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ANTI-HIV PHARMACEUTICAL COMPOSITION

Foreign code F210010298
File No. (S2019-0456-N0)
Posted date Jan 28, 2021
Country WIPO
International application number 2020JP021080
International publication number WO 2020241737
Date of international filing May 28, 2020
Date of international publication Dec 3, 2020
Priority data
  • P2019-102088 (May 31, 2019) 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.
Scope of claims (In Japanese)[請求項1]
 下記式(I):
[化1]
(省略)
[式(I)中、X及びYは、それぞれ独立にC又はNを表し、Zは、C又は結合を表し、Ra及びRbは、それぞれ独立に、水素又は置換されてもよいフェニル基を表すか互いに一緒になってXとYとともに置換されてもよい6員炭素環を形成し、R 1は、C1~C5のアルキル基又はアルケニル基、フェニル基、ベンジル基、あるいは2-モルホリノエチル基を表す。]で表される化合物、又はその薬学的に許容される塩を有効成分として含むHIVの治療又は予防のための医薬組成物。

[請求項2]
 下記式(II):
[化2]
(省略)
[式(II)中、R 2は、C1~C5のアルキル基又はアルケニル基、ベンジル基、あるいは2-モルホリノエチル基を表す。]で表される化合物、又はその薬学的に許容される塩を有効成分として含む、請求項1に記載の医薬組成物。

[請求項3]
 上記式(II)において、R 2は、C1~C3のアルキル基又はアルケニル基である、請求項2に記載の医薬組成物。

[請求項4]
 上記式(II)において、R 2は、メチル基、エチル基、及びアリル基からなる群より選ばれる、請求項2に記載の医薬組成物。

[請求項5]
 上記式(II)において、R 2は、ベンジル基又は2-モルホリノエチルである、請求項2に記載の医薬組成物。

[請求項6]
 下記式(III):
[化3]
(省略)
[式(III)中、R 3は、C1~C5のアルキル基又はアルケニル基、あるいはフェニル基を表す。]で表される化合物、又はその薬学的に許容される塩を有効成分として含む、請求項1に記載の医薬組成物。

[請求項7]
 上記式(III)において、R 3は、C1~C3のアルキル基又はアルケニル基である、請求項6に記載の医薬組成物。

[請求項8]
 上記式(III)において、R 3は、メチル基、エチル基、及びアリル基からなる群より選ばれる、請求項6に記載の医薬組成物。

[請求項9]
 上記式(III)において、R 3は、フェニル基である請求項6に記載の医薬組成物。

[請求項10]
 以下の化合物:
[化4]
(省略)
からなる群から選ばれる化合物又はその薬学的に許容される塩を有効成分として含む、請求項2に記載の医薬組成物。

[請求項11]
 以下の化合物:
[化5]
(省略)
からなる群から選ばれる化合物又はその薬学的に許容される塩を有効成分として含む、請求項2に記載の医薬組成物。

[請求項12]
 以下の化合物:
[化6]
(省略)
からなる群から選ばれる化合物又はその薬学的に許容される塩を有効成分として含む、請求項6に記載の医薬組成物。

[請求項13]
 他の抗HIV薬と併用されることを特徴とする請求項1から12のいずれか一つに記載の医薬組成物。

[請求項14]
 前記他の抗HIV薬が、化学療法剤、抗レトロウイルス阻害剤、サイトカイン、ヒドロキシウレア、Gagタンパク質に結合するモノクローナル抗体、又は他のレトロウイルス複製の阻害剤である、請求項13に記載の医薬組成物。

[請求項15]
 抗HIV活性を有する物質をスクリーニングする方法であって、以下の工程:
(a)HIV-1の野生型キャプシドを発現する細胞から調製したキャプシドとともに候補物質を緩衝液中で37±2℃の温度にてインキュベートする工程、ここで、該細胞は、HIV-1の野生型キャプシドの発現プラスミドを用いて形質転換した細胞であり、キャプシド以外のHIV-1由来の成分を発現しない細胞である、及び
(b)キャプシドの崩壊を検出し、対照に対し、キャプシドの崩壊が抑制された物質を選択する工程、
を含むスクリーニング方法。

[請求項16]
 前記工程(b)は、無傷(intact)のキャプシドの抗原量を、抗キャプシド抗体を用いて測定する工程である、請求項15に記載のスクリーニング方法。
  • 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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