CN1192439A - 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl) purine and pharmaceutical composition containing same - Google Patents
2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl) purine and pharmaceutical composition containing same Download PDFInfo
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Abstract
2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl) purine is a novel compound represented by formula 1, which is used to prevent or treat the infection induced by virus. A pharmaceutical composition containing the compound is provided, in which the R is isopropyl, propyl or eshyl.
Description
The present invention relates to have the compound and the pharmaceutical composition thereof of the novelty of antiviral activity.
European patent application 0141927 has disclosed compound 9-(4-hydroxyl-3-methylol fourth-1-yl) guanidine, is called Penciclovir (penciclovir), and pharmacy acceptable salt, has also disclosed their antiviral activity simultaneously.Penciclovir thinks that according to document content powerful activity is arranged, especially to bleb family virus, effective as herpes simplex virus type 1, herpes simplex virus type 2, varicella zoster virus and Epstein-Barr virus and hepatitis b virus, but very low (the pharmaceutical chemistry magazine (J.Med.Chem.) 1987 of utilization ratio when giving the human body oral administration according to present report, 30,1636; Biocide chemotherapy (Antimicrob Agent Chemother) .1988,32 358; 1994,38,719).
UK Patent Application 2130204 has disclosed another kind of antiviral compound 2-amino-9-(2-'-hydroxyethoxy ylmethyl) purine.This compound is also referred to as 6-deoxidation acyclovir, it is the absorbed power height in gi tract, and the XOD in being present in human body is converted into 9-(2-'-hydroxyethoxy ylmethyl) guanidine in a large number, be called acyclovir (acyclovir) (Proc.Natl.Acad.Sci.U.S.A.1984,81,3209).
European patent application 0182024 has disclosed the 2-aminopurine derivative.Among this, 2-amino-9-(4-acetoxy-3-acetoxy-methyl fourth-1-yl) purine is called as Famciclovir (famciclovir), can be at gi tract by high absorption, and be converted into Penciclovir apace through XOD and esterification enzyme in vivo.
European patent application 0182024 has also disclosed 2-amino-9-(3-methylol-4-methoxycarbonyl oxygen Ji Ding-1-yl) purine, and be lower than from Famciclovir from the peak concentration of the Penciclovir of 2-amino-9-(3-methylol-4-methoxycarbonyl oxygen Ji Ding-1-yl) purine in the blood.
The present inventor is based on extensively discovering completely, and purine compound is oral can be absorbed efficiently for 2-amino-9-(3-methylol-4-alkoxy-carbonyl oxy fourth-1-yl), and Penciclovir is reclaimed in urine by high density ground as a result.
Therefore an object of the present invention is to provide 2-amino-9-(3-methylol-4-alkoxy-carbonyl oxy fourth-1-yl) purine compound and pharmacy acceptable salt thereof with effective antiviral activity.
Another object of the present invention provides the pharmaceutical composition of this class antiviral compound that contains the pharmacy significant quantity.
The present invention relates to 2-amino-9-(3-methylol-4-alkoxy-carbonyl oxy fourth-1-yl) purine compound of effective antiviral activity, it is represented by following formula 1:
Wherein R is selected from sec.-propyl, propyl group and ethyl.
R is that the example of alkyl comprises ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, amyl group, isopentyl, tert-pentyl etc.The preferred alkyl of R is sec.-propyl, propyl group and ethyl, corresponding compounds is 2-amino-9-(3-methylol-4-isopropoxy carbonyl oxygen Ji Ding-1-yl) purine, 2-amino-9-(3-methylol-4-propoxycarbonyl oxygen Ji Ding-1-yl) purine and 2-amino-9-(3-methylol-4-ethoxy carbonyl oxygen Ji Ding-1-yl) purine.
The present invention can be prepared according to following reaction process by the compound of formula 1 representative:
Be used for the initial substance of synthetic The compounds of this invention, formula 2 compounds are well-known in the art, can easily prepare by known method (organic chemistry magazine, 1981,46,3204).
According to reaction process, at first by with 1,1 '-carbonyl dimidazoles obtained formula 3 compounds to formula 2 compound treatment 3-72 hours to make it cyclisation under backflow in tetrahydrofuran (THF) (below be called THF).
Then, be converted into the alcohol of formula 4 by catalytic hydrogenation formula 3 compounds.The hydrogenation of this reaction under 10-50 ℃ of temperature, is carried out as catalyzer with palladium carbon under the hydrogen pressure of 15-60psi.
Then, make formula 4 compounds and MeSO
2Cl is under-20 to 50 ℃ of temperature, at CH
2Cl
2In Et
3Under existing, N reacts 1-24 hour to obtain the sulfonyl methane ester cpds of formula 5.
Formula 5 compounds with 2-amino-6-chloro-purine under 0-100 ℃, at N, among the N '-dimethyl formamide (below be called DMF) and at Cs
2CO
3Exist down and handled production 6 compounds 1-72 hour.
Make formula 6 compounds with palladium carbon under 10-50 ℃ of temperature as catalyzer, under about 15-60psi hydrogen pressure, at CH
3In the CN/DMF mixed solvent, at Et
3Carry out hydrogenation under the existence of N, obtain the 6-deoxy compound of formula 7.
At last, deoxy compound by making formula 7 and excessive alcohol are in containing the chloroform solvent of silica gel, and reaction makes the target compound of formula 1 under refluxing.Used alcohol is the definition alcohols material as above of wherein R.
The target compound for preparing in aforesaid method can comprise with conventional method, separates and purifying with recrystallization method as column chromatography.
2-amino-9-of the present invention (3-methylol-4-alkoxy-carbonyl oxy fourth-1-yl) purine compound can be used for preventing or treats because the infection that bleb family virus and hepatitis b virus cause.Preferably, the compound oral administration is to the human body administration.
According to patient's age, physical appearance and body weight, the pharmacy effective dose of compound of the present invention can change in the scope of 1-100 mg/kg body weight/day, and preferred range is the 5-50 mg/kg/day.In the effective dosage ranges of such every day, can be administered once every day or repeatedly.
Formula 1 compound or its pharmacy acceptable salt can be used for pharmaceutical composition by prescription.Therefore, another aspect of the present invention has provided a kind of anti-viral pharmaceutical compositions, comprises formula 1 compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier or vehicle and/or other additive.Pharmaceutically acceptable carrier or vehicle can be solid, as lactose, kaolin, sucrose, crystalline cellulose, W-Gum, talcum powder, colloid, agar, stearic acid, sodium starch glycol, Magnesium Stearate, recitine and sodium-chlor, or be liquid form, as glycerine, peanut oil, polyvinylpyrrolidone, sweet oil, ethanol, phenylcarbinol, propylene glycol and water.
Liquid preparations for oral administration can be various forms, during as use solid carrier or vehicle, can be tablet, capsule, powder agent, granule, suppository and dragee.When using the carrier that is fit to the obtaining liq composition, can be suspension agent, syrup, Gelseal, gel and paste.
As mentioned above, but formula 1 compound of the present invention and the administration of pharmaceutically acceptable carrier oral administration thereof, can be extremely usefully as the treatment virus infection, particularly treat the effective therapeutant in the infection of bleb family virus and hepatitis Type B virus, because Penciclovir can keep the concentration of maximum in vivo.
Can to the present invention better understanding be arranged for the embodiment that sets forth by following, but these embodiment are for limiting the present invention.
Preparation embodiment 1
5-(2-benzyl oxygen base ethyl)-1,3-diox-2-ketone: formula 3 compounds
To the 2-that is stirring (2-benzyl oxygen base ethyl) propane-1, add 1 in the solution of 3-glycol (15.30 grams, 72.9 mmoles) in anhydrous THF (1 liter), 1 '-carbonyl dimidazoles (14.18 grams, 87.4 mmoles) allows solution reflux 4 hours.Add 1, behind 1 '-carbonyl dimidazoles (3.54g.21.9 mmole), allow solution reflux again 2 hours.Add 0.3 equivalent 1,1 '-carbonyl dimidazoles (3.54 grams, 21.9 mmoles) then refluxed 2 hours again.After reaction is finished, make the solution drying of gained by evaporation, the oily residue is dissolved in EtOAc (600 milliliters).Solution separates the water that obtains and uses NaCl saturated with 1N HCl (600 milliliters) washing, then with EtOAc extraction (600 milliliters * 3).Solution among the EtOAc that merges is through anhydrous MgSO
4Drying is filtered and the vacuum-evaporation drying.The residue of oil phase is used the MPLC purifying on silica gel, (2: 1, v/v) wash-out obtained the title compound (13.50 grams, 79%) of white solid with the EtOAc-hexanes mixtures.This solid Et
2The O recrystallization.
1H?NMR(CDCl
3/TMS)：δ1.60-1.75(m，2H，CHCHCH
2)
2，2.36-2.48(m，1H，CH)，3.54(t，J＝5.7Hz，2H，CHCH
2CH
2)，4.12(dd，J＝11.1Hz，9.3Hz，2H，(C＝O)OCH
ax)，4.41(dd，J＝11.1Hz，4.8Hz，2H，(C＝O)OCH
eq)，4.49(s，2H，OCH
cPh)，7.28-7.35(m，5H，ArH)；
13C?NMR(CDCl
3)：δ?27.57，29.41，66.96，71.93，73.16，127.60，127.82，128.45，137.71，148.44.
Preparation embodiment 2
5-(2-hydroxyethyl)-1,3-Er Evil-2-ketone: formula 4 compounds
Handle the 5-(2-benzyl oxygen base ethyl)-1 that is stirring with 10% palladium carbon (1.00 gram), the solution of 3-diox-2-ketone (12,50 grams, 53.0 mmoles) in anhydrous THF (300 milliliters), and use H
2Gas scrubbing three times.Allow mixture use filling H
2The H that provides of balloon
2Under the atmosphere, in room temperature, stirred 3 hours, filter then.It almost is purified title compound that vacuum boils off organic solvent, and it is light yellow oil (7.73 grams, 100%), and it can be used for next step and need not to be further purified.
1H?NMR(CDCl
3/TMS)：δ1.62(m，2H，CHCH
2CH
2)，2.40-2.55(m，1H，CH)，2.66(brs，1H，OH)，3.74(t，J＝5.7Hz，2H，CH
2OH)，4.19(dd，J＝10.8Hz，9.0Hz，2H，(C＝O)OCH
ax)，4.51(dd，J＝10.8Hz，4.8Hz，2H，(C＝O)OCH
eq)。
13C?NMR(CDCl
3)：δ28.94，29.80，59.45，72.18，149.03.
Preparation embodiment 3
5-(2-methane sulfonyl oxygen base ethyl)-1,3-diox-2-ketone: formula 5 compounds
To being cooled to 0 ℃, the 5-that is stirring (2-hydroxyethyl)-1,3-diox-2-ketone (4.50 grams, 30.8 mmoles) is at anhydrous CH
2Cl
2Solution (40ml) slowly adds Net
3(9.36g, 92.5 mmoles) are added dropwise to MsCl (3.88 grams, 33.9 mmoles) with syringe then.The mixture of gained further stirred 30 minutes down at 0 ℃, filtered the vacuum-evaporation dried filtrate.Through the MPLC purifying, (9: 1, v/v) wash-out obtained the title compound (5.77g, 84%) of white solid to residue then with EtOAc, use as early as possible with the EtOAc-hexanes mixtures on silica gel.
1H?MNR(CDCl
3/TMS)：δ1.91(m，2H，CHCH
2CH
2)，2.40-2.51(m，1H，CH)，3.06(s，3H，CH
3)，4.21(dd，J＝11.1Hz，7.8Hz，2H，(C＝O)OCH
ax)，4.34(t，J＝6.3Hz，2H，CHCH
2CH
2)，4.52(dd，J＝11.1Hz，3.9Hz，2H，(C＝O)OCH
eq)。
13C?NMR(CDCl
3)：δ27.35，28.37，37.62，66.22，71.15，147.89。
Preparation embodiment 4
2-amino-6-chloro-9-(2-(2-Oxy-1,3-diox-5-yl) ethyl) purine: formula 6 compounds
Make 2-amino-6-chloro-purine (9.49 grams, 56.0 mmoles) and 5-(2-methane sulfonyl oxygen base ethyl)-1,3-diox-2-ketone (12.54 grams, 56.0 mmoles) and Cs
2CO
3(22.8g, 70.0 mmoles) mixture in dry DMF (150 milliliters) is at room temperature and N
2Stirred 16 hours under the atmosphere.Filtering mixt, the vacuum-evaporation dried filtrate.The SiO of residue in the presence of DMF
2Last absorption is at SiO
2EtOAc-CH then, through the MPLC purifying, is used in the location, top of post
3CN-NEt
3(49: 49: 2, v/v/v) wash-out obtained the title compound (8.02 grams, 48%) of white solid to mixture, uses CH
3The CN-THF-hexanes mixtures (1: 4: 10, v/v/v) recrystallization.
1H?NMR(DMSO-d
6/TMS)：δ1.86(m，2H，CHCH
2CH
2)，2.07-2.19(m，1H，CH)，4.13(t，J＝7.2Hz，2H，NCH
2)，4.21(dd，J＝10.5Hz，7.8Hz，2H，(C＝O)OCH
ax)，4.46(dd，J＝10.5Hz，4.2Hz，2H，(C＝O)OCH
eq)，6.90(brs，2H，NH
2)，8.17(s，1H，H-8)；
13C?NMR(DMSO-d
6)：δ26.78，27.97，40.27，71.01，123.30，143.04，147.83，140.35，154.06，159.72。
Preparation embodiment 5
2-amino-9-(2-(2-Oxy-1,3-diox-5-yl) ethyl) purine: formula 7 compounds
Use NEt
3(543mg, 5.37 mmoles) and 10% palladium carbon (60 milligrams) are handled 2-amino-6-chloro-9-(2-(2-Oxy-1,3-diox-5-yl) ethyl) purine at anhydrous CH
3The solution that is stirring in CN (25 milliliters) and the dry DMF (10 milliliters) is used H
2Gas scrubbing three times.At room temperature, with filling H
2Balloon stirred filtering mixt 3 hours.The vacuum-evaporation dried filtrate.Make the residue powdered obtain the white solid (427 milligrams, 90%) of title compound after adding a small amount of pure EtOH (2 milliliters).Use CH
3The CN-THF-hexanes mixtures (1: 4: 10, v/v/v) recrystallization.
1H?NMR(DMSO-d
6/TMS)：δ1.84(m，2H，CHCH
2CH
2)，2.07-2.17(m，1H，CH)，4.14(t，J＝7.1Hz，2H，NCH
2)，4.22(dd，J＝10.8Hz，8.1Hz，2H(C＝O)OCH
ax)，4.46(dd，J＝10.8Hz，4.5Hz，2H，(C＝O)OCH
eq)，6.51(brs，2H，NH
2)，8.11(s，1H，H-8)，8.57(s，1H，H-6)；
13C?NMR(DMSO-d
6)：δ26.90，28.11，40/45，71.03，126.79，142.57，147.83，148.95，152.98，160.42。
Embodiment 1
2-amino-9-(3-methylol-4-ethoxy carbonyl oxygen Ji Ding-1-yl) purine (compound 1)
Under nitrogen atmosphere, handle 2-amino-9-(2-(2-Oxy-1,3-diox-5-yl) ethyl) purine (395 milligrams, 1.50 mmoles) and anhydrous SiO with EtOH (40 milliliters)
2(4.0g) at CHCl
3Solution in (20 milliliters), and under 72 ℃, heated 24 hours.After the cooling, filter reaction mixture, vacuum-evaporation filtrate is to doing.Residue with the MPLC purifying, is used MeOH-CHCl on silica gel
3(1: 9, v/v) wash-out obtained title compound to mixture, obtains white solid behind EtOAc-hexanes mixtures recrystallization.
Yield: 87%
1H NMR (CDCl
3/ TMS): δ 1.29 (t, J=7.2Hz, 3H, CH
2CH
3), 1.85-2.02 (m, 2H, CHCH
2CH
2), 1.98-2.06 (m, 1H, CH), 3.64-3.76 (m, 2H, CHCH
2OH), 4.12-4.28 (m, 6H, NCH
2And 2OCH), 5.53 (br s, 2H, NH
2), 7.79 (s, 1H, H-8), 8.64 (s, 1H, H-6);
13C?NMR(CDCl
3)：δ14.15，28.65，37.87，41.09，61.64，64.23，67.66，127.87，142.39，149.70，152.98，155.26，159.79。
Embodiment 2
2-amino-9-(3-methylol-4-propoxycarbonyl oxygen Ji Ding-1-yl) purine (compound 2)
Except using the 1-propyl alcohol to replace the ethanol, other same procedure with embodiment 1 prepares target compound.
Yield: 89%
1H NMR (CDCl
3/ TMS): δ 0.96 (t, J=7.5Hz, 3H, CH
2CH
3), 1.62-1.76 (m, 2H, CH
2CH
3), 1.84-2.01 (m, 2H, CHCH
2CH
2), 1.97-2.06 (m, 1H, CH), 3.72 (m, 2H, CHCH
2OH), 4.13 (t, J=6.9Hz, 2H, OCH
2CH
2), 4.18-4.30 (m, 4H, NCH
2And OCH
2CH), 5.18 (brs, 2H, NH
2), 7.18 (s, 1H, H-8), 8.69 (s, 1H, H-6);
13C?NMR(CDCl
3)：δ10.07，21.90，28.66，37.88，41.09，61.66，67.66，69.83，127.89，142.38，149.72，152.98，155.41，159.80。
Embodiment 3
2-amino-9-(3-methylol-4-isopropoxy carbonyl oxygen Ji Ding-1-yl) purine (compound 3)
Except using the 1-Virahol to replace the ethanol, other prepares target compound with embodiment 1 identical method.
Yield: 64%
1H NMR (CDCl
3/ TMS): δ 1.29 (d, J=6.3Hz, 6H, CH (CH
3)
2), 1.85-2.01 (m, 2H, CHCH
2CH
2), 1.98-2,10 (m, 1H, CH), 3.71 (m, 2H, CHCH
2OH), 4.15-4.28 (m, 4H, NCH
2And OCH
2CH), 4.87 (detached peaks, J=6.3Hz, 1H, CH (CH
3)
2), 5.47 (brs, 2H, NH
2), 7.79 (s, 1H, H-8), 8.66 (s, 1H, H-6);
13C?NMR(CDCl
3)：δ21.67，28.68，37.89，41.09，61.71，67.44，72.30，127.92，142.38，149.73，152.99，154.81，159.78。
Embodiment 4
2-amino-9-(3-methylol-4-butoxy carbonyl oxygen Ji Ding-1-yl) purine (compound 4)
Except using the 1-butanols to replace the ethanol, other similarity method with embodiment 1 prepares target compound.
Yield: 69%
1H NMR (CDCl
3/ TMS): δ 0.94 (t, J=7.4Hz, 3H, CH
2CH
3), 1.40 (m, 2H, CH
2CH
3), 1.66 (m, 2H, CH
2CH
2CH
3), 1.84-2.02 (m, 2H, CHCH
2CH
2), 1.99-2.06 (m, 1H, CH), 3.72 (m, 2H, CHCH
2OH), 4.15 (t, J=6.8Hz, 2H, OCH
2CH
2CH
2), 4.18-4.34 (m, 4H, NCH
2And OCH
2CH), 5.19 (brs, 2H, NH
2), 7.78 (s, 1H, H-8), 8.69 (s, 1H, H-6);
13C?NMR(CDCl
3)：δ13.55，18.81，28.66，30.54，37.88，41.09，61.65，67.66，68.14，127.88，142.38，149.71，152.97，155.41，159.80。
Embodiment 5
2-amino-9-(3-methylol-4-isobutoxy carbonyl oxygen Ji Ding-1-yl) purine (compound 5)
Other uses embodiment 1 similar methods to prepare target compound the ethanol except replacing with 2-methyl isophthalic acid-propyl alcohol.
Yield: 87%
1H NMR (CDCl
3/ TMS): δ 0.95 (d, J=6.6Hz, 6H, CH (CH
3)
2), 1.85-2.12 (m, 4H, CHCH
2CH
2And CH (CH
3)
2), 3.73 (m, 2H, CHCH
2OH), 3.92 (d, J=6.9Hz, 2H, OCH
2CH), 4.18-4.29 (m, 4H, NCH
2And OCH
2), 5.25 (br s, 2H, NH
2), 7.78 (s, 1H, H-8), 8.69 (s, 1H, H-6);
13C?NMR(CDCl
3)：δ18.85，27.74，28.74，37.87，41.04，62.00，67.62，74.34，128.17，142.34，149.86，153.12，155.54，159.78。
Embodiment 6
2-amino-9-(3-methylol-4-pentyloxy carbonyl oxygen Ji Ding-1-yl) purine (compound 6)
Except using the 1-amylalcohol to replace the ethanol, other prepares target compound with embodiment 1 similar methods.
Yield: 74%
1H NMR (CDCl
3/ TMS): δ 0.91 (t, J=7.1Hz, 3H, CH
2CH
3), 1.34 (m, 4H, CH
2CH
2CH
3), 1.67 (m, 2H, CH
2CH
2CH
2CH
3), 1.85-2.10 (m, 3H, CHCH
2CH
2), 3.72 (, m2H, CHCH
2OH), 4.13 (t, J=6.9Hz, 2H, OCH
2CH
2), 4.18-4.31 (m, 4H, NCH
2And OCH), 5.15 (br s, 3H, NH
2), 7.78 (s, 1H, H-8), 8.69 (s, 1H, H-6);
13C?NMR(CDCl
3)：δ13.88，22.24，27.77，28.30，28.74，37.85，41.01，62.14，67.57，68.52，128.29，142，32，149.97，153.13，155.53，159.74。
Embodiment 7
2-amino-9-(3-methylol-4-isopentyl oxygen base ketonic oxygen Ji Ding-1-yl) purine (compound 7)
Except replacing the ethanol, prepare target compound with the same procedure of embodiment 1 with 3-methyl isophthalic acid-butanols.
Yield: 84%
1H NMR (CDCl
3/ TMS): δ 0.93 (t, J=6.9Hz, 6H, CH (CH
3)
2), 1.56 (m, 2H, CHCH
2CH
2), 1.71 (detached peaks, J=6.9Hz, 1H, CH (CH
3)
2), 1.88-2.11 (m, 3H, CHCH
2CH
2), 3.73 (m, 2H, CHCH
2OH), 4.17 (t, J=6.9Hz, 2H, OCH
2CH
2), 4.18-4.28 (m, 4H, NCH
2And OCH
2), 5.28 (br s, 2H, NH
2), 7.78 (s, 1H, H-8), 8.96 (s, 1H, H-6);
13C?NMR(CDCl
3)：δ22.36，24.79，28.74，37.25，37.87，41.04，62.02，67.00，67.60，128.17，142.32，149.88，153.10，155.47，159.78。Active substance 250 lactose 145 starch 50 polyvinylpyrrolidones 50 Magnesium Stearates 5 of embodiment 8 component consumption (milligram/sheet) embodiment 3
Amount to 500
Make active substance, lactose and starch, and polyvinylpyrrolidonesolution solution is mixed and pulverizing, the coarse particles phase that obtains wetting, dry then, sieve, and be mixed with tablet with Magnesium Stearate.Active substance 250 lactose 225 sodium starch glycols 10 polyvinylpyrrolidones 10 Magnesium Stearates 5 of embodiment 9 component consumption (milligram/sheet) embodiment 3
Amount to 500
Make active substance, lactose and starch, and polyvinylpyrrolidonesolution solution is mixed and pulverizing, the coarse particles phase that obtains wetting, drying is sieved, and is mixed with Magnesium Stearate then, is enclosed in to prepare capsule in the hard gelatin capsule.Embodiment 10
The measurement of availability in the oral route body
Come availability in the body of mensuration formula 1 compound oral administration by the total amount that exists of measuring Penciclovir in the urine with HPLC.After giving active substance with the oral dose of 200 micromoles/kg body weight for male ICR mouse (25-30 restrain body weight), 48 hours urine of collection under the help of metabolic cage.In order to prevent the growth of bacterium in the urine, add 5% sodium azide solution in the urine of amount in reclaiming cage with the 0.4ml/100ml urine.The urine of collecting is through 0.45 micron membrane filtration.Analyze the concentration of Penciclovir in the filtrate with HPLC by following process:
Damping fluid is through C
18Symmetrical posts is divided the three phases wash-out with the speed of 1 ml/min: stage 1:100% buffer A (0.1% phosphoric acid salt) balance wash-out 10 minutes; Stage 2:100% buffer A was to 55% buffer A and 45% buffer B (containing 0.1% phosphatic 80% acetonitrile) mixture gradient elution 25 minutes; Stage 3:55% buffer A and 45% buffer B mixture balance wash-out 4 minutes.On post before the dress lotus sample by stablizing in 10 minutes with 100% buffer A wash-out.The UV of post effluent liquid is absorbed in 248nm and measures.Measure availability in the body that oral administration gives sample by the amount of Penciclovir in the urine relatively.
Following table 1 has provided the Penciclovir that 6 mouse collect in the urine and has reclaimed %.Oral back 48 hours of table 1 compound is from the spray former times in the urine
The recovery % of Lip river Wei
1??????????????????????????????????????????50
2??????????????????????????????????????????51
3??????????????????????????????????????????53
4??????????????????????????????????????????38
5??????????????????????????????????????????38
6??????????????????????????????????????????47
7 51 Famciclovir 482-amino-9-(3-methylol-4-methoxycarbonyl fourth-1-yl) purine 45
Be easy in data presentation in the table 1 formula 1 chemical combination object of the present invention absorb, be converted into Penciclovir in a large number in oral back.Should be noted that oral administration of compound 3 back 48 hours recovery % from the Penciclovir of urine have reached 53%, it is 48% and 45% all higher than Oral famciclovir and 2-amino-9-'s (3-methylol-4-methoxycarbonyl oxygen Ji Ding-1-yl).Embodiment 11
Water-soluble
Water-soluble for mensuration formula 1 compound adds excessive compound in the entry, allows the mixture eddy current mix 1 minute, and ultrasonic 1 minute, eddy current mixed 3 minutes then, and ultrasonic again 1 minute, high degree of agitation 5 minutes was to obtain saturated solution then.These saturated solutions filter through 0.45 micron filtering membrane, and dilution is after the UV-spectrometry.By measuring the solubleness of compound in water with the optical density of 290nm place compound and the UV curve ratio of standard.Following table 2 has provided solubleness.Solubleness in the table 2 compound water
(mg/ml; 20 ℃) as seen, the solubility of compound 3 in water is very high from table 2 for 14.1 purine for 1 20.02 68.03 138.84 15.05 1.56 4.27 5.62-amino-9-(3-methylol-4-methoxycarbonyl oxygen Ji Ding-1-yl). Embodiment 12
Stability in the water
The solution that contains formula 1 compound is diluted to 2.5mM to 125 μ M with sodium phosphate buffer (pH6.0, pH7.4 and pH8.0) and simulated gastric fluid (pH1.2), then at once 37 ℃ of following culture solution.Take out 100 microlitre samples at regular intervals from reaction solution, (pH7.0) mixes with the 0.1M phosphate buffered saline buffer.After this, by HPLC to the hyle of diluent quantitatively to measure the transformation period of compound.The results are shown in following table 3.The table 3 compound transformation period (my god)
PH1.2 pH6.0 pH7.4 pH8.01 35 112 7 32 29 89 10 43 88＞200 61 264 29 74 11 55 28 87 17 86 25 17 7 57 24 65 11 62-amino-9-(3-methylol-4-methoxycarbonyl fourth-1-yl) purine 23 18 1 0.5
Though formula 1 compound exhibits thereupon pH increase the trend that its stability reduces, when finding that they are very stable at the pH value place of test, the stability of specilization compound 3 in water is more superior.
Embodiment 13
Single dose toxicity research in the Sprague-Dawley mouse
Before test, give 6-the complete feeding ball diet of Sprague-Dawley mouse (male: 162-174 restrain body weight, and is female: 127-139 restrains body weight) and the water in age in week for 50 ± 20% times at 23 ± 3 ℃, relative humidity.
5 male and 5 oral or quiet notes compounds 3 of female mouse are given in each test, observe clinical symptom, death, body weight and pathology in 14 days.In case animal dead autopsy at once is with observation appearance and all organ and tissues, and the recording exceptional situation.The fixedly heart of autopsy organ, lung, liver, kidney and spleen, and be kept in 10% formalin solution.The result is shown in following table 4 and 5.Table 4: the result who gives the mouse oral administration
| Sex | Dosage (mg/kg) | The dead animal number | Dead percentage ratio (%) | ????LD 5????(mg/kg) |
| Male | ????0 | ????0/5 | ????0 | ??3500-5000 |
| ????2500 | ????0/5 | ????0 | ||
| ????3500 | ????1/5 | ????20 | ||
| ????5000 | ????3/5 | ????60 | ||
| Female | ????0 | ????0/5 | ????0 | ??3500-5000 |
| ????2500 | ????0/5 | ????0 | ||
| ????3500 | ????0/5 | ????0 | ||
| ????5000 | ????3/5 | ????60 |
Table 5: the result who gives the quiet notes administration of mouse
| Sex | Dosage (mg/kg) | The dead animal number | Dead percentage ratio (%) | ????LD 5????(mg/kg) |
| Male | ????0 | ????0/5 | ????0 | ????392 ??(342-449) |
| ????250 | ????0/5 | ????0 | ||
| ????350 | ????1/5 | ????20 | ||
| ????500 | ????5/5 | ????100 | ||
| Female | ????0 | ????0/5 | ????0 | ????366 ??(310-432) |
| ????250 | ????0/5 | ????0 | ||
| ????350 | ????2/5 | ????40 | ||
| ????500 | ????5/5 | ????100 |
Embodiment 14
Beagle is carried out single agent oral administration toxicity research
Before test, 21 ± 3 ℃, humidity give for 50 ± 20% times 7 monthly age beagles (male: the 7.8-9.4 kg body weight, female: the 6.8-7.6 kg body weight) feeding.
Give two dog and two bitch oral administration of compound 3 of test group, in 14 days, observe clinical symptom, death, body weight and feed.Dead animal is carried out autopsy comprises outside and internal examination with record pathologic condition.Unusual organ and organize all fixing and be stored in 10% brown your Malin's solution, the result is as shown in table 6 below.
Table 6: the result who gives the dog oral administration
| Sex | Dosage (mg/kg) | The dead animal number | Dead percentage ratio (%) |
| Male | ????0 | ????0/2 | ????0 |
| ????125 | ????0/2 | ????0 | |
| ????500 | ????0/2 | ????0 | |
| ????2000 | ????0/2 | ????0 | |
| Female | ????0 | ????0/2 | ????0 |
| ????125 | ????0/2 | ????0 | |
| ????500 | ????0/2 | ????0 | |
| ????2000 | ????0/2 | ????0 |
In sum, the data presentation of embodiment gained, the compound of formula 1 representative with keep Penciclovir in vivo the availability of high density absorb, thereby shown effective antiviral activity.
The present invention discloses with narrative method, is understood that terminology used here for narration usefulness, and non-limiting usefulness.
The present invention can have many modifications and variation to above-mentioned technology.Therefore, be understood that the present invention can implement in the appending claims scope, and be not only to implement as specification sheets is described.
Claims (3)
1. 2-amino-9-(3-methylol-4-alkoxy-carbonyl oxy fourth-1-yl) purine of following formula 1 representative, and pharmacy acceptable salt:
Wherein R is sec.-propyl, propyl group or ethyl.
2. antiviral agent comprises 2-amino-9-(3-methylol-4-alkoxy-carbonyl oxy fourth-1-yl) purine of the pharmacy effective dose of following formula 1 representative:
Wherein R is sec.-propyl, propyl group or ethyl.
3. the purposes of antiviral agent as claimed in claim 2 in the infection that prevention or treatment are caused by bleb family virus and hepatitis Type B virus.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR97-7148 | 1997-03-05 | ||
| KR19970007148 | 1997-03-05 | ||
| KR1019980006924A KR100257663B1 (en) | 1997-03-05 | 1998-03-03 | 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purine and pharmaceutical composition containing the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1192439A true CN1192439A (en) | 1998-09-09 |
Family
ID=26632555
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98107140A Pending CN1192439A (en) | 1997-03-05 | 1998-03-05 | 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl) purine and pharmaceutical composition containing same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1192439A (en) |
-
1998
- 1998-03-05 CN CN98107140A patent/CN1192439A/en active Pending
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