Metabolically stable prodrugs
AssigneesTSRL, Inc., The Regents of the University of Michigan
InventorsElke Lipka, Eric Simon, Andy D. White, Kim M. Hutchings, Xinmin Gan
Life of this patent
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Abstract
Provided are prodrugs of various therapeutic agents that provide enhanced bioavailability of the therapeutic agent, and methods of treatment conditions in a subject by administration of the one or prodrugs. As provided herein a prodrug includes a therapeutic agent covalently attached to a cap, the cap having a structure according to formula (I) where: R1 is a branched or linear substituted or unsubstituted C2-C6 alkyl, alkenyl, or alkynl; X is —S(0)2-; R2 is a branched or linear substituted or unsubstituted C4-C20 alkyl, alkenyl, or alkynyl; and R3 is —H, C3-C5 cycloalkyl, C3-C5 cycloheteroalkyl, —C(CH3)3, —CF3, —C(CF3)3, or a substituted or unsubstituted phenyl.
Claims15
A prodrug consisting of an anti-infective therapeutic agent and a cap having a structure according to formula (I):
- the anti-infective therapeutic agent comprising a phosphonate, said anti-infective therapeutic agent covalently attached to the cap by said phosphonate, the cap having a structure according to formula (I)
- where:
- R1 is a branched or linear substituted or unsubstituted C2-C6 alkyl, alkenyl, or alkynyl;
- X is —S(O)2—;
- R2 is a linear substituted or unsubstituted C4-C20 alkyl, alkenyl, or alkynyl;
- and
- R3 is substituted or unsubstituted C3-C5 cycloalkyl, an unsubstituted C3-C5 cycloheteroalkyl, or a substituted or unsubstituted phenyl;
- or
- R3 is a radical having a structure according to formula (III) or formula (IV):
- where:
- R11, R12, R13, R14, and R15 are independently chosen from (C1-C12) alkyl, —CF3, or —OH, or —H;
- wherein said anti-infective therapeutic agent has a structure according to formula (II):
- where R4 is chosen from the following groups:
- where B=A and W=CH2OH and the therapeutic agent is(S)-9-[(2S)-3-hydroxy-2-phosphonylmethoxypropyl]adenine;
- or B=A and W=H and the therapeutic agent is phosphonomethoxy-ethyl-adenine;
- or B=DAP and W=CH3 and the therapeutic agent is 9-[2-(R)-(phosphonomethoxy) propyl]-2,6-diaminopurine;
- or B=A and W=CH2F and the therapeutic agent is(S)-9-(3-fluoro-2-phosphonylmethoxypropyl) adenine;
- or B=DAP and W=CH2F and the therapeutic agent is(S)-9-[3-fluoro-2-phosphonylmethoxypropyl]diaminopurine;
- or B=G and W=CH2F and the therapeutic agent is(S)-9-(3-fluoro-2-phosphonylmethoxypropyl) guanine;
- or B=DAP and W=CH2F and the therapeutic agent is (R)-(S)-9-[3-fluoro-2-phosphonylmethoxypropyl]diaminopurine;
- or B=G and W=CH2F and the therapeutic agent is (R)-9-(3-fluoro-2-phosphonylmethoxypropyl) guanine;
- or B=7-deaza-G and W=H and the therapeutic agent is 7-deaza-9-(2-phosphonylmethoxyethyl) guanine;
- or B=8-aza-G and W=H and the therapeutic agent is 9-(2-phosphonylmethoxyethyl)-8-aza-guanine;
- or B=8-aza-G and W=CH3 and the therapeutic agent is (R)-(2-(phosphonomethoxy) propyl)-8-aza-guanine;
- or B=DAPy and W=H and the therapeutic agent is 6-[2-(phosphonomethoxy) ethoxy]-2,4-diaminopyrimidine;
- or B=DAPy and W=CH3 and the therapeutic agent is (R)-6-[2-(phosphonomethoxy) ethoxy]-2,4-diaminopyrimidine;
- and R6 is H or —R1XR2R3 (formula I)
- thereby forming said prodrug;
- or salts thereof,
- wherein as defined as element B, A is adenine, G is guanine, DAP is 2,6-diaminopurine, 7-deaza-G is 7-deaza-guanine, 8-aza-G is 8-aza-guanine, and DAPy is 2,4-diaminopyrimidine.
Dependencies are inferred from the claim text.