(+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3,15-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3,15-dione
• 英文别名: 20-ethyl-6,7-difluoro-20-hydroxy-17-oxa-3,13-diazapentacyclo[11.9.0.02,11.04,9.015,21]docosa-1(22),2(11),3,5,7,9,15(21)-heptaene-14,18-dione
• 化学式: C₂₁H₁₆F₂N₂O₄
• 分子量: 398.366
• InChiKey: LFQCJSBXBZRMTN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  29
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  79.7
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  Boc-beta-丙氨酸 、 (+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3,15-dione 生成
  参考文献：
  名称：

  Comptothecin analogues, preparation methods therefor, use thereof as drugs, and pharmaceutical compositions containing said analogues

  摘要：

  该化合物的结构如下所示，其中取代基的定义如规范中所述，以及其无毒、药用可接受的盐，可用于治疗病毒感染、寄生虫病和癌症的治疗。

  公开号：

  US06339091B1
• 作为产物：
  描述：

  1-{3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl}-1-propanone 在 palladium on activated charcoal 盐酸 、 palladium diacetate 、 氢气 、 sodium acetate 、 tetra(n-tert-butyl)ammonium bromide 、 三苯基膦 、 三氟乙酸 、 锌 、 偶氮二甲酸二乙酯 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 60.17h， 生成 (+)-5-ethyl-9,10-difluoro-5-hydroxy-4,5,13,15-tetrahydro-1H,3H-oxepino[3',4':6,7]indolizino[1,2-b]quinoline-3,15-dione
  参考文献：
  名称：

  Homocamptothecins:  Synthesis and Antitumor Activity of Novel E-Ring-Modified Camptothecin Analogues

  摘要：

  Homocamptothecin (hCPT), a camptothecin (CPT) analogue with a seven membered beta-hydroxylactone which combines enhanced plasma stability and potent topoisomerase I (Topo I)-mediated activity, is an attractive template for the elaboration of new anticancer agents. Like CPT, hCPT carries an asymmetric tertiary alcohol and displays stereoselective inhibition of Topo I. The preparation and biological screening of racemic hCPT analogues are described. The 10 hCPTs tested were better Topo I inhibitors than CPT. Fluorinated hCPTs 23c,d,f,g were found to have potent cytotoxic activity on A427 and PC-3 tumor cell lines. Their cytotoxicity remained high on the K562adr and MCF7mdr cell. lines, which overexpress a functionally active P-glycoprotein. Fluorinated hCPTs were more efficacious in vivo than CPT on HT-29 xenografts. In this model, a tumor growth delay of 25 days was reached with hCPT 23g at a daily dose of 0.32 mg/kg, compared to 4 days with CPT at 0.625 mg/kg. Thus difluorinated hCPT 23g warrants further investigation as a novel Topo I inhibitor with high cytotoxicity toward tumor cells and promising in vivo efficacy.

  DOI：

  10.1021/jm980400l

文献信息

• AGENT FOR PREVENTING OR TREATING PANCREAS CANCER, OVARY CANCER OR LIVER CANCER CONTAINING NOVEL WATER-SOLUBLE PRODRUG
  申请人：CHUGAI SEIYAKU KABUSHIKI KAISHA

  公开号：EP1938823A1

  公开（公告）日：2008-07-02

  Preventive or therapeutic agents for pancreatic cancer, ovarian cancer, or liver cancer of the present invention comprise a water-soluble prodrug represented by formula 1 described below, or a pharmaceutically acceptable salt, or a hydrate or solvate of the prodrug or pharmaceutically acceptable salt, (wherein, R1 represents a hydrogen atom, or a C1-C6 alkyl group; W represents a divalent group comprising a tertiary amino group or a divalent group comprising a sulfonyl group, and Y represents a residue of a compound represented by Y-OH comprising an alcoholic hydroxyl group, wherein said Y-OH is a camptothecin, a taxane, or an anticancer nucleotide).

  预防或治疗胰腺癌、卵巢癌或肝癌的本发明药剂包括下述式子所代表的水溶性前药，或者前药的药用可接受盐，或者前药或药用可接受盐的水合物或溶剂化合物， （其中， R1代表氢原子，或者C1-C6烷基； W代表包含三级胺基团或含磺酰基团的二价基团，以及 Y代表由Y-OH所代表的化合物残基，包括含有醇羟基的醇羟基化合物残基，其中所述的Y-OH是一种喜树碱、紫杉醇或抗癌核苷酸）。
• New analogues of camptothecin, their use as medicaments and the pharmaceutical compositions containing them
  申请人：——

  公开号：US20030004150A1

  公开（公告）日：2003-01-02

  A compound of the formula 1 wherein the substituents are defined as in the specification which compounds are useful in the treatment of cancer.

  其中取代基如规范中所定义的化合物的化学式，这些化合物在癌症治疗中很有用。
• Method for identifying an enzyme to design anti-cancer compounds
  申请人：——

  公开号：US20030138864A1

  公开（公告）日：2003-07-24

  The present invention relates to a method for identification of enzymes that are preferentially expressed in certain tumor tissue as compared with rapidly growing normal cells or tissue, use of said enzymes for the compound design to generate an active anti-cancer substance selectively in tumor tissue, compounds designed based on said enzymes, their pharmaceutically acceptable salts as well as pharmaceutical composition thereof.

  本发明涉及一种酶的鉴定方法，该酶在某些肿瘤组织中与快速生长的正常细胞或组织相比表达优势，利用该酶设计化合物以在肿瘤组织中选择性地生成活性抗癌物质，基于该酶设计的化合物、其药学上可接受的盐以及药物组成物。
• [EN] OPTICALLY PURE CAMPTOTHECIN ANALOGUES, OPTICALLY PURE SYNTHESIS INTERMEDIATE AND METHOD FOR PREPARING SAME<br/>[FR] ANALOGUES OPTIQUEMENT PURS DE LA CAMPTOTHECINE, INTERMEDIAIRE DE SYNTHESE OPTIQUEMENT PUR ET SON PROCEDE DE PREPARATION
  申请人：SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES (S.C.R.A.S.)

  公开号：WO1999011646A1

  公开（公告）日：1999-03-11

  (EN) The invention concerns novel camptothecin analogues and in particular products corresponding to the following formulae: (+)-5-ethyl-9, 10-difluoro-5-hydroxy-4, 5,13,15-tetrahydro-1H, 3H-oxepino[3',4':6, 7]indolizino[1,2-b] quinoline-3,15-dione; (+)-1-[9-chloro-5- ethyl-5-hydroxy-10-methyl-3, 15-dioxo-4,5,13, 15-tetrahydro-1H,3H-oxepinol[3' ,4':6,7]indolizino [1,2-b]quinoline-12-ylmethyl] -4-methyl-hexahydropyridinium chloride; their application as medicine, pharmaceutical compositions containing them and their use for producing antitumoral, antiviral or antiparasitic medicines. The invention also concerns a novel synthesis intermediate of said products and a method for preparing said intermediate.(FR) L'invention concerne de nouveaux analogues de la camptothécine et en particulier les produits répondant aux formules suivantes: (+)-5-éthyl-9, 10-difluoro-5-hydroxy-4, 5,13,15-tétrahydro-1H, 3H-oxépino[3',4':6, 7]indolizino[1,2-b] quinoline-3,15-dione; (+)-chlorure de 1-[9-chloro-5- éthyl-5-hydroxy-10-méthyl-3, 15-dioxo-4,5,13, 15-tétrahydro-1H,3H-oxépino[3' ,4':6,7]indolizino [1,2-b]quinolin-12-ylméthyl] -4-méthyl-hexahydropyridinium; leur application comme médicaments, les compositions pharmaceutiques les renfermant et leur utilisation pour la réalisation de médicaments antitumoraux, antiviraux ou antiparasitaires. Elle concerne également un nouvel intermédiaire dans la synthèse des produits susmentionnés ainsi qu'un procédé de préparation dudit intermédiaire.

  本发明涉及新型喜树碱类似物，特别是以下配方的产物：(+)-5-乙基-9,10-二氟-5-羟基-4,5,13,15-四氢-1H，3H-氧-3'，4'：6,7]吲哚并[1,2-b]喹啉-3,15-二酮；(+)-1-[9-氯-5-乙基-5-羟基-10-甲基-3,15-二氧-4,5,13,15-四氢-1H，3H-氧-3'，4'：6,7]吲哚并[1,2-b]喹啉-12-基甲基]-4-甲基-六氢吡啶盐酸盐；它们作为药物的应用，含有它们的制药组合物以及它们用于制备抗肿瘤，抗病毒或抗寄生虫药物的用途。本发明还涉及所述产品的新合成中间体以及制备所述中间体的方法。
• Novel Water-Soluble Prodrugs
  申请人：Umeda Isao

  公开号：US20080015157A1

  公开（公告）日：2008-01-17

  An objective of the present invention is to provide water-soluble prodrugs that can be administered parenterally, and which show excellent water solubility and small interspecies or individual differences and are rapidly converted to the active form by chemical conversion. This invention provides water-soluble prodrugs represented by formula (1), or pharmaceutically acceptable salts, or hydrates or solvates thereof, (wherein, R 1 represents a hydrogen atom, or C1-C6 alkyl group; W represents a divalent group comprising a tertiary amino group or sulfonyl group; and Y represents a residue of a compound represented by Y—OH comprising an alcoholic hydroxyl group).

  本发明的目的是提供可经由肌肉注射给药的水溶性前药，其具有优异的水溶性、小的种间或个体差异，并且可通过化学转化迅速转化为活性形式。本发明提供了由式(1)表示的水溶性前药，或其药学上可接受的盐、水合物或溶剂化物，其中R1代表氢原子或C1-C6烷基；W代表包含三级胺基或磺酰基的二价基团；Y代表由Y-OH表示的化合物的残基，该化合物包括醇羟基。