4 = H, halo, T, Cy, CF3 or OT; X = O, S, CT'2, CO, SO, SO2, NH, NT (optionally substituted in T by Ph or pyridyl), N(COT), N(COG), N(T-CONHT), di-(1-3C alkylamino)-carbonyl (sic) or 1-3C alkylimino (sic); R5 = H, CN, or -T-NH2 or amidino (both optionally substituted by an in vivo cleavable group); Y1-Y4 = CR or N, provided that not more than two R groups are N; R = H, F, Cl, Br, 1-3C n-alkyl, OT' or NT'2, provided that not more than two R groups are other than H; or R5+R (in the 4-position relative to X) = -C(NH2)=N-X'- (with X' bonded at the 4-position relative to X); X' = CH2, CH2CH2, O, NH or CH=CH; Het = 5-membered heteroaryl (optionally substituted by 1-2 T, and containing one N(T'), O or S and optionally 1-2 further N) or its partially hydrogenated (specifically dihydro) derivative, or 6-membered heteroaryl containing 1-3 N (all optionally fused to a benzene ring); T = 1-3C alkyl; T' = H or T; G = 1-3C carboxyalkyl; Cy = 3-7C cycloalkyl; and T'' = 1-3C alkyl (optionally substituted by COOH, CON(T')-G or (other than on the  alpha -C) OH, OG, NH2 or N(T')-G). 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; all methyl or methoxy groups are optionally substituted by 1-3 F.  An Independent claim is also included for the preparation of (I).