Metabolically stable alkoxyalkyl esters of antiviral or antiproliferative phosphonates, nucleoside phosphonates and nucleoside phosphates
View Patent ↗The present invention relates to phosphonate, nucleoside phosphonate or nucleoside phosphate compounds, compositions containing them, processes for obtaining them, and their use in treating a variety of medical disorders, in particular viral infections, cancers and the like.
1. A nucleoside phosphate selected from the group of compounds having the following structures:
wherein
R is selected from the group consisting of —R 1 —O—R 2 , wherein R 1 is selected from the group consisting of an optionally substituted C 1 to C 11 alkyl group and R 2 is selected from the group consisting of a C 6 to C 17 alkyl group or a C 6 to C 17 alkenyl group;
wherein
said C 6 to C 17 alkyl group is substituted with one or more alkyl groups selected from the group consisting of methyl, ethyl, propyl, or cycloalkyl, including cyclopropyl and/or one or more halogens selected from the group consisting of F, Cl, Br and I; and further wherein said C 6 to C 17 alkyl group includes one or more substituents at or near the terminal position of the alkyl group; and
wherein
said C 6 to C 17 alkenyl group is optionally-substituted with an alkyl group selected from the group consisting of methyl, ethyl, propyl, a cycloalkyl group including, cyclopropyl and/or one or more halogens selected from the group consisting of F, Cl, Br and I; and further wherein the said C 6 to C 17 alkenyl group contains one or more double bonds, including a terminal double bond;
B is selected from a purine or pyrimidine base; and
A is a counterion selected from the group consisting of H + , Li + , Na + , K + , NH 4 + , tetraalkyl ammonium and other tertiary amine salts including triethylamine.
2. The phosphate of claim 1 wherein R is selected from the group of compounds having the following structure:
wherein p is selected from 1 to 11 and q is selected from 6 to 17.
3. The phosphate of claim 1 wherein R is selected from the group of compounds having the following structure:
wherein p is selected from 1 to 11 and q is selected from 6 to 17.
4. The phosphate of claim 1 wherein R is selected from the group of compounds having the following structure:
wherein p is selected from 1 to 11 and q is selected from 6 to 17 and X is a halogen.
5. The phosphate of claim 4 wherein X is F.
6. The phosphate of claim 1 wherein R is selected from the group of compounds having the following structure:
wherein p is selected from 1 to 11 and q is selected from 6 to 17 and X is independently selected from a halogen.
7. The phosphate of claim 6 wherein X is F.
8. The phosphate of claim 1 wherein R is selected from the group of compounds having the following structures:
9. The nucleoside phosphate of claim 1 wherein R is selected to prevent or decrease metabolic degradation of the phosphonate.
10. The nucleoside phosphate of claim 1 wherein said phosphate is selected from an antiviral or an antineoplastic agent.
11. The nucleoside phosphate of claim 10 , wherein said antiviral agent is a derivative of a compound selected from the group consisting of acyclovir, ganciclovir, AZT, ddI, ddA, d4T, ddC, 3TC, FTC, 2′-C-methyl adenosine, 2′-C-methyl guanosine, 7-deaza-2′-methyl adenosine, 2′-C-methyl cytosine, DAPD, L-FMAU, entecavir, telbivudine and various β-L-2′-deoxycytidine, β-L-2′-deoxyadenine and β-L-2′-deoxythymidine.
12. The nucleoside phosphate of claim 10 wherein said antineoplastic agent is selected from the group consisting of 2′-deoxy-2′,2′-difluorocytidine (gemcitibine), (E)-2′-deoxy-2′-fluoromethylene-cytidine (FMdC), or 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinosyl)cytosine (4′-thio-FAC), Ara-C, Ara-G, 5-fluorouridine, 5-fluoro-deoxyuridine, (R)-deoxycoformycin, and fludarabine.
13. A pharmaceutical composition comprising a nucleoside phosphate according to claim 1 and a pharmaceutically acceptable carrier.