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PRODUCTION METHOD FOR TETRAHYDROISOQUINOLINE RING-CONTAINING COMPOUND

外国特許コード F200010162
整理番号 (S2018-0458-N0)
掲載日 2020年6月3日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2019JP009128
国際公開番号 WO 2019176732
国際出願日 平成31年3月7日(2019.3.7)
国際公開日 令和元年9月19日(2019.9.19)
優先権データ
  • 特願2018-048897 (2018.3.16) JP
  • 特願2018-144906 (2018.8.1) JP
発明の名称 (英語) PRODUCTION METHOD FOR TETRAHYDROISOQUINOLINE RING-CONTAINING COMPOUND
発明の概要(英語) [Problem] To provide a production method capable of easily synthesizing a compound having a structure in which a plurality of tetrahydroisoquinoline rings are linked together, using a reduced number of steps.
[Solution] It was found that a non-naturally-occurring intermediate compound having a pentacyclic backbone in which tetrahydroisoquinoline rings are linked together, can be quickly one-pot synthesized by reacting a tyrosine derivative with a non-naturally-occurring aldehyde substrate having a particular structure by using a nonribosomal peptide synthetase. Also, it was found that saframycins and analogs thereof can be easily and highly efficiently obtained using a non-naturally-occurring aldehyde substrate having a particular structure, where adaptiveness to an enzyme reaction is ensured, and chemical transformation of the intermediate after formation of the backbone can be freely performed.
従来技術、競合技術の概要(英語) BACKGROUND ART
Anti-neoplastic alkaloid saframycin represented as a group, a plurality of rings coupled (THIQ) tetrahydroisoquinolin complex five-ring compound having a skeleton. For example, class A saframycin saframycin (compound 1) and Y3 (compound 2) is equal to or less than saframycin has a structure shown in. In addition to sharing the same five ring-natural backbone groups, jornamycin A, M regnier la clarithromycin, such as 743 (compound 3-5) ecteinascidin, a number of analogs have been reported. Compound is 1-4, which is constituted by only two THIQ, iminium cation generated from the DNA in the guanine bases aminonitrile alkyl group has a function. In addition, protein-protein interaction site and a nucleic acid having alkyl site 5 is the braking anti-cancer compounds ('trabectedin', '') as has been in clinical application.
Has such a unique structure, and exhibit excellent damping tetrahydroisoquinoline alkaloid compound gun for the group, the total synthesis of various studies have been actively developed (Non-Patent Document 1 and 2) has. In addition, extremely complex multi-ring structure 743 to the control of the above-mentioned anti-cancer agent (compound 5) is ecteinascidin, culture (compound 6) cyano safra singh obtained from the multi-stage semi-synthetic and (21 step) is supplied to the (non-patent document 3). However, these previously reported the synthesis step, the starting material is complicated and, moreover, to carry out the reaction product needs to be isolated and purified, it requires a step of synthesizing the multi-stage problem that the production efficiency.
On the other hand, heretofore, the inventors of the invention, the catalyst A saframycin biosynthesis of the peptide synthetase (NRPS) non-ribosome-dependent protein SfmC module is, the original function of a polypeptide not promote the formation, between the aldehyde and amino acid long-chain fatty acids of the imine formation and subsequent cyclization catalyst Pictet-Spengler (PS) type can be, the fifth ring skeleton THIQ ring form having the characteristics specifically reported an enzyme (non-patent document 4). However, other functional groups in the molecule there are many, such enzymes essential for the reaction of long chain fatty acid portion is selectively removed so as to be extremely difficult. Therefore, utilizing the reaction with the enzyme and the fifth ring skeleton after formed, there is an object of new chemically modified analogs saframycin chemical synthesis is limited.
  • 出願人(英語)
  • ※2012年7月以前掲載分については米国以外のすべての指定国
  • TOKYO UNIVERSITYOF AGRICULTURE AND TECHNOLOGY
  • HOKKAIDO UNIVERSITY
  • 発明者(英語)
  • OGURI HIROKI
  • TANIFUJI RYO
  • OIKAWA HIDEAKI
国際特許分類(IPC)
指定国 National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DJ DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JO JP KE KG KH KN KP KR KW KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
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