A novel acyclic nucleoside analogue and its pharmaceutical composition

A composition and drug technology, applied in the field of medicine, can solve the problems of nephrotoxicity risk, drug resistance, low absorption efficiency of target cells, etc.

Active Publication Date: 2020-11-03
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although TDF is currently one of the most effective antiretroviral drugs and antiviral guidelines in many countries have recommended it as the first-line anti-HIV / HBV drug, it still has certain defects, mainly including low absorption efficiency of target cells, Drug resistance and potential risk of nephrotoxicity

Method used

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  • A novel acyclic nucleoside analogue and its pharmaceutical composition
  • A novel acyclic nucleoside analogue and its pharmaceutical composition
  • A novel acyclic nucleoside analogue and its pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1 Preparation of (R)-9-{2-[(hexadecyloxy-d6-propyl)phosphomethoxy]propyl}adenine, that is, the compound Thing T-1, concrete synthetic steps are as follows:

[0053]

[0054] Step 1 Synthesis of (R)-9-(2-hydroxypropyl)adenine (compound 3).

[0055] Add adenine (4.0g, 29.6mmol) and (R)-propylene carbonate (3.45g, 33.8mmol) into the reaction flask, add 4.5mL DMF to dissolve, heat to 130°C for overnight reaction, TLC detects that the reaction is complete, then cool down To 100°C, add 14mL of toluene and 0.47g of methanesulfonic acid (keep the internal temperature at 100-110°C), then add 11mL of toluene to obtain a homogeneous suspension, gradually cool down to room temperature, then cool down to 0°C for 1 hour, The filtered white solid was vacuum-dried to obtain 5.77 g of product, yield 100%. LC-MS(APCI): m / z=194.3(M+1) + .

[0056] Step 2 Synthesis of diethyl[[(p-toluenesulfonyl)oxy]methyl]phosphate (compound 5).

[0057]Add diethyl hydroxymethyl phosphat...

Embodiment 2

[0066] Example 2 Preparation of (R)-9-{2-[(hexadecyloxy-2-d2-propyl)phosphomethoxy]propyl}adenine, namely Compound T-2, the specific synthesis steps are as follows:

[0067]

[0068] Step 1 Synthesis of diethyl 2-d2-malonate (compound 11).

[0069] Diethyl malonate (4.0g, 25mmol), potassium carbonate (345mg, 2.5mmol) and 15mL of heavy water were added into a microwave reaction vial, sealed and placed in a microwave reactor and heated to 85°C for 45 minutes. After cooling down to room temperature, ethyl acetate was added to extract three times, the organic phases were combined, washed with saturated brine, concentrated and purified by column chromatography to obtain 3.63 g of the target product with a yield of 90.7%. LC-MS(APCI): m / z=163.1(M+1) + .

[0070] Step 2 Synthesis of 2-d2-1,3-propanediol (compound 12).

[0071] Compound 11 (2.26g, 13.94mmol) was added to the reaction flask, dissolved in 50mL of anhydrous tetrahydrofuran, and lithium aluminum hydride (1.06g, ...

Embodiment 3

[0076] Example 3 Preparation of (R)-9-{2-[(hexadecyloxy-1,3-d4-propyl)phosphomethoxy]propyl}adenine, namely Compound T-3, the specific synthesis steps are as follows:

[0077]

[0078] Step 1 Synthesis of 1,3-d4-1,3-propanediol (compound 14).

[0079] Diethyl malonate (1.0g, 6.24mmol) was added to the reaction flask, dissolved in 20mL of anhydrous tetrahydrofuran, under ice bath, deuterated lithium aluminum hydride (0.52g, 12.5mmol) was added in batches, and the addition was completed. The reaction was stirred overnight at room temperature. The reaction was quenched by adding a small amount of decahydrate and sodium sulfate in an ice bath, and the insoluble matter was removed by filtration. The filtrate was concentrated to obtain the crude product of the target product, which was dried in vacuo to obtain 263 mg, with a yield of 52.6%. LC-MS(APCI): m / z=81.1(M+1) + .

[0080] Step 2 Synthesis of 3-hexadecyloxy-1,3-d4-1-propanol (compound 15).

[0081] Add hexadecane b...

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Abstract

Provided in the present invention is a new type acyclic nucleoside analogue and a pharmaceutical composition thereof, wherein the new type nucleoside analogue is the compound as shown by formula (I), or a crystal form, a pharmaceutically acceptable salt, a prodrug, a stereisomer, a hydrate or a solvate thereof. The compound of the present invention can inhibit the activity of a nucleoside reverse transcriptase, and at the same time, has a better pharmacodynamics / pharmacokinetics performance. The compound has a good applicability and high safety, and can be used to prepare drugs for treating diseases related to viral infections.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a novel acyclic nucleoside analog and a pharmaceutical composition thereof, which can be used for treating diseases related to virus infection. Background technique [0002] AIDS is a serious disease caused by HIV infection. Since the first AIDS case was reported in 1981, nearly 70 million people worldwide have been infected with HIV and more than 20 million people have died of AIDS. In the past 20 years, although effective drug treatment has reduced the death rate of AIDS, millions of people are still infected with HIV every year, and the number of AIDS patients in the world has been on the rise. [0003] Hepatitis B (hepatitis B) is a worldwide epidemic infectious disease with high incidence, strong infectivity, and serious harm to human health. At present, about 2 billion people in the world have been infected with hepatitis B virus (HBV), and 350 million of them...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561C07B59/00A61K31/675A61P31/18A61P31/20
CPCA61K31/675C07B59/00C07F9/6561
Inventor 王义汉赵九洋
Owner SHENZHEN TARGETRX INC
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