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Acyclic nucleoside phosphamide D-amino-acid ester derivative, preparation method of derivative salt and application of derivative to antiviral effect

A technology of cyclic nucleoside phosphoramide and nucleoside phosphoramide is applied in the field of treating and/or preventing HIV infection or/and HBV infection of patients, and can solve the problems of easy hydrolysis to TFV, nephrotoxicity and the like

Inactive Publication Date: 2016-11-30
洛阳聚慧新材料科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of TDF is that it is easily hydrolyzed into TFV in plasma
On the other hand, in patients with impaired renal function, TDF may pose a risk of nephrotoxicity

Method used

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  • Acyclic nucleoside phosphamide D-amino-acid ester derivative, preparation method of derivative salt and application of derivative to antiviral effect
  • Acyclic nucleoside phosphamide D-amino-acid ester derivative, preparation method of derivative salt and application of derivative to antiviral effect
  • Acyclic nucleoside phosphamide D-amino-acid ester derivative, preparation method of derivative salt and application of derivative to antiviral effect

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1: (((((R)-1-(6-amino-9H-purin-9-yl)prop-2-yl)oxy)methyl)(phenoxy)phosphoryl)-D- Alanine Isopropyl Fumarate (18)

[0068]

[0069] Step 1: Synthesis of N-Boc-D-alanine isopropyl ester (16)

[0070]

[0071] Dissolve N-Boc-D-alanine 15 (5.0g, 26.4mmol) and isopropanol (1.92g, 31.9mmol) in dichloromethane (50mL), under nitrogen protection, ice bath to 0°C, add 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (7.47g, 38.9mmol), then add 4-dimethylaminopyridine (DMAP) in three batches ( 0.32g, 2.6mmol), slowly raised to room temperature, reacted for 12 hours, added dichloromethane (25mL) to dilute, the reaction solution was washed with saturated sodium bicarbonate (20mL x2), saturated brine (20mL x2), and anhydrous sulfuric acid Sodium-dried, filtered, and the filtrate was concentrated under reduced pressure, purified by column chromatography using silica gel column chromatography with eluent petroleum ether:ethyl acetate=10:1 (3% concentrate...

Embodiment 2

[0084] Example 2: (((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)-D- Alanine Isobutyl Fumarate (21)

[0085]

[0086] Step 1: Synthesis of N-Boc-D-alanine isobutyl ester (19)

[0087]

[0088] Dissolve N-Boc-D-alanine 15 (4.0g, 21.1mmol) and isobutanol (1.89g, 25.6mmol) in dichloromethane (40mL), under nitrogen protection, ice-bath to 0°C, add EDC (5.9g, 30.7mmol), then add DMAP (0.25g, 2.0mmol) in three batches, slowly rise to room temperature, react for 12 hours, add dichloromethane (18mL) to dilute, and the reaction solution is washed with saturated sodium bicarbonate ( 16mL x2), washed with saturated brine (15mL x2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) (3 % concentrated sulfuric acid in methanol solution) to obtain N-Boc-D-alanine isobutyl ester 19 (3.68 g, yield: 71%).

[008...

Embodiment 3

[0104] Example 3: (((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)-D- Alanine Cyclohexyl Fumarate (24)

[0105]

[0106] Step 1: Synthesis of N-Boc-D-alanine cyclohexyl ester (22)

[0107]

[0108] N-Boc-D-alanine 15 (5g, 26.4mmol) and cyclohexanol (3.2g, 32mmol) were dissolved in dichloromethane (50mL), under nitrogen protection, ice-bathed to 0°C, EDC ( 7.47g, 38.9mmol), then add DMAP (0.32g, 2.6mmol) in three batches, slowly rise to room temperature, react for 12 hours, add dichloromethane (30mL) to dilute, and react with saturated sodium bicarbonate (25mL x2 ), washed with saturated brine (20mL x2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) (3% Concentrated sulfuric acid methanol solution for color development) to obtain N-Boc-D-alanine cyclohexyl ester 22 (5.6 g, yield: 79%).

[010...

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Abstract

The invention belongs to the field of medical chemical antiviral effects, and relates to an acyclic nucleoside phosphamide D-amino-acid ester derivative, a preparation method of derivative salt and an application of the derivative to the antiviral effects. The invention further provides a compound comprising the derivative, a stereoisomer of the derivative, pharmaceutically acceptable salt, a hydrate, a solvate or crystal and drug combination and an application of the compound or combination to treatment and / or prevention of Aids and hepatitis B virus infection. The in vivo activity of the compound is remarkably superior to that of a pro-drug of acyclic nucleoside phosphamide L-amino-acid ester, and the compound has obvious clinical application values.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry antiviral, and in particular relates to a new class of acyclic nucleoside phosphoramide D-amino acid ester derivatives or stereoisomers thereof, and non-cyclic nucleoside phosphoramide D-amino acid ester derivatives or stereoisomers thereof. The composition of the conformation is used as an antiviral drug, especially for treating and / or preventing HIV-infected or / and HBV-infected patients. Background technique [0002] There are two types of human immunodeficiency virus (HIV), HIV-1 and HIV-2. Patients severely infected with HIV-1 cause immunodeficiency (ARC and AIDS), which can easily lead to fatal infections. HIV is one of the most serious infectious diseases in the world. In 2012, 35 million people worldwide were infected with AIDS, 2.7 million new cases were added, and 2.3 million people died of AIDS. The latest research shows that the number of HIV infections among adolescents is on the r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/18A61P31/20
CPCC07F9/65616
Inventor 杨学聪游国战刘洪海杨松峰
Owner 洛阳聚慧新材料科技有限公司
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