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Phosphamide nucleosides compound, pharmaceutically acceptable salt and application thereof, and pharmaceutical composition

A technology for phosphoramide nucleosides and compounds is applied in pharmaceutical compositions, phosphoramide nucleosides and pharmaceutically acceptable salts and application fields thereof, and can solve problems such as nephrotoxicity and instability

Inactive Publication Date: 2017-01-11
张红利 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, TDF also has disadvantages. It is unstable in plasma and is easily hydrolyzed into TFV. On the other hand, for patients with renal function defects, TDF may cause the risk of nephrotoxicity.

Method used

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  • Phosphamide nucleosides compound, pharmaceutically acceptable salt and application thereof, and pharmaceutical composition
  • Phosphamide nucleosides compound, pharmaceutically acceptable salt and application thereof, and pharmaceutical composition
  • Phosphamide nucleosides compound, pharmaceutically acceptable salt and application thereof, and pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] 1-(((cyclohexyloxy)carbonyl)oxy)ethyl(((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl base) (phenoxy)phosphoryl)-L-alanine ethyl ester fumarate (6)

[0089]

[0090] Step 1: Synthesis of 1-(((cyclohexyloxy)carbonyl)oxy)ethyl(tert-butoxycarbonyl)-L-alanine (3)

[0091]

[0092] Under the protection of nitrogen, the DMF (15ml) solution of Boc-L-alanine (2.0g, 10.5mmol) was added dropwise to the DMF (16mL) reaction solution of potassium carbonate (2.9g, 21.1mmol) at 0°C, dropwise After completion, react at room temperature for 30 minutes, cool to 0°C, compound 2 (4.3 g, 21.1 mmol) is added dropwise to the reaction solution, and rise to room temperature to react overnight. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to column chromatography with petroleum ether:ethyl acetate=20:1 to obtain compound 3, 2.0g, 53% .

[0093] ...

Embodiment 2

[0110] Example 2 ((isopropyl)oxy)methyl ((((R)-1-(6-amino-9H-purin-9-yl)prop-2-yl)oxy)methyl)( Phenoxy)phosphoryl)-L-alanine (10)

[0111]

[0112] Step 1: Synthesis of ((isopropoxycarbonyl)oxy(tert-butoxycarbonyl)-L-alanine (8)

[0113]

[0114]A solution of N-Boc-L-alanine (2.5g, 13.2mmol) in DMF (10ml) was added dropwise to ice-bathed potassium carbonate (3.65g, 26.4mmol) and sodium iodide (3.96g, 26.4mmol) in DMF (30 mL) mixture was stirred at room temperature for 30 minutes, cooled to 0°C, compound 7 (4.03 g, 26.4 mmol) was added, and stirred overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, and the obtained organic phase was anhydrous Na 2 SO 4 Drying, silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20:1) gave compound 8, 2.46g, 61%. 1 H NMR (400MHz, CDCl 3 ): δ1.31-1.44 (m, 18H), 4.35-4.39 (m, 1H), 4.91-4.94 (m, 1H), 5.03-5.04 (m, 1H), 5.74-5.84 (m, 2H).

[0115] Step 2: Synth...

Embodiment 3

[0123] Example 3: ((((((R)-1-(6-amino-9H-purin-9-yl)prop-2-yl)oxy)methyl)(phenoxy)phosphoryl)- L-alanyl)oxy)methyl pivalate (14)

[0124]

[0125] Step 1: Synthesis of (((tert-butoxycarbonyl)-L-alanyl)oxy)methylpivalate (12)

[0126]

[0127] Boc-L-alanine (2g, 10.5mmol) in DMF (9mL) was added dropwise to ice-bathed potassium carbonate (2.92g, 21.1mmol) and sodium iodide (3.16g, 21.1mmol) in DMF (28mL) The mixture was stirred and reacted at room temperature for 30 minutes, then cooled to 0°C, compound 11 (3.18 g, 21.1 mmol) was added, and stirred overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, and the obtained organic phase was anhydrous Na 2 SO 4 Drying, silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20:1) gave compound 12, 1.49g, 47%. 1 H NMR (400MHz, CDCl 3 ): δ1.18-1.58 (m, 21H), 4.22-4.31 (m, 1H), 4.99 (m, 1H), 5.72-5.84 (m, 2H).

[0128] Step 2: Synthesis of ((L-alanyl)oxy)m...

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Abstract

The invention provides a phosphamide nucleosides compound as shown in a formula (I). Compared with the prior art, the phosphamide nucleosides compound has the advantages that the phosphamide nucleosides compound has antiviral activity which is remarkably higher than that of TAF on aspects of HIV resisting and hepatitis B resisting; the HIV resisting activity of some compounds is about 10 times higher than that of the TAF, and the hepatitis B resisting activity of the same compounds is also 2-5 times higher than that of the TAF; moreover, the phosphamide nucleosides compound has stable chemical properties and is difficult to hydrolyze by hydrolytic enzymes; compared with the TAF, the phosphamide nucleosides compound has superiority on aspect of toxicity and especially renal toxicity, and patients suffering from HIV and / or HBV can be effectively treated by the compound or isomer thereof at a low clinic dosage.

Description

technical field [0001] The invention belongs to the technical field of medicine and antivirus, and in particular relates to phosphoramidite nucleoside compounds, pharmaceutically acceptable salts, applications and pharmaceutical compositions thereof. Background technique [0002] There are two types of human immunodeficiency virus (HIV), HIV-1 and HIV-2, and severe HIV-1 infection can cause immunodeficiency (ARC and AIDS) in patients. 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 nearly 2.3 million people died of AIDS. The latest research shows that the number of HIV infections among teenagers is on the rise, so it is still necessary to develop new drugs with high efficiency and low toxicity and new drug combinations for the treatment and prevention of AIDS. In 2015, the HIV drug market was US$24.23 billion, growing at an annual rate of 8.6%, and is expecte...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/685A61K31/695A61P31/18
CPCC07F9/65616
Inventor 张红利杨光
Owner 张红利
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