ethyl 3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoate | 1254699-98-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: ethyl 3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoate
• 英文别名: ethyl 3-[[(2R)-1-benzyl-5-oxopyrrolidine-2-carbonyl]amino]-2-hydroxy-4-phenylbutanoate
• CAS: 1254699-98-3
• 化学式: C₂₄H₂₈N₂O₅
• 分子量: 424.497
• InChiKey: JWRVROWGJFXYFR-SNCIUUNGSA-N

物化性质

• 沸点：
  693.3±55.0 °C(Predicted)
• 密度：
  1.249±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  31
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  95.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoate 在 二氯乙酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 乙醇 、 二氯甲烷 、 水 、 二甲基亚砜 为溶剂， 反应 16.17h， 生成 化合物 T14178
  参考文献：
  名称：

  Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as selective calpain inhibitors with enhanced metabolic stability

  摘要：

  Aberrant activation of calpain has been observed in various pathophysiological disorders including neurode-generative diseases such as Alzheimer's Disease. Here we describe our efforts on ketoamide-based 1-benzyl-5-oxopyrrolidine-2-carboxamides as a novel series of highly selective calpain inhibitors mitigating the metabolic liability of carbonyl reduction. The most advanced compound from this new series, namely A-1212805 (ABT-957, Alicapistat) proceeded to clinical phase I studies.

  DOI：

  10.1016/j.bmcl.2019.05.034
• 作为产物：
  描述：

  D-谷氨酸 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 48.17h， 生成 ethyl 3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoate
  参考文献：
  名称：

  Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as selective calpain inhibitors with enhanced metabolic stability

  摘要：

  Aberrant activation of calpain has been observed in various pathophysiological disorders including neurode-generative diseases such as Alzheimer's Disease. Here we describe our efforts on ketoamide-based 1-benzyl-5-oxopyrrolidine-2-carboxamides as a novel series of highly selective calpain inhibitors mitigating the metabolic liability of carbonyl reduction. The most advanced compound from this new series, namely A-1212805 (ABT-957, Alicapistat) proceeded to clinical phase I studies.

  DOI：

  10.1016/j.bmcl.2019.05.034

文献信息

• [EN] CARBOXAMIDE COMPOUNDS AND THEIR USE AS CALPAIN INHIBITORS<br/>[FR] COMPOSÉS DE CARBOXAMIDE ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE LA CALPAÏNE
  申请人：ABBOTT GMBH & CO KG

  公开号：WO2010128102A1

  公开（公告）日：2010-11-11

  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, R3a, R3b, R4, Q, Y, A 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 (Ia) and (Ib) in which R1, r, R2b, R3a, R3b, R4, Y and X have the meanings mentioned in the claims, including the tautomers thereof and the pharmaceutically suitable salts thereof. Of these compounds those are preferred wherein Y is a moiety CH2-CH2, CH2-CH2-CH2, N(Ry#)-CH2, N(Ry#)-CH2-CH2 or CH=CH-CH=, each optionally having 1 or 2 H-atoms replaced with identical or different radicals Ry, wherein Ry and Ry# have the meanings mentioned in the claims.

  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，该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通式（I）的化合物，其中R1、R2、R3a、R3b、R4、Q、Y、A和X具有权利要求和说明中提及的含义，以及它们的互变异构体和药用盐。特别地，这些化合物具有通式（Ia）和（Ib），其中R1、r、R2b、R3a、R3b、R4、Y和X具有权利要求中提及的含义，包括它们的互变异构体和药用盐。在这些化合物中，首选Y是一个基团CH2-CH2、CH2-CH2-CH2、N(Ry#)-CH2、N(Ry#)-CH2-CH2或CH=CH-CH=，每个基团可选择地用1或2个氢原子替换为相同或不同的基团Ry，其中Ry和Ry#具有权利要求中提到的含义。
• 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
  申请人：Abbott Laboratories

  公开号：US08283363B2

  公开（公告）日：2012-10-09

  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, R3a, R3b, R4, Q, Y, A 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 Ia and Ib in which R1, r, R2b, R3a, R3b, R4, Y and X have the meanings mentioned in the claims, including the tautomers thereof and the pharmaceutically suitable salts thereof. Of these compounds those are preferred wherein Y is a moiety CH2—CH2, CH2—CH2—CH2, N(Ry#)—CH2, N(Ry#)—CH2—CH2 or CH═CH—CH═, each optionally having 1 or 2 H-atoms replaced with identical or different radicals Ry, wherein Ry and Ry# have the meanings mentioned in the claims.

  本发明涉及新型羧酰胺化合物及其用于制造药物的用途。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。这些羧酰胺化合物是通式I的化合物，其中R1、R2、R3a、R3b、R4、Q、Y、A和X具有权利要求和说明书中提到的含义，它们的互变异构体和药学上适用的盐。特别是，这些化合物具有通式Ia和Ib，其中R1、r、R2b、R3a、R3b、R4、Y和X具有权利要求中提到的含义，包括它们的互变异构体和药学上适用的盐。其中，首选Y是一个基团CH2-CH2、CH2-CH2-CH2、N（Ry#）-CH2、N（Ry#）-CH2-CH2或CH═CH-CH═，每个基团可选地用1或2个H原子替换为相同或不同的基团Ry，其中Ry和Ry#具有权利要求中提到的含义。
• CARBOXAMIDE COMPOUNDS AND THEIR USE AS CALPAIN INHIBITORS
  申请人：Mack Helmut

  公开号：US20110086879A1

  公开（公告）日：2011-04-14

  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 , R 4 , Q, Y, A 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 Ia and Ib in which R 1 , r, R 2b , R 3a , R 3b , R 4 , Y and X have the meanings mentioned in the claims, including the tautomers thereof and the pharmaceutically suitable salts thereof. Of these compounds those are preferred wherein Y is a moiety CH 2 —CH 2 , CH 2 —CH 2 —CH 2 , N(R y# )—CH 2 , N(R y# )—CH 2 —CH 2 or CH═CH—CH═, each optionally having 1 or 2 H-atoms replaced with identical or different radicals R y , wherein R y and R y# have the meanings mentioned in the claims.

  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。这些羧酰胺化合物是通式I的化合物，其中R1、R2、R3a、R3b、R4、Q、Y、A和X具有所述权利要求和说明书中提到的含义，它们的互变异构体和药学上适用的盐。特别是，化合物具有通式Ia和Ib，其中R1、r、R2b、R3a、R3b、R4、Y和X具有所述权利要求中提到的含义，包括其互变异构体和药学上适用的盐。其中，首选Y是CH2-CH2、CH2-CH2-CH2、N（Ry#）-CH2、N（Ry#）-CH2-CH2或CH=CH-CH=的基团，每个基团可选择性地用相同或不同的基团Ry替换1或2个氢原子，其中Ry和Ry#具有所述权利要求中提到的含义。
• 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。