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Method for the production of pyrrolidine-1,2-dicarboxylic acid-1-(phenyl(-amide))-2-(phenyl(-amide)) derivatives and 1-(phenylcarbamoyl)-pyrrolidine-2-carboxylic acid derivatives as intermediate products
Method for the production of pyrrolidine-1,2-dicarboxylic acid-1-(phenyl(-amide))-2-(phenyl(-amide)) derivatives and 1-(phenylcarbamoyl)-pyrrolidine-2-carboxylic acid derivatives as intermediate products
1,2-bis(phenylaminocarbonyl)-pyrrolidine compounds (I) and their derivatives, salts, solvates and stereoisomers, including their mixtures in all proportions, are new. [Image] R : hydrogen, X, A, XCO- or ACO-; R 1hydrogen, oxo, X, A, hydroxy, OA, ACOO-, ACONH-, ACONA-, azido, amino, nitro, cyano, carboxy, COOA, CONH 2, CONA 2, allyloxy, propargyloxy, benzyloxy, =N-OH, =N-OA, -OCH 2CHOHCH 2OH, AOCO-(CH 2) mO-, -O(CH 2) mCOOH or -O(CH 2) mOA; R 2hydrogen, halo or A; R 3monocyclic, (un)saturated or aromatic heterocycle with 1-4 nitrogen, oxygen and/or sulfur, optionally substituted by 1-3 of halo, A, OA, cyano, (CH 2) nOH, NR 4R 5, =NH, =N-OH, =N-OA, COOA and/or oxo, or its is CONR 4R 5, or R 2 and R 3 together form -CH=CH-NH- or CH 2CH 2-NH, where one hydrogen can be replaced by ACO- or AOCO-; R 4 and R 5hydrogen or A, or together form a 3-5C alkylene, optionally substituted by A, halo, OA and/or oxo; X : aryl, aralkyl, Het or Het-alkyl; aryl : (bi)phenyl or naphthyl, optionally substituted by 1-3 of halo, A, hydroxy, amino, nitro, cyano, COOH, CONH 2, NHCOA, NHCONH 2, NHSO 2A, CHO, COA, SO 2NH 2, SO 2A, -CH 2COOH or -OCH 2COOH; Het : mono- or bi-cyclic, (un)saturated or aromatic heterocycle with 1-4 N, O and/or S atoms, optionally substituted by 1-3 of halo, A, benzyl, cycloalkyl, hydroxy, amino, NHCONH 2, nitro, cyano, -CH 2COOH, -CH 2CONH 2, NHCOA, NR 3SO 2A, CHO, SO 2NH 2, SO 2A and/or oxo; A : 1-10C linear, branched or cyclic alkyl with up to 7 hydrogen replaced by fluoro and/or chloro; halo : fluoro, chloro, bromo or iodo; m : 1-6; n : 0-6. Independent claims are also included for the following: (1) three methods for preparing (I); and (2) kit comprising, in separate containers, a dose of (I) and a dose of another pharmaceutical. ACTIVITY : Thrombolytic; Anticoagulant; Cardiant; Antiarteriosclerotic; Antiinflamamtory; Cerebroprotective; Antianginal; Vasotropic; Antimigraine; Auditory; Cytostatic; Antidiabetic. MECHANISM OF ACTION : Inhibition of coagulation factors, particularly Xa but also VIIa, IXa and thrombin. The compound (2R,4R)-4-methoxypyrrolidin-1,2-dicarboxylic acid 1-[(4-ethynylphenyl)amide]-2-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]amide} had IC50 against factor Xa of 1.3 nM and against tissue factor/factor VIIa 1.9 nM.
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机译：1,2-双（苯基氨基羰基）-吡咯烷化合物（I）及其衍生物，盐，溶剂化物和立体异构体，包括其所有比例的混合物，都是新的。 [图像] R：氢，X，A，XCO-或ACO-; R 1>氢，氧，X，A，羟基，OA，ACOO-，ACONH-，ACONA-，叠氮基，氨基，硝基，氰基，羧基，COOA，CONH 2，CONA 2，烯丙氧基，炔丙基氧基，苄氧基= N -OH，= N-OA，-OCH 2 CHOHCH 2OH，AOCO-（CH 2）mO-，-O（CH 2）mCOOH或-O（CH 2）mOA; R 2＞氢，卤素或A; R 3>具有1-4个氮，氧和/或硫的单环，（不）饱和或芳族杂环，任选被1-3个卤素，A，OA，氰基，（CH 2）nOH，NR 4> R 5取代>，= NH，= N-OH，= N-OA，COOA和/或氧代，或其为CONR 4> R 5>或R 2>和R 3>一起形成-CH = CH-NH-或CH 2CH 2-NH，其中一个氢可以被ACO-或AOCO-取代; R 4和R 5氢或A，或一起形成3-5C亚烷基，任选被A，卤素，OA和/或氧代取代; X：芳基，芳烷基，Het或Het-烷基;芳基:(联）苯基或萘基，可选地被1-3个卤素，A，羟基，氨基，硝基，氰基，COOH，CONH 2，NHCOA，NHCONH 2，NHSO 2A，CHO，COA，SO 2NH 2，SO取代2A，-CH 2COOH或-OCH 2COOH; Het：具有1-4个N，O和/或S原子的单或双环，（不）饱和或芳族杂环，任选被1-3个卤素，A，苄基，环烷基，羟基，氨基，NHCONH 2取代，硝基，氰基，-CH 2COOH，-CH 2CONH 2，NHCOA，NR 3> SO 2A，CHO，SO 2NH 2，SO 2A和/或氧代; A：1-10C的直链，支链或环状烷基，最多有7个氢被氟和/或氯取代;卤素：氟，氯，溴或碘; m：1-6; n：0-6。还包括以下方面的独立权利要求：（1）三种制备方法（I）; （2）试剂盒，在单独的容器中包含一定剂量的（I）和一定剂量的另一种药物。活动：溶栓;抗凝物;卡迪恩抗动脉硬化;抗炎药;脑保护抗心绞痛变压性抗偏头痛;听觉细胞抑制抗糖尿病。作用机理：抑制凝血因子，特别是Xa，但也抑制VIIa，IXa和凝血酶。化合物（2R，4R）-4-甲氧基吡咯烷基-1,2-二羧酸1-[（（4-乙炔基苯基）酰胺] -2-{[[4-（2-氧代-2H-吡啶-1-基）苯基]]酰胺}对Xa因子的IC50为1.3 nM，对组织因子/ VIIa因子的IC50为1.9 nM。
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