(R)-2-(2-(叔丁氧基)-2-氧代乙基)-4-甲基戊酸 | 112245-04-2

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 中文名称: (R)-2-(2-(叔丁氧基)-2-氧代乙基)-4-甲基戊酸
• 英文名称: (R)-2-(2-(tert-butoxy)-2-oxoethyl)-4-methylpentanoic acid
• 英文别名: t-butyl (R)-2-isobutylsuccinate；(2R)-2-[(tert-Butoxycarbonyl)methyl]-4-(methyl)pentanoic acid；(2R)-4-methyl-2-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]pentanoic acid
• CAS: 112245-04-2
• 化学式: C₁₂H₂₂O₄
• 分子量: 230.304
• InChiKey: NPIMKSLXCPUXPD-SECBINFHSA-N

物化性质

• 沸点：
  324.7±25.0 °C(Predicted)
• 密度：
  1.021±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：
  7
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  63.6
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H315,H319,H335
• 储存条件：
  存储条件：2-8℃，请保持干燥并密封。

反应信息

• 作为反应物：
  描述：

  (R)-2-(2-(叔丁氧基)-2-氧代乙基)-4-甲基戊酸 在 四(三苯基膦)钯 三正丁基氢锡 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 生成 [1S-(1β,2α,3α)]-1-[(2-(R)-isobutyl-4-tert-butoxycarboxyl)butanoyl]amino-3-(4-methoxyphenyl)-2-triisopropylsilyloxymethylcyclopropane
  参考文献：
  名称：

  设计，合成和评估带有环丙烷衍生肽模拟物作为P1'和P2'替代物的基质金属蛋白酶抑制剂。

  摘要：

  我们先前已经使用三取代的环丙烷作为肽替代物，以在许多重要酶的已知假肽抑制剂中诱导构象限制。环丙烷衍生的肽模拟物是新颖的，因为它们是少数以预定方式局部定向肽主链和氨基酸侧链的替代物。尽管已使用这些二肽等排体来模拟模仿chi（1）空间的gauche（-）构象的氨基酸侧链，但尚未评估它们将侧链投射为反方向的能力。作为朝着这个目标迈出的第一步，制备了构象受限的假肽8和10以及它们相应的柔性类似物9和11并作为基质金属蛋白酶（MMP）的抑制剂进行了测试。这些化合物是4和5的类似物 已知是有效的MMP抑制剂。相对于环丙烷上的肽主链取代基，预测8中的异丙基侧链和10中的芳环的反方向对应于5的P1'和P2'侧链与MMP结合时的已知方向。因此，明确设计了8和10，以探测MMP的S1'或S2'结合口袋的拓扑特征。他们还被设计来探索P1'-P2'酰胺基的重要性，该基团已知在几种MMP抑制剂复合物中形成高度保守的

  DOI：

  10.1021/jo0110698
• 作为产物：
  描述：

  4-甲基戊酸 在 正丁基锂 、 双氧水 、 sodium hexamethyldisilazane 、 三乙胺 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 19.0h， 生成 (R)-2-(2-(叔丁氧基)-2-氧代乙基)-4-甲基戊酸
  参考文献：
  名称：

  N-Thiazolylamide-based free fatty-acid 2 receptor agonists: Discovery, lead optimization and demonstration of off-target effect in a diabetes model

  摘要：

  Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp3 content (Fsp(3)) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (Delta LLE = 0.3, Delta Fsp(3) = 0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.

  DOI：

  10.1016/j.bmc.2018.09.015

文献信息

• N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S: In silico design, synthesis and biochemical characterization
  作者：Carina Lemke、Lorenzo Cianni、Christian Feldmann、Erik Gilberg、Jiafei Yin、Fernanda dos Reis Rocho、Daniela de Vita、Ulrike Bartz、Jürgen Bajorath、Carlos A. Montanari、Michael Gütschow

  DOI：10.1016/j.bmcl.2020.127420

  日期：2020.9

  A library of cathepsin S inhibitors of the dipeptide nitrile chemotype, bearing a bioisosteric sulfonamide moiety, was synthesized. Kinetic investigations were performed at four human cysteine proteases, i.e. cathepsins S, B, K and L. Compound 12 with a terminal 3-biphenyl sulfonamide substituent was the most potent (Ki = 4.02 nM; selectivity ratio cathepsin S/K = 5.8; S/L = 67) and 24 with a 4’-fluoro-4-biphenyl

  合成了具有生物等排性磺酰胺部分的二肽腈化学型的组织蛋白酶S抑制剂库。在四种人半胱氨酸蛋白酶，即组织蛋白酶S，B，K和L上进行了动力学研究。具有末端3-联苯磺酰胺取代基的化合物12最有效（K i = 4.02 nM；组织蛋白酶S / K的选择性比= 5.8； S / L = 67）和24用4'-氟-4-联苯基磺酰胺取代基的最有选择性的组织蛋白酶S抑制剂（ķ我= 35.5纳米;选择性比率组织蛋白酶S / K = 57; S / L = 31）。电脑 设计和生化评估强调了磺酰胺键对选择性的影响以及就组织蛋白酶S的相应结合位点而言P2和P3取代基的可能转换。
• Hydrazine derivatives
  申请人：Hoffmann-La Roche Inc..

  公开号：US06265446B1

  公开（公告）日：2001-07-24

  Hydrazine derivatives of the formula wherein R1 represents lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl, R2 represents heterocyclyl or NR5R6, R3 represents hydrogen, lower alkyl, halo-lower alkyl, cyano-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, heterocyclyl-lower alkyl, heterocyclylcarbonyl-lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, heteroaryl or aryl-lower alkyl, R4 represents lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl or a grouping of the formula -Z-aryl, -Z-heterocyclyl or —(CH2)n—, CH═CR7R8, R5 and R6 each independently represent hydrogen or lower alkyl, R7 and R8 each independently represent hydrogen or lower alkyl or R7 and R8 together represent lower alkylene in which one CH2 group is optionally replaced by a hetero atom, X and Z each represent a spacer group, and n stands for 0, 1 or 2, and their pharmaceutically acceptable salts thereof, inhibit the release of tumor necrosis factor alpha (TNF-&agr;) from cells. They can be used as medicaments, especially in the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory diseases, tumors, cachexia, cardiovascular diseases, fever, haemorrhage and sepsis.

  氢肼衍生物的化学式如下： 其中R1代表较低的烷基、较低的烯基、较低的环烷基、较低的环烷基-较低的烷基、芳基或芳基-较低的烷基，R2代表杂环烷基或NR5R6，R3代表氢、较低的烷基、卤代-较低的烷基、氰基-较低的烷基、羟基-较低的烷基、氨基-较低的烷基、较低的烷氧基-较低的烷基、较低的烷氧羰基-较低的烷基、较低的环烷基-较低的烷基、芳基-较低的烷基、杂环烷基-较低的烷基、杂环烷基羰基-较低的烷基、较低的烯基、较低的炔基、较低的环烷基、芳基、杂芳基或芳基-较低的烷基，R4代表较低的烷基、较低的烯基、较低的环烷基、较低的环烷基-较低的烷基或化学式-Z-芳基、-Z-杂环烷基或—(CH2)n—、CH═CR7R8的基团，R5和R6各自独立地代表氢或较低的烷基，R7和R8各自独立地代表氢或较低的烷基，或者R7和R8一起代表较低的烷基，其中一个 基团可选择性地被一个杂原子取代，X和Z各自代表一个间隔基团，n代表0、1或2，以及它们的药学上可接受的盐，可以抑制细胞释放肿瘤坏死因子α（TNF-α）。它们可用作药物，特别是用于治疗炎症和自身免疫性疾病、骨关节炎、呼吸道疾病、肿瘤、消瘦症、心血管疾病、发热、出血和败血症。
• Macrocyclic compounds as metalloprotease inhibitors
  申请人：DuPont Pharmaceuticals Company

  公开号：US06281352B1

  公开（公告）日：2001-08-28

  This invention relates to macrocyclic molecules which inhibit metalloproteinases, including aggrecanase, and the production of tumor necrosis factor (TNF). In particular, the compounds are inhibitors of metalloproteinases involved in tissue degradation and inhibitors of the release of tumor necrosis factor. The present invention also relates to pharmaceutical compositions comprising such compounds and to methods of using these compounds for the treatment of inflammatory diseases.

  这项发明涉及抑制金属蛋白酶（包括聚集素酶）和肿瘤坏死因子（TNF）产生的大环分子。具体来说，这些化合物是涉及组织降解的金属蛋白酶的抑制剂，也是肿瘤坏死因子释放的抑制剂。本发明还涉及包括这些化合物的药物组合物，以及使用这些化合物治疗炎症性疾病的方法。
• Compounds as inhibitor of tumor necrosis factor alpha release
  申请人：Hoffmann-La Roche Inc.

  公开号：US06239151B1

  公开（公告）日：2001-05-29

  The invention provides hydrazine derivatives of the formula wherein R1 is lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl; R2 is an acyl group derived from an &agr;-, &bgr;-, &ggr;- or &dgr;-(amino, hydroxy or thiol)carboxylic acid in which the amino, hydroxy or thiol group is optionally lower alkylated or the amino group is optionally acylated, sulphonylated or amidated and in which any functional group present in a side-chain is optionally protected, or a group of the formula Het(CH2)mCO; R3 is hydrogen, lower alkyl, halo-lower alkyl, cyano-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, heterocyclyl-lower alkyl, heterocyclylcarbonyl-lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl-lower alkenyl, aryl or heterocyclyl; R4 is lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl or a grouping of the formula X-aryl, X-heteroaryl or —(CH2)n—CH═CR5R6; R5 and R6 together are lower alkylene in which one CH2 group is optionally replaced by a hetero atom; Het is heterocyclyl; X is a spacer group; m is 0, 1, 2, 3 or 4; and n is 1 or 2; and their pharmaceutically acceptable salts inhibit the release of tumour necrosis factor alpha (TNF-&agr;) from cells. They can be used as medicaments, especially in the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory diseases, tumours, cachexia, cardiovascular diseases, fever, haemorrhage and sepsis.

  该发明提供了以下结构的肼衍生物 其中R1是较低的烷基、较低的烯基、较低的环烷基、较低的环烷基-较低的烷基、芳基或芳基-较低的烷基；R2是从α-、β-、γ-或δ-(氨基、羟基或硫醇)羧酸衍生的酰基，其中氨基、羟基或硫醇基可选择性地被较低的烷基化，或氨基可选择性地被酰化、磺酰化或酰胺化，并且侧链中存在的任何官能团可选择性地被保护，或者是Het(CH2)mCO的结构；R3是氢、较低的烷基、卤代较低的烷基、氰基-较低的烷基、氨基-较低的烷基、羟基-较低的烷基、较低的烷氧基-较低的烷基、较低的烷氧羰基-较低的烷基、较低的环烷基-较低的烷基、芳基-较低的烷基、杂环烷基-较低的烷基、杂环烷基羰基-较低的烷基、较低的烯基、较低的炔基、较低的环烷基、芳基-较低的烯基、芳基或杂环烷基；R4是较低的烷基、较低的烯基、较低的环烷基、较低的环烷基-较低的烷基或X-芳基、X-杂环芳基或—( )n—CH=CR5R6的结构；R5和R6一起是较低的烷基，其中一个 基可选择性地被杂原子取代；Het是杂环烷基；X是间隔基；m为0、1、2、3或4；n为1或2；它们的药学上可接受的盐抑制肿瘤坏死因子α(TNF-α)从细胞中释放。它们可用作药物，特别是用于治疗炎症和自身免疫性疾病、骨关节炎、呼吸道疾病、肿瘤、消瘦症、心血管疾病、发热、出血和败血症。
• Cyclic hydrazine derivatives
  申请人：Hoffmann-La Roche Inc.

  公开号：US06281363B1

  公开（公告）日：2001-08-28

  Hydrazine derivatives and their pharmaceutically acceptable salts useful for the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory diseases, tumors, cachexia, cardiovascular disease, fever, hemorrhage, and sepsis.

  肼衍生物及其药用盐可用于治疗炎症和自身免疫性疾病、骨关节炎、呼吸道疾病、肿瘤、消瘦症、心血管疾病、发热、出血和败血症。