(R)-2-(1,3-双(苄氧基)-1,3-二氧代丙-2-基)-4-甲基戊酸 | 155947-71-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: (R)-2-(1,3-双(苄氧基)-1,3-二氧代丙-2-基)-4-甲基戊酸
• 英文名称: (2R)-2-[2-(benzyloxy)-1-(benzyloxycarbonyl)-2-oxoethyl]-4-methylpentanoic acid
• 英文别名: benzyl 2<(benzyloxy)carbonyl>-3(R)-(hydroxycarbonyl)-5-methylhexanoate；benzyl (3R)-(2-benzyloxycarbonyl-3-carboxy-5-methyl)hexanoate；2-benzyloxycarbonyl-3R-isobutyl succinic acid 1-benzyl ester；2-benzyloxycarbonyl-3(R)-hydroxycarbonyl-5-methylhexanic acid benzyl ester；1,1,2-Pentanetricarboxylic acid, 4-methyl-, 1,1-bis(phenylmethyl) ester, (R)-；(2R)-2-[1,3-dioxo-1,3-bis(phenylmethoxy)propan-2-yl]-4-methylpentanoic acid
• CAS: 155947-71-0
• 化学式: C₂₃H₂₆O₆
• 分子量: 398.456
• InChiKey: NXIKOYYFZGXXFC-LJQANCHMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  29
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  89.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (R)-2-(1,3-双(苄氧基)-1,3-二氧代丙-2-基)-4-甲基戊酸 在 palladium on activated charcoal 哌啶 、 水 、 氢气 、 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 N,N-二甲基甲酰胺 为溶剂， 反应 21.0h， 生成 (3R)-5-methyl-3-[[(2S)-1-(methylamino)-1-oxo-3-(5,6,7,8-tetrahydronaphthalen-1-yl)propan-2-yl]carbamoyl]-2-methylidenehexanoic acid
  参考文献：
  名称：

  Inhibition of Membrane-Type 1 Matrix Metalloproteinase by Hydroxamate Inhibitors:  An Examination of the Subsite Pocket

  摘要：

  The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (Delta MT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an a-branched alkyl group is critical for the binding toward Delta MT1, while the introduction of a bulky group at the a-position of hydroxamic acid seems to diminish the activity against Delta MT1. Summation of the data on the sensitivity of Delta MT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of Delta MT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against Delta MT1 over MMP-1, but no selectivity between Delta MT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.

  DOI：

  10.1021/jm970404a
• 作为产物：
  描述：

  二苄基马来酸酯 在 potassium tert-butylate 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 96.0h， 生成 (R)-2-(1,3-双(苄氧基)-1,3-二氧代丙-2-基)-4-甲基戊酸
  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

• Fas LIGAND SOLUBILIZATION INHIBITOR
  申请人：KANEBO LTD.

  公开号：EP0848957A1

  公开（公告）日：1998-06-24

  A Fas ligand solubilization inhibitor which comprises, as the active ingredient, a compound of the generic formula (I) having a matrix metalloproteinase inhibitory activity or its pharmaceutically acceptable salt. The drug is useful in the prevention or treatment of diseases caused by solubilized Fas ligand, such as hepatitis, GVHD, AIDS, autoimmune diseases, etc.

  一种Fas配体溶解抑制剂，其活性成分为具有基本结构式（I）的化合物，具有基质金属蛋白酶抑制活性或其药用盐。该药物可用于预防或治疗由溶解的Fas配体引起的疾病，如肝炎、移植物抗宿主病、艾滋病、自身免疫疾病等。
• Use of the Ireland-Claisen Rearrangement in the Synthesis of 2,3-Disubstituted Succinates
  作者：Lisa M. Pratt、Stephen A. Bowles、Sally F. Courtney、Christopher Hidden、Christopher N. Lewis、Fionna M. Martin、Richard S. Todd

  DOI：10.1055/s-1998-1703

  日期：1998.5

  The Ireland-Claisen rearrangement was employed in a convenient one-pot stereoselective procedure for the synthesis of 2,3-disubstituted succinates (1).

  爱尔兰-克莱森重排法被用于一种方便的一锅立体选择性合成2,3-二取代琥珀酸酯（1）的方法中。
• Stereoselective Michael addition of benzylamines to homochiral methylenebutanedioates
  作者：Alexander N. Chernaga、Stephen G. Davies、Christopher N. Lewis、Richard S. Todd

  DOI：10.1039/a907060e

  日期：——

  The Michael addition of benzylamine to the homochiral methylenebutanedioate 10 gave an adduct 11 in good yield with high stereoselectivity. By performing the reaction in methanol the (2R,3R) diastereoisomer 11 was obtained in 88% de, which was increased to 98% de after recrystallisation of the primary amine derivative 13. The ratio of diastereoisomers was reversed by performing the reaction in aprotic solvents, with the (2R,3S) diastereoisomer 12 being obtained in 40% de in tetrahydrofuran. The Michael adduct 11 is formed under kinetic control. The primary amine 15 is a key intermediate in the synthesis of novel matrix metalloproteinase inhibitors.

  将苄胺与同手性的亚甲基丁二酸酯 10 进行迈克尔加成，可得到加合物 11，收率高，立体选择性强。在甲醇中进行反应后，得到的(2R,3R)非对映异构体 11 的立体选择性为 88%，在重结晶伯胺衍生物 13 后，立体选择性提高到 98%。在壬烷溶剂中进行反应时，非对映异构体的比例发生了逆转，在四氢呋喃中得到的(2R,3S)非对映异构体 12 的de 为 40%。迈克尔加合物 11 是在动力学控制下形成的。伯胺 15 是合成新型基质金属蛋白酶抑制剂的关键中间体。
• [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。
• [EN] CYTOSTATIC HYDROXAMIC ACID DERIVATIVES<br/>[FR] DERIVES CYTOSTATIQUES D'ACIDE HYDROXAMIQUE
  申请人：BRITISH BIOTECH PHARMACEUTICALS LIMITED

  公开号：WO1998011063A1

  公开（公告）日：1998-03-19

  (EN) Compounds of formula (1) wherein R4 is an ester or thioester group, and R, R1, R2 and R3 are as defined in the specification are inhibitors of rapidly dividing tumour cells.(FR) Composés représentés par la formule (1) dans laquelle R4 représente un groupe ester ou thioester et R, R1, R2 et R3 sont tels qu'ils sont définis dans le descriptif, ces composés étant des inhibiteurs de la division rapide de cellules cancéreuses.

  (中文) 公式（1）中，R4为酯或硫酯基团，R，R1，R2和R3如规范中所定义，是快速分裂肿瘤细胞的抑制剂。