Prodrugs of phosphonate nucoleotide analogues
AssigneeGilead Sciences, Inc.
InventorsMark W. Becker, Harlan H. Chapman, Tomas Cihlar, Eugene J. Eisenberg, Gong-Xin He, Michael R. Kernan, William A. Lee, Ernest J. Prisbe, John C. Rohloff, Mark L. Sparacino
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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) having substituent groups as defined herein. Compositions of these novel compounds in pharmaceutically acceptable excipients and their use in therapy and prophylaxis are provided.
Claims10
A method for antiviral therapy comprising administering a therapeutically effective amount of a diastereomerically enriched compound having the structure (3)
- which contains less than 40% by weight of diastereomer (4)
- wherein R1 is an oxyester which is hydrolyzable in vivo, or hydroxyl;
- B is a heterocyclic base;
- R2 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 R1 and R2 are hydroxyl;
- E is —(CH2)2—, —CH(CH3)CH2—, —CH(CH2F)CH2—, —CH(CH2OH)CH2—, —CH(CH═CH2)CH2—, —CH(C═CH)CH2—, —CH(CH2N3)CH2—,
- —CH(R6)OCH(R6′)—, —CH(R9)CH2O— or —CH(R8)O—, wherein the right hand bond is linked to the heterocyclic base;
- the broken line represents an optional double bond;
- R4 and R5 are independently hydrogen, hydroxy, halo, amino or a substituent having 1-5 carbon atoms selected from acyloxy, alkyoxy, alkylthio, alkylamino and dialkylamino;
- R6 and R6′ are independently H, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C2-C7 alkanoyl;
- R7 is independently H, C1-C6 alkyl, or are taken together to form —O— or —CH2—;
- R8 is H, C1-C6 alkyl, C1-C6 hydroxyalkyl or C1-C6 haloalkyl;
- and
- R9 is H, hydroxymethyl or acyloxymethyl;
- and its salts, free base, and solvates.
A method for antiviral therapy comprising administering a therapeutically effective amount of a diastereomerically enriched compound having the structure (5a)
- which contains less than 40% by weight of diastereomer (5b)
- wherein
- R5 is methyl or hydrogen;
- R6 independently is H, alkyl, alkenyl, alkynyl, aryl or arylalkyl, or R6 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;
- R7 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;
- R11 is amino, alkylamino, oxo, or dialkylamino;
- and
- R12 is amino or H;
- and its salts, tautomers, free base and solvates.
A method for antiviral therapy comprising administering a therapeutically effective amount of a diastereomerically enriched compound having the structure (6)
- and its salts, tautomers, free base and solvates.
A method for antiviral therapy comprising administering a therapeutically effective amount of a diastereomerically enriched compound having the structure (7)
- which contains less than 40% of diastereomer (7a)
Dependencies are inferred from the claim text.