METHODS OF TREATING ATHEROSCLEROSIS

1 . (canceled)

2 . A method for the prevention and treatment of atherosclerosis, which method comprises administering to a patient, in need thereof, a therapeutically effective amount of an adenosine A 3 receptor antagonist, or a pharmaceutically acceptable salt thereof.

3 . A method according to claim 1 or 2 , wherein an adenosine A 3 receptor antagonist is a compound of the formula

wherein

A is imidazole, pyrazole, or triazole;

R is —C(X)R 1 , —C(X)—N(R 1 ) 2 , —C(X)OR 1 , —C(X)SR 1 , —SO b R 1 , —SO b OR 1 , —SO b SR 1 , or —SO b —N(R 1 ) 2 ;

R 1 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, wherein each R 1 can be the same or different; or, if linked to a nitrogen atom, then taken together with the nitrogen atom, —N(R 1 ) 2 forms an azetidine ring or a 5- or 6-membered heterocyclic ring optionally containing one or more additional heteroatoms selected from the group consisting of N, O, and S;

R 2 is hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

R 3 is furan, pyrrole, thiophene, benzofuran, benzypyrrole, benzothiophene, optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, acyloxy, acylamino, aralkyl, aryl, substituted aryl, aryloxy, azido, carboxy, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, alkylthio, substituted alkylthio, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl, —SO 2 -heteroaryl, and trihalomethyl;

X is O, S, or NR'; and

b is 1 or 2;

or a pharmaceutically acceptable salt thereof.

4 - 10 . (canceled)

11 . A method according to claim 3 , wherein

R represents —C(X)—N(R 1 ) 2 in which

R 1 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, wherein each R 1 can be the same or different; or, if linked to a nitrogen atom, then taken together with the nitrogen atom, —N(R 1 ) 2 forms an azetidine ring or a 5- or 6-membered heterocyclic ring optionally containing one or more additional heteroatoms selected from the group consisting of N, O, and S;

X is O;

or a pharmaceutically acceptable salt thereof.

12 . A method according to claim 11 , wherein

R represents —C(O)—N(R 1 ) 2 in which each R 1 is different from each other, one being hydrogen;

A represents a pyrazole ring of the formula

or a pharmaceutically acceptable salt thereof.

13 . A method according to claim 12 , wherein a compound of formula (I) has the following formula

wherein

R 2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;

R 3 is furan;

R 4 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle;

or a pharmaceutically acceptable salt thereof.

14 . A method according to claim 13 , wherein the compound of formula (II) is selected from the group consisting of:

or in each case, a pharmaceutically acceptable salt thereof.

15 . A method according to claim 3 , wherein the compound of formula (I) is selected from the group consisting of:

5-{[(3-Chlorophenyl)amino]carbonyl}amino-8-methyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-{[(4-Methoxyphenyl)amino]carbonyl}amino-8-methyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-{[(3-Chlorophenyl)amino]carbonyl}amino-8-ethyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-{[(4-Methoxyphenyl)amino]carbonyl}amino-8-ethyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-{[(3-Chlorophenyl)amino]carbonyl}amino-8-propyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-{[(4-Methoxyphenyl)amino]carbonyl}amino-8-propyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-{[(3-Chlorophenyl)amino]carbonyl}amino-8-butyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-{[(4-Methoxyphenyl)amino]carbonyl}amino-8-butyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-{[(3-Chlorophenyl)amino]carbonyl}amino-8-isopentyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-{[(4-Methoxyphenyl)amino]carbonyl}amino-8-isopentyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-{[(3-Chlorophenyl)amino]carbonyl}amino-8-(2-isopentenyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-{[(4-Methoxyphenyl)amino]carbonyl}amino-8-(2-isopentenyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-{[(3-Chlorophenyl)amino]carbonyl}amino-8-(2-phenylethyl)-2 (2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-{[(4-Methoxyphenyl)amino]carbonyl}amino-8-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-{[(3-Chlorophenyl)amino]carbonyl}amino-8-(3-phenylpropyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-{[(4-Methoxyphenyl)amino]carbonyl}amino-8-(3-phenylpropyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-[(Benzyl)carbonyl]amino-8-isopentyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

5-[(Benzyl)carbonyl]amino-8-(3-phenylpropyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine;

N-[4-(Diethylamino)phenyl]-N′-[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-5-yl]urea;

N-[8-Methyl-2-(2-furyl)-8H-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-5-yl]-N′-[4-(dimethylamino)phenyl]urea;

N-[2-(2-Furyl)-8-methyl-8H-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-5-yl]-N′-[4-(morpholin-4-ylsulfonyl)phenyl]urea;

N-[2-(2-Furyl)-8-methyl-8H-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-5-yl]-N′-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}urea; and

N-[2-(2-Furyl)-8-methyl-8H-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidin-5-yl]-N′-pyridin-4-ylurea;

or a pharmaceutically acceptable salt thereof.

16 . A method according to claim 1 or 2 , wherein an adenosine A 3 receptor antagonist is a compound of the formula

wherein

R is —C(X)R 1 , —C(X)—N(R 1 ) 2 , —C(X)OR 1 , —C(X)SR 1 , —SO b R 1 , —SO b OR 1 , —SO b SR 1 , or —SO b —N(R 1 ) 2 ;

R 1 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, substituted heteroaryl, or heterocyclyl, wherein each R 1 may be the same or different; or, if linked to a nitrogen atom, then taken together with the nitrogen atom, —N(R 1 ) 2 forms an azetidine ring or a 5- to 6-membered heterocyclic ring optionally containing one or more heteroatoms selected from N, O, and S;

R 2 is hydrogen, halogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

R 3 is furan, pyrrole, thiophene, benzofuran, benzypyrrole, benzothiophene, optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, acyloxy, acylamino, alkaryl, aryl, substituted aryl, aryloxy, azido, carboxy, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, thioalkyl, substituted thioalkyl, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl, —SO 2 -heteroaryl, and trihalomethyl;

X is O, S, or NR 1 ;

b is 1 or 2;

or a pharmaceutically acceptable salt thereof.

17 - 23 . (canceled)

24 . A method according to claim 16 , wherein

R represents —C(X)—N(R 1 ) 2 in which X is O; and wherein each R 1 can be the same or different;

or a pharmaceutically acceptable salt thereof.

25 . A method according to claim 16 , wherein the compound of formula (III) is selected from the group consisting of:

5-{[4-Methoxyphenyl)amino]carbonyl}amino-9-chloro-2-(2-furyl)-1,2,4-triazolo[1,5-c]quinazoline; and

5-{[3-Chlorophenyl)amino]carbonyl}amino-9-chloro-2-(2-furyl)-1,2,4-triazolo[1,5-c]quinazoline;

or a pharmaceutically acceptable salt thereof.

26 . A method according to claim 2 , wherein an adenosine A 3 receptor antagonist is a compound of the formula

wherein

X is CH or N;

R 1 and R 2 are each independently hydrogen, alkyl, substituted alkyl, aralkyl, substituted aralkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, or substituted aryl;

R 3 is aryl, substituted aryl, alkyl, substituted alkyl, aralkyl, or substituted aralkyl;

R 4 is hydrogen, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl; and

one of the dashed lines represents a double bond and the other represents a single bond;

or a pharmaceutically acceptable salt thereof.

27 . A method according to claim 26 , wherein

R 1 is aralkyl;

R 2 is alkyl;

R 4 is hydrogen, alkyl or substituted alkyl;

or a pharmaceutically acceptable salt thereof.

28 . A method according to claim 26 , wherein the adenosine A 3 receptor antagonist is a compound of the formula

wherein

R 1 and R 2 are each independently hydrogen, alkyl, substituted alkyl, aralkyl, substituted aralkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, or substituted aryl;

R 3 is aryl, substituted aryl, alkyl, substituted alkyl, aralkyl, or substituted aralkyl;

R 4 is hydrogen, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl;

or a pharmaceutically acceptable salt thereof.

29 . A method according to claim 28 , wherein

R 1 is aralkyl;

R 2 is alkyl;

R 4 is hydrogen, alkyl or substituted alkyl;

or a pharmaceutically acceptable salt thereof.

30 . A method according to claim 26 , wherein the adenosine A 3 receptor antagonist is a compound of the formula

wherein

R 1 and R 2 are each independently hydrogen, alkyl, substituted alkyl, aralkyl, substituted aralkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, or substituted aryl;

R 3 is aryl, substituted aryl, alkyl, substituted alkyl, aralkyl, or substituted aralkyl;

R 4 is hydrogen, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl;

or a pharmaceutically acceptable salt thereof.

31 . A method according to claim 30 , wherein

R 1 is aralkyl;

R 2 is alkyl;

R 4 is hydrogen, alkyl or substituted alkyl;

or a pharmaceutically acceptable salt thereof.

32 . A method according to claim 26 , wherein the adenosine A 3 receptor antagonist is selected from the group consisting of:

1-Benzyl-7-phenyl-3-propyl-1H-pyrrolo[1,2-f]purine-2,4(3H,6H)-dione;

1-Benzyl-7-phenyl-3-propyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

1-Benzyl-7-(4-methoxyphenyl)-3-propyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

1-Benzyl-7-(biphenyl-4-yl)-3-propyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

1-Benzyl-7-(4-fluorophenyl)-3-propyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

7-Phenyl-1,3-dipropyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

1,3-Diisobutyl-7-phenyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

1-Benzyl-7-methyl-3-propyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

1,3-Dimethyl-7-phenyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

7-(Biphenyl-4-yl)-1,3-dimethyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

7-(4-Chlorophenyl)-1,3-dimethyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

7-(4-Bromophenyl)-1,3-dimethyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

7-(4-Fluorophenyl)-1,3-dimethyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

7-(4-Methoxyphenyl)-1,3-dimethyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

1-Benzyl-7-methyl-3-propyl-1H-pyrrolo[1,2-f]purine-2,4(3H,6H)-dione;

1-Benzyl-7-ethyl-3-propyl-1H-pyrrolo[1,2-f]purine-2,4(3H,6H)-dione;

1-Benzyl-6,7-dimethyl-3-propyl-1H-pyrrolo[1,2-f]purine-2,4(3H,6H)-dione;

1-Benzyl-7-ethyl-3-propyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

1-Benzyl-7-isopropyl-3-propyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

1-Benzyl-7-t-butyl-3-propyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

1-Benzyl-7-cyclopropyl-3-propyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

1-Benzyl-7-cyclohexyl-3-propyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

1-Benzyl-6,7-dimethyl-3-propyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

1-Benzyl-7-ethyl-6-methyl-3-propyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione; and

1,3,7-Trimethyl-1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione;

or a pharmaceutically acceptable salt thereof.

33 . A method according to claim 2 , wherein the method further comprises the prevention of stroke and heart attack.

34 - 35 . (canceled)

36 . A method for the prevention and treatment of atherosclerosis, which method comprises administering to a mammal, in need thereof, a therapeutically effective amount of a combination of an adenosine A 3 receptor antagonist, or a pharmaceutically acceptable salt thereof, and an adenosine A 2B receptor antagonist, or a pharmaceutically acceptable salt thereof.

37 . A method according to claim 36 , wherein the method further comprises the prevention of stroke and heart attack.