CN101633672B - Novel nucleoside compound as well as preparation method and application thereof - Google Patents
Novel nucleoside compound as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a novel nucleoside compound shown as the general formula (I) as well as a preparation method and an application thereof. The compound has antiviral activity and is used for preparing antiviral medicines.
Description
Technical field
The present invention relates to the synthetic field of organic chemistry.Specifically, relate to novel nucleoside compound and preparation method thereof, and the midbody that obtains by this preparation method.The invention still further relates to of the application of above-mentioned novel nucleoside compound in antiviral field.
Background technology
Add up according to the World Health Organization; About 3.5～400,000,000 people of whole world hepatitis B virus (HBV) carrier account for more than 5% of global population (Margolis H S, Hepatitis B virus infection [J] .Bull World Health Organ; 1998,76 (Suppl2): 152～153).China is one of hepatitis B district occurred frequently, and hepatitis B virus carriers 1.3 hundred million people are arranged approximately, has every year 300000 people to die from chronic hepatitis approximately; Wherein 70% viral hepatitis is hepatitis B (Yao Guangbi; The treatment [J] of prospect chronic viral hepatitis. liver, 2002,7 (1): 62～64).
Adefovir ester is the ucleosides antiviral of new generation of Gilead Science company development, in September, 2002 in U.S.'s Initial Public Offering, be widely used in the treatment of chronic hepatitis B.Its rapidly complete in vivo metabolism is parent drug Adefovir (PEMA); Phosphoric acid turns to active metabolite di-phosphate Adefovir under the cell kinase effect; This product and enzyme nature substrate Deoxy-ATP (dATP) competition; Suppress HBV archaeal dna polymerase (HBV reversed transcriptive enzyme), or after being incorporated into the viral DNA chain, make it that chain termination take place; PMEA itself also can be integrated directly in the HBV DNA chain, forms DNA chain termination, make HBV DNA chain stop to duplicate, thereby it has the effect of stronger inhibition HBV dna replication dna.
In recent years, on the Adefovir architecture basics, seek new Adefovir ester analogs and obtained bigger progress with better antiviral activity.Li Shuxin etc. have kept the chain-like structure of Adefovir; 2-amino-6-chloropurine is modified; A series of nucleoside compounds have been synthesized in design, research show wherein 2 compounds have than adefovir ester more significantly antiviral activity (Li Shuxin etc., the synthetic and anti-hepatitis B virus activities research [J] of novel nucleoside phosphonate ester compound. Chinese pharmaceutical chemistry magazine; 2007,17 (6): 344～347).Yuequan Shen research group finds; VITAMIN B4 amino is substituted; Or after chain C2 replaced by methyl, the new compound and the avidity of substrate all had tangible minimizing than Adefovir, show that chain-like structure and adenine base are important group (the Proc Natl Acad Sci USA of Adefovir antiviral activity; 2004,101 (9): 3242～3247).
The present invention is based on above-mentioned research; On the basis that keeps VITAMIN B4 ring and side chain phosphonic acid ester structure, side-chain structure is modified; Introduce aromatic group, the synthetic a series of new nucleoside compounds of design are sought the novel nucleoside compound with potential antiviral activity.
Following embodiment further specifies the present invention, but does not do any restriction.
Summary of the invention
The object of the present invention is to provide one type of novel nucleoside compound, this compounds is to dna virus such as hepatitis B virus has or have stronger antiviral activity potentially.
Compound provided by the present invention is general structure (I) compound and salt thereof:
Wherein:
R
1Expression C
1-C
6Side chain, straight chain or cyclic alkyl, these alkyl can be replaced by hydroxyl, oxygen, sulphur, halogen;
Ar representes aryl, substituted aryl; Wherein the substituting group of Ar can be methyl, ethyl, propyl group low alkyl group; Hydroxyl, methoxyl group, oxyethyl group, amino, cyanic acid, nitro, sulfonamido, carbalkoxy; And/or one or more in the halogen, its position of substitution can be ortho position, a position or contraposition;
R
2, R
3Can be similar and different, and be independently selected from H, C
1-C
10Saturated or undersaturated side chain or straight-chain alkyl, aromatic base or aryl, CH
2COOR
5, CH
2OCOR
5, CH
2OCOOR
5R
2And R
3Can be interconnected to form a cyclic group;
R
5Expression C
1-C
10Saturated or undersaturated side chain or straight-chain alkyl, aromatic base or aryl, preferred tertiary butyl, sec.-propyl.
Wherein the part preferred compound is following:
Another object of the present invention provides a kind of preparation method of above-claimed cpd.General formula (I) compound can be by following path of preparing:
a)DMF/P(OEt)
3；b)DMF/5％NaOH/ω-dihalogenoalkane；c)DMF/Base/Adenine；
d)CH
3CN/(CH
3)
3SiBr；e)NMP/(Et)
3N/R
2X?or?R
3X
Wherein X represent halogen (F, Cl, Br, I); R
1, R
2, R
3Ditto.Compound I I and triethyl-phosphite reaction obtain III, and III obtains IV with two halohydrocarbons reactions under the NaOH effect, and IV and VITAMIN B4 react under the basic catalyst effect and obtain V, and V hydrolysis under bromotrimethylsilane catalysis obtains VI, follows and R
2X or R
3X reaction dehydrohalogenation gets compound I.
The novel method of wherein never reporting in a kind of prior art of synthetic employing of The compounds of this invention III; Prepare with compound I I and triethyl-phosphite single step reaction; Its temperature of reaction can be 50-150 ℃, preferred 80 ℃-95 ℃ reactions down, more preferably 90 ℃ of reactions down.
Said basic catalyst can be sodium hydride, lithium hydride, hydrolith, salt of wormwood, DBU, yellow soda ash, cesium carbonate, Pottasium Hydroxide, sodium hydroxide, calcium hydroxide, ammoniacal liquor, triethylamine, sodium amide, sodium hydrogencarbonate, saleratus, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, tert-butyl alcohol magnesium, trimethyl carbinol lithium.
The present invention also provides the midbody that obtains according to above path of preparing, i.e. compound IV, V and VI, and these compounds and preparation method thereof had not all had report in the prior art.
Further aspect of the present invention provides the application of above-mentioned novel nucleoside compound in antiviral.
Pharmacological activity experiment results shows that compound 2,17,32,47,62 of the present invention has the antiviral activity stronger than Adefovir, and it can be used as activeconstituents, is used to prepare anti-virus infection, like the medicine of hepatitis B virus infection.
Can also be added with one or more pharmaceutically acceptable carriers in the said medicine, like pharmaceutically acceptable thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, lubricant, flavouring agent, sweeting agent etc.
Nucleoside compound of the present invention is that the medicine of activeconstituents preparation can be various ways such as tablet, pulvis, capsule, granula, oral liquid and injection formulations.The medicine of above-mentioned various formulations all can be according to the ordinary method preparation of pharmaceutical field.
Embodiment
Synthesizing of embodiment 14-hydroxybenzene methyl-phosphorous acid diethyl ester
Add 4-salicylic alcohol 12.4g (0.10mol) in the 100mL round-bottomed bottle, triethyl-phosphite 16.6g (0.10mol), DMF50mL, in 90 ℃ of stirring reaction 3h, underpressure distillation, residue adds ether 110mL, washing, anhydrous Na SO
4Drying is filtered, and filtrating is concentrated into dried, obtains off-white color solid 28.1g, and mp 88-89 ℃, yield 85.0%.
Synthesizing of embodiment 24-(2-bromine oxethyl) phenmethyl diethyl phosphonate
Add 4-hydroxybenzene methyl-phosphorous acid diethyl ester 4.88g (0.02mol) in the 100mL three-necked bottle, glycol dibromide 9.40g (0.06mol), DMF20mL, 5%NaOH aqueous solution 45mL, 80 ℃ of stirring reaction 8h, CH is used in cooling
2Cl
2Extract, organic layer is used the 5%NaOH solution washing, uses saturated NaCl solution washing more once, anhydrous MgSO
4Dry 4h filters, and filtrate decompression is steamed and desolventized, and obtains yellow oily liquid 3.71g, yield 52.9%.
IR(CH
2Cl
2)cm
-1：3035，2980，2929，2906，1611，1583，1511，1455，1390，1246，1054，1027，963，851
1H?NMR(300MHz，CDCl
3)，δ(ppm)：1.24(6H，t)，3.08(2H，d)，3.62(2H，t)，3.98-4.04(4H，m)，4.27(2H，t)，6.85-7.27(4H，m)
Synthesizing of embodiment 39-[2-[(4-diethoxy phosphonium mesitoyl ylmethyl) phenoxy] ethyl] VITAMIN B4 (1)
Add VITAMIN B4 2.95g (0.02mol), 4-(2-bromine oxethyl) phenmethyl diethyl phosphonate 7.02g (0.02mol), anhydrous K in the 100mL round-bottomed bottle
2CO
32.8g, DMF 40mL, in 100 ℃ of stirring reaction 4h, cooling is filtered, and filtrate decompression concentrates, and residue is used the Virahol recrystallization, obtains off-white color solid 4.36g, and mp153-154 ℃, yield 51.8%.
ESI/MS(m/z)：406[M+H]
+，428[M+Na]
+
IR(KBr)cm
-1：3403，3132，2986，1661，1601，1512，1483，1253，1048，1021，971，840
1H?NMR(300MHz，CDCl
3)，δ(ppm)：1.23(6H，t)，3.06(2H，d)，3.94-4.03(4H，m)，4.30(2H，t)，4.60(2H，t)，5.81(2H，brs)，6.79-7.26(4H，m)，7.99(1H，s)，8.36(1H，s)
Synthesizing of embodiment 49-[2-[(4-(phosphonomethyl)) phenoxy] ethyl] VITAMIN B4 (2)
Add 9-[2-[(4-diethoxy phosphonium mesitoyl ylmethyl) phenoxy] ethyl] VITAMIN B4 4.05g (0.01mol) in the 100mL three-necked bottle, acetonitrile 30mL stirs logical N
210min adds bromotrimethylsilane 9.18g (0.06mol), continues logical N
210min, 30 ℃ of stirring reaction 15h, reaction solution is evaporated to dried; Residuum adds acetone 20mL, drips water 3mL and becomes settled solution, stirs 2h in the ice bath and separates out the off-white color solid; Suction filtration, filter cake washs with small amount of acetone, oven dry; Obtain off-white powder shape solid 3.15g, mp＞250 ℃, yield 90.0%.
ESI/MS(m/z)：350[M+H]
+
IR(KBr)cm
-1：3392，3060，3031，2962，1703，1609，1512，1464，1413，1247，1115，1049，997，938，833
1H?NMR(300MHz，DMSO-d
6)，δ(ppm)：2.88(2H，d)，4.36(2H，t)，4.63(2H，t)，6.68(2H，brs)，6.80-7.14(4H，m)，8.49(1H，s)，8.55(1H，s)
Synthesizing of embodiment 59-[2-[[two (pivaloyloxymethoxy) (phosphonomethyl)s of 4-] phenoxy] ethyl] VITAMIN B4 (3)
Add 9-[2-[(4-(phosphonomethyl)) phenoxy] ethyl] VITAMIN B4 1.75g (0.005mol) in the 100mL three-necked bottle, chloromethyl pivalate 7.52g (0.05mol), N-Methyl pyrrolidone (NMP) 10mL, triethylamine 2.02g; 50 ℃ of stirring reaction 12h add ETHYLE ACETATE 30mL, stir 0.5h, filter; Filtrate water 10 * 2mL washing, the organic layer concentrating under reduced pressure, residue adds acetone 5mL, and 30 ℃ of stirrings drip isopropyl ether down until there being the off-white color material to occur; Continue in the ice bath to stir low temperature crystallization, freeze overnight, suction filtration; Filter cake in vacuum is dry, obtains off-white color solid 1.01g, and mp118-120 ℃, yield 35.0%.
ESI/MS(m/z)：578[M+H]+
1H?NMR(300MHz，CDCl
3)，δ(ppm)：1.20(18H，s)，3.17(2H，d)，4.01(2H，t)，4.52(2H，t)，5.60(4H，m)，5.99(2H，s)，6.80-7.21(4H，m)，8.01(s，1H)，8.37(1H，s)
Synthesizing of embodiment 64-(3-bromine propoxy-) phenmethyl diethyl phosphonate
Compound method with reference to 4-among the embodiment 2 (2-bromine oxethyl) phenmethyl diethyl phosphonate makes yellow oil, yield 56.3%.
IR(CH
2Cl
2)cm
-1：3035，2980，2930，1611，1583，1511，1473，1391，1246，1178，1054，1028，964，851
1H?NMR(300MHz，CDCl
3)，δ(ppm)：1.24(6H，t)，2.28-2.31(2H，m)，3.08(2H，d)，3.58(2H，t)，3.97-4.03(4H，m)，4.08(2H，t)，6.84-7.28(4H，m)
Synthesizing of embodiment 79-[3-[(4-diethoxy phosphonium mesitoyl ylmethyl) phenoxy] propyl group] VITAMIN B4 (16)
Compound method with reference to 9-among the embodiment 3 [2-[(4-diethoxy phosphonium mesitoyl ylmethyl) phenoxy] ethyl] VITAMIN B4 (1) makes the off-white color solid, and mp161-163 ℃, yield 54.4%.
ESI/MS(m/z)：420[M+H]
+，442[M+Na]
+
IR(KBr)cm
-1：3285，3139，3031，2974，2930，1677，1606，1575，1511，1477，1302，1213，1031，959，844
1H?NMR(300MHz，CDCl
3)，δ(ppm)：1.25(6H，t)，2.04(2H，m)，3.08(2H，d)，3.94(2H，t)，4.01(4H，m)，4.44(2H，t)，5.65(2H，brs)，6.80-7.26(4H，m)，7.80(1H，s)，8.37(1H，s)
Synthesizing of embodiment 89-[3-[(4-(phosphonomethyl)) phenoxy] propyl group] VITAMIN B4 (17)
Compound method with reference to 9-among the embodiment 4 [2-[(4-(phosphonomethyl)) phenoxy] ethyl] VITAMIN B4 (2) makes the off-white color solid, mp＞250 ℃, yield 90.7%.
ESI/MS(m/z)：364[M+H]
+
IR(KBr)cm
-1：3391，3227，3033，2962，2778，1688，1609，1595，1510，1473，1454，1249，1196，1126，985，932.824
1H?NMR(300MHz，DMSO-d
6)，δ(ppm)：2.27-2.34(2H，m)，2.88(2H，d)，3.98(2H，t)，4.44(2H，t)，6.72-7.16(4H，m)，7.01(2H，brs)，8.45(1H，s)，8.57(1H，s)
Synthesizing of embodiment 99-[3-[[two (pivaloyloxymethoxy) (phosphonomethyl)s of 4-] phenoxy] propyl group] VITAMIN B4 (18)
Compound method with reference to 9-among the embodiment 5 [2-[[two (pivaloyloxymethoxy) (phosphonomethyl)s of 4-] phenoxy] ethyl] VITAMIN B4 (3) makes the off-white color solid, and mp132-134 ℃, yield 34.5%.
ESI/MS(m/z)：592.4[M+H]
+
1H?NMR(300MHz，CDCl
3)，δ(ppm)：1.25(18H，s)，2.28(2H，m)，3.21(2H，d)，3.96(2H，t)，4.44(2H，t)，5.59(4H，m)，6.14(2H，s)，6.79-7.20(4H，m)，7.96(1H，s)，8.32(1H，s)
Synthesizing of embodiment 104-(4-bromine butoxy) phenmethyl diethyl phosphonate
Compound method with reference to 4-among the embodiment 2 (2-bromine oxethyl) phenmethyl diethyl phosphonate makes yellow oil, yield 53.5%.
IR(CH
2Cl
2)cm
-1：3034，2979，2920，2907，2871，1611，1582，1511，1474，1442，1391，1297，1248，1178，1054，1028，963，851
1H?NMR(300MHz，CDCl
3)，δ(ppm)：1.25(6H，t)，1.91-1.95(2H，m)，2.04-2.06(2H，m)，3.08(2H，d)，3.48(2H，t)，3.96(2H，t)，4.00-4.03(4H，m)，6.81-7.22(4H，m)
Synthesizing of embodiment 119-[4-[(4-diethoxy phosphonium mesitoyl ylmethyl) phenoxy] butyl] VITAMIN B4 (31)
Compound method with reference to 9-among the embodiment 3 [2-[(4-diethoxy phosphonium mesitoyl ylmethyl) phenoxy] ethyl] VITAMIN B4 (1) makes the off-white color solid, and mp173-175 ℃, yield 58.5%.
ESI/MS(m/z)：434.0[M+H]
+，456.1[M+Na]
+
IR(KBr)cm
-1：3450，3296，3240，3112，2953，2865，1677，1602，1572，1509，1479，1414，1309，1247，1190，1053，1028，952，842
1H?NMR(500MHz，CDCl
3)，δ(ppm)：1.24(6H，t)，1.81-1.84(2H，m)，2.10-2.13(2H，m)，3.07(2H，d)，3.98(2H，t)，4.02(4H，m)，4.29(2H，t)，5.60(2H，brs)，6.80-7.26(4H，m)，7.82(1H，s)，8.37(1H，s)
Synthesizing of embodiment 129-[4-[(4-(phosphonomethyl)) phenoxy] butyl] VITAMIN B4 (32)
Compound method with reference to 9-among the embodiment 4 [2-[(4-(phosphonomethyl)) phenoxy] ethyl] VITAMIN B4 (2) makes the off-white color solid, mp＞250 ℃, yield 88.4%.
ESI/MS(m/z)：378.1[M+H]
+
IR(KBr)cm
-1：3408，3207，3067，3033，2948，2867，1700，1613，1512，1469，1416，1235，1176，1111，999，936，834
1H?NMR(300MHz，DMSO-d
6)，δ(ppm)：1.65-1.69(2H，m)，1.93-1.98(2H，m)，2.86(2H，d)，3.89(2H，t)，4.21(2H，t)，6.77-7.13(4H，m)，7.36(2H，brs)，8.12(1H，s)，8.18(1H，s)
Synthesizing of embodiment 139-[4-[[two (pivaloyloxymethoxy) (phosphonomethyl)s of 4-] phenoxy] butyl] VITAMIN B4 (33)
Compound method with reference to 9-among the embodiment 5 [2-[[two (pivaloyloxymethoxy) (phosphonomethyl)s of 4-] phenoxy] ethyl] VITAMIN B4 (3) makes the off-white color solid, and mp126-127 ℃, yield 33.3%.
ESI/MS(m/z)：606.5[M+H]
+
1H?NMR(300MHz，CDCl
3)，δ(ppm)：1.20(18H，s)，1.65(2H，m)，1.89(2H，m)，2.99(2H，d)，3.94(2H，t)，4.45(2H，t)，5.57(4H，m)，6.46(2H，s)，6.76-7.15(4H，m)，7.89(1H，s)，8.15(1H，s)
The antiviral activity of embodiment 14 test candidate compounds
Solution and compound method:
Prepare with the DMEM nutrient solution according to design dose groups concentration during test.
Preservation condition: 4 ℃ of refrigerators are preserved.
Positive control drug:
Adefovir (self-control)
Preservation condition: 4 ℃ of refrigerators are preserved.
The cell in vitro model:
The 2.2.15 cell of hepatitis B virus (HBV) dna clone transfection human liver cancer cell (HepG2) (HepG22.2.15 cell).
With the external restraining effect that HBsAg and HBeAg are expressed of HepG22.2.15 cell evaluation objective compound:
The HepG22.2.15 cell is cultivated with DMEM nutrient solution (containing 10% foetal calf serum, 100U/mL penicillium mould, 100U/mL Streptomycin sulphate, 100 μ g/mLG418 and 2mmol/L L-glutaminate), 37 ℃, 5%CO
2Incubator in cultivate.With 0.06% trypsinase the HepG22.2.15 cell is dispersed into the individual cells suspension, by 3 * 10
4Cells/well is inoculated in 96 orifice plates, uses the pastille nutrient solution instead after 2 days.Each compound final concentration is respectively 16,8,4,2,1,0.5,0.25,0.125,0 μ mol/L, and each concentration is established 3 repeating holes.With cytosis after 12 days, suct clear liquid, measure HBsAg, HBeAg with ELISA (enzyme-linked immunosorbent assay) method, calculate the half-inhibition concentration (IC of each compound
50), experiment repetition 3 times.With the positive control drug of Adefovir, test shows that compound 2,17,32,47,62 external anti-hepatitis B virus activitieies are better than Adefovir.
The compound anti-hepatitis B virus activities
Embodiment 15 is according to the present invention, the instance of tablet
Compound 3 10g
Microcrystalline Cellulose 81g
Starch 90g
Sodium starch glycolate 5g
Talcum powder 2g
Get above-mentioned prescription, process tablet, about 1000 according to ordinary method.
Embodiment 16 is according to the present invention, capsular instance
Compound 3 20g
Microcrystalline Cellulose 100g
Starch 82g
Magnesium Stearate 2g
Sodium laurylsulfate 2g
Get above-mentioned prescription, process capsule, about 1000 according to ordinary method.
Claims (8)
1. the novel nucleoside compound of general formula such as I:
Wherein: R
1Be expressed as propylidene, butylidene, pentylidene or hexylidene; Ar representes 1, the 4-phenylene; R
2, R
3Expression hydrogen.
2. the preparation method of the said general formula of claim 1 (I) compound is characterized in that, may further comprise the steps:
a)DMF/P(OEt)
3；b)DMF/5％NaOH/ω-dihalogenoalkane；c)DMF/Base/Adenine；
d)CH
3CN/(CH
3)
3SiBr；e)NMP/(Et)
3N/R
2X?or?R
3X
Wherein X represents halogen F, Cl, Br or I; R
1, R
2, R
3Ditto; Compound I I and triethyl-phosphite reaction obtain III, and III obtains IV with two halohydrocarbons reactions, and IV and VITAMIN B4 react under triethylamine or the effect of Carbon Dioxide calcium and obtain V, and V hydrolysis under bromotrimethylsilane catalysis obtains VI, follows and R
2X or R
3X reaction dehydrohalogenation gets compound I.
3. preparation method as claimed in claim 2 is characterized in that: compound I I and triethyl-phosphite temperature of reaction are 50 ℃～150 ℃.
4. preparation method as claimed in claim 2 is characterized in that: said basic catalyst is sodium hydride, lithium hydride, hydrolith, salt of wormwood, DBU, yellow soda ash, cesium carbonate, Pottasium Hydroxide, sodium hydroxide, calcium hydroxide, ammoniacal liquor, triethylamine, sodium amide, sodium hydrogencarbonate, saleratus, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, tert-butyl alcohol magnesium, trimethyl carbinol lithium.
5. antiviral contains the described compound of claim 1 of significant quantity.
6. the application of the described compound of claim 1 in the preparation antiviral.
7. a pharmaceutical composition contains right and requires 1 described compound.
8. the described compsn of claim 7 is characterized in that said compsn is tablet, capsule.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1506370A (en) * | 2002-12-05 | 2004-06-23 | 杭州华东医药集团生物工程研究所有限 | Prepn process of Adefovir dipivalate |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1506370A (en) * | 2002-12-05 | 2004-06-23 | 杭州华东医药集团生物工程研究所有限 | Prepn process of Adefovir dipivalate |
Non-Patent Citations (2)
| Title |
|---|
| 李宗韦.STN检索报告.《STN检索报告》.2011, * |
| 郭晓敏.阿德福韦酯合成路线图解.<中国医药工业杂志>.2008,707-709. * |
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