Compounds having the structural formula Ior a pharmaceutically acceptable salt thereof, wherein:

BACKGROUND

The present invention relates to adenosine A2areceptor antagonists, the use of said compounds in the treatment of central nervous system diseases, in particular Parkinson's disease, and to pharmaceutical compositions comprising said compounds.

Adenosine is known to be an endogenous modulator of a number of physiological functions. At the cardiovascular system level, adenosine is a strong vasodilator and a cardiac depressor. On the central nervous system, adenosine induces sedative, anxiolytic and antiepileptic effects. On the respiratory system, adenosine induces bronchoconstriction. At the kidney level, it exerts a biphasic action, inducing vasoconstriction at low concentrations and vasodilation at high doses. Adenosine acts as a lipolysis inhibitor on fat cells and as an antiaggregant on platelets.

Adenosine action is mediated by the interaction with different membrane specific receptors which belong to the 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, A2band A3. A1and A3are high-affinity, inhibiting the activity of the enzyme adenylate cyclase, and A2aand A2bare low-affinity, stimulating the activity of the same enzyme. Analogs of adenosine able to interact as antagonists with the A1, A2a, A2band A3receptors have also been identified.

Selective antagonists for the A2areceptor are of pharmacological interest because of their reduced level of side affects. In the central nervous system, A2aantagonists can have antidepressant properties and stimulate cognitive functions. Moreover, data has shown that A2areceptors are present in high density in the basal ganglia, known to be important in the control of movement. Hence, A2aantagonists can improve motor impairment due to neurodegenerative diseases such as Parkinson's disease, senile dementia as in Alzheimer's disease, and psychoses of organic origin.

Some xanthine-related compounds have been found to be A1receptor selective antagonists, and xanthine and non-xanthine compounds have been found to have high A2aaffinity with varying degrees of A2avs. A1selectivity. Certain imidazolo- and pyrazolo-substituted triazolo-pyrimidine adenosine A2areceptor antagonists have been disclosed previously, for example in WO 95/01356; WO 97/05138; and WO 98/52568. Certain pyrazolo-substituted triazolo-pyrimidine adenosine A2areceptor antagonists are disclosed in U.S. Ser. No. 09/207,143, filed May 24, 2001. Certain imidazolo-substituted triazolo-pyrimidine adenosine A2areceptor antagonists are disclosed in U.S. Provisional Application 60/329,567, filed Oct. 15, 2001. U.S. Pat. No. 5,565,460 discloses certain triazolo-triazines as antidepressants; EP 0976753 and WO 99/43678 disclose certain triazolo-pyrimidines as adenosine A2areceptor antagonists; and WO 01/17999 discloses certain triazolo pyridines as adenosine A2areceptor antagonists.

SUMMARY OF THE INVENTION

The present invention relates to a compound represented by the structural formula I

n is 0, 1 or 2; and

R and R1are independently selected from the group consisting of H and alkyl.

Another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I in a pharmaceutically acceptable carrier.

Yet another aspect of the invention is a method of treating central nervous system diseases such as depression, cognitive diseases and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, senile dementia or psychoses, and stroke, comprising administering at least one compound of formula I to a mammal in need of such treatment.

The invention also relates to the treatment of attention related disorders such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD). The invention also relates to the treatment or prevention of Extra-Pyramidal Syndrome (e.g., dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia), the treatment of primary (idiopathic) dystonia, and 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 at least one compound of formula I to a mammal in need of such treatment. The invention further relates to treatment of abnormal movement disorders such as restless leg syndrome (RLS) or periodic limb movement in sleep (PLMS), comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of formula I.

In particular, the invention is drawn to the method of treating Parkinson's disease comprising administering at least one compound of formula I to a mammal in need of such treatment.

Still another aspect of the invention is a method of treating Parkinson's disease with a combination of at least one compound of formula I and one or more agents useful in the treatment of Parkinson's disease, for example dopamine; a dopaminergic agonist; an inhibitor of monoamine oxidase, type B (MAO-B); a DOPA decarboxylase inhibitor (DCI); a catechol-O-methyltransferase (COMT) inhibitor; or a (N-methyl-D-aspartic acid) (NMDA) receptor antagonist. Also claimed is a pharmaceutical composition comprising at least one compound of formula I and one or more agents known to be useful in the treatment of Parkinson's in a pharmaceutically acceptable carrier.

The invention also comprises a method of treating EPS, dystonia, RLS or PLMS comprising administering a combination of at least one compound of formula I with another agent useful in treating RLS or PLMS, such as levodopa/carbidopa, levodopa/benserazide, a dopamine agonist, a benzodiazepine, an opioid, an anticonvulsant or iron, to a patient in need thereof.

In the method comprising the administration of the combination of the invention, one or more compounds of formula I and one or more other anti-Parkinson's agents can be administered simultaneously or sequentially in separate dosage forms. Similarly, one or more compounds of formula I and one or more other agents useful in treating EPS, dystonia, RLS or PLMS can be administered simultaneously or sequentially in separate dosage forms. Therefore, also claimed is a kit comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat Parkinson's disease wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of formula I in a pharmaceutically acceptable carrier, and wherein, in separate containers, one or more pharmaceutical compositions each comprise an effective amount of an agent useful in the treatment of Parkinson's disease, EPS, dystonia, RLS or PLMS in a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

Referring to compounds of formula I above, preferred compounds of formula I are those wherein n is 1. Also preferred are compounds of formula I wherein R and R1are each H.

Preferred compounds are those of Examples 2, 8, 12, 13 and 31, shown below.

As used herein, the term “alkyl” means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl and n-pentyl.

Alkoxy means an alkyl-O-group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.

The term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.

When any variable (e.g., X2, etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence.

Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella,Pro-drugs as Novel Delivery Systems(1987) 14 of the A.C.S. Symposium Series, and inBioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term “prodrug” means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

“Effective amount” or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.

It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention).

Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by theIUPAC1974 Recommendations. The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively.

Polymorphic forms of the compounds of Formula I, and of the salts, solvates, esters and prodrugs of the compounds of Formula I, are intended to be included in the present invention.

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of the substitutable ring carbon atoms.

As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:

represents

Compounds of formula I are prepared by general methods known in the art. Preferably, the compounds of formula I are prepared by the methods shown in the following reaction schemes. In the Schemes and examples that follow, the following abbreviations are used:

In general, compounds of this invention can be synthesized by combining dichlorides of type 1 and hydrazines of type 2. The intermediates of type 3 are then treated with phosgene to form the cyclic compounds of type 4, which are then converted to the target examples 5 by treatment with ammonia under microwave conditions (Scheme 1).

Compounds of types 6 and 7 are made similarly from phenyl hydrazine 8 and phenethyl hydrazine 9 respectively (Scheme 2).

The dichlorides 1 are available from anthranilic acids of type 10 in two steps via condensation with KOCN or urea followed by treatment with POCl3(Scheme 3).

The hydrazines 2 are readily available from benzyl bromides of type 12 or benzyl chlorides of type 13 in two steps via displacement of the halide with tert-butyl carbazate and removal of the Boc protecting group with HCl (Scheme 4).

PREPARATIVE EXAMPLES

4-Fluorobenzyl chloride (0.9 ml, 0.0076 mol) was added to tert-butyl carbazate (4 g, 4 eq) in EtOH (10 ml). DIPEA (1.25 ml, 1 eq) was added and the mixture heated at 60° C. for 3 h. After cooling to rt, the mixture was diluted with EtOAc, washed with NH4Cl(sat), NaHCO3(sat), dried (MgSO4), and concentrated to give an oil. Purification by column chromatography (0-20% EtOAc in hexane) gave 650 mg of a residue that was dissolved in 1,4-dioxane/water (7 ml/0.7 ml) and treated with 4M HCl in dioxane (7 ml). After 5 h, ether was added and the resulting precipitate collected to give 451 mg of the title compound.1H NMR (DMSO) δ 3.97 (s, 2H), 7.16 (t, J=8.8 Hz, 2H), 7.37-7.41 (m, 2H).

Using procedures similar to those for preparative example 1, the following preparative examples were synthesized from the appropriate starting materials.

3-Fluorobenzyl bromide (0.93 ml, 0.0076 mol) was added to tert-butyl carbazate (4 g, 4 eq) in EtOH (10 ml). The mixture heated at 60° C. for 40 min. After cooling to rt, the mixture was diluted with EtOAc, washed with NH4Cl(sat), NaHCO3(sat), dried (MgSO4), and concentrated to give an oil. Purification by column chromatography (0-20% EtOAc in hexane) gave 1.07 g of a residue that was dissolved in 1,4-dioxane/water (13.6 ml/1.4 ml) and treated with 4M HCl in dioxane (13.6 ml). After 5 h, the mixture was concentrated to a residue, EtOAc was added and the resulting solid collected by filtration to give 600 mg of the title compound.1H NMR (DMSO) δ 4.0 (s, 2H), 7.08-7.13 (m, 1H), 7.19 (t, J=12.4 Hz, 2H), 7.33-7.38 (m, 1H).

Using procedures similar to those outlined above for preparative example 9, the following preparative examples were synthesized from the appropriate starting materials.

Benzoyleneurea (40 g, 0.25 mol) was dissolved in POCl3(200 ml), N,N-dimethylaniline (13.2 ml, 0.113 mol) was added and the mixture heated at 130° C. for 5 h. The mixture was then cooled to rt and added to ice; after standing at rt overnight, the mixture was filtered to give a solid which was purified by column chromatography (CH2Cl2) to give the title compound 29, 14 5 g.1H NMR (CDCl3) δ 7.67-7.74 (m, 1H), 7.94-7.98 (m, 2H), 8.22 (d, J=8.8 Hz, 1H).

3-Fluoroanthranilic acid (3 g, 0.019 mol) was suspended in water/AcOH (107 ml/1.18 ml). KOCN (2 g, 1.3 eq) in water (11 ml) was added dropwise at 35° C. Once the addition was complete the mixture was heated at 35° C. for 3 h. The mixture was cooled to 0° C. and NaOH (40 g) was added, maintaining the temperature below 40° C. The resulting solid was collected, dissolved in hot water, acidified to pH 3 and 1.5 g (0.0083 mol) of solid was collected by filtration. The solid was dissolved in POCl3(9 ml), N,N-dimethylaniline (0.65 ml, 0.0051 mol) was added and the mixture heated at 130° C. for 5 h. The mixture was then cooled to rt and added to ice; the resulting solid was collected to give compound 30.1H NMR (DMSO) δ 7.80-7.86 (m, 1H), 8.00 (dd, J=10, 8 Hz, 1H), 8.08 (d, J=8 Hz, 1H).

Using procedures similar to those outlined above for preparative example 30, the following preparative examples were synthesized from the appropriate anthranilic acid.

6-Trifluoromethylanthranilic acid (1.485 g, 0.00724 mol) and urea (1.8 g, 4.1 eq) were heated together at 210° C. for 15 min; after cooling to 4, the residue was taken up in hot 2N NaOH, cooled to 0° C. and acidified to pH 3. The resulting solid was suspended in POCl3(9 ml) and treated with N,N-dimethylaniline (0.38 ml), then heated at 135° C. for 5 h. The mixture was poured onto ice and the solid collected to give 798 mg of 42.1H NMR (DMSO) δ 8.19 (t, J=8.4 Hz, 1H), 8.29 (d, J=8.8 Hz, 1H), 8.35 (d, J=7.2 Hz, 1H).

Compound P29 (200 mg, 0.001 mol) and compound P7 (291 mg, 1.1 eq) were dissolved in THF (8 ml), DIPEA (0.88 ml, 5 eq) was added and the mixture was stirred for 2 h. NH4Cl(sat)was added and the mixture extracted with EtOAc; the extracts were dried (MgSO4) and concentrated. The residue was treated with ether and the resulting 300 mg of solid was collected by filtration (MH+=355.2).

The product of step 1 (300 mg, 0.00085 mol) was dissolved in THF (12 ml), DIPEA (0.227 ml, 1.5 eq) then phosgene (0.68 ml of a 20% solution in toluene) was added. After stirring for 30 min, NH4Cl(sat)was added and the mixture extracted with CH2Cl2, dried (MgSO4), and concentrated. The residue was treated with EtOAc and the resulting 288 mg of solid was collected by filtration (MH+=379.2).

The product of step 2 (100 mg, 0.000264 mol) was suspended in EtOH (4 ml) and 2M NH3in EtOH (0.46 ml, 3.3 eq) was added. The mixture was heated at 80° C. for 20 minutes by microwave. After cooling to rt the solid was collected to give 74 mg of the title compound (Example 1). LCMS MH+=360.2.

Using procedures similar to those outlined above for example 1, the following examples were prepared from the appropriate starting materials.

Because of their adenosine A2areceptor antagonist activity, compounds of the present invention are useful in the treatment of depression, cognitive function diseases and neurodegenerative diseases such as Parkinson's disease, senile dementia as in Alzheimer's disease, psychoses, attention deficit disorders, EPS, dystonia, RLS and PLMS. In particular, the compounds of the present invention can improve motor-impairment due to neurodegenerative diseases such as Parkinson's disease.

The other agents known to be useful in the treatment of Parkinson's disease that can be administered in combination with the compounds of formula I include: L-DOPA; dopaminergic agonists such as quinpirole, ropinirole, pramipexole, pergolide and bromocriptine; MAO-B inhibitors such as deprenyl and selegiline; DOPA decarboxylase inhibitors such as carbidopa and benserazide; COMT inhibitors such as tolcapone and entacapone; and NMDA receptor antagonists such as amantadine. Amantadine is used as an adjunct to L-DOPA treatment for control of L-DOPA induced dyskinesia.

Adenosine A2aantagonists of the invention can also be co-administered with the antipsychotic agents known to cause the EPS and tricyclic antidepressants known to cause dystonia.

Antipsychotic agents causing the EPS treated by adenosine A2areceptor antagonists and for use in combination with adenosine A2areceptor 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.

Tricyclic antidepressants causing dystonia treated by adenosine A2areceptor 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 phenyloin, carbamazepine and gabapentin.

Dopamine agonists useful in treating RLS and PLMS include pergolide, pramipexole, ropinerole, fenoldopam and cabergoline.

Benzodiazepines useful in treating PRLS and PLMS include clonazepam, triazolam and temazepam.

The antipsychotics, tricyclic antidepressants, anticonvulsants, dopamine agonists, opioids and benzodiazepines are commercially available and are described in the literature, e.g., in The Physicians' Desk Reference (Montvale: Medical Economics Co., Inc., 2001).

One to three other agents can be used in combination with the compounds of formula I, preferably one.

The pharmacological activity of the compounds of the invention was determined by the following in vitro and in vivo assays to measure A2areceptor activity.

Human Adenosine A2aand A1Receptor Competition Binding Assay Protocol

A2a: To determine non-specific binding, add 100 nM CGS 15923 (RBI, Natick, Mass.). Working stock is prepared at 400 nM in compound dilution buffer.

Prepare 1 mM stock solutions of compounds in 100% DMSO. Dilute in compound dilution buffer. Test at 10 concentrations ranging from 3 μM to 30 pM. Prepare working solutions at 4× final concentration in compound dilution buffer.

Perform assays in deep well 96 well plates. Total assay volume is 200 μl. Add 50 μl compound dilution buffer (total ligand binding) or 50 μl CGS 15923 working solution (A2anon-specific binding) or 50 μl NECA working solution (A1non-specific binding) or 50 μl of drug working solution. Add 50 μl ligand stock ([3H]-SCH 58261 for A2a, [3H]-DPCPX for A1). Add 100 μl 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 μl Microscint 20 (Packard), and count using the Packard TopCount Microscintillation Counter. Determine IC50values by fitting the displacement curves using an iterative curve fitting program (Excel). Determine Ki values using the Cheng-Prusoff equation.

Haloperidol-Induced Catalepsy in the Rat

Male Sprague-Dawley rats (Charles River, Calco, Italy) weighing 175-200 g are used. The cataleptic state is induced by the subcutaneous administration of the dopamine receptor antagonist haloperidol (1 mg/kg, sc), 90 min before testing the animals on the vertical grid test. For this test, the rats are placed on the wire mesh cover of a 25×43 plexiglass 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 (decent latency) is measured maximally for 120 sec.

The selective A2Aadenosine antagonists under evaluation are administered orally at doses ranging between 1 and 30 mg/kg, 1 and 4 h before scoring the animals. Also, the selective A2Aadenosine antagonists under evaluation are administered subcutaneously at doses ranging between 10 and 30 mg/kg, 1 and 4 h before scoring the animals.

6-OHDA Lesion of the Middle Forebrain Bundle in Rats

Adult male Sprague-Dowley rats (Charles River, Calco, Como, Italy), weighing 275-300 g, are used in all experiments. The rats are housed in groups of 4 per cage, with free access to food and water, under controlled temperature and 12 hour light/dark cycle. The day before the surgery the rats are fasted over night with water ad libitum.

Unilateral 6-hydroxydopamine (6-OHDA) lesion of the middle forebrain bundle is performed according to the method described in Ungerstedt et al,Brian Research,24 (1970), p. 485-493, and Ungerstedt,Eur. J. Pharmacol.,5 (1968), p. 107-110, with minor changes. Briefly, the animals are anaesthetized with chloral hydrate (400 mg/kg, ip) and treated with desipramine (10 mpk, ip) 30 min prior to 6-OHDA injection in order to block the uptake of the toxin by the noradrenergic terminals. Then, the animals are placed in a stereotaxic frame. The skin over the skull is reflected and the stereotaxic coordinates (−2.2 posterior from bregma (AP), +1.5 lateral from bregma (ML), 7.8 ventral from dura (DV) are taken, according to the atlas of Pellegrino et al (Pellegrino L. J., Pellegrino A. S. and Cushman A. J.,A Stereotaxic Atlas of the Rat Brain,1979, New York: Plenum Press). A burr hole is then placed in the skull over the lesion site and a needle, attached to a Hamilton syringe, is lowered into the left MFB. Then 8 μg 6-OHDA-HCl is dissolved in 4 μl of saline with 0.05% ascorbic acid as antioxidant, and infused at the constant flow rate of 1 μl/1 min using an infusion pump. The needle is withdrawn after additional 5 min and the surgical wound is closed and the animals left to recover for 2 weeks.

Two weeks after the lesion the rats are administered with L-DOPA (50 mg/kg, ip) plus Benserazide (25 mg/kg, ip) and selected on the basis of the number of full contralateral turns quantified in the 2 h testing period by automated rotameters (priming test). Any rat not showing at least 200 complete turns/2 h is not included in the study.

Selected rats receive the test drug 3 days after the priming test (maximal dopamine receptor supersensitivity). The new A2Areceptor antagonists are administered orally at dose levels ranging between 0.1 and 3 mg/kg at different time points (i.e., 1, 6, 12 h) before the injection of a subthreshold dose of L-DOPA (4 mpk, ip) plus benserazide (4 mpk, ip) and the evaluation of turning behavior.

Using the above test procedures, the following results were obtained for preferred and/or representative compounds of the invention.

Results of the binding assay on compounds of the invention showed A2aKi values of about 4 to about 1800 nM, with preferred compounds showing Ki values between 4 and 100 nM, more preferably between 4 and 20 nM. Representative preferred compounds and their Ki values are listed in the following table:

Selectivity is determined by dividing Ki for A1 receptor by Ki for A2a receptor. Compounds of the invention have a selectivity ranging from about 1 to about 1600. Preferred are compounds are those wherein the selectivity is >100.

Preferred compounds showed about a 20-40% decrease in descent latency when tested for anti-cataleptic activity in rats.

One to three compounds of formula I can be administered in the method of the invention, preferably one.

For preparing pharmaceutical compositions from the compounds described by 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 5 to about 70 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.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection.

Liquid form preparations may also include solutions for intranasal administration.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

The quantity of active compound of formula I 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.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

The amount and frequency of administration of the compounds of the invention and the pharmaceutically acceptable salts thereof 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 compounds of formula I is oral administration of from 10 mg to 2000 mg/day preferably 10 to 1000 mg/day, in two to four divided doses to provide relief from central nervous system diseases such as Parkinson's disease or the other disease or conditions listed above.

The doses and dosage regimen of the other agents used in the treatment of Parkinson's disease 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. It is expected that when the combination of a compound of formula I and another agent useful for treating Parkinson's disease, EPS, dystonia, RLS or PLMS is administered, lower doses of the components will be effective compared to the doses of the components administered as monotherapy. When administered in combination, the compound(s) of formula I and the other agent(s) for treating Parkinson's disease, EPS, dystonia, RLS or PLMS 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 another every six hours, or when the preferred pharmaceutical compositions are different, e.g. one is preferably a tablet and one is a capsule. A kit comprising the separate dosage forms is therefore advantageous.