Immunosuppresive effects of pteridine derivatives

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.

1 - 17 . (canceled)  
   
   
       18 . A poly-substituted pteridinedione being represented by the formula (I),  
     
       
         
         
             
             
         
       
     
     wherein Y 1  and Y 2  are both oxygen, and none of R 3  and R 4  is hydrogen, and: 
 R 2  is a radical selected from the group consisting of C 1-7  alkyl; C 2-7  alkenyl; aryl; alkylaryl; ω-hydroxy C 1-7  alkyl; ω-epoxy C 1-7  alkyl; ω-carboxy C 1-7  alkyl (wherein the carboxy group may be acid, ester, thioester, acid halide or amide); ω-cyano C 1-7  alkyl; arylalkyl; arylalkenyl; heterocyclic-substituted alkyl; heterocyclic-substituted alkenyl; groups having the formula —S—R (i.e. wherein a sulfur atom is attached to the nitrogen atom of the pteridine ring) wherein R is a monovalent group selected from the group consisting of C 1-7  alkyl, aryl and C 3-10  cycloalkyl and wherein the said monovalent group is optionally substituted with one or more substituents selected from the group consisting of amino, amino-acid, alkylamino, arylamino, cycloalkylamino, carboxylic acid, carboxylic ester, sulfonic acid and phosphonic acid; and optionally substituted heterocyclic radicals;  
 R 1  is a radical independently defined as R 2 , or is hydrogen;  
 R 3  and R 4  are independently selected from halogen and aryl substituted with one or more substituents selected from the group consisting of halogen, C 1-4  alkyl, C 2-7  alkenyl, C 2-7  alkynyl, C 1-4  haloalkyl, C 1-4  alkoxy, hydroxyl, sulfhydryl, amino, C 3-10  cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C 1-7  alkyl, thio C 3-10  cycloalkyl, thioaryl, thiohetero-cyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, hydroxylamino, cyano, carboxylic acid or esters or thioesters or amides thereof, thiocarboxylic acid or esters or thioesters or amides thereof, C 1-7  alkylamino, cycloalkyl-amino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydra-zino, alkylhydrazino and phenylhydrazino;  
 or a pharmaceutically acceptable salt or an enantiomer thereof.  
 
   
   
       19 . A poly-substituted pteridinedione according to  claim 18 , wherein R 1  and R 2  are independently selected from the group consisting of benzyl, phenyl, 2-phenylethyl, butyric acid, butyric acid ester, butyronitrile, 2-hydroxyethyl, 2-morpholinoethyl, 2-piperidinoethyl, 2-pyrrolidinoethyl, ethyl acetate, 4-butyramido, N-methyl-4-butyramido, N-propyl-4-butyramido, ethyl and methyl.  
   
   
       20 . A poly-substituted pteridinedione according to  claim 18 , wherein R 4  is chloro or bromo.  
   
   
       21 . A poly-substituted pteridinedione according to  claim 19 , wherein R 4  is chloro or bromo.  
   
   
       22 . A poly-substituted pteridinedione according to  claim 18 , wherein R 3  is selected from the group consisting of 4-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2,6-diisopropyl-4-bromophenyl, pentafluorophenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 2,6-dichlorophenyl, 2-fluorophenyl, 3-methoxyphenyl, 3,5-dichlorophenyl, 3,4-dimethoxyphenyl, 4-methylphenyl, 2,6-dimethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl and 4-hydroxyphenyl.  
   
   
       23 . A poly-substituted pteridinedione according to  claim 18 , wherein R 1  is hydrogen and R 2  is selected from the group consisting of benzyl, methyl and ethyl.  
   
   
       24 . A poly-substituted pteridinedione according to  claim 18 , being selected from the group consisting of: 
 1-methyl-6-(4′-methoxyphenyl)-7-chloro-lumazine,    1-methyl-6-(4′-methylphenyl)-7-chloro-lumazine,    1-methyl-6-(3′,4′-dimethoxyphenyl)-7-chloro-lumazine,    1-methyl-6-(4′-chlorophenyl)-7-chloro-lumazine,    7-chloro-6-(4-methoxyphenyl)-1-methyl-lumazine,    7-chloro-6-(3,4-dimethoxyphenyl)-1-methyl-lumazine,    7-chloro-6-(4-fluorophenyl)-1-methyl-lumazine,    7-chloro-6-(3-methoxyphenyl)-1-methyl-lumazine,    7-chloro-(2,6-dimethoxyphenyl)-1-methyl-lumazine,    7-chloro-(2-chlorophenyl)-1-methyl-lumazine,    7-chloro-3-(chlorophenyl)-1-methyl-lumazine,    7-chloro-6-(4-cyanophenyl)-1-methyl-lumazine,    7-bromo-6-(3,4-dimethoxyphenyl)-1-methyl-lumazine,    7-bromo-6-(4-methoxyphenyl)-1-methyl-lumazine,    7-chloro-1-methyl-6-(4-methylphenyl)-lumazine,    7-chloro-6-(4-chlorophenyl)-1-methyl-lumazine,    7-chloro-6-(3,4-dimethoxyphenyl)-3-(ethyl butyrate)-1-methyl-lumazine,    7-chloro-6-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)-1-methyllumazine,    7-chloro-3-(ethyl butyrate)-1-methyl-6-(4-methoxyphenyl)-lumazine,    7-chloro-1,3-dimethyl-6-(4-methoxyphenyl)-lumazine,    7-bromo-6-(3,4-dimethoxyphenyl)-3-(ethylbutyrate)-1-methyl-lumazine,    7-bromo-3-(ethylbutyrate)-1-methyl-6-(4-methoxyphenyl)-lumazine,    7-bromo-1-methyl-3-(2-morpholinoethyl)-6-(3,4dimethoxyphenyl)-lumazine,    3-(ethyl butyrate)-7-fluoro-1-methyl-6-(4-methoxyphenyl)-lumazine,    7-bromo-1,3-dimethyl-6-(4-hydroxyphenyl)-lumazine, and    7-bromo-6-(3,4-dimethoxyphenyl)-3-(isopropyl butyrate)-1-methyl-lumazine.    
   
   
       25 . A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a poly-substituted pteridinedione being represented by the formula (I),  
     
       
         
         
             
             
         
       
     
     wherein Y 1  and Y 2  are both oxygen, and none of R 3  and R 4  is hydrogen, and: 
 R 2  is a radical selected from the group consisting of C 1-7  alkyl; C 2-7  alkenyl; aryl; alkylaryl; ω-hydroxy C 1-7  alkyl; ω-epoxy C 1-7  alkyl; ω-carboxy C 1-7  alkyl (wherein the carboxy group may be acid, ester, thioester, acid halide or amide); ω-cyano C 1-7  alkyl; arylalkyl; arylalkenyl; heterocyclic-substituted alkyl; heterocyclic-substituted alkenyl; groups having the formula —S—R (i.e. wherein a sulfur atom is attached to the nitrogen atom of the pteridine ring) wherein R is a monovalent group selected from the group consisting of C 1-7  alkyl, aryl and C 3-10  cycloalkyl and wherein the said monovalent group is optionally substituted with one or more substituents selected from the group consisting of amino, amino-acid, alkylamino, arylamino, cycloalkylamino, carboxylic acid, carboxylic ester, sulfonic acid and phosphonic acid; and optionally substituted heterocyclic radicals;  
 R 1  is a radical independently defined as R 2 , or is hydrogen;  
 R 3  and R 4  are independently selected from halogen and aryl substituted with one or more substituents selected from the group consisting of halogen, C 1-4  alkyl, C 2-7  alkenyl, C 2-7  alkynyl, C 1-4  haloalkyl, C 1-4  alkoxy, hydroxyl, sulfhydryl, amino, C 3-10  cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C 1-7  alkyl, thio C 3-10  cycloalkyl, thioaryl, thiohetero-cyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, hydroxylamino, cyano, carboxylic acid or esters or thioesters or amides thereof, thiocarboxylic acid or esters or thioesters or amides thereof, C 1-7  alkylamino, cycloalkyl-amino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydra-zino, alkylhydrazino and phenylhydrazino;  
 or a pharmaceutically acceptable salt or an enantiomer thereof.  
 
   
   
       26 . A pharmaceutical composition according to  claim 25 , further comprising one or more biologically-active drugs selected from the group consisting of immunosuppressant and/or immunomodulator drugs, antineoplastic drugs, and antiviral agents.  
   
   
       27 . A pharmaceutical composition according to  claim 25 , further comprising an immunomodulator drug 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.  
   
   
       28 . A pharmaceutical composition according to  claim 25 , further comprising an immunosuppressant drug selected from the group consisting of cyclosporin A, substituted xanthines, pentoxyfylline, tacrolimus, rapamycin, leflunomide, malononitrilamides, mycophenolic acid and salts thereof, adrenocortical steroids, azathioprine, brequinar, gusperimus, 6-mercaptopurine, mizoribine, chloroquine, hydroxychloroquine and monoclonal antibodies with immunosuppressive properties.  
   
   
       29 . A pharmaceutical composition according to  claim 25 , further comprising an antineoplastic drug selected from the group consisting of alkaloids, alkylating agents, alkyl sulfonates, aziridines, ethylenimines, methylmelamines, nitrogen mustards, nitrosoureas, antibiotics, antimetabolites, folic acid analogues, purine analogues and pyrimidine analogues, enzymes, interferon and platinum complexes.  
   
   
       30 . A pharmaceutical composition according to  claim 25 , further comprising an antiviral agent selected from the group consisting of HIV-1 IN inhibitors, nucleoside reverse transcriptase inhibitors, zidovudine, lamivudine, didanosine, stavudine, zalcitabine, non-nucleoside reverse transcriptase inhibitors, nevirapine, delavirdine, 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.  
   
   
       31 . A method of prevention or treatment of a pathologic condition selected from the group consisting of: 
 transplant rejections and autoimmune disorders,    cardiovascular disorders,    disorders of the central nervous system, and    cell proliferative disorders,    said method comprising administering a therapeutically effective amount of a poly-substituted pteridinedione being represented by the formula (I)                          wherein Y 1  and Y 2  are both oxygen, and none of R 3  and R 4  is hydrogen, and:    R 2  is a radical selected from the group consisting of C 1-7  alkyl; C 2-7  alkenyl; aryl; alkylaryl; ω-hydroxy C 1-7  alkyl; ω-epoxy C 1-7  alkyl; ω-carboxy C 1-7  alkyl (wherein the carboxy group may be acid, ester, thioester, acid halide or amide); ω-cyano C 1-7  alkyl; arylalkyl; arylalkenyl; heterocyclic-substituted alkyl; heterocyclic-substituted alkenyl; groups having the formula —S—R (i.e. wherein a sulfur atom is attached to the nitrogen atom of the pteridine ring) wherein R is a monovalent group selected from the group consisting of C 1-7  alkyl, aryl and C 3-10  cycloalkyl and wherein the said monovalent group is optionally substituted with one or more substituents selected from the group consisting of amino, amino-acid, alkylamino, arylamino, cycloalkylamino, carboxylic acid, carboxylic ester, sulfonic acid and phosphonic acid; and optionally substituted heterocyclic radicals;    R 1  is a radical independently defined as R 2 , or is hydrogen;    R 3  and R 4  are independently selected from halogen and aryl substituted with one or more substituents selected from the group consisting of halogen, C 1-4  alkyl, C 2-7  alkenyl, C 2-7  alkynyl, C 1-4  haloalkyl, C 1-4  alkoxy, hydroxyl, sulfhydryl, amino, C 3-10  cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C 1-7  alkyl, thio C 3-10  cycloalkyl, thioaryl, thiohetero-cyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, hydroxylamino, cyano, carboxylic acid or esters or thioesters or amides thereof, thiocarboxylic acid or esters or thioesters or amides thereof, C 1-7  alkylamino, cycloalkyl-amino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydra-zino, alkylhydrazino and phenylhydrazino;    or a pharmaceutically acceptable salt or an enantiomer thereof.    
   
   
       32 . The method of prevention or treatment according to  claim 31 , wherein said poly-substituted pteridinedione is administered in combination with one or more biologically-active drugs selected from the group consisting of immunosuppressant and/or immunomodulator drugs, antineoplastic drugs, and antiviral agents.