ANTIVIRAL PHOSPHONATE ANALOGS

• US 20090275535A1
• Filed: 07/01/2008
• Published: 11/05/2009
• Est. Priority Date: 04/25/2003
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Watkins, William J., Cho, Aesop, Fardis, Maria, Markevitch, David Y., Chong, Lee S., Kim, Choung U., Boojamra, Constantine G., Ray, Adrian S., Prasad, Vidya K., Lee, Christopher P., Chen, Xiaowu, Swaminathan, Sundaramoorthi, Kirschberg, Thorsten, Chen, James M., Huang, Alan X., Oare, David A., Hirschmann, Ralph F., Jin, Haolun, Sherlock, Rosemarie, Zhang, Jennifer R., Lee, William A., Cannizzaro, Carina, Pyun, Hyung-Jung, Mackman, Richard L.
• Granted Patent: US 8,022,083 B2
• Time in Patent Office: Days
• US Class Current: 514/81
• CPC Class Codes: A61K 31/662 Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 475/00 Heterocyclic compounds containing pteridine ring systems
• CPC Class Codes: C07F 9/4075 Esters with hydroxyalkyl compounds
• CPC Class Codes: C07F 9/5728 condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/58 Pyridine rings
• CPC Class Codes: C07F 9/60 Quinoline or hydrogenated quinoline ring systems
• CPC Class Codes: C07F 9/65031 having the nitrogen atoms in the positions 1 and 2
• CPC Class Codes: C07F 9/650905 having the nitrogen atoms in the positions 1 and 2
• CPC Class Codes: C07F 9/653 : Five-membered rings
• CPC Class Codes: C07F 9/6539 : Five-membered rings
• CPC Class Codes: C07F 9/65515 : the oxygen atom being part of a five-membered ring
• CPC Class Codes: C07F 9/655354 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/6561 : containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
• 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 15/00 : Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
• CPC Class Codes: C07H 17/00 : Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
• CPC Class Codes: C07H 19/056 : Triazole or tetrazole radicals
• CPC Class Codes: C07H 19/10 : with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/20 : with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 21/00 : Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention is related to phosphorus substituted compounds with antiviral activity, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

Claims

1. A conjugate of the following formula:

or a pharmaceutically acceptable salt or solvate thereof;

wherein;

B is selected from adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O⁶-methylguanine, N⁶-methyladenine, O⁴-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, substituted triazole, and pyrazolo[3,4-d]pyrimidine;

X is selected from O, C(R₁)₂, OC(R^y)₂, NR and S;

Z is independently selected from H, OH, OR, NR₂, CN, NO₂, SH, SR, F, Cl, Br, and I;

Y¹ is independently O, S, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR), or N—

NR₂;

Y² is independently O, CR₂, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR), N—

NR₂, S, S—

S, S(O), or S(O)₂;

M2 is 0, 1 or 2;

R^y is independently H, F, Cl, Br, I, OH, —

C(═

Y¹)R, —

C(═

Y¹)OR, —

C(═

Y¹)N(R)₂, —

N(R)₂, —

⁺N(R)₃, —

SR, —

S(O)R, —

S(O)₂R, —

S(O)(OR), —

S(O)₂(OR), —

OC(═

Y¹)R, —

OC(═

Y¹)OR, —

OC(═

Y¹)(N(R)₂), —

SC(═

Y¹)R, —

SC(═

Y¹)OR, —

SC(═

Y¹)(N(R)₂), —

N(R)C(═

Y¹)R, —

N(R)C(═

Y¹)OR, or —

N(R)C(═

Y¹)N(R)₂, amino (—

NH₂), ammonium (—

NH₃⁺), alkylamino, dialkylamino, trialkylammonium, C₁-C₈ alkyl, C₁-C₈ alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈ alkylthiol, alkylsulfone (—

SO₂R), arylsulfone (—

SO₂Ar), arylsulfoxide (—

SOAr), arylthio (—

SAr), sulfonamide (—

SO₂NR₂), alkylsulfoxide (—

SOR), ester (—

C(═

O)OR), amido (—

C(═

O)NR₂), 5-7 membered ring lactam, 5-7 membered ring lactone, nitrile (—

CN), azido (—

N₃), nitro (—

NO₂), C₁-C₈ alkoxy (—

OR), C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₁-C₈ alkenyl, C₁-C₈ substituted alkenyl, C₁-C₈ alkynyl, C₁-C₈ substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heterocycle, C₂-C₂₀ substituted heterocycle, polyethyleneoxy, or W³;

or when taken together, R^y forms a carbocyclic ring of 3 to 7 carbon atoms;

R^x is independently R^y, a protecting group, or the formula;

wherein;

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and

R is C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₁-C₈ alkenyl, C₁-C₈ substituted alkenyl, C₁-C₈ alkynyl, C₁-C₈ substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heterocycle, C₂-C₂₀ substituted heterocycle, or a protecting group; and

W³ is W⁴ or W⁵, where W⁴ is R, —

C(Y¹)R^y, —

C(Y¹)W⁵, —

SO₂R^y, or —

SO₂W⁵; and

W⁵ is a carbocycle or a heterocycle wherein W⁵ is independently substituted with 0 to 3 R^y groups.

2. The conjugate of claim 1 wherein C₁-C₈ substituted alkyl, C₁-C₈ substituted alkenyl, C₁-C₈ substituted alkynyl, C₆-C₂₀ substituted aryl, and C₂-C₂₀ substituted heterocycle are independently substituted with one or more substituents selected from F, Cl, Br, I, OH, —

NH₂, —

NH₃⁺, —

NHR, —

NR₂, —

NR₃⁺, C₁-C₈ alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈ alkylthiol, —

SO₂R, —

SO₂Ar, —

SOAr, —

SAr, —

SO₂NR₂, —

SOR, —

CO₂R, —

C(═

O)NR₂, 5-7 membered ring lactam, 5-7 membered ring lactone, —

CN, —

N₃, —

NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈ alkyl, C₃-C₁₂ carbocycle, C₆-C₂₀ aryl, C₂-C₂₀ heterocycle, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety.

3. The conjugate of claim 1 wherein protecting group is selected from a carboxyl ester, a carboxamide, an aryl ether, an alkyl ether, a trialkylsilyl ether, a sulfonic acid ester, a carbonate, and a carbamate.

4. The conjugate of claim 1 wherein W⁵ is selected from the structures:

5. The conjugate of claim 1 wherein X is O and each R^y is H.

6. The conjugate of claim 1 wherein the conjugate is a resolved enantiomer having the structure:

7. The conjugate of claim 1 wherein the conjugate is a resolved enantiomer having the structure:

8. The conjugate of claim 1 having the structure:

9. The conjugate of claim 1 having the structure:

10. The conjugate of claim 1 having the structure:

11. The conjugate of claim 1 having the structure:

12. The conjugate of claim 1 having the structure:

13. The conjugate of claim 1 having the structure:

wherein R² is H or C₁-C₈ alkyl.

14. The conjugate of claim 1 having the structure:

15. The conjugate of claim 1 having the structure:

16. The conjugate of claim 14 wherein Z is H.

17. The conjugate of claim 14 wherein B is adenine.

18. The conjugate of claim 14 having the structure:

wherein Y^2c is O, N(R^y) or S.

19. The conjugate of claim 18 having the structure:

20. The conjugate of claim 19 wherein Y^2c is O.

21. The conjugate of claim 19 wherein Y^2c is N(CH₃).

22. The conjugate of claim 1 wherein substituted triazole has the structure:

23. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a conjugate as described in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

24. A method for promoting an anti-viral effect in vitro or in vivo comprising contacting a sample in need of such treatment with a conjugate as described in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

25. A method of inhibiting a viral infection in an animal, comprising administering an effective amount of a conjugate as described in claim 1, or a pharmaceutically acceptable salt or solvate thereof, to the animal.

26. A compound of formula:

or a pharmaceutically acceptable salt or solvate thereof.

27. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula:

or a pharmaceutically acceptable salt or solvate thereof.

28. A method for promoting an anti-viral effect in vitro or in vivo comprising contacting a sample in need of such treatment with a compound of formula:

or a pharmaceutically acceptable salt or solvate thereof.

29. A method of inhibiting a viral infection in an animal, comprising administering an effective amount of compound of formula:

or a pharmaceutically acceptable salt or solvate thereof, to the animal.