Immunosuppressive effects of pteridine derivatives

• US 20030236255A1
• Filed: 05/23/2003
• Published: 12/25/2003
• Est. Priority Date: 02/02/1999
• Status: Active Grant

• Current Assignee: 4 AZA Bioscience NV
• Original Assignee: 4 AZA Bioscience NV
• Inventors: Herdewijn, Piet Andre Maurits Maria, Pfleiderer, Wolfgang Eugen, Waer, Mark Jozef Albert
• Granted Patent: US 6,946,465 B2
• Time in Patent Office: Days
• US Class Current: 514/228.5
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 475/02 with an oxygen atom directly attached in position 4
• 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

Abstract

Novel poly-substituted pteridinediones (lumazines), and mono- or polysubstituted 2-thiolumazines, 4-thiolumazines or 2,4-dithiolumazines, having disclosed substituents in positions 1, 3, 6 and 7 of the pteridine ring, and pharmaceutically acceptable salts thereof, are useful as biologically active ingredients in preparing pharmaceutical compositions especially for the treatment or prevention of a CNS disorder, a cell proliferative disorder, a viral infection, an immune or auto-immune disorder or a transplant rejection. Combinations of the pteridine derivatives of the invention with an immunosuppressant or immunomodulator drug, an antineoplastic drug or an antiviral agent, providing potential synergistic effects, are also disclosed.

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.