CN1465582A - Nucleotide analogs, medicinal compositions having same and use thereof - Google Patents
Nucleotide analogs, medicinal compositions having same and use thereof Download PDFInfo
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- CN1465582A CN1465582A CNA021234698A CN02123469A CN1465582A CN 1465582 A CN1465582 A CN 1465582A CN A021234698 A CNA021234698 A CN A021234698A CN 02123469 A CN02123469 A CN 02123469A CN 1465582 A CN1465582 A CN 1465582A
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Abstract
The present invention discloses nucleotide analogues, their preparation method and application. These compounds can be used as antiviral drugs, including DNA virus and RNA virus.
Description
Technical field
The present invention relates to nucleotide analog and preparation method thereof and application
Background technology
The present invention relates to a compounds, nucleoside phosphoric acid ester, to virus of AIDS, dna virus such as hepatitis B virus and RNA viruses have very strong activity, because the strong polarity of its phosphate group of nucleoside phosphorylase class is difficult for seeing through gastrointestinal membranes, so phosphotidic obtains its prodrug.The medicine with treatment future that obtains is modified in all these esterifications at present, its chemical property is all unstable, therefore need modify the Nucleotide medicine from new approach, to improve existing drug bioavailability, improve distribution in its body, improve stability of drug and to reduce this class medicine gastrointestinal side effect as feeling sick, vomiting waits and renal toxicity.
Capecitabine is a fluorine pyrimidine aminomethyl formic ether compounds of Hoffmann-La Roche company exploitation, it is the Fluracil prodrug, external a few no cytotoxicity effect, but oral then can be successively after entering in the body in liver a kind of 60kDa Procaine esterase and the effect that is present in the cytidine deaminase in liver and the tumor tissues be converted into 5 '-deoxidation-5-fluorine cytidine and 5 '-'-Deoxy-5-fluorouridine.This two metabolite is non-activity still, and wherein the latter has only the hydrolytic action that is subjected to thymidine phosphine acidifying enzyme more just can finally generate 5 FU 5 fluorouracil, and then produces cellulotoxic effect.Though right thymidine phosphine acidifying enzyme can be multiple tissue expressions such as gi tract and normal breast, its cell concn is low than some human-like tumour, especially mammary cancer and colon cancer cell.This actual target administration effect of capecitabine and " tumour activation " character mean that its side effect will be significantly less than Fluracil.And II clinical trial phase result has really also confirmed the above-mentioned theory supposition: the bone marrow depression of capecitabine and alopecia toxicity are very low, though it reports that maximum side reactions comprise diarrhoea, feel sick, vomiting, stomatitis, fatigue and hand-sufficient syndromes etc., but these side effects are except that the latter, all the other are all than Fluracil few (little), and all side effects all are easy to handle and reverse, and most of symptoms often can also be died away.Capecitabine in April, 1998 successively obtain beautiful, add, the approval of state such as Switzerland, its indication is that standard chemotherapy pharmaceutical pack is drawn together the metastatic breast cancer that anthracene nucleus medicaments such as taxol and Dx are failed to respond to any medical treatment.
Inspired by this; carry out the carbalkoxyl modification by purine 6-bit amino or pyrimidine 4-bit amino to The compounds of this invention; to improve the physico-chemical property of parent drug, improve existing drug bioavailability and reduce this class medicine gastrointestinal side effect as feeling sick vomiting etc. and renal toxicity.Water-soluble and the fat-soluble all extreme differences of one of them parent compound (PMEA) of known The compounds of this invention, its fusing point has very high lattice energy greater than 250 ℃, and these character have had a strong impact on its bioavailability.By the acidylate to 6-amino, the amino of sealing had both reduced its lattice energy; it is fat-soluble to have improved medicine again, helps phosphonate group and combines with viscous protein in the stomach chamber, generates neutral ion pair mixture; mechanism by passive diffusion is passed lipid film, thereby improves its bioavailability.
In addition, compound disclosed in this invention is after human oral absorbs, can in human liver, the specificity Procaine esterase be isomerase A, be converted into active medicine, but can not be converted into active medicine (Drugs ofthe Future 1996,21 (4): 358-360), thereby produce actual liver guide effect by the foreign matter enzyme B of liver and other organ, improve the distribution of medicine in liver, medicine to other tissue or organ side effect as feel sick, vomiting and renal toxicity will obviously reduce.
Summary of the invention
The purpose of this invention is to provide a class ucleosides antiviral agent, these antiviral agents have stronger antiviral activity to RNA viruses and dna virus such as acquired immune deficiency syndrome (AIDS), hepatitis B virus.
Compound provided by the present invention is the salt of formula (I) compound and this compound thereof.
Formula (I)
Here: R
1And R
2Can be similar and different and be independently selected from OR
4, NH
2, NHR
5Or N (R
5)
2Deng group; In some cases, R
1And R
2Can be interconnected to form a cyclic group; Under the other situation, R
1And R
2Can with R
3Connect and remove to form a cyclic group.
R
3Expression C
1-C
20The group that straight or branched alkyl, these alkyl can be contained hydroxyl, oxygen, nitrogen, halogen atom replaces, and works as R
3Be CH (CH
2OR
6) CH
2The time, R
1And R
2Represent hydroxyl respectively, R
6It is a hydrolyzable ester group.
R
4Expression hydrogen, CH
2C (O) NR
5 2, CH
2C (O) OR
5, CH
2OC (O) R
5, CH
2OC (O) OR
5, CH (R
5) OC (O) OR
5, CH (R
5) OC (O) R
5(its steric configuration is R, S or RS), CH
2C (R
5) 2CH2OH, or CH
2OR
5, R
4Can also be saturated or undersaturated straight or branched C
1-C
20Alkyl, aryl or aralkyl, these groups can be contained hydroxyl, oxygen, nitrogen, the group of halogen atom replaces.
B is independently selected from following groups
Or
R
5Expression C
1-C
20Alkyl, aromatic base or aralkyl, these groups can be replaced by the group that contains hydroxyl, oxygen, nitrogen, halogen atom;
R
7Be selected from hydrogen, fluorine, methyl or trifluoromethyl.
The formed salt of The compounds of this invention, its character does not have particular restriction, when the phosphate of formula of the present invention (I) compound has one or 2 phosphorus carboxyls " to expose ", is used as the treatment time spent, can form salt with alkali.For example, form salt as sodium, potassium, lithium with basic metal; Salt with alkaline-earth metal such as barium or calcium formation; Salt with other metal such as magnesium or aluminium formation; Also can form salt, as the salt that forms with guanidine or triethylamine with organic bases; Also can form salt, as the salt that forms with Methionin or arginine with alkali ammonia acidic amino acid.
The method that provides a kind of production The compounds of this invention easily and effectively of the present invention second.Formula (I) compound can be by following path of preparing:
Fig. 1
As R
1, R
2=-OH, then formula (I) compound can be by following path of preparing.
Fig. 2
When base is VITAMIN B4, can prepare by the same method, be about to adenine nucleotide behind aceticanhydride/pyridine acetyl, then with chloro-formic ester in the presence of triethylamine, react the carbalkoxyl thing, afterwards deacetylation gets target compound in aqueous sodium hydroxide solution.
The compounds of this invention has the antiviral activity of nucleosides, is the medicine of activeconstituents with it, can be used for this class or prevention dna virus or picornavirus infection diseases associated.
In addition, in said medicine, can also contain one or more pharmaceutically acceptable carriers.Described carrier comprises the conventional thinner of pharmaceutical field, vehicle, and weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricants etc. can also add flavouring agent, sweeting agent etc. in case of necessity.
Medicine of the present invention can be made tablet, pulvis, granula, capsule, various ways such as oral liquid and injecting drug use.The medicine of above-mentioned each formulation all can be according to the ordinary method preparation of pharmaceutical field.
EmbodimentEmbodiment 1:6-isobutyl oxygen formamido--9-[2-[two (pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine (1-A)
In 100ml three neck round-bottomed flasks, add 2g 9-[2-[two (pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine is dissolved in the 10ml dry methylene chloride, and the ice bath cooling is down; add the 0.5g triethylamine, then add the 0.6g isobutyl chlorocarbonate, after raw material reaction is complete; water decomposition on the rocks; dilute hydrochloric acid is washed 1 time, washes drying 2 times; concentrate; silica gel column chromatography gets product 1.8g with the methylene dichloride wash-out, productive rate 78.3%.Mass spectrum (FAB) 602 (M+1).Ultimate analysis C
25H
40N
5O
10P calculated value: C49.92%, H6.66%, N11.65%, P5.19%.Measured value: C49.67%, H6.45%, N11.72%, P5.27%.
Prepare following compounds by the same method:
Positive butyloxy formylamido-the 9-[2-[two of 6-(pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine (2-A);
The positive penta oxygen formamido--9-[2-[two of 6-(pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine (3-A);
The just own oxygen formamido--9-[2-[two of 6-(pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine (4-A);
6-oxygen formamido--9-[2-[in positive heptan two (pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine (5-A);
The positive hot oxygen formamido--9-[2-[two of 6-(pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine (6-A);
6-oxygen formamido--9-[2-[in the positive ninth of the ten Heavenly Stems two (pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine (7-A) or
6-oxygen formamido--9-[2-[in the positive last of the ten Heavenly stems two (pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine (8-A).Embodiment 2:6-isobutyl oxygen formamido--9-[2-[two (the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine (1-B)
In 100ml three neck round-bottomed flasks, add 2g 9-[2-[two (the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine is dissolved in the 10ml dry methylene chloride, and the ice bath cooling is down; add the 0.5g triethylamine; then add 0.6 isobutyl chlorocarbonate, after raw material reaction is complete, water decomposition on the rocks; wash 2 times; drying concentrates silica gel column chromatography; get product 2.1g with the methylene dichloride wash-out, productive rate 87.6%.Mass spectrum (FAB) 606 (M+1).Ultimate analysis C
23H
36N
5O
12P calculated value: C45.62%, H5.95%, N11.57%, P5.12%.Measured value: C45.43%, H6.11%, N11.49%, P5.25%.
Prepared following compounds with method: the positive butyloxy formylamido-9-[2-[two of 6-(the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine (2-B); The positive penta oxygen formamido--9-[2-[two of 6-(the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine (3-B); The just own oxygen formamido--9-[2-[two of 6-(the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine (4-B); 6-oxygen formamido--9-[2-[in positive heptan two (the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine (5-B); The positive hot oxygen formamido--9-[2-[two of 6-(the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine (6-B); 6-oxygen formamido--9-[2-[in the positive ninth of the ten Heavenly Stems two (the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine (7-B) and 6-oxygen formamido--9-[2-[in the positive last of the ten Heavenly stems two (the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine (8-B).Embodiment 3:2-(6-isobutyl oxygen formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester (1-C)
In 100ml three neck round-bottomed flasks, add 2g 2-(VITAMIN B4-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester, be dissolved in the 10ml dry methylene chloride, the ice bath cooling adds the 0.5g triethylamine down, then adds the 0.6g isobutyl chlorocarbonate, after raw material reaction is complete, drying is washed in water decomposition on the rocks 2 times, concentrate, silica gel column chromatography gets product 1.6g with the methylene dichloride wash-out, productive rate 67.1%.Mass spectrum (FAB) 620 (M+1).Ultimate analysis C
24H
38N
5O
10P calculated value: C46.53%, H6.14%, N11.31%, P5.00%.Measured value: C46.78%, H6.02%, N11.48%, P5.21%.
Prepared following compounds with method:
2-(the positive butyloxy formylamido of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester (2-C);
2-(the positive penta oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester (3-C);
2-(the just own oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester (4-C);
2-(6-oxygen in positive heptan formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester (5-C);
2-(the positive hot oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester (6-C);
2-(6-oxygen in positive ninth of the ten Heavenly Stems formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester (7-C) and 2-(6-oxygen in positive last of the ten Heavenly stems formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester (8-C).Embodiment 4:2-(6-isobutyl oxygen formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester (1-D)
In 100ml three neck round-bottomed flasks, add 2g 2-(6-amido-9H purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester, be dissolved in the 10ml dry methylene chloride, the ice bath cooling adds the 0.5g triethylamine down, then adds the 0.6g isobutyl chlorocarbonate, after raw material reaction is complete, drying is washed in water decomposition on the rocks 2 times, concentrate, silica gel column chromatography gets target compound 1.7g with the methylene dichloride wash-out, productive rate 71.2%.Mass spectrum (FAB) 616 (M+1).Ultimate analysis C
26H
42N
5O
10P calculated value: C50.73%, H6.83%, N11.38%, P5.04%.Measured value: C50.87%, H6.64%, N11.25%, P5.19%.
Prepared following compounds with method:
2-(the positive butyloxy formylamido of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester (2-D);
2-(the positive penta oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester (3-D);
2-(the just own oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester (4-D);
2-(6-oxygen in positive heptan formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester (5-D);
2-(the positive hot oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester (6-D);
2-(6-oxygen in positive ninth of the ten Heavenly Stems formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester (7-D) and 2-(6-oxygen in positive last of the ten Heavenly stems formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester (8-D).Embodiment 5:2-(the positive penta oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid (1-E)
The preparation of (1.2-the positive penta oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid dibenzyl ester
In 100ml three neck round-bottomed flasks, add 2g 2-(6-amido-9H purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid dibenzyl ester, be dissolved in the 10ml dry methylene chloride, the ice bath cooling adds the 0.5g triethylamine down, then adds the 0.7g n-amyl chlorocarbonate, after raw material reaction is complete, drying is washed in water decomposition on the rocks 2 times, concentrate, silica gel column chromatography gets target compound 1.9g with the methylene dichloride wash-out, productive rate 76.4%.Mass spectrum (FAB) 582 (M+1).
The preparation of (2.2-the positive penta oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid
1.5g 2-(the positive penta oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid dibenzyl ester, in the presence of 1.0g Pd/C (5%), the 5atm hydrogenolysis gets target compound 0.8g, productive rate 77.3%.Mass spectrum (FAB) 402 (M+1).Ultimate analysis C
15H
24N
5O
6P calculated value: C44.89%, H5.99%, N17.46%, P7.73%.Measured value: C45.12%, H5.72%, N17.35%, P7.87%.
Prepared following compounds with method:
2-(6-isobutyl oxygen formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid (2-E);
2-(the positive butyloxy formylamido of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid (3-E);
2-(the just own oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid (4-E);
2-(6-oxygen in positive heptan formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid (5-E);
2-(the positive hot oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid (6-E);
2-(6-oxygen in positive ninth of the ten Heavenly Stems formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid (7-E);
2-(6-oxygen in positive last of the ten Heavenly stems formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid (8-E);
2-(6-n-undecane oxygen formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid (9-E);
2-(6-n-dodecane oxygen formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid (10-E) and
2-(6-n-hexadecane oxygen formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid (11-E).The preparation of embodiment 6:2-(the positive penta oxygen formamido-of 6--9H-purine-9-yl) ethoxyl methyl phosphonic acids (1-F) 1.2-(the positive penta oxygen formamido-of 6--9H-purine-9-yl) ethoxyl methyl phosphonic acids dibenzyl ester
In 100ml three neck round-bottomed flasks, add 2g 2-(6-amido-9H purine-9-yl) ethoxyl methyl phosphonic acids dibenzyl ester, be dissolved in the 10ml dry methylene chloride, the ice bath cooling adds triethylamine 0.5g down, then adds n-amyl chlorocarbonate 0.7g, after raw material reaction was complete, water decomposition on the rocks was washed 2 times, dry, concentrate, column chromatography gets target compound 2.1g with the methylene dichloride wash-out, productive rate 84.0%, mass spectrum (FAB) 568 (M+1).(2.2-the positive penta oxygen formamido-of 6--9H-purine-9-yl) ethoxyl methyl phosphonic preparation
2g 2-(the positive penta oxygen formamido-of 6--9H-purine-9-yl) ethoxyl methyl phosphonic acids dibenzyl ester, in the presence of 1.5g Pd/C (5%), the 5atm hydrogenolysis gets target compound 1.2g, productive rate 87.9%.Mass spectrum (FAB) 388 (M+1).Ultimate analysis C
14H
22N
5O
6P calculated value: C43.41%, H5.68%, N18.09%, P8.01%.Measured value: C43.70%, H5.47%, N17.82%, P7.86%.
Prepared following compounds with method:
2-(6-isobutyl oxygen formamido--9H-purine-9-yl) ethoxyl methyl phosphonic acids (2-F);
2-(the positive butyloxy formylamido of 6--9H-purine-9-yl) ethoxyl methyl phosphonic acids (3-F);
2-(the just own oxygen formamido-of 6--9H-purine-9-yl) ethoxyl methyl phosphonic acids (4-F);
2-(6-oxygen in positive heptan formamido--9H-purine-9-yl) ethoxyl methyl phosphonic acids (5-F);
2-(the positive hot oxygen formamido-of 6--9H-purine-9-yl) ethoxyl methyl phosphonic acids (6-F);
2-(6-oxygen in positive ninth of the ten Heavenly Stems formamido--9H-purine-9-yl) ethoxyl methyl phosphonic acids (7-F);
2-(6-oxygen in positive last of the ten Heavenly stems formamido--9H-purine-9-yl) ethoxyl methyl phosphonic acids (8-F);
2-(6-n-undecane oxygen formamido--9H-purine-9-yl) ethoxyl methyl phosphonic acids (9-F);
2-(6-n-dodecane oxygen formamido--9H-purine-9-yl) ethoxyl methyl phosphonic acids (10-F) and
2-(6-n-hexadecane oxygen formamido--9H-purine-9-yl) ethoxyl methyl phosphonic acids (11-F).Embodiment 7: The compounds of this invention is to the restraining effect of 2.2.15 emiocytosis HBsAg and HBeAg.
2.2.15 cell draws from air hospital Viral Laboratory, Guangzhou, with DMEM nutrient solution (GIBCO), nutrient solution adds 10% foetal calf serum, G418 100 μ g/ml (GIBCO), and 0.03% glutamine is transferred pH to 6.48 with 0.23%HePes.Take by weighing an amount of sample and add 0.2ml DMSO, add 3.79ml 2%DMEM fully after the dissolving and filter, degerming gets the pastille nutrient solution, with 0.06% trypsinase the 2.2.15 cell is dispersed into the individual cells suspension, by 3 * 10
4Cells/well concentration is inoculated in 96 orifice plates, uses the pastille nutrient solution after 2 days instead.With cytosis after 12 days, suct clear liquid and be ELISA and measure HBsAg, HBeAg, remaining cell is measured drug cell toxicity with mtt assay.
HBeAg HBsAg compound TC50 (μ m) ID50 (μ m) TI TC50 (μ m) ID50 (μ m) TI3-A 4.0 0.2 20 4.0 0.35 11.43-B 5.3 0.32 16.6 5.3 0.48 11.03-C 6 0.25 24 6 0.51 15.73-D 9 0.4 22.5 9 0.67 13.41-E 6.5 0.3 21.7 6.5 0.55 13.08-E 12 0.3 40.0 12 0.47 25.51-F 10 0.24 41.7 10 0.28 35.78-F 13.1 0.27 48.5 13.1 0.36 36.4TC50: medicine is to 2.2.15 cell half toxic concentration. IC50:the drug level that for HBsAg or HBeAg inhibiting rate is at 50% o'clock.
Claims (17)
1. formula (I) compound and this compound pharmacy acceptable salt
Formula (I)
In the formula, R
1And R
2Can be similar and different and be independently selected from OR
4, NH
2, NHR
5Or N (R
5)
2Deng group; R
1And R
2Can be interconnected to form cyclic group, perhaps a R
1And R
2With R
3Be connected to form a cyclic group;
R
3Expression C
1-C
20The group that straight or branched alkyl, these alkyl can be contained hydroxyl, oxygen, nitrogen, halogen atom replaces, and works as R
3Be CH (CH
2OR
6) CH
2The time, R
1And R
2Represent hydroxyl respectively, R
6It is a hydrolyzable ester group.
R
4Expression hydrogen, CH
2C (O) NR
5 2, CH
2C (O) OR
5, CH
2OC (O) R
5, CH
2OC (O) OR
5, CH (R
5) OC (O) OR
5, CH (R
5) OC (O) R
5(its steric configuration is R, S or RS), CH
2C (R
5)
2CH
2OH, or CH
2OR
5, R
4Be C
1-C
20The group that saturated or undersaturated straight or branched alkyl, aryl or aryl, these groups can be contained hydroxyl, oxygen, nitrogen or halogen atom replaces;
R
5Expression C
1-C
20Saturated or undersaturated straight or branched alkyl, aromatic base or aryl, these groups can be replaced by the group that contains hydroxyl, oxygen, nitrogen or halogen atom;
B is independently selected from following groups
Or
R
7Be hydrogen, fluorine, methyl or trifluoromethyl.
2. compound according to claim 1 is characterized in that it has following structural (II):
Formula (II)
R
1And R
2Define as claim 1; Y represents hydrogen, methyl, methylol, CH
2OX or replacement or do not replace low alkyl group are when Y is CH
2OX, R
1And R
2Can independently be selected from hydroxyl; X is a hydrolysable group.
3. according to the described compound of claim 1, it is characterized in that described compound has following structural (III):
Formula (III)
R
8And R
9Can be identical or different and be independently selected from NR
12Or oxygen; R
10And R
11Can be identical or different and be independently selected from hydrogen or R
5R
12Represent hydrogen or low alkyl group; M and n can be identical or different and be independently selected from 0 or 1; B and R
5Such as claim 1 definition; Y such as claim 2 definition.
4. compound according to claim 2 is characterized in that described compound has following structural (IV) or (V):
Formula (IV)
Formula V
R wherein
1, R
2Definition according to claim 1.
5. compound according to claim 4 is characterized in that described compound is:
2-(6-isobutyl oxygen formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester;
2-(the positive butyloxy formylamido of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester;
2-(the positive penta oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester;
2-(the just own oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester;
2-(6-oxygen in positive heptan formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester;
2-(the positive hot oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester;
2-(6-oxygen in positive ninth of the ten Heavenly Stems formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester or 2-(6-oxygen in positive last of the ten Heavenly stems formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(the different third oxygen methanoyl) methyl] ester.
6. compound according to claim 4 is characterized in that described compound is:
2-(6-isobutyl oxygen formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester;
2-(the positive butyloxy formylamido of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester;
2-(the positive penta oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester;
2-(the just own oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester;
2-(6-oxygen in positive heptan formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester;
2-(the positive hot oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester;
2-(6-oxygen in positive ninth of the ten Heavenly Stems formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester or 2-(6-oxygen in positive last of the ten Heavenly stems formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid two [(new pentane acyloxy) methyl] ester.
7. compound according to claim 4 is characterized in that described compound structure is as follows:
2-(6-isobutyl oxygen formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid;
2-(the positive butyloxy formylamido of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid;
2-(the positive penta oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid;
2-(the just own oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid;
2-(6-oxygen in positive heptan formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid;
2-(the positive hot oxygen formamido-of 6--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid;
2-(6-oxygen in positive ninth of the ten Heavenly Stems formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid;
2-(6-oxygen in positive last of the ten Heavenly stems formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid;
2-(6-n-undecane oxygen formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid;
2-(6-n-dodecane oxygen formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid or
2-(6-n-hexadecane oxygen formamido--9H-purine-9-yl)-1 (R)-methyl ethoxy methyl-phosphorous acid.
8. compound according to claim 7, the salt that it is characterized in that described compound is pharmaceutically acceptable inorganic base salts.
9. compound according to claim 8 is characterized in that described inorganic base salts is sodium salt, sylvite, calcium salt, lithium salts, barium salt or magnesium salts.
10. 2 described compounds as requested is characterized in that described compound has following structural (VI):
Formula (VI)
R wherein
1, R
2Definition according to claim 1.
11., it is characterized in that described compound is according to the described compound of claim 10:
6-isobutyl oxygen formamido--9-[2-[two (pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine;
Positive butyloxy formylamido-the 9-[2-[two of 6-(pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine;
The positive penta oxygen formamido--9-[2-[two of 6-(pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine;
The just own oxygen formamido--9-[2-[two of 6-(pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine;
6-oxygen formamido--9-[2-[in positive heptan two (pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine;
The positive hot oxygen formamido--9-[2-[two of 6-(pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine;
6-oxygen formamido--9-[2-[in the positive ninth of the ten Heavenly Stems two (pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine or
6-oxygen formamido--9-[2-[in the positive last of the ten Heavenly stems two (pivalyl oxygen methoxyl group) phosphoryl methoxy base] ethyl] purine.
12., it is characterized in that described compound is according to the described compound of claim 10:
6-isobutyl oxygen formamido--9-[2-[two (the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine;
Positive butyloxy formylamido-the 9-[2-[two of 6-(the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine;
The positive penta oxygen formamido--9-[2-[two of 6-(the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine;
The just own oxygen formamido--9-[2-[two of 6-(the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine;
6-oxygen formamido--9-[2-[in positive heptan two (the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine;
The positive hot oxygen formamido--9-[2-[two of 6-(the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine;
6-oxygen formamido--9-[2-[in the positive ninth of the ten Heavenly Stems two (the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine or 6-oxygen formamido--9-[2-[in the positive last of the ten Heavenly stems two (the different third oxygen methanoyl methoxyl group) phosphoryl methoxy base] ethyl] purine.
13. compound according to claim 10 is characterized in that described compound is:
2-(6-isobutyl oxygen formamido--9H-purine-9-yl) ethoxyl methyl phosphonic acids;
2-(the positive butyloxy formylamido of 6--9H-purine-9-yl) ethoxyl methyl phosphonic acids;
2-(the positive penta oxygen formamido-of 6--9H-purine-9-yl) ethoxyl methyl phosphonic acids;
2-(the just own oxygen formamido-of 6--9H-purine-9-yl) ethoxyl methyl phosphonic acids;
2-(6-oxygen in positive heptan formamido--9H-purine-9-yl) ethoxyl methyl phosphonic acids;
2-(the positive hot oxygen formamido-of 6--9H-purine-9-yl) ethoxyl methyl phosphonic acids;
2-(6-oxygen in positive ninth of the ten Heavenly Stems formamido--9H-purine-9-yl) ethoxyl methyl phosphonic acids;
2-(6-oxygen in positive last of the ten Heavenly stems formamido--9H-purine-9-yl) ethoxyl methyl phosphonic acids;
2-(6-n-undecane oxygen formamido--9H-purine-9-yl) ethoxyl methyl phosphonic acids;
2-(6-n-dodecane oxygen formamido--9H-purine-9-yl) ethoxyl methyl phosphonic acids or
2-(6-n-hexadecane oxygen formamido--9H-purine-9-yl) ethoxyl methyl phosphonic acids.
14. compound according to claim 13, the salt that it is characterized in that described compound is pharmaceutically acceptable inorganic base salts.
15. compound according to claim 14 is characterized in that described inorganic base salts is sodium salt, sylvite, calcium salt, lithium salts, barium salt or magnesium salts.
16. an antiviral contains any one described compound of the claim 1 to 15 of significant quantity.
17. the application of any described compound in the claim 1 to 15 in the preparation anti-tumor drug.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA021234698A CN1465582A (en) | 2002-07-01 | 2002-07-01 | Nucleotide analogs, medicinal compositions having same and use thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA021234698A CN1465582A (en) | 2002-07-01 | 2002-07-01 | Nucleotide analogs, medicinal compositions having same and use thereof |
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| CN (1) | CN1465582A (en) |
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| WO2009046573A1 (en) * | 2007-10-11 | 2009-04-16 | Beijing Shiqiao Bio-Pharmaceutical Co., Ltd | Liver targeting adefovir prodrug and its medical use |
| CN101003550B (en) * | 2006-12-30 | 2010-05-19 | 河南省分析测试研究中心 | 8- halogenated adenine nucleotide compound , synthetic method, medical application |
| CN102228463B (en) * | 2005-06-13 | 2012-12-19 | 博瑞生物医药技术(苏州)有限公司 | Tenofovir crystals |
| CN101759720B (en) * | 2008-12-26 | 2013-01-23 | 上海信旗医药科技有限公司 | Acyclic nucleoside phosphonate compounds or pharmaceutically acceptable salts thereof, preparation method, application, intermediate compounds thereof, and medicinal composition containing same |
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