叔-丁基3A-苯甲基-2-甲基-3-氧亚基-3A,4,6,7-四氢-2H-吡唑并[4,3-C]吡啶-5(3H)-甲酸基酯 | 193274-02-1

• 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: 叔-丁基3A-苯甲基-2-甲基-3-氧亚基-3A,4,6,7-四氢-2H-吡唑并[4,3-C]吡啶-5(3H)-甲酸基酯
• 英文名称: 2,3a,4,5,6,7-hexahydro-2-methyl-3-oxo-3a-(phenylmethyl)-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid 1,1-dimethylethyl ester
• 英文别名: 3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester；3a-(R)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester；3a-(R,S)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]-pyridine-5-carboxylic acid tert-butyl ester；3a-(R)-Benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5carboxylic acid tert-butyl ester；tert-Butyl 3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5(3H)-carboxylate；tert-butyl 3a-benzyl-2-methyl-3-oxo-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
• CAS: 193274-02-1
• 化学式: C₁₉H₂₅N₃O₃
• 分子量: 343.426
• InChiKey: LJEFSCMTXQOJJQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  62.2
• 氢给体数：
  0
• 氢受体数：
  4

安全信息

• 储存条件：
  密封保存，在干燥处，2-8℃

反应信息

• 作为反应物：
  描述：

  叔-丁基3A-苯甲基-2-甲基-3-氧亚基-3A,4,6,7-四氢-2H-吡唑并[4,3-C]吡啶-5(3H)-甲酸基酯 在 N-羟基-7-氮杂苯并三氮唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 生成 卡普瑞林
  参考文献：
  名称：

  Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs)

  摘要：

  Novel pyrazolinone-piperidine dipeptide derivatives were synthesized and evaluated as growth hormone secretagogues (GHSs). Two analogues, capromorelin (5, CP-424391-18, hGHS-R1a K-i=7 nM, rat pituicyte EC50=3 nM) and the des-methyl analogue 5c (hGHS-R1a K-i=17 nM, rat pituicyte EC50 = 3 nM), increased plasma GH levels in an anesthesized rat model, with ED50 values less than 0.05 mg/kg iv. Capromorelin showed enhanced intestinal absorption in rodent models and exhibited superior pharmacokinetic properties, including high bioavailabilities in two animal species [F(rat) = 65%, F(dog) = 44%]. This short-duration GHS was orally active in canine models and was selected as a development candidate for the treatment of musculoskeletal frailty in elderly adults. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(02)00433-9
• 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 甲基肼 作用下， 以 乙醇 为溶剂， 反应 8.0h， 生成 叔-丁基3A-苯甲基-2-甲基-3-氧亚基-3A,4,6,7-四氢-2H-吡唑并[4,3-C]吡啶-5(3H)-甲酸基酯
  参考文献：
  名称：

  Combinations of &bgr;3 agonists and growth hormone secretagogues

  摘要：

  这项发明涉及包括β3肾上腺素受体激动剂在内的药物组合物，其中包括(4-(2-(2-(6-氨基吡啶-3-基)-2(R)-羟乙基氨基)乙氧基)苯乙酸)和生长激素或生长激素促分泌剂，以及这些化合物或其前药的药用可接受盐。该发明还涉及使用这些组合物治疗动物中的肥胖、糖尿病、高血压和衰弱，特别是在人类中的方法。

  公开号：

  US06657063B1

文献信息

• 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。
• Growth-hormone secretagogues
  申请人：——

  公开号：US20020049196A1

  公开（公告）日：2002-04-25

  This invention is directed to compounds of the formula 1 and the pharmaceutically-acceptable salts thereof, where the substituents are as defined in the Specification, which are growth hormone secretogogues and which increase the level of endogenous growth hormone. The compounds of this invention are useful for the treatment and prevention of osteoporosis, congestive heart failure, frailty associated with aging, obesity; accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, or accelerating the recovery of burn patients or patients having undergone major surgery; improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis or renal homeostasis. The compounds of the present invention are also useful in treating osteoporosis when used in combination with: a bisphosphonate compound such as alendronate; estrogen, premarin, and optionally progesterone; an estrogen agonist or antagonist; or calcitonin, and pharmaceutical compositions useful therefor. Further, the present invention is directed to pharmaceutical compositions useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises an effective amount of a compound of the present invention and a growth hormone secretagogue selected from GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 or B-HT920. The invention is also directed to intermediates useful in the preparation of compounds of formula I.

  本发明涉及公式1的化合物及其药学上可接受的盐，其中取代基如规范中所定义，是生长激素分泌素，能够增加内源性生长激素的水平。本发明的化合物用于治疗和预防骨质疏松症、充血性心力衰竭、与衰老有关的虚弱、肥胖症；加速骨折修复、减轻重大手术后的蛋白质分解反应、减少慢性疾病引起的消瘦和蛋白质流失、加速伤口愈合或加速烧伤患者或接受重大手术的患者的恢复；改善肌肉力量、运动能力、皮肤厚度、代谢稳态或肾脏稳态。本发明的化合物在与双磷酸盐化合物（如阿仑膦酸盐）、雌激素、孕马血浆、以及可选的孕激素搭配使用时，也有用于治疗骨质疏松症的作用，或与降钙素一起使用，以及药学组合物的使用方法。此外，本发明还涉及用于增加人类或其他动物内源性生长激素产生或释放的药学组合物，该组合物包括本发明化合物的有效量和选择自GHRP-6、Hexarelin、GHRP-1、生长激素释放因子（GRF）、IGF-1、IGF-2或B-HT920的生长激素分泌素。本发明还涉及用于制备公式I化合物的中间体。
• Treatment of insulin resistance with growth hormone secretagogues
  申请人：——

  公开号：US20030100561A1

  公开（公告）日：2003-05-29

  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, 1 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.

  本发明涉及治疗哺乳动物胰岛素抵抗的方法，包括向该哺乳动物施用公式I，其中变量在说明书中定义的化合物的有效量，或其立体异构混合物、对映异构体富集物、对映异构体纯物、对映异构体纯物或其药学上可接受的盐和前药。公式I的化合物是生长激素分泌素，因此对于增加内源性生长激素水平非常有用。在另一个方面，本发明提供了某些中间体，这些中间体在合成上述化合物中非常有用，并且提供了某些合成上述中间体和公式I化合物的方法。本发明还涉及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）和公式I化合物的组合的方法。
• Process for the preparation of pyrazolopyridine tartrates
  申请人：Pfizer Products Inc.

  公开号：EP1449842A1

  公开（公告）日：2004-08-25

  This invention relates to a multistep process for the preparation of an L-tartrate salt of formula XX which is an intermediate in the preparation of growth hormone secretagogues.

  本发明涉及一种制备式 XX 的 L-酒石酸盐的多步骤工艺，该 L-酒石酸盐是制备生长激素促泌剂的中间体。
• Discovery and biological characterization of capromorelin analogues with extended half-lives
  作者：Philip A. Carpino、Bruce A. Lefker、Steven M. Toler、Lydia C. Pan、John R. Hadcock、Marianne C. Murray、Ewell R. Cook、Joseph N. DiBrino、Shari L. DeNinno、Kristin L. Chidsey-Frink、William A. Hada、John Inthavongsay、Sharon K. Lewis、F.Michael Mangano、Michelle A. Mullins、David F. Nickerson、Oicheng Ng、Christine M. Pirie、John A. Ragan、Colin R. Rose、David A. Tess、Ann S. Wright、Li Yu、Michael P. Zawistoski、John C. Pettersen、Paul A. DaSilva-Jardine、Theresa C. Wilson、David D. Thompson

  DOI：10.1016/s0960-894x(02)00734-5

  日期：2002.11

  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.