4-tert.butyl-2(R)-isobutyl-3(S)-methylsuccinate | 135775-09-6

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 4-tert.butyl-2(R)-isobutyl-3(S)-methylsuccinate
• 英文别名: 2(R)-[1(S)-(tert-butyloxycarbonyl)ethyl]-4-methylpentanoic acid；(2R)-4-methyl-2-[(2S)-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]pentanoic acid
• CAS: 135775-09-6
• 化学式: C₁₃H₂₄O₄
• 分子量: 244.331
• InChiKey: VZSMNJBNPMXSLM-VHSXEESVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  17
• 可旋转键数：
  7
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  63.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-tert.butyl-2(R)-isobutyl-3(S)-methylsuccinate 在 甲酸 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 生成 (2R,3S)-N4-Benzyloxy-2-isobutyl-3-methyl-N1-((S)-methylcarbamoyl-phenyl-methyl)-succinamide
  参考文献：
  名称：

  Synthesis and biological evaluation of orally active matrix metalloproteinase inhibitors

  摘要：

  The synthesis and biological evaluation of orally active inhibitors of matrix metalloproteinase are reported. Modifications of the P2' position and the a-substituent of hydroxamic acid derivatives were carried out, and revealed that the P2' substituent influenced the MMP inhibitory activities in vitro and in plasma after oral administration. The hydroxamates with phenylglycine at the P2' position were absorbed well orally. Compound 15e, which exhibited the longest duration of inhibitory activity in plasma after oral administration among the phenylglycine derivatives (5a-5d, 15a, 15c, 15e), was evaluated in a rat adjuvant arthritis model. A reduction in hind foot pad swelling and improvements of some inflammatory parameters were demonstrated when the compound was administered orally. These results indicate the potential of MMP inhibitors for rheumatoid arthritis. (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0968-0896(97)00028-x
• 作为产物：
  描述：

  2(R)-Isobutyl-3(S)-methylsuccinic acid 1-<4(S)-(phenylmethyl)-2-oxooxazolidinamide>-4-(tert-butyl ester) 在 lithium hydroxide 、 双氧水 作用下， 以 四氢呋喃 为溶剂， 以76%的产率得到4-tert.butyl-2(R)-isobutyl-3(S)-methylsuccinate
  参考文献：
  名称：

  Synthesis and biological evaluation of orally active matrix metalloproteinase inhibitors

  摘要：

  The synthesis and biological evaluation of orally active inhibitors of matrix metalloproteinase are reported. Modifications of the P2' position and the a-substituent of hydroxamic acid derivatives were carried out, and revealed that the P2' substituent influenced the MMP inhibitory activities in vitro and in plasma after oral administration. The hydroxamates with phenylglycine at the P2' position were absorbed well orally. Compound 15e, which exhibited the longest duration of inhibitory activity in plasma after oral administration among the phenylglycine derivatives (5a-5d, 15a, 15c, 15e), was evaluated in a rat adjuvant arthritis model. A reduction in hind foot pad swelling and improvements of some inflammatory parameters were demonstrated when the compound was administered orally. These results indicate the potential of MMP inhibitors for rheumatoid arthritis. (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0968-0896(97)00028-x

文献信息

• NOVEL HYDROXAMIC ACID DERIVATIVES
  申请人：Daiichi Fine Chemical Co., Ltd.

  公开号：EP1179529A1

  公开（公告）日：2002-02-13

  Disclosed are compounds which have not only potent metalloproteinase-inhibiting activity but also amazingly excellent bioavailability and biological activity in vivo, including the property of being well absorbed via oral routes, thereby serving as useful pharmaceuticals, intermediates and processes for the production thereof. The disclosed compounds of the formula (I): wherein R1 is hydrogen, or a hydroxy-protecting group; R2 is hydrogen, or an amino-protecting group; R3, R7, and R8, which may be identical or different, are each independently hydrogen, hydroxy, unsubstituted or optionally substituted (C1-C6) alkyl, or unsubstituted or optionally substituted aryl-(C1-C6) alkyl; R4 is unsubstituted or optionally substituted (C1-C6) alkyl, or unsubstituted or optionally substituted aryl-(C1-C6) alkyl; R5 is hydrogen, unsubstituted or optionally substituted alkyl, unsubstituted or optionally substituted aralkyl, or a carboxy-protecting group; R6 is hydrogen, hydroxy, amino, and a group of the formula: -X-Y wherein X is oxygen, (C1-C6) alkylene or phenylene, Y is a group of the formula: -A-B or -B, wherein A is (C1-C6) alkylene, imino, and (C1-C6) alkyleneimino, and B is hydrogen, amino, amidino, sulfonyl, acylimidoyl, unsubstituted or optionally substituted imidazolyl, unprotected or optionally protected bis(phosphono)methyl or unprotected or optionally protected bis(phosphono)hydroxymethyl; or salts thereof are useful for pharmaceutical and/or veterinary compositions, particularly as metalloproteinase inhibitors which inhibit matrix metalloproteinases or tumor necrosis factor-α-converting enzymes (TNF-α convertases).

  本公开的化合物不仅具有强大的金属蛋白酶抑制活性，而且在体内具有出色的生物利用度和生物活性，包括经口途径吸收良好的特性，因此可用作有用的药物、中间体和生产过程。公开的化合物的结构式（I）如下：其中R1是氢或羟基保护基；R2是氢或氨基保护基；R3、R7和R8可以相同也可以不同，分别独立地是氢、羟基、未取代或可选择取代的（C1-C6）烷基，或未取代或可选择取代的芳基-（C1-C6）烷基；R4是未取代或可选择取代的（C1-C6）烷基，或未取代或可选择取代的芳基-（C1-C6）烷基；R5是氢、未取代或可选择取代的烷基、未取代或可选择取代的芳基烷基，或羧基保护基；R6是氢、羟基、氨基，以及下式的基团：-X-Y，其中X是氧、（C1-C6）烷基或苯基，Y是下式的基团：-A-B或-B，其中A是（C1-C6）烷基、亚胺基和（C1-C6）烷基亚胺基，B是氢、氨基、酰胺基、磺酰基、乙酰亚胺基，未取代或可选择取代的咪唑基，未保护或可选择保护的双（膦酸甲基）或未保护或可选择保护的双（膦酸羟甲基）；或其盐在制药和/或兽医组合物中具有用途，尤其作为抑制基质金属蛋白酶或肿瘤坏死因子-α转化酶（TNF-α转化酶）的金属蛋白酶抑制剂。
• Amino acid derivatives
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP0497192A2

  公开（公告）日：1992-08-05

  The invention provides compounds of the formula wherein A represents the group R1 represents hydrogen, amino, protected amino, acylamino or lower alkyl optionally substituted by aryl, hydroxy, protected hydroxy, amino, protected amino, acylamino, maleimido, succinimido, naphthalimido, 2,3-dihydro-1,3-dioxo-lH-benz[d,e]isoquinol-2-yl, carboxy, protected carboxy, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, carboxy-lower alkanoylamino, pyrrolidino or morpholino; R2 represents hydrogen or lower alkyl optionally substituted by aryl, amino, protected amino, di(lower alkyl)- amino, guanidino, carboxyl, protected carboxyl, carbamoyl, mono(lower alkyl) carbamoyl, di(lower alkyl)-carbamoyl, di(lower alkoxy)phosphinyl, dihydroxyphosphinyl, pyrrolidino, piperidino or morpholino; R3 represents hydrogen or lower alkyl optionally substituted by hydroxy, protected hydroxy, amino or protected amino; R4 represents hydrogen, hydroxy, lower alkoxy or benzyloxy; and R5 represents hydrogen or halogen and their pharmaceutically acceptable salts. These compounds are useful for the control or prevention of degenerative joint diseases or for the treatment of invasive tumours, atherosclerosis or multiple sclerosis. They can be manufactured according to known methods.

  本发明提供了式中化合物 其中 A 代表基团 R1代表氢、氨基、受保护氨基、酰氨基或任选被芳基取代的低级烷基、羟基、受保护羟基、氨基、受保护氨基、酰氨基、马来酰亚胺基、琥珀酰亚胺基、萘酰亚胺基、2、3-二氢-1,3-二氧代-lH-苯并[d,e]异喹啉-2-基、羧基、受保护的羧基、氨基甲酰基、单（低级烷基）氨基甲酰基、二（低级烷基）氨基甲酰基、二（低级烷基）氨基、羧基-低级烷酰氨基、吡咯烷基或吗啉基；R2 代表氢或被芳基、氨基、受保护氨基、二（低级烷基）-氨基、胍基、羧基、受保护羧基、氨基甲酰基、单（低级烷基）氨基甲酰基、二（低级烷基）-氨基甲酰基、二（低级烷氧基）膦酰基、二羟基膦酰基、吡咯烷基、哌啶基或吗啉基任选取代的低级烷基；R3 代表氢或任选被羟基、受保护羟基、氨基或受保护氨基取代的低级烷基；R4 代表氢、羟基、低级烷氧基或苄氧基；R5 代表氢或卤素及其药学上可接受的盐类。这些化合物可用于控制或预防退行性关节疾病，或治疗侵袭性肿瘤、动脉粥样硬化或多发性硬化症。它们可以按照已知的方法制造。
• US5304549A
  申请人：——

  公开号：US5304549A

  公开（公告）日：1994-04-19
• Synthesis and biological evaluation of orally active matrix metalloproteinase inhibitors
  作者：Ryoichi Hirayama、Minoru Yamamoto、Takahiro Tsukida、Konomi Matsuo、Yuji Obata、Fumio Sakamoto、Shoji Ikeda

  DOI：10.1016/s0968-0896(97)00028-x

  日期：1997.4

  The synthesis and biological evaluation of orally active inhibitors of matrix metalloproteinase are reported. Modifications of the P2' position and the a-substituent of hydroxamic acid derivatives were carried out, and revealed that the P2' substituent influenced the MMP inhibitory activities in vitro and in plasma after oral administration. The hydroxamates with phenylglycine at the P2' position were absorbed well orally. Compound 15e, which exhibited the longest duration of inhibitory activity in plasma after oral administration among the phenylglycine derivatives (5a-5d, 15a, 15c, 15e), was evaluated in a rat adjuvant arthritis model. A reduction in hind foot pad swelling and improvements of some inflammatory parameters were demonstrated when the compound was administered orally. These results indicate the potential of MMP inhibitors for rheumatoid arthritis. (C) 1997 Elsevier Science Ltd.