ES2349535T3 - METHOD OF TREATMENT OF AN ANXIETY DISORDER. - Google Patents

Abstract

The use of an A2A adenosine receptor antagonist selected from the group consisting of: (i) (E) -8- (3,4-dimethoxystyryl) -1,3-diethyl-7-methylxanthine (Compound A) (ii) ( E) -1,3,7-trimethyl-8- (3,4,5-trimethoxystyryl) xanthine (Compound B) (iii) 5-amino-2- (2-furyl) -7- [4- (3- hydroxy-3- methylbutyl) piperazinyl] [1,2,4] triazolo [1,5-c] pyrimidine (Compound C) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of an anxiety disorder .

Description

FIELD OF THE INVENTION

The present invention relates to the treatment of an anxiety disorder which comprises administering at least one specific adenosine A2A receptor antagonist. BACKGROUND OF THE INVENTION Anxiety disorders

Anxiety disorders are a group of psychological problems whose key characteristics include excessive anxiety, fear, anguish, avoidance and compulsive rituals and produce or result in excessive morbidity; overuse of health services and functional dysfunction. They are among the most frequent psychiatric conditions in the United States and in most other countries. Through cultures there is a fairly uniform incidence of the disease. In most cases, women are more likely than men to experience anxiety disorders. Chronic anxiety disorders can increase the mortality rate related to cardiovascular diseases and therefore the correct diagnosis and rapid onset of treatment must be made.

Anxiety disorders listed in the Statistical and Diagnostic Manual of Mental Disorders (Fourth Revised Edition, 1994, published by the American Psychiatric Association, Washington, DC, United States, pages 393-444), includes panic disorder with and without agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia, obsessive compulsive disorder (OCD), posttraumatic stress disorder (PTSD), acute stress disorder, generalized anxiety disorder (GAD), anxiety disorder due to general medical condition, substance-induced anxiety disorder, and anxiety disorders not otherwise specified. Panic disorder with and without agoraphobia

Panic disorder is an anxiety disorder whose essential characteristic is the presence of recurrent panic attacks (ie specific periods of intense fear or discomfort with at least four associated characteristic symptoms). Attacks usually last minutes (or rarely, hours), are unexpected and do not tend, as in simple phobia, to occur immediately before or during exposure to a situation that almost always causes anxiety. The "unexpected" aspect of attacks is an essential feature of the disorders. Panic attacks typically begin with the sudden onset of apprehension or intense fear and are accompanied by physical symptoms such as dyspnea, dizziness, fainting, asphyxiation, palpitations, trembling, sweating, shock, nausea, numbness, hot flashes or chills, chest pain or Similary. Panic disorder can be associated with agoraphobia, in severe cases in which the affected person can practically not leave home.

Approximately one third to one half of the individuals diagnosed with panic disorder, in collective samples, also suffer from agoraphobia, however in clinical samples a higher agoraphobia rate has been detected. Agoraphobia without a history of panic disorder

Agoraphobia is a condition characterized by the characteristic of anxiety when being in places or situations from which it could be difficult (or embarrassing) to escape or where help may not be available in case of having a panic attack or similar symptoms. to panic (for example, fear of having a sudden dizziness attack or a sudden diarrhea attack). Agoraphobia occurs in the context of panic disorder with agoraphobia and agoraphobia without a history of panic disorder. The essential features of agoraphobia without a history of panic disorder are similar to those of panic disorder with agoraphobia except that the focus of fear is on the occurrence of disabling or extremely embarrassing symptoms similar to panic or limited attacks of symptoms instead of complete panic attacks

Almost all individuals (over 95%) who have agoraphobia also have a current diagnosis (or history) of panic disorders. On the other hand, it has been indicated that the prevalence of agoraphobia without a history of panic disorder, in epidemiological samples, is higher than in panic disorder with agoraphobia. Obsessive compulsive disorder (OCD)

The main symptom is the recurring obsession (i.e., recurring and intrusive thoughts, images or impulses that produce accentuated anxiety) and / or compulsions (i.e. repetitive mental behaviors or acts that are performed to reduce the anxiety generated by one of the obsessions ) of sufficient gravity to cause suffering, loss of time

or significantly interfere with a person's routine or normal lifestyle. Anxiety is an associated feature of this disorder: an affected person may, for example, show a phobic avoidance of situations that involve the cause of the obsession. Typical obsessions are related to pollution, mistrust (including lack of self-confidence) and disturbing sexual or religious thoughts. Typical compulsions include washing, checking, ordering things and counting. Social phobia

Social phobia is characterized by the persistent fear of social or work situations in which shame may occur. Typical situations feared or avoided by individuals with social phobia include attending parties, meetings, eating and writing in front of other people, speaking in public, chatting, meeting new people and other related situations. Exposure to social or work situations almost invariably causes an immediate anxiety response, as well as sweating, trembling, acceleration

or palpitation of the heartbeat, mental confusion and a desire to escape. Avoidance and social isolation can also become extreme, especially in the more generalized condition. Alcohol abuse is over commonly associated with social phobia than any other disorder of anxiety and often represents an attempt at self-medication of social fears Post-traumatic stress disorder (PTSD)

The main characteristic symptoms involve re-experiencing a traumatic situation (ie psychologically disturbing), the avoidance of stimuli associated with this situation, the numbness of general sensitivity and increased waking state. The "situations" that concern are outside the range of common experiences such as the simple death of a loved one, chronic illnesses and marital conflicts. Generalized anxiety disorder (GAD)

GAD is a condition whose main characteristic is unreal or excessive anxiety and worries about two or more life circumstances for six months or more. The concern should be experienced as difficult to control and during this time the affected person is concerned about the matter for more days than it is not. When the person is anxious, he shows signs of motor tension, autonomous hyperactivity, vigilance and scrutiny. Specific phobia

Specific phobia is an anxiety disorder in which the essential characteristic is a persistent fear of a particular stimulus, which may be an object or a situation, other than the fear of having a panic attack or humiliating or embarrassing social situations (which found within the social phobia). Examples include aerophobia, acrophobia, zoophobia, trypanophobia and tocophobia. Simple phobias can be called "specific" phobias and, in general in the population, exposure to phobic stimuli almost invariably leads to an immediate anxiety response.

Multiple causes that cause anxiety disorders are suspected, especially a combination of genetic component, early growth and development and subsequent life experiences. Anxiety disorders are treated with some form of counseling or psychotherapy or pharmacotherapy (drug therapy), alone or in combination. The medication typically used to treat patients with anxiety disorders are benzodiazepines, selective serotonin reuptake inhibitors (SSRIs) and buspirone.

Benzodiazepines are an extensive class of relatively safe and widely prescribed medications that have rapid and profound hypnotic and anti-anxiety sedative effects. For the treatment of anxiety-related disorders drugs within the SSRI class are used such as panic disorder, agoraphobia, OCD, social phobia, post-traumatic stress disorder, specific phobia and broader anxiety disorders [Kaplan & Sadock 's Comprehensive textbook of psychiatry 7th edition, 1,1441-1498 (1999)]. Buspirone is a relatively selective partial agonist of the 5HT1A receptor, approved by the FDA as an anxiolytic, very useful for the treatment of GAD and currently frequently used as a supplement to SSRIs [Kaplan & Sadock's Comprehensive textbook of psychiatry 7th edition, 1, 1441-1498 (1999)].

For GAD it seems that this is effective in pharmacological and psychological treatments. However, most medication studies are based on old criteria for GAD (which have already been substantially reviewed), there is evidence that a range of pharmacological interventions may be useful for GAD, including buspirone, imipramine and a variety of benzodiazepines Pharmacotherapy is considered to be less effective in GAD than in some other anxiety disorders [Kaplan and Sadock's Comprehensive textbook of psychiatry 7th edition, 1, 1441-1498 (1999)]. Usually the treatment is a behavioral exposure. The medication is occasionally used to relieve anticipatory anxiety associated with the start of exposure treatment. For this purpose, low doses of benzodiazepines and β-adrenergic receptor antagonists can be used on a basis as needed.

Concerns have been expressed about possible side effects of some of the medications used to treat anxiety disorder, particularly as regards benzodiazepines. Common side effects associated with these medications, which may decrease during the course of treatment, include sedation, fatigue, ataxia, inarticulate pronunciation and amnesia. Benzodiazepines may also produce drug dependence (i.e. physiological or behavioral symptoms after discontinuation of use).

Therefore there is a continuing need for new agents that are effective and safe anxiolytics. Adenosine A2A receptors

It is known that adenosine acts through four subtypes of major receptors, A1, A2A, A2B and A3, which have been characterized according to their primary sequences [Pharmacol. Rev., 46, 143-156 (1994)]. A2A adenosine receptors are abundant in the basal ganglia, especially in the caudate-putamen, nucleus accumbens and olfactory tubercle in various species [Brain Res., 519, 333-337 (1990)]. Basal ganglia are a critical component of subcortical circuits involved in the integration of sensorimotor, associative and limbic information to produce motor behavior. In the caudate-putamen, one of the main nuclei in the basal ganglia, the adenosine A2A receptors are located in various neurons and have been shown to modulate the neurotransmission of γ-aminobutyric acid (GABA), acetylcholine and glutamate [J. Neurochem., 66, 1882-1888 (1996); J.

Neurosci., 16, 605-611 (1996); J. Physiol., 532,423-434 (2001); Neuroscience, 100.53-62 (2000); Trends Pharmacol. Sci., 18,338-344 (1997); and Biosci. Biotechnol Biochem., 65,1447-1457 (2001)]. In addition, A2A adenosine receptor antagonists show significant antiparkinsonian activity [Ann. Neurol., 43, 507-513 (1998); Neurology, 52, 1673-1677 (1999); and Biosci. Biotechnol Biochem., 65,1447-1457 (2001)]. Additionally, current studies suggest linking the expectation of reward, attention and knowledge with behavior in the basal ganglia.

More recently, the neuroprotective effect of an A2A adenosine receptor antagonist has been demonstrated in MPTP-induced dopaminergic neurodegeneration [J. Neurochem., 80, 262-270 (2002); and J. Neurosci., 21, RC143 (1-6) (2001)].

It is known that some components of xanthine show antagonistic activity against the A2A adenosine receptor, activity against anti-Parkinson's disease, antidepressant activity, inhibitory activity on neurodegeneration, or the like (US Pat. Nos. 5,484,920; 5,587,378; and 5,543,415; EP 1016407A1; etc.)

It has been described that (E) -3- (3-Hydroxypropyl) -1-propyl-8-styryxxanthin has an anxiolytic activity [Society for Neuroscience Abstracts, (2000) Vol. 26, No. 1-2, p. Summary Nº-868.17. print Meeting Info .: 30th Annual Meeting of the Society of Neuroscience New Orleans, LA, USA 04-09 November, 2000].

It has been indicated that some triazolopyrimidines have an affinity towards the A2A receptor (WO 02/48145 etc.).

A combination of an A2A adenosine receptor antagonist and an antidepressant or anxiolytic agent has been described (WO 03/022283). However, there are no data demonstrating the effect of the combination of an A2A adenosine receptor antagonist and an anxiolytic in the previous publication. SUMMARY OF THE INVENTION

The object of the present invention is to provide a method for the treatment of an anxiety disorder, such as a panic disorder, agoraphobia, obsessive compulsive disorder, social phobia, post-traumatic stress disorder, generalized anxiety disorder, specific phobia or Similary. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the following aspects (1) to (7).

(1) The use of an A2A adenosine receptor antagonist selected from the group consisting of:

(i)

(E) -8- (3,4-dimethoxystyryl) -1,3-diethyl-7-methylxanthine (Compound A)

(ii)

 (E) -1,3,7-trimethyl-8- (3,4,5-trimethoxystyryl) xanthine (Compound B)

image 1

image 1

(iii) 5-amino-2- (2-furyl) -7- [4- (3-hydroxy-3-methylbutyl) piperazinyl] [1,2,4] triazolo [1,5-c] pyrimidine (Compound C)

image 1

10 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of an anxiety disorder.

(2) The use according to item 1 wherein the A2A adenosine receptor antagonist is (E) -8- (3,4-dimethoxystyryl) -1,3-diethyl-7-methylxanthine or a pharmaceutically acceptable salt of the same.

15 (3) The use according to point 1 or 2, in which the anxiety disorder is a generalized anxiety disorder.

(4) The use according to any one of items 1 to 2, in which the anxiety disorder is selected from the group consisting of panic disorder, agoraphobia, obsessive compulsive disorder, social phobia, disorder by

20 post-traumatic stress and specific phobia.

(5)

An adenosine A2A receptor antagonist as defined in item 1 or 2 for use in the treatment of an anxiety disorder.

(6)

 The adenosine A2A receptor antagonist according to item 5, in which the anxiety disorder is generalized anxiety disorder.

5 (7) The A2A adenosine receptor antagonist according to item 5, in which the anxiety disorder is selected from the group consisting of panic disorder, agoraphobia, obsessive compulsive disorder, social phobia, post-stress disorder Traumatic and specific phobia.

Anxiety disorder includes panic disorder, agoraphobia,

10 obsessive compulsive disorder, social phobia, posttraumatic stress disorder, generalized anxiety disorder, specific phobia and other anxiety disorders.

The A2A adenosine receptor antagonist used in the present invention is selected from: 15 (E) -8- (3,4-dimethoxystyryl) -1,3-diethyl-7-methylxanthine (hereinafter referred to as Compound A ) shown below image 1

(E) -1,3,7-trimethyl-8- (3,4,5-trimethoxystyryl) xanthine (hereinafter referred to as Compound B) shown below image 1

twenty

5-amino-2- (2-furyl) -7- [4- (3-hydroxy-3-methylbutyl) piperazinyl] [1,2,4] triazolo [1,5-c] pyrimidine (hereinafter referred to as Compound C) shown below

image 1

and pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts of the compounds useful in the present invention include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts and amino acid addition salts. Pharmaceutically acceptable acid addition salts include inorganic acid addition salts such as hydrochloride, sulfate, nitrate and phosphate and organic acid addition salts such as acetate, maleate, fumarate and citrate; Pharmaceutically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt; pharmaceutically acceptable ammonium salts include ammonium and tetramethylammonium; Pharmaceutically acceptable organic amine addition salts include addition salts with morpholine or piperidine and pharmaceutically acceptable amino acid addition salts include addition salts with lysine, glycine or phenylalanine.

The anxiolytic other than the A2A adenosine receptor antagonist used in the method of the present invention is not limited as long as it has anti-anxiety activity. Examples of the anxiolytic include tryptamine reuptake inhibitors such as buspirone, sertraline, paroxetine, nefazodone and fluoxetine; GABA receptor agonists such as benzodiazepines (for example diazepam, tofisopam, alprazolam and flutoprazepam); corticotropin release factor antagonists such as pivagabine; and MAO inhibitors such as amisulpride.

The production of the compounds useful in the present invention and the pharmaceutically acceptable salts thereof, can be carried out by one skilled in the art as demonstrated by the teachings of United States Patents, PCT or European patent application publications indicated above, or similar.

Pharmaceutical compositions for administration according to the present invention comprise at least one A2A adenosine receptor antagonist as an active ingredient (or ingredients) optionally combined with a pharmaceutically acceptable carrier (or carriers). These compositions can be administered by any means that achieve their desired purposes. A person skilled in the art can easily determine the amounts and regimens for the administration of pharmaceutical compositions in the treatment of patients suffering from anxiety disorders.

The pharmaceutical compositions described herein can be administered by any suitable method that includes, without limitation, orally; intranasally, intrapulmonary, parenteral, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intraduodenal, transdermal or buccal injection.

The dosage administered is an effective amount and depends on the age, health and weight of the patient, type of prior or simultaneous treatment, if any, frequency of treatment and the nature of the desired effect. When an appropriate dosage is determined, several factors are typically taken into account. These factors include the age, sex and weight of the patient, the condition to be treated, the severity of the condition and the form of the drug to be administered.

An "effective amount" is the amount sufficient to influence a desired beneficial or clinical outcome. An effective amount can be administered in one or more doses.

Adenosine A2A receptor antagonists can preferably be administered in an amount of about 0.001 to about 20.0 mg per kilogram of body weight. A dosage range of about 0.01 to about 10 mg per kilogram of body weight is more preferable. Since the A2A adenosine receptor antagonists used in the present invention will eventually be removed from the bloodstream, readministration of the pharmaceutical compositions is indicated and preferred.

The A2A adenosine receptor antagonists used in the present invention can also be administered in the form of an implant when combined with a biodegradable delayed-release transporter. Alternatively, the active ingredients can be formulated as a transdermal patch for the continuous release of the active ingredient (or ingredients). Methods for preparing implants and patches are well known in the art [Remington's Pharmaceutical Sciences 18th Edition (1990), E. W. Martin ed., Mack Publishing Co., Pa; and Kydonieus ed. (1992) Treatise on controlled drug delivery Marcel Dekker, NY].

In terms of treatment, an effective amount is the amount that is sufficient to alleviate, improve, stabilize, reverse or decrease the progression of the disease or disorder or otherwise reduce the pathological consequences of the disease or disorder. The attending physician generally determines the effective amount based on case by case and is within the specialty in the art.

In addition to the active ingredient (or ingredients), the pharmaceutical composition useful in the present invention may also contain a suitable pharmaceutically acceptable carrier such as an excipient that facilitates the preparation of the active ingredient (or ingredients) in a pharmaceutically acceptable preparation. Preferably, the preparations, particularly those preparations that can be administered orally and that can be used for the preferred type of administration, such as tablets, troches or capsules and also preparations that can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or oral administration, they contain from about 0.1 to 99 percent, preferably from about 20 to 85 percent of the active ingredient (or ingredients), together with the excipient. Liquid preparations may, for example, be prepared by dissolving or dispersing the active ingredient (or ingredients) in a liquid excipient, such as water, saline, aqueous dextrose, glycerol

or ethanol The pharmaceutical compositions may also contain another medicinal agent (or agents), pharmaceutical agent (or agents), carrier (carriers) or auxiliary substance (or substances), such as a wetting or emulsifying agent (or agents), or agent (agents) pH buffers.

The pharmaceutical compositions useful in the present invention are administered by an appropriate mode for the composition form. Typical pathways include the subcutaneous, intramuscular, intraperitoneal, intradermal, oral, intranasal and intrapulmonary (ie aerosol). The pharmaceutical compositions, useful in the present invention, for use in humans are typically administered orally.

Pharmaceutical compositions for oral, intranasal administration

or topically they can be provided in solid, semi-solid or liquid forms, including tablets, capsules, powders, liquids and suspensions. Pharmaceutical compositions for injection can be supplied as liquid solutions or suspensions, as emulsions or as solid forms suitable for dissolution or suspension in liquid before injection. For administration via the respiratory tract, a preferred pharmaceutical composition is one that provides a solid, powder or liquid aerosol when used with an appropriate aerosol device. Although not necessary, pharmaceutical compositions are preferably provided in unit dosage forms suitable for administration of a precise amount. The present invention also contemplates forms of delayed release or prolonged release, in which relatively constant levels of the active ingredient (or ingredients) are provided for a prolonged period.

Adenosine A2A receptor antagonists can be administered in a manner compatible with the dosage formulation and in such amount to be therapeutically effective. Systemic dosages depend on the age, weight and condition of the patient and the route of administration.

Pharmaceutical compositions useful in the present invention are prepared in a known manner. The preparation of the pharmaceutical compositions is carried out in accordance with generally accepted procedures for the preparation of pharmaceutical preparations [eg, Remington's Pharmaceutical Sciences 18th Edition (1990), E. W. Martin ed., Mack Publishing Co., Pa]. Depending on the use and the desired mode of administration, it may be desirable to process the active ingredient further in the preparation of the pharmaceutical compositions. Appropriate processing may include sterilizing, mixing with appropriate non-toxic and non-interfering components, dividing into dosage units and introducing into a device for administration.

Pharmaceutical preparations for oral use can be obtained by combining the active ingredient (or ingredients) with a solid excipient (or excipients), optionally crushing the resulting mixture and processing, the granule mixture, then adding an auxiliary (or auxiliary), if You want or need to get tablets.

Suitable excipients include fillers such as saccharides, for example, lactose, sucrose, mannitol or sorbitol; cellulose derivatives; zinc compounds and / or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate; binders such as starch paste, using, for example, corn starch, wheat starch, rice starch or potato starch; jelly; tragacanth and / or polyvinylpyrrolidone.

Auxiliaries include flow regulating agents and lubricants, such as silica, talc, stearic acid or salts thereof and / or polyethylene glycol. The tablets, oblong tablets or capsular cores are provided with suitable coatings that, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions or organic solvents or mixtures of suitable solvents. To produce coatings resistant to gastric juices, ie enteric coatings, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropyl methylcellulose phthalate are used. Dyes or pigments may be added to the tablets or coatings, for example, to identify or characterize dose combinations of the active ingredient.

Other pharmaceutical compositions, which can be used orally, include pressure adjustment capsules made of gelatin, as well as soft hermetic capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The pressure adjustment capsules may contain the active ingredient (or ingredients) in the form of granules, which may be mixed with a filler (or fillers) such as lactose, binders such as starches and / or a lubricant (lubricants) such as talc or magnesium stearate and, optionally, a stabilizer (or stabilizers). In soft capsules, the active ingredient (or ingredients) is preferably dissolved or suspended in a suitable liquid, such as fatty oils or liquid paraffin. In addition, a stabilizer (or stabilizers) may be added.

When in the method of treating an anxiety disorder, the A2A adenosine receptor antagonist is used in combination with an anxiolytic, other than the A2A adenosine receptor antagonist, which comprises administering an effective amount of at least one receptor antagonist. of adenosine A2A in combination with an anxiolytic, other than the A2A adenosine receptor antagonist of the present invention, it is preferable that the A2A adenosine receptor antagonist and the anxiolytic, which is not the A2A adenosine receptor antagonist, may administered to a patient in need, as a single preparation or as a combination of multiple preparations, provided that the two active ingredients are formulated in one preparation and in a combination of more than two preparations. Additionally, when the A2A adenosine receptor antagonist and the anxiolytic receptor, other than the A2A adenosine receptor antagonist, are used or administered as a combination of multiple preparations, these preparations can be used or administered simultaneously or separately in different moments

When the A2A adenosine receptor antagonist and the anxiolytic, other than the A2A adenosine receptor antagonist, are administered as a combination of multiple preparations, for example, the first component (a) comprises the A2A adenosine receptor antagonist and The second component (b) comprises the other anxiolytic, other than the A2A adenosine receptor antagonist, can be independently formulated in a preparation to prepare a kit for treatment and administered using the kit for the same object by the same route or by different routes, simultaneously or separately at different times.

Examples of the kit include those that comprise the content and more than two packages (for example a vial or an envelope) that are not limited in terms of material, shape or similar as long as they do not cause the denaturation of the ingredients, which are the content , due to the external temperature or the light during storage, elution of the chemical ingredients of the container and the like and that they are in a form to allow the first component and the second previous component, which are the content, to be administered by different routes (for example a tube or similar) or by the same route. More specifically, examples of the kit include the tablet kit, injection or the like.

The following non-limiting Test Examples further illustrate the present invention. All references cited in this document are

Incorporate here by reference. Test Example 1: Hole-Board Test on the mouse The method followed that described in Arch. Int. Pharmacodyn. Ther., 147, 372387 (1964) with a slight modification.

5 The mice were placed individually on a square board (35 x 35 cm) raised 60 cm above the ground, which contained 16 equidistant holes (25 mm diameter). During a 5-minute trial, the number of times the mouse inserted the head into the holes (intrusions) was counted.

10 The test compound or vehicle was administered orally 60 minutes before the test. Results: Table 1-A shows the effect of Compound A on the Board Test with Holes in the mouse.

15 Compound A significantly increased the number of intrusions (+ 63%) and advanced quadrants (+ 92%) to 3 mg / kg. Data were analyzed by comparing the result of a group tested with that of a vehicle control group using a Student's t-test for unrelated samples.

20 Table 1-A

TREATMENT (mg / kg) oral -60 min

NUMBER OF INTROMISIONS NUMBER OF TICKETS IN THE 4 QUADRANTS

mean ± e.t.m.

P value % change of control  mean ± e.t.m. P value % change of control

Vehicle

28.6 ± 2.4 - - 12.7 ± 0.8 -

Compound A (3)

46.7 ± 3.2 *** 0.000 + 63% 24.4 ± 1.7 *** 0.000 + 92%

***: p <0.001

Table 1-B shows the effect of Compound B on the Board Test with Holes in the mouse. Compound B significantly increased the number of intrusions (+ 45%) to 3 mg / kg.

Data were analyzed by comparing the result of a test group 25 with that of a vehicle control group using a Student's t-test for unrelated samples.

Table 1-B

TREATMENT (mg / kg) oral -60 min

NUMBER OF INTROMISIONS

mean ± e.t.m

P value % change of control

Vehicle

30.2 ± 3.9 - -

Compound B (3)

43.9 ± 4.2 * 0.0315 + 45%

*: p <0.05

Table 1-C shows the effect of Compound C on the Board Test with Holes in the mouse. Compound C significantly increased the number of intrusions (+ 55%) to 10 mg / kg.

Data were analyzed by comparing the result of a group tested with that of a vehicle control group using a Student's t-test for unrelated samples.

Table 1-C

TREATMENT (mg / kg) oral -60 min

NUMBER OF INTROMISIONS

mean ± e.t.m.

P value % change of control

Vehicle

30.2 ± 3, 9 - -

Compound C (10)

46.9 ± 3.4 ** 0.0074 + 55%

**: p <0.01

10 Test Example 2: Marble Burial Assay in the Mouse The method followed that described in Eur. J. Pharmacol., 126, 223-229 (1986) with a slight modification. Mice exposed to a new object (marbles) tend to bury them in sawdust (bed).

15 Mice were placed individually in transparent plastic cages with 25 colored marbles (diameter 1.5 cm) 5 cm from the sawdust bed. The cage was then covered with a similar cage facing up.

At the end of a 30-minute trial, the number of marbles buried in sawdust (50% or more) was counted. 20 The test compound or vehicle was administered orally 60

minutes before the test. Results: Table 2-A shows the effect of Compound A on the Test of

Burying Marbles in the mouse. Compound A significantly decreased the number of buried marbles to 3 mg / kg (-50%).

Data were analyzed by comparing the result of a group tested with that of a vehicle control group using a Student's t-test for unrelated samples.

Table 2-A

TREATMENT (mg / kg) oral -60 min

NUMBER OF SONGS BURIED IN THE SERRIN

mean ± e.t.m.

P value % change of control

Vehicle

20.9 ± 1.4 - -

Compound A (3)

10.5 ± 2.9 ** 0.004 -fifty%

**: p <0.01

Table 2-B demonstrates the effect of Compound B on the Marble Burial Assay in the mouse. 10 Compound B significantly reduced the number of marbles buried in sawdust (-55%) to 3 mg / kg.

Data were analyzed by comparing the result of a group tested with that of a vehicle control group using a Student's t-test for unrelated samples.

15 Table 2-B

TREATMENT (mg / kg) oral -60 min.

NUMBER OF SONGS BURIED IN THE SERRIN

mean ± e.t.m.

P value % change of control

Vehicle

20.6 ± 1.1 - -

Compound B (3)

9.3 ± 1.9 *** 0.0001 -55%

***: p <0.001

Table 2-C demonstrates the effect of Compound C on the Marble Burial Assay in the mouse.

Compound C decreased the number of marbles buried in sawdust (-17%) to 10 mg / kg.

Data were analyzed by comparing the result of a group tested with that of a vehicle control group using a Student's t-test for unrelated samples.

Table 2-C

TREATMENT (mg / kg) oral

NUMBER OF SONGS BURIED IN THE SERRIN

-60 min

mean ± e.t.m. P value % change of control

Vehicle

20.9 ± 1.1 - -

Compound C (10)

17.0 ± 1.6 0.08 -17%

5 Test Example 3: Helplessness learned in the rat The method followed that described in J. Exp. Psychol., 74, 1-9 (1967) with a slight modification. On the first day, each rat was preconditioned in the shuttle box individually providing inescapable plantar electric shocks.

10 A constant current (1.3 mA) discharge generator provided unusable diffuse discharges on the floor grid during the 50-minute preconditioning period. Control rats were also placed individually in the same chamber for 50 minutes, but discharges were not provided. The second day were performed consecutively

15 adapted avoidance training sessions (FR1: alarm 10 seconds, plantar discharge 0.6 mA; time interval, 5 seconds; 10 seconds / test, 15 escape tests) and test sessions (FR2: plantar discharge 0.6 mA; time interval, 10 seconds; plantar discharge 0.5 seconds, 0.6 mA; time interval, 10 seconds; 15 seconds / test,

20 15 trials). The FR1 session consisted of 15 trials during which a single discharge ended the response on the shuttle and the rats learned to escape the discharges. Subsequently, the FR2 session consisted of 15 trials during which each rat had to pass through the shuttle box from one side to the other and then go through it again until the discharge was finished. In

After one test the discharge (0.6 mA) ended automatically when the appropriate response requirement did not match within 20 seconds of the beginning of the discharge. The test compound or vehicle was administered orally 60 minutes before the test. The percent response to escape was calculated from the following

formula: Percentage of escape response (%)

= Number of escape responses produced / 15 x 100

The percentage of response between trials was calculated from the following formula:

Percentage of response between trials (%)

= Number of crossings on the shuttle during the period between trial / 15 x 100

Results:

Figure 1 shows the effect of compound A on the Assisted Helplessness Test in the rat.

Data were analyzed by comparing the result of a group tested with that of a vehicle control group using a Steel test.

Compound A invested in a dose-dependent manner the escape failure at 1.25 mg / kg and more with a single treatment but did not increase cross-trials between trials. Test Example 4: Test of the Elevated Cross Maze in the rat

The method followed the one described in Naunyn. Schmied. Arch. Pharmacol., 327, 1-5 (1984) with a slight modification.

The maze consisted of 4 arms of the same length and width (50 x 10 cm) arranged in the form of a plus sign (+). Two opposite arms were enclosed in walls 40 cm high (closed arms). The other 2 arms had no walls (open arms). The labyrinth rose 50 cm above the ground. A rat was placed in the center of the cross labyrinth and allowed to explore for 5 minutes. The number of entries inside the open and closed arms and the time spent inside the open arms were recorded.

The test compound or vehicle was administered orally 60 minutes before the test, respectively.

Results:

Table 3-A shows the effect of Compound A in the Raised Cross Maze Test in the rat.

Compound A significantly increased the number of entries in the open arm (+ 184%) and the time spent in the open arms (+ 268%) to 3 mg / kg.

Data were analyzed by comparing the result of a group tested with that of a vehicle control group using a Student's t-test for unrelated samples.

Table 3-A

TREATMENT (mg / kg) oral -60 min

OPEN ARMS

NUMBER OF ENTRIES

TIME CONSUMED (s)

mean ± e.t.m.

P value % change of control  mean ± e.t.m. P value % change of control

Vehicle

1.9 ± 0.3 - - 38.9 ± 7.7 - -

Compound A

5.4 ± 0.7 *** <0.001 + 184% 143 ± 20.9 *** <0.001 + 268%

***: p <0.001

Table 3-B shows the effect of Compound B in the 5 Elevated Cross Maze Test in the rat.

Compound B significantly increased the number of entries in the open arms (+ 222%) and the time spent in the open arms (+ 505%) to 1 mg / kg.

The data were analyzed by comparing the result of a group tested 10 with that of a vehicle control group using a Student's t-test for unrelated samples. Table 3-B

TREATMENT (mg / kg) oral -60 min

OPEN ARMS

NUMBER OF ENTRIES

TIME CONSUMED (s)

mean ± e.t.m.

P value % change of control  mean ± e.t.m. P value % change of control

Vehicle

1.8 ± 0.8 - - 15.6 ± 8.1 - -

Compound B

5.8 ± 0.8 ** 0.0042 + 222% 94.4 ± 15.2 *** <0.001 + 505%

**: p <0.01, ***: p <0.001

Table 3-C shows the effect of Compound C in the Raised Elevated Maze Test in the rat. 15 Compound C increased the number of entries in the open arm (+ 83%) and the time spent in the open arms (+ 109%) to 30 mg / kg.

Data were analyzed by comparing the result of a group tested with that of a vehicle control group using a Student's t-test for unrelated samples.

twenty

Table 3-C

TREATMENT (mg / kg) oral -60 min

OPEN ARMS

NUMBER OF ENTRIES

TIME CONSUMED (s)

mean ± e.t.m.

P value % change of control  mean ± e.t.m. P value % change of control

Vehicle

2.3 ± 0.5 - - 26.4 ± 6.6 - -

Compound C (30)

4.2 ± 0.8 0.0503 + 83% 55.2 ± 10.7 * 0.0245 + 109%

*: p <0.05

Test Example 5: Social Relationship Test in the Rat The method followed that described in Br. J. Pharmacol., 62, 19-24 (1978) with a slight modification.

A pair of male rats were placed in opposite corners of an open space without a roof (50 x 50 x 50 cm) and allowed to relate. The time spent in the active social relationship was recorded (ie sniffing, chasing, grooming, riding, dragging below or above the partner)

10 during a 10 minute session.

The test compound or vehicle was administered orally 60 minutes before the test, with each rat of the same pair receiving the same treatment.

Results: Table 4-A shows the effect of Compound A on the Social Relationship Test in the rat. Compound A significantly increased the time spent in the active social ratio to 57% to 3 mg / kg. Data were analyzed by comparing the result of a test group 20 with that of a vehicle control group using a Student's t-test for unrelated samples.

Table 4-A

TREATMENT (mg / kg) oral -60 min

TIME CONSUMED IN THE ACTIVE SOCIAL RELATIONSHIP (s)

mean ± e.t.m.

P value % change of control

Vehicle

97.5 ± 8.7 - -

Compound A (3)

153 ± 11.2 ** 0.001 + 57%

**: p <0.01

Table 4-B shows the effect of Compound B on the Social Relationship Test in the rat. 5 Compound B significantly increased the time spent in the active social ratio to 58% to 3 mg / kg.

Data were analyzed by comparing the result of a group tested with that of a vehicle control group using a Student's t-test for unrelated samples.

10 Table 4-B

TREATMENT (mg / kg) oral -60 min

TIME CONSUMED IN THE ACTIVE SOCIAL RELATIONSHIP (s)

mean ± e.t.m.

P value % change of control

Vehicle

89.0 ± 5.7 - -

Compound B (3)

141 ± 6.8 "* 0.0001 + 58%

***: p <0.001

Table 4-C shows the effect of Compound C on the Social Relationship Test in the rat. Compound C significantly increased the time spent in the active social ratio to 35% to 30 mg / kg.

Data were analyzed by comparing the result of a group tested with that of a vehicle control group using a Student's t-test for unrelated samples.

Table 4-C

TREATMENT (mg / kg) oral -60 min

TIME CONSUMED IN THE ACTIVE SOCIAL RELATIONSHIP (s)

mean ± e.t.m.

P value % change of control

Vehicle

96.2 ± 8.2 - -

Compound C (3)

130 ± 9.7 " 0.0016 + 35%

**: p <0.01

Test Example 6: Board Test with Holes in Mice The method followed that described in Arch. Int. Pharmacodyn. Ther., 147, 3725 387 (1964) with a slight modification.

The mice were placed individually on a square board (35 x 35 cm) raised 60 cm above the ground, which contained 16 equidistant holes (25 mm diameter). The number of intrusions that occurred during a 5-minute trial was counted.

The test compound or vehicle was administered orally 60 minutes before the test or intraperitoneally 30 minutes before the test, either alone or in combination with other agents. The following agents were used: benzodiazepines, SSRIs, 5-HT1 receptor agonists or other anxiolytic agents.

The data were analyzed by comparing the effects of the test compound with those of the combination. Test Example 7: Marble Burial Assay in Mice

The method followed that described in Eur. J. Pharmacol., 126, 223-229 (1986) with a slight modification. 20 Mice exposed to a new object (marbles) tend to bury them in the sawdust bed.

The mice were placed individually in transparent plastic cages with 25 colored marbles (1.5 cm diameter) in the sawdust bed. The cage was covered with a similar cage facing up.

25 The number of marbles buried in sawdust (50% or more) at the end of a 30-minute trial was counted. The test compound or vehicle was administered orally 60 minutes before the test both alone and in combination with

buspirone or fluoxetine. Results: Table 5 shows the effect of the complementary treatment of

compound A with buspirone or fluoxetine in the 5-Marble Burial Assay in mice.

Simple administration of Compound A (1 mg / kg), buspirone (15 mg / kg) or fluoxetine (20 mg / kg) showed no significant effect. However, co-administration of Compound A with buspirone or fluoxetine significantly decreased the number of marbles buried in the

10 sawdust 43% or 52%, respectively.

Data were analyzed by comparing the result of a treated group with that of a vehicle control group using a Student's t-test for unrelated samples.

Table 5

TREATMENT (mg / kg) oral -60 min

NUMBER OF SONGS BURIED IN THE SERRIN

mean ± e.t.m.

P value % change of control

Vehicle

17.1 ± 1.6 - -

Compound A (1)

14.1 ± 1.6 0.219 -18%

buspirone (15)

12.7 ± 1.8 0.084 -26%

Compound A (1) + buspirone (15)

9.8 + 2.1 * 0.010 -43%

fluoxetine (20)

13.6 ± 2.5 0.230 -twenty%

Compound A (1) + fluoxetine (20)

8.2 ± 2.4 * 0.010 -52%

*: p <0.05

15 Test Example 8: Cross Raised Labyrinth Test in the Rat The method followed that described in Naunyn. Schmied. Arch. Pharmacol., 327, 1-5 (1984) with a slight modification. The maze consisted of 4 arms of the same length and width (50 x 10 cm) arranged in the form of a plus sign (+). Two opposite arms were

20 enclosed by walls 40 cm high (arms closed). The other 2 arms had no walls (open arms). The labyrinth rose 50 cm above the ground. A rat was placed in the center of the cross labyrinth and allowed to explore for 5 minutes.

The number of entries in the open and closed arms and the time spent in the open arms were recorded. The test compound or vehicle was administered orally 60 minutes before the test alone or in combination with alprazolam. 5 Results:

Table 6 shows the effect of the complementary treatment of Compound A with alprazolam in the Raised Cross Labyrinth Test in the rat.

Both compound A and alprazolam alone showed effect

10 moderate to 1 mg / kg, while the combination of both compounds resulted in a greater effect on the number of entries in the open arms (+ 239%) and the time consumed in the open arms (+ 139%).

Data were analyzed by comparing the result of a treated group with that of a vehicle control group using a Student's t-test for 15 unrelated samples. Table 6

TREATMENT (mg / kg) oral -60 min

OPEN ARMS

NUMBER OF ENTRIES

TIME CONSUMED (s)

mean ± e.t.m.

P value % change of control  mean ± e.t.m. P value % change of control

Vehicle

2.3 ± 0.6 - - 37.4 ± 9.5 - -

compound A

3.8 ± 0.6 0,112 + 65% 55.2 ± 12.1 0.255 + 48%

alprazolam (1)

4.4 ± 0.9 * 0.045 + 91% 57.3112.8 0.216 + 53%

Compound A (1) + alprazolam (1)

7.8 ± 1.1 *** <0.001 + 239% 89.2 ± 12.4 ** 0.002 + 139%

*: p <0.05; ** = p <0.01; *** = p <0.001

Test Example 9: Expression of the immediate early c-fos gene Two to three hours after administration of the test compound in rats or mice, all brains were removed, embedded in

20 the OCT compound and frozen in dry ice. Cuts were made in coronary sections on the cryostat, thawed on the slide covered with gelatin and stored at -80 ° C until further processing. The sections were then hybridized with the antisense RNA probes specific for c-fos transcripts. Antisense RNA probes were prepared by T3, T7 or SP6 polymerases using [35S] CTP or UTP under conventional conditions. The labeled probes were subjected to partial alkaline hydrolysis to reduce the average probe length to approximately 150 nucleotides. Hybridizations were performed as described in Nature, 58.424-428 (1995). Then all slides for autoradiography were processed in order to visualize the hybridized signals.

Immunohistochemical methods were performed to map cell groups with FOS positive nuclei. Test Example 10: Vogel Conflict Test in the Rat

The method followed that described in Psychopharmacol., 21, 1-7 (1971) with a slight modification.

Male Wistar rats (160-200 g) were deprived of water for 48 hours before the test session consisting of a period of 5 minutes. Then, each rat was placed in a test box (25 x 30 x 25 cm). The rats were allowed to explore at the waterhole to drink water. When the rat drank a drop of water, the electric current (0.16 mA, duration of 0.2 seconds) was supplied from the floor grid. The number of downloads taken in the punishment session of the 5-minute trial was measured.

The test compound or vehicle was administered orally 60 minutes before the test, respectively.

Results:

Table 7 shows the effect of Compounds C and D on the Vogel Clonflict Assay in the rat. Compound D is a reference compound.

Compounds C and D significantly increased the number of discharges (Compound C: + 118.8%, Compound D: + 89.5%) to 1 mg / kg.

Data were analyzed by comparing the result of a group tested with that of a vehicle control group using a Student's t-test for unrelated samples.

Table 7

TREATMENT (mg / kg) oral -60 min

NUMBER OF DOWNLOADS

mean ± e.t.m.

P value change of control

vehicle

4.8 ± 1.3 - -

Compound C (1)

10.5 ± 2.1 * 0.029 + 118.8%

vehicle

5.7 ± 0.8 - -

Compound D (1)

10.8 ± 1.6 * 0.021 + 89.5%

*: p <0.05

Among the tests described above, the board test Holes (Test Examples 1 and 6) is a model of anxiety disorder, 5 especially for TAG [Eur. J. Pharmacol., 350, 21-29 (1998); and Pol. J.

Pharmacol., 49, 79-84 (1997)].

The marble burial trial (Test examples 2 and 7) is a model of anxiety disorder, especially for OCD [Jpn. J. Pharmacol., 68, 65-70 (1995)].

10 Learned helplessness (Test Example 3) is a model of anxiety disorder, especially for PTSD [Green et al. In: Behavioral models in psychopharmacology: theoretical, industrial, and clinical perspectives, Cambridge University Press, p.21-49 (1991); and Ann. NY Acad. Sci., 821, 332351, (1997)].

15 The cross-raised labyrinth trial (Test Examples 4 and 8) is a model of anxiety disorder, especially for GAD, panic disorder, agoraphobia and specific phobia [Psychopharmacol., 161, 314-323 (2002); Jpn J. Psychopharmacol., 15, 125-133 (1995), and Pol. J. Pharmacol., 49, 7984 (1997)].

20 The social interaction trial (Test Example 5) is a model of anxiety disorder, especially for GAD and social phobia [Physiol. Behav., 71, 551-557 (2000)].

The Vogel conflict test (Test Example 10) is a model of anxiety disorder, especially for GAD [Eur. J. Pharmacol., 463, 25 67-96 (2003)]. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 represents the effects of Compound A on defenselessness

learned (LH) in the rat.

Each column represents the average proportion (± ETM) of the escape response (behavior directed to the escape; bars with points) and the interensay response (general motor activity; bars with plot) during the

5 FR2 test.

## means p <0.01 against the Normal group and * y ** means p <0.05 and p <0.01 against the Cont-IES group, respectively (n = 10). BEST MODES FOR CARRYING OUT THE INVENTION

In the following examples some embodiments of the present invention are described. Example 1: Tablets Tablets were prepared, in a conventional manner, with the following composition. Compound A (40 g) was mixed with 286.8 g of lactose and 60 g of

15 potato starch, followed by the addition of 120 g of a 10% aqueous solution of hydroxypropyl cellulose. The resulting mixture was kneaded, granulated, and then dried by a conventional method. The granules were refined to provide granules used to prepare tablets. After mixing the granules with 1.2 g of magnesium stearate, the mixture formed

20 in tablets each containing 20 mg of the active ingredient using a compressor (Model RT-15, Kikusui) with 8 mm diameter mortar mallets.

The prescription is shown in Table 8.

Table 8 Lactose Compound Potato Starch Hydroxypropyl Cellulose Magnesium Stearate

Example 2: Capsules 20 mg 143.4 mg 30 mg 6 mg 0.6 mg 200 mg

Capsules were prepared, in a conventional manner, with the following

composition.

Compound A (200 g) was mixed with 995 g of Avicel and 5 g of

magnesium stearate. The mixture was introduced into hard capsules No. 4, each with a capacity of 120 mg, using a capsule loader (Model LZ-64, Zanashi) to provide capsules each containing 20 mg of the active ingredient.

5 The prescription is shown in Table 9.

Table 9 Compound A 20 mg Avicel 99.5 mg Magnesium Stearate

0.5 mg 200 mg

Example 3: Injections Injections were prepared in a conventional manner with the following composition. Compound A (1 g) was dissolved in 100 g of purified soybean oil,

10 followed by the addition of 12 g of egg yolk lecithin and 25 g of glycerin for injection. The resulting mixture was taken up to 1,000 ml with distilled water for injection, carefully mixed and emulsified by a conventional method. The resulting dispersion was subjected to aseptic filtration using 0.2 µm disposable membrane filters and then introduced

Aseptically in glass vials in 2 ml parts to provide injections containing 2 mg of the active ingredient per vial. The prescription is shown in Table 10.

Table 10 Compound A 2 mg Purified Soybean Oil 200 mg Purified Egg Yolk Lecithin 24 mg Glycerin for injection 50 mg Distilled Water for injection

1.72 mg 2.00 ml

Example 4: Tablets Tablets were prepared, in a conventional manner, with the following composition. Compound A (20 g) and sertraline (20 g) were mixed with 286.8 g of

lactose and 60 g of potato starch, followed by the addition of 120 g of a 10% aqueous solution of hydroxypropyl cellulose. The resulting mixture was kneaded, granulated, and then dried by a conventional method. The granules were refined to give granules used to prepare tablets.

5 After mixing the granules with 1.2 g of magnesium stearate, the mixture was formed into tablets, each containing 10 mg of Compound A and 10 mg of sertraline, using a compressor (Model RT-15, Kikusui) with 8 mm diameter mortar mallets.

The prescription is shown in Table 11.

Table 11

Compound A 10 mg

Sertraline 10 mg

Lactose 143.4 mg

Potato Starch 30 mg

Hydroxypropyl Cellulose 6 mg

Magnesium Stearate 0.6 mg 200 mg

10

Claims (6)

1. The use of an A2A adenosine receptor antagonist selected from the group consisting of:

(i)

 (E) -8- (3,4-dimethoxystyryl) -1,3-diethyl-7-methylxanthine (Compound A)

(ii)

 (E) -1,3,7-trimethyl-8- (3,4,5-trimethoxystyryl) xanthine (Compound B)

image 1 image 1 (iii) 5-amino-2- (2-furyl) -7- [4- (3-hydroxy-3-methylbutyl) piperazinyl] [1,2,4] triazolo [1,5-c] pyrimidine (Compound C) image 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of an anxiety disorder. 2. The use according to claim 1 wherein the A2A adenosine receptor antagonist is (E) -8- (3,4-dimethoxystyryl) -1,3-diethyl-7-methylxanthine or a pharmaceutically acceptable salt thereof. 3. The use according to claim 1 or 2, wherein the anxiety disorder is generalized anxiety disorder. 4. The use according to any one of claims 1 to 2, in the anxiety disorder is selected from the group consisting of panic disorder, agoraphobia, obsessive compulsive disorder, social phobia, post-traumatic stress disorder and specific phobia . 5

5.

An A2A adenosine receptor antagonist as defined in claim 1 or 2 for use in the treatment of an anxiety disorder.

6.

The A2A adenosine receptor antagonist according to the

10 claim 5, wherein the anxiety disorder is generalized anxiety disorder. 7. The A2A adenosine receptor antagonist according to claim 5, wherein the anxiety disorder is selected from the group 15 consisting of a panic disorder, agoraphobia, obsessive compulsive disorder, social phobia, post-traumatic stress disorder and specific phobia.