ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2-fluorophenyl)butanoate | 1432511-81-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2-fluorophenyl)butanoate
• 英文别名: ethyl (3S)-3-[[(R)-tert-butylsulfinyl]amino]-3-(2-fluorophenyl)butanoate
• CAS: 1432511-81-3
• 化学式: C₁₆H₂₄FNO₃S
• 分子量: 329.436
• InChiKey: YEFBJGVZCQVBKN-KSFYIVLOSA-N

物化性质

• 沸点：
  442.5±55.0 °C(Predicted)
• 密度：
  1.171±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  22
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  74.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2-fluorophenyl)butanoate 在 二异丁基氢化铝 作用下， 以 甲苯 为溶剂， 反应 3.0h， 以28%的产率得到(R)-N-((S)-2-(2-fluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide
  参考文献：
  名称：

  β-Secretase (BACE1) Inhibitors with High in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer’s Disease

  摘要：

  An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pK(a) and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF A beta 40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of A beta 40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.

  DOI：

  10.1021/jm400225m
• 作为产物：
  描述：

  2'-氟苯乙酮 在 titanium(IV) tetraethanolate 、 Wilkinson's catalyst 、 diethylzinc 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 生成 ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(2-fluorophenyl)butanoate
  参考文献：
  名称：

  [EN] 6-AMINO-5-FLUORO-5-(FLUOROMETHYL)-2,3,4,5-TETRAHYDROPYRIDIN-2-YL-PHENYL-5-(METHOXY-D3)-PYRAZINE-2-CARBOXAMIDES AND FLUORINATED DERIVATIVES THEREOF AS BACE1 INHIBITORS
  [FR] 6-AMINO-5-FLUORO-5-(FLUOROMÉTHYL)-2,3,4,5-TÉTRAHYDROPYRIDIN-2-YL-PHÉNYL-5-(MÉTHOXY-D3)-PYRAZINE-2-CARBOXAMIDES ET LEURS DÉRIVÉS FLUORÉS EN TANT QU'INHIBITEURS BACE1

  摘要：

  该发明提供了用于治疗神经退行性或认知疾病，包括阿尔茨海默病的Formula (I)的胍化合物。

  公开号：

  WO2018114910A1

文献信息

• Trifluoromethyl Dihydrothiazine‐Based β‐Secretase (BACE1) Inhibitors with Robust Central β‐Amyloid Reduction and Minimal Covalent Binding Burden
  作者：Kosuke Anan、Yasuyoshi Iso、Takuya Oguma、Kenji Nakahara、Shinji Suzuki、Takahiko Yamamoto、Eriko Matsuoka、Hisanori Ito、Gaku Sakaguchi、Shigeru Ando、Kenji Morimoto、Naoki Kanegawa、Yasuto Kido、Tomoyuki Kawachi、Tamio Fukushima、Ard Teisman、Vijay Urmaliya、Deborah Dhuyvetter、Herman Borghys、Nigel Austin、An Van Den Bergh、Peter Verboven、Francois Bischoff、Harrie J. M. Gijsen、Yoshinori Yamano、Ken-ichi Kusakabe

  DOI：10.1002/cmdc.201900478

  日期：2019.11.20

  The β-site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as β-secretase) is a promising target for the treatment of Alzheimer's disease. A pKa lowering approach over the initial leads was adopted to mitigate hERG inhibition and P-gp efflux, leading to the design of 6-CF3 dihydrothiazine 8 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluoro

  β-位淀粉样蛋白前体蛋白裂解酶1（BACE1，也称为β-分泌酶）是治疗阿尔茨海默氏病的有希望的靶标。采用pKa降低初始引线的方法来减轻hERG抑制和P-gp外排，从而设计出6-CF3二氢噻嗪8（N-（3-（（4S，6S）-2-amino-4-methyl -6-（三氟甲基）-5,6-二氢-4H-1,3-噻嗪-4-基）-4-氟苯基）-5-氰基吡啶啉）。优化8导致发现15（N-（3-（（4S，6S）-2-氨基-4-甲基-6-（三氟甲基）-5,6-二氢-4H-1,3-噻嗪- 4-yl）-4-氟苯基）-5-（氟甲氧基）吡嗪-2-羧酰胺）具有出色的效能，hERG抑制，P-gp外排和代谢稳定性之间的平衡。甚至在0.16 mg / kg的剂量下，口服8也会引起犬Aβ的强烈降低。反映出降低的hERG抑制活性，高剂量时未观察到QTc延长。在人肝微粒体中使用[14 C] -KCN进行亲核试剂捕获测定，实现了1
• [EN] 2-AMINO-3-FLUORO-3-(FLUOROMETHYL)-6-METHYL-6-PHENYL-3,4,5,6-TETRAHYDROPYRIDINS AS BACE1 INHIBITORS<br/>[FR] 2-AMINO-3-FLUORO-3-(FLUOROMÉTHYL)-6-MÉTHYL-6-PHÉNYL-3,4,5,6-TÉTRAHYDROPYRIDINES COMME INHIBITEURS DE BACE1
  申请人：H LUNDBECK AS

  公开号：WO2017025559A1

  公开（公告）日：2017-02-16

  The present invention provides compounds of Formula (I) for the treatment of neurodegenerative or cognitive diseases. The method further provides for piperidine-2-one and piperidine-2-thione intermediates to compounds of formula (I).

  本发明提供了用于治疗神经退行性或认知疾病的化合物(I)的方法。该方法还提供了哌啶-2-酮和哌啶-2-硫酮中间体到化合物(I)的转化。
• [EN] DIHYDROTHIAZINE DERIVATIVES<br/>[FR] DÉRIVÉS DE DIHYDROTHIAZINE
  申请人：SHIONOGI & CO

  公开号：WO2017061534A1

  公开（公告）日：2017-04-13

  The present invention provides a compound which has an effect of inhibiting amyloid β production, especially an effect of inhibiting 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 formula (I) wherein R1 is alkyl or haloalkyl, R2 is H or halogen, R3 is H, alkyl, alkyloxyalkyl or haloalkyl optionally substituted with cycloalkyl, R4 is H or halogen, -X= is -CH= or -N=, ring B is a substituted or unsubstituted aromatic carbocycle, a substituted or unsubstituted aromatic heterocycle or the like, or a pharmaceutically acceptable salt thereof.

  本发明提供了一种具有抑制淀粉样蛋白β产生的作用，特别是抑制BACE1的作用，并且作为治疗或预防由淀粉样蛋白β蛋白的产生、分泌和/或沉积引起的疾病的治疗或预防剂的化合物。其中R1为烷基或卤代烷基，R2为H或卤素，R3为H、烷基、烷氧基烷基或卤代烷基，可选择地与环烷基取代，R4为H或卤素，-X=为-CH=或-N=，环B为取代或未取代的芳香碳环、取代或未取代的芳香杂环等，或其药用可接受盐。
• 2-amino-3-fluoro-3-(fluoromethyl)-6-methyl-6-phenyl-3,4,5,6-tetrahydropyridines as BACE1 inhibitors
  申请人：H. Lundbeck A/S

  公开号：US10011596B2

  公开（公告）日：2018-07-03

  The present invention provides compounds of Formula I for the treatment of neurodegenerative or cognitive diseases. The method further provides for piperidine-2-one and piperidine-2-thione intermediates to compounds of formula I.

  本发明提供了式 I 的化合物 用于治疗神经退行性疾病或认知疾病。该方法进一步提供了式 I 化合物的哌啶-2-酮和哌啶-2-硫酮中间体。
• 2-Amino-3-Fluoro-3-(Fluoromethyl)-6-Methyl-6-Phenyl-3,4,5,6-Tetrahydropyridines as BACE1 Inhibitors
  申请人：H. Lundbeck A/S

  公开号：US20170044151A1

  公开（公告）日：2017-02-16

  The present invention provides compounds of Formula I for the treatment of neurodegenerative or cognitive diseases. The method further provides for piperidine-2-one and piperidine-2-thione intermediates to compounds of formula I.