Patent DE-19939463-A1 (DE)
Title: Tryptase inhibitors useful e.g. for treating inflammatory or allergic disease, arteriosclerosis or neoplasia, comprising new or known 2-phenethyl-benzimidazole-5-carboxamides
Inventor: ANDERSKEWITZ RALF
IPC: C07D403/06
Filed: 1999-08-20
Abstract: The use of 2-(2-(4-(amidino or aminomethyl)-phenyl)-ethyl)-benzimidazol-5-yl-carboxylic acid amides (I) as tryptase inhibiting drugs is new.   The use of 2-(2-(4-(amidino or aminomethyl)-phenyl)-ethyl)-benzimidazol-5-yl-carboxylic acid amides of formula (I), including their tautomers, racemates, enantiomers, diastereomers and mixtures or acid addition salts, is claimed for the preparation of medicaments for the treatment or prophylaxis of diseases against which tryptase inhibitors are effective.  R1  = 1-10C alkyl (optionally substituted (os) by 1-3 of alkoxy, phenoxy, hydroxyphenoxy, alkoxyphenoxy, 3-6C cycloalkyl, NH2, mono- or dialkylamino, alkylcarbonylamino, carbamoyl, N-alkylcarbamoyl or benzylcarbonylamino); phenylalkyl (os in the ring by 1-3 of alkyl, CF3, F, Cl, Br, COOH and alkoxycarbonyl); Het; or -(1-4C) alkylene-Het;  Het  = 5- or 6-membered, saturated or unsaturated heterocycle, which contains 1-3 of O, N and S as heteroatom(s); is os by 1-3 of alkyl, phenyl (os by alkyl) or benzyl (os by alkyl); and is optionally fused with a benzene ring;  R2  = -C(=NH)NH2 or CH2NH2; R3, R4  = H; 1-6C alkyl (os by 1 or 2 of COOH, alkoxycarbonyl, 3-6C cycloalkyl, NH2, mono- or dialkylamino, NHPh, N(Ph)2, NHCH2Ph, N(CH2Ph)2, alkylcarbonylamino, C(=NH)NH2 or NHC(=NH)NH2); -(1-4C) alkylene-phenyl (os in the alkylene bridge by Ph, COOH or alkoxycarbonyl; and os in the ring by 1-3 of alkyl, alkoxy, F, Cl, Br, COOH, alkoxycarbonyl, NH2, mono- or dialkylamino, NHPh, N(Ph)2, NHCH2Ph, N(CH2Ph)2, alkylcarbonylamino, C(=NH)NH2 or NHC(=NH)NH2); Het'; -(1-4C) alkylene-Het'; or 3-8C cycloalkyl, naphthyl or phenyl (os by 1-3 of alkyl, alkoxy, phenoxy, benzyloxy, CF3, F, Cl, Br, COOH or alkoxycarbonyl); or NR3R4  = 5-7 membered saturated or unsaturated heterocycle, optionally containing 1 or 2 further O, N or S heteroatom(s) and os by one or more of alkyl, 5-6C cycloalkyl, benzyl (os by alkyl), pyridyl or phenyl (os by alkyl, alkoxy or OH);  Het' = 5-7 membered, saturated or unsaturated heterocycle, which contains 1-4 of O, N and S as heteroatom(s); is os by 1-3 of alkyl, phenyl or benzyl; and is optionally fused with a benzene ring; and unless specified otherwise alkyl and alkoxy moieties have 1-4C.  Independent claims are included for:  (1) (I; R3 = R'3; R4 = R'4) (including their tautomers, racemates, enantiomers, diastereomers and mixtures or acid addition salts) as new compounds; (2) new prodrugs of formula (II) (including their tautomers, racemates, enantiomers, diastereomers and mixtures or acid addition salts); (3) new nitrile intermediates of formula (III); and (4) methods for the preparation of the new compounds (I) and (II).  R'3  = 1-6C alkyl (os by 1 or 2 of NH2, mono- or dialkylamino, NHPh, N(Ph)2, NHCH2Ph, N(CH2Ph)2, alkylcarbonylamino, C(=NH)NH2 or NHC(=NH)NH2); benzyl (os in the ring, directly or via a 1-4C alkylene bridge, by 1 or 2 of NH2, mono- or dialkylamino, NHPh, N(Ph)2, NHCH2Ph, N(CH2Ph)2, alkylcarbonylamino, C(=NH)NH2 or NHC(=NH)NH2); -(2-4C) alkylene-phenyl (os in the alkylene bridge by Ph, COOH or alkoxycarbonyl; and os in the ring by 1 or 2 of NH2, mono- or dialkylamino, NHPh, N(Ph)2, NHCH2Ph, N(CH2Ph)2, alkylcarbonylamino, C(=NH)NH2 or NHC(=NH)NH2); or -(1-4C) alkylene-Het'';  R'4  = H; 1-6C alkyl (os by 1 or 2 of COOH, alkoxycarbonyl or 3-6C cycloalkyl); -(1-4C) alkylene-phenyl (os in the alkylene bridge by Ph; and os in the ring by 1-3 of alkyl, alkoxy, F, Cl, Br, COOH or alkoxycarbonyl); or -(1-4C) alkylene-Het'''; or NR'3R'4  = heterocycle as defined for NR3R4;  Het''  = 5- or 6-membered, saturated or unsaturated heterocycle, which contains 1-3 of O, N and S as heteroatom(s) and is os by 1-3 of alkyl, phenyl or benzyl;  Het'''  = 5-7 membered, saturated or unsaturated heterocycle, which contains one O, N and S heteroatom; is os by 1-3 of alkyl, phenyl or benzyl; and is optionally fused with a benzene ring;  R''3  = as R'3; or alkyl substituted by C(NH2)=NOH, C(NH2)=NCOO-alkyl or C(NH2)=NCOO-alkyl-Ph';  R5  = OH, (1-8C) alkoxycarbonyl or -COO-alkyl-Ph';  Ph'  = phenyl (os by alkyl or alkoxy).