(4R)-4-(5-bromo-2-fluorophenyl)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid 2,2-dioxide 1,1-dimethylethyl ester | 1398113-03-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (4R)-4-(5-bromo-2-fluorophenyl)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid 2,2-dioxide 1,1-dimethylethyl ester
• 英文别名: (R)-tert-butyl 4-(5-bromo-2-fluorophenyl)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide；tert-butyl (4R)-4-(5-bromo-2-fluorophenyl)-4-methyl-2,2-dioxooxathiazolidine-3-carboxylate
• CAS: 1398113-03-5
• 化学式: C₁₄H₁₇BrFNO₅S
• 分子量: 410.261
• InChiKey: OTFINARLERSRHH-AWEZNQCLSA-N

物化性质

• 沸点：
  441.6±55.0 °C(Predicted)
• 密度：
  1.533±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  81.3
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (4R)-4-(5-bromo-2-fluorophenyl)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid 2,2-dioxide 1,1-dimethylethyl ester 在 盐酸 、 sodium methylate 、 caesium carbonate 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 96.5h， 生成 (R)-3-(5-bromo-2-fluorophenyl)-1-methoxy-3-methyl-3,4-dihydropyrrolo[1,2-a]pyrazine
  参考文献：
  名称：

  Evaluation of a Series of β-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads

  摘要：

  Despite several years of research, only a handful of beta-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimers disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. Herein we present a set of novel heteroaryl-fused piperazine amidine inhibitors designed to lower the basicity of the key, enzyme binding, amidine functionality. This study resulted in the identification of highly potent (IC50 <= 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux.

  DOI：

  10.1021/acsmedchemlett.9b00181
• 作为产物：
  描述：

  (R)-tert-butyl (2-(5-bromo-2-fluorophenyl)-1-hydroxypropan-2-yl)carbamate 在 ruthenium trichloride 、 sodium periodate 、 氯化亚砜 作用下， 以 水 、 乙腈 为溶剂， 反应 66.5h， 生成 (4R)-4-(5-bromo-2-fluorophenyl)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid 2,2-dioxide 1,1-dimethylethyl ester
  参考文献：
  名称：

  Evaluation of a Series of β-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads

  摘要：

  Despite several years of research, only a handful of beta-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimers disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. Herein we present a set of novel heteroaryl-fused piperazine amidine inhibitors designed to lower the basicity of the key, enzyme binding, amidine functionality. This study resulted in the identification of highly potent (IC50 <= 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux.

  DOI：

  10.1021/acsmedchemlett.9b00181

文献信息

• AMINO-DIHYDROTHIAZINE AND AMINO-DIOXIDO DIHYDROTHIAZINE COMPOUNDS AS BETA-SECRETASE ANTAGONISTS AND METHODS OF USE
  申请人：Amgen Inc.

  公开号：US20140107109A1

  公开（公告）日：2014-04-17

  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 A 4 , A 5 , A 6 , A 8 , R 1 , R 2 , R 3 , R 7 and n of Formula I, independently, are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and corresponding 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 Formula II and sub-formula embodiments thereof, intermediates and processes and methods useful for the preparation of compounds of Formulas I-II.

  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： 其中化学式I中的变量A4、A5、A6、A8、R1、R2、R3、R7和n在此独立地被定义。该发明还提供了包含这些化合物的药物组合物，以及这些化合物和组合物用于治疗与A-beta斑块形成和沉积相关的疾病和/或症状的对应用途，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的化合物及其亚式化合物，中间体和用于制备化学式I-II化合物的有用过程和方法。
• [EN] BICYCLIC HETEROCYCLE DERIVATIVES HAVING SELECTIVE BACE1 INHIBITORY ACTIVITY<br/>[FR] DÉRIVÉS D'HÉTÉROCYCLES BICYCLIQUES AYANT UNE ACTIVITÉ INHIBITRICE SÉLECTIVE DE BACE1
  申请人：SHIONOGI & CO

  公开号：WO2019208509A1

  公开（公告）日：2019-10-31

  The present invention provides a compound which has an effect of inhibiting amyloid β production, especially an effect of inhibiting selective BACE1, and which is useful as a therapeutic or prophylactic agent for diseases induced by production, secretion and/or deposition of amyloid β proteins. A compound of the formula (IA) or the like, wherein -A1- is alkylene optionally substituted with one or more halogen; R2 is substituted or unsubstituted alkyl or the like; R3 and R4 are each independently a hydrogen atom, halogen, alkyl or haloalkyl or the like; R5 is a hydrogen atom or halogen; A4 is N or CR6 wherein R6 is a hydrogen atom, halogen, or substituted or unsubstituted alkyl; A5 is NR7 or CR8R9; A6 is CR18 or N; R18 is a hydrogen atom; R7 is substituted or unsubstituted alkyl; R8 and R9 are each independently a hydrogen atom, halogen, alkyl or haloalkyl or the like; and Ring B is bicyclic ring; or a pharmaceutically acceptable salt thereof.

  本发明提供了一种化合物，具有抑制淀粉样蛋白β生成的作用，特别是具有抑制选择性BACE1的作用，并且对于由淀粉样蛋白β蛋白的生成、分泌和/或沉积引起的疾病作为治疗或预防剂是有用的。式（IA）或类似的化合物，其中-A1-是烷基，可选地取代一个或多个卤素；R2是取代或未取代的烷基或类似物；R3和R4分别独立地是氢原子、卤素、烷基或卤代烷基或类似物；R5是氢原子或卤素；A4是N或CR6，其中R6是氢原子、卤素，或取代或未取代的烷基；A5是NR7或CR8R9；A6是CR18或N；R18是氢原子；R7是取代或未取代的烷基；R8和R9分别独立地是氢原子、卤素、烷基或卤代烷基或类似物；环B是双环环；或其药学上可接受的盐。
• [EN] 5,6-DIHYDRO-IMIDAZO[1,2-a]PYRAZIN-8-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE)<br/>[FR] DÉRIVÉS 5,6-DIHYDRO-IMIDAZO[1,2-A]PYRAZIN-8-YLAMINE UTILES EN TANT QU'INHIBITEURS DE BÊTA SECRÉTASE (BACE)
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2012085038A1

  公开（公告）日：2012-06-28

  The present invention relates to novel 5,6-dihydro-imidazo[1,2-a]pyrazin-8- ylamine derivatives as inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, BACE1, Asp2, or memapsin2. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, cerebrovascular amyloid angiopathy, multi- infarct dementia, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease or dementia associated with beta-amyloid.

  本发明涉及作为β-分泌酶抑制剂的新型5,6-二氢咪唑[1,2-a]吡嗪-8-胺衍生物，也称为β-位点淀粉样蛋白裂解酶、BACE、BACE1、Asp2或memapsin2。该发明还涉及包含这些化合物的药物组合物，用于制备这些化合物和组合物的方法，以及将这些化合物和组合物用于预防和治疗涉及β-分泌酶的疾病，如阿尔茨海默病（AD）、轻度认知障碍、老年痴呆、带有Lewy小体的痴呆、脑血管淀粉样血管病、多梗死性痴呆、唐氏综合征、与中风相关的痴呆、与帕金森病相关的痴呆或与β-淀粉样蛋白相关的痴呆。
• [EN] 4-AMINO-6-PHENYL-5,6-DIHYDROIMIDAZO[1,5-A]PYRAZINE DERIVATIVES AS INHIBITORS OF BETA-SECRETASE (BACE)<br/>[FR] DÉRIVÉS DE 4-AMINO-6-PHÉNYL-5,6-DIHYDRO-IMIDAZO[1,5-A]PYRAZINE UTILISÉS COMME INHIBITEURS DE LA BÊTA-SÉCRÉTASE (BACE)
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2014198853A1

  公开（公告）日：2014-12-18

  The present invention relates to novel 5,6-dihydroimidazo[1,5-a]pyrazinyl derivatives as inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, in particular BACE1 and/or BACE2 (wherein BACE1, is also known as Asp2, or memapsin2 and BACE2 is also known as Asp1, Memapsin 1 or DRAP). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease, dementia of the Alzheimer's type, dementia associated with beta-amyloid, age-related macular degeneration, type 2 diabetes and other metabolic disorders.

  本发明涉及新颖的5,6-二氢咪唑并[1,5-a]吡嗪基衍生物，作为β-分泌酶抑制剂，也称为β-位点淀粉样蛋白裂解酶，BACE，特别是BACE1和/或BACE2（其中BACE1也称为Asp2，或memapsin2，BACE2也称为Asp1，Memapsin 1或DRAP）。该发明还涉及包含这些化合物的药物组合物，制备这些化合物和组合物的方法，以及利用这些化合物和组合物预防和治疗涉及β-分泌酶的疾病，如阿尔茨海默病（AD），轻度认知障碍，老年痴呆，带有Lewy小体的痴呆，唐氏综合症，与中风相关的痴呆，与帕金森病相关的痴呆，阿尔茨海默型痴呆，与β-淀粉样蛋白相关的痴呆，年龄相关性黄斑变性，2型糖尿病和其他代谢性疾病。
• [EN] 4-AMINO-6-PHENYL-5,6-DIHYDROIMIDAZO[1,5-A]PYRAZIN-3(2H)-ONE DERIVATIVES AS INHIBITORS OF BETA-SECRETASE (BACE)<br/>[FR] DÉRIVÉS DE 4-AMINO-6-PHÉNYL-5,6-DIHYDRO-IMIDAZO[1,5-A]PYRAZIN-3(2H)-ONE UTILISÉS COMME INHIBITEURS DE LA BÊTA-SÉCRÉTASE (BACE)
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2014198851A1

  公开（公告）日：2014-12-18

  The present invention relates to novel 5,6-dihydroimidazo[1,5-a]pyrazin-3(2H)-one derivatives as inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, in particular BACE1 and/or BACE2 (wherein BACE1, is also known as Asp2, or memapsin2 and BACE2 is also known as Asp1, Memapsin 1 or DRAP). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease, dementia of the Alzheimer's type, dementia associated with beta-amyloid, age-related macular degeneration, type 2 diabetes and other metabolic disorders.

  本发明涉及一种新型的5,6-二氢咪唑并[1,5-a]吡嗪-3(2H)-酮衍生物，作为β-分泌酶抑制剂，也称为β-位点淀粉样蛋白裂解酶，BACE，特别是BACE1和/或BACE2（其中BACE1也称为Asp2，或memapsin2，BACE2也称为Asp1，Memapsin 1或DRAP）。该发明还涉及包含这些化合物的药物组合物，制备这些化合物和组合物的方法，以及利用这些化合物和组合物预防和治疗涉及β-分泌酶的疾病，如阿尔茨海默病（AD），轻度认知障碍，老年痴呆，带有Lewy小体的痴呆，唐氏综合征，与中风相关的痴呆，与帕金森病相关的痴呆，阿尔茨海默型痴呆，与β-淀粉样蛋白相关的痴呆，年龄相关性黄斑变性，2型糖尿病和其他代谢性疾病的治疗。