Immunosuppresive effects of pteridine derivatives
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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.
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Citations
32 Claims
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1-17. -17. (canceled)
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18. A poly-substituted pteridinedione being represented by the formula (I),
wherein Y1 and Y2 are both oxygen, and none of R3 and R4 is hydrogen, and: -
R2 is a radical selected from the group consisting of C1-7 alkyl;
C2-7 alkenyl;
aryl;
alkylaryl;
ω
-hydroxy C1-7 alkyl;
ω
-epoxy C1-7 alkyl;
ω
-carboxy C1-7 alkyl (wherein the carboxy group may be acid, ester, thioester, acid halide or amide);
ω
-cyano C1-7 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 C1-7 alkyl, aryl and C3-10 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;
R1 is a radical independently defined as R2, or is hydrogen;
R3 and R4 are independently selected from halogen and aryl substituted with one or more substituents selected from the group consisting of halogen, C1-4 alkyl, C2-7 alkenyl, C2-7 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, hydroxyl, sulfhydryl, amino, C3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C1-7 alkyl, thio C3-10 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, C1-7 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. - View Dependent Claims (19, 20, 21, 22, 23, 24)
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25. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a poly-substituted pteridinedione being represented by the formula (I),
wherein Y1 and Y2 are both oxygen, and none of R3 and R4 is hydrogen, and: -
R2 is a radical selected from the group consisting of C1-7 alkyl;
C2-7 alkenyl;
aryl;
alkylaryl;
ω
-hydroxy C1-7 alkyl;
ω
-epoxy C1-7 alkyl;
ω
-carboxy C1-7 alkyl (wherein the carboxy group may be acid, ester, thioester, acid halide or amide);
ω
-cyano C1-7 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 C1-7 alkyl, aryl and C3-10 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;
R1 is a radical independently defined as R2, or is hydrogen;
R3 and R4 are independently selected from halogen and aryl substituted with one or more substituents selected from the group consisting of halogen, C1-4 alkyl, C2-7 alkenyl, C2-7 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, hydroxyl, sulfhydryl, amino, C3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C1-7 alkyl, thio C3-10 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, C1-7 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. - View Dependent Claims (26, 27, 28, 29, 30)
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31. A method of prevention or treatment of a pathologic condition selected from the group consisting of:
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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 Y1 and Y2 are both oxygen, and none of R3 and R4 is hydrogen, and;
R2 is a radical selected from the group consisting of C1-7 alkyl;
C2-7 alkenyl;
aryl;
alkylaryl;
ω
-hydroxy C1-7 alkyl;
ω
-epoxy C1-7 alkyl;
ω
-carboxy C1-7 alkyl (wherein the carboxy group may be acid, ester, thioester, acid halide or amide);
ω
-cyano C1-7 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 C1-7 alkyl, aryl and C3-10 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;
R1 is a radical independently defined as R2, or is hydrogen;
R3 and R4 are independently selected from halogen and aryl substituted with one or more substituents selected from the group consisting of halogen, C1-4 alkyl, C2-7 alkenyl, C2-7 alkynyl, C1-4 haloalkyl, C1-4 alkoxy, hydroxyl, sulfhydryl, amino, C3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C1-7 alkyl, thio C3-10 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, C1-7 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. - View Dependent Claims (32)
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Specification