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New N-substituted benzamide derivatives are tyrosine kinase KDR and FLT inhibitors useful e.g. for treating tumors, psoriasis, rheumatoid arthritis, diabetic retinopathy or liver sclerosis
New N-substituted benzamide derivatives are tyrosine kinase KDR and FLT inhibitors useful e.g. for treating tumors, psoriasis, rheumatoid arthritis, diabetic retinopathy or liver sclerosis
N-Substituted benzamide derivatives (I) are new. Also new are methyl benzoate derivative intermediates (II). N-Substituted benzamide derivatives (I) (including thioamide, amine and amidine analogs) are new. [Image] W : O, S, H 2 or NR 8; Z 1a direct bond, =NR 10, =N-, optionally branched 1-12C alkyl or -(CR aR b) m-(CR cR d) n-(CR eR f) o-; m, n, o : 0-3; R a-R fH, F, 1-4C alkyl or =NR 10; or R a + R c and/or R d + R ea bond; or 1 or 2 of R a-R fupto 3C bridge with R 1 or R 7; R 1alkyl, 2-12C alkenyl, 3-12C alkynyl, 3-10C cycloalkyl or 3-10C cycloalkenyl (all optionally substituted by at least one of halo and alkyl), or aryl or heteroaryl (both optionally substituted by one or more of halo, alkyl, 1-alkoxy, mono- or polyhaloalkyl and mono- or polyhaloalkoxy); R 2, R 3H, OH or XR 11; X : 2-6C alkyl, 2-6C alkenyl or 2-6C alkynyl; R 11mono- or bicyclic aryl or heteroaryl (all os by one or more of halo, alkyl, alkoxy or OH); R 4-R 6H or halo; or alkoxy, alkyl or carboxyalkyl (all optionally substituted by one or more halo), or R 4 + R 5methylenedioxy; R 7H or alkyl, or forms an up to 3C bridge with R a-R f or R 1; R 8, R 10H or alkyl; alkyl moieties have 1-6C unless specified otherwise; provided that: (i) R 2/R 3 are not H/H, H/OH or OH/H and (ii) R 1 = is not triazole. An independent claim is included for new methyl benzoate derivative intermediates of formula (II) and their isomers and salts. [Image] R 2', R 3'H or XR 11', but not both H, and R 11'phenyl or pyridyl (both optionally substituted by alkyl). - ACTIVITY : Cytostatic; antipsoriatic; antirheumatic; antiarthritic; ophthalmological; antidiabetic; nephrotropic; immunosuppressive; antiinflammatory; hepatotropic; antiarteriosclerotic; neuroprotective. - MECHANISM OF ACTION : Tyrosine kinase KDR inhibitor; tyrosine kinase FLT inhibitor; vascular endothelial growth factor (VEGF) receptor phosphorylation inhibitor. N-(4-n-propylphenyl)-2-(4-pyridylethyl)-benzamide (Ia) exhibited an IC 50 value 0.2 mu M for inhibition of both tyrosine kinases KDR and FLT.
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机译:N-取代的苯甲酰胺衍生物(I)是新的。苯甲酸甲酯衍生物中间体(II)也是新的。 N-取代的苯甲酰胺衍生物(I)(包括硫代酰胺,胺和am类似物)是新的。 [图像] W:O,S,H 2或NR 8; Z 1>直接键,= NR 10,= N-,任选地分支的1-12C烷基或-(CR aR b)m-(CR cR d)n-(CR eR f)o-; m,n,o:0-3; R a-R fH,F,1-4C烷基或= NR 10; R a + R c和/或R d + R ea键;或或具有R 1或R 7的R a-R ftoto 3C桥中的1或2个; R 1烷基,2-12C烯基,3-12C炔基,3-10C环烷基或3-10C环烯基(均可选地被卤素和烷基中的至少一个取代),或芳基或杂芳基(均可选地被一个或多个卤素取代) ,烷基,1-烷氧基,单或多卤代烷基和单或多卤代烷氧基); R 2,R 3H,OH或XR 11; X:2-6C烷基,2-6C烯基或2-6C炔基; R 11为单环或双环芳基或杂芳基(所有os为卤素,烷基,烷氧基或OH中的一个或多个); R 4-R 6H或卤素;烷氧基,烷基或羧基烷基(全部任选地被一个或多个卤素取代),或R 4 + R 5亚甲基二氧基;或R 7H或烷基,或与R a-R f或R 1形成高达3C的桥; R 8,R 10H或烷基;除非另有说明,否则烷基部分具有1-6C;前提是:(i)R 2 / R 3不是H / H,H / OH或OH / H,并且(ii)R 1 =不是三唑。对于式(II)的新的苯甲酸甲酯衍生物中间体及其异构体和盐,包括独立的权利要求。 [图像] R 2',R 3'H或XR 11',但不同时包括H和R 11'苯基或吡啶基(均被烷基取代)。 -活动:细胞抑制;牛皮癣抗风湿性抗关节炎眼科的抗糖尿病嗜肾免疫抑制消炎(药;促肝的抗动脉硬化;具有神经保护作用。 -作用机理:酪氨酸激酶KDR抑制剂;酪氨酸激酶FLT抑制剂;血管内皮生长因子(VEGF)受体磷酸化抑制剂。 N-(4-正丙基苯基)-2-(4-吡啶乙基)-苯甲酰胺(Ia)的IC 50值为0.2μM,可抑制酪氨酸激酶KDR和FLT。
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