New carbonyl-substituted carbocyclic or heterocyclic compounds, are factor Xa and factor VIIa inhibitors useful e.g. for treating thrombosis, myocardial infarction, arteriosclerosis, inflammation or tumors

摘要

Carbonyl-substituted carbocyclic or heterocyclic compounds (I), having a side-chain terminated by a substituted carbocyclic or heterocyclic group, are new. Also new are related pyrrolidine-carboxylic acid derivatives (IA) and cyclopentane-carboxylic acid derivatives (IB); and new intermediates (I-1) and (I-2). Carbonyl compounds of formula (I) and their derivatives, solvates and stereoisomers (including mixtures in all proportions) are new. [Image] R 1, R 2H, =O, A, ethynyl, OR 3, N(R 3) 2, NO 2, CN, N 3; or R 1 + R 2group completing a bicyclic or spiro-cyclic 3-7 membered carbocycle or heterocycle with 0-3 N, O and/or S atoms; Q : -(C(R 4) 2) n-; R 3H, A, CH 2CCH, CH 2CCMe, CH 2CH(OH)CH 2OH, CH 2CH(OH)CH 2NH 2, CH 2CH(OH)CH 2-Het', -Q-Ar', -Q-Het', -Q-cycloalkyl, -Q-COOA or -Q-N(R 4) 2; R 4H or A; W : N, CR 3 or sp 2-hybridized C; E : group completing a 3-7 membered carbocycle or heterocycle; D : mono- or bicyclic aromatic carbocycle or heterocycle, optionally substituted; G : Q, -Q-NR 3-, -Q-O-, -Q-S- or -(C(R 4)=C(R 4)) n-; X : -Q-CONR 3-Q-, -Q-NR 3CO-Q-, -Q-NR 3-Q-, -Q-O-Q-, -Q-CO-Q- or -Q-COO-Q-; Y : alkylene, cycloalkylene, Het-diyl or Ar-diyl; T : mono- or bicyclic saturated or unsaturated carbocycle or heterocycle, optionally substituted; A : 1-10C alkyl, optionally having 1 or 2 CH 2 groups replaced by O, S or CH=CH and os by 1-7 F; Ar, Ar' : phenyl, naphthyl or biphenylyl (all optionally substituted) and; Het, Het' : mono- or bicyclic saturated, unsaturated or aromatic optionally substituted heterocycle; n : 0-2; o : 1-3. Independent claims are included for: (a) the preparation of (I); (b) the following new pyrrolidine-carboxylic acid derivatives (IA) and their derivatives, solvates and stereoisomers (including mixtures in all proportions): (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-((4-chlorophenyl)-amide) 2-(1'-methyl-(1,4')-bipiperidin-4-yl)-amide); (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-((4-chlorophenyl)-amide) 2-((3,4,5,6-tetrahydro-2H-(1,4')-bipyridin-4-yl)-amide); (2R,4R)-4-ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-((4-chlorophenyl)-amide) 2-((3,4,5,6-tetrahydro-2H-(1,4')-bipyridin-4-yl)-amide); (2R,4R)-4-hydroxy-2-(4-pyridin-4-yl-piperazine-1-carbonyl)-pyrrolidine-1-carboxylic acid (4-chlorophenyl)-amide; (2R,4R)-4-hydroxy-2-(4-(2-methoxyphenyl)-piperazine-1-carbonyl)-pyrrolidine-1-carboxylic acid (4-chlorophenyl)-amide; (2R,4R)-2-(4-(4-fluorophenyl)-piperazine-1-carbonyl)-4-hydroxy-pyrrolidine-1-carboxylic acid (4-chlorophenyl)-amide; (2R,4R)-4-hydroxy-2-(4-hydroxy-4-(4-methoxyphenyl)-piperidine-1-carbonyl)-pyrrolidine-1-carboxylic acid (4-chlorophenyl)-amide; (2R,4R)-4-hydroxy-2-(4-pyridin-2-yl)-piperazine-1-carbonyl)-pyrrolidine-1-carboxylic acid (4-chlorophenyl)-amide; (2R,4R)-2-(4-(4-ethyl-piperazin-1-yl)-piperidine-1-carbonyl)-4-hydroxy-pyrrolidine-1-carboxylic acid (4-chlorophenyl)-amide; (2R,4R)-2-(4-(4,6-diethyl-pyrimidin-2-yl)-piperazine-1-carbonyl)-4-hydroxy-pyrrolidine-1-carboxylic acid (4-chlorophenyl)-amide; (2R,4R)-4-hydroxy-2-(4-(1-methyl-piperidin-4-yl)-piperazine-1-carbonyl)-pyrrolidine-1-carboxylic acid (4-chlorophenyl)-amide; (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-((4-chlorophenyl)-amide) 2-((2-(2-dimethylamino-ethoxy)-4-morpholin-4-yl)-phenyl)-amide); (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-((4-chlorophenyl)-amide) 2-((2-ethoxy-4-morpholin-4-yl-phenyl)-amide); and (c) (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-((4-chlorophenyl)-amide) 2-((4-morpholin-4-yl-2-propoxy-phenyl)-amide); (d) the following new cyclopentane-carboxylic acid derivatives (IB) and their derivatives, solvates and stereoisomers (including mixtures in all proportions): (rac.)-2-(3-(4-chlorophenyl)-ureido)-cyclopentane-carboxylic acid (4-(3-oxo-morpholin-4-yl)-phenyl)-amide; and (rac.)-2-(3-(4-chlorophenyl)-ureido)-cyclopentane-carboxylic acid (3-methyl-4-(3-oxo-morpholin-4-yl)-phenyl)-amide; and (e) new intermediates of formulae (I-1), and (I-2) and their isomers and salts [Image] D 1phenyl, pyridyl, thienyl, imidazolyl or furyl, substituted by halo; R 1 1H, OH, 1-6C alkoxy or ethynyl; R 2 1H, OH, 1-6C alkoxy or 1-6C alkyl; E 1, W 1groups together completing a pyrrolidine-1,2-diyl, piperidine-1,2-diyl or oxazolidine-3,4- or 3,5-diyl ring; G 1(CH 2) n, (CH 2) nNH, CH=CH or CH=CHCH=CH; R 1 2H, =O, COOR 3 2, OH; R 2H, =O, OH, OA' or 1-6C alkyl; or R 1 + R 2a spiro-bonded membered carbocycle; R 3 2H or A'; Y 21,3- or 1,4-phenylene (os); T 2heterocycle substituted by 1 or 2 =O; and A' : 1-6C alkyl. The full definitions are given in the DEFINITIONS (Full Definitions) field. ACTIVITY : Thrombolytic; anticoagulant; cardiant; antiarteriosclerotic; antiinflammatory; cerebroprotective; antianginal; vasotropic; antimigraine; cytostatic; antiarthritic; antidiabetic. MECHANISM OF ACTION : Factor Xa inhibitor; factor VIIa inhibitor. (I) may also inhibit serine proteases such as factor IXa and thrombin. In receptor affinity assays, (R)-pyrrolidine-1,2-dicarboxylic acid 1-(4-chlorophenyl)-amide) 2-((4-(3-oxo-morpholin-4-yl)-phenyl)-amide (Ia) had IC 5 0 18 nM for factor Xa and 23 nM for factor VIIa.