4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylic acid ethyl ester | 224048-13-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylic acid ethyl ester
• 英文别名: 4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl)cyclohex-3-enecarboxylic acid ethyl ester；4-(3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl)-cyclohex-3-ene-carboxylic acid ethyl ester；ethyl 4-[3-ethyl-1-(4-fluorophenyl)indazol-6-yl]cyclohex-3-ene-1-carboxylate
• CAS: 224048-13-9
• 化学式: C₂₄H₂₅FN₂O₂
• 分子量: 392.473
• InChiKey: PNNVKHPICCNMIV-UHFFFAOYSA-N

物化性质

• 沸点：
  478.4±45.0 °C(Predicted)
• 密度：
  1.20±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  44.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylic acid ethyl ester 在 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 、 乙酸乙酯 为溶剂， 生成 4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylic acid
  参考文献：
  名称：

  THERAPEUTICALLY ACTIVE COMPOUNDS BASED ON INDAZOLE BIOISOSTERE REPLACEMENT OF CATECHOL IN PDE4 INHIBITORS

  摘要：

  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）。

  公开号：

  US20020058687A1
• 作为产物：
  描述：

  4-[3-Ethyl-1-(4-fluorophenyl)-1 H-indazol-6-yl]-4-hydroxycyclohexanecarboxylic acid ethyl ester 生成 4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylic acid ethyl ester 、 4-cyano-4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohexanecarboxylic acid ethyl ester
  参考文献：
  名称：

  Substituted indazole derivatives and related compounds

  摘要：

  本发明涉及式I化合物及其药学上可接受的盐，其中R2a和R2b各自独立地选自基本上由氢和以下所述的取代基组成的组，条件是R2a和R2b中仅有一个，而非两者，必须独立地选为氢，所述取代基包括：式(Ia)和(Ib)中的虚线各自独立地且可选择地表示单键或双键，条件是在式(Ia)中，两条虚线不能同时都表示双键；并且R、R1、R3、R4、R5、R6、R7、R18和m如定义所述。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)IV型或肿瘤坏死因子(TNF)产生的方法。

  公开号：

  US06211222B1

文献信息

• PROKINETIC AGENTS FOR TREATING GASTRIC HYPOMOTILITY AND RELATED DISORDERS
  申请人：——

  公开号：US20030176421A1

  公开（公告）日：2003-09-18

  Stasis is treated or prevented in all or any part or parts of the stomach of a patient, especially a human patient, in need of such treatment, where said stasis results from hypomotility in the stomach, particularly gastric hypomotility with delayed emptying of the liquid and/or solid contents of the stomach. Gastric or gastrointestinal disorders are also treated which are characterized by one or more symptoms selected from pain, nausea, vomiting, heartburn, postprandial discomfort, indigestion and gastroesophageal reflux. Such treatment or prevention is achieved by administering to the patient a therapeutically effective amount of an inhibitor of phosphodiesterase-4 (PDE4), including isozyme subtypes thereof, sufficient to treat or prevent such hypomotility or gastric or gastrointestinal disorder in said patient. The PDE4 inhibitor comprises a compound of Formula (IA) or (IB): 1 where in a preferred embodiment, R is cyclopentyl or cyclohexyl; R 1 is (C 1 -C 2 ) alkyl; one of R 2 a and R 2 b is hydrogen and the other is a substituent of partial Formula (1.0.0) above, where the dashed line represents a single bond, m is 0, R 113 and R 114 are in a cis relationship to each other, R 113 is cyano, R 115 is hydrogen, and R 114 is carboxy, —CH 2 OH, or —CH 2 C(═O)NH 2 . Pharmaceutical compositions are also described which are useful for carrying out the above-mentioned methods of treatment and prevention, and which are also useful in the treatment of a gastric or gastrointestinal disorder in a patient which comprises with respect to said patient, (i) a sign or concomitant of diabetic neuropathy, anorexia nervosa, achlorhydria, gastrointestinal surgery, post-surgical recovery in the period of emergence from general anesthesia; or the administration of morphine and morphine-like opioids; (ii) a secondary aspect of a primary disease or disorder in said patient which is organic, wherein said disease or disorder involves particularly a gastroenteric or gastroesophageal organ or tissue, or an organ or tissue of the central nervous system of said patient; or (iii) an adverse side effect of a different therapeutic agent administered to said patient in the course of treating another unrelated disease or disorder in said patient.

  本发明涉及一种治疗或预防患者（尤其是人类患者）胃部任何部位或全部的停滞，其中该停滞是由于胃肠道低动力性，尤其是胃肠道低动力性导致胃液和/或固体食物的排空延迟。同时，本发明还涉及治疗或预防胃或胃肠道疾病，这些疾病的特征是疼痛、恶心、呕吐、胃灼热、餐后不适、消化不良和胃食管反流中的一个或多个症状。通过向患者施用磷酸二酯酶-4（PDE4）的抑制剂，包括其同工酶亚型，治疗或预防该患者的低动力性或胃或胃肠道疾病所需的治疗剂量就可以实现。所述PDE4抑制剂包括化合物公式（IA）或（IB）的化合物：其中在一种优选实施例中，R为环戊基或环己基；R1为（C1-C2）烷基；R2a和R2b中的一个是氢，另一个是上述部分式（1.0.0）的取代基，其中虚线表示单键，m为0，R113和R114在相互的顺式关系下，R113为氰基，R115为氢，R114为羧基，-CH2OH或-CH2C（═ O）NH2。本发明还描述了药物组合物，用于执行上述治疗和预防方法，并且还用于治疗患者的胃或胃肠道疾病，该患者具有以下特征：（i）糖尿病神经病变、厌食症、无酸胃、胃肠道手术、全身麻醉恢复期间的术后恢复；或吗啡和吗啡样的阿片类药物的使用的标志或伴随症状；（ii）该患者的原发性疾病或疾病的次要方面是器质性疾病或疾病，其中该疾病或疾病特别涉及该患者的胃肠道或胃食管器官或组织，或该患者的中枢神经系统的器官或组织；或（iii）在治疗该患者的另一种无关疾病或疾病的过程中向该患者施用的不同治疗剂的不良副作用。
• 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：
• Indazole bioisostere replacement of catechol in therapeutically active compounds
  申请人：Pfizer Inc

  公开号：US06391872B1

  公开（公告）日：2002-05-21

  Therapeutically active compositions of matter and member species thereof are described which comprise indazole-containing compounds, said compounds and their therapeutic activity resulting directly from an indazole-for-catechol bioisostere replacement of a catechol-containing compound having the same therapeutic activity, where non-catechol substituents are the same or homologous before and after said replacement, and wherein said compositions of matter comprise a compound of Formula (I1) or (I2): or a pharmaceutically acceptable salt thereof, wherein in a preferred embodiment RC is hydrogen; RA is cyclohexyl; and RB is ethyl. Ra and Rb are each individually and independently hydrogen or non-catechol substituents of said compounds resulting directly from an indazole-for-catechol bioisostere replacement of said catechol-containing compound having said therapeutic activity, where said non-catechol substituents are the same or homologous before and after said replacement, provided that both of Ra and Rb cannot be hydrogen at the same time. The therapeutic activity involved may comprise cholinesterase inhibitory activity, adrenergic &agr;1-antagonist and &bgr;1-agonist activity, calcium channel inhibitory activity, antineoplastic activity, and phosphodiesterase type IV inhibitory activity.

  本文描述了包含吲唑类化合物的治疗活性组合物及其成员种类，所述化合物及其治疗活性是由于将具有相同治疗活性的邻二酚含量化合物的邻二酚与吲唑的生物同位素替换而直接产生的，其中非邻二酚取代基在替换前后相同或同系，在所述物质组合中包括式（I1）或（I2）的化合物或其药学上可接受的盐，其中在优选实施例中，RC为氢；RA为环己基；RB为乙基。Ra和Rb各自且独立地为氢或所述化合物的非邻二酚取代基，该取代基是由于将具有所述治疗活性的邻二酚含量化合物的邻二酚与吲唑的生物同位素替换而直接产生的，其中所述非邻二酚取代基在替换前后相同或同系，但Ra和Rb不能同时为氢。所述治疗活性可能包括胆碱酯酶抑制活性、肾上腺素α1-拮抗剂和β1-激动剂活性、钙通道抑制活性、抗肿瘤活性和磷酸二酯酶IV抑制活性。
• Prokinetic agents for treating gastric hypomotility and related disorders
  申请人：PFIZER INC.

  公开号：EP1040829A2

  公开（公告）日：2000-10-04

  The invention describes the use of PDE-4 (phosphodiesterase-4) inhibitors in the treatment or prevention of gastric stasis resulting from hypomotility of the stomach (with delayed emptying of the liquid and/or solid contents of the stomach). More particularly said inhibitors are indazole derivatives such as (1H-indazol-6-yl)-cyclohexane or cyclohexene carboxylic acid derivatives, carbonitriles, amides or esters thereof. Gastric or gastrointestinal disorders, which may also be caused by adverse effects of therapeutic agents, of surgical operations or concomitant or secondary aspects of another disease, which include pain, nausea, vomiting, heartburn, postprandial discomfort, indigestion and gastro-esophageal reflux, can be prevented or treated with pharmaceutical compositions containing said PDE-4 indazole inhibitors.

  本发明描述了 PDE-4（磷酸二酯酶-4）抑制剂在治疗或预防胃蠕动减弱（胃中液体和/或固体内容物排空延迟）导致的胃淤血中的应用。 更特别的是，所述抑制剂是吲唑衍生物，如（1H-吲唑-6-基）-环己烷或环己烯羧酸衍生物、碳腈、酰胺或其酯。胃肠功能紊乱也可能是由治疗药物、外科手术或其他疾病的并发或继发不良反应引起的，包括疼痛、恶心、呕吐、胃灼热、餐后不适、消化不良和胃食管反流，可以用含有所述 PDE-4 吲唑抑制剂的药物组合物来预防或治疗。
• INDAZOLE BIOISOSTERE REPLACEMENT OF CATECHOL IN THERAPEUTICALLY ACTIVE COMPOUNDS
  申请人：Pfizer Products Inc.

  公开号：EP1028946A1

  公开（公告）日：2000-08-23