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D, L-guanosine nucleoside analog monophosphate, and preparation method and application thereof

A technology of guanine nucleoside and purine nucleoside, applied in the field of nucleoside antiviral drugs, can solve the problems of poor stability, poor pharmacokinetic properties and stability, no guanosine analogs, etc., and achieves a mild preparation method, The effect of improving antiviral activity and good chemical stability

Inactive Publication Date: 2015-06-24
PEKING UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0005] Among nucleoside antivirals, didanosine (ddI), zalcitabine (ddC) in 2',3'-dideoxy and 2',3'-dideoxydidehydronucleoside analogues And stavudine (D4T) has been approved by the FDA to develop antiviral drugs, but there are no guanosine analogues, mainly because 2'3'-dideoxydidehydroguanosine (D4G) and 2'3' - Poor pharmacokinetic properties and stability of dideoxyguanosine (ddG)
Literature (Shirasaka, T.; Murakami, K.; Ford, H., Jr.; Kelley, J.A.; Yoshioka, H.; Kojima, E.; Aoki, S.; Broder, S.; Mitsuya, H., Lipophilic Halogenated congeners of 2', 3'-dideoxypurine nucleotides active against human immunodeficiency virus in vitro[J].Proc.Natl.Acad.Sci.US A.1990, 87(23), 9426-9430.) report, ddG and D4G The prodrug and original drug of the present invention have better antiviral activity, and have certain prospect to be developed into the antiviral drug of clinical application, but, the stability of ddG and D4G is very poor under acidic condition, in order to improve its chemical stability, improve Metabolic properties, literature (Ray, A.S.; Yang, Z.J.; Chu, C.K.; Anderson, K.S., Novel use of a guanosine prodrug approach to convert 2', 3'-didehydro-2', 3'-dideoxyguanosine into a viable antiviral agent [J].Antimicrob.Agents Chemother.2002, 46(3), 887-891.) reported the prodrug modification of ddG and D4G, which mainly carried out different amine substitutions at the 6-position of the base, and the chemical compounds obtained The stability is significantly improved, and the fat solubility is significantly enhanced. After being absorbed, the substituent at position 6 is removed under the action of intracellular enzymes to obtain the original drug and play an antiviral role.

Method used

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  • D, L-guanosine nucleoside analog monophosphate, and preparation method and application thereof
  • D, L-guanosine nucleoside analog monophosphate, and preparation method and application thereof
  • D, L-guanosine nucleoside analog monophosphate, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] [Example 1] 2-amino-6-cyclopropylamino-9-2', 3'-dideoxydidehydro-β-L-purine nucleoside-5'-diethyl monophosphate (L-IA- a) Preparation

[0078] (1) Preparation of Compound IV Take 6-chloro-guanine base (10.0g, 59.0mmol) in a 500mL round-bottom bottle, and after argon pumping three times, add 100mL of 1,2-dichloroethane (DCE), The system was in a suspended state, then added 20 mL of N, O-bistrimethylsilylacetamide (BSA), placed in a preheated 80°C oil bath and refluxed for 40 minutes to obtain a clear solution, after cooling to room temperature, added L-tetraacetyl ribose (Compound III) (10.0g, 31.4mmol) in DCE (40mL) solution, then add trimethylsilyl trifluoromethanesulfonate (TMSOTf) 10mL, continue to reflux for 4h, remove the oil bath, pour the reaction solution into In the ice-saturated saturated sodium bicarbonate solution, there are bubbles and precipitates. After the bubbling stops, the precipitates are removed by filtration, extracted with 300mL×2 dichloromethane...

Embodiment 2

[0085] [Example 2] 2-amino-6-cyclopropylamino-9-2', 3'-dideoxy-β-L-purine nucleoside-5'-diethyl monophosphate (L-IIA-a) preparation

[0086] Take compound L-IA-a (5 mg, 0.012 mmol), dissolve it in anhydrous methanol (3 mL), add 10% Pd / C (3 mg), react on a hydrogenation instrument at 60 psi for 2 h, remove the catalyst by filtration, and evaporate the solvent to obtain White solid compound L-IIA-a (4 mg, 80%). 1 H NMR (400MHz, CDCl 3 )δ7.70 (s, 1H, 8-H), 6.14-6.11 (m, 1H, 1'-H), 5.76 (brs, 1H, 6-NH), 4.89 (brs, 2H, 2-NH 2 ), 4.38-4.29(m, 2H, 5’-H), 4.19-4.15(m, 1H, 4’-H), 4.12-4.05(m, 4H, H-POCH 2 ), 2.99(m, 1H, H-a), 2.60-2.52(m, 1H, 2'-H), 2.49-2.40(m, 1H, 2'-H), 2.21-2.15(m, 2H, 3'- H), 1.34-1.29 (m, 6H, H-CH 3 ), 0.88-0.83 (m, 2H, H-b 1 ), 0.63-0.59 (m, 2H, H-b 2 ). 13 CNMR (101MHz, CDCl 3 )δ135.75, 115.19, 85.24, 79.27, 79.19, 68.33, 68.27, 64.19, 64.13, 31.94, 29.84, 23.85, 16.29, 16.23, 7.60. 31 P NMR (162MHz, CDCl 3 )δ-0.76.MS (ESI-TOF + )m / z 427[M+H] + ;44...

Embodiment 3

[0087] [Example 3] 2-amino-6-(1-pyrrolidinyl)-9-2',3'-dideoxy-2',3'-didehydro-β-L-purine nucleoside-5' - Preparation of diethyl monophosphate (L-IA-b)

[0088] Take compound X-A (70mg, 0.175mmol), dissolve it in anhydrous acetonitrile (5mL), add pyrrolidine (0.7mL), react at room temperature for 20min, evaporate the solvent to dryness, and separate the sample with silica gel under normal pressure column (ethyl acetate:methanol=20 : 1) Compound L-IA-b (65 mg, 85%) was obtained as a white solid. 1 H NMR (400MHz, CDCl 3 )δ7.55(s, 1H, 8-H), 6.93(s, 1H, 1'-H), 6.37-6.36(m, 1H, 2'-H), 6.07-6.05(m, 1H, 3' -H), 5.05(s, 1H, 4'-H), 4.83(s, 2H, 2-NH 2 ), 4.15-4.12(m, 2H, 5'-H), 4.07-3.97(m, 4H, H-POCH 2 ), 3.66 (brs, 3 ). 13 C NMR (101MHz, CDCl 3)δ159.93, 153.66, 152.32, 134.40, 132.90, 126.73, 115.34, 87.78, 85.07, 84.98, 67.75, 67.69, 64.14, 64.08, 16.20, 16.16, 16.09. 31 PNMR (162MHz, CDCl 3 )δ-0.97.HRMS (ESI-TOF + )m / z calcd.for C 18 h 28 N 6 o 5 P[M+H] + 439.18533; fou...

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Abstract

The invention discloses D, L-guanosine nucleoside analog monophosphate, and a preparation method and application thereof. The structural formula of D, L-guanosine nucleoside analog monophosphate is respectively represented by general formula (I) or (II), wherein R1 is amino, fatty amino, naphthenic amino or pyrrolidinyl, and R2 is fatty amino or alkoxy. D, L-guanosine nucleoside analog monophosphate has good chemical stability and pharmacokinetic stability and overcomes the shortcomings that active medicine D4G and ddG are low in stability and poor in pharmacokinetic stability and the like, simultaneously the single phosphorylation rate-limiting step in the metabolic process can be omitted, and antiviral activity is reinforced. The preparation method of D, L-guanosine nucleoside analog monophosphate is mild, simple and convenient to operate and high in yield. Antiviral activity tests show that compounds represented by the general formula (I) and (II) have a certain antiviral activities and can be applied to preparation of medicines resisting HIV virus, HBV virus, HCV virus or HSV virus.

Description

technical field [0001] The present invention relates to nucleoside analogs, in particular to D, L-guanosine nucleoside analog monophosphate and its preparation method, the present invention also relates to the D, L-guanine nucleoside analog monophosphate in the preparation of antiviral The use in medicine belongs to the field of nucleoside antiviral 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 first nucleoside antivir...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/14A61P31/20A61P31/18A61P31/22
Inventor 杨振军杨先桃潘德林关注郭颖
Owner PEKING UNIV
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