2-(3-phenyl-1H-pyrazol-1-yl)nicotinic acid | 1037828-54-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 2-(3-phenyl-1H-pyrazol-1-yl)nicotinic acid
• 英文别名: 2-(3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxylic acid；2-(3-phenylpyrazol-1-yl)pyridine-3-carboxylic acid
• CAS: 1037828-54-8
• 化学式: C₁₅H₁₁N₃O₂
• 分子量: 265.271
• InChiKey: GECOTWFLLICYCK-UHFFFAOYSA-N

物化性质

• 沸点：
  509.6±40.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  68
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(3-phenyl-1H-pyrazol-1-yl)nicotinic acid 在 lithium hydroxide monohydrate 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 34.0h， 生成 N-(3-hydroxy-4-(methoxyamino)-4-oxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide
  参考文献：
  名称：

  [EN] CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF
  [FR] MODULATEURS DE CALPAÏNE ET LEURS UTILISATIONS THÉRAPEUTIQUES

  摘要：

  小分子钙蛋白酶调节剂化合物，包括其药用可接受的盐，可以包含在药物组合物中。这些化合物可以通过与主体内的CAPN1、CAPN2和/或CAPN9酶接触来抑制钙蛋白酶，或与钙蛋白酶抑制剂竞争性结合。这些化合物和组合物也可以被用于治疗纤维化疾病或纤维化疾病的继发疾病状态或病情。

  公开号：

  WO2019190885A1
• 作为产物：
  描述：

  2-氯烟酸乙酯 在 18-冠醚-6 、 potassium carbonate 、 potassium iodide 、 sodium hydroxide 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 生成 2-(3-phenyl-1H-pyrazol-1-yl)nicotinic acid
  参考文献：
  名称：

  发现新型和高度选择性的钙蛋白酶抑制剂可治疗阿尔茨海默氏病：2-（3-苯基-1 H-吡唑-1-基）-烟酰胺

  摘要：

  钙蛋白酶的过度激活与多种病理疾病有关，包括缺血/再灌注损伤，白内障形成和神经退行性疾病，例如阿尔茨海默氏病（AD）。在本文中，我们描述了我们的努力，从而导致了基于酮酰胺的2-（3-苯基-1 H-吡唑-1-基）烟酰胺与相关半胱氨酸蛋白酶组织蛋白酶，其他蛋白酶和与之相关的半胱氨酸蛋白酶的选择性具有很高的选择性。受体。在一系列与AD相关的临床前模型中，广泛的疗效表明，抑制钙蛋白酶代表了一种有吸引力的方法，具有治疗AD的潜在益处。

  DOI：

  10.1021/acs.jmedchem.7b00731

文献信息

• Carboxamide compounds and their use as calpain inhibitors
  申请人：Kling Andreas

  公开号：US20080234330A1

  公开（公告）日：2008-09-25

  The present invention relates to novel carboxamide compounds and their use for the manufacture of a medicament. The carboxamide compounds are inhibitors of calpain (calcium dependant cysteine proteases). The invention therefore also relates to the use of these carboxamide compounds for treating a disorder associated with an elevated calpain activity. The carboxamide compounds are compounds of the general formula I in which R 1 , R 2 , R 3a , R 3b , W, Y and X have the meanings mentioned in the claims and the description, the tautomers thereof and the pharmaceutically suitable salts thereof. In particular, the compounds have the general formula I-A.a′ and I-A.a″ in which m, E, R 1 , R 3a , R 3b , R 2 , R y , R w and R w6 * have the meanings mentioned in the claims, n is 0, 1 or 2, the tautomers thereof and the pharmaceutically suitable salts thereof.

  本发明涉及新型羧酰胺化合物及其用于制备药物的用途。这些羧酰胺化合物是钙蛋白酶（依赖于钙的半胱氨酸蛋白酶）的抑制剂。因此，本发明还涉及利用这些羧酰胺化合物治疗与升高的钙蛋白酶活性相关的疾病。这些羧酰胺化合物是具有一般式I的化合物，其中R1、R2、R3a、R3b、W、Y和X具有所述权利要求书和说明中提到的含义，其互变异构体和药用盐。具体而言，这些化合物具有一般式I-A.a′和I-A.a″，其中m、E、R1、R3a、R3b、R2、Ry、Rw和Rw6*具有权利要求书中提到的含义，n为0、1或2，其互变异构体和药用盐。
• CARBOXAMIDE COMPOUNDS AND THEIR USE AS CALPAIN INHIBITORS V
  申请人：Kling Andreas

  公开号：US20110152265A1

  公开（公告）日：2011-06-23

  The present invention relates to novel carboxamide compounds and their use for the manufacture of a medicament. The carboxamide compounds are inhibitors of calpain (calcium dependant cysteine proteases). The invention therefore also relates to the use of these carboxamide compounds for treating a disorder associated with an elevated calpain activity. The carboxamide compounds are compounds of the general formula I in which R 1 , R 2 , R 3 R 4 , R 5 , m and n have the meanings mentioned in the claims and the description, the tautomers thereof, the hydrates thereof and the pharmaceutically suitable salts thereof. Of these compounds those are preferred wherein R 1 is optionally substituted phenyl-C 1 -C 2 -alkyl or hetaryl-C 1 -C 2 -alkyl, R 2 is optionally substituted aryl, hetaryl, aryl-C 1 -C 6 -alkyl, aryl-C 2 -C 6 -alkenyl or hetaryl-C 1 -C 4 -alkyl, R 3 is C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 2 -C 4 -alkenyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 2 -alkyl, or phenyl-C 1 -C 3 -alkyl, R 4 and R 5 independently of one another are halogen, CF 3 , CHF 2 , CH 2 F, C 1 -C 2 -alkyl or C 1 -C 2 -alkoxy, and m and n independently of one another are 0 or 1.

  本发明涉及新型羧酰胺化合物及其用于制备药物的用途。这些羧酰胺化合物是钙依赖性半胱氨酸蛋白酶（calpain）的抑制剂。因此，本发明还涉及使用这些羧酰胺化合物用于治疗与升高的calpain活性相关的疾病。这些羧酰胺化合物是通式I的化合物，其中R1、R2、R3、R4、R5、m和n在权利要求书和说明书中提到了它们的含义，它们的互变异构体，水合物和药学上适宜的盐。其中，偏好使用R1为可选取代的苯基-C1-C2-烷基或杂环基-C1-C2-烷基，R2为可选取代的芳基，杂环基，芳基-C1-C6-烷基，芳基-C2-C6-烯基或杂环基-C1-C4-烷基，R3为C1-C3-烷基，C1-C3-卤代烷基，C2-C4-烯基，C3-C6-环烷基，C3-C6-环烷基-C1-C2-烷基或苯基-C1-C3-烷基，R4和R5各自独立地是卤素，CF3，CHF2，CH2F，C1-C2-烷基或C1-C2-烷氧基，而m和n各自独立地为0或1。
• CARBOXAMIDE COMPOUNDS AND THEIR USE AS CALPAIN INHIBITORS IV
  申请人：Kling Andreas

  公开号：US20110152325A1

  公开（公告）日：2011-06-23

  The present invention relates to novel carboxamide compounds and their use for the manufacture of a medicament. The carboxamide compounds are inhibitors of calpain (calcium dependant cysteine proteases). The invention therefore also relates to the use of these carboxamide compounds for treating a disorder associated with an elevated calpain activity. The carboxamide compounds are compounds of the general formula I in which R 1 , R 2 , R 3 R 4 , R 5 , m and n have the meanings mentioned in the claims and the description, the tautomers thereof, the hydrates thereof and the pharmaceutically suitable salts thereof. Of these compounds those are preferred wherein R 1 is optionally substituted phenyl-C 1 -C 2 -alkyl or hetaryl-C 1 -C 2 -alkyl, R 2 is optionally substituted aryl, hetaryl, aryl-C 1 -C 6 -alkyl, aryl-C 2 -C 6 -alkenyl or hetaryl-C 1 -C 4 -alkyl, R 3 is C 3 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 2 -C 4 -alkenyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 2 -alkyl, C 3 -C 6 -heterocycloalkyl-C 1 -C 2 -alkyl, phenyl-C 1 -C 3 -alkyl, pyridin-2-yl-C 1 -C 3 -alkyl or 1,3-benzoxazol-2-yl-methyl, R 4 and R 5 independently of one another are halogen, CF 3 , CHF 2 , CH 2 F, C 1 -C 2 -alkyl or C 1 -C 2 -alkoxy, and m and n independently of one another are 0 or 1.

  本发明涉及新型羧酰胺化合物及其用于制备药物的用途。这些羧酰胺化合物是钙依赖性半胱氨酸蛋白酶(calpain)的抑制剂。因此，本发明还涉及使用这些羧酰胺化合物治疗与升高的calpain活性相关的疾病的用途。这些羧酰胺化合物是一般式I的化合物，其中R1、R2、R3、R4、R5、m和n具有权利要求书和说明中提到的含义，它们的互变异构体、水合物和药学上适用的盐也是如此。在这些化合物中，优选的是R1为可选取代的苯基-C1-C2-烷基或杂环基-C1-C2-烷基，R2为可选取代的芳基、杂环基、芳基-C1-C6-烷基、芳基-C2-C6-烯基或杂环基-C1-C4-烷基，R3为C3-C4-烷基、C1-C4-卤代烷基、C2-C4-烯基、C3-C6-环烷基、C3-C6-环烷基-C1-C2-烷基、C3-C6-杂环环烷基-C1-C2-烷基、苯基-C1-C3-烷基、吡啶-2-基-C1-C3-烷基或1,3-苯并噁唑-2-基-甲基，R4和R5独立地是卤素、CF3、CHF2、CH2F、C1-C2-烷基或C1-C2-烷氧基，m和n独立地为0或1。
• Carboxamide compounds and their use as calpain inhibitors V
  申请人：Kling Andreas

  公开号：US09051304B2

  公开（公告）日：2015-06-09

  The present invention relates to novel carboxamide compounds and their use for the manufacture of a medicament. The carboxamide compounds are inhibitors of calpain (calcium dependant cysteine proteases). The invention therefore also relates to the use of these carboxamide compounds for treating a disorder associated with an elevated calpain activity. The carboxamide compounds are compounds of the general formula I in which R1, R2, R3 R4, R5, m and n have the meanings mentioned in the claims and the description, the tautomers thereof, the hydrates thereof and the pharmaceutically suitable salts thereof. Of these compounds those are preferred wherein R1 is optionally substituted phenyl-C1-C2-alkyl or hetaryl-C1-C2-alkyl, R2 is optionally substituted aryl, hetaryl, aryl-C1-C6-alkyl, aryl-C2-C6-alkenyl or hetaryl-C1-C4-alkyl, R3 is C1-C3-alkyl, C1-C3-haloalkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C2-alkyl, or phenyl-C1-C3-alkyl, R4 and R5 independently of one another are halogen, CF3, CHF2, CH2F, C1-C2-alkyl or C1-C2-alkoxy, and m and n independently of one another are 0 or 1.

  本发明涉及新型羧酰胺化合物及其用于制备药物的用途。这些羧酰胺化合物是钙依赖性半胱氨酸蛋白酶(calpain)的抑制剂。因此，本发明还涉及使用这些羧酰胺化合物治疗与升高的calpain活性有关的疾病。这些羧酰胺化合物是通式I的化合物，在其中R1、R2、R3、R4、R5、m和n具有所述权利要求和描述中提到的含义，它们的互变异构体、水合物和药学上适宜的盐也属于本发明的保护范围。其中，偏好使用R1为可选取代的苯基-C1-C2-烷基或杂环基-C1-C2-烷基，R2为可选取代的芳基、杂环基、芳基-C1-C6-烷基、芳基-C2-C6-烯基或杂环基-C1-C4-烷基，R3为C1-C3-烷基、C1-C3-卤代烷基、C2-C4-烯基、C3-C6-环烷基、C3-C6-环烷基-C1-C2-烷基或苯基-C1-C3-烷基，R4和R5各自独立地为卤素、CF3、CHF2、CH2F、C1-C2-烷基或C1-C2-烷氧基，m和n各自独立地为0或1。
• Carboxamide compounds and their use as calpain inhibitors IV
  申请人：Kling Andreas

  公开号：US08598211B2

  公开（公告）日：2013-12-03

  The present invention relates to novel carboxamide compounds and their use for the manufacture of a medicament. The carboxamide compounds are inhibitors of calpain (calcium dependant cysteine proteases). The invention therefore also relates to the use of these carboxamide compounds for treating a disorder associated with an elevated calpain activity. The carboxamide compounds are compounds of the general formula I in which R1, R2, R3 R4, R5, m and n have the meanings mentioned in the claims and the description, the tautomers thereof, the hydrates thereof and the pharmaceutically suitable salts thereof. Of these compounds those are preferred wherein R1 is optionally substituted phenyl-C1-C2-alkyl or hetaryl-C1-C2-alkyl, R2 is optionally substituted aryl, hetaryl, aryl-C1-C6-alkyl, aryl-C2-C6-alkenyl or hetaryl-C1-C4-alkyl, R3 is C3-C4-alkyl, C1-C4-haloalkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C2-alkyl, C3-C6-heterocycloalkyl-C1-C2-alkyl, phenyl-C1-C3-alkyl, pyridin-2-yl-C1-C3-alkyl or 1,3-benzoxazol-2-yl-methyl, R4 and R5 independently of one another are halogen, CF3, CHF2, CH2F, C1-C2-alkyl or C1-C2-alkoxy, and m and n independently of one another are 0 or 1.

  本发明涉及新型羧酰胺化合物及其用于制备药物的用途。羧酰胺化合物是钙依赖性半胱氨酸蛋白酶（calpain）的抑制剂。因此，本发明还涉及使用这些羧酰胺化合物治疗与升高的calpain活性相关的疾病。这些羧酰胺化合物是通式I的化合物，其中R1、R2、R3、R4、R5、m和n在权利要求书和说明书中提到其含义，其互变异构体，其水合物和其药学上适宜的盐。其中，优选的是R1为可选取代的苯基-C1-C2-烷基或杂环基-C1-C2-烷基，R2为可选取代的芳基，杂环基，芳基-C1-C6-烷基，芳基-C2-C6-烯基或杂环基-C1-C4-烷基，R3为C3-C4-烷基，C1-C4-卤代烷基，C2-C4-烯基，C3-C6-环烷基，C3-C6-环烷基-C1-C2-烷基，C3-C6-杂环环烷基-C1-C2-烷基，苯基-C1-C3-烷基，吡啶-2-基-C1-C3-烷基或1,3-苯并噁唑-2-基-甲基，R4和R5彼此独立地是卤素，CF3，CHF2，CH2F，C1-C2-烷基或C1-C2-烷氧基，m和n彼此独立地是0或1。