1-{2-[6-chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol | 1027273-63-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-{2-[6-chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol
• 英文别名: 1-[2-[6-chloro-8-(3-fluorophenyl)-9-methylpurin-2-yl]ethynyl]cyclopentan-1-ol
• CAS: 1027273-63-7
• 化学式: C₁₉H₁₆ClFN₄O
• 分子量: 370.814
• InChiKey: KTNFCHSEMNFPOK-UHFFFAOYSA-N

物化性质

• 沸点：
  606.7±65.0 °C(Predicted)
• 密度：
  1.40±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  63.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-{2-[6-chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol 在 氨 作用下， 以 乙醇 为溶剂， 反应 20.0h， 生成 1-{2-(6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol
  参考文献：
  名称：

  2-Alkynyl-8-aryl-9-methyladenines as Novel Adenosine Receptor Antagonists:  Their Synthesis and Structure−Activity Relationships toward Hepatic Glucose Production Induced via Agonism of the A_2B Receptor

  摘要：

  Novel adenosine antagonists, 2-alkynyl-8-aryl-9-methyladenine derivatives, were synthesized as candidate hypoglycemic agents. These analogues were evaluated for inhibitory activity on N-ethylcarboxamidoadenosine (NECA)-induced glucose production in primary cultured rat hepatocytes. In general, aromatic moieties at the 8-position and alkynyl groups at the 8-position had significantly increased activity compared to unsubstituted compounds. The preferred substituents at the 8-position of adenine were the 2-furyl and 3-fluorophenyl groups. In modifying the alkynyl side chain, change of the ring size, cleavage of the ring, and removal of the hydroxyl group were well tolerated. The order of the stimulatory effects of adenosine agonists on rat hepatocytes was NECA > CPA > CGS21680, which is consistent with involvement of the A(2B) receptor. In Chinese hamster ovary cells stably transfected with human A(2B) receptor cDNA, one of the compounds potent in hepatocytes, 15o (IC50 = 0.42 muM), antagonized NECA-induced stimulation of cyclic AMP production (IC50 = 0.063 muM). This inhibitory effect was much more potent than those of FK453, KF17837, and L249313 which have been reported to be respectively A(1), A(2A), and A(3) selective antagonists. These findings agree very well with the result that, compared to 15o, these selective antagonists for each receptor subtype showed only marginal effects in rat hepatocytes. These results suggest that adenosine agonist-induced glucose production in rat hepatocytes is mediated through the A(2B) receptor. Furthermore, 15o showed hypoglycemic activity in an animal model of noninsulin-dependent diabetes mellitus, the KK-A(y) mice. It is possible that inhibition of hepatic glucose production via the A(2B) receptor could be at least one of the mechanisms by which 15o exerts its in, vivo effects. Further elaboration of this group of compounds may afford novel antidiabetic agents.

  DOI：

  10.1021/jm990499b
• 作为产物：
  描述：

  6-chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinylamine 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 二碘甲烷 、 三乙胺 、 亚硝酸异戊酯 作用下， 以 四氢呋喃 为溶剂， 反应 3.5h， 生成 1-{2-[6-chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol
  参考文献：
  名称：

  2-Alkynyl-8-aryl-9-methyladenines as Novel Adenosine Receptor Antagonists:  Their Synthesis and Structure−Activity Relationships toward Hepatic Glucose Production Induced via Agonism of the A_2B Receptor

  摘要：

  Novel adenosine antagonists, 2-alkynyl-8-aryl-9-methyladenine derivatives, were synthesized as candidate hypoglycemic agents. These analogues were evaluated for inhibitory activity on N-ethylcarboxamidoadenosine (NECA)-induced glucose production in primary cultured rat hepatocytes. In general, aromatic moieties at the 8-position and alkynyl groups at the 8-position had significantly increased activity compared to unsubstituted compounds. The preferred substituents at the 8-position of adenine were the 2-furyl and 3-fluorophenyl groups. In modifying the alkynyl side chain, change of the ring size, cleavage of the ring, and removal of the hydroxyl group were well tolerated. The order of the stimulatory effects of adenosine agonists on rat hepatocytes was NECA > CPA > CGS21680, which is consistent with involvement of the A(2B) receptor. In Chinese hamster ovary cells stably transfected with human A(2B) receptor cDNA, one of the compounds potent in hepatocytes, 15o (IC50 = 0.42 muM), antagonized NECA-induced stimulation of cyclic AMP production (IC50 = 0.063 muM). This inhibitory effect was much more potent than those of FK453, KF17837, and L249313 which have been reported to be respectively A(1), A(2A), and A(3) selective antagonists. These findings agree very well with the result that, compared to 15o, these selective antagonists for each receptor subtype showed only marginal effects in rat hepatocytes. These results suggest that adenosine agonist-induced glucose production in rat hepatocytes is mediated through the A(2B) receptor. Furthermore, 15o showed hypoglycemic activity in an animal model of noninsulin-dependent diabetes mellitus, the KK-A(y) mice. It is possible that inhibition of hepatic glucose production via the A(2B) receptor could be at least one of the mechanisms by which 15o exerts its in, vivo effects. Further elaboration of this group of compounds may afford novel antidiabetic agents.

  DOI：

  10.1021/jm990499b

文献信息

• Purine derivatives and adenosine A2 receptor antagonists serving as preventives/remedies for diabetes
  申请人：Eisai Co., Ltd.

  公开号：US06579868B1

  公开（公告）日：2003-06-17

  The present invention provides a preventive or therapeutic agent of a new type for diabetes mellitus and diabetic complications on the basis of an adenosine A2 receptor antagonistic action. A purine compound represented by the formula (I), its pharmacologically acceptable salt or hydrates thereof has an adenosine A2 receptor antagonistic action and is useful for prevention or therapy of diabetes mellitus and diabetic complications. In addition, adenosine A2 receptor antagonists having different structures from those of the compounds described above, for example KW6002, are also effective for prevention or therapy of diabetes mellitus and diabetic complications. In the formula, W is —CH2CH2—, —CH═CH— or —C≡C—; R1 is: (in the formula, X is hydrogen atom, hydroxyl group, a lower alkyl group, a lower alkoxy group, etc.; and R5 and R6 are the same as or different from each other and each represents hydrogen atom, a lower alkyl group, a cycloalkyl group, etc.) and the like; R2 is an amino group, etc. which maybe substituted with a lower alkyl group, etc.; R3 is a cycloalkyl group, an optionally substituted aryl group, etc.; and R4 is a lower alkyl group etc.

  本发明提供了一种新型的糖尿病和糖尿病并发症的预防或治疗剂，基于腺苷A2受体拮抗作用。由式（I）表示的嘌呤化合物及其药理学上可接受的盐或水合物具有腺苷A2受体拮抗作用，并可用于预防或治疗糖尿病和糖尿病并发症。此外，具有与上述化合物不同结构的腺苷A2受体拮抗剂，例如KW6002等，也对预防或治疗糖尿病和糖尿病并发症有效。在该式中，W为—CH2CH2—、—CH═CH—或—C≡C—；R1为：（在该式中，X为氢原子、羟基、较低的烷基基团、较低的烷氧基团等；而R5和R6相同或不同，各自代表氢原子、较低的烷基基团、环烷基基团等）等；R2为氨基等，可能被较低的烷基基团等取代；R3为环烷基基团、可选择性取代的芳基基团等；R4为较低的烷基基团等。
• PURINE DERIVATIVES AND ADENOSINE A2 RECEPTOR ANTAGONISTS SERVING AS PREVENTIVES/REMEDIES FOR DIABETES
  申请人：Eisai Co., Ltd.

  公开号：EP1054012A1

  公开（公告）日：2000-11-22

  The present invention provides a preventive or therapeutic agent of a new type for diabetes mellitus and diabetic complications on the basis of an adenosine A2 receptor antagonistic action. A purine compound represented by the formula (I), its pharmacologically acceptable salt or hydrates thereof has an adenosine A2 receptor antagonistic action and is useful for prevention or therapy of diabetes mellitus and diabetic complications. In addition, adenosine A2 receptor antagonists having different structures from those of the compounds described above, for example KW6002, are also effective for prevention or therapy of diabetes mellitus and diabetic complications. In the formula, W is -CH2CH2-, -CH=CH- or -C≡C-; R1 is: (in the formula, X is hydrogen atom, hydroxyl group, a lower alkyl group, a lower alkoxy group, etc.; and R5 and R6 are the same as or different from each other and each represents hydrogen atom, a lower alkyl group, a cycloalkyl group, etc.) and the like; R2 is an amino group, etc. which may be substituted with a lower alkyl group, etc.; R3 is a cycloalkyl group, an optionally substituted aryl group, etc.; and R4 is a lower alkyl group, etc.

  本发明提供了一种基于腺苷 A2 受体拮抗作用的新型糖尿病和糖尿病并发症预防或治疗剂。 由式（I）代表的嘌呤化合物、其药理上可接受的盐或其水合物具有腺苷 A2 受体拮抗作用，可用于预防或治疗糖尿病和糖尿病并发症。此外，与上述化合物结构不同的腺苷 A2 受体拮抗剂，例如 KW6002，也可有效预防或治疗糖尿病和糖尿病并发症。 式中，W为-CH2CH2-、-CH=CH-或-C≡C-；R1为： (式中，X 是氢原子、羟基、低级烷基、低级烷氧基等；R5 和 R6 彼此相同或不同，各自代表氢原子、低级烷基、环烷基等）等；R2 是可被低级烷基等取代的氨基等；R3 是环烷基、任选取代的芳基等；R4 是低级烷基等。
• Purine compounds and adenosine A2 receptor antagonist as preventive or therapeutic agent for diabetes mellitus
  申请人：Eisai Co. Ltd

  公开号：EP1300147A1

  公开（公告）日：2003-04-09

  The present invention relates to the use of A2 receptor antagonists and their pharmacologically acceptable salts or hydrates for preparing medicaments for preventing or treating diabetes mellitus or diabetic complications, and for preparing improving agents for impaired glucose tolerance, potentiating agent for insulin sensitivity or medicaments for preventing or treating obesity.

  本发明涉及 A2 受体拮抗剂及其药理学上可接受的盐或水合物用于制备预防或治疗糖尿病或糖尿病并发症的药物，以及用于制备改善糖耐量受损的药物、提高胰岛素敏感性的药物或预防或治疗肥胖症的药物。
• USRE039112E1
  申请人：——

  公开号：——

  公开（公告）日：——
• US6579868B1
  申请人：——

  公开号：US6579868B1

  公开（公告）日：2003-06-17