5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid | 1174323-36-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid
• CAS: 1174323-36-4
• 化学式: C₇H₅F₃N₂O₃
• 分子量: 222.124
• InChiKey: CENCSYPHQKYCJZ-UHFFFAOYSA-N

物化性质

• 沸点：
  283.3±40.0 °C(Predicted)
• 密度：
  1.528±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  72.3
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid 生成 N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-chloro-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide
  参考文献：
  名称：

  PERFLUORINATED 5,6-DIHYDRO-4H-1,3-OXAZIN-2-AMINE COMPOUNDS AS BETA-SECRETASE INHIBITORS AND METHODS OF USE

  摘要：

  本发明提供了一类新的化合物，用于调节β-分泌酶（BACE）活性。这些化合物的通用公式为I： 其中变量A4，A5，A6，A8，公式I中的R1和R2，R3和R7各自独立定义如下。本发明还提供了包含这些化合物的药物组合物，以及使用这些化合物和组合物治疗与A-β斑块形成和沉积相关的疾病和/或状况，这些疾病和/或状况是由BACE的生物活性引起的。这样的BACE介导的疾病包括，例如，阿尔茨海默病，认知缺陷，认知障碍，精神分裂症和其他中枢神经系统疾病。本发明进一步提供了公式II和III的化合物，以及其子公式的实施例，中间体和用于制备公式I-III化合物的过程和方法。

  公开号：

  US20140249104A1
• 作为产物：
  描述：

  5-氯吡嗪-2-羧酸甲酯 在 水 、 caesium carbonate 、 sodium hydroxide 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 74.0h， 生成 5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid
  参考文献：
  名称：

  BACE INHIBITORS

  摘要：

  本发明提供了一种III式化合物：其中A是：以及Z、R1、R2、R3和R4如本文所定义，或其药学上可接受的盐。

  公开号：

  US20140371212A1

文献信息

• [EN] SUBSTITUTED BENZAMIDE DERIVATIVES<br/>[FR] DÉRIVÉS DE BENZAMIDE SUBSTITUÉS
  申请人：HOFFMANN LA ROCHE

  公开号：WO2011076678A1

  公开（公告）日：2011-06-30

  The invention relates to compounds of formula I wherein R is hydrogen or lower alkyl; R1 is -(CH2)n-(O)o-heterocycloalkyl or -C(O)-heterocycloalkyl, wherein the heterocycloalkyl group is optionally substituted by lower alkyl, hydroxy, halogen or by -(CH2)p-aryl; n is 0, 1 or 2; o is 0 or 1; p is 0, 1 or 2; R2 is CF3, cycloalkyl, optionally substituted by lower alkoxy or halogen, or is indan-2-yl, or is heterocycloalkyl, optionally substituted by heteroaryl, or is aryl or heteroaryl, wherein the aromatic rings are optionally substituted by one or two substituents, selected from lower alkyl, halogen, heteroaryl, hydroxy, CF3, OCF3, OCH2CF3, OCH2-cycloalkyl, OCH2C(CH2OH)(CH2C1)(CH3), S-lower alkyl, lower alkoxy, CH2-lower alkoxy, lower alkinyl or cyano, or by-C(O)-phenyl, -O-phenyl, -O- CH2-phenyl, phenyl or -CH2-phenyl, and wherein the phenyl rings may optionally be substituted by halogen, -C(O)-lower alkyl, -C(O)OH or -C(O)O-lower alkyl, or the aromatic rings are optionally substituted by heterocycloalkyl, OCH2-oxetan-3-yl or O-tetrahydropyran-4-yl, optionally substituted by lower alkyl; X is a bond, -NR'-, -CH2NH-, -CHR''-, -(CHR'')q-O-, -O-(CHR'')q- or -(CH2)2-; Y is a bond or -CH2- R' is hydrogen or lower alkyl, R'' is hydrogen, lower alkyl, CF3, lower alkoxy, q is 0, 1, 2 or 3; or to a pharmaceutically suitable acid addition salt thereof. It has now been found that the compounds of formula I have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinsons disease, neurodegenerative disorders such as Alzheimers disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

  该发明涉及以下式I的化合物，其中R是氢或较低的烷基；R1是-(CH2)n-(O)o-杂环烷基或-C(O)-杂环烷基，其中杂环烷基基团可选择地被较低的烷基，羟基，卤素或-(CH2)p-芳基取代；n为0、1或2；o为0或1；p为0、1或2；R2为CF3，环烷基，可选择地被较低的烷氧基或卤素取代，或为茚-2-基，或为杂环烷基，可选择地被杂芳基取代，或为芳基或杂芳基，其中芳香环可选择地被来自较低的烷基，卤素，杂芳基，羟基，CF3，OCF3，OCH2CF3，OCH2-环烷基，OCH2C(CH2OH)(CH2C1)(CH3)，S-较低的烷基，较低的烷氧基，CH2-较低的烷氧基，较低的炔基或氰基，或-C(O)-苯基，-O-苯基，-O-CH2-苯基，苯基或-CH2-苯基选择的一个或两个取代基取代，其中苯环可选择地被卤素，-C(O)-较低的烷基，-C(O)OH或-C(O)O-较低的烷基取代，或芳香环可选择地被杂环烷基，OCH2-氧杂环戊烷-3-基或O-四氢吡喃-4-基，可选择地被较低的烷基取代；X为键，-NR'-，-CH2NH-，-CHR''-，-(CHR'')q-O-，-O-(CHR'')q-或-(CH2)2-；Y为键或-CH2-；R'为氢或较低的烷基，R''为氢，较低的烷基，CF3，较低的烷氧基，q为0、1、2或3；或其药学上适宜的酸盐。现已发现，该式I的化合物对痕量胺相关受体（TAARs）具有良好的亲和力，特别是对于TAAR1。这些化合物可用于治疗抑郁症，焦虑症，躁郁症，注意力缺陷多动障碍（ADHD），与压力有关的疾病，如精神分裂症，帕金森病等神经疾病，阿尔茨海默病等神经退行性疾病，癫痫，偏头痛，高血压，物质滥用和代谢性疾病，如进食障碍，糖尿病，糖尿病并发症，肥胖症，血脂异常，能量消耗和吸收异常，体温稳态异常，睡眠和昼夜节律异常，以及心血管疾病。
• [EN] PERFLUORINATED CYCLOPROPYL FUSED 1,3-OXAZIN-2-AMINE COMPOUNDS AS BETA-SECRETASE INHIBITORS AND METHODS OF USE<br/>[FR] COMPOSÉS À BASE DE 1,3-OXAZIN-2-AMINE FUSIONNÉE AVEC DU CYCLOPROPYLE PERFLUORÉ UTILISABLES EN TANT QU'INHIBITEURS DE LA BÊTA-SÉCRÉTASE ET LEURS PROCÉDÉS D'UTILISATION
  申请人：AMGEN INC

  公开号：WO2014138484A1

  公开（公告）日：2014-09-12

  PERFLUORINATED CYCLOPROPYL FUSED 1,3-OXAZIN-2-AMINE COMPOUNDS AS BETA-SECRETASE INHIBITORS AND METHODS OF USE ABSTRACT OF THE DISCLOSURE The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula I: INSERT STRUCTURE HERE} I wherein variables A4, A5, A6, A8, each of Ra, Rb, R1, R2, R3 and R7 of Formula I, independently, are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and uses of the compounds and compositions for treatment of disorders and/or conditions related to A-beta plaque formation and deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairments, schizophrenia and other central nervous system conditions. The invention further provides compounds of Formulas II and III, and sub-formula embodiments thereof, intermediates and methods for preparing compounds of the invention.

  本发明提供了一类新的化合物，用于调节β-分泌酶（BACE）活性。这些化合物具有一般的化学式I：在此插入结构} I，其中变量A4、A5、A6、A8，以及化学式I中的每个Ra、Rb、R1、R2、R3和R7，在本文中分别定义。该发明还提供了包含这些化合物的药物组合物，以及用于治疗与A-beta斑块形成和沉积相关的疾病和/或症状的化合物和组合物的用途，这些疾病和症状是由BACE的生物活性引起的。这种由BACE介导的疾病包括阿尔茨海默病、认知缺陷、认知障碍、精神分裂症和其他中枢神经系统疾病。该发明还提供了化学式II和III的化合物，以及其亚式化合物、中间体和制备本发明化合物的方法。
• SUBSTITUTED BENZAMIDES
  申请人：Groebke Zbinden Katrin

  公开号：US20110152245A1

  公开（公告）日：2011-06-23

  The invention relates to compounds of formula wherein R, R 1 , R 2 , X, and Y are as defined herein and to a pharmaceutically suitable acid addition salt thereof. Compounds of formula I have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The compounds can be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

  该发明涉及以下式的化合物 其中R、R1、R2、X和Y如本文所定义，并且其药学上适宜的酸盐。 式I的化合物对痕量胺相关受体（TAARs）具有良好的亲和力，特别是对TAAR1。这些化合物可用于治疗抑郁症、焦虑障碍、双相情感障碍、注意缺陷多动障碍（ADHD）、与压力有关的障碍、如精神分裂症的精神障碍、如帕金森病的神经疾病、如阿尔茨海默病的神经退行性疾病、癫痫、偏头痛、高血压、物质滥用和代谢性障碍，如进食障碍、糖尿病、糖尿病并发症、肥胖症、血脂异常、能量消耗和吸收障碍、体温稳态障碍、睡眠和昼夜节律障碍，以及心血管疾病。
• Iminothiadiazine Dioxide Compounds as BACE Inhibitors, Compositions and Their Use
  申请人：Merck Sharp & Dohme Corp.

  公开号：US20150307465A1

  公开（公告）日：2015-10-29

  In its many embodiments, the present invention provides certain iminothiadiazine dioxide compounds, including compounds Formula (I): and include stereoisomers thereof, and pharmaceutically acceptable salts of said compounds stereoisomers, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , ring A, ring B, m, n, p, -L 1 -, -L 2 -, and -L 3 - is selected independently and as defined herein. The novel iminothiadiazine dioxide compounds of the invention have surprisingly been found to exhibit properties which are expected to render them advantageous as BACE inhibitors and/or for the treatment and prevention of various pathologies related to β-amyloid (“Aβ”) production. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use in treating pathologies associated with amyloid beta (Aβ) protein, including Alzheimer's disease, are also disclosed.

  本发明提供了多种形式的亚氨基噻二唑二氧化物化合物，包括公式(I)的化合物： 包括它们的立体异构体，以及所述立体异构体的药用可接受盐，其中R1、R2、R3、R4、R5、R9、环A、环B、m、n、p、-L1-、-L2-和-L3-都是独立选择且按本文定义。发明的新型亚氨基噻二唑二氧化物化合物出人意料地被发现具有预期的特性，使其作为BACE抑制剂以及/或用于治疗和预防与β-淀粉样蛋白（“Aβ”）生成相关的各种病理学具有优势。还公开了包含一个或多个此类化合物（单独使用和与一个或多个其他活性成分组合使用）的药物组合物，以及它们的制备方法和用于治疗与淀粉样β（Aβ）蛋白相关的病理学，包括阿尔茨海默病的方法。
• [EN] CYCLOPROPYL FUSED THIAZIN-2-AMINE COMPOUNDS AS BETA-SECRETASE INHIBITORS AND METHODS OF USE<br/>[FR] COMPOSÉS THIAZIN-2-AMINE FUSIONNÉE À UN GROUPEMENT CYCLOPROPYLE UTILISÉS EN TANT QU'INHIBITEURS DE LA BÊTA-SECRÉTASE ET LEURS PROCÉDÉS D'UTILISATION
  申请人：AMGEN INC

  公开号：WO2016022724A1

  公开（公告）日：2016-02-11

  The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula (I): wherein variables A4, A5, A6, A8, and each of Ra, Rb, R1, R2, R3 and R7 of Formula (I), independently, are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and uses of the compounds and compositions for treatment of disorders and/or conditions related to A-beta plaque formation and 15 deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimers Disease, cognitive deficits, cognitive impairments, schizophrenia and other central nervous system conditions. The invention further provides compounds of Formulas (II) and (III), and sub-formula embodiments thereof, intermediates and methods for preparing compounds of the invention.

  本发明提供了一类新的化合物，用于调节β-分泌酶（BACE）活性。这些化合物具有一般式（I）：其中一般式（I）中的变量A4、A5、A6、A8，以及Ra、Rb、R1、R2、R3和R7各自独立地在此定义。该发明还提供了包括这些化合物的药物组合物，以及用于治疗与A-beta斑块形成和沉积相关的疾病和/或症状的化合物和组合物的用途，这些疾病和症状是由BACE的生物活性引起的。这种由BACE介导的疾病包括，例如，阿尔茨海默病、认知缺陷、认知障碍、精神分裂症和其他中枢神经系统疾病。该发明还提供了一般式（II）和（III）的化合物，以及其亚式形式、中间体和制备本发明化合物的方法。