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ANTI-HIV PHARMACEUTICAL COMPOSITION

Foreign code F210010298
File No. (S2019-0456-N0)
Posted date 2021年1月28日
Country 世界知的所有権機関(WIPO)
International application number 2020JP021080
International publication number WO 2020241737
Date of international filing 令和2年5月28日(2020.5.28)
Date of international publication 令和2年12月3日(2020.12.3)
Priority data
  • 特願2019-102088 (2019.5.31) JP
Title ANTI-HIV PHARMACEUTICAL COMPOSITION
Abstract The purpose of the present invention is to provide a novel small molecule having anti-HIV activity. The purpose of the present invention is also to provide a novel anti-HIV drug that targets an HIV-1 capsid. The present invention provides a novel compound having anti-HIV activity and represented by formula(I): [In formula (I), X and Y each independently represent C or N, Z represents C or a bond, Ra and Rb each independently represent hydrogen or an optionally substituted phenyl group, or together form an optionally substituted six-membered carbon ring together with X and Y, R1 represents a C1-C5 alkyl group or alkenyl group, a phenyl group, a benzyl group, or a 2-morpholinethyl group].
Outline of related art and contending technology BACKGROUND ART
HIV particles are spherical about 120 nm in diameter and include: envelopes consisting of lipid bimembranes derived from host cells transplanted with viral glycoprotein Env (gp120 , gp41); There is a matrix (MA), which is one of the viral protein groups of Gag lining the envelope, and there is a frustoconical core, which also consists of capsid (CA) protein, which is one of the Gag. Inside the core is the viral genome of positive single-stranded RNA surrounded by nucleocapsid protein (NC) and dimerized.
Autoimmune disease (AIDS) is caused by HIV. Two genetically distinct types of HIV have been isolated from aids patients, so-called HIV-1 and HIV-2. HIV-1 is a common type globally distributed, while HIV-2 mainly causes aids in western Africa.
HIV is a retrovirus, and similar to many viruses, HIV is also infected in the infection cycle by taking the form of viral particle (virion). HIV-1 virions are spherical and contain a high electron density pyramidal core, which is enveloped in a lipid envelope derived from the host cell membrane. The viral score contains (1) major capsid protein p24 (CA), (2) nucleocapsid protein p7/p9 (NC), (3) 2 copies of genomic RNA, and (4) 3 viral enzyme (protease (PR), reverse transcriptase (RT), and integrase). The viral score is encased in a matrix protein, so-called p17, which is located below the viral envelope. The viral envelope carries two viral glycoproteins, gp120 and gp41.
The genome of HIV proviruses contains gag, pol, and env genes, which encode a variety of viral proteins. The gag and pol gene products are first translated into large precursor proteins, which are cleaved by viral proteases to produce mature proteins.
Ca is first synthesized as a region within the Gag precursor polyprotein of 55kDa. Approximately 4,000 copies of Gag assemble at the plasma membrane and germinate to form immature viral particles. After germination, Ca is released when the Gag is cleaved by proteolysis, and the Ca triggers the conformation of the capsid particles to change, which promotes the construction of the capsid particles. Two copies of the viral genome and infectious agents are encompassed within the central pyramidal capsid of the mature virion.
Existing anti-HIV-1 agents have been developed targeting reverse transcriptase, protease, and integrase, which are mainly viral side enzymes. However, due to the high rate of mutation caused by HIV-1 reverse transcriptase and the high tolerance of HIV-1 enzymes to genetic mutations, problems with the emergence of drug-resistant strains have occurred. Therefore, it is urgent to develop new therapeutics that block the proliferation of HIV-1 with a mechanism that is quite different from current therapeutics, including the matrix proteins that form the membrane of the outermost layer of Gag protein group (HIV-1, which is a skeletal factor of HIV-1; Inhibition of), such as capsid proteins encompassing the HIV-1 gene within the virus, nucleocapsid proteins acting as chaperones of the viral gene, is an attractive target for virology and development, but has not yet been in clinical use for HIV-1 Gag protein inhibitors.
Some recent studies have shown that proper Ca construction is critical to viral infectivity. Ca mutations that inhibit Ca construction are lethal, and mutations that alter Ca stability significantly attenuate replication. Ca is a highly conserved region (NpL 1: V. Novitsky , et al . , J Virol , 2002 , 76: 5435-51 , HIV Sequence Compendium 2014 , Los Alamos National Laboratory , USA). Ca is thus interested as a promising antiviral target. Several reports have been made as HIV-1 CA inhibitors. (Non-Patent Document 2: F. Li , et al . PNAS vol . 100 , no. 23 , pp.13555-13560 , 2003), which is reported as a Ca maturation inhibitor that inhibits the eventual cleavage by proteases between Ca and p2. The capsid assembly inhibitor (CAI) is a peptide of 12-mer that binds to the C-terminal side of Ca, and exhibits an effect of suppressing virus germination from infected cells (NpL 3: Jana Sticht , et. al . , Nat Struct Mol Biol , pp. 671-677 , 2005). N-(3-chloro-4-methylphenyl)-N0-{2-[({5-[(dimethylamino)-methyl]-2-furyl}-methyl)-sulfanyl] ethyl} urea) (CAP-1) is (NpL 4: Chun Tang , et al . , J Mol Biol , vol . 327 , pp. 1013-1020 , 2003), which is a compound that binds to the N-terminus of Ca. (NpL 5: Wada S. Blair , PLoS Pathog , vol . , 6 , Issue 12 , e1001220 , 2010) reported that PF-3450074 over-promotes Ca multimeric stabilization and inhibits normal Ca function.
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • KUMAMOTO UNIVERSITY
  • Inventor
  • AMANO Masayuki
  • NAKAMURA Tomofumi
IPC(International Patent Classification)
Specified countries 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 ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN WS 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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