Derivatives of pyridoxine for inhibiting HIV integrase
View Patent ↗The present invention relates to compounds of Formula I or pharmaceutically acceptable salts, solvates or formulations thereof. Compounds of Formula I inhibit HIV-integrase enzyme and are useful for preventing and treating of HIV infection, acquired immune deficiency syndrome (AIDS), AIDS-related complex (ARC), hepatitis C, and other diseases and conditions caused or mediated by HIV infection.
1. A compound of formula I,
wherein:
X is H or OH;
Y is H or OH;
R 1 is H or halogen (F, Cl, Br, I);
R 2 is H or halogen (F, Cl, Br, I);
R 3 is H, C 1-6 alkyl, C 1-6 fluoroalkyl, or benzyl;
R 4 is H, C 1-6 alkyl, or benzyl; and
R 5 is H or C 1-6 alkyl; or
pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 and of formula Ia,
wherein:
X is OH;
Y is H or OH;
R 1 is H or halogen (F, Cl, Br, I);
R 2 is H or halogen (F, Cl, Br, I);
R 3 is H, C 1-6 alkyl or benzyl;
R 4 is H, C 1-6 alkyl or benzyl; and
R 5 is H or C 1-6 alkyl; or
pharmaceutically acceptable salts thereof.
3. A compound according to claim 1 and of formula Ib,
wherein:
X is OH;
Y is H or OH;
R 1 is H or halogen (F, Cl, Br, I);
R 2 is H or halogen (F, Cl, Br, I);
R 3 is H, C 1-6 alkyl or benzyl;
R 4 is H, C 1-6 alkyl or benzyl; and
R 5 is H or C 1-6 alkyl; or
pharmaceutically acceptable salts thereof.
4. The compound of claim 1 selected from the group consisting of:
(R)-5-((3-Chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;
5-(4-fluorobenzyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide; and
(S)-5-((3-Chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide; or pharmaceutically acceptable salts thereof.
5. A compound of formula Ic,
wherein:
X is O or N—OH;
Y is H or OH;
R 1 is H or halogen (F, Cl, Br, I);
R 2 is H or halogen (F, Cl, Br, I);
R 3 is H, C 1-6 alkyl or benzyl;
R 4 is H, C 1-6 alkyl or benzyl; and
R 5 is H or C 1-6 alkyl; or
pharmaceutically acceptable salts thereof.
6. A compound selected from:
(R)-5-((3-Chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;
5-(4-fluorobenzyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;
5-((4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide;
5-((4-fluorophenyl)(hydroxy)methyl)-N-hydroxy-N,2,2-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxamide;
5-((4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)-N-methylpicolinamide;
5-((4-fluorophertyl)(hydroxy)methyl)-3-hydroxy-4-(hydroxymethyl)-N-methoxypicolinamide;
5-(4-fluorobenzyl)-N,3-dihydroxy-4-methylpicolinamide;
5-((4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-methylpicolinamide;
5-(4-fluorobenzoyl)-N,3-dihydroxy-4-methylpicolinamide;
(E)-5-((4-fluorophenyl)(hydroxyimino)methyl)-N,3-dihydroxy-4-methylpicolinamide; and
(S)-5-((3-Chloro-4-fluorophenyl)(hydroxy)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide; or
pharmaceutically acceptable salts thereof.
7. A pharmaceutical composition comprising a compound according to any of claim 1 , 5 , or 6 , and a pharmaceutically acceptable carrier of diluent.
8. A pharmaceutical composition comprising a compound according to any of claim 1 , 5 , or 6 , at least one additional HIV-inhibiting agent, and a pharmaceutically acceptable carrier of diluent.
9. A method of inhibiting HIV replication in a cell, said method comprising contacting said cell with a compound according to any of claim 1 , 5 , or 6 in an amount sufficient to inhibit HIV replication.
10. The method of claim 9 , said method further comprising contacting said cell with at least one additional HIV inhibiting agent.
11. The method of claim 10 , wherein said HIV inhibiting agent is selected from the group consisting of an entry inhibitor, a protease inhibitor, a reverse transcriptase inhibitor, a fusion inhibitor, and an integrase inhibitor.