CN101293899A - Acyclic nucleoside phosphonate derivative and medicine use thereof - Google Patents

Acyclic nucleoside phosphonate derivative and medicine use thereof Download PDF

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CN101293899A
CN101293899A CNA2007100976004A CN200710097600A CN101293899A CN 101293899 A CN101293899 A CN 101293899A CN A2007100976004 A CNA2007100976004 A CN A2007100976004A CN 200710097600 A CN200710097600 A CN 200710097600A CN 101293899 A CN101293899 A CN 101293899A
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purine
amino
sulfenyl
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trifluoroethyl
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CN101293899B (en
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仲伯华
陈兰福
牛俊奇
吴狄
马华智
廖明阳
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Institute of Pharmacology and Toxicology of AMMS
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    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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Abstract

The invention relates to an acyclic nucleoside phosphonate shown in formula I, and nontoxic pharmaceutically-acceptable salts, hydrates or solvates thereof, wherein the definition of each substituting group refers to the description. The invention also relates to a preparation method of the compound shown in formula I, a pharmaceutical composition thereof containing the compound, and an application thereof in preparing drugs for treating HBV infection.

Description

Acyclic nucleoside phosphate ester derivative and medicinal use thereof
Technical field
The present invention relates to have potent anti-hepatitis B virus activities and than the acyclic nucleoside phosphate ester derivative of low cytotoxicity, its preparation method and be used to prepare the purposes of the medicine for the treatment of hepatitis B virus infection.
Background technology
Hepatitis B is the major disease that threatens people's life health, and the fundamental way of treatment hepatitis B is an antiviral therapy.Clinical effective anti-hepatic-B virus medicine is mainly Interferon, rabbit and lamivudine at present.But the efficient of interferon therapy has only 30-50%, and has the toxic side effect of dose limitation.For example, lamivudine has definite anti-HBV effect, and still, life-time service easily produces resistance, and continuous use is after 2 years, and chemical sproof incidence can cause the serious consequences such as acute attack of hepatitis thus up to 40-50%.
Nucleotide analog does not need phosphorylation in cell, therefore can overcome the resistance of lamivudine, and self does not produce resistance.Its representative drugs adefovir ester is got permission listing the America and Europe.But adefovir ester has certain cytotoxicity, and clinical application can produce Toxicity of Kidney; And similar to lamivudine, adefovir ester is treated after drug withdrawal, the knock-on of hepatitis B virus duplication can occur, causes the recurrence of hepatitis B.
According to the successful experience of inverase research, the therapy of the COCKTAIL by drug combination can effectively overcome resistance, accelerates the removing of virus.Hepatitis B infected number is more than 10 times of HIV number of the infected, but compares with inverase, and clinical effective anti-hepatic-B virus medicine is also very few.
European patent EP 0785208 discloses the following a series of acyclic nucleoside phosphate ester compounds of structure:
Figure A20071009760000081
Wherein, R 1Representation alkoxy, single substituting group such as alkyl; R 2Represent hydrogen or alkyl, R 3And R 4Represent hydrogen, alkyl etc.Two (2,2,2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of compound 2-amino-6-(4-anisole sulfenyl)-9-[2-[wherein] propyl group]-purine (MCC-478) entered clinical study.
Still press for the new anti-hbv drug of research and development with different structure characteristics and mechanism of action.
Summary of the invention
The acyclic nucleoside phosphate ester derivative and the non-toxicity pharmacy acceptable salt thereof that the purpose of this invention is to provide formula I representative with anti-hepatitis B virus activities, hydrate or solvate:
Wherein,
The sulfydryl that purine skeleton is 6 is connected in five yuan of different positionss on the hetero-aromatic ring,
X represents S or O atom;
Y represents methyl, methoxyl group or the halogen atom that replaces on the different positions on five yuan of hetero-aromatic rings,
R 1Represent H or methyl;
Each R 2Represent H, CH independently of one another 2CF 3, CH 2-OCOR 3Or CH 2OCOOR 3
R 3Represent C 2-C 6Alkyl or substituted alkyl, described substituting group is selected from methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-or tertiary butyl etc.
Therefore, one aspect of the present invention relates to the acyclic nucleoside phosphate ester derivative of formula I representative, and non-toxicity pharmacy acceptable salt, hydrate or solvate:
Figure A20071009760000091
Wherein,
The sulfydryl that purine skeleton is 6 is connected in five yuan of different positionss on the hetero-aromatic ring,
X represents S or O atom;
Y represents methyl, methoxyl group or the halogen atom that replaces on the different positions on five yuan of hetero-aromatic rings,
R 1Represent H or methyl;
Each R 2Represent H, CH independently of one another 2CF 3, CH 2-OCOR 3Or CH 2OCOOR 3
R 3Represent C 2-C 6Alkyl or substituted alkyl, described substituting group is selected from methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-or tertiary butyl etc.
Another aspect of the present invention relates to the acyclic nucleoside phosphate ester derivative and the non-toxicity pharmacy acceptable salt thereof of above-mentioned formula I representative, the preparation method of hydrate or solvate.
Another aspect of the present invention relates to acyclic nucleoside phosphate ester derivative and the non-toxicity pharmacy acceptable salt thereof that comprises above-mentioned formula I representative, the pharmaceutical composition of hydrate or solvate and one or more pharmaceutical carrier or vehicle.
Another aspect of the present invention relates to the acyclic nucleoside phosphate ester derivative and the non-toxicity pharmacy acceptable salt thereof of above-mentioned formula I representative, and hydrate or solvate are used to prepare the purposes of the medicine for the treatment of hepatitis B virus infection.
According to the present invention, preferred compound is selected from:
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(thiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(thiene-3-yl--) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(3 methyl thiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(5-thiotolene-2-base-) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(furans-3-base-) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(5-methoxythiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(4-methoxythiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(5-methoxyl group furans-2-base-) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(5-chlorothiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine (I a-9);
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(4-chlorothiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine;
2-amino-6-(thiophene-2-base-) sulfenyl-9-(2-phosphonium mesitoyl methoxy ethyl)-purine;
2-amino-6-(thiene-3-yl--) sulfenyl-9-(2-phosphonium mesitoyl methoxy ethyl)-purine;
2-amino-6-(furans-3-base-) sulfenyl-9-(2-phosphonium mesitoyl methoxy ethyl)-purine;
Two (new pentane acyloxy methoxyl group) the phosphonium mesitoyl methoxy ethyls of 2-amino-6-(thiophene-2-base-) sulfenyl-9-[2-]-purine;
Two (new pentane acyloxy methoxyl group) the phosphonium mesitoyl methoxy ethyls of 2-amino-6-(thiene-3-yl--) sulfenyl-9-[2-]-purine;
Two (new pentane acyloxy methoxyl group) the phosphonium mesitoyl methoxy ethyls of 2-amino-6-(furans-3-base-) sulfenyl-9-[2-]-purine;
Two (isopropoxy carbonyl Oxymethoxy) phosphonium mesitoyl methoxy-ethyls of 2-amino-6-(thiophene-2-base-) sulfenyl-9-[2-]-purine;
Two (isopropoxy carbonyl Oxymethoxy) phosphonium mesitoyl methoxy-ethyls of 2-amino-6-(thiene-3-yl--) sulfenyl-9-[2-]-purine;
Two (new pentane acyloxy-methyl) phosphonium mesitoyl methoxy-ethyls of 2-amino-6-(furans-3-base-) sulfenyl-9-[2-]-purine;
Two (2,2, the 2-trifluoroethyl) phosphonium mesitoyl methoxies of 2-amino-6-(thiophene-2-base-) sulfenyl-9-[2-[] propyl group]-purine;
Two (2,2, the 2-trifluoroethyl) phosphonium mesitoyl methoxies of 2-amino-6-(thiene-3-yl--) sulfenyl-9-[2-[] propyl group]-purine; With
Two (2,2, the 2-trifluoroethyl) phosphonium mesitoyl methoxies of 2-amino-6-(furans-3-base-) sulfenyl-9-[2-[] propyl group]-purine.
Formula I compound of the present invention can prepare by following synthetic route:
Specifically, at first make trifluoroethanol and phosphorus trichloride 80-90 ℃ of stirring reaction 4 hours, fractionation makes three-(2,2, the 2-trifluoroethyl) phosphorous acid esters; Make ethylene chlorhydrin or 2-propylene chlorohydrin and Paraformaldehyde 96 under ice bath cooling with the dry hydrogen chloride effect under, generate 2-chloroethyl chloromethyl ether or 2-chloropropyl chloromethyl ether; Make then 2-chloroethyl chloromethyl ether or 2-chloropropyl chloromethyl ether and above-mentioned make three-(2,2, the 2-trifluoroethyl) phosphorous acid ester is in the reaction in 5 hours of 160 ℃ of stirring reactions, obtain two (2,2, the 2-trifluoroethyl) inferior phosphoryl ethyl chloride or two (2,2, the 2-trifluoroethyl) inferior phosphoryl propyl chloride, its again with 2-amino-6-chloro-purine at 80 ℃ of-100 ℃ of stirring reactions, obtain key intermediate III; Next make intermediate III and replacement or unsubstituted 2/3-mercapto-thiophene or 2/3-sulfydryl furans obtain R at 80 ℃ of-120 ℃ of stirring reactions 2Target compound Ia for trifluoroethyl; Ia and bromotrimethylsilane are reacted in stirring at room, make the trifluoro ethyl ester hydrolysis after, obtain the free acid Ib of target compound, Ib again with alkanoyloxymethyl chlorine or alkoxycarbonyloxy methyl chloride at room temperature reaction, can obtain R 2Be CH 2-OCOR 3Or CH 2OCOOR 3Target compound Ic, R wherein 3Define among the formula I as described above.
Therefore, the acyclic nucleoside phosphate ester derivative of formula I representative of the present invention and the preparation of non-toxicity pharmacy acceptable salt thereof can be described as:
(a) make the reaction of trifluoroethanol and phosphorus trichloride, make three-(2,2, the 2-trifluoroethyl) phosphorous acid esters:
CF 3CH 2OH+PCl 3→P(OCH 2CF 3) 3
(b) make ethylene chlorhydrin (R 1=H) or 2-propylene chlorohydrin (R 1=CH 3) with Paraformaldehyde 96 under the dry hydrogen chloride effect, generate 2-chloroethyl chloromethyl ether or 2-chloropropyl chloromethyl ether:
(c) three-(2,2, the 2-trifluoroethyl) phosphite reactions that 2-chloroethyl chloromethyl ether that step (b) obtains or 2-chloropropyl chloromethyl ether and step (a) are made; obtain two (2,2, the 2-trifluoroethyl) inferior phosphoryl ethyl chloride or two (2; 2, the 2-trifluoroethyl) inferior phosphoryl propyl chloride:
Figure A20071009760000131
(d) product of step (c) and 2-amino-6-chloro-purine are reacted, obtain key intermediate III:
(e) make intermediate III that step (d) obtains and replacement or unsubstituted 2/3-mercapto-thiophene or the reaction of 2/3-sulfydryl furans obtain the special case formula Ia compound of formula I compound:
Figure A20071009760000133
R wherein 2Be trifluoroethyl;
(f) make the trifluoro ethyl ester hydrolysis of formula Ia compound after, obtain another special case formula Ib free acid of formula I compound:
Figure A20071009760000134
(g) formula Ib compound is reacted with alkanoyloxymethyl chlorine or alkoxycarbonyloxy methyl chloride again, can obtain another special case formula Ic compound of formula I compound:
Figure A20071009760000141
Wherein, R 2Be CH 2-OCOR 3Or CH 2OCOOR 3, R 3Define among the formula I as described above.
Term among the present invention " pharmacologically acceptable salt " can be the pharmaceutical salts that forms with mineral acid, for example vitriol, hydrochloride, hydrobromate, phosphoric acid salt; Also can be to form pharmaceutical salts, for example acetate, oxalate, Citrate trianion, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt, maleate etc. with organic acid.The compound that has acidic-group among the formula I of the present invention can form pharmaceutical salts with basic metal or alkaline-earth metal such as sodium ion, potassium ion, ammonium ion, calcium ion, zine ion, magnesium ion etc., and is preferred but be not limited to sodium salt, sylvite, magnesium salts or calcium salt.
The compounds of this invention or its pharmacologically acceptable salt can form solvate, for example hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that discharges described activeconstituents in vivo after the metabolism metabolism.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.
As mentioned above, The compounds of this invention can be used for preparing the medicine for the treatment of hepatitis B virus infection.
The compounds of this invention or its pharmacologically acceptable salt can be separately or with the form administration of pharmaceutical composition.Pharmaceutical composition of the present invention can be made into various suitable formulations according to route of administration.Use acceptable carrier on one or more physiology, comprise vehicle and auxiliary agent, they help active compound is processed into can be at the preparation that pharmaceutically uses.The appropriate formulations form depends on selected route of administration, can make according to general knowledge well known in the art.
Route of administration can be oral, non-enteron aisle or topical, preferred oral and injection form administration.Can comprise capsule and tablet etc. by oral pharmaceutical preparation.Patient swallows when having any problem, and also can adopt Sublingual tablet or other non-mode administrations of swallowing.The compounds of this invention also can be prepared and be used for administered parenterally or transdermal administration or mucosal.It will be understood by those skilled in the art that The compounds of this invention can adopt suitable drug delivery system (DDS) to obtain more favourable effect.
It may be noted that in addition, The compounds of this invention using dosage and using method depend on all multifactor, comprise activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of patient's age, body weight, sex, natural health situation, nutritional status, compound.Preferred using dosage is between 0.01～100mg/kg body weight/day.
Embodiment
Following embodiment is used for explaining particularly the present invention, yet scope of the present invention is not limited to following embodiment.
Used all raw materials and reagent all can be by commercially available in the reaction.
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of embodiment 12-amino-6-(thiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine (I a-1)
1.1 the 2-mercapto-thiophene is synthetic
The 2.86g magnesium chips is suspended in the 48ml anhydrous diethyl ether, under nitrogen, in 1 hour, drips 16 gram 2-bromothiophenes.Dropwise, back flow reaction is 3 hours again.Then, reaction solution is cooled to-45 ℃, adds 3.16g powder sulphur,, in stirring at room reaction 1.5 hours, add 5ml water and 36.8ml 6M hydrochloric acid again in-45 ℃ of stirring reactions 1.5 hours.With ether extraction 3 times, 40ml/ time, merge organic layer, with the saturated salt washing, use dried over mgso again.Evaporated under reduced pressure, fractionation gets 4.5g, 120 ℃/0.1mmHg of boiling point.
1.2 two (2,2,2-trifluoroethyl oxygen the base)-phosphonium mesitoyl methoxies of 2-[]-ethyl chloride synthetic
In 46 gram trifluoroethanols, add 21 gram phosphorus trichlorides, 80-90 ℃ of stirring reaction 4 hours.Fractional distillation gets three-(2,2, the 2-trifluoroethyl) phosphorous acid esters, 41 grams, 130-131 ℃/74-78mmHg.
26 gram ethylene chlorhydrins and 10 gram Paraformaldehyde 96s are suspended in the 50ml methylene dichloride ice bath cooling; Stir down, in 0 ℃ of logical dry hydrogen chloride 10 hours, branch vibration layer with organic layer Calcium Chloride Powder Anhydrous drying, distilled behind the elimination solid, obtains chloroethyl chloromethyl ether 24 and restrains boiling point 78-82 ℃/30mmHg
With 18 gram chloroethyl chloromethyl ethers and 40 gram three-(2,2, the 2-trifluoroethyl) phosphorous acid esters mixing, in 160 ℃ of stirring reactions 5 hours.Behind the pressure reducing and steaming solvent, fractionation obtains two (2,2, the 2-trifluoroethyl)-phosphonoethyl chlorine, boiling point 125-128 ℃/3mmHg.
1.3 two (2,2,2-trifluoroethyl oxygen the base)-phosphonium mesitoyl methoxies of 2-amino-6-chloro-9-[] ethyl-purine (III 1) synthetic
30 gram 2-amino-6-chloropurines and 27ml DBU are added in the 700ml dimethyl formamide, stirred 1 hour in 80 ℃.Add two (2,2, the 2-trifluoroethyl) phosphonoethyl chlorine, 83 grams again, stirred cooling back evaporated under reduced pressure 5 hours in 100 ℃.Separate with silica gel column chromatography,, obtain III with chloroform/methanol (1:0.05) wash-out 125.6 gram, fusing point 102-103 ℃.
1H-NMR：δ(ppm，CDCl 3)：7.82(s，1H)；5.18(b，2H)；4.40(m，4H)；4.30(t，2H)；3.95(m，4H)。
1.4 two (2,2,2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(thiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine (I aSynthesizing-1)
In the 100ml dimethyl formamide, add 7.8 gram III 1, 2.2ml triethylamine and 4 gram 2-mercapto-thiophenes, stirred cooling, evaporated under reduced pressure 2 hours in 100 ℃.Residue separates with silica gel column chromatography, with chloroform/methanol (1: 0.05) wash-out.Collect required component, evaporated under reduced pressure obtains Compound I a-13.41 grams, productive rate 37.4%.
1H-NMR：δ(ppm，CDCl 3)：7.73(s，1H)；7.58-7.60(dd，1H)；7.35(dd，1H)；7.12-7.14(dd，1H)；4.92(b，2H)；4.33-4.42(m，4H)；4.26-4.28(t，2H)；3.92-3.94(m，4H)。
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of embodiment 2 2-amino-6-(thiene-3-yl--) sulfenyl-9-[2-[] ethyl]-purine (I a-2)
Replace the 2-bromothiophene with 3 bromo thiophene, the method with reference to 1.1, preparation 3-mercapto-thiophene.
Method with reference to 1.4 replaces 2-mercapto-thiophene and III with the 3-mercapto-thiophene 1Reaction, preparation I a-2, productive rate 34.6%.
1H-NMR：δ(ppm，CDCl 3)：7.78(s，1H)；7.55-7.59(d，1H)；7.35(d，1H)；7.03(s，1H)；4.92(b，2H)；4.33-4.42(m，4H)；4.26-4.28(t，2H)；3.92-3.94(m，4H)。
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of embodiment 3 2-amino-6-(3 methyl thiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine (I a-3)
Replace the 2-bromothiophene with 3-methyl-2-bromothiophene, the method with reference to 1.1, preparation 3-methyl-2-mercapto-thiophene.
Method with reference to 1.4 replaces 2-mercapto-thiophene and III with 3-methyl-2-mercapto-thiophene 1Reaction, preparation I a-3, productive rate 28.2%.
1H-NMR：δ(ppm，CDCl 3)：7.78(s，1H)；7.50-7.54(d，1H)；7.25-7.30(d，1H)；4.92(b，2H)；4.33-4.42(m，4H)；4.26-4.28(t，2H)；3.92-3.94(m，4H)；2.37(s，3H)。
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of embodiment 4 2-amino-6-(5-thiotolene-2-base-) sulfenyl-9-[2-[] ethyl]-purine (I a-4)
Replace the 2-bromothiophene with 5-methyl-2-bromothiophene, the method with reference to 1.1, preparation 5-methyl-2-mercapto-thiophene.
Method with reference to 1.4 replaces 2-mercapto-thiophene and III with 5-methyl-2-mercapto-thiophene 1Reaction, preparation I a-4, productive rate 20.6%.
1H-NMR：δ(ppm，CDCl 3)：7.78(s，1H)；7.54(s，1H)；7.23(s ，1H)；4.92(b，2H)；4.33-4.42(m，4H)；4.26-4.28(t，2H)；3.92-3.94(m，4H)；2.31(s，3H)。
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of embodiment 5 2-amino-6-(furans-3-base-) sulfenyl-9-[2-[] ethyl]-purine (I a-5)
Replace the 2-bromothiophene with 3-bromine furans, the method with reference to 1.1, preparation 3-sulfydryl furans.
Method with reference to 1.4 replaces 2-mercapto-thiophene and III with 3-sulfydryl furans 1Reaction, preparation I a-5, productive rate 30.5%.
1H-NMR：δ(ppm，CDCl 3)：7.78(s，1H)；7.25(d，1H)；7.13(d，1H)；6.64(m，1H)；4.92(b，2H)；4.33-4.42(m，4H)；4.26-4.28(t，2H)；3.92-3.94(m，4H)。
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of embodiment 6 2-amino-6-(5-methoxythiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine (I a-6)
6.1 2-methoxyl group-5-bromothiophene is synthetic
5 gram 2-methoxythiophene are dissolved in 6.6 milliliters of methylene dichloride, under the stirring at room, drip 6.5 gram bromines.Dropwise restir 1 hour.Add 5 milliliters of saturated sodium sulfite solution termination reactions.Divide water-yielding stratum, organic layer with 10 milliliters of washings, is used anhydrous sodium sulfate drying again.Filter, evaporate to dryness gets 3.42 gram 2-methoxyl group-5-bromothiophenes.
6.2 two (2,2,2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(5-methoxythiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine (I aSynthesizing-6)
Replace the 2-bromothiophene with 2-methoxyl group-5-bromothiophene, the method with reference to 1.1, preparation 2-methoxyl group-5-mercapto-thiophene.
Method with reference to 1.4 replaces 2-mercapto-thiophene and III with 2-methoxyl group-5-mercapto-thiophene 1Reaction, preparation I a-6, productive rate 18.1%.
1H-NMR：δ(ppm，CDCl 3)：7.73(s，1H)；7.55(d，1H)；7.32(d，1H)；4.92(b，2H)；4.33-4.42(m，4H)；4.26-4.28(t，2H)；3.92-3.94(m，4H)，3.86(s，3H)。
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of embodiment 7 2-amino-6-(4-methoxythiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine (I a-7)
Replace the 2-methoxythiophene with the 3-methoxythiophene, the method with reference to 6.1, preparation 3-methoxyl group-5-bromothiophene.
Replace the 2-bromothiophene with 3-methoxyl group-5-bromothiophene, the method with reference to 1.1, preparation 3-methoxyl group-5-mercapto-thiophene.
Method with reference to 1.4 replaces 2-mercapto-thiophene and III with 3-methoxyl group-5-mercapto-thiophene 1Reaction, preparation I a-7, productive rate 12.8%.
1H-NMR：δ(ppm，CDCl 3)：7.73(s，1H)；7.30(s，1H)；7.16(s，1H)；4.92(b，2H)；4.33-4.42(m，4H)；4.26-4.28(t，2H)；3.92-3.94(m，4H)；3.86(s，3H)。
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of embodiment 8 2-amino-6-(5-methoxyl group furans-2-base-) sulfenyl-9-[2-[] ethyl]-purine (I a-8)
Replace the 2-methoxythiophene with 2-methoxyl group furans, the method with reference to 6.1, preparation 3-methoxyl group-5-bromine furans.
Replace the 2-bromothiophene with 3-methoxyl group-5-bromine furans, the method with reference to 1.1, preparation 3-methoxyl group-5-sulfydryl furans.
Method with reference to 1.4 replaces 2-mercapto-thiophene and III with 3-methoxyl group-5-sulfydryl furans 1Reaction, preparation I a-8, productive rate 30.5%.
1H-NMR：δ(ppm，CDCl 3)：7.78(s，1H)；7.25(d，1H)；7.13(d，1H)；6.64(m，1H)；4.92(b，2H)；4.33-4.42(m，4H)；4.26-4.28(t，2H)；3.92-3.94(m，4H)，3.84(s，3H)。
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of embodiment 9 2-amino-6-(5-chlorothiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine (I a-9)
Replace the 2-methoxythiophene with the 2-chlorothiophene, the method with reference to 6.1, preparation 2-chloro-5-bromothiophene.
Replace the 2-bromothiophene with 2-chloro-5-bromothiophene, the method with reference to 1.1, preparation 2-chloro-5-mercapto-thiophene.
Method with reference to 1.4 replaces 2-mercapto-thiophene and III with 2-chloro-5-mercapto-thiophene 1Reaction, preparation I a-9, productive rate 17.5%.
1H-NMR：δ(ppm，CDCl 3)：7.73(s，1H)；7.52(d，1H)；7.25(d，1H)；4.92(b，2H)；4.33-4.42(m，4H)；4.26-4.28(t，2H)；3.92-3.94(m，4H)。
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of embodiment 10 2-amino-6-(4-chlorothiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine (I a-10)
Replace the 2-methoxythiophene with the 3-chlorothiophene, with reference to the method for embodiment 6.1, preparation 3-chloro-5-bromothiophene.
Replace the 2-bromothiophene with 3-chloro-5-bromothiophene, with reference to the method for embodiment 1.1, preparation 3-chloro-5-mercapto-thiophene.
With reference to the method for embodiment 1.4, replace 2-mercapto-thiophene and III with 3-chloro-5-mercapto-thiophene 1Reaction, preparation I a-10, productive rate 13.4%.
1H-NMR：δ(ppm，CDCl 3)：7.73(s，1H)；7.32(s，1H)；7.14(s，1H)；4.92(b，2H)；4.33-4.42(m，4H)；4.26-4.28(t，2H)；3.92-3.94(m，4H)。
Embodiment 11 2-amino-6-(thiophene-2-base-) sulfenyl-9-(2-phosphonium mesitoyl methoxy ethyl)-purine (I b-1)
Under nitrogen, with I a-12g is suspended in the anhydrous second cyanogen of 20ml, adds the 7g bromotrimethylsilane, stirring at room 16 hours, and silica gel thin-layer detects raw material and disappears.Decompression is spin-dried for solvent, gets residue, adds 10ml water, produces white precipitate, adds 12ml acetone, stirring at room 14 hours.Filter, filter cake 5ml acetone is washed 2 times, wash 1 time, get I with the 5ml anhydrous diethyl ether b-11.2g, 210 ℃ of fusing points (decomposition), productive rate 85.7%.
1H-NMR：δ(ppm，CDCl 3)：7.82(s，1H)；7.51-7.56(dd，1H)；7.32(dd，1H)；7.06-7.10(dd，1H)；4.79(b，2H)；4.23-4.25(t，2H)；3.91-3.93(m，4H)。。
Embodiment 12 2-amino-6-(thiene-3-yl--) sulfenyl-9-(2-phosphonium mesitoyl methoxy ethyl)-purine (I b-2)
With reference to the method for embodiment 11, use I a-2 replace I a-1 with bromotrimethylsilane reaction, preparation I b-2,215 ℃ of fusing points (decomposition), productive rate 76.4%.
1H-NMR：δ(ppm，CDCl 3)：7.75(s，1H)；7.55-7.59(d，1H)；7.35(d，1H)；7.03(s，1H)；4.92(b，2H)；4.26-4.28(t，2H)；3.92-3.94(m，4H)。
Embodiment 13 2-amino-6-(furans-3-base-) sulfenyl-9-(2-phosphonium mesitoyl methoxy ethyl)-purine (I b-3)
With reference to the method for embodiment 11, use I a-5 replace I a-1 with bromotrimethylsilane reaction, preparation I b-3,215 ℃ of fusing points (decomposition), productive rate 70.6%.
1H-NMR：δ(ppm，CDCl 3)：7.78(s，1H)；7.25(d，1H)；7.13(d，1H)；6.64(m，1H)；4.92(b，2H)；4.26-4.28(t，2H)；3.92-3.94(m，4H)。
Two (new pentane acyloxy methoxyl group) the phosphonium mesitoyl methoxy ethyls of embodiment 14 2-amino-6-(thiophene-2-base-) sulfenyl-9-[2-]-purine (I c-1)
Under nitrogen, in reactor, add 5ml exsiccant acetonitrile successively, 0.5g I b-1,1g N '-dicyclohexyl-4-morpholine amidine and 1.3g pivalyl chloride methyl esters were in stirring at room 24 hours.With the reaction mixture evaporated under reduced pressure, separate with silica gel column chromatography, with methylene chloride (95: 5) wash-out, get I c-10.32g.
1H-NMR：δ(ppm，CDCl 3)：7.76(s，1H)；7.51-7.56(dd，1H)；7.32(dd，1H)；7.06-7.10(dd，1H)；5.65(m，4H)；5.02(b，2H)；4.11(t，2H)；3.80(t，2H)；3.52(d，2H)；2.52(s，3H)；1.21(s，18H)。
Two (new pentane acyloxy methoxyl group) the phosphonium mesitoyl methoxy ethyls of embodiment 15 2-amino-6-(thiene-3-yl--) sulfenyl-9-[2-]-purine (I c-2)
With reference to the method for embodiment 14, use I b-2 replace I b-1 with pivalyl chloride methyl esters reaction, preparation I c-2, productive rate 24%.
1H-NMR：δ(ppm，CDCl 3)：7.76(s，1H)；7.55-7.59(d，1H)；7.35(d，1H)；7.03(s，1H)；5.65(m，4H)；5.02(b，2H)；4.11(t，2H)；3.80(t，2H)；3.52(d，2H)；2.52(s，3H)；1.21(s，18H)。
Two (new pentane acyloxy methoxyl group) the phosphonium mesitoyl methoxy ethyls of embodiment 16 2-amino-6-(furans-3-base-) sulfenyl-9-[2-]-purine (I c-3)
With reference to the method for embodiment 14, use I b-3 replace I b-1 with pivalyl chloride methyl esters reaction, preparation I c-3, productive rate 20.9%.
1H-NMR：δ(ppm，CDCl 3)：7.78(s，1H)；7.25(d，1H)；7.13(d，1H)；6.64(m，1H)；5.65(m，4H)；5.02(b，2H)；4.11(t，2H)；3.80(t，2H)；3.52(d，2H)；2.52(s，3H)；1.21(s，18H)。
Two (isopropoxy carbonyl Oxymethoxy) phosphonium mesitoyl methoxy-ethyls of embodiment 17 2-amino-6-(thiophene-2-base-) sulfenyl-9-[2-]-purine (I c-4)
Under nitrogen, with 0.5g I b-1 is added in the 10ml dimethyl formamide, adds the 0.4g triethylamine then, and 0.6g chloromethyl sec.-propyl carbonic ether stirred 24 hours in 50 ℃ of oil baths.With the reaction mixture evaporated under reduced pressure, separate with silica gel column chromatography, with methylene dichloride/Virahol (95: 5) wash-out, get I c-4 0.23g.
1H-NMR：δ(ppm，CDCl 3)：7.76(s，1H)；7.51-7.56(dd，1H)；7.32(dd，1H)；7.06-7.10(dd，1H)；5.9(b，2H)；5.55-5.7(m，4H)；4.82-5.02(m，2H)；4.36(dd，1H)；4.14(dd，2H)；3.9-3.99(m，2H)；3.7(dd，1H)；1.29-1.32(m.12H)；1.17(d，3H)。
Two (isopropoxy carbonyl Oxymethoxy) phosphonium mesitoyl methoxy-ethyls of embodiment 18 2-amino-6-(thiene-3-yl--) sulfenyl-9-[2-]-purine (I c-5)
With reference to the method for embodiment 17, use I b-2 replace I b-1 with chloromethyl sec.-propyl carbonate reaction, the preparation I c-5, productive rate 10.6%.
1H-NMR：δ(ppm，CDCl 3)：7.76(s，1H)；7.55-7.59(d，1H)；7.35(d，1H)；7.03(s，1H)；5.9(b，2H)；5.55-5.7(m，4H)；4.82-5.02(m，2H)；4.36(dd，1H)；4.14(dd，2H)；3.9-3.99(m，2H)；3.7(dd，1H)；1.29-1.32(m.12H)；1.17(d，3H)。
Two (new pentane acyloxy-methyl) phosphonium mesitoyl methoxy-ethyls of embodiment 19 2-amino-6-(furans-3-base-) sulfenyl-9-[2-]-purine (I c-6)
With reference to the method for embodiment 17, use I b-3 replace I b-1 with chloromethyl sec.-propyl carbonate reaction, the preparation I c-6, productive rate 18%.
1H-NMR：δ(ppm，CDCl 3)：7.76(s，1H)；7.25(d，1H)；7.13(d，1H)；6.64(m，1H)；5.9(b，2H)；5.55-5.7(m，4H)；4.82-5.02(m，2H)；4.36(dd，1H)；4.14(dd，2H)；3.9-3.99(m，2H)；3.7(dd，1H)；1.29-1.32(m.12H)；1.17(d，3H)。
Two (2,2, the 2-trifluoroethyl) phosphonium mesitoyl methoxies of embodiment 20 2-amino-6-(thiophene-2-base-) sulfenyl-9-[2-[] propyl group]-purine (I aSynthesizing-11)
Reference method 1.2 replaces ethylene chlorhydrin and trioxymethylene reaction to obtain 1-chloro-2-chlorine methoxy-propyl, the latter and three-(2 by 1-chloro-2-propanol; 2, the 2-trifluoroethyl) phosphite reactions, obtain two (2; 2, the 2-trifluoroethyl)-the phosphono propyl chloride, boiling point 80-84 ℃/25-30mmHg.
Reference method 1.3, two (2,2, the 2-trifluoroethyl)-phosphono propyl chloride and 2-amino-6-chloropurine condensation obtain two (2,2, the 2-the trifluoroethyl)-phosphonium mesitoyl methoxies of 2-amino-6-chloro-9-[] propyl group-purine III 2, fusing point: 119-120 ℃.
1H-NMR：δ(ppm，CDCl 3)：7.85(s，1H)；5.20(b，2H)；4.35-4.40(m，4H)；4.96-4.06(m，2H)；3.78-3.82(m，1H)；3.53-3.57(d，2H)，1.28-1.30(d，3H)。
Reference method 1.4 is used III 2Replace III 1With the reaction of 2-mercapto-thiophene, obtain I a-11, productive rate 11.8%.
1H-NMR：δ(ppm，CDCl 3)：7.58-7.60(dd，1H)；7.35(dd，1H)；7.12-7.14(dd，1H)；4.85(b，2H)；4.42-4.48(m，4H)；4.00-4.03(m，2H)；3.90(s，3H)；3.86(s，3H)；3.76-3.80(m，1H)；3.51-3.55(d，2H)，1.27-1.29(d，3H)。
Two (2,2, the 2-trifluoroethyl) phosphonium mesitoyl methoxies of embodiment 21 2-amino-6-(thiene-3-yl--) sulfenyl-9-[2-[] propyl group]-purine (I aSynthesizing-12)
Reference method 1.4 is used III 2Replace III 1With the reaction of 3-mercapto-thiophene, obtain I a-12, productive rate 12.4%.
1H-NMR：δ(ppm，CDCl 3)：7.78(s，1H)；7.55-7.59(d，1H)；7.35(d，1H)；7.03(s，1H)；4.85(b，2H)；4.42-4.48(m，4H)；4.00-4.03(m，2H)；3.90(s，3H)；3.86(s，3H)；3.76-3.80(m，1H)；3.51-3.55(d，2H)，1.27-1.29(d，3H)。
Two (2,2, the 2-trifluoroethyl) phosphonium mesitoyl methoxies of embodiment 22 2-amino-6-(furans-3-base-) sulfenyl-9-[2-[] propyl group]-purine (I aSynthesizing-13)
Reference method 1.4 is used III 2Replace III 1With the reaction of 3-sulfydryl furans, obtain I a-13, productive rate 14%.
1H-NMR：δ(ppm，CDCl 3)：7.78(s，1H)；7.25(d，1H)；7.13(d，1H)；6.64(m，1H)；4.85(b，2H)；4.42-4.48(m，4H)；4.00-4.03(m，2H)；3.90(s，3H)；3.86(s，3H)；3.76-3.80(m，1H)；3.51-3.55(d，2H)，1.27-1.29(d，3H)。
Embodiment 23 biological activity determinations
With Hep G 2.2.15 cells in vitro test method determination restraining effect and the cytotoxicity of target compound to HBV DNA.
Experimental technique
Measure the restraining effect of target compound to HBV DNA by quantitative PCR method: Hep G2.2.15 cell cultures is hatched in the 5%CO2 incubator in the DMEM nutrient solution that contains 10% calf serum.Then with cell inoculation in 96 orifice plates, cell count 3 * 10 4, continue to cultivate, when cell density reaches about 80%, discard old nutrient solution, add the new nutrient solution that contains the different concns medicine, 3 parallel holes are set; Changed nutrient solution every 2 days.After administration the 10th day, get 100 μ l supernatants, by the method for quantitative PCR, measure the content of HBV DNA, calculate 50% inhibition concentration, be IC 50Value.
Measure the cytotoxicity of target compound by mtt assay: Hep G 2Cell cultures is hatched in the 5%CO2 incubator in the DMEM nutrient solution that contains 10% calf serum.Then with cell inoculation in 96 orifice plates, cell count 5 * 10 4, continue to cultivate 3 days, add the new nutrient solution that contains the different concns medicine, 3 parallel holes are set; After administration the 3rd day, add MTT to 7.5mg/ml, continue to cultivate 2 hours, supernatant discarded adds and contains 10% tween X-100 Virahol, and 120 μ l/ holes add 0.4 μ l/ hole again, measure the absorption at 540nm place with enzyme connection instrument, calculate 50% inhibition concentration, are CC 50Value.The results are shown in Table 1.
The IC of table 1. The compounds of this invention 50Value and CC 50Value
Figure A20071009760000251

Claims (5)

1. the acyclic nucleoside phosphate ester derivative and the non-toxicity pharmacy acceptable salt thereof of formula I representative, hydrate or solvate:
Figure A2007100976000002C1
Wherein,
The sulfydryl that purine skeleton is 6 is connected in five yuan of different positionss on the hetero-aromatic ring,
X represents S or O atom;
Y represents methyl, methoxyl group or the halogen atom that replaces on the different positions on five yuan of hetero-aromatic rings,
R 1Represent H or methyl;
Each R 2Represent H, CH independently of one another 2CF 3, CH 2-OCOR 3Or CH 2OCOOR 3
R 3Represent C 2-C 6Alkyl or substituted alkyl, described substituting group is selected from methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-or tertiary butyl etc.
2. the compound of claim 1, it is selected from:
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(thiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(thiene-3-yl--) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(3 methyl thiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(5-thiotolene-2-base-) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(furans-3-base-) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(5-methoxythiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(4-methoxythiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(5-methoxyl group furans-2-base-) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(5-chlorothiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine;
Two (2,2, the 2-trifluoroethyl oxygen base) phosphonium mesitoyl methoxies of 2-amino-6-(4-chlorothiophene-2-base-) sulfenyl-9-[2-[] ethyl]-purine;
2-amino-6-(thiophene-2-base-) sulfenyl-9-(2-phosphonium mesitoyl methoxy ethyl)-purine;
2-amino-6-(thiene-3-yl--) sulfenyl-9-(2-phosphonium mesitoyl methoxy ethyl)-purine;
2-amino-6-(furans-3-base-) sulfenyl-9-(2-phosphonium mesitoyl methoxy ethyl)-purine;
Two (new pentane acyloxy methoxyl group) the phosphonium mesitoyl methoxy ethyls of 2-amino-6-(thiophene-2-base-) sulfenyl-9-[2-]-purine;
Two (new pentane acyloxy methoxyl group) the phosphonium mesitoyl methoxy ethyls of 2-amino-6-(thiene-3-yl--) sulfenyl-9-[2-]-purine;
Two (new pentane acyloxy methoxyl group) the phosphonium mesitoyl methoxy ethyls of 2-amino-6-(furans-3-base-) sulfenyl-9-[2-]-purine;
Two (isopropoxy carbonyl Oxymethoxy) phosphonium mesitoyl methoxy-ethyls of 2-amino-6-(thiophene-2-base-) sulfenyl-9-[2-]-purine;
Two (isopropoxy carbonyl Oxymethoxy) phosphonium mesitoyl methoxy-ethyls of 2-amino-6-(thiene-3-yl--) sulfenyl-9-[2-]-purine;
Two (new pentane acyloxy-methyl) phosphonium mesitoyl methoxy-ethyls of 2-amino-6-(furans-3-base-) sulfenyl-9-[2-]-purine;
Two (2,2, the 2-trifluoroethyl) phosphonium mesitoyl methoxies of 2-amino-6-(thiophene-2-base-) sulfenyl-9-[2-[] propyl group]-purine;
Two (2,2, the 2-trifluoroethyl) phosphonium mesitoyl methoxies of 2-amino-6-(thiene-3-yl--) sulfenyl-9-[2-[] propyl group]-purine; With
Two (2,2, the 2-trifluoroethyl) phosphonium mesitoyl methoxies of 2-amino-6-(furans-3-base-) sulfenyl-9-[2-[] propyl group]-purine.
3. the acyclic nucleoside phosphate ester derivative and the non-toxicity pharmacy acceptable salt thereof of formula I representative, the preparation method of hydrate or solvate, this method comprises:
(a) make the reaction of trifluoroethanol and phosphorus trichloride, make three-(2,2, the 2-trifluoroethyl) phosphorous acid esters:
CF 3CH 2OH+PCl 3→P(OCH 2CF 3) 3
(b) make ethylene chlorhydrin or 2-propylene chlorohydrin and Paraformaldehyde 96 under the dry hydrogen chloride effect, generate 2-chloroethyl chloromethyl ether or 2-chloropropyl chloromethyl ether:
(c) three-(2,2, the 2-trifluoroethyl) phosphite reactions that 2-chloroethyl chloromethyl ether that step (b) obtains or 2-chloropropyl chloromethyl ether and step (a) are made; obtain two (2,2, the 2-trifluoroethyl) inferior phosphoryl ethyl chloride or two (2; 2, the 2-trifluoroethyl) inferior phosphoryl propyl chloride:
Figure A2007100976000004C2
(d) product of step (c) and 2-amino-6-chloro-purine are reacted, obtain key intermediate III:
(e) make intermediate III that step (d) obtains and replacement or unsubstituted 2/3-mercapto-thiophene or the reaction of 2/3-sulfydryl furans obtain the special case formula I a compound of formula I compound:
Figure A2007100976000005C1
R wherein 2Be trifluoroethyl;
(f) make the trifluoro ethyl ester hydrolysis of formula Ia compound after, obtain another special case formula Ib free acid of formula I compound:
Figure A2007100976000005C2
(g) formula Ib compound is reacted with alkanoyloxymethyl chlorine or alkoxycarbonyloxy methyl chloride again, can obtain another special case formula Ic compound of formula I compound:
Figure A2007100976000005C3
Wherein, R 2Be CH 2-OCOR 3Or CH 2OCOOR 3, R 3Define among the formula I as described above.
4. pharmaceutical composition, it comprises the described formula I acyclic nucleoside phosphate ester of claim 1 derivative, its non-toxicity pharmacy acceptable salt, hydrate or solvate and one or more pharmaceutically acceptable carrier or vehicle.
5. the described formula I acyclic nucleoside phosphate ester of claim 1 derivative, its non-toxicity pharmacy acceptable salt, hydrate or solvate are used to prepare the purposes of the medicine for the treatment of hepatitis B virus infection.
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CN102093422A (en) * 2009-12-10 2011-06-15 中国人民解放军军事医学科学院毒物药物研究所 Acyclic nucleoside phosphonate derivative and medicinal application thereof
CN111377961A (en) * 2018-12-27 2020-07-07 张家港市国泰华荣化工新材料有限公司 Preparation method of tri (fluoroalkyl) phosphite ester
CN111087383A (en) * 2019-12-20 2020-05-01 贵州省欣紫鸿药用辅料有限公司 Production method of 2-mercaptothiophene

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