Top > Search of International Patents > ANTI-HIV PHARMACEUTICAL COMPOSITION

ANTI-HIV PHARMACEUTICAL COMPOSITION NEW_EN

Foreign code F190009938
File No. (S2018-0222-N0)
Posted date Oct 24, 2019
Country WIPO
International application number 2018JP047049
International publication number WO 2019124509
Date of international filing Dec 20, 2018
Date of international publication Jun 27, 2019
Priority data
  • P2017-244763 (Dec 21, 2017) JP
Title ANTI-HIV PHARMACEUTICAL COMPOSITION NEW_EN
Abstract The purpose of the present invention is to provide a novel low-molecular-weight molecule that has anti-HIV activity. The purpose of the present invention is also to provide a novel anti-HIV drug that targets the HIV-1 capsid. The present invention provides novel compounds that are represented by formula (I) and have anti-HIV activity. [In the formula, X represents C or N, R1 represents a halogen, a hydroxyl, a nitro, a methyl, an ethyl, a methoxy, a halogenated methyl, or an amino, R2 represents a hydrogen or a phenyl, R3 represents a hydrogen or a methyl, R4 represents a hydrogen or a hydroxyl, R5 represents a hydrogen, a halogenated methyl, or an acetyl, R6 represents a hydrogen or a halogen, R7 represents a hydrogen, a methyl, or a halogenated methyl, R8 represents a hydrogen or a fluorine when X is C, and n is 1 or 2. When R1 is a hydroxyl, R4 is a hydroxyl.]
Outline of related art and contending technology BACKGROUND ART
HIV a spherical shape with a diameter of about 120nm of the particles, (gp120, gp41) viral glycoproteins Env is planted in the lipid bilayer membrane derived from the host cell from the envelope, the envelope of the viral proteins Gag lining (MA) which is one of the group matrix protein, also inside the capsid proteins Gag (CA) is one of a circular truncated cone shape made of the presence of the core. (NC) the nucleocapsid protein to the inside of the core surrounded by the couple of single-stranded RNA are positive and the presence of viral genome.
HIV (AIDS) is caused by an autoimmune disease. Genetically different from one type of 2 HIV, AIDS and HIV-1 is a so-called isolated from a patient HIV-2 respectively. HIV-1 is, a world-wide distribution general type and, on the other hand, in a West African HIV-2 is mainly caused in AIDS.
HIV is retroviral and, as a number of viruses, viral HIV infection cycle (of the individual) in the form of a particle to the infection. HIV-1 virions spherical, a high electron density of the first core and the cone, which is derived from a host cell membrane lipid envelope wrapped around. The major (1) capsid the virus (CA) p24 (NC) p7/p9, (2) nucleocapsid protein, (3) RNA 2 copies of the genome, and (4) one of the viral enzyme 3 (protease (PR), (RT) reverse transcriptase, integrase) containing. Matrix protein the virus, are covered with a so-called p17, which is located on the lower side of the viral envelope. Is one of the viral envelope glycoprotein 2, gp120 and gp41 are attached.
HIV viral genome of the gag, pol, and env genes with, a variety of these encoding a viral protein. Gag and pol gene products of the first, large precursors are translated into protein, the protein, is cleaved by the protease of the virus, to produce the mature protein.
CA first, the Gag 55kDa polyprotein precursors are combined as an area in the. Gag about 4,000 copies of the collected plasma membrane, such as premature budding to form a viral particle. After sowing, Gag is cleaved by proteolysis and free CA, which is triggered by a three-dimensional structure is changed, this change in the construction of the particles is promoted the capsid. 2 Copies of the viral genome and infectivity of the enzyme is essential, within the capsid of mature virions included in the center of the cone.
Existing anti-HIV-1 agent is, on the side of a main virus reverse transcriptase enzyme, a protease, integrase is developed as a target, such as medical treatment for a long time (life time) due to the appearance of drug resistant strains in question to be the most involved with. Therefore, the receiver is quite different from the current therapeutic agent for inhibiting the growth of the HIV-1 overdraw a new therapy is an urgent need for development of, in the structure of the HIV-1 form factor Gag protein group (HIV-1 thickness of the outermost layer to form a matrix proteins, virus is HIV-1 gene to wrap the capsid proteins, viral genes such as acting as a chaperone the nucleocapsid protein) inhibition, virology, pharmaceutical discovery is attractive to the target, for the HIV-1 Gag protein inhibitor has not reached yet the clinical application.
Of several recent studies, construction of an appropriate virus capsid infectivity is shown a very important role. Construction variant is lethal and the inhibiting of CA, CA to alter the stability of the mutated to significantly attenuated replication. In addition, stored in the CA is very area (non-patent document 1: V. Novitsky, et al., J Virol, 2002, 76: 5435-51, HIV Sequence Compendium 2014, Los Alamos National Laboratory, USA). Therefore, the target of interest as a promising anti-virus CA are collected. HIV-1 CA as an inhibitor, has been reported some embodiments. (PA-457) is Bevirimat, p2 between the CA and finally by protease inhibiting cleavage CA as maturation inhibitors have been reported (Non-Patent Document 2: F. Li, et al. PNAS vol. 100, No. 23, pp.13555-13560, 2003). Capsid assembly (CAI) is an inhibitor, on the side of the terminal C of the CA to 12-mer peptide and, the virus from the infected cells to develop the effect of suppressing (Non-Patent Document 3: Jana Sticht, et. al., Nat Struct Mol Biol, pp. 671-677, 2005). {2-[ ({5-[ (Dimethylamino) -methyl]-2-furyl} -methyl) -sulfanyl]ethyl} N-(3-chloro-4-methylphenyl) -N'- (CAP-1) is urea, N of the CA is attached to the end compound (Non-Patent Document 4: Chun Tang, et al., J Mol Biol, vol. 327, pp. 1013-1020, 2003). PF-3450074 is, a large amount of excess to accelerate the stabilization of CA, CA and to inhibit the function of the normal have been reported (Non-Patent Document 5: Wada S. Blair, PLoS Pathog, vol., 6, Issue 12, e1001220, 2010).
Scope of claims (In Japanese)[請求項1]
 下記式(I):
[化1]
(省略)
[式(I)中、Xは、C又はNを表し、R 1は、ハロゲン、ヒドロキシ、ニトロ、メチル、エチル、メトキシ、ハロゲン化メチル、又はアミノを表し、R 2は、水素又はフェニルを表し、R 3は、水素又はメチルを表し、R 4は、水素又はヒドロキシを表し、R 5は、水素、ハロゲン化メチル、又はアセチルを表し、R 6は、水素又はハロゲンを表し、R 7は、水素、メチル、又はハロゲン化メチルを表し、R 8は、XがCの場合は、水素又はフッ素を表し、nは、1又は2を表す。但し、R 1がヒドロキシの場合は、R 4はヒドロキシである。]
で表される化合物、又はその薬学的に許容されるその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 1は、ハロゲン、ヒドロキシ、ニトロ、メチル、エチル、メトキシ、ハロゲン化メチル、又はアミノを表し、R 2は、水素又はフェニルを表し、R 4は、水素又はヒドロキシを表し、R 5は、水素、ハロゲン化メチル、又はアセチルを表し、R 6は、水素又はハロゲンを表し、R 7は、水素又はハロゲン化メチルを表し、R 8は、水素又はフッ素を表す。但し、R 1がヒドロキシの場合は、R 4はヒドロキシである。]
で表される化合物、又はその薬学的に許容されるその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 1及びR 4はヒドロキシを表す、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 6はハロゲン、R 8はフッ素である、請求項3に記載の化合物、又は薬学的に許容されるその塩。

[請求項5]
 上記式(II)において、R 1及びR 6はハロゲンである、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 1は、ハロゲン、ヒドロキシ、ニトロ、メチル、エチル、メトキシ、ハロゲン化メチル、又はアミノを表し、R 3は、水素又はメチルを表し、R 6は、ハロゲンを表し、R 7は、水素又はメチルを表す。]
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はメチルを表し、R 6は、Br又はIを表す、請求項6に記載の医薬組成物。

[請求項8]
 以下の化合物:
[化4]
(省略)
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9]
 以下の化合物:
[化5]
(省略)
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10]
 他の抗HIV薬と併用されることを特徴とする請求項1~9のいいずれか一つに記載の医薬組成物。

[請求項11]
 有効成分として、さらに他の抗HIV薬を含む請求項1~9のいずれか一つに記載の医薬組成物。

[請求項12]
 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10又は11に記載の医薬組成物。

[請求項13]
 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の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する工程、
を含むスクリーニング方法。

[請求項14]
 前記工程(b)は、無傷の(intact)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13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
  • NATIONAL UNIVERSITY CORPORATION KUMAMOTO UNIVERSITY
  • Inventor
  • AMANO, Masayuki
  • NAKAMURA, Tomofumi
  • SUGIURA, Masaharu
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 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
Please contact us by E-mail or telephone if you have any interests on this patent.

PAGE TOP

close
close
close
close
close
close