CN104072558B - 5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid with HIV (human immunodeficiency virus)-resistant activity and preparation method thereof - Google Patents
5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid with HIV (human immunodeficiency virus)-resistant activity and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of 5 substituted pyrimidines nucleoside tetrahydro-thiazoles hybrids with HIV (human immunodeficiency virus)-resistant activity and preparation method thereof.Technical scheme main points are: have 5 substituted pyrimidines nucleoside tetrahydro-thiazoles hybrids of HIV (human immunodeficiency virus)-resistant activity, and it has a following structure:
Description
Technical field
The present invention relates to a class and there is the Pyrmidine nucleoside derivatives of resisting HIV (HIV) activity, specifically relate to
And a kind of 5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid with HIV (human immunodeficiency virus)-resistant activity and preparation method thereof.
Background technology
Acquired immune deficiency syndrome (AIDS) is a kind of infectious disease being infected by HIV (human immunodeficiency virus) (HIV) and causing.Copied at HIV
Cheng Zhong, hiv reverse transcriptase (RT) plays a very important role.Therefore, with hiv reverse transcriptase for the new AntiHIV1 RT activity of shot design
Medicine, it has also become related drugs research and development are commonly used and one of very effective means.The hiv reverse transcriptase developed at present presses down
Preparation class medicine can be divided into nucleoside inhibitor (NRTIs) and Non-nucleoside-type inhibitors (NNRTIs) two kinds from structure.These
Hiv reverse transcriptase inhibitor is generally of significant curative effect, but also tends to bring certain toxic and side effects and life-time service meeting
Produce drug resistance.For solving the problems referred to above, the present invention intends by the method for chemosynthesis efabirenz
(NRTI) construction unit and non-nucleoside reverse transcriptase inhibitor (NNRTI) construction unit are incorporated in same target molecule, power
Figure is jointly acted on by two kinds of different inhibitor and is cooperated, and reaches to improve activity, overcome drug resistance and delay virus
The purpose that variation occurs.
Research shows, 3'-azido-3'-deoxythymidine (AZT), 3'-deoxy-2', 3'-
The Pyrmidine nucleoside derivatives such as didehydrothymidine (d4T) and 3'-deoxy-3'-fluorothymidine (FLT) are equal
Having good HIV (human immunodeficiency virus)-resistant activity, some is widely used the most clinically；On the other hand, the non-nucleosides compound such as tetrahydro-thiazoles
Also show that the multiple biological activity including AntiHIV1 RT activity.Based on background above, we design via 5-formylpyrimidin nucleoside
With cysteamine or the condensation reaction of cysteine ester, prepare 5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid, thus by pyrimidine core
Glycosides construction unit combines with tetrahydro-thiazoles construction unit.By the combination of two kinds of pharmacophoric groups, more preferably resist to obtain to have
The novel hybride body class medicine of HIV activity.Structure, synthetic method and AntiHIV1 RT activity currently, with respect to this kind of hybrid inhibitor are lived
Property, it is not reported.
Summary of the invention
Present invention solves the technical problem that and there is provided a kind of 5-substituted pyrimidines nucleoside-tetrahydrochysene thiophene with HIV (human immunodeficiency virus)-resistant activity
Azoles hybrid, this compounds has potential medical value, and it is anti-that the pharmaceutical composition containing this compounds can be used for preparation
AIDS-treating medicine.
Another technical problem that the present invention solves there is provided a kind of there is HIV (human immunodeficiency virus)-resistant activity 5-substituted pyrimidines nucleoside-
The preparation method of tetrahydro-thiazoles hybrid, the method synthetic route is short, and preparation process is simple.
The technical scheme is that the 5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid with HIV (human immunodeficiency virus)-resistant activity, it is special
Levy and be: described 5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid has a structure that
A
Wherein: R1Represent the one in following groups: (2R, 4S, 5S)-4-azido-2,3,4,5-tetrahydrochysene-5-acetyl
Oxygen methylfuran-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 furan-2-base, (2R, 5S)-2,5-dihydro-5-hydroxymethylfurans-2-base, (2R, 5S)-
2,3,4,5-tetrahydrochysene-5-acetyl-o-methyl furan-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 furan-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 furan
Mutter-2-base, (2R, 4S, 5R)-4-fluoro-2,3,4,5-tetrahydrochysene-5-hydroxymethylfurans-2-base, (2R, 3R, 4R, 5R)-3,4-two
Acetoxyl group-2,3,4,5-tetrahydrochysene-5-acetyl-o-methyl furan-2-base or (2R, 3R, 4S, 5R)-3,4-dihydroxy-2,3,4,
5-tetrahydrochysene-5-hydroxymethylfurans-2-base, corresponding structural formula is respectively as follows:、 、、 、、、、、、、Or, R2Under representative
One in row group: hydrogen or alkoxyl formyl, corresponding structural formula is respectively as follows :-H or-CO2CnH2n+1, n=1 ~ 10, wherein
Alkyl in alkoxyl formyl is straight chained alkyl or branched alkyl.
5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid of the present invention can be formed with pharmaceutically acceptable acid or alkali
Addition salts.
The preparation method of the 5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid with HIV (human immunodeficiency virus)-resistant activity of the present invention, its
It is characterised by that synthesis step is as follows: by R15-formylpyrimidin nucleoside compound (1) and cysteamine (hydrochloric acid for different substituents
Salt) or cysteine ester hydrochloride (2) mixing, it is placed in solvent, in the presence of base, in 20 ~ 120oC stirs reaction, TLC with
Track monitoring terminates to reaction, obtains target product A, and its concrete reaction equation is as follows:
,
Wherein R1、R2It is as defined in formula A.
Reactant of the present invention (1) is the one in following compounds: 5-formoxyl-3'-azido-2', 3'-
Double deoxidation-5'-acetoxyl group uridines, 5-formoxyl-3'-azido-2', 3'-double deoxyuridine, 5-first
Acyl group-2', 3'-double deoxidation-2', 3'-double dehydrogenation-5'-acetoxyl group uridine, 5-formoxyl-2', 3'-is double de-
Oxygen-2', 3'-double dehydrogenation uridine, 5-formoxyl-2', 3'-double deoxidation-5'-acetoxyl group uridine, 5-first
Acyl group-2', 3'-double deoxyuridine, 5-formoxyl-2'-deoxidation-3', 5'-biacetyl epoxide uridine, 5-first
Acyl group-2'-deoxyuridine, 5-formoxyl-3'-fluoro-2', the double deoxidation-5'-acetoxyl group uridine of 3'-,
5-formoxyl-3'-fluoro-2', 3'-double deoxyuridine, 5-formoxyl-2', 3', 5'-triacetoxyl group uracil
Nucleoside or 5-formoxyl uridine.
Reactant of the present invention (2) is the one in following compounds: cysteamine, Mercaptamine or half Guang ammonia
Acid esters hydrochlorate.
Cysteine ester hydrochloride of the present invention is the one in cysteine alkyl ester salt hydrochlorate, and wherein alkyl is
Straight chained alkyl within 10 carbon or branched alkyl.
Alkali of the present invention is sodium acetate, potassium acetate, ammonium acetate, sodium carbonate, potassium carbonate, sodium bicarbonate or bicarbonate
Potassium.
Solvent of the present invention be water, methanol, ethanol, N,N-dimethylformamide, acetonitrile, oxolane, acetone, two
One or more mixed solvent in chloromethanes, chloroform, benzene and toluene.
The invention still further relates to the pharmaceutical composition with HIV (human immunodeficiency virus)-resistant activity, it is characterised in that described have HIV (human immunodeficiency virus)-resistant activity
Pharmaceutical composition be by 5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid A or its formed with pharmaceutically acceptable acid or alkali
Addition salts and pharmaceutically acceptable auxiliaries composition.
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 utilizes 5-formylpyrimidin nucleoside compound (1) and cysteamine (hydrochlorate) or cysteine ester hydrochloride
(2) condensation reaction, has efficiently synthesized 5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid, and this preparation method synthetic route is short, system
Standby process is simple.Live it addition, 5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid provided by the present invention has significant AntiHIV1 RT activity
Property, containing 5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid A or its addition salts formed with pharmaceutically acceptable acid or alkali
Pharmaceutical composition can be used for the treatment of acquired immune deficiency syndrome (AIDS).
Detailed description of the invention
Following example contribute to understanding the present invention, but are not limited to present disclosure.
Embodiment 1
The conjunction of the double deoxidation-5'-acetoxyl group uridine (a) of 5-(tetrahydro-thiazoles-2-base)-3'-fluoro-2', 3'-
Become
Double deoxidation-5'-acetoxyl group the uridine diphosphate of 5-formoxyl-3'-fluoro-2', 3'-it is sequentially added in reaction bulb
Glycosides (0.300 g, 1 mmol), Mercaptamine (0.170 g, 1.5 mmol), sodium acetate (0.123 g, 1.5 mmol)
With methanol (20 mL), under room temperature, stirring reaction is to having reacted (TLC tracking and monitoring).After decompression removes methanol, add acetic acid
Ethyl ester (20 mL), and successively with water, saturated nacl aqueous solution washing.Gained organic facies anhydrous sodium sulfate is dried, and is spin-dried for, residual
Thing is stayed to obtain white solid product a(0.305 g through pillar layer separation), yield 85%.
Structural formula and the structural characterization data of product a are as follows:
Product a is the mixture of a pair isomer, and the ratio of the molal quantity of two isomers is 1:1.1H NMR (400
MHz, CDCl3) 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,
CDCl3) 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 tetrahydro-thiazoles-2-base)-2'-deoxidation-3', 5'-biacetyl epoxide uridine (b)
Synthesis
5-formoxyl-2'-deoxidation-3', 5'-biacetyl epoxide uridine (0.340 it is sequentially added in reaction bulb
G, 1 mmol), acthiol-J hydrochlorate (0.257 g, 1.5 mmol), potassium acetate (0.147 g, 1.5 mmol) and two
Chloromethanes (20 mL), return stirring reaction terminates (TLC tracking and monitoring) to reaction.Wash with water, saturated nacl aqueous solution successively
Washing, organic facies anhydrous sodium sulfate is dried, and is spin-dried for, and residue obtains yellow solid product b(0.430 g through pillar layer separation),
Yield 94%.
Structural formula and the structural characterization data of product b are as follows:
Product b is the mixture of a pair isomer, and the ratio of the molal quantity of two isomers is 1:1.4.1H NMR (400
MHz, CDCl3) 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, CDCl3) 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
The double deoxyuridine (c) of 5-(4'-ethoxycarbonyl tetrahydro-thiazoles-2-base)-3'-azido-2', 3'-
Synthesis
Reaction bulb is sequentially added into the double deoxyuridine of 5-formoxyl-3'-azido-2', 3'-(0.281 g,
1 mmol), ethylcysteine hydrochloride (0.279 g, 1.5 mmol), sodium bicarbonate (0.126 g, 1.5 mmol) and two
Chloromethanes (20 mL), is stirred at room temperature reaction and terminates (TLC tracking and monitoring) to reaction.Wash with water, saturated nacl aqueous solution successively
Washing, organic facies anhydrous sodium sulfate is dried, and is spin-dried for, and residue obtains yellow solid product c(0.326 g through pillar layer separation),
Yield 79%.
Structural formula and the structural characterization data of product c are as follows:
Product c is the mixture of a pair isomer, and the ratio of the molal quantity of two isomers is 1:1.1H NMR (400
MHz, CDCl3) 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, CDCl3) 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 tetrahydro-thiazoles-2-base)-2', the conjunction of 3', 5'-triacetoxyl group uridine (d)
Become
5-formoxyl-2' it is sequentially added in reaction bulb, and 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 methanol (20
ML), return stirring reaction terminates (TLC tracking and monitoring) to reaction.After decompression removes methanol, add ethyl acetate (20 mL),
And wash with water, saturated nacl aqueous solution successively, organic facies anhydrous sodium sulfate is dried, and is spin-dried for, and residue is through pillar layer separation
Obtain yellow solid product d(0.323 g), yield 61%.
Structural formula and the structural characterization data of product d are as follows:
Product d is the mixture of a pair isomer, and the ratio of the molal quantity of two isomers is 1:1.6.1H NMR (400
MHz, CDCl3) 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, CDCl3) 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
Double dehydrogenation-5'-acetoxyl group the uridine of 5-(tetrahydro-thiazoles-2-base)-2', 3'-double deoxidation-2', 3'-
The synthesis of (e)
5-formoxyl-2', 3'-double deoxidation-2', 3'-double dehydrogenation-5'-acetoxyl group urine it is sequentially added in reaction bulb
Pyrimidine nucleoside (0.280 g, 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 and monitoring).After chloroform removed under pressure, add
Ethyl acetate (20 mL), and successively with water, saturated nacl aqueous solution washing.Gained organic facies anhydrous sodium sulfate is dried, rotation
Dry, residue obtains white solid product e(0.197 g through pillar layer separation), yield 58%.
Structural formula and the structural characterization data of product e are as follows:
Product e is the mixture of a pair isomer, and the ratio of the molal quantity of two isomers is 1:1.1H NMR (400
MHz, DMSO-d6) 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-d6) 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
Suppression HIV replicates experiment in vitro
The Anti-HIV-1 Active of 5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid and AntiHIV1 RT activity-2 activity are respectively at HIV-1
Testing in IIIB Strain and HIV-2 ROD Strain, host cell is MT-4 type.First MT-4 cell is sick with HIV
Poison infect, infect concentration be the cell culture infective dose of CCID50(50%) 100 times.Then by 100 μ L inhibition of HIV senses
MT-4 cell suspension of dye is transferred in well plates, mixes with the testing drug of the 100 appropriate concentration of μ L and is placed on 5%
CO2In the incubator of atmosphere, cultivate 5-7 days under the temperature conditions of 37 ° of C.Measure cell survival rate, calculate the 50% of medicine and press down
Concentration (IC processed50).
Claims (2)
1. there is the preparation method of the 5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid of HIV (human immunodeficiency virus)-resistant activity, it is characterised in that synthesis step
Rapid as follows: by R1For the 5-formylpyrimidin nucleoside compound 1 of different substituents and Mercaptamine or cysteine ester salt
Hydrochlorate 2 mixing is placed in solvent, in the presence of base, prepares in 20 ~ 120 DEG C of stirring reactions, and its concrete reaction equation is as follows:
,
Wherein R1For、、、、、、、、
、、Or, R2For-H or-CO2CnH2n+1, n=1 ~ 10, should-
CO2CnH2n+1In alkyl be straight chained alkyl or branched alkyl, described alkali is sodium acetate, potassium acetate, ammonium acetate, sodium carbonate, carbon
Acid potassium, sodium bicarbonate or potassium bicarbonate, described solvent is water, methanol, ethanol, DMF, acetonitrile, tetrahydrochysene furan
Mutter, one or more mixed solvent in acetone, dichloromethane, chloroform, benzene and toluene.
The preparation side of the 5-substituted pyrimidines nucleoside-tetrahydro-thiazoles hybrid with HIV (human immunodeficiency virus)-resistant activity the most according to claim 1
Method, it is characterised in that: described cysteine ester hydrochloride is the one in cysteine alkyl ester salt hydrochlorate, and wherein alkyl is
Straight chained alkyl within 10 carbon or branched alkyl.
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| CN102603837A (en) * | 2011-12-27 | 2012-07-25 | 河南师范大学 | Novel 5-substituted pyrimidine nucleoside derivative and preparation method of novel 5-substituted pyrimidine nucleoside derivative |
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2013
- 2013-03-26 CN CN201310097898.4A patent/CN104072558B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP0322384B1 (en) * | 1987-11-03 | 1996-03-13 | Medivir Aktiebolag | Nucleosides for use in therapy |
| CN102603837A (en) * | 2011-12-27 | 2012-07-25 | 河南师范大学 | Novel 5-substituted pyrimidine nucleoside derivative and preparation method of novel 5-substituted pyrimidine nucleoside derivative |
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