N1-异戊烷-D-亮氨酰胺 | 111507-07-4

• 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
• 中文名称: N1-异戊烷-D-亮氨酰胺
• 英文名称: D-leucine isopentylamide
• 英文别名: D-leucine isoamylamide；Pentanamide, 2-amino-4-methyl-N-(3-methylbutyl)-, (R)-；(2R)-2-amino-4-methyl-N-(3-methylbutyl)pentanamide
• CAS: 111507-07-4
• 化学式: C₁₁H₂₄N₂O
• 分子量: 200.324
• InChiKey: HCDLAJHOIWLVLK-SNVBAGLBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  14
• 可旋转键数：
  6
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.91
• 拓扑面积：
  55.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  N1-异戊烷-D-亮氨酰胺 、 阿洛司他丁酸 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以78%的产率得到(2S,3S)-Oxirane-2,3-dicarboxylic acid 2-{[(S)-3-methyl-1-(3-methyl-butylcarbamoyl)-butyl]-amide} 3-{[(R)-3-methyl-1-(3-methyl-butylcarbamoyl)-butyl]-amide}
  参考文献：
  名称：

  Ester and amide derivatives of E64c as inhibitors of platelet calpains

  摘要：

  Ester and amide derivatives of E64c, (+)-(2S,3S)-3-[[(S)-3-methyl-1-[(3-methylbutyl)carbamoyl]butyl]carbamoyl]-2-oxiranecarboxylic acid, an inhibitor of calpains, were synthesized and tested for ability to inhibit calpain in lysed cells, ability to enter intact cells, and ability to inhibit calpain in intact cells. The esters were from halogen-substituted alcohols and alcohols with increasing size. There were no appreciable differences in the inhibitory potency of any of the halogen-substituted esters from ethyl to trifluoroethyl, indicating that ease of hydrolysis of this class of ester is not important for activity. The only ester with impaired activity was the largest, Z-leucyl-norleucyl, which was about 5% as effective as the ethyl ester, E64d. Amides of amino acid esters also had impaired activity. To explore the possibility of targeting E64c derivatives to specific cells, esters and amides of E64c with 5-hydroxytryptamine were tested on the rationale that the active 5-hydroxytryptamine uptake mechanism of platelets might selectively concentrate the drug in platelets. Both the ester and amide inhibited calpain in lysed cells, but only the ester inhibited in intact cells. The 5-hydroxytryptamine ester showed no advantage over the ethyl ester in entering platelets.

  DOI：

  10.1021/jm00089a015
• 作为产物：
  描述：

  BOC-D-亮氨酸 在 盐酸 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 乙酸乙酯 为溶剂， 生成 N1-异戊烷-D-亮氨酰胺
  参考文献：
  名称：

  Efficient synthetic method for ethyl (+)-(2S,3S)-3-((S)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl)-2-oxiranecarboxylate (EST), a new inhibitor of cysteine proteinases.

  摘要：

  Ethly (+)-(2S, 3S)-3-[(S)-3-甲基-1-(3-甲基丁基氨基甲酰基)丁基氨基甲酰基]-2-环氧羧酸酯（EST；la）预计将作为治疗肌肉萎缩症的口服药物，因为它对与疾病相关的肌纤维蛋白降解中涉及的半胱氨酸蛋白酶具有强大的抑制活性。通过广泛的研究，旨在开发一种适用于工业应用的新合成方法，发现L-精氨酸可以作为新的高效分离剂，用于获得光学纯的L-反-环氧富马酸（3a），而使用对硝基苯酚的活性酯方法在乙基L-反-环氧富马酸（7a）和L-亮氨酸异戊酰胺（8a）之间的偶联反应中非常有效，因为副产物的生成极少。为了检查反-环氧富马酸和亮氨酸部分的立体化学对半胱氨酸蛋白酶抑制活性的贡献，采用类似的方法合成了la的二叠体（lb-d），并测量了la-d对木瓜蛋白酶的灭活速率常数。化合物la，具有L-反-环氧富马酸和L-亮氨酸部分，显示出其中最强的活性。

  DOI：

  10.1248/cpb.35.1098

文献信息

• Novel Drugs for Dementia
  申请人：Ternansky Robert

  公开号：US20080227806A1

  公开（公告）日：2008-09-18

  The invention is directed to compounds that are prodrugs containing a chemical delivery system (CDS) moiety and a cysteine protease inhibitor moiety. The CDS moiety targets the prodrug to the brain or central nervous system. The cysteine protease inhibitor inhibits cysteine proteases upon release from the prodrug. Cysteine protease inhibitors are effective for treating dementia, Alzheimer's disease and vascular dementia. Targeting the brain or central nervous system offers significant advantages in treating these conditions and diseases. A preferred CDS prodrug is a dihydrotrigoneline CDS moiety coupled to an epoxysuccinyl peptide cysteine protease inhibitor moiety.

  本发明涉及一种含有化学递送系统（CDS）基团和半胱氨酸蛋白酶抑制剂基团的前药化合物。CDS基团将前药定位于大脑或中枢神经系统。半胱氨酸蛋白酶抑制剂在从前药中释放后抑制半胱氨酸蛋白酶。半胱氨酸蛋白酶抑制剂对治疗痴呆症、阿尔茨海默病和血管性痴呆症有效。定位于大脑或中枢神经系统在治疗这些疾病和症状方面具有显著的优势。首选的CDS前药是将二氢三角线CDS基团与环氧丙酰肽半胱氨酸蛋白酶抑制剂基团耦合。
• N-Haloacetyl-amino-acid amides as active-site-directed inhibitors of papain and cathepsin B
  作者：C Giordano、C Gallina、V Ottaviano、V Consalvi、R Scandurra

  DOI：10.1016/0223-5234(92)90018-v

  日期：1992.12

  A series of N-haloacetyl-amino-acid amides were synthesized and tested as models of cysteine-protease inhibitors. They irreversibly inactivated papain and cathepsin B via a reversible enzyme--inhibitor intermediate. Apparent second-order rate constants of inactivation ranging from 65 to 16 700 M-1 s-1 were observed. Reactivity against papain, as compared to glutathione, was increased 16 400-fold for N-bromoacetyl-leucine isopentylamide and 25 700-fold for the corresponding iodoacetyl derivative; these increases are probably due to proximity effects. No inhibition of trypsin, chymotrypsin and porcine pancreatic elastase was observed. Haloacetamides represent an interesting class of easily synthesized, efficient. irreversible inhibitors of cysteine proteases, which have low non-specific alkylating properties.
• WO2007/38772
  申请人：——

  公开号：——

  公开（公告）日：——
• [EN] NOVEL DRUGS FOR DEMENTIA<br/>[FR] NOUVEAUX MEDICAMENTS CONTRE LA DEMENCE
  申请人：TERNANSKY ROBERT

  公开号：WO2007038772A1

  公开（公告）日：2007-04-05

  [EN] The invention is directed to compounds that are prodrugs containing a chemical delivery system (CDS) moiety and a cysteine protease inhibitor moiety. The CDS moiety targets the prodrug to the brain or central nervous system. The cysteine protease inhibitor inhibits cysteine proteases upon release from the prodrug. Cysteine protease inhibitors are effective for treating dementia, Alzheimer's disease and vascular dementia. Targeting the brain or central nervous system offers significant advantages in treating these conditions and diseases. A preferred CDS prodrug is a dihydrotrigoneline CDS moiety coupled to an epoxysuccinyl peptide cysteine protease inhibitor moiety.
  [FR] L'invention concerne des composés qui sont des promédicaments contenant un fragment de système de délivrance chimique ("chemical delivery system" ou CDS) et un fragment d'inhibiteur de cystéine protéase. Le fragment CDS cible le promédicament sur le cerveau ou le système nerveux central. L'inhibiteur de cystéine protéase inhibe les cystéine protéases lors de la libération du promédicament. Les inhibiteurs de cystéine protéase sont efficaces dans le traitement de la démence, de la maladie d'Alhzheimer et de la démence vasculaire. Le ciblage du cerveau ou du système nerveux central offre des avantages significatifs dans le traitement de ces états et maladies. Un médicament CDS préféré est composé d'un fragment CDS de dihydrotrigoneline couplé à un fragment d'inhibiteur de cystéine protéase de peptide d'époxysuccinile.
• Ester and amide derivatives of E64c as inhibitors of platelet calpains
  作者：Zhenya Huang、Eleanor B. McGowan、Thomas C. Detwiler

  DOI：10.1021/jm00089a015

  日期：1992.5

  Ester and amide derivatives of E64c, (+)-(2S,3S)-3-[[(S)-3-methyl-1-[(3-methylbutyl)carbamoyl]butyl]carbamoyl]-2-oxiranecarboxylic acid, an inhibitor of calpains, were synthesized and tested for ability to inhibit calpain in lysed cells, ability to enter intact cells, and ability to inhibit calpain in intact cells. The esters were from halogen-substituted alcohols and alcohols with increasing size. There were no appreciable differences in the inhibitory potency of any of the halogen-substituted esters from ethyl to trifluoroethyl, indicating that ease of hydrolysis of this class of ester is not important for activity. The only ester with impaired activity was the largest, Z-leucyl-norleucyl, which was about 5% as effective as the ethyl ester, E64d. Amides of amino acid esters also had impaired activity. To explore the possibility of targeting E64c derivatives to specific cells, esters and amides of E64c with 5-hydroxytryptamine were tested on the rationale that the active 5-hydroxytryptamine uptake mechanism of platelets might selectively concentrate the drug in platelets. Both the ester and amide inhibited calpain in lysed cells, but only the ester inhibited in intact cells. The 5-hydroxytryptamine ester showed no advantage over the ethyl ester in entering platelets.