(2S,3R)-3-isobutyl-2-hydroxysuccinic acid | 157604-22-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羟基酸及其衍生物
• 英文名称: (2S,3R)-3-isobutyl-2-hydroxysuccinic acid
• 英文别名: Butanedioic acid, 2-hydroxy-3-(2-methylpropyl)-, (2S,3R)-；(2S,3R)-2-hydroxy-3-(2-methylpropyl)butanedioic acid
• CAS: 157604-22-3
• 化学式: C₈H₁₄O₅
• 分子量: 190.196
• InChiKey: JTQSCAHKZKQYOM-RITPCOANSA-N

物化性质

• 沸点：
  319.2±27.0 °C(Predicted)
• 密度：
  1.280±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  13
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  94.8
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2,2-二甲氧基丙烷 、 (2S,3R)-3-isobutyl-2-hydroxysuccinic acid 在 对甲苯磺酸 作用下， 反应 2.5h， 以83%的产率得到(2R)-2-[(4S)-2,2-二甲基-5-氧代-1,3-二氧戊环-4-基]-4-甲基戊酸
  参考文献：
  名称：

  Matrix Metalloproteinase Inhibitors:  A Structure−Activity Study

  摘要：

  Modifications around the dipeptide-mimetic core of a hydroxamic acid based matrix metalloproteinase inhibitor were studied. These variations incorporated a variety of natural, unnatural, and synthetic amino acids in addition to modifications of the P1' and P3' substituents. The results of this study indicate the following structural requirements: (1) Two key hydrogen bonds must be present between the enzyme and potent substrates. (2) Potent inhibitors must possess strong zinc-binding functionalities. (3) The potential importance of the hydrophobic group at position R3 as illustrated by its ability to impart greater relative potency against stromelysin when larger hydrophobic groups are used. (4) Requirements surrounding the nature of the amino acid appear to be more restrictive for stromelysin than for neutrophil collagenase, 72 kDa gelatinase, and 92 kDa gelatinase. These requirements may involve planar fused-ring aryl systems and possibly hydrogen-bonding capabilities.

  DOI：

  10.1021/jm970494j
• 作为产物：
  描述：

  (2S,3R)-3-methallyl-2-hydroxysuccinic acid dimethyl ester 在 palladium on activated charcoal sodium hydroxide 、 氢气 作用下， 以 甲醇 为溶剂， 反应 26.0h， 生成 (2S,3R)-3-isobutyl-2-hydroxysuccinic acid
  参考文献：
  名称：

  Matrix Metalloproteinase Inhibitors:  A Structure−Activity Study

  摘要：

  Modifications around the dipeptide-mimetic core of a hydroxamic acid based matrix metalloproteinase inhibitor were studied. These variations incorporated a variety of natural, unnatural, and synthetic amino acids in addition to modifications of the P1' and P3' substituents. The results of this study indicate the following structural requirements: (1) Two key hydrogen bonds must be present between the enzyme and potent substrates. (2) Potent inhibitors must possess strong zinc-binding functionalities. (3) The potential importance of the hydrophobic group at position R3 as illustrated by its ability to impart greater relative potency against stromelysin when larger hydrophobic groups are used. (4) Requirements surrounding the nature of the amino acid appear to be more restrictive for stromelysin than for neutrophil collagenase, 72 kDa gelatinase, and 92 kDa gelatinase. These requirements may involve planar fused-ring aryl systems and possibly hydrogen-bonding capabilities.

  DOI：

  10.1021/jm970494j

文献信息

• [EN] NATURAL AMINO ACID DERIVATIVES AS METALLOPROTEINASE INHIBITORS<br/>[FR] DERIVES D'ACIDES AMINES NATURELS UTILISES COMME INHIBITEURS DE LA METALLOPROTEINASE
  申请人：BRITISH BIOTECH PHARMACEUTICALS LIMITED

  公开号：WO1994002446A1

  公开（公告）日：1994-02-03

  (EN) Compounds of Formula (I) wherein R2 represents a group R6-A- wherein A represents a divalent straight or branched, saturated or unsaturated hydrocarbon chain of up to 6 C atoms which may be interrupted by an O or S atom, and R6 represents hydrogen or an optionally substituted phenyl, cycloalkyl or cycloalkenyl group; R3 represents the characterising side chain of a natural alpha amino acid other than proline, and in which any polar substituents are optionally protected; R4 represents hydrogen or methyl; R5 represents hydrogen, C1-C6 alkyl or a group D-(C1-C6 alkyl) wherein D represents hydroxy, (C1-C6)alkoxy, (C1-C6)alkylthio, acylamino, optionally substituted phenyl, or a heterocyclic group, NH2, or a mono- or di-(C1-C6 alkyl) amine or a heterocyclic group; or R3 and R5 taken together represent a divalent, saturated or unsaturated hydrocarbon chain of from 8-14 C atoms, which may be interrupted by an O, S or N heteroatom, or a salt, solvate or hydrate thereof.(FR) On décrit des composés de la formule (I) où R2 représente un groupe R6-A- où A représente une chaîne hydrocarbonée divalente droite ou ramifiée, saturée ou non, allant jusqu'à 6 atomes de C et pouvant être interrompue par un atome de O ou S, et R6 représente hydrogène ou un groupe phényle, cycloalkyle, ou cycloalcényle éventuellement substitué; R3 représente la chaîne latérale caractéristique d'un acide aminé alpha naturel, autre que la proline, où tout substituant polaire est éventuellement protégé; R4 représente hydrogène ou méthyle; R5 représente hydrogène, C1-C6 alkyle ou un groupe D-(C1-C6 alkyle) où D représente hydroxy, (C1-C6)alcoxy, (C1-C6)alkylthio, acylamino, phényle éventuellement substitué ou un groupe hétérocyclique, NH2, ou une mono- ou di-(C1-C6 alkyle) amine ou un groupe hétérocyclique; ou bien R3 et R5 représentent conjointement une chaîne hydrocarbonée divalente, saturée ou non, allant de 8 à 14 atomes de C, qui peut être interrompue par un hétéroatome de O, S, ou N. On décrit aussi un des sels, solvats ou hydrates de ces composés.

  化合物的化学式为(I)，其中R2代表一个R6-A-基团，其中A代表一个直链或支链、饱和或不饱和的双价碳氢链，最多可达6个碳原子，其中可以插入O或S原子，而R6代表氢或一个可选择替换的苯基、环烷基或环烯基基团；R3代表一种天然α氨基酸的特征侧链，不包括脯氨酸，其中任何极性取代基均可选择保护；R4代表氢或甲基；R5代表氢、C1-C6烷基或一个D-(C1-C6烷基)基团，其中D代表羟基、(C1-C6)氧烷基、(C1-C6)硫烷基、酰胺基、可选择取代的苯基或一个杂环基团、NH2或一种单烷基或二烷基胺或一个杂环基团；或者R3和R5共同代表一个双价的、饱和或不饱和的碳氢链，长度为8-14个碳原子，其中可以插入一个O、S或N杂原子，或其盐、溶剂化合物或水合物。
• [EN] METALLOPROTEINASE INHIBITORS<br/>[FR] INHIBITEURS DE METALLOPROTEINASE
  申请人：BRITISH BIOTECH PHARMACEUTICALS LIMITED

  公开号：WO1995019956A1

  公开（公告）日：1995-07-27

  (EN) Matrix metalloproteinase inhibiting compounds of formula (I), wherein X is a -CO2H or -CONHOH group; R4 is a phenyl or 5- or 6-membered heteroaryl ring wherein any ring nitrogen atom may be oxidised as an N-oxide, which may be optionally fused to a benzene ring or to a 5-, 6- or 7-membered heterocyclic ring, and wherein any of the rings may be optionally substituted.(FR) Composés inhibiteurs de métalloprotéinase matricielle représentés par la formule (I) dans laquelle X représente un groupe -CO2H ou -CONHOH, R4 représente un noyau phényle ou hétéroaryle à 5 ou 6 éléments dans lequel tout atome d'azote du noyau peut être oxydé pour former un N-oxyde, et qui peut être éventuellement fusionné à un noyau benzènique ou à un noyau hétérocyclique à 5, 6 ou 7 éléments et dans lequel chacun des noyaux peut être éventuellement substitué.

  (I)式中的基质金属蛋白酶抑制化合物，其中X是-CO2H或-CONHOH基团；R4是苯基或5-或6-成员杂环环，其中任何环氮原子均可氧化为N-氧化物，可选择性地与苯环或5-、6-或7-成员杂环环融合，并且任何环均可选择性地被取代。
• Hydrazine derivatives
  申请人：Hoffmann-La Roche Inc.

  公开号：US06235787B1

  公开（公告）日：2001-05-22

  Hydrazine derivatives of the formula wherein Y is CO or SO2; R1 is lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl; R2 is lower alkyl, halo-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl or aryl when Y is SO2 and is lower alkyl, halo-lower alkyl, lower alkoxy, lower alkoxycarbonyl, acyl, lower cycloalkyl, aryl, aryl-lower alkyl, aryl-lower alkoxy or NR5R6 when Y is CO; and R3 is hydrogen, lower alkyl optionally substituted by cyano, amino, hydroxy, lower alkoxy, lower alkoxycarbonyl, heterocyclyl or heterocyclylcarbonyl, lower alkenyl, lower alkynyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl, aryl or heterocyclyl; or R2 and R3 together form the residue of a 5-, 6- or 7-membered cyclic amide, cyclic imide, cyclic sulphonamide or cyclic urethane group; R4 is lower alkyl, hydroxy-lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl or a group of the formula X-aryl, X-heteroaryl or —(CH2)1-2—CH═CR7R8; X is a spacer group; R5 and R6 each individually are hydrogen, lower alkyl or aryl-lower alkyl; and R7 and R8 together represent a lower alkylene group in which one methylene group is optionally replaced by a hetero atom; and their pharmaceutically acceptable salts inhibit not only the release of tumour necrosis factor (TNF-&agr;) and transforming growth factor (TGF-&agr;) from cells, but also keratinocyte proliferation. They are useful as medicaments, especially for the treatment of inflammation, fever, hemorrhage, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis or psoriasis.

  该公式的肼衍生物，其中Y为CO或SO2; R1为低碳基，低烯基，低环烷基，低环烷基-低碳基，芳基或芳基-低碳基; 当Y为SO2时，R2为低碳基，卤代低碳基，芳基-低碳基，芳基-低烯基或芳基; 当Y为CO时，R2为低碳基，卤代低碳基，低烷氧基，低烷氧羰基，酰基，低环烷基，芳基，芳基-低碳基，芳基-低烷氧基或NR5R6; R3为氢，低碳基，可选地被氰基，氨基，羟基，低烷氧基，低烷氧羰基，杂环烷基或杂环烷基羰基取代的低碳基，低烯基，低炔基，低环烷基，低环烷基-低碳基，芳基-低碳基，芳基-低烯基，芳基或杂环烷基取代的低碳基; 或R2和R3一起形成5、6或7元环酰胺、环内酰亚胺、环磺酰胺或环脲基的残基; R4为低碳基，羟基-低碳基，低烯基，低环烷基，低环烷基-低碳基或公式X-芳基，X-杂环芳基或—（CH2）1-2—CH═CR7R8的基团; X为间隔基团; R5和R6各自为氢、低碳基或芳基-低碳基; R7和R8一起表示一个低碳亚基，其中一个亚甲基团可选地被杂原子取代; 以及它们的药学上可接受的盐不仅抑制肿瘤坏死因子（TNF-&agr;）和转化生长因子（TGF-&agr;）的释放，而且抑制角质细胞增殖。它们可用作药物，特别是用于治疗炎症，发热，出血，败血症，类风湿性关节炎，骨关节炎，多发性硬化或银屑病。
• Dioxolane intermediates
  申请人：BRITISH BIOTECH PHARMACEUTICALS LIMITED

  公开号：EP0754688A2

  公开（公告）日：1997-01-22

  Compounds of formula (V) : wherein R2 represents a group R6-A- wherein A represents a divalent straight or branched, saturated or unsaturated hydrocarbon chain of up to 6 C atoms which may be interrupted by an O or S atom, and R6 represents hydrogen or an optionally substituted phenyl, cycloalkyl or cycloalkenyl group; and the groups R12 and R13 are hydrogen, alkyl, phenyl or substituted phenyl; and activated derivatives thereof are useful as intermediates in the preparation of matrix metalloproteinase inhibitors..

  式 (V) 的化合物： 其中 R2 代表基团 R6-A-，其中 A 代表由多达 6 个 C 原子组成的二价直链或支链、饱和或不饱和烃链，可被 O 原子或 S 原子打断，R6 代表氢或任选取代的苯基、环烷基或环烯基；基团 R12 和 R13 为氢、烷基、苯基或取代苯基；其活化衍生物可用作制备基质金属蛋白酶抑制剂的中间体。
• NOVEL METALLOPROTEINASE INHIBITORS
  申请人：FUJI YAKUHIN KOGYO KABUSHIKI KAISHA

  公开号：EP1038864A1

  公开（公告）日：2000-09-27

  Compounds having not only a high metalloproteinase inhibitory activity but also remarkably improved medicinal applicability in vivo (oral absorbability, etc.) and biological activities and thus being useful a drugs; intermediates in the process for producing the same; and a process for producing these compounds. Specifically, compounds represented by general formula (I) or salts thereof, useful in medicinal and/or veterinary compositions, in particular; metalloproteinase inhibitors inhibiting matrix metalloproteinases and tumor necrosis factor-α (TNF-α) convertase; wherein R1 represents hydrogen or a hydroxy-protective group; R2 represents hydrogen or an amino-protective group; R3, R7 and R8 represent each hydrogen, hydroxy, alkyl, etc.; R4 represents alkyl, arylalkyl, etc.; R5 and R6 are the same or different and each represents hydrogen, alkyl, cycloalkyl, etc.; and R9 represents hydrogen, hydroxy, amino, etc.

  不仅具有较高的金属蛋白酶抑制活性，而且具有明显改善的体内药用性（口服吸收性等）和生物活性，因而可用作药物的化合物；生产这些化合物的中间体；以及生产这些化合物的工艺。具体地说，通式(I)代表的化合物或其盐，可用于药物和/或兽药组合物，特别是；金属蛋白酶抑制剂，可抑制基质金属蛋白酶和肿瘤坏死因子-α（TNF-α）转化酶；其中 R1 代表氢或羟基保护基团；R2 代表氢或氨基保护基团；R3、R7 和 R8 分别代表氢、羟基、烷基等；R4 代表烷基、氨基保护基团、羟基、烷基等。R4 代表烷基、芳烷基等；R5 和 R6 相同或不同，各自代表氢、烷基、环烷基等；R9 代表氢、羟基、氨基等。