N-(3-methylphenylcarbamoyl)-(L)-isoleucyl-(L)-tryptophanol | 161708-77-6

• 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-methylphenylcarbamoyl)-(L)-isoleucyl-(L)-tryptophanol
• 英文别名: (2S,3S)-N-[(2S)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl]-3-methyl-2-[(3-methylphenyl)carbamoylamino]pentanamide
• CAS: 161708-77-6
• 化学式: C₂₅H₃₂N₄O₃
• 分子量: 436.554
• InChiKey: ZIAOYKLNSSUNPL-NYDSKATKSA-N

物化性质

• 熔点：
  185-186 °C
• 沸点：
  701.998±60.00 °C(Press: 760.00 Torr)(predicted)
• 密度：
  1.222±0.06 g/cm3(Temp: 25 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  106
• 氢给体数：
  5
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-(3-methylphenylcarbamoyl)-(L)-isoleucyl-(L)-tryptophanol 在 pyridine-SO3 complex 、 二甲基亚砜 、 三乙胺 作用下， 反应 0.83h， 生成 (2S,3S)-N-[(2S)-1-(1H-indol-3-yl)-3-oxopropan-2-yl]-3-methyl-2-[(3-methylphenyl)carbamoylamino]pentanamide
  参考文献：
  名称：

  Synthesis of Peptide Aldehyde Derivatives as Selective Inhibitors of Human Cathepsin L and Their Inhibitory Effect on Bone Resorption

  摘要：

  Cathepsin L, a lysosomal cysteine protease, is secreted by osteoclasts and participates in bone collagen degradation. In a search for cathepsin L inhibitors as antiosteoporotic agents, a series of peptide aldehyde derivatives were prepared by two synthetic approaches, DMSO oxidation of the corresponding alcohol derivatives and DIBAL-H reduction of the corresponding N,O-dimethylhydroxylamide derivatives, and evaluated for inhibitory activity against human cathepsin L and for inhibitory effects on bone resorption. Some of the peptide aldehyde derivatives including alpha-acylamino aldehyde derivatives showed potent activities. Among these compounds, N-(1-naphthalenylsulfonyl-L-isoleucyl-L-tryptophanal (12) was selected as a candidate for further investigation. Compound 12, a potent, selective, and reversible inhibitor of human cathepsin L with an IC50 Of 1.9 nM, inhibited the release of Ca2+ and hydroxyproline from bone in in vitro bone culture system and also prevented bone loss in ovariectomized mice at an oral dose of 50 mg/kg.

  DOI：

  10.1021/jm9803065
• 作为产物：
  描述：

  N-benzyloxycarbonyl-(L)-isoleucyl-(L)-tryptophanol 在 palladium on activated charcoal 氢气 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 4.5h， 生成 N-(3-methylphenylcarbamoyl)-(L)-isoleucyl-(L)-tryptophanol
  参考文献：
  名称：

  Synthesis of Peptide Aldehyde Derivatives as Selective Inhibitors of Human Cathepsin L and Their Inhibitory Effect on Bone Resorption

  摘要：

  Cathepsin L, a lysosomal cysteine protease, is secreted by osteoclasts and participates in bone collagen degradation. In a search for cathepsin L inhibitors as antiosteoporotic agents, a series of peptide aldehyde derivatives were prepared by two synthetic approaches, DMSO oxidation of the corresponding alcohol derivatives and DIBAL-H reduction of the corresponding N,O-dimethylhydroxylamide derivatives, and evaluated for inhibitory activity against human cathepsin L and for inhibitory effects on bone resorption. Some of the peptide aldehyde derivatives including alpha-acylamino aldehyde derivatives showed potent activities. Among these compounds, N-(1-naphthalenylsulfonyl-L-isoleucyl-L-tryptophanal (12) was selected as a candidate for further investigation. Compound 12, a potent, selective, and reversible inhibitor of human cathepsin L with an IC50 Of 1.9 nM, inhibited the release of Ca2+ and hydroxyproline from bone in in vitro bone culture system and also prevented bone loss in ovariectomized mice at an oral dose of 50 mg/kg.

  DOI：

  10.1021/jm9803065

文献信息

• Alcohol or aldehyde derivatives and their use
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US05639781A1

  公开（公告）日：1997-06-17

  The present invention provides a cathepsin L inhibitor containing a compound of the formula: ##STR1## wherein R.sup.1 is a hydrogen atom or an arylalkyl, heterocyclic-alkyl or lower alkyl group which may be substituted; R.sup.2 and R.sup.3 independently are a hydrogen atom or a hydrocarbon residue which may be substituted; R.sup.4 is an alkanoyl, sulfonyl, carbonyloxy, carbamoyl or thiocarbamoyl group which may be substituted; X is formula: --CHO or --CH.sub.2 OB (wherein B is a hydrogen atom or a protecting group of hydroxyl group); m and n independently are an integer of 0 or 1; provided that R.sup.4 is an alkanoyl group substituted by aryl, a sulfonyl group substituted by aryl having more than 9 carbon atoms or by lower alkyl, or a carbamoyl or thiocarbamoyl group which may be substituted when R.sup.1 is an unsubstituted lower alkyl, arylalkyl on methylthioethyl group, R.sup.2 and R.sup.3 independently are a lower alkyl or arylalkyl, X is --CHO, m is 1 and n is 0 or 1, or a salt thereof. Compound (I) is useful as a prophylactic/therapeutic agent for osteoporosis.

  本发明提供了一种含有化合物的半胱氨酸蛋白酶L抑制剂，其化学式为：##STR1## 其中R.sup.1是氢原子或可以被取代的芳基烷基，杂环烷基烷基或较低烷基；R.sup.2和R.sup.3分别是可以被取代的氢原子或碳氢基；R.sup.4是可以被取代的烷酰基，磺酰基，羰氧基，氨基甲酰基或硫脲甲酰基；X是公式：--CHO或--CH.sub.2 OB（其中B是氢原子或羟基的保护基）；m和n分别是0或1的整数；前提是当R.sup.1是未取代的较低烷基，芳基烷基或甲基硫乙基时，R.sup.4是被芳基取代的烷酰基，被具有9个以上碳原子的芳基或较低烷基取代的磺酰基，或者是可以被取代的氨基甲酰基或硫脲甲酰基，R.sup.2和R.sup.3分别是较低烷基或芳基烷基，X是--CHO，m为1，n为0或1，或其盐。化合物（I）可用作预防/治疗骨质疏松症的药物。
• Derivatives of L-tryptophanal and their use as medicinals
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US05498728A1

  公开（公告）日：1996-03-12

  The present invention provides a cathepsin L inhibitor containing a compound of the formula: ##STR1## wherein R.sup.1 is a hydrogen atom or an arylalkyl, heterocyclic-alkyl or lower alkyl group which may be substituted; R.sup.2 and R.sup.3 independently are a hydrogen atom or a hydrocarbon residue which may be substituted; R.sup.4 is an alkanoyl, sulfonyl, carbonyloxy, carbamoyl or thiocarbamoyl group which may be substituted; X is formula: --CHO or --CH.sub.2 OB (wherein B is a hydrogen atom or a protecting group of hydroxyl group); m and n independently are an integer of 0 or 1; provided that R.sup.4 is an alkanoyl group substituted by aryl, a sulfonyl group substituted by aryl having more than 9 carbon atoms or by lower alkyl, or a carbamoyl or thiocarbamoyl group which may be substituted when R.sup.1 is an unsubstituted lower alkyl, arylalkyl on methylthioethyl group, R.sup.2 and R.sup.3 independently are a lower alkyl or arylalkyl, X is --CHO, m is 1 and n is 0 or 1, or a salt thereof. Compound (I) is useful as a prophylactic/therapeutic agent for osteoporosis.

  本发明提供了一种含有式为：##STR1##的化合物的半胱氨酸蛋白酶L抑制剂，其中R.sup.1为氢原子或取代的芳基烷基，杂环基烷基或低级烷基；R.sup.2和R.sup.3独立地为氢原子或可取代的碳氢残基；R.sup.4为可取代的烷酰基，磺酰基，羰氧基，氨基甲酰基或硫脲甲酰基；X为公式：--CHO或--CH.sub.2 OB（其中B为氢原子或羟基保护基）；m和n独立地为0或1的整数；前提是当R.sup.1为未取代的低级烷基，芳基烷基或甲基硫乙基时，R.sup.4为取代的烷酰基，芳基取代的磺酰基具有9个以上的碳原子或低级烷基，或可取代的氨基甲酰基或硫脲甲酰基，R.sup.2和R.sup.3独立地为低级烷基或芳基烷基，X为--CHO，m为1，n为0或1，或其盐。化合物（I）可用作骨质疏松症的预防/治疗药物。
• Alcohol or aldehyde derivatives as cathepsin L inhibitor and bone resorption inhibitor
  申请人：TAKEDA CHEMICAL INDUSTRIES, LTD.

  公开号：EP0611756A2

  公开（公告）日：1994-08-24

  The present invention provides a cathepsin L inhibitor containing a compound of the formula: wherein R¹ is a hydrogen atom or an arylalkyl, heterocyclic-alkyl or lower alkyl group which may be substituted; R² and R³ independently are a hydrogen atom or a hydrocarbon residue which may be substituted; R⁴ is an alkanoyl, sulfonyl, carbonyloxy, carbamoyl or thiocarbamoyl group which may be substituted; X is formula: -CHO or -CH₂OB (wherein B is a hydrogen atom or a protecting group of hydroxyl group); m and n independently are an integer of 0 or 1; provided that R⁴ is an alkanoyl group substituted by aryl, a sulfonyl group substituted by aryl having more than 9 carbon atoms or by lower alkyl, or a carbamoyl or thiocarbamoyl group which may be substituted when R¹ is an unsubstituted lower alkyl, arylalkyl on methylthioethyl group, R² and R³ independently are a lower alkyl or arylalkyl, X is -CHO, m is 1 and n is 0 or 1, or a salt thereof. Compound (I) is useful as a prophylactic/therapeutic agent for osteoporosis.

  本发明提供了一种含有式化合物的凝血酶 L 抑制剂： 其中，R¹为氢原子或可被取代的芳烷基、杂环烷基或低级烷基；R²和R³各自为氢原子或可被取代的烃残基；R⁴为可被取代的烷酰基、磺酰基、羰氧基、氨基甲酰基或硫代氨基甲酰基；X为式：-CHO或-CH₂OB（其中 B 为氢原子或羟基保护基团）；m 和 n 分别为 0 或 1 的整数；条件是 R⁴ 是被芳基取代的烷酰基、被具有 9 个以上碳原子的芳基或低级烷基取代的磺酰基、或当 R¹ 是未取代的低级烷基、芳烷基或甲硫基时可能被取代的氨基甲酰基或硫代氨基甲酰基，R² 和 R³ 独立地是低级烷基或芳烷基，X 是 -CHO，m 是 1，n 是 0 或 1，或其盐。 化合物 (I) 可用作骨质疏松症的预防/治疗剂。
• US5498728A
  申请人：——

  公开号：US5498728A

  公开（公告）日：1996-03-12
• US5639781A
  申请人：——

  公开号：US5639781A

  公开（公告）日：1997-06-17