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Last Updated: March 28, 2024

Claims for Patent: 8,637,531


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Summary for Patent: 8,637,531
Title:Pyrido(3,2-d)pyridmidines useful for treating viral infections
Abstract: This invention provides pyrido(3,2-d)pyrimidine derivatives represented by the structural formula (I), wherein: R.sub.1 is amino, R.sub.4 is hydrogen, and R.sub.2 and R.sub.3 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.
Inventor(s): Bondy; Steven S. (Danville, CA), Watkins; William J. (Saratoga, CA), Chong; Lee S. (Newark, CA), Herdewijn; Piet Andre Maurits Maria (Rotselaar/Wexemaal, BE), De Jonghe; Steven Cesar Alfons (Brugge, BE)
Assignee: Gilead Sciences, Inc. (Foster City, CA)
Application Number:12/519,500
Patent Claims:1. A pyrido(3,2-d)pyrimidine derivative represented by the structural formula: ##STR00037## wherein: R.sub.1 is amino, R.sub.2 is selected from the group consisting of C.sub.1-6 alkyl thio-C.sub.1-6 alkoxy, C.sub.2-6 alkenyloxy, C.sub.2-6 alkynyloxy, C.sub.3-10 cycloalkenyloxy, C.sub.3-10 cycloalkenyl-C.sub.1-6 alkoxy, C.sub.1-6 alkylsulfonyl C.sub.1-6 alkoxy, arylsulfonyl C.sub.1-6 alkoxy, 2-propoxyethoxy, 2-ethoxy-1-propoxy, 2-isopropoxyethoxy, 2,2-difluoroethoxy, cyclobutoxy, cyclopentylmethoxy, 1-cyclopropylethoxy, 2-cyclopropylethoxy, cyclopentoxy, 3-methyl-3-methoxybutoxy, tetrahydrofuranyl-oxy, 1-ethylpropoxy, morpholinyl-propoxy, morpholinylbutoxy, cyclohexyloxy, tetrahydro-pyranoxy, tetrahydropyranmethoxy, tetrahydrofuranmethoxy, 1-methoxy-2-propoxy and oxetan-3-yloxy; R.sub.3 is selected from the group consisting of halogen, heterocyclic and aryl groups, wherein said heterocyclic or aryl groups are optionally substituted with one or more substituents selected from the group consisting of amino, amino-C.sub.4-4 alkyl, acyl, di-C.sub.1-4 alkylaminocarbonyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.1-4 alkyl, carboxylic acid, hydroxy, halogen, halo-C.sub.1-4 alkyl, hydroxy-C.sub.1-4 alkyl, halo-C.sub.1-4 alkoxy, C.sub.2-8 alkenyl, C.sub.1-2 alkylenedioxy, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkylcarbonyl-amino di-C.sub.1-4 alkylamino, di-C.sub.1-4 alkylamino-C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkoxy, aryloxy, formyl, heterocyclic, heterocyclic-oxy, tri-C.sub.1-4 alkylammonium-C.sub.1-4alkyl, C.sub.1-4 alkylcarbonyl, C.sub.1-4 alkylcarbonylamino, arylsulfonyl and heterocyclic-substituted C.sub.1-4 alkyl, and R.sub.4 is hydrogen, or a pharmaceutical acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof.

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

5. A pyrido(3,2-d)pyrimidine derivative according to claim 1, wherein R.sub.3 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 R.sub.3 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 R.sub.3 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 R.sub.3 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.

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)pyrimidin- e, 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)pyrim- i-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)pyr- imidine, 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)pyri- midine, 2-amino-4-[hexahydro-furo(2,3-b)furan-3-oxy]-6-(4-fluorophenyl)-py- rido(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)pyrimidin- e, 2-acetamido-4-(tetrahydropyran-2-methoxy)-6-chloro-pyrido(3,2-d)pyrimid- ine, 2-acetamido-4-(tetrahydro-2-furanylmethoxy)-6-chloro-pyrido(3,2-d)pyr- imidine, 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)pyr- imidine, 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)p- yrimidine, 2-amino-4-(tetrahydro-3-furanylmethoxy)-6-(4-fluorophenyl)-pyri- do(3,2-d)pyrimidine, 2-amino-4-(tetrahydro-3-tetrahydrofuranylmethoxy)-6-(4-fluorophenyl)-pyri- do-(3,2-d) pyrimidine, 2-amino-4-[(S)-1-methoxy-2-propoxy]-6-(4-fluorophenyl)-pyrido(3,2-d)pyrim- idine, 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)pyrimi- dine, 2-amino-4-(2-isopropoxyethoxy)-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)p- yrimidine, 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)pyri- midine, 2-amino-4-(cyclobutoxy)-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)pyrimi- dine, 2-amino-4-(cyclopentylmethoxy)-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)p- yrimidine, 2-amino-4-(cyclopentoxy)-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)py- rimidine, 2-amino-4-(3-methyl-3-methoxybutoxy)-6-(3,4-dimethoxyphenyl)pyri- do(3,2-d)pyrimidine, 2-amino-4-(2-methyl-3-buten-2-oxy)-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)py- rimidine, 2-amino-4-(3-pentyn-1-oxy)-6-(3,4-dimethoxyphenyl)pyrido(3,2-d)p- yrimidine, 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)pyr- imidine, 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)pyr- imidine, 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)p- yrimidine, 2-amino-4-(tetrahydro-3-furanylmethoxy)-6-(2-formylphenyl)-pyri- do(3,2-d)pyrimidine, 2-amino-4-[(S)-1-methoxy-2-propoxy]-6-(2-formylphenyl)-pyrido(3,2-d)pyrim- idine, 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)py- rimidine, 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)pyri- midine, and 2-amino-4-[(R)-1-methoxy-2-propoxy]-6-(4-carboxyphenyl)-pyrido(3,2-d)pyri- midine.

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.

Details for Patent 8,637,531

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Kadmon Pharmaceuticals Llc INFERGEN interferon alfacon-1 Injection 103663 10/06/1997 ⤷  Try a Trial 2026-12-26
Emd Serono, Inc. REBIF interferon beta-1a Injection 103780 03/07/2002 ⤷  Try a Trial 2026-12-26
Emd Serono, Inc. REBIF interferon beta-1a Injection 103780 12/17/2004 ⤷  Try a Trial 2026-12-26
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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