N-(3-Acetylthio-2-methylpropanoyl)-N-cyclopentylglycine t-butyl ester | 78773-70-3

• 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: N-(3-Acetylthio-2-methylpropanoyl)-N-cyclopentylglycine t-butyl ester
• 英文别名: tert-butyl 2-[(3-acetylsulfanyl-2-methylpropanoyl)-cyclopentylamino]acetate
• CAS: 78773-70-3
• 化学式: C₁₇H₂₉NO₄S
• 分子量: 343.488
• InChiKey: GTTWHPJRNFCXCC-UHFFFAOYSA-N

物化性质

• 沸点：
  457.8±38.0 °C(Predicted)
• 密度：
  1.11±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  23
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  89
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-(3-Acetylthio-2-methylpropanoyl)-N-cyclopentylglycine t-butyl ester 在 氮气 、 氨 、 盐酸 、 水 、 magnesium sulfate 、 乙酸乙酯 、 hexanes 作用下， 以 甲醇 为溶剂， 反应 1.17h， 以afforded 30 g (70%) of N-(3-mercapto-2-methyl-propanoyl)-N-cyclopentylglycine t-butyl ester as an oil的产率得到N-(3-mercapto-2-methyl propanoyl)-N-cyclopentyl glycine-t-butyl ester
  参考文献：
  名称：

  Compounds having angiotensin converting enzyme inhibitory activity and

  摘要：

  本发明公开了同时具有肾素-血管紧张素系统酶抑制活性和利尿活性的新化合物。该化合物由一般式##STR1##表示，其中X为##STR2##其中R.sub.1、R.sub.2、R.sub.3、R.sub.4、R.sub.5和R.sub.6分别为氢、烷基、烯基、炔基、苯基-烷基和环烷基，可以相同也可以不同；n为0到4的整数，包括4；M为烯基、炔基、环烷基、环烷基-烷基、多环烷基、多环烷基-烷基、芳基、芳基-烷基、杂芳基、杂芳基-烷基、杂环烷基、杂环烷基-烷基、融合芳基-环烷基、融合芳基-环烷基-烷基、融合杂芳基-环烷基、融合杂芳基-环烷基-烷基、烷氧基烷基、烷硫基烷基、烷基氨基-烷基或二烷基氨基烷基，或M和R.sub.6与M键合的氮和R.sub.6键合的碳一起形成一个含有3或4个环碳原子的饱和未取代杂环基；Y为羟基、烷氧基、氨基或取代氨基、氨基烷酰基、芳氧基、氨基烷氧基或羟基烷氧基；Z.sub.1和Z.sub.2分别为化学键、基团X.sub.3--(CH.sub.2).sub.m、氨基酸基团或基团X.sub.3--(CH.sub.2).sub.m--X.sub.3，其中X.sub.3为氧、硫或NH，m为0到4的整数；A和B分别与R.sub.1相同或为卤素、三氟甲基、OR.sub.1、NO.sub.2、NR.sub.1R.sub.2、SO.sub.2NH.sub.2、CN、SR.sub.1、SOR.sub.1、SO.sub.2R.sub.1、CONR.sub.1R.sub.2、COOR.sub.1；C为氢烷基、杂环烯基、氨基、--CR.sub.1.dbd.CR.sub.2--、##STR3##氨基烷基、呋喃基甲基氨基、氨基芳基或氨基苯甲基；X.sub.1和X.sub.2分别为S、SO、SO.sub.2、NR.sub.1、O、化学键、(CR.sub.9R.sub.10).sub.m、--CR.sub.9.dbd.CR.sub.10--和CHOH，但至少一个X.sub.1和X.sub.2为(CR.sub.9R.sub.10).sub.m，其中R.sub.9和R.sub.10分别为氢或低烷基，m为1到5的整数；Ar为二价芳基或杂芳基；R.sub.7和R.sub.8分别为氢、烷基、卤素、氰基、羟基、烷氧基、氨基、烷基氨基、二烷基氨基、巯基、烷基巯基、硝基、三氟甲基、羧基、羧基烷氧基、COY和NHCONHR.sub.1，其中R.sub.1和Y如上所定义；以及其药学上可接受的盐。

  公开号：

  US04661515A1
• 作为产物：
  描述：

  环戊胺 在 三乙胺 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 反应 16.0h， 生成 N-(3-Acetylthio-2-methylpropanoyl)-N-cyclopentylglycine t-butyl ester
  参考文献：
  名称：

  Angiotensin-converting enzyme inhibitors. New orally active antihypertensive (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives

  摘要：

  A variety of N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives was synthesized and their ability in inhibiting the activity of angiotensin-converting enzyme (ACE) was examined in vitro and in vivo. The acylthio derivatives prepared are assumed to act as prodrugs since they are much less active than the corresponding free SH compounds in vitro and can be expected to act in vivo only after conversion to the free sulfhydryl compounds. A number of these compounds are potent ACE inhibitors that lowered blood pressure in Na-deficient, conscious spontaneously hypertensive rats (SHR), a high renin model. One of the most active members of the series was (S)-N-cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1 -oxopropyl]glycine (REV 3659-(S), pivopril). Structure-activity relationships are discussed.

  DOI：

  10.1021/jm00379a013

文献信息

• Antihypertensive amides
  申请人：USV Pharmaceutical Corporation

  公开号：US04256761A1

  公开（公告）日：1981-03-17

  Compounds of the structure: ##STR1## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are hydrogen, alkyl, alkenyl, alkynyl, phenyl-alkyl, or cycloalkyl, n is an integer from 0 to 4 inclusive, M is alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, polycycloalkyl, polycyclo-alkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, hetero-cycloalkyl, hetero-cycloalkyl-alkyl, alkoxyalkyl, alkylthioalkyl, alkylamino-alkyl, dialkylamino-alkyl, fused aryl-cycloalkyl, fused aryl-cycloalkyl-alkyl, fused heteroaryl-cycloalkyl, or fused heteroaryl-cycloalkyl-alkyl, Y is hydroxy, alkoxy, amino, or substituted amino, aminoalkanoyl, aryloxy, aminoalkoxy, or hydroxyalkoxy, and R.sub.7 is hydrogen, alkanoyl, carboxylalkanoyl, hydroxyalkanoyl, amino-alkanoyl, cyano, amidino, carbalkoxy, ZS, or ##STR2## wherein Z is hydrogen, alkyl, hyroxyalkyl, aminoalkyl or the radical ##STR3## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, n, M and Y are as described above; and where Y is hydroxy their non-toxic, pharmaceutically acceptable alkali metal, alkaline earth metal, and amine salts.

  结构化合物：##STR1## 其中 R.sub.1、R.sub.2、R.sub.3、R.sub.4、R.sub.5 和 R.sub.6 为氢、烷基、烯基、炔基、苯基-烷基或环烷基，n 为0至4之间的整数，M 为烯基、炔基、环烷基、环烷基-烷基、多环烷基、多环烷基-烷基、芳基、芳基-烷基、杂环芳基、杂环芳基-烷基、杂环烷基、杂环烷基-烷基、烷氧基烷基、烷基硫基烷基、烷基氨基烷基、二烷基氨基烷基、融合芳基-环烷基、融合芳基-环烷基-烷基、融合杂环芳基-环烷基或融合杂环芳基-环烷基-烷基，Y 为羟基、烷氧基、氨基或取代氨基、氨基烷酰基、芳氧基、氨基烷氧基或羟基烷氧基，R.sub.7 为氢、烷酰基、羧酰烷酰基、羟基烷酰基、氨基-烷酰基、氰基、胺基、羧酯基、ZS 或 ##STR2## 其中 Z 为氢、烷基、羟基烷基、氨基烷基或基团 ##STR3## 其中 R.sub.1、R.sub.2、R.sub.3、R.sub.4、R.sub.5、R.sub.6、n、M 和 Y 如上所述；当 Y 为羟基时，它们的非毒性、药学上可接受的碱金属、碱土金属和胺盐。
• Angiotensin-converting enzyme inhibitors: new orally active 1,4-thiazepine-2,5-diones, 1,4-thiazine-2,5-diones, and 1,4-benzothiazepine-2,5-diones possessing antihypertensive activity
  作者：Jerry W. Skiles、John T. Suh、Bruce E. Williams、Paul R. Menard、Jeffrey N. Barton、Bernard Loev、Howard Jones、Edward S. Neiss、Alfred Schwab

  DOI：10.1021/jm00155a032

  日期：1986.5

  most active thiazines in rats, po, were 42 and 45. Of the benzothiazepines studied, 22a was the most active in inhibiting ACE in the conscious normotensive rat, ID50 = 0.15 mg/kg, po. The acute antihypertensive effects of oral administration of a number of these compounds on mean arterial pressure and heart rate were studied in spontaneously hypertensive rats (SHR) maintained on a sodium-deficient diet

  一系列1,4-噻嗪-2,5-二酮，1,4-噻嗪-2,5-二酮和1,4-苯并硫氮杂-2,5-二酮的制备及其抑菌活性检查了体内和体外的血管紧张素转换酶（ACE）。这些化合物被假定为前药，因为它们在与大鼠血浆一起温育或经0.1 N HCl水溶液或磷酸盐缓冲液（pH 7.4）处理时会发生快速的开环反应，以产生相应的无生物活性的SH化合物。噻嗪类23-25和30在向大鼠口服给药时是ACE的有效抑制剂，其效力与卡托普利（1）相当。大鼠中最活跃的噻嗪类化合物分别为42和45。在所研究的苯并硫氮平中，22a在有意识的正常血压大鼠中抑制ACE的活性最高，ID50 = 0.15 mg / kg，po。
• Compounds having angiotensin converting enzyme inhibitory activity and
  申请人：USV Pharmaceutical Corporation

  公开号：US04661515A1

  公开（公告）日：1987-04-28

  Novel compounds possessing both angiotensin enzyme inhibitory activity and diuretic activity are disclosed. The compounds are represented by the general formula ##STR1## in which X is ##STR2## in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are hydrogen, alkyl, alkenyl, alkynyl, phenyl-alkyl, and cycloalkyl, and may be the same or different; n is an integer from 0 to 4 inclusive; M is alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, polycycloalkyl, polycycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl, hetero-cyloalkyl, hetero-cycloalkyl-alkyl, fused aryl-cycloalkyl, fused aryl-cycloalkyl-alkyl, fused heteroaryl-cycloalkyl, fused heteroaryl-cycloalkyl-alkyl, alkoxyalkyl, alkylthioalkyl, alkylamino-alkyl, or dialkylaminoalkyl, or M and R.sub.6 taken together with the nitrogen to which M is bonded and the carbon to which R.sub.6 is bonded form a saturated unsubstituted heterocyclic group containing 3 or 4 ring carbon atoms; Y is hydroxy, alkoxy, amino, or substituted amino, aminoalkanoyl, aryloxy, aminoalkoxy, or hydroxyalkoxy; Z.sub.1 and Z.sub.2 each is a chemical bond, the group X.sub.3 --(CH.sub.2).sub.m, an amino acid group or the group X.sub.3 --(CH.sub.2).sub.m --X.sub.3 wherein X.sub.3 is oxygen, sulfur or NH and m is an integer from 0 to 4 inclusive; A and B each is the same as R.sub.1 or halogen, trifluoromethyl, OR.sub.1, NO.sub.2, NR.sub.1 R.sub.2, SO.sub.2 NH.sub.2, CN, SR.sub.1, SOR.sub.1, SO.sub.2 R.sub.1, CONR.sub.1 R.sub.2, COOR.sub.1 ; C is hydrogen alkyl, heteroallyl, amino, --CR.sub.1 .dbd.CR.sub.2 --, ##STR3## aminoalkyl, furfurylmethylamino, aminoaryl or aminobenzyl; X.sub.1 and X.sub.2 are each S, SO, SO.sub.2, NR.sub.1, O, chemical bond, (CR.sub.9 R.sub.10).sub.m, --CR.sub.9 .dbd.CR.sub.10 --, and CHOH, with the proviso that at least one of X.sub.1 and X.sub.2 be (CR.sub.9 R.sub.10).sub.m, wherein R.sub.9 and R.sub.10 are each hydrogen or lower alkyl, and m is an integer from 1 to 5; Ar is a divalent arylene or heteroarylene; and R.sub.7 and R.sub.8 are each hydrogen, alkyl, halo, cyano, hydroxy, alkoxy, amino, alkylamino, dialkylamino, mercapto, alkylmercapto, nitro, trifluoromethyl, carboxy, carbalkoxy, COY and NHCONHR.sub.1 wherein R.sub.1 and Y are as hereindefined; and pharmaceutically-acceptable salts thereof.

  本发明揭示了一种同时具有血管紧张素酶抑制活性和利尿活性的新型化合物。该化合物由一般式##STR1##表示，其中X是##STR2##其中R.sub.1、R.sub.2、R.sub.3、R.sub.4、R.sub.5和R.sub.6是氢、烷基、烯基、炔基、苯基-烷基和环烷基，可以相同也可以不同；n是0到4的整数；M是烯基、炔基、环烷基、环烷基-烷基、多环烷基、多环烷基-烷基、芳基、芳基-烷基、杂芳基、杂芳基-烷基、杂环烷基、杂环烷基-烷基、融合芳基-环烷基、融合芳基-环烷基-烷基、融合杂芳基-环烷基、融合杂芳基-环烷基-烷基、烷氧基烷基、烷硫基烷基、烷基氨基-烷基或二烷基氨基烷基，或M和R.sub.6与M键结的氮和R.sub.6键结的碳形成一个饱和未取代的含有3或4个环碳原子的杂环基；Y是羟基、烷氧基、氨基或取代氨基、氨基酰基、芳氧基、氨基烷氧基或羟基烷氧基；Z.sub.1和Z.sub.2分别是化学键、X.sub.3--(CH.sub.2).sub.m、氨基酸基团或X.sub.3--(CH.sub.2).sub.m--X.sub.3，其中X.sub.3是氧、硫或NH，m是0到4的整数；A和B分别与R.sub.1相同或是卤素、三氟甲基、OR.sub.1、NO.sub.2、NR.sub.1 R.sub.2、SO.sub.2 NH.sub.2、CN、SR.sub.1、SOR.sub.1、SO.sub.2 R.sub.1、CONR.sub.1 R.sub.2、COOR.sub.1；C是氢烷基、杂烯基、氨基、--CR.sub.1.dbd.CR.sub.2--、##STR3##氨基烷基、呋喃甲基氨基、氨基芳基或氨基苯基；X.sub.1和X.sub.2分别是S、SO、SO.sub.2、NR.sub.1、O、化学键、(CR.sub.9 R.sub.10).sub.m、--CR.sub.9.dbd.CR.sub.10--和CHOH，但至少有一个X.sub.1和X.sub.2是(CR.sub.9 R.sub.10).sub.m，其中R.sub.9和R.sub.10分别是氢或低烷基，m是1到5的整数；Ar是二价芳基或杂芳基；R.sub.7和R.sub.8分别是氢、烷基、卤素、氰基、羟基、烷氧基、氨基、烷基氨基、二烷基氨基、巯基、烷基巯基、硝基、三氟甲基、羧基、羧基烷氧基、COY和NHCONHR.sub.1，其中R.sub.1和Y如上所定义；以及其药学上可接受的盐。
• SKILES, J. W.;SUH, J. T.;WILLIAMS, B. E.;MENARD, P. R.;BARTON, J. N.;LOEV+, J. MED. CHEM., 1986, 29, N 5, 784-796
  作者：SKILES, J. W.、SUH, J. T.、WILLIAMS, B. E.、MENARD, P. R.、BARTON, J. N.、LOEV+

  DOI：——

  日期：——
• Compounds having angiotensin converting enzyme inhibitory activity and diuretic activity
  申请人：RORER INTERNATIONAL (OVERSEAS) INC.

  公开号：EP0100053B1

  公开（公告）日：1987-10-21