(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide | 512776-95-3

• 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: (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide
• 英文别名: (2S)-N-[3-(Trifluoromethyl)-4-cyanophenyl]-2-methyloxirane-2alpha-carboxamide；(2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyloxirane-2-carboxamide
• CAS: 512776-95-3
• 化学式: C₁₂H₉F₃N₂O₂
• 分子量: 270.211
• InChiKey: UQUQTWDUTIAAAY-NSHDSACASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  65.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide 在 二甲基硫 、 三氟化硼乙醚 、 potassium carbonate 作用下， 以 二氯甲烷 、 丁酮 为溶剂， 反应 8.0h， 生成 (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(4-hydroxyphenoxy)-2-methylpropanamide
  参考文献：
  名称：

  Facile radiosynthesis of new carbon-11-labeled propanamide derivatives as selective androgen receptor modulator (SARM) radioligands for prostate cancer imaging

  摘要：

  The androgen receptor (AR) is an attractive target for the treatment and molecular imaging of prostate cancer. New carbon-11-labeled propanamide derivatives were first designed and synthesized as selective androgen receptor modulator (SARM) radioligands for prostate cancer imaging using the biomedical imaging technique positron emission tomography (PET). The target tracers, (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(2-[C-11]methoxyphenoxy)-2-methylpropanamide ([C-11]8a), (S)-2-hydroxy-3-(2-[C-11]methoxyphenoxy)-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide ([C-11]8e), (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(4-[C-11]methoxyphenoxy)-2-methyl-propanamide ([C-11]8c) and (S)-2-hydroxy-3-(4-[C-11]methoxyphenoxy)-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide ([C-11]8g), were prepared by O-[C-11]methylation of their corresponding precursors, (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(2-hydroxyphenoxy)-2-methylpropanamide (9a), (S)-2-hydroxy-3-(2-hydroxyphenoxy)-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide (9b), (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(4-hydroxyphenoxy)-2-methyl-propanamide (9c) and (S)-2-hydroxy-3-(4-hydroxyphenoxy)-2-methyl-N-(4-nitro-3-(trifluoromethyl)-phenyl)propanamide (9d), with [C-11]CH3OTf under basic conditions and isolated by a simplified C-18 solid-phase extraction (SPE) method in 55 +/- 5% (n = 5) radiochemical yields based on [C-11]CO2 and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 23 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EDS) was 277.5 +/- 92.5 GBq/mu mol (n = 5). (C) 2011 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.steroids.2011.08.005
• 作为产物：
  描述：

  N-(4-氰基-3-三氟甲基苯基)甲基丙烯酰胺 在 4-二甲氨基吡啶 、 四氧化锇 、 potassium carbonate 、 N-甲基吗啉氧化物 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 水 、 丙酮 、 叔丁醇 为溶剂， 反应 16.08h， 生成 (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide
  参考文献：
  名称：

  Process for making bicalutamide and intermediates thereof

  摘要：

  Bicalutamide及/或其中间体是通过使用对氟苯磺酸盐作为试剂制备的。

  公开号：

  US20040068135A1

文献信息

• New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity
  作者：Dong-Jin Hwang、Yali He、Suriyan Ponnusamy、Michael L. Mohler、Thirumagal Thiyagarajan、Iain J. McEwan、Ramesh Narayanan、Duane D. Miller

  DOI：10.1021/acs.jmedchem.8b00973

  日期：2019.1.24

  propanamides (series II and III) were discovered as selective androgen receptor degraders (SARDs). Initial studies of androgen receptor (AR) antagonist (1) and agonist (2) propanamides yielded a tertiary aniline (3) with novel SARD activity but poor metabolic stability. Cyclization to II and III produced submicromolar AR antagonism and protein degradation selective to AR and AR splice variant (AR SV). II and

  在寻找晚期前列腺癌（PCs）的小分子治疗方法的过程中，发现了一系列新颖的吲哚基和吲哚基丙酰胺（II和III系列）作为选择性雄激素受体降解剂（SARDs）。对雄激素受体（AR）拮抗剂（1）和激动剂（2）丙酰胺的初步研究产生了具有新型SARD活性但代谢稳定性较差的叔苯胺（3）。环化至II和III产生亚微摩尔的AR拮抗作用，并对AR和AR剪接变体（AR SV）产生选择性的蛋白质降解。二和三维持对enzalutamide耐药（Enz-R）突变的ARs和PC细胞的效力，并且对Enz-R异种移植物有效，表明它们具有治疗晚期PCs的潜力。新型SARD的设计，合成和生物学活性，可潜在地用于治疗各种PC，包括去势抵抗性，Enz-R和/或AR SV依赖性的晚期PC，这些已知PC通常无法用已知的激素疗法治疗讨论。
• Pyrazol-1-yl-propanamides as SARD and Pan-Antagonists for the Treatment of Enzalutamide-Resistant Prostate Cancer
  作者：Yali He、Dong-Jin Hwang、Suriyan Ponnusamy、Thirumagal Thiyagarajan、Michael L. Mohler、Ramesh Narayanan、Duane D. Miller

  DOI：10.1021/acs.jmedchem.0c00943

  日期：2020.11.12

  We report herein the design, synthesis, and pharmacological characterization of a library of novel aryl pyrazol-1-yl-propanamides as selective androgen receptor degraders (SARDs) and pan-antagonists that exert broad-scope AR antagonism. Pharmacological evaluation demonstrated that introducing a pyrazole moiety as the B-ring structural element in the common A-ring–linkage–B-ring nonsteroidal antiandrogens’

  我们在此报告了作为选择性雄激素受体降解剂 (SARDs) 和泛拮抗剂的新型芳基吡唑-1-基-丙酰胺库的设计、合成和药理学表征，它们具有广泛的 AR 拮抗作用。药理学评估表明，在常见的 A 环-连接-B 环非甾体类抗雄激素的一般药效团中引入吡唑部分作为 B 环结构元件，允许开发具有独特 SARD 和泛拮抗剂活性的新小分子支架甚至与我们最近发布的 AF-1 结合 SARD 相比，例如 UT-155 ( 9 ) 和 UT-34 ( 10）。新型 B 环吡唑表现出有效的 AR 拮抗剂活性，包括有希望的分布、代谢和药代动力学特性，以及广谱 AR 拮抗剂特性，包括有效的体内抗肿瘤活性。26a能够对源自恩杂鲁胺抗性 (Enz-R) VCaP 细胞系的异种移植物诱导 80% 的肿瘤生长抑制。这些结果代表了开发用于治疗 Enz-R 前列腺癌的新型 AR 拮抗剂的进展。
• [EN] SELECTIVE ANDROGEN RECEPTOR DEGRADER (SARD) LIGANDS AND METHODS OF USE THEREOF<br/>[FR] LIGANDS DE SARD - COMPOSÉS DE DÉGRADATION SÉLECTIFS DE RÉCEPTEURS DES ANDROGÈNES - ET MÉTHODES D'UTILISATION
  申请人：UNIV TENNESSEE RES FOUND

  公开号：WO2017214634A1

  公开（公告）日：2017-12-14

  This invention is directed to pyrrole, pyrazole, imidazole, triazole, and morpholine based selective androgen receptor degrader (SARD) compounds including heterocyclic anilide rings and their synthetic precursors, R-isomers, and non-hydroxylated and/or non-chiral propanamides, and pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, triple negative breast cancer, other cancers expressing the androgen receptor, androgenic alopecia or other hyperandrogenic dermal diseases, Kennedy's disease, amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.

  该发明涉及吡咯、吡唑、咪唑、三唑和吗啉基选择性雄激素受体降解剂（SARD）化合物，包括含有杂环苯胺环的合成前体、R-异构体以及非羟基化和/或非手性的丙酰胺，以及在治疗前列腺癌、晚期前列腺癌、去势耐药性前列腺癌、三阴性乳腺癌、其他表达雄激素受体的癌症、雄激素性脱发或其他高雄激素皮肤疾病、肯尼迪病、肌萎缩性侧索硬化（ALS）、腹主动脉瘤和子宫肌瘤等方面的制药组合物和用途，以及用于降低受试者中雄激素受体全长（AR-FL）的水平，包括致病性或耐药突变、AR-剪接变体（AR-SV）和AR的致病性多谷氨酸（polyQ）多态性的方法。
• Haloacetamide and azide substituted compounds and methods of use thereof
  申请人：Dalton T. James

  公开号：US20050085449A1

  公开（公告）日：2005-04-21

  The present invention relates to a novel class of anti-cancer compounds, which contain a haloacetamide or azide moiety and are, in one embodiment, alkylating agents. These agents, either alone or in a composition, are useful for treating cancer, preventing cancer, delaying the progression of cancer, treating and/or preventing the recurrence of cancer, suppressing, inhibiting or reducing the incidence of cancer, or inducing apoptosis in a cancer cell. Accordingly, the present invention provides a) methods of treating cancer in a subject; b) methods of preventing cancer in a subject; c) methods of delaying the progression of cancer in a subject; d) methods of treating the recurrence of cancer in a subject; e) methods of preventing the recurrence of cancer in a subject; f) methods of suppressing, inhibiting or reducing the incidence of cancer in a subject; and g) methods of inducing apoptosis in a cancer cell; by administering to the subject an anti-cancer compound of the present invention or an analog or metabolite thereof, its N-oxide, ester, pharmaceutically acceptable salt, hydrate, or any combination thereof as described herein.

  本发明涉及一类新型的抗癌化合物，其中包含卤代乙酰胺或叠氮基团，并且在一个实施例中，它们是烷基化剂。这些化合物，无论是单独使用还是作为组合物使用，可用于治疗癌症、预防癌症、延缓癌症进展、治疗和/或预防癌症复发、抑制、阻断或减少癌症发生率，或在癌细胞中诱导凋亡。因此，本发明提供了a)治疗受试者癌症的方法；b)预防受试者癌症的方法；c)延缓受试者癌症进展的方法；d)治疗受试者癌症复发的方法；e)预防受试者癌症复发的方法；f)抑制、阻断或减少受试者癌症发生率的方法；以及g)诱导癌细胞凋亡的方法；通过向受试者给予本发明的抗癌化合物或其类似物或代谢物、其N-氧化物、酯、药学上可接受的盐、水合物，或本文所述的任何组合物。
• [EN] SELECTIVE ANDROGEN RECEPTOR DEGRADER (SARD) LIGANDS AND METHODS OF USE THEREOF<br/>[FR] LIGANDS DE SARD - COMPOSÉS DE DÉGRADATION SÉLECTIFS DES RÉCEPTEURS AUX ANDROGÈNES - ET MÉTHODES D'UTILISATION
  申请人：GTX INC

  公开号：WO2016172358A1

  公开（公告）日：2016-10-27

  This invention provides novel indole, indazole, benzimidazole, indoline, quinolone, isoquinoline, and carbazole selective androgen receptor degrader (SARD) compounds, pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, androgenic alopecia or other hyper androgenic dermal diseases, Kennedy's disease, amyotrophic lateral sclerosis (ALS), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic and/or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.

  这项发明提供了新型吲哚、吲哚唑、苯并咪唑、吲哚啉、喹啉、异喹啉和咔唑选择性雄激素受体降解剂（SARD）化合物，以及在治疗前列腺癌、晚期前列腺癌、去势抵抗性前列腺癌、雄激素性脱发或其他高雄激素皮肤疾病、肯尼迪病、肌萎缩侧索硬化（ALS）和子宫肌瘤方面的药物组合物和用途，以及用于降低受试者体内雄激素受体全长（AR-FL）包括病原性和/或耐药突变、AR剪接变体（AR-SV）和AR病原性多谷氨酸（polyQ）多态性的水平的方法。