RU2002118614A - TREATMENT OF HUMAN IMMUNO DEFICIENCY VIRUS INFECTION WITH MEDICINAL STABILITY - Google Patents

Claims (21)

1. A method of treating a drug-resistant human immunodeficiency virus infection in a subject in need thereof, wherein an effective amount of a lipid analog of a phosphonoformate-containing pharmaceutically active compound is administered to said subject. 2. The method according to claim 1, where the lipid analogue has the following structure:

where R ₁ and R ₁ 'independently are —H, optionally substituted —O (C ₁ -C ₂₄ ) alkyl, —O (C ₁ -C ₂₄ ) alkenyl, —S (C ₁ -C ₂₄ ) alkyl, —S (C ₁ -C ₂₄ ) alkenyl, -O (C ₁ -C ₂₄ ) acyl, -S (C ₁ -C ₂₄ ) acyl, where at least one of R ₁ and R ₁ ′ is not —H, and where said alkenyl has from 1 to about 6 double bonds, and said acyl may have from 1 to about 6 double bonds; R ₂ and R ₂ ′ independently represent —H, optionally substituted —O (C ₁ -C ₇ ) alkyl, —O (C ₁ -C ₇ ) alkenyl, —S (C ₁ -C ₇ ) alkyl, —S ( C ₁ -C ₇ ) alkenyl, -O (C ₁ -C ₇ ) acyl, -S (C ₁ -C ₇ ) acyl, -N (C ₁ -C ₇ ) acyl, -NH (C ₁ -C ₇ ) alkyl, —N ((C ₁ -C ₇ ) alkyl) ₂ , oxo, halogen, —NH ₂ , —OH or —SH; R ₃ is a phosphonoformate which is bound either through its carboxyl group or through its phosphonate group, to a functional group on a possible linker L or to the oxygen present on Cα, and when R ₃ is linked through its phosphonate group, then the carboxylate group of said phosphonoformate has the following structure:

where R _y represents -H or alkyl, or Na ⁺ , K ⁺ , NH $\genfrac{}{}{0ex}{}{\text{+}}{\text{4}}$ , or any other physiologically acceptable cation, X, if present, is

L, if present, is a bifunctional linker molecule of the formula -J- (CR ₂ ) _t -G-, where t = 1 - 24, J and G independently are -O-, -S-, -C (O) O- or —NH—, and R is —H, alkyl or alkenyl; m is 0-6; n = 0 or 1. 3. The method according to claim 2, where m = 0, 1 or 2. 4. The method according to claim 3, where m = 1. 5. The method according to claim 4, where R ₁ represents —O (C ₁₈ ) alkyl, and R ₁ ′ represents H, R ₂ represents —OH, —Omethyl or Oethyl, and R ₂ ′ represents —H, each of R ₂ and R ₂ 'on Cα is —H, R ₃ is phosphonoformate, and n = 0. 6. The method of claim 5, wherein R ₂ is —OH. 7. The method according to claim 5, where R ₂ represents-Methyl. 8. The method according to claim 5, where R ₂ represents-Oethyl. 9. The method of claim 1, wherein said HIV is resistant to a reverse transcriptase inhibitor (s). 10. The method of claim 9, wherein said reverse transcriptase inhibitors are nucleoside analogues. 11. The method of claim 10, wherein said nucleoside analogues are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), lamivudine (ZTS), stavudine (d4T), emirivine (FTC), DAPD, DXG, tenofovir, adefovir or abacavir. 12. The method according to claim 11, where these nucleoside analogues are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC) or lamivudine (3TC). 13. The method of claim 12, wherein said nucleoside analogue is zidovudine (AZT). 14. The method of claim 9, wherein said reverse transcriptase inhibitors are non-nucleoside analogues. 15. The method of claim 14, wherein said non-nucleoside analogs are nevirapine, delavirdine, or efavirenz. 16. The method according to claim 1, where the specified HIV is resistant to protease inhibitors. 17. The method according to clause 16, where these protease inhibitors are saquinavir, indinavir, ritonavir, agenerase or DMP-450. 18. A method of treating a viral infection caused by AZT-resistant strains of HIV, in which an effective amount of a lipid analogue of a phosphonoformate-containing pharmaceutically active compound is administered to a subject in need thereof. 19. The method according to p, where the lipid analogue has the following structure:

where R ₁ and R ₁ 'independently are —H, optionally substituted —O (C ₁ -C ₂₄ ) alkyl, —O (C ₁ -C ₂₄ ) alkenyl, —S (C ₁ -C ₂₄ ) alkyl, —S (C ₁ -C ₂₄ ) alkenyl, -O (C ₁ -C ₂₄ ) acyl, -S (C ₁ -C ₂₄ ) acyl, where at least one of R ₁ and R ₁ ′ is not —H, and where said alkenyl has from 1 to about 6 double bonds, and said acyl may have from 1 to about 6 double bonds; R ₂ and R ₂ ′ independently represent —H, optionally substituted —O (C ₁ -C ₇ ) alkyl, —O (C ₁ -C ₇ ) alkenyl, —S (C ₁ -C ₇ ) alkyl, —S ( C ₁ -C ₇ ) alkenyl, -O (C ₁ -C ₇ ) acyl, -S (C ₁ -C ₇ ) acyl, -N (C ₁ -C ₇ ) acyl, -NH (C ₁ -C ₇ ) alkyl, —N ((C ₁ -C ₇ ) alkyl) ₂ , oxo, halogen, —NH ₂ , —OH or —SH; R ₃ is a phosphonoformate which is bound either through its carboxyl group or through its phosphonate group, to a functional group on a possible linker L or to the oxygen present on Cα, and when R ₃ is linked through its phosphonate group, then the carboxylate group of said phosphonoformate has the following structure:

where R _y represents -H or alkyl, or Na ⁺ , K ⁺ , Nh $\genfrac{}{}{0ex}{}{\text{+}}{\text{4}}$ , or any other physiologically acceptable cation; X, if present, is

L, if present, is a bifunctional linker molecule of the formula -J- (CR ₂ ) _t G-, where t = 1 - 24, J and G independently represent -O-, -S-, -C (O) O - or —NH—, and R is —H, alkyl or alkenyl; m is 0-6; n = 0 or 1. 20. A method of treating a viral infection in a mammal in which an effective amount of a lipid analogue of a phosphonoformate-containing pharmaceutically active compound in combination with AZT is administered to a subject in need thereof. 21. The method according to claim 20, where the specified lipid analogue has the following structure:

where R ₁ and R ₁ 'independently are —H, optionally substituted —O (C ₁ -C ₂₄ ) alkyl, —O (C ₁ -C ₂₄ ) alkenyl, —S (C ₁ -C ₂₄ ) alkyl, —S (C ₁ -C ₂₄ ) alkenyl, -O (C ₁ -C ₂₄ ) acyl, -S (C ₁ -C ₂₄ ) acyl, where at least one of R ₁ and R ₁ ′ is not —H, and where said alkenyl has from 1 to about 6 double bonds, and said acyl may have from 1 to about 6 double bonds; R ₂ and R ₂ ′ independently represent —H, optionally substituted —O (C ₁ -C ₇ ) alkyl, —O (C ₁ -C ₇ ) alkenyl, —S (C ₁ -C ₇ ) alkyl, —S ( C ₁ -C ₇ ) alkenyl, -O (C ₁ -C ₇ ) acyl, -S (C ₁ -C ₇ ) acyl, -N (C ₁ -C-) acyl, -NH (C ₁ -C ₇ ) alkyl, —N ((C ₁ -C ₇ ) alkyl) ₂ , oxo, halogen, —NH ₂ , —OH or —SH; R ₃ is a phosphonoformate which is bound either through its carboxyl group or through its phosphonate group, to a functional group on a possible linker L or to the oxygen present on Cα, and when R ₃ is linked through its phosphonate group, then the carboxylate group of said phosphonoformate has the following structure:

where R _y represents -H or alkyl, or Na ⁺ , K ⁺ , NH $\genfrac{}{}{0ex}{}{\text{+}}{\text{4}}$ , or any other physiologically acceptable cation; X, if present, is

L, if present, is a bifunctional linker molecule of the formula -J- (CR ₂ ) _t -G-, where t = 1 - 24, J and G independently are -O-, -S-, -C (O) O- or —NH—, and R is —H, alkyl or alkenyl; m is 0-6; n = 0 or 1.