| 摘要 |
<p>Mono- or bicyclic (hetero)aromatic compounds (I), having a side-chain containing two carbocyclic or heterocyclic groups linked via a chain containing an amide, amine or ether group (e.g. 2-phenyl-2H-pyrazole-3-carboxylic acid N-4-(thioxo- or imino-heterocyclyl)-phenyl-amides), are new. Mono- or bicyclic (hetero)aromatic compounds of formula (I) and their derivatives, solvates and stereoisomers (including mixtures in all proportions) are new. [Image] D : saturated or partially or completely unsaturated 3- or 4-membered alkylene, optionally (i) having 1-3 C-atoms replaced by N and/or 1 or 2 C-atoms replaced by O and/or S (provided that not more than 3 C-atoms in total replaced, (ii) substituted on C or N by 1-3 of halo, A, -(C(R3>)2)n-Ar, -(C(R3>)2)n-Het, -(C(R3>)2)n-cycloalkyl, OR2>, N(R2>)2, NO2, CN, COOR2>, CON(R2>)2, NR2>COA, NR2>SO2A, COR2>, SO2NR2> and/or S(O)nA and/or (iii) having one CH2 replaced by CO; or D is absent; M : phenyl ring or aromatic heterocycle containing 1 or 2 of N, O and/or S; R1>, R1>1>H, halo, A, OR2>, N(R2>)2, NO2, CN, COOR2>, CON(R2>)2, CSN(R2>)2, -(C(R3>)2)n-Ar, -(C(R3>)2)n-Het, -(C(R3>)2)n-cycloalkyl, -(C(R3>)2)n-N(R3>)2, -C(=NH)NH2 (optionally monosubstituted by COR3>, COOR3>, OR3>, OCOR3>, OCOOR3> or an amino-protecting group), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl or 5-methyl-1,2,4-oxadiazol-3-yl; R2>H, A, -(C(R3>)2)n-Ar, -(C(R3>)2)n-Het, -(C(R3>)2)n-cycloalkyl, -(C(R3>)2)n-N(R3>)2 or -(C(R3>)2)n-OR3>; R3>H or A; W : mono- or bicyclic saturated, unsaturated or aromatic carbocycle or heterocycle, containing 0-4 of N, O and/or S, optionally substituted (os) by 1 or 2 R2>; X : CONR2>, CONR2>C(R3>)2, C(R3>)2NR2>, C(R3>)2NR2>C(R3>)2, C(R3>)2O, C(R3>)2OC(R3>)2 or NR2>CO; Y : alkylene, cycloalkylene, Het-diyl or Ar-diyl; T : mono- or bicyclic saturated, unsaturated or aromatic carbocycle or heterocycle, containing 0-4 of N, O and/or S, substituted by 1 or 2 of =S, =NR2>, =N-CN, =N-NO2, =NOR2>, =NCOR2>, =NCOOR2> or =N-OCOR2> and os by 1-3 of halo, A, -(C(R3>)2)n-Ar, -(C(R3>)2)n-Het, -(C(R3>)2)n-cycloalkyl, OR3>, N(R3>)2, NO2, CN, COOR2>, CON(R2>)2, NR2>COA, NR2>CON(R2>)2, NR2>SO2A, COR2>, SO2NR2> and/or S(O)nA; A : 1-10C alkyl, optionally having 1 or 2 CH2 groups replaced by O, S and/or CH=CH and os by 1-7 F; Ar : phenyl, naphthyl or biphenylyl (all os by 1-3 of halo, A, OR3>, N(R3>)2, NO2, CN, COOR3>, CON(R3>)2, NR3>COA, NR3>CON(R3>)2, NR3>SO2A, COR3>, SO2N(R3>)2, S(O)mA, -(C(R3>)2)n-COOR2>1> or -O-(C(R3>)2)q-COOR2>1>); R2>1>H, A, -(C(R3>)2)n-Ar', -(C(R3>)2)n-Het', -(C(R3>)2)n-cycloalkyl, -(C(R3>)2)n-N(R3>)2 or -(C(R3>)2)n-OR3>; Ar' : phenyl or benzyl (both os by 1 or 2 halo); Het : mono- or bicyclic saturated, unsaturated or aromatic heterocycle containing 1-4 of N, O and/or S, os by 1-3 of =O, =S, =N(R3>)2, halo, A, -(C(R3>)2)n-Ar, -(C(R3>)2)n-Het', -(C(R3>)2)n-cycloalkyl, -(C(R3>)2)n-OR2>1>, -(C(R3>)2)n-N(R2>1>)2, NO2, CN, -(C(R3>)2)n-COOR2>1>, -(C(R3>)2)n-CON(R2>1>)2, -(C(R3>)2)n-NR2>1>COA, NR2>1>CON(R2>1>)2, -(C(R3>)2)n-NR2>1>SO2A, COR2>1>, SO2NR2>1> and/or S(O)mA; Het' : mono- or bicyclic saturated, unsaturated or aromatic heterocycle containing 1 or 2 of N, O and/or S, os by 1 or 2 of =O, =S, =N(R3>)2, halo, A, OR2>1>1>, N(R2>1>1>)2, NO2, CN, COOR2>1>1>, CON(R2>1>1>)2, -NR2>1>1>COA, NR2>1>1>CON(R2>1>1>)2, NR2>1>1>SO2A, COR2>1>1>, SO2NR2>1>1> and/or S(O)mA; R2>1>1>H, A, -(C(R3>)2)n-Ar', -(C(R3>)2)n-cycloalkyl, -(C(R3>)2)n-N(R3>)2 or -(C(R3>)2)n-OR3>; m, n : 0-2; and q : 1-3. An independent claim is included for the preparation of (I). 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 other serine proteases such as factor IXa and thrombin. In receptor affinity assays, 2-(3-aminomethyl-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid N-(4-(2-imino-piperidin-1-yl)-phenyl)-amide (Ia) had IC50 9.6 nM for factor Xa and 23 nM for factor VIIa.</p> |
