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A substituted adenine compound and its pharmaceutical composition

A compound and pharmaceutical technology, applied in the field of medicine, can solve problems such as toxic side effects and high price

Active Publication Date: 2020-04-10
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The existing treatments for chronic hepatitis B mainly include interferon, nucleoside drugs, and thymosin, but long-term use of these drugs will cause serious side effects or drug resistance, and they are expensive

Method used

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  • A substituted adenine compound and its pharmaceutical composition
  • A substituted adenine compound and its pharmaceutical composition
  • A substituted adenine compound and its pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1 Preparation of 9-{(R)-2-[((S)-{[(S)-1-(isopropoxycarbonyl) ethyl]amino}-2,4,6-d3-phenoxyphos Acyl) methoxyl group] propyl group} adenine, namely compound T-1, molecular formula is as follows:

[0050]

[0051] Synthesize using the following route:

[0052]

[0053]

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

[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 to react overnight, and spot the plate to detect that the reaction is complete. 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 , filtered white solid, and dried in vacuo to obtain 5.77 g of product, yield 100%. LC-MS(APCI): m / z=194.3(M+1)+ .

[0056] Step 2 Synth...

Embodiment 2

[0070] Example 2 Preparation of 9-{(R)-2-[((S)-{[(S)-1-(d7-isopropoxycarbonyl)ethyl]amino}phenoxyphosphoryl)methoxy]propane Base} adenine, namely compound T-2, its molecular formula is:

[0071]

[0072] Adopt the following synthetic route:

[0073]

[0074]

[0075] Step 1 (R)-Synthesis of 9-[2-(phenoxyphosphorylmethoxy)propyl]adenine (Compound 8).

[0076] Add compound 4 (2.4g, 8.36mmol), phenol (1.62g, 16.72mmol) and 6.5ml of NMP into the reaction flask, heat to 85°C, add triethylamine (1.04g, 10.3mmol), heat up to 100°C, add Dicyclohexylcarbodiimide (2.81g, 13.63mmol) was raised to 120°C and stirred for 16 hours. Spot the plate to detect the disappearance of the raw materials and cool down to 45°C, add 4.8ml of water, cool down to room temperature, filter to remove insoluble matter, wash the filter cake with 2.5ml of water, concentrate the filtrate, add 4ml of water, adjust the pH to 11 with NaOH, and extract with chloroform for 3 -4 times, the aqueous phase wa...

Embodiment 3

[0083] Example 3 Preparation of 9-{(R)-2-[((S)-{[(S)-1-(isopropoxycarbonyl)ethyl]amino}-d5-phenoxyphosphoryl)methoxy] Propyl}adenine, namely compound T-3, its molecular formula is:

[0084]

[0085] Adopt following synthetic route:

[0086]

[0087] Step 1 Synthesis of 2,3,4,5,6-d5-phenol (Compound 11).

[0088] Add phenol (2.0g, 21.25mmol), 5% Pt / C (0.4g, 20wt%) and 34ml of heavy water in the reaction flask, replace the hydrogen 3-4 times, react at room temperature for 24 hours, remove the catalyst by filtration, and use the After washing with dichloromethane, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography to obtain 1.6 g of compound 11 with a yield of 80%. LC-MS(APCI): m / z=100.4(M+1) + .

[0089] Step 2 Synthesis of (R)-9-[2-(d5-phenoxyphosphorylmethoxy)propyl]adenine (compound 12).

[0090] Add compound 4 (2.4g, 8.36mmol), compound 11 (1.66g, ...

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Abstract

Disclosed are a substituted adenine compound and a pharmaceutical composition thereof, the substituted adenine compound being a compound of a formula (I), or a crystalline form, pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof. The compound of the present invention can inhibit activity of a nucleoside reverse transcriptase and also has improved pharmacodynamic / pharmacokinetic properties; the compound has high applicability, is safe to use, and can be used for the preparation of a pharmaceutical composition for the treatment of viral infection-associated diseases, thereby having great market potential.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a substituted adenine compound and a pharmaceutical composition thereof, which can be used for treating diseases related to virus infection. Background technique [0002] Nucleoside reverse transcriptase inhibitors (NRTIs), which are synthetic HIV DNA reverse transcriptase substrate deoxynucleotide analogs, are converted into active nucleoside triphosphate derivatives in vivo, and natural deoxynucleoside triphosphates Glycoside competitively combines with HIV reverse transcriptase (RT), inhibits the function of RT, and hinders the synthesis of provirus. The structure of NRTIs is similar to that of nucleosides, which are derivatives of dideoxynucleosides, which can compete with intracellular nucleotides for binding to reverse transcriptase, thereby terminating the reverse transcription reaction. [0003] Nucleotide HIV reverse transcriptase inhibitors act on the acti...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/675A61P31/18A61P31/12
CPCA61K31/675C07F9/6561
Inventor 王义汉赵九洋
Owner SHENZHEN TARGETRX INC
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