首页> 外国专利> New 2-pyridin-2-yl-pyrazol-3(2H)-one compounds are hypoxia inducible factor activators useful to treat e.g. lower limb ischemia, angina pectoris, myocardial infarction, atherosclerosis, pulmonary hypertension, glaucoma and kidney diseases

New 2-pyridin-2-yl-pyrazol-3(2H)-one compounds are hypoxia inducible factor activators useful to treat e.g. lower limb ischemia, angina pectoris, myocardial infarction, atherosclerosis, pulmonary hypertension, glaucoma and kidney diseases

机译：新的2-吡啶-2-基-吡唑-3（2H）-一化合物是可用于治疗例如缺氧的缺氧诱导因子激活剂。下肢缺血，心绞痛，心肌梗塞，动脉粥样硬化，肺动脉高压，青光眼和肾脏疾病

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2-Pyridin-2-yl-pyrazol-3(2H)-one compounds (I) and their base or acid addition salts are new. 2-Pyridin-2-yl-pyrazol-3(2H)-one compounds of formula (I) and their base or acid addition salts are new. R : -SO 2-NR3R4, H, halo, halo-1-5C alkyl, CO 2R5 or -SO 2-R4; R1 : -W1-(3-6C) cycloalkyl, heterocycloalkyl group not containing nitrogen atom or -W1-aryl, -W1-heteroaryl, -W1-heterocycloalkyl, -W1-COOR5-, or -W1-CONR5R6- (where the aryl, heteroaryl and heterocycloalkyl are optionally substituted on a carbon atom by one or more substituents of halo, (1-5C)alkyl, -(1-5C)alkylene-O-(1-5C)alkyl, (1-5C)alkoxy, hydroxy, halo(1-5C)alkyl, CN, -O(1-5C)alkylene-O-(1-5C)alkyl, -O-(1-5C)alkyl-NR5R6, -SO 2-(1-5C)-alkyl, NR5R6 or -CO 2R5), when R1 is heterocycloalkyl comprising N, then it optionally bearing a substituent comprising 1-5C alkyl; R2 : H, 1-5C alkyl, -(1-5C)alkylene-O-(1-5C)alkyl, halo(1-5C)alkyl, -W1-COOR5, -W1-CONHR5, or -W1-CO-NR5R6; n : 0-2; W1 : 1-5C alkylene (optionally substituted by -(CH 2) n-CO 2-R5 or -(CH 2) n-CO-NR5R6) or 3-6C cycloalkylene; either R3, R4 : H, (1-5C)alkyl, 3-6C cycloalkyl, -(1-5C)alkylene-O-(1-5C)alkyl, aryl, -CH 2-aryl, heteroaryl, heterocycloalkyl, -W1-OH, -W1-CHOH-CH 2OH, -W1-CO 2-R5, -W1-R5R6 or -W1-O-(CH 2) n-aryl, where the cycloalkyl and heterocycloalkyl are optionally substituted on at least one carbon atom by (1-5C)alkyl, (1-5C)alkoxy, OH, -W1-R5R6 or -W1-CO 2-R5 and on at least one heteroatom comprising N optionally substituted by at least one 1-5C alkyl in heterocycloalkyl group, provided that when R3 and R4 are same, they cannot be a hydrogen atom; or NR3R4 : heterocycloalkyl optionally substituted on at least one carbon atom and/or, where appropriate, on at least one heteroatom by at least one (1-5C) alkyl and -CH 2-aryl; R5, R6 : H, 1-5C alkyl, or halo-1-5C alkyl; either R3, R4 : H, (1-5C)alkyl, (3-6C) cycloalkyl, -(1-5C)alkyl-(1-5C) alkoxy, aryl, -CH 2-aryl or heteroaryl; or NR3R4 : heterocycloalkyl optionally substituted on C or heteroatom by one or more substituents of 1-5C alkyl or -CH 2-aryl; and R5, R6 : H or (1-5C)alkyl. Provided that (I) excludes: 4-benzyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(2,4-dichlorobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(4-methoxybenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(4-bromobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 2-(pyridin-2-yl)-4-[2-(trifluoromethyl)benzyl]-1,2-dihydro-3H-pyrazol-3-one, 4-(4-chlorobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4- (1,3-benzodioxol-5-ylmethyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(3-methylbenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(2-chlorobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(4-methylbenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(3-chlorobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-(4-tert-butylbenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-benzyl-5-methyl-2-(pyridin-2-yl)-1, 2-dihydro-3H-pyrazol-3-one, 5-methyl-4-(1-phenylethyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one, 4-benzyl-2-(6-chloropyridin-2-yl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one, and 4-{1-[4-(diethylamino)phenyl]ethyl}-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one. Independent claims are included for: (1) the preparation of (I); (2) a combination of (I) with one or other active compounds useful in the treatment of hypertension, heart failure, diabetes and anemia; and (3) process of homogeneous test for direct measurement by beta-galactosidase complementation of the amount of hypoxia-inducible factor-1 (HIF1) alpha protein in the cell nucleus, preferably human embryonic kidney (HEK) cells, after treatment of cells by one of the compounds to be tested, comprising: (a) inoculating, the cells in a suitable culture medium; (b) adding compounds to be tested to an appropriate concentration in an appropriate solvent to cells previously inoculated in culture medium; (c) incubating cells thus prepared in an incubator at 37[deg] C, preferably for 6 hours; (d) lysing the cells with a lysis buffer containing a chemiluminescent substrate of the beta-galactosidase; (e) incubating in the dark before reading and measuring the luminescence which is depending on the activity of beta galactosidase. [Image] ACTIVITY : Cardiovascular-Gen.; Vasotropic; Cardiant; Antianginal; Antiarteriosclerotic; Cerebroprotective; Hypotensive; Respiratory-Gen.; Ophthalmological; Nephrotropic; Neuroprotective; Antianemic; CNS-Gen.; Muscular-Gen.; Antidiabetic. MECHANISM OF ACTION : Hypoxia inducible factor (HIF) activator. The ability of (I) to activate the HIF was tested using erythropoietin kit. The results showed that 6-(4-(3-[2-(dimethylamino)ethoxy]benzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-ethyl-N- phenylpyridine-3-sulfonamide hydrochloride exhibited EC 5 0 value of 2E-06 M.

机译：2-吡啶-2-基-吡唑-3（2H）-一化合物（I）及其碱或酸加成盐是新的。式（I）的2-吡啶-2-基-吡唑-3（2H）-一化合物及其碱或酸加成盐是新的。 R：-SO 2 -NR 3 R 4，H，卤素，卤素-1-5C烷基，CO 2R5或-SO 2-R4; R1：-W1-（3-6C）环烷基，不含氮原子的杂环烷基或-W1-芳基，-W1-杂芳基，-W1-杂环烷基，-W1-COOR5-或-W1-CONR5R6-（其中芳基，杂芳基和杂环烷基在碳原子上任选地被卤素，（1-5C）烷基，-（1-5C）亚烷基-O-（1-5C）烷基，（1-5C）烷氧基，羟基，卤代（1-5C）烷基，CN，-O（1-5C）亚烷基-O-（1-5C）烷基，-O-（1-5C）烷基-NR5R6，-SO 2-（1-5C ）-烷基，NR 5 R 6或-CO 2 R 5），当R 1是包含N的杂环烷基时，则其任选地带有包含1-5C烷基的取代基; R 2：H，1-5C烷基，-（1-5C）亚烷基-O-（1-5C）烷基，卤代（1-5C）烷基，-W1-COOR5，-W1-CONHR5或-W1-CO- NR5R6; n：0-2; W1：1-5C亚烷基（任选地被-（CH 2）n-CO 2-R5或-（CH 2）n-CO-NR5R6取代）或3-6C亚环烷基; R 3，R 4：H，（1-5C）烷基，3-6C环烷基，-（1-5C）亚烷基-O-（1-5C）烷基，芳基，-CH 2-芳基，杂芳基，杂环烷基，-W1 -OH，-W1-CHOH-CH 2OH，-W1-CO 2-R5，-W1-R5R6或-W1-O-（CH 2）n-芳基，其中环烷基和杂环烷基任选在至少一个碳上被取代原子被（1-5C）烷基，（1-5C）烷氧基，OH，-W1-R5R6或-W1-CO 2-R5所取代，并且在至少一个包含N的杂原子上，该杂原子可选地被杂环烷基中的至少一个1-5C烷基取代基团，条件是当R3和R4相同时，它们不能为氢原子;或NR 3 R 4：杂环烷基，其任选地在至少一个碳原子上和/或在适当的情况下在至少一个杂原子上被至少一个（1-5C）烷基和-CH 2-芳基取代; R5，R6：H，1-5C烷基或卤代1-5C烷基; R3，R4：H，（1-5C）烷基，（3-6C）环烷基，-（1-5C）烷基-（1-5C）烷氧基，芳基，-CH 2-芳基或杂芳基;或NR 3 R 4：在C或杂原子上任选地被一个或多个1-5C烷基或-CH 2-芳基取代基取代的杂环烷基;或R 5，R 6：H或（1-5C）烷基。前提是（I）不包括：4-苄基-2-（吡啶-2-基）-1,2-二氢-3H-吡唑-3-酮，4-（2,4-二氯苄基）-2-（吡啶- 2-基）-1,2-二氢-3H-吡唑-3-一，4-（4-甲氧基苄基）-2-（吡啶-2-基）-1,2-二氢-3H-吡唑-3-一，4-（4-溴苄基）-2-（吡啶-2-基）-1,2-二氢-3H-吡唑-3-酮，2-（吡啶-2-基）-4- [2-（三氟甲基））苄基] -1,2-二氢-3H-吡唑-3-酮，4-（4-氯苄基）-2-（吡啶-2-基）-1,2-二氢-3H-吡唑-3-酮， 4-（1,3-苯并二恶唑-5-基甲基）-2-（吡啶-2-基）-1,2-二氢-3H-吡唑-3-酮，4-（3-甲基苄基）-2-（吡啶-2-基）-1,2-二氢-3H-吡唑-3-一，4-（2-氯苄基）-2-（吡啶-2-基）-1,2-二氢-3H-吡唑-3-一，4-（4-甲基苄基）-2-（吡啶-2-基）-1,2-二氢-3H-吡唑-3-一，4-（3-氯苄基）-2-（吡啶-2-基）-1,2-二氢-3H-吡唑-3-one，4-（4-叔丁基苄基）-2-（吡啶-2-基）-1,2-二氢-3H-吡唑-3-酮， 4-苄基-5-甲基-2-（吡啶-2-基）-1、2-二氢-3H-吡唑-3-酮，5-甲基-4-（1-苯乙基）-2-（吡啶-2 -基）-1,2-二氢-3H-吡唑-3-一，4-苄基-2-（6-氯吡啶-2-基）-5-甲基-1,2-二氢-3H-吡唑-3-酮和4- {1- [4-（二乙氨基）苯基]乙基} -5-甲基-2-（吡啶-2-基）-1，2-二氢-3H-吡唑-3-一。独立索赔包括：（1）（I）的制备; （2）（I）与一种或多种用于治疗高血压，心力衰竭，糖尿病和贫血的活性化合物的组合; （3）通过β-半乳糖苷酶互补直接测定细胞核（优选人胚肾（HEK）细胞）中的缺氧诱导因子-1（HIF1）α蛋白含量的均质测试方法，一种待测试的化合物，包括：（a）将细胞接种在合适的培养基中; （b）将适当浓度的待测化合物在适当的溶剂中添加到预先接种在培养基中的细胞中; （c）将由此制备的细胞在培养箱中于37℃孵育6小时; （d）用含有β-半乳糖苷酶化学发光底物的裂解缓冲液裂解细胞; （e）在黑暗中孵育，然后阅读并测量取决于β半乳糖苷酶活性的发光。 [图像]活动：心血管创。变压性卡迪恩抗心绞痛抗动脉硬化;脑保护降压;呼吸器;眼科嗜肾具有神经保护作用;抗贫血; CNS-Gen .;肌肉型;抗糖尿病。作用机理：缺氧诱导因子（HIF）激活剂。使用促红细胞生成素试剂盒测试了（I）激活HIF的能力。结果表明6-（4-（3- [2-（二甲基氨基）乙氧基]苄基）-3-甲基-5-氧代-2,5-二氢-1H-吡唑-1-基）-N-乙基- N-苯基吡啶-3-磺酰胺盐酸盐的EC 5 0值为2E-06M。

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公开/公告号FR2949466A1

专利类型
公开/公告日2011-03-04

原文格式PDF
申请/专利权人 SANOFI AVENTIS;
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申请/专利号FR20090004092
发明设计人 ALTENBURGER JEAN MICHEL;FOSSEY VALERIE;ILLIANO STEPHANE;MANETTE GERALDINE;
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申请日2009-08-28
分类号C07D401/04;C07D409/14;C07D401/14;C07D213/71;C07D213/06;C07D231/08;C07D333/48;A61K31/4439;A61P9;A61P13/12;A61P25/28;
国家 FR
入库时间 2022-08-21 17:45:52

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