USE OF IMIDAZOPYRIMIDINE OR IMIDAZOTRIAZINE COMPOUNDS FOR PREVENTION, ALLEVIATION, OR TREATMENT OF COGNITIVE DISORDERS, OR FOR IMPROVING COGNITIVE FUNCTION

Abstract

The present invention relates to a use of imidazopyrimidine or imidazotriazine compounds of Chemical Formula 1, or pharmaceutically acceptable salts, solvates, or hydrates thereof, for preventing, alleviating or treating cognitive disorder or for improving enhancing cognitive function.

Claims

1. A composition comprising a therapeutically effective amount of an imidazopyrimidine or imidazotriazine compound of Chemical Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof: ##STR00004## in Chemical Formula 1, X is CH or N; Z is O or S; R.sub.1 is C.sub.6-C.sub.12 aryl unsubstituted or substituted with one or more substituents selected from halo, hydroxy, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 alkylthio, amino, di(C.sub.1-C.sub.5 alkyl)amino, cyano, formyl, halo-C.sub.1-C.sub.5 alkyl, hydroxy-C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy-C.sub.1-C.sub.5 alkyl, carbamoyloxy-C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkyl-C(O)O—C.sub.1-C.sub.5 alkyl, a 5- or 6-membered heterocycloalkyl-C.sub.1-C.sub.5 alkyl having 1 to 3 heteroatoms selected from N, O and S, and di(C.sub.1-C.sub.5 alkyl)amino-C.sub.1-C.sub.5 alkyl; or 5- to 12-membered unsaturated heterocyclyl having 1 to 5 heteroatoms selected from N, O and S, unsubstituted or substituted with one or more substituents selected from halo, hydroxy, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, and halo-C.sub.1-C.sub.5 alkyl; R.sub.2 is C.sub.6-C.sub.12 aryl unsubstituted or substituted with one or more substituents selected from halo, deuterium, hydroxy and C.sub.1-C.sub.5 alkyl; or 5- to 12-membered unsaturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, unsubstituted or substituted with one or more substituents selected from halo and C.sub.1-C.sub.5 alkyl.

2. The composition according to claim 1, wherein R.sub.1 is phenyl unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 alkylthio, amino, di(C.sub.1-C.sub.5 alkyl)amino, cyano, formyl, halo-C.sub.1-C.sub.5 alkyl, hydroxy-C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy-C.sub.1-C.sub.5 alkyl, carbamoyloxy-C.sub.1-C.sub.5 alkyl and C.sub.1-C.sub.5 alkyl-C(O)O—C.sub.1-C.sub.5 alkyl; or 5- to 10-membered unsaturated heterocyclyl having 1 to 3 heteroatoms selected from N, O and S, unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy and halo-C.sub.1-C.sub.5 alkyl.

3. The composition according to claim 1, wherein R.sub.2 is phenyl unsubstituted or substituted with 1 to 5 substituents selected from halo, deuterium, hydroxy and C.sub.1-C.sub.5 alkyl; or 5- or 6-membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S, unsubstituted or substituted with 1 to 3 substituents selected from halo and C.sub.1-C.sub.5 alkyl.

4. The composition according to claim 1, wherein X is CH or N; Z is O; R.sub.1 is phenyl unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 alkylthio, amino, di(C.sub.1-C.sub.5 alkyl)amino, cyano, formyl, halo-C.sub.1-C.sub.5 alkyl, hydroxy-C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy-C.sub.1-C.sub.5 alkyl, carbamoyloxy-C.sub.1-C.sub.5 alkyl or C.sub.1-C.sub.5 alkyl-C(O)O—C.sub.1-C.sub.5 alkyl; or 5- to 9-membered unsaturated heterocyclyl having 1 or 2 heteroatoms selected from N, O or S, unsubstituted or substituted with 1 or 2 substituents selected from halo, hydroxy, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy and halo-C.sub.1-C.sub.5 alkyl; and R2 is phenyl unsubstituted or substituted with 1 to 5 substituents selected from halo, deuterium, hydroxy and C.sub.1-C.sub.5 alkyl; or 6-membered heteroaryl having 1 or 2 nitrogen atoms, unsubstituted or substituted with 1 or 2 substituents selected from halo and C.sub.1-C.sub.5 alkyl.

5. The composition according to claim 1, wherein R.sub.1 is phenyl unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 alkylthio, amino, di(C.sub.1-C.sub.5 alkyl)amino, cyano, formyl, halo-C.sub.1-C.sub.5 alkyl, hydroxy-C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy-C.sub.1-C.sub.5 alkyl, carbamoyloxy-C.sub.1-C.sub.5 alkyl and C.sub.1-C.sub.5 alkyl-C(O)O—C.sub.1-C.sub.5 alkyl; 1,3-benzodioxolyl unsubstituted or substituted with 1 or 2 halo; or pyridyl or pyrimidinyl unsubstituted or substituted with 1 or 2 substituents selected from halo, hydroxy, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy and halo-C.sub.1-C.sub.5 alkyl, and R.sub.2 is phenyl unsubstituted or substituted with 1 to 5 substituents selected from halo, deuterium, hydroxy and C.sub.1-C.sub.5 alkyl; or pyridyl unsubstituted or substituted with 1 or 2 substituents selected from halo and C.sub.1-C.sub.5 alkyl.

6. The composition according to claim 1, wherein X is CH; Z is O; R.sub.1 is phenyl unsubstituted or substituted with 1 to 3 substituents selected from halo, hydroxy, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 alkylthio, amino, halo-C.sub.1-C.sub.5 alkyl, hydroxy-C.sub.1-C.sub.5 alkyl and C.sub.1-C.sub.5 alkoxy-C.sub.1-C.sub.5 alkyl; and R2 is pyridyl unsubstituted or substituted with 1 or 2 substituents selected from halo and C.sub.1-C.sub.5 alkyl.

7. The composition according to claim 1, wherein the imidazopyrimidine or imidazotriazine compound of Chemical Formula 1 is selected from the following compounds: 6-(4-fluorophenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine; 6-[4-fluoro-2-(trifluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine; 6-(4-fluoro-2-methyl-phenyl)-2-[(5-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine; 6-(4-fluorophenyl)-2-[(5-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine; [5-fluoro-2-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl]methanol; and 6-[4-fluoro-2-(fluoromethyl)phenyl]-2-(2-pyridyloxymethyl)im idazo[1,2-a]pyrimidine.

8-12. (canceled)

13. The composition according to claim 1, which is prepared for administration to a mammal.

14. The composition according to claim 1, comprising 0.1 to 500 mg/kg (body weight) of the imidazopyrimidine or imidazotriazine compound of Chemical Formula 1.

15. The composition according to claim 1, which is for oral administration or for parenteral administration selected from the group consisting of intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, vaginal administration, intrapulmonary administration and rectal administration.

16. The composition according to claim 1, further comprising one or more drugs selected from the group consisting of dimethylamylamine, methylphenidate, amphetamine, tacrine, rivastigmine, galantamine, donepezil, memantine, tolcapone, levodopa, atomoxetine, clonidine, pramipexole, guanfacine, and fexofenadine.

17-27. (canceled)

28. A method for prevention, alleviation or treatment of cognitive disorder, or for improving cognitive function in a subject, comprising: administering to the subject a therapeutically effective amount of an imidazopyrimidine or imidazotriazine compound of claim 1.

29. The method according to claim 28, which is for preventing, alleviating or treating symptoms of cognitive disorder.

30. The method according to claim 29, wherein the symptoms of cognitive disorder are decreased attention, decreased language ability, decreased spatial-temporal ability, decreased reasoning ability, or decreased judgment.

31. The method according to claim 28, which is for alleviating or treating a disease associated with cognitive disorder.

32. The method according to claim 31, wherein the disease associated with cognitive disorder is selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Alzheimer type dementia, presenile dementia, early onset Alzheimer's disease, senile dementia, Lewy body corpuscle dementia, micro-infarct dementia, AIDS-related dementia, HIV-dementia, dementia associated with Lewy bodies, Down's syndrome associated dementia, Pick's disease, recent short-term memory impairment, age-associated cognitive disorder, age-associated memory impairment, drug-associated cognitive disorder, immunodeficiency syndrome-associated cognitive disorder, vascular disease-associated cognitive impairment, cognitive impairment associated with schizophrenia, Parkinson's disease-associated cognitive impairment, cognitive disorders associated with epilepsy, depression-associated cognitive disorder, cognitive disorders associated with bipolar disorder, obsessive compulsive disorder-associated cognitive disorder, post-traumatic stress disorder, attention deficit disorder, attention deficit hyperactivity disorder, and learning deficit disorder.

33. The method according to claim 32, wherein the disease associated with cognitive disorder is selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Alzheimer type dementia, presenile dementia, early onset Alzheimer's disease, senile dementia, recent short-term memory impairment, age-associated cognitive disorder, age-associated memory impairment, drug-associated cognitive disorder, and cognitive impairment associated with schizophrenia.

34. The method according to claim 28, wherein the subject is a mammal.

35. The method according to claim 28, wherein 0.1 to 500 mg/kg (body weight) of the imidazopyrimidine or imidazotriazine compound of Chemical Formula 1 is administered.

36. The method according to claim 28, wherein one or more drugs selected from the group consisting of dimethylamylamine, methylphenidate, amphetamine, tacrine, rivastigmine, galantamine, donepezil, memantine, tolcapone, levodopa, atomoxetine, clonidine, pramipexole, guanfacine, and fexofenadine are additionally administered.

37-45. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0278] FIG. 1 is results showing the effect of a test compound (0.03, 0.1, and 0.3 mg/kg) on a rat model exhibiting cognitive ability decreased by treatment with dizocilpine in an object recognition test.

[0279] FIG. 2 is results showing the effect of a test compound (0.1, 0.3, and 1 mg/kg) on a rat model exhibiting cognitive ability decreased by treatment with dizocilpine in a Y-maze test.

[0280] FIG. 3 is results showing the effect of a test compound (0.1 and 0.3 mg/kg) on a natural forgetting rat model in an object recognition test.

[0281] FIG. 4 is results showing the effect of a test compound (1 and 3 mg/kg) on a natural forgetting rat model in an object recognition test.

DETAILED DESCRIPTION

[0282] Hereinafter, the present invention will be described in more detail through Examples. However, these Examples are only for illustration of one or more embodiments, and the scope of the invention is not limited thereto.

Preparation Example: Preparation of Test Compound

[0283] According to the method described in Example 113 of International Publication No. WO 2016/137260, 6-[4-fluoro-2-(trifluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine (test compound) was prepared.

Example 1: Effect on Rat Model Exhibiting Cognitive Ability Decreased by Treatment with Dizocilpine in Object Recognition Test

[0284] As an animal model of cognitive disorder, an animal model of which the cognitive ability was decreased by administering dizocilpine, a cognitive inhibitor, was used.

Experimental Animal

[0285] Male rats (Wistar, 4 weeks old, Orient Bio Co., Ltd.) were purchased and acclimatized for one week or more in an animal cage. The experimental animals were raised in a light-controlled environment (illuminated for 12 hours/nonilluminated for 12 hours) and stored and managed according to the laboratory animal care standards of the Institutional Animal Care and Use Committee (IACUC) in an environment where a temperature of 19° C. to 25° C. and a relative humidity of 30% to 70% were maintained and water and food could be freely available. The rats were stabilized for one week or more, and then used for an object recognition test. The rats were randomly divided into groups and the test was performed under illumination.

Drug

[0286] To create an animal model inducing symptoms of decreased cognitive ability, the experimental animals were treated with dizocilpine, an N-methyl-D-aspartate (NMDA) receptor inhibitor.

[0287] Dizocilpine (purchased from Sigma) was dissolved in physiological saline used as a vehicle to be freshly prepared, and subcutaneously administered at a dose of 0.1 mg/kg in a volume of 1 ml per 1 kg of rat body weight 30 minutes before training. To a control group, only physiological saline was administered.

[0288] The test compound was dissolved in 5% DMSO (dimethyl sulfoxide) in 10% Cremophor, and orally administered at doses of 0.03, 0.1, and 0.3 mg/kg in a volume of 1 ml per 1 kg of rat body weight one hour before training. To a control group, only vehicle (5% DMSO in 10% Cremophor) was administered.

Object Recognition Test

[0289] Each rat was handled by the experimenter for 3 minutes or more, and box acclimation for 3 minutes was performed two times in an empty box before the experiment. After administration of vehicle or test compound intraperitoneally at a dose of 1 mg/kg one hour before training and of vehicle or dizocilpine subcutaneously 30 minutes before training, the rats were boxed for training. Training was conducted by exposing the rats in a box in which two identical plastic cylinders or stainless square pyramids were placed. One hour after training, the test was performed in a box in which one plastic cylinder and one stainless square pyramid was placed. During the test, the time during which the rat explored each object was measured. The test results were analyzed using a stainless square pyramid as a novel object in the case of rats trained in a box in which two plastic cylinders were placed and a plastic cylinder as a novel object in the case of rats trained in a box in which two stainless steel pyramids were placed.

Statistical Analysis of Experimental Results

[0290] The recognition index was calculated based on the time during which the object was explored, the data on the recognition index between groups was analyzed by one-way analysis of variance (ANOVA) and Dunnett's multiple comparison test, and then the effect was defined as significant when p<0.05. All results were expressed as mean±SEM.

Test Results

[0291] The recognition index of the negative control group treated with only dizocilpine was 49.77±1.03 seconds, and a significant decrease in cognitive function compared to that of the vehicle group, which is a positive control group, having a recognition index of 63.29±1.56 seconds was observed (P<0.001). When dizocilpine and the test compound were administered together, the recognition indexes of the 0.1 mg/kg administration group and the 0.3 mg/kg administration group were 57.95±1.8 seconds and 57.62±1.89 seconds, respectively, and significant cognitive function recovery compared to the negative control group exhibiting decreased cognitive function was observed (both P<0.01).

[0292] The analysis results of recognition index of a rat model exhibiting cognitive ability decreased by treatment with dizocilpine in an object recognition test using a test compound are summarized in Table 1.

TABLE-US-00001 TABLE 1 Analysis results of recognition index of rat model exhibiting cognitive ability decreased by treatment with dizocilpine in object recognition test using test compound Dosage Recognition Dizocilpine Test compound index.sup.1) Treated drug (mg/kg, sc.sup.2)) (mg/kg, po.sup.3)) (mean ± SEM) Vehicle NT.sup.4) NT 63.29 ± 1.56 Dizocilpine 0.1 NT 49.77 ± 1.03 Dizocilpine and test 0.1 0.03 51.95 ± 1.79 compound Dizocilpine and test 0.1 0.1 57.95 ± 1.8 compound Dizocilpine and test 0.1 0.3 57.62 ± 1.89 compound .sup.1)Recognition index = exploring time of novel object/total exploring time (identical object + novel object) × 100 .sup.2)sc = Subcutaneously .sup.3)po = Oral administration (per os) .sup.4)NT = Not treated

[0293] From this, a synergistic increase in recovery effect on the impairment of cognitive function has been confirmed as a result of administration of the test compound.

Example 2: Effect on Rat Model Exhibiting Cognitive Ability Decreased by Treatment with Dizocilpine in Y-Maze Test

Experimental Animal

[0294] Male rats (Wistar, 4 weeks old, Orient Bio Co., Ltd.) were purchased and acclimatized for one week or more in an animal cage. The experimental animals were raised in a light-controlled environment (illuminated for 12 hours/nonilluminated for 12 hours) and stored and managed according to the laboratory animal care standards of the Institutional Animal Care and Use Committee in an environment where a temperature of 19° C. to 25° C. and a relative humidity of 30% to 70% were maintained and water and food could be freely available. The rats were stabilized for one week or more, and then used for a Y-maze test. The rats were randomly divided into groups and the test was performed under illumination.

Drug

[0295] To create an animal model inducing symptoms of decreased cognitive ability, experimental animals were treated with dizocilpine, an NMDA receptor inhibitor.

[0296] Dizocilpine (purchased from Sigma) was dissolved in physiological saline used as a vehicle to be freshly prepared, and subcutaneously administered at a dose of 0.1 mg/kg in a volume of 1 ml per 1 kg of rat body weight 30 minutes before training. To a control group, only physiological saline was administered.

[0297] The test compound was dissolved in 5% DMSO in 9.5% Cremophor, and orally administered at doses of 0.1, 0.3, and 1 mg/kg in a volume of 5 ml per 1 kg of rat body weight one hour before training. To a control group, only vehicle (5% DMSO in 9.5% Cremophor) was administered.

Y-Maze Test

[0298] The rats were handled by the experimenter for 3 minutes for two days, and a Y-maze test was performed the next day. After administration of vehicle or test compound intraperitoneally one hour before test and of vehicle or dizocilpine subcutaneously 30 minutes before test, the Y-maze test was performed for 5 minutes by placing the rat at the end of one arm in the Y-maze and allowing the rat to move freely. The three arms positioned at the same angle in the Y-maze had the same length of 45 cm, the same width of 10 cm, and the same height of 20 cm. A case where a rat visited three different arms in succession was defined as an alternation behavior.

Statistical Analysis of Experimental Results

[0299] The alternation rate was determined by identifying the alternation behavior of the rat based on the visit record to each arm in the Y-maze test, the data on the alternation rate between groups was analyzed by one-way ANOVA and Dunnett's multiple comparison test, and then the effect was defined as significant when p<0.05. All results were expressed as mean±SEM.

Test Results

[0300] The alternation rate of the negative control group treated with only dizocilpine was 49.2±5.3 seconds, and a significant decrease in cognitive function compared to the vehicle group, which is a positive control group, having an alternation rate of 70.1±2.8 seconds was observed (P<0.001). When dizocilpine and the test compound were administered together, the alternation rate of the 0.1 mg/kg administration group was 67.3±3.5 seconds, and significant cognitive function recovery compared to the negative control group exhibiting decreased cognitive function was observed (P<0.001).

[0301] The alternation rate of the 0.3 mg/kg administration group of the test compound was 57.3±5.7 seconds, and a tendency toward the recovery of cognitive function was observed compared to the control group exhibiting decreased cognitive function.

[0302] The analysis results of alternation rate of a rat model exhibiting cognitive ability decreased by treatment with dizocilpine in a Y-maze test using a test compound are summarized in Table 2.

TABLE-US-00002 TABLE 2 Analysis results of alternation rate of rat model exhibiting cognitive ability decreased by treatment with dizocilpine in Y-maze test using test compound Dosage Alternation Dizocilpine Test compound rate.sup.1) Treated drug (mg/kg, sc.sup.2)) (mg/kg, po.sup.3)) (mean ± SEM) Vehicle NT.sup.4) NT 70.1 ± 2.8 Dizocilpine 0.1 NT 49.2 ± 5.3 Dizocilpine and test 0.1 0.1 67.3 ± 3.5 compound Dizocilpine and test 0.1 0.3 57.3 ± 5.7 compound Dizocilpine and test 0.1 1 49.9 ± 7.2 compound .sup.1)Alternation rate = number of actual alternation behaviors/maximum possible number of alternation behaviors × 100 [maximum possible number of alternation behaviors = number of total entries − 2] .sup.2)sc = Subcutaneously .sup.3)po = Oral administration (per os) .sup.4)NT = Not treated

[0303] From this, a synergistic increase in recovery effect on the impairment of cognitive function has been confirmed as a result of administration of the test compound.

Example 3: Effect on Rat Model Undergone Natural Forgetting in Object Recognition Test

[0304] As an animal model of cognitive disorder, a natural forgetting model in which natural forgetting occurred over time was used.

Experimental Animal

[0305] Male rats (Wistar, 4 weeks old, Orient Bio Co., Ltd.) were purchased and acclimatized for one week or more in an animal cage. The experimental animals were raised in a light-controlled environment (illuminated for 12 hours/nonilluminated for 12 hours) and stored and managed according to the laboratory animal care standards of the Institutional Animal Care and Use Committee in an environment where a temperature of 19° C. to 25° C. and a relative humidity of 30% to 70% were maintained and water and food could be freely available. The rats were stabilized for one week or more, and then used for an object recognition test. The rats were randomly divided into groups and the test was performed under illumination.

Drug

[0306] The test compound was dissolved in 5% DMSO in 10% Cremophor, and orally administered at a dose of 1 mg/kg one hour before training. To a control group, only vehicle (5% DMSO in 10% Cremophor) was administered.

Object Recognition Test

[0307] Each rat was handled by the experimenter for 3 minutes or more, and box acclimation for 3 minutes was performed two times in an empty box before the experiment. After administration of vehicle or test compound intraperitoneally one hour before training at a dose of 1 mg/kg, the rats were boxed for training. Training was conducted by exposing the rats in a box in which two identical plastic cylinders or stainless square pyramids were placed. The test was performed 24 hours after training in a box in which one plastic cylinder and one stainless square pyramid was placed. During the test, the time during which the rat explored each object was measured. The test results were analyzed using a stainless square pyramid as a novel object in the case of rats trained in a box in which two plastic cylinders were placed and a plastic cylinder as a novel object in the case of rats trained in a box in which two stainless steel pyramids were placed.

Statistical Analysis of Experimental Results

[0308] The recognition index was calculated based on the time during which the object was explored, the data on the recognition index between groups was analyzed by one-way ANOVA and Dunnett's multiple comparison test, and then the effect was defined as significant when p<0.05. All results were expressed as mean±SEM.

Test Results

[0309] The experiment was performed two times according to the dose of the test compound. In the first experiment, the recognition index in the vehicle group, which is a control group, was 48.61±1.87 seconds and did not statistically differ from 50 which was the recognition index when the group was not able to distinguish the identical object from a novel object but explored for exactly the same time, and it was thus confirmed that sufficient natural forgetting occurred for 24 hours.

[0310] When the test compound was administered at 0.1 mg/kg and 0.3 mg/kg, the recognition indexes were 56.57±2.37 seconds and 59.77±2.64 seconds, respectively, and were significantly different from that in the control group undergone natural forgetting (P<0.05, P<0.01, respectively).

[0311] The analysis results of recognition index of a rat model undergone natural forgetting in an object recognition test using a test compound (0.1 mg/kg and 0.3 mg/kg) are summarized in Table 3.

TABLE-US-00003 TABLE 3 Analysis results of recognition index of rat model undergone natural forgetting in object recognition test using test compound (0.1 mg/kg and 0.3 mg/kg) Dosage of test compound Recognition index.sup.1) Treated drug (mg/kg, po .sup.2)) (mean ± SEM) Vehicle NT .sup.3) 48.61 ± 1.87 Test compound 0.1 56.57 ± 2.37 Test compound 0.3 59.77 ± 2.64 .sup.1)Recognition index = exploring time of novel object/total exploring time(identical object + novel object) × 100 .sup.2) po = Oral administration (per os) .sup.3) NT = Not treated

[0312] In the second experiment as well, the recognition index in the vehicle group, which is a control group, was 51.20±2.61 seconds, and did not statistically differ from 50 which was the recognition index when the group was not able to distinguish the identical object from a novel object but explored for exactly the same time, and it has been thus confirmed that sufficient natural forgetting occurred for 24 hours.

[0313] When the test compound was administered at 1 mg/kg, the recognition index was 60.91±2.72 seconds and was significantly different from that in the control group undergone natural forgetting (P<0.01). The recognition index in the 3 mg/kg administration group of the test compound was 56.20±2.27 seconds, and this indicates that natural forgetting is alleviated compared to the control group undergone natural forgetting.

[0314] The analysis results of recognition index of a rat model undergone natural forgetting in an object recognition test using a test compound (1 mg/kg and 3 mg/kg) are summarized in Table 4.

TABLE-US-00004 TABLE 4 Analysis results of recognition index of rat model undergone natural forgetting in object recognition test using test compound (1 mg/kg and 3 mg/kg) Dosage of test compound Recognition index.sup.1) Treated drug (mg/kg, po .sup.2)) (mean ± SEM) Vehicle NT .sup.3) 51.20 ± 2.61 Test compound 1 60.91 ± 2.72 Treated drug 3 56.20 ± 2.27 .sup.1)Recognition index = exploring time of novel object/total exploring time (identical object + novel object) × 100 .sup.2) po = Oral administration (per os) .sup.3) NT = Not treated

[0315] From the experimental results in such a natural forgetting model, the natural forgetting alleviating effect of the test compound through enhancement of cognitive function in a normal cognitive state has been confirmed.