A group of six-carbocycle nucleoside analogue, its synthesis method and antiviral application

A carbocyclic nucleoside and analog technology, applied in the field of six-membered carbocyclic nucleoside analogs, can solve problems such as no new compounds

Inactive Publication Date: 2008-08-20
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The adenine nucleoside analogs, guanosine nucleoside analogs, inosine nucleoside analogs, mercaptopurine nucleoside analogs, and 6-chloro-purine nucleoside analogs of six-membered carbocyclic polyols provided by the present invention , 2-amino-6-chloro-purine nucleoside analogues, cytidine nucleoside analogues, 5-fluorocytidine nucleoside analogues, uridine nucleoside analogues, 5-fluorouridine nucleoside analogues, thymidine nucleus Glycoside analogs, and the salt complexes of said compound and acid (1:1), are new compounds that have not been reported so far.

Method used

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  • A group of six-carbocycle nucleoside analogue, its synthesis method and antiviral application
  • A group of six-carbocycle nucleoside analogue, its synthesis method and antiviral application
  • A group of six-carbocycle nucleoside analogue, its synthesis method and antiviral application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1 : 3-O-methyl-D-inositol-5-(9'-adenine) nucleoside and 3-O-methyl-D-inositol-4-(9'-adenosine) nucleoside (compound Syntheses numbered 1a and 1b) respectively

[0057] (1) Synthesis of 1,2:5,6-di-O-isopropylidene-3-O-methyl-D-inositol

[0058] After adding 25mLDMF, 50mL 2,2-di-methoxypropane and 150mL acetone in a 500mL three-necked flask, add 10.0g (51.5mmol) of 3-O-methyl-D-inositol, 380mg of p-toluenesulfonic acid ( 2.0mmol) and anhydrous magnesium sulfate 9.0g, the suspension was stirred at room temperature for 16 hours, 1.0g of sodium bicarbonate was added, stirred for half an hour and then filtered, the filter residue was washed 3 times with ethyl acetate and combined with the filtrate, concentrated under reduced pressure Recrystallize with a mixed solvent of n-hexane and ether in equal proportions to obtain 12.6 g (46.0 mmol, 89%), the crude product can be directly used in the next step reaction. Melting point: 95-96°C, [α] D 20 -41.5° (c 0.021g / mL,...

Embodiment 2

[0069] Example 2 : 3-O-methyl-D-inositol-5-(1'-cytosine) nucleoside and 3-O-methyl-D-inositol-4-(1'-cytosine) nucleoside (compound Numbered respectively 2a and 2b) synthesis

[0070] (1) Synthesis of 1,2:5,6-di-O-isopropylidene-3-O-methyl-D-inositol

[0071] Synthesized as in Example 1 (1) method and conditions.

[0072] (2) Synthesis of 1,2:5,6-di-O-isopropylidene-3-O-methyl-4-methanesulfonyl-D-inositol

[0073] Synthesize as embodiment 1 (2) method and condition.

[0074] (3) Synthesis of 3-O-methyl-4-methanesulfonyl-D-inositol

[0075] Synthesize as embodiment 1 (3) method and condition.

[0076] (4) Synthesis of 3-O-methyl-4,5-epoxy-D-inositol

[0077] Synthesized as in Example 1 (4) method and conditions.

[0078] (5) 3-O-methyl-D-inositol-5-(1'-cytosine) nucleoside and 3-O-methyl-D-inositol-4-(1'-cytosine) nucleoside (compound numbers are respectively 2a and 2b) synthetic

[0079] Add 352mg (2mmol) of epoxy compound and 333mg (3mmol) of dry cytosine into a three-...

Embodiment 3

[0083] Implementation 3 : Synthesis of 3-O-methyl-D-inositol-5-(9'-adenine) nucleoside fumaric acid complex (1c)

[0084] The synthetic method of 3-O-methyl-D-inositol-5-(9'-adenine) nucleoside fumaric acid complex (1c) is as follows: 3-O-methyl-D-inositol-5- (9'-Adenine) nucleoside 311mg (1mmol) mixed with fumaric acid 124mg (1mmol) and 2ml of isopropanol, the resulting mixture was stirred at 50 ° C until the solid was completely dissolved, then cooled at room temperature to precipitate crystals, filtered to obtain a solid , and the product was washed with ether, dried in vacuo to obtain 318 mg, the yield was 73%, except for 3-O-methyl-D-inositol-5-(9'-adenine) nucleoside signal in 1H NMR (DMSO), The signal of fumaric acid double bond hydrogen was shown at δ (ppm) 6.216 (s, 2H).

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Abstract

The disclosed six-membered carbocyclic nucleoside analogues comprise: adenosine analogue, guanosine analogue, carnine analogue, mercaptopurine riboside analogue, cytidine analogue, 5-fluorocytidine analogue, uridine analogue, 5-fluorouridine analogue, and thymidine analogue as well as their acceptable salts formed by equimolar acid in pharmacy. Wherein, the opposite five-step synthesis method using the pinitol, acetone, methane sulfonyl chloride, p-toluenesulfonyl chloride, benzene sulfochloride, and nucleoside base as materials; the pyridine, water, glacial acetic acid, absolute methanol, DMSO, N, N-DMF as the solvent; the p-toluenesulfonic acid, 2, 2-dimethoxylpropane, anhydrous NaSO4, NaHCO3, triethylamine, and anhydrous K2CO3 as the catalyst. This invention restrains specially the replication of HIV and herpesvirus.

Description

Technical field: [0001] The present invention relates to a group of six-membered carbocyclic nucleoside analogs and complexes (1:1) of said six-membered carbocyclic nucleoside analogs and acid; aspects of application. Background technique: [0002] In recent years, nucleoside drugs have received widespread attention as the main therapeutic drugs for viral diseases. Nucleoside drugs used to treat human immunodeficiency virus (human immunodificiency virus, HIV) and herpes simplex virus (herpes simplex virus, HSV) infection are generally HIV virus reverse transcriptase inhibitors and HSV virus deoxyribonucleic acid (deoxyribonucleic acid) acid, DNA polymerase inhibitor. Nucleoside drugs are still the most effective drugs against HIV and HSV (Tang Yanbo, Li Zhuorong, Research Progress of Nucleoside Antiviral Drugs, Chinese Journal of Biochemical Pharmaceuticals, Volume 25, No. 1, 2004: 44- 47; Li Zicheng, Chen Shuhua, Jiang Ning, Lu Ding. Research progress of nucleoside antiv...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H7/06C07H1/00A61P31/12A61K31/7052
Inventor 娄红祥詹天荣马玉道范培红
Owner SHANDONG UNIV
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