3-<(acetylthio)methyl>-2-oxo-1-azacyclodecane-10-carboxylic acid

• 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-<(acetylthio)methyl>-2-oxo-1-azacyclodecane-10-carboxylic acid
• 英文别名: trans 3-(Acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid；(2R,9S)-9-(acetylsulfanylmethyl)-10-oxoazecane-2-carboxylic acid
• 化学式: C₁₃H₂₁NO₄S
• 分子量: 287.38
• InChiKey: JNSGCXKEBNBERY-GHMZBOCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  109
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-<(acetylthio)methyl>-2-oxo-1-azacyclodecane-10-carboxylic acid 在 N-甲基吗啉 、 lithium hydroxide 、 正丁基锂 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 5.25h， 生成 trans-N-<<3(R)-<(acetylthio)methyl>-2-oxo-1-azacyclodec-10(S)-yl>carbonyl>-4-hydroxy-L-proline ethyl ester
  参考文献：
  名称：

  Design and synthesis of an orally active macrocyclic neutral endopeptidase 24.11 inhibitor

  摘要：

  A potent macrocyclic inhibitor of neutral endopeptidase (NEP) 24.11 was designed using a computer model of the active site of thermolysin. This 10-membered ring lactam represents a general mimic for any hydrophobic dipeptide in which the two amino acid side chains bind to an enzyme in a contiguous orientation. The parent 10-membered ring lactam was synthesized and exhibited excellent potency as an NEP 24.11 inhibitor (IC50 = 3 nM). In order to improve oral bioavailability, various functionality was attached to the macrocycle. These modifications lead to CGS 25155, an orally active NEP 24.11 inhibitor that slows down the degradation of the cardiac hormone atrial natriuretic factor, producing a lowering of blood pressure in the DOCA-salt rat model of hypertension.

  DOI：

  10.1021/jm00076a009
• 作为产物：
  描述：

  ethyl 3-methylidene-2-oxo-1-azacyclodecane-10-carboxylate 在 吡啶 、 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 1.25h， 生成 3-<(acetylthio)methyl>-2-oxo-1-azacyclodecane-10-carboxylic acid
  参考文献：
  名称：

  Design and synthesis of an orally active macrocyclic neutral endopeptidase 24.11 inhibitor

  摘要：

  A potent macrocyclic inhibitor of neutral endopeptidase (NEP) 24.11 was designed using a computer model of the active site of thermolysin. This 10-membered ring lactam represents a general mimic for any hydrophobic dipeptide in which the two amino acid side chains bind to an enzyme in a contiguous orientation. The parent 10-membered ring lactam was synthesized and exhibited excellent potency as an NEP 24.11 inhibitor (IC50 = 3 nM). In order to improve oral bioavailability, various functionality was attached to the macrocycle. These modifications lead to CGS 25155, an orally active NEP 24.11 inhibitor that slows down the degradation of the cardiac hormone atrial natriuretic factor, producing a lowering of blood pressure in the DOCA-salt rat model of hypertension.

  DOI：

  10.1021/jm00076a009

文献信息

• Certain macrocyclic lactam derivatives
  申请人：Ciba-Geigy Corporation

  公开号：US05426103A1

  公开（公告）日：1995-06-20

  The invention relates to macrocyclic lactam derivatives of formula I ##STR1## wherin R is hydrogen or acyl; m is an integer from 4 to 9 inclusive; n is 1 or 2; p is zero, 1 or 2; X is --CONH-- or --NHCO--; Y is S, O or CH.sub.2 ; R.sub.1 is --COOH; or R.sub.1 is ##STR2## in which R.sub.2 is hydrogen, lower alkyl, aryl-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, mercapto-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, or carboxy-lower alkyl, R.sub.3 is hydrogen or lower alkyl, and q is zero or an integer from 1 to 5 inclusive; or R.sub.1 is ##STR3## in which R.sub.4 is hydrogen, lower alkyl, lower alkoxy, hydroxy or acyloxy, and r is 1 or 2; or R.sub.1 is ##STR4## in which s is 1 or 2; or R.sub.1 is ##STR5## in which R.sub.5 and R.sub.6 independently represent hydrogen, lower alkyl, C.sub.5 - or C.sub.6 -cycloalkyl, (hydroxy-, acyloxy or lower alkoxy-) lower alkyl, carbocyclic or heterocyclic monocyclic aryl, or (hydroxy-, acyloxy- or alkoxy-) lower alkyloxy-lower alkyl; or R.sub.5 and R.sub.6 together with the nitrogen to which they are attached represent pyrrolidino, piperidino, morpholino, piperazino or N-alkylpiperazino; and macrocyclic sulfur and oxygen containing lactam ring isomers in which a CH.sub.2 group of (CH.sub.2).sub.m in formula I is is replaced by O or S, and Y represents CH.sub.2 ; and pharmaceutically acceptable prodrug esters of any above said compound with a free carboxyl group; and pharmaceutically acceptable salts of any said compounds with a free acid or basic salt forming group; pharmaceutical compositions comprising said compounds; methods for the preparation of said compounds and for the preparation of intermediates; and methods of treating disorders in mammals which are responsive to the inhibition of neutral endopeptidases by administration of said compounds to mammals in need of such treatment.

  本发明涉及公式I的大环内酰胺衍生物，其中R是氢或酰基；m是4到9之间的整数；n为1或2；p为零，1或2；X为--CONH--或--NHCO--；Y为S、O或CH.sub.2；R.sub.1为--COOH；或R.sub.1为##STR2## 其中R.sub.2为氢、低级烷基、芳基-低级烷基、氨基-低级烷基、羟基-低级烷基、酰氧基-低级烷基、低烷氧基-低级烷基、巯基-低级烷基、低级烷基-(硫、亚硫酰或磺酰)-低级烷基或羧基-低级烷基，R.sub.3为氢或低级烷基，q为零或1到5之间的整数；或R.sub.1为##STR3## 其中R.sub.4为氢、低级烷基、低烷氧基、羟基或酰氧基，r为1或2；或R.sub.1为##STR4## 其中s为1或2；或R.sub.1为##STR5## 其中R.sub.5和R.sub.6独立地表示氢、低级烷基、C.sub.5-或C.sub.6-环烷基、(羟基、酰氧基或低烷氧基-)低级烷基、环烷基或杂环烷基单环芳基，或(羟基、酰氧基或烷氧基-)低烷氧基-低级烷基；或R.sub.5和R.sub.6与它们连接的氮一起表示吡咯啉基、哌啶基、吗啉基、哌嗪基或N-烷基哌嗪基；以及公式I中的(CH.sub.2).sub.m的CH.sub.2基被O或S替换的大环硫和氧含有内酰胺环异构体，Y表示CH.sub.2；以及任何上述化合物的具有自由羧基的药物可接受的前药酯和具有自由酸或碱盐形成基团的任何所述化合物的药物可接受的盐；包含所述化合物的制药组合物；制备所述化合物和中间体的方法；以及通过将所述化合物用于需要此类治疗的哺乳动物的治疗而抑制中性内肽酶的方法。