1,3,5-Triazine derivatives as ligands for human adenosine-A3 receptors

1. A compound of the formula (1):

wherein:

R 1 represents halogen, alkyl(1-3C), O-alkyl(1-3C), CF 3 , NH 2 , N-(di)-alkyl(1-3C), N-(di)-alkenyl(1-3C), N-(di)-alkynyl(1-3C), N-alkyl(1-3C)alkenyl(1-3C), N-alkyl(1-3C)alkynyl(1-3C), N-alkenyl(1-3C)alkynyl(1-3C) or an optionally substituted cyclic amine containing from 2 to 8 carbons in the ring;

R 2 , R 3 and R 4 independently represent H, halogen, alkyl(1-3C), CF 3 , OH, O-alkyl(1-3C), phenoxy, hydroxyalkyl(1-3C), alkoxy(1-2C)-alkyl(1-2C), phenyl, N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF 3 , SCH 3 , SOCH 3 , SO 2 CH 3 or R 2 and R 3 together with the phenyl ring to which they are attached, represent an optionally substituted benzofuran, dihydrobenzofuran, benzodioxane, benzodioxolane or naphthalene ring system,

X represents NH, N-alkyl(1-3C), CH 2 , O, S;

Y represents a group of the general formula (A), (B) or (C):

in which:

R 5 is either OH or CH 2 OH;

R 6 represents H, alkyl(1-3C), phenyl, NH 2 , N-(di)-alkyl(1-3C), OH, O-alkyl(1-3C) or hydroxyalkyl(1-2C);

n has the value of 0, 1 or 2;

R 7 represents alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C),

R 8 and R 9 independently represent H, halogen, alkyl(1-3C), CF 3 , OH, O-alkyl(1-3C), N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF 3 , SCH 3 , SOCH 3 , or SO 2 CH 3 ;

R 10 represents H or alkyl(1-3C);

R 11 represents H, alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C); and

Z represents NOH, NOalkyl(1-3C), O or S;

a compound having formula (1) in which the substituents on one or more asymmetrical carbon atoms are in either the R-configuration or the S-configuration, a stereoisomer of a compound of formula (1), a prodrug of a compound of formula (1), or a pharmacologically acceptable salt of any of the foregoing.

2. The compound of the formula (1) as claimed in claim 1 wherein R 1 represents halogen, alkyl(1-3C), O-alkyl(1-3C), CF 3 , NH 2 or N-(di)-alkyl(1-3C); R 2 , R 3 and R 4 independently represent H, halogen, alkyl(1-3C), CF 3 , OH, O-alkyl(1-3C), phenyl, N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF 3 , SCH 3 , SOCH 3 , SO 2 CH 3 , or R 2 and R 3 together with the phenyl ring to which they are attached, represent a benzofuran, benzodioxane, or benzodioxolane ring system, X represents NH, N-alkyl(1-3C), CH 2 , O, or S, Y represents a group of the general formula (A) or (B), in which R 5 is either OH or CH 2 OH; R 6 represents H, alkyl(1-3C), phenyl, NH 2 , N-(di)-alkyl(1-3C), OH, O-alkyl(1-3C) or hydroxyalkyl (1-2C); n has the value of 0, 1 or 2; R 7 represents alkyl(1-3C), benzyl or hydroxyalkyl(1-2C); R 8 and R 9 independently represent H, halogen, alkyl(1-3C), CF 3 , OH, O-alkyl(1-3C), N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF 3 , SCH 3 , SOCH 3 , or SO 2 CH 3 ; and R 10 represents H.

3. The compound of the formula (1) as claimed in claim 1 wherein Y is a group of the formula (A).

4. The compound of the formula (1) as claimed in claim 2 wherein Y is a group of the formula (A).

5. The compound of the formula (1) as claimed in claim 1 wherein Y is a group of the formula (B).

6. The compound of the formula (1) as claimed in claim 2 wherein Y is a group of the formula (B).

7. The compound of the formula (1) as claimed in claim 1 wherein Y is a group of the formula (C).

8. The compound of the formula (1) as claimed in claim 1 wherein R 1 is Cl, R 2 is H, X is NH, R 6 is H, n is 1, Z is O, and R 10 is H.

9. The compound of the formula (1) as claimed in claim 1 wherein R 1 is Cl, R 2 is H, X is NH, R 5 is 3—CH 2 OH, R 6 is H, n is 1, R 7 is CH 3 ; R 8 is H; R 9 is H, Z is O, R 10 is H, and R 11 is CH 3 .

10. The compound as claimed in claim 1 having formula (8) or an enantiomer thereof:

11. The compound as claimed in claim 1 having formula (9):

12. A pharmaceutical composition comprising a pharmacologically active amount of one or more compounds as claimed in claim 1 , and one or more pharmaceutically acceptable carriers.

13. A method of treating at least one inflammatory disease involving one or more adenosine-A 3 receptors, or that can be treated via manipulation of one or more adenosine-A 3 receptors, wherein the at least one inflammatory disease is chosen from arthritis, multiple sclerosis, asthma, and psoriasis, in a human patient comprising administering to the patient an effective amount of one or more compounds of the formula (1):

wherein:

R 1 represents halogen, alkyl(1-3C), O-alkyl(1-3C), CF 3 , NH 2 , N-(di)-alkyl(1-3C), N-(di)-alkenyl(1-3C), N-(di)-alkynyl(1-3C), N-alkyl(1-3C)alkenyl(1-3C), N-alkyl(1-3C)alkynyl(1-3C), N-alkenyl(1-3C)alkynyl(1-3C) or an optionally substituted cyclic amine containing from 2 to 8 carbons in the ring;

R 2 , R 3 and R 4 independently represent H, halogen, alkyl(1-3C), CF 3 , OH, O-alkyl(1-3C), phenoxy, hydroxyalkyl(1-3C), alkoxy(1-2C)-alkyl(1-2C), phenyl, N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF 3 , SCH 3 , SOCH 3 , SO 2 CH 3 or R 2 and R 3 together with the phenyl ring to which they are attached, represent an optionally substituted benzofuran, dihydrobenzofuran, benzodioxane, benzodioxolane or naphthalene ring system;

X represents NH, N-alkyl(1-3C), CH 2 , O, S or a carbon-carbon bond;

Y represents a group of the general formula (A), (B) or (C):

in which:

R 5 is either OH or CH 2 OH;

R 6 represents H, alkyl(1-3C), phenyl, NH 2 , N-(di)-alkyl(1-3C), OH, O-alkyl(1-3C) or hydroxyalkyl(1-2C);

n has the value of 0, 1 or 2;

R 7 represents alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C);

R 8 and R 9 independently represent H, halogen, alkyl(1-3C), CF 3 , OH, O-alkyl(1-3C), N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF 3 , SCH 3 , SOCH 3 , or SO 2 CH 3 ;

R 10 represents H or alkyl(1-3C);

R 11 represents H, alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C); and

Z represents NOH, NOalkyl(1-3C), O or S;

one or more compounds having formula (1) in which the substituents on one or more asymmetrical carbon atoms are in either the R-configuration or the S-configuration, one or more stereoisomers of a compound of formula (1), one or more prodrugs of a compound of formula (1), one or more pharmacologically acceptable salts of any of the foregoing, or a combination of two or more of any of the foregoing.

14. A method of treating Parkinson's disease in a human patient comprising administering to the patient an effective amount of one or more compounds of the formula (1):

wherein:

R 1 represents halogen, alkyl(1-3C), O-alkyl(1-3C), CF 3 , NH 2 , N-(di)-alkyl(1-3C), N-(di)-alkenyl(1-3C), N-(di)-alkynyl(1-3C), N-alkyl(1-3C)alkenyl(1-3C), N-alkyl(1-3C)alkynyl(1-3C), N-alkenyl(1-3C)alkynyl(1-3C) or an optionally substituted cyclic amine containing from 2 to 8 carbons in the ring;

R 2 , R 3 and R 4 independently represent H, halogen, alkyl(1-3C), CF 3 , OH, O-alkyl(1-3C), phenoxy, hydroxyalkyl(1-3C), alkoxy(1-2C)-alkyl(1-2C), phenyl, N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF 3 , SCH 3 , SOCH 3 , SO 2 CH 3 or R 2 and R 3 together with the phenyl ring to which they are attached, represent an optionally substituted benzofuran, dihydrobenzofuran, benzodioxane, benzodioxolane or naphthalene ring system;

X represents NH, N-alkyl(1-3C), CH 2 , O, S or a carbon-carbon bond;

Y represents a group of the general formula (A), (B) or (C):

in which:

R 5 is either OH or CH 2 OH;

R 6 represents H, alkyl(1-3C), phenyl, NH 2 , N-(di)-alkyl(1-3C), OH, O-alkyl(1-3C) or hydroxyalkyl(1-2C);

n has the value of 0, 1 or 2;

R 7 represents alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C);

R 8 and R 9 independently represent H, halogen, alkyl(1-3C), CF 3 , OH, O-alkyl(1-3C), N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF 3 , SCH 3 , SOCH 3 , or SO 2 CH 3 ;

R 10 represents H or alkyl(1-3C);

R 11 represents H, alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C); and

Z represents NOH, NOalkyl(1-3C), O or S;

one or more compounds having formula (1) in which the substituents on one or more asymmetrical carbon atoms are in either the R-configuration or the S-configuration, one or more stereoisomers of a compound of formula (1), one or more prodrugs of a compound of formula (1), one or more pharmacologically acceptable salts of any of the foregoing, or a combination of two or more of any of the foregoing.