Antiviral phosphonate compounds and methods therefor
View Patent ↗Pharmaceutical compositions comprise a nucleotide analog with a phosphonate group at a concentration effective to act as a substrate and/or inhibitor of a viral polymerase, and especially of the HCV RNA dependent RNA polymerase.
1. A nucleotide analog having a structure according to Formula 1 or Formula 2,
wherein Z 1 and Z 2 are independently H, alkyl, halogen, OR 5 , SR 5 , NR 5 R 6 , CO-alkyl, CO-aryl, or CO-alkoxyalkyl, and wherein W is H, OR 5 , SR 5 , NR 5 R 6 , NH(NR 5 R 6 ), N(alkyl)(NR 5 R 6 ), CN, C(O)NR 5 R 6 , C(NH)NR 5 R 6 , or halogen;
wherein V is hydrogen, halogen, OR 5 , SR 5 , NR 5 R 6 , NH(NR 5 R 6 ), N(alkyl)(NR 5 R 6 ), CN, C(O)NR 5 R 6 , or C(NH)NR 5 R 6 , and wherein Y is H, alkyl, halogen, OR 5 , SR 5 , NR 5 R 6 , CO-alkyl, CO-aryl, or CO-alkoxyalkyl;
X is a covalent bond between the C4′-atom of the sugar and the carbon atom in the phosphonate group, O, CH 2 , CHR 5 , CHHalogen, or C(Halogen) 2 ;
D is CH 2 , CHHalogen, or C(Halogen) 2 ;
R 1 R 2 are independently H, or phosphate;
R 1 ′, R 2 ′, R 3 ′, and R 4 ′ are independently H or alkyl, with the proviso that at least one of R 1 ′, R 2 ′, R 3 ′, and R 4 ′ is alkyl;
R 3 and R 4 are independently H, phosphate, acyl, or alkyl;
R 5 and R 6 are independently H, alkyl, or acyl.
2. The nucleotide analog of claim 1 wherein the nucleotide analog has a structure according to Formula 1.
3. The nucleotide analog of claim 1 wherein X is a covalent bond between the C4′-atom of the sugar and the carbon atom in the phosphonate group, O, or CH 2 , and wherein at least one of R 1 ′R 2 ′R 3 ′, and R 4 ′ is CH 3 .
4. The nucleotide analog of claim 3 wherein R 2 ′ is CH 3 .
5. The nucleotide analog of claim 3 wherein Z 1 and Z 2 are H, and wherein W is NR 5 R 6 .
6. The nucleotide analog of claim 1 wherein the nucleotide analog has a structure according to Formula 2.
7. The nucleotide analog of claim 6 wherein X is a covalent bond between the C4′-atom of the sugar and the carbon atom in the phosphonate group, O, or CH 2 , and wherein at least one of R 1 , R 2 ′, R 3 ′, and R 4 ′ is CH 3 .
8. The nucleotide analog of claim 7 wherein R 2 ′ is CH 3 .
9. The nucleotide analog of claim 7 wherein Y is H or CH 3 , and wherein V is OH or NR 5 R 6 .
10. A prodrug of a nucleotide analog having a structure according to Formula 3 or Formula 4,
wherein Z 1 and Z 2 are independently H, alkyl, halogen, OR 5 , SR 5 , NR 5 R 6 , CO-alkyl, CO-aryl, or CO-alkoxyalkyl, and wherein W is H, OR 5 , SR 5 , NR 5 R 6 , NH(NR 5 R 6 ), N(alkyl)(NR 5 R 6 ), CN, C(O)NR 5 R 6 , C(NH)NR 5 R 6 , or halogen;
wherein V is hydrogen, halogen, OR 5 , SR 5 , NR 5 R 6 , NH(NR 5 R 6 ), N(alkyl)(NR 5 R 6 ), CN, C(O)NR 5 R 6 , or C(NH)NR 5 R 6 , and wherein Y is H, alkyl, halogen, OR 5 , SR 5 , NR 5 R 6 , CO-alkyl, CO-aryl, or CO-alkoxyalkyl;
X is a covalent bond between the C4′-atom of the sugar and the carbon atom in the phosphonate group, O, CH 2 , CHR 5 , CHHalogen, or C(Halogen) 2 ;
D is CH 2 CHHalogen, or C (Halogen) 2 ;
R 1 ′, R 2 ′, R 3 ′, and R 4 ′ are independently H or alkyl, with the proviso that at least one of R 1 ′, R 2 ′, R 3 ′, and R 4 ′ is alkyl:
R 3 and R 4 are independently H, phosphate, acyl, or alkyl;
R 5 and R 6 are independently H, alkyl, or acyl;
R 1 and R 2 together are
wherein:
X 1 , W 1 , and W 2 are independently selected from the group consisting of H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or
together X 1 and X 2 are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both O groups attached to the phosphorous; or
together X 1 and X 2 are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom that is fused to an aryl group at the beta and gamma position to the O attached to the phosphorous; or
together X 1 and W 1 are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from an O attached to the phosphorous; or
together X 2 and W 1 are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and X 1 must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or
together W 1 and W 2 are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and X 1 must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; wherein
X 2 is selected from the group consisting of —CHR 12 OH, —CHR 12 OC(O)R 13 , —CHR 12 OC(S)R 13 , —CHR 12 OC(S)OR 13 , —CHR 12 OC(O)SR 13 , —CHR 12 OCO 2 R 13 , —OR 12 , SR 12 , —CHR 12 N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR 12 2 )OH, —CH(C≡CR 12 )OH, —R 12 , —NR 12 2 , —OCOR 13 , —OCO 2 R 13 , —SCOR 13 , —SCO,R 2 R 13 , —NHCOR 12 , —NHCO 2 R 13 , —CH 2 NHaryl, —(CH 2 ) p —OR 14 , and —(CH 2 ) p —SR 14 ;
p is 2 or 3;
R 12 is selected from the group consisting of R 13 and —H;
R 13 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl; and
R 14 is selected from the group consisting of —H and lower acyl.
11. The nucleotide analog or prodrug of any of claims 1 , 2 , 6 , or 10 , wherein R 1 ′, R 2 ′, R 3 ′, and R 1 ′ are independently H or methyl, provided that at least one of R 1 ′, R 2 ′, R 3 ′ and R 4 ′ is methyl.
12. The nucleotide analog or prodrug of 11 , wherein only one of R 1 ′, R 2 ′, R 3 ′, and R 4 ′ is methyl.
13. A pharmaceutical composition comprising a nucleotide analog or prodrug according to any one of claims 1 , 2 , 6 , or 10 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
14. A pharmaceutical composition comprising a nucleotide analog or prodrug according to claim 12 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
15. A method of treating a hepatitis C infection in a human, comprising administering to said human an effective amount of a nucleotide analog or prodrug according to any one of claims 1 , 2 , 6 , or 10 , or a pharmaceutically acceptable salt thereof.
16. A method of treating a hepatitis C infection in a human, comprising administering to said human an effective amount of a nucleotide analog or prodrug according to claim 12 , or a pharmaceutically acceptable salt thereof.