6-(3-氯-4-氟苯基)-4,4-二甲基-1H-苯并[d][1,3]噁嗪-2(4h)-酮 | 304854-45-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 中文名称: 6-(3-氯-4-氟苯基)-4,4-二甲基-1H-苯并[d][1,3]噁嗪-2(4h)-酮
• 英文名称: 6-(3-Chloro-4-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one
• 英文别名: 6-(3-chloro-4-fluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one；wyeth 4j；6-(3-chloro-4-fluorophenyl)-4,4-dimethyl-1H-benzo[d][1,3]oxazin-2(4H)-one；6-(3-chloro-4-fluorophenyl)-4,4-dimethyl-1H-3,1-benzoxazin-2-one
• CAS: 304854-45-3
• 化学式: C₁₆H₁₃ClFNO₂
• 分子量: 305.736
• InChiKey: PRCXSDHAGJJCKC-UHFFFAOYSA-N

物化性质

• 沸点：
  381.8±42.0 °C(Predicted)
• 密度：
  1.275±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  38.3
• 氢给体数：
  1
• 氢受体数：
  3

安全信息

• 海关编码：
  2934999090

反应信息

• 作为反应物：
  描述：

  6-(3-氯-4-氟苯基)-4,4-二甲基-1H-苯并[d][1,3]噁嗪-2(4h)-酮 在 劳森试剂 作用下， 以 甲苯 为溶剂， 生成 6-(3-Chloro-4-fluorophenyl)-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione
  参考文献：
  名称：

  Novel 6-aryl-1,4-dihydrobenzo[d]oxazine-2-thiones as potent, selective, and orally active nonsteroidal progesterone receptor agonists

  摘要：

  The functional activity of 6-aryl benzoxazinone-based progesterone (PR) antagonists changed to PR agonism when the 2-carbonyl group was replaced by a 2-thiocarbonyl moiety. Based on this finding novel 6-aryl benzoxazine-2-thiones were synthesized and evaluated as PR agonists in various in vitro and in vivo assays. Several analogues had sub-nanomolar in vitro potency and showed excellent oral activities in rats. Compounds 15 and 29 had similar potencies to medroxyprogesterone acetate (MPA) in the in vitro T47D alkaline phosphatase assay and in vivo rat decidualization model. In contrast to MPA, 29 was highly selective (> 500-fold) for PR over glucocorticoid and androgen receptors. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(03)00128-8
• 作为产物：
  描述：

  溴伏克辛 在 四(三苯基膦)钯 、 正丁基锂 、 sodium carbonate 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 正己烷 、 水 为溶剂， 反应 3.5h， 生成 6-(3-氯-4-氟苯基)-4,4-二甲基-1H-苯并[d][1,3]噁嗪-2(4h)-酮
  参考文献：
  名称：

  6-Aryl-1,4-dihydro-benzo[d][1,3]oxazin- 2-ones:  A Novel Class of Potent, Selective, and Orally Active Nonsteroidal Progesterone Receptor Antagonists

  摘要：

  Novel 6-aryl-1,4-dihydro-benzo[d][1,3]oxazin-2-ones were synthesized and tested as progesterone receptor (PR) antagonists. These compounds were potent and showed good selectivity for PR over other steroid receptors such as the glucocorticoid and androgen receptors (e.g., greater than 80-fold selectivity at PR for 4h). Numerous 6-aryl benzoxazinones (e.g., 4h-j) were active orally in the uterine decidualization and component C3 assays in the rats. In these in vivo models, 4h had potencies comparable to mifepristone (1).

  DOI：

  10.1021/jm025555e

文献信息

• Cyclocarbamate derivatives as progesterone receptor modulators
  申请人：——

  公开号：US20020049204A1

  公开（公告）日：2002-04-25

  This invention provides compounds of Formula (I): 1 wherein R 1 and R 2 may be single substituents or fused to form spirocyclic or hetero-spirocyclic rings; R 3 is H, OH, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 6 alkenyl, substituted C 1 to C 6 alkenyl, alkynyl, or substituted alkynyl, COR C ; R C is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl; R 4 is H, halogen, CN, NO 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, alkynyl, or substituted alkynyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, amino, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl; and R 5 is selected from a trisubstituted benzene ring of a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO 2 or NR 6 and containing one or two independent substituents from the group including H, halogen, CN, NO 2 , amino, and C 1 to C 3 alky, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, COR F , or NR G COR F ; or pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions and methods using the compounds as antagonists of the progesterone receptor.

  这项发明提供了Formula (I)的化合物： 其中R1和R2可以是单个取代基或融合形成螺环或杂环螺环；R3为H、OH、NH2、C1到C6烷基、取代的C1到C6烷基、C3到C6烯基、取代的C1到C6烯基、炔基或取代的炔基、CORC；RC为H、C1到C3烷基、取代的C1到C3烷基、芳基、取代的芳基、C1到C3烷氧基、取代的C1到C3烷氧基、C1到C3氨基烷基或取代的C1到C3氨基烷基； R4为H、卤素、CN、NO2、C1到C6烷基、取代的C1到C6烷基、炔基或取代的炔基、C1到C6烷氧基、取代的C1到C6烷氧基、氨基、C1到C6氨基烷基或取代的C1到C6氨基烷基；R5从包括O、S、SO、SO2或NR6的1、2或3个杂原子的五元或六元环的三取代苯环中选择，并含有来自包括H、卤素、CN、NO2、氨基和C1到C3烷基、C1到C3烷氧基、C1到C3氨基烷基、CORF或NRGCORF的一个或两个独立取代基；或其药学上可接受的盐，以及将这些化合物用作孕激素受体拮抗剂的药物组合物和方法。
• Combination regimens using progesterone receptor modulators
  申请人：Wyeth

  公开号：US06444668B1

  公开（公告）日：2002-09-03

  This invention relates to cyclic combination therapies and regimens utilizing substituted indoline derivative compounds which are antagonists of the progesterone receptor having the general structure: wherein R1 and R2 may be single substituents or fused to form spirocyclic or hetero-spirocyclic rings; R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 allyl C3 to C6 alkenyl, substituted C1 to C6 alkenyl, alkynyl, or substituted alknyl, CORC; RC is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; R4 is H, halogen, CN, NO2, C1 to C6 alkyl, substituted C1 to C6 alkyl alkynyl, or substituted alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, amino, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl; and R5 is selected from a trisubstituted benzene ring of a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO2 or NR6 and containing one or two independent substituents from the group including H, halogen, CN, NO2, amino, and C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORF, or NRGCORF; or pharmaceutically acceptable salt thereof. These methods of treatment may be used for contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, or inmization of side effects or cyclic menstrual bleeding. Additional uses of the invention include stimulation of food intake.

  这项发明涉及利用替代吲哚啉衍生物化合物的循环组合疗法和方案，这些化合物是孕激素受体拮抗剂，具有以下一般结构： 其中R1和R2可以是单个取代基或融合形成螺环或杂环螺环；R3为H、OH、NH2、C1至C6烷基、取代的C1至C6烯丙基、C3至C6烯基、取代的C1至C6烯基、炔基或取代的炔基、CORC；RC为H、C1至C3烷基、取代的C1至C3烷基、芳基、取代的芳基、C1至C3烷氧基、取代的C1至C3烷氧基、C1至C3氨基烷基、或取代的C1至C3氨基烷基；R4为H、卤素、CN、NO2、C1至C6烷基、取代的C1至C6烷基炔基、或取代的炔基、C1至C6烷氧基、取代的C1至C6烷氧基、氨基、C1至C6氨基烷基、或取代的C1至C6氨基烷基；R5从包含O、S、SO、SO2或NR6的1、2或3个杂原子的五元或六元环的三取代苯环中选择，并含有来自包括H、卤素、CN、NO2、氨基和C1至C3烷基、C1至C3烷氧基、C1至C3氨基烷基、CORF或NRGCORF的一个或两个独立取代基；或其药学上可接受的盐。这些治疗方法可用于避孕或用于治疗和/或预防继发性闭经、功能性出血、子宫平滑肌瘤、子宫内膜异位症；多囊卵巢综合征、子宫内膜、卵巢、乳腺、结肠、前列腺的癌瘤和腺癌，或减轻副作用或循环性月经出血。该发明的其他用途包括促进食物摄入。
• [EN] CYCLOTHIOCARBAMATE DERIVATIVES AS PROGESTERONE RECEPTOR MODULATORS<br/>[FR] DERIVES DE CYCLOTHIOCARBAMATE TENANT LIEU DE MODULATEURS DU RECEPTEUR DE PROGESTERONE
  申请人：AMERICAN HOME PROD

  公开号：WO2000066570A1

  公开（公告）日：2000-11-09

  The present invention provides compounds which are agonists of the progesterone receptor and have structures (I) or (II) wherein R1 and R2 are independent substituents selected from the group of H, optionally substituted C1 to C6 alkyl, alkenyl, alkynyl, or alkynyl groups C3 to C8 cycloalkyl, aryl, substituted aryl, or heterocyclic groups, or COR?A or NRBCORA; or R1 and R2¿ are fused to form an optionally substituted 3 to 8 membered Spiro cyclic alkyl or alkenyl ring or a Spiro cyclic ring containing one to three heteroatoms selected from O, S and N; RA is selected from H, amino, or optionally substituted C¿1? to C3 alkyl, aryl, C1 to C3 alkoxy, or C1 to C3 aminoalkyl groups; R?B¿ is H, C¿1? to C3 alkyl, or substituted C1 to C3 alkyl; R?3¿ is H, OH, NH¿2 COR?C, or optionally substituted C¿1? to C6 alkyl, C3 to C6 alkenyl, or alkynyl groups; R?C¿ is selected from H or optionally substituted C¿1? to C3 alkyl, aryl, C1 to C3 alkoxy, or C1 to C3 aminoalkyl groups; Q?1¿ is S, NR?7; or CR8R9, R5¿ is an optionally trisubstituted benzene ring or an optionally substituted five or six membered heterocyclic ring with 1, 2, or 3 ring heteroatoms selected from the group of O, S, SO, SO¿2? or NR?6¿; or a pharmaceutically acceptable salt thereof, as well as methods of using these compounds for contraception and the treatment of progesterone-related maladies.

  本发明提供了具有结构（I）或（II）的孕激素受体激动剂化合物，其中R1和R2是独立的取代基，选自H，可选取代的C1至C6烷基，烯基，炔基或C3至C8环烷基，芳基，取代芳基或杂环基，或COR？A或NRBCORA; 或R1和R2¿融合形成可选取代的3至8环螺环烷基或烯基环或含有1至3个杂原子（选自O，S和N）的螺环状环；RA选自H，氨基或可选取代的C¿1？至C3烷基，芳基，C1至C3烷氧基或C1至C3氨基烷基基团；R?B¿选自H，C¿1？至C3烷基或取代的C1至C3烷基；R?3¿选自H，OH，NH¿2 COR?C，或可选取代的C¿1？至C6烷基，C3至C6烯基或炔基基团；R?C¿选自H或可选取代的C¿1？至C3烷基，芳基，C1至C3烷氧基或C1至C3氨基烷基基团；Q?1¿选自S，NR?7; 或CR8R9，R5¿为可选的三取代苯环或带有1、2或3个选自O，S，SO，SO¿2？或NR?6¿的杂环的可选取代的五元或六元环；或其药学上可接受的盐，以及使用这些化合物进行避孕和治疗孕激素相关疾病的方法。
• Cyclothiocarbamate derivatives as progesterone receptor modulators
  申请人：Zhang Puwen

  公开号：US20060142280A1

  公开（公告）日：2006-06-29

  Methods of using compounds which are progesterone receptor agonists for contraception and the treatment of progesterone-related maladies alone or in combination with an estrogen receptor agonist or progesterone receptor antagonist are provided. These compounds have the structure: wherein R 1 , R 2 , R 3 , R 4 , R 5 , and Q 1 are defined herein.

  本方法提供了使用具有孕激素受体激动剂作用的化合物进行避孕和单独或与雌激素受体激动剂或孕激素受体拮抗剂联合治疗孕激素相关疾病的方法。这些化合物具有以下结构： 其中，R1、R2、R3、R4、R5和Q1在此定义。
• CYCLOTHIOCARBAMATE DERIVATIVES AS PROGESTERONE RECEPTOR MODULATORS
  申请人：Zhang Puwen

  公开号：US20090281096A1

  公开（公告）日：2009-11-12

  Methods of using compounds which are progesterone receptor agonists for contraception and the treatment of progesterone-related maladies alone or in combination with an estrogen receptor agonist or progesterone receptor antagonist are provided. These compounds have the structure: wherein R 1 , R 2 , R 3 , R 4 , R 5 , and Q 1 are defined herein.

  本发明提供了使用化合物作为孕激素受体激动剂进行避孕和治疗孕激素相关疾病的方法，这些化合物可以单独使用或与雌激素受体激动剂或孕激素受体拮抗剂联合使用。这些化合物具有以下结构：其中R1，R2，R3，R4，R5和Q1如本文所定义。