Z-8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid | 75902-92-0

• 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-8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid
• 英文别名: (Z)-8-bromo-2-[(2,2-dimethylcyclopropanecarbonyl)amino]oct-2-enoic acid
• CAS: 75902-92-0
• 化学式: C₁₄H₂₂BrNO₃
• 分子量: 332.238
• InChiKey: WTVLQRGPKGVBFJ-XFFZJAGNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  19
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.71
• 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-8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid 在 氨 作用下， 以 水 为溶剂， 反应 4.0h， 以78%的产率得到(Z)-8-Amino-2-[(2,2-dimethyl-cyclopropanecarbonyl)-amino]-oct-2-enoic 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
• 作为产物：
  描述：

  2,2-二甲基环丙甲酰胺 、 8-bromo-2-oxooctanoic acid 以 甲苯 为溶剂， 以55%的产率得到Z-8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic 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

• Thienamycin renal peptidase inhibitors
  申请人：Merck & Co., Inc.

  公开号：US05147868A1

  公开（公告）日：1992-09-15

  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-acylamino-3-monosubstituted propenoates.

  提供了一种新颖的化学化合物，可以选择性地抑制二肽酶（E.C.3.4.13.11）的代谢，因此与抗菌产品结合使用时具有用处。这些化学化合物是z-2-酰氨基-3-单取代丙烯酸酯。
• Combination of thienamycin-type antibiotics with dipeptidase inhibitors
  申请人：Merck & Co., Inc.

  公开号：US04539208A1

  公开（公告）日：1985-09-03

  A novel antibacterial drug combination is provided, one component being a fused ring .beta.-lactam, such as thienamycin and its semi-synthetic derivatives, and the other component is a dipeptidase (E.C. 3.4.13.11) inhibitor. The dual-component combination is formulated so that 1 to 3 parts by weight of the .beta.-lactam compound are employed for 30 to 1 parts by weight of the inhibitor compound.

  提供了一种新型抗菌药物组合，其中一个成分是融合环β-内酰胺，如噻呋霉素及其半合成衍生物，另一个成分是二肽酶（E.C. 3.4.13.11）抑制剂。双组分组合物的配方使得β-内酰胺化合物的重量为1至3份，而抑制剂化合物的重量为30至1份。
• 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。
• Use of substituted propenoates to prevent nephrotoxicity of certain
  申请人：Merck & Co., Inc.

  公开号：US04668504A1

  公开（公告）日：1987-05-26

  Antibiotics to prevent nephrotoxicity.

  使用抗生素以预防肾毒性。
• Combination of 2-substituted carbapenems with dipeptidase inhibitors
  申请人：Merck & Co., Inc.

  公开号：US05071843A1

  公开（公告）日：1991-12-10

  A combination of a carbapenem of the formula: ##STR1## where R is H or CH.sub.3 and R.sup.1 is ##STR2## with a renal dipeptidase inhibitor is disclosed.

  本发明揭示了一种将式子为##STR1##的碳青霉烯类抗生素（其中R为H或CH.sub.3，R.sup.1为##STR2##）与肾脏二肽酶抑制剂结合使用的方法。