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NOVEL COMPOUND HAVING LYSINE-SPECIFIC DEMETHYLATING ENZYME 1 INHIBITORY ACTIVITY, METHOD FOR PRODUCING SAME AND USE OF SAME NEW

外国特許コード F190009741
整理番号 (S2017-0827-N0)
掲載日 2019年5月7日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2018JP025702
国際公開番号 WO 2019009412
国際出願日 平成30年7月6日(2018.7.6)
国際公開日 平成31年1月10日(2019.1.10)
優先権データ
  • 特願2017-134173 (2017.7.7) JP
発明の名称 (英語) NOVEL COMPOUND HAVING LYSINE-SPECIFIC DEMETHYLATING ENZYME 1 INHIBITORY ACTIVITY, METHOD FOR PRODUCING SAME AND USE OF SAME NEW
発明の概要(英語) The present invention addresses the problem of providing a novel compound having high LSD1 inhibitory activity, high selectivity for LSD1 inhibition, and/or having useful therapeutic effects for various diseases. One embodiment of the present invention relates to: a compound represented by formula (I) [in the formula, the meanings of L and A are as defined in the specification and claims], a stereoisomer thereof, a salt of the compound or the stereoisomer, or a solvate of the compound or the stereoisomer. Another embodiment of the present invention also relates to: a method for producing a compound represented by formula (I), a stereoisomer thereof or a salt of the compound or the stereoisomer, or a solvate of the compound or the stereoisomer; and an LSD1 inhibitor, a medicine and a pharmaceutical composition that contain said compound, the stereoisomer thereof, a salt of the compound or the stereoisomer, or a solvate of the compound or the stereoisomer as an effective component.
従来技術、競合技術の概要(英語) BACKGROUND ART
Including a human in the eukaryotic cell nuclei, chromatin activity, that is controlled by post-translational modification. For example, N-histone chromatin in the terminal regions, methylation or acetylation of the lysine residues of post-translational modifications such as are known to be. Constituting a protein lysine residue side-chain methyl groups added to the cell whether the demethylation (i.e., of the methylation reaction reversibility of the cell) will be, until the November 2004 report is not deterministic. To December 2004, an enzyme histone demethylating lysine specific demethylation enzymes 1 (hereinafter, 'LSD1' will be also denoted as) /lysine demethylation enzymes have been reported by 1A(Lysine-specific demethylase 1/lysine demethylase 1A,LSD1/KDM1A), demethylation of the histone protein in the cell occur in a passive (non-patent document 1) shown.
LSD1/KDM1A is, dividing yeast eukaryotic species of a protein stored in between. LSD1/KDM1A is, as another name, a domain containing amine oxidase flavin 2(amine oxidase flavin-containing domain 2,AOF2) or histone deacetylase BRAF - also denoted as 110(BRAF-histone deacetylase complex 110,BHC110) enzyme complex. LSD1 Is, flavin adenine dinucleotide (hereinafter, also referred to 'FAD') as a coenzyme oxidase which is one type of. LSD1 Is, in which dimethyl monomethylated or histone H3 lysine residues of the protein side chain amine demethylation. Demethylation of the remaining group is the major target, histone H3 protein lysine residues from the N end 4 (K4) (Non-Patent Document 1) in. LSD1 De by methylated histone H3 is the major protein, also other, non-histone nuclear protein p53, Dnmt1, E2F1 and the like MYPT1, the demethylation by LSD1 have been reported. Mammals including humans, and LSD1 have sequence homology demethylation enzymes and type 1, a lysine specific demethylation enzymes 2 (hereinafter, 'LSD2' and are also described), referred to as LSD2/KDM1B. LSD2 Also, as a FAD coenzyme oxidase and, de-methylation of histone H3 can be K4.
LSD1 Enzyme active sites, such as a low-molecular compound can be inhibited by forming the structure. Therefore, a large number of targeted inhibit LSD1 have been developed.
For example, Non-Patent Document 2 and the 3, 2-is (2-PCPA) phenylcyclopropyl amine, in the FAD coenzyme LSD1 by inactivating, LSD1 to describe the inhibitory activity.
Non-Patent Document 4 is, the crystal structure of the molecular design based on analysis of LSD1, LSD1 selective inhibition of the compound having activity S2101 described was obtained. S2101 Is a compound, the phenyl ring of the chemical modification 2-PCPA structure.
Patent Document 1 is, in the formula I 2-PCPA analog compounds represented. Is this document, the compound having inhibitory activity are described LSD1. This document describes, by alkylation N-2-PCPA to, improved inhibitory activity against LSD1 may be described.
Patent Document 2, and 4 is 3, the aryl or heteroaryl ring having 2 to-1-at the amine skeleton (I) cyclopropane compound represented by the formula described. Is this document, these compounds having LSD1 inhibitory activity are described.
LSD1 Is, acute myeloid leukemia stem cells and stem cell diseases such as glioblastoma associated cell, and a high expression or function. Therefore, the inhibitor LSD1, acute myeloid leukemia, brain tumors such as glioblastomas, small cell lung cancer, myelodysplastic syndrome and non-Hodgkin's lymphoma diseases exert a therapeutic effect is expected (non-patent document 5-9).
  • 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
  • RIKEN
  • NAGOYA CITY UNIVERCITY
  • Jichi Medical University
  • NAGOYA UNIVERSITY
  • 発明者(英語)
  • UMEHARA Takashi
  • SATO Shin
  • KOYAMA Hiroo
  • YAMAMOTO Hirofumi
  • KONDO Yutaka
  • KATSUSHIMA Keisuke
  • FURUKAWA Yusuke
  • KIKUCHI Jiro
  • KODA Yasuko
国際特許分類(IPC)
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