3-Oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester | 218163-74-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 3-Oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester
• 英文别名: 2-(2,2,2-Trifluoroethyl)-3-oxo-3a-(2-pyridylmethyl)-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester；tert-butyl 3-oxo-3a-(pyridin-2-ylmethyl)-2-(2,2,2-trifluoroethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
• CAS: 218163-74-7
• 化学式: C₁₉H₂₃F₃N₄O₃
• 分子量: 412.412
• InChiKey: LQWWDJUXLSOIGV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  75.1
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3-Oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester 在 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 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 生成 tert-butyl N-[1-[[(2R)-1-[(3aR)-3-oxo-3a-(pyridin-2-ylmethyl)-2-(2,2,2-trifluoroethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-3-[(2,4-difluorophenyl)methoxy]-1-oxopropan-2-yl]amino]-2-methyl-1-oxopropan-2-yl]carbamate
  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：

  2-氯甲基吡啶 在 sodium hydride 、 溶剂黄146 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 生成 3-Oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester
  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

• 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。
• Tartrate salt of a substituted dipeptide as growth hormone secretagogue
  申请人：Pfizer Inc.

  公开号：US06248717B1

  公开（公告）日：2001-06-19

  This invention is directed to the (L)-tartaric acid salt of 2-amino-N-{1-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo{4,3-c}pyridin-5-yl]-ethyl]-2-methyl-propionamide which is a growth hormone secretagogue and as such is 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 compound. The (L)-tartaric acid salt of the compound of this invention is useful in the treatment and/or prevention of osteoporosis, insulin resistance and other conditions or diseases associated with growth hormone deficiency. The (L)-tartaric acid salt of the compound of the present invention is also useful in treating osteoporosis when used in combination with: a bisphosphonate compound; estrogen, Premarin, and optionally progesterone; an estrogen agonist or antagonist; or calcitonin. Further, the present invention is directed to pharmaceutical compositions. This invention is further directed to methods comprising administering to a human or other animal a combination of an alpha-2 adrenergic agonist and the (L)-tartaric acid salt of the compound of this invention.

  这项发明涉及(L)-酒石酸盐，该盐是2-氨基-N-[1-(2,4-二氟苯甲氧基甲基)-2-氧代-2-[3-氧代-3a-吡啶-2-基甲基-2-(2,2,2-三氟乙基)-2,3,3a,4,6,7-六氢吡唑[4,3-c]吡啶-5-基]-乙基]-2-甲基丙酰胺，是一种生长激素分泌素，因此可用于增加内源性生长激素水平。在另一个方面，这项发明提供了一些在合成上述化合物时有用的中间体。本发明的化合物的(L)-酒石酸盐在治疗和/或预防骨质疏松症、胰岛素抵抗和其他与生长激素缺乏有关的疾病或病症方面具有用处。本发明的化合物的(L)-酒石酸盐在与双膦酸盐化合物、雌激素、孕马尿素和可选的孕激素结合使用时，也可用于治疗骨质疏松症；或与雌激素激动剂或拮抗剂；或降钙素结合使用时，也可用于治疗骨质疏松症。此外，本发明涉及药物组合物。本发明还涉及方法，包括向人类或其他动物施用α-2肾上腺素受体激动剂和本发明的化合物的(L)-酒石酸盐的组合。
• Tartrate salt of a substituded dipeptide as growth hormone secretagogue
  申请人：——

  公开号：US20010016570A1

  公开（公告）日：2001-08-23

  This invention is directed to the (L)-tartaric acid salt of 2-amino-N-{1 -(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-[3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoroethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide which is a growth hormone secretagogue and as such is 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 compound. The (L)-tartaric acid salt of the compound of this invention is useful for the treatment and/or prevention of osteoporosis, insulin resistance and other conditions or diseases associated with growth hormone deficiency. The (L)-tartaric acid salt of the compound of the compound of the present invention is also useful in treating osteoporosis when used in combination with: a bisphosphonate compound; estrogen, Premarin, and optionally progesterone; an estrogen agonist or antagonist; or calcitonin. Further, the present invention is directed to pharmaceutical compositions. This invention is further directed to methods comprising administering to a human or other animal a combination of an alpha-2 adrenergic agonist and the (L)-tartaric acid salt of the compound of this invention.

  本发明涉及2-氨基-N-【1-(R)-(2,4-二氟苯甲氧甲基)-2-氧代-2-【3-氧代-3a-(R)-吡啶-2-基甲基]-2-(2,2,2-三氟乙基)-2,3,3a,4,6,7-六氢吡唑[4,3-c]吡啶-5-基】-乙基-2-甲基丙酰胺的(L)-酒石酸盐，其为生长激素分泌剂，因此对于增加内源性生长激素水平是有用的。在另一个方面，本发明提供了某些在合成前述化合物中有用的中间体。本发明所述化合物的(L)-酒石酸盐对于治疗和/或预防骨质疏松症、胰岛素抵抗和其他与生长激素缺乏有关的疾病或症状是有用的。本发明所述化合物的(L)-酒石酸盐在与双磷酸盐化合物、雌激素、普瑞玛林和可选孕激素、雌激素激动剂或拮抗剂或降钙素联合使用时，还可用于治疗骨质疏松症。此外，本发明还涉及制药组合物。本发明进一步涉及方法，包括向人类或其他动物施用α-2肾上腺素受体激动剂和本发明化合物的(L)-酒石酸盐的组合。
• 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。