Claims
- 1. A poly-substituted pteridinedione (lumazine), or a mono- or polysubstituted 2-thiolumazine, 4-thiolumazine or 2,4-dithiolumazine being represented by the general formula (I),
- 2. A poly-substituted pteridinedione (lumazine), or a mono- or polysubstituted 2-thiolumazine, 4-thiolumazine or 2,4-dithiolumazine according to claim 1, wherein R1 and R2 are each methyl.
- 3. A poly-substituted pteridinedione (lumazine), or a mono- or polysubstituted 2-thiolumazine, 4-thiolumazine or 2,4-dithiolumazine according to claim 1, wherein R4 is chloro.
- 4. A poly-substituted pteridinedione (lumazine), or a mono- or polysubstituted 2-thiolumazine, 4-thiolumazine or 2,4-dithiolumazine according to claim 1, wherein R4 is hydrogen.
- 5. A poly-substituted pteridinedione (lumazine), or a mono- or polysubstituted 2-thiolumazine, 4-thiolumazine or 2,4-dithiolumazine according to claim 1, wherein R3 is cyano.
- 6. A poly-substituted pteridinedione (lumazine), or a mono- or polysubstituted 2-thiolumazine, 4-thiolumazine or 2,4-dithiolumazine according to claim 1, being selected from the group consisting of:
1,3-dimethyl-6-[(E)-2-(pyrid-3-yl)vinyl]lumazine, 1,3-dimethyl-6-[(E)-2-(pyrid-4-yl)vinyl]lumazine, 6-(1,2-dibromo-2-phenylethyl)-1,3-dimethyllumazine, 1,3-dimethyl-6-[(E)-4-(phenyl)butadienyl]lumazine, 6-(1,2-dibromo-2-(methoxycarbonyl)ethyl)-1,3-dimethyllumazine, 6-(2-bromo-2-methoxycarbonyl-ethenyl)-1,3-dimethyllumazine, 6-[(2-acetyl-2-ethoxycarbonyl)acetyl]-1,3-dimethyllumazine, 6-[2,2-(diethoxycarbonyl)acetyl]-1,3-dimethyllumazine, 6-(1-methoxy-2-methoxycarbonyl)ethenyl)-1,3-dimethyllumazine, 1,3-dimethyl-6-[(2-nitro)ethenyl]lumazine, 6-[(1-hydroxy-2-nitro)ethyl]-1,3-dimethyllumazine, 6-[(1-ethylthio-2-nitro)ethyl]-1,3-dimethyllumazine, 1,3-dimethyl-7-[(E)-2-(pyrid-2-yl)vinyl]lumazine, 1,3-dimethyl-7-[(E)-2-(pyrid-3-yl)vinyl]lumazine, 1,3-dimethyl-7-[(E)-2-(pyrid-4-yl)vinyl]lumazine, 1,3-dimethyl-7-[(E)-4-(phenyl)butadienyl]lumazine, 7-[1,2-dibromo-2-(methoxycarbonyl)ethyl)-1,3-dimethyllumazine, 7-[(E)-2-methoxycarbonylethenyl]lumazine, 7-(1,2-dibromo-2-phenylethyl)-1,3-dimethyllumazine, 7-(1-bromo-2-phenyl)ethenyl-1,3-dimethyllumazine, 1,3-dimethyl-7-(E)-styryllumazine, 1,3-dimethyl-6-phenyl-7-mercaptolumazine, 7-methoxy-1,3-dimethyl-6-phenyllumazine, 7-chloro-1,3-dimethyl-6-phenyllumazine, 6-benzoyl-7,8-dihydro-1,3-dimethyl-7-(4-methoxyphenyl)lumazine, 6-benzoyl-1,3-dimethyl-7-(4-methoxyphenyl)lumazine, 6-benzoyl-7,8-dihydro-1,3-dimethyl-7-phenyllumazine, 6-benzoyl-1,3-dimethyl-7-phenyllumazine, 7-methoxy-1,3-dimethyl-6-styryllumazine, 7-hydroxy-1,6-diphenyllumazine, 7-hydroxy-6-phenyl-1,3-di-n-propyllumazine, 6-formyl-7-hydroxy-1,3-dimethyl-lumazine, 6-hydroxy-7-formyl-1,3-dimethyl-lumazine, 6-cyano-7-chloro-1,3-dimethyl-lumazine, 6-ethylcarboxylate-7-chloro-1,3-dimethyl-lumazine, 6-(1,3-dioxolanyl)-7-chloro-1,3-dimethyl-lumazine, 6-dichloromethyl-7-chloro-1,3-dimethyl-lumazine, 6-chloro-7-cyano-1,3-dimethyl-lumazine, 6-cyano-7-isobutylamino-1,3-dimethyl-lumazine, 6-cyano-7-benzylamino-1,3-dimethyl-lumazine, 6-cyano-7-acetenylamino-1,3-dimethyl-lumazine, 6-cyano-7-cyclohexylamino-1,3-dimethyl-lumazine, 6-cyano-7-dibutylamino-1,3-dimethyl-lumazine, 6-cyano-7-imidazolyl-1,3-dimethyl-lumazine, 6-cyano-7-mercaptoisopropyl-1,3-dimethyl-lumazine, 6-cyano-7-mercaptobenzyl-1,3-dimethyl-lumazine, 6-ethylcarboxylate-7-n-butylamino-1,3-dimethyl-lumazine, 6-ethylcarboxylate-7-neopentylamino-1,3-dimethyl-lumazine, 6-ethylcarboxylate-7-(2-propenylamino)-1,3-dimethyl-lumazine, 6-ethylcarboxylate-7-piperidinyl-1,3-dimethyl-lumazine, 6-ethylcarboxylate-7-phenylhydrazino-1,3-dimethyl-lumazine, 6-ethylcarboxylate-7-mercaptoethyl-1,3-dimethyl-lumazine, 6-formyl-7-isopropylamino-1,3-dimethyl-lumazine, 6-formyl-7-hydroxyethylamino-1,3-dimethyl-lumazine, 6-formyl-7-(1-azacycloheptyl)-1,3-dimethyl-lumazine, 6-formyl-7-thiomorpholino-1,3-dimethyl-lumazine, 6-formyl-7-cyclopropylamino-1,3-dimethyl-lumazine, 6-dichloromethyl-7-mercaptobenzyl-1,3-dimethyl-lumazine, 6-dichloromethyl-7-ethylmercaptoacetate-1,3-dimethyl-lumazine, 6-benzylamino-1,3,7-trimethyl-lumazine, 6-pyrrolidinyl-1,3,7-trimethyl-lumazine, 6-chloro-7-piperidyl-1,3-diimethyl-lumazine, 7-(2-phenylethenyl)-1,3,6-trimethyl-lumazine, 6-[2-(p-trifluoromethylphenyl)ethenyl]-1,3-dimethyllumazine, 6-[2-(p-trifluoromethylphenyl)ethenyl]-1,3-dimethyllumazine, 6-[2-phenylethenyl]-1,3-dimethyllumazine, 6-[2-(p-trifluoromethoxyphenyl)ethenyl]-1,3-dimethyllumazine, 6-cyano-7-ethylmercaptoacetate-1,3-dimethyllumazine, 3-methyl-6-phenyl-7-chloro-lumazine, 1-methyl-6-phenyl-7-hydroxy-lumazine, 1-methyl-6-(4′-methoxyphenyl)-7-hydroxy-lumazine, 1-methyl-6-(4′-methylphenyl)-7-hydroxy-lumazine, 1,6-diphenyl-7-hydroxy-lumazine, 1-benzyl-6-phenyl-7-hydroxy-lumazine, 1-methyl-6-(3′,4′-dimethoxyphenyl)-7-hydroxy-lumazine, 1-methyl-6-(4′-chlorophenyl)-7-hydroxy-lumazine, 1-methyl-6-phenyl-7-chloro-lumazine, 1-methyl-6-(4′-methoxyphenyl)-7-chloro-lumazine, 1-methyl-6-(4′-methylphenyl)-7-chloro-lumazine, 1,6-diphenyl-7-chloro-lumazine, 1-benzyl-6-phenyl-7-chloro-lumazine, 1-methyl-6-(3′,4′-dimethoxyphenyl)-7-chloro-lumazine, 1-methyl-6-(4′-chlorophenyl)-7-chloro-lumazine, 1,3-dimethyl-6-phenyl-7-phenoxylumazine, 1,3-dimethyl-6-phenyl-7-piperidinolumazine, 1,3-dimethyl-6-phenyl-7-morpholinolumazine, 1,3-dimethyl-6-phenyl-7-(4′-N-acetyl)piperazinolumazine, 1,3-dimethyl-6-phenyl-7-isopropylaminolumazine
- 7. A pharmaceutically acceptable salt of a poly-substituted pteridinedione (lumazine), or a mono- or polysubstituted 2-thiolumazine, 4-thiolumazine or 2,4-dithiolumazine represented by the general formula (II)
- 8. A pharmaceutically acceptable salt according to claim 7, being obtained from a salt-forming acid or base selected from the group consisting of inorganic acids, organic monocarboxylic or dicarboxylic acids, inorganic bases and organic bases.
- 9. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and one or more poly-substituted pteridinedione (lumazine), or a mono- or polysubstituted 2-thiolumazine, 4-thiolumazine or 2,4-dithiolumazine represented by the general formula (II)
- 10. A pharmaceutical composition according to claim 9, wherein R1 and R2 are each methyl.
- 11. A pharmaceutical composition according to claim 9, wherein R4 is chloro.
- 12. A pharmaceutical composition according to claim 9, wherein R4 is hydrogen.
- 13. A pharmaceutical composition according to claim 9, wherein R3 is cyano.
- 14. A pharmaceutical composition according to claim 9, wherein the poly-substituted pteridinedione (lumazine), or mono- or polysubstituted 2-thiolumazine, 4-thiolumazine or 2,4-dithiolumazine is selected from the group consisting of:
1,3-dimethyl-6-[(E)-2-(pyrid-3-yl)vinyl]lumazine, 1,3-dimethyl-6-[(E)-2-(pyrid-4-yl)vinyl]lumazine, 6-(1,2-dibromo-2-phenylethyl)-1,3-dimethyllumazine, 1,3-dimethyl-6-[(E)-4-(phenyl)butadienyl]lumazine, 6-(1,2-dibromo-2-(methoxycarbonyl)ethyl)-1,3-dimethyllumazine, 6-(2-bromo-2-methoxycarbonyl-ethenyl)-1,3-dimethyllumazine, 6-[(2-acetyl-2-ethoxycarbonyl)acetyl]-1,3-dimethyllumazine, 6-[2,2-(diethoxycarbonyl)acetyl]-1,3-dimethyllumazine, 6-(1-methoxy-2-methoxycarbonyl)ethenyl)-1,3-dimethyllumazine, 1,3-dimethyl-6-[(2-nitro)ethenyl]lumazine, 6-[(1-hydroxy-2-nitro)ethyl]-1,3-dimethyllumazine, 6-[(1-ethylthio-2-nitro)ethyl]-1,3-dimethyllumazine, 1,3-dimethyl-7-[(E)-2-(pyrid-2-yl)vinyl]lumazine, 1,3-dimethyl-7-[(E)-2-(pyrid-3-yl)vinyl]lumazine, 1,3-dimethyl-7-[(E)-2-(pyrid-4-yl)vinyl]lumazine, 1,3-dimethyl-7-[(E)-4-(phenyl)butadienyl]lumazine, 7-[1,2-dibromo-2-(methoxycarbonyl)ethyl)-1,3-dimethyllumazine, 7-[(E)-2-methoxycarbonylethenyl]lumazine, 7-(1,2-dibromo-2-phenylethyl)-1,3-dimethyllumazine, 7-(1-bromo-2-phenyl)ethenyl-1,3-dimethyllumazine, 1,3-dimethyl-6-(E)-styryllumazine, 1,3-dimethyl-7-(E)-styryllumazine, 1,3-dimethyl-6-phenyl-7-mercaptolumazine, 7-methoxy-1,3-dimethyl-6-phenyllumazine, 7-chloro-1,3-dimethyl-6-phenyllumazine, 6-benzoyl-7,8-dihydro-1,3-dimethyl-7-(4-methoxyphenyl)lumazine, 6-benzoyl-1,3-dimethyl-7-(4-methoxyphenyl)lumazine, 6-benzoyl-7,8-dihydro-1,3-dimethyl-7-phenyllumazine, 6-benzoyl-1,3-dimethyl-7-phenyllumazine, 7-methoxy-1,3-dimethyl-6-styryllumazine, 7-hydroxy-1,6-diphenyllumazine, 7-hydroxy-6-phenyl-1,3-di-n-propyllumazine, 6-formyl-7-hydroxy-1,3-dimethyl-lumazine, 6-hydroxy-7-formyl-1,3-dimethyl-lumazine, 6-cyano-7-chloro-1,3-dimethyl-lumazine, 6-ethylcarboxylate-7-chloro-1,3-dimethyl-lumazine, 6-(1,3-dioxolanyl)-7-chloro-1,3-dimethyl-lumazine, 6-dichloromethyl-7-chloro-1,3-dimethyl-lumazine, 6-chloro-7-cyano-1,3-dimethyl-lumazine, 6-cyano-7-isobutylamino-1,3-dimethyl-lumazine, 6-cyano-7-benzylamino-1,3-dimethyl-lumazine, 6-cyano-7-acetenylamino-1,3-dimethyl-lumazine, 6-cyano-7-cyclohexylamino-1,3-dimethyl-lumazine, 6-cyano-7-dibutylamino-1,3-dimethyl-lumazine, 6-cyano-7-imidazolyl-1,3-dimethyl-lumazine, 6-cyano-7-mercaptoisopropyl-1,3-dimethyl-lumazine, 6-cyano-7-mercaptobenzyl-1,3-dimethyl-lumazine, 6-ethylcarboxylate-7-n-butylamino-1,3-dimethyl-lumazine, 6-ethylcarboxylate-7-neopentylamino-1,3-dimethyl-lumazine, 6-ethylcarboxylate-7-(2-propenylamino)-1,3-dimethyl-lumazine, 6-ethylcarboxylate-7-piperidinyl-1,3-dimethyl-lumazine, 6-ethylcarboxylate-7-phenylhydrazino-1,3-dimethyl-lumazine, 6-ethylcarboxylate-7-mercaptoethyl-1,3-dimethyl-lumazine, 6-formyl-7-isopropylamino-1,3-dimethyl-lumazine, 6-formyl-7-hydroxyethylamino-1,3-dimethyl-lumazine, 6-formyl-7-(1-azacycloheptyl)-1,3-dimethyl-lumazine, 6-formyl-7-thiomorpholino-1,3-dimethyl-lumazine, 6-formyl-7-cyclopropylamino-1,3-dimethyl-lumazine, 6-dichloromethyl-7-mercaptobenzyl-1,3-dimethyl-lumazine, 6-dichloromethyl-7-ethylmercaptoacetate-1,3-dimethyl-lumazine, 6-benzylamino-1,3,7-trimethyl-lumazine, 6-pyrrolidinyl-1,3,7-trimethyl-lumazine, 6-chloro-7-piperidyl-1,3-diimethyl-lumazine, 7-(2-phenylethenyl)-1,3,6-trimethyl-lumazine, 6-[2-(p-trifluoromethylphenyl)ethenyl]-1,3-dimethyllumazine, 6-[2-(p-trifluoromethylphenyl)ethenyl]-1,3-dimethyllumazine, 6-[2-phenylethenyl]-1,3-dimethyllumazine, 6-[2-(p-trifluoromethoxyphenyl)ethenyl]-1,3-dimethyllumazine, 6-cyano-7-ethylmercaptoacetate-1,3-dimethyllumazine, 3-methyl-6-phenyl-7-chloro-lumazine, 1-methyl-6-phenyl-7-hydroxy-lumazine, 1-methyl-6-(4′-methoxyphenyl)-7-hydroxy-lumazine, 1-methyl-6-(4′-methylphenyl)-7-hydroxy-lumazine, 1,6-diphenyl-7-hydroxy-lumazine, 1-benzyl-6-phenyl-7-hydroxy-lumazine, 1-methyl-6-(3′,4′-dimethoxyphenyl)-7-hydroxy-lumazine, 1-methyl-6-(4′-chlorophenyl)-7-hydroxy-lumazine, 1-methyl-6-phenyl-7-chloro-lumazine, 1-methyl-6-(4′-methoxyphenyl)-7-chloro-lumazine, 1-methyl-6-(4′-methylphenyl)-7-chloro-lumazine, 1,6-diphenyl-7-chloro-lumazine, 1-benzyl-6-phenyl-7-chloro-lumazine, 1-methyl-6-(3′,4′-dimethoxyphenyl)-7-chloro-lumazine, 1-methyl-6-(4′-chlorophenyl)-7-chloro-lumazine, 1,3-dimethyl-6-phenyl-7-phenoxylumazine, 1,3-dimethyl-6-phenyl-7-piperidinolumazine, 1,3-dimethyl-6-phenyl-7-morpholinolumazine, 1,3-dimethyl-6-phenyl-7-(4′-N-acetyl)piperazinolumazine, and 1,3-dimethyl-6-phenyl-7-isopropylaminolumazine.
- 15. A pharmaceutical composition according to claim 9, further comprising one or more biologically-active drugs selected from the group consisting of immunosuppressant and/or immunomodulator drugs, antineoplastic drugs, and antiviral agents.
- 16. A pharmaceutical composition according to claim 9, further comprising one or more immunosuppressant drugs selected from the group consisting of cyclosporin A; substituted xanthines, e.g. pentoxyfylline; tacrolimus; rapamycin and derivatives thereof, leflunomide or an active metabolite or an analog thereof; mycophenolic acid and salts thereof; adrenocortical steroids, azathioprine, brequinar, gusperimus, 6-mercaptopurine, mizoribine, chloroquine, hydroxychloroquine and monoclonal antibodies with immunosuppressive properties.
- 17. A pharmaceutical composition according to claim 9, further comprising one or more immunomodulator drugs selected from the group consisting of acemannan, amiprilose, bucillamine, ditiocarb sodium, imiquimod, Inosine Pranobex, interferon-β, interferon-γ, lentinan, levamisole, pidotimod, romurtide, platonin, procodazole, propagermanium, thymomodulin, thymopentin and ubenimex.
- 18. A pharmaceutical composition according to claim 9, further comprising one or more antineoplastic drugs selected from the group consisting of alkaloids, alkylating agents, alkyl sulfonates, aziridines, ethylenimines, methylmelamines, nitrogen mustards, nitrosoureas, antibiotics, antimetabolites, folic acid analogs, purine analogs, pyrimidine analogs, enzymes, interferon and platinum complexes.
- 19. A pharmaceutical composition according to claim 9, further comprising one or more antiviral agents selected from the group consisting of retroviral enzyme inhibitors, HIV-1 IN inhibitors, nucleoside reverse transcriptase inhibitors, zidovudine, lamivudine, didanosine, stavudine, zalcitabine, non-nucleoside reverse transcriptase inhibitors, nevirapine, delavirdine, other reverse transcriptase inhibitors, foscarnet sodium, HIV-1 protease inhibitors, saquinavir, ritonavir, indinavir, nelfinavir, acyclovir, cidofovir, cytarabine, edoxudine, famciclovir, floxuridine, ganciclovir, idoxuridine, penciclovir, sorivudine, trifluridine, valaciclovir, vidarabine, kethoxal, methisazone, moroxydine, podophyllotoxin, ribavirine, rimantadine, stallimycine, statolon, tromantadine and xenazoic acid.
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of pending U.S. application Ser. No. 09/890,500, filed Oct. 30, 2001, which is the National Stage of International Application No. PCT/EP00/00938, filed Feb. 2, 2000, which was published in English under PCT Article 21(2), and which claims the benefit of U.S. Provisional Application Nos. 60/118,235, 60/118,282, and 60/118,295, each filed Feb. 2, 1999; the disclosures of which are incorporated by reference in their entirety.
Provisional Applications (3)
|
Number |
Date |
Country |
|
60118282 |
Feb 1999 |
US |
|
60118235 |
Feb 1999 |
US |
|
60118295 |
Feb 1999 |
US |
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
09890500 |
Oct 2001 |
US |
Child |
10444158 |
May 2003 |
US |