CN104072558A - 5-substituted pyrimidine nucleoside-thiazolidine hybrid with anti-HIV activity and preparation method thereof - Google Patents

5-substituted pyrimidine nucleoside-thiazolidine hybrid with anti-HIV activity and preparation method thereof Download PDF

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CN104072558A
CN104072558A CN201310097898.4A CN201310097898A CN104072558A CN 104072558 A CN104072558 A CN 104072558A CN 201310097898 A CN201310097898 A CN 201310097898A CN 104072558 A CN104072558 A CN 104072558A
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thiazolidine
hybrid
hiv
formyl radical
base
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CN104072558B (en
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范学森
张新迎
李坤
郭胜海
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SHANGHAI ZHAOWEI BIOENGINEERING Co.,Ltd.
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Henan Normal University
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Abstract

The invention discloses a 5-substituted pyrimidine nucleoside-thiazolidine hybrid with anti-HIV activity and a preparation method thereof. The main point of a technical scheme provided in the invention is that the 5-substituted pyrimidine nucleoside-thiazolidine hybrid with anti-HIV activity has a structure as described in the specification. The invention also discloses the preparation method for the 5-substituted pyrimidine nucleoside-thiazolidine hybrid and a pharmaceutical composition with anti-HIV activity. The 5-substituted pyrimidine nucleoside-thiazolidine hybrid provided by the invention has substantial anti-HIV activity; and the pharmaceutical composition containing the 5-substituted pyrimidine nucleoside-thiazolidine hybrid A or an addition salt formed by the hybrid and pharmaceutically acceptable acid or alkali thereof can be used for treatment of AIDS.

Description

There is 5-substituted pyrimidines nucleosides-thiazolidine hybrid of HIV (human immunodeficiency virus)-resistant activity and preparation method thereof
Technical field
The present invention relates to a class and there is the active Pyrmidine nucleoside derivatives of anti-human immunodeficiency virus (HIV), be specifically related to a kind of 5-substituted pyrimidines nucleosides-thiazolidine hybrid with HIV (human immunodeficiency virus)-resistant activity and preparation method thereof.
Background technology
Acquired immune deficiency syndrome (AIDS) is a kind of communicable disease causing that infected by human immunodeficiency virus (HIV).In the reproduction process of HIV, hiv reverse transcriptase (RT) plays a very important role.Therefore, take hiv reverse transcriptase as the new inverase of shot design, become related drugs and researched and developed one of conventional and very effective means.The hiv reverse transcriptase inhibitor class medicine of developing at present can be divided into two kinds, nucleoside inhibitor (NRTIs) and non-nucleoside inhibitor (NNRTIs) structure.These hiv reverse transcriptase inhibitors have significant curative effect conventionally, but also tend to bring certain toxic side effect and life-time service can produce resistance.For addressing the above problem, the present invention intends by the method for chemosynthesis, efabirenz (NRTI) structural unit and non-nucleoside reverse transcriptase inhibitor (NNRTI) structural unit being incorporated in same target molecule, try hard to, by the acting in conjunction of two kinds of different inhibitor and cooperation mutually, reach and improve activity, overcome resistance and delay the object that virus variation occurs.
Research shows, 3'-azido-3'-deoxythymidine (AZT), 3'-deoxy-2', the Pyrmidine nucleoside derivatives such as 3'-didehydrothymidine (d4T) and 3'-deoxy-3'-fluorothymidine (FLT) all have good HIV (human immunodeficiency virus)-resistant activity, and some is widely used clinically; On the other hand, the non-nucleosides compound such as thiazolidine also demonstrates the multiple biological activity that comprises anti-HIV.Based on above background, we design the condensation reaction via 5-formyl radical pyrimidine nucleoside and cysteamine or cysteine ester, preparation 5-substituted pyrimidines nucleosides-thiazolidine hybrid, thus pyrimidine nucleoside structural unit and thiazolidine structural unit are combined.By the combination of two kinds of pharmacophoric groups, to obtain the novel hybride body class medicine with better HIV (human immunodeficiency virus)-resistant activity.At present, structure, synthetic method and HIV (human immunodeficiency virus)-resistant activity about this class hybrid inhibitor, be not reported.
Summary of the invention
The technical problem that the present invention solves has been to provide a kind of 5-substituted pyrimidines nucleosides-thiazolidine hybrid with HIV (human immunodeficiency virus)-resistant activity, and this compounds has potential pharmaceutical use, and the pharmaceutical composition that contains this compounds can be used for preparing anti-AIDS drug.
Another technical problem that the present invention solves has been to provide a kind of preparation method with 5-substituted pyrimidines nucleosides-thiazolidine hybrid of HIV (human immunodeficiency virus)-resistant activity, and the method synthetic route is short, and preparation process is simple.
Technical scheme of the present invention is: have 5-substituted pyrimidines nucleosides-thiazolidine hybrid of HIV (human immunodeficiency virus)-resistant activity, it is characterized in that: described 5-substituted pyrimidines nucleosides-thiazolidine hybrid has following structure:
A
Wherein: R 1represent a kind of in following groups: (2R, 4S, 5S)-4-azido--2, 3, 4, 5-tetrahydrochysene-5-acetyl-o-methyl furans-2-base, (2R, 4S, 5S)-4-azido--2, 3, 4, 5-tetrahydrochysene-5-hydroxymethylfurans-2-base, (2R, 5S)-2, 5-dihydro-5-acetyl-o-methyl furans-2-base, (2R, 5S)-2, 5-dihydro-5-hydroxymethylfurans-2-base, (2R, 5S)-2, 3, 4, 5-tetrahydrochysene-5-acetyl-o-methyl furans-2-base, (2R, 5S)-2, 3, 4, 5-tetrahydrochysene-5-hydroxymethylfurans-2-base, (2R, 4S, 5R)-4-acetoxyl group-2, 3, 4, 5-tetrahydrochysene-5-acetyl-o-methyl furans-2-base, (2R, 4S, 5R)-4-hydroxyl-2, 3, 4, 5-tetrahydrochysene-5-hydroxymethylfurans-2-base, (2R, 4S, 5R)-4-fluoro-2, 3, 4, 5-tetrahydrochysene-5-acetyl-o-methyl furans-2-base, (2R, 4S, 5R)-4-fluoro-2, 3, 4, 5-tetrahydrochysene-5-hydroxymethylfurans-2-base, (2R, 3R, 4R, 5R)-3, 4-diacetoxy-2, 3, 4, 5-tetrahydrochysene-5-acetyl-o-methyl furans-2-base or (2R, 3R, 4S, 5R)-3, 4-dihydroxyl-2, 3, 4, 5-tetrahydrochysene-5-hydroxymethylfurans-2-base, corresponding structural formula is respectively: , , , , , , , , , , or , R 2represent a kind of in following groups: hydrogen or alkoxyl formyl, corresponding structural formula is respectively :-H or-CO 2c nh 2n+1, n=1 ~ 10, wherein the alkyl in alkoxyl formyl is straight chained alkyl or branched-chain alkyl.
5-substituted pyrimidines nucleosides-thiazolidine hybrid of the present invention can form additive salt with pharmaceutically acceptable acid or alkali.
The preparation method with 5-substituted pyrimidines nucleosides-thiazolidine hybrid of HIV (human immunodeficiency virus)-resistant activity of the present invention, is characterized in that synthesis step is as follows: by R 1for the 5-formyl radical pyrimidine nucleoside compound of different substituents ( 1) and cysteamine (hydrochloride) or cysteine ester hydrochloride ( 2) mix, be placed in solvent, under the existence of alkali, in 20 ~ 120 oc stirring reaction, TLC tracking monitor to reaction finishes, and obtains target product a, its concrete reaction equation is as follows:
，
R wherein 1, R 2be suc as formula adefined.
Reactant of the present invention ( 1) be a kind of in following compounds: 5-formyl radical-3'-azido--2', two deoxidation-5'-acetoxyl group the uridines of 3'-, 5-formyl radical-3'-azido--2', the two deoxyuridines of 3'-, 5-formyl radical-2', two deoxidation-the 2' of 3'-, two dehydrogenation-5'-acetoxyl group the uridines of 3'-, 5-formyl radical-2', two deoxidation-the 2' of 3'-, the two dehydrogenation uridines of 3'-, 5-formyl radical-2', two deoxidation-5'-acetoxyl group the uridines of 3'-, 5-formyl radical-2', the two deoxyuridines of 3'-, 5-formyl radical-2'-deoxidation-3', 5'-di-acetyl oxygen base uridine, 5-formyl radical-2'-deoxyuridine, 5-formyl radical-3'-fluoro-2', two deoxidation-5'-acetoxyl group the uridines of 3'-, 5-formyl radical-3'-fluoro-2', the two deoxyuridines of 3'-, 5-formyl radical-2', 3', 5'-triacetoxyl group uridine or 5-formyl radical uridine.
Reactant of the present invention ( 2) be a kind of in following compounds: cysteamine, Mercaptamine or cysteine ester hydrochloride.
Cysteine ester hydrochloride of the present invention is a kind of in halfcystine alkyl ester salt hydrochlorate, and wherein alkyl is that 10 carbon are with interior straight chained alkyl or branched-chain alkyl.
Alkali of the present invention is sodium acetate, potassium acetate, ammonium acetate, sodium carbonate, salt of wormwood, sodium bicarbonate or saleratus.
Solvent of the present invention is one or more the mixed solvent in water, methyl alcohol, ethanol, DMF, acetonitrile, tetrahydrofuran (THF), acetone, methylene dichloride, chloroform, benzene and toluene.
The invention still further relates to the pharmaceutical composition with HIV (human immunodeficiency virus)-resistant activity, it is characterized in that the described pharmaceutical composition with HIV (human immunodeficiency virus)-resistant activity is by 5-substituted pyrimidines nucleosides-thiazolidine hybrid aor itself and pharmaceutically acceptable acid or the formed additive salt of alkali and pharmaceutically acceptable auxiliaries form.
The pharmaceutical composition with HIV (human immunodeficiency virus)-resistant activity of the present invention can be used for preparing anti-AIDS drug.
The present invention utilize 5-formyl radical pyrimidine nucleoside compound ( 1) and cysteamine (hydrochloride) or cysteine ester hydrochloride ( 2) condensation reaction, efficiently synthesized 5-substituted pyrimidines nucleosides-thiazolidine hybrid, this preparation method's synthetic route is short, preparation process is simple.In addition, 5-substituted pyrimidines nucleosides-thiazolidine hybrid provided by the present invention has significant HIV (human immunodeficiency virus)-resistant activity, contains 5-substituted pyrimidines nucleosides-thiazolidine hybrid aor the pharmaceutical composition of itself and pharmaceutically acceptable acid or the formed additive salt of alkali can be used for the treatment of acquired immune deficiency syndrome (AIDS).
Embodiment
Following examples contribute to understand the present invention, but are not limited to content of the present invention.
Embodiment 1
5-(thiazolidine-2-yl)-3'-fluoro-2', the two deoxidation-5'-acetoxyl group uridines of 3'-( a) synthetic
In reaction flask, add successively 5-formyl radical-3'-fluoro-2'; two deoxidation-5'-acetoxyl group uridine (0.300 g of 3'-; 1 mmol), Mercaptamine (0.170 g; 1.5 mmol), sodium acetate (0.123 g; 1.5 mmol) and methyl alcohol (20 mL), under room temperature stirring reaction to having reacted (TLC tracking monitor).Decompression is removed after methyl alcohol, then adds ethyl acetate (20 mL), and water, saturated nacl aqueous solution washing successively.Gained organic phase anhydrous sodium sulfate drying, is spin-dried for, and residue obtains white solid product through column chromatography separation a(0.305 g), yield 85%.
Product astructural formula and structural characterization data as follows:
Product abe the mixture of a pair of isomer, the ratio of the mole number of two isomer is 1:1. 1H?NMR?(400?MHz,?CDCl 3)?δ:?2.05-2.17?(m,?4H),?2.56-2.65?(m,?1H),?2.88-3.10?(m,?3H),?3.24-3.34?(m,?1H),?4.17-4.30?(m,?2H),?4.36-4.43?(m,?1H),?5.08-5.25?(m,?1H),?5.32?(s,?1H),?6.21-6.25?(m,?1H),?7.53?(s,?0.5H),?7.59?(s,?0.5H).? 13C?NMR?(100?MHz,?CDCl 3)?δ:?20.91,?20.98,?35.87,?35.97,?38.18,?38.39,?52.32,?53.65,?63.54,?63.64,?63.76,?66.23,?66.37,?82.38,?82.61,?82.64,?85.67,?85.71,?92.91,?113.17,?113.88,?135.67,?136.98,?150.09,?150.14,?162.77,?170.59.?MS:?m/z?360?[MH] +.
Embodiment 2
5-(4'-methoxycarbonyl base thiazolidine-2-yl)-2'-deoxidation-3', 5'-di-acetyl oxygen base uridine ( b) synthetic
In reaction flask, add successively 5-formyl radical-2'-deoxidation-3'; 5'-di-acetyl oxygen base uridine (0.340 g; 1 mmol), acthiol-J hydrochloride (0.257 g; 1.5 mmol), potassium acetate (0.147 g; 1.5 mmol) and methylene dichloride (20 mL), return stirring reaction to reaction finishes (TLC tracking monitor).Water, saturated nacl aqueous solution washing successively, organic phase anhydrous sodium sulfate drying, is spin-dried for, and residue obtains yellow solid product through column chromatography separation b(0.430 g), yield 94%.
Product bstructural formula and structural characterization data as follows:
Product bbe the mixture of a pair of isomer, the ratio of the mole number of two isomer is 1:1.4. 1H?NMR?(400?MHz,?CDCl 3)?δ:?2.02-2.05?(m,14.4H),?2.12-2.20?(m,?2.4H),?2.38-2.20?(m,?2.4H),?2.95?(t,? J?=?9.6?Hz,?1H),?3.06-3.09?(m,?1.4H),?3.20-3.28?(m,?2.4H),?3.66-3.68?(m,?7.2H),?3.84-3.88?(m,?1H),?4.14-4.33?(m,?8.6H),?5.13-5.15?(m,?2.4H),?5.24?(s,?1H),?5.51?(s,?1.4H),?6.19?(t,? J?=?7.6?Hz,?2.4H),?7.60?(s.?1.4H),?7.74?(s,?1H).? 13C?NMR?(100?MHz,?CDCl 3)?δ:?20.69,?20.74,?20.84,?37.49,?37.56,?52.51,?63.79,?64.44,?64.58,?65.34,?65.49,?74.21,?74.33,?82.25,?82.45,?85.29,?85.51,?111.93,?113.92,?149.99,?150.07,?162.45,?162.68,?170.43,?170.53,?171.13,?171.63,?175.17.?MS:?m/z?458?[MH] +.
Embodiment 3
5-(4'-ethoxycarbonyl thiazolidine-2-yl)-3'-azido--2', the two deoxyuridines of 3'-( c) synthetic
In reaction flask, add successively 5-formyl radical-3'-azido--2'; two deoxyuridine (0.281 g of 3'-; 1 mmol), ethylcysteine hydrochloride (0.279 g; 1.5 mmol), sodium bicarbonate (0.126 g; 1.5 mmol) and methylene dichloride (20 mL), in stirring at room reaction to reaction, finish (TLC tracking monitor).Water, saturated nacl aqueous solution washing successively, organic phase anhydrous sodium sulfate drying, is spin-dried for, and residue obtains yellow solid product through column chromatography separation c(0.326 g), yield 79%.
Product cstructural formula and structural characterization data as follows:
Product cbe the mixture of a pair of isomer, the ratio of the mole number of two isomer is 1:1. 1H?NMR?(400?MHz,?CDCl 3)?δ:?1.19-1.24?(m,?6H),?2.38?(br?s,?4H),?2.93-2.98?(m,?1H),?3.02-3.06?(m,?1H),?3.21-3.30?(m,?2H),?3.69-3.77?(m,?2H),?3.86-3.99?(m,?5H),?4.11-4.19?(m,?7H),?4.27-4.31?(m,?1H),?4.34-4.38?(m,?1H),?5.36?(s,?1H),?5.52?(s,?1H),?6.03?(d,? J?=?5.6?Hz,?1H),?6.11?(d,? J?=?5.6?Hz,?1H)，7.92?(s,?1H),?8.22?(s,?1H).? 13C?NMR?(100?MHz,?CDCl 3)?δ:?14.05,?37.44,?37.75,?37.94,?60.53,?60.67,?61.56,?61.62,?63.40,?63.59,?64.63,?64.75,?65.30,?65.59,?81.82,?85.95,?86.11,?112.06,?113.64,?137.13,?137.99,?149.87,?162.39,?162.66,?170.59,?171.02,?171.15.?MS:?m/z?413?[MH] +.
Embodiment 4
5-(4'-ethoxycarbonyl thiazolidine-2-yl)-2', 3', 5'-triacetoxyl group uridine ( d) synthetic
In reaction flask, add successively 5-formyl radical-2'; 3'; 5'-triacetoxyl group uridine (0.398 g; 1 mmol), ethylcysteine hydrochloride (0.279 g; 1.5 mmol), potassium acetate (0.147 g; 1.5 mmol) and methyl alcohol (20 mL), return stirring reaction to reaction finishes (TLC tracking monitor).Decompression is removed after methyl alcohol, then adds ethyl acetate (20 mL), and water, saturated nacl aqueous solution washing successively, and organic phase anhydrous sodium sulfate drying, is spin-dried for, and residue obtains yellow solid product through column chromatography separation d(0.323 g), yield 61%.
Product dstructural formula and structural characterization data as follows:
Product dbe the mixture of a pair of isomer, the ratio of the mole number of two isomer is 1:1.6. 1H?NMR?(400?MHz,?CDCl 3)?δ:?1.18-1.25?(m,?7.8H),?1.96-2.10?(m,?23.4H),?2.94-3.04?(m,?2.6H),?3.21-3.31?(m,?2.6H),?3.87?(t,? J?=?7.2?Hz,?1H),?4.07-4.10?(m,?1.6H),?4.14-4.17?(m,?5.2H),?4.28-4.35?(m,?7.8H),?5.32-5.36?(m,?6.2H),?5.57?(s,?1.6H),?5.97-6.02?(m,?2.6H),?7.51?(s,?1.6H),?7.72?(s,?1H),?9.85?(br?s,?2.6H).? 13C?NMR?(100?MHz,?CDCl 3)?δ:?14.00,?14.09,?20.36,?20.46,?20.72,?20.82,?20.96,?30.85,?37.40,?60.33,?61.62,?63.25,?64.12,?64.41,?65.15,?65.66,?70.28,?72.22,?72.67,?79.86,?80.03,?87.45,?112.86,?115.32,?136.09,?149.97,?150.12,?162.31,?169.66,?170.41,?170.45,?170.81,?171.27.?MS:?m/z?531?[MH] +.
Embodiment 5
5-(thiazolidine-2-yl)-2', the two deoxidation-2' of 3'-, the two dehydrogenation-5'-acetoxyl group uridines of 3'-( e) synthetic
In reaction flask, add successively 5-formyl radical-2'; two deoxidation-the 2' of 3'-; two dehydrogenation-5'-acetoxyl group uridine (0.280 g of 3'-; 1 mmol), Mercaptamine (0.170 g; 1.5 mmol), sodium acetate (0.123 g; 1.5 mmol) and chloroform (20 mL), return stirring reaction is to having reacted (TLC tracking monitor).Decompression is removed after chloroform, then adds ethyl acetate (20 mL), and water, saturated nacl aqueous solution washing successively.Gained organic phase anhydrous sodium sulfate drying, is spin-dried for, and residue obtains white solid product through column chromatography separation e(0.197 g), yield 58%.
Product estructural formula and structural characterization data as follows:
Product ebe the mixture of a pair of isomer, the ratio of the mole number of two isomer is 1:1. 1H?NMR?(400?MHz,?DMSO- d 6)?δ:?2.03?(s,?3H),?2.71-2.73?(m,?1H),?2.80-2.81?(m,?1H),?3.00?(s,?1H),?3.10-3.14?(m,?1H),?4.03-4.21?(m,?2H),?4.96?(s,?1H),?5.30?(s,?1H),?6.03?(s,?1H),?6.42-6.43?(m,?1H),?6.79-6.81?(m,?1H),?7.34-7.35?(m,?1H),?11.44?(br?s,?1H).? 13C?NMR?(100?MHz,?DMSO- d 6)?δ:?21.04,?35.41,?35.54,?52.23,?52.38,?64.91,?65.60,?65.96,?84.13,?84.23,?90.08,?90.16,?115.07,?126.92,?127.18,?133.94,?134.32,?135.12,?135.23,?150.71,?150.85,?162.89,?162.96,?172.72,?170.89.?MS:?m/z?340?[MH] +.
Embodiment 6
Suppress HIV and copy experiment in vitro
The Anti-HIV-1 Active of 5-substituted pyrimidines nucleosides-thiazolidine hybrid and anti-HIV-2 activity are tested respectively in HIV-1 IIIB virus strain and HIV-2 ROD virus strain, and host cell is MT-4 type.First by MT-4 cells HIV virus infection, the cell cultures infective dose that to infect concentration be CCID50(50%) 100 times.Then MT-4 cell suspensions of 100 μ L HIV virus infectiones are transferred in well plates, mixed and be placed on 5% CO with the testing drug of the appropriate concentration of 100 μ L 2in the incubator of atmosphere, under the temperature condition of 37 ° of C, cultivate 5-7 days.Measure cell survival rate, calculate 50% inhibition concentration (IC of medicine 50).

Claims (10)

1. 5-substituted pyrimidines nucleosides-thiazolidine hybrid with HIV (human immunodeficiency virus)-resistant activity, is characterized in that: described 5-substituted pyrimidines nucleosides-thiazolidine hybrid has following structure:
A
Wherein: R 1represent a kind of in following groups: (2R, 4S, 5S)-4-azido--2, 3, 4, 5-tetrahydrochysene-5-acetyl-o-methyl furans-2-base, (2R, 4S, 5S)-4-azido--2, 3, 4, 5-tetrahydrochysene-5-hydroxymethylfurans-2-base, (2R, 5S)-2, 5-dihydro-5-acetyl-o-methyl furans-2-base, (2R, 5S)-2, 5-dihydro-5-hydroxymethylfurans-2-base, (2R, 5S)-2, 3, 4, 5-tetrahydrochysene-5-acetyl-o-methyl furans-2-base, (2R, 5S)-2, 3, 4, 5-tetrahydrochysene-5-hydroxymethylfurans-2-base, (2R, 4S, 5R)-4-acetoxyl group-2, 3, 4, 5-tetrahydrochysene-5-acetyl-o-methyl furans-2-base, (2R, 4S, 5R)-4-hydroxyl-2, 3, 4, 5-tetrahydrochysene-5-hydroxymethylfurans-2-base, (2R, 4S, 5R)-4-fluoro-2, 3, 4, 5-tetrahydrochysene-5-acetyl-o-methyl furans-2-base, (2R, 4S, 5R)-4-fluoro-2, 3, 4, 5-tetrahydrochysene-5-hydroxymethylfurans-2-base, (2R, 3R, 4R, 5R)-3, 4-diacetoxy-2, 3, 4, 5-tetrahydrochysene-5-acetyl-o-methyl furans-2-base or (2R, 3R, 4S, 5R)-3, 4-dihydroxyl-2, 3, 4, 5-tetrahydrochysene-5-hydroxymethylfurans-2-base, corresponding structural formula is respectively: , , , , , , , , , , or , R 2represent a kind of in following groups: hydrogen or alkoxyl formyl, corresponding structural formula is respectively :-H or-CO 2c nh 2n+1, n=1 ~ 10, wherein the alkyl in alkoxyl formyl is straight chained alkyl or branched-chain alkyl.
2. 5-substituted pyrimidines nucleosides-thiazolidine hybrid with HIV (human immunodeficiency virus)-resistant activity according to claim 1, is characterized in that: described 5-substituted pyrimidines nucleosides-thiazolidine hybrid can form additive salt with pharmaceutically acceptable acid or alkali.
3. the preparation method with 5-substituted pyrimidines nucleosides-thiazolidine hybrid of HIV (human immunodeficiency virus)-resistant activity claimed in claim 1, is characterized in that synthesis step is as follows: by R 1for the 5-formyl radical pyrimidine nucleoside compound of different substituents ( 1) and cysteamine (hydrochloride) or cysteine ester hydrochloride ( 2) mix, be placed in solvent, under the existence of alkali, in 20 ~ 120 oc stirring reaction, TLC tracking monitor to reaction finishes, and obtains target product a, its concrete reaction equation is as follows:
，
R wherein 1, R 2be suc as formula adefined.
4. the preparation method with 5-substituted pyrimidines nucleosides-thiazolidine hybrid of HIV (human immunodeficiency virus)-resistant activity according to claim 3, is characterized in that: described reactant ( 1) be a kind of in following compounds: 5-formyl radical-3'-azido--2', two deoxidation-5'-acetoxyl group the uridines of 3'-, 5-formyl radical-3'-azido--2', the two deoxyuridines of 3'-, 5-formyl radical-2', two deoxidation-the 2' of 3'-, two dehydrogenation-5'-acetoxyl group the uridines of 3'-, 5-formyl radical-2', two deoxidation-the 2' of 3'-, the two dehydrogenation uridines of 3'-, 5-formyl radical-2', two deoxidation-5'-acetoxyl group the uridines of 3'-, 5-formyl radical-2', the two deoxyuridines of 3'-, 5-formyl radical-2'-deoxidation-3', 5'-di-acetyl oxygen base uridine, 5-formyl radical-2'-deoxyuridine, 5-formyl radical-3'-fluoro-2', two deoxidation-5'-acetoxyl group the uridines of 3'-, 5-formyl radical-3'-fluoro-2', the two deoxyuridines of 3'-, 5-formyl radical-2', 3', 5'-triacetoxyl group uridine or 5-formyl radical uridine.
5. the preparation method with 5-substituted pyrimidines nucleosides-thiazolidine hybrid of HIV (human immunodeficiency virus)-resistant activity according to claim 3, is characterized in that: described reactant ( 2) be a kind of in following compounds: cysteamine, Mercaptamine or cysteine ester hydrochloride.
6. the preparation method with 5-substituted pyrimidines nucleosides-thiazolidine hybrid of HIV (human immunodeficiency virus)-resistant activity according to claim 5, it is characterized in that: described cysteine ester hydrochloride is a kind of in halfcystine alkyl ester salt hydrochlorate, and wherein alkyl is that 10 carbon are with interior straight chained alkyl or branched-chain alkyl.
7. the preparation method with 5-substituted pyrimidines nucleosides-thiazolidine hybrid of HIV (human immunodeficiency virus)-resistant activity according to claim 3, is characterized in that: described alkali is sodium acetate, potassium acetate, ammonium acetate, sodium carbonate, salt of wormwood, sodium bicarbonate or saleratus.
8. the preparation method with 5-substituted pyrimidines nucleosides-thiazolidine hybrid of HIV (human immunodeficiency virus)-resistant activity according to claim 3, it is characterized in that: described solvent is one or more the mixed solvent in water, methyl alcohol, ethanol, DMF, acetonitrile, tetrahydrofuran (THF), acetone, methylene dichloride, chloroform, benzene and toluene.
9. a pharmaceutical composition with HIV (human immunodeficiency virus)-resistant activity, is characterized in that: the described pharmaceutical composition with HIV (human immunodeficiency virus)-resistant activity is by 5-substituted pyrimidines nucleosides-thiazolidine hybrid aor itself and pharmaceutically acceptable acid or the formed additive salt of alkali and pharmaceutically acceptable auxiliaries form.
10. the pharmaceutical composition with HIV (human immunodeficiency virus)-resistant activity claimed in claim 9 can be used for preparing anti-AIDS drug.
CN201310097898.4A 2013-03-26 2013-03-26 5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid with HIV (human immunodeficiency virus)-resistant activity and preparation method thereof Active CN104072558B (en)

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