USE OF IMIDAZOPYRIMIDINE OR IMIDAZOTRIAZINE COMPOUND FOR PREVENTION, ALLEVIATION, OR TREATMENT OF DEVELOPMENTAL DISABILITY

Abstract

The present invention relates to a use, for the prevention, alleviation or treatment of developmental disability, of an imidazopyrimidine or imidazotriazine compound of chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

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 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 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 R.sub.2 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)imidazo[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 developmental 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, wherein the developmental disorder is selected from the group consisting of pervasive developmental disorder, autism, autistic spectrum disorder, fragile X syndrome, a developmental disorder caused by fragile X syndrome, a developmental disorder exhibiting symptoms similar to those of fragile X syndrome, Angelman syndrome, a developmental disorder caused by Angelman syndrome, a developmental disorder exhibiting symptoms similar to those of Angelman syndrome, Rett syndrome, a developmental disorder caused by Rett syndrome, a developmental disorder exhibiting symptoms similar to those of Rett syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), Asperger's syndrome, a developmental disorder caused by Asperger's syndrome, a developmental disorder exhibiting symptoms similar to those of Asperger's syndrome, childhood disintegrative disorder, a developmental disorder caused by childhood disintegrative disorder, a developmental disorder exhibiting symptoms similar to those of childhood disintegrative disorder, Landau-Kleffner syndrome, a developmental disorder caused by Landau-Kleffner syndrome, a developmental disorder exhibiting symptoms similar to those of Landau-Kleffner syndrome, Prader-Willi syndrome, a developmental disorder caused by Prader-Willi syndrome, a developmental disorder exhibiting symptoms similar to those of Prader-Willi syndrome, 22q11.2 deletion syndrome, a developmental disorder caused by 22q11.2 deletion syndrome, a developmental disorder exhibiting symptoms similar to those of 22q11.2 deletion syndrome, tardive dyskinesia, a developmental disorder caused by tardive dyskinesia, a developmental disorder exhibiting symptoms similar to those of tardive dyskinesia, seizure disorder, a developmental disorder caused by seizure disorder, a developmental disorder exhibiting symptoms similar to those of seizure disorder, Williams syndrome, a developmental disorder caused by Williams syndrome, and a developmental disorder exhibiting symptoms similar to those of Williams syndrome.

30. The method according to claim 29, wherein the developmental disorder is selected from the group consisting of fragile X syndrome, a developmental disorder caused by fragile X syndrome, a developmental disorder exhibiting symptoms similar to those of fragile X syndrome, Angelman syndrome, a developmental disorder caused by Angelman syndrome, a developmental disorder exhibiting symptoms similar to those of Angelman syndrome, Rett syndrome, a developmental disorder caused by Rett syndrome, and a developmental disorder exhibiting symptoms similar to those of Rett syndrome.

31. The method according to claim 28, wherein the developmental disorder is selected from the group consisting of fragile X syndrome, a developmental disorder caused by fragile X syndrome, and a developmental disorder exhibiting symptoms similar to those of fragile X syndrome.

32. The method according to claim 31, which is for preventing, alleviating or treating symptoms of developmental disorder.

33. The method according to claim 32, wherein the symptoms of developmental disorder are developmental delays, learning disability, intellectual disability, socio-behavioral disorder or seizures.

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 a stimulant, an antidepressant, an antipsychotic, an antiepileptic, and an anxiolytic are additionally administered.

37-45. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0288] FIG. 1 is results showing the effect of long-term (6 weeks) administration of a test compound (2 mg/kg, twice a day) on reduced fear conditioning in a contextual fear conditioning experiment performed using an Fmr1 gene knockout mouse model.

[0289] FIG. 2 is results showing the effect of long-term (6 weeks) administration of a test compound (2 mg/kg, twice a day) on an Fmr1 gene knockout mouse model in an open field test.

[0290] FIG. 3 is results showing the effect of long-term (6 weeks) administration of a test compound (2 mg/kg, twice a day) on an Fmr1 gene knockout mouse model in a marble burying test.

DETAILED DESCRIPTION

[0291] 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

[0292] 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: Anticonvulsant Efficacy Experiment on Audiogenic Seizure, Contextual Fear Conditioning Experiment, Open Field Test, and Marble Burying Test in Fmr1 Gene Knockout Mouse Model

[0293] An Fmr1 gene knockout mouse model was used as an animal model of fragile X syndrome. This model lacks FMRP protein due to disruption of the Fmr1 gene. Typical phenotypes of this mouse model include audiogenic seizure, hyperlocomotor activity, cognitive deficit, concentration deficit disorder, and the like.

[0294] Experimental Animal

[0295] Male Fmr1 C57BL/6J knock-out mice derived from the early group imported from Jackson Laboratories were used in the experiments. The experimental animals were raised in a light-controlled environment (illuminated for 12 hours/nonilluminated for 12 hours) and maintained at a temperature of 21° C.±2° C. and a relative humidity of about 55%±5%. Food and water were ad libitum fed. An anticonvulsant efficacy experiment on audiogenic seizure, a contextual fear conditioning experiment, an open field test, and a marble burying test in the Fmr1 gene knockout mouse model was performed by Fragile X Syndrome Drug Validation Initiative (FRAXA-DVI). The mice were randomly divided into groups and the test was performed under illumination.

[0296] Drug

[0297] The test compound was dissolved in 10% DMSO (dimethylsulfoxide)+30% PEG 300 in DW (distilled water), and administered intraperitoneally at a dose of 2 mg/kg twice a day for 6 weeks. To a control group, vehicle (10% DMSO (dimethylsulfoxide)+30% PEG 300 in DW (distilled water)) was administered.

[0298] Test Group

[0299] 1. Wild-type mice—administered with vehicle

[0300] 2. Fmr1 gene knockout mice—administered with vehicle

[0301] 3. Wild-type mice—administered with test compound at 2 mg/kg

[0302] 4. Fmr1 gene knockout mice—administered with test compound at 2 mg/kg

[0303] Ten mice per group were used.

[0304] Audiogenic Seizure Test

[0305] After the vehicle or test compound was administered intraperitoneally at a dose of 2 mg/kg twice a day for 6 weeks, the mice were placed in a chamber and exposed to an alarm. The response of the mice during the test was evaluated numerically by the following criteria according to the intensity of seizure, and the survival rate was also observed.

[0306] 0: No response

[0307] 1: Wild running and jumping

[0308] 2: Clonic seizures

[0309] 3: Clonic-tonic seizures

[0310] 4: Tonic seizures

[0311] 5: Respiratory arrest

[0312] Contextual Fear Conditioning Experiment

[0313] After the vehicle or test compound was administered intraperitoneally at a dose of 2 mg/kg twice a day for 6 weeks, training and an efficacy test were performed, respectively. The chamber was cleaned with 70% ethanol every time mouse was changed. The mouse was placed in a conditioned chamber and an electric shock (unconditioned stimulus) was applied. To conduct a drug efficacy test on contextual memory, the mice were placed in the same chamber, and then left for 5 minutes without shock or other obstructions, and freezing behavior, defined as complete loss of movement except breathing, was observed.

[0314] Open Field Test

[0315] After the vehicle or test compound was administered intraperitoneally at a dose of 2 mg/kg twice a day for 6 weeks, an open field test was performed to observe the efficacy behavior of mice who fearlessly stepped out to the center of the open field. Before the test, the mice were acclimatized to the laboratory and then placed in the center of the open field to measure their activity. The number of times the mouse crossed the center of the open field was measured by the breakage of the horizontal beam due to the mouse's movement. The test room was cleaned every time the mouse was changed.

[0316] Marble Burying Test

[0317] After the vehicle or test compound was administered intraperitoneally at a dose of 2 mg/kg twice a day for 6 weeks, a hippocampal function-dependent marble burying test was performed. In a mouse cage, 16 transparent marbles were placed in a 4×4 arrangement so that ⅔ of the marble was submerged in the bedding. The mouse was placed and left for 30 minutes, then the number of marbles buried by the mouse was counted.

[0318] Statistical Analysis

[0319] After data analysis by ANOVA, the effect was defined as significant when p<0.05. All results were expressed as mean±SEM.

[0320] Test Result

[0321] The results of anticonvulsant efficacy test on audiogenic seizure using a test compound are summarized in Table 1.

TABLE-US-00001 TABLE 1 Results of anticonvulsant efficacy test on audiogenic seizure using test compound Vulnerability to Wild Seizures of 3 Survival audiogenic Test group running or more points rate seizure Wild type—vehicle 0/10 0/10 10/10  0% Fmr1 gene 9/10 8/10  2/10 90% knockout—vehicle Wild type—test 0/10 0/10 10/10  0% compound Fmr1 gene 6/10 5/10  5/10 60% knockout—test compound

[0322] In wild-type mice, no mice showed audiogenic seizure phenotype in the vehicle-administered group and the test compound-administered group. In the vehicle-administered group of Fmr1 gene knockout mice, there were nine wild running mice, and eight mice showed seizures of 3 or more points among these, and the eight mice all died because of respiratory arrest. The vulnerability to audiogenic seizure is the proportion of wild running mice, and thus, the vulnerability to audiogenic seizure was 90% in the vehicle-treated group of Fmr1 gene knockout mice. In the test compound-administered group of Fmr1 gene knockout mice, there were six wild running mice, and five mice showed seizures of 3 or more points among these, and the five mice all died because of respiratory arrest. Hence, the vulnerability to audiogenic seizure was 60%. From this, it has been found that in Fmr1 gene knockout mice, the vulnerability to audiogenic seizure of the test compound-administered group was decreased to 60% from 90%, which was the vulnerability to audiogenic seizure of the vehicle-administered group.

[0323] The percent of freezing behavior during the contextual fear conditioning experiment is illustrated in FIG. 1. As a result of ANOVA analysis, the vehicle-administered Fmr1 gene knockout mice showed significantly decreased freezing behavior compared to the wild-type mice. In Fmr1 gene knockout mice, the test compound-administered group showed significantly increased freezing behavior compared to the vehicle-administered group, and showed freezing behavior to a degree similar to that in the vehicle-administered wild-type mice. In other words, the result indicate that the fear learning ability in Fmr1 gene knockout mice is improved.

[0324] As a result of the open field test, the number of times the mouse crossed the center is illustrated in FIG. 2. The vehicle-administered Fmr1 gene knockout mice and the test compound-administered Fmr1 gene knockout mice both had a P value of 0.0001 or less and showed a significant increase in movement compared to the wild-type mice.

[0325] As a result of the marble burying test, the number of marbles buried is illustrated in FIG. 3. The vehicle-administered Fmr1 gene knockout mice buried more marbles than the wild-type mice. The test compound-administered group of Fmr1 gene knockout mice also showed a statistical difference compared to the wild-type mice, but the number of buried marbles in the test compound-administered group of Fmr1 gene knockout mice increased compared to that in the vehicle-administered group of Fmr1 gene knockout mice.