环己基肼甲磺酸盐 | 224048-31-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机磺酸及其衍生物
• 中文名称: 环己基肼甲磺酸盐
• 英文名称: cyclohexylhydrazine mesylate
• 英文别名: cyclohexylhydrazine;methanesulfonic acid
• CAS: 224048-31-1
• 化学式: CH₄O₃S*C₆H₁₄N₂
• 分子量: 210.298
• InChiKey: FTOYDYKCGJSVDH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.29
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  101
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  环己基肼甲磺酸盐 、 2,4-二氟苯丙酮 在 sodium acetate 作用下， 以 甲苯 为溶剂， 反应 12.0h， 以98%的产率得到1-环己基-3-乙基-6-氟-1H-吲唑
  参考文献：
  名称：

  选择性 PDE4/TNFα 抑制剂的合成

  摘要：

  描述了一种选择性 PDE4/TNFα 抑制剂 cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexaminecarboxy 酸 (1) 的两种合成方法。第一种合成依赖于使用 TMSCN 将叔苄醇溶剂解成腈，以及在酯水解之前将酯差向异构化到其热力学有利位置。已证明选择性受两种非对映体酯的水解速率控制。第二种合成被证明更有效，并使用了一种新型的亲核芳族取代氟吲唑与叔腈的阴离子。该路线的另一个关键要素是在叔腈存在下仲腈的选择性 Pinner 反应。

  DOI：

  10.1021/op010223p
• 作为产物：
  描述：

  环己酮 在 硼烷四氢呋喃络合物 作用下， 以 四氢呋喃 、 正己烷 、 甲苯 为溶剂， 反应 4.5h， 生成 环己基肼甲磺酸盐
  参考文献：
  名称：

  Development and Scale Up of a Route to Cyclohexylhydrazine Dimethanesulfonate

  摘要：

  A mild, high-yielding synthesis of cyclohexylhydrazine dimethanesulfonate has been developed that is suitable for further scale up, The process consists of three chemical steps: condensation of cyclohexanone with tert-butyl carbazate, reduction of the hydrazone carboxylate to a hydrazine carboxylate with borane-THF, and hydrolysis, decarboxylation, and derivatization with methanesulfonic acid. From studies using a reaction calorimeter, it was determined that the last stage of the process occurs in two discrete steps, requiring 2 equiv of methanesulfonic acid. The first equivalent of acid is consumed by N-protonation, Deprotection of the Boc group occurs with the second equivalent of acid, as evident by the gas evolution, The heat of reaction for the acid addition was determined to be 57.7 kJ/kg and represents an adiabatic temperature rise of 27.4 degreesC.

  DOI：

  10.1021/op0002904

文献信息

• THERAPEUTICALLY ACTIVE COMPOUNDS BASED ON INDAZOLE BIOISOSTERE REPLACEMENT OF CATECHOL IN PDE4 INHIBITORS
  申请人：——

  公开号：US20020058687A1

  公开（公告）日：2002-05-16

  Therapeutically active compositions of matter are described which are useful for treating or preventing diseases and conditions comprising inflammatory diseases including joint inflammation, Crohn's disease, and inflammatory bowel disease; respiratory diseases such as chronic obstructive pulmonary disease (COPD) including asthma, chronic bronchitis, and pulmonary emphysema; infectious diseases including endotoxic shock and toxic shock syndrome; immune diseases including systemic lupus erythematosis and psoriasis; and other diseases including bone resorption diseases and reperfusion injury; wherein said composition of matter comprises a compound which is an inhibitor of phosphodiesterase isozyme 4 (PDE4) and wherein an indazole is one essential component of said compound's overall chemical structure, and wherein said indazole constitutes a bioisosteric replacement of a catechol component or functional derivative thereof in a known compound having the same said therapeutic activity and the same remaining said components of its overall chemical structure. Included are compounds of Formula (IA) or (IB), wherein R 2 a and R 2 b are independently selected from the group consisting essentially of hydrogen and hereinafter recited substituents, provided that one, but not both of R 2 a and R 2 b must be independently selected as hydrogen, wherein said substituents comprise moieties including the following: (IC), (ID), (IE), (IF), (ILA), (ILB), (IIC), (IID), (IIE), (IIF), (IIG), (IIH), (III), (IIIA), (IIIB), (IIIC), (IIID), (IIIE), (IIIF), (IIIG), (IIIH), (IIII), (IIIJ), (IIIK), (IIIL), (IIIM), (IIIN), (IIIO), (IIIP), (IIIR), (IIIS), (IIIT), (IV), (VA), (VB), (VC), (VD), (VE a ), (VE), (VF), (VG), (VH), (VI), (VJ), (VK), (VL), (VM). 1

  本发明描述了具有治疗活性的物质组合物，其对于治疗或预防包括炎症性疾病（如关节炎症、克罗恩病和炎症性肠病）、呼吸系统疾病（如慢性阻塞性肺病（COPD），包括哮喘、慢性支气管炎和肺气肿）、感染性疾病（包括内毒素休克和中毒性休克综合征）、免疫性疾病（包括系统性红斑狼疮和银屑病）以及其他疾病（包括骨吸收疾病和再灌注损伤）具有用途；其中所述物质组合物包含一种化合物，该化合物是磷酸二酯酶同工酶4（PDE4）的抑制剂，并且其中吲唑是该化合物整体化学结构的一个基本组成部分，并且所述吲唑构成了已知具有相同治疗活性和相同剩余整体化学结构组成部分的化合物中儿茶酚组分或其功能衍生物的生物等排替换。包括具有式（IA）或（IB）的化合物，其中R2a和R2b独立地选自包括氢和以下所述取代基的组，条件是R2a和R2b中只有一个，但不能同时都选自氢，其中所述取代基包括以下基团：（IC），（ID），（IE），（IF），（ILA），（ILB），（IIC），（IID），（IIE），（IIF），（IIG），（IIH），（III），（IIIA），（IIIB），（IIIC），（IIID），（IIIE），（IIIF），（IIIG），（IIIH），（IIII），（IIIJ），（IIIK），（IIIL），（IIIM），（IIIN），（IIIO），（IIIP），（IIIR），（IIIS），（IIIT），（IV），（VA），（VB），（VC），（VD），（VEa），（VE），（VF），（VG），（VH），（VI），（VJ），（VK），（VL），（VM）。
• Substituted indazole derivatives and related compounds
  申请人：Pfizer Inc

  公开号：US06127398A1

  公开（公告）日：2000-10-03

  The invention relates to compounds of the formula I ##STR1## and pharmaceutically acceptable salts thereof, wherein R.sub.2.sup.a and R.sub.2.sup.b are independently selected from the group consisting essentially of hydrogen and hereinafter recited substituents, provided that one, but not both of R.sub.2.sup.a and R.sub.2.sup.b must be independently selected as hydrogen, wherein said substituents comprise: ##STR2## wherein the dashed lines in formulas (Ia) and (Ib) independently and optionally represent a single or double bond, provided that in formula (Ia) both dashed lines cannot both represent double bonds at the same time; and R, R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.18 and m are as defined. The invention further relates to intermediates for the preparation of the compounds of formula I, and to pharmaceutical compositions containing, and methods of using, the compounds of formula I, or acceptable salts thereof, for the inhibition of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (TNF) in a mammal.

  本发明涉及式I化合物 ##STR1## 及其药学上可接受的盐，其中R2a和R2b独立地选自基本上由氢和以下所述的取代基组成的组，前提是R2a和R2b中的一个，但不是两者都必须独立地选为氢，其中所述取代基包括： ##STR2## 其中式(Ia)和(Ib)中的虚线独立地且可选择地表示单键或双键，前提是在式(Ia)中两个虚线不能同时都表示双键；并且R、R1、R3、R4、R5、R6、R7、R18和m如所定义。本发明还涉及用于制备式I化合物的中间体，以及含有式I化合物或其可接受的盐的药物组合物，以及使用这些化合物或其可接受的盐来抑制哺乳动物中的磷酸二酯酶(PDE)类型IV或肿瘤坏死因子(TNF)产生的方法。
• Methods of preparing 4-cyano-4 (substituted indazole)
  申请人：——

  公开号：US06005118A1

  公开（公告）日：1999-12-21

  An improved process for preparing a compound of Formula (I): ##STR1## comprising: (a) treating a compound of Formula (Ia): ##STR2## with an alcohol comprising a compound of Formula (Ib-A) and an acid comprising a compound of Formula (Ib-B): ##STR3## wherein R.sub.a is selected from the group consisting essentially of hydrogen; (C.sub.1 -C.sub.6) alkyl; phenyl and (C.sub.1 -C.sub.3) alkyl-phenyl wherein said phenyl groups are optionally substituted by one or two substituents selected from the group consisting essentially of --(C.sub.1 -C.sub.4) alkyl; --O(C.sub.1 -C.sub.3) alkyl; Br; and Cl; and HX is an acid selected from the group consisting essentially of hydrobromic acid; hydrochloric acid; sulfuric acid; sulfonic acid; and aliphatic and aromatic sulfonic acids selected from the group consisting essentially of methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, benzylsulfonic acid, p-toluene sulfonic acid, and camphorsulfonic acid, whereby HX provides the acidic conditions which result in formation of a salt of the corresponding imidate of Formula (Ic): ##STR4## and (b) hydrolyzing said compound of Formula (Ic) to provide said compound of Formula (I).

  一种改进的制备式(I)化合物的方法：##STR1## 包括：(a) 用式(Ia)化合物处理一种含有式(Ib-A)化合物的醇和含有式(Ib-B)化合物的酸：##STR3## 其中R.sub.a选自由氢、(C.sub.1-C.sub.6)烷基、苯基和(C.sub.1-C.sub.3)烷基-苯基的组成，其中所述苯基可以选择地被一个或两个来自--(C.sub.1-C.sub.4)烷基、--O(C.sub.1-C.sub.3)烷基、Br和Cl的基团取代，HX是从羟溴酸、盐酸、硫酸、磺酸和脂肪族和芳香族磺酸中选择的酸，所述脂肪族和芳香族磺酸包括甲磺酸、三氟甲磺酸、苯磺酸、苄基磺酸、对甲苯磺酸和樟脑磺酸，从而HX提供酸性条件，导致形成相应的咪唑酰胺盐的生成，式(Ic)：##STR4## 和(b) 水解所述式(Ic)化合物以提供所述式(I)化合物。
• Methods of preparing 4-cyano-4-(substituted indazole)cyclohexane-carboxylic acids useful as PDE4 inhibitors
  申请人：Pfizer Products Inc.

  公开号：EP0915089A3

  公开（公告）日：2004-02-25

  An improved process for preparing a compound of Formula (I): comprising:(a) treating a compound of Formula (la):    with an alcohol comprising a compound of Formula (Ib-A) and an acid comprising a compound of Formula (Ib-B):    whereinRa is selected from the group consisting essentially of hydrogen; (C1-C6) alkyl; phenyl and (C1-C3) alkyl-phenyl wherein said phenyl groups are optionally substituted by one or two substituents selected from the group consisting essentially of -(C1-C4) alkyl; -O(C1-C3) alkyl; Br; and Cl; andHX is an acid selected from the group consisting essentially of hydrobromic acid; hydrochloric acid; sulfuric acid; sulfonic acid; and aliphatic and aromatic sulfonic acids selected from the group consisting essentially of methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, benzylsulfonic acid, p-toluene sulfonic acid, and camphorsulfonic acid, whereby HX provides the acidic conditions which result in formation of a salt of the corresponding imidate of Formula (Ic): and(b) hydrolyzing said compound of Formula (Ic) to provide said compound of Formula (I).

  一种制备公式（I）化合物的改进方法，包括：（a）用公式（la）的化合物处理含有公式（Ib-A）化合物的醇和含有公式（Ib-B）化合物的酸：其中Ra从基本上由氢;（C1-C6）烷基;苯基和（C1-C3）烷基苯基组成，其中所述苯基基团可选地被一个或两个取代基所取代，所述取代基被选自基本上由-(C1-C4）烷基; -O（C1-C3）烷基; Br;和Cl组成的基团; HX是选自羟溴酸;盐酸;硫酸;磺酸;以及选自基本上由甲烷磺酸，三氟甲烷磺酸，苯磺酸，苄基磺酸，对甲苯磺酸和樟脑磺酸的脂肪族和芳香族磺酸的酸中选择的酸，其中HX提供酸性条件，从而形成公式（Ic）相应咪唑酯的盐;和（b）水解所述公式（Ic）的化合物，以提供所述公式（I）的化合物。
• Therapeutically active compounds based on indazole bioisostere replacement of catechol in PDE4 inhibitors
  申请人：——

  公开号：US20030158189A1

  公开（公告）日：2003-08-21

  Therapeutically active compositions of matter are described which are useful for treating or preventing diseases and conditions comprising inflammatory diseases including joint inflammation, Crohn's disease, and inflammatory bowel disease; respiratory diseases such as chronic obstructive pulmonary disease (COPD) including asthma, chronic bronchitis, and pulmonary emphysema; infectious diseases including endotoxic shock and toxic shock syndrome; immune diseases including systemic lupus erythematosis and psoriasis; and other diseases including bone resorption diseases and reperfusion injury; wherein said composition of matter comprises a compound which is an inhibitor of phosphodiesterase isozyme 4 (PDE4) and wherein an indazole is one essential component of said compound's overall chemical structure, and wherein said indazole constitutes a bioisosteric replacement of a catechol component or functional derivative thereof in a known compound having the same said therapeutic activity and the same remaining said components of its overall chemical structure. Included are compounds of Formula (IA) or (IB): 1 wherein R 2 a and R 2 b are independently selected from the group consisting essentially of hydrogen and hereinafter recited substituents, provided that one, but not both of R 2 a and R 2 b must be independently selected as hydrogen, wherein said substituents comprise moieties including the following: 2

  本文描述了治疗或预防包括关节炎、克罗恩病和炎症性肠病在内的炎症性疾病；慢性阻塞性肺疾病（COPD）包括哮喘、慢性支气管炎和肺气肿等呼吸系统疾病；感染性疾病包括内毒素性休克和毒性休克综合征；免疫性疾病包括系统性红斑狼疮和银屑病；以及其他疾病包括骨吸收性疾病和再灌注损伤的有用的活性物质组合物。其中，该物质组合物包括一种磷酸二酯酶同工酶4（PDE4）抑制剂化合物，其中吲唑是该化合物整体化学结构的必要组分之一，该吲唑构成了一种已知具有相同治疗活性和其整体化学结构中的相同其余组分的化合物中儿茶酚组分或其官能衍生物的生物等构替代物。包括式（IA）或（IB）的化合物：其中R2a和R2b独立地选自包括氢和以下列出的取代基的基团，前提是R2a和R2b中的一个，但不是两个都必须独立地选为氢，其中这些取代基包括以下基团：