Prodrug compounds and uses therof
Provided herein are cyclic phosphorus-containing prodrug compounds, their preparation and their uses, such as treating diseases via modulating molecular targets in the liver.
1. A compound of Formula III:
wherein:
R 1 is selected from the group consisting of, M, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
R 6 is selected from the group consisting of Cl, OH, NH 2 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 alkyloxy, an optionally substituted alkylamino, and —OP(O)(R) 2 ;
R 7 is selected from the group consisting of OH, an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 alkyloxy;
M is a biological agent or part of a biological agent or a prodrug of a biological agent;
X and X′ are independently O or NR 3
Y′ is O;
R 3 is selected from the group consisting of H, a C 1 -C 6 alkyl, and a heteroalkyl;
or a stereoisomer or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein M is a nucleoside antiviral or anticancer agent.
3. The compound of claim 1 , wherein M is a lipid modulator.
4. The compound of claim 1 , wherein M is a nuclear hormone receptor modulator.
5. The compound claim 1 , wherein M is at least one selected from the group consisting of: a HCV polymerase inhibitor, a reverse transcriptase inhibitor, a DNA synthesis inhibitor, an RNA synthesis inhibitor, and an antimetabolic agent.
6. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
7. A method of treating a disease, disorder or condition in the liver of a subject comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.
8. A method of treating a disease, disorder or condition by intervening in a molecular pathway or target in the liver in a subject comprising:
administering an effective amount of the compound of claim 1 to a subject in need thereof.
9. A method of treating a disease, disorder or condition in the liver or a disease, disorder or condition in which the physiological or pathogenic pathways involve the liver in a subject, comprising:
administering an effective amount of the compound of claim 1 to the subject.
10. A method of treating hepatitis, liver cancer, liver fibrosis, malaria, viral infection, parasitic infection, cancer, fatty liver, diabetes, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia or a hormonal condition in a subject comprising:
administering an effective amount of the compound of claim 1 to the subject.
11. The method of claim 7 , further comprising administering an effective amount of an additional therapeutic agent to the subject in need thereof.
12. The method of claim 7 , wherein the subject is a mammal.
13. The method of claim 7 , wherein the subject is a human.
14. A method of intervening in a molecular pathway or modulating a target in a cell comprising contacting the cell with the compound of claim 1 .
15. The method of claim 14 , wherein the cell is in vivo.
16. The method of claim 14 , wherein the cell is ex vivo.
17. The method of claim 14 , wherein the cell is a hepatocyte.
18. The method of claim 14 , wherein the cell is mammalian.
19. The method of claim 14 , wherein the cell is human.