MX2008004876A - Adenosine a2a receptor antagonists for the treatment of extra-pyramidal syndrome and other movement disorders - Google Patents

Abstract

There is disclosed a method for the treatment or prevention of Extra Pyramidal syndrome (EPS), dystonia, restless legs 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;also claimed are pharmaceutical compositions consisting of an adenosine A2a receptor antagonist in combination with an antipsychotic agent, an anticonvulsant agent, lithium or an opioid.

Description

ANTAGONISTS OF THE ADENOSIN A2A RECEIVER FOR THE TREATMENT OF EXTRA-PYRAMIDAL SYNDROME AND OTHER MOVEMENT DISORDERS FIELD OF THE INVENTION The present invention relates to the use of A2a adenosine receptor antagonists for the treatment of a variety of neurological syndromes involving the extra-pyramidal motor system (ie, extra-pyramidal syndrome) that occurs after acute and chronic use of almost all anti-psychotic drugs. The invention also relates to the use of A2a adenosine receptor antagonists for the treatment of other abnormal movement disorders such as Restless Legs Syndrome (RLS) and periodic movement of the legs during sleep (PLMS). The invention also relates to pharmaceutical compositions that consist of an adenosine A2a receptor antagonist and an anti-psychotic agent for the treatment of EPS, and to pharmaceutical compositions that consist of an A2a receptor antagonist and another agent useful for the treatment of others. Abnormal movement disorders such as RLS or PLMS.

BACKGROUND OF THE INVENTION The extra-pyramidal syndrome (EPS) is a collective term for a series of adverse neurological reactions associated with the use of anti-psychotic drugs. There are six different categories of neurological syndromes related to EPS, of which four, dystonia, akathisia, pseudo-parkinsonism (parkinsonian syndrome), and tardive dyskinesia, are particularly frequent in patients taking anti-psychotic medications. Dystonia is a painful spasm of the muscle groups of, in particular, the neck, jaw, back, pharynx and larynx. It is more common in young men who are treated with anti-psychotic drugs, but can also be associated with the use of cocaine, tricyclic antidepressants, lithium and anti-convulsants such as phenytoin and carbamazepine. Pseudo-parkinsonism is manifested as a hysteria (rigidity, inflexibility and slow voluntary movement, stopping, shuffling) and tremors and these symptoms develop weeks or months after the initiation of therapy. Acatisia manifests as strong and subjective internal sensations of anguish or malaise characterized by motive restlessness. Sometimes confused with agitation or anxiety, this common syndrome is often under-diagnosed and is the last sensitive to treatment. The late dysquiensia is a syndrome that appears to the last one associated with the chronic use of neuroleptic drugs. It occurs more frequently in elderly patients and is characterized by stereotypic, repetitive, involuntary, rapid choreiform movements of the face, eyelids, mouth, tongue, extremities and trunk. EPS is more frequent with the use of typical anti-psychotic agents but it has also been reported with the use of atypical agents. Typical anti-psychotics include loxapine, haloperidol, chlorpromazine, prochlorperazine and thiothixene. Atypical anti-steroids include clozapine, olanzapine, loxapine, quetiapine, ziprasidone, risperidone, aripiprazole, sertindole, and zotepine. "Acatis also" is a feature of RLS and PLMS, as well as PLMD (periodic movement of the legs (or limb)). 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 typical symptoms of RLS, but who exhibit periodic movements of the legs 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 ropinerol, benzodiazepines, opioids, seizures and iron (ferrous sulfate). RLS and PLMS have been described extensively 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 specific membrane receptors that belong to the superfamily 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, 2b, and A3. Adenosine analogues capable of interacting as antagonists with A ^ A2a, A2b, and A3 receptors have also been identified. In the CNS, the data showed that A2a receptors are present in high density in the basal ganglia, known to be important in fine motor movement control. In addition, selective antagonists for the A2a receptor are of pharmacological interest because of their demonstrated efficacy in reducing motor damage thereby improving function in neurodegenerative diseases such as Parkinson's disease and related movement disorders (e.g., Huntington's disease). ). It appears that A2a antagonists demonstrate a reduced risk of side effects (eg, no dyskinesia) compared to current dopaminergic therapies that result 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 selective antagonists of the A-i receptor, and xanthine and non-xanthine compounds have been found to have high A2a affinity with varying degrees of selectivity of A2a vs.. Ai. Adenosine A2a receptor antagonists have been previously described, for example in WO 95/01356 and US 6,630,475.

BRIEF DESCRIPTION OF THE INVENTION The invention relates to a method for the treatment or prevention of extrapyramidal syndrome (eg, dystonia, acatasia, pseudo-parkinsonism and tardive dyskinesia) comprising the administration of a therapeutically effective amount of a receptor antagonist. A2a of adenosine to a patient who needs it. In particular, this method is for the treatment or prevention of EPS in patients treated with an anti-psychotic agent that has the secondary effect of inducing EPS. The A2a adenosine receptor antagonist can be administered after the EPS symptoms have manifested, or an A2a adenosine receptor antagonist can be administered at the beginning of the administration of an anti-psychotic agent in order to prevent EPS is presented The invention, therefore, also includes a method for the treatment or prevention of EPS induced by an anti-psychotic agent comprising the administration of a combination of an antipsychotic agent and an A2a adenosine antagonist to a patient in need thereof. . More particularly, the invention relates to the method of using certain A2a adenosine antagonists for mono-therapy or combination therapy. The invention also relates to the treatment of abnormal, idiopathic and drug-induced movement disorders. More specifically, the invention relates to the treatment of abnormal, idiopathic and drug-induced movement disorders wherein hypo- and / or hyperkinetic movement is a primary feature of the condition. For example, in the treatment of primary (idiopathic) dystonia, and the treatment or prevention of dystonia in patients exhibiting dystonia as a result of treatment with a tricyclic anti-depression, lithium or an anticonvulsant, or who have used cocaine, comprising the administration of a therapeutically effective amount of a ~ adenosine A2a receptor antagonist to a patient in need thereof. When dystonia is caused by treatment with a tricyclic anti-depressant, lithium or an anti-convulsant, the A2a adenosine receptor antagonist may be administered after symptoms of dystonia have manifested, or an adenosine A2a receptor antagonist can be administered at the beginning of the administration of a tricyclic antidepressant, lithium or an anti-convulsant for the purpose of preventing the occurrence of dystonia. The invention, therefore, also includes a method of treating or preventing dystonia induced by a tricyclic anti-depressant, lithium or an anti-convulsive comprising the administration of a combination of an adenosine A2a antagonist and a tricyclic anti-depressant. , lithium or an anti-convulsant to a patient who needs it. The invention also relates to the treatment of RLS or PLMS, which comprises administering to a patient in need thereof a therapeutically effective amount of an A2a adenosine receptor antagonist. The invention also comprises a method for the treatment of RLS or PLMS comprising the administration of a combination of an adenosine A2a antagonist with another agent useful in the treatment of RLS or PLMS, such as levodopa / carbidopa, levodopa / benserazide, a Dopamine agonist, a benzodiazepine, an opioid, an anti-convulsant or iron, to a patient who needs it. In another aspect, this invention relates to a device comprising, in separate containers in a single package, pharmaceutical compositions-to be used in combination to treat it to prevent EPS caused by treatment with an antipsychotic agent, wherein a container it 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 anti-psychotic agent. In another aspect, this invention relates to a kit comprising, in separate containers in a single package, pharmaceutical compositions to be used in combination to treat or prevent dhistonia caused by treatment with a tricyclic anti-depressant, lithium or an anti-convulsant. , wherein a 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 anti-depressant, lithium or an anti-convulsant. 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 a container comprises a pharmaceutical composition comprising an effective amount of an antagonist. of the A2a adenosine receptor 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 anti- convulsive or iron. In yet another aspect, this invention relates to a fixed dose pharmaceutical composition for the treatment or prevention of EPS that consists of a therapeutically effective amount of a combination of an adenosine A2a receptor antagonist and an anti-sciatic agent and a carrier. pharmaceutically acceptable. Furthermore, the invention relates to a fixed-dose pharmaceutical composition for the treatment of prevention of dystonia caused by treatment with lithium or an anti-convulsive consisting of a therapeutically effective amount of a combination of an adenosine A2a receptor antagonist and lithium or an anti-convulsant and a pharmaceutically acceptable carrier. The invention also relates to a fixed dose pharmaceutical composition for the treatment of RLS or PLMS which comprises a therapeutically effective amount of a combination of an A2a adenosine receptor antagonist and an opioid, an anti-seizure or iron and a carrier. pharmaceutically acceptable. The invention also relates to the use of an adenosine A2a receptor antagonist for the preparation of a medicament for the treatment or prevention of EPS, dystonia, RLS or PLMS, individually or in combination with other agents discussed above.

-BREVE DESCRIPTION PE THE DRAWINGS A more complete understanding of the invention can be obtained by reading the following description together with the accompanying drawings in relation to EPS induced by haloperidol in Cebus apella monkeys. Figure 1A illustrates the effect of a compound A (1-30 mg / kg, p.o.) on a maximum EPS score. Figure 1B represents the average delay at the start of EPS for each treatment group using compound A compared to a vehicle control group. Figure 2A illustrates the effect of a compound B (3-100 mg / kg, p.o.) on a maximum EPS score. Figure 2B represents the average delay at the start of EPS for each treatment group using compound B compared to a vehicle control group.

DETAILED DESCRIPTION OF THE INVENTION Any A2a adenosine 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 A 2a receptor antagonists include the compounds described in various patents and patent applications, for example, WO 95/01356; US 5,565,460; US 6,630,475, B2; US 5,935,964; US 6,653,315; US 6,916,811; US 2003/0212080; US 6,875,772; and US 6,787,541 B1. Specifically, these patents and applications describe the following compounds. US 6,630,475 B2 describes compounds having the structural formula I or a pharmaceutically acceptable salt thereof, wherein R is R1-furanyl, R1-thienyl, R1-pyridyl, N-oxide of R1-pyridyl, R1-oxazolyl, R10-phenyl, R1-pyrrolyl or cycloalkenyl of C4-C6; X is C2-C6 alkylene or -C (0) CH2-; Y is -N (R2) CH2CH2N (R3) -, -OCH2CH2N (R2) -, -O-, -S-, -CH2S-, - (CH2) 2-NH-, or Z is R5-phenyl, R5-phenyl-alkyl (C6), R5-heteroaryl, diphenylmethyl, R6-C (0) -, R6-S02-, R6-OC (O) -, R7-N (R8) -C (0) -, R7-N (R8) -C (S) -, HN N- i phenyl-CH (OH) -, or phenyl-C (= NOR2) -; or when Q is H O is also phenylamino or pyridylamino; or Z and Y together are R1 is 1 to 3 substituents independently selected from hydrogen, C -? - C6 alkyl, -CF3, halogen, -N02, -NR12R13, C? -C6 alkoxy, C6 alkylthio, CrC6 alkylsulfonyl, and C5 alkylsulfonyl. C6; R2 and R3 are independently selected from the group it consists of hydrogen and C-Cß alkyl; m and n are independently 2-3; What is it I Í I I | _N_, -C- -C C- 0 _c ^ H CN 'OH COCH3. R4 is 1-2 substituents selected "irrespective of group consisting of hydrogen and C 1 -C 6 alkyl, or two R 4 substituents in the same carbon can form = 0; R5 is 1 to 5 substituents independently selected from group consisting of hydrogen, halogen, (C- | -C6) alkyl, hydroxy, (C? -C6) alkoxy, -CN, di (C6 alkyl) amine, CF3, -OCF3, acetyl , -N02, hydroxyalkoxy of (C? -C6), (d-C6) alkoxy-alkoxy of (CrC6), di- ((C-? - C6) alkoxy) C-alkoxy C6, (C? -C6) alkoxy-alkoxy (C? -C6) -alkoxy carboxy-alkoxy of (C -? - C6), alkoxycarbonyl (CrC6) -alkoxy (C6), cycloalkyl (C3-C6) -alkoxy (CI-CT), di- (alkyl (Cr6)) amino-alkoxy (Cr6), morpholinyl, (C6) alkyl- S02-, (C C6) -SO- alkyl, (C -? - C6) alkoxy, tetrahydropyranyloxy, alkylcarbonyl (C -? - C6) -alcoxy (C C), alkoxycarbonyl (CrC6), alkylcarbonyloxy (C-i-C) - alkoxy (C? -C6), -SO2NH2, phenoxy, or adjacent R5 substituents junt -0-CF2-O- or -0-CF2CF2-0- and form a ring with the carbon atoms to which they are attached; R ° is alkyl of (C C6), R-phenyl, R-phenylalkyl of (C C6), thienyl, pyridyl, cycloalkyl of (C3-C6), alkyl of (CrC6) -OC (0) -NH-alkyl of (C -? - C6) -, di- (alkyl (CrC6)) aminomethyl, or -R7-is-alkyl of (CrC6), R5-phenyl or -R5-phenylalkyl of (C? -C6); R8 is hydrogen or (C-i-C) alkyl; or R7 and R8 together are - (CH2) pA- (CH2) q, where 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 join; R9 is 1-2 groups independently selected from hydrogen, (C -? - C6) alkyl, hydroxy, (CrC6) alkoxy, halogen, -CF3 and (C? -C6) alkoxy (CrC6) alkoxy; R10 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl of (C-pCß), hydroxy, alkoxy of (CrC6), -CN, -NH2, alkylamino of (C -? - C6), di - ((C? -C6) alkyl) amino, -CF3, -OCF3 and -S (0) or (C6) alkyl; R11 is H, (C6) alkyl, phenyl, benzyl, (C2-C6) alkenyl, alkoxy (CrC6) -alkyl (C -? - C6), di (C? -C6) alkyl) amino-alkyl of (C C6), pyrrolidinyl-alkyl of (CrC6) or piperidino-alkyl of (C? -C6); R 12 is H or (C C 6) alkyl; and R 13 is alkyl (C C 6) -C (O), or alkyl of (C C 6) -S02-.

Preferred compounds of formula I are those wherein R is R -furanyl, R1-thienyl, R -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. And it is preferably with Q preferably being nitrogen. Preferably, m and n are each 2, and R4 is H. A preferred definition for Z ~ is R5 = phenol, 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 formula IA where R and Z-Y are as defined in the following table: Other useful adenosine A2a receptor antagonists include those described in WO 95/01356 as compounds having the structural formula II wherein: A is a pyrazole, imidazole or triazole ring; R is hydrogen; (Ci-Cß) alkyl; (C3-C7) alkenyl; (C3-C7) alkynyl; cycloalkyl of (C3-C7); (C1-C5) alkyl substituted with one or more halogen atoms, hydroxy groups, (CrC4) alkoxy, (C3-C7) cycloalkyl, groups of formula -NR ^, -CONR ^; aryl optionally substituted with halogen atoms, alkoxy groups of (CrC4), alkyl of (C1-C4), nitro, amino, cyano, haloalkyl of (CrC4), haloalkoxy of (CrC4), carboxy, carboxyamido; (C7-C10) aralkyl wherein the aryl portion may 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 member 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; RLR2, which are the same or different, are hydrogen, (C1-C5) alkyl, (C7-C6) aralkyl, phenyl, or taken together with the nitrogen to which they are attached, form an azetidine ring or a ring 5-6 membered heterocyclic containing one or more heteroatoms such as N, O, S and n is an integer from 2 to 5. Preferably, compounds of formula II are those wherein R is hydrogen, (C? -C8) alkyl ), aryl or aralkyl of (C7-C? 0), optionally substituted, preferably with halogen atoms. US 5,935,964 discloses adenosine A2a receptor A2a antagonist compounds having the structural formula lll wherein A is pyrazole, imidazole or triazole ring; R is Ri and R2, which are the same or different, are H, OH, halogen, (C4) alkoxy, (C4) alkyl, nitro, amino, cyano, (C1-C4) haloalkyl, haloalkoxy (CT) -C4), carboxy or carboxyamido; or the OH group, together with one of R < ? or R2, or RT and R2, can form a methylenedioxy group -O-CH2-0-; and n is an integer of 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 A2a receptor antagonist compounds having the structural formulas IVA and IVB, wherein the IVA formula is wherein R 1 represents hydrogen, substituted and unsubstituted lower alkyl, or substituted or unsubstituted lower alkanoyl, - R 2 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted cycloalkyl, substituted aryl or unsubstituted, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heterocyclic group; R3 represents a substituted or unsubstituted heterocyclic group; X represents a single bond, O, S, S (O), S (O) 2, or NR 4 (wherein R 4 represents hydrogen, or substituted or unsubstituted lower alkyl, or R 2 and NR 4 combine to form a saturated heterocyclic group from 4 to 6 members substituted or unsubstituted); and A represents N or CR5 (wherein R5 represents hydrogen or a substituted or unsubstituted lower alkyl); and where formula IVB is wherein R6 represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group; Y represents O, S, or NR7 (wherein R7 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted 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 unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, or a heterocyclic group substituted or not replaced; and B and the two adjacent carbon atoms combine to form a carbocyclic or heterocyclic, monocyclic or bicyclic, partially saturated or unsaturated, substituted or unsubstituted group. US 6,653,315 discloses adenosine A2a receptor antagonist compounds having the structural formula V or a pharmaceutically acceptable salt thereof, wherein R is R 1 -heteroaryl, R 10 -phenyl, (C 4 -C 6) cycloalkenyl, C (= CH 2) ) CH3, -C = C-CH3, -C = C-CH2-OR2G-CH = C (CH3) 2, X is alkylene of (C C6), -C (O) CH2- or -C (O) N (R2) CH2-; Y is N (R2) CH2CH2N (R3) -, -OCH2CH2N (R2) -, -O-, -S-, -CH2S-, (CH2) 2-3-N (R2) -, R5-divalent heteroaryl, Z is R5-phenyl, R5-phenyl-(C6) alkyl, R5-heteroaryl, R5-bicyclic heteroaryl, R5-benzofused heteroaryl, diphenylmethyl or R6-C (0) -; or when Y is Z is also R6-S02-, R7-N (R8) -C (0) -, R7-N (R8) -C (S) - or R6OC (0) -; or when Q is - CH ~ Z is also phenylamino or pyridylamino; or Z and Y together are 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, (CrC6) alkyl, -CF3, halogen, -N02, -NR12R13, (C) alkoxy C6), alkylthio of (C? -C6), alkylsulfinyl of (C -? - C6), alkylsulfonyl of (C? -C6), - COOR7 or -C (0) NR2R3; R2 and R3 are independently selected from the group it consists of hydrogen and C? -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 that consists from l i l i I -N-. -CH- -C- -C- v -c- CN 'OH COCH J provided that at least one of Q and Q1 is O - C 'H - • R4 is 1-2 substituents selected independently from group consisting of hydrogen, C? -C6 alkyl, 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, C- | -C6 alkyl, hydroxy, alkoxy, C C6, -CN, dialkylamino of (C C6), -CF3, -OCF3, acetyl, -N02-, hydroxyalkoxy of (C? -C6), alkoxy (C -? - C6) -alkoxy (C -? - C6) ), dialkoxy (C? -C6) -alkoxy (Ci-Cd), alkoxy (Ci-C? J-alkoxy (CrC6) -alkoxy (CrC6), carboxyalkoxy of (C? -C6), alkoxycarbonyl (C? -C6) - alkoxy (C Ce), (C3-C6) cycloalkyl-alkoxy (Ci-Cß), dialkylamino (C C6) -alkoxy (C C6), morpholinyl, alkyl (d-C6) -S02-, alkyl (C C6) - S? 2-alkoxy (C? -C6), tetrahydropyranyloxy, alkylcarbonyl (C? -C6) -alkoxy (CrC6), alkoxycarbonyl (C6), alkylcarbonyloxy (C6) -alkoxy (d-C?), -S02NH2- phenoxy, ( (R20) 2-P (0) -CH2-0- and (R20) 2-P (0) -; or adjacent R5 substituents together are -O-CH2-O-, -O-CH2CH2-O-, -0-CF2-O- or -0-CF2CF2-0.- and form a ring with the carbon atoms to which they are attached. United; R6 is (C6) alkyl, R5-phenyl, R5-phenylalkyl (C ^ Ce), thienyl, pyridyl, cycloalkyl (C3-C6), alkyl (C6-6) -OC (0) -NH-alkyl (Ci-Ce), dialkylaminomethyl (CI-CT) or N alkyl of (C C6) -0 ^ 0.

R7 is (C6) alkyl, R5-phenyl or R5-phenylalkyl (C6); R8 is hydrogen or CrC6 alkyl; or R7 and R8 together are - (CH2) P- A- (CH2) q, where 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 substituents independently selected from the group consisting of hydrogen, C-Cß alkyl, hydroxy, Ci-Cß alkoxy, halogen, -CF3 and alkoxy (Ci-CβJ-alkoxy (CrC6); R10 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, d-C6 alkyl, hydroxy, d-C6 alkoxy, -CN, -NH2, CrC6 alkylamino, dialkylamino of (CrC6), -CF3, -OCF3, -S ( O) 0-2-alkyl (d-C6) and -CH2-S02-phenyl; R11 is H, d-Ce alkyl, phenyl, benzyl, C2-C6 alkenyl, alkoxy (CrC6) -alkyl (d-C6) ), dialkylamino (d-C6) -alkyl (C C6), pyrrolidinylalkyl (C? -C6) or piperidinoalkyl of (CrC6); R12 is H or C6 alkyl, R13 is H, alkyl (d-C6) - C (O) or alkyl (d-C6) -S02-; R14 is H, halogen, d-C6 alkyl, hydroxyalkyl of (d-C6), C6 alkoxy-alkyl (C6-6), thioalkyl of ( CrC6), alkylthio (C? -C6) -alkyl (d-C6) or NR2R3-alkyl (C6), and R15 is H, halogen, d-C6alkyl or C6alkoxy, Preferred compounds of the formula ula 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 wherein X is alkylene, preferably ethylene. And it is preferably I where Q is KJ or -r CuH- "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. preferably H, haloalkyl, alkoxy, hydroxyalkoxy or alkoxyalkoxy, R6 is preferably R5 ^ phenyl, Preferred specific compounds of formula V are those of formula VA where R and Z-Y are as defined in the following table: US 6,916,811 discloses useful adenosine A2a receptor antagonist compounds having the structural formula VI or the pharmaceutically acceptable solvate of said compound, wherein: R is selected from the group consisting of R1-furanyl-, R1-thienyl, R1-pyridyl-, R1-oxazolyl-, R1-pyrrolyl- and R2-aryl-; X is - (CH2) "-; Y is a piperidinyl, pyrrolidinyl or azepanyl group with an aryl or heteroaryl radical fused to two adjacent carbon atoms in Y, wherein X is attached to the N atom of the piperidinyl, pyrrolidinyl or azepanyl group; Q is 1-4 substituents, which may be the same or different, and are independently selected from the group consisting of hydrogen, cycloalkyl, cycloheteroaryl, amino, aryl, aralkyl, heteroaryl, alkyl, CF3, CN, halogen, N02, alkoxy, alkoxyalkoxy, cycloalkylalkoxy, acyloxy, alkylamino, acylamino, alkylsulfonamino, alkylaminosulfonyl, dialkylaminosulfonyl, NH2S02 and hydroxy; n is 1 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 N02; 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, alkylamine, acylamino, alkylsulfonamido, alkylaminosulfonyl, dialkylaminosulfonyl, aminosulfonyl and hydroxy. In a preferred embodiment of compounds of formula VI, Y is wherein A1 is N-X, and A2 and A3 are each CRR5, or A1 and A3 are each CR4R5, and A2 is N-X, or A1 and A2 are each CR4R4, and A3 is N-X; A4 is CR4R5; Z1, Z2, Z3 and Z4, which may be the same or different, each is independently selected from the group consisting of N and CR3, with the proviso that Z1, Z2, Z3 or Z4 and N and the remainder are CR3; Z5 is NR5, O, 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, d-C6 alkyl, CF3, CN, halogen, N02, C-C-alkoxy, C-C6-acyloxy, d-C6-alkylamino, d-C6, d-C6 alkylsulfonamino, d-C6 alkylaminosulfonyl, d-Cβ dialkylaminosulfonyl, NH2S02, and hydroxy; R4 is selected from the group consisting of hydrogen, hydroxyalkyl, aryl, aralkyl, d-C6 alkyl, CI-CT alkoxy, CF3, CN, halogen 7 7"hydroxy and NO2, and R5 is hydrogen or d-alkyl. Cβ- Preferred specific examples of compounds of formula VI include compounds of the formula: US2003 / 0212080 discloses useful adenosine A2a receptor antagonist compounds having the structural formula VII or its pharmaceutically acceptable salt or solvate; wherein: R is selected from the group consisting of R4-heteroaryl, R5-phenyl, (C4-C6) cycloalkenyl, -C (= CH2) CH3, -C = C-CH3, R2 is selected from the group consisting of WX, -NR19 (CH2) mWX, and -NR19CH (CH3) -WX, or R2 is selected from the group consisting of alkyl, alkenyl and -NR18R19, wherein said alkyl, alkenyl or -NR18R19 is optionally substituted by -WX; 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 may be the same or different, and are independently selected from the group consisting of hydrogen, (d-C6) alkyl, -CF3, halogen, -N02, -NR15R16, (C2-) alkoxy C6), alkylthio of (C? -C6), alkylsulfinyl of (d-C6), alkylsulfonyl of (C C6), -COOR17 and -C (0) NR6R7; R5 is 1 to 5 substituents, which may be the same or different, and are independently selected from the group consisting of hydrogen, halogen, (C6) alkyl, hydroxy, (CrC6) alkoxy, -CN, -NH2, alkylamino of (d-C6), dialkylamino of (d-C6), -CF3, -OCF3, -S (O) 0-2-alkyl (d-C6) and -CH2S02-phenyl; R6 and R7, which may be the same or different, are each selected from the group consisting of hydrogen and (d-C6) alkyl; R8 is 1 to 5 substituents, which may be the same or different, and are independently selected from the group consisting of hydrogen, halogen, (Ci-Cß) alkyl, hydroxy, Ci-Cß alkoxy, -CN, amino, dialkylamino of (C C6), -CF3, -OCF3, acetyl, -NO2, hydroxyalkoxy of (d-C6), alkoxy (C -? - C6) -alkoxy (d-C6), dialkoxy (CC "6) -alkoxy ( C C6), alkoxy (d-C6) -alkoxy (C? -C6) -alkoxy (C C6), carboxyalkoxy of (CrC6), alkoxycarbonyl (d-C6) -alkoxy (d-C6), cycloalkyl (C3-C6) ) -alkoxy (d-C6), dialkylamino (CrC6) -alkoxy (C? -C6), morpholinyl, alkyl (d-C6) -S02-, alkyl (d-C6) -SO2-alkoxy (d-C6), tetrahydropyranyloxy, alkylcarbonyl (C? -C6) -alkoxy (d-C6), alkoxycarbonyl (C? -C6), alkylcarbonyloxy (C? -C6) -alkoxy (d-C6), -SO2NH2, phenoxy, -O-CH2-P (O) (OR6) 2, and -P (0) (OR6) 2; or adjacent R8 substituents together are -0-CH2-0, -0-CH2CH2-O-, -0-CF2-0- or -0-CF2CF2-0- and form a ring with the carbon atoms to which they are attached; R9 is selected from the group consisting of (C? -C6) alkyl, R8-aryl, R8-arylalkyl (C6), thienyl, pyridyl, cycloalkyl (C3-C6), alkyl (d-C6) -OC ( 0) -NH-alkyl (C6), dialkylaminomethyl (C6), cycloheteroalkylalkyl (d-C6), aryloxyalkyl (d-C6), alkoxyalkyl (C6-6) and R10 alkyl is 1-2 substituents, which may be the same or different, and are independently selected from the group consisting of hydrogen, (d-C6) alkyl, R5-aryl and R4-heteroaryl, or two substituents R10 on the same carbon can form = O; R11 is hydrogen or (d-C6) alkyl; -C (O) -alkyl, or R17 and R11 taken together are - (CH2) pA- (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; R12 is 1-2 substituents, which may be the same or different, and are independently selected from the group consisting of hydrogen, (d-C6) alkyl, hydroxy, (C-? - C6) alkoxy, halogen, and - CF3; R13 is selected from the group consisting of H, (d-C6) alkyl, phenyl, benzyl, (C2-C6) alkenyl, (d-C6) alkoxy-C6 alkyl, dialkylamino (d-C6) - alkyl (d-C6), pyrrolidinylalkyl of (C? -C6) and piperidinoalkyl of (d-C6); R 4 is selected from the group consisting of H, halogen, (C? -C6) alkyl or (d-C6) alkoxy; R15 is selected from the group consisting of H and (d-C6) alkyl; R16 is selected from the group consisting of H, alkyl (d-Cß) -C (O) - and alkyl (d-C6) -S02-; R17 is selected from the group consisting of (d-C6) alkyl, hydroxyalkyl (CrC6), cycloalkyl-de- (C3-C6), alkoxy (d-C6) -alkoxy (C1-C6), alkoxy of (d-) C6), alkoxy (d-C6) -alkyl (d-C6), allyl, propargyl, R8-heteroaryl-, R8-aryl- and R8-aryl-alkyl (C6-C6) -; R18 is selected from the group consisting of a bond, -CH2-, -CH (OH) -, -CH (CH3) -, -C (CH3) n-, - (CH2) n- and -O (CH2) n -, R19 is selected from the group consisting of H, alkyl of (C d), alkyl (d-C6) -cycloalkyl (d-Cß), cycloalkyl (d-C6) -alkyl (C? -C6) ) and (C6) alkoxy-alkyl (C6); Q and Q1 may be the same or different and each is independently selected from the group consisting of: ? 3 • 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 may 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 may 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 ~ X is selected from the group consisting of H, NH2, -N (R6) (CH2) S-aryl, -N (R6) (CH2) 5-heteroaryl, -N (R6) (CH2) m + 1 -OH, and -N (CH3) 2, or X is -R18-YZ; Y is selected from the group consisting of -N (R6) CH2CH2N (R7) -, -N (R6) (CH2) n-aryl, -OCH2CH2N (R6) -, -O-, -S-, -CH2S., - (CH2) 2-3-N (R6) -, R8-divalent heteroaryl, and Z is selected from the group consisting of H, alkyl, alkoxyalkyl, R8-aryl, R8-arylalkyl (d-Cß), -R8-heteroaryl-, R8-bicycloalkyl, aminoalkyl, alkylamino, NH2, -N- (R6) (CH2) 6-aryl, -N (R6) (CH2) s-heteroaryl, -N (R6) C (0) OR17, alkylcycloheteroalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkoxycycloheteroalkyl, heteroaryl, R8-benzofused heteroaryl, diphenylmethyl and R9-C (OR)-; or when Y is Z can be -OH, Rs-SO2, R1"7- MN (/ DR1" 1) (CH2) s-C (0) -, R > 1? 7'-0C (0) -, R j1? 7 -O (CH2) n (C (O) -, heteroaryl-benzofused- (CH2) nC (0) -, benzofused heteroaryl (CH2) n- or R17-N (R11) -C (S) -; or < \ »17 n? when Q is i Z can also be RR N-, phenylamino or pyridylamino; or Z and Y taken together are selected from the group consisting of Q > -4 Preferred compounds of formula VII are those that have the following structures: US 6,875,772 describes useful adenosine A2a receptor antagonist compounds having the structural formula VIII or its pharmaceutically acceptable salt, wherein: A is C (R1) or N; R1 and R1a are independently selected from the group consisting of H, (CrC6) alkyl, halo, CN and -CF3; Y is -O-, -S-, -SO-, -S02-, R5-heteroaryldityl, R5-arylene or p and q are independently 2-3; Q and Q1 are independently selected from the group consisting of with the condition that at least one of Q and Q1 be N- j R is R -aryl, R -heteroaryl, R -alkenyl (C2-C6) or R -alkynyl (C2-C6); R2 is R5-aryl, R5-heteroaryl, R5-arylalkyl (d-C6) or R5-heteroarylalkyl (C6); or R2-Y is U, V and W are independently selected from the group consisting of N and CR1, with the proviso that at least one of U, V and W is CR1; n is 1, 2 or 3; and (a) A is C (R1) and X is -C (R3) (R3a) -, -C (O) -, -O-, -S-, -SO-, -S02-, 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-, -S02-, R4 -arylene -N (R9) - or R4-heteroaryldiyl, with the proviso that when X is -N (R9) - or R4-heteroaryldiyl, R2 is not phenyl or phenylalkyl of (Ci-Cß); or (b) A is N, X is -N (R9) -, Y is R5arylene and R2 is or n is 2 or 3; and (c) A is N and X is -C (R3) (R3a) -, -C (O) -, -O-, -S-, -SO-, -S02-, - 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 (0) 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 or n is 0; and (d) A is N, Y is a bond, X is -N (R9) -, and R2 is (e) A is N, X is -N (Ra) - and Y and R 2 j:. wherein Z is -C (0) -CH2-, -C (0) -CH (C?-C6 alkyl) -, -CH2-CH (d-C6 alkyl) -, or -CH (d-C6 alkyl) -CH2-; R3 and R3a are independently selected from the group consisting of H, -OH, C6 alkyl, hydroxy (d-Ce), alkoxy (CI-CT) -alkyl (C-Cß), amino-alkyl (C6-C6) , alkylamino (d-C6) -alkyl and dialkylamino (d-C6) -alkyl (Ci-Cß); R4 is 1-3 substituents selected from the group consisting of H, (C6) alkyl, -OH, (d-C6) alkoxy, (C6) alkoxy-alkoxy (C6), halo, -CF3 and - CN; R5 is 1-3 substituents independently selected from the group consisting of H, (d-Cß) alkyl, -OH, (d-Cß) alkoxy, (C6) alkoxy-alkyl (d-C6), alkoxy (d) -C6) -alcoxy (C? -C6), halo, -CF3, -CN, -NH2, alkylamino of (CrC6), dialkylamino of (CrC6), aminoalkyl of (dd), alkylamino (CrC6) -alkyl (C ? -C6), dialkylamino (d-C6) -alkyl (d-C6), alkanoylamino of (CrC6), alkanesulfonylamino of (C? -C6), alkylthio of (dd), alkylthio (C? -C6) -alkyl ( C? -C6), R6-alkenyl (C2-C6), R6-alkynyl (C2-C6), hydroxyalkyl (dd), alkoxy (CrCe) -C (0) -amino, or heterocycloalkylalkyl (d-C6); R6 is 1 to 3 substituents independently selected from the group consisting of H, -OH, (CrC6) alkoxy and halo; R7 and R7a are independently selected from the group consisting of H. (d-C6) alkyl, (d-C6) alkoxy-alkyl (d-C6), R8-aryl and R8-heteroaryl, or a substituent R7 and one R7a in the same carbon they can form = 0; R8 is 1 to 3 substituents independently selected from H, alkyl of (CrC6), -OH, alkoxy of (d-d), alkoxy (CrCe) -alkoxy (C6), halo, -CF3 and -CN; R9 and R9a are independently selected from the group consisting of H, (Ci-d) alkyl, (C2-C6) hydroxyalkyl, (C6-C6) alkoxy-(C2-C6) alkyl, (C2-C6) aminoalkyl , alkylamino (C? -C6) -alkyl (C2-C6), dialkylamino (C6-C6) -alkyl (C2-C6), haloalkenyl (C3-C6), CF3-alkyl (dd), alkenyl (C3-C6) ), cycloalkyl of (dd) and cycloalkyl (C2-C6) -alkyl (C? -C6); and R10 is H, -C (O) -O-alkyl (d-C6), R5-aryl, -C (0) -alkyl (dd), -C (O) - (R5-aryl) or R5-arylalkyl (d-C6).

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 wherein X is -O-, -S-, -N (R9) - or R4-arylene, with compounds wherein X is -N (R9) being more preferred. R9 is preferably d- alkyl. Preferred definitions for Y are a bond or piperazinyl. R2 is preferably R5-aryl. When Y and / or R2 is Q is preferably N, Q1 is preferably N, p and q are each preferably 2, each of R7 and R7a is preferably hydrogen, and R10 is preferably -C (0) -0-alkyl (C C6), -C (0) -alkyl (C? -C6) or -C (O) - (R5-aryl). R 5 is preferably 1 or 2 substituents selected from the group consisting of H, (C 1 -C 6) alkoxy, alkoxy (CrC 6) -alkoxy (CrC 6) halo and -CF 3. R4 is preferably H, halo or (d-C6) alkyl. R3 and R3a are preferably independently selected from H and (d-C6) alkyl. R9a is preferably H or (C6) alkyl. R6 is preferably hydrogen. Preferred specific examples of compounds of formula VIII include compounds of the formula in the table: US 6,787,541 discloses useful adenosine A2a receptor antagonist compounds having the structural formula IX twenty where: X is O or S; Ri and R2 are independently selected from hydrogen, alkyl, aryl, hydroxy, alkoxy, aryloxy, cyano, nitro, C02R7, COR7, OCOR, CONR7R8, CONR7NR8R9, OCONR7R8, NR7R8, NR7COR8, NR7CONR8R9, NR7C02R8, NR7S02R8, NR7CONR8NR9R10, NR7NR8C02R9, NR7NR8CONR9R10, NR7SO2NR8R9, S02R7, SOR7, SR7 and S02NR7R8, or R, and R2 together form a carbonyl group (C = 0), an oxime group (C = NOR-p), an imine group (C = NRn) or a group hydrazine (C = NNR-pR- | 2) or Ri and R2 together form a carbocyclic or heterocyclic ring of 5, 6 or 7 members; R3 is alkyl or aryl; R, R5 and R6 are independently selected from hydrogen, alkyl, aryl, halogen, hydroxy, nitro, cyano, alkoxy, aryloxy, C02R7, COR7, OCOR7, S02R7, SOR7, SR7, S02NR7R8, CONR7R8, CONR7NR8R9, OCONR7R8, NR7R8, NR7COR8 , NR7CONR8R9, NR7C02R8, NR7S02R8, CR7 -NOR8, NR7CONR8NR9R10, NR7NR8C02R9, NR7NR8CONR9R10, S02NR7NR8R9, NR7S02NR8R9, NR7NR8S02R9, NR7NR8C02R9, NR7NR8R9 and NR7CSNR8R9, or R5 and R6 together form a carbocyclic or heterocyclic ring of 5, 6 or 7 members; and R, R8, R9, Rio, Rn and R12 are independently selected from hydrogen, alkyl and aryl, or their pharmaceutically acceptable salt or prodrug. US 5,484,920 discloses useful adenosine A2a receptor antagonist compounds having the structural formula X R2 X or its pharmaceutically acceptable salt, wherein R1, R2 and R3 are independently H, lower alkyl, lower alkenyl or lower alkynyl; R4 is cycloalkyl, - (CH2) n -R5 or R5 is optionally substituted aryl or optionally substituted heterocyclic; Y1 and Y2 are independently H, halogen or lower alkyl; Z is optionally substituted aryl, optionally substituted heterocyclic or R6 is H, OH, lower alkyl, lower alkoxy, halogen, nitro or amino; m is 1, 2 or 3; and X1 and X2 are independently O or S. Preferred compounds of formula X are those wherein R1 and R2 are methyl or ethyl; R3 is H or lower alkyl; R4 is Y1 and Y2 are each H; X1 and X2 are each O; and Z is optionally substituted aryl of the formula wherein at least one of R ', R ° and Ra is lower alkyl or lower alkoxy and the other is H; and R10 is H or lower alkyl, or Z is where R6 and m are as defined above. Also preferred compounds of formula X are those wherein R1 and R2 are independently H, propyl, butyl, lower alkenyl or lower alkynyl; R4 is • X1 and X2 are each O; Z is naphthyl optionally substituted or where R6, m, are defined above. Other A2a antagonists contemplated for use in the invention include: piperazine-substituted triazolo [1, 5-c] pyrimidines described in US. 6,545,000; triazolo [1, 5-c] pyrimidines described in US 6,222,035; xanthine derivatives described in US 5,703,085; xanthine derivatives in US 5,756,735; thiazole derivatives described in WO 2005/063743 having the formula XI wherein n is 0, 1, 2 or 3; R1 is cycloalkyl, optionally substituted aryl, alicyclic or heteroaryl heterocyclic; R2 includes halogen, alkyl, optionally substituted aryl, alicyclic heterocyclic, heteroaryl and -COR8; and R3 and R4 independently include H, optionally substituted alkyl, optionally substituted aralkyl, and -COR12, 2-aminoquinazoline derivatives described in JP2005154434; triazolo [1, 5-c] pyrimidines described in EP 1544200; 2-aminoquinoline derivatives described in JP 2005132834; triazolo [1, 5-c] pyrimidines described in WO 2003/068776; triazolo [1, 5-a] pyrimidines described in WO 2003/020723; triazolo [1, 5-a] pyrimidines described in WO 1999/43678; pyrrolo [2,3-d] pyrimidines described in US 2004/0092537; thieno- and furan-pyrimidines described in US 2004/0097524; triazolo-pyrimidines described in US 2004/0097526; purine derivatives described in US 2004/0102459; pyrazolo [3,4-d] pyrimidines described in US 2004/0116447; pyrimidine compounds described in WO 2005/079800 having the formula XII ° RS? N R1 or its pharmaceutically acceptable salt, wherein: R-i is optionally substituted alkyl, alkenyl or alkynyl, or -NR6R7, -OR8, -SR9 or halogen; R2 is aryl or optionally substituted heteroaryl attached via a carbon atom; R3 is H; optionally substituted alkyl, alkenyl, alkynyl or cycloalkyl; halogen; OH; u -OR10; R4 is H; optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl; R5 is H or optionally substituted alkyl, alkenyl, alkynyl or cycloalkyl; or R and R5 together form a 5- or 6-membered heterocyclic ring; R6 is H or optionally substituted alkyl, alkenyl, alkynyl or cycloalkyl; R7, R8, R9 and R-io are optionally substituted alkyl, alkenyl, alkynyl or cycloalkyl; or R6 and R7 together form a 5- or 6-membered heterocyclic ring; pyrimidine compounds described in WO 2005/079801 having the formula XIII or its pharmaceutically acceptable salt, wherein: R-, is H or -NH2; R2 is aryl or optionally substituted heteroaryl attached via a carbon atom; R3 is H; optionally substituted alkyl, alkenyl, alkynyl or cycloalkyl, halogen, OH; u -OR? 0; R is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or optionally substituted heteroaryl; R5 is H or optionally substituted alkyl, alkenyl, alkynyl or cycloalkyl; or R4 and R5 together form a 5- or 6-membered heterocyclic ring; R-io is optionally substituted alkyl; thiazolopyridines described in US 2005/0065151; 2-acylaminobenzothiazole derivatives described in US 6,872,833; benzoxazole derivatives described in US 2004/0152702; carboxamidobenzothiazole derivatives described in US 6,734,179; 7-phenyl-benzo [b] thiophene amide derivatives described in US 6,730,670; 7-amino-carboxamidobenzothiazole derivatives described in US 6,713,499; 7-heterocycle-substituted benzothiazole amide derivatives described in US 6,727,247; 2- (substituted aroylamino) -7-morpholin-benzothiazole derivatives described in US 6,624,163; 2-aminoacyl-7-morpholinyl-benzothiazole derivatives described in US 6,596,718; nicotin- and isonicotinamide benzothiazole derivatives described in US 6,620,811; 2- (pyridine-acylamino) -7-morpholinyl-benzothiazole derivatives described in US 6,599,901; 5-methoxy-8-aryl-triazolo [1, 5-a] pyridine derivatives described in US 6,693,116; amides of 8-amino-triazolo [1, 5-a] pyridine-6-carboxylic acid described in US 6,689,790; 5- (phenyl or thiophenyl) -triazolo [1,5-a] pyridine derivatives described in US 6,514,989; 7-substituted 5-aminotriazole [1,5-a] pyridine derivatives described in US 6,506,772; 2- (substituted amino) -benzothiazole derivatives described in US 6,521,754; pyrimidinamines pyridinamines described in US 6,586,441; 5-amino substituted triazolo [1, 5-a] pyridine derivatives described in US 6,355,653; 2,6-bis-heteroaryl-4-aminopyrimidines described in WO 2005/058883; 4-pyrrolopyrimidinyl-benzenesulfonamide derivatives described in WO 2003/082873; benzofuran derivatives described in WO 2005/073210; benzofuran derivatives described in JP 2005126374; N-thiazolylbenzamide derivatives described in WO 2005/039572; triazolopyrazine derivatives described in WO 2004/092177; triazolotriazines and their derivatives described in WO 2004/092173; triazolo- and pyrazolo [1, 5-c] pyrimidine derivatives described in WO 2004/092172; triazolo- and pyrazolo [1, 5-c] pyrimidine derivatives described in WO 2004/092171; and triazolotriazine and pyrazolotriazine derivatives described in WO 2004/092179. The patents and applications of E.U.A. cited here are incorporated herein for reference. A2a adenosine receptor antagonists are prepared by known methods as described in the patents and applications cited. As used herein, "patient" means a mammal, especially a human. It is contemplated that more than one of the A2a adenosine receptor antagonists (e.g., 2 or 3) may be administered to treat EPS, dystonia, RLS or PLMS; preferably, an A2a adenosine receptor antagonist is administered. Anti-psychotic agents that cause EPS treated by A2a adenosine receptor antagonists and for use in combination with A2a adenosine receptor antagonists include typical and atypical anti-psychotic agents. Common anti-psychotics include loxapine, haloperidol, chlorpromazine, prochlorperazine and thiothixene. Atypical anti-steroids include clozapine, olanzapine, loxapine, quetiapine, ziprasidone, risperidone, aripiprazole, sertindole, and zotepine.

Tricyclic antidepressants that cause dystonia treated by A2a adenosine receptor antagonists include perphenazine, amitriptyline, desipramine, doxepin, trimipramine, and protriptyline. Anticonvulsants that can cause dystonia, but may also be useful in the treatment of RLS or PLMS include phenytoin, carbamazepine and gabapentin. Dopamine agonists useful in the treatment of RLS and PLMS include pergolide, pramipexole, ropinerol, phenyldopam and cabergoline. Opioids' useful in the treatment of PRLS and PLMS include codeine, hydrocodone, oxycodone, propoxyphene and tramadol. Benzodiazepines useful in the treatment of PRLS and PLMS include clonazepam, triazolam and temazepam. Anti-steroids, tricyclic antidepressants, anticonvulsants, dopamine agonists, opioids and benzodiazepines are commercially available and are described in the literature, for example, The Physicians Desk Reference (Montvale: Medical Economics Co., Inc., 2001). It is contemplated that two or more A2a receptor agonists could be administered in combination with one or more other agents (eg, anti-steroids, tricyclic antidepressants, anticonvulsants, dopamine agonists, opioids or benzodiazepines), although the administration of an agonist of A2a in combination with another agent is preferably for each of the indications. The administration of separate dosage forms of antagonist (s) A2a and the other agent (s) is a preferred embodiment.

Another preferred embodiment are fixed dose pharmaceutical compositions, ie, single dosage forms consisting of antagonist (s) of the A2a receptor in combination with another agent (s) for the treatment or prevention of EPS, dystonia, RLS or PLMS and a pharmaceutically acceptable carrier. Preferred fixed dose compositions consist of an A2a receptor antagonist and another agent for the treatment or prevention of EPS, dystonia, RLS or PLMS and a pharmaceutically acceptable carrier. Preferred A2a adenosine antagonists are those described in US 6,630,475. A particularly preferred compound of the invention is compound A of the formula or its pharmaceutically acceptable salt or solvate, described in US. 6,630,475 and listed as the first compound in the frame of compounds of structure I. Another preferred compound is compound B of the formula or its pharmaceutically acceptable salt or solvate, described in US 5,484,920 and known as istradefilin. Compounds useful in the method of the invention will show utility as A2a adenosine receptor antagonists in these assays.

Membrane sources of the competition binding assay protocol of the Agg and Ai receptor of human adenosine A2a membranes of the human adenosine A2a receptor, catalog # RB-HA2a, receptor biology, Inc., Beltsville, MD. They are diluted to 17 μg / 100 μl in membrane dilution pH regulator (see below).

Test pH regulators Membrane dilution pH regulator: regulated Dulbecco phosphate pH salt solution (Gibco / BRL) + 10 mM MgCl2.

Compound dilution pH regulator pH regulated saline solution with Dulbecco's phosphate (Gibco / BRL) + 10 mM MgCl2 supplemented with 1.6 mg / ml methyl cellulose and 16% DMSO. Prepared fresh daily.

Ligands A2a: Usual Synthesis [3H] -SCH 58261, Amersham Pharmacy Biotech, Piscataway, NJ. The stock solution is prepared in a 1 nM pH regulator of membrane dilution. Final assay concentration is 0.5 nM. A- ,: [3HJ-DPCPX, Amersham Pharmacy Biotech, Piscataway, NJ. The stock solution is prepared in 2 mM of a membrane dilution pH regulator. Final assay concentration is 1 nM.

Non-specific binding A2a: To determine the non-specific binding, 100 nM of CGS 15923 (RBI, Natick, MA) is added. The working mother solution is prepared at 400 nM in the pH regulator of compound dilution. A-i: To determine the non-specific binding, 100 μM of ÑECA (RBI, Natick, MA) is added. The working mother solution is prepared at 400 μM in the pH regulator of compound dilution.

Composition Dilution 1 mM stock solutions of compounds are prepared in 100% DMSO. It is diluted in pH regulator of compound dilution. It is tested in 10 concentrations ranging from 3 μM to 30 pM. The working solutions are prepared in a final 4X concentration in pH regulator of compound dilution.

Test procedure Tests are carried out on 96-well narrow plates. The total assay volume is 200 μl. 50 .mu.l of pH regulator compound dilution (ligand binding total) or 50 ul of working solution CGS 15923 (A2a non-specific binding) or 50 .mu.l of solution NECA working (Ai non-specific binding) or 50 are added μl of drug work solution. 50 ul of stock solution of ligand ([3H] -SCH 58261 for A2a [3H] -DPCPX for A ^ are added. 100 ul of diluted membranes containing the appropriate receptor was added. This mixture. Incubate at room temperature for 90 minutes. are collected using a Brandel cell harvester on filter plates Packard GF / B. 45 .mu.l of Microscint 20 (Packard) are added and counted using the counter Microscintillation Packard TopCount. IC50 values are determined by curve fitting of displacement using an interactive curve fitting program (Excel) The Ki values are determined using the Cheng-Prusoff equation.

Haloperidol-induced catalepsy in rats Male Sprague-Dawley rats (Charles River, Calco, Italy) weighing 175-200 g are used. The cataleptic state is induced by subcutaneous administration of the haloperidol dopamine receptor antagonist (1 mg / kg, se), 90 minutes before testing the animals in vertical grid test. For this first test, the rats are placed on the wire mesh covered with a 25x43 plexiglass cage placed at an angle of approximately 70 degrees with the bench. The rat is placed on the grid with the four legs abducted and extended ("frog posture"). The use of such unnatural posture is essential for the specificity of this test for catalepsy. The period of time of placement of the legs until the first removal of complete of one leg (descendant latency) is measured maximally for 120 seconds. The selective adenosine A2a antagonists under evaluation are administered orally in doses ranging from 0.03 to 3 mg / kg, 1 and 4 hours before the animals register. In separate experiments, the anti-cataleptic effects are determined for the reference compound, L-DOPA (25, 50 and 100 mg / kg, ip). The following example shows the use of adenosine A2a antagonists to attenuate the Extra-Pyramidal Syndrome (EPS) displayed in Cebus apella monkeys sensitive dopamine D2 antagonist, haloperidol receptor.

EXAMPLE A colony of seven Cebus apella monkeys that are previously sensitized to the chronic effects of haloperidol, exhibit EPS when acute haloperidol is administered (0.3 mg / kg, p.o). Compound A is administered orally (p.o.) in doses of 0.3-30 mg / kg, in conjunction with haloperidol. Compound B is administered orally (p.o.) in doses of 3-100 mg / kg), in conjunction with haloperidol. The studies are conducted using a design within subjects such that each monkey receives all 6 treatments (vehicle and 5 doses of compound A) in a balanced, cross-linked design. In all studies, the group of seven monkeys exhibits baseline EPS levels when dosed with haloperidol. Compound A produces a dose-dependent reduction in the maximum EPS marker (Figure 1A), as well as a dose-dependent delay at the beginning of EPS (Figure 1 B). At a dose of 1 mg / kg, compound A prevents the start of EPS in a monkey, and delays the onset of EPS for 1 hour. Compound A, at a dose of 3 mg / kg, prevents the onset of EPS in two monkeys, and delays the start of EPS by almost 2 hours in the rest of the monkeys. At 10 and 30 mg / kg, compound A prevents the onset of EPS in three monkeys and delays the onset of EPS by an average of 2.3-2.9 hr. Compound B produces a reduction in the maximum EPS marker (Figure 2A), as well as a dose-dependent delay at the start of EPS (Figure 2B). Additionally, compound B prevents the onset of EPS in a monkey at 3-30 mg / kg, and in two monkeys at doses of 57 and 100 mg / kg. Clinical guidelines for the treatment of RLS and PLMS have been established: see A.L. Chesson et al, SIeep, 22, 7 (1999), p. 961-8. The efficacy of A2a adenosine antagonists in the treatment of RLS and PLMS can be determined by a method analogous to the clinical method described in the literature by pramipexole and ropinerol by Weimerskirch et al, Annals of Pharmacotherapy, 35, 5 (2001), p. 627-30. For the preparation of pharmaceutical compositions of the compounds useful in the method of this invention, pharmaceutically acceptable, inert carriers can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, seals and suppositories. The powders and tablets may be comprised from about 0.1 to about 99 percent active ingredient. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, seals and capsules can be used as solid dosage forms suitable for oral administration. For preparation of suppositories, a low casting cela such as a mixture of fatty acid glycerides or cocoa butter first melts, and the active ingredient is dispersed homogeneously here as by agitation. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool and thereby solidifies. Liquid form preparations include solutions, suspensions and emulsions. As an example, water or propylene glycol-water solutions for parenteral injection may be mentioned. 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, briefly before use, to liquid form preparations for both oral or parenteral administrations. Said liquid forms include solutions, suspensions and emulsions. The compounds useful in the method of the invention can also be transdermally administrating. 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 A2a adenosine receptor antagonist and the anti-steroid are administered orally. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into unit doses containing the appropriate amounts of the active component, for example, an effective amount to achieve the desired purpose. The amount of A2a adenosine receptor antagonist in a unit dose of preparation can 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. The current dosage used can be varied depending on the requirements of the patient and the severity of the condition to be treated. The determination of the proper dosage for a particular situation is within the experience of the technique. Generally, treatment starts with smaller dosages that are less than the optimal dose of the compound. Therefore, the dosage is increased by small increments until the optimum effect under the circumstances is achieved. For convenience, the total daily dosage can be divided and administered in portions during the day if desired. The amount and frequency of administration of the A2a adenosine 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 the severity of the symptoms to be treated. A usual recommended dosage regimen for an A2a adenosine receptor antagonist is oral administration of approximately 10 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 their dosage range. The dose and dose regimen of the other agents used in combination with A2a adenosine receptor antagonists, ie, anti-psychotic, tricyclic antidepressants, anticonvulsants, dopamine agonists, benzodiazepines, opioids, lily or iron, will be determined by the physician. clinical attention in view of the approved doses and dosage regimen in the explanatory sign, taking into account the age, sex and condition of the patient and the severity of the disease. When administered in combination, the A2a adenosine receptor antagonist and the other agent can be administered simultaneously or consecutively. This is particularly useful when the components of the combination are preferably provided in different dosage schedules, for example, one component is administered daily and the other every six hours, or when the preferred pharmaceutical compositions are different, for example one is preferably a tablet. and one is a capsule. It is therefore advantageous to provide the A2a adenosine receptor antagonist and the other agent in a kit comprising, in separate containers in a single package, the pharmaceutical compositions for use in combination to treat or prevent EPS, dystonia, RLS or PLMS, wherein a 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 condition indicated. Those of skill in the art will recognize that a dosage form for one of the components of the combination can be modified to contain an A2a adenosine receptor antagonist and another agent, for example, an adenosine A2a receptor antagonist and an anti-adenosine receptor antagonist. synotic or an A2a adenosine receptor antagonist and a dopamine agonist.

Although 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. Said alternatives, modifications and variations are intended to fall within the essence and scope of the present invention.

Claims (15)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical composition comprising a combination of an A2a adenosine receptor antagonist and an anti-psychotic agent and a pharmaceutically acceptable carrier.

2. The composition according to claim 1, further characterized in that the anti-psychotic agent is a typical anti-psychotic agent selected from the group consisting of loxapine, haloperidol, chlorpromazine, prochlorperazine and thiothixene or a selected atypical anti-psychotic agent. from the group consisting of clozapine, olanzapine, loxapine, quetiapine, ziprasídone, risperidone, aripiprazole, sertindole, or zotepine.

3. The composition according to claim 2, further characterized in that the A2a adenosine receptor antagonist is selected from the group consisting of compounds of formula I or a pharmaceutically acceptable salt thereof, wherein R is R1-furanyl, R1-thienyl, R1-pyridyl, N-oxide of R -pyridyl, R1-oxazolyl, R10-phenyl, R1-pyrrolyl or cycloalkenyl of C-C6; X is C2-C6 alkylene or -C (0) CH2-; Y is -N (R2) CH2CH2N (R3) -, -OCH2CH2N (R2) -, -O-, -S-, -CH2S-, - ( CH2) 2-NH-, or and Z is R -phenyl, R -phenyl-(C? -C6) alkyl, R -heteroaryl, diphenylmethyl, Rb-C (0) -, R ° -S02-, RD-OC (0) -, - O -c- phenyl-CH (OH) -, or phenol (= NOR; or when Q is HZ is also phenylamino or pyridylamino; or Z and Y together are R1 is 1 to 3 substituents independently selected from hydrogen, d-C6 alkyl, -CF3, halogen, -N02, -NR1 R13, C6 alkoxy, alkylthio CrC6, d-C6 alkylsulfinyl, and d-C6 alkylsulfonyl; R2 and R3 are independently selected from the group consisting of hydrogen and alkyl of d-C6; m and n are independently 2-3; Q is 1 1 1 -N- -c- -c 1 -c 0 _c_ 'i H CN OH COCH 3. I R4 is 1-2 substituents independently selected from the group consists of hydrogen and alkylated from d-d, or two R4 substituents in the same carbon can form = 0; R5 is 1 to 5 selected substituents independently of the group consisting of hydrogen, halogen, C-rd alkyl, hydroxy, (C? -C6) alkoxy, -CN, di (alkyl (d-C6)) amino, CF3, -OCF3, acetyl, -NO2 , hydroxyalkoxy of (d-C6), alkoxy of (C -? - C6) -alkoxy of (d-C6), di- (alkoxy (CrC6)) alkoxy of C C6, alkoxy (CrC6) -alkoxy (C? - C6) -alkoxy (d-C6), carboxy-alkoxy of (CrC6), alkoxycarbonyl (CrC6) -alkoxy (dd), cycloalkyl (C3-C6) -alkoxy (CrC6), di- (alkyl (CrC6)) amino-alkoxy (dd), morpholinyl, alkyl of ( C? -Ce) -S02-, (d-C6) -SO- alkyl, (dd) alkoxy, tetrahydro-diynyloxy, alkylcarbonyl (d-C6) -alcoxy (C? -C6), alkoxycarbonyl of (C? -C6), alkylcarbonyloxy (d-d) - ( alkoxy (C? -C6), -S02NH2, phenoxy, or adjacent R5 substituents together are -0-CH2-0-, -0-CH2CH2-0-, -0-CF3-0-0 -0-CF2CF2-O- and form a ring with the carbon atoms to which they are attached. unite R6 is alkyl of (C6), R5-phenyl, R5-phenylalkyl of (dd), thienyl, pyridyl, cycloalkyl of (C3-C6), alkyl of (d-Ce) -OC (0) -NH-alkyl (C d) -, di- (C 1 -C 6) aminomethyl, or R7 is (d-d) alkyl, R5-phenyl or R5-phenylalkyl of (d-C6); R8 is hydrogen or (d-C6) alkyl; or R7 and R8 together are - (CH2) pA- (CH2) q, where p and q are independently 2 or 3 and A is a bond ^ CH ^, -S- or -O-, and form a ring with nitrogen at which join; R9 is 1-2 groups independently selected from hydrogen, (d-C6) alkyl, hydroxy, (d-C6) alkoxy, halogen, -CF3 and (d-C6) alkoxy-alkoxy (d-C6); R10 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, (d-C6) alkyl, hydroxy, (dd) alkoxy, -CN, -NH2, (CrCe) alkylamino, di- (alkyl ( CrC6)) amino, -CF3, -OCF3 and -S (O) 0-2alkyl of (C C6); R11 is H, alkyl of (dd), phenyl, benzyl, alkenyl of (C2-C6), alkoxy (C6) -alkyl (dd), di (alkyl (CrCe)) amino-alkyl of (CrC6), pyrrolidinyl- alkyl (dd) or piperidino-alkyl (dd); R 12 is H or (C C 6) alkyl; and R13 is (C6) alkylC (0), or (C6) alkyl -S02-; and compounds of structural formula X R2 X or its pharmaceutically acceptable salt, wherein R1, R2 and R3 are independently H, lower alkyl, lower alkenyl or lower alkynyl; R4 is cycloalkyl, - (CH2) n -R5 or n is 0, 1, 2, 3 or 4; R5 is optionally substituted aryl or optionally substituted heterocyclic; Y1 and Y2 are independently H, halogen or lower alkyl; Z is optionally substituted aryl, optionally substituted heterocyclic or R6 is H, OH, lower alkyl, lower alkoxy, halogen, nitro or amino; m is 1, 2 or 3; and X1 and X2 are independently O or S.

4. The composition according to claim 3, further characterized in that the A2a adenosine receptor antagonist is or its pharmaceutically acceptable salt or solvate.

5. The composition according to claim 2, further characterized in that the A2a adenosine receptor antagonist is or its pharmaceutically acceptable salt or solvate.

6. The composition according to claim 2, further characterized in that the A2a adenosine receptor antagonist is or its pharmaceutically acceptable salt or solvate.

7. A pharmaceutical composition comprising a combination of an adenosine A2a receptor antagonist and an anticonvulsant and a pharmaceutically acceptable carrier.

8. The composition according to claim 7, further characterized in that the anti-convulsant is selected from the group consisting of phenytoin, carbamazepine and gabapentin.

9. The composition according to claim 8, further characterized in that the A2a adenosine receptor antagonist is or its pharmaceutically acceptable salt or solvate.

10. A pharmaceutical composition comprising a combination of an adenosine A2a receptor antagonist and a pharmaceutically acceptable carrier.

11. The composition according to claim 10, further characterized in that the A2a adenosine receptor antagonist is or its pharmaceutically acceptable salt or solvate.

12. A pharmaceutical composition comprising a combination of an A2a adenosine receptor antagonist and an opioid and a pharmaceutically acceptable carrier.

13. The composition according to claim 12, further characterized in that the opioid is selected from the group consisting of codeine; hydrocodone, oxycodone, propoxyphene and tramadol.

14. The composition according to claim 13, further characterized in that the A2a adenosine receptor antagonist is or its pharmaceutically acceptable salt or solvate.

15. The use of an adenosine A2a receptor antagonist selected from the group consisting of or its pharmaceutically acceptable salt or solvate, for the manufacture of a medicament useful for the treatment or prevention of extra-pyramidal syndrome in a patient in need thereof, wherein the extra-pyramidal syndrome has been caused by treatment with sertindole or zotepine .