Guanylhydrazones useful for treating diseases associated with T cell activation
View Patent ↗There is disclosed a method for treating diseases and disorders involving T cell activation and HIV-infection using the p38 mitogen activated protein kinase (MAPK) signaling pathway as a target for intervention. There is further disclosed a use for guanylhydrazone-substituted compounds to treat diseases and disorders related to T cell activation and HIV-infection.
1. A method for treating HIV, comprising administering an effective HIV-treating amount of a guanylhydrazone-substituted compound to a subject known to have HIV, wherein the guanylhydrazone-substituted compound is CNI-1493.
2. The method according to claim 1 , wherein said treating further comprises inhibiting a p38 MAP kinase signaling pathway and reducing HIV replication in said subject.
3. The method according to claim 1 , further comprising administering an additional therapeutic agent.
4. The method according to claim 3 , wherein the additional therapeutic agent is an anti-viral agent.
5. The method according to claim 3 , wherein the additional therapeutic agent is a reverse transcriptase inhibitor.
6. The method according to claim 3 , wherein the additional therapeutic agent is an HIV protease inhibitor.
7. The method according to claim 3 , wherein the additional therapeutic agent is a preintegration complex inhibitor.
8. A method for treating HIV, comprising administering an effective HIV-treating amount of a guanylhydrazone-substituted compound to a subject known to have HIV, wherein the guanylhydrazone-substituted compound has the formula:
wherein X 2 =GhyCH—, GhyCCH 3 — or H—; X 1 , X′ 1 and X′ 2 , independently=GhyCH— or GhyCCH 3 —; Z=—NH(CO)NH—, —(C 6 H 4 )—, —(C 5 NH 3 )— or -A-(CH 2 ) n -A-, n=2-10, which is unsubstituted, mono- or di-C-methyl substituted, or a mono or di-unsaturated derivative thereof; and A independently=—NH(CO)—, —(CO)NH—, —NH(CO)NH—, —NH— or —O— and salts thereof.
9. The method of claim 8 , further comprising administering one or more retrovirus inhibitor selected from the group consisting of reverse transcriptase inhibitor, HIV protease inhibitor, and preintegration complex inhibitor.
10. The method of claim 9 , wherein the retrovirus inhibitor is one or more reverse transcriptase inhibitor selected from the group consisting of 3′azido-3′-thymidine (AZT); dideoxyinosine (ddl); 2′,3′-dideoxyadenosine (ddA); 2′,3′-dideoxyguanosine (ddG); 2′,3′-dideoxyinosine (ddI); 2′,3′-dideoxycytidine (ddC); 2′,3′-dideoxythymidine (ddT); 2′,3′-dideoxy-dideoxythymidine (d4T); 3TC; 2′,3′-dideoxy-2′-fluoronucleosides; 2′,3′-dideoxy-2′-fluoroadenosine; 2′,3′-dideoxy-2′-fluoroinosine; 2′,3′-dideoxy-2′-fluorothymidine; 2′,3′-dideoxy-2′-fluorocytosine; 2′,3′-dideoxy-2′,3′-didehydro-2′-fluoronucleoside; 2′,3′-dideoxy-2′,3′-didehydro-2′-fluorothymidine (Fd4T); 2′3′-dideoxy-2′-beta-fluoroadenosine (F-ddA); 2′,3′-dideoxy-2′-beta-fluoroinosine (F-ddI); and 2′,3′-dideoxy-2-beta-fluorocytosine (F-ddC).
11. The method of claim 8 , wherein the guanylhydrazone-substituted compound is a salt.
12. The method of claim 11 , wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, acetate, citrate, tartrate, lactate, and malate salt.
13. A method for treating HIV, comprising administering an effective HIV-treating amount of a guanylhydrazone-substituted compound to a subject known to have HIV, wherein the guanylhydrazone-substituted compound has the formula:
wherein X 1 and X 2 =H; X′ 1 and X′ 2 independently=GhyCH— or GhyCCH 3 —; Z=-A-(CH 2 ) n -A-, n=3-8; and A=—NH(CO)—, —(CO)NH— or —NH(CO)NH—; and salts thereof.
14. A method for treating HIV, comprising administering an effective HIV-treating amount of a guanylhydrazone-substituted compound to a subject known to have HIV, wherein the guanylhydrazone-substituted compound has the formula:
wherein X 1 , and X 2 =H; X′ 1 and X′ 2 independently =GhyCH— or GhyCCH3—, and Z═—O—(CH 2 ) 2 —O—, and salts thereof.
15. A method for treating HIV, comprising administering an effective HIV-treating amount of a guanylhydrazone-substituted compound to a subject known to have HIV, wherein the guanylhydrazone-substituted compound has the formula:
wherein X 2 =GhyCH—, GhyCCH 3 — or H—; X 1 , X′ 1 and X′ 2 =GhyCH— or GhyCCH 3 —; and Z=—O—(CH 2 ) n —O—, n=2-10, and salts thereof.
16. A method for treating HIV, comprising administering an effective HIV-treating amount of a guanylhydrazone-substituted compound to a subject known to have HIV, wherein the guanylhydrazone-substituted compound has the formula:
wherein n=3-8; X 2 and X′ 2 =GhyCH—, GhyCCH 3 — or H—; X 1 and X′ 1 =GhyCH— or GhyCCH 3 —; and salts thereof.
17. The method of claim 16 , further comprising administering one or more retrovirus inhibitor selected from the group consisting of reverse transcriptase inhibitor, HIV protease inhibitor, and preintegration complex inhibitor.
18. The method of claim 17 , wherein the retrovirus inhibitor is one or more reverse transcriptase inhibitor selected from the group consisting of 3′azido-3′-thymidine (AZT); dideoxyinosine (ddl); 2,3-dideoxyadenosine (ddA); 2′,3′-dideoxyguanosine (ddG); 2′,3′-dideoxyinosine (ddI); 2′,3′-dideoxycytidine (ddC); 2′,3′-dideoxythymidine (ddT); 2′,3′-dideoxy-dideoxythymidine (d4T); 3TC; 2′,3′-dideoxy-2′-fluoronucleosides; 2′,3′-dideoxy-2′-fluoroadenosine; 2′,3′-dideoxy-2′-fluoroinosine; 2′,3′-dideoxy-2′-fluorothymidine; 2′,3′-dideoxy-2′-fluorocytosine; 2′,3′-dideoxy-2′,3′-didehydro-2′-fluoronucleoside; 2′,3′-dideoxy-2′,3′-didehydro-2′-fluorothymidine (Fd4T); 2′3′-dideoxy-2′-beta-fluoroadenosine (F-ddA); 2′,3′-dideoxy-2′-beta-fluoroinosine (F-ddI); and 2′,3′-dideoxy-2′-beta-fluorocytosine (F-ddC).
19. The method of claim 16 , wherein the guanylhydrazone-substituted compound is a salt.
20. The method of claim 19 , wherein the salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, acetate, citrate, tartrate, lactate, and malate salt.