3A-苯甲基-2-甲基-4,5,6,7-四氢-2H-吡唑并[4,3-C]吡啶-3(3AH)-酮 | 193274-04-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 3A-苯甲基-2-甲基-4,5,6,7-四氢-2H-吡唑并[4,3-C]吡啶-3(3AH)-酮
• 英文名称: 3a-(R)-Benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one
• 英文别名: (±)-3a-benzyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3(3aH)-one；3a-benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-3-one；3A-benzyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3(3aH)-one；3a-benzyl-2-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-one
• CAS: 193274-04-3
• 化学式: C₁₄H₁₇N₃O
• 分子量: 243.308
• InChiKey: SRIVSGVZUKSXSC-UHFFFAOYSA-N

物化性质

• 沸点：
  371.8±52.0 °C(Predicted)
• 密度：
  1.25±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  44.7
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3A-苯甲基-2-甲基-4,5,6,7-四氢-2H-吡唑并[4,3-C]吡啶-3(3AH)-酮 在 盐酸 、 N-羟基-7-氮杂苯并三氮唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 生成
  参考文献：
  名称：

  Discovery and biological characterization of capromorelin analogues with extended half-lives

  摘要：

  New tert-butyl, picolyl and fluorinated analogues of capromorelin (3), a short-acting growth hormone secretagogue (GHS), were prepared as part of a program to identify long-acting GHSs that increase 24-h plasma lGF-1 levels. Compounds 4c and 4d (ACD LogD values greater than or equal to2.9) displayed extended plasma elimination half-lives in dogs, primarily due to high volumes of distribution, but showed weak GH secretagogue activities in rats (ED(50)s > 10 mg/kg). A less lipophilic derivative 4 (ACD LogD = 1.6) exhibited a shorter canine half-life, but stimulated GH secretion in two animal species. Repeat oral dosing of 4 in dogs for 29 days (6 mg/kg) resulted in a significant down-regulation of the post dose GH response and a 60 and 40% increase in IGF-1 levels relative to pre-dose levels at the 8- and 24-h post dose time points. Compound 4 (CP-464709-18) has been selected as a development candidate for the treatment of frailty. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)00734-5
• 作为产物：
  描述：

  1-叔丁基-3-苄基-4-氧代哌啶-1,3-二羧酸-3-甲酯 在 溶剂黄146 、 三氟乙酸 作用下， 以 乙醇 、 甲苯 为溶剂， 生成 3A-苯甲基-2-甲基-4,5,6,7-四氢-2H-吡唑并[4,3-C]吡啶-3(3AH)-酮
  参考文献：
  名称：

  Discovery and biological characterization of capromorelin analogues with extended half-lives

  摘要：

  New tert-butyl, picolyl and fluorinated analogues of capromorelin (3), a short-acting growth hormone secretagogue (GHS), were prepared as part of a program to identify long-acting GHSs that increase 24-h plasma lGF-1 levels. Compounds 4c and 4d (ACD LogD values greater than or equal to2.9) displayed extended plasma elimination half-lives in dogs, primarily due to high volumes of distribution, but showed weak GH secretagogue activities in rats (ED(50)s > 10 mg/kg). A less lipophilic derivative 4 (ACD LogD = 1.6) exhibited a shorter canine half-life, but stimulated GH secretion in two animal species. Repeat oral dosing of 4 in dogs for 29 days (6 mg/kg) resulted in a significant down-regulation of the post dose GH response and a 60 and 40% increase in IGF-1 levels relative to pre-dose levels at the 8- and 24-h post dose time points. Compound 4 (CP-464709-18) has been selected as a development candidate for the treatment of frailty. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)00734-5

文献信息

• [EN] SUBSTITUTED PIPERIDINE AND PIPERAZINE DERIVATIVES AS MELANOCORTIN-4 RECEPTOR MODULATORS<br/>[FR] DERIVES DE PIPERIDINE ET DE PIPERAZINE SUBSTITUES UTILISES EN TANT QUE MODULATEURS DU RECEPTEUR DE LA MELANOCORTINE-4
  申请人：MYOCONTRACT LTD

  公开号：WO2004083208A1

  公开（公告）日：2004-09-30

  The present invention relates to novel substituted piperidine and piperazine derivatives as melanocortin-4 receptor (MC-4R) modulators. MC-4R agonists of the invention can be used for the treatment of disorders and diseases such as obesity, diabetes and sexual dysfunction, whereas the MC-4R antagonists are useful for the treatment of disorders and diseases such as cancer cachexia, muscle wasting, anorexia, anxiety and depression. All diseases and disorders, where the regulation of the MC-4R is involved, can be treated with the compounds of the invention.

  本发明涉及一种新型的替代哌啶和哌嗪衍生物，作为黑色素皮质素-4受体（MC-4R）调节剂。本发明的MC-4R激动剂可用于治疗肥胖、糖尿病和性功能障碍等疾病，而MC-4R拮抗剂可用于治疗癌症恶病质、肌肉消耗、厌食症、焦虑和抑郁等疾病。所有涉及MC-4R调节的疾病和障碍均可使用本发明的化合物治疗。
• Treatment of insulin resistance with growth hormone secretagogues
  申请人：Pfizer Inc.

  公开号：US06448263B1

  公开（公告）日：2002-09-10

  This invention is directed to methods of treating insulin resistance in a mammal which comprise administering an effective amount of a compound of formula I, where the variables are defined in the specification, or the stereoisomeric mixtures, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomers, or the pharmaceutically acceptable salts and prodrugs thereof to said mammal. The compounds of formula I are growth hormone secretagogues and as such are useful for increasing the level of endogenous growth hormone. In another aspect this invention provides certain intermediates which are useful in the synthesis of the foregoing compounds and certain processes useful for the synthesis of said intermediates and the compounds of formula I. This invention is further directed to methods comprising administering to a human or other animal a combination of a functional somatostatin antagonist such as an alpha-2 adrenergic agonist and a compound of formula I.

  这项发明涉及治疗哺乳动物的胰岛素抵抗方法，包括向该哺乳动物施用化合物I的有效量，其中变量在规范中定义，或其立体异构混合物、对映异构体富集物、对映异构体纯物、对映体富集物或对映体纯异构体，或其药学上可接受的盐和前药。化合物I是生长激素分泌素，因此对于增加内源生长激素水平是有用的。在另一个方面，这项发明提供了一些在合成上述化合物中有用的中间体，以及对合成所述中间体和化合物I有用的某些过程。这项发明进一步涉及方法，包括向人类或其他动物施用功能性生长抑素拮抗剂，如α-2肾上腺素受体激动剂和化合物I的组合。
• Process for preparing growth hormone secretagogues
  申请人：——

  公开号：US20020002283A1

  公开（公告）日：2002-01-03

  This invention relates to improved processes for preparing compounds of Formula II, 1 and compounds of Formula III, 2 wherein R 1 , R 2 , R 3 and Prt are defined as set forth in the specification.

  这项发明涉及改进的制备公式II的化合物和公式III的化合物的过程，其中R1、R2、R3和Prt的定义如规范中所述。
• [EN] SERINE DERIVATIVES AS GHRELIN RECEPTOR AGONISTS<br/>[FR] DÉRIVÉS DE SÉRINE UTILES EN TANT QU'AGONISTES DU RÉCEPTEUR DE LA GHRÉLINE
  申请人：RAQUALIA PHARMA INC

  公开号：WO2016021191A1

  公开（公告）日：2016-02-11

  The present invention relates to novel compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example as modulators of the growth hormone secretagogue receptor (also referred to as the ghrelin receptor or GHSRla receptor) and/or for the treatment and/or prophylaxis of a disorder mediated by the ghrelin receptor.

  本发明涉及式(I)的新型化合物或其药学上可接受的盐或溶剂，其制备方法，包含它们的制药组合物以及它们在治疗中的使用，例如作为生长激素分泌素受体的调节剂（也称为胃泌素受体或GHSRla受体）和/或治疗和/或预防由胃泌素受体介导的疾病。
• Practical synthesis of capromorelin, a growth hormone secretagogue, via a crystallization-induced dynamic resolution
  作者：Colin R. Rose、Michael P. Zawistoski、Bruce A. Lefker、F. Michael Mangano、Ann S. Wright、Philip A. Carpino

  DOI：10.1016/j.bmc.2016.12.015

  日期：2017.2

  A practical synthesis of capromorelin (1), a growth hormone secretagogue, is described that utilizes as a key step a crystallization-induced dynamic resolution (CIDR) of (±)-3a-benzyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3(3aH)-one [(±)-2] by L-tartaric acid salt formation, yielding (R)-2.L-tartaric acid in high chemical yield (>85%) and with diastereomeric excess (de) of ∼98%. Treatment

  描述了一种实际的合成Capromorelin（1）（一种生长激素促分泌剂），该方法利用（±）-3a-苄基-2-甲基-4,5,6的结晶诱导动态拆分（CIDR）作为关键步骤， 7四氢-2 ħ -吡唑并[4,3- c ^ ]吡啶-3-（四氢-3aH-） -酮（±） - 2 ]由大号-酒石酸盐的形成，得到（- [R ）- 2.大号-酒石酸在化学收率高（> 85％），非对映异构体过量（de）为〜98％。的处理（[R ）- 2.大号-酒石酸用氢氧化铵提供（- [R ）- 2不会损失手性纯度。原位产生的（R）-2与（R）-3-（苄氧基）-2-（2-（叔丁氧基羰基）-2-甲基丙酰胺基）丙酸[（R）-3 ]偶合，主要得到一个N -Boc保护的己内莫林[（1 R，3a R）-4 ]的非对映异构体。该过程用于从（±）-2制备大量的己内莫林，以支持临床前毒理学研究。