3-[2-[[(1S,2R,3R,4R)-3-(hydroxymethyl)-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoic acid | 142758-00-7

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: 3-[2-[[(1S,2R,3R,4R)-3-(hydroxymethyl)-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoic acid
• CAS: 142758-00-7
• 化学式: C₁₇H₂₂O₄
• 分子量: 290.359
• InChiKey: DNWFBGWVSAZOKD-FXUDXRNXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  21
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  66.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-[2-[[(1S,2R,3R,4R)-3-(hydroxymethyl)-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoic acid 在 palladium hydroxide - carbon chromium(VI) oxide 、 盐酸 、 四氯化碳 、 草酰氯 、 硫酸 、 氢气 、 1-羟基苯并三唑 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 N,N-二异丙基乙胺 、 N,N-二甲基甲酰胺 、 N,N'-二环己基碳二亚胺 、 三苯基膦 、 copper(ll) bromide 作用下， 以 二氯甲烷 、 氯仿 、 乙酸乙酯 、 丙酮 、 乙腈 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 63.92h， 生成 methyl 3-[2-[[(1S,2R,3S,4R)-3-(4-carbonochloridoyl-1,3-oxazol-2-yl)-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoate
  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：

  3-(2-溴苯基)丙酸甲酯 在 palladium dihydroxide 吡啶 、 chromium(VI) oxide 、 4-二甲氨基吡啶 、 sodium hydroxide 、 硫酸 、 氢气 、 叔丁基锂 、 二异丁基氢化铝 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 丙酮 、 甲苯 为溶剂， -100.0~25.0 ℃ 、101.33 kPa 条件下， 反应 19.0h， 生成 3-[2-[[(1S,2R,3R,4R)-3-(hydroxymethyl)-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoic acid
  参考文献：
  名称：

  间亚苯基7-氧杂双环[2.2.1]庚烷血栓烷A2拮抗剂。Semicarbazoneω-链。

  摘要：

  制备了一系列手性联苯间7-氧杂双环[2.2.1]庚烷半咔唑酮19-26，并对其体外血栓烷（TxA2）拮抗活性和体内作用时间进行了评估。发现19-26的效力高度依赖于亚间苯环的取代模式，并且以大于间位大于邻位的顺序降低。SQ 35,091（25），[1S-（1 alpha，2 alpha，3 alpha，4 alpha）]-2-[[3-[[[[（（苯基氨基）羰基]肼基]甲基] -7-氧杂双环[2.2.1 [庚基-2-基]甲基]苯丙酸被鉴定为有效且长效的TxA2拮抗剂。在富含人血小板的血浆中，SQ 35,091抑制了花生四烯酸（800 microM）和U-46,619（10 microM）诱导的聚集，I50值分别为3和12 nM。相反，大于1000 microM时未观察到对ADP（20 microM）诱导的聚集的抑制。用[3H] -SQ 29,548进行的受体结合研究表明，SQ 35,091是

  DOI：

  10.1021/jm00113a030

文献信息

• 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。
• 7-Oxabicycloheptane imidazole prostaglandin analogs useful in the treatment of thrombotic and vasospastic diseases
  申请人：E.R. SQUIBB & SONS, INC.

  公开号：EP0447188A2

  公开（公告）日：1991-09-18

  7-Oxabicycoheptane imidazole prostaglandin analogs are provided which are useful in treating thrombotic and vasospastic disease and have the structural formula wherein m is 0, 1, 2, 3 or 4; n is 1, 2 or 3; and p is 1, 2 or 3; Z is -CH=CH-, -CH2CH2- or wherein Y is 0 or a single bond ; R is C02H, CO2lower alkyl, C02alkali metal, CONHS02R2 (wherein R2 is lower alkyl or aryl) or -CH2-5-tetrazolyl; A is CHOH, C=O, (wherein R3 is H or lower alkyl), or a single bond ; R1 is lower alkyl, aryl, cycloalkyl or H, R1 can be H only when A is a single bond.

  提供了可用于治疗血栓性和血管痉挛性疾病的 7-氧杂双环庚烷咪唑前列腺素类似物，其结构式为 其中m是0、1、2、3或4；n是1、2或3；p是1、2或3；Z是-CH=CH-、-CH2CH2-或-CH2CH2-。 其中 Y 是 0 或单键；R 是 C02H、CO2lower 烷基、C02 碱金属、CONHS02R2（其中 R2 是低级烷基或芳基）或 -CH2-5-四唑基；A 是 CHOH、C=O、 (其中 R3 为 H 或低级烷基）或单键；R1 为低级烷基、芳基、环烷基或 H，只有当 A 为单键时，R1 才可以是 H。
• 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。
• Heterocyclic ketone prostaglandin analogs
  申请人：E.R. SQUIBB & SONS, INC.

  公开号：EP0497085A1

  公开（公告）日：1992-08-05

  Prostaglandin analogs useful in treating thrombotic and vasospastic disease having the structural formula wherein:    m is 1, 2, or 3;    n is 0, 1, 2 or 3;    R¹ is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl or heteroarylalkyl, each of R¹ being unsubstituted or optionally substituted with alkyl, aryl, cycloalkyl, or cycloalkylalkyl;    R² is CO₂R, CONHSO₂R³, CONHR⁴;    R is hydrogen, alkyl, or alkali metal;    X is O or NH;    Y is -O-, a single bond or vinylene, except that Y cannot be -O- when n is 0;    Z is -CH=CH-, -(CH₂)₂-, or    and the remaining symbols are as defined in the specification.

  用于治疗血栓性和血管痉挛性疾病的前列腺素类似物，其结构式为 其中 m 是 1、2 或 3 n 是 0、1、2 或 3； R¹ 是氢、烷基、烯基、炔基、芳基、芳烷基、环烷基、环烷基烷基、环杂烷基、环杂烷基烷基、杂芳基或杂芳基烷基，每个 R¹ 是未取代的或任选被烷基、芳基、环烷基或环烷基烷基取代的； R² 是 CO₂R、CONHSO₂R³、CONHR⁴； R 是氢、烷基或碱金属； X 是 O 或 NH； Y 是-O-、单键或乙烯基，但当 n 为 0 时，Y 不能是-O-； Z 是-CH=CH-，-(CH₂)₂-，或 其余符号与说明书中的定义相同。
• Heterocyclic amido prostaglandin analogs
  申请人：E.R. SQUIBB & SONS, INC.

  公开号：EP0497629A1

  公开（公告）日：1992-08-05

  Prostaglandin analogs useful in treating thrombotic and vasospastic disease having the structural formula wherein:    m is 1, 2, or 3;    n is 0, 1, 2 or 3;    R is CO₂R′, CH₂OH, CONHSO₂R³, CONHR⁴, or -CH₂-5-tetrazolyl;    R′ is hydrogen, alkyl, or alkali metal;    X is O or NH;    Y is -O-, a single bond or vinylene, except that Y cannot be -O- when n is 0 and if Y is vinylene, then n=0;    Z is -CH=CH-, -(CH₂)₂-, or and the remaining symbols are as defined in the specification.

  用于治疗血栓性和血管痉挛性疾病的前列腺素类似物，其结构式为 其中 m 是 1、2 或 3 n 是 0、1、2 或 3； R 是 CO₂R′、CH₂OH、CONHSO₂R³、CONHR⁴ 或 -CH₂-5-四唑基； R′ 是氢、烷基或碱金属； X 是 O 或 NH； Y 是-O-、单键或乙烯基，但当 n 为 0 时 Y 不能是-O-，如果 Y 是乙烯基，则 n=0； Z 是-CH=CH-，-(CH₂)₂-，或 其余符号与说明书中的定义相同。