Preparation of pyrrolidine-1,2-dicarboxanilide derivatives for use as factor Xa inhibiting antithrombotic agents, comprises reacting pyrrolidine-2-carboxylic acid with phenyl isocyanate then aniline derivative

摘要

Preparation of pyrrolidine-1,2-dicarboxylic acid dianilide derivatives (I) involves reacting a pyrrolidine-2-carboxylic acid (II) with a phenyl isocyanate (III) and then reacting the obtained 1-phenylcarbamoyl-pyrrolidine-2-carboxylic acid (IV) with an aniline derivative (V). The intermediates (IV) are new compounds. The preparation of pyrrolidine-1,2-dicarboxylic acid dianilide derivatives of formula (I), or their derivatives, solvates or stereoisomers (including mixtures in all proportions), involves: (a) reacting a pyrrolidine-2-carboxylic acid of formula (II) with an isocyanate of formula (III); and (b) reacting the obtained 1-phenylcarbamoyl compound of formula (IV) with an aniline derivative of formula (V). [Image] [Image] [Image] R : halo or ethynyl; R 1H, =O, halo, A, OH, OA, OCO-A, NHCO-A, N(A)CO-A, N 3, NH 2, NO 2, CN, COOH, COOA, CONH 2, CONHA, CON(A) 2, allyloxy, propargyloxy, benzyloxy, =N-OH or =N-OA; R 2H, halo or A; R 32-oxo-piperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2-oxo-1H-pyridin-1-yl, 3-oxo-morpholin-4-yl, 4-oxo-1H-pyridin-1-yl, 2-oxo-1H-pyrazin-1-yl, 2-oxo-imidazolidin-1-yl, 2-imino-piperidin-1-yl, 2-imino-pyrrolidin-1-yl, 3-imino-morpholin-4-yl, 2-imino-imidazolidin-1-yl, 2-imino-1H-pyrazin-1-yl, 2,6-dioxo-piperidin-1-yl, 2-oxo-piperazin-1-yl, 2,6-dioxo-piperazin-1-yl, 2,5-dioxo-pyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl, 3-oxo-2H-pyridazin-2-yl, 2-oxo-azepan-1-yl, 2-aza-bicyclo-(2.2.2)-octan-3-on-2-yl, 5,6-dihydro-1H-pyrimidin-2-oxo-1-yl, 2-oxo-(1,3)-oxazinan-3-yl or 4H-(1,4)-oxazin-4-yl (all optionally substituted by 1 or 2 of A or OA); A : 1-10C linear, branched or cyclic alkyl, optionally substituted by 1-7 F. An independent claim is also included for the intermediate (IV), and its derivatives, solvates and stereoisomers (including mixtures in all proportions). ACTIVITY : Thrombolytic; anticoagulant; cardiant; antiarteriosclerotic; antiinflammatory; cerebroprotective; antianginal; vasotropic; cytostatic. MECHANISM OF ACTION : Factor Xa inhibitor; Coagulation inhibitor. No biological data given.