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CN100398542C - Substituted 1,2,3- triazolepyridine compound with HIV-resistant activity, preparation method and uses - Google Patents

Substituted 1,2,3- triazolepyridine compound with HIV-resistant activity, preparation method and uses Download PDF

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CN100398542C
CN100398542C CNB2006101702825A CN200610170282A CN100398542C CN 100398542 C CN100398542 C CN 100398542C CN B2006101702825 A CNB2006101702825 A CN B2006101702825A CN 200610170282 A CN200610170282 A CN 200610170282A CN 100398542 C CN100398542 C CN 100398542C
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CN1995042A (en
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杨铭
袁德凯
庞瑞芳
张春雷
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Peking University
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Abstract

The invention discloses a compound with formula (II) and medical acceptable acid or alkali additional salt and drug, wherein the R4 is (CH2)nR5,(CH2)nNHR5,(CH2)nOR5,(CH2)nSR5, (CH2)nCOR5,(CH2)nCONHR5; R5 is C1-6 alkyl, substituted amino C1-6 alkyl, mono-guanidino C1-6 alkyl, diguanidino C1-6 alkyl; n is 1-4; Ra can be the same as or different from Rb.

Description

Replacement 1,2,3-triazoles and pyrimidine new compound with HIV (human immunodeficiency virus)-resistant activity, Preparation method and use
The present invention relates to substituted purin and its analogue and replace 1,2,3-triazoles class new compound.Such new compound has keying action to the TAR RNA zone of HIV-1mRNA, can suppress combining of HIV-1 Tat and TARRNA, thereby duplicating of viral interference produces antiviral activity.Suppress HIV-1 replication in vitro experimental result and show, do not showing under the toxic dosage, such compound exhibits good antiviral activity, the experimental result of this and in-vitro transcription matches.
HIV TAR RNA is the genome structure that is present in the newborn mRNA 5 ' end of HIV-1 virus, its effect in the HIV-1 virus replication is and the HIV-1Tat protein binding, thereby activate transcribing of virus, promote the virus transcription thing to prolong, improve the transcriptional level of complete mRNA, virus is effectively duplicated.Present being primarily aimed at virus replication and transcribing the key enzyme in two stages of anti-HIV-1 medicine: proteolytic enzyme and reversed transcriptive enzyme, but these two kinds of enzymes are because the variation and the genetic heterogeneity and very easily produce resistance of virus itself have limited the use and the curative effect of this type of medicine to a certain extent.Therefore, the investigator gets back in the fundamental research of HIV-1 virus once more, has found the vital role in the HIV-1 life cycle of being combined in of Tat albumen and TAR RNA.Therefore HIV-1Tat TAR RNA interacts becomes one of focus of HIV research field in recent years.At present, some research institutions being arranged abroad is the research of target inverase being engaged in Tat TAR RNA interaction; This seminar is that domestic the development the earliest carries out the seminar that medicinal design is synthetic and antiviral activity is estimated to this target spot, has applied for relevant patent, and has delivered many pieces of research papers.Therefore,, find a kind of medicine of new anti-HIV-1, just can reach the purpose of curing the AIDS VICTIMS if can be action target spot with TAR RNA.
The molecular structure of related compound is a brand new among the present invention, proves the effectively material of anti-HIV-1 through evaluated biological activity, therefore can be used for the treatment of AIDS.
The present invention is more definite relates to (I) and (II) compound.
Figure C20061017028200051
Wherein:
R 1The group of representative is selected from:
S (CH 2) nR 3, R wherein 3Represent wherein R 3Represent amino (C 1~C 6) alkyl, substituted-amino (C 1~C 6) alkyl, single guanidine radicals (C that replaces 1~C 6) alkyl, two replacement guanidine radicals (C 1~C 6) alkyl, the moieties of each group can be a straight or branched, n is 1~4 integer,
S (CH 2) nCOR 3, S (CH 2) nCONHR 3, (CH 2) nR 3, (CH 2) nNHR 3, (CH 2) nOR 3, (CH 2) nSR 3, (CH 2) nCOR 3(CH 2) nCONHR 3R wherein 3Be as defined above,
R 2The group of representative is selected from:
Hydrogen, straight or branched (C 1~C 6) alkyl, aryl, heterocycle, amido straight or branched (C 1~C 6) alkyl, hydroxyl straight or branched (C 1~C 6) alkyl, aryl straight or branched (C 1~C 6) alkyl, heterocycle straight or branched (C 1~C 6) alkyl,
R 4The group of representative is selected from:
(CH 2) nR 5, R wherein 5The group of representative is selected from: amino straight or branched (C 1~C 6) alkyl, substituted-amino straight or branched (C 1~C 6) alkyl, single guanidine radicals straight or branched (C 1~C 6) alkyl, two guanidine radicals straight or branched (C 1~C 6) alkyl, n is 1~4 integer,
(CH 2) nNHR 5, (CH 2) nOR 5, (CH 2) nSR 5, (CH 2) nCOR 5(CH 2) nCONHR 5R wherein 5Be as defined above,
Ra and Rb can be identical or different, and the group of representative independent of each other is selected from hydrogen, straight or branched (C 1~C 6) alkyl, amino, straight or branched alkyl (C 1~C 6) amino, aryl, heterocycle, aryl amine, heterocycle amido ...
All compounds and at pharmaceutically acceptable acid or the formed additive salt of alkali,
Undoubtedly:
--" aryl " can be understood that phenyl, naphthyl, tetralyl, dihydro naphthyl, indenyl or 2,3-dihydro indenyl, optional is separately replaced by one or more identical or different groups, and substituting group is selected from halogen, hydroxyl, cyano group, nitro, straight or branched (C 1~C 6) alkyl, straight or branched (C 1~C 6) alkoxyl group, amino, straight or branched amino (C 1~C 6) alkyl,--wherein each alkoxyl group part can be a straight or branched--, straight or branched (C 1~C 6) acyl group, straight or branched (C 1~C 6) alkoxy carbonyl, straight or branched (C 1~C 6) alkyl amino-carbonyl and oxo.
--" heterocycle " be understood that saturated or undersaturated list-or-bicyclic groups, have aromatics and non-aromatic character, have 5 to 12 annular atomses, contain one, heteroatoms that two or three are identical or different, heteroatoms is selected from oxygen, nitrogen, sulphur, what heterocycle was understood that to choose wantonly is replaced by one or more identical or different substituting groups, and substituting group is selected from halogen, hydroxyl, straight or branched (C 1~C 6) alkyl, straight or branched (C 1~C 6) alkoxyl group, nitro, oxo and amino is (arbitrarily by one or two straight or branched (C 1~C 6) the alkyl replacement).
In heterocycle, can be symbolic and do not add any restriction mention pyridyl, thienyl, furyl, imidazolyl, 4-H-pyrans-4-ketone, pyrazinyl, pyrimidyl, isoxazolyl, tetrazyl, pyrryl, pyrazolyl, quinolyl, isoquinolyl, pyrrolidyl, piperidyl, piperazinyl, 1,2, the 3-thiadiazolyl group ...
In pharmaceutically acceptable acid, what can not add restriction mentions hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetate, trifluoroacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, citric acid, xitix, oxalic acid, methylsulfonic acid, dextrocamphoric acid etc.
In the alkali that pharmacy is accepted, what can not add any restriction mentions sodium hydroxide, potassium hydroxide, triethylamine, TERTIARY BUTYL AMINE etc.
According to a kind of favourable change example, preferably The compounds of this invention is, wherein, and R 1Be S (CH 2) nCOR 3, n=1, wherein R 3Define suc as formula (I).R 4Be (CH 2) nCOR 5, n=1, wherein R 5Define suc as formula (II).According to a kind of favourable change example, preferred substituted R 1Be CONR 3aR 3bWherein work as R 3aWhen representing hydrogen atom, R 3bRepresent amino (C 1~C 6) alkyl, guanidine radicals (C 1~C 6) alkyl.Preferred substituents R 4Be (CH 2) nCONR 5aR 5bWherein work as R 5aWhen representing hydrogen atom, R 5bRepresent amino (C 1~C 6) alkyl, guanidine radicals (C 1~C 6) alkyl.
According to the present invention, preferred substituted R 2Be hydrogen atom and amido straight chain (C 1~C 6) alkyl.Especially advantageously R 2Represent hydrogen atom and N, N-dimethyl amido propyl group, N, N-diethyl amido ethyl.
According to the present invention, preferred compound is:
N-(2-amino-ethyl)-2-(2-diethyl amido-6-methyl-9H-purine-8-sulfydryl) ethanamide
N-(3-aminopropyl)-2-(2-diethyl amido-6-methyl-9H-purine-8-sulfydryl) ethanamide
N-(2-amino-ethyl)-2-[2-diethyl amido-9-(2-diethyl amido ethyl)-6-methyl-9H-purine-8-sulfydryl] ethanamide
N-(3-aminopropyl)-2-[2-diethyl amido-9-(2-diethyl amido ethyl)-6-methyl-9H-purine-8-sulfydryl] ethanamide
N-(2-amino-ethyl)-2-[2-diethyl amido-9-(3-dimethyl amido propyl group)-6-methyl-9H-purine-8-sulfydryl] ethanamide
N-(3-aminopropyl)-2-[2-diethyl amido-9-(3-dimethyl amido propyl group)-6-methyl-9H-purine-8-sulfydryl] ethanamide
N-(the 2-amino-ethyl)-2-(ethanamide of 5-diethyl amido-7-methyl-[1,2,3] triazole [4,5-d] and pyrimidine-3-)
N-(the 3-aminopropyl)-2-(ethanamide of 5-diethyl amido-7-methyl-[1,2,3] triazole [4,5-d] and pyrimidine-3-)
2-(2-diethyl amido-6-methyl-9H-purine-8-sulfydryl)-N-(2-GE)-ethanamide
2-(2-diethyl amido-6-methyl-9H-purine-8-sulfydryl)-N-(3-guanidine radicals propyl group)-ethanamide
2-[2-diethyl amido-9-(2-diethyl amido ethyl)-6-methyl-9H-purine-8-sulfydryl]-N-(2-GE)-ethanamide
2-[2-diethyl amido-9-(2-diethyl amido ethyl)-6-methyl-9H-purine-8-sulfydryl]-N-(3-guanidine radicals propyl group)-ethanamide
2-[2-diethyl amido-9-(3-diethyl amido propyl group)-6-methyl-9H-purine-8-sulfydryl]-N-(2-GE)-ethanamide
2-[2-diethyl amido-9-(3-diethyl amido propyl group)-6-methyl-9H-purine-8-sulfydryl]-N-(3-guanidine radicals propyl group)-ethanamide
2-(5-diethyl amido-7-methyl-[1,2,3] triazole [4,5-d] and pyrimidine-3-)-N-(2-GE) ethanamide
2-(5-diethyl amido-7-methyl-[1,2,3] triazole [4,5-d] and pyrimidine-3-)-N-(3-guanidine radicals propyl group) ethanamide
The formed additive salt of preferred compound and they and pharmaceutically acceptable acid or alkali constitutes the part of complete content of the present invention.
The invention still further relates to the preparation method of formula (I) compound and formula (II) compound, it is characterized in that using (III) compound as raw material:
Figure C20061017028200081
Wherein, Ra, Rb are as defined above.
According to the replacement condition of organic synthesis routine, obtain formula (IV) compound with ammonia (amine) reaction:
Figure C20061017028200082
Wherein Ra, Rb, R 2Be as defined above.
According to the reaction conditions of nitroreduction in the organic synthesis, be amino (amido) with the nitro construction recovery in the formula (IV), obtain the formula V compound:
Wherein Ra, Rb, R 2Be as defined above.
According to the ring-closure reaction condition in the organic synthesis, make the reaction of this formula V compound and dithiocarbonic anhydride obtain formula (VI) compound; Obtain formula (VII) compound with acid and Sodium Nitrite effect:
Figure C20061017028200092
Wherein Ra, Rb, R 2Be as defined above.
According to alkylating reaction conditions in the organic synthesis, make formula (VI) compound and (VII) compound react under base catalysis with ethyl chloroacetate respectively, obtain formula (VIII) compound and formula (IX) compound respectively:
Figure C20061017028200093
Wherein Ra, Rb, R 2Be as defined above.
According to the amidation condition of routine,, use formula (XI) compound treatment formula (IX) compound with formula (X) compound treatment formula (VIII) compound:
R 3aNHR 3b(X) R 5aNHR 5b(XI)
R wherein 3a, R 3b, R 5a, R 5bBe as defined above.
Obtain formula (Ia) compound, i.e. specific examples of formula (I) compound and formula (IIa) compound, i.e. a specific examples of formula (II) compound:
Figure C20061017028200094
R wherein a, R b, R 2, R 3a, R 3b, R 5a, R 5bBe as defined above.
Formula (Ia) compound and formula (IIa) compound are placed respectively under formula (XII) compound effects:
Figure C20061017028200095
Obtain (Ib) compound, i.e. specific examples of formula (I) compound and formula (II) compound, i.e. a specific examples of formula (IIb) compound:
Figure C20061017028200101
R wherein a, R b, R 2, R 3a, R 5aBe as defined above.
Compound (Ia) and (IIa), (Ib) and (IIb) constitute the integral body of this compound.If necessary, these compounds carry out purifying according to conventional purifying process, and if necessary, the usefulness that can choose wantonly pharmaceutically acceptable acid or alkali is converted into additive salt.
Formula (III), (X), (XI), (XII) compound are commercial available compounds, or the compound that obtains according to the currently known methods of organic synthesis.
The invention still further relates to pharmaceutical composition, comprise at least a formula (I) and formula (II) compound or with pharmaceutically acceptable acid or the formed additive salt of alkali as activeconstituents, independent or pharmaceutically acceptable, inert, nontoxic vehicle or carrier in conjunction with one or more.
In according to drug regimen of the present invention, can mention especially and be applicable to oral, parenteral (intravenously, muscle or subcutaneous), through skin or transdermal, intranasal, rectum, through those of eye or respiratory administration, especially tablet or drageeing, Sublingual tablet, cachet, capsule, tincture, suppository, creme, ointment, skin gel, injectable or drinkable preparation, aerosol, eye drops or nasal drop etc.
The compounds of this invention has the anti-HIV-1 activity.Therefore the drug regimen that contains at least a formula (I) or formula (II) compound can be used for the treatment of AIDS.
As medicine, because dosage is different because of patient age and body weight, route of administration, disease character and seriousness and any other treatment of being accepted.
The following example is set forth and is limited the present invention absolutely not:
Raw materials used and reagent is known product, or according to the product of known operation preparation.
The structure of compound described in embodiment and the synthesis step be according to routine spectroscopic techniques (infrared, NMR, EI mass spectrum, FAB+--mass spectrum ...
Embodiment 1:N-(2-amino-ethyl)-2-(2-diethyl amido-6-methyl-9H-purine-8-sulfydryl) ethanamide
Steps A: N 2, N 2-diethyl-6-methyl-5-nitro-pyrimidine-2, the 4-diamines
With 2-N, N-diethyl amido-4-chloro-6-methyl-5-nitro-pyrimidine 1.0g is with the 20ml anhydrous alcohol solution, adds 26% 5ml strong aqua, and stirring at normal temperature 12h steams and removes ethanol and excessive ammonia, and the washing after drying must be expected product.
Step B:N 2, N 2-diethyl-6-methyl-pyrimidine-2,4, the 5-triamine
With the product 2.21g that obtains in the steps A with the dissolving of 30ml anhydrous methanol, normal temperature and pressure hydrogenating reduction under the 10%Pd/C 0.11g catalysis, behind the reaction 24h, filtration catalizer, steaming desolventizes, and must expect product.
Step C:2-N 2, N 2-diethylin-6-methyl purine-8-thioketones
Product 1.9g among the step B is dissolved in the 20ml dehydrated alcohol, adds KOH 0.56g, stir normal temperature dropping dithiocarbonic anhydride 0.5ml down, dropwise back normal-temperature reaction 1h, reflux 5h.Steam and remove ethanol, resistates is with the 15ml water dissolution, and the HCl with 15% regulates pH=3, generates a large amount of white solids, and the dehydrated alcohol recrystallization obtains the expection product.
The ethyl thioglycolate of step D:(2-diethyl amido-6-methyl-9H-purine-8-)
Product 1.5g among the step C is dissolved in contains ethyl chloroacetate 1.16g, Anhydrous potassium carbonate 1.3g, in the tetrahydrofuran (THF) of the 50ml of potassiumiodide 0.05g, stirring at normal temperature reaction 12h, the filtering inorganic salt, filtrate concentrates the back column chromatography must expect product.
Step e: N-(2-amino-ethyl)-2-(2-diethyl amido-6-methyl-9H-purine-8-sulfydryl) ethanamide
Product 5a 0.45g among the step D is dissolved in the anhydrous methanol that 10ml contains the 0.42g 1 backflow 8h under the nitrogen protection.Remove solvent and part 1 under reduced pressure, column chromatography must be expected product.
Faint yellow dope
FAB+MS:337
1H?NMR:3.49,3.44,3.23,2.67,2.43,1.10
Embodiment 2:N-(3-aminopropyl)-2-(2-diethyl amido-6-methyl-9H-purine-8-sulfydryl) ethanamide
Operation steps uses 1 with embodiment 1 in step e, the 3-propylene diamine is as reactant.
Faint yellow dope
FAB+MS:351
1H?NMR:3.49,3.21,3.15,3.00,2.50,2.41,2.20,1.50,1.20,0.98
Embodiment 3:N-(2-amino-ethyl)-2-[2-diethyl amido-9-(2-diethyl amido ethyl)-6-methyl-9H-purine-8-sulfydryl] ethanamide
Operation steps is used N with embodiment 1 in steps A, the N-diethyl ethylenediamine is as reactant.
Yellow oil
FAB+MS:437.2(M+1)
1H?NMR:8.59,4.06,3.83,3.62~3.69,3.29~3.35,2.75~2.82,2.63,2.56~2.63,1.10~1.27,
Embodiment 4:N-(3-aminopropyl)-2-[2-diethyl amido-9-(2-diethyl amido ethyl)-6-methyl-9H-purine-8-sulfydryl] ethanamide
Operation steps uses 1 with embodiment 3 in step e, the 3-propylene diamine is as reactant.
Yellow oil
FAB+MS:450.7(M+1)
1H?NMR:8.57,4.03~4.08,3.82,3.66,3.30~3.37,2.60~2.79,2.55,2.52~2.58,1.56~1.65,1.00~1.20
Embodiment 5:N-(2-amino-ethyl)-2-[2-diethyl amido-9-(3-dimethyl amido propyl group)-6-methyl-9H-purine-8-sulfydryl] ethanamide
Operation steps is used N with embodiment 1 in steps A, N-dimethyl-1, and the 3-propylene diamine is as reactant.
Yellow oil
FAB+MS:422.0
1H?NMR:8.54,4.04~4.09,3.84,3.66,3.29~3.35,2.78~2.82,2.57,2.32,2.24,1.93~1.98,1.20
Embodiment 6:N-(3-aminopropyl)-2-[2-diethyl amido-9-(3-dimethyl amido propyl group)-6-methyl-9H-purine-8-sulfydryl] ethanamide
Operation steps uses 1 with embodiment 5 in step e, the 3-propylene diamine is as reactant.
Yellow oil
FAB+MS:436.8
1H?NMR:4.03~4.08,3.83,.3.66,3.30~3.34,2.68~2.71,2.55,2.30~2.35,2.24,1.92~1.97,1.56~1.63,1.19
Embodiment 7:N-(the 2-amino-ethyl)-2-(ethanamide of 5-diethyl amido-7-methyl-[1,2,3] triazole [4,5-d] and pyrimidine-3-)
Step F: 5-diethylin-7-methyl-3H-[1,2,3] triazolo [4,5-d] pyrimidine
With 1.1g N 2, N 2-diethyl-6-methyl-pyrimidine-2,4,5-triamine are dissolved in the acetate of 3ml 36%, drip the aqueous solution that 2ml contains the 0.45g Sodium Nitrite at-5 ℃, and 4h is reacted in the back under 35 ℃ of water-baths.In reaction mixture impouring 100ml cold water,, promptly get and expect product the solid filtering drying of separating out.
Yellow crystals
169~171 ℃ of fusing points,
EI-MS:206
1H?NMR:3.81,2.84,1.63,1.39
Step G:(5-diethyl amido-7-methyl-[1,2,3] triazolo [4,5-d] pyrimidine-3-)-ethyl acetate
The product 0.8g that obtains in the step F is dissolved in the acetone that 30ml contains 0.6g ethyl chloroacetate, 0.6g Anhydrous potassium carbonate and 0.05g potassiumiodide, and back flow reaction 8h is spin-dried for solvent behind the filtering inorganic salt, and column chromatography obtains the expection product.
Yellow crystals
90~92 ℃ of fusing points
EI-MS:292
1H?NMR:5.21,4.24,3.72,2.80,1.33,1.21
Step H:N-(the 2-amino-ethyl)-2-(ethanamide of 5-diethyl amido-7-methyl-[1,2,3] triazole [4,5-d] and pyrimidine-3-)
Product 0.5g among the step G is dissolved in the dehydrated alcohol that 15ml contains the 0.52g quadrol nitrogen
Reflux 8h under the gas shiled, j remove solvent and part quadrol under reduced pressure, and column chromatography must be expected product.
White solid
163~166 ℃ of fusing points
EI-MS:306
1H?NMR:5.14,3.73,3.34,2.80,2.78,1.65,1.24
Embodiment 8:N-(the 3-aminopropyl)-2-(ethanamide of 5-diethyl amido-7-methyl-[1,2,3] triazole [4,5-d] and pyrimidine-3-)
Operation steps uses 1 with embodiment 7 in step G, the 3-propylene diamine is as reactant.
White solid
155~157 ℃ of fusing points
EI-MS:320
1H?NMR:5.11,3.73,3.39,2.78,2.71,1.55,1.47,1.21
Embodiment 9:2-(2-diethyl amido-6-methyl-9H-purine-8-sulfydryl)-N-(2-GE)-ethanamide
Step I: 0.15g sulphur trioxide urea monohydrate is added 15ml in batches be dissolved with in the dehydrated alcohol of the compound that 0.4g embodiment 1 obtains in 1h under 35 ℃,, steam and desolventize column chromatography purification at 35~45 ℃ of insulation reaction 2h.
Light yellow sticky solid
FAB+MS:379.8
1H?NMR:4.10,3.90,3.32,3.20,2.62,1.02
Embodiment 10:2-(2-diethyl amido-6-methyl-9H-purine-8-sulfydryl)-N-(3-guanidine radicals propyl group)-ethanamide
Operation is with embodiment 9, and the compound that use embodiment 2 obtains in step I is as reactant.
Light yellow sticky solid
FAB+MS:393.4
1H?NMR:3.48,3.08,3.20,2.63,2.43,1.50,1.20,1.01
Embodiment 11:2-[2-diethyl amido-9-(2-diethyl amido ethyl)-6-methyl-9H-purine-8-sulfydryl]-N-(2-GE)-ethanamide
Operation is with embodiment 9, and the compound that use embodiment 3 obtains in step I is as reactant.
Light yellow sticky solid
FAB+MS:479.1(M+1)
1H?NMR:4.63,4.28,3.81,3.43,3.21~3.24,3.11~3.23,2.99~3.06,2.34,1.13,0.97,
Embodiment 12:2-[2-diethyl amido-9-(2-diethyl amido ethyl)-6-methyl-9H-purine-8-sulfydryl]-N-(3-guanidine radicals propyl group)-ethanamide
Operation is with embodiment 9, and the compound that use embodiment 4 obtains in step I is as reactant.
Light yellow sticky solid
FAB+MS:493.4(M+1)
1HNMR:4.59,3.76,3.28~3.33,3.12~3.17,3.00~3.10,2.41,1.40~1.70,1.13,1.00
Embodiment 13:2-[2-diethyl amido-9-(3-diethyl amido propyl group)-6-methyl-9H-purine-8-sulfydryl]-N-(2-GE)-ethanamide
Operation is with embodiment 9, and the compound that use embodiment 5 obtains in step I is as reactant.
Light yellow sticky solid
FAB+MS:464.9
1HNMR:4.26~4.31,3.61,3.46,3.18~3.29,3.01~3.07,2.68,2.40,2.16~2.21,0.99
Embodiment 14:2-[2-diethyl amido-9-(3-diethyl amido propyl group)-6-methyl-9H-purine-8-sulfydryl]-N-(3-guanidine radicals propyl group)-ethanamide
Operation is with embodiment 9, and the compound that use embodiment 6 obtains in step I is as reactant.
Light yellow sticky solid
FAB+MS:477.8
1H?NMR:4.30,3.61,3.48,3.37,3.04~3.17,2.68,2.41,2.19,1.62,0.99
Embodiment 15:2-(5-diethyl amido-7-methyl-[1,2,3] triazole [4,5-d] and pyrimidine-3-)-N-(2-GE) ethanamide
Operation is with embodiment 9, and the compound that use embodiment 7 obtains in step I is as reactant.
Light yellow sticky solid
FAB+MS:349.5(M+1)
1H?NMR:5.10,3.48~3.56,3.55,3.10,2.53,1.08
Embodiment 16:2-(5-diethyl amido-7-methyl-[1,2,3] triazole [4,5-d] and pyrimidine-3-)-N-(3-guanidine radicals propyl group) ethanamide
Operation is with embodiment 9, and the compound that use embodiment 8 obtains in step I is as reactant.
Light yellow sticky solid
FAB+MS:362.7
1H?NMR:5.10,3.50,3.17,2.99,2.56,1.64,1.01
Embodiment 18: the combination of transcriptional level antagonism HIV-1Tat TAR RNA
We have successfully made up two plasmids, and one is Tat gene expression plasmid (plasmid I), and another is to be promotor with the HIV-1LTR fragment, contains the plasmid (plasmid II) of E.C. 2.3.1.28 (CAT) reporter gene.Behind the transfection Escherichia coli, cut evaluation through enzyme and obtain positive colony.Utilize calcium phosphate to mediate this two kinds of plasmid cotransfection 293T cells, add 3 kinds of samples after 24 hours, concentration is 30 μ mol/L.Collect 48 hours culture supernatant, usefulness CAT ELISA test kit detects the CAT activity in the supernatant liquor under the 405/490nm wavelength.Investigate sample to the interactional influence of Tat-TAR.
With the CAT activity that do not add sample plasmid I, II cotransfection system is 100%, represents the CAT activity of application of sample cotransfection system with relative reactivity.
Embodiment 19: suppress HIV-1 and duplicate experiment in vitro.
Adopt MT 4Cell and HIV IIIB strain are tested, and the virus quantity of use is respectively 100TCID 50And 1000TCID 50(tissue cultured dose) .MT 4Medicine under cell and HIV IIIB strain and the various dose was cultivated after 5 days, examined under a microscope CPE (cytopathy---cavity, swelling, fusion etc.).
Set up five groups of experiments:
Contrast: medicine+MT 4Cell
Blank: MT 4Cell+HIV IIIB
Negative control: water+MT 4Cell+HIV IIIB
Positive control: AZT+MT 4Cell+HIV IIIB
Experimental group: medicine+MT 4Cell+HIV IIIB.

Claims (5)

1. formula (II) compound, or it is in pharmaceutically-acceptable acid addition:
Figure C2006101702820002C1
Wherein:
R 4The group of representative is selected from: (CH 2) nCONHR 5, R wherein 5The group of representative is selected from: amino C 1-6Alkyl, guanidine radicals C 1-6Alkyl, n are 1~4 integers,
The group of Ra, Rb representative independently of one another is selected from hydrogen atom, straight or branched C 1-6Alkyl, amino, straight or branched C 1-6Alkyl amine group, aryl, arylamine group,
The aryl of wherein mentioning is selected from halogen, hydroxyl, straight or branched C 1-6Alkyl, amino, amino straight or branched C 1-6The phenyl that substituting group replaced of alkyl, naphthyl, tetralyl, indenyl or 2,3-dihydro indenyl.
2. according to formula (II) compound of claim 1, or it is in pharmaceutically-acceptable acid addition:
Wherein:
R 4Be (CH 2) nCONHR 5, n=1 wherein, R 5For 2-amino-ethyl, 3-aminopropyl, 2-GE or 3-guanidine radicals propyl group arbitrarily one of them, Ra is N, N-diethyl amido, Rb are methyl.
3.R 4The preparation method of the formula of n=1 (II) compound in the definition is characterized in that using (III) compound as raw material:
Figure C2006101702820002C2
Wherein, Ra, Rb are defined as claim 1,
According to the replacement condition of organic synthesis routine, obtain formula (IV) compound with the amine reaction:
Figure C2006101702820002C3
R wherein 2Be H, Ra, Rb are defined as claim 1,
According to the reaction conditions of nitroreduction in the organic synthesis, be amino with the nitro construction recovery in the formula (IV), obtain the formula V compound:
Figure C2006101702820003C1
R wherein 2Be H, Ra, Rb are defined as claim 1,
According to the ring-closure reaction condition in the organic synthesis, make this formula V compound and acid and Sodium Nitrite effect obtain formula (VII) compound:
Figure C2006101702820003C2
Wherein Ra, Rb are defined as claim 1,
According to alkylating reaction conditions in the organic synthesis, (VII) compound and ethyl chloroacetate are reacted under base catalysis, obtain formula (IX) compound:
Figure C2006101702820003C3
Wherein Ra, Rb are defined as claim 1,
According to the amidation condition of routine, use formula (XI) compound treatment formula (IX) compound:
R 5aNHR 5b(XI)
R wherein 5aBe hydrogen, R 5bBe amino C 1-6Alkyl,
Obtain R 4A specific examples of the formula of n=1 (II) compound is formula (IIa) compound in the definition:
Figure C2006101702820003C4
Wherein Ra, Rb, R 5a, R 5bBe as defined above,
Randomly, with formula (IIa) compound and the reaction of formula (XII) compound:
Obtain R 4Another specific examples of the formula of n=1 (II) compound is formula (IIb) compound in the definition:
Figure C2006101702820004C1
R wherein a, R bBe as defined above, R 5aBe guanidine radicals C 1-6Alkyl.
4. pharmaceutical composition, comprise at least a formula any (II) compound or its pharmaceutically-acceptable acid addition as activeconstituents, independent or pharmaceutically acceptable, inert, nontoxic vehicle or carrier in conjunction with one or more according to claim 1-2.
5. the application of the formula any (II) compound in the medicine of preparation AIDS resisting according to claim 1 to 2.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1496262A (en) * 2001-01-10 2004-05-12 О Triazolo [4, 5-d ] pyrimidine derivatives and their use as purinergic receptor antagonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1496262A (en) * 2001-01-10 2004-05-12 О Triazolo [4, 5-d ] pyrimidine derivatives and their use as purinergic receptor antagonists

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人免疫缺陷病毒调控蛋白Tat及其相关药物研究进展. 陈钊,邵一鸣.国外医学.病毒学分册,第9卷第6期. 2002
人免疫缺陷病毒调控蛋白Tat及其相关药物研究进展. 陈钊,邵一鸣.国外医学.病毒学分册,第9卷第6期. 2002 *
抗人类免疫缺陷病毒-1 活性小分子生物效应机制的研究. 庞瑞芳,郝美荣,杨铭.中国药物与临床,第3卷第5期. 2003
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