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Nucleoside compounds with HIV-1/HBV viral replication inhibition activity, preparation methods thereof, and antiviral applications thereof

A compound, cyclic nucleoside technology, applied in the field of nucleoside compounds, can solve the problems of poor membrane permeability, sufficient concentration of infected parts, no antiviral activity, etc., and achieve good fat solubility, low toxicity, and high activity Effect

Active Publication Date: 2013-08-07
洛阳聚慧新材料科技有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] As a prodrug, it has no antiviral activity itself. After entering the body, the original drug must be freed to exert its curative effect, and some drugs are hydrolyzed before being absorbed into the blood; in addition, the released original drug tenofovir is also due to membrane penetration Due to the problem of poor sex, it is quickly excreted from the body and it is difficult to maintain a sufficient concentration in the infected part, resulting in only about 28% of its bioavailability in the human body.

Method used

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  • Nucleoside compounds with HIV-1/HBV viral replication inhibition activity, preparation methods thereof, and antiviral applications thereof
  • Nucleoside compounds with HIV-1/HBV viral replication inhibition activity, preparation methods thereof, and antiviral applications thereof
  • Nucleoside compounds with HIV-1/HBV viral replication inhibition activity, preparation methods thereof, and antiviral applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1: (R)-9-[2-[[isopropoxycarbonyloxymethyl[(S)-1-(ethoxycarbonyl)] ethyl] phosphoramidate methoxy] propyl] adenine (COP231 ) preparation

[0051]

[0052] In a 50ml round bottom flask, add (R)-9-[2-(phosphomethoxy)propyl]adenine (tenofovir, PMPA) (1.3g, 4.5mmol), triethylamine (7ml , 5.08g, 50.2mmol), chloromethyl isopropyl carbonate (0.265ml, 0.305g, 2mmol) and N-methyl-2-pyrrolidone (14ml), stirred at 60°C for 15h, evaporated the solvent, and used Ethyl acetate: ethanol=10:1 silica gel column chromatography, obtain intermediate compound: (R)-9-{2-[(isopropoxycarbonyloxymethyl) phosphomethoxy] propyl group} adenine (C0P02) (0.68g, 1.68mmol) yield 37.3%.

[0053] In a 50ml round bottom flask, add COP02 (8.47g, 21mmol), L-alanine ethyl ester hydrochloride (6.6g, 43mmol), 2,2'-dithiodipyridine (9.03g, 41mmol), Triethylamine (11.04g, 15.2ml, 109mmol), triphenylphosphine (11.2g, 43mmol) and pyridine (25ml), after closed stirring at 65°C for 16h, evaporate th...

Embodiment 2

[0054] Embodiment 2: (R)-9-[2-[[isopropoxycarbonyloxymethyl [(S)-1-(isobutoxycarbonyl)] ethyl] phosphoramidate methoxy] propyl] adenine ( Preparation of COP232)

[0055]

[0056] Synthesized in a similar manner to Example 1: (R)-9-[2-[[isopropoxycarbonyloxymethyl[(S)-1-(isobutoxycarbonyl)]ethyl]phosphoramidate methoxy]propane Base] adenine (COP232). 1 H NMR (400MHz, CDCl 3 )δ,(ppm):0.87-0.95(6H,m,2×CH 3 ), 1.17-1.45 (12H, m, 4×CH 3 ),1.84-2.00(1H,m,CH),3.60-3.71(1H,m,OCH),3.83-4.00(4H,m,COOCH,COOCH 2 and NCH), 4.08-4.18 (2H, m, OCH 2 P),4.25-4.46(2H,m,NCH 2 ),4.87-4.98(1H,m,NH),5.57-5.73(2H,m,OCH 2 O),6.60(2H,s,NH 2 ),7.96-8.03(1H,d,H on the purine ring),8.29-8.36(1H,d,H on the purine ring).ESI-MS:[M+H] + 531.3, [M+Na] + 553.2

Embodiment 3

[0057] Embodiment 3: (R)-9-[2-[[isopropoxycarbonyloxymethyl[(S)-1-(neopentyloxycarbonyl)] ethyl] phosphoramidate methoxy] propyl] adenine ( Preparation of COP233)

[0058]

[0059] Synthesized in a similar manner to Example 1: (R)-9-[2-[[isopropoxycarbonyloxymethyl[(S)-1-(neopentyloxycarbonyl)]ethyl]phosphoramidate methoxy]propane Base] adenine (COP233). 1 H NMR (400MHz, CDCl 3 )δ,(ppm):0.94(9H,s,3×CH 3 ),1.17-1.22(3H,d,CH 3 ), 1.26-1.32 (6H, m, 2×CH 3 ),1.40-1.46(3H,d,CH 3 ),3.60-3.87(3H,m,2×COOCH and NCH),3.88-3.95(2H,m,COOCH 2 ),4.08-4.39(4H,m,OCH 2 Pand NCH 2 ),4.86-4.97(1H,m,NH),5.57-5.73(2H,m,OCH 2 O),6.46(2H,s,NH 2 ),7.99(1H,s,H on the purine ring),8.33(1H,s,H on the purine ring).ESI-MS:[M+H] + 545.4, [M+Na] + 567.3

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Abstract

The invention discloses acyclic nucleoside compounds with an HIV-1 / HBV viral replication inhibition activity, preparation methods thereof, and antiviral applications thereof. The invention also discloses a general formula I of the compounds. R1 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C5-6 aryl, or C5-12 aralkyl. R2 is a side chain of any natural or pharmaceutically acceptable amino acid. When the side chain contains carboxyl, the carboxyl is esterified optionally by using alkyl or aryl. The invention also discloses preparation methods of the compounds represented by the structural general formula I and a structural general formula II, and medicine compositions comprising the compounds. As a result of experiments, the compounds provided by the invention have the activity of inhibiting HIV-1 / HBV viral replication. One of the compounds has activity higher by more than 385 times that of a current AIDS-treating medicine tenofovir disoproxil fumarate (TDF), and higher fat-solubility than TDF. The compounds can be used in developments of medicines used for treating AIDS or hepatitis B.

Description

Technical field: [0001] The present invention relates to a group of nucleoside compounds, in particular to a group of acyclic nucleoside compounds with activity of inhibiting HIV-1 / HBV virus replication, preparation method and antiviral application. Background technique: [0002] In the treatment of viral infectious diseases in humans, the problem of viral drug resistance has become increasingly prominent. Compared with cyclic nucleoside reverse transcriptase inhibitors, tenofovir, an acyclic nucleoside compound, has obvious advantages in preventing viral drug resistance, and it is effective for virus strains resistant to cyclic nucleoside drugs. The incidence of drug resistance is low, and the toxicity is relatively small, which can be used to treat patients who are co-infected with HIV-1 and HBV. However, due to the negative charge of the phosphate group, the polarity is too strong, and the biofilm permeability is poor, resulting in very low bioavailability, so that it ca...

Claims

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Application Information

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IPC IPC(8): A61P31/18A61K31/675C07F9/6561A61P31/20
Inventor 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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