2'-Fluoronucleoside phosphonates as antiviral agents

• US 20070225249A1
• Filed: 03/22/2007
• Published: 09/27/2007
• Est. Priority Date: 03/23/2006
• Status: Active Grant

• Current Assignee: Cocrystal Pharma, Inc.
• Original Assignee: Cocrystal Pharma, Inc.
• Inventors: Shi, Junxing
• Granted Patent: US 8,895,531 B2
• Time in Patent Office: Days
• US Class Current: 514/49
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C07F 9/65586 at least one of the hetero rings does not contain nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

The present invention includes compounds and compositions of ^R-2′-fluoronucleoside phosphonates, as well as methods to treat HIV, HBV, HCV or abnormal cellular proliferation comprising administering said compounds or compositions.

Claims

1. A compound having the formula (I) or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:

a) X is O, S, SO₂, or CH₂;

b) Z is O, S, or NH;

c) n is 1 or 2;

d) R¹ is H or CH₃;

e) R² and R³ are independently a hydrogen, halogen (F, Cl, Br, I), OH, OR′

, SH, SR′

, N₃, NH₂, NHR′

, CN, OCOR′

, OCOOR′

, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆ such as CF₃ and CH₂CH₂F, lower alkenyl of C₂-C₆ such as CH═

CH₂, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆ such as CH═

CHCl, CH═

CHBr and CH═

CHI, lower alkynyl of C₂-C₆ such as C≡

CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆ such as CH₂OH and CH₂CH₂OH, lower alkyl acid of C₂-C₆ such as CH₂COOH and CH₂CH₂COOH, lower alkyl acid ester of C₂-C₆ such as CH₂COOR′ and

CH₂CH₂COOR′

;

f) R⁴ and R⁵ are independently a hydrogen, phosphate, diphosphate, or a group that is preferentially removed in a hepatocyte to yield the corresponding OH group. The term “

preferentially removed in a hepatocyte”

as used herein means at least part of the group is removed in a hepatocyte at a rate higher than the rate of removal of the same group in a non-hepatocytic cell (e.g., fibroblast or lymphocyte). It is therefore contemplated that the removable group includes all pharmaceutically acceptable groups that can be removed by a reductase, esterase, cytochrome P450 or any other specific liver enzyme. Alternative contemplated groups may also include groups that are not necessarily preferentially removed in a hepatocyte, but effect at least some accumulation and/or specific delivery to a hepatocyte (e.g., esters with selected amino acids, including valine, leucine, isoleucine, or polyarginine or polyaspartate);

g) Base is a heterocycle containing at least one nitrogen,

6. The compound of claim 1 comprising a 2′

-fluoronucleoside phosphonate of the formula;

or its pharmaceutically acceptable salt or prodrug thereof.

7. The compound of claim 1 comprising a 2′

-fluoronucleoside phosphonate of the formula;

its pharmaceutically acceptable salt or prodrug thereof.

14. A pharmaceutical composition comprising the compound of claim 1, 2, 3 or 4 and a pharmaceutically acceptable carrier, diluent, vehicle or excipient.

15. The pharmaceutical composition of claim 14 further comprising a compound selected from the group consisting of cytokines, protease inhibitors, antiviral agents, proteases, caspase inhibitors, antibodies and protease inhibitors.

16. A method of preventing or treating abnormal cellular proliferation, a viral infection, an autoimmune disorder, or a symptom thereof in a subject in need thereof comprising administering to the subject an effective amount the composition of claim 14.

2. A compound having the formula (II) or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:

a) X is O, S, SO₂, or CH₂;

b) Z is O, S, or NH;

c) R¹ is H or CH₃;

d) R² and R³ are independently a hydrogen, halogen (F, Cl, Br, I), OH, OR′

, SH, SR′

, N₃, NH₂, NHR′

, CN, OCOR′

, OCOOR′

, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆ such as CF₃ and CH₂CH₂F, lower alkenyl of C₂-C₆ such as CH═

CH₂, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆ such as CH═

CHCl, CH═

CHBr and CH═

CHI, lower alkynyl of C₂-C₆ such as C≡

CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆ such as CH₂OH and CH₂CH₂OH, lower alkyl acid of C₂-C₆ such as CH₂COOH and CH₂CH₂COOH, lower alkyl acid ester of C₂-C₆ such as CH₂COOR′ and

CH₂CH₂COOR′

;

e) R⁴ and R⁵ are independently a hydrogen, phosphate, diphosphate, or a group that is preferentially removed in a hepatocyte to yield the corresponding OH group;

f) Base is a heterocycle containing at least one nitrogen.

5. The compound of claim 2 comprising a 2′

-fluoronucleoside phosphonate of the formula;

its pharmaceutically acceptable salt or prodrug thereof.

3. A compound having the formula (III) or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:

a) X is O, S, SO₂, or CH₂;

b) n is 1 or 2;

c) R⁴ and R⁵ are independently hydrogen, phosphate, diphosphate, or a group that is preferentially removed in a hepatocyte to yield the corresponding OH group.

d) Base is a heterocycle containing at least one nitrogen.

9. The compound of claim 3 comprising a 2′

-fluoronucleoside phosphonate of the formula;

its pharmaceutically acceptable salt or prodrug thereof.

10. The compound of claim 3 comprising a 2′

-fluoronucleoside phosphonate of the formula;

its pharmaceutically acceptable salt or prodrug thereof.

12. The compound of claim 3 comprising a 2′

-fluoronucleoside phosphonate of the formula;

its pharmaceutically acceptable salt or prodrug thereof.

13. The compound of claim 3 comprising a 2′

-fluoronucleoside phosphonate of the formula;

its pharmaceutically acceptable salt or prodrug thereof.

4. A compound having the formula (IV) or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:

a) X is O, S, SO₂, or CH₂;

b) Z is O, S, or NH;

c) R⁴ and R⁵ are independently a hydrogen, phosphate, diphosphate, or a group that is preferentially removed in a hepatocyte to yield the corresponding OH group.

8. The compound of claim 4 comprising a 2′

-fluoronucleoside phosphonate of the formula;

its pharmaceutically acceptable salt or prodrug thereof.

11. The compound of claim 4 comprising a 2′

-fluoronucleoside phosphonate of the formula;

its pharmaceutically acceptable salt or prodrug thereof.