3(RS)-[(4-carboxyphenylcarbonyl)-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane | 105080-02-2

• 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: 3(RS)-[(4-carboxyphenylcarbonyl)-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane
• 英文别名: 4-[[(2S)-3-methyl-1-oxo-1-[(2S)-2-[(1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl)carbamoyl]pyrrolidin-1-yl]butan-2-yl]carbamoyl]benzoic acid
• CAS: 105080-02-2
• 化学式: C₂₄H₃₀F₃N₃O₆
• 分子量: 513.514
• InChiKey: FGNPKLCZJAUKFU-RGBJRUIASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  36
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  133
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N,N-二甲基乙二胺 、 3(RS)-[(4-carboxyphenylcarbonyl)-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane 在 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 为溶剂， 反应 18.0h， 以46%的产率得到1-N-[2-(dimethylamino)ethyl]-4-N-[(2S)-3-methyl-1-oxo-1-[(2S)-2-[(1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl)carbamoyl]pyrrolidin-1-yl]butan-2-yl]benzene-1,4-dicarboxamide
  参考文献：
  名称：

  Discovery and Biological Activity of Orally Active Peptidyl Trifluoromethyl Ketone Inhibitors of Human Neutrophil Elastase

  摘要：

  Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMKs) possessing an N-terminal diarylacylsulfonamide, such as ICI 200,880 and ICI 200,355, displayed unparalleled protectin against the lung damage induced by human neutrophil elastase (HNE) when the inhibitors were administered intratracheally. Since the diarylacylsulfonamides were designed specifically to afford a long residence time in the lung, it was not unexpected that inhibitors from this class of TFMKs were not active when administered orally. Upon evaluating a large number of peptidyl TFMKs possessing a variety of N-terminal groups, several compounds were identified which demonstrated oral activity. Compounds were evaluated for their oral activity by measuring their ability to inhibit the increase in lung weight relative to body weight (Lw/Bw), the increase in red blood cells, and the increase in white blood cells induced by intratracheally administered HNE (100 mu g/hamster). A number of tripeptidyl trifluoromethyl ketones containing neutral N-terminal groups displayed good oral activity, while those containing basic, acidic, or polar groups did not. Compound 50, possessing an N-terminal 4-(CH3O)C6H4CO group, was particularly effective, reducing Lw/Bw by 77%, red cells by 89%, and white cells by 91% when dosed at 37.5 mg/kg orally. Thus, by modifying the N-terminal group of tripeptidyl TFMKs, inhibitors can be designed which are effective in vivo when administered either orally or intratracheally.

  DOI：

  10.1021/jm960819g
• 作为产物：
  描述：

  对苯二甲酸单甲酯 在 sodium hydroxide 、 乙酸酐 、 二甲基亚砜 、 1-羟基苯并三唑一水物 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 54.0h， 生成 3(RS)-[(4-carboxyphenylcarbonyl)-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane
  参考文献：
  名称：

  Discovery and Biological Activity of Orally Active Peptidyl Trifluoromethyl Ketone Inhibitors of Human Neutrophil Elastase

  摘要：

  Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMKs) possessing an N-terminal diarylacylsulfonamide, such as ICI 200,880 and ICI 200,355, displayed unparalleled protectin against the lung damage induced by human neutrophil elastase (HNE) when the inhibitors were administered intratracheally. Since the diarylacylsulfonamides were designed specifically to afford a long residence time in the lung, it was not unexpected that inhibitors from this class of TFMKs were not active when administered orally. Upon evaluating a large number of peptidyl TFMKs possessing a variety of N-terminal groups, several compounds were identified which demonstrated oral activity. Compounds were evaluated for their oral activity by measuring their ability to inhibit the increase in lung weight relative to body weight (Lw/Bw), the increase in red blood cells, and the increase in white blood cells induced by intratracheally administered HNE (100 mu g/hamster). A number of tripeptidyl trifluoromethyl ketones containing neutral N-terminal groups displayed good oral activity, while those containing basic, acidic, or polar groups did not. Compound 50, possessing an N-terminal 4-(CH3O)C6H4CO group, was particularly effective, reducing Lw/Bw by 77%, red cells by 89%, and white cells by 91% when dosed at 37.5 mg/kg orally. Thus, by modifying the N-terminal group of tripeptidyl TFMKs, inhibitors can be designed which are effective in vivo when administered either orally or intratracheally.

  DOI：

  10.1021/jm960819g

文献信息

• Elastase-inhibiting peptides bearing a C-terminal trifluoromethylketone
  申请人：Fujisawa Pharmaceutical Co., Ltd.

  公开号：US05430025A1

  公开（公告）日：1995-07-04

  Trifluoromethylketone compounds of the formula: ##STR1## wherein R.sup.1 is C.sub.1-6 alkyl which has one or two substituents selected from carboxy, esterified carboxy and di-C.sub.1-6 alkylcarbamoyl; phenyl(C.sub.1-6)alkyl, the phenyl moiety of which may have halogen or nitro or amino substituents and the alkyl moiety of which may have carboxy or esterified carboxy substituents; halo-phenyl; morpholino; or morpholino(C.sub.1-6)alkyl, R.sup.2 and R.sup.3 are each C.sub.1-6 alkyl, X is --or --NH--, and ##STR2## and pharmaceutically acceptable salts thereof are useful for inhibiting human elastase.

  式为：##STR1##其中R.sup.1是C.sub.1-6烷基，其具有一个或两个取自羧基，酯化羧基和二C.sub.1-6烷基氨基的取代基；苯基(C.sub.1-6)烷基，其苯基可能具有卤素，硝基或氨基取代基，烷基可能具有羧基或酯化羧基取代基；卤代苯基；吗啉基；或吗啉基(C.sub.1-6)烷基，R.sup.2和R.sup.3均为C.sub.1-6烷基，X为--或--NH--，以及其药学上可接受的盐对于抑制人类弹性蛋白酶是有用的。
• Trifluoromethylketone derivatives, processes for preparation thereof and
  申请人：Fujisawa Pharmaceutical Co., Ltd.

  公开号：US05296591A1

  公开（公告）日：1994-03-22

  The trifluoromethylketone derivatives (I) and pharmaceutically acceptable salts thereof have a human leukocyte elastase inhibiting activity and are useful as human leukocyte elastase inhibitors for treating or preventing degenerative diseases. The trifluoromethylketone derivatives (I) have the following formula: ##STR1## wherein R.sup.1 is C.sub.1-6 alkyl which has one or two substituents selected from carboxy, esterified carboxy and di-C.sub.1-6 alkylcarbamoyl; phenyl(C.sub.1-6) alkyl, the phenyl moiety of which may have halogen or nitro or amino substituents and the alkyl moiety of which may have carboxy or esterified carboxy substituents; halo-phenyl; morpholino; or morpholino(C.sub.1-6) alkyl, R.sup.2 and R.sup.3 are each C.sub.1-6 alkyl, X is -- or --NH--, and Y is ##STR2## and pharmaceutically acceptable salts thereof.

  三氟甲基酮衍生物(I)及其药学上可接受的盐具有人类白细胞弹性蛋白酶抑制活性，并可用作治疗或预防退行性疾病的人类白细胞弹性蛋白酶抑制剂。三氟甲基酮衍生物(I)的化学式如下：##STR1## 其中，R1是C1-6烷基，其具有一个或两个取自羧基、酯化羧基和二C1-6烷基碳酰胺基的取代基；苯基(C1-6)烷基，其苯基部分可能具有卤素、硝基或氨基取代基，而其烷基部分可能具有羧基或酯化羧基取代基；卤代苯基；吗啉基；或吗啉(C1-6)烷基，R2和R3均为C1-6烷基，X为--或--NH--，Y为##STR2##及其药学上可接受的盐。
• Trifluoromethylketone tripeptide derivatives
  申请人：FUJISAWA PHARMACEUTICAL CO., LTD.

  公开号：EP0494071A2

  公开（公告）日：1992-07-08

  New trifluoromethylketone derivatives of the following formula : wherein R1 is lower alkyl which has one or two substituents selected from carboxy, esterified carboxy and di-lower alkylcarbamoyl ; phenyl(lower)alkyl, the phenyl moiety of which may have halogen or nitro or amino and the alkyl moiety of which may have carboxy or esterified carboxy ; halo-phenyl ; morpholino ; or morpholino(lower)alkyl, R2 and R3 are each lower alkyl, X is - or -NH-, and Y is and pharmaceutically acceptable salt thereof, processes for their preparation and pharmaceutical compositions comprising them.

  下式的三氟甲基酮新衍生物 ： 其中 R1 是低级烷基，其上有一个或两个取代基，选自羧基、酯化羧基和二低级烷基氨基甲酰基；苯基（低级）烷基，其苯基可带有卤素或硝基或氨基，其烷基可带有羧基或酯化羧基；卤代苯基；吗啉基；或吗啉基（低级）烷基、 R2 和 R3 各为低级烷基、 X 是-或-NH-，以及 Y 是 及其药学上可接受的盐、它们的制备工艺和包含它们的药物组合物。
• US5296591A
  申请人：——

  公开号：US5296591A

  公开（公告）日：1994-03-22
• US5430025A
  申请人：——

  公开号：US5430025A

  公开（公告）日：1995-07-04