SQ 33961 | 139067-88-2

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: SQ 33961
• 英文别名: <1S-(1α,2α,3α,4α)>-2-<<3-<4-<<(4-cyclohexylbutyl)amino>carbonyl>-2-oxazolyl>-7-oxabicyclo<2.2.1>hept-2-yl>methyl>benzenepropanoic acid；[1S-(1α, 2α, 3α, 4α)]-2-[[3-[4-[[(4-cyclohexylbutyl) amino]-carbonyl]-2-oxazolyl]-7-oxabicyclo [2.2.1]hept-2-yl]methyl]benzenepropanoic acid；[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-Cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]methyl]benzenepropanoic acid；[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-cyclohexylbutyl) amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid；[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid；(1S-(1α,2α,3α,4α))-2-{[3-(4-{[(4-cyclohexylbutyl)amino]carbonyl}-2-oxazolyl)-7-oxabicyclo[2.2.1]hept-2-yl]methyl}benzenepropanoic acid；3-[2-[[(1S,2R,3S,4R)-3-[4-(4-cyclohexylbutylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoic acid
• CAS: 139067-88-2
• 化学式: C₃₀H₄₀N₂O₅
• 分子量: 508.658
• InChiKey: MWTFNTGEEFCRGV-ZEIIVYBKSA-N

物化性质

• 沸点：
  717.2±50.0 °C(Predicted)
• 密度：
  1.180±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  37
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  102
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  SQ 33961 在 氯化铵 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 60.0h， 以10%的产率得到<1S-(1α,2α,3α,4α)>-2-<<3-<4-<<(4-cyclohexylbutyl)amino>carbonyl>-2-oxazolyl>-7-oxabicyclo<2.2.1>hept-2-yl>methyl>benzenepropanamide
  参考文献：
  名称：

  Interphenylene 7-oxabicyclo[2.2.1]heptane oxazoles. Highly potent, selective, and long-acting thromboxane A2 receptor antagonists

  摘要：

  A series of interphenylene 7-oxabicyclo[2.2.1]heptane oxazoles (2) were prepared and evaluated for their thromboxane (TxA2) antagonistic activity in vitro and duration of action in vivo. Examination of the carboxyl side chain indicated that the interphenylene ring substitution pattern and, to a lesser extent, chain length were important factors in determining TxA2 antagonistic potency. For the carboxyl side chain, ortho substitution, a single methylene spacer between the interphenylene and oxabicycloheptane rings, and a propionic acid side-chain length were determined to be optimal. With respect to the oxazole side chain a wide range of amide substituents with diverse structures and lipophilicities were compatible with potent antagonistic activity. Finally. an acidic functional group on the alpha-chain and a hydrogen bond acceptor on the 4-position of the oxazole ring were critical for potent activity. From the analogs prepared 42 {BMS-180,291: [(+)-1S-(1alpha,2alpha,3alpha,4alpha)]-2-[[3-[4-[(n-pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid} was found to be a potent, selective, and orally-active TxA2 antagonist with a long duration of action and has been selected as a candidate for clinical development. In human platelet-rich plasma, 42 inhibited arachidonic acid (800 muM) and U-46,619 (10 muM) induced aggregation with I50 values of 7 and 21 nM, respectively. Radioligand binding studies of 42 with [H-3]-SQ 29,548 showed a K(d) value of 4.0 +/- 1.0 nM in human platelet membranes. Both in vitro and in vivo studies indicated 42 was devoid of direct agonistic activity. In vivo 42 (0.2 mg/kg, po) showed extended protection (T50 = 14.4 h) from U-46,619 (2 mg/kg, iv) induced death in mice, and a single oral dose of 42 (3 mg/kg) abolished U46,619-induced platelet aggregation ex vivo in African green monkeys for >24 h.

  DOI：

  10.1021/jm00062a013
• 作为产物：
  描述：

  苯基-4-丁胺 在 platinum(IV) oxide lithium hydroxide 、 氢气 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 溶剂黄146 为溶剂， 25.0 ℃ 、372.32 kPa 条件下， 反应 6.25h， 生成 SQ 33961
  参考文献：
  名称：

  Interphenylene 7-oxabicyclo[2.2.1]heptane oxazoles. Highly potent, selective, and long-acting thromboxane A2 receptor antagonists

  摘要：

  A series of interphenylene 7-oxabicyclo[2.2.1]heptane oxazoles (2) were prepared and evaluated for their thromboxane (TxA2) antagonistic activity in vitro and duration of action in vivo. Examination of the carboxyl side chain indicated that the interphenylene ring substitution pattern and, to a lesser extent, chain length were important factors in determining TxA2 antagonistic potency. For the carboxyl side chain, ortho substitution, a single methylene spacer between the interphenylene and oxabicycloheptane rings, and a propionic acid side-chain length were determined to be optimal. With respect to the oxazole side chain a wide range of amide substituents with diverse structures and lipophilicities were compatible with potent antagonistic activity. Finally. an acidic functional group on the alpha-chain and a hydrogen bond acceptor on the 4-position of the oxazole ring were critical for potent activity. From the analogs prepared 42 {BMS-180,291: [(+)-1S-(1alpha,2alpha,3alpha,4alpha)]-2-[[3-[4-[(n-pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid} was found to be a potent, selective, and orally-active TxA2 antagonist with a long duration of action and has been selected as a candidate for clinical development. In human platelet-rich plasma, 42 inhibited arachidonic acid (800 muM) and U-46,619 (10 muM) induced aggregation with I50 values of 7 and 21 nM, respectively. Radioligand binding studies of 42 with [H-3]-SQ 29,548 showed a K(d) value of 4.0 +/- 1.0 nM in human platelet membranes. Both in vitro and in vivo studies indicated 42 was devoid of direct agonistic activity. In vivo 42 (0.2 mg/kg, po) showed extended protection (T50 = 14.4 h) from U-46,619 (2 mg/kg, iv) induced death in mice, and a single oral dose of 42 (3 mg/kg) abolished U46,619-induced platelet aggregation ex vivo in African green monkeys for >24 h.

  DOI：

  10.1021/jm00062a013

文献信息

• 7-oxabicycloheptyl substituted heterocyclic amide or ester prostaglandin
  申请人：E. R. Squibb & Sons, Inc.

  公开号：US05100889A1

  公开（公告）日：1992-03-31

  7-Oxabicycloheptane substituted prostaglandin analogs useful in treating thrombotic and vasopastic disease have the structural formula ##STR1## wherein m is 1, 2 or 3; n is 1, 2, 3 or 4; Z is --(CH.sub.2).sub.2 --, --CH.dbd.CH-- or ##STR2## wherein Y is O, a single bond or vinyl, with the proviso that when n is 0, if Z is ##STR3## then Y cannot be O, and Z is --CH.dbd.CH--, n is 1, 2, 3 or 4; and when Y=vinyl, n=0; R is CO.sub.2 H, CO.sub.2 lower alkyl, CH.sub.2 OH, CO.sub.2 alkali metal, CONHSOR.sup.3, CONHR.sup.3a or --CH.sub.2 --5-tetrazolyl, X is O, S or NH; and where R.sup.1, R.sup.2, R.sup.3 and R.sup.3a are as defined herein.

  7-氧杂双环庚烷取代前列腺素类似物在治疗血栓性和血管痉挛性疾病中有用，其结构式为##STR1##其中m为1、2或3；n为1、2、3或4；Z为--(CH.sub.2).sub.2 --、--CH.dbd.CH--或##STR2##其中Y为O、单键或乙烯基，但当n为0时，若Z为##STR3##则Y不能为O，Z为--CH.dbd.CH--，n为1、2、3或4；当Y=乙烯基时，n=0；R为CO.sub.2 H、CO.sub.2 较低烷基、CH.sub.2 OH、CO.sub.2 碱金属、CONHSOR.sup.3、CONHR.sup.3a或--CH.sub.2 --5-四唑基，X为O、S或NH；R.sup.1、R.sup.2、R.sup.3和R.sup.3a的定义如本文所述。
• Interphenylène 7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analogs useful in the treatment of thrombotic and vasopastic disease
  申请人：E.R. SQUIBB & SONS, INC.

  公开号：EP0391652A1

  公开（公告）日：1990-10-10

  Interphenylene 7-oxabicycloheptane substituted prostaglandin analogs are provided which are useful in treating thrombotic and vasospastic disease and have the structural formula wherein m is 1, 2 or 3; n is 0, 1, 2, 3 or 4; Y is O, vinyl or a single bond, with the proviso that when n is 0, Y is a single bond; R is CO₂H, CO₂alkali metal, CO₂lower alkyl, CH₂OH, CONHSO₂R³, CONHR3a or 5-tetrazolyl, with the proviso that when R is 5-tetrazolyl, n is other than 0; X is O, S or NH; R¹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aralkyl, cycloalkyl, cyclo­alkylalkyl, saturated heterocycle, saturated heterocyclicalkyl, aromatic heterocycle, aromatic heterocyclicalkyl or amido; each optionally substituted with an alkyl, aryl, cycloalkyl, or cycloalkylalkyl; and R² is hydrogen, lower alkyl, aryl, or aralkyl, or R¹ and R² together with the N to which they are linked form a 5- to 8- membered ring; R³ is lower alkyl, aryl or aralkyl and R3a is hydrogen, lower alkyl, aroyl or aralkyl.

  提供了可用于治疗血栓性和血管痉挛性疾病的间苯 7-氧杂双环庚烷取代的前列腺素类似物，其结构式为 其中 m为1、2或3 n 是 0、1、2、3 或 4； Y 是 O、乙烯基或单键，但当 n 为 0 时，Y 是单键； R 是 CO₂H、CO₂碱金属、CO₂低级烷基、CH₂OH、CONHSO₂R³、CONHR3a 或 5-四唑基，但当 R 是 5-四唑基时，n 不是 0； X 是 O、S 或 NH； R¹ 是氢、低级烷基、低级烯基、低级炔基、芳基、芳烷基、环烷基、环烷基烷基、饱和杂环基、饱和杂环烷基、芳香杂环基、芳香杂环烷基或氨基；每个基团可任选被烷基、芳基、环烷基或环烷基烷基取代；以及 R² 是氢、低级烷基、芳基或芳烷基，或 R¹ 和 R² 与它们连接的 N 一起形成一个 5 至 8 个成员的环； R³ 是低级烷基、芳基或芳烷基，R3a 是氢、低级烷基、芳基或芳烷基。
• Use of a thromboxane A2 receptor antagonist for the manufacture of a medicament for the treatment of ulcerative gastrointestinal conditions
  申请人：E.R. SQUIBB & SONS, INC.

  公开号：EP0448274A2

  公开（公告）日：1991-09-25

  A method is provided for protecting against and/or treating ulcerative gastrointestinal conditions, including anti-inflammatory drug-induced gastrointestinal ulcers, using a thromboxane A₂ receptor antagonist. In addition, a combination is provided which includes a thromboxane A₂ receptor antagonist and an anti-inflammatory agent which combination may be used to treat inflammatory conditions, such as arthritis, while inhibiting formation of and/or treating gastrointestinal ulcers.

  本发明提供了一种使用血栓素 A₂受体拮抗剂防止和/或治疗胃肠道溃疡病的方法，包括抗炎药物诱发的胃肠道溃疡。此外，还提供了一种组合物，其中包括血栓素 A₂受体拮抗剂和一种消炎药，该组合物可用于治疗关节炎等炎症，同时抑制胃肠道溃疡的形成和/或治疗胃肠道溃疡。
• 7-Oxabicycloheptyl substituted heterocyclic thioamide prostaglandin analogs useful in the treatment of thrombotic and vasospastic disease
  申请人：E.R. SQUIBB & SONS, INC.

  公开号：EP0476994A1

  公开（公告）日：1992-03-25

  7-Oxabicycloheptane substituted prostaglandin analogs useful in treating thrombotic and vasospastic disease have the structural formula wherein m is 1, 2 or 3; n is 1, 2, 3 or 4; Z is -(CH₂)₂-, -CH=CH- or wherein Y is O, a single bond or vinyl, with the proviso that when n is O, if Z is then Y cannot be O, and when Z is -CH=CH-, n is 1, 2, 3 or 4; and when Y=vinyl, n=0; R is CO₂H, CO₂lower alkyl, CH₂OH, CO₂alkali metal, CONHSOR³, CONHR3a or -CH₂-5-tetrazolyl, X is O, S or NH; and where R¹, R², R³ and R3a are as defined herein.

  可用于治疗血栓性和血管痉挛性疾病的 7-氧杂双环庚烷取代的前列腺素类似物的结构式为 其中 m 是 1、2 或 3；n 是 1、2、3 或 4；Z 是-(CH₂)₂-、-CH=CH- 或-(CH₂)₂-。 其中 Y 是 O、单键或乙烯基，但当 n 是 O 时，如果 Z 是 则 Y 不能为 O，当 Z 为-CH=CH-时，n 为 1、2、3 或 4；当 Y= 乙烯基时，n=0；R 为 CO₂H、CO₂低级烷基、CH₂OH、CO₂碱金属、CONHSOR³、CONHR3a 或-CH₂-5-四唑基，X 为 O、S 或 NH；其中 R¹、R²、R³ 和 R3a 如本文所定义。
• COMPOSITIONS AND METHODS OF TREATING SYSTEMIC SCLEROSIS OR PULMONARY ARTERIAL HYPERTENSION
  申请人：Cumberland Pharmaceuticals, Inc.

  公开号：EP3804717A1

  公开（公告）日：2021-04-14

  The present invention is directed to methods of treating, preventing, and/or ameliorating systemic sclerosis or pulmonary arterial hypertension, by administration of a therapeutically effective amount of ifetroban, or a pharmaceutically acceptable salt thereof.

  本发明涉及通过服用治疗有效量的伊伐曲班或其药学上可接受的盐来治疗、预防和/或改善系统性硬化症或肺动脉高压的方法。