Z-7-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid | 78834-74-9

• 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: Z-7-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid
• 英文别名: 7-Bromo-2-[(2,2-dimethyl-cyclopropanecarbonyl)-amino]-hept-2-enoic acid；(Z)-7-bromo-2-[(2,2-dimethylcyclopropanecarbonyl)amino]hept-2-enoic acid
• CAS: 78834-74-9
• 化学式: C₁₃H₂₀BrNO₃
• 分子量: 318.211
• InChiKey: YKNGZCCOZCQYAG-POHAHGRESA-N

物化性质

• 沸点：
  518.0±50.0 °C(Predicted)
• 密度：
  1.371±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  18
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  66.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  Z-7-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid 在 碳酸氢钠 、 sodium sulfite 作用下， 以 乙醇 、 水 为溶剂， 反应 4.0h， 以68%的产率得到(Z)-2-(2,2-dimethylcyclopropanecarboxamido)-7-sulfo-2-heptenoic acid sodium salt
  参考文献：
  名称：

  Inhibition of the mammalian .beta.-lactamase renal dipeptidase (dehydropeptidase-I) by Z-2-(acylamino)-3-substituted-propenoic acids

  摘要：

  The title enzyme deactivates the potent carbapenem antibiotic imipenem in the kidney, producing low antibiotic levels in the urinary tract. A series of (Z)-2-(acylamino)-3-substituted-propenoic acids (3) are specific, competitive inhibitors of the enzyme capable of increasing the urinary concentration of imipenem in vivo. Many of the compounds were prepared in one step from an alpha-keto acid and a primary amide. The optimum R2 groups are 2,2-dimethyl, -dichloro, and -dibromocyclopropyl. With R2 = 2,2-dimethylcyclopropyl (DMCP), a wide variety of R3 groups including alkyl, oxa- and thiaalkyl, and alkyl groups containing acidic, basic, and neutral substituents give effective inhibitors with Ki values of 0.02-1 microM and a range of pharmacokinetic properties. By resolution of enantiomers and X-ray crystallography, the enzyme-inhibitory activity of the DMCP group was found to reside with the 1S isomer. The cysteinyl compound 176 (cilastatin, MK-0791) has the desired pharmacological properties and has been chosen for combination with imipenem.

  DOI：

  10.1021/jm00389a018
• 作为产物：
  描述：

  ethyl 7-bromooxoheptanoate 在 氢溴酸 、 溶剂黄146 作用下， 以 甲苯 为溶剂， 反应 1.25h， 生成 Z-7-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid
  参考文献：
  名称：

  Inhibition of the mammalian .beta.-lactamase renal dipeptidase (dehydropeptidase-I) by Z-2-(acylamino)-3-substituted-propenoic acids

  摘要：

  The title enzyme deactivates the potent carbapenem antibiotic imipenem in the kidney, producing low antibiotic levels in the urinary tract. A series of (Z)-2-(acylamino)-3-substituted-propenoic acids (3) are specific, competitive inhibitors of the enzyme capable of increasing the urinary concentration of imipenem in vivo. Many of the compounds were prepared in one step from an alpha-keto acid and a primary amide. The optimum R2 groups are 2,2-dimethyl, -dichloro, and -dibromocyclopropyl. With R2 = 2,2-dimethylcyclopropyl (DMCP), a wide variety of R3 groups including alkyl, oxa- and thiaalkyl, and alkyl groups containing acidic, basic, and neutral substituents give effective inhibitors with Ki values of 0.02-1 microM and a range of pharmacokinetic properties. By resolution of enantiomers and X-ray crystallography, the enzyme-inhibitory activity of the DMCP group was found to reside with the 1S isomer. The cysteinyl compound 176 (cilastatin, MK-0791) has the desired pharmacological properties and has been chosen for combination with imipenem.

  DOI：

  10.1021/jm00389a018

文献信息

• 2-(Cyclopropane-carboxamido)-2-alkenoic acids, their esters and salts, and antibacterial compositions comprising the same and a thienamycin-type compound
  申请人：Merck & Co., Inc.

  公开号：EP0048301A1

  公开（公告）日：1982-03-31

  ω-(2-Amino-2-carboxyethylthiol-2-(cyclopropane- carboxamido)-2-alkenoic acids, their esters and salts of the formula in the Z configuration, wherein R2 is 2,2-dimethylcyclopropyl or 2,2-dichlorocyclopropyl; R' is hydrogen, loweralkyl of 1-6 carbon atoms, dialkylaminoalkyl with 1-6 carbon atoms in each alkyl group, or a pharmaceutically acceptable cation; R3 is an alkylene chain of 3-7 carbon atoms, having a terminal substituent which is 2-amino-2-carboxyethylthio, or 1-(phosphono)ethylamino which selectively inhibit the metabolism of dipeptidase (E.C:3.4.13.11) and therefore are useful in combination with antibacterial products, by preference with the thienamycin class of compounds.

  该文本描述的是公式为Z构型的2-氨基-2-羧基乙硫基-2-(环丙烷羧酰胺)-2-烯酸及其酯类和盐类，其中R2为2,2-二甲基环丙基或2,2-二氯环丙基；R'为氢、1-6碳原子的低级烷基、每个烷基中有1-6碳原子的二烷基氨基烷基或药学上可接受的阳离子；R3为一个碳数为3-7的烷基链，具有一个终端取代基，该取代基为2-氨基-2-羧基乙硫基或1-(膦酸)乙基氨基，可选择性地抑制二肽酶(E.C:3.4.13.11)的代谢，因此在与抗菌产品结合使用时有用，优选与头孢曲松类化合物结合使用。
• Dipeptidase inhibitors
  申请人：Merck & Co., Inc.

  公开号：US04406902A1

  公开（公告）日：1983-09-27

  Novel chemical compounds are provided which selectively inhibit the metabolism of dipeptidase (E.C.3.4.13.11) and therefore are useful in combination with antibacterial products. These chemical compounds are Z-2-(2,2-dimethylcyclo-propanecarboxamido)-.omega.-pyridylthio-2-alkenoic acids (and related arylthio and heterocyclylthio analogs).

  本发明提供了一些新型化合物，其选择性地抑制二肽酶（E.C.3.4.13.11）的代谢，因此可与抗菌产品结合使用。这些化合物是Z-2-(2,2-二甲基环丙烷羧酰胺)-ω-吡啶硫基-2-烯酸（及相关的芳基硫和杂环硫类似物）。
• Antibacterial compositions comprising a beta-lactam-type compound and a 3-substituted propenoate
  申请人：Merck & Co., Inc.

  公开号：EP0028778A1

  公开（公告）日：1981-05-20

  An antibacterial composition comprising (a) cephaloridine and a 3-substituted propenoate of either of the formula wherein e.g. R2 and R3 are hydrocarbon radicals; a terminal hydrogen in R3 can be replaced by several groups; R' is hydrogen or C1-C6 alkyl or dialkylaminoalkyl, n is 3 to 5 and Y is heterocyclic or phenyl optionally substituted with hydroxyl, oxo, carboxyl, or methyl or (b) thienamycin, N-guanyl or N-formimidoyl thienamycin and a compound of formula II. The propenoate compounds prevent nephrotoxicity of the antibiotics. The antibiotic to propenoate weight ratio is from about 1 to 0.1-3.

  一种抗菌组合物，包括(a) 头孢里定和式中任一的 3-取代的丙烯酸酯 其中，例如 R2 和 R3 是烃基；R3 中的末端氢可被多个基团取代；R'是氢或 C1-C6 烷基或二烷基氨基烷基，n 是 3 至 5，Y 是杂环或苯基，可任选被羟基、氧代、羧基或甲基取代；或 (b) 噻喃霉素、N-鸟苷酰基或 N-甲酰亚胺酰基噻喃霉素和式 II 的化合物。丙烯酸盐化合物可防止抗生素的肾毒性。抗生素与丙烯酸酯的重量比约为 1 至 0.1-3。
• Z-omega-substituted thio-2-(2,2-dimethylcyclopropanecarboxamido)-2-alkenoic acids, a process for preparing and an antibacterial composition containing the same
  申请人：Merck & Co., Inc.

  公开号：EP0049389A1

  公开（公告）日：1982-04-14

  Novel chemical compounds and a process for preparing them are provided. These compounds selectively inhibit the metabolism of dipeptidase (E.C.3.4.13.11) and therefore are useful in combination with antibacterial products. These chemical compounds are Z-2-(2,2-dimethylcyclopropane- carboxamidol-ω-pyridylthio-2-alkenoic acids (and related arylthio and heterocyclylthio analogs) of the general formula: wherein n is an integer from 3-5, Y is pyridyl, pyrimidinyl, tetrazolyl, imidazolyl, thiadiazolyl, thiazolinyl, or phenyl, optionally having 1 or 2 substituents which are hydroxyl, oxo, carboxyl, or methyl; and the loweralkyl (C1-6) esters and pharmaceutically acceptable salts thereof.

  本研究提供了新型化合物及其制备方法。这些化合物选择性地抑制二肽酶（E.C.3.4.13.11）的代谢，因此可与抗菌产品结合使用。这些化合物是通式为 Z-2-(2,2-二甲基环丙烷-羧酰胺醇-ω-吡啶巯基-2-烯酸（以及相关的芳基巯基和杂环巯基类似物）： 其中 n 为 3-5 的整数，Y 为吡啶基、嘧啶基、四唑基、咪唑基、噻二唑基、噻唑啉基或苯基，可选具有 1 或 2 个羟基、氧代、羧基或甲基的取代基；及其低级烷基 (C1-6) 酯和药学上可接受的盐。
• Antibacterial composition of thienamycin type compound and a dipeptidase inhibitor
  申请人：Merck & Co., Inc.

  公开号：EP0048025A1

  公开（公告）日：1982-03-24

  Novel compounds of the general formula wherein R2 is 2,2-dimethylcyclopropyl or 2,2-dichlorocyclopropyl; R1 is hydrogen, loweralkyl of 1-6 carbon atoms, dialkylaminoalkyl, or a pharmaceutically acceptable cation; R3 is a hydrocarbon chain of 3-7 carbon atoms, optionally having a terminal substituent which is trimethylammonium, amidino, guanidino, 2-amino-2-carboxyethyl- thio, or ureido, which selectively inhibit the metabolism of dipeptidase (E.C.3.4.13.11) and therefore are useful in combination with antibacterial products by preference with the thienamycin class of compounds.

  通式中 R2 为 2,2-二甲基环丙基或 2,2-二氯环丙基；R1 为氢、1-6 个碳原子的低级烷基、二烷基氨基烷基或药学上可接受的阳离子；R3 为 3-7 个碳原子的烃链，任选具有一个末端取代基，该取代基为三甲基铵、脒基、胍基、2-氨基-2-羧乙基硫代或脲基，可选择性地抑制二肽酶（E.C.3.4.13.11）的代谢，因此可优先与噻吩霉素类化合物结合使用。