US20090029967A1

US20090029967A1 - Adenosine a2a receptor antagonists for the treatment of extra-pyramidal syndrome and other movement disorders

Info

Publication number: US20090029967A1
Application number: US12/181,736
Authority: US
Inventors: Michael Grzelak; John Hunter; Annamarie Pond; Geoffrey Vaity
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme LLC
Priority date: 2002-12-19
Filing date: 2008-07-29
Publication date: 2009-01-29
Also published as: JP2013136592A; JP2006514697A; TW200505927A; US7414058B2; ES2354875T3; EP1578409B1; AU2003304527A1; JP2011006431A; CN1728990A; EP1578409A1; HK1074585A1; US20040138235A1; MXPA05006790A; EP2269596A3; AU2010214749B2; WO2005044245A1; BR0317436A; EP2269596A2; NZ540493A; CN100415217C

Abstract

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

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application 60/435,321, filed Dec. 19, 2002.

FIELD OF THE INVENTION

The present invention relates to the use of adenosine A_2areceptor antagonists for the treatment of a variety of neurological syndromes involving the extra-pyramidal motor system (i.e. Extra-Pyramidal Syndrome) that occur following the acute and chronic use of almost all antipsychotic drugs. The invention also relates to the use of adenosine A_2areceptor antagonists for the treatment of other abnormal movement disorders such as restless leg syndrome (RLS) and periodic limb movement in sleep (PLMS).

BACKGROUND OF THE INVENTION

Extra-Pyramidal Syndrome (EPS) is a collective term for a series of adverse neurological reactions associated with the use of antipsychotic drugs. There are six different categories of EPS-related neurological syndromes of which four, dystonia, akathisia, pseudoparkinsonism (parkinsonian syndrome), and tardive dyskinesia, are particularly prevalent in patients taking antipsychotic medication. Dystonia is a painful spasm of the muscle groups of, in particular, the neck, jaw, back, pharynx, and larynx. It is most common in young males being treated with antipsychotic drugs, but can also be associated with the use of cocaine, tricyclic antidepressants, lithium and anticonvulsants such as phenyloin and carbamazepine. Pseudoparkinsonism manifests itself as akinesia (rigidity, stiffness and slow voluntary motion, stooped, shuffling walk) and tremor and these symptoms develop within weeks or months after initiation of therapy. Akathisia manifests itself as strong, subjective inner feelings of distress or discomfort characterized by motor restlessness. Often mistaken for agitation or anxiety, this common syndrome is frequently under-diagnosed and is the least responsive to treatment. Tardive dyskinesia is a late-appearing syndrome associated with chronic use of neuroleptic drugs. It occurs more frequently in older patients and is characterized by stereotypical, repetitive, involuntary, quick choreiform movements of the face, eyelids, mouth, tongue, extremities and trunk.
EPS is more prevalent with the use of typical antipsychotic agents but has also been reported with the use of atypical agents. Typical antipsychotics include loxapine, haloperidol, chlorpromazine, prochlorperazine and thiothixene. Atypical antipsychotics include clozapine, olanzapine, loxapine, quetiapine, ziprasidone and risperidone.
Akathisia is also a characteristic of RLS and PLMS, as well as PLMD (periodic leg (or limb) movement disorder). RLS is a common disorder that causes patients to have an irresistible and unpleasant desire to move their legs; it usually manifests during periods of inactivity and/or at night, and can disturb sleep. Patients who do not have the typical RLS symptoms, but who do exhibit periodic leg movements that adversely impact sleep, are diagnosed with PLMS. Treatments for RLS and PLMS have included levodopa/carbidopa, levodopa/benserazide, dopamine agonists such as pramipexole and ropinerole, benzodiazepines, opioids, anticonvulsants and iron (ferrous sulfate). RLS and PLMS have been extensively described in the literature, for example by Saletu et al, Neuropsvchobiology, 41, 4 (2000), p. 190-9.
The purine nucleotide, adenosine, is known to be an endogenous modulator of a number of physiological functions in the central (CNS) and peripheral nervous systems.
Adenosine exerts its biological actions through a class of membrane specific receptors which belong to the super family of receptors coupled with G proteins. Biochemical and pharmacological studies, together with advances in molecular biology, have allowed the identification of at least four subtypes of adenosine receptors: A₁, A_2a, A_2band A₃. Analogs of adenosine able to interact as antagonists with the A₁, A_2a, A_2band A₃receptors have also been identified.
In the CNS, data has shown that A_2areceptors are present in high density in the basal ganglia, known to be important in the control of fine motor movement. Moreover, selective antagonists for the A_2areceptor are of pharmacological interest because of their demonstrated efficacy in reducing motor impairment thereby improving function in neurodegenerative diseases such as Parkinson's disease and related movement disorders (e.g. Huntington's Disease). A_2aantagonists appear to demonstrate a reduced side-effect liability (e.g. no dyskinesia) compared to current dopaminergic therapies resulting in an improved therapeutic index. A_2aantagonists may also have antidepressant properties and stimulate cognitive functions. Some xanthine-related compounds have been found to be A₁receptor selective antagonists, and xanthine and non-xanthine compounds have been found to have high A_2aaffinity with varying decrees of A_2avs. A₁selectivity. Adenosine A_2areceptor antagonists have been disclosed previously, for example in WO 95/01356 and U.S. Pat. No. 6,630,475.

SUMMARY OF THE INVENTION

This invention relates to a method for the treatment or prevention of Extra-Pyramidal Syndrome (e.g., dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia) comprising administering a therapeutically effective amount of an adenosine A_2areceptor antagonist to a patient in need thereof. In particular, this method is for the treatment or prevention of EPS in patients treated with an antipsychotic agent that has the side effect of inducing EPS. The adenosine A_2areceptor antagonist can be administered after the symptoms of EPS have manifested, or an adenosine A_2areceptor antagonist can be administered at the onset of administering an antipsychotic agent in order to prevent EPS from occurring. The invention, therefore, also includes a method of treating or preventing EPS induced by an antipsychotic agent comprising administering a combination of an antipsychotic agent and an adenosine A_2aantagonist to a patient in need thereof. More particularly, the invention relates to the method of using of certain adenosine A_2aantagonists for the monotherapy or the combined therapy.
The invention also relates to the treatment of primary (idiopathic) dystonia, and to the treatment or prevention of dystonia in patients who exhibit dystonia as a result of treatment with a tricyclic antidepressant, lithium or an anticonvulsant, or who have used cocaine, comprising administering a therapeutically effective amount of an adenosine A_2areceptor antagonist to a patient in need thereof. When dystonia is caused by treatment with a tricyclic antidepressant, lithium or an anticonvulsant, the adenosine A_2areceptor antagonist can be administered after the symptoms of dystonia have manifested, or an adenosine A_2areceptor antagonist can be administered at the onset of administering a tricyclic antidepressant, lithium or an anticonvulsant in order to prevent dystonia from occurring. The invention, therefore, also includes a method of treating or preventing dystonia induced by a tricyclic antidepressant, lithium or an anticonvulsant comprising administering a combination of an adenosine A_2aantagonist and a tricyclic antidepressant, lithium or an anticonvulsant to a patient in need thereof.
The invention also relates to the treatment of RLS or PLMS, comprising administering to a patient in need thereof a therapeutically effective amount of an adenosine A_2areceptor antagonist. The invention also comprises a method of treating RLS or PLMS comprising administering a combination of an adenosine A_2aantagonist with another agent useful in treating RLS or PLMS, such as levodopa/carbidopa, levodopa/benserazide, a dopamine agonist, a benzodiazepine, an opioid, an anticonvulsant or iron, to a patient in need thereof.
In another aspect, this invention relates to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat or prevent EPS caused by treatment with antipsychotic agent, wherein one container comprises a pharmaceutical composition comprising an effective amount of an adenosine A_2areceptor antagonist in a pharmaceutically acceptable carrier, and wherein a separate container comprises a pharmaceutical composition comprising an effective amount of an antipsychotic agent.
In another aspect, this invention relates to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat or prevent dystonia caused by treatment with a tricyclic antidepressant, lithium or an anticonvulsant, wherein one container comprises a pharmaceutical composition comprising an effective amount of an adenosine A_2areceptor antagonist in a pharmaceutically acceptable carrier, and wherein a separate container comprises a pharmaceutical composition comprising an effective amount of a tricyclic antidepressant, lithium or an anticonvulsant.
In another aspect, this invention relates to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat RLS or PLMS, wherein one container comprises a pharmaceutical composition comprising an effective amount of an adenosine A_2areceptor antagonist in a pharmaceutically acceptable carrier, and wherein a separate container comprises a pharmaceutical composition comprising an effective amount of levodopa/carbidopa, levodopa/benserazide, a dopamine agonist, a benzodiazepine, an opioid, an anticonvulsant or iron.
The invention also relates to the use of an adenosine A_2areceptor antagonist for the preparation of a medicament for treating or preventing EPS, dystonia, RLS or PLMS, alone or in combination with the other agents discussed above.

DETAILED DESCRIPTION OF THE DRAWINGS

A more complete understanding of the invention may be obtained by reading the following description in conjunction with the appended figures relating to haloperidol-induced EPS in Cebus apella monkeys.

FIG. 1A illustrates the effect of Compound A (1-30 mg/kg, p.o.) on maximum EPS score.

FIG. 1B represents the mean delay in onset of EPS for each treatment group compared to a vehicle control group.

DETAILED DESCRIPTION OF THE INVENTION

Any adenosine A_2areceptor antagonist is contemplated for use in the method of this invention. Suitable adenosine A_2areceptor antagonists useful in the method of the invention can be identified by the binding assay described below. Specific examples of suitable adenosine A_2aantagonists include the compounds disclosed in several patents and patent applications, e.g. WO 95/01356; U.S. Pat. No. 5,565,460; U.S. Pat. No. 6,630,475 B2; U.S. Pat. No. 5,935,964; WO 03/032996; WO 03/048165; WO 03/048164; WO 03/048163; and WO 01/02409. Specifically, these patents and applications disclose the following compounds.
U.S. Pat. No. 6,630,475 B2 discloses compounds having the structural formula I
or a pharmaceutically acceptable salt thereof, wherein
R is R¹-furanyl, R¹-thienyl, R¹-pyridyl, R¹-pyridyl N-oxide, R¹-oxazolyl, R¹⁰-phenyl, R¹-pyrrolyl or C₄-C₆cycloalkenyl;
X is C₂-C₆alkylene or —C(O)CH₂—;
Y is —N(R²)CH₂CH₂N(R³)—, —OCH₂CH₂N(R²)—, —O—, —S—, —CH₂S—, —(CH₂)₂—NH—, or
and
Z is R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, R⁵-heteroaryl, diphenylmethyl, R⁶—C(O)—,

R⁶—SO, R⁶—OC(O)—, R⁷—N(R⁸)—C(O)—, R⁷—N(R⁸)—C(S)—,

phenyl-CH(OH)—, or phenyl-C(═NOR²)—; or when Q is
Z is also phenylamino or pyridylamino;
or
Z and Y together are
R¹is 1 to 3 substituents independently selected from hydrogen, C₁-C₆-alkyl, —CF₃, halogen, —NO₂, —NR¹²R¹³, C₁-C₆alkoxy, C₁-C₆alkylthio, —C₆alkylsulfinyl, and C₁-C₆alkylsulfonyl;
R²and R³are independently selected from the group consisting of hydrogen and C₁-C₆alkyl;
m and n are independently 2-3;
Q is
R⁴is 1-2 substituents independently selected from the group consisting of hydrogen and C₁-C₆alkyl, or two R⁴substituents on the same carbon can form ═O;
R⁵is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C₁-C₆alkyl, hydroxy, C₁-C₆alkoxy, —CN, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, acetyl, —NO₂, hydroxy(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy, di-((C₁-C₆)-alkoxy)(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy-(C₁-C₆)-alkoxy, carboxy(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl(C₁-C₆)alkoxy, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkoxy, morpholinyl, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO—(C₁-C₆)alkoxy, tetrahydropyranyloxy, (C₁-C₆)alkylcarbonyl(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)alkylcarbonyloxy(C₁-C₆)-alkoxy, —SO₂NH₂, phenoxy,
or adjacent R⁵substituents together are —O—CH₂—O—, —O—CH₂CH₂—O—, —O—CF₂—O— or —O—CF₂CF₂—O— and form a ring with the carbon atoms to which they are attached;
R⁶is (C₁-C₆)alkyl, R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, thienyl, pyridyl, (C₃-C₆)-cycloalkyl, (C₁-C₆)alkyl-OC(O)NH—(C₁-C₆)alkyl-, di-((C₁-C₆)alkyl)aminomethyl, or
R⁷is (C₁-C₆)alkyl, R⁵-phenyl or R⁵-phenyl(C₁-C₆)alkyl;
R⁸is hydrogen or C₁-C₆alkyl; or R⁷and R⁸together are —(CH₂)_p-A-(CH₂)_q, wherein p and q are independently 2 or 3 and A is a bond, —CH₂—, —S— or —O—, and form a ring with the nitrogen to which they are attached;
R⁹is 1-2 groups independently selected from hydrogen, C₁-C₆alkyl, hydroxy, C₁-C₆alkoxy, halogen, —CF₃and (C₁-C₆)alkoxy(C₁-C₆)alkoxy;
R¹⁰is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C₁-C₆alkyl, hydroxy, C₁-C₆alkoxy, —CN, —NH₂, C₁-C₆alkylamino, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃and —S(O)_0-2(C₁-C₆)alkyl;
R¹¹is H, C₁-C₆alkyl, phenyl, benzyl, C₂-C₆alkenyl, C₁-C₆alkoxy(C₁-C₆)alkyl, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkyl, pyrrolidinyl(C₁-C₆)alkyl or piperidino(C₁-C₆)alkyl;
R¹²is H or C₁-C₆alkyl; and
R¹³is (C₁-C₆)alkyl-C(O)— or (C₁-C₆)alkyl-SO₂—.
Preferred compounds of formula I are those wherein R is R¹-furanyl, R¹-thienyl, R¹-pyrrolyl or R¹⁰-phenyl, more preferably R¹-furanyl. R¹is preferably hydrogen or halogen. Another group of preferred compounds is that wherein X is alkylene, preferably ethylene. Y is preferably
wherein Q is
with Q preferably being nitrogen. Preferably, m and n are each 2, and R⁴is H. A preferred definition for Z is R⁵-phenyl, R⁵-heteroaryl, R⁶—C(O)— or R⁶—SO₂—. R⁵is preferably H, halogen, alkyl, alkoxy, hydroxyalkoxy or alkoxyalkoxy. R⁶is preferably R⁵-phenyl.
Preferred specific compounds of formula I are those of the formula IA
wherein R and Z-Y are as defined in the following table:


Z—Y—	R

Other useful adenosine A_2areceptor antagonists include those disclosed in WO 95/01356 as compounds having the structural formula II
wherein:
A is pyrazole, imidazole or a triazole ring;
R is hydrogen; C₁-C₈alkyl; C₃-C₇alkenyl; C₃-C₇alkynyl; C₃-C₇cycloalkyl; C₁-C₅alkyl substituted with one or more halogen atoms, hydroxy groups, C₁-C₄alkoxy, C₃-C₇cycloalkyl, groups of formula —NR₁R₂, —CONR₁R₂; aryl optionally substituted with halogen atoms, C₁-C₄alkoxy groups, C₁-C₄alkyl, nitro, amino, cyano, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, carboxy, carboxyamido; C₇-C₁₀aralkyl in which the aryl moiety can be substituted with one or more of the substituents indicated above for the aryl group; a group of formula —(CH₂)_m-Het, wherein Het is a 5-6 membered aromatic or non aromatic heterocyclic ring containing one or more heteroatoms selected from N, O, S and m is an integer from 1 to 5;
R₁, R₂which are the same or different, are hydrogen, C₁-C₅alkyl, C₇-C₁₀aralkyl, phenyl, or taken together with the nitrogen they are linked to, form an azetidine ring or a 5-6 membered heterocyclic ring containing one or more heteroatoms such as N, O, S and n is an integer from 2 to 5.
Preferably, compounds of formula II are those wherein R is hydrogen, C₁-C₈alkyl, aryl or C₇-C₁₀aralkyl optionally substituted, preferably with halogen atoms.
U.S. Pat. No. 5,935,964 discloses useful adenosine A_2areceptor antagonist compounds having the structural formula III
wherein A is pyrazole, imidazole or triazole ring;
R is
R₁and R₂, which are the same or different, are H, OH, halogen, C₁-C₄alkoxy, C₁-C₄alkyl, nitro, amino, cyano, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, carboxy or carboxamido; or the OH group, together with one of R₁or R₂, or R₁and R₂, can form a methylenedioxy group —O—CH₂—O—; and
n is an integer from 0-4.
Preferred compounds of formula III are those wherein A is pyrazolo[4,3-e] or 1,2,3-triazolo[5,4-e].
U.S. Pat. No. 5,565,460 discloses useful adenosine A_2areceptor antagonist compounds having the structural formulas IVA and IVB, wherein formula IVA is
wherein R¹represents hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower alkanoyl;
R²represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heterocyclic group;
R³represents a substituted or unsubstituted heterocyclic group;
X represents a single bond, O, S, S(O), S(O)₂, or NR⁴(in which R⁴represents hydrogen, or substituted or unsubstituted lower alkyl; or R²and NR⁴are combined to form a substituted or unsubstituted 4 to 6-membered saturated heterocyclic group): and
A represents N or CR⁵(in which R⁵represents hydrogen, or a substituted or unsubstituted lower alkyl); and
wherein formula IVB is
wherein R⁶represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group;
Y represents O, S, or NR⁷(in which R⁷represents substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl);
R⁸represents 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 substituted or unsubstituted heterocyclic group; and
B and the adjacent two carbon atoms are combined to form a substituted or unsubstituted, partially saturated or unsaturated, monocyclic or bicyclic, carbocyclic or heterocyclic group.
WO 03/032996 discloses useful adenosine A_2areceptor antagonist compounds having the structural formula V
or a pharmaceutically acceptable salt thereof, wherein
R is R¹-heteroaryl, R¹⁰-phenyl, C₄-C₆cycloalkenyl, <(═CH₂)CH₃, —C≡C—CH₃, —C≡C—CH₂—OR², —CH═C(CH₃)₂,
X is C₁-C₆alkylene, —C(O)CH₂— or —C(O)N(R²)CH₂—;
Y is —N(R²)CH₂CH₂N(R^{3)—, —OCH} ₂CH₂N(R²)—, —O—, —S—, —CH₂S—, —(CH₂)_2-3—N(R²)—, R⁵-divalent heteroaryl,
and
Z is R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, R⁵-heteroaryl, R⁵-bicyclic heteroaryl, R⁵-benzofused heteroaryl, diphenylmethyl or R⁶—C(O)—; or when Y is
Z is also R⁶—SO₂—, R⁷—N(R⁸)—C(O)—, R⁷—N(R⁸)—C(S)— or R⁶OC(O)—; or when Q is
Z is also phenylamino or pyridylamino;
or Z and Y together are
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;
R¹is 1 to 3 substituents independently selected from hydrogen, C₁-C₆-alkyl, —CF₃, halogen, —NO₂, —NR¹²R¹³, C₁-C₆alkoxy, C₁-C₆alkylthio, C₁-C₆alkylsulfinyl, C₁-C₆alkylsulfonyl, —COOR⁷or —C(O)NR²R³;
R²and R³are independently selected from the group consisting of hydrogen and C₁-C₆alkyl;
m and n are independently 2-3;
p and q are independently 0-2;
Q and Q¹are independently selected from the group consisting of
provided that at least one of Q and Q¹is
R⁴is 1-2 substituents independently selected from the group consisting of hydrogen, C₁-C₆alkyl, R¹-aryl and R¹-heteroaryl, or two R⁴substituents on the same carbon can form ═O;
R⁵is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C₁-C₆alkyl, hydroxy, C₁-C₆alkoxy, —CN, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, acetyl, —NO₂, hydroxy(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy, di-((C₁-C₆)-alkoxy)(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy-(C₁-C₆)alkoxy, carboxy(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl(C₁-C₆)alkoxy, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkoxy, morpholinyl, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—(C₁-C₆)alkoxy, tetrahydropyranyloxy, (C₁-C₆)alkylcarbonyl(C₁-C₆)alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)alkylcarbonyloxy(C₁-C₆)-alkoxy, —SO₂NH₂, phenoxy,
(R²O)₂—P(O)—CH₂—O— and (R²O)₂—P(O)—; or adjacent R⁵substituents together are —O—CH₂—O—, —O—CH₂CH₂—O—, —O—CF₂—O— or —O—CF₂CF₂—O— and form a ring with the carbon atoms to which they are attached;
R⁶is (C₁-C₆)alkyl, R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, thienyl, pyridyl, (C₃-C₆)-cycloalkyl, (C₁-C₆)alkyl-OC(O)NH—(C₁-C₆)alkyl-, di-((C₁-C₆)alkyl)aminomethyl, or
R⁷is (C₁-C₆)alkyl, R⁵-phenyl or R⁵-phenyl(C₁-C₆)alkyl;
R⁸is hydrogen or C₁-C₆alkyl; or R⁷and R⁸together are —(CH₂)_pA-(CH₂)_q, wherein p and q are independently 2 or 3 and A is a bond, —CH₂—, —S— or —O—, and form a ring with the nitrogen to which they are attached;
R⁹is 1-2 substituents independently selected from the group consisting of hydrogen, C₁-C₆alkyl, hydroxy, C₁-C₆alkoxy, halogen, —CF₃and (C₁-C₆)alkoxy-(C₁-C₆)alkoxy;
R¹⁰is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C₁-C₆alkyl, hydroxy, C₁-C₆alkoxy, —CN, —NH₂, C₁-C₆alkylamino, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, —S(O)_0-2(C₁-C₆)alkyl and —CH₂—SO₂-phenyl;
R¹¹is H, C₁-C₆alkyl, phenyl, benzyl, C₂-C₆alkenyl, C₁-C₈alkoxy(C₁-C₆)alkyl, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkyl, pyrrolidinyl(C₁-C₆)alkyl or piperidino(C₁-C₆)alkyl;
R¹²is H or C₁-C₆alkyl;
R¹³is H, (C₁-C₆)alkyl-C(O)— or (C₁-C₆)alkyl-SO₂—;
R¹⁴is H, halogen, C₁-C₆alkyl, hydroxy(C₁-C₆)alkyl, C₁-C₆alkoxy(C₁-C₆)alkyl, thio(C₁-C₆)alkyl, (C₁-C₆)alkylthio(C₁-C₆)alkyl or NR²R³—(C₁-C₆)alkyl; and
R¹⁵is H, halogen, C₁-C₆alkyl or C₁-C₆alkoxy.
Preferred compounds of formula V are those wherein R is R¹-furanyl, R¹-thienyl, R¹-pyrrolyl, R¹-pyridyl or R¹⁰-phenyl, more preferably R¹-furanyl or R¹⁰-phenyl. R¹is preferably hydrogen or halogen. R¹⁰is preferably hydrogen, halogen, alkyl or —CF₃. Another group of preferred compounds is that wherein X is alkylene, preferably ethylene. Y is preferably
wherein Q is
with Q preferably being nitrogen. Preferably, m and n are each 2, and R⁴is H. A preferred definition for Z is R⁵-phenyl or R⁵-heteroaryl. R⁵is preferably H, halogen, alkyl, alkoxy, hydroxyalkoxy or alkoxyalkoxy. R⁶is preferably R⁵-phenyl.
Preferred specific compounds of formula V are those of the formula VA
wherein R and Z-Y are as defined in the following table:


	Z—Y	R

WO 03/048165 discloses useful adenosine A_2areceptor antagonist compounds having the structural formula VI
or a pharmaceutically acceptable salt or solvate of said compound, wherein:
R is selected from the group consisting of R¹-furanyl-, R¹-thienyl-, R¹-pyridyl-, R¹oxazolyl-, R¹-pyrrolyl- and R²-aryl-;
X is —(CH₂)_n—;
Y is a piperidinyl, pyrrolidinyl or azepanyl group with an aryl or heteroaryl moiety fused to two adjacent carbon atoms on Y, wherein X is attached to the N atom of the piperidinyl, pyrrolidinyl or azepanyl group;
Q is 1-4 substituents, which can be the same or different, and are independently selected from the group consisting of hydrogen, cycloalkyl, cycloheteroalkyl, amino, aryl, aralkyl, heteroaryl, alkyl, CF₃, CN, halogen, NO₂, alkoxy, alkoxyalkoxy, cycloalkylalkoxy, acyloxy, alkylamino, acylamino, alkylsulfonamino, alkylaminosulfonyl, dialkylaminosulfonyl, NH₂SO₂—, and hydroxy;
n is 1 to 4;
R¹is 1-3 substituents, which may be the same or different, and are independently selected from the group consisting of hydrogen, alkyl, CF₃, halogen and NO₂; and
R²is 1-3 substituents, which may be the same or different, and are independently selected from the group consisting of hydrogen, alkyl, CF₃, halogen, NO₂, alkoxy, acyloxy, alkylamino, acylamino, alkylsulfonamido, alkylaminosulfonyl, dialkylaminosulfonyl, aminosulfonyl, and hydroxyl.
In a preferred embodiment of compounds of formula VI, Y is
wherein A¹is N—X, and A²and A³each are CR⁴R⁵, or

- A¹and A³each are CR⁴R⁵, and A²is N—X, or
- A¹and A²each are CR⁴R⁵, and A³is N—X;

A⁴is CR⁴R⁵;
Z¹, Z², Z³and Z⁴, which can the same or different, are each independently selected from the group consisting of N and CR³, provided that 0-2 of Z¹, Z², Z³or Z⁴are N and the remainder are CR³;
Z⁵is NR⁵, O, S or CR⁴R⁵;
Z⁶is N or CR³;
Z⁷is N or CR³;
m is an integer from 0 to 2;
R³is selected from the group consisting of hydrogen, cycloalkyl, amino, aryl, heteroaryl, C₁-C₆-alkyl, CF₃, CN, halogen, NO₂, C₁-C₆-alkoxy, C₁-C₆-acyloxy, C₁-C₆-alkylamino, C₁-C₆-acylamino, C₁-C₆-alkylsulfonamino, C₁-C₆-alkylaminosulfonyl, C₁-C₆-dialkylaminosulfonyl, NH₂—SO₂—, and hydroxy;
R⁴is selected from the group consisting of hydrogen, hydroxyalkyl, aryl, aralkyl, C₁-C₆-alkyl, C₁-C₆-alkoxy, CF₃, CN, halogen, hydroxy, and NO₂; and
R⁵is hydrogen or C₁-C₆alkyl.
Preferred specific examples of compounds of formula VI include compounds of the formula:
WO 03/048164 discloses useful adenosine A_2areceptor antagonist compounds having the structural formula VII
or a pharmaceutically acceptable salt or solvate thereof; wherein:
R is selected from the group consisting of R⁴-heteroaryl, R⁵-phenyl, (C₄-C₆)cycloalkenyl, —C(═CH₂)CH₃, —C≡C—CH₃,

—H═C(CH₃)₂,

and —CH═CH—CH₃;

R²is selected from the group consisting of —W—X, —NR¹⁹(CH₂)_m—W—X, and —NR¹⁹CH(CH₃)—W—X, or
R²is selected from the group consisting of alkyl, alkenyl and —NR¹⁸R¹⁹, wherein said alkyl, alkenyl or —NR¹⁸R¹⁹is optionally substituted by —W—X;
R³is selected from the group consisting of H, halo, alkyl, trifluoromethyl, alkoxy, alkoxyalkyl, hydroxyalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, aminoalkyl, aryl, heteroaryl, and CN;
R⁴is 1 to 3 substituents, which can be the same or different, and are independently selected from the group consisting of hydrogen, (C₁-C₆)-alkyl, —CF₃, halogen, —NO₂, —NR¹⁵R¹⁶, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkylsulfinyl, (C₁-C₆)alkylsulfonyl, —COOR¹⁷and —C(O)NR⁶R⁷;
R⁵is 1 to 5 substituents, which can be the same or different, and are independently selected from the group consisting of hydrogen, halogen, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, —CN, —NH₂, (C₁-C₆)alkylamino, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, —S(O)_0-2(C₁-C₆)alkyl and —CH₂—SO₂-phenyl;
R⁶and R⁷, which can be the same or different, are each independently selected from the group consisting of hydrogen and (C₁-C₆)alkyl;
R⁸is 1 to 5 substituents, which can be the same or different, and are independently selected from the group consisting of hydrogen, halogen, (C₁-C₆)alkyl, hydroxy, C₁-C₆alkoxy, —CN, amino, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, acetyl, —NO₂, hydroxy(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy, di-((C₁-C₆)-alkoxy)(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy-(C₁-C₆)-alkoxy, carboxy(C₁-C₆)-alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl(C₁-C₆)alkoxy, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkoxy, morpholinyl, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—(C₁-C₆)alkoxy, tetrahydropyranyloxy, (C₁-C₆)alkylcarbonyl(C₁-C₆)-alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylcarbonyloxy(C₁-C₆)-alkoxy, —SO₂NH₂, phenoxy,

—O—CH₂—P(O)(OR⁶)₂,- and —P(O)(OR⁵)₂; or

adjacent R⁸substituents together are —O—CH₂—O—, —O—CH₂CH₂—O—, —O—CF₂—O—or
—O—CF₂CF₂—O— and form a ring with the carbon atoms to which they are attached;
R⁹is selected from the group consisting of (C₁-C₆)alkyl, R⁸-aryl-, R⁸-aryl(C₁-C₆)alkyl-, thienyl, pyridyl, (C₃-C₆)-cycloalkyl, (C₁-C₆)alkyl-OC(O)—NH—(C₁-C₆)alkyl-, di-((C₁-C₆)alkyl)aminomethyl, cycloheteroalkyl(C₁-C₆)alkyl, aryloxy(C₁-C₆)alkyl, alkoxy(C₁-C₆)alkyl and
R¹⁰is 1-2 substituents, which can be the same or different, and are independently selected from the group consisting of hydrogen, (C₁-C₆)alkyl, R⁵-aryl and R⁴-heteroaryl, or two R¹⁰substituents on the same carbon can form ═O;
R¹¹is hydrogen or (C₁-C₆)alkyl; —C(O)alkyl, or R¹⁷and R¹¹taken together are —(CH₂)_p-A-(CH₂)_q, wherein p and q are each independently 2 or 3 and A is selected from the group consisting of a bond, —CH₂—, —S— and —O—, and form a ring with the nitrogen to which they are attached;
R¹²is 1-2 substituents, which can be the same or different, and are independently selected from the group consisting of hydrogen, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, halogen, and —CF₃;
R¹³is selected from the group consisting of H, (C₁-C₆)alkyl, phenyl, benzyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkyl, pyrrolidinyl(C₁-C₆)alkyl and piperidino(C₁-C₆)alkyl;
R¹⁴is selected from the group consisting of H, halogen, (C₁-C₆)alkyl or (C₁-C₆)alkoxy;
R¹⁵is selected from the group consisting of H and (C₁-C₆)alkyl;
R¹⁶is selected from the group consisting of H, (C₁-C₆)alkyl-C(O)— and (C₁-C₆)alkyl-SO₂—;
R¹⁷is selected from the group consisting of (C₁-C₆)alkyl, (C₁-C₆)hydroxyalkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, allyl, propargyl, R⁸-heteroaryl-, R⁸-aryl- and R⁸-aryl(C₁-C₆)alkyl-;
R¹⁸is selected from the group consisting of a bond, —CH₂—, —CH(OH)—, —CH(CH₃)—, —C(CH₃)_n—, —(CH₂)_n—, and —O(CH₂)_n—,
R¹⁹is selected from the group consisting of H, (C₁-C₆)alkyl, (C₁-C₆)alkyl(C₁-C₆)cycloalkyl, (C₁-C₆)cycloalkyl(C₁-C₆)alkyl and (C₁-C₆)alkoxy(C₁-C₆)alkyl;
Q and Q¹can be the same or different and are each independently selected from the group consisting of
m and n are each independently 1-3;
p and q are each independently 0-2;
s is 0-4;
W is aryl or heteroaryl having 1-3 heteroatoms, which can be the same or different, and are independently selected from the group consisting of N, O and S, and wherein said aryl or heteroaryl is optionally substituted with 1-3 substituents, which can be the same or different, and are independently selected from the group consisting of alkyl, aryl, alkylcycloalkyl, halo, hydroxy, hydroxyalkyl, alkoxy, alkylalkoxy, alkoxyalkoxy, —NR⁶R⁷, (C₂-C₆)alkene, and —CN, or
X is selected from the group consisting of H, NH₂, —N(R⁶)(CH₂)_s-aryl, —N(R⁶)(CH₂)_s-heteroaryl, —N(R⁶)(CH₂)_m+1—OH, and —N(CH₃)₂, or
X is —R¹⁸—Y-Z;
Y is selected from the group consisting of —N(R⁶)CH₂CH₂N(R⁷)—, —N(R⁶)(CH₂)_naryl, —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-aryl(C₁-C₆)alkyl-, R⁸-heteroaryl-, R⁸-bicyclicalkyl-, aminoalkyl, alkylamino, NH₂, —N—(R⁶)(CH₂)_s-aryl, —N(R⁶)(CH₂)_s-heteroaryl, —N(R⁶)C(O)OR¹⁷, alkylcycloheteroalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkoxycycloheteroalkyl, heteroaryl; R⁸-benzofused heteroaryl-, diphenylmethyl and R⁹—C(O)—; or
when Y is
Z can also be —OH, R⁹—SO₂—, R¹⁷—N(R¹¹)(CH₂)_s—C(O), R¹⁷—OC(O)—, R¹⁷—O(CH₂)_nC(O)—, benzofused heteroaryl(CH₂)_nC(O)—, benzofused heteroaryl(CH₂)_n— or R¹⁷—N(R¹¹)—C(S)—;
or
when Q is
Z can also be R¹⁷R¹¹N—, phenylamino or pyridylamino; or
Z and Y taken together are selected from the group consisting of
Preferred compounds of formula VII are those having the following structures:
WO 03/048163 discloses useful adenosine A_2areceptor antagonist compounds having the structural formula VII
or a pharmaceutically acceptable salt thereof, wherein:
A is C(R¹) or N;
R¹and R^1aare independently selected from the group consisting of H, (C₁-C₆)-alkyl, halo, CN and —CF₃;
Y is —O—, —S—, —SO—, —SO₂—, R⁵-heteroaryldiyl, R⁵-arylene or
p and q are independently 2-3;
Q and Q¹are independently selected from the group consisting of
provided that at least one of Q and Q¹is
R is R^5-aryl, R^5-heteroaryl, R⁶—(C₂-C₆)alkenyl or R⁶—(C₂-C₆)alkynyl;
R²is R^5-aryl, R^5-heteroaryl, R^5-aryl(C₁-C₆)alkyl or R^5-heteroaryl(C₁-C₆)alkyl; or R²—Y is
U, V, and W are independently selected from the group consisting of N and CR¹, provided that at least one of U, V and W is CR¹;
n is 1, 2 or 3; and

- (a) A is C(R¹) and X is —C(R³)(R^3a)—, —C(O)—, —O—, —S—, —SO—, —SO₂—, R⁴-arylene, R⁴-heteroarldiyl, or —N(R⁹)—; or A is C(R¹), Y is a bond, and X is —C(R³)(R^3a), —C(O)—, —O—, —S—, —SO—, —SO₂—, R⁴-arylene, —N(R⁹)— or R⁴-heteroaryldiyl, provided that when X is —N(R⁹)— or R⁴-heteroaryldiyl, R²is not phenyl or phenyl-(C₁-C₆)alkyl; or
- (b) A is N, X is —N(R⁹)—, Y is R⁵-arylene and R²is

or n is 2 or 3; and

- (c) A is N and X is —C(R³)(R^3a)—, —C(O)—, —O—, —S—, —SO—, —SO₂—, —N(R⁹)—, R⁴-arylene or R⁴-heteroaryldiyl; or A is N, Y is a bond and X is —C(O)—, —N(R⁹)—, R⁴-arylene or R⁴-heteroaryldiyl; or A is N, Y is —N(R^9a), —C(O)N(R^9a)— or —O—(CH₂)₂—N(R^9a)—, and X is —N(R⁹)—; or A is N, X is —N(R⁹)—, and Y and R²together are

or n is 0; and

- (d) A is N, Y is a bond, X is —N(R⁹)—, and R²is

- (e) A is N, X is —N(R⁹)— and Y and R²together are

- - wherein Z is —(O)—CH₂—, —C(O)—CH(C₁-C₆alkyl), —CH₂—CH(C₁-C₆alkyl)-, or —CH(C₁-C₆alkyl)-CH₂—;

R³and R^3aare independently selected from the group consisting of H, —OH, C₁-C₆alkyl, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl and di(C₁-C₆)alkylamino(C₁-C₆)alkyl;
R⁴is 1-3 substituents selected from the group consisting of H, (C₁-C₆)alkyl, —OH, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo, —CF₃, and —CN;
R⁵is 1-3 substituents independently selected from the group consisting of H, (C₁-C₆)alkyl, —OH, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo, —CF₃, —CN, —NH₂, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, amino(C₁-C₆)-alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl, (C₁-C₆)alkanoyl-amino, (C₁-C₆)alkanesulfonylamino, (C₁-C₆)alkylthio, (C₁-C₆)alkylthio(C₁-C₆)alkyl,
R⁶—(C₂-C₆)alkenyl, R⁶—(C₂-C₆)alkynyl, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy-C(O)-amino, or heterocycloalkyl(C₁-C₆)alkyl;
R⁶is 1 to 3 substituents independently selected from the group consisting of H, —OH, (C₁-C₆)alkoxy and halo;
R⁷and R^7aare independently selected from the group consisting of H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, R⁸-aryl and R⁸-heteroaryl, or an R⁷and an R^7asubstituent on the same carbon can form ═O;
R⁸is 1 to 3 substituents independently selected from H, (C₁-C₆)alkyl, —OH, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy, halo, —CF₃, and —CN;
R⁹and R^9aare independently selected from the group consisting of H, (C₁-C₆)alkyl, hydroxy(C₂-C₆)alkyl, (C₁-C₆)alkoxy(C₂-C₆)alkyl, amino(C₂-C₆)alkyl, (C₁-C₆)alkylamino(C₂-C₆)alkyl, di(C₁-C₆)alkylamino(C₂-C₆)alkyl, halo-(C₃-C₆)alkenyl, CF₃—(C₁-C₆)alkyl, (C₃-C₆)alkenyl, (C₃-C₆)cycloalkyl and (C₃-C₆)cycloalkyl-(C₁-C₆)alkyl; and
R¹⁰is H, —C(O)—O—(C₁-C₆)alkyl, R⁵-aryl, —C(O)—(C₁-C₆)alkyl, —C(O)—(R⁵-aryl) or R⁵-aryl-(C₁-C₆)alkyl.
Preferred compounds of formula VIII are those wherein A is N. R is preferably furyl. R^1ais preferably hydrogen. Another group of preferred compounds is that wherein X is —O—, —S—, —N(R⁹)— or R⁴-arylene, with compounds wherein X is —N(R⁹)— being more preferred. R⁹is preferably C₁-C₆alkyl. Preferred definitions for Y are a bond or piperazinyl. R²is preferably R⁵-aryl. When Y and/or R²is
Q is preferably N, Q¹is preferably N, p and q are each preferably 2, each R⁷and R^7ais preferably hydrogen, and R¹⁰is preferably —C(O)—O—(C₁-C₆)alkyl, —C(O)—(C₁-C₆)alkyl or —C(O)—(R⁵-aryl). R⁵is preferably 1 or 2 substituents selected from the group consisting of H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)-alkoxy, halo and —CF₃. R⁴is preferably H, halo or (C₁-C₆)alkyl. R³and R^3aare preferably independently selected from H and (C₁-C₆)alkyl. R^9ais preferably H or (C₁-C₆)alkyl. R⁶is preferably hydrogen.
Preferred specific examples of compounds of formula VIII include compounds of the formula
wherein R²—Y—(CH₂)_n—N(R⁹)— is as defined in the table:


R²—Y—(CH₂)_n—N(R⁹)—

WO 01/02409 discloses useful adenosine A_2areceptor antagonist compounds having the structural formula IX
wherein
X is O or S;
R₁and R₂are independently selected from hydrogen, alkyl, aryl, hydroxy, alkoky, aryloxy, cyano, nitro, CO₂R₇, COR₇, OCOR₇, CONR₇R⁸, CONR₇NR₈R₉, OCONR₇R₈, NR₇R₈, NR₇COR₈, NR₇CONR₈R₉, NR₇CO₂R₈, NR₇SO₂R₈, NR₇CONR₈NR₉R₁₀, NR₇NR₈CO₂R₉, NR₇NR₈CONR₉R₁₀, NR₇SO₂NR₈R₉, SO₂R₇, SOR₇, SR₇and SO₂NR₇R₈, or R₁and R₂together form a carbonyl group (C═O), an oxime group (C═NOR₁₁), an imine group (C═NR₁) or a hydrazine group (C═NNR₁₁R₁₂), or R₁and R₂together form a 5, 6 or 7 membered carbocyclic or heterocyclic ring;
R₃is alkyl or aryl;
R₄, R₅and R₆ate independently selected from hydrogen, alkyl, aryl, halogen, hydroxy, nitro, cyano, alkoxy, aryloxy, CO₂R₇, COR₇, OCOR₇, SO₂R₇, SOR₇, SR₇, SO₂NR₇R₈, CONR₇R₈, CONR₇NR₈R₉, OCONR₇R₈, NR₇R₈, NR₇COR₈, NR₇CONR₈R₉, NR₇CO₂R₈, NR₇SO₂R₈, CR₇═NOR₈, NR₇CONR₈NR₉R₁₀, NR₇NR₈CO₂R₉, NR₇NR₈CONR₉R₁₀, SO₂NR₇NR₈R₉, NR₇SO₂NR₈R₉, NR₇NR₈SO₂R₉, NR₇NR₈CO₂R₉, NR₇NR₈R₉and NR₇CSNR₈R₉, or R₅and R₆together form a 5, 6 or 7 membered carbocyclic or heterocyclic ring; and
R₇, R₈, R₉, R₁₀, R₁₁and R₁₂are independently selected from hydrogen, alkyl and aryl, or a pharmaceutically acceptable salt or prodrug thereof.
The US patents and applications cited herein are incorporated herein by reference. The adenosine A_2areceptor antagonists are prepared by known methods as described in the cited patents and applications.
As used herein, “patient” means a mammal, especially a human.
It is contemplated that more than one adenosine A_2areceptor antagonist (e.g., 2 or 3) can be administered to treat EPS, dystonia, RLS or PLMS; preferably, one adenosine A_2areceptor antagonist is administered.
Antipsychotic agents causing the EPS treated by adenosine A_2areceptor antagonists and for use in combination with adenosine A_2areceptor 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 A_2areceptor 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.
Opioids useful in treating PRLS and PLMS include codeine, hydrocodone, oxycodone, propoxyphene and tramadol.
Benzodiazepines useful in treating PRLS and PLMS include clonazepam, triazolam and temazepam.
The antipsychotics, tricyclic antidepressants, anticonvulsants, dopamine agonists, opioids and benzodiazepines are commercially available and are described in the literature, e.g., in The Physicians' Desk Reference (Montvale: Medical Economics Co., Inc., 2001).
It is contemplated that two or more A_2areceptor antagonists could be administered in combination with one or more other agents (e.g., antipsychotics, tricyclic antidepressants, anticonvulsants, dopamine agonists, opioids or benzodiazepines), although administration of one A_2aantagonist in combination with one other agent is preferred for each of the indications. While administration of separate dosage forms of the A_2aantagonist(s) and the other agent(s) are preferred, it is also contemplated that the other agent(s) could be combined in a single dosage form with the A_2areceptor antagonist(s) for the treatment or prevention of EPS, dystonia, RLS or PLMS.
Preferred adenosine A_2aantagonists are those described in U.S. Pat. No. 6,630,475.
A particularly preferred compound of the invention is Compound A of the formula
or a pharmaceutically acceptable salt or solvate thereof, disclosed in U.S. Pat. No. 6,630,475 and listed as the first compound in the table of compounds of structure I.
Compounds useful in the method of the invention will show utility as adenosine A_2areceptor antagonists in these assays.

Human Adenosine A_2aand A₁Receptor Competition Binding Assay Protocol

Membrane sources: A_2a: Human A_2aAdenosine Receptor membranes, Catalog #RB-HA2a, Receptor Biology, Inc., Beltsville, Md. Dilute to 17 μg/100 μl in membrane dilution buffer (see below).
Assay Buffers Membrane dilution buffer: Dulbecco's Phosphate Buffered Saline (Gibco/BRL)+10 mM MgCl₂.
Compound Dilution Buffer: Dulbecco's Phosphate Buffered Saline (Gibco/BRL)+10 mM MgCl₂supplemented with 1.6 mg/ml methyl cellulose and 16% DMSO. Prepared fresh daily.
Ligands: A_2a: [3H]-SCH 58261, custom synthesis, AmershamPharmacia Biotech, Piscataway, N.J. Stock is prepared at 1 nM in membrane dilution buffer. Final assay concentration is 0.5 nM.
A₁: [3H]-DPCPX, AmershamPharmacia Biotech, Piscataway, N.J. Stock is prepared at 2 nM in membrane dilution buffer. Final assay concentration is 1 nM.

Non-Specific Binding:

A_2a: To determine non-specific binding, add 100 nM CGS 15923 (RBI, Natick, Mass.). Working stock is prepared at 400 nM in compound dilution buffer.
A₁: To determine non-specific binding, add 100 μM NECA (RBI, Natick, Mass.). Working stock is prepared at 400 μM in compound dilution buffer.

Compound Dilution:

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

Assay Procedure:

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 (A_2anon-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 A_2a, [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 plexiglas cage placed at an angle of about 70 degrees with the bench table. The rat is placed on the grid with all four legs abducted and extended (“frog posture”). The use of such an unnatural posture is essential for the specificity of this test for catalepsy. The time span from placement of the paws until the first complete removal of one paw (descent latency) is measured maximally for 120 sec.
The selective A_2aadenosine antagonists under evaluation are administered orally at doses ranging between 0.03 and 3 mg/kg, 1 and 4 h before scoring the animals.
In separate experiments, the anti-cataleptic effects were determined for the reference compound, L-DOPA (25, 50 and 100 mg/kg, ip),
For preparing pharmaceutical compositions from the compounds useful in the method of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 0.1 to about 99 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection.
Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds useful in the method of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably the adenosine A_2areceptor antagonist and the antipsychotic are administered orally.
Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of adenosine A_2areceptor antagonist in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, more preferably from about 1 mg to 300 mg, according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
The amount and frequency of administration of the adenosine A_2areceptor antagonist useful in the method of the invention will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended dosage regimen for an adenosine A_2areceptor antagonist is oral administration of about 10 mg to 2000 mg/day preferably 10 to 1000 mg/day, in two to four divided doses to provide relief from the effects of EPS, dystonia, RLS or PLMS. The compounds are non-toxic when administered within this dosage range.
The doses and dosage regimen of the other agents used in combination with the adenosine A_2areceptor antagonists, i.e., the antipsychotics, tricyclcic antidepressants, anticonvulsants, dopamine agonists, benzodiazepines, opioids, lithium or iron, will be determined by the attending clinician in view of the approved doses and dosage regimen in the package insert, taking into consideration the age, sex and condition of the patient and the severity of the disease. When administered in combination, the adenosine A_2areceptor antagonist and the other agent can be administered simultaneously or sequentially. This is particularly useful when the components of the combination are preferably given on different dosing schedules, e.g., one component is administered daily and the other every six hours, or when the preferred pharmaceutical compositions are different, e.g. one is preferably a tablet and one is a capsule. It is therefore advantageous to provide the adenosine A_2areceptor antagonist and the other agent in a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat or prevent EPS, dystonia, RLS or PLMS, wherein one container comprises a pharmaceutical composition comprising an effective amount of an adenosine A_2areceptor antagonist in a pharmaceutically acceptable carrier, and wherein a separate container comprises a pharmaceutical composition comprising an effective amount of another agent appropriate to treat the indicated condition.
Those skilled in the art will recognize that a dosage form for one of the components of the combination can be modified to contain both an adenosine A_2areceptor antagonist and another agent, e.g., an adenosine A_2areceptor antagonist and an antipsychotic or an adenosine A_2areceptor antagonist and a dopamine agonist.
The following example shows the use of adenosine A_2aantagonists to attenuate the Extra-Pyramidal Syndrome (EPS) displayed in cebus apella monkeys sensitized to the dopamine D₂receptor antagonist, haloperidol.

EXAMPLE

A colony of seven Cebus apella monkeys that were previously sensitized to the chronic effects of haloperidol, exhibit EPS when administered haloperidol acutely (0.3 mg/kg, p.o.). Compound A was administered orally (p.o.) at doses of 0.3-30 mg/kg, in conjunction with haloperidol. The studies were conducted using a within-subjects design such that each monkey received all 6 treatments (vehicle and 5 doses of Compound A) in a crossover, balanced design. In all the studies, the group of seven monkeys exhibited baseline levels of EPS when dosed with haloperidol.
Compound A produced a dose-dependent reduction in the maximum EPS score (FIG. 1A), as well as a dose-dependent delay in the onset of EPS (FIG. 1B). At a dose of 1 mg/kg, Compound A prevented the onset of EPS in one monkey, and delayed the onset of EPS by 1 hr. Compound A, at a dose of 3 mg/kg, prevented the onset of EPS in two monkeys, and delayed the onset of EPS by almost 2 hr in the remaining monkeys. At 10 and 30 mg/kg, Compound A prevented the onset of EPS in three monkeys and delayed the onset of EPS by an average of 2.3-2.9 hr.
Clinical guidelines for the treatment of RLS and PLMS have been established: see A. L. Chesson et al, Sleep, 22, 7 (1999), p. 961-8. Efficacy of adenosine A_2aantagonists in treating RLS and PLMS can be determined by a method analogous to the clinical method described in the literature for pramipexole and ropinerole by Weimerskirch et al, Annals of Pharmacotherapy, 35, 5 (2001), p. 627-30.
While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

1. A method for the treatment or prevention of Extra-Pyramidal Syndrome or dystonia comprising administering a therapeutically effective amount of an adenosine A2a receptor antagonist to a patient in need thereof.

2. The method of claim 1 wherein the adenosine A2a antagonist is a compound of the formula

or a pharmaceutically acceptable salt thereof, wherein

R is R¹-furanyl, R¹-thienyl, R¹-pyridyl, R¹-pyridyl N-oxide, R¹-oxazolyl, R¹⁰-phenyl, R¹-pyrrolyl or C₄-C₆cycloalkenyl;

X is C₂-C₆alkylene or —C(O)CH₂—;

Y is —N(R²)CH₂CH₂N(R³)—, —OCH₂CH₂N(R²)—, —C—, —S—, —CH₂S—, —(CH₂)₂—NH—, or

and

Z is R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, R⁵-heteroaryl, diphenylmethyl, R⁶—C(O)—, R⁶—SO₂—, R⁶—OC(O)—, R⁷—N(R⁸)—C(O)—, R⁷—N(R⁸)—C(S)—,

phenyl-CH(OH)—, or phenyl-C(═NOR²)—; or when Q is

Z is also phenylamino or pyridylamino;

or

Z and Y together are

R¹is 1 to 3 substituents independently selected from hydrogen, C₁-C₆-alkyl, —CF₃, halogen, —NO₂, —NR¹²R¹³, C₁-C₆alkoxy, C₁-C₆alkylthio, C₁-C₆alkylsulfinyl, and C₁-C₆alkylsulfonyl;

R²and R³are independently selected from the group consisting of hydrogen and C₁-C₆alkyl;

m and n are independently 2-3;

Q is

R⁴is 1-2 substituents independently selected from the group consisting of hydrogen and C₁-C₆alkyl, or two R⁴substituents on the same carbon can form ═O;

R⁵is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C₁-C₆alkyl, hydroxy, C₁-C₆alkoxy, —CN, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, acetyl, —NO₂, hydroxy(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy, di-((C₁-C₆)-alkoxy)(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy-(C₁-C₆)-alkoxy, carboxy(C₁-C₆)alkoxy, (C₁-C₆)-alkoxycarbonyl(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl(C₁-C₆)alkoxy, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkoxy, morpholinyl, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO—(C₁-C₆)alkoxy, tetrahydropyranyloxy, (C₁-C₆)alkylcarbonyl(C₁-C₆)alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)alkylcarbonyloxy(C₁-C₆)-alkoxy, —SO₂NH₂, phenoxy,

or adjacent R⁵substituents together are —O—CH₂—O—, —O—CH₂CH₂—O—, —O—CF₂—O— or —O—CF₂CF₂—O— and form a ring with the carbon atoms to which they are attached;

R⁶is (C₁-C₆)alkyl, R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, thienyl, pyridyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyl-OC(O)—NH—(C₁-C₆)alkyl-, di-((C₁-C₈)alkyl)aminomethyl, or

R⁷is (C₁-C₆)alkyl, R⁵-phenyl or R⁵-phenyl(C₁-C₆)alkyl;

R⁸is hydrogen or C₁-C₆alkyl; or R⁷and R⁶together are —(CH₂)_p-A-(CH₂)_q, wherein p and q are independently 2 or 3 and A is a bond, —CH₂—, —S— or —O—, and form a ring with the nitrogen to which they are attached;

R⁹is 1-2 groups independently selected from hydrogen, C₁-C₆alkyl, hydroxy, C₁-C₆alkoxy, halogen, —CF₃and (C₁-C₆)alkoxy(C₁-C₆)alkoxy;

R¹⁰is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C₁-C₆alkyl, hydroxy, C₁-C₆alkoxy, —CN, —NH₂, C₁-C₆alkylamino, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃and —S(O)_0-2(C₁-C₆)alkyl;

R¹¹is H, C₁-C₆alkyl, phenyl, benzyl, C₂-C₆alkenyl, C₁-C₆alkoxy(C₁-C₆)alkyl, di-((C₁-C₆)_{alkyl)amino(C} ₁-C₆)alkyl, pyrrolidinyl(C₁-C₆)alkyl or piperidino(C₁-C₆)alkyl;

R¹²is H or C₁-C₆alkyl; and

R¹³is (C₁-C₆)alkyl-C(O)— or (C₁-C₆)alkyl-SO₂—.

3. The method of claim 2 wherein the adenosine A2a receptor antagonist is selected from the group consisting of compounds of the formula

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

Z—Y— R

or a pharmaceutically acceptable salt or solvate thereof.

4. The method of claim 3 wherein the adenosine A2a receptor antagonist is

or a pharmaceutically acceptable salt or solvate thereof.

5. The method of claim 1 for treating or preventing Extra-Pyramidal Syndrome.

6. The method of claim 5 wherein the Extra-Pyramidal Syndrome has been caused by treatment with a typical antipsychotic agent or an atypical antipsychotic agent.

7. The method of claim 6 wherein the typical antipsychotic agent is selected from the group consisting of loxapine, haloperidol, chlorpromazine, prochlorperazine and thiothixene, and the atypical antipsychotic agent is selected from the group consisting of clozapine, olanzapine, loxapine, quetiapine, ziprasidone and risperidone

8. The method of claim 5 further comprising administering an antipsychotic agent in combination with the adenosine A_2areceptor antagonist.

9. The method of claim 8 wherein the antipsychotic agent is a typical antipsychotic agent selected from the group consisting of loxapine, haloperidol, chlorpromazine, prochlorperazine and thiothixene, or an atypical antipsychotic agent selected from the group consisting of clozapine, olanzapine, loxapine, quetiapine, ziprasidone and risperidone.

10. A kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat or prevent EPS caused by treatment with antipsychotic agent, wherein one container comprises a pharmaceutical composition comprising an effective amount of an adenosine A_2areceptor antagonist in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an effective amount of an antipsychotic agent.

11. A method of claim 1 for the treatment of idiopathic dystonia or dystonia caused by the use of cocaine.

12. The method of claim 1 for the treatment or prevention of dystonia caused by treatment with a tricyclic antidepressant, lithium or an anticonvulsant.

13. The method of claim 12 further comprising administering a tricyclic antidepressant, lithium or an anticonvulsant in combination with the adenosine A2a receptor antagonist.

14. The method of claim 13 wherein the tricyclic antidepressant is selected from the group consisting of perphenazine, amitriptyline, desipramine, doxepin, trimipramine and protriptyline, and the anticonvulsant is selected from the group consisting of phenyloin, carbamazepine and gabapentin.

15. A kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat or prevent dystonia caused by treatment with a tricyclic antidepressant, lithium or an anticonvulsant, wherein one container comprises a pharmaceutical composition comprising an effective amount of an adenosine A_2areceptor antagonist in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an effective amount of a tricyclic antidepressant, lithium or an anticonvulsant.

16. A method of treating restless leg syndrome or periodic leg movement in sleep comprising administering a therapeutically effective amount of an adenosine A2a receptor antagonist to a patient in need thereof.

17. The method of claim 16 wherein the adenosine A2a antagonist is a compound of the formula

or a pharmaceutically acceptable salt thereof, wherein

X is C₂-C₆alkylene or —C(O)CH₂—;

Y is —N(R²)CH₂CH₂N(R³)—, —OCH₂CH₂N(R²)—, —O—, —S—, —CH₂S—, —(CH₂)₂—NH—, or

and

phenyl-CH(OH), or phenyl-C(═NOR²)—; or when Q is

Z is also phenylamino or pyridylamino;

or

Z and Y together are

m and n are independently 2-3;

Q is

R⁵is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C₁-C₆alkyl, hydroxy, C₁-C₆alkoxy, —CN, di-((C₁-C₆)alkyl)amino, —CF₃, —OCF₃, acetyl, —NO₂, hydroxy(C₁-C₆)alkoxy, (C₁-C₆)-alkoxy(C₁-C₆)alkoxy, di-((C₁-C₆)-alkoxy)(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy-(C₁-C₆)-alkoxy, carboxy(C₁-C₆) alkoxy, (C₁-C₆)-alkoxycarbonyl(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl(C₁-C₆)alkoxy, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkoxy, morpholinyl, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO—(C₁-C₆)alkoxy, tetrahydropyranyloxy, (C₁-C₆)alkylcarbonyl(C₁-C₆)alkoxy, (C₁-C₆)-alkoxycarbonyl, (C₁-C₆)alkylcarbonyloxy(C₁-C₆)-alkoxy, —SO₂NH₂, phenoxy,

R⁶is (C₁-C₆)alkyl, R⁵-phenyl, R⁵-phenyl(C₁-C₆)alkyl, thienyl, pyridyl, (C₃-C₆)-cycloalkyl, (C₁-C₆)alkyl-OC(O)—NH—(C₁-C₆)alkyl-, di-((C₁-C₆)alkyl)aminomethyl, or

R⁷is (C₁-C₆)alkyl, R⁵-phenyl or R⁵-phenyl(C₁-C₆)alkyl;

R⁸is hydrogen or C₁-C₆alkyl; or R⁷and R⁸together are —(CH₂)_p-A-(CH₂)_q, wherein p and q are independently 2 or 3 and A is a bond, —CH₂—, —S— or —O—, and form a ring with the nitrogen to which they are attached;

R¹¹is H, C₁-C₆alkyl, phenyl, benzyl, C₂-C₆alkenyl, C₁-C₆alkoxy(C₁-C₆)alkyl, di-((C₁-C₆)alkyl)amino(C₁-C₆)alkyl, pyrrolidinyl(C₁-C₆)alkyl or piperidino(C₁-C₆)alkyl;

R¹²is H or C₁-C₆alkyl; and

R¹³is (C₁-C₆)alkyl-C(O)— or (C₁-C₆)alkyl-SO₂—.

18. The method of claim 16 further comprising administering levodopa/carbidopa, levodopa/benserazide, a dopamine agonist, a benzodiazepine, an opioid, an anticonvulsant or iron in combination with the adenosine A2a receptor antagonist.

19. A kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat or prevent restless leg syndrome or periodic leg movement in sleep, wherein one container comprises a pharmaceutical composition comprising an effective amount of an adenosine A2a receptor antagonist in a pharmaceutically acceptable carrier, and wherein a separate container comprises a pharmaceutical composition comprising an effective amount of a dopamine agonist, benzodiazepine, opioid, anticonvulsant or iron.