CA2510655C

CA2510655C - Uses of adenosine a2a receptor antagonists

Info

Publication number: CA2510655C
Application number: CA2510655A
Authority: CA
Inventors: Michael Grzelak; John C. Hunter; Annamarie Pond; Geoffrey Varty
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme Corp
Priority date: 2002-12-19
Filing date: 2003-12-17
Publication date: 2010-11-16
Anticipated expiration: 2023-12-17
Also published as: CA2510655A1

Abstract

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

Description

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 A2a 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 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,, A2a, 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 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). A2a antagonists appear to demonstrate a reduced side-effect liability (e.g. no dyskinesia) compared to current dopaminergic therapies resulting in an improved therapeutic index. A2a 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 A2a affinity with varying degrees of A2a vs. A, selectivity. Adenosine A2a 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 A2a 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 A2a 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 A2a antagonist to a patient in need thereof.
More particularly, the invention relates to the method of using of certain adenosine A2a 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 A2a receptor antagonist to a patient in need thereof. When dystonia is caused by treatment with a tricyclic antidepressant, lithium or an anticonvulsant, the adenosine A2a receptor antagonist can be administered after the symptoms of 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 A2a 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 A2a receptor antagonist. The invention also comprises a method of treating RLS or PLMS comprising administering a combination of an adenosine A2a 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 A2a 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 A2a 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 A2a receptor antagonist in a pharmaceutically acceptable carrier, and wherein a separate container comprises a pharmaceutical composition comprising an effective amount of Ievodopa/carbidopa, levodopa/benserazide, a dopamine agonist, a benzodiazepine, an opioid, an anticonvulsant or iron.

The invention also relates to a pharmaceutical composition for use in the 5 treatment or prevention of EPS caused by treatment with an antipsychotic agent, comprising a compound of the invention, as described herein, and a pharmaceutically acceptable carrier.

The invention also relates to the use of an adenosine Ala receptor antagonist 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 Ala receptor antagonist is contemplated for use in the method of this invention. Suitable adenosine A2a receptor antagonists useful in the method of the invention can be identified by the binding assay described below. Specific examples of suitable adenosine Ala 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

NN-N
N
Z-Y-X-N
N I

-5a-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)CHr;
Y is -N(R2)CH2CH2N(R3)-, -OCH2CH2N(R2)-, -0-, -S-, -CH2S-, -(CH2)2-NH-, or (CH2)m -Q N-(CHA R4 and Z is R5-phenyl, R5-phenyl(C1-C6)alkyl, R5-heteroaryl, diphenylmethyl, R6-C(O)-, HN),N-R6-S02-, R6-OC(O)-, R-N(R8)-C(O)-, R'-N(R$)-C(S)-, 0 , phenyl-CH(OH)-, or -C-phenyl-C(=NOR2)-; or when Q is H , Z is also phenylamino or pyridylamino;
or Z and Y together are Rq]N-, 0, \ \ N- r N - N R11ON=-CN-H N-, HN N
O

R10 O)CN- , R - (\ -Rio 10 Rio _ R
R'~/~ or an N-oxide thereof, / N- or ---N N- , R1 is I 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 I I I I I
-N- -C- -C- -C-I , or -~-H CN ' OH COCH3.
, R4 is 1-2 substituents independently selected from the group consisting of hydrogen and C1-C6alkyi, or two R4 substituents on the same carbon can form =0;
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, (i 1-C6 alkyl) (O
O

-C=NOR t o- ; or adjacent R5 substituents together are -O-CH2-O-, -0-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 <N' (C1-C6)alkyl-OHO
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 -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-C6 alkenyl, C1-C6 alkoxy(C1-C6)alkyl, di-((C1-C6)alkyl)amino(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl or piperidino(Cl-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 CH2)m -Q N-alkylene, preferably ethylene. Y is preferably (CHA R4 wherein Q is 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, R6-C(O)-or R6-SO2-. R5 is preferably H, halogen, alkyl, alkoxy, hydroxyalkoxy or alkoxyalkoxy. R6 is preferably R5-phenyl.
Preferred specific compounds of formula I are those of the formula IA

NN-N
Z-Y~ N~R
N
IA
wherein R and Z-Y are as defined in the following table:
Z-Y- R
F O
F N N -&N \--j N- 0"
F O
F N N-0"
F
~OCH3 0 O 0\-/jI N-/ N-0\/

C ('(c5)) N N-0"
F _ O
H3CO ' ~ N N-0"

F O
CI N- 0\/

C F/-\ 0\/
O N-/ N-F
--CN n O
F / ) - N N - N

F F
F N \ _ / I N -F
F N N-Other useful adenosine A2a receptor antagonists include those disclosed in WO 95/01356 as compounds having the structural formula II

N ~
,N
R AI N
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; CI-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, CI-C4 alkoxy groups, C1-C4 alkyl, nitro, amino, cyano, C1-C4 haloalkyl, Cl-C4 haloalkoxy, carboxy, carboxyamido; C7-Clo 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 1 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.

Preferably, compounds of formula II are those wherein R is hydrogen, C1-C8 alkyl, aryl or C7-Clo aralkyl optionally substituted, preferably with halogen atoms.

US 5,935,964 discloses useful adenosine Ala receptor antagonist compounds 5 having the structural formula III

O
N
/N
R A I /N
N' _NH2 Ill wherein A is pyrazole, imidazole or triazole ring;
R is -(CH2)n R1 ~I`j OH

10 R, and R2, which are the same or different, are H, OH, halogen, C1-C4 alkoxy, C1-C4 alkyl, nitro, amino, cyano, C1-C4 haloalkyl, C1-C4 haloalkoxy, carboxy or carboxamido; or the OH group, together with one of R1 or R2, or R1 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 R2X~N~A IVA
wherein R' 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 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 N-~
,N
ONY

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 A2a receptor antagonist compounds having the structural formula V

NN-N R
Z-Y-X-N N
~=N

or a pharmaceutically acceptable salt thereof, wherein R is R1-heteroaryl, R10-phenyl, C4-C6 cycloalkenyl, -C(=CH2)CH3, -C-C-CHs, 2 or -C=C-CH2-OR , -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- q N- -Q Q

or (CH2 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 (CH2Yn R4 Z is also R6-SO2-, R7-N(R8)-C(O)-, R7-N(R8)-C(S)- or R6OC(O)-;
I
or when Q is -CH-, Z is also phenylamino or pyridylamino;
or Z and Y together are N- %HN N~N- ~N R11ON~N-o `--' FN-CN-N R5 N /-` N

~N- 1\\ - _~ - N-R,~ _ or an N-oxide thereof, 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, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, -COOR 7 or -C(O)NR2R3;

R2 and R3 are independently selected from the group consisting of hydrogen and Cl-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- -C- _C and -9-CN ' OH COCH3 I I
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, C1-C6alkyl, R1-aryl and R1-heteroaryl, or two R4 substituents on the same carbon can form =0;
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, -N02, hydroxy(C1-C6)alkoxy, P-C6)-alkoxy(C1-C6)alkoxy, di-((Ci-C6)-alkoxy)(Cj-C6)alkoxy, (CI-C6)-alkoxy(C1-C6)alkoxy-(CI-C6)-alkoxy, carboxy(Ci-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-SO2-(C--C6)alkoxy, tetra hyd ropyra nyloxy, (C1-C6)alkylcarbonyl(Ci-C6)-alkoxy, (Ci-C6)-alkoxycarbonyl, (C1-C6)alkylcarbonyloxy(Ci-C6)-alkoxy, -SO2NH2, phenoxy, (CI-C6 alkyl) g,o -C=NOR2 0-, (R20)2-P(O)-CH2-O- and (R20)2-P(O)-; or adjacent R5 substituents together are -0-CH2-0-, -0-CH2CH2-0-, -0-CF2-0- or -0-CF2CF2-0-and form a ring with the carbon atoms to which they are attached;
R6 is (Ci-C6)alkyl, R5-phenyl, R5-phenyl(Ci-C6)alkyl, thienyl, pyridyl, (C3-C6)-cycloalkyl, (C1-C6)alkyl-OC(O)-NH-(Ci-C6)alkyl-, di-((CI-C6)alkyl)aminomethyl, or (C1-C6)alkyl-O'O

R' is (Ci-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 -0-, and form a ring with the nitrogen to which they are attached;

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-(CT-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, -S(O)0_2(C1-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(C1-C6)alkyl or piperidino(C1-C6)alkyl;
R12 is H or C1-C6 alkyl;
R13 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-(C1-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 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 'N-preferably ethylene. Y is preferably (CHA 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

NN-N R
Z-Y~N ~N~
VA
wherein R and Z-Y are as defined in the following table:
Z-Y- R

0\/
0-&N -N
-N N-F O
F
N N-0"

N

/
H3C{ ~>-N N- O/

r - F

N N

_ F
O \ NON-N N-WO 03/048165 discloses useful adenosine Ala receptor antagonist compounds having the structural formula VI

Q N WN
~--R
Y` ~ - 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 R1-furanyl-, R1-thienyl-, R1-pyridyl-, Rl-oxazolyl-, R'-pyrrolyl- and R2-aryl-;
X is -(CH2),,-;

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 3=Z4 A: 2 z7 Al, 2 Al Z1 A Z6 ` A ZS A
Z Zi A4 A3 'Z5 A4 A3 'Z6, A4 A3 M or or wherein A' is N-X, and A2 and A3 each are CR4R5, or A' 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;
Z6 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, Cl-C6-alkoxy, Cl-C6-acyloxy, Cl-C6-alkylamino, Cl-C6-acylamino, Cl-C6-alkylsulfonamino, Cl-C6-alkylaminosulfonyl, C6-dialkylaminosulfonyl, NH2-SO2-, and hydroxy;
R4 is selected from the group consisting of hydrogen, hydroxyalkyl, aryl, aralkyl, C1-C6-alkyl, Cj-C6-alkoxy, CF3, CN, halogen, hydroxy, and N02; and R5 is hydrogen or CI-C6 alkyl.
Preferred specific examples of compounds of formula VI include compounds of the formula:

NJ_N O
N
N-NJN O
N\N
( OMe NH2 O N~N'N O
N-\_N ~N \
NJ

Meo NN-N O
I , N--\-N N \
NJ
Meo NH2 Meo NN-N O
N-\-N -N \
N-Meo Ph NH2 Meo NIJ'N-N O
N~N ~N \

N-WO 03/048164 discloses useful adenosine Ala receptor antagonist compounds having the structural formula VII

NN-N R
R2 ~N

or a pharmaceutically acceptable salt or solvate thereof; wherein:
R is selected from the group consisting of R4-heteroaryl, R5-phenyl, (C4-C6)cycloalkenyl, -C(=CH2)CH3, -C.C-CH3, 0 0 , -CH=C(CH3)2, OH, 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 -NR18R19, 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)alkylsulfinyl, (C1-C6)alkylsulfonyl, -COOR17 and -C(O)NR6R7;
R5 is 1 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)0_2(C1-C6)alkyl 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)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-S02-, (C1-C6)alkyl-SO2-(C1-C6)alkoxy, tetrahydropyranyloxy, (C1-C6)alkylcarbonyl(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl, (C1-C6)alkylcarbonyloxy(C1-C6)-alkoxy, -SO2NH2, phenoxy, .19 (i l-C6 alkyl) 0 p-,LC{i3 ~'-C=NOR13 Oft, O-~ 0 -O-CH2-P(O)(OR6)2,- and -P(O)(OR6)2; or adjacent R8 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;
R9 is selected from the group consisting of (Cj-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, a.ryloxy(C1-C6)alkyl, alkoxy(C1-C6)alkyl and (C1-C6)alkyl-OO
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 R11 taken together are -(CH2)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, (C1-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)alkyl, di-((C1-C6)alkyl)amino(CT-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-;

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, -CH2-, -CH(OH)-, 5 -CH(CH3)-, -C(CH3)õ-, -(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 Q1 can be the same or different and are each independently selected from the group consisting of {~.

nn, =,{,, I ^I
2-N -C- ~ ~ -C- ~ ~ -c- and -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, -NR 6R7, (C2-C6)alkene, and -CN, or 20 X is selected from the group consisting of H, NH2, -N(R6)(CH2)5-aryl, -N(R6)(CH2)S-heteroaryl, -N(R6)(CH2)n,+1-0H, and -N(CH3)2, or X is -R16-Y-Z;
Y is selected from the group consisting of -N(R6)CH2CH2N(R7)-, -N(R6)(CH2)õ aryl, -OCH2CH2N(R6)-, -0-, -S-, -CH2S-, -(CH2)2.3-N(R6)-, R8-divalent heteroaryl, )P CH2) \
N-'~ q N. -Q Q
and (CH2)R10; and Z is selected from the group consisting of H, alkyl, alkoxyalkyl, R8-aryl-, R8-aryI(C1-C6)alkyl-, R8-heteroaryl-, R8-bicyclicalkyl-, aminoalkyl, alkylamino, NH2i -N-(R 6)(CH2)S-aryl, -N(R6)(CH2)5-heteroaryl, -N(R6)C(O)OR17, alkylcycloheteroalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkoxycycloheteroalkyl, heteroaryl;

benzofused heteroaryl-, diphenylmethyl and R9-C(O)-; or when Y is CH2)m\
I-Q Q
(CH2)\Rio Z can also be -OH, R9-S02-, R17-N(R11)(CH2)S-C(O)-, R17-OC(O)-, R17-O(CH2)nC(O)-, benzofused heteroaryl(CH2)nC(O)-, benzofused heteroaryl(CH2)n- or R17-N(R11)-C(S)-;
or when Q is -CH-~ , Z can also be R17R11N-, phenylamino or pyridylamino; or Z and Y taken together are selected from the group consisting of CO
- / N- R4_N3-N 6 R$ R6R4NR
or R8 / \

f" R13ON2N-~
(~N N- HNN _ O
REL 8L - ~(~Jj ~CN- RS~~\ R \\-\/

~\ -,/~ or an N-oxide thereof, INA

r0>0-1 O=O-N-O and -- H N

Preferred compounds of formula VII are those having the following structures:

NIN'N O
I \ \ "

~'N 0 NOMe NN '/"N"') NN-N O
NNI N
OM~ O~ 0 NH2 OMe ON~N NJ-.,N-N O
N \I
O O ~ I \ \N

CN N O Et0 NN~ N, N}-~\ N \ ~N
N
H

O~S\N~ NJ-1N-N 0 Et NH2 N N
EtOUN
'I NI
kN'N~--~~O~I NH

N N-^) N N-~,N jN
Et NH2 OCH3 N N)I-IN-N O

O N \ ~N \ I O / NH2 N N~N,N 0 N \ I
\ I N
N N

N N N O
NN N O
N N F rN \ ,N
\\ NJ / N~ NJ
O" v O
H
iO 'O

NH2 N N_N 0 Ni N,N O
\ \ N
N
HO and WO 03/048163 discloses useful adenosine A2a receptor antagonist compounds. having the structural formula VIII

N
A~N' )~~~-R
R2-Y-(CH2)n X R1a N
Vlll or a pharmaceutically acceptable salt thereof, wherein:
A is C(R) or N;
R1 and Rya are independently selected from the group consisting of H, (C1-C6)-alkyl, halo, CN and -CF3;
Y is -0-, -5-, -SO-, -SO2-, R5-heteroaryldiyl, R5-arylene or R7 R7a (C)p Q'I (C)4 R7 R7a p and q are independently 2-3;
Q and Q1 are independently selected from the group consisting of I
-N- -C- -C- -C- and -9-H CN ' OH COCH3 , 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 R5"aryl, R5-heteroaryl, R5-aryl(C1-C6)alkyl or R5-heteroaryl(C1-C6)alkyl;
or R2-Y is V "W
U~
U, V, and W are independently selected from the group consisting of N and CR1, provided that at least one of U, V and W is CR1;
n is 1, 2 or 3; and (a) A is C(R) and X is -C(R3)(R3a)-, -C(O)-, -0-, -S-, -SO-, -SO2-, R4-arylene, R4-heteroaryldiyl, or -N(R9)-; 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 R7a (C)p 1-1 ~Q1-R (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)-, 10 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 (C)p RioN~ jQ1-( \)q R7 R7a or n is 0; and (d) A is N, Y is a bond, X is -N(R9)-, and R2 is RIO-N R1o_N
or Q or (e) A is N, X is -N(R9)- and Y and R2 together are R7 R7a (C)p R'o-Q, jQ~-Z-( \)q R7 R7a wherein Z is -C(O)-CH2-, -C(O)-CH(C1-C6 alkyl)-, -CH2-CH(C1-C6 alkyl)-, or -CH(C1-C6 alkyl)-CH2-;

R3 and R3a are independently selected from the group consisting of H, -OH, C1-C6 alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-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, (C1-C6)alkoxy(C1-C6)alkoxy, halo, -CF3, and -CN;
R5 is 1-3 substituents independently selected from the group consisting of H, (C1-C6)alkyl, -OH, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-06)-alkoxy, halo, -CF3, -CN, -NH2, (C1-C6)alkylamino, di(C1-C6)alkylamino, amino(C1-C6)-alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkanoyl-10 amino, (C1-C6)alkanesulfonylamino, (C1-C6)alkylthio, (C1-C6)alkylthio(C1-C6)alkyl, R6-(C2-C6)alkenyl, R6-(C2-C6)alkynyl, hydroxy(C1-C6)alkyl, (C1-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, (C1-C6)alkoxy and halo;
15 R7 and R7a are independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, R8-aryl and R8-heteroaryl, or an R7 and an R7a substituent on the same carbon can form =0;
R8 is 1 to 3 substituents independently selected from H, (C1-C6)alkyl, -OH, (C1-C6)alkoxy, (CT-C6)alkoxy(C1-C6)alkoxy, halo, -CF3, and -CN;
20 R9 and R9a are independently selected from the group consisting of H, (C1-C6)alkyl, hydroxy(C2-C6)alkyl, (C1-C6)alkoxy(C2-C6)alkyl, amino(C2-C6)alkyl, (C1-C6)alkylamino(C2-C6)alkyl, di(C1-C6)alkylamino(C2-C6)alkyl, halo-(C3-C6)alkenyl, CF3-(C1-C6)alkyl, (C3-C6)alkenyl, (C3-C6)cycloalkyl and (C3-C6)cycloalkyl-(C1-C6)alkyl;
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-(C1-C6)alkyl.

Preferred compounds of formula VIII are those wherein A is N. R is preferably furyl.
R1a is preferably hydrogen. Another group of preferred compounds is that wherein X
is -0-, -5-, -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 R7 R7a R7 R7a (C)P (C)p R1o-Q-- jQ1- R10-N~
% X)q ( X)4 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 1 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. R9a is preferably H or (C1-C6)alkyl. R6 is preferably hydrogen.
Preferred specific examples of compounds of formula VIII include compounds of the formula NN"N O
R2-Y-(CH2)n N N

wherein R2-Y-(CH2)n-N(R9)- is as defined in the table:
R -Y-(CH2)õ-N(R )-N
F
OMe N
F

F
F J N /-Me N
F

0-- N a \~N~N" ~\
OMe F N/--\N-\ Me ~--Me -I N
F

0-.&N / N
N
OMe N
~-OMe O Q -N JN~ Me OMe F

0- N N f\
a !-/ ~N Me ~OMe WO 01/02409 discloses useful adenosine Ala receptor antagonist compounds having the structural formula IX

R, R3 X N

N'~' R4 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, NR7CONR8R9, NR7CO2R8, NR7SO2R8, NR7CONR8NR9R1o, NR7NR8C02R9, NR7NR8CONR9R10, NR7SO2NR8R9, S02R7, SOR7, SR7 and SO2NR7R8, 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 carbocyclic 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, S02NR7R8,, CONR7R8, CONR7NR8R9, OCONR7R8, NR7R8, NR7COR8, NR7CONR8R9i NR7CO2R8, NR7SO2R8, CR7=NOR8, NR7CONR8NR9R1o, NR7NR8C02R9i NR7NR8CONR9R10r S02NR7NR8R9, NR7SO2NR8R9, NR7NR8SO2R9, NR7N%C02R9i NR7NR8R9 and NR7CSNR8Rg, or Rs and R6 together form a 5, 6 or 7 membered carbocyclic or heterocyclic ring; and R7, R8, R9, Rio, R1, 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 clozapine, 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 clonazepam, 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).

It is contemplated that two or more A2a 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 A2a antagonist in combination with one other agent is preferred for each of the indications. While administration of separate dosage forms of the A2a 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 A2a 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 N'K N-N o F - N \-~ 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 I.
Compounds useful in the method of the invention will show utility as adenosine A2a receptor antagonists in these assays.
Human Adenosine A2. and A, Receptor Competition Binding Assay Protocol Membrane sources: A2a: Human A2a Adenosine Receptor membranes, Catalog #RB-HA2a, 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 (Gibco/BRL) +
10 mM MgCI2 supplemented with 1.6 mg/ml methyl cellulose and 16% DMSO.
Prepared fresh daily.
Ligands: A2a: [3H]-SCH 58261, custom synthesis, AmershamPharmacia Biotech, Piscataway, NJ. Stock is prepared at 1 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.

Non-specific Binding:
A2a: 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 pl. 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

15 for A2a, [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 pl 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.
Haloperidol-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 A2a, 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.

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 A2a 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.

The quantity of adenosine A2a 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 A2a receptor antagonists, i.e., the antipsychotics, tricyclcic 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 Ala 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 A2a 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 A2a 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 A2a 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.
Example 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 I 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 al, Sleep, 22, 7 (1999), p. 961-8. Efficacy of adenosine A2a 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 Pharmacotherapy, 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 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.

Claims

Claims:

1. The use of an adenosine A2a receptor antagonist for the preparation of a medicament for the treatment or prevention of Extra-Pyramidal Syndrome (EPS) caused by treatment with an antipsychotic agent, wherein the adenosine A2a antagonist is a compound of the formula (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)-, -O-, -S-, -CH2S-, -(CH2)2-NH-, or 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)-, , phenyl-CH(OH)-, or phenyl-C(=NOR)-; or when Q is , Z is also phenylamino or pyridylamino;

or Z and Y together are 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 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, 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 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(0)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:

wherein R and Z-Y are as defined in the following table:

or a pharmaceutically acceptable salt thereof.

3. The use of Claim 2, wherein the adenosine A2a receptor antagonist is:

or a pharmaceutically acceptable salt thereof.

4. The use of Claim 2, wherein the adenosine A2a receptor antagonist is:

or a pharmaceutically acceptable salt thereof.

5. The use of any one of claims 1 to 4, wherein the antipsychotic agent is an atypical antipsychotic agent selected from the group consisting of clozapine, olanzapine, loxapine, quetiapine, ziprasidone and risperidone.

6. The use of any one of claims 1 to 4, wherein the antipsychotic agent is a typical antipsychotic agent selected from the group consisting of loxapine, haloperidol, chlorpromazine, prochlorperazine and thiothixene.

7. The use of claim 5 or 6, further comprising the use of said antipsychotic agent for the preparation of a medicament for use in combination with the adenosine A2a receptor antagonist medicament.

8. A kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat or prevent Extra-Pyramidal Syndrome (EPS) caused by treatment with an antipsychotic agent, wherein one container comprises a pharmaceutical composition comprising an effective amount of an adenosine A2a receptor antagonist which is a compound of the formula (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)-, -O-, -S-, -CH2S-, -(CH2)2-NH-, or 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)-, , phenyl-CH(OH)-, or phenyl-C(=NOR2)-; or when Q is , Z is also phenylamino or pyridylamino;

or Z and Y together are 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 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, 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 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 R13 is (C1-C6)alkyl-C(O)- or (C1-C6)alkyl-SO2-, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an effective amount of the antipsychotic agent in a pharmaceutically acceptable carrier;
and instruction for use thereof.

9. The kit of claim 8, wherein the adenosine A2a receptor antagonist is selected from the group consisting of compounds of the formula:

wherein R and Z-Y are as defined in the following table:

or a pharmaceutically acceptable salt thereof.

10. The kit of Claim 9, wherein the adenosine A2a receptor antagonist is:

or a pharmaceutically acceptable salt thereof.

11. The kit of Claim 9, wherein the adenosine A2a receptor antagonist is:

or a pharmaceutically acceptable salt thereof.

12. The kit of any one of claims 8 to 11, wherein the antipsychotic agent is a typical antipsychotic agent selected from the group consisting of loxapine, haloperidol, chlorpromazine, prochlorperazine and thiothixene.

13. The kit of any one of claims 8 to 11, wherein the antipsychotic agent is an atypical antipsychotic agent selected from the group consisting of clozapine, olanzapine, loxapine, quetiapine, ziprasidone and risperidone.

14. An adenosine A2a receptor antagonist for use in the treatment or prevention of Extra-Pyramidal Syndrome (EPS) caused by treatment with an antipsychotic agent, wherein the adenosine A2a antagonist is a compound of the formula (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)-, -O-, -S-, -CH2S-, -(CH2)2-NH-, or 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)-, , phenyl-CH(OH)-, or phenyl-C(=NOR2)-; or when Q is , Z is also phenylamino or pyridylamino;

or Z and Y together are 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 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, 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 R7 is (C1-C6)alkyl, R5-phenyl or R5-phenyl(C1-C6)alkyl;
R8 is hydrogen or C1-C6 alkyl; or R7 and R 8 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 R13 is (C1-C6)alkyl-C(O)- or (C1-C6)alkyl-SO2-.

15. The adenosine A2a receptor antagonist of claim 14, selected from the group consisting of compounds of the formula:

wherein R and Z-Y are as defined in the following table:

or a pharmaceutically acceptable salt thereof.

16. The adenosine A2a receptor antagonist of Claim 15, which is:
or a pharmaceutically acceptable salt thereof.

17. The adenosine A2a receptor antagonist of Claim 15, which is:
or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition for use in the treatment or prevention of Extra-Pyramidal Syndrome (EPS) caused by treatment with an antipsychotic agent, comprising an adenosine A2a receptor antagonist of the formula (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)-, -O-, -S-, -CH2S-, -(CH2)2-NH-, or 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)-, phenyl-CH(OH)-, or phenyl-C(=NOR2)-; or when Q is , Z is also phenylamino or pyridylamino;

or Z and Y together are or an N-oxide thereof, R1 is 1 to 3 substituents independently selected from hydrogen, C1-C6-alkyl, -CF3, halogen, -NO2, -NR 12R13, 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 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, 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 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 R13 is (C1-C6)alkyl-C(O)- or (C1-C6)alkyl-SO2-; and a pharmaceutically acceptable carrier therefor.

19. The pharmaceutical composition of claim 18, wherein the adenosine A2a receptor antagonist is selected from the group consisting of compounds of the formula:

wherein R and Z-Y are as defined in the following table:
or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition of Claim 19, wherein the adenosine A1, receptor antagonist is:

or a pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition of Claim 19, wherein the adenosine A2a receptor antagonist is:

or a pharmaceutically acceptable salt thereof.

22. The pharmaceutical composition of any one of claims 18 to 21, wherein the antipsychotic agent is a typical antipsychotic agent selected from the group consisting of loxapine, haloperidol, chlorpromazine, prochlorperazine and thiothixene.

23. The pharmaceutical composition of any one of claims 18 to 21, wherein the antipsychotic agent is an atypical antipsychotic agent selected from the group consisting of clozapine, olanzapine, loxapine, quetiapine, ziprasidone and risperidone.