MXPA06005965A - Preventive and/or therapeutic agent for higher brain dysfunction - Google Patents

Abstract

A preventive and/or therapeutic agent for higher brain dysfunctions which contains as an active ingredient a xanthane derivative represented, for example, by the following formula (I) or a pharmacologically acceptable salt thereof:(I) (II) wherein R1, R2, and R3 are the same or different and each represents hydrogen, lower alkyl, lower alkenyl, or lower alkynyl;R4 represents cycloalkyl, -(CH2)n-R5, or the formula (II) given above;and X1 and X2 are the same or different and each represents oxygen or sulfur.

Description

AGENTS TO PREVENT AND / OR TREAT HIGH BRAIN DYSFUNCTIONS FIELD OF THE INVENTION The present invention generally relates to agents for preventing and / or treating high cerebral dysfunctions comprising, as an active ingredient, a xanthine derivative or a pharmaceutically acceptable salt thereof.

Background of the invention The high cerebral dysfunctions in general mean that high cerebral functions to execute the daily life, such as memory, thought, recognition, action, learning, language and attention, are harmed by cerebral deteriorations due to several causes. Examples of these include brain dysfunction caused by brain impairment due to illness, accident or aging, such as (1) hemispatial negligence (visual perception defects characterized by deterioration to be noticed in the middle of the space while patients are aware of observing the total space); (2) aphasia (Wernicke's aphasia (fluent aphasia), Brocka's aphasia (non-fluent aphasia), defect or loss of language function that includes "speech, hearing, learning or Ref.:173034 writing "relative to the comprehension or expression of words; (3) apraxia (ideokinetic apraxia, ideomotor apraxia; impairments characterized by difficulties in executing the deliberate movement and action, or the movement of accusation and action even though their hands and legs can be moved); (4) agnosia (asomatognosia (anosognosia); imbalances in the recognition of the body, for example, in which the patient does not recognize their own body parts, considering parts of the body lost, or not recognizing positively the event of paralysis, visual agnosia, prosopagnosia, auditory agnosia, a loss of ability to recognize which is the object despite the ability to identify it visually, auditory or tactile elements), (5) memory impairments (amnesia, impairments characterized by difficulties in memory and learning (particularly difficulty in memory of new things)); (6) executive dysfunction (impairment) characterized by difficulties in carrying out activities, that is, information arrangements, planning, consideration of a process and practice); (7) aprosexia (decreased attention and ability to concentrate); (8) emotional behavior and impairments (referring to states such as excitement in insignificant things and acting impulsively, panic in an attack of surprising anxiety, and decreasing spontaneity in reverse) [see; Merck Manual, 17th edition, section 169, Total Rehabilitation, vol.11, p. 605-608 (1983); Shin Seirikagaku taipei (A Survey of New Physiological Science) 12, p.1-5 (1988), edited by Toshio Suzuki, Igaku-Shoin Ltd.]. Diseases that cause lesions in the brain which are causes of high brain dysfunctions, for example, trauma to the head (eg, extradural hematoma, subdural hematoma, cerebral contusion, intracerebral hemorrhage, etc.), cerebrovascular accidents (eg. ., intracerebral hemorrhage, cerebral infarction, cerebral apoplexy, hypoxic encephalopathy, subarachnoid hemorrhage, moyamoya disease, etc.), infections (eg, encephalitis, AIDS encephalopathy, etc.), autoimmune diseases (eg systemic lupus erythematosus, nervous disease from Beh? et, etc.), toxic diseases (eg, alcoholism, carbon monoxide poisoning, drug abuse, etc.) brain tumor, and the like. On the other hand, many of the xanthine derivatives including the compound represented by the formula (I) which will be described later have been known to have, for example, anti-Parkinsonian action, exciting action of the central nerve, suppressive action in neurodegeneration, and similar (referring to Japanese Examined Publication of Patent Application No. 26,516 / 1972; Japanese Unexamined Publication of Patent Application No. 211,856 / 1994; Japanese Unexamined Publication of Patent Application No. 239,862 / 1994; Japanese Unexamined Publication of Patent Application No. 016,559 / 1994; WO 99/12546 etc.). They are also known to have antagonistic action towards the adenosine A2 receptor, antidepressant action, anti-asthma action, surprising action for bone resorption, hypoglycemic action, suppressive action towards thrombocytosis, and the like [WO92 / 06976, WO94 / 01114, W095 / 23165 , W099 / 35147; Journal of Medicinal Chemistry (J.Med.Chem.), Vol.34, p.1431 (1991); Journal of Medicinal Chemistry (J.Med.Chem.), Vol.36, p.1333 (1993)].

BRIEF DESCRIPTION OF THE INVENTION An object of the present invention is to provide agents for preventing and / or treating high cerebral dysfunction comprising, as an active ingredient, for example, a xanthine derivative or a pharmaceutically acceptable salt thereof, and the like. The present invention relates to the following (1) to (14). (1) An agent for preventing and / or treating high cerebral dysfunction comprising, as an active ingredient, a xanthine derivative represented by the formula (I): [wherein R1, R2 and R3 are the same or different, and represent a hydrogen atom, lower alkyl, lower alkenyl or lower alkynyl; R4 represents cycloalkyl, - (CH2) n -R5 (in which R5 represents substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group, and n represents an integer from 0 to 4) or a group represented by formula (II) : (in which Y1 and Y2 are the same or different, and represent a hydrogen atom, halogen or lower alkyl); and Z represents substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group); X1 and X2 are the same or different, and represent an oxygen atom or a sulfur atom] or a pharmaceutically acceptable salt thereof. (2) The agent for preventing and / or treating high cerebral dysfunction according to the above (1), in which X1 and X2 each is an oxygen atom. (3) The agent for preventing and / or treating high cerebral dysfunction according to that of above (1) or (2), wherein R4 is a group represented by formula (II): (in which Y1, Y2 and Z each have the same meanings as defined above). (4) The agent for preventing and / or treating high cerebral dysfunction according to the above (3), in which Y1 and Y2 are both hydrogen atoms. (5) The agent for preventing and / or treating high dysfunction according to those above (3) or (4), wherein Z is substituted or unsubstituted aryl or a group represented by the formula (III): (in which R6 represents a hydrogen atom, hydroxy, lower alkyl, lower alkoxy, halogen, nitro or amino, and m represents an integer from 1 to 3). (6) The agent for preventing and / or treating high cerebral dysfunction according to any of the above (1) to (5), in which the cerebral dysfunction is a high cerebral dysfunction caused by brain damage. (7) The agent for preventing and / or treating high cerebral dysfunction according to the above (6), in which the brain damage is brain damage due to aging. (8) The agent for preventing and / or treating high cerebral dysfunction according to the above (6), in which the brain damage is brain damage due to disorder selected from the group consisting of head trauma and stroke . (9) The agent for preventing and / or treating high cerebral dysfunction according to any of the above (1) to (8), in which the high cerebral dysfunction is a deterioration of the high brain function selected from the group which consists of memory, thought, recognition, action and learning. (10) The agent for preventing and / or treating high cerebral dysfunction according to any of the above (1) to (8), in which the high cerebral dysfunction is a cerebral dysfunction selected from the group consisting of agnosia, amnesia and apraxia. (11) The agent to prevent and / or treat high cerebral dysfunction according to any of the above (1) to (8), in which the high cerebral dysfunction is a deterioration in memory. (12) The agent for preventing and / or treating high cerebral dysfunction according to any of the above (1) to (8), in which the high cerebral dysfunction is a deterioration in learning. (13) A method for preventing and / or treating high cerebral dysfunction which comprises administering an effective amount of xanthine derivative represented by formula (I): [wherein R1, R2, R3, R4, X1 and X2 each have the same meanings as defined above] or a pharmaceutically acceptable salt thereof. (14) Use of a xanthine derivative represented by the formula (I): [wherein R1, R2, R3, R ^ X1 and X2 each have the same meanings as defined above] or a pharmaceutically acceptable salt for the preparation of an agent to prevent and / or treat high cerebral dysfunction. In the present invention, "high cerebral dysfunctions" means that "high cerebral dysfunctions to develop daily life, such as memory, thinking, recognition, action, learning, language and attention, are damaged by brain injuries due to various causes". In particular, examples of those that include "high brain dysfunction" caused by "brain deterioration" due to illness, accident or aging. More especially, examples of those that include high brain dysfunction caused by brain deterioration due to illness, accident or aging, such as (1) hemispatial negligence; (2) aphasia (Wernicke's aphasia (fluent aphasia), Broca's aphasia (non-fluent aphasia) and the like); (3) apraxia; (4) agnosia (somatagnosia (anosognosia), visual agnosia, prosopagnosia, auditory agnosia and the like); (5) memory impairments (amnesia and the like); (6) dysfunctions to perform activities; (7) aprosexia; and (8) emotional and behavioral impairments. Diseases that cause "brain injuries" which are causes of these brain dysfunctions including, for example, head trauma (eg, extradural hematoma, subdural hematoma, cerebral contusion, intracerebral hemorrhage, etc.), cerebrovascular accidents ( eg, intracerebral hemorrhage, cerebral infarction, cerebral apoplexy, hypoxic encephalopathy, subarachnoid hemorrhage, moyamoya disease, etc.), infections (eg, encephalitis, encephalopathy AIDS, etc.), autoimmune diseases (eg, lupus erythematosus) systemic, Beh? et nerve disease, etc.), toxic diseases (eg, alcoholism, carbon dioxide poisoning, drug abuse, etc.), brain tumor, and the like. In particular, "impairments of high cerebral functions" which can be prevented and / or treated in an appropriate manner by agents to prevent and / or treat high cerebral dysfunctions of the present invention include, for example, impairments of memory, thinking, action, learning and the like, and functions combined with one or more of them, that is, recognition, knowledge, execution and the like. Among them, one or more of the impairments of high brain functions selected from impairments of memory, thought, action, learning, recognition, knowledge and execution may be preventable and / or treated.

In addition, in particular, the "high cerebral dysfunctions", which can be prevented and / or adequately treated by agents to prevent and / or treat high cerebral dysfunctions of the present invention, including "high cerebral dysfunctions" caused by "brain lesions" due to illness, accident or aging as described above. Among them, hemispatial negligence, apraxia, agnosia, deterioration in memory, impairments in learning, dysfunctions to perform activities and they can be adequately prevented and / or treated. In the definition of each group in the formula (I): Examples of lower alkyl and the lower alkyl portion of lower alkoxy include straight or branched chain alkenyl groups having from 1 to 6 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl. Examples of lower alkenyl include straight or branched chain alkenyl groups having from 2 to 6 carbons, such as vinyl, allyl, methacryl, crotyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl and 5-hexenyl.

Examples of lower alkynyl include straight chain alkenyls or branched chain groups having from 2 to 6 carbons, such as ethynyl, propargyl, 2-butynyl, 3-butynyl, 2-pentynyl, 4-pentynyl, 2-hexynyl, 5- Hexynyl and 4-methyl-2-pentynyl. Examples of cycloalkyl include cycloalkyl groups having from 3 to 8 carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Halogen means a fluorine, chlorine, bromine and iodine atom. Examples of aryl include those having 6 to 14 carbons, such as phenyl, naphthyl and anthryl. Examples of the heterocyclic group include 5- or 6-membered monocyclic heterocyclic groups containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom; bicyclic or tricyclic fused ring heterocyclic groups containing at least one atom selected from a nitrogen atom, - an oxygen atom and a sulfur atom in which 3- to 8-membered rings are fused and the like. Specific examples of these include, in particular, furyl, thienyl, pyrrolyl, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, triazinyl, purinyl, pyrazinyl, pyridazinyl, benzimidazolyl, 2-oxobenzozidazolyl, benzotriazolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, 1, 3 -benzodioxolyl, 1,4-benzodioxanyl, 3,4-dihydro-2H-1, 5-benzodioxepinyl, indazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, naft iridinyl, quinoxalinyl, pyrazolyl, quinazolinyl, cinnolinyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothizaolyl, dihydroisoquinolyl, tetrahydroquinolyl and hydrobenzopyranyl. The substituted aryl and the substituted heterocyclic group have from 1 to 3 substituents which are the same or different, such as lower alkyl, lower alkenyl, lower alkynyl, hydroxy, substituted or unsubstituted lower alkoxy, halogen, nitro, amino, lower alkylamino , di-lower alkylamino, trifluoromethyl, trifluoromethoxy, aralkyl, aralkyloxy, aryl, aryloxy, lower alkanoyl, lower alkanoyloxy, aroyl, aroyloxy, arylalkyloxyloxy, carboxy, lower alkoxycarbonyl, lower alkylcarbamoyl, lower di-alkylcarbamoyl, sulfo, lower alkoxysulfonyl, lower alkylsulfamoyl and di-lower alkylsulfamoyl. The lower alkyl portion of the lower alkyl described above, lower alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyl, lower alkanoyloxy, lower alkoxycarbonyl, lower alkylcarbamoyl, lower di-alkylcarbamoyl, lower alkoxysulfonyl, lower alkylsulfamoyl, and lower di-alkylsulfamoyl have the same meaning as described above of lower alkyl. Halogen, lower alkenyl and lower alkynyl have the same meanings as described above in this regard. Two lower alkyl portions of di-lower alkylamino, the lower di-alkylcarbamoyl and the lower di-alkylsulfamoyl may be the same or different. A portion of the aryl of the aryl and the aryloxy is the same as the aryl described above, and examples of the aralkyl portion of the aralkyl and the aralkyloxy include benzyl, phenethyl and the like. Examples of an aroyl portion in the aroyl and the aroyloxy include benzoyl, naphthoyl and the like. Examples of an arylalkyl portion of arylalkyloxy are benzyl, phenethyl and the like. Examples of the substituent (s) in the substituted alkoxy include hydroxy, lower alkoxy, halogen, amino, azido, carboxy, lower alkoxycarbonyl, and the like. In this, a lower alkyl portion of the lower alkoxy and the lower alkoxycarbonyl has the same meaning as the lower alkyl described above, and the halogen has the same meaning as described above. After this, a compound represented by the formula (I) will be referred to as Compound (I). Examples of the pharmaceutically acceptable salt of Compound (I) are acceptable pharmaceutical salts with addition of acid, metal salt, ammonium salt, salt with addition of organic amine, salt with addition of amino acid and the like. Examples of acceptable pharmaceutical salts with addition of compound (I) include an inorganic acid salt such as chloride, sulfate and phosphate; and an organic acid salt such as acetate, maleate, fumarate, tartrate, citrate and methanesulfonate. Examples of the pharmaceutically acceptable metal salts include an alkali metal salt such as sodium salt and potassium salt; alkaline earth metal salt such as magnesium salt and calcium salt; aluminum salt; zinc salt and the like. Examples of acceptable pharmaceutical ammonium salts include ammonium and tetramethylammonium. Examples of the pharmaceutically acceptable salt with addition of organic mine include an addition of morpholine salt or piperidine. Examples of acceptable pharmaceutical salts with addition of amino acid include an addition of lysine, glycine or phenylalanine. The compound (I) is capable of being produced by a process disclosed in Japanese Publication Examined from Patent Application No. 26,516 / 1972; Journal of Medicinal Chemistry (J. Med. Chem.), Vol.34, p.1431 (1991); Journal of Medicinal (J.Med.Chem.), Vol.36, p. 1333 (1993); WO 92/06976; Japanese Unexamined Publication of Patent Application No. 211, 856/1994; Japanese Unexamined Publication of Patent Application No. 211,856 / 1994; WO 95/23165; Japanese Unexamined Publication of Patent Application No. 16559/1994; WO 94/01114; WO 99/12546; WO 99/35147 and the like, or by a process similar to this. The desired compound in each production process can be isolated and purified by a purification method which has been commonly used in synthetic organic chemistry such as filtration, extraction, washing, drying, concentration, recrystallization and various chromatographies. When it is desired to obtain a salt of Compound (I), in the case in which Compound (I) is produced in the salt form, it can be purified like this, but in which it is produced in its free form, This can be converted into a salt, after being dissolved or suspended in an appropriate solvent followed by the addition of an appropriate acid or base. In addition, Compound (I) and acceptable pharmaceutical salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also used as the agents for preventing and / or treating high cerebral dysfunctions of the present invention. For some Compounds (I), optical isomers and the like may exist, and all possible isomers including them and mixtures thereof may be used as the agents for preventing and / or treating high cerebral dysfunctions of the present invention. Specific examples of Compound (I) are shown in Table 1.

Table 1 Compound No, The effect of the present invention will be explained by the following Test Examples.

Test Example 1: Test for active avoidance learning The experiment was carried out using 10 SD male rats (body weight: 220-280 gr) for a group. Using a transfer box apparatus consisting of two boxes (TK-401s; Unicom), the rats were prepared to learn and train (escape training) behavior conditioned to avoidance. In a test in the escape training, an alarm stimulus for light and ringing sound as a conditioned stimulus was given to the rats for 8 seconds. When the rat does not move inside to the next box in 4 seconds from the start of the alarm stimulus (avoidance behavior by alarm stimulus), an unconditioned stimulus was given to the rat by an electric current flow of 3 mA in the floor grid for 4 seconds (reinforcement learning factor). The test is repeated at time intervals of 5 seconds, and the escape training was repeated 50 tests / l training / 1 day p.or - 10 days. The test compound was used as a suspension in injectable distilled water containing 0.3% Tween-80 (by Otsuka Pharmaceutical Co., Ltd., solution 0.3% Tween-80) and orally administered to each of the rats at a time. dose of 10 mL / kg 1 hour before the test (Group administered with the test compound). Separately, a 0.3% T een-80 solution was administered orally to each of the rats at a dose of 10 mL / kg 1 hour before the test (group administered with solvent). For analysis of the results of the test, several parameters were entered into a personal computer (NEC, PC-982lXe) and the avoidance speed (%) (average in 10 rats, the rats which took avoidance behavior by a stimulus of alarm was observed as a successful escape, the avoidance speed when the rat is successful in escaping all 50 tests was observed as 100%) and the reaction timeout change (the time required for completion of the total test ) were compared with those of the group administered with solvent. The analysis was carried out by a resolution test. Table 2 shows the results. Table 2 Resolution test: * ~ p < 0.05; ** = p < 0.01 From the results above, the following ones become clear. In the group administered with compound, the avoidance avoidance speed was greater than the group administered with solvent (90.8%). In addition, in Compound 2 (3.0 mg / kg) of the administered group, the rate of withdrawal increased significantly (p <0.01, resolution test). On the other hand, in the group administered with Compound-2, the total test was completed within a shorter period of time than that of the group administered with solvent (99.1 seconds). In the group administered with compound 1 (0.3 mg / kg) and the group administered with Compound 1 (3.0 mg / kg), the time required for the completion of the total tests was significantly reduced (p <0.05 and p < 0.01, in this respect, resolution test). Test Example 2: Passive avoidance learning test The experiment was carried out using 32 female albino rats (body weight: around 100 gr) for a group. Test for passive avoidance learning was conducted in a test box (40 cm x 31 cm x 29 cm) in which a stainless steel grid was extended on the floor in such a way that an electrical shock of 1.1 mA was given in a manner random In the test box, a plastic tray (15 cm x 5 cm) of 0.5 cm thickness was placed in a corner to cover the floor; and the test box comprises a mechanism that when a rat placed on the plate walks on the floor grid, the rat receives an electric shock. Normally, the rat that receives an immediate electric shock gets from the plastic tray but leaves the tray; then the rat is again given an electric shock. Normally, the rat gradually changes its behavior with repetition of the shock (learning and training), and at the end it remains in the plastic tray (passive avoidance behavior). After the training and learning, the rats that maintained the memory were selected and used for the test based on memory maintenance test as mentioned above. Each of the rats was placed in the plastic tray, and from this time as in the initial point, (1) in the case that the rat left the tray in 60 seconds and (2) in the case in which the rat did not resist to leave by delicate thrust after a lapse of 60 seconds, the rat was judged not to maintain learning memory for passive avoidance behavior. The test compound was used as a suspension thereof in distilled water containing 0.3% T een-80; A scopolamine was used as a solution thereof in distilled water (by Sigma). For each of the rats which learned the passive avoidance behavior, immediately after the learning, 1 mgr / kgr (2 mL / kgr volume) of scopolamine (subcutaneous administration) was administered simultaneously (group administered with the test compound ); and 2 hours after administration, the rats were evaluated if they maintained the learning memory of passive avoidance behavior. Separately, each of the rats that learned the passive avoidance behavior, immediately after learning, 2 mL / kg of solution volume 0.3% Tween-80 was only administered orally, and the rats were referred to as a group administered with solvent; while in the same way, each of the rats administered with 1 mgr / kg of scopolamine (2mL / kg volume) subcutaneously, were referred to a group of scopolamine administered. The results of the test were analyzed by means of the two-tailed Chi-square test comparing the speed of the rats exhibiting the passive avoidance behavior with that of the group administered with scopolamine. Table 3 shows the results. . Table 3 Two square test washings Chi; * = p < 0.05 From the results above, the following is clear. In a group administered with scopolamine whose damage to the memory process was caused by administration of scopolamine, the speed of the rats showing the passive avoidance behavior was markedly diminished in comparison with that of the group administered with solvent. On the other hand, in the group to which Compound 2 was simultaneously supplied with scopolamine (group administered with test compound), the speed of the rats exhibiting passive, avoidance behavior was increased significantly compared to that of the administered group with scopolamine (p <0.05: two-tailed Chi-square test).

Example test 3: Labyrinth learning test in rats prepared by bilateral ligation of the common carotid arteries The test was carried out according to the methods described in the following references. (1) Minutes. Neuropathol. 87, p.484-492 (1994) (2) Brain Res., Vol. 729, p.55-65 (1996) (3) Neuroscience, vol. 79, p. 1039-1050 (1997) (4) Nicho-yakuri-shi, vol.113, p.85-95 (1999) (5) Stroke, vol.26, p.1415-1422 (1995) (6) Non-shinkei , vol.49, p.639-644 (1997) (7) Jpn. J. Pharmacol., Vol. 75, p.443-446 (1997) The experiment was carried out using 10 female Wistar rats (body weight 210-310 gr) per group. Under anesthesia with pentobarbital, the necks of the rats were cut and the common carotid bilateral arteries were ligated (bound rats). Separately, the necks of the rats were cut but the common carotid bilateral arteries were not ligated (sham operation of rats). Under anesthesia with pentobarbital, the rat was placed in an apparatus to fix the brain of the rat (Nasishige; SR-6). Hydrogen electrodes (Unique Medical; UHE-100, IS needle type) were inserted into a brain coordinate (A2.0, L2.0, D-2.0). Indifferent hydrogen electrode (Unique Medical) was placed in the neck of the rats. Artificial respiration was applied to the rat through a respiratory device (Shinano Seisakusyo; SN-480-7), through which about 40 L of hydrogen gas was inhaled by force 2 or 3 times at intervals of about 15 minutes. In the labyrinth learning test, a grayish radial labyrinth of vinyl chloride was used. The labyrinth was placed 50 cm above the floor and constituted of 8 radially extended paths (12 cm x 60 cm) and a central platform, in which a hole (3 cm in diameter, 1 cm deep) was placed in each end of the path and milk was placed as a reward. The run the maze learning test was developed twice. In the first run, the reward milk was placed in all the gaps of the 8 lanes, among which 4 lanes were blocked by blocks in such a way that the rat did not enter the lanes. In the first run, the rat was able to enter the labyrinth freely. When the rat returned to the platform after obtaining 4 milk holes it was restricted by a cylinder placed on the platform, during which the blocks on the 4 paths were removed. Ten seconds after the rat was restrained, the cylinder was removed and the second run was developed. In the second run, the rat was able to obtain milk placed in the hollows of the 4 remaining paths. At the same time, the frequency of the selection of the paths required to obtain the 4 milk hollows was registered until the run 16 of the selection was completed. The labyrinth learning test was initiated 4 weeks after bilateral ligation of the common carotid arteries. The first run and the second run were conducted as a single test; and the training of 2 tests was done at intervals of around 15 minutes and for 10 consecutive days. The average frequency of selection in the first and second tests was observed as a learning result. The paths in which the blocks were placed in the first run were determined according to each rat and were kept constant during the test period. The test compound was used as a suspension thereof in distilled water for injection with 0.5% methylcellulose (MC) (Otsuka Pharmaceutical Co.) and was administered orally for each of the rats bound at a dose of 10 mL / kgr. volume one hour before the start of the first test (group administered with the test compound). Separately, to each of the rats with operation In contrast, each of the bound rats, 0.5% MC solution alone, was administered orally at a dose of 10 mL / kg volume one hour before the start of the first test., respectively, and were referred for fake operation of group and group of administered with solvent, respectively. The results of the tests were analyzed by Bonferroni-type multiple test procedures by comparing the frequency of path selection (Frequency of path selection) required to obtain 4 milk gaps in the second run of the learning test of labyrinth in the group administered with solvent. Figure 1 shows the results. From the above mentioned results, the following is clear. In the group administered with solvent, the path selection frequency increased significantly compared to the group with fake operation, indicating a decrease in the learning result (p <; 0.01; Bonferroni type multiple test procedures). In the group administered with the compound to which Compound 1 was administered (1 mg / kg) and Compound 1 (3 mg / kg) respectively, decreased learning results caused by bilateral ligation of the common carotid arteries improved significantly , respectively (p < 0.025 &p < 0. 005; Multiple test procedures type Bonferroni).

Test Example 4: Test for learning of an alternate problem postponed (non-corresponding to sample) The test was carried out in a manner similar to the method as described in Drug Dev. Res., 35, p.83-95 (1996).

The experiment was carried out using 10 male Wistar rats (Han) (body weight 200-250 gr) for a group. We used a Skinner box (30 cm x 25 cm x 30 cm) equipped with 3 effort-type levers (center, left and right sides) connected to a feeding container (supplying 45 mgr of diet pellets). The control of the test condition and the accumulation of data were automatically conducted when connecting to a MED program system. PC Each rat received learning and effort lever training, and from there on learning and training the alternative problem postponed. In the learning and training of the effort lever, the rat learned and was trained in such a way that the diet could be obtained by pushing from any center, left and right effort type levers. In the subsequent learning and training of the postponed alternate problem, the rat learned and was trained so that the diet could be obtained by thrusting first of any left and right lever, and then the pushed lever was removed; then, 5 seconds later, both levers left and right were presented, but the diet was only provided when the opposite side of the push lever was pushed forward. The time of presentation of each lever was set at 20 seconds, and if the rat did not push the lever within the time, the lever was removed, and the subsequent test started 10 seconds after it. The test compound was used as a suspension thereof in distilled injectable water containing 0.5% methylcellulose (MC) (Outsuka Pharmaceutical Co.) And was administered orally for each of the rats that learned and trained the lever by pushing a dose of 10 mL / kgr volume once a day from the beginning of learning and training of an alternative problem postponed continuously for a week (group administered with the test compound). Separately, to each of the rats which learned and trained the pushed lever, 0.5% MC of solution alone was administered orally at a dose of 10 mL / kgr volume once a day from the beginning of the learning and training of an alternate problem postponed continuously for 1 week, and the rats were referred to as a group administered with solvent. The accuracy of the speed for the reaction was indicated by the speed (%) of the left and right lever selected correctly (average of 10 rats), and the results of the test were analyzed by an ANOVA student test manner. Table 4 shows the results. Table 4 Student test: NS = not significant; * = p < 0.05; ++ = p < 0.01 Of the above mentioned results, the following is clear. In the postponed alternate problem test, the accuracy of the rate for the reaction of the group administered with compound-2 increased significantly compared to that of the group administered with solvent. The speed accuracy for the reaction after one week (Speed accuracy for the speed reaction in one week) increased significantly to 50.6 ± 1.5 (%) in contrast to the group administered with solvent 45.4 + 1.6 (%). From the results of the Test examples of Examples 1 to 4 as mentioned above, it was elucidated that compounds (I) or pharmaceutically acceptable salts thereof have effects of improvement and / or increase in high brain functions such as memory , learning, thinking, action, cognition, recognition and execution. In other words, it was shown that compounds (I) or pharmaceutically acceptable salts thereof are useful as agents for preventing and / or treating high cerebral dysfunctions (e.g., hemiespatial negligence, apraxia, agnosia, memory impairment, learning impairment, dysfunctions to perform activities and the like, caused by brain injuries due to diseases, accidents or aging). Compound (I) or a pharmaceutically acceptable salt thereof can be used as is or in various pharmaceutical dosage forms. The pharmaceutical composition of the present invention can be worked up by a uniform mixing of Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient in an effective dose with a pharmaceutically acceptable carrier. It is preferred in such a way that a pharmaceutically acceptable composition is in a convenient unit dosage form for administration such as rectal or oral administration or parenteral administration (including subcutaneous, intravenous and intramuscular). In the preparation of a composition in an orally administered form, any pharmaceutically acceptable useful carrier can be used. In the case of an oral liquid preparation such as a suspension and syrup, it can be made using water, saccharide such as sucrose, sorbitol and fructose, glycol such as polyethylene glycol and propylene glycol, oil such as sesame oil, olive oil and soybean oil, antiseptic agent such as p-hydroxybenzoate, flavoring such as strawberry and mint flavor, etc. In the case of diluted powder, pill, capsule and tablet, this can be prepared using excipient such as lactose, glucose, sucrose and mannitol, disintegrating agent such as starch and sodium alginate, lubricant such as magnesium stearate and talc, binders such such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin, surfactant such as fatty acid ester, plasticizers such as glycillin, and the like. Tablets and capsules are the most useful agents being administered per os because their administration is easy. In the manufacture of tablets and capsules, a solid pharmaceutical carrier is used.

Injection preparations can be prepared using a carrier comprising distilled water, salt solution, glucose solution or a mixture of brine and glucose solution, or the like. In this case, it is prepared as a solution, suspension or dispersion using an appropriate adjuvant according to the conventional method. The compound (I) or a pharmaceutically acceptable salt thereof can be administered orally in the pharmaceutical dosage form described above or parenterally as injections. Although the effective dose and frequency of administration of this varies depending on the form of administration, age and body weight of a patient, symptom, etc., this is appropriate to administer 1 to 100 mg / 60 kg / day or, preferably , 1 to 20 mg / 60 kgr / day once a day or several times a day. Brief description of the figures Fig. 1 shows the effect of compound 1 on the labyrinth learning test in rats prepared by bilateral ligation of the common carotid arteries. The ordinate indicates the frequency of the path selection (Frequency selection of the lanes) required to obtain the 4 milk gaps in the second run in the maze learning test. The abscissa indicates the number of days elapsed (days) after the start of the test. Each path in the graph has the following meanings. ~: Feigned operation group -0-: Group administered with solvent -? - .- (1 mgr / kgr) -group administered with Compound 1 -D-: (3 mg / kg) -group administered with Compound 1 Best method for carrying out the invention The embodiments of the present invention are illustrated in detail below referring to the examples. Example 1: Tablets Tablets comprising the following composition are prepared by a conventional method. Compound 1 (40 gr), 286.8 gr of lactose and 60 g of potato starch are mixed and 120 g of 10% of an aqueous solution of hydroxypropyl cellulose is added to it. The mixture is kneaded by a conventional method, granulated, dried and subjected to selection of particle size to give granules for processing into tablets. Magnesium stearate (1.2 g) is added to it and mixed together and subjected to rattling using a tabletting machine (RT-15 made by Kikushisha) that has drills with 8 mm diameter to make tablets (each tablet contains 20 mgr of ingredient active) .

Prescription Compound 1 20 mgr Lactose 143.3 mgr Potato starch 30 mgr Hydroxypropyl cellulose 6 mgr Magnesium stearate 0.6 mgr 200 mgr Example 2: Capsule preparations Capsule preparations comprising the following composition are prepared by a conventional method. Compound 2 (200 g), 995 g of Avicel and 5 g of magnesium stearate are mixed by a conventional method. The mixture is filled into hard capsules No. 4 (capacity of one capsule is 120 mgr) using a capsule filling machine (type LZ-64, manufactured by Zanasi) to prepare capsule preparations (each capsule containing 20 mgr of the active ingredient ).

Prescription Compound 2 20 mgr Avicel 99.5 mgr Magnesium stearate 0.5 mgr 120 mgr Example 3: Injection preparations The injection preparations comprising the following composition are prepared by a conventional method. Compound 3 (1 g) is dissolved in 100 g of pure soybean oil and 12 g of pure yolk lecithin and 25 g of glycerol for injection are added to it. The mixture is made using 1000 mL of distilled water for injection by a conventional method followed by kneading and emulsification. The resulting dispersion is subjected to an aseptic filtration using a membrane filter of a disposable 0.2 μm type and each 2 mL of this is aseptically filled into a glass jar to prepare injection preparations (each vial contains 2 mgr of the ingredient active) .

Prescription Compound 3 2 mgr Pure soybean oil 200 mgr Pure yolk lecithin 24 mgr Glycerol for injection 50 mgr Distilled water for injection 1.72 mgL 2.00 mL Example 4: Anal suppositories A preparation for rectal administration comprising the following composition is prepared by a method conventional Witepsol ™ H15 (produced by Dynamite Nobel) (678.8 gr) and 290.9 gr of Witepsol ™ E75 (produced by Dynamite Nobel) are melted at 40 to 50 ° C. Compound 4 (2.5 gr), 13.6 g of primary potassium phosphate and 14.2 g of secondary sodium phosphate are mixed uniformly with the above mentioned and dispersed. After that, the mixed / dispersed product is filled into suppository molds made of plastic followed by gradual cooling to prepare anal suppositories (each preparation contains 2.5 mgr of the active ingredient).

Prescription Compound 4 2.5 mgr Witespol ™ H15 678.8 mgr Witespol ™ E75 290.9 mgr Primary potassium phosphate 13.6 mgr Second sodium phosphate 14.2 mgr 1,000 mg Industrial Applicability The present invention provides agents for preventing and / or treating high cerebral dysfunctions comprising, as an active ingredient, for example, a xanthine derivative or a pharmaceutically acceptable salt thereof. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (13)

CLAIMS "Having described the invention as above, it is claimed as property contained in the following claims." 1. An agent to prevent and / or treat high cerebral dysfunction characterized in that it comprises, as an active ingredient, a xanthine derivative represented by the formula (I): [wherein R1, R2 and R3 are the same or different, and represent a hydrogen atom, lower alkyl, lower alkenyl or lower alkynyl; R4 represents cycloalkyl, - (CH2) n -R5 (in which R5 represents substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic group, and n represents an integer from 0 to 4) or a group represented by formula (II) :
1. Y2 (in which Y1 and Y2 are the same or different, and represent a hydrogen atom, halogen or lower alkyl, and Z represents substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group); X1 and X2 are the same or different, and represent an oxygen atom or a sulfur atom] or a pharmaceutically acceptable salt thereof.
2. 2. The agent for preventing and / or treating high cerebral dysfunction according to claim 1, characterized in that X1 and X2 each is an oxygen atom.
3. 3. The agent for preventing and / or treating high cerebral dysfunction according to claim 1 or 2, characterized in that R4 is a group represented by the formula (II): (in which Y1, Y2 and Z each have the same meanings as defined above).
4. 4. The agent for preventing and / or treating high cerebral dysfunction according to claim 3, characterized in that Y1 and Y2 are both hydrogen atoms.
5. 5. The agent for preventing and / or treating high cerebral dysfunction according to claim 3 or 4, characterized in that Z is unsubstituted or substituted aryl or a group represented by the formula (III): (in which R6 represents a hydrogen atom, hydroxy, lower alkyl, lower alkoxy, halogen, nitro or amino, and m represents an integer from 1 to 3).
6. 6. The agent for preventing and / or treating high cerebral dysfunction according to any of claims 1 to 5, characterized in that the cerebral dysfunction is a high cerebral dysfunction caused by brain damage.
7. 7. The agent for preventing and / or treating high cerebral dysfunction according to claim 6, characterized in that the brain damage is brain damage due to aging.
8. 8. - The agent for preventing and / or treating high cerebral dysfunction according to claim 6, characterized in that the brain damage is brain damage due to disorder selected from the group consisting of head trauma and stroke.
9. 9. - The agent for preventing and / or treating high cerebral dysfunction according to any of claims 1 to 8, characterized in that the high cerebral dysfunction is a deterioration of the high cerebral function selected from the group consisting of memory, thought, recognition, action and learning.
10. 10. The agent for preventing and / or treating high cerebral dysfunction according to any of claims 1 to 8, characterized in that the high cerebral dysfunction is a cerebral dysfunction selected from the group consisting of agnosia, amnesia and apraxia.
11. 11. - The agent for preventing and / or treating high cerebral dysfunction according to any of claims 1 to 8, characterized in that the high cerebral dysfunction is a deterioration in memory.
12. 12. The agent for preventing and / or treating high cerebral dysfunction according to any of claims 1 to 8, characterized in that the high cerebral dysfunction is a deterioration in learning.
13. 13. - The use of a xanthine derivative represented by the formula (I): [wherein R- ^ R, R, R, X and X each have the same meanings as defined above] or a pharmaceutically acceptable salt thereof for the preparation of an agent for preventing and / or treating high cerebral dysfunction.