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D, L-guanosine analogs, preparation methods thereof and applications thereof

A kind of technology of guanosine and purine nucleoside

Inactive Publication Date: 2011-11-09
PEKING UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, ddG and D4G are very poorly stable under acidic conditions
It is reported in the literature that D4G has a half-life of only 2 minutes in a solution of pH=7 and rapidly decomposes into bases and furfural, so it cannot be used as a drug for clinical use.
In addition, ddG and D4G have high polarity and poor fat solubility, so they also have certain difficulties when used as oral drugs

Method used

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  • D, L-guanosine analogs, preparation methods thereof and applications thereof
  • D, L-guanosine analogs, preparation methods thereof and applications thereof
  • D, L-guanosine analogs, preparation methods thereof and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Example 1 The preparation of 2-amino-6-methylamino-9-2', 3'-dideoxydidehydro-β-D-purine nucleoside (D-Ia)

[0102] (1) Preparation of compound IV, 6-chloro-2 aminopurine base (1 g) was placed in a 50 mL three-neck flask, replaced with argon, and then dry DCE (10 mL) was added thereto; the system was in a suspended state at this time. Then BSA (2 mL) was added thereto, placed in an oil bath preheated to 80° C., and refluxed for 1 hour under the protection of argon, the system gradually became clear. The oil bath was removed and allowed to cool to room temperature, then a solution of D-tetraacetylribose (1 g) in DCE (4 mL) and TMSOTf (1 mL) was added thereto, heated to 80° C., and refluxed for 5 h under protection of argon. Remove the oil bath and pour it into ice saturated NaHCO 3 In the solution (20mL), bubbles and a large amount of sediment appeared. After the bubbling stopped, the precipitate was removed by filtration, extracted with DCM (20 mL), and the organic pha...

Embodiment 2

[0108] Example 2 Preparation of 2-amino-6-dimethylamino-9-2', 3'-dideoxydidehydro-β-D-purine nucleoside (D-Ib)

[0109] Suspend compound D-VIII (130mg, 0.486mmol) in ethanol (5mL), add aqueous dimethylamine solution (10mL), and reflux at 95°C for 1 hour. After the reaction of the raw materials is complete, the solvent is evaporated to dryness, and the sample is mixed with silica gel on an atmospheric pressure column. Separation (dichloromethane:methanol=120:1) gave white foamy solid product D-Ib (112mg), yield 88%. UV(MeOH) λ max 222nm (ε19214), 281.5 (ε12112); 1 H NMR (300MHz, CDCl 3 )δ7.51(s, 1H, 8-H), 6.67-6.70(m, 2H, 1'-H and OH), 6.376-6.41(m, 1H, 2'-H), 5.929-5.949(m, 1H, 3'-H), 5.07-5.08 (m 1H, 4'-H), 4.62 (brs, 2H, 2-NH 2 ), 4.06-4.01, 3.85-3.90 (m, 1H, 1H, 5'-H), 3.44 (brs, 6H, CH 3 ); 13 C NMR (125MHz, DMSO-d 6 )δ160.3, 155.4, 135.0, 134.0, 125.7, 113.4, 87.6, 87.2, 63.1, 62.8, 26.8; [α] D 20 -19.1 (c 0.18, MeOH).

Embodiment 3

[0110] Example 3 Preparation of 2-amino-6-cyclopropylamino-9-2', 3'-dideoxydidehydro-β-D-purine nucleoside (D-Ic)

[0111] Take compound D-VIII (100mg, 0.374mmol) and suspend it in ethanol (5mL), add cyclopropylamine (1mL), stir at room temperature for 36 hours, evaporate the solvent, and separate the sample under reduced pressure on silica gel (dichloromethane:methanol= 100:1) to obtain white foamy solid product D-Ic (89mg), yield 86%. UV(MeOH)λ max 224.5nm(ε16314), 284.5nm(ε12477); 1 H NMR (500MHz, DMSO-d 6 )δ7.72(s, 1H, 8-H), 7.32(brs, 1H, 6-NH), 6.75-6.76(m, 1H, 1'-H), 6.41-6.43(m, 1H, 2'- H), 6.07-6.09 (m, 1H, 3'-H), 5.85 (brs, 2H, 2-NH 2 ), 5.03-5.05(t, 1H, 5'-OH), 4.82-4.85(m, 1H, 4'-H), 3.54-3.60(m, 2H, 5'-H), 3.04(s, 1H, H-a), 0.560-0.68 (brs, 4H, H-b); 13 C NMR (125M Hz, DMSO-d 6 )δ160.2, 155.9 135.162, 134.0, 125.7, 113.3, 87.6, 87.2, 63.1, 6.4, 5.6; [α] D 20 -22.4 (c 0.21, MeOH).

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Abstract

The invention discloses D, L-guanosine analogs, preparation methods thereof and applications thereof. The structural formulas of the analogs are respectively represented by a general formula I or a general formula II, wherein R is hydrogen, amino, piperidyl, morpholinyl or pyrrolidinyl. The good chemical stability and the pharmacokinetic stability showed by the D, L-guanosine analogs of the invention make up for shortages of low stability, poor pharmacokinetic stability and the like existing in D4G and ddG. The preparation methods of the D, L-guanosine analogs have the advantages of mild reaction, simplicity and high yield. Antiviral activity testing shows that the compounds with the general formula I or the general formula II which have excellent antiviral activity can be applied to prepare anti-HIV drugs, anti-HBV drugs, anti-HCV drugs or anti-HSV drugs.

Description

technical field [0001] The present invention relates to nucleoside analogs, especially to D, L-guanosine nucleoside analogs and a preparation method thereof. The present invention also relates to the use of the D, L-guanosine nucleoside analogs in the preparation of antiviral drugs, belonging to The field of nucleoside drugs. Background technique [0002] Viruses are a class of microorganisms that do not have a cell structure but have life characteristics such as heredity and replication. Viral diseases are common and frequently-occurring diseases that seriously endanger human health. According to statistics, about 60% of epidemic infectious diseases are caused by virus infection. There are more than 150 kinds of human pathogenic viruses, which are divided into two categories: DNA viruses and RNA viruses. The most harmful viral diseases include viral hepatitis, influenza, measles, herpes and AIDS. [0003] Since the late 1950s when iodine uridine (IDU) was successfully u...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/16A61K31/52A61P31/12A61P31/18A61P31/20A61P31/14A61P31/22A61P1/16
Inventor 杨振军谢璐佳郭颖潘德林曹颖莉关注张礼和
Owner PEKING UNIV
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