ethyl 2-oxo-1-azacyclodecane-10-carboxylate | 150126-66-2

• 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: ethyl 2-oxo-1-azacyclodecane-10-carboxylate
• 英文别名: ethyl 10-oxoazecane-2-carboxylate
• CAS: 150126-66-2
• 化学式: C₁₂H₂₁NO₃
• 分子量: 227.304
• InChiKey: IOAJHCFFSRLFPA-UHFFFAOYSA-N

物化性质

• 沸点：
  383.7±35.0 °C(Predicted)
• 密度：
  1.014±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  55.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ethyl 2-oxo-1-azacyclodecane-10-carboxylate 在 五氯化磷 、 溴 、 碘 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 以57%的产率得到ethyl 3-bromo-2-oxo-1-azacyclodecane-10-carboxylate
  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：

  2-氧代环壬烷羧酸乙酯 在 sodium azide 、 甲烷磺酸 作用下， 以 氯仿 为溶剂， 反应 4.0h， 以40%的产率得到ethyl 2-oxo-1-azacyclodecane-10-carboxylate
  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：US05244889A1

  公开（公告）日：1993-09-14

  The invention relates to macrocyclic lactam derivatives of formula I ##STR1## wherein 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 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.

  该发明涉及公式I的大环内酰胺衍生物，其中R为氢或酰基；m为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CH2；R1为--COOH；或R1为其中R2为氢、较低烷基、芳基-较低烷基、氨基-较低烷基、羟基-较低烷基、酰氧基-较低烷基、较低烷氧基-较低烷基、巯基-较低烷基、较低烷基-(硫、亚硫酰基或砜基)-较低烷基或羧基-较低烷基，R3为氢或较低烷基，q为零或1到5之间的整数；或R1为其中R4为氢、较低烷基、较低烷氧基、羟基或酰氧基，r为1或2；或R1为其中s为1或2；或R1为其中R5和R6独立地代表氢、较低烷基、C5-或C6-环烷基、(羟基、酰氧基或较低烷氧基-)较低烷基、碳环或杂环单环芳基，或(羟基、酰氧基或烷氧基-)较低烷氧基-较低烷基；或R5和R6连同它们连接的氮原子代表吡咯烷基、哌啶烷基、吗啉烷基、哌嗪基或N-烷基哌嗪基；以及在公式I中(CH2)m的一个CH2基被O或S替换的大环硫和氧含有内酰胺环异构体，Y代表CH2；以及具有游离羧基的上述任何化合物的药学上可接受的前药酯；以及具有游离酸或碱性盐形成基团的任何上述化合物的药学上可接受的盐；包括所述化合物的制剂；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中来抑制中性内肽酶以治疗哺乳动物中的疾病的方法。
• Macrocyclic lactams as inhibitors of atrial natriuretic factors (ANF)-degrading neutral endopeptidase (NEP)
  申请人：CIBA-GEIGY AG

  公开号：EP0544620A1

  公开（公告）日：1993-06-02

  The invention relates to macrocyclic lactam derivatives of formula I wherein 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 CH₂; R₁ is -COOH; or R₁ is in which R₂ 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, R₃ is hydrogen or lower alkyl, and q is zero or an integer from 1 to 5 inclusive; or R₁ is in which R₄ is hydrogen, lower alkyl, lower alkoxy, hydroxy or acyloxy, and r is 1 or 2; or R₁ is in which s is 1 or 2; or R₁ is in which R₅ and R₆ independently represent hydrogen, lower alkyl, C₅- or C₆-cycloalkyl, (hydroxy-, acyloxy or lower alkoxy-) lower alkyl, carbocyclic or heterocyclic monocyclic aryl, or (hydroxy-, acyloxy- or alkoxy-) lower alkyloxy-lower alkyl; or R₅ and R₆ 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 CH₂ group of (CH₂)m in formula I is replaced by O or S, and Y represents CH₂; 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.

  本发明涉及式 I 的大环内酰胺衍生物 其中 R 是氢或酰基；m 是 4 至 9（包括 9）的整数；n 是 1 或 2；p 是 0、1 或 2；X 是 -CONH- 或 -NHCO-；Y 是 S、O 或 CH₂；R₁ 是 -COOH；或 R₁ 是 其中 R₂ 是氢、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、低级烷氧基-低级烷基、巯基-低级烷基、低级烷基-（硫基、亚磺酰基或磺酰基）-低级烷基或羧基-低级烷基，R₃ 是氢或低级烷基，且 q 是零或 1 至 5（包括 5）的整数；或 R₁ 是 其中 R₄ 是氢、低级烷基、低级烷氧基、羟基或酰氧基，且 r 是 1 或 2；或 R₁ 是 其中 s 为 1 或 2；或 R₁ 是 其中R₅和R₆各自代表氢、低级烷基、C₅-或C₆-环烷基、(羟基-、酰氧基-或低级烷氧基-)低级烷基、碳环或杂环单环芳基或(羟基-、酰氧基-或烷氧基-)低级烷氧基-低级烷基；或 R₅ 和 R₆ 与它们所连接的氮一起代表吡咯烷基、哌啶基、吗啉基、哌嗪基或 N-烷基哌嗪基；以及大环硫氧内酰胺环异构体，其中式 I 中 (CH₂)m 的 CH₂ 基团被 O 或 S 取代，Y 代表 CH₂；以及上述任何化合物的药学上可接受的带有游离羧基的原药酯；以及任何上述化合物的药学上可接受的带有游离酸或碱性成盐基团的盐；包含上述化合物的药物组合物；制备上述化合物和制备中间体的方法；以及通过向需要治疗的哺乳动物施用上述化合物来治疗对中性内肽酶抑制有反应的哺乳动物疾病的方法。
• US5244889A
  申请人：——

  公开号：US5244889A

  公开（公告）日：1993-09-14
• US5426103A
  申请人：——

  公开号：US5426103A

  公开（公告）日：1995-06-20
• Design and synthesis of an orally active macrocyclic neutral endopeptidase 24.11 inhibitor
  作者：Lawrence J. MacPherson、Erol K. Bayburt、Michael P. Capparelli、Regine S. Bohacek、Frank H. Clarke、Rajendra D. Ghai、Yumi Sakane、Carol J. Berry、Jane V. Peppard、Angelo J. Trapani

  DOI：10.1021/jm00076a009

  日期：1993.11

  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.