Pyrido(3,2-d)pyridmidines useful for treating viral infections

• US 8,637,531 B2
• Filed: 12/24/2007
• Issued: 01/28/2014
• Est. Priority Date: 12/26/2006
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Bondy, Steven S., Watkins, William J., Chong, Lee S., Herdewijn, Piet Andre Maurits Maria, De Jonghe, Steven Cesar Alfons
• Primary Examiner(s): Leeser, Erich A
• Application Number:
  US12/519,500
• Publication Number:
  US 20100048559A1
• Time in Patent Office: 2,227 Days
• Field of Search: 514/264.1, 544/264.11
• US Class Current: 514/264.1
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

This invention provides pyrido(3,2-d)pyrimidine derivatives represented by the structural formula (I), wherein: R₁ is amino, R₄ is hydrogen, and R₂ and R₃ together provide a specific substitution pattern, pharmaceutical acceptable addition salts, stereochemical isomeric forms, N-oxides, solvates and pro-drugs thereof, are useful in the treatment of hepatitis C.

Claims

1. A pyrido(3,2-d)pyrimidine derivative represented by the structural formula:

2. A pyrido(3,2-d)pyrimidine derivative according to claim 1, wherein R₃ is a mono-substituted phenyl group, wherein the substituent of said phenyl group is located in para position with respect to the pyrido(3,2-d)pyrimidinyl core.

3. A pyrido(3,2-d)pyrimidine derivative according to claim 1, wherein R₃ is a di-substituted phenyl group, wherein one substituent of said phenyl group is located in para position with respect to the pyrido(3,2-d)pyrimidinyl core.

4. A pyrido(3,2-d)pyrimidine derivative according to claim 1, wherein R₃ is a tri-substituted phenyl group.

5. A pyrido(3,2-d)pyrimidine derivative according to claim 1, wherein R₃ is a tri-substituted phenyl group wherein at least two substituents are identical.

6. A pyrido(3,2-d)pyrimidine derivative according to claim 1, wherein R₃ is a mono-substituted phenyl group and wherein the substituent of said phenyl group is located in meta position with respect to the pyrido(3,2-d)pyrimidinyl core.

7. A pyrido(3,2-d)pyrimidine derivative according to claim 1, wherein R₃ is a mono-substituted phenyl group and wherein the substituent of said phenyl group is located in ortho position with respect to the pyrido(3,2-d)pyrimidinyl core.

8. A pyrido(3,2-d)pyrimidine derivative according to claim 1, wherein R₃ is a di-substituted phenyl group, wherein one substituent of said phenyl group is located in ortho position with respect to the pyrido(3,2-d)pyrimidinyl core.

9. A pyrido(3,2-d)pyrimidine derivative according to claim 1, being selected from the group consisting of:

2-amino-4-(4-pentyn-1-oxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(3-pentyn-1-oxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(2-pentyn-1-oxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(4-pentyn-2-oxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(1-pentyn-3-oxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-[2-(methylsulfonyl)ethoxy]-6-(4-fluorophenyl)-pyrido(3,2-d) pyrimidine,

2-amino-4-[2-(phenylsulfonyl)ethoxy]-6-(4-fluorophenyl)-pyrido(3,2-d) pyrimidine,

2-amino-4-(3-butyn-1-oxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(2-butyn-1-oxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(2-propyn-1-oxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(3-buten-1-oxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(2-buten-1-oxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(1-octen-3-oxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(2-cyclohexen-1-oxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(3-cyclohexen-1-methoxy)-6-(4-fluorophenyl)pyrido(3,2-d) pyrimidine, and

2-amino-4-(1,6-heptadien-4-oxy)-6-(4-fluorophenyl)pyrido(3,2-d) pyrimidine.

11. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a pyrido(3,2-d)pyrimidine derivative according to claim 1.

12. A pharmaceutical composition according to claim 11, further comprising one or more antiviral agents.

13. A method of treatment of a patient suffering from a viral infection, comprising administering to said patient an effective amount of a pyrido(3,2-d)pyrimidine derivative according to claim 1.

14. A method of treatment according to claim 13, further comprising administering, simultaneously or sequentially, one or more other antiviral agents.

15. A method of treatment according to claim 13, wherein said viral infection is a HCV infection.

16. A method of treatment according to claim 14, wherein said viral infection is a HCV infection.

17. A pharmaceutical composition according to claim 12, further comprising one or more antiviral agents selected from the group consisting of interferons, ribavirin analogs, NS5b polymerase inhibitors, HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV and mixtures thereof.

18. A method according to claim 16, further comprising administering, simultaneously or sequentially, one or more other antiviral agents selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta, infergen+actimmune, IFN-omega with DUROS, albuferon, locteron, Albuferon, Rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated IFN-beta, rebetol, copegus, viramidine (taribavirin), NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554, GSK625433, SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, ITMN-191, MX-3253 (celgosivir), UT-231B, IDN-6556, ME 3738, LB-84451, MitoQ, benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, phenylalanine derivatives, GS-9190, A-831, A-689, zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497 (merimepodib).

19. A pharmaceutical composition according to claim 12 further comprising one or more antiviral agents selected from the group consisting of ribavirin, (pegylated)interferon, HIV-1 IN inhibitors, zidovudine, lamivudine, didanosine, stavudine, nevirapine, delavirdine, foscamet sodium, saquinavir, ritonavir, indinavir, nelfinavir, acemannan, acyclovir, adefovir, alovudine, alvircept, amantadine, aranotin, arildone, atevirdine, pyridine, cidofovir, cipamfylline, cytarabine, desciclovir, disoxaril, edoxudine, enviradene, enviroxime, famciclovir, famotine, fiacitabine, fialuridine, floxuridine, fosarilate, fosfonet, ganciclovir, idoxuridine, kethoxal, lobucavir, memotine, methisazone, penciclovir, pirodavir, somantadine, sorivudine, tilorone, trifluridine, valaciclovir, vidarabine, viroxime, zinviroxime, moroxydine, podophyllotoxin, ribavirine, rimantadine, stallimycine, statolon, tromantadine and xenazoic acid;

and their pharmaceutically acceptable salts.

10. A pyrido(3,2-d)pyrimidine derivative selected from the group consisting of:

2-amino-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidin-4(3H)thione,

2-amino-4-methylthio-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-(2-propoxyethoxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(2-butoxyethoxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(1-ethoxy-2-propoxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(2-isopropoxyethoxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(2,2-difluoroethoxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-[2-(methylthio)ethoxy]-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(cyclobutoxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(cyclopentylmethoxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(cyclopentoxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(3-methyl-3-methoxybutoxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimi-dine,

2-amino-4-(2-methyl-3-buten-2-oxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(3-pentyn-1-oxy)-6-(4-fluorophenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(1,2,4-triazolyl)-6-(4-fluorophenyl)-pyrido (3,2-d)pyrimidine,

2-amino-4-[3(S)-tetrahydrofuranyloxy]-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-[3(R)-tetrahydrofuranyloxy]-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-[2-(methylsulfonyl)ethoxy]-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-[hexahydro-furo(2,3-b)furan-3-oxy]-6-(4-fluorophenyl)-pyrido(3,2-d) pyrimidine,

2-acetamido-4-cyclohexyloxy-6-chloro-pyrido(3,2-d)pyrimidine,

2-acetamido-4-(tetrahydro-2H-pyran-4-oxy)-6-chloro-pyrido(3,2-d)pyrimidine,

2-acetamido-4-(tetrahydropyran-2-methoxy)-6-chloro-pyrido(3,2-d)pyrimidine,

2-acetamido-4-(tetrahydro-2-furanylmethoxy)-6-chloro-pyrido(3,2-d)pyrimidine,

2-acetamido-4-(tetrahydro-2-furanylmethoxy)-6-chloro-pyrido(3,2-d)pyrimidine,

2-acetamido-4-(tetrahydro-3-furanylmethoxy)-6-chloro-pyrido-(3,2-d) pyrimidine,

2-acetamido-4-[(S)-1-methoxy-2-propoxy]-6-chloro-pyrido(3,2-d)pyrimidine,

2-acetamido-4-[(R)-1-methoxy-2-propoxy]-6-chloro-pyrido(3,2-d)pyrimidine,

2-amino-4-cyclohexyloxy-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-(tetrahydro-2H-pyran-4-oxy)-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-(tetrahydropyran-2-methoxy)-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-(tetrahydro-2-furanylmethoxy)-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-(tetrahydro-3-furanylmethoxy)-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-(tetrahydro-3-tetrahydrofuranylmethoxy)-6-(4-fluorophenyl)-pyrido-(3,2-d) pyrimidine,

2-amino-4-[(S)-1-methoxy-2-propoxy]-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-[(R)-1-methoxy-2-propoxy]-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine,

2-amino-6-(3,4-dimethoxyphenyl)-pyrido(3,2-d)pyrimidin-4(3H)-thione,

2-amino-4-methylthio-6-(3,4-dimethoxyphenyl)-pyrido(3,2-d) pyrimidine,

2-amino-4-(1-ethoxy-2-propoxy)-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(2-isopropoxyethoxy)-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(2,2-difluoroethoxy)-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-[2-(methylthio)ethoxy]-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(cyclobutoxy)-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(cyclopentylmethoxy)-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(cyclopentoxy)-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(3-methyl-3-methoxybutoxy)-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(2-methyl-3-buten-2-oxy)-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-(3-pentyn-1-oxy)-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)pyrimidine,

2-amino-4-[3(S)-tetrahydrofuranyloxy]-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-[3(R)-tetrahydrofuranyloxy]-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-[2-(methylsulfonyl)ethoxy]-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-[hexahydrofuro(2,3-b)furan-3-oxy]-6-(4-fluorophenyl)-pyrido(3,2-d) pyrimidine,

2-amino-4-cyclohexyloxy-6-(2-formylphenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-(tetrahydro-2H-pyran-4-oxy)-6-(2-formylphenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-(tetrahydropyran-2-methoxy)-6-(2-formylphenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-(tetrahydro-2-furanylmethoxy)-6-(2-formylphenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-(tetrahydro-3-furanylmethoxy)-6-(2-formylphenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-[(S)-1-methoxy-2-propoxy]-6-(2-formylphenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-[(R)-1-methoxy-2-propoxy]-6-(2-formylphenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-cyclohexyloxy-6-(4-carboxyphenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-(tetrahydro-2H-pyran-4-oxy)-6-(4-carboxyphenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-(tetrahydropyran-2-methoxy)-6-(4-carboxyphenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-(tetrahydro-2-furanylmethoxy)-6-(4-carboxyphenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-(tetrahydro-3-furanylmethoxy)-6-(4-carboxyphenyl)-pyrido(3,2-d)pyrimidine,

2-amino-4-[(S)-1-methoxy-2-propoxy]-6-(4-carboxyphenyl)-pyrido(3,2-d)pyrimidine, and

2-amino-4-[(R)-1-methoxy-2-propoxy]-6-(4-carboxyphenyl)-pyrido(3,2-d)pyrimidine.