5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarbonyl chloride | 1165946-61-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarbonyl chloride
• 英文别名: 5-chloro-6-isopropoxynicotinoyl chloride；5-chloro-6-(1-methylethyloxy)-3-pyridinecarboxylic acid chloride；5-chloro-6-propan-2-yloxypyridine-3-carbonyl chloride
• CAS: 1165946-61-1
• 化学式: C₉H₉Cl₂NO₂
• 分子量: 234.082
• InChiKey: SJPSSGHPDLDMCP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  14
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  39.2
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarbonyl chloride 在 吡啶 、 水 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 sodium hydroxide 作用下， 以 乙醇 、 二氯甲烷 、 甲苯 、 乙腈 为溶剂， 反应 10.0h， 生成 sodium 3-(6-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl)propanoate
  参考文献：
  名称：

  Discovery of a Selective S1P₁ Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate

  摘要：

  Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (SIP) G-protein-coupled receptors (S1P(1) and S1P(3-5)). It has been postulated that fingolimod's efficacy is due to S1P(1) agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P(3) agonism. We have discovered a series of selective S1P(1), agonists, which includes 3-[6- (5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl- 3,4-dihydro-2(1H)-isoquinolinyl]propanoate, 20, a potent, S1P(3)-sparing, orally active S1P(1) agonist. Compound 20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P(3) is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.

  DOI：

  10.1021/ml2000214
• 作为产物：
  描述：

  1-methylethyl 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylate 在 草酰氯 、 sodium hydroxide 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 17.0h， 生成 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarbonyl chloride
  参考文献：
  名称：

  Optimization of Sphingosine-1-phosphate-1 Receptor Agonists: Effects of Acidic, Basic, and Zwitterionic Chemotypes on Pharmacokinetic and Pharmacodynamic Profiles

  摘要：

  The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P(1) receptors, while a variety of side effects have been ascribed to its S1P(3) receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P(1) receptor agonism. Here we describe a study of the tolerance of the S1P(1) and S1P(3) receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P(1) receptor agonists with good selectivity vs S1P(3) receptors, efficacy at <1 mg/kg oral doses, and developability properties suitable for progression into preclinical development.

  DOI：

  10.1021/jm5010336

文献信息

• [EN] (3,4-DISUBSTITUTED)PROPANOIC CARBOXYLATES AS S1P (EDG) RECEPTOR AGONISTS<br/>[FR] CARBOXYLATES PROPANOIQUES 3,4-DISUSBSTITUES UTILISES EN TANT QU'AGONISTES DU RECEPTEUR S1P (EDG)
  申请人：MERCK & CO INC

  公开号：WO2005058848A1

  公开（公告）日：2005-06-30

  The present invention encompasses compounds of Formula A: A as well as the pharmaceutically acceptable salts thereof. The compounds are S1P1/Edg1 receptor agonists and thus have immunosuppressive, anti-inflammatory and hemostatic activities by modulating leukocyte trafficking, sequestering lymphocytes in secondary lymphoid tissues, and enhancing vascular integrity. The invention is also directed to pharmaceutical compositions containing such compounds and methods of treatment or prevention.

  本发明涵盖了化合物A的公式：A以及其药用可接受的盐。这些化合物是S1P1/Edg1受体激动剂，因此通过调节白细胞的运动、在次生淋巴组织中滞留淋巴细胞以及增强血管完整性而具有免疫抑制、抗炎和止血活性。该发明还涉及含有这些化合物的药物组合物以及治疗或预防的方法。
• OXADIAZOLE SUBSTITUTED INDAZOLE DERIVATIVES FOR USE AS SPHINGOSINE 1-PHOSPHATE 1 (S1P1) RECEPTOR AGONISTS
  申请人：Bailey James

  公开号：US20120283297A1

  公开（公告）日：2012-11-08

  Oxadiazole substituted indazole derivatives of formula (I) or pharmaceutical salts thereof having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their uses in the treatment of various disorders mediated by S1P1 receptors are disclosed.

  氧代唑取代吲唑衍生物的化学式（I）或其药用盐具有药理活性，公开了它们的制备方法、含有它们的药物组合物以及它们在治疗由S1P1受体介导的各种疾病中的用途。
• [EN] COMPOUNDS<br/>[FR] COMPOSÉS
  申请人：GLAXO GROUP LTD

  公开号：WO2009133136A1

  公开（公告）日：2009-11-05

  The present invention relates to novel oxadiazole derivatives having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.

  这项发明涉及具有药理活性的新型噁二唑衍生物，其制备方法，含有它们的药物组合物以及它们在治疗各种疾病中的用途。
• [EN] OXADIAZOLE DERIVATIVES ACTIVE ON SPHINGOSINE-1-PHOSPHATE (SIP)<br/>[FR] DÉRIVÉS D'OXADIAZOLE ACTIFS SUR LA SPHINGOSINE-1-PHOSPHATE (S1P)
  申请人：GLAXO GROUP LTD

  公开号：WO2009080725A1

  公开（公告）日：2009-07-02

  The present application discloses oxadiazole based compounds of Formula (I) active on sphingosine-1-phosphate (S1P) in particular useful to treat lupus erythematosus. A is phenyl or a 5 or 6-membered heteroaryl ring; R1 is up to two substituents independently selected from halogen, C(1-3)aIkoxy, C(1-3)flyoroalkyl, cyano, optionally substituted phenyl. C(1-3)fluoroalkoxy. C(1-6)alkyl and C(3-6)Cyctoalkyl; R2 is hydrogen, halogen or C(1-4)alkyl; B is a 7 membered saturated ring selected from the following: Formulae (a) (b) (c) R3 is hydrogen or (CH2)1-4MCO2H; R4 is hydrogen or C(1-3)alkyl optionally interrupted by oxygen;

  本申请披露了一种基于噁二唑的化合物，其化学式为（I），对神经酰胺-1-磷脂酸（S1P）具有活性，特别适用于治疗红斑狼疮。其中，A为苯基或5或6元杂环芳基环；R1为最多两个取代基，可独立选择自卤素、C（1-3）烷氧基、C（1-3）氟烷基、氰基、可选择取代的苯基、C（1-3）氟烷氧基、C（1-6）烷基和C（3-6）环烷基；R2为氢、卤素或C（1-4）烷基；B为以下选项中的7元饱和环之一：（a）（b）（c）；R3为氢或（CH2）1-4MCO2H；R4为氢或C（1-3）烷基，可由氧原子中断。
• COMPOUNDS
  申请人：HEER Jag Paul

  公开号：US20100174065A1

  公开（公告）日：2010-07-08

  The present invention relates to novel oxadiazole derivatives having pharmacological activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.

  本发明涉及具有药理活性的新型噁二唑衍生物，其制备方法，含有它们的药物组合物以及它们在治疗各种疾病中的用途。