|Title:||Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability|
|Abstract:||Novel compounds are provided that comprise esters of antiviral phosphonomethoxy nucleotide analogs with carbonates and/or carbamates having the structure --OC(R.sup.2).sub.2 OC(O)X(R).sub.a, wherein R.sup.2 independently is H, C.sub.1 -C.sub.12 alkyl, aryl, alkenyl, alkynyl, alkyenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, azido, nitro or OR.sup.3 in which R.sup.3 is C.sub.1 -C.sub.12 alkyl; X is N or O; R is independently H, C.sub.1 -C.sub.12 alkyl, aryl, alkenyl, alkynyl, alkyenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, azido, nitro, --O--, --N.dbd., --NR.sup.4 --, --N(R.sup.4).sub.2 -- or OR.sup.3, R.sup.4 independently is --H or C.sub.1 -C.sub.8 alkyl, provided that at least one R is not H; and a is 1 or 2, with the proviso that when a is 2 and X is N, (a) two R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, or (b) one R additionally can be OR.sup.3. The compounds are useful as intermediates for the preparation of antiviral compounds or oligonucleotides, or are useful for administration directly to patients for antiviral therapy of prophylaxis. Embodiments are particularly useful when administered orally.|
|Inventor(s):||Arimilli; Murty N. (Fremont, CA), Cundy; Kenneth C. (Belmont, CA), Dougherty; Joseph P. (New York, NY), Kim; Choung U. (San Carlos, CA), Oliyai; Reza (Foster City, CA), Stella; Valentino J. (Lawrence, KS)|
|Assignee:||Gilead Sciences, Inc. (Foster City, CA)|
|Filing Date:||May 29, 2002|
|Claims:||1. A method for preparing a compound of formula (1) ##STR33## |
comprising reacting a compound of formula (4) ##STR34##
with LC(R.sup.2).sub.2 OC(O)X(R).sub.a wherein, B is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-yl; X is N or O; R is independently --H, C.sub.1 -C.sub.12 alkyl, C.sub.5 -C.sub.12 aryl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, C.sub.7 -C.sub.12 alkenylaryl, C.sub.7 -C.sub.12 alkynylaryl, or C.sub.6 -C.sub.12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or --OR.sup.3 in which R.sup.3 is C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl or C.sub.5 -C.sub.12 aryl; R.sup.1 is hydrogen, --CH.sub.3, --CH.sub.2 OH, --CH.sub.2 F, --CH.dbd.CH.sub.2, or --CH.sub.2 N.sub.3, or R.sup.1 and R.sup.8 are joined to form --CH.sub.2 --; R.sup.2 independently is hydrogen or C.sub.1 -C.sub.6 alkyl provided that at least one R.sup.2 is hydrogen; L is a leaving group; R.sup.8 is hydrogen or --CHR.sup.2 --O--C(O)--OR, or R.sup.8 is joined with R.sup.1 to form .[.--C.sub.2 --.]. .Iadd.--CH.sub.2.Iaddend.; and a is 1 when X is O, or 1 or 2 when X is N, with the proviso that when a is 2 and X is N, (a) two N-linked R groups can be taken together to form N-containing carbocycle or oxygen-containing heterocycle, (b) one N-linked R additionally can be --OR.sup.3 or (c) both N-linked R groups can be H. .Iadd.
2. The method of claim 1 comprising conducting the reaction using at least about 1.0 equivalent of L--CHR.sup.2 --O--C(O)--OR..Iaddend..Iadd.
3. The method of claim 1 comprising conducting the reaction in the presence of an organic base in an organic solvent at a reaction temperature of about 4-100.degree. C. for about 4-72 hours..Iaddend..Iadd.
4. The method of claim 1 wherein the compound of formula (1) is recovered by forming a salt, precipitating the salt and recovering the precipitated salt..Iaddend..Iadd.
5. The method of claim 4 wherein the salt is formed from sulfuric acid, phosphoric acid, lactic acid, or citric acid..Iaddend.
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