WO2014000541A1

WO2014000541A1 - Acyclic nucleotide analogue, preparation method therefor, and application thereof

Info

Publication number: WO2014000541A1
Application number: PCT/CN2013/076066
Authority: WO
Inventors: 谢永美; 魏于全; 李炯; 耿福能
Original assignee: 四川好医生攀西药业有限责任公司; 四川大学
Priority date: 2012-06-29
Filing date: 2013-05-22
Publication date: 2014-01-03
Also published as: CN102887901A; CN102887901B

Abstract

The present invention relates to the technical field of chemically synthesized drugs, and in particular, to an acyclic nucleotide analogue, a preparation method therefor, and an application thereof in an antiviral drug. A technical problem to be solved by the present invention is to provide a novel acyclic nucleotide analogue, having a structure represented by formula (I). The acyclic nucleotide analogue of the present invention has an antiviral efficacy and provides a new choice for the development of antiviral drugs.

Description

Acyclic nucleotide analogue and preparation method and application thereof

Technical field

The invention belongs to the technical field of chemical synthetic drugs, and particularly relates to acyclic nucleotide analogs, a preparation method thereof and application in antiviral drugs.

Background technique

Diseases caused by viral infections such as viral hepatitis and AIDS are major diseases that seriously threaten human health. International research on antiviral drugs has made important progress, and some clinically effective antiviral drugs have been discovered, such as interferon, lamivudine, telbivudine, clafidine, entecavir, adefovir dipivoxil, Norfovirtide, zidovudine, stavudine, nevirapine, indinavir and valaciclovir. As an important family of nucleoside antiviral drugs, open-loop nucleoside compounds have low toxicity, good tolerance and broad-spectrum anti-DNA virus activity, and have strong killing effect on drug-resistant strains. They play an important role in the field of antiviral therapy. Status, among which acyclic nucleotide antiviral drugs represented by tenofovir and adefovir dipivoxil are hotspots in recent years (Tang YB, Peng ZG, Liu ZY, et al. Bioorganic & Medicinal Chemistry Letters , 2007, 17(22): 6350-6353 ) ₀ Studies have shown that adefovir dipivoxil and tenofovir disoproxil fumarate (TDF) are effective against lamivudine-resistant strains, The inhibitory constant of norfovirtide on DNA polymerase is 5 times that of adefovir. In vitro, TDF is effective against a variety of viruses, including those resistant to nucleoside reverse transcriptase inhibitors. Tenofovir is approved by the FDA in 2001 and 2008 for the treatment of HIV and HBV infection. Recent studies have found that tenofovir disoproxil has a good therapeutic effect on HCV infection (Tuma P, Vispo E, Barrei) Ro P, Soriano V. Enferm Infecc Microbiol Clin. 2008, 26 (Suppl 8): 31 -37). Like other antiretroviral drugs, TDF can also cause viral resistance. Increasing the concentration of TDF in the in vitro MT-2 cell line produces a virus strain that survives in 2 μΜ TDF. In addition, tenofovir can cause acute renal failure, Fanconi syndrome, proteinuria or tubular necrosis.

In summary, although open-loop nucleosides have been greatly developed, there are still problems of drug resistance and side effects. Therefore, exploring and developing new antiviral drugs remains an urgent research topic.

Summary of the invention

A first technical problem to be solved by the present invention is to provide a novel class of acyclic nucleotide analogs having the structure shown in Formula I:

I

among them

Is one of hydrogen, hydrazine, halogen, amino, hydroxy, nitro, nitrile, fluoromethyl;

Is hydrogen, hydrazine, halogen, amino, hydroxy, nitro, nitrile, fluoromethyl, linear or branched or cyclic ~

a C ₆ alkylamino group, a linear or branched ~ alkoxy group, a substituted aryloxy group or a substituted aryl thio group; R ₃ is one of hydrogen, hydrazine, halogen, amino, nitro, nitrile, fluoromethyl, linear or branched ~-alkylamino;

R4 is one of hydrogen, hydrazine, cyclopropyl, linear or branched or cyclic alkyl, fluoromethyl, hydroxymethyl;

,

Z is 0, S or Se; Χι X _{2 is} independently 0, S or NH;

R ₆ , R _{7 are} independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, aryl or aralkyl, or R ₆ , R _{7 are} independently 1 to 3 selected from alkylamino, alkyl Aminoalkyl, dialkylaminoalkyl, dialkylamino, hydroxy, oxo, halogen, amino, alkylthio, alkoxyalkyl, aryloxy, aryloxyalkyl, aryloxyoxy An alkyl group substituted with a substituent of an arylalkoxyalkyl group, a haloalkyl group, a nitro group, a nitroalkyl group, an azido group, an azidoalkyl group, an alkanoyl group, an alkanoylalkyl group, a carboxyl group or an alkanoylamino group Alkenyl, alkynyl, aryl or aralkyl;

It is hydrogen, hydrazine, aryl, linear or branched dC ₆ alkyl, linear or branched dC ₆ haloalkyl, benzyl. It is one of a linear or branched or cyclic alkane, substituted aryl group. As a preferred embodiment of the present invention, among the above compounds, hydrogen, halogen, amino, and nitrile groups; preferably, hydrogen, hydrazine, halogen, and most preferably hydrogen and hydrazine.

As a preferred embodiment of the present invention, among the above compounds, hydrogen, hydrazine, halogen, amino group and hydroxyl group; preferred are hydrogen, amino group and hydroxyl group; and most preferred is an amino group.

As a preferred embodiment of the present invention, among the above compounds, hydrogen, hydrazine, halogen, or amino group; preferred are hydrogen and halogen.

As a preferred embodiment of the present invention, in the above compound, R4 is hydrogen, hydrazine, methyl or hydroxymethyl; preferred is hydrogen, hydrazine, methyl; and most preferred is methyl.

As a preferred embodiment of the present invention, the above _compounds: Z is 0, S or Se; preferably 0, and S; and most preferably 0.

R _{7 is} independently hydrogen,

氘, 素, aryl, -OH,

-CF ₃

Further preferably, R6, R ₇ is independently hydrogen, deuterium, x, X

Preferably, Z is 0, and the structural formula is as follows:

II

As a preferred embodiment of the present invention, among the above compounds,

Is hydrogen, hydrazine, aryl, linear or branched alkyl, linear or branched dC ₆ haloalkyl, benzyl, more preferably aryl; preferably Z is 0, the structural formula is as follows:

III

As a preferred embodiment of the present invention, in the above compound, R ₅ is

, which is a linear or branched or cyclic alkane, a substituted aryl group; preferably a substituted aryl group; preferably Z is 0, and the structural formula is as follows:

IV.

The invention also provides a process for the preparation of the acyclic nucleotide analogue of formula I: When R ₅ is Χ _{2 -} ί 3⁄4, the route is as follows:

Compound 1 and Compound 2 are condensed under basic conditions to obtain Compound 3, and Compound 3 and Compound 4 are alkylated under basic conditions to directly obtain Compound 5; or

Compound 3 is first reacted with compound 6 to give compound 7, and then deprotected to give compound 8, compound 8 with halogenated hydrocarbon, phenol

Io Ru is independently alkyl, alkenyl, alkynyl, aryl or aralkyl; Xi, Χ ₂ , Υι Υ _{2 are} independently 0, S or NH;

when

When the route is as follows:

10 12 Compound 9 is reacted with an acid chloride reagent to obtain phosphonic acid chloride compound 10, and compound 10 is reacted with compound 11 under organic basic conditions, 12;

When

When the route is as follows:

Route A:

14

After adding the compound 9 and the compound 13, the organic base and the dehydrating agent are reacted, ethyl acetate is added, washed with water, sodium hydrogencarbonate, saturated brine, dried, filtered, concentrated under reduced pressure,

Route B:

Compound 9 is reacted with an acid chloride reagent to obtain a phosphonic acid chloride compound 10, and compound 10 is reacted with compound 13 under organic basic conditions to give compound 14.

The present invention also provides the use of the above acyclic nucleotide analog for the preparation of a treatment for chronic hepatitis B, hepatitis C or AIDS.

The pharmaceutical composition is prepared by adding an auxiliary agent for the active ingredient to the drug; the active ingredient is at least one of a pharmaceutically acceptable salt, a hydrate or a solvate thereof of the above acyclic nucleotide analog;

The pharmaceutically acceptable salt of the compound is an inorganic salt or an organic salt such as a hydrochloride, a sulfate, a fumarate, a methanesulfonate, a sulfonate or the like.

The acyclic nucleotide analog of the present invention has antiviral efficacy and provides a new choice for the development of antiviral drugs. detailed description

among them

Preferred are hydrogen, helium, halogen, amino, nitrile groups, more preferred are hydrogen, helium, halogen, and most preferred are hydrogen and helium. Is hydrogen, hydrazine, halogen, amino, hydroxy, nitro, nitrile, fluoromethyl, linear or branched or cyclic ~ C ₆ alkylamino, straight or branched ~ alkoxy, substituted aromatic One of a baseoxy group or a substituted arylthio group; preferred are hydrogen, hydrazine, halogen, amino group, hydroxyl group, more preferred are hydrogen, amino group, hydroxyl group, and most preferably an amino group. Is one of hydrogen, hydrazine, halogen, amino, nitro, nitrile, fluoromethyl, linear or branched ~^alkylamino;

Preferred are hydrogen, helium, halogen, amino, and more preferred are hydrogen and halogen.

R4 is hydrogen, hydrazine, cyclopropyl, linear or branched or cyclic, alkyl, fluoromethyl, hydroxymethyl; preferably hydrogen, hydrazine, methyl or hydroxymethyl, More preferred are hydrogen, hydrazine, methyl, and most preferred is methyl.

* indicates that the compound may be a racemate, R type or S type.

, —

For ^X 2 ^_R 7

,

Xi X _{2 is} independently 0, S or NH;

Z is 0, S or Se; preferably O and S; most preferably O;

R _{7 is} independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, aryl or aralkyl, or R _{7 is} independently 1 to 3 selected from alkylamino, alkylaminoalkyl, Alkylaminoalkyl, dialkylamino, hydroxy, oxo, halogen, amino, alkylthio, alkoxyalkyl, aryloxy, aryloxyalkyl, aryloxyoxy, arylalkoxy Alkyl, alkenyl, alkyne substituted with a substituent of an alkyl group, a haloalkyl group, a nitro group, a nitroalkyl group, an azido group, an azidoalkyl group, an alkanoyl group, an alkanoylalkyl group, a carboxyl group or an alkanoylamino group Base, Fang

Preferably, R _{7 is} independently hydrogen, helium,

The substituent is -H, halogen, aryl, -OH, -CF ₃ ,

It is preferred in one step that Re and R _{7 are} independently hydrogen

, m ,

It is hydrogen, hydrazine, aryl, linear or branched dC ₆ alkyl, linear or branched dC ₆ haloalkyl, benzyl. It is one of a linear or branched or cyclic alkane, a substituted aromatic group; preferably a substituted aromatic group. When R ₅ , the route is as follows:

Compound 1 and Compound 2 are condensed under basic conditions to give Compound 3, and Compound 3 and Compound 4 are subjected to alkylation under basic conditions to give Compound 5 directly.

Further, the compound 3 can be first reacted with the easily available starting material compound 6 to obtain the compound 7, and then deprotected to obtain the compound 8. The compound 8 is reacted with a halogenated hydrocarbon, a phenol or an amine under certain conditions to obtain a compound 5.

Ru is independently an alkyl group, an alkenyl group, an alkynyl group, an aryl group or an aralkyl group.

Χι Χ ₂ , Υι Υ ₂ Independent is 0, S or NH.

0,

People

When R _{5 is} used, the preparation method of the acyclic nucleotide analog represented by Formula I is as follows:

9 〗 0 12

Compound 9 is reacted with an acid chloride reagent to obtain phosphonic acid chloride compound 10, and compound 10 is reacted with compound 11 under organic basic conditions to obtain compound 12; When

The preparation method of the acyclic nucleotide analog represented by Formula I is as follows: Route A:

9 14

The compound 9 and the compound 13, the organic base and the dehydrating agent are added to the solvent, and after reacting for a certain period of time, ethyl acetate is added, and the mixture is washed with water, sodium hydrogencarbonate and brine, dried, filtered, and evaporated. 14. The reaction solvent is selected from the group consisting of hydrazine, hydrazine-dimethylformamide, hydrazine, hydrazine-dimethylacetamide, dimethyl sulfoxide, hydrazine-methylpyrrolidone, and the like; the organic base is selected from 1,8-diazabicyclo[ 5.4.0] undec-7-ene, 4-dimethylaminopyridine, hydrazine, hydrazine-diisopropylethylamine, triethylamine, etc.; the dehydrating agent is selected from dicyclohexylcarbodiimide (DCC), Ν,Ν'-diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), HATU-O azobenzene And triazole]-Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate (HATU), 1H-benzotriazole small oxytripyrrolidinyl hexafluorophosphate (PyBOP), Ν , Ν'-carbonyldiimidazole (DCI) and the like. Route Β:

The invention also provides the use of an acyclic nucleotide analog of formula I for the treatment of chronic hepatitis B, hepatitis C or AIDS.

The pharmaceutical composition is prepared by adding an excipient commonly used for the active ingredient to a drug; the active ingredient is at least one of a pharmaceutically acceptable salt, a hydrate or a solvate thereof of the compound of the formula I.

Add 5.26 g of 4-aminopyrazolo[3,4-d]pyrimidine to a 250 mL round bottom flask, add 200 mL of DMF and 83 mg of sodium hydroxide, heat the reaction to 140 ° C, and slowly add dropwise 3.90 mL of R-propylene carbonate, after the addition The reaction was carried out at 140 ° C for 16 hours. TLC (DCM: MeOH = 8:1) was found to be complete. The solvent was evaporated under reduced pressure and the residue was applied to silica gel column chromatography.

1H NM (DMSO-t e, 400 Hz) δ 8.16 ( s, 1H ), 8.08 ( s, 1H ), 7.63 ( s, 2H ), 4.28-4.22 ( m, 1H ), 4.13 ( d, 2H, J= 5.6 Hz ), 3.37 ( s, 1H ), 1.03 ( d, 3H, J=5.6 Hz ).

In a 100 mL flask, add 11.24 g of (R) - 1 - (2-hydroxypropyl)-4-aminopyrazolo[3,4-d]pyrimidine, 23.5 mL of N,N-dimethylformamide Methyl acetal (DMF-DMA) was added to 50 mL of chloroform. Protect with nitrogen and stir at room temperature overnight. TLC assay (DCM: MeOH = 9:1) until the reaction was complete. The solvent was evaporated under reduced pressure to give a white crystallite.

Example 3 Preparation of (R)-N4-dimethylaminomethylene-1-"2-di(ethylphosphonomethoxy)propyl-propyl 1-pyrazole"3Adl pyrimidine

In a 500 mL flask, 11.4 g of (R)-N ⁴ -dimethylaminomethylene-1 - (2-hydroxypropyl)-pyrazolo[3,4-d]pyrimidine and 14.1 mL of p-toluene were added. Diethyl acyloxymethylphosphonate, then 300 mL of toluene was added, and 5.51 g of NaH was added under ice salt bath. Protect with nitrogen and stir at room temperature overnight. TLC was detected (DCM: MeOH = 10:1) until the reaction was completed. The solvent was distilled off under reduced pressure, and the solid was dissolved in 100 ml of dichloromethane, and glacial acetic acid was added dropwise with stirring, and the pH was adjusted to 8-9. It was extracted three times with dichloromethane, dried over anhydrous magnesium sulfate, and evaporated. Silica gel column chromatography gave ll.Olg as a white solid. Yield: όΟ /^ΗΝΜΙ (CDC1 ₃ , 400 Ηζ) δ 8.79 (s, lH), 8.44 (s, lH), 8.05 (s, lH), 4.53- 4.47(m,lH), 4.29-4.25(m,lH), 4.10-4.05(m,lH), 4.00-3.86(m,4H), 3.71-3.57(m,2H), 3.15(d,6H,J =9.2 Hz), 1.19-1.12 (m, 9H).

In a 100 mL round bottom flask, 2.12 g of ( ) -N ⁴ -dimethylaminomethylene-1-[2-di(ethylphosphonomethoxy)propyl]-pyrazolo[3,4- d] Pyrimidine, 50 mL of 80% acetic acid, heated to reflux for 2 hours. TLC detection

(DCM: MeOH = 10:1) until the reaction was completed. The solvent was evaporated under reduced pressure to give a pale yellow oil. EtOAc (EtOAc) It was extracted three times with ethyl acetate, and the organic layer was washed with saturated sodium chloride. Dry over anhydrous sodium sulfate, suction filtered, and then evaporated. This was separated by silica gel column chromatography to yield white crystals: 1.

1H NM (CDC1 ₃ , 400Hz) 58.35(s,lH), 8.01(s,lH), 7.52(s,2H), 4.58-4.53 (m,lH),

4.36-4.331(m,lH), 4.17-4.13(m,lH), 4.09-3.96(m,4H), 3.81-3.65(m,2H), 1.27-1.21 (m,9H) o

In a lOOmL round bottom flask, 9.18 g of ( ) - 1-[2-di(ethylphosphonomethoxy)propyl]-4-aminopyrazolo[3,4-d]pyrimidine and 50 mL of acetonitrile were added. 17 mL of trimethylbromosilane was added with stirring. The reaction was stirred at room temperature overnight. TLC was detected (DCM: MeOH = 10:1) until the reaction was completed. The solvent was evaporated under reduced pressure to give a pale yellow solid. Add 10 mL of water to dissolve, pH is about 1, add ammonia to adjust the pH value of 8-9, and distill it under reduced pressure. The mixture was separated by a cation exchange resin, and eluted with water until the effluent was neutral, and then the product was eluted with 10% ammonia water, and distilled to give a white solid 6.3 g. The mixture was separated by an anion exchange resin, and the mixture was eluted with water and then evaporated to afford a neutral product of 10% glacial acetic acid. The product was distilled off under reduced pressure to give a white solid 3.46 g. The total yield was 52.3%.

1H NM (DMSO-t3⁄4,400Hz) 510.27 (s,2H), 8.41(s,lH), 8.05(s,lH), 8.25(d,2H,J=8.8Hz), 4.43-4.25(m,2H) , 4.03-3.99 (m, lH), 3.50 (d, 2H, J = 9.2 Hz), 1.07 (d, 3H, J = 6.4 Hz).

Example 6 Preparation of (R)-l-(2-phosphonomethoxypropyl)-4-aminopyrazolo-3,4-dl-pyrimidine-di(isopropoxycarbonyloxymethyl)ester

In a 10 mL flask, 200 mg of (R)-l-(2-phosphonomethoxypropyl)-4-aminopyrazolo[3,4-d]pyrimidine and 3 mL of N-methylpyrrolidone (NMP) were added. The system was heated to 45 ° C, 0.282 g of triethylamine (TEA) was added. After all the solids were dissolved, 0.225 g of tetrabutylammonium bromide (TBAB) was added, the temperature was raised to 50 ° C, and 0.531 g of chloromethylisopropyl was added. The base carbonate (9) was reacted at this temperature for 4 hours. TLC was detected (DCM: MeOH = 10:1) until the reaction was completed. Cooled to room temperature, was added 40mL of ethyl acetate, 20 mL of water, the organic layer was separated, the aqueous layer the organic layer was washed three times (15mLx3) ₀ were combined, washed with ethyl acetate and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, It was distilled under reduced pressure to give a pale yellow solid. The residue was purified by silica gel column chromatography elut372

1H NMR (CDC1 ₃ , 400 Hz) δ 8.385 (s, 1H ), 7.945 (s, 1H), 5.730 (s, 2H ), 5.547 (m, 4H ), 4.996-4.888 (m, 4H ), 4.569-4.512 (m, 2H), 4.387 (m, 2H), 4.158-4.097 (m, lH), 1.316 (d, 12H, J = 6.4 Hz), 1.269 (d, 3H, J = 8.8 Hz).

Example 7-9

The compound charge ratio and other operations were the same as in Example 6 except that the halogenated hydrocarbon was different, and the obtained compound was shown in Table 1. 1

Buy Example 10 1-"(R)-2-""(S)-""(S)-l-(well propyloxycarbonyl)ethyl 1 amino 1 oxy acyl methoxy) propyl 1 Preparation of -4-aminopyrazolo[3,4-d]pyrimidine

2.87 g of (R)-l-(2-phosphonomethoxypropyl)-4-aminopyrazolo[3,4-d]pyrimidine, 1.88 g of phenol and 20 ml of N-methylpyrrolidone, heated to 80 °C, then 1.7 ml of triethylamine was added. 3.4 g of dicyclohexylcarbodiimide was dissolved in 10 ml of N-methylpyrrolidone, added dropwise to the above solution, and then refluxed for 20 hours, cooled, filtered to remove the precipitate, concentrated and dried, and then subjected to column chromatography to give 2.5 g of intermediate. body. Add 20 ml of acetonitrile to the intermediate, add 2 ml of thionyl chloride below 40 ° C, then stir at 75 ° C until the solid dissolves. After the reaction is completed, concentrate to dryness, add 30 ml of dichloromethane, and cool to 0 to 20 ° C. 1.8 g of isopropyl L-alanine was dissolved in 20 ml of dichloromethane, added dropwise to the reaction system, and then 2 ml of triethylamine was added thereto, and the mixture was allowed to warm to room temperature. After completion of the reaction, the solution was washed with a sodium hydrogencarbonate solution, dried over sodium sulfate, concentrated, and then evaporated to give 1.9 g of compound 1-[(())[[(S)-[[(S)-l- (Isopropoxycarbonyl)ethyl]amino]phenoxyphosphonomethoxy)propyl]-4-aminopyrazolo[3,4-d]pyrimidine, total yield 39.9%.

Example 11 (R)-l-(2-phosphonomethoxypropyl)-4-aminopyrazolo-3,4-dl-pyrimidine-di(isopropoxycarbonyloxymethyl)ester-rich 5-acid salt

In a 10 mL round bottom flask, 1.04 g of the compound (R) 1-(2-phosphonomethoxypropyl)- 4-aminopyrazolo[3,4-d]pyrimidine-II prepared in Example 6 was added. (Isopropoxycarbonyloxymethyl)ester, 4 mL of isopropanol, 255.2 mg of fumaric acid. Heat to 50 ° C and stir the reaction for 2 hours. Slowly cool to 0 ° C and precipitate a white solid. Filtration, recrystallization from isopropanol to give 1.lg of the desired product (R)-l-(2-phosphonomethoxypropyl)-4-aminopyrazolo[3,4-d]pyrimidine- (Isopropoxycarbonyloxymethyl) ester fumarate, yield 86.5%.

Example 12-15

According to the operation of Example 11, the compound prepared in Example 7-10 was reacted with fumaric acid in isopropanol to give a compound as shown in Table 2.

Test Example 1 In vitro anti-HBV activity

a. Inhibition of HBV DNA

Take HepG2.2.15 cells in logarithmic growth phase, adjust the cell concentration to l l0 ⁴ /ml with DMM medium containing 10% fetal bovine serum, and add ΙΟΟμΙ^ single cell suspension to 96-well culture plate at 37 °C. The cells were cultured under 5% C0 ₂ conditions, and the cells were added to the experimental group at different concentrations of 100 μΙ 7 wells. The positive control group was given different concentrations of telbivudine and continued to culture. The culture solution was taken out at 3 days and 6 days, and an equal volume of the drug solution was added. The culture solution was taken out on the 9th day and placed at 20 ° C until use. At the same time, the same volume of medium was supplemented for the determination of MTT, and whether the drug was toxic to the cells at each experimental concentration was examined.

b. Cytotoxicity experiment

Table 3 Inhibition of HBV DNA by compounds

Except for the difference in drug concentration, the other procedures are the same as in part a, and are used to determine the half-toxic concentration of the drug to the cells (CC ₅ .). The results are shown in Table 3:

The anti-HBV activity of the drug was evaluated using a Selectivity Index (SI), which was calculated according to the following formula:

SI=CC ₅₀ /EC ₅₀

When Sl > 2, it indicates that the drug is effective and low toxicity; when 1 ≤ SI ≤ 2, it indicates that the drug is effective and toxic; when Sl < 1, it indicates that the drug has toxic effects. The larger the SI value, the stronger the inhibitory effect of the compound on HBV and the lower the cytotoxicity.

It can be seen from the results in Table 3 that the obtained nucleoside analog has a good inhibitory effect on the secretion of HBV DNA by HBV2.2.15 cells, and the selection index is much larger than 2, and the selection index of some of the compounds is much larger than that of the marketed drug tenofovir. Select the index.

The invention has obtained experimentally obtained compounds having better anti-hepatitis B virus, hepatitis C virus, HIV virus and herpes virus, and has good application prospects.

Claims

Claim

1. An acyclic nucleotide analogue having the structural formula I:

I

among them

a C ₆ alkylamino group, a linear or branched ~ alkoxy group, a substituted aryloxy group or a substituted aryl thio group; hydrogen, hydrazine, halogen, amino, nitro, nitrile, fluoro One of a methyl group, a linear chain or a branched alkyl group;

R4 is hydrogen, hydrazine, cyclopropyl, linear or branched or cyclic one of alkyl, fluoromethyl or hydroxymethyl;

For ^X 2 ^_R 7

Z is 0, S or Se; Xi X _{2 is} independently 0, S or NH;

R _{7 is} independently hydrogen, deuterium, alkyl, alkenyl, alkynyl, aryl or aralkyl, or R _{7 is} independently 1 to 3 selected from alkylamino, alkylaminoalkyl, Alkylaminoalkyl, dialkylamino, hydroxy, oxo, halogen, amino, alkylthio, alkoxyalkyl, aryloxy, aryloxyalkyl, aryloxyoxy, arylalkoxy Alkyl, alkenyl substituted by a substituent of an alkyl group, a halogenated fluorenyl group, a nitro group, a nitroalkyl group, an azido group, an azidoalkyl group, an alkanoyl group, an alkanoylalkyl group, a carboxyl group or an alkanoylamino group , alkynyl, aryl or aralkyl;

Is hydrogen, hydrazine, aryl, linear or branched dC ₆ alkyl, linear or branched dC ₆ haloalkyl, benzyl; one of linear or branched or cyclic ~ alkane, substituted aryl Kind.

The acyclic nucleotide analog according to claim 1, which is characterized by: hydrogen, hydrazine, halogen, amino, nitrile group; preferably, hydrogen, hydrazine, halogen, and most preferably hydrogen and hydrazine; .

The acyclic nucleotide analog according to claim 1 or 2, wherein R ₂ is hydrogen, hydrazine, halogen, Amino group, hydroxyl group; preferred are hydrogen, amino group, hydroxyl group; most preferred is an amino group.

The acyclic nucleotide analogue according to any one of claims 1 to 3, wherein R ₃ is hydrogen, hydrazine, halogen or amino; preferably hydrogen and halogen.

The acyclic nucleotide analog according to any one of claims 1 to 4, wherein R4 is hydrogen, hydrazine, methyl or hydroxymethyl; preferably hydrogen, hydrazine, methyl; The best is methyl.

The acyclic nucleotide analogue according to any one of claims 1 to 5, wherein Z is 0, S or Se; preferably 0 and S; most preferably 0.

7. The acyclic nucleotide analogue according to claim 6, wherein:

for

, R _{7 is} independently hydrogen, helium, d

C ₄ alkyl; the substituent is -H, halogen, aryl, -0H

One step is preferably, - independently hydrogen, helium,

; The preferred Ζ is 0, and the structural formula is as follows:

R ₅

Is hydrogen, hydrazine, aryl, linear or branched dC ₆ alkyl, linear or branched dC, haloalkyl, benzyl, more preferably aryl; preferably Z is 0, the formula is as follows:

III

for

And R ₉ is a linear or branched or cyclic aryl group, and a substituted aryl group in the substituted aryl group; preferably Ζ is 0, and the structural formula is as follows:

IV.

The acyclic nucleotide analog according to claim 1, wherein the structural formula is

9. A process for the preparation of an acyclic nucleotide analogue of formula I, characterized in that:

when

Compound 3 is first reacted with compound 6 to give compound 7, which is then deprotected to give compound 8, which is reacted with a halogenated hydrocarbon, phenol or amine to give compound 5:

Compound 9 is reacted with an acid chloride reagent to obtain a phosphonic acid chloride compound 10, and compound 10 is reacted with compound 11 under organic basic conditions to obtain compound 12;

When

When the route is as follows:

Route Α:

9 14

Route B:

9 10 14 The compound 9 is reacted with an acid chloride reagent to obtain a phosphonochlorine compound 10, and the compound 10 is reacted with the compound 13 under organic basic conditions to obtain a compound 14.

10. Use of an acyclic nucleotide analog according to any one of claims 1-8 for the preparation of a chronic hepatitis B, hepatitis C or AIDS.

11. A pharmaceutical composition prepared by the addition of a pharmaceutical auxiliary to a pharmaceutically acceptable salt, a hydrate or a solvate thereof, wherein the active ingredient is added to a pharmaceutically acceptable salt of a compound according to any one of claims 1-8; At least one

12. A pharmaceutical composition according to claim 11 wherein the pharmaceutically acceptable salt of the compound is:

13. A pharmaceutical composition according to claim 12 wherein the pharmaceutically acceptable salt of the compound is:

14. Use of a pharmaceutical composition according to claim 12 or 13 for the preparation of a medicament for the treatment of chronic hepatitis B, hepatitis C or AIDS.