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CD4 mimetic compounds with anti-HIV activity

A compound, HIV-1 technology, applied in organic active ingredients, drug combinations, organic chemistry, etc., can solve the problems of high cytotoxicity, low water solubility, and low anti-HIV activity, and achieve low cytotoxicity and high anti-HIV activity. , the effect of prolonging the half-life

Pending Publication Date: 2022-06-24
NAT UNIV CORP KUMAMOTO UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, NBD-556 has problems such as low anti-HIV activity, high cytotoxicity, and low water solubility. Research on the structure and activity of NBD-556 as a lead compound is actively carried out (non-patent literature 5-8)

Method used

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  • CD4 mimetic compounds with anti-HIV activity
  • CD4 mimetic compounds with anti-HIV activity
  • CD4 mimetic compounds with anti-HIV activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] [Example 1 Synthesis 1 of the compound of the present invention]

[0099] Compounds of the present invention with PEG chains were synthesized by the following synthetic scheme of steps.

[0100] [Chemical formula 12]

[0101]

[0102] To a solution of compound 1 (13.0 g, 20.0 mmol) in MeOH (67 mL) was added SOCl at 0 °C 2 (1.6 mL, 22 mmol). The reaction mixture was stirred at room temperature for 17 hours, then the mixture was concentrated under reduced pressure to give a crude mixture as a white powder. to CH 2 Cl 2 To the crude mixture in (219 mL) was added piperidine (9.32 g, 109.5 mmol). The reaction mixture was stirred at room temperature for 2 hours and then subjected to silica gel column chromatography (CHCl). 3 / MeOH=10 / 1) to obtain compound 3 (N ω -((2,2,4,6,7-Pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)-L-arginine methyl ester) as a white powder (7.61 g , the yield is 87%).

[0103] 1 H NMR (500MHz, CDCl 3 )δ1.45(s,6H),1.59-1.66(m,2H),1.79-1....

Embodiment 2

[0114] [Example 2 Synthesis 2 of the compound of the present invention]

[0115] In the same manner as in Example 1, compounds with different PEG chain lengths were synthesized.

[0116] [Chemical formula 16]

[0117]

[0118] To compound 4 (1.06 g, 1.97 mmol) in CHCl at 0 °C 3 (17.9mL) HOBt·H was added to the solution 2 O (301.7 mg, 1.97 mmol), EDCI·H 2 O (0.378 g, 1.97 mmol), m-PEG11-amine (1.00 g, 1.79 mmol), and DIPEA (0.61 mL, 3.58 mmol). The reaction mixture was stirred at room temperature overnight, then saturated NH was added 4 The reaction was quenched with aqueous Cl, and the reaction was quenched with CH 2 Cl 2 extraction, then the organic phase was passed over MgSO 4 Concentrate to dryness. To the crude mixture in THF (19.7 mL) was added IN aqueous LiOH (0.39 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then the mixture was filtered, quenched by the addition of 1N aq. 3 extraction. Pass the organic phas...

Embodiment 3

[0123] [Example 3 Synthesis 3 of the compound of the present invention]

[0124] In the same manner as in Example 1, compounds with different PEG chain lengths were synthesized.

[0125] [Chemical formula 18]

[0126]

[0127] To CH of compound 4 (49 mg, 91.9 μmol) at 0 °C 2 Cl 2 (91 μL) was added m-PEG23-amine (100 mg, 91.9 μmol), EDCI·H 2 O(19.4mg, 101μmol), HOBt·H 2 O (13.7 mg, 101 μmmol), and DIPEA (32 μL, 184 μmol). The reaction mixture was stirred at room temperature overnight, then washed with saturated NH 4 The reaction was quenched with aqueous Cl, and the reaction was quenched with CH 2 Cl 2 extraction, then the organic phase was passed over MgSO 4 Concentrate to dryness. To the crude mixture in THF (426 μL) was added IN aqueous LiOH (92.2 μL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then the mixture was filtered and washed with NH 4 Aqueous Cl quenched with CHCl 3 extraction. Pass the organic phase ove...

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Abstract

Provided are CD4 mimetic compounds that have increased effectiveness in anti-HIV therapy, with further increased in vivo kinetics. Provided is a compound represented by general formula (I) [in the formula, R1 represents-C2H4 (OC2H4) n-OCH3, or CmH2m + 1, R2 represents O or NH, n is 3 to 25, and m is 4 to 22. ] or a salt thereof; and an HIV infection inhibitor containing the compound or the salt thereof as an active ingredient.

Description

technical field [0001] The present invention relates to novel CD4 mimetic compounds with anti-HIV activity. In more detail, the present invention relates to CD4 mimetic compounds with improved in vivo kinetics. Background technique [0002] Human immunodeficiency virus (human immunodeficiency virus: HIV) is considered to be a virus that causes acquired immunodeficiency syndrome (AIDS). There are three main ways of HIV infection: sexual contact, infection caused by blood transfusion or blood products, and mother-to-child infection. There is no risk of air infection. As of now, about 74.9 million people worldwide are infected with HIV, of which 32 million die from AIDS-related diseases. At present, AIDS has been successfully suppressed by chemotherapy using agents, but a radical cure of AIDS has not been achieved. [0003] HIV-1 and HIV-2 exist in HIV, and HIV-1 is classified into subtypes A to K. HIV-1 is more common in the Western Hemisphere, Europe, Asia, central, south...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/20A61K31/4468A61K39/42A61P31/18
CPCC07D221/20A61K31/4468A61K39/42A61P31/18A61K2300/00A61P43/00A61K31/438
Inventor 松下修三吉村和久玉村启和增田亚美高桥耕平小早川拓也原田惠嘉三浦智行
Owner NAT UNIV CORP KUMAMOTO UNIV
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