methyl (2S)-2-(benzyloxycarbonylamino)-4-(tetrazol-5-yl)butyrate | 65882-90-8

• 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: methyl (2S)-2-(benzyloxycarbonylamino)-4-(tetrazol-5-yl)butyrate
• 英文别名: methyl (2S)-2-benzyloxycarbonylamino-4-(5-tetrazolyl)butyrate；methyl L-2-benzyloxycarbonylamino-4-(5-tetrazolyl)butanoate；methyl (2S)-2-benzyloxycarbonylamino-4-(tetrazole-5-yl)butyrate；methyl (2S)-2-benzyloxycarbonylamino-4-(tetrazol-5-yl)butyrate；methyl (2S)-2-(phenylmethoxycarbonylamino)-4-(2H-tetrazol-5-yl)butanoate
• CAS: 65882-90-8
• 化学式: C₁₄H₁₇N₅O₄
• 分子量: 319.32
• InChiKey: NLFPDMRYQJELPQ-NSHDSACASA-N

物化性质

• 密度：
  1.332±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  23
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  119
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  methyl (2S)-2-(benzyloxycarbonylamino)-4-(tetrazol-5-yl)butyrate 在 10percent Pd/C 氢气 、 三乙胺 、 焦碳酸二乙酯 作用下， 以 乙醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 28.0h， 生成 methyl (2S)-2-{4-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzamido}-4-{1[((1R)-1-(methoxycarbonyl)ethyl)carbamoylmethyl]tetrazol-5-yl}butyrate
  参考文献：
  名称：

  Design and Synthesis of Cyclopenta[g]quinazoline-Based Antifolates as Inhibitors of Thymidylate Synthase and Potential Antitumor Agents^,

  摘要：

  Following the development of raltitrexed, the synthesis of nonpolyglutamatable inhibitors of TS that do not use the reduced folate carrier (RFC) for cellular entry should provide compounds which overcome mechanisms of resistance to folate-based inhibitors of TS that are associated with decreased/altered folylpolyglutamate synthetase (FPGS) expression and/or an impaired RFC. Examination of a computer graphics model of the humanized Escherichia coli TS enzyme with quinazoline inhibitors of TS, such as 1 bound in the active site of the enzyme, suggested that conformational restriction introduced by bridging the C9 with C7 to form a pentacycle may be beneficial for binding to TS. That led to the synthesis of a series of potent cyclopenta[g]quinazoline-based inhibitors of the enzyme in which the glutamyl residue associated with classical antifolates was replaced with a variety of glutamate-derived ligands; the most potent inhibitor being the L-Glu-gamma-D-GluT(alpha) derivative 7j. In the mouse L1210:1565 cell line (mutant RFC), the majority of these compounds had activity equal or only slightly greater compared with the parental L1210 cell line, indicating a reduced dependence on the RFC for cellular uptake in the L1210 cell line.

  DOI：

  10.1021/jm991119p
• 作为产物：
  描述：

  (S)-methyl 2-(((benzyloxy)carbonyl)amino)-4-cyanobutanoate 在 盐酸 、 三甲基甲硅烷基锡 作用下， 生成 methyl (2S)-2-(benzyloxycarbonylamino)-4-(tetrazol-5-yl)butyrate
  参考文献：
  名称：

  非谷氨酸型吡咯并[2,3-d]嘧啶类抗叶酸药。I：含有谷氨酸的四唑同类物的吡咯并[2，3-d]嘧啶抗叶酸酯的合成和生物学性质。

  摘要：

  N- [4- [3-（2,4-二氨基-7H-吡咯并[2,3-d]嘧啶-5-基）丙基]苯甲酰基]的谷氨酸部分的α-或γ-羧基用1H-四唑环取代-L-谷氨酸（1b，TNP-351）及其相关化合物（1a），所得化合物对二氢叶酸还原酶（DHFR）和鼠类纤维肉瘤Meth A的生长具有抑制作用检查细胞。γ-四唑类似物（2）被发现比TNP-351更有效的DHFR抑制剂，并强烈抑制Meth A细胞的生长。另一方面，尽管α-四唑类似物（3）的DHFR抑制活性与TNP-351相当，但它们对Meth A细胞的活性却低得多。这些发现表明，α-羧基在通过减少的叶酸载体有效吸收中起着重要作用，

  DOI：

  10.1248/cpb.43.230

文献信息

• Anti-cancer compounds
  申请人：British Technology Group Limited

  公开号：US05747499A1

  公开（公告）日：1998-05-05

  Cyclopentaquinazoline of the formula (I): ##STR1## wherein R.sup.1 is hydrogen, amino, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 hydroxyalkyl or C.sub.1-4 fluoroalkyl; wherein R.sup.2 is hydrogen, C.sub.1-4 alkyl, C.sub.3-4 alkenyl, C.sub.3-4 alkynyl, C.sub.2-4 hydroxyalkyl, C.sub.2-4 halogenoalkyl or C.sub.1-4 cyanoalkyl; Ar.sup.1 is phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl which may optionally bear one or two substituents selected from halogeno, hydroxy, amino, nitro, cyano, trifluoromethyl, C.sub.1-4 alkyl and C.sub.1-4 alkoxy; and wherein R.sup.3 is a group of the formula: --A.sup.1 --Ar.sup.2 --A.sup.2 --Y.sup.1 in which A.sup.1, A.sub.2, Y.sup.1 and Ar.sub.2 are defined in claim 1; or a pharmaceutically acceptable salt or ester there of are of therapeutic value particularly in the treatment of cancer.

  公式（I）的环戊喹唑啉：其中R.sup.1是氢，氨基，C.sub.1-4烷基，C.sub.1-4烷氧基，C.sub.1-4羟基烷基或C.sub.1-4氟烷基；其中R.sup.2是氢，C.sub.1-4烷基，C.sub.3-4烯基，C.sub.3-4炔基，C.sub.2-4羟基烷基，C.sub.2-4卤代烷基或C.sub.1-4氰基烷基；Ar.sup.1是苯基，噻吩二基，噻唑二基，吡啶二基或嘧啶二基，可以选择性地带有一个或两个取代基，所述取代基选自卤素，羟基，氨基，硝基，氰基，三氟甲基，C.sub.1-4烷基和C.sub.1-4烷氧基；其中R.sup.3是以下式的基团：--A.sup.1--Ar.sup.2--A.sup.2--Y.sup.1，其中A.sup.1，A.sub.2，Y.sup.1和Ar.sub.2如权利要求1中定义；或其药学上可接受的盐或酯在治疗癌症方面具有治疗价值。
• Tricyclic compounds with pharmaceutical activity
  申请人：Zeneca Limited

  公开号：US05789417A1

  公开（公告）日：1998-08-04

  The invention relates to tricyclic compounds of formula (I) ##STR1## wherein R.sup.1 is hydrogen, amino, (1-4C)alkyl, (1-4C)alkoxy, hydroxy-(1-4C)alkyl or fluoro-(1-4C)alkyl; R.sup.2 is hydrogen, (1-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, hydroxy-(2-4C)alkyl, halogeno-(2-4C)alkyl or cyano-(1-4C)alkyl; Ar is optionally-substituted phenylene, thiophenediyl, thiazolediyl, pyridinediyl or pyrimidinediyl; and R.sup.3 includes a group of the formula --NHCH(CO.sub.2 H)--A.sup.1 --Y.sup.1 wherein A.sup.1 is (1-6C)alkylene and Y.sup.1 is carboxy, tetrazol-5-yl, N-\x9b(1-4C)alkylsulphonyl!carbamoyl, N(phenylsulphonyl)carbamoyl, tetrazol-5-ylthio, tetrazol-5-ylsulphinyl or tetrazol-5-ylsulphonyl; or pharmaceutically-acceptable salts or esters thereof; to processes for their manufacture; to pharmaceutical compositions containing them; and to their use as anti-cancer agents.

  该发明涉及式(I)的三环化合物，其中R.sup.1为氢、氨基、(1-4C)烷基、(1-4C)烷氧基、羟基-(1-4C)烷基或氟代-(1-4C)烷基；R.sup.2为氢、(1-4C)烷基、(3-4C)烯基、(3-4C)炔基、羟基-(2-4C)烷基、卤代-(2-4C)烷基或氰基-(1-4C)烷基；Ar为选择性取代的苯基、噻吩二基、噻唑二基、吡啶二基或嘧啶二基；R.sup.3包括式--NHCH(CO.sub.2 H)--A.sup.1 --Y.sup.1的基团，其中A.sup.1为(1-6C)烷基，Y.sup.1为羧基、噻唑-5-基、N-(1-4C)烷基磺酰基!氨基甲酰基、N(苯基磺酰基)氨基甲酰基、噻唑-5-基硫基、噻唑-5-基亚硫基或噻唑-5-基磺基；或其药学上可接受的盐或酯；以及制备它们的方法；含有它们的药物组合物；以及它们作为抗癌剂的用途。
• Synthesis of novel quinazoline-based antifolates with modified glutamate side chains as potential inhibitors of thymidylate synthase and antitumour agents
  作者：Vassilios Bavetsias、Graham M.F. Bisset、Rosemary Kimbell、F.Thomas Boyle、Ann L. Jackman

  DOI：10.1016/s0040-4020(97)00851-x

  日期：1997.9

  7-dimethyl-4-oxo-6-quinazolinyl)-methyl]-N-prop-2-ynylamino]-2-fluorobenzoic acid (24), and finally removal of the protecting groups. The resulting quinazoline-based antifolates with modified glutamate side chains, and in particular, the tetrazole derivatives 26 and 29 displayed potent TS and L1210 cell growth inhibitory activities (e.g., for 26: TS IC50 = 2.4 nM, L1210 IC50 = 1.3 μM).

  合成了几种新型的抗叶酸剂，它们是2-脱氨基-2-甲基-N 10-炔丙基-5,8-二氮杂壬酸的衍生物，作为胸苷酸合酶（TS）的抑制剂和抗肿瘤剂。这是通过首先开发通往关键中间体Glu-Ome-γ-ψ[CSNH] Glu（OEt）-OEt（8），Glu-OBu t -γ -ψ[CH 2 NH] Glu（OBu t）-的途径来完成的将OBu t（16），Glu-OMe-γ-ψ[CN 4 ] Gly-OMe（23）及其2,5-二取代的区域异构体（22），然后将DEPC偶联至4- [ N- [3,4-二氢-2-甲基-4-氧代-6-喹唑啉基）-甲基] -N-丙-2-炔基氨基]苯甲酸（9）或4- [ N -[（3,4-二氢-2,7-二甲基-4-氧代-6-喹唑啉基）-甲基] -N-丙-2-炔基氨基] -2-氟苯甲酸（24），最后除去保护基。所得的具有修饰的谷氨酸侧链的基于喹唑啉的抗叶酸剂，尤其是四唑衍生物2
• [EN] (SUBSTITUTED)ACYL DIPEPTIDYL INHIBITORS OF THE ICE/ced-3 FAMILY OF CYSTEINE PROTEASES<br/>[FR] INHIBITEURS ACYLE(SUBSTITUE) DIPEPTIDYLE DE LA FAMILLE ICE/ced-3 DES CYSTEINES PROTEASES
  申请人：IDUN PHARMACEUTICALS INC

  公开号：WO2000023421A1

  公开（公告）日：2000-04-27

  This invention is directed to novel (substituted)acyl dipeptidyl ICE/ced-3 family inhibitor compounds. The invention is also directed to pharmaceutical compositions containing these compounds, as well as the use of such compositions in the treatment of patients suffering inflammatory, autoimmune and neurodegenerative diseases, for the prevention of ischemic injury, and for the preservation of organs that are to undergo a transplantation procedure.

  本发明涉及新型（取代）酰基二肽酶ICE / ced-3家族抑制剂化合物。本发明还涉及含有这些化合物的制药组合物，以及将这些组合物用于治疗患有炎症，自身免疫和神经退行性疾病的患者，预防缺血性损伤，并用于保护即将进行移植手术的器官。
• (Substituted)Acyl dipeptidyl inhibitors of the ICE/ced-3 family of cysteine proteases
  申请人：——

  公开号：US20040259804A1

  公开（公告）日：2004-12-23

  This invention is directed to novel (substituted) acyl dipeptidyl ICE/ced-3 family inhibitor compounds. The invention is also directed to pharmaceutical compositions containing these compounds, as well as the use of such compositions in the treatment of patients suffering inflammatory, autoimmune and neurodegenerative diseases, for the prevention of ischemic injury, and for the preservation of organs that are to undergo a transplantation procedure.

  本发明涉及新型（取代的）酰基二肽酰 ICE/ced-3 家族抑制剂化合物。本发明还涉及含有这些化合物的制药组合物，以及在治疗患有炎症、自身免疫和神经退行性疾病的患者、预防缺血性损伤以及保护即将进行移植手术的器官等方面使用这种组合物的用途。