CN1966514A - Novel acyclic nucleoside phosphonate and its medical use - Google Patents
Novel acyclic nucleoside phosphonate and its medical use Download PDFInfo
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- CN1966514A CN1966514A CN 200510117768 CN200510117768A CN1966514A CN 1966514 A CN1966514 A CN 1966514A CN 200510117768 CN200510117768 CN 200510117768 CN 200510117768 A CN200510117768 A CN 200510117768A CN 1966514 A CN1966514 A CN 1966514A
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- trifluoroethyl
- propyl group
- phosphonium mesitoyl
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- mesitoyl methoxy
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Abstract
This invention provides trifluoroacetate derivatives of (R)-PMPA or (R)-PMPDAP represented by formula I and their non-toxic biological pharmaceutical acceptable salts, wherein R1 is H or NH2, R2 is H or COO-R3, and R3 is C1-C10 alkyl or phenyl substituted C1-C3 alkyl. This invention also provides drug combinations with acyclic nucleoside phosphonates as shown in formula I and their non-toxic pharmaceutical acceptable salts as active ingredients, and their applications in antiviral drugs, especially in anti-HBV and anti-HIV drugs.
Description
Technical field
The present invention relates to new acyclic nucleoside phosphate ester and non-toxicity pharmacy acceptable salt thereof.These acyclic nucleoside phosphate esters have higher oral administration biaavailability, can optionally discharge the antiviral activity composition at liver after entering in the body.The invention still further relates to and comprise such acyclic nucleoside phosphate ester and non-toxicity pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents and as the purposes of antiviral.
Background technology
By the disease due to the virus infection such as viral hepatitis and acquired immune deficiency syndrome (AIDS) is the major disease that threatens human health.Though the research of antiviral makes important progress, some clinical effective antiviral have been found.Be used for the treatment of hepatitis B as Interferon, rabbit, lamivudine, adefovir ester and Entecavir etc., zidovudine, stavudine, nevirapine, Indinavir etc. are used for the treatment of acquired immune deficiency syndrome (AIDS).But these compounds also have many side effects; And during prolonged application, virus can develop immunity to drugs in variation.Therefore, also need the better antiviral of new pharmacological property.
(R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (R)-and 9-[2-(Phosphonomethoxy) propyl] adenine, (R)-and PMPA} and (R)-9-[2-(phosphono methoxyl group) propyl group]-2, the 6-diaminopurine (R)-and 9-[2-(Phosphonomethoxy) propyl]-2,6-diamino-purine, (R)-PMPDAP} is the acyclic nucleoside phosphonate compounds, has the retroviral activity of stronger inhibition, in in-vitro evaluation, demonstrate anti-preferably HIV and anti-HBV effect, and cytotoxicity is lower.But because polarity is too big, (R)-PMPA and (R)-the PMPDAP oral administration biaavailability is low, and oral administration is difficult to reach effective treatment concentration.
Summary of the invention
The trifluoro ethyl ester derivative and the non-toxicity pharmacy acceptable salt thereof that the purpose of this invention is to provide (the R)-PMPA of formula I representative or (R)-PMPDAP:
Wherein, R
1Be H or NH
2, R
2Represent H or COO-R
3, R
3Be C
1-C
6The C that replaces of alkyl or phenyl
1-C
3Alkyl.
The present invention also provides the acyclic nucleoside phosphate ester shown in the formula I and non-toxicity pharmacy acceptable salt thereof the pharmaceutical composition as activeconstituents.
The present invention also provides acyclic nucleoside phosphate ester shown in the formula I and non-toxicity pharmacy acceptable salt thereof, and comprise the acyclic nucleoside phosphate ester shown in the formula I and non-toxicity pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents as the antiviral purposes of anti-hepatitis b and anti-hiv drug particularly.
Embodiment
The following examples can further be described the present invention, yet these embodiment should be as the restriction to scope of the present invention.
Compound of the present invention can prepare according to following synthetic route:
With (R)-methyl lactate is raw material, is reacted into benzyl oxide protection hydroxyl with cylite; Then ester bond is become alcohol with tetrahydrochysene lithium aluminium reducing, chloro, catalytic hydrogenation is sloughed benzyl oxide, obtains (R)-1-chloro-2-propanol; R-1-chloro-2-propyl alcohol and Paraformaldehyde 96/HCl reaction obtains (R)-1-chloro-2-chlorine methoxy propane, the latter and three-(2,2, the 2-trifluoroethyl)-phosphite reactions, obtain (R)-2-[two-(2,2, the 2-trifluoroethyl) phosphonium mesitoyl methoxy]-propyl chloride, again with VITAMIN B4 or 2,6-diaminopurine reaction, preparation (R)-9-{2-[two-(2,2,2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-VITAMIN B4 or (R)-9-{2-[two-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-2,6 diaminopurines; (R)-and 9-{2-[is two-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-VITAMIN B4 or (R)-9-{2-[two-(2; 2; the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group-2,6 diaminopurines again with chloro-formic ester reaction, prepare corresponding carbamate derivatives.
Embodiment 1 9-{2-[pair-(trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-VITAMIN B4 (I
1) preparation
1.1 (R)-1-chloro-2-propanol synthetic
In 1200 milliliters of dimethyl formamides, add 208 grams (2mol) (R)-methyl lactate, the ice bath cooling is stirred the sodium hydride that in batches adds 96 gram (2.4mol) 60% down, stirring reaction 1 hour.Drip 408 gram (2.4mol) cylites then, drip off the back and under ice bath, stirred 4 hours, at room temperature continue to stir 48 hours.Pressure reducing and steaming DMF separates residue with silica gel column chromatography, use ethyl acetate: sherwood oil (1: 9) wash-out, collect required component, and evaporated under reduced pressure gets 188 gram oily liquids.
To go up step product 186 grams (0.98mol) and be dissolved in the 1200ml anhydrous tetrahydro furan, ice bath adds 60 gram tetrahydrochysene lithium aluminium in batches under stirring, at room temperature continue after adding to stir 4 hours.Under ice bath, slowly drip 20ml water.Dropwise, drip the potassium hydroxide solution of 60ml 15% again.Filter, filter residue is given a baby a bath on the third day after its birth inferior with ether.Merge washing filtrate, the pressure reducing and steaming organic solvent.With residue extracted with diethyl ether 3 times, merge ether extraction liquid, use anhydrous magnesium sulfate drying.Evaporated under reduced pressure is separated residue with silica gel column chromatography, use ethyl acetate: sherwood oil: methyl alcohol (2: 8: 0.5) wash-out, collect required component, and evaporated under reduced pressure gets 122 gram oily liquids.
In the new thionyl chloride that steams of 240 grams (2.0mol), stir to drip down and go up step product 120 grams (0.72mol).After adding, back flow reaction 2 hours, the unreacted thionyl chloride of pressure reducing and steaming is dissolved in ether with residue, and the Calcium Chloride Powder Anhydrous drying is used in water, 10% sodium carbonate solution and washing in succession.Evaporated under reduced pressure is separated residue with silica gel column chromatography, use ethyl acetate: sherwood oil (1: 9) wash-out, collect required component, and evaporated under reduced pressure gets 91 gram oily liquids.
To go up step product 90 grams and be added in 1200 ml methanol, add the palladium-charcoal of 10 grams 10%, catalytic hydrogenation.Reaction is spent the night, and filters.The filtrate rotation is boiled off solvent,, collect the cut of 70-72 ℃/70mmHg, get (R)-1-chloro-2-propanol 37.5 grams, [α] the residue fractionation
20 D=-22.3 ° (1% chloroform soln).
1.2 three-(2,2, the 2-trifluoroethyl)-phosphorous acid ester
In 100 gram trifluoroethanols, add 50 gram phosphorus trichlorides, 85 ℃ of stirring reactions 4 hours.Fractionation, the cut of 135-141 ℃/80-84mmHg of collection gets three-(2,2, the 2-trifluoroethyl) phosphorous acid esters, 91 grams.
1.3 2-[is two--(2,2, the 2-trifluoroethyl) phosphonium mesitoyl methoxy]-propyl chloride
36 gram (R)-1-chloro-2-propanol and 18 gram Paraformaldehyde 96s are suspended in 100 milliliters of methylene dichloride the ice bath cooling.Stir down and feed the exsiccant hydrogen chloride gas, continue 24 hours.After the reaction solution washing, with the calcium chloride drying.Filter, evaporated under reduced pressure gets (R)-1-chloro-2-chlorine methoxy propane 32.7 grams.
With 32 gram 1-chloro-2-chlorine methoxy propanes and 80 gram three-(2,2, the 2-trifluoroethyl) phosphorous acid esters mixing, 160 ℃ of stirring reactions 5 hours.The pressure reducing and steaming solvent, the cut of fractionation 80-84 ℃/25-30mmHg gets (R)-2-[pair-(2,2, the 2-trifluoroethyl) phosphonium mesitoyl methoxy]-propyl chloride 51 grams.
1.4 (R)-9-{2-[is two-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-VITAMIN B4 adds 10 gram VITAMIN B4 and 3 and restrains 60% sodium hydride in the 150ml dimethyl formamide.Add (R)-2-[pair-(2,2, the 2-trifluoroethyl) phosphonium mesitoyl methoxy then]-propyl chloride 25 grams, stirred 4 hours at 100 ℃, with the reaction solution evaporated under reduced pressure.Residue is separated with silica gel column chromatography,, obtains (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy with chloroform/methanol (1: 0.05) wash-out]-propyl group }-VITAMIN B4 9.5 grams.Proton nmr spectra: δ (DMSO-d
6, ppm): 8.21 (s, 1H); 7.7 (s, 1H); (5.26 heavy water exchange back disappears for s, 2H); 4.64 (m, 4H); 4.58 (m, 1H); 4.18 (d, 2H); 4.06 (d, 2H); 1.22 (d, 3H).
Embodiment 2 (R)-9-{2-[is two--(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-2,6-diaminopurine (I
2) preparation
Method according to embodiment 1.4 replaces VITAMIN B4 with 2,6-diaminopurine, with (R)-2-[two-(2; 2, the 2-trifluoroethyl) phosphonium mesitoyl methoxy]-the propyl chloride reaction, it is two to make (R)-9-{2-[--and (2; 2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-2,6-diaminopurine (I
2).Proton nmr spectra: δ (DMSO-d
6, ppm): 7.85 (s, 1H); (5.78 heavy water exchange back disappears for s, 2H); (5.32 heavy water exchange back disappears for s, 2H); 4.69 (m, 4H); 4.58 (m, 1H); 4.21 (d, 2H); 4.06 (d, 2H); 1.23 (d, 3H).
Embodiment 3 (R)-9-{2-[pair-(trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-methoxycarbonyl amido-purine (I
3) preparation
With 1 gram I
1With 30 milliliters of methylene dichloride dissolvings, add 2.0 milliliters of anhydrous pyridines, reaction solution is cooled to-40 ℃.Stir down and drip 0.4 milligram of methyl-chloroformate in the solution of 10 milliliters of methylene dichloride.Add the back and stirred 30 minutes, again in stirring at room 30 minutes.With the reaction solution evaporate to dryness, residue is separated with silica gel column chromatography, use chloroform: methyl alcohol (96: 4) wash-out gets I
5440 milligrams, proton nmr spectra: δ (DMSO-d
6, ppm): 10.0 (heavy water exchange back disappears for s, 1H); 8.65 (s, 1H); 8.36 (s, 1H); 4.63-4.69 (m, 4H); 4.54 (m, 1H); 4.18 (d, 2H); 4.06 (d, 2H); 3.76 (s, 3H); 1.24 (d, 3H).
Embodiment 4 (R)-9-{2-[pair-(trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-ethoxycarbonyl amido-purine (I
4) preparation
Method according to embodiment 3 replaces methyl-chloroformate with Vinyl chloroformate, with I
1Reaction makes (R)-9-{2-[pair-(trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-ethoxycarbonyl amido-purine (I
4), proton nmr spectra: δ (DMSO-d
6, ppm): 9.66 (heavy water exchange back disappears for s, 1H); 8.60 (s, 1H); 8.32 (s, 1H); 4.60-4.64 (m, 4H); 4.54 (m, 1H); 4.22 (q, 2H); 4.16 (d, 2H); 4.07 (d, 2H); 1.30 (t, 3H); 1.24 (d, 3H).
Embodiment 5 (R)-9-{2-[pair-(trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-third oxygen formamido--purine (I
5) preparation
Method according to embodiment 3 replaces methyl-chloroformate with propyl chloroformate, with I
1Reaction makes (R)-9-{2-[pair-(trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-third oxygen formamido--purine (I
5), proton nmr spectra: δ (CDCl
3, ppm): 8.76 (s, 1H); 8.15 (s, 1H); 4.51 (m, 1H); 4.36-4.40 (m, 4H); 4.25 (t, 2H); 4.00 (d, 2H); 3.95 (d, 2H); 1.75 (m, 2H); 1.24 (d, 3H); 1.00 (t, 3H).
Embodiment 6 (R)-9-{2-[pair-(trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-butyloxy formylamido-purine (I
6) preparation
Method according to embodiment 3 replaces methyl-chloroformate with butyl chlorocarbonate, with I
1Reaction makes (R)-9-{2-[pair-(trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-butyloxy formylamido-purine (I
6), proton nmr spectra: δ (CDCl
3, ppm): 8.77 (s, 1H); 8.17 (s, 1H); 4.51 (m, 1H); 4.35-4.41 (m, 4H); 4.28 (t, 2H); 4.00 (d, 2H); 3.96 (d, 2H); 1.72 (m, 2H); 1.45 (m, 2H); 1.24 (d, 3H); 0.96 (t, 3H).
Embodiment 7 (R)-9-{2-[pair-(trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-isobutyl oxygen formamido--purine (I
7) preparation
Method according to embodiment 3 replaces methyl-chloroformate with isobutyl chlorocarbonate, with I
1Reaction makes (R)-9-{2-[pair-(trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-isobutyl oxygen formamido--purine (I
7), proton nmr spectra: δ (CDCl
3, ppm): 8.77 (s, 1H); 8.17 (s, 1H); 4.51 (m, 1H); 4.35-4.43 (m, 4H); 4.08 (d, 2H); 4.00 (d, 2H); 3.96 (d, 2H); 2.04 (m, 1H); 1.24 (d, 3H); 1.00 (d, 6H).
Embodiment 8 (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-methoxycarbonyl amido-2-aminopurine (I
8) preparation
According to the method for embodiment 3, use I
2Replace I
1,, make (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy with the methyl-chloroformate reaction]-propyl group }-6-methoxycarbonyl amido-2-aminopurine (I
8).Proton nmr spectra: δ (DMSO-d
6, ppm): 9.96 (heavy water exchange back disappears for s, 1H); 7.86 (s, 1H); (6.35 heavy water exchange back disappears for s, 2H); 4.64-4.70 (m, 4H); 4.20 (m, 1H); 4.14 (d, 2H); 3.87 (d, 2H); 3.66 (s, 3H); 1.23 (d, 3H).
Embodiment 9 (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-ethoxycarbonyl amido-2-aminopurine (I
9) preparation
According to the method for embodiment 3, use I
2Replace I
1,, make (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy with the Vinyl chloroformate reaction]-propyl group }-6-ethoxycarbonyl amido-2-aminopurine (I
9).Proton nmr spectra: δ (DMSO-d
6, ppm): 9.96 (heavy water exchange back disappears for s, 1H); 7.86 (s, 1H); (6.35 heavy water exchange back disappears for s, 2H); 4.64-4.70 (m, 4H); 4.23 (q, 2H); 4.20 (m, 1H); 4.14 (d, 2H); 3.87 (d, 2H); 1.29 (t, 3H); 1.23 (d, 3H).
Embodiment 10 (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-third oxygen formamido--2-aminopurine (I
10) preparation
According to the method for embodiment 3, use I
2With the propyl chloroformate reaction, make (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-third oxygen formamido--2-aminopurine (I
9).Proton nmr spectra: δ (DMSO-d
6, ppm): 9.88 (heavy water exchange back disappears for s, 1H); 7.86 (s, 1H); (6.35 heavy water exchange back disappears for s, 2H); 4.65-4.68 (m, 4H); 4.20 (m, 1H); 4.14 (d, 2H); 4.02 (t, 2H); 3.87 (d, 2H); 1.60 (m, 2H); 1.23 (d, 3H); 0.92 (t, 3H).
Embodiment 11 (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-butyloxy formylamido-2-aminopurine (I
11) preparation
According to the method for embodiment 3, use I
2With the butyl chlorocarbonate reaction, make (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-butyloxy formylamido-2-aminopurine (I
11).Proton nmr spectra: δ (DMSO-d
6, ppm): 9.88 (heavy water exchange back disappears for s, 1H); 7.85 (s, 1H); (6.31 heavy water exchange back disappears for s, 2H); 4.65-4.68 (m, 4H); 4.20 (m, 1H); 4.14 (d, 2H); 4.03 (t, 2H); 3.87 (d, 2H); 1.72 (m, 2H); 1.45 (m, 2H); 1.24 (d, 3H); 0.96 (t, 3H).
Embodiment 12 (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-isobutyl oxygen formamido--2-aminopurine (I
12) preparation
According to the method for embodiment 3, use I
2With the isobutyl chlorocarbonate reaction, make (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-the different oxygen formamido--2-aminopurine of 6-(I
12).Proton nmr spectra: δ (DMSO-d
6, ppm): 9.90 (heavy water exchange back disappears for s, 1H); 7.86 (s, 1H); (6.33 heavy water exchange back disappears for s, 2H); 4.63-4.70 (m, 4H); 4.20 (m, 1H); 4.13 (d, 2H); 3.84-3.88 (m, 4H); 1.90 (m, 1H); 1.24 (d, 3H); 0.91 (d, 6H).
Embodiment 13 (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-penta oxygen formamido--2-aminopurine (I
13) preparation
According to the method for embodiment 3, use I
2With the amyl chlorocarbonate reaction, make (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-penta oxygen formamido--2-aminopurine (I
13).Proton nmr spectra: δ (DMSO-d
6, ppm): 10.08 (heavy water exchange back disappears for s, 1H); 7.85 (s, 1H); (6.31 heavy water exchange back disappears for s, 2H); 4.65-4.68 (m, 4H); 4.20 (m, 1H); 4.14 (d, 2H); 4.03 (t, 2H); 3.87 (d, 2H); 1.67 (m, 2H); 1.22-1.45 (m, 6H); 0.86 (t, 3H).
Embodiment 14 (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-the own oxygen formamido--2-aminopurine of 6-(I
14) preparation
According to the method for embodiment 3, use I
2With the own ester reaction of chloroformic acid, make (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-the own oxygen formamido--2-aminopurine of 6-(I
14).Proton nmr spectra: δ (DMSO-d
6, ppm): 10.12 (heavy water exchange back disappears for s, 1H); 7.85 (s, 1H); (6.31 heavy water exchange back disappears for s, 2H); 4.65-4.68 (m, 4H); 4.20 (m, 1H); 4.14 (d, 2H); 4.03 (t, 2H); 3.87 (d, 2H); 1.67 (m, 2H); 1.22-1.44 (m, 8H); 0.87 (t, 3H).
Embodiment 15 (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-the positive hot oxygen formamido--2-aminopurine (I of 6-
15) preparation
According to the method for embodiment 3, use I
2With the octyl chloroformate reaction, make (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-the positive hot oxygen formamido--2-aminopurine (I of 6-
15).Proton nmr spectra: δ (DMSO-d
6, ppm): 10.10 (heavy water exchange back disappears for s, 1H); 7.85 (s, 1H); (6.31 heavy water exchange back disappears for s, 2H); 4.65-4.68 (m, 4H); 4.20 (m, 1H); 4.14 (d, 2H); 4.03 (t, 2H); 3.87 (d, 2H); 1.67 (m, 2H); 1.22-1.44 (m, 12H); 0.85 (t, 3H).
Embodiment 16 (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-benzyloxy formamido--2-aminopurine (I
16) preparation
According to the method for embodiment 3, use I
2With the chloroformic acid benzyl ester reaction, make (R)-9-{2-[pair-(2,2, the 2-trifluoroethyl)-phosphonium mesitoyl methoxy]-propyl group }-6-benzyloxy formamido--2-aminopurine (I
16).Proton nmr spectra: δ (DMSO-d
6, ppm): 10.10 (heavy water exchange back disappears for s, 1H); 7.85 (s, 1H); 7.44-7.46 (dd, 2H); 7.37-7.40 (m, 3H); (6.31 heavy water exchange back disappears for s, 2H); 5.32 (s, 2H); 4.65-4.68 (m, 4H); 4.20 (m, 1H); 4.14 (d, 2H); 3.87 (d, 2H); 1.24 (d, 3H).
Reference example 1 (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 [(R)-PMPA] synthetic
Under nitrogen, with I
12.0 gram is dissolved in 30 milliliters of acetonitriles, adds 3 milliliters of bromotrimethylsilanes, stirring at room 6 hours, and the pressure reducing and steaming solvent adds 10ml water, produces white precipitate, adds 10ml acetone, stirring at room 4 hours.Filter, filter cake is washed with small amount of acetone, get the off-white color solid 1.4g of (R)-PMPA, 275 ℃ of fusing points (decomposition); [α]
20 D=+21.0 ° (0.5%0.1M hydrochloric acid soln).Document (U.S. Pat 6653296): fusing point is greater than 279 ℃, [α] D=+21.2 ° (0.5%0.1M hydrochloric acid soln).
Reference example 2 (R)-9-[2-(phosphono methoxyl group) propyl group]-2,6-diaminopurine [(R)-PMPDAP] synthetic
According to the method for reference example 1, use I
2Replace I
1With the bromotrimethylsilane reaction, get (R)-PMPDAP, 285 ℃ of fusing points (decomposition); [α]
20 D=-26.3 ° (0.5%0.1M hydrochloric acid soln).Document (U.S. Pat 6653296): fusing point is greater than 287 ℃, [α]
D=-26.1 ° (0.5%0.1M hydrochloric acid soln).
Bioactive mensuration
1 external anti-hepatitis B virus activities and Cytotoxic mensuration
Hep G 2.2.15 cell cultures in the DMEM nutrient solution that contains 10% calf serum, is inoculated in 96 orifice plates cell count 3 * 10
4Hatch in the 5%CO2 incubator in/hole, when cell density reaches 80%, abandons old nutrient solution, adds the new nutrient solution that contains different concns medicine to be measured, and 200 μ l/ holes are provided with 3 parallel holes; Changed nutrient solution every 2 days.After administration the 10th day, get 100 μ l supernatants, measure the content of HBV DNA with the method for quantitative PCR, calculate 50% inhibition concentration, be IC
50Value.
In 96 orifice plates of having got 100 μ l supernatants, add the MTT of 7.5mg/ml, 30 μ l/ holes continue to cultivate 3 hours, after abandoning supernatant, add the acid isopropyl alcoholic solution that contains 10% tween X-100,120 μ l/ holes, with the absorption at enzyme connection instrument mensuration 540nm place, calculate 50% inhibition concentration, be CC
50Value.
Experimental result sees Table 1:
External anti-hepatitis B virus activities of table 1 and cytotoxicity
| Compound | IC 50(μM) | CC 50(μM) |
| PMPA | 1.34 | ＞100 |
| PMPDAP | 0.18 | ＞100 |
| I 1 | 0.09 | 84 |
| I 2 | 0.014 | ＞100 |
| I 3 | 1.46 | 120 |
| I 4 | 0.75 | ＞100 |
| I 5 | 0.52 | ＞100 |
| I 6 | 0.32 | ＞100 |
| I 7 | 0.43 | ＞100 |
| I 8 | 0.27 | ＞100 |
| I 9 | 0.18 | ＞100 |
| I 10 | 0.14 | ＞100 |
| I 11 | 0.08 | 61 |
| I 12 | 0.09 | ＞100 |
| I 13 | 0.06 | 87 |
| I 14 | 0.26 | ＞100 |
| I 15 | 0.76 | ＞100 |
| I 16 | 0.85 | ＞100 |
The comparison of 2 oral administration biaavailabilities
Reference (Starrett JE, et al.Jmed Chem 1994; 37:1857-1864.) method, by measuring behind the rat oral administration content of active medicine (R)-PMPA in the urine or (R)-PMPDAP, with (R)-PMPA or (R)-the PMPDAP intravenously administrable after content in the urine compare, investigate bioavailability of medicament.
Fasting is 12 hours before all animals administers, every group of 3 rats.Intravenous (IV) drug is made into the normal saline solution of 15 mg/ml, by the tail vein injection administration; It is the aqueous solution that 3 mg/ml contain 5% methyl-sulphoxide that oral pharmaceutical are made into concentration.Dosage is equivalent to (R)-PMPA of 30 milligrams/kilogram or (R)-PMPDAP.48 hours urine after the collection administration, reference (Naesens L, et al.Clin Chem 1992; 38:480-485.) method, measure the content of (R)-PMPA in the urine or (R)-PMPDAP.Calculate the bioavailability of oral administration according to following formula:
Bioavailability=[M
1]
0 → 48h/ [M
2]
0 → 48h* 100%
[M
1]
0 → 48hBe the total amount of homaluria medicine in behind the oral administration 48 hours, [M
2]
0 → 48hTotal amount for homaluria medicine in after the quiet notes administration 48 hours.
Table 2 rat oral administration biaavailability relatively
| Compound | Bioavailability (%) |
| PMPA | 8.2 |
| PMPDAP | 7.4 |
| I 1 | 34.1 |
| I 2 | 29.6 |
| I 4 | 17.8 |
| I 5 | 24.5 |
| I 6 | 30.7 |
| I 7 | 26.9 |
| I 9 | 14.3 |
| I 10 | 20.4 |
| I 11 | 32.8 |
| I 12 | 31.0 |
| I 13 | 25.3 |
| I 16 | 23.7 |
The evaluation of liver target in the 3 mouse bodies
Get the Baclb/c mouse of quality 20-25g, random packet, every group of 12 mouse.The testing compound of fasting 50 milligrams of/kilogram dosage of orally give after 12 hours; Respectively at 10,30,60 and 120 minutes, get 3 animals, blood sampling is got liver and is made homogenate; With blood plasma and liver homogenate centrifugal after, get supernatant, reference (Naesens L, et al.Clin Chem 1992; 38:480-485.) method, measure the content of (R)-PMPA in blood and the liver or (R)-PMPDAP.The results are shown in Table 3:
The evaluation result of liver target in the table 3 mouse body
| Compound | Time (min) | Blood plasma Chinese traditional medicine concentration (μ g/ml) | Blood plasma Chinese traditional medicine concentration (μ g/g) |
| I 1 | 10 | 27.2 | 34.7 |
| 30 | 8.9 | 25.1 | |
| 60 | 4.2 | 11.8 | |
| 120 | 3.8 | 11.2 | |
| I 2 | 10 | 28.5 | 36.3 |
| 30 | 15.9 | 23.9 | |
| 60 | 5.8 | 15.0 | |
| 120 | 5.4 | 14.5 | |
| I 6 | 10 | 10.2 | 30.6 |
| 30 | 7.8 | 27.4 | |
| 60 | 6.9 | 25.2 | |
| 120 | 6.7 | 21.9 | |
| I 13 | 10 | 12.8 | 29.5 |
| 30 | 11.2 | 28.8 | |
| 60 | 8.1 | 24.2 | |
| 120 | 7.4 | 22.3 |
Claims (3)
1, the acyclic nucleoside phosphate ester of formula I representative and non-toxicity pharmacy acceptable salt thereof:
Wherein, R
1Be H or NH
2, R
2Represent H or COO-R
3, R
3Be C
1-C
6The C that replaces of alkyl or phenyl
1-C
3Alkyl.
2, acyclic nucleoside phosphate ester shown in the formula I and non-toxicity pharmacy acceptable salt thereof are as the pharmaceutical composition of activeconstituents.
3, acyclic nucleoside phosphate ester shown in the formula I and non-toxicity pharmacy acceptable salt thereof, and comprise the acyclic nucleoside phosphate ester shown in the formula I and non-toxicity pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents as the antiviral purposes of anti-hepatitis b and anti-hiv drug particularly.
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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 |
| CN101445515A (en) * | 2007-11-26 | 2009-06-03 | 张家港市国泰华荣化工新材料有限公司 | Method for preparing perfluor alkyl ethide phosphite ester |
| CN104230987A (en) * | 2014-08-15 | 2014-12-24 | 上海科一生物医药有限公司 | [1-halo-(2-propoxy)]-methylphosphoric acid compounds as well as preparation and application thereof |
| CN105518011A (en) * | 2014-04-21 | 2016-04-20 | 四川海思科制药有限公司 | Method for preparing phosphoramidate derivative and intermediates thereof, and method for preparing intermediates |
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
| CN111559980A (en) * | 2020-06-16 | 2020-08-21 | 湖南方盛制药股份有限公司 | Ornidazole isomer and preparation method thereof |
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2005
- 2005-11-14 CN CN 200510117768 patent/CN1966514A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009046573A1 (en) * | 2007-10-11 | 2009-04-16 | Beijing Shiqiao Bio-Pharmaceutical Co., Ltd | Liver targeting adefovir prodrug and its medical use |
| CN101445515A (en) * | 2007-11-26 | 2009-06-03 | 张家港市国泰华荣化工新材料有限公司 | Method for preparing perfluor alkyl ethide phosphite ester |
| CN101445515B (en) * | 2007-11-26 | 2013-04-24 | 张家港市国泰华荣化工新材料有限公司 | Method for preparing perfluor alkyl ethide phosphite ester |
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
| CN105518011A (en) * | 2014-04-21 | 2016-04-20 | 四川海思科制药有限公司 | Method for preparing phosphoramidate derivative and intermediates thereof, and method for preparing intermediates |
| CN104230987A (en) * | 2014-08-15 | 2014-12-24 | 上海科一生物医药有限公司 | [1-halo-(2-propoxy)]-methylphosphoric acid compounds as well as preparation and application thereof |
| CN104230987B (en) * | 2014-08-15 | 2016-09-21 | 上海科一生物医药有限公司 | A kind of [1-halo-(2-propoxyl group)]-methylphosphonic acid compounds and preparation thereof and application |
| CN111559980A (en) * | 2020-06-16 | 2020-08-21 | 湖南方盛制药股份有限公司 | Ornidazole isomer and preparation method thereof |
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