| 摘要 |
<p>Pyrazolidine-1,2-dicarboxylic acid diamide derivatives (I) are new. Pyrazolidine-1,2-dicarboxylic acid diamide derivatives of formula (I), and their derivatives, salts, solvates and stereoisomers (including mixtures in all proportions), are new. [Image] R : H, A, COA, halo, ethynyl, -CC-A or -CC-COA; R 1>H, =O, A, OH, OA, OCOA, OCO(CH 2) nPh', OCO(CH 2) n-cycloalkyl, NHCOA, N(A)COA, N(A)COPh', N 3, NH 2, NO 2, CN, COOH, COOA, CONH 2, CONHA, CON(A) 2, allyloxy, propargyloxy, benzyloxy, =N-OH, =N-OA or b=CF 2; Ph' : phenyl (optionally substituted (os) by 1-3 of A, OA or halo); R 2>H, halo or A; R 3>saturated, unsaturated or aromatic heterocycle containing 1-4 of N, O and/or S (os by 1-3 of halo, A, OA, CN, (CH 2) nOH, (CH 2) n-halo, NR 4>R 5>, =NH, =NOH, =NOA and/or =O); or CONR 4>R 5>; R 4>, R 5>H or A; R 4>+R 5>3-5C alkylene chain (os by A, halo, OA and/or =O); A : 1-10C linear, branched or cyclic alkyl, optionally substituted by 1-7 F; n : 0-4. Independent claims are also included for: (a) the preparation of (I); (b) pyrazolidine-1-carboxamide intermediates of formulae (III-1) and (III-2), and their isomers and salts, as new compounds, provided that if R 1> = OH then the OH group is protected and (in (III-2)) if R 1> = H then R is not Cl; (c) N-protected pyrazolidine intermediates of formula (VI), and their isomers, as new compounds; and (d) the preparation of (VI). [Image] R 1> 1>OH or OR 6>; R 6>silyl protecting group; R 7>tert. butoxycarbonyl (BOC) or benzyloxycarbonyl (Z). ACTIVITY : Thrombolytic; Anticoagulant; Cardiant; Antiarteriosclerotic; Antiinflammatory; Cerebroprotective; Antianginal; Vasotropic; Antimigraine; Cytostatic; Antiarthritic; Antidiabetic. MECHANISM OF ACTION : Factor Xa inhibitor; Factor VIIa inhibitor. In receptor affinity assays, pyrazolidine-1,2-dicarboxylic acid 1-(4-bromophenyl)-amide) 2-((4-(2-oxo-2H-pyridin-1-yl)-phenyl)-amide) (Ia) had IC 5 0 of 55 nM for factor Xa and 120 nM for factor VIIa.</p> |
