Preparation of non-cyclic nucleotide phosphoamides and salts thereof and application of non-cyclic nucleotide phosphoamides and salts thereof in aspect of antivirus

A technology of cyclic nucleotide phosphoramide and nucleotide phosphoramide, which is applied in the field of patients with or/and HBV infection, and can solve problems such as incomplete cure of drug resistance, side effects, and patient cessation

Active Publication Date: 2016-06-15
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

IFN-α shows clinical benefit in 60% of patients, and 7% clearance rate, but severe side effects, leading many patients to stop treatment
Nucleoside drugs can be taken orally, have low toxicity, and are effective in almost all patients, but incomplete cure and drug resistance are a problem

Method used

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  • Preparation of non-cyclic nucleotide phosphoamides and salts thereof and application of non-cyclic nucleotide phosphoamides and salts thereof in aspect of antivirus
  • Preparation of non-cyclic nucleotide phosphoamides and salts thereof and application of non-cyclic nucleotide phosphoamides and salts thereof in aspect of antivirus
  • Preparation of non-cyclic nucleotide phosphoamides and salts thereof and application of non-cyclic nucleotide phosphoamides and salts thereof in aspect of antivirus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] step 1:

[0063] Isopropyl(tert-butoxycarbonyl)-L-alanine-3,3,3-d 3 (47)

[0064] L-Boc-alanine-3,3,3-d 3 (20 g, 0.104 mol) was dissolved in dry dichloromethane (400 mL), followed by the addition of isopropanol (6.87 g, 0.114 mol). The reaction solution was cooled to 0°C-5°C, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCHCl) (30.02g, 0.156mol) and 4-di Methylaminopyridine (DMAP) (1.2g, 0.0104mol). The mixture was slowly raised to room temperature, stirred overnight, diluted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated , silica gel column chromatography (eluent: petroleum ether / ethyl acetate: 100 / 10) to obtain compound 47, 18.2g, 75%. 1 HNMR (400MHz, DMSO-d 6 ): δ7.24(d,1H), 4.90(m,1H), 3.92(m,1H), 1.14-1.37(m,15H). MS-ESI:235.32(M+H) + .

[0065] Step 2:

[0066]

[0067] L-alanine isopropyl ester-3,3,3-d 3 Hydrochlor...

Embodiment 2

[0083] The same method is used to synthesize phosphoramide D-amino acid isopropyl ester:

[0084]

[0085] Isopropyl((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)(phenoxy)phosphoryl)- D-alanine-3,3-3-d 3 Fumarate (51)

[0086] Isopropyl((R)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yloxy)methyl)(phenoxy)phosphoryl)- D-alanine 3,3-3-d 3

[0087] (3) (0.4g, 0.83mmol), add fumaric acid (88mg, 0.75mmol) to 9mL acetonitrile, reflux until all solids are dissolved, filter hot, cool to 5°C, stand at 5°C for 12 hours, filter , washed with 4 mL of acetonitrile to obtain 0.3 g of white solid, 61%. 1 HNMR (400MHz, DMSO-d 6 ):13.13(s,2H),8.11,8.14(2s,2H),7.02-7.34(m,5H),6.63(s,2H),5.59(m,1H),4.84(m,1H),3.83- 4.26(m,6H),1.04-1.15(m,9H). MS-ESI:480.5(M+H) + .

[0088] The following compounds and corresponding fumarates were synthesized by the same method:

[0089]

[0090] Reaction 2

[0091]

Embodiment 3

[0093] step 1:

[0094]

[0095] Propan-2-yl 2-d(tert-butoxycarbonyl)-L-alanine (53)

[0096] L-Boc-alanine (2.18 g, 11.5 mmol) was dissolved in dry dichloromethane (40 mL), followed by the addition of 2-deuteroisopropanol (0.98 mL, 12.6 mmol). The reaction solution was cooled to 0°C-5°C, and EDCHCl (3.31g, 17.2mmol) and DMAP (140mg, 1.15mmol) were added in batches. The mixture was slowly raised to room temperature, stirred overnight, diluted with dichloromethane, and the organic phase was washed with saturated Sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and silica gel column chromatography (eluent: petroleum ether / ethyl acetate: 100 / 10) gave compound 53, 1.87g, 70%.1 HNMR (400MHz, DMSO-d 6 ): δ7.23(d,1H),3.91(m,1H),1.12-1.38(m,18H). MS-ESI:233.3(M+H) + .

[0097] Step 2:

[0098]

[0099] Propan-2-yl 2-d L-alanine hydrochloride (54)

[0100] Propan-2-yl 2-d(tert-butoxycarbonyl)-L-alanine (53) (1g, 4.3mmol) wa...

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Abstract

The invention belongs to the field of antivirus in medical chemistry, and relates to preparation of non-cyclic nucleotide phosphoamides and salts thereof and application of the non-cyclic nucleotide phosphoamides and salts thereof in treating human immunodeficiency virus (HIV), hepatitis B, hepatitis B virus (HBV) and other virus infection diseases. The non-cyclic nucleotide phosphoamides, and isomers, pharmaceutically acceptable salts, hydrates, solvates or crystals thereof have the general formula I of which the structure is disclosed in the specification. The invention also provides a pharmaceutical composition containing the compounds and isomers, pharmaceutically acceptable salts, hydrates, solvates or crystals thereof, and application of the compounds or composition in treating and/or preventing HIV and HBV infection. The compounds provided by the invention have the advantages of favorable anti-HIV and HBV activities, low oral dosage and low toxicity.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and anti-virus, and in particular relates to a new class of deuterated acyclic nucleotide phosphoramide compounds or their isomers and compounds containing deuterated acyclic nucleotide phosphoramide compounds or their isomers Combination medicine is used as an antiviral application, especially for treating HIV-infected or / and HBV-infected patients. Background technique [0002] Human immunodeficiency virus type 1 (HIV-1, AIDS) remains one of the most contagious diseases in the world. Although humans have developed a variety of drugs and methods for prevention and treatment, the current situation is that HIV-1 infection is still in a pandemic state. An estimated 39 million people worldwide are infected with AIDS, and about 4 million die each year. In 2009 alone, there were approximately 2.7 million new HIV infections. There are currently 22 drugs approved by the FDA for the treatment of AIDS,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/18A61P31/20A61P1/16
CPCC07F9/65616
Inventor 杨学聪游国战刘洪海
Owner 洛阳聚慧新材料科技有限公司
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