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|Title:||Prodrugs of phosphonate nucleotide analogues|
|Abstract:||A novel method has led to the identification of novel mixed ester-amidates of PMPA for retroviral or hepadnaviral therapy, including compounds of structure (5a) ##STR00001## having substituent groups as defined herein. Compositions of these novel compounds in pharmaceutically acceptable excipients and their use in therapy and prophylaxis are provided.|
|Inventor(s):||Becker; Mark W. (Belmont, CA), Chapman; Harlan H. (La Honda, CA), Cihlar; Tomas (Foster City, CA), Eisenberg; Eugene J. (San Carlos, CA), He; Gong-Xin (Fremont, CA), Kernan; Michael R. (Pacifica, CA), Lee; William A. (Los Altos, CA), Prisbe; Ernest J. (Los Altos, CA), Rohloff; John C. (Mountain View, CA), Sparacino; Mark L. (Morgan Hill, CA)|
|Assignee:||Gilead Sciences, Inc. (Foster City, CA)|
1. A diastereomerically enriched compound having the structure (3) ##STR00034## which contains less than 40% by weight of the diastereomer (4) ##STR00035## wherein
R.sup.1 is an oxyester which is hydrolyzable in vivo, or hydroxyl; B is a heterocyclic base; R.sup.2 is hydroxyl, or the residue of an amino acid bonded to the P atom through an amino group of the amino acid and having each carboxy substituent of the
amino acid optionally esterified, but not both of R.sup.1 and R.sup.2 are hydroxyl; E is --(CH.sub.2).sub.2--, --CH(CH.sub.3)CH.sub.2--, --CH(CH.sub.2F)CH.sub.2--, --CH(CH.sub.2OH)CH.sub.2--, --CH(CH.dbd.CH.sub.2)CH.sub.2--, --CH(C.ident.CH)CH.sub.2--,
--CH(CH.sub.2N.sub.3)CH.sub.2--, ##STR00036## --CH(R.sup.6)OCH(R.sup.6)--, --CH(R.sup.9)CH.sub.2O-- or --CH(R.sup.8)O--, wherein the right hand bond is linked to the heterocyclic base; the broken line represents an optional double bond; R.sup.4 and
R.sup.5 are independently hydrogen, hydroxy, halo, amino or a substituent having 1-5 carbon atoms selected from acyloxy, alkyoxy, alkylthio, alkylamino and dialkylamino; R.sup.6 and R.sup.6'are independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
hydroxyalkyl, or C.sub.2-C.sub.7 alkanoyl; R.sup.7 is independently H, C.sub.1-C.sub.6 alkyl, or are taken together to form --O-- or --CH.sub.2--; R.sup.8 is H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 hydroxyalkyl or C.sub.1-C.sub.6 haloalkyl; and
R.sup.9 is H, hydroxymethyl or acyloxymethyl; and their salts, free base, and solvates.
2. The compound of claim 1 containing less than 20% by weight of the diastereomer (4).
3. The compound of claim 1 containing less than 5% by weight of the diastereomer (4).
4. A diastereomerically enriched compound having the structure (5a) ##STR00037## which contains less than 40% by weight of diastereomer (5b) ##STR00038## wherein R.sup.5 is methyl or hydrogen; R.sup.6 independently is H, alkyl, alkenyl, alkynyl, aryl or arylalkyl, or R.sup.6 independently is alkyl, alkenyl, alkynyl, aryl or arylalkyl which is substituted with from 1 to 3 substituents selected from alkylamino, alkylaminoalkyl, dialkylaminoalkyl, dialkylamino, hydroxyl, oxo, halo, amino, alkylthio, alkoxy, alkoxyalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylalkoxyalkyl, haloalkyl, nitro, nitroalkyl, azido, azidoalkyl, alkylacyl, alkylacylalkyl, carboxyl, or alkylacylamino; R.sup.7 is the side chain of any naturally-occurring or pharmaceutically acceptable amino acid and which, if the side chain comprises carboxyl, the carboxyl group is optionally esterified with an alkyl or aryl group; R.sup.11 is amino, alkylamino, oxo, or dialkylamino; and R.sup.12 is amino or H; and its salts, tautomers, free base and solvates.
5. The compound of claim 4 containing less than 20% by weight of the diastereomer (5b).
6. The compound of claim 4 containing less than 5% by weight of the diastereomer (5b).
7. A diastereomerically enriched compound of structure (6) ##STR00039## and its salts, tautomers, free base and solvates.
8. A diastereomerically enriched compound of structure (7) ##STR00040## which contains less than 40% of diastereomer (7a) ##STR00041##
9. The compound of claim 8 containing less than 20% by weight of the diastereomer (7a).
10. The compound of claim 8 containing less than 5% by weight of the diastereomer (7a).
11. A composition comprising a compound of any of claims 1-8 or 2-10 and a pharmaceutically effective excipient.
12. The composition of claim 11 wherein the excipient is a gel.
13. The composition of claim 11 which is suitable for topical administration.
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