CROSS REFERENCE TO RELATED APPLICATIONS 0001 This application claims the benefit of U.S. Provisional Application 60/435,321, filed Dec. 19, 2002.

FIELD OF THE INVENTION 0002 The present invention relates to the use of adenosine A2a 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 0003 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. 0004 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. 0005 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. 0006 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. 0007 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: A1, A2a, A2b and A3. Analogs of adenosine able to interact as antagonists with the A1, A2a, A2b and A3 receptors have also been identified. 0008 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 A1 receptor selective antagonists, and xanthine and non-xanthine compounds have been found to have high A2a affinity with varying degrees of A2a vs. A1 selectivity. Adenosine A2a receptor antagonists have been disclosed previously, for example in WO 95/01356 and U.S. Pat. No. 6,630,475.

SUMMARY OF THE INVENTION 0009 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 A2a 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. 0010 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 A2a 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. 0011 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. 0012 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. 0013 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. 0014 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 levodopa/carbidopa, levodopa/benserazide, a dopamine agonist, a benzodiazepine, an opioid, an anticonvulsant or iron. 0015 The invention also relates to the use of an adenosine A2a 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 0016 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. 0017 FIG. 1A illustrates the effect of Compound A (1-30 mg/kg, p.o.) on maximum EPS score. 0018 FIG. 1B represents the mean delay in onset of EPS for each treatment group compared to a vehicle control group.

DETAILED DESCRIPTION OF THE INVENTION 0019 Any adenosine A2a 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 A2a antagonists include the compounds disclosed in several patents and patent applications, e.g. WO 95/01356; U.S. Pat. No. 5,565,460; U.S. Pat. No. 6,630,475 B2; U.S. Pat. No. 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. 0020 U.S. Pat. No. 6,630,475 B2 discloses compounds having the structural formula I 1

0021 or a pharmaceutically acceptable salt thereof, wherein 0022 R is R1-furanyl, R1-thienyl, R1-pyridyl, R1-pyridyl N-oxide, R1-oxazolyl, R10-phenyl, R1-pyrrolyl or C4-C6 cycloalkenyl; 0023 X is C2-C6 alkylene or C(O)CH2; 0024 Y is N(R2)CH2CH2N(R3), OCH2CH2N(R2), O, S, CH2S, (CH2)2NH, or 2

0025 and 0026 Z is R5-phenyl, R5-phenyl(C1-C6)alkyl, R5-heteroaryl, diphenylmethyl, R6C(O), R6SO2, R6OC(O), R7N(R8)C(O), R7N(R8)C(S), 3

0027 phenyl-CH(OH), or phenyl-C(NOR2); or when Q is 4

0028 Z is also phenylamino or pyridylamino; or 0029 Z and Y together are 5

0030 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; 0031 R2 and R3 are independently selected from the group consisting of hydrogen and C1-C6 alkyl; 0032 m and n are independently 2-3; 0033 Q is 6

0034 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; 0035 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, 7

0036 or adjacent R5 substituents together are OCH2O, OCH2CH2O, OCF2O or OCF2CF2O and form a ring with the carbon atoms to which they are attached; 0037 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 8

0038 R7 is (C1-C6)alkyl, R5-phenyl or R5-phenyl(C1-C6)alkyl; 0039 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; 0040 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; 0041 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; 0042 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; 0043 R12 is H or C1-C6 alkyl; and 0044 R13 is (C1-C6)alkyl-C(O) or (C1-C6)alkyl-SO2. 0045 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 alkylene, preferably ethylene. Y is preferably 9

0046 wherein Q is 10

0047 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, R6C(O) or R6SO2. R5 is preferably H, halogen, alkyl, alkoxy, hydroxyalkoxy or alkoxyalkoxy. R6 is preferably R5-phenyl. 0048 Preferred specific compounds of formula I are those of the formula IA 11

0049 wherein R and Z-Y are as defined in the following table: 1ZYR

0050 Other useful adenosine A2a receptor antagonists include those disclosed in WO 95/01356 as compounds having the structural formula II 36

0051 wherein: 0052 A is pyrazole, imidazole or a triazole ring; 0053 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 haloalkoxy, 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, O, S and m is an integer from 1 to 5; 0054 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, O, S and n is an integer from 2 to 5. 0055 Preferably, compounds of formula II are those wherein R is hydrogen, C1-C8 alkyl, aryl or C7-C10 aralkyl optionally substituted, preferably with halogen atoms. 0056 U.S. Pat. No. 5,935,964 discloses useful adenosine A2a receptor antagonist compounds having the structural formula III 37

0057 wherein A is pyrazole, imidazole or triazole ring; 0058 R is 38

0059 R1 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 OCH2O; and 0060 n is an integer from 0-4. 0061 Preferred compounds of formula III are those wherein A is pyrazolo4,3-e or 1,2,3-triazolo5,4-e. 0062 U.S. Pat. No. 5,565,460 discloses useful adenosine A2a receptor antagonist compounds having the structural formulas IVA and IVB, wherein formula IVA is 39

0063 wherein R1 represents hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower alkanoyl; 0064 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; 0065 R3 represents a substituted or unsubstituted heterocyclic group; 0066 X represents a single bond, O, 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 0067 A represents N or CR5 (in which R5 represents hydrogen, or a substituted or unsubstituted lower alkyl); and 0068 wherein formula IVB is 40

0069 wherein R6 represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group; 0070 Y represents O, S, or NR7 (in which R7 represents substituted or unsubstituted lower alkyl, substituted or unubstituted cycloalkyl, or substituted or unsubstituted aryl); 0071 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 0072 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. 0073 WO 03/032996 discloses useful adenosine A2a receptor antagonist compounds having the structural formula V 41

0074 or a pharmaceutically acceptable salt thereof, wherein 0075 R is R1-heteroaryl, R10-phenyl, C4-C6 cycloalkenyl, C(CH2)CH3, CCCH3, CCCH2OR2 , CHC(CH3)2, 42

0076 X is C1-C6 alkylene, C(O)CH2 or C(O)N(R2)CH2; 0077 Y is N(R2)CH2CH2N(R3), OCH2CH2N(R2), O, S, CH2S, (CH2)2-3N(R2), R5-divalent heteroaryl, 43

0078 and 0079 Z is R5-phenyl, R5-phenyl(C1-C6)alkyl, R5-heteroaryl, R5-bicyclic heteroaryl, R5-benzofused heteroaryl, diphenylmethyl or R6C(O); 0080 or when Y is 44

0081 Z is also R6SO2, R7N(R8)C(O), R7N(R8)C(S) or R6OC(O); 0082 or when Q is 45

0083 Z is also phenylamino or pyridylamino; 0084 or Z and Y together are 46

0085 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; 0086 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, COOR7 or C(O)NR2R3; 0087 R2 and R3 are independently selected from the group consisting of hydrogen and C1-C6 alkyl; 0088 m and n are independently 2-3; 0089 p and q are independently 0-2; 0090 Q and Q1 are independently selected from the group consisting of 47

0091 provided that at least one of Q and Q1 is 48

0092 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 O; 0093 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-SO2(C1-C6)alkoxy, tetrahydropyranyloxy, (C1-C6)alkylcarbonyl(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl, (C1-C6)alkylcarbonyloxy(C1-C6)-alkoxy, SO2NH2, phenoxy, 49

0094 (R2O)2P(O)CH2O and (R2O)2P(O); or adjacent R5 substituents together are OCH2O, OCH2CH2O, OCF2O or OCF2CF2Oand form a ring with the carbon atoms to which they are attached; 0095 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 50

0096 R7 is (C1-C6)alkyl, R5-phenyl or R5-phenyl(C1-C6)alkyl; 0097 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; 0098 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; 0099 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 CH2SO2-phenyl; 0100 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; 0101 R12 is H or C1-C6 alkyl; 0102 R13 is H, (C1-C6)alkyl-C(O) or (C1-C6)alkyl-SO2; 0103 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 0104 R15 is H, halogen, C1-C6 alkyl or C1-C6 alkoxy. 0105 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, preferably ethylene. Y is preferably 51

0106 wherein Q is 52

0107 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. 0108 Preferred specific compounds of formula V are those of the formula VA 53

0109 wherein R and Z-Y are as defined in the following table: 2ZYR

0110 WO 03/048165 discloses useful adenosine A2a receptor antagonist compounds having the structural formula VI 74

0111 or a pharmaceutically acceptable salt or solvate of said compound, wherein: 0112 R is selected from the group consisting of R1-furanyl-, R1-thienyl-, R1-pyridyl-, R1-oxazolyl-, R1-pyrrolyl- and R2-aryl-; 0113 X is (CH2)n; 0114 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; 0115 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; 0116 n is 1 to 4; 0117 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 0118 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. 0119 In a preferred embodiment of compounds of formula VI, Y is 75

0120 wherein A1 is NX, and A2 and A3 each are CR4R5, or 0121 A1 and A3 each are CR4R5, and A2 is NX, or 0122 A1 and A2 each are CR4R5, and A3 is NX; 0123 A4 is CR4R5; 0124 Z1, 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; 0125 Z5 is NR5, O, S or CR4R5; 0126 Z6 is N or CR3; 0127 Z7 is N or CR3; 0128 m is an integer from 0 to 2; 0129 R3is 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-alkylamino, C1-C6-acylamino, C1-C6-alkylsulfonamino, C1-C6-alkylaminosulfonyl, C1-C6-dialkylaminosulfonyl, NH2SO2, and hydroxy; 0130 R4 is selected from the group consisting of hydrogen, hydroxyalkyl, aryl, aralkyl, C1-C6-alkyl, C1-C6-alkoxy, CF3, CN, halogen, hydroxy, and NO2; and 0131 R5 is hydrogen or C1-C6 alkyl. 0132 Preferred specific examples of compounds of formula VI include compounds of the formula: 76

0133 WO 03/048164 discloses useful adenosine A2a receptor antagonist compounds having the structural formula VII 77

0134 or a pharmaceutically acceptable salt or solvate thereof; wherein: 0135 R is selected from the group consisting of R4-heteroaryl, R5-phenyl, (C4-C6)cycloalkenyl, C(CH2)CH3, CCCH3, 78

0136 CHC(CH3)2, 79

0137 and CHCHCH3; 0138 R2 is selected from the group consisting of WX, NR19(CH2)mWX, and NR19CH(CH3)WX, or 0139 R2 is selected from the group consisting of alkyl, alkenyl and NR18R19, wherein said alkyl, alkenyl or NR18R19 is optionally substituted by WX; 0140 R3 is selected from the group consisting of H, halo, alkyl, trifluoromethyl, alkoxy, alkoxyalkyl, hydroxyalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, aminoalkyl, aryl, heteroaryl, and CN; 0141 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; 0142 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 CH2SO2-phenyl; 0143 R6 and R7, which can be the same or different, are each independently selected from the group consisting of hydrogen and (C1-C6)alkyl; 0144 R8 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, 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-SO2, (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, 80

0145 OCH2P(O)(OR6)2, and P(O)(OR6)2; or 0146 adjacent R8 substituents together are OCH2O, OCH2CH2O, OCF2Oor 0147 OCF2CF2O and form a ring with the carbon atoms to which they are attached; 0148 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, alkoxy(C1-C6)alkyl and 81

0149 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 O; 0150 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 O, and form a ring with the nitrogen to which they are attached; 0151 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; 0152 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(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl and piperidino(C1-C6)alkyl; 0153 R14 is selected from the group consisting of H, halogen, (C1-C6)alkyl or (C1-C6)alkoxy; 0154 R15 is selected from the group consisting of H and (C1-C6)alkyl; 0155 R16 is selected from the group consisting of H, (C1-C6)alkyl-C(O) and (C1-C6)alkyl-SO2; 0156 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-; 0157 R18 is selected from the group consisting of a bond, CH2, CH(OH), CH(CH3), C(CH3)n, (CH2)n, and O(CH2)n, 0158 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; 0159 Q and Q1 can be the same or different and are each independently selected from the group consisting of 82

0160 m and n are each independently 1-3; 0161 p and q are each independently 0-2; 0162 s is 0-4; 0163 W is aryl or heteroaryl having 1-3 heteroatoms, which can be the same or different, and are independently selected from the group consisting of N, O 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 0164 X is selected from the group consisting of H, NH2, N(R6)(CH2)s-aryl, N(R6)(CH2)s-heteroaryl, N(R6)(CH2)m1OH, and N(CH3)2, or 0165 X is R18Y-Z; 0166 Y is selected from the group consisting of N(R6)CH2CH2N(R7), N(R6)(CH2)naryl, OCH2CH2N(R6), O, S, CH2S, (CH2)2-3N(R6), R8-divalent heteroaryl, 83

0167 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, N(R6)(CH2),-aryl, N(R6)(CH2)s-heteroaryl, N(R6)C(O)OR17, alkylcycloheteroalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkoxycycloheteroalkyl, heteroaryl; R8-benzofused heteroaryl-, diphenylmethyl and R9C(O); or 0168 when Y is 84

0169 Z can also be OH, R9SO2, R17N(R11)(CH2)sC(O), R17OC(O), R17O(CH2)nC(O), benzofused heteroaryl(CH2)nC(O), benzofused heteroaryl(CH2)n or R17N(R11)C(S); or 0170 when Q is 85

0171 Z can also be R17R11N, phenylamino or pyridylamino; or 0172 Z and Y taken together are selected from the group consisting of 86

0173 Preferred compounds of formula VII are those having the following structures: 88

0174 WO 03/048163 discloses useful adenosine A2a receptor antagonist compounds having the structural formula VIII 91

0175 or a pharmaceutically acceptable salt thereof, wherein: 0176 A is C(R1) or N; 0177 R1 and R1a are independently selected from the group consisting of H, (C1-C6)-alkyl, halo, CN and CF3; 0178 Y is O, S, SO, SO2, R5-heteroaryldiyl, R5-arylene or 92

0179 p and q are independently 2-3; 0180 Q and Q1 are independently selected from the group consisting of 93

0181 provided that at least one of Q and Q1 is 94

0182 R is R5-aryl, R5--heteroaryl, R6(C2-C6)alkenyl or R6(C2-C6)alkynyl; 0183 R2 is R5-aryl, R5-heteroaryl, R5-aryl(C1-C6)alkyl or R5-heteroaryl(C1-C6)alkyl; or R2Y is 95

0184 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; 0185 n is 1, 2or 3; and 0186 (a) A is C(R1) and X is C(R3)(R3a), C(O), O, 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), O, S, 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 0187 (b) A is N, X is N(R9), Y is R5-arylene and R2 is 96

0188 or n is 2 or 3; and 0189 (c) A is N and X is C(R3)(R3a), C(O), O, 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 O(CH2)2N(R9a), and X is N(R9); or A is N, X is N(R9), and Y and R2 together are 97

0190 or n is 0; and 0191 (d) A is N, Y is a bond, X is N(R9), and R2 is 98

0192 (e) A is N, X is N(R9) and Y and R2 together are 99

0193 wherein Z is C(O)CH2, C(O)CH(C1-C6 alkyl), CH2CH(C1-C6 alkyl)-, or CH(C1-C6 alkyl)-CH2; 0194 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; 0195 R4 is 1-3 substituents selected from the group consisting of H, (C1-C6)alkyl, OH, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, halo, CF3, and CN; 0196 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-C6)-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-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; 0197 R6 is 1 to 3 substituents independently selected from the group consisting of H, OH, (C1-C6)alkoxy and halo; 0198 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 O; 0199 R8 is 1 to 3 substituents independently selected from H, (C1-C6)alkyl, OH, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, halo, CF3, and CN; 0200 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 0201 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. 0202 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 O, 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 100

0203 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. 0204 Preferred specific examples of compounds of formula VIII include compounds of the formula 101

0205 wherein R2Y(CH2)nN(R9) is as defined in the table: 3R2Y(CH2)nN(R9)

102

103

104

105

106

107

108

109

110

111

0206 WO 01/02409 discloses useful adenosine A2a receptor antagonist compounds having the structural formula IX 112

0207 wherein 0208 X is O or S; 0209 R1 and R2 are independently selected from hydrogen, alkyl, aryl, hydroxy, alkoky, aryloxy, cyano, nitro, CO2R7, COR7, OCOR7, CONR7R8, CONR7NR8R9, OCONR7R8, NR7R8, NR7COR8, NR7CONR8R9, NR7CO2R8, NR7SO2R8, NR7CONR8NR9R10, NR7NR8CO2R9, NR7NR8CONR9R10, NR7SO2NR8R9, SO2R7, SOR7, SR7 and SO2NR7R8, or R1and R2 together form a carbonyl group (CO), an oxime group (CNOR11), an imine group (CNR11) or a hydrazine group (CNNR11R12), or R1and R2 together form a 5, 6 or 7 membered carbocyclic or heterocyclic ring; 0210 R3 is alkyl or aryl; 0211 R4, R5 and R6 ate independently selected from hydrogen, alkyl, aryl, halogen, hydroxy, nitro, cyano, alkoxy, aryloxy, CO2R7, COR7, OCOR7, SO2R7, SOR7, SR7, SO2NR7R8, CONR7R8, CONR7NR8R9, OCONR7R8, NR7R8, NR7COR8, NR7CONR8R9, NR7CO2R8, NR7SO2R8, CR7NOR8, NR7CONR8NR9R10, NR7NR8CO2R9, NR7NR8CONR9R10, SO2NR7NR8R9, NR7SO2NR8R9, NR7NR8SO2R9, NR7NR8CO2R9, NR7NR8R9 and NR7CSNR8R9, or R5 and R6 together form a 5, 6 or 7 membered carbocyclic or heterocyclic ring; and 0212 R7, R8, R9, R10, R11 and R12 are independently selected from hydrogen, alkyl and aryl, or a pharmaceutically acceptable salt or prodrug thereof. 0213 The US patents and applications cited herein are incorporated herein by reference. The adenosine A2a receptor antagonists are prepared by known methods as described in the cited patents and applications. 0214 As used herein, patient means a mammal, especially a human. 0215 It is contemplated that more than one adenosine A2a receptor antagonist (e.g., 2 or 3) can be administered to treat EPS, dystonia, RLS or PLMS; preferably, one adenosine A2a receptor antagonist is administered. 0216 Antipsychotic agents causing the EPS treated by adenosine A2a receptor antagonists and for use in combination with adenosine A2a receptor antagonists include typical and atypical antipsychotic agents. Typical antipsychotics include loxapine, haloperidol, chlorpromazine, prochlorperazine and thiothixene. Atypical antipsychotics include clozapine, olanzapine, loxapine, quetiapine, ziprasidone and risperidone. 0217 Tricyclic antidepressants causing dystonia treated by adenosine A2a 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. 0218 Dopamine agonists useful in treating RLS and PLMS include pergolide, pramipexole, ropinerole, fenoldopam and cabergoline. 0219 Opioids useful in treating PRLS and PLMS include codeine, hydrocodone, oxycodone, propoxyphene and tramadol. 0220 Benzodiazepines useful in treating PRLS and PLMS include clonazepam, triazolam and temazepam. 0221 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). 0222 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. 0223 Preferred adenosine A2a antagonists are those described in U.S. Pat. No. 6,630,475. 0224 A particularly preferred compound of the invention is Compound A of the formula 113

0225 or a pharmaceutically acceptable salt or solvate thereof, disclosed in U.S. Pat. No. 6,630,475 and listed as the first compound in the table of compounds of structure I. 0226 Compounds useful in the method of the invention will show utility as adenosine A2a receptor antagonists in these assays. 0227 Human Adenosine A2a and A1 Receptor Competition Binding Assay Protocol Membrane sources: A2a: Human A2a Adenosine Receptor membranes, Catalog RB-HA2a, Receptor Biology, Inc., Beltsville, Md. Dilute to 17 g/100 l in membrane dilution buffer (see below). 0228 Assay Buffers: Membrane dilution buffer: Dulbecco's Phosphate Buffered Saline (Gibco/BRL)10 mM MgCl2. 0229 Compound Dilution Buffer: Dulbecco's Phosphate Buffered Saline (Gibco/BRL)10 mM MgCl2 supplemented with 1.6 mg/ml methyl cellulose and 16% DMSO. Prepared fresh daily. 0230 Ligands: A2a: 3H-SCH 58261, custom synthesis, AmershamPharmacia Biotech, Piscataway, N.J. Stock is prepared at 1 nM in membrane dilution buffer. Final assay concentration is 0.5 nM. 0231 A1: 3H-DPCPX, AmershamPharmacia Biotech, Piscataway, N.J. Stock is prepared at 2 nM in membrane dilution buffer. Final assay concentration is 1 nM. 0232 Non-Specific Binding: 0233 A2a: To determine non-specific binding, add 100 nM CGS 15923 (RBI, Natick, Mass.). Working stock is prepared at 400 M in compound dilution buffer. 0234 A1: To determine non-specific binding, add 100 M NECA (RBI, Natick, Mass.). Working stock is prepared at 400 M in compound dilution buffer. 0235 Compound Dilution: 0236 Prepare 1 mM stock solutions of compounds in 100% DMSO. Dilute in compound dilution buffer. Test at 10 concentrations ranging from 3 M to 30 pM. Prepare working solutions at 4 final concentration in compound dilution buffer. 0237 Assay Procedure: 0238 Perform assays in deep well 96 well plates. Total assay volume is 200 l. Add 50 l compound dilution buffer (total ligand binding) or 50 l CGS 15923 working solution (A2a non-specific binding) or 50 l NECA working solution (A1 non-specific binding) or 50 l of drug working solution. Add 50 l ligand stock (3H-SCH 58261 for A2a, 3H-DPCPX for A1). Add 100 l 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 l Microscint 20 (Packard), and count using the Packard TopCount Microscintillation Counter. Determine IC50 values by fitting the displacement curves using an iterative curve fitting program (Excel). Determine Ki values using the Cheng-Prusoff equation. 0239 Haloieridol-Induced Catalepsy in the Rat 0240 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 animals on the vertical grid test. For this test, the rats are placed on the wire mesh cover of a 2543 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 complete removal of one paw (descent latency) is measured maximally for 120 sec. 0241 The selective A2A adenosine antagonists under evaluation are administered orally at doses ranging between 0.03 and 3 mg/kg, 1 and 4 h before scoring the animals. 0242 In separate experiments, the anti-cataleptic effects were determined for the reference compound, L-DOPA (25, 50 and 100 mg/kg, ip), 0243 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. 0244 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. 0245 Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. 0246 Liquid form preparations may also include solutions for intranasal administration. 0247 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. 0248 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. 0249 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. 0250 Preferably the adenosine A2a receptor antagonist and the antipsychotic are administered orally. 0251 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. 0252 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 1 mg to 300 mg, according to the particular application. 0253 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. 0254 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. 0255 The doses and dosage regimen of the other agents used in combination with the adenosine A2a 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 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. 0256 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 A2a receptor antagonist and a dopamine agonist. 0257 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 0258 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. 0259 Compound A produced a dose-dependent reduction in the maximum EPS score (FIG. 1A), as well as a dose-dependent delay in the onset of EPS (FIG. 1B). 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. 0260 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. 0261 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.