USES OF ADENOSINE A2A RECEPTOR ANTAGONISTS

UTILISATIONS D'ANTAGONISTES DES RECEPTEURS DE L'ADENOSINE A<SB>2A</SB>

English Abstract

There is disclosed a method for the treatment or prevention of Extra Pyramidal
syndrome (EPS), distonia, restless leg syndrome (RLS) comprising the
administration of an adenosine A2a receptor antagonist, alone or in
combination
with other agents useful for treating EPS, distonia, RSL or PLMS.

Claims

35
Claims:
1. Use of an adenosine A2a receptor antagonist for the preparation of a
medicament for the treatment or prevention of dystonia, wherein the adenosine
A2a receptor antagonist is a compound of the formula (I):
<IMG>
or a pharmaceutically acceptable salt thereof, wherein
R is R1-furanyl, R1-thienyl, R1-pyridyl, R1-pyridyl N-oxide, R1-oxazolyl,
R10-phenyl, R1-pyrrolyl or C4-C6 cycloalkenyl;
X is C2-C6 alkylene or -C(O)CH2-;
Y is -N(R2)CH2CH2N(R3)-, -OCH2CH2N(R2)-, -O-, -S-, -CH2S-,
-(CH2)2-NH-, or
<IMG>
and
Z is R5-phenyl, R5-phenyl(C1-C6)alkyl, R5-heteroaryl, diphenylmethyl,
R6-C(O)-, R6-SO2-, R6-OC(O)-, R7-N(R8)-C(O)-, R7-N(R8)-C(S)-, <IMG>,
phenyl-CH(OH)-, or phenyl-C(=NOR2)-; or when Q is <IMG> , Z is also
phenylamino or pyridylamino;
or

36
Z and Y together are
<IMG> or an N-oxide thereof, <IMG>
R1 is 1 to 3 substituents independently selected from hydrogen, C1-C6-
alkyl, -CF3, halogen, -NO2, -NR12R13, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6
alkylsulfinyl, and C1-C6 alkylsulfonyl;
R2 and R3 are independently selected from the group consisting of:
hydrogen and C1-C6 alkyl;
m and n are independently 2-3;
Q is
<IMG>
R4 is 1-2 substituents independently selected from the group consisting
of hydrogen and C1-C6alkyl, or two R4 substituents on the same carbon can
form =O;
R5 is 1 to 5 substituents independently selected from the group consisting
of hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -CN, di-((C1-
C6)alkyl)amino, -CF3, -OCF3, acetyl, -NO2, hydroxy(C1-C6)alkoxy, (C1-C6)-
alkoxy(C1-C6)alkoxy, di-((C1-C6)-alkoxy)(C1-C6)alkoxy, (C1-C6)-alkoxy(C1-

37
C6)alkoxy-(C1-C6)-alkoxy, carboxy(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl(C1-
C6)alkoxy, (C3-C6)cycloalkyl(C1-C6)alkoxy, di-((C1-C6)alkyl)amino(C1-
C6)alkoxy, morpholinyl, (C1-C6)alkyl-S02-, (C1-C6)alkyl-SO-(C1-C6)alkoxy,
tetrahydropyranyloxy, (C1-C6)alkylcarbonyl(C1-C6)-alkoxy, (C1-C6)-
alkoxycarbonyl, (C1-C6)alkylcarbonyloxy(C1-C6)-alkoxy, -SO2NH2, phenoxy,
<IMG>
or adjacent R5 substituents together are -O-CH2-O-, -O-CH2CH2-O-, -O-CF2-O-
or -O-CF2CF2-O- and form a ring with the carbon atoms to which they are
attached;
R6 is (C1-C6)alkyl, R5-phenyl, R5-phenyl(C1-C6)alkyl, thienyl, pyridyl,
(C3-C6)-cycloalkyl, (C1-C6)alkyl-OC(O)-NH-(C1-C6)alkyl-, di-((C1-
C6)alkyl)aminomethyl, or
<IMG>
R7 is (C1-C6)alkyl, R5-phenyl or R5-phenyl(C1-C6)alkyl;
R8 is hydrogen or C1-C6 alkyl; or R7 and R8 together are -(CH2)p-A-
(CH2)q, wherein p and q are independently 2 or 3 and A is a bond, -CH2-, -S-
or
-O-, and form a ring with the nitrogen to which they are attached;
R9 is 1-2 groups independently selected from hydrogen, C1-C6 alkyl,
hydroxy, C1-C6 alkoxy, halogen, -CF3 and (C1-C6)alkoxy(C1-C6)alkoxy ;
R10 is 1 to 5 substituents independently selected from the group
consisting of hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -CN,

38
-NH2, C1-C6alkylamino, di-((C1-C6)alkyl)amino, -CF3, -OCF3 and -S(O)0-2(C1-
C6)alkyl;
R11 is H, C1-C6 alkyl, phenyl, benzyl, C2-C6 alkenyl, C1-C6 alkoxy(C1-
C6)alkyl, di-((C1-C6)alkyl)amino(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl or
piperidino(C1-C6)alkyl;
R12 is H or C1-C6 alkyl; and
R13 is (C1-C6)alkyl-C(O)- or (C1-C6)alkyl-SO2-.
2. The use of claim 1, wherein the adenosine A2a receptor antagonist is
selected from the group consisting of compounds of the formula:
<IMG>
wherein R and Z-Y are as defined in the following table:
<IMG>

39
<IMG>
or a pharmaceutically acceptable salt or solvate thereof.
3. The use of Claim 2, wherein the adenosine A2a receptor antagonist is:
<IMG>
or a pharmaceutically acceptable salt or solvate thereof.

40
4. The use of any one of claims 1 to 3 for the treatment of idiopathic
dystonia or dystonia caused by the use of cocaine.
5. The use of any one of claims 1 to 3 for the treatment or prevention of
dysonia caused by treatment with a tricyclic antidepressant, lithium or an
anticonvulsant.
6. The use of claim 5 further comprising the use of a tricyclic
antidepressant, lithium or an anticonvulsant for the preparation of a
medicament for use in combination with the adenosine A2a receptor antagonist
medicament.
7. The use of claim 6, wherein the tricyclic antidepressant is selected from
the group consisting of perphenazine, amitriptyline, desipramine, doxepin,
trimipramine and protriptyline, and the anticonvulsant is selected from the
group consisting of phenytoin, carbamazepine and gabapentin.
8. A kit comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat or prevent
dystonia, wherein one container comprises a pharmaceutical composition
comprising an adenosine A2a receptor antagonist in a pharmaceutically
acceptable carrier, and wherein, a separate container comprises a
pharmaceutical composition comprising an antipsychotic agent in a
pharmaceutically acceptable carrier and instructions for use thereof, and
wherein the adenosine A2a receptor antagonist is a compound of the formula
<IMG>

41
or a pharmaceutically acceptable salt thereof, wherein
R is R1-furanyl, R1-thienyl, R1-pyridyl, R1-pyridyl N-oxide, R1-oxazolyl,
R10-phenyl, R1-pyrrolyl or C4-C6 cycloalkenyl;
X is C2-C6 alkylene or -C(O)CH2-;
Y is -N(R2)CH2CH2N(R3)-, -OCH2CH2N(R2)-, -O-, -S-, -CH2S-,
-(CH2)2-NH-, or
<IMG>
and
Z is R5-phenyl, R5-phenyl(C1-C6)alkyl, R5-heteroaryl, diphenylmethyl,
R6-C(O)-, R6-SO2-, R6-OC(O)-, R7-N(R8)-C(O)-, R7-N(R8)-C(S)-, <IMG>,
phenyl-CH(OH)-, or phenyl-C(=NOR2)-; or when Q is <IMG>, Z is also
phenylamino or pyridylamino;
or
Z and Y together are
<IMG>

42
<IMG>
or an N-oxide thereof, <IMG>
R1 is 1 to 3 substituents independently selected from hydrogen, C1-C6-alkyl,
-CF3, halogen, -NO2, -NR12R13, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6
alkylsulfinyl, and C1-C6 alkylsulfonyl;
R2 and R3 are independently selected from the group consisting of
hydrogen and C1-C6 alkyl;
m and n are independently 2-3;
Q is
<IMG>
R4 is 1-2 substituents independently selected from the group consisting
of hydrogen and C1-C6alkyl, or two R4 substituents on the same carbon can
form =O;
R5 is 1 to 5 substituents independently selected from the group consisting
of hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -CN, di-((C1-
C6)alkyl)amino, -CF3, -OCF3, acetyl, -NO2, hydroxy(C1-C6)alkoxy, (C1-C6)-
alkoxy(C1-C6)alkoxy, di-((C1-C6)-alkoxy)(C1-C6)alkoxy, (C1-C6)-alkoxy(C1-
C6)alkoxy-(C1-C6)-alkoxy, carboxy(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl(C1-
C6)alkoxy, (C3-C6)cycloalkyl(C1-C6)alkoxy, di-((C1-C6)alkyl)amino(C1-
C6)alkoxy, morpholinyl, (C1-C6)alkyl-SO2-, (C1-C6)alkyl-SO-(C1-C6)alkoxy,
tetrahydropyranyloxy, (C1-C6)alkylcarbonyl(C1-C6)-alkoxy, (C1-C6)-
alkoxycarbonyl, (C1-C6)alkylcarbonyloxy(C1-C6)-alkoxy, -SO2NH2, phenoxy,

43
<IMG>
or adjacent R5 substituents together are -O-CH2-O-, -O-CH2CH2-O-, -O-CF2-O-
or -O-CF2CF2-O- and form a ring with the carbon atoms to which they are
attached;
R6 is (C1-C6)alkyl, R5-phenyl, R5-phenyl(C1-C6)alkyl, thienyl, pyridyl,
(C3-C6)-cycloalkyl, (C1-C6)alkyl-OC(O)-NH-(C1-C6)alkyl-, di-((C1-
C6)alkyl)aminomethyl, or
<IMG>
R7 is (C1-C6)alkyl, R5-phenyl or R5-phenyl(C1-C6)alkyl;
R8 is hydrogen or C1-C6 alkyl; or R7 and R8 together are -(CH2)p-A-
(CH2)q, wherein p and q are independently 2 or 3 and A is a bond, -CH2-, -S-
or
-O-, and form a ring with the nitrogen to which they are attached;
R9 is 1-2 groups independently selected from hydrogen, C1-C6 alkyl,
hydroxy, C1-C6 alkoxy, halogen, -CF3 and (C1-C6)alkoxy(C1-C6)alkoxy ;
R10 is 1 to 5 substituents independently selected from the group
consisting of hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -CN, -
NH2, C1-C6alkylamino, di-((C1-C6)alkyl)amino, -CF3, -OCF3 and -S(O)0-2(C1-
C6)alkyl;
R11 is H, C1-C6 alkyl, phenyl, benzyl, C2-C6 alkenyl, C1-C6 alkoxy(C1-
C6)alkyl, di-((C1-C6)alkyl)amino(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl or
piperidino(C1-C6)alkyl;
R12 is H or C1-C6 alkyl; and

44
R13 is (C1-C6)alkyl-C(O)- or (C1-C6)alkyl-SO2-.
9. A kit comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat or prevent
dystonia caused by treatment with a tricyclic antidepressant, lithium or an
anticonvulsant, wherein one container comprises a pharmaceutical composition
comprising an adenosine A2a receptor antagonist in a pharmaceutically
acceptable carrier, and wherein, a separate container comprises a
pharmaceutical composition comprising a tricyclic antidepressant, lithium or
an
anticonvulsant in a pharmaceutically acceptable carrier, and instructions for
use
thereof and wherein the adenosine A2a receptor antagonist is a compound of the
formula (I):
<IMG>
or a pharmaceutically acceptable salt thereof, wherein
R is R1-furanyl, R1-thienyl, R1-pyridyl, R1-pyridyl N-oxide, R1-oxazolyl,
R10-phenyl, R1-pyrrolyl or C4-C6 cycloalkenyl;
X is C2-C6 alkylene or -C(O)CH2-;
Y is -N(R2)CH2CH2N(R3)-, -OCH2CH2N(R2)-, -O-, -S-, -CH2S-, -
(CH2)2-NH-, or
<IMG>
and

45
Z is R5-phenyl, R5-phenyl(C1-C6)alkyl, R5-heteroaryl, diphenylmethyl,
<IMG>
R6-C(O)-, R6-SO2-, R6-OC(O)-, R7-N(R8)-C(O)-, R7-N(R8)-C(S)-,
<IMG>
phenyl-CH(OH)-, or phenyl-C(=NOR2)-; or when Q is , Z is also
phenylamino or pyridylamino;
or
Z and Y together are
<IMG>
<IMG> <IMG> <IMG>
or an N-oxide thereof, or
R1 is 1 to 3 substituents independently selected from hydrogen, C1-C6-alkyl,
-CF3, halogen, -NO2, -NR12R13, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6
alkylsulfinyl, and C1-C6 alkylsulfonyl;
R2 and R3 are independently selected from the group consisting of
hydrogen and C1-C6 alkyl;
m and n are independently 2-3;
Q is
<IMG>

46
R4 is 1-2 substituents independently selected from the group consisting
of hydrogen and C1-C6alkyl, or two R4 substituents on the same carbon can
form =O;
R5 is 1 to 5 substituents independently selected from the group consisting
of hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -CN, di-((C1-
C6)alkyl)amino, -CF3, -OCF3, acetyl, -NO2, hydroxy(C1-C6)alkoxy, (C1-C6)-
alkoxy(C1-C6)alkoxy, di-((C1-C6)-alkoxy)(C1-C6)alkoxy, (C1-C6)-alkoxy(C1-
C6)alkoxy-(C1-C6)-alkoxy, carboxy(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl(C1-
C6)alkoxy, (C3-C6)cycloalkyl(C1-C6)alkoxy, di-((C1-C6)alkyl)amino(C1-
C6)alkoxy, morpholinyl, (C1-C6)alkyl-SO2-, (C1-C6)alkyl-SO-(C1-C6)alkoxy,
tetrahydropyranyloxy, (C1-C6)alkylcarbonyl(C1-C6)-alkoxy, (C1-C6)-
alkoxycarbonyl, (C1-C6)alkylcarbonyloxy(C1-C6)-alkoxy, -SO2NH2, phenoxy,
<IMG>
or adjacent R5 substituents together are -O-CH2-O-, -O-CH2CH2-O-, -O-CF2-
O- or -O-CF2CF2-O- and form a ring with the carbon atoms to which they are
attached;
R6 is (C1-C6)alkyl, R5-phenyl, R5-phenyl(C1-C6)alkyl, thienyl, pyridyl,
(C3-C6)-cycloalkyl, (C1-C6)alkyl-OC(O)-NH-(C1-C6)alkyl-, di-((C1-
C6)alkyl)aminomethyl, or
<IMG>
R7 is (C1-C6)alkyl, R5-phenyl or R5-phenyl(C1-C6)alkyl;

47
R8 is hydrogen or C1-C6 alkyl; or R7 and R8 together are -CH2)p-A-
(CH2)q, wherein p and q are independently 2 or 3 and A is a bond, -CH2-, -S-
or
-O-, and form a ring with the nitrogen to which they are attached;
R9 is 1-2 groups independently selected from hydrogen, C1-C6 alkyl,
hydroxy, C1-C6 alkoxy, halogen, -CF3 and (C1-C6)alkoxy(C1-C6)alkoxy ;
R10 is 1 to 5 substituents independently selected from the group
consisting of hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -CN,
-NH2, C1-C6alkylamino, di-((C1-C6)alkyl)amino, -CF3, -OCF3 and -S(O)0-2(C1-
C6)alkyl;
R11 is H, C1-C6 alkyl, phenyl, benzyl, C2-C6 alkenyl, C1-C6 alkoxy(C1-
C6)alkyl, di-((C1-C6)alkyl)amino(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl or
piperidino(C 1-C6)alkyl;
R12 is H or C1-C6 alkyl; and
R13 is (C1-C6)alkyl-C(O)- or (C1-C6)alkyl-SO2-.
10. Use of an adenosine A2a receptor antagonist for the preparation of a
medicament for treating restless leg syndrome or periodic leg movement in
sleep, wherein the adenosine A2a receptor antagonist is a compound of the
formula (I):
<IMG>
or a pharmaceutically acceptable salt thereof, wherein
R is R1-furanyl, R1-thienyl, R1-pyridyl, R1-pyridyl N-oxide, R1-oxazolyl,
R10-phenyl, R1-pyrrolyl or C4-C6 cycloalkenyl;
X is C2-C6 alkylene or -C(O)CH2-;
Y is -N(R2)CH2CH2N(R3)-, -OCH2CH2N(R2)-, -O-, -S-, -CH2S-,
-(CH2)2-NH-, or

48
<IMG>
and
Z is R5-phenyl, R5-phenyl(C1-C6)alkyl, R5-heteroaryl, diphenylmethyl,
<IMG>
R6-C(O)-, R6-SO2-, R6-OC(O)-, R7-N(R8)-C(O)-, R7-N(R8)-C(S)-,
<IMG>
phenyl-CH(OH)-, or phenyl-C(=NOR2)-; or when Q is , Z is also
phenylamino or pyridylamino;
or
Z and Y together are
<IMG>
<IMG>
or an N-oxide thereof, <IMG>
R1 is 1 to 3 substituents independently selected from hydrogen, C1-C6-
alkyl, -CF3, halogen, -NO2, -NR12R13, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6
alkylsulfinyl, and C1-C6 alkylsulfonyl;
R2 and R3 are independently selected from the group consisting of
hydrogen and C1-C6 alkyl;

49
m and n are independently 2-3;
Q is
<IMG>
R4 is 1-2 substituents independently selected from the group consisting
of hydrogen and C1-C6alkyl, or two R4 substituents on the same carbon can
form =O;
R5 is 1 to 5 substituents independently selected from the group consisting
of hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -CN, di-((C1-
C6)alkyl)amino, -CF3, -OCF3, acetyl, -NO2, hydroxy(C1-C6)alkoxy, (C1-C6)-
alkoxy(C1-C6)alkoxy, di-((C1-C6)-alkoxy)(C1-C6)alkoxy, (C1-C6)-alkoxy(C1-
C6)alkoxy-(C1-C6)-alkoxy, carboxy(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl(C1-
C6)alkoxy, (C3-C6)cycloalkyl(C1-C6)alkoxy, di-((C1-C6)alkyl)amino(C1-
C6)alkoxy, morpholinyl, (C1-C6)alkyl-SO2-, (C1-C6)alkyl-SO-(C1-C6)alkoxy,
tetrahydropyranyloxy, (C1-C6)alkylcarbonyl(C1-C6)-alkoxy, (C1-C6)-
alkoxycarbonyl, (C1-C6)alkylcarbonyloxy(C1-C6)-alkoxy, -SO2NH2, phenoxy,
<IMG>
or adjacent R5 substituents together are -O-CH2-O-, -O-CH2CH2-O-, -O-CF2-O-
or -O-CF2CF2-O- and form a ring with the carbon atoms to which they are
attached;
R6 is (C1-C6)alkyl, R5-phenyl, R5-phenyl(C1-C6)alkyl, thienyl, pyridyl,
(C3-C6)-cycloalkyl, (CI-C6)alkyl-OC(O)-NH-(C1-C6)alkyl-, di-((C1-
C6)alkyl)aminomethyl, or

50
<IMG>
R7 is (C1-C6)alkyl, R5-phenyl or R5-phenyl(C1-C6)alkyl;
R8 is hydrogen or C1-C6 alkyl; or R7 and R8 together are -(CH2)p-A-
(CH2)q, wherein p and q are independently 2 or 3 and A is a bond, -CH2-, -S-
or
-O-, and form a ring with the nitrogen to which they are attached;
R9 is 1-2 groups independently selected from hydrogen, C1-C6 alkyl,
hydroxy, C1-C6 alkoxy, halogen, -CF3 and (C1-C6)alkoxy(C1-C6)alkoxy ;
R10 is 1 to 5 substituents independently selected from the group
consisting of hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -CN,
-NH2, C1-C6alkylamino, di-((C1-C6)alkyl)amino, -CF3, -OCF3 and -S(O)0-2(C1-
C6)alkyl;
R1 is H, C1-C6 alkyl, phenyl, benzyl, C2-C6 alkenyl, C1-C6 alkoxy(C1-
C6)alkyl, di-((C1-C6)alkyl)amino(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl or
piperidino(C1-C6)alkyl;
R12 is H or C1-C6 alkyl; and
R13 is (C1-C6)alkyl-C(O)- or (C1-C6)alkyl-SO2-.
11. The use of claim 10 further comprising the use of levodopa/carbidopa,
levodopa/benserazide, a dopamine agonist, a benzodiazepine, an opioid, an
anticonvulsant or iron for the preparation of a medicament for use in
combination with the adenosine A2a receptor antagonist medicament.
12. A kit comprising, in separate containers in a single package,
pharmaceutical compositions for use in combination to treat or prevent
restless

51
leg syndrome or periodic leg movement in sleep, wherein one container
comprises a pharmaceutical composition comprising an adenosine A2a receptor
antagonist in a pharmaceutically acceptable carrier, and wherein a separate
container comprises a pharmaceutical composition comprising a dopamine
agonist, benzodiazepine, opioid, anticonvulsant or iron in a pharmaceutically
acceptable carrier and instructions for use thereof and wherein the adenosine
A2a receptor antagonist is a compound of the formula (I):
<IMG>
or a pharmaceutically acceptable salt thereof, wherein
R is R1-furanyl, R1-thienyl, R1-pyridyl, R1-pyridyl N-oxide, R1-oxazolyl,
R10-phenyl, R1-pyrrolyl or C4-C6 cycloalkenyl;
X is C2-C6 alkylene or -C(O)CH2-;
Y is -N(R2)CH2CH2N(R3)-, -OCH2CH2N(R2)-, -O-, -S-, -CH2S-, -
(CH2)2-NH-, or
<IMG>
and
Z is R5-phenyl, R5-phenyl(C1-C6)alkyl, R5-heteroaryl, diphenylmethyl,
<IMG>
R6-C(O)-, R6-SO2-, R6-OC(O)-, R7-N(R8)-C(O)-, R7-N(R8)-C(S)-,

52
<IMG>
phenyl-CH(OH)-, or phenyl-C(=NOR2)-; or when Q is , Z is also
phenylamino or pyridylamino;
or
Z and Y together are
<IMG>
<IMG> <IMG> or <IMG>
or an N-oxide thereof,
R1 is 1 to 3 substituents independently selected from hydrogen, C1-C6-
alkyl, -CF3, halogen, -NO2, -NR12R13, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6
alkylsulfinyl, and C1-C6 alkylsulfonyl;
R2 and R3 are independently selected from the group consisting of
hydrogen and C1-C6 alkyl;
m and n are independently 2-3;
Q is
<IMG>
R4 is 1-2 substituents independently selected from the group consisting
of hydrogen and C1-C6alkyl, or two R4 substituents on the same carbon can
form =O;

53
R5 is 1 to 5 substituents independently selected from the group consisting
of hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -CN, di-((C1-
C6)alkyl)amino, -CF3, -OCF3, acetyl, -NO2, (C1-C6)-
alkoxy(C1-C6)alkoxy, di-((C1-C6)-alkoxy)(C1-C6)alkoxy, (C1-C6)-alkoxy(C1-
C6)alkoxy-(C1-C6)-alkoxy, carboxy(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl(C1-
C6)alkoxy, (C3-C6)cycloalkyl(C1-C6)alkoxy, di-((C1-C6)alkyl)amino(C1-
C6)alkoxy, morpholinyl, (C1-C6)alkyl-SO2-, (C1-C6)alkyl-SO-(C1-C6)alkoxy,
tetrahydropyranyloxy, (C1-C6)alkylcarbonyl(C1-C6)-alkoxy, (C1-C6)-
alkoxycarbonyl, (C1-C6)alkylcarbonyloxy(C1-C6)-alkoxy, -SO2NH2, phenoxy,
<IMG>
or adjacent R5 substituents together are -O-CH2-O-, -O-CH2CH2-O-, -O-CF2-O-
or -O-CF2CF2-O- and form a ring with the carbon atoms to which they are
attached;
R6 is (C1-C6)alkyl, R5-phenyl, R5-phenyl(C1-C6)alkyl, thienyl, pyridyl,
(C3-C6)-cycloalkyl, (C1-C6)alkyl-OC(O)-NH-(C1-C6)alkyl-, di-((C1-
C6)alkyl)aminomethyl, or
<IMG>
R7 is (C1-C6)alkyl, R5-phenyl or R5-phenyl(C1-C6)alkyl;
R8 is hydrogen or C1-C6 alkyl; or R7 and R8 together are -(CH2)p-A-
(CH2)q, wherein p and q are independently 2 or 3 and A is a bond, -CH2-, -S-
or
-O-, and form a ring with the nitrogen to which they are attached;

54
R9 is 1-2 groups independently selected from hydrogen, C1-C6 alkyl,
hydroxy, C1-C6 alkoxy, halogen, -CF3 and (C1-C6)alkoxy(C1-C6)alkoxy ;
R10 is 1 to 5 substituents independently selected from the group
consisting of hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -CN,
-NH2, C1-C6alkylamino, di-((C1-C6)alkyl)amino, -CF3, -OCF3 and -S(O)0-2(C1-
C6)alkyl;
R11 is H, C1-C6 alkyl, phenyl, benzyl, C2-C6 alkenyl, C1-C6 alkoxy(C1-
C6)alkyl, di-((C1-C6)alkyl)amino(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl or
piperidino(C1-C6)alkyl;
R12 is H or C1-C6 alkyl; and
R13 is (C1-C6)alkyl-C(O)- or (C1-C6)alkyl-SO2-.

Description

CA 02710829 2010-08-03
1
USES OF ADENOSINE A2A RECEPTOR ANTAGONISTS
This application is a Divisional of CA 2,510,655.
15 FIELD OF THE INVENTION
The present invention relates to the use of adenosine Ala receptor antagonists
for the treatment of a variety of neurological syndromes involving the extra-
pyramidal
motor system (i.e. Extra-Pyramidal Syndrome) that occur following the acute
and
chronic use of almost all antipsychotic drugs. The invention also relates to
the use of
adenosine Ala receptor antagonists for the treatment of other abnormal
movement
disorders such as restless leg syndrome (RLS) and periodic limb movement in
sleep
(PLMS).
BACKGROUND OF THE INVENTION
Extra-Pyramidal Syndrome (EPS) is a collective term for a series of adverse
neurological reactions associated with the use of antipsychotic drugs. There
are six
different categories of EPS-related neurological syndromes of which four,
dystonia,
akathisia, pseudoparkinsonism (parkinsonian syndrome), and tardive dyskinesia,
are
particularly prevalent in patients taking antipsychotic medication. Dystonia
is a painful
spasm of the muscle groups of, in particular, the neck, jaw, back, pharynx,
and larynx.
It is most common in young males being treated with antipsychotic drugs, but
can
also be associated with the use of cocaine, tricyclic antidepressants, lithium
and
anticonvulsants such as phenytoin and carbamazepine. Pseudoparkinsonism
manifests itself as akinesia (rigidity, stiffness and slow voluntary motion,
stooped,
shuffling walk) and tremor and these symptoms develop within weeks or months
after

CA 02710829 2010-08-03
2
initiation of therapy. Akathisia manifests itself as strong, subjective inner
feelings of
distress or discomfort characterized by motor restlessness. Often mistaken for
agitation or anxiety, this common syndrome is frequently under-diagnosed and
is the
least responsive to treatment. Tardive dyskinesia is a late-appearing syndrome
associated with chronic use of neuroleptic drugs. It occurs more frequently in
older
patients and is characterized by stereotypical, repetitive, involuntary, quick
choreiform
movements of the face, eyelids, mouth, tongue, extremities and trunk.
EPS is more prevalent with the use of typical antipsychotic agents but has
also
been reported with the use of atypical agents. Typical antipsychotics include
loxapine, haloperidol, chlorpromazine, prochlorperazine and thiothixene.
Atypical
antipsychotics include clozapine, olanzapine, loxapine, quetiapine,
ziprasidone and
risperidone.
Akathisia is also a characteristic of RLS and PLMS, as well as PLMD (periodic
leg (or limb) movement disorder). RLS is a common disorder that causes
patients to
have an irresistible and unpleasant desire to move their legs; it usually
manifests
during periods of inactivity and/or at night, and can disturb sleep. Patients
who do not
have the typical RLS symptoms, but who do exhibit periodic leg movements that
adversely impact sleep, are diagnosed with PLMS. Treatments for RLS and PLMS
have included levodopa/carbidopa, levodopa/benserazide, dopamine agonists such
as pramipexole and ropinerole, benzodiazepines, opioids, anticonvulsants and
iron
(ferrous sulfate). RLS and PLMS have been extensively described in the
literature,
for example by Saletu et al, Neuropsychobiology, 41, 4 (2000), p. 190-9.
The purine nucleotide, adenosine, is known to be an endogenous modulator of
a number of physiological functions in the central (CNS) and peripheral
nervous
systems.
Adenosine exerts its biological actions through a class of membrane specific
receptors which belong to the super family of receptors coupled with G
proteins.
Biochemical and pharmacological studies, together with advances in molecular
biology, have allowed the identification of at least four subtypes of
adenosine
receptors: A,, A2ai A2b and A3. Analogs of adenosine able to interact as
antagonists
with the A,, A2a, A2b and A3 receptors have also been-identified.
In the CNS, data has shown that A2a receptors are present in high density in
the basal ganglia, known to be important in the control of fine motor
movement.
Moreover, selective antagonists for the A2a receptor are of pharmacological
interest

CA 02710829 2010-08-03
3
because of their demonstrated efficacy in reducing motor impairment thereby
improving function In neurodegenerative diseases such as Parkinson's disease
and
related movement disorders (e.g. Huntington's Disease). A2. antagonists appear
to
demonstrate a reduced side-effect liability (e.g. no dyskinesia) compared to
current
dopaminergic therapies resulting in an improved therapeutic index. Ara
antagonists
may also have antidepressant properties and stimulate cognitive functions.
Some
xanthine-related compounds have been found to be A, receptor selective
antagonists, and xanthine and non-xanthine compounds have been found to have
high Ala affinity with varying degrees of Ala vs. A, selectivity. Adenosine
Ala receptor
antagonists have been disclosed previously, for example in WO 95/01356 and
US 6,630,475.
SUMMARY OF THE INVENTION
This invention relates to a method for the treatment or prevention of Extra-
Pyramidal Syndrome (e.g., dystonia, akathisia, pseudoparkinsonism and tardive
dyskinesia) comprising administering a therapeutically effective amount of an
adenosine Ala receptor antagonist to a patient In need thereof. In particular,
this
method is for the treatment or prevention of EPS In patients treated with an
antipsychotic agent that has the side effect of inducing EPS. The adenosine
Ala
receptor antagonist can be administered after the symptoms of EPS have
manifested, or an adenosine Ala receptor antagonist can be administered at the
onset of administering an antipsychotic agent in order to prevent EPS from
occurring.
The invention, therefore, also includes a method of treating or preventing EPS
induced by an antipsychotic agent comprising administering a combination of an
antipsychotic agent and an adenosine Ala antagonist to a patient in need
thereof.
More particularly, the Invention relates to the method of using of certain
adenosine
A28 antagonists for the monotherapy or the combined therapy.
The invention also relates to the treatment of primary (idiopathic) dystonia,
and
to the treatment or prevention of dystonia in patients who exhibit dystonia as
a result
of treatment with a tricyclic antidepressant, lithium or an anticonvulsant, or
who have
used cocaine, comprising administering a therapeutically effective amount of
an
adenosine Ala receptor antagonist to a patient in need thereof. When dystonia
is
caused by treatment with a tricyclic antidepressant, lithium or an
anticonvulsant, the
adenosine Ala receptor antagonist can be administered after the symptoms of

CA 02710829 2010-08-03
4
dystonia have manifested, or an adenosine Ala receptor antagonist can be
administered at the onset of administering a tricyclic antidepressant, lithium
or an
anticonvulsant in order to prevent dystonia from occurring. The invention,
therefore,
also includes a method of treating or preventing dystonia induced by a
tricyclic
antidepressant, lithium or an anticonvulsant comprising administering a
combination
of an adenosine Ala antagonist and a tricyclic antidepressant, lithium or an
anticonvulsant to a patient in need thereof.
The invention also relates to the treatment of RLS or PLMS, comprising
administering to a patient In need thereof a therapeutically effective amount
of an
adenosine Ala receptor antagonist. The invention also comprises a method of
treating RLS or PLMS comprising administering a combination of an adenosine
A2.
antagonist with another agent useful in treating RLS or PLMS, such as
levodopa/carbidopa, levodopa/benserazide, a dopamine agonist, a
benzodiazepine,
an opioid, an anticonvulsant or iron, to a patient in need thereof.
In another aspect, this invention relates to a kit comprising, in separate
containers in a single package, pharmaceutical compositions for use in
combination
to treat or prevent EPS caused by treatment with antipsychotic agent, wherein
one
container comprises a pharmaceutical composition comprising an effective
amount of
an adenosine Ala receptor antagonist in a pharmaceutically acceptable carrier,
and
wherein a separate container comprises a pharmaceutical composition comprising
an
effective amount of an antipsychotic agent.
In another aspect, this invention relates to a kit comprising, in separate
containers in a single package, pharmaceutical compositions for use in
combination
to treat or prevent dystonia caused by treatment with a tricyclic
antidepressant, lithium
or an anticonvulsant, wherein one container comprises a pharmaceutical
composition
comprising an effective amount of an adenosine Ate, receptor antagonist in a
pharmaceutically acceptable carrier, and wherein a separate container
comprises a
pharmaceutical composition comprising an effective amount of a tricyclic
antidepressant, lithium or an anticonvulsant.
In another aspect, this invention relates to a kit comprising, in separate
containers in a single package, pharmaceutical compositions for use in
combination
to treat RLS or PLMS, wherein one container comprises a pharmaceutical
composition comprising an effective amount of an adenosine Ala receptor
antagonist
in a pharmaceutically acceptable carrier, and wherein a separate container
comprises

CA 02710829 2010-08-03
a pharmaceutical composition comprising an effective amount of
levodopa/carbidopa,
levodopa/benserazide, a dopamine agonist, a benzodiazepine, an opioid, an
anticonvulsant or iron.
The invention also relates to the use of an adenosine A2a receptor antagonist
5 for the preparation of a medicament for treating or preventing EPS,
dystonia, RLS or
PLMS, alone or in combination with the other agents discussed above.
DETAILED DESCRIPTION OF THE DRAWINGS
A more complete understanding of the invention may be obtained by reading
the following description in conjunction with the appended figures relating to
haloperidol-induced EPS in Cebus apella monkeys.
Figure 1A illustrates the effect of Compound A (1-30 mg/kg,'p.o.) on maximum
EPS
score.
Figure 1 B represents the mean delay in onset of EPS for each treatment group
compared to a vehicle control group.
DETAILED DESCRIPTION OF THE INVENTION
Any adenosine A2a receptor antagonist is contemplated for use in the method
of this invention. Suitable adenosine Ala receptor antagonists useful in the
method of
the invention can be identified by the binding assay described below. Specific
examples of suitable adenosine A2a antagonists include the compounds disclosed
in
several patents and patent applications, e.g. WO 95/01356; US 5,565,460; US
6,630,475 B2; US 5,935,964; WO 03/032996; WO 03/048165; WO 03/048164; WO
03/048163; and WO 01/02409. Specifically, these patents and applications
disclose
the following compounds.
US 6,630,475 B2 discloses compounds having the structural formula I
NH2
NN"NR
~ '` N
Z-Y-X-N
N I
or a pharmaceutically acceptable salt thereof, wherein
R is R1-furanyl, R1-thienyl, R1-pyridyl, R1-pyridyl N-oxide, R1-oxazolyl,
R10-phenyl, R1-pyrrolyl or C4-C6 cycloalkenyl;
X is C2-C6 alkylene or -C(O)CH2-;
Y is -N(R2)CH2CH2N(R3)-, -OCH2CH2N(R2)-, -0-, -S-, -CH2S-, -(CH2)2-NH-, or

CA 02710829 2010-08-03
6
~(CH2)m
-Q N-
%
(CH\R4
and
Z is R5-phenyl. R5 phenyl(C1-C6)alkyl, R5-heteroaryl, diphenylmethyl, Rs-C(O)-
,
HNxN-
R6-S02-, R6-OC(O)-, R7-N(R8)-C(O)-, R7 N(R)-C(S)-, 0 , phenyl-CH(OH)-, or
-C-
phenyl-C(=NOR)-; or when Q Is H , Z Is also phenylamino or pyridylamino;
or
Z and Y together are
R \ _
N 1 \ - r N N l Ri 1ONN_
H N HN N 1.~
O
io N-
R10 _ I O)CN- R
_
CA
Rio Rio
R~_3 _ or an N-oxide thereof, R'O
\ N- or
-N - N- ;
R1 is I to 3 substituents independently selected from hydrogen, C1-C6-alkyl,
-CF3, halogen, -NO2, -NR 12R13, C1-C6 alkoxy, C1-C6 alkylthio, Cj-C6
alkylsulfinyl, and
C1-C6 alkylsulfonyl;
R2 and R3 are independently selected from the group consisting of hydrogen
and C1-C6 alkyl;
.m and n are independently 2-3;
Q is
I I I I I
-N- -c- , -- -C-
I cor -c-
H N ' OH COCH3 ;
R4 is 1-2 substituents independently selected from the group consisting of
hydrogen and C1-C6alkyl, or two R4 substituents on the same carbon can form
=0;
R5 is I to 5 substituents independently selected from the group consisting of
hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -CN, di-((C1-
C6)alkyl)amino,

CA 02710829 2010-08-03
7
-CF3, -OCF3, acetyl, -NO2, hydroxy(C1-C6)alkoxy, (C1-C6)-alkoxy(C1-C6)alkoxy,
di-((C1-
Cs)-alkoxy)(C1-C6)alkoxy, (C1-C6)-alkoxy(C1-C6)alkoxy-(C1-C6)-alkoxy,
carboxy(C1-C6)-
alkoxy, (C1-Cs)-alkoxycarbonyl(C1-C6)alkoxy, (C3-C6)cycloalkyl(C1-C6)alkoxy,
di-((C1-C6)alkyl)amino(C1-C6)alkoxy, morpholinyl, (C1-C6)alkyl-SO2-, (C1-
C6)alkyl-SO.
(C1-C6)alkoxy, tetrahydropyranyloxy, (C1-C6)alkylcarbonyl(C1-C6)-alkoxy, (C1-
C6)-
alkoxycarbonyl, (C~1-C6)alkylcarbonyloxy(C1-C6)-alkoxy, -SO2NH2, phenoxy,
(i 1-C6 alkyl) 1 O
-C=NOR2 cCH3
O- ; or adjacent R5 substituents together are -O-CH2-O-, -O-
CH2CH2-O-, -0-CF2-O- or -O-CF2CF2-O- and form a ring with the carbon atoms to
which they are attached;
R6 is (C1-C6)alkyl, R5 phenyl, R5 phenyl(C1-C6)alkyl, thienyl, pyridyl, (C3-
C6)-
cycloalkyl, (C1-C6)alkyl-OC(O)-NH-(C1-C6)alkyl-, di-((C1-C6)alkyl)aminomethyl,
or
(C1-C6)aIkyl-OHO
R7 is (C1-C6)alkyl, R5-phenyl or R5-phenyl(C1-C6)alkyl;
R8 is hydrogen or C,-C6 alkyl; or R7 and R8 together are -(CHOP-A-(CI2)q,
wherein p and q are independently 2 or 3 and A is a bond, -CHr, -S- or-0-, and
form a ring with the nitrogen to which they are attached;
R9 is 1-2 groups independently selected from hydrogen, C1-C6 alkyl, hydroxy,
C1-C6 alkoxy, halogen, -CF3 and (C1-C6)alkoxy(C1-C6)alkoxy ;
R10 is I to 5 substituents independently selected from the group consisting of
hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -CN, -NH2, C1-
C6alkylamino,
di-((C1-C6)alkyl)amino, -CF3, -OCF3 and -S(O)0.2(C1-C6)alkyl;
R11 is H, C1-C6 alkyl, phenyl, benzyl, C2-Ce alkenyl, C1-C6 alkoxy(C1-
C6)alkyl,
di-((C1-C6)alkyl)amino(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl or piperidino(C1-
C6)alkyl;
R12 is H or C1-C6 alkyl; and
R13 is (C1-C6)alkyl-C(O)- or (C1-C6)alkyl-SO2-.
Preferred compounds of formula I are those wherein R is R1-furanyl, R1-
thienyl, R1-pyrrolyl or R10-phenyl, more preferably R1-furanyl. R1 is
preferably
hydrogen or halogen. Another group of preferred compounds is that wherein X is

CA 02710829 2010-08-03
8
CH2)fn
-Q ~N--
alkylene, preferably ethylene. Y is preferably (CH2y~R4 wherein Q is
I I
-N- or -CH- , with Q preferably being nitrogen. Preferably, m and n are each
2,
and R4 is H. A preferred definition for Z is R5-phenyl, R5-heteroaryl, RS-C(O}
or R6-
SO2-. R5 is preferably H, halogen, alkyl, alkoxy, hydroxyalkoxy or
alkoxyalkoxy. Rs is
preferably R5 phenyl.
Preferred specific compounds of formula I are those of the formula IA
NH2
N)I~N-N
Z-Y N
-N` R IA
wherein R and Z-Y are as defined in the following table:
Z-Y R
F O
F N N- ` /
n O
N N-
F O
F \ N N- /
F
OCH3 0
OCH3 F O
o v-
F O
H3C0 N N-
H 0\/
3CO
F O
CI nN - /
N

CA 02710829 2010-08-03
9
rOCH3
N N-
F
F--C C,>,-N N- 0\0/ N
H3C N N N- \ O/
F F
F N N-
F l
F v-
Other useful adenosine Ala receptor antagonists include those disclosed in
WO 95/01356 as compounds having the structural formula II
0
N ~
,N
R A
N NH2 II
wherein:
A is pyrazole, imidazole or a triazole ring;
R is hydrogen; C1-C8 alkyl; C3-C7 alkenyl; C3-C7 alkynyl; C3-C7 cycloalkyl; C1-
C5
alkyl substituted with one or more halogen atoms, hydroxy groups, C1-C4
alkoxy, C3-
C7 cycloalkyl, groups of formula -NR1R2, -CONR1R2; aryl optionally substituted
with
halogen atoms, C1-C4 alkoxy groups, C1-C4 alkyl, nitro, amino, cyano, C1-C4
haloalkyl,
C1-C4 haloaikoxy, carboxy, carboxyamido; C7-C10 aralkyl in which the aryl
moiety can
be substituted with one or more of the substituents indicated above for the
aryl group;
a group of formula -(CH2)m-Het, wherein Het is a 5-6 membered aromatic or non
aromatic heterocyclic ring containing one or more heteroatoms selected from N,
0, S
and m is an integer from I to 5;
R1, R2 which are the same or different, are hydrogen, C1-C5 alkyl, C7-C10
aralkyl, phenyl, or taken together with the nitrogen they are linked to, form
an
azetidine ring or a 5-6 membered heterocyclic ring containing one or more
heteroatoms such as N, 0, S and n is an integer from 2 to 5.

CA 02710829 2010-08-03
Preferably, compounds of formula II are those wherein R is hydrogen, Cr-C8
alkyl, aryl or CrCio aralkyl optionally substituted, preferably with halogen
atoms.
US 5,935,964 discloses useful adenosine Aza receptor antagonist compounds
5 having the structural formula III
0
N
,N
R AN
N NH2 III
wherein A is pyrazole, imidazole or triazole ring;
R is
~R2
- (CH2)n-(~ ' _ j R1
OH
10 Ri and R2, which are the same or different, are H, OH, halogen, Ci-C4
alkoxy,
C,-C4 alkyl, nitro, amino, cyano, C1-C4 haloalkyl, C1-C4 haloalkoxy, carboxy
or
carboxamido; or the OH group, together with one of RI or R2, or Rj and R2, can
form
a methylenedioxy group -O-CH2-O-; and
n is an integer from 0-4.
Preferred compounds of formula III are those wherein A is pyrazolo[4,3-e] or
1,2,3-triazolo[5,4-e].
US 5,565,460 discloses useful adenosine Ala receptor antagonist compounds
having the structural formulas IVA and IVB, wherein formula IVA is
NHR'
N'N-N-R3
R2X~N~A IVA
wherein R1 represents hydrogen, substituted or unsubstituted lower alkyl, or
substituted or unsubstituted lower alkanoyl;
R2 represents hydrogen, substituted or unsubstituted lower alkyl, substituted
or
unsubstituted lower alkenyl, substituted or unubstituted cycloalkyl,
substituted- or

CA 02710829 2010-08-03
11
unsubstituted aryl, substituted or unsubstituted aralkyl, or a substituted or
unsubstituted heterocyclic group;
R3 represents a substituted or unsubstituted heterocyclic group;
X represents a single bond, 0, S, S(O), S(O)2, or NR4 (in which R4 represents
hydrogen, or substituted or unsubstituted lower alkyl; or R2 and NR4 are
combined to
form a substituted or unsubstituted 4 to 6-membered saturated heterocyclic
group):
and
A represents N or CR5 (in which R5 represents hydrogen, or a substituted or
unsubstituted lower alkyl); and
wherein formula IVB is
R6
B N
Y
R8 IVB
wherein R6 represents substituted or unsubstituted aryl, or a substituted or
unsubstituted heterocyclic group;
Y represents 0, S, or NR7 (in which R7 represents substituted or unsubstituted
lower alkyl, substituted or unubstituted cycloalkyl, or substituted or
unsubstituted aryl);
R8 represents hydrogen, substituted or unsubstituted lower alkyl, substituted
or
unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl,
substituted or
unubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted
aralkyl, or a substituted or unsubstituted heterocyclic group; and
B and the adjacent two carbon atoms are combined to form a substituted or
unsubstituted, partially saturated or unsaturated, monocyclic or bicyclic,
carbocyclic or
heterocyclic group.
WO 03/032996 discloses useful adenosine Ala receptor antagonist
compounds having the structural formula V
NH2
NN- N
~-R
Z-Y-X- -- N
~--
N
R14 V
or a pharmaceutically acceptable salt thereof, wherein
R is R1-heteroaryl, R10-phenyl, C4-C6 cycloalkenyl, -C(=CH2)CH3, -C-C-CHs,

CA 02710829 2010-08-03
12
2 )or ~Ol
-C=C-CHrOR , -CH=C(CH3)2, 0
X is C1-C6 alkylene, -C(O)CH2- or -C(O)N(R2)CH2-;
Y is -N(R2)CH2CH2N(R3)-, -OCH2CH2N(R2)-, -0-, -S-, -CH2S-, -(CH2)2.3-N(R2)-,
R5-divalent heteroaryl,
)p (CH2)m
-N- ~N-- -Q
or (CHI\R4
and
Z is R5-phenyl, R5-phenyl(C1-C6)alkyl, R5-heteroaryl, R5-bicyclic heteroaryl,
R5-benzofused heteroaryl, diphenylmethyl or R6-C(O)-;
or when Y is
CH2)m
-Q Qi---
(CH2y\R4
Z is also R6-S02-, R7-N(R)-C(O)-, R7-N(R8)-C(S)- or R60C(O)-;
I
or when Q is -CH-, Z is also phenylamino or pyridylamino;
or Z and Y together are
N- ' HN \< N- %\ ,\/, R11ON=-CN-'
O N_CN-
O R10NR5~\
R10 I )CN- - _\-~N- N N
9 l=/Ri R10 R10 ~~ or an N-oxide thereof, N-
N N-
or Y and Z together form a piperidinyl or pyrrolidinyl ring fused to a
monocyclic or
bicyclic aryl or a monocyclic or bicyclic heteroaryl ring wherein X is
attached to the N
atom of the piperidinyl or pyrrolidinyl ring;
R1 is 1 to 3 substituents independently selected from hydrogen, C1-C6-alkyl,
-CF3, halogen, -NO2, -NR12R13, CI-C6 alkoxy, C1-C6 alkylthio, C1-C6
alkylsulfinyl, C1-
C6 alkylsulfonyl, -000R' or -C(O)NR2R3;

CA 02710829 2010-08-03
13
R2 and R3 are independently selected from the group consisting of hydrogen
and C1-C6 alkyl;
m and n-are independently 2-3;
p and q are independently 0-2;
Q and Q1 are independently selected from the group consisting of
I I I I I
-N- -CH- -C- -C--
' I I and -C_
CN ' OH COCH3
provided that at least one of Q and Q1 is -N- or -CH- ;
R4 is 1-2 substituents independently selected from the group consisting of
hydrogen, Ci-C6alkyl, R1-aryl and R1-heteroaryl, or two R4 substituents on the
same
carbon can form =0;
R5 is I to 5 substituents independently selected from the group consisting of
hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -CN, di-((Ci-
C6)alkyl)amino,
-CF3, -OCF3, acetyl, -NO2, hydroxy(C1-C6)alkoxy, (C1-C6)-alkoxy(Ci-C6)alkoxy,
di-((Ci-
C6)-alkoxy)(Ci-C6)alkoxy, (C1-C6)-alkoxy(Ci-C6)alkoxy-(Ci-C6)-alkoxy,
carboxy(Ci-C6)-
alkoxy, (C1-C6)-alkoxycarbonyl(C1-C6)alkoxy, (C3-C6)cycloalkyl(C1-C6)alkoxy,
di-((Ci-C6)alkyl)amino(C1-C6)alkoxy, morpholinyl, (Ci-C6)alkyl-SO2-, (Ci-
C6)alkyl-S02-
(C1-C6)alkoxy, tetrahydropyranyloxy, (C1-C6)alkylcarbonyl(C1-C6)-alkoxy, (C1-
C6)-
alkoxycarbonyl, (C1-C6)alkylcarbonyloxy(C1-C6)-alkoxy, -SO2NH2, phenoxy,
(i 1-C6 alkyl) 0 O
-C=NOR2 CH3
' o- , (R2O)2-P(O)-CH2-O- and (R20)2-P(O)-; or adjacent R5
substituents together are -O-CH2-O-, -0-CH2CH2-O-, -0-CF2-O- or -0-CF2CF2-O-
and form a ring with the carbon atoms to which they are attached;
R6 is (Ci-C6)alkyl, R5-phenyl, R5-phenyl(C1-C6)alkyl, thienyl, pyridyl, (C3-
C6)-
cycloalkyl, (Ci-C6)alkyl-OC(O}NH-(C1-C6)alkyl-, di-((C1-C6)alkyl)aminomethyl,
or
--
(C1-C6)alkyl-O'I__O
R7 is (C1-C6)alkyl, R5-phenyl or R5-phenyl(C1-C6)alkyl;
R8 is hydrogen or C1-C6 alkyl; or R7 and R8 together are -{CI2)p-A-(CH2)q,
wherein p and q are independently 2 or 3 and A is a bond, -CH2-, -S- or -0-,
and
form a ring with the nitrogen to which they are attached;

CA 02710829 2010-08-03
14
R9 is 1-2 substituents independently selected'from the group consisting of
hydrogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, halogen, -CF3 and (C1-C6)alkoxy-
(C1-C6)alkoxy; .
R70 is I to 5 substituents independently selected from the group consisting of
hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -CN, -NH2, C1-
C6alkylamino,
di-((CI-C6)alkyl)amino, -CF3, -OCF3, -S(O)a2(Ci-C6)alkyl and -CH2-SO2-phenyl;
R11 is H, C1-C6 alkyl, phenyl, benzyl, C2-C6 alkenyl, C1-C6 alkoxy(C1-
C6)alkyl,
di-((C1-C6)alkyl)amino(C1-C6)alkyl, pyrrolidinyl(C,-C6)alkyl or piperidino(Cj-
C6)alkyl;
R12 is H or C1-C6 alkyl;
R 13 is H, (C1-C6)alkyl-C(O)- or (C1-C6)alkyl-SO2-;
R14 is H, halogen, C1-C6 alkyl, hydroxy(C1-C6)alkyl, C1-C6 alkoxy(C1-C6)alkyl,
thio(C1-C6)alkyl, (C1-C6)alkylthio(C1-C6)alkyl or NR2R3-(C,-C6)alkyl; and
R15 is H, halogen, C1-C6 alkyl or C1-C6 alkoxy.
Preferred compounds of formula V are those wherein R is R1-furanyl, R1-
thienyl, R1-pyrrolyl, R1-pyridyl or R10-phenyl, more preferably R1-furanyl or
R10-
phenyl. R1 is preferably hydrogen or halogen. R10 is preferably hydrogen,
halogen,
alkyl or -CF3. Another group of preferred compounds is that wherein X is
alkylene,
CH2)m
-Q preferably ethylene. Y is preferably (CH2\R4 wherein Q is -N- or -CH-, with
Q preferably being nitrogen. Preferably, m and n are each 2, and R4 is H. A
preferred definition for Z is R5-phenyl or R5-heteroaryl. R5 is preferably H,
halogen,
alkyl, alkoxy, hydroxyalkoxy or alkoxyalkoxy. R6 is preferably R5-phenyl.
Preferred specific compounds of formula V are those of the formula VA
NH2
NN-N
Z-Y~N N}--R
VA
wherein R and Z-Y are as defined in the following table:
Z-Y- R
OCH3 0
0 ~ ~ N 1-- \ /

CA 02710829 2010-08-03
Q-o-
F _ O
/
/ N N"
OCH3
F
N
H3C C\/-Nr H3C--CN C - )
(0CH3 F
-of, \---/ --0
CI F3C
r-N
(OCH3 -of,
OCH3 N
N =
N - 0
WO 03/048165 discloses useful adenosine Ala receptor antagonist
compounds having the structural formula VI
NH2
II NWN
Y` R
N
X-N
N VI
5 or a pharmaceutically acceptable salt or solvate of said compound, wherein:
R is selected from the group consisting of R'-furanyl-, R1-thienyl-, R1-
pyridyl-,
R1-oxazolyl-, R'-pyrrolyl- and R2-aryl-;
X is -(CH2)õ-;

CA 02710829 2010-08-03
16
Y is a piperidinyl, pyrrolidinyl or azepanyl group with an aryl or heteroaryl
moiety fused to two adjacent carbon atoms on Y, wherein X is attached to the N
atom
of the piperidinyl, pyrrolidinyl or azepanyl group;
Q is 1-4 substituents, which can be the same or different, and are
independently selected from the group consisting of hydrogen, cycloalkyl,
cycloheteroalkyl, amino, aryl, aralkyl, heteroaryl, alkyl, CF3, CN, halogen,
NO2, alkoxy,
alkoxyalkoxy, cycloalkylalkoxy, acyloxy, alkylamino, acylamino,
alkylsulfonamino,
alkylaminosulfonyl, dialkylaminosulfonyl, NH2SO2-, and hydroxy;
n is I to 4;
R1 is 1-3 substituents, which may be the same or different, and are
independently selected from the group consisting of hydrogen, alkyl, CF3,
halogen
and NO2; and
R2 is 1-3 substituents, which may be the same or different, and are
independently selected from the group consisting of hydrogen, alkyl, CF3,
halogen,
NO2, alkoxy, acyloxy, alkylamino, acylamino, alkylsulfonamido,
alkylaminosulfonyl,
dialkylaminosulfonyl, aminosulfonyl, and hydroxyl.
In a preferred embodiment of compounds of formula VI, Y is
1 7 1 1
Z3 A~A2 Z A,A2 '~ A-A2
Z 1 4 A3 Z5 A A3 ? Zs' 3
Z A A
~m m
~ ff
or m or
wherein Al is N-X, and A2 and A3 each are CR4R5, or
Al and A3 each are CR4R5, and A2 is N-X, or
Al and A2 each are CR4R5, and A3 is N-X;
A4 is CR4R5;
Z', Z2, Z3 and Z4 , which can the same or different, are each independently
selected from the group consisting of N and CR3, provided that 0-2 of Z1, Z2,
Z3 or Z4
are N and the remainder are CR3;
Z5 is NR5, 0, S or CR4R5;
Z8 is N or CR3;
Z7 is N or CR3;
m is an integer from 0 to 2;
R3 is selected from the group consisting of hydrogen, cycloalkyl, amino, aryl,
heteroaryl, C1-C6-alkyl, CF3, CN, halogen, NO2, C1-C6-alkoxy, C1-C6-acyloxy,
C1-C6-

CA 02710829 2010-08-03
17
alkylamino, Ci-C6-acylamino, C1-C6-alkylsulfonamino, C1-C6-alkylaminosulfonyl,
Ci-
C6-dialkylaminosulfonyl, NH2-SO2-, and hydroxy;
R¾ is selected from the group consisting of hydrogen, hydroxyaikyl, aryl,
aralkyl, C1-C6-alkyl, Ci-C6-alkoxy, CF3, CN, halogen, hydroxy, and N02; and
R5 Is hydrogen or C1-C6 alkyl.
Preferred specific examples of compounds of formula VI include compounds of
the formula:
12
("OMe NH2
N--~N.N~ O
C~~ `-N \ 1N'
2
M ~ N~ N- O
l /N N
M NH2
MeO N---N- O
N
M Ph NH2
MeO N'JIN'N
WO 03/048164 discloses useful adenosine A28 receptor antagonist
compounds having the structural formula VII
NH2
N'N-NCR
R2 ,N
R3 Vil

CA 02710829 2010-08-03
18
or a pharmaceutically acceptable salt or solvate thereof; wherein:
R is selected from the group consisting of R4-heteroaryl, R5 phenyl, (C4-
0 ) E)
C6)cycloalkenyl, --C(=CH2)CH3r -CEC-CH3,
o , -CH=C(CH3)2,
and -CH=CH-CH3;
R2 Is selected from the group consisting of -W-X, -NR19(CH2)m-W X, and -
NR19CH(CH3)-W X, or
R2 is selected from the group consisting of alkyl, alkenyl and -NR18R79,
wherein
said alkyl, alkenyl or -NR18R19 is optionally substituted by -W-X;
R3 is selected from the group consisting of H, halo, alkyl, trifluoromethyl,
alkoxy, alkoxyalkyl, hydroxyalkyl, alkylamino, alkylaminoalkyl, dialkylamino,
dialkylaminoalkyl, aminoalkyl, aryl, heteroaryl, and CN;
R4 is 1 to 3 substituents, which can be the same or different, and are
independently selected from the group consisting of hydrogen, (C1-C6)-alkyl, -
CF3,
halogen, -NO2, -NR15R16, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-
C6)alkylsuifinyl, (C1-
C6)alkylsulfonyl, -COOR17 and -C(O)NR6R7;
R51S1 to 5 substituents, which can be the same or different, and are
independently selected from the group consisting of hydrogen, halogen, (C1-
C6)alkyl,
hydroxy, (C1-C6)alkoxy, -CN, -NH2, (C1-C6)alkylamino, di-((C1-C6)alkyl)amino, -
CF3, -
OCF3, -S(O)o.2(C1-C6)alkyI and -CH2-SO2-phenyl;
R6 and R7, which can be the same or different, are each independently
selected from the group consisting of hydrogen and (C1-C6)alkyl;
R8 is I to 5 substituents, which can be the same or different, and are
independently selected from the group consisting of hydrogen, halogen, (C1-
C6)alkyl,
hydroxy, C1-C6 alkoxy, -CN, amino, di-((C1-C6)alkyi)amino, -CF3, -OCF3,
acetyl, -NO2,
hydroxy(C1-C6)alkoxy, (C1-C6)-aikoxy(C1-C6)alkoxy, di-((C1-C6)-alkoxy)(C1-
C6)alkoxy,
(C1-C6)-alkoxy(C,-C6)alkoxy-(C1-C6)-alkoxy, carboxy(C1-C6)-alkoxy, (C1-C6)-
alkoxycarbonyl(C1-C6)alkoxy, (C3-C6)cydoalkyl(C1-C6)alkoxy, dl-((C1-
C6)alkyl)amino(C1-C6)alkoxy, morpholinyl, (C1-C6)alkyl-SO2-, (C1-C6)alkyl-SO2-
(C1-
C6)alkoxy, tetrahydropyranyloxy, (C1-C6)alkylcarbonyl(C1-C6)-alkoxy, (C1-C6)-
alkoxycarbonyl, (C1-C6)alkylcarbonylo)cy(C1-C6)-alkoxy, -SO2NH2, phenoxy,

CA 02710829 2010-08-03
.19
T1-C6 ak4) OCH3
--C=NOR13 , _Or;
-O-CH2-P(O)(OR6)2; and -P(O)(OR6)2; or
adjacent R6 substituents together are --O-CH2-O-, -O-CH2CH2-O-, -0-CF2-O-
or
-O-CF2CF2-O- and form a ring with the carbon atoms to which they are
attached;
R9 is selected from the group consisting of (C1-C6)alkyl, R8-aryl-, R8-aryl(C1-
C6)alkyl-, thienyl, pyridyl, (C3-C6)-cycloalkyl, (C1-C6)alkyl-OC(O)-NH-(C1-
C6)alkyl-, di-
((C1-C6)alkyl)aminomethyl, cycloheteroalkyl(C1-C6)alkyl, aryloxy(C1-C6)alkyl,
atkoxy(C1-C6)alkyl and
(C1-C6)alkyl-O O
R10 is 1-2 substituents, which can be the same or different, and are
independently selected from the group consisting of hydrogen, (C1-C6)alkyl, R5-
aryl
and R4-heteroaryl, or two R10 substituents on the same carbon can form =0;
R11 is hydrogen or (C1-C6)alkyl; -C(O)alkyl, or R17 and R" taken together are
-(CI2)p A-(CH2)q, wherein p and q are each independently 2 or 3 and A is
selected
from the group consisting of a bond, -CH2-, -S- and -0-, and form a ring with
the
nitrogen to which they are attached;
R12 is 1-2 substituents, which can be the same or different, and are
independently selected from the group consisting of hydrogen, (C1-C6)alkyl,
hydroxy,
(Ci-C6)alkoxy, halogen, and -CF3;
R13 is selected from the group consisting of H, (C1-C6)alkyl, phenyl, benzyl,
(C2-C6)alkenyl, (C1-C6)alkoxy(C1-C6)a1kyl, di-((C1-C6)alkyl)amino(C1-C6)alkyl,
pyrrolidinyl(C1-C6)alkyl and piperidino(C1-C6)alkyl;
R14 is selected from the group consisting of H, halogen, (C1-C6)alkyl or (C1-
C6)alkoxy;
R15 is selected from the group consisting of H and (C1-C6)alkyl;
R16 is selected from the group consisting of H, (C1-C6)alkyl-C(O)- and (C1-
C6)alkyl-S02-;

CA 02710829 2010-08-03
R17 is selected from the group consisting of (C1-C6)alkyl, (C1-
C6)hydroxyalkyl,
(C3-C6)cycloalkyl, (C1-C6)alkoxy(C1-C6)alkoxy, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-
C6)alkyl, allyl, propargyl, R8 heteroaryl-, R8-aryl- and R8-aryl(C1-C6)alkyl-;
R18 is selected from the group consisting of a bond, -CHr, -CH(OH)-,
5 -CH(CH3)-, -C(CH3)n-, -(CH2)õ-, and -O(CH2)n-,
R19 is selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkyl(C1-
C6)cycloalkyl, (C1-C6)cycloalkyl(C1-C6)alkyl and (C1-C6)alkoxy(C1-C6)alkyl;
Q and Q' can be the same or different and are each independently selected
from the group consisting of
and
-N-~ , - - - --c-
10 H , CN , OH , COCH3
m and n are each independently 1-3;
p and q are each independently 0-2;
s is 0-4;
W is aryl or heteroaryl having 1-3 heteroatoms, which can be the same or
15 different, and are independently selected from the group consisting of N, 0
and S,
and wherein said aryl or heteroaryl is optionally substituted with 1-3
substituents,
which can be the same or different, and are independently selected from the
group
consisting of alkyl, aryl, alkylcycloalkyl, halo, hydroxy, hydroxyalkyl,
alkoxy,
alkylalkoxy, alkoxyalkoxy, -NR6R7, (C2-C6)alkene, and -CN, or
20 X is selected from the group consisting of H, NH2, -N(R6)(CH2)5-aryl, -
N(R)(CH2)5-heteroaryl, -N(R6)(CH2)m+1-OH, and -N(CH3)2, or
Xis -R1B-YZ;
Y is selected from the group consisting of -N(R6)CH2CH2N(R7)-,
-N(R6)(CH2)naryl, -OCH2CH2N(R6)-, -0-, -S-, -CH2S-, -(CH2)24-N(R6)-, R8-
divalent
heteroaryl,
(CH2)m
)N )9 N- -Q Q'-
and (CH2Y R'0; and
Z is selected from the group consisting of H, alkyl, alkoxyalkyl, R8-aryl-, R8-
aryl(C1-C6)alkyl-, R8-heteroaryl-, R8-bicyclicalkyl-, aminoalkyl, alkylamino,
NH2,

CA 02710829 2010-08-03
21
-N-(R6)(CH2)s-aryl, -N(R6)(CH2)s-heteroaryl, -N(R6)C(O)OR17,
alkylcycloheteroalkyl,
cycloheteroalkyl, cycloheteroalkylalkyl, alkoxycycloheteroalkyl, heteroaryl;
R8-
benzofused heteroaryl-, diphenylmethyl and R9-C(O)-; or
when Y is
(CH2)m
QI-I
(CH2Y R10
Z can also be -OH, R9-SO2-, R17-N(R11)(CH2)s-C(O)-, R17 OC(O)-, R17-O(CH2)1
C(O)-,
benzofused heteroaryl(CH2)õC(O)-, benzofused heteroaryl(CH2)õ- or R11-N(R11)-
C(S)-;
or
when Q is Z can also be R17R11N-, phenylamino or pyridylamino; or
Z and Y taken together are selected from the group consisting of
CO _I R8 / \ / N R& NI- N R8 ; / N~- "' s RBR4N~
R12 ~ ~
\/ N-c' ~ N N- / r N N
` % = \ / R13ONCN-~
H HN' , N
O
12 RS R8 R \`
or an N-oxide thereof,
N - N- .
R 14
COO>Q--I O=O-N- N/ and H N
8NN.
Preferred compounds of formula VII are those having the following structures:
NH2
N N'N O
'
N

CA 02710829 2010-08-03
22
NH2 O NH2
OMe NN'N 0I NN~kN-N 0
NN' N
ZZ,
O NH2
o'
0
1
OMe vN "J~N"') NJ'N N O
O O ~,N I ~ \ `
x`/ 0 / NH2
EN) 2 EtOAN Nom" NO
N N,N p (( ON
-01
H
NH2
N~N
\ON
Et NH2
EtOyN N~N,N 0 NH2
O N ()----N ~N~N'N -_- O
N
Et NH2 OCH3
N N~N-N 0
O ON O NH2
O~ NH2 N') N~N'N O
ON NJ,,N_N}-O N \ "J,
N
N ,
-0 N
NH2 NH2
N0 NrN NN-N OI
~N N F rN N
NJ

CA 02710829 2010-08-03
23
NH2
NH2 N;J~k N-N .--(
W NrN ~N~
liz~t
HO N \ I /
and
WO 03/048163 discloses useful adenosine A2a receptor antagonist
compounds. having the structural formula VIII
NH2
N N'N
\>-R
~ ~N
R2-Y-(CH2)n X fa
R VIII
or a pharmaceutically acceptable salt thereof, wherein:
A is C(R) or N;
R' and R1a are independently selected from the group consisting of H, (CrC6)-
alkyl, halo, CN and -CF3;
Y is -0-, -S-, -SO-, -SO2-, R5-heteroaryldiyl, R5-arylene or
Re 0
(C)P
-Q~
i \)Q
R7 R7a
p and q are independently 2-3;
Q and Q' are independently selected from the group consisting of
I I I I I
-N- -C- -C- -C-
I I and -C-
H CN ' OH COCH3,
1
provided that at least one of Q and Q' is -N-;
R is R5-aryl, R5"heteroaryl, R6-(C2-C6)alkenyl or R6-(C2-C6)alkynyl;
R2 is R57aryl, R5-heteroaryl, R5-aryl(Ci-C6)alkyl or R5heteroaryl(C1-C6)alkyl;
or R2-Y is
I/W)
USN
U, V, and W are independently selected from the group consisting of N and
CR', provided that at least one of U, V and W is CR';
n is 1, 2 or 3; and

CA 02710829 2010-08-03
24
(a) A is C(R1) and X is -C(R3XR)-, -C(O)-, -0-, -S-, -SO-, -SO2-,
R4-arylene, R4-heteroaryldiyl, or -N(R); or A is C(R1), Y is a bond, and X is
-C(R3)(R3a)-, -C(O)-, -0-, -5-, -SO-, -SO2-, R4-arylene, -N(R9)- or R4
heteroaryldiyl,
provided that when X Is -N(R9)- or R4-heteroaryldiyl, R2 is not phenyl or
phenyl-
(C1-C6)alkyl; or
(b) A is N, X is -N(R9)-, Y is R5-arylene and R2 is
R7 Feb
C
R10--N- ~
(C)q
R7 R7a
or n is 2 or 3; and
(c) A is N and X is -C(R3)(R3a)-, -C(O)-, -0-, -S-, -SO-, -SO2-, -N(R9)-,
R4-arylene or R4-heteroaryldiyl; or A is N, Y is a bond and X is -C(O}, -N(R9)-
,
R4-arylene or R4-heteroaryldiyl; or A is N, Y is -N(R9a)-, -C(O)N(R9a)- or
-0-(CH2)2-N(R9a)-, and X is -N(R9)-; or A is N, X is -N(R9)-, and Y and R2
together
are
R7 R7a
11-1 (C
R10-NI )
(C)q
R7 R7a
or n is 0; and
(d) A Is N, Y is a bond, X is -N(R9)-, and R2 is
R10_N R10,._N
or
Q ; or
(e) A is N, X is -N(R9)- and Y and R2 together are
R7 R7a
(C )p
R10-Q~ "-l-Q1--Z-.
( G)q
R7 R7a
wherein Z is -C(O)-CH2-, -C(0)-CH(C1-C6 alkyl)-, -CH2-CH(C1-C6 alkyl)-,
or -CH(C1-C5 alkyl)-CH2-;

CA 02710829 2010-08-03
R3 and R3a are independently selected from the group consisting of H, -OH,
CI-C6 alkyl, hydroxy(Ci-C6)alkyl, (Ci-Ce)alkoxy(Ci-C6)alkyl, amino(C1-
C6)alkyl,
(C1-C6)alkylamino(Ci-C6)alkyl and di(C1-C6)alkylamino(C1-C6)alkyl;
R4 is 1-3 substituents selected from the group consisting of H, (C1-C6)alkyl,
5 -OH, (C1-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkoxy, halo, -CF3, and -CN;
R5 is 1-3 substituents independently selected from the group consisting of H,
(C1-C6)alkyl, -OH, (CI-C6)alkoxy, (Ci-C6)aikoxy(Ci-C6)aikyl, (C1-C6)alkoxy(Ci-
C6}
alkoxy, halo, -CF3, -CN, -NH2, (Ci-C6)alkylamino, di(Ci-C6)alkylamino,
amino(Ci-C6)-
alkyl, (C1-C6)alkylamino(Ci-C6)alkyl, di(Ci-C6)aikylamino(Ci-C6)alkyl, (Ci-
C6)alkanoyl-
10 amino, (Ci-C6)alkanesulfonylamino, (C1-C6)alkylthio, (C1-C6)alkylthio(C1-
C6)aikyl,
R6-(C2-C6)alkenyl, R6-(C2-C6)alkynyl, hydroxy(C1-C6)alkyl, (Ci-C6)alkoxy-
C(O}amino,
or heterocycloalkyl(C1-C6)alkyl;
R6 is 1 to 3 substituents independently selected from the group consisting of
H,
-OH, (Ci-C6)alkoxy and halo;
15 Re and 0 are independently selected from the group consisting of H, (C1-
C6)alkyl, (Ci-C6)alkoxy(C1-C6)alkyl, R6-aryl and R6-heteroaryl, or an R' and
an R7a
substituent on the same carbon can form =0;
R8 is I to 3 substituents independently selected from H, (Ci-C6)alkyl, -OH,
(C1-C6)alkoxy, (Ci-C6)alkoxy(Ci-C6)alkoxy, halo, -CF3, and -CN;
20 R9 and R9a are independently selected from the group consisting of H,
(CT-C6)alkyl, hydroxy(C2-C6)alkyl, (Ci-C6)alkoxy(C2-C6)alkyl, amino(C2-
C6)alkyl,
(C1-C6)alkylamino(C2-C6)alkyl, di(Ci-C6)alkylamino(C2-C6)alkyl, halo-(C3-
C6)alkenyl,
CF3-(C1-C6)alkyl, (C3-C6)alkenyl, (C3-C6)cycloalkyl and (C3-C6)cycioalkyl-(C1-
C6)alkyi;
and
25 R10 is H, -C(O)-O-(C1-C6)alkyl, R5-aryl, -C(O)-(C1-C6)alkyl, -C(O)-(R5-
aryl) or
R5-aryl-(Ci-C6)alkyi.
Preferred compounds of formula VIII are those wherein A is N. R is preferably
furyl.
Ria is preferably hydrogen. Another group of preferred compounds is that
wherein X
is -0-, -S-, -N(R9)- or R4-arylene, with compounds wherein X is -N(R9)- being
more
preferred. R9 is preferably C1-C6 alkyl. Preferred definitions for Y are a
bond or
piperazinyl. R2 is preferably R5-aryl. When Y and/or R2 is

CA 02710829 2010-08-03
26
R7 R7a R7 R7a
(C)p (C)p
R10-Q~ 1--Q1- R10-N~ (C )q (C)a
R7 R7a or R7 R7a
Q is preferably N, Q1 is preferably N, p and q are each preferably 2, each R7
and R7a
is preferably hydrogen, and R10 is preferably -C(O)-O-(C1-C6)alkyl, -C(O)-(C1-
C6)alkyl
or -C(O)-(R5-aryl). R5 is preferably I or 2 substituents selected from the
group
consisting of H, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)-alkoxy, halo and -CF3. R4
is
preferably H, halo or (C1-C6)alkyl. R3 and R3a are preferably independently
selected
from H and (C1-C6)alkyl. Rga is preferably H or (C1-C6)alkyl. R6 is preferably
hydrogen.
Preferred specific examples of compounds of formula VIII include compounds
of the formula
NH2
NN'N 0
R2-Y-(CH2)n N9 N
R9
wherein R2-Y-(CH2)n-N(R9)- is as defined in the table:
R -Y-(CH2)n-N(R)-
F N V~NCH3
F
~OMe
F
N
F
F Q \fN--\'--N /<
F
F N \--/ N--\\__N /-Me
Q VN~N
OMe

CA 02710829 2010-08-03
27
~-, Me
F N _~ -~ >--Me
N
F
0- N P
\-/N-N\-N
OMe
O N ~_ /-CF3
N
OMe
O U -\,__ Me
OMe F
0- N
a
V Me
`OMe
WO 01/02409 discloses useful adenosine Ala receptor antagonist compounds
having the structural formula IX
R2
R1 R3
X N
R6
N Rq
R5 IX
wherein
Xis0orS;
R1 and R2 are independently selected from hydrogen, alkyl, aryl, hydroxy,
alkoky, aryloxy, cyano, nitro, C02R7, COR7, OCOR7, CONR7R8, CONR7NR8R9,
OCONR7R8, NR7R8, NR7COR8, NR7CONR3R9, NR7CO2R8, NR7SO2R8,
NR7CONR8NR9R1o, NR7NR8CO2R9, NR7NR8CONR9R10, NR7SO2NR8R9, S02R7,
SOR7, SR7 and S02NR7R8, or R1and R2 together form a carbonyl group (C=O), an
oxime group (C=NOR11), an imine group (C=NR11) or a hydrazine group
(C=NNR11R12), or R1and R2 together form a 5, 6 or 7 membered carbocydic or
heterocyclic ring;
R3 is alkyl or aryl;
R4, R5 and R6 ate independently selected from hydrogen, alkyl, aryl, halogen,
hydroxy, nitro, cyano, alkoxy, aryloxy, C02R7, COR7, OCOR7, S02R7, SOR7, SR7,
SO2NR7R8, , CONR7R8, CONR7NR8R9, OCONR7R8, NR7R8, NR7COR8,

CA 02710829 2010-08-03
28
NR7CONR8R9r NRTCO2R8, NR7SO2Rs, CRT=NOR8, NR7CONReNR9R1o,
NR7NR8CO2R9i NR7NR8CONR9R10, SO2NR7NR8R9, NR7SO2NR8R9, NR7NR8SO2R9,
NR7NR8CO2R9, NR7NR8R9 and NR7CSNRBR9, or R5 and R6 together form a 5, 6 or 7
membered carbocyciic or heterocyclic ring; and
R7, R8, R9, R10s R11 and R12 are independently selected from hydrogen, alkyl
and aryl, or a pharmaceutically acceptable salt or prodrug thereof.
The adenosine Ala receptor antagonists are prepared by known methodb
as described In the cited patents and applications.
As used herein, "patient' means a mammal, especially a human.
It is contemplated that more than one adenosine Ala receptor antagonist (e.g.,
2 or 3) can be administered to treat EPS, dystonia, RLS or PLMS; preferably,
one
adenosine Ala receptor antagonist is administered.
Antipsychotic agents causing the EPS treated by adenosine Ala receptor
antagonists and for use in combination with adenosine Ala receptor antagonists
include typical and atypical antipsychotic agents. Typical antipsychotics
include
loxapine, haloperidol, chlorpromazine, prochiorperazine and thiothixene.
Atypical
antipsychotics include dozapine, olanzapine, loxapine, quetiapine, ziprasidone
and
risperidone.
Tricyclic antidepressants causing dystonia treated by adenosine Ala receptor
antagonists include perphenazine, amitriptyline, desipramine, doxepin,
trimipramine
and protriptyline. Anticonvulsants which may cause dystonia, but which also
may be
useful In treating ERLS or PLMS include phenytoin, carbamazepine and
gabapentin.
Dopamine agonists useful in treating RLS and PLMS include pergolide,
pramipexole, ropinerole, fenoldopam and cabergoline.
Opioids useful in treating PRLS and PLMS include codeine, hydrocodone,
oxycodone, propoxyphene and tramadol.
Benzodiazepines useful in treating PRLS and PLMS include donazepam,
triazolam and temazepam.
The antipsychotics, tricyclic antidepressants, anticonvulsants, dopamine
agonists, opioids and benzodiazepines are commercially available and are
described
in the literature, e.g., in The Physicians' Desk Reference (Montvale: Medical
Economics Co., Inc., 2001).

CA 02710829 2010-08-03
29
It Is contemplated that two or more Ala receptor antagonists could be
administered in combination with one or more other agents (e.g.,
antipsychotics,
tricyclic antidepressants, anticonvulsants, dopamine agonists, opioids or
benzodiazepines), although administration of one Ala antagonist in combination
with
one other agent is preferred for each of the indications. While administration
of
separate dosage forms of the Ala antagonist(s) and the other agent(s) are
preferred,
it is also contemplated that the other agent(s) could be combined in a single
dosage
form with the Asa receptor antagonist(s) for the treatment or prevention of
EPS,
dystonia, RLS or PLMS.
Preferred adenosine A2a antagonists are those described in US 6,630,475.
A particularly preferred compound of the invention is Compound A of the
formula
F NH2
l-~ ~
NN-N O
x --0
F / \ `N --\-N ~N
N (A)
or a pharmaceutically acceptable salt or solvate thereof, disclosed in US
6,630,475
and listed as the first compound in the table of compounds of structure 1.
Compounds useful in the method of the invention will show utility as adenosine
Ala receptor antagonists in these assays.
Human Adenosine Ate and A, Receptor Competition Binding Assay Protocol
Membrane sources: Ala: Human Ala Adenosine Receptor membranes, Catalog
#RB-I-IA2a, Receptor Biology, Inc., Beltsville, MD. Dilute to 17 pg/100 pl in
membrane dilution buffer (see below).
Assay Buffers: Membrane dilution buffer: Dulbecco's Phosphate Buffered Saline
(Gibco/BRL) + 10 mM MgCI2.
Compound Dilution Buffer: Dulbecco's Phosphate Buffered Saline (GibcoBRL) +
10 mM MgCI2 supplemented with 1.6 mg/ml methyl cellulose and 16% DMSO.
Prepared fresh daily.
Ligands: Ala: [3H]-SCH 58261, custom synthesis, AmershamPharmacia Biotech,
Piscataway, NJ. Stock is prepared at I nM in membrane dilution buffer. Final
assay
concentration is 0.5 nM.
A,: [3H]- DPCPX, AmershamPharmacia Biotech, Piscataway, NJ. Stock is
prepared at 2 nM in membrane dilution buffer. Final assay concentration is I
nM.

CA 02710829 2010-08-03
Non-specific Binding:
Ate: To determine non-specific binding, add 100 nM CGS 15923 (RBI, Natick,
MA). Working stock is prepared at 400 nM in compound dilution buffer.
A,: To determine non-specific binding, add 100 pM NECA (RBI, Natick, MA).
5 Working stock is prepared at 400 pM in compound dilution buffer.
Compound Dilution:
Prepare 1 mM stock solutions of compounds in 100% DMSO. Dilute in
compound dilution buffer. Test at 10 concentrations ranging from 3 pM to 30
pM.
Prepare working solutions at 4X final concentration in compound dilution
buffer.
10 Assay procedure:
Perform assays in deep well 96 well plates. Total assay volume is 200 p1. Add
50 pl compound dilution buffer (total ligand binding) or 50 pl CGS 15923
working
solution (A2a non-specific binding) or 50 pl NECA working solution (A, non-
specific
binding) or 50 pl of drug working solution. Add 50 pl ligand stock ([3H]-SCH
58261
15 for Ala, [3H]- DPCPX for A,). Add 100 pl of diluted membranes containing
the
appropriate receptor. Mix. Incubate at room temperature for 90 minutes.
Harvest
using a Brandel cell harvester onto Packard GF/B filter plates. Add 45 PI
Microscint
20 (Packard), and count using the Packard TopCount Microscintillation Counter.
Determine IC50 values by fitting the displacement curves using an iterative
curve
20 fitting program (Excel). Determine Ki values using the Cheng-Prusoff
equation.
Haooperidol-induced catalepsy in the rat
Male Sprague-Dawley rats (Charles River, Calco, Italy) weighing 175-200 g are
used. The cataleptic state is induced by the subcutaneous administration of
the
dopamine receptor antagonist haloperidol (1 mg/kg, sc), 90 min before testing
the
25 animals on the vertical grid test. For this test, the rats are placed on
the wire mesh
cover of a 25x43 plexiglas cage placed at an angle of about 70 degrees with
the
bench table. The rat is placed on the grid with all four legs abducted and
extended
("frog posture"). The use of such an unnatural posture is essential for the
specificity
of this test for catalepsy. The time span from placement of the paws until the
first
30 complete removal of one paw (descent latency) is measured maximally for 120
sec.
The selective A2, adenosine antagonists under evaluation are administered
orally at doses ranging between 0.03 and 3 mg/kg, I and 4 h before scoring the
animals.

CA 02710829 2010-08-03
31
In separate experiments, the anti-cataleptic effects were determined for the
reference compound, L-DOPA (25, 50 and 100 mg/kg, ip),
For preparing pharmaceutical compositions from the compounds useful in the
method of this invention, inert, pharmaceutically acceptable carriers can be
either
solid or liquid. Solid form preparations include powders, tablets, dispersible
granules,
capsules, cachets and suppositories. The powders and tablets may be comprised
of
from about 0.1 to about 99 percent active ingredient. Suitable solid carriers
are
known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar,
lactose. Tablets, powders, cachets and capsules can be used as solid dosage
forms
suitable for oral administration.
For preparing suppositories, a low melting wax such as a mixture of fatty acid
glycerides or cocoa butter is first melted, and the active ingredient is
dispersed
homogeneously therein as by stirring. The molten homogeneous mixture is then
poured into convenient sized molds, allowed to cool and thereby solidify.
Liquid form preparations include solutions, suspensions and emulsions. As an
example may be mentioned water or water-propylene glycol solutions for
parenteral
injection.
Liquid form preparations may also include solutions for intranasal
administration.
Aerosol preparations suitable for inhalation may include solutions and solids
in
powder form, which may be in combination with a pharmaceutically acceptable
carrier, such as an inert compressed gas.
Also included are solid form preparations which are intended to be converted,
shortly before use, to liquid form preparations for either oral or parenteral
administration. Such liquid forms include solutions,, suspensions and
emulsions.
The compounds useful in the method of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of creams,
lotions,
aerosols and/or emulsions and can be included in a transdermal patch of the
matrix
or reservoir type as are conventional in the art for this purpose.
Preferably the adenosine Ala receptor antagonist and the antipsychotic are
administered orally.
Preferably, the pharmaceutical preparation is in unit dosage form. In such
form, the preparation is subdivided into unit doses containing appropriate
quantities of
the active component, e.g., an effective amount to achieve the desired
purpose.

CA 02710829 2010-08-03
32
The quantity of adenosine A, receptor antagonist in a unit dose of preparation
may be varied or adjusted from about 0.1 mg to 1000 mg, more preferably from
about
I mg to 300 mg, according to the particular application.
The actual dosage employed may be varied depending upon the requirements
of the patient and the severity of the condition being treated. Determination
of the
proper dosage for a particular situation is within the skill of the art.
Generally,
treatment is initiated with smaller dosages which are less than the optimum
dose of
the compound. Thereafter, the dosage is increased by small increments until
the
optimum effect under the circumstances is reached. For convenience, the total
daily
dosage may be divided and administered in portions during the day if desired.
The amount and frequency of administration of the adenosine A2a receptor
antagonist useful in the method of the invention will be regulated according
to the
judgment of the attending clinician considering such factors as age, condition
and
size of the patient as well as severity of the symptoms being treated. A
typical
recommended dosage regimen for an adenosine A2a receptor antagonist is oral
administration of about 10 mg to 2000 mg/day preferably 10 to 1000 mg/day, in
two to
four divided doses to provide relief from the effects of EPS, dystonia, RLS or
PLMS.
The compounds are non-toxic when administered within this dosage range.
The doses and dosage regimen of the other agents used in combination with
the adenosine A2. receptor antagonists, i.e., the antipsychotics, tricycicic
antidepressants, anticonvulsants, dopamine agonists, benzodiazepines, opioids,
lithium or iron, will be determined by the attending clinician in view of the
approved
doses and dosage regimen in the package insert, taking into consideration the
age,
sex and condition of the patient and the severity of the disease. When
administered
in combination, the adenosine A2a receptor antagonist and the other agent can
be
administered simultaneously or sequentially. This is particularly useful when
the
components of the combination are preferably given on different dosing
schedules,
e.g., one component is administered daily and the other every six hours, or
when the
preferred pharmaceutical compositions are different, e.g. one is preferably a
tablet
and one is a capsule. It is therefore advantageous to provide the adenosine
A2,,
receptor antagonist and the other agent in a kit comprising, in separate
containers in
a single package, pharmaceutical compositions for use in. combination to treat
or
prevent EPS, dystonia, RLS or PLMS, wherein one container comprises a
pharmaceutical composition comprising an effective amount of an adenosine Al.

CA 02710829 2010-08-03
33
receptor antagonist in a pharmaceutically acceptable carrier, and wherein a
separate
container comprises a pharmaceutical composition comprising an effective
amount of
another agent appropriate to treat the indicated condition.
Those skilled in the art will recognize that a dosage form for one of the
components of the combination can be modified to contain both an adenosine Aza
receptor antagonist and another agent, e.g., an adenosine A2a receptor
antagonist
and an antipsychotic or an adenosine Ala receptor antagonist and a dopamine
agonist.
The following example shows the use of adenosine A2a antagonists to
attenuate the Extra-Pyramidal Syndrome (EPS) displayed in cebus apella monkeys
sensitized to the dopamine D2 receptor antagonist, haloperidol.
Exam le
A colony of seven Cebus apella monkeys that were previously sensitized to the
chronic effects of haloperidol, exhibit EPS when administered haloperidol
acutely (0.3
mg/kg, p.o.). Compound A was administered orally (p.o.) at doses of 0.3-30
mg/kg, in
conjunction with haloperidol. The studies were conducted using a within-
subjects
design such that each monkey received all 6 treatments (vehicle and 5 doses of
Compound A) in a crossover, balanced design. In all the studies, the group of
seven
monkeys exhibited baseline levels of EPS when dosed with haloperidol.
Compound A produced a dose-dependent reduction in the maximum EPS
score (Figure 1A), as well as a dose-dependent delay in the onset of EPS
(Figure
1 B). At a dose of 1 mg/kg, Compound A prevented the onset of EPS in one
monkey,
and delayed the onset of EPS by 1 hr. Compound A, at a dose of 3 mg/kg,
prevented
the onset of EPS in two monkeys, and delayed the onset of EPS by almost 2 hr
in the
remaining monkeys. At 10 and 30 mg/kg, Compound A prevented the onset of EPS
in three monkeys and delayed the onset of EPS by an average of 2.3-2.9 hr.
Clinical guidelines for the treatment of RLS and PLMS have been established:
see A. L. Chesson et at, Sleep, 22, 7 (1999), p. 961-8. Efficacy of adenosine
Ala
antagonists in treating RLS and PLMS can be determined by a method analogous
to
the clinical method described in the literature for pramipexole and ropinerole
by
Weimerskirch et al, Annals of Pharmacotherapv, 35, 5 (2001), p. 627-30.
While the present invention has been described in conjunction with the
specific
embodiments set forth above, many alternatives, modifications and variations
thereof

CA 02710829 2010-08-03
34
will be apparent to those of ordinary skill in the art. All such alternatives,
modifications and variations are intended to fall within the spirit and scope
of the
present invention.

Representative Drawing