RU2835510C1 - Use of imidazopyrimidines or imidazotriazines for preventing, relieving or treating cognitive impairment, or for improving cognitive function - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: group of inventions relates to the field of pharmaceutics, namely to a method for preventing, relieving or treating cognitive impairment, or improving cognitive function in a subject, and to the use of a compound of a defined structure for preventing, relieving or treating cognitive impairment, or for improving cognitive function. Method of preventing, relieving or treating cognitive impairment, or improving cognitive function in a subject, which involves administering to a subject a therapeutically effective amount of 6-[4-fluoro-2-(trifluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine or a pharmaceutically acceptable salt, solvate or hydrate thereof. Use of 6-[4-fluoro-2-(trifluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine or a pharmaceutically acceptable salt, solvate or hydrate thereof for preventing, relieving or treating cognitive impairment, or to improve cognitive function.

EFFECT: said group of inventions enables to effectively prevent, relieve or treat cognitive disorders and improve cognitive function.

18 cl, 4 dwg, 4 tbl, 3 ex

Description

[Field of technology to which the invention relates]

The present invention relates to the use of imidazopyrimidines or imidazotriazines of chemical formula 1, or pharmaceutically acceptable salts, solvates or hydrates thereof, for the prevention, alleviation or treatment of cognitive impairment, or for the improvement of cognitive function:

[Chemical formula 1]

in chemical formula 1, X, Z, R ₁ and R ₂ are as defined in the present invention.

[State of the art]

The human brain has the ability to receive, store and retrieve information for decades. This set of information, namely learning, changes the physiological state of specific neurons in the process of encoding the memory. These physiological changes are changes in the activity of the cells caused by learning. are part of the neural code for this memory. These changes can occur through the expression or action of ion channels that excite neurons to a greater or lesser extent. This can lead to an increase or decrease in the action potential or can be manifested more indirectly by changing other electrical signals. Learning can occur through the process of nerve growth with new connections or, conversely, the process of nerve elimination to remove existing connections. Learning can also occur through the process of cell signal adaptation by changing the overall ability of neurons to integrate different types of signals, or also lead to morphological and functional changes in synapses that increase or decrease the ability of neurons. The molecular and cellular engrams formed by all the neurons involved in this learning act as guides that provide additional retrieval of information in the memory. After encoding the "index" of memory engram cells, the cell relationships associated with concepts are consolidated and logically regulated efficiently through the process of simplification according to perceptual concepts. However, the number of memory engrams continues to accumulate over time. Therefore, in the process of forgetting, the efficiency of the brain's capacity to remove unused or infrequently used memory engrams is further increased. All processes of forming and regulating memory engrams so that information about previously learned events or contents can be recalled and recognized later are cognitive processes (Davis & Zhong, 2017, "The Biology of Forgetting-A Perspective." Neuron. Aug 2;95(3):490-503).

Improvement of cognitive function means that the cell activities are carried out in the direction in which new connections are well formed in the process of nerve growth, the process of signal adaptation is consolidated or the interrelations of cells associated with concepts are more logical in receiving, storing and receiving information. Alternatively, improvement of cognitive function is the prevention of cognitive impairment in the direction in which the necessary memory engrams are lost in the process of forgetting, namely, with the natural deterioration of the body, a similar memory engram is formed that prevents the correct receipt of desired information or difficult memory restoration due to changes in the structure of memory engrams.

Cognitive impairment is a neurological disorder in which memory, attention, language skills, judgment, etc. are impaired in the cognitive process and vary from very mild to severe pathological conditions. Mild cognitive impairment is a pathological condition in which the ability to perform daily activities is preserved and the ability to perform instrumental activities is possible, but cognitive function is impaired. Dementia is a pathological condition in which cognitive function is impaired so that it interferes with daily life. Mild cognitive impairment may occur as a temporary impairment during the onset of dementia. In addition, aging, genetics, cardiovascular disease, etc. are considered risk factors for cognitive impairment.

[Disclosure of invention]

[Technical task]

The object of the present invention is a method for preventing, alleviating or treating cognitive impairment, or for improving cognitive function.

Another object of the present invention is the use of an imidazopyrimidine or imidazotriazine of chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for the prevention, alleviation or treatment of cognitive impairment, or for improving cognitive function:

[Chemical formula 1]

in chemical formula 1, X, Z, R ₁ and R ₂ are as defined in the present invention.

[Problem solution]

The present invention relates to a medicinal product for preventing, alleviating or treating cognitive impairment, or for improving cognitive function, which comprises a therapeutically effective amount of an imidazopyrimidine or imidazotriazine of chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[Chemical formula 1]

in chemical formula 1,

X stands for CH or N;

Z means O or S;

R ₁ is C ₆ -C ₁₂ aryl, unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio, amino, di(C ₁ -C ₅ alkyl)amino, cyano, formyl, halo-C ₁ -C ₅ alkyl, hydroxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl, carbamoyloxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkyl-C(O)OC ₁ -C ₅ alkyl, 5- or 6-membered heterocycloalkyl-C ₁ -C ₅ alkyl containing from 1 to 3 heteroatoms selected from from the group consisting of N, O and S, or di(C ₁ -C ₅ alkyl)amino-C ₁ -C ₅ alkyl; and 5-12-membered unsaturated heterocyclyl containing from 1 to 5 heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, hydroxy group, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy group, and halo-C ₁ -C ₅ alkyl;

R ₂ is C ₆ -C ₁₂ aryl, unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, deuterium, hydroxy group and C ₁ -C ₅ alkyl; or 5-12-membered unsaturated heterocyclyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted by one or more substituents selected from the group consisting of halogen and C ₁ -C ₅ alkyl.

The present invention also relates to a pharmaceutical composition for preventing, alleviating or treating cognitive impairment, or for improving cognitive function, which comprises a therapeutically effective amount of an imidazopyrimidine or imidazotriazine of chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and additionally one or more pharmaceutically acceptable carriers.

The present invention also relates to a method for preventing, alleviating or impairing cognitive ability, or improving cognitive function, which comprises administering to a subject a therapeutically effective amount of an imidazopyrimidine or imidazotriazine of chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The present invention also relates to the use of an imidazopyrimidine or imidazotriazine of chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for preventing, alleviating or treating cognitive impairment, or for improving cognitive function.

In one embodiment of the present invention, R ₁ in chemical formula 1 is phenyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogen, hydroxy, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio, amino, di(C ₁ -C ₅ alkyl)amino, cyano, formyl, halo-C ₁ -C ₅ alkyl, hydroxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl, carbamoyloxy-C ₁ -C ₅ alkyl and C ₁ -C ₅ alkyl-C(O)OC ₁ -C ₅ alkyl; or 5-10 membered unsaturated heterocyclyl containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogen, hydroxy group, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy group and halo-C ₁ -C ₅ alkyl.

According to another embodiment of the present invention, R ₂ in chemical formula 1 is phenyl, unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of halogen, deuterium, hydroxy group and C ₁ -C ₅ alkyl; or 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen and C ₁ -C ₅ alkyl.

According to another embodiment of the present invention, in chemical formula 1,

X stands for CH or N;

Z means O;

R ₁ is phenyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxy, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio, amino, di(C ₁ -C ₅ alkyl)amino, cyano, formyl, halo-C ₁ -C ₅ alkyl, hydroxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl, carbamoyloxy-C ₁ -C ₅ alkyl and C ₁ -C ₅ alkyl-C(O)OC ₁ -C ₅ alkyl; or 5- to 9-membered unsaturated heterocyclyl containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, hydroxy, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy and halo-C ₁ -C ₅ alkyl; and

R ₂ is phenyl, unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of halogen, deuterium, hydroxy group and C ₁ -C ₅ alkyl; or 6-membered heteroaryl containing 1 or 2 nitrogen atoms, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen and C ₁ -C ₅ alkyl.

According to another embodiment of the present invention, in chemical formula 1,

R ₁ is phenyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxy, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio, amino, di(C ₁ -C ₅ alkyl)amino, cyano, formyl, halo-C ₁ -C ₅ alkyl, hydroxy-C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl, carbamoyloxy-C ₁ -C ₅ alkyl and C ₁ -C ₅ alkyl-C(O)OC ₁ -C ₅ alkyl; 1,3-benzodioxolyl, unsubstituted or substituted with 1 or 2 halogen; or pyridyl or pyrimidinyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen, hydroxy, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy and halo-C ₁ -C ₅ alkyl, and

R ₂ is phenyl, unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of halogen, deuterium, hydroxy group and C ₁ -C ₅ alkyl; or pyridyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen and C ₁ -C ₅ alkyl.

According to another embodiment of the present invention, in chemical formula 1,

X stands for CH;

Z means O;

R ₁ is phenyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxy, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio, amino, halo-C ₁ -C ₅ alkyl, hydroxy-C ₁ -C ₅ alkyl and C ₁ -C ₅ alkoxy-C ₁ -C ₅ alkyl; and

R ₂ is pyridyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of halogen and C ₁ -C ₅ alkyl.

Typical compounds of chemical formula 1 provided in the present invention include:

6-(2-fluorophenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

2-phenoxymethyl-6-phenylimidazo[1,2-a]pyrimidine;

6-(2,4-difluorophenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(2-methoxyphenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(2-methylphenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methylphenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(2,3-difluorophenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(4-fluorophenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(3-aminophenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(2-aminophenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(3-amino-6-methylphenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(3-amino-4-fluorophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

6-(3-chloro-4-fluorophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

6-(2-dimethylaminophenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(2-chloro-4-fluorophenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(2-hydroxyphenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(3-hydroxyphenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-trifluoromethylphenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

6-(3,4-difluorophenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(2-methoxy-4-fluorophenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(4-fluoro-3-methoxyphenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(4-chloro-2-methoxyphenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(4-cyano-2-methoxyphenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(7-fluorobenzo[1,3]dioxol-4-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-hydroxymethylphenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methylthiophenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(2-amino-4-fluorophenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

6-(2,4-difluoro-5-methoxyphenyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

6-(2-fluoropyridin-3-yl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(6-methoxypyridin-3-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

6-(6-fluoropyridin-3-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

6-(4-methylpyridin-3-yl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(2,6-difluoropyridin-3-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

6-(6-chloropyridin-3-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

6-(2-fluoropyridin-4-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

6-(3-chloropyridin-4-yl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

6-(4-chlorophenyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(6-fluoro-4-methyl-3-pyridyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

6-(6-fluoro-5-methyl-3-pyridyl)-2-phenoxymethylimidazo[1,2-a]pyrimidine;

6-(5-fluoro-2-pyridyl)-2-phenyxymethylimidazo[1,2-a]pyrimidine;

6-(2,4-difluorophenyl)-2-(3-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methoxyphenyl)-2-(3-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-3-hydroxyphenyl)-2-(3-fluorophenoxymethyl)-imidazo[1,2-a]pyrimidine;

6-(2-aminophenyl)-2-(3-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

6-(3-chloropyridin-4-yl)-2-(3-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-methylpyridin-3-yl)-2-(3-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

6-(2,4-difluorophenyl)-2-(4-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methylphenyl)-2-(4-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

6-(3-chloropyridin-4-yl)-2-(4-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

6-(2,6-dimethylphenyl)-2-(4-fluorophenoxymethyl)imidazo[1,2-a]pyrimidine;

2-[(4-fluorophenoxy)methyl]-6-(6-fluoro-3-pyridyl)imidazo[1,2-a]pyrimidine;

4-[[6-(4-fluorophenyl)imidazo[1,2-a]pyrimidin-2-yl]methoxy]phenol;

2-[(4-fluorophenoxy)methyl]-6-(4-fluorophenyl)imidazo[1,2-a]pyrimidine;

2-[(3-fluorophenoxy)methyl]-6-(4-fluorophenyl)imidazo[1,2-a]pyrimidine;

2-fluoro-5-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]phenol;

2-[(4-fluorophenoxy)methyl]-6-phenylimidazo[1,2-a]pyrimidine;

5-fluoro-2-[2-[(3-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]phenol;

5-fluoro-2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]phenol;

6-(4-fluorophenyl)-2-[(2,3,4,5,6-pentadeuteriophenoxy)methyl]imidazo[1,2-a]pyrimidine;

2-[(4-fluorophenoxy)methyl]6-(o-tolyl)imidazo[1,2-a]pyrimidine;

6-(5-fluoro-2-methylphenyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

2-[(4-fluorophenoxy)methyl]-6-(2-fluoro-4-pyridyl)imidazo[1,2-a]pyrimidine;

2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]phenol;

6-(2-fluoro-4-methylphenyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

2-[(4-fluorophenoxy)methyl]-6-[6-(trifluoromethyl)-3-pyridyl]imidazo[1,2-a]pyrimidine;

2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

6-(2-chloro-4-fluorophenyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

4-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]-3-methoxybenzonitrile;

6-(4-chloro-2-methoxyphenyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

2-fluoro-5-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

6-(2,6-difluoro-3-pyridyl)-2-[(3-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

5-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]-2-methylaniline;

4,5-difluoro-2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]-5-methylaniline;

5-chloro-2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]-4-methylaniline;

5-fluoro-2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

2-[(4-fluorophenoxy)methyl]-6-(4-methyl-3-pyridyl)imidazo[1,2-a]pyrimidine;

2-[(3-fluorophenoxy)methyl]-6-(2-fluoro-4-pyridyl)imidazo[1,2-a]pyrimidine;

2-[(3-fluorophenoxy)methyl]-6-[6-(trifluoromethyl)-3-pyridyl)imidazo[1,2-a]pyrimidine;

2-[(3-fluorophenoxy)methyl]-6-(6-fluoro-3-pyridyl)imidazo[1,2-a]pyrimidine;

2-[(3-fluorophenoxy)methyl]-6-(2-fluoro-3-pyridyl)imidazo[1,2-a]pyrimidine;

6-(5,6-difluoro-3-pyridyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

5-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]-2-methoxyaniline;

2-[(4-fluorophenoxy)methyl]-6-(5-fluoro-2-pyridyl)imidazo[1,2-a]pyrimidine;

2-[(4-fluorophenoxy)methyl]-6-(5-methoxy-2-pyridyl)imidazo[1,2-a]pyrimidine;

6-(4-chloro-3-pyridyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

6-(5-chloro-3-pyridyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

2-[(4-fluorophenoxy)methyl]-6-(5-methoxy-3-pyridyl)imidazo[1,2-a]pyrimidine;

5-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]pyridin-2-ol;

6-(6-fluoro-5-methyl-3-pyridyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

2-[(4-fluorophenoxy)methyl]-6-(6-methyl-3-pyridyl)imidazo[1,2-a]pyrimidine;

2-[(3-fluorophenoxy)methyl]-6-(5-fluoro-2-pyridyl)imidazo[1,2-a]pyrimidine;

2-[(3-fluorophenoxy)methyl]-6-[4-fluoro-2-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine;

4-[2-[(3-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]-3-methoxybenzonitrile;

[5-fluoro-2-[2-[(3-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]phenyl]methanol;

[5-fluoro-2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]phenyl]methanol;

6-(4-fluoro-2-methylsulfanylphenyl)-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine;

2-[(4-fluorophenoxy)methyl]-6-(2-methoxy-4-pyridyl)imidazo[1,2-a]pyrimidine;

2-[2-[(3-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]-4-methylaniline;

5-fluoro-2-[2-[(3-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

6-(4-fluorophenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(2-methylphenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methoxyphenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(2,4-difluorophenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methylphenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(2,3-difluorophenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(5-fluoro-2-methylphenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(3-fluoro-2-methylphenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(7-fluoro-2H-benzo[1,3]dioxol-4-yl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-chloro-2-methoxyphenyl)-2-(pyridin-2-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(3-fluoro-2-methoxyphenyl)-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

6-[4-fluoro-2-(trifluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methylphenyl)-2-[(5-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

6-(2-ethylphenyl)-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methylphenyl)-2-[(4-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

6-(2-fluoro-4-methylphenyl)-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methoxyphenyl)-2-[(4-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

2-[(5-fluoro-2-pyridyl)oxymethyl]-6-[4-fluoro-2-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine;

6-(2,4-difluorophenyl)-2-[(4-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

6-(3-fluoro-2-methoxyphenyl)-2-[(4-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

6-(2,3-difluorophenyl)-2-[(4-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluorophenyl)-2-[(4-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

6-(3-fluoro-2-methylphenyl)-2-[(5-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

2-[(4-fluoro-2-pyridyl)oxymethyl]-6-[4-fluoro-2-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine;

2-[(5-fluoro-2-pyridyl)oxymethyl]-6-(o-tolyl)imidazo[1,2-a]pyrimidine;

6-(4-chloro-2-methylphenyl)-2-[(5-fluoro-2-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

6-(2,4-dimethylphenyl)-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;

2-(2-pyridyloxymethyl)-6-[6-(trifluoromethyl)-3-pyridyl]imidazo[1,2-a]pyrimidine;

2-[(5-fluoro-2-pyridyl)oxymethyl]-6-[6-(trifluoromethyl)-3-pyridyl]imidazo[1,2-a]pyrimidine;

6-(5-fluoro-2-pyridyl)-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

2-fluoro-5-[2-[(5-fluoro-2-pyridyl)oxymethyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

2-fluoro-5-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]aniline;

[5-fluoro-2-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl]methanol;

3-methoxy-4-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]benzonitrile;

4-[2-[(5-fluoro-2-pyridyl)oxymethyl]imidazo[1,2-a]pyrimidin-6-yl]-3-methoxybenzonitrile;

6-(4-fluoro-2-methylsulfanylphenyl)-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

[5-fluoro-2-[2-[(5-fluoro-2-pyridyl)oxymethyl]imidazo[1,2-a]pyrimidin-6-yl]phenyl]methanol;

4-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]benzonitrile;

6-[4-fluoro-2-(methoxymethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

[2-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]-5-(trifluoromethyl)phenyl]methanol;

6-(2-isopropylphenyl)-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

4-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]-3-(trifluoromethyl)benzaldehyde;

6-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluorophenyl)-2-(pyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methoxyphenyl)-2-(pyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(2,4-difluorophenyl)-2-(pyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methylphenyl)-2-(pyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-hydroxyphenyl)-2-(pyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methoxyphenyl)-2-(pyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(2,4-difluorophenyl)-2-(pyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(2-methylphenyl)-2-(5-fluoropyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methylphenyl)-2-(5-fluoropyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methoxyphenyl)-2-(5-fluoropyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-hydroxyphenyl)-2-(5-fluoropyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(2,4-difluorophenyl)-2-(6-fluoropyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methylphenyl)-2-(6-fluoropyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methylphenyl)-2-(2-fluoropyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methylphenyl)-2-(5-chloropyridin-3-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(2,4-difluorophenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methylphenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-methoxyphenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluorophenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(2,3-difluorophenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(2-fluorophenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-hydroxyphenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(2-methylphenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(2-hydroxyphenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluoro-2-hydroxymethylphenyl)-2-(2-fluoropyridin-4-yloxymethyl)imidazo[1,2-a]pyrimidine;

6-(4-fluorophenyl)-2-[(5-fluoro-3-pyridyl)oxymethyl)imidazo[1,2-a]pyrimidine;

2-[(2-chloro-4-pyridyl)oxymethyl]-6-(4-fluorophenyl)imidazo[1,2-a]pyrimidine;

2-[(5-fluoro-3-pyridyl)oxymethyl]-6-[4-fluoro-2-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine;

2-[(2-fluoro-4-pyridyl)oxymethyl]-6-[4-fluoro-2-(trifluoromethyl)phenyl]imidazo[1,2-a]pyrimidine;

5-fluoro-2-[2-[(5-fluoro-3-pyridyl)oxymethyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

5-fluoro-2-[2-[(2-fluoro-4-pyridyl)oxymethyl]imidazo[1,2-a]pyrimidin-6-yl]aniline;

[5-fluoro-2-[2-[(5-fluoro-3-pyridyl)oxymethyl]imidazo[1,2-a]pyrimidin-6-yl]phenyl]methanol;

2-(2,4-difluorophenyl)-6-(phenoxymethyl)imidazo[1,2-b][1,2,4]triazine;

2-(2,4-difluorophenyl)-6-((pyridin-4-yloxy)methyl)imidazo[1,2-b][1,2,4]triazine;

2-(2,4-difluorophenyl)-6-((pyridin-2-yloxy)methyl)imidazo[1,2-b][1,2,4]triazine;

2-(4-fluorophenyl)-6-((pyridin-4-yloxy)methyl)imidazo[1,2-b][1,2,4]triazine;

2-(2-methylphenyl)-6-((pyridin-4-yloxy)methyl)imidazo[1,2-b][1,2,4]triazine;

2-(2,4-difluorophenyl)-6-((2-fluoropyridin-4-yloxy)methyl)imidazo[1,2-b][1,2,4]triazine;

2-(4-fluoro-2-methylphenyl)-6-((2-fluoropyridin-4-yloxy)methyl)imidazo[1,2-b][1,2,4]triazine;

2-(2-methylphenyl)-6-((2-fluoropyridin-4-yloxy)methyl)imidazo[1,2-b][1,2,4]triazine;

2-[4-fluoro-2-(trifluoromethyl)phenyl]-6-(2-pyridyloxymethyl)imidazo[1,2-b][1,2,4]triazine;

2-(3-fluoro-2-methylphenyl)-6-(2-pyridyloxymethyl)imidazo[1,2-b][1,2,4]triazine;

2-(4-fluoro-2-methylphenyl)-6-(2-pyridyloxymethyl)imidazo[1,2-b][1,2,4]triazine;

2-[4-chloro-2-(trifluoromethyl)phenyl]-6-(2-pyridyloxymethyl)imidazo[1,2-b][1,2,4]triazine;

2-(4-chloro-2-methylphenyl)-6-(2-pyridyloxymethyl)imidazo[1,2-b][1,2,4]triazine;

2-(4-fluoro-2-methylphenyl)-6-(2-pyridyloxymethyl)imidazo[1,2-b][1,2,4]triazine;

2-(4-fluoro-2-methylphenyl)-6-[(5-fluoro-2-pyridyl)oxymethyl]imidazo[1,2-b][1,2,4]triazine;

[5-fluoro-2-[2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidin-6-yl]phenyl]methylcarbamate;

[5-fluoro-2-[2-(phenoxymethyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl]methylcarbamate;

[5-fluoro-2-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl]methylcarbamate;

[5-fluoro-2-[2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidin-6-yl]phenyl]methyl acetate;

6-[2-(chloromethyl)-4-fluorophenyl]-2-[(4-fluorophenoxy)methyl)imidazo[1,2-a]pyrimidine;

6-[4-fluoro-2-(fluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine; And

6-[4-fluoro-2-(fluoromethyl)phenyl]-2-[(4-fluorophenoxy)methyl]imidazo[1,2-a]pyrimidine.

More preferred typical compounds of chemical formula 1 provided in the present invention include:

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-methylphenyl)-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.

The imidazopyrimidine or imidazotriazine of chemical formula 1 can be prepared using known compounds or compounds that can be easily prepared by a person skilled in the art of compound synthesis. In particular, the method for preparing the compound of chemical formula 1 is described in detail in International Application Publication No. WO 2016/137260 A1, which is incorporated herein by reference. The compound of chemical formula 1 can be chemically synthesized according to a method described in the literature, and the following is just one typical method, but the scope of the present invention is not limited since the order of individual operations in each case can be selected selectively.

Imidazopyrimidine or imidazotriazine of chemical formula 1 can be used to prevent, alleviate, or treat cognitive impairment, or to improve cognitive function.

Imidazopyrimidine or imidazotriazine of chemical formula 1 can also be used to prevent, relieve, or treat symptoms of cognitive impairment.

Symptoms of cognitive impairment may manifest in many ways, including decreased memory, decreased attention, decreased language proficiency, decreased spatial-temporal ability, decreased comprehension, decreased judgment, disorganized thinking, slow thinking, difficulty understanding, poor concentration, loss of problem solving ability, unstable memory, difficulty expressing thoughts, difficulty integrating thoughts, feelings, and behavior, or difficulty eliminating inappropriate thoughts. These symptoms manifest as repeating the same words, repeating the same questions, difficulty communicating content due to loss, loss of direction, and inaccurate recall of names, times, or places.

In one embodiment, an imidazopyrimidine or imidazotriazine of chemical formula 1 can be used to alleviate or treat a cognitive impairment-related disorder.

The disorder associated with cognitive impairment may comprise one or more selected from the group consisting of: mild cognitive impairment, Alzheimer's disease, Alzheimer's type dementia, presenile dementia, early onset Alzheimer's disease, senile dementia, dementia with Lewy bodies, microinfarct dementia, AIDS-related dementia, HIV dementia, Lewy body-related dementia, Down syndrome-related dementia, Pick's disease, early short-term memory impairment, age-related cognitive impairment, age-related memory impairment, drug-related cognitive impairment, immunodeficiency syndrome-related cognitive impairment, vascular-related cognitive impairment, schizophrenia-related cognitive impairment, Parkinson's disease-related cognitive impairment, epilepsy-related cognitive impairment, depression-related cognitive impairment cognitive impairment, bipolar disorder-associated cognitive impairment, obsessive-compulsive disorder-associated cognitive impairment, post-traumatic stress disorder, attention deficit disorder, attention deficit hyperactivity disorder, and learning disorder.

In one embodiment, the cognitive impairment-related disease is selected from the group consisting of: mild cognitive impairment, Alzheimer's disease, dementia of the Alzheimer's type, presenile dementia, early onset Alzheimer's disease, senile dementia, early short-term memory impairment, age-related cognitive impairment, age-related memory impairment, drug-related cognitive impairment, and schizophrenia-related cognitive impairment.

Therefore, the drug or pharmaceutical composition provided in the present invention can be used for preventing, alleviating or treating diseases associated with cognitive impairment, but the scope of the present invention is not limited to these diseases.

In addition, the medicament or pharmaceutical composition provided in the present invention can be used to prevent, alleviate or treat symptoms of cognitive impairment, and the symptoms include, but are not limited to, decreased attention, decreased language proficiency, decreased spatial-temporal ability, decreased comprehension ability or decreased judgment.

The efficacy of the compound of chemical formula 1 for cognitive impairment can be tested using a known model. As an animal model related to the prevention and treatment of cognitive impairment, an animal model in which cognition is impaired by the administration of a cognitive inhibitor can be used. As an animal model for improving cognitive function, a natural forgetting model in which natural forgetting occurs over time can be used. Of these, an animal model in which cognition is impaired by the action of dizocilpine (MK-801) is widely used as a drug efficacy test tool for developing therapeutic agents for the treatment of cognitive impairment (NMWJ de Bruin et al., Neurobiology of learning and memory , 2016, Vol. 133, p. 100-117). The rat model of natural forgetting is also used as a drug efficacy test to develop therapeutics to enhance cognitive function (MV King et al., Neuropharmacology 47 (2004) 195–204 ) .

The dose of imidazopyrimidine or imidazotriazine of chemical formula 1 for preventing, alleviating or treating a disease usually varies depending on the severity of the disease and the body weight and metabolic status of the subject being treated. "Therapeutically effective amount" for an individual patient means an amount sufficient to provide the above-mentioned pharmacological effect, namely, a therapeutic effect. In a therapeutically effective amount of the compound of chemical formula 1, the compound can be contained in a pharmaceutical composition in an amount of 0.1 to 500 mg/kg (body weight), preferably 0.5 to 100 mg/kg (body weight) per day when administered to mammals including humans. Such a pharmaceutical composition can be administered once a day or administered in divided doses of two or more times per day.

The compound of the present invention can be administered by conventional methods used for administering therapeutic agents, such as oral, parenteral, intravenous, intramuscular, subcutaneous or rectal administration.

The medicament or pharmaceutical composition in one embodiment of the present invention may comprise a therapeutically effective amount of a compound selected from the group consisting of imidazopyrimidines or imidazotriazines provided in the present invention, their pharmaceutically acceptable salts, solvates or hydrates, and combinations thereof.

Pharmaceutically acceptable salts include acid addition salts or base addition salts and stereochemically isomeric forms thereof. A salt includes any salt that retains the activity of the parent compound in the subject to which it is administered and does not produce undesirable effects and is not particularly limited. Such a salt includes inorganic and organic salts, and can be, for example, salts of acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, ethanesulfonic acid, lactic acid, bicarboxylic acid, bisulfates, bitactrates, oxalic acid, butyric acid, calcium ethylenediaminetetraacetate, camsilic acid, carbonic acid, chlorobenzoic acid, citric acid, ethylenediaminetetraacetic acid, toluenesulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, pamoic acid, gluconic acid, glucolilarsanilic acid, methyl nitric acid, polygalacturonic acid, hexylresorcinol, malonic acid, hydroxybamic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactobionic acid, mandelic acid, lauryl sulfuric acid, mucic acid, napsylic acid, muconic acid, p-nitromethanesulfonic acid, hexamino acid, pantothenic acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, salicylic acid, sulfamic acid, sulfanilic acid, methanesulfonic acid or α-lipoic acid. In addition, the salt form with a base includes, for example, alkali metal and alkaline earth metal salts such as ammonium salts, lithium salts, sodium salts, potassium salts, magnesium salts and calcium salts; for example, salts with organic bases such as benzathine, N-methyl-D-glucamine, hydrabamine; and, for example, salts with amino acids such as arginine and lysine. The salt form can also be converted into the free form by treatment with a suitable base or acid. The term "addition salt" includes solvates that a compound of chemical formula 1 and its salts can form. Such solvates are, for example, hydrates and alcoholates.

The drug or pharmaceutical composition in one embodiment of the present invention may be suitable for oral administration or parenteral administration, preferably for oral administration. In the case of parenteral administration, the drug or pharmaceutical composition may be suitable for parenteral administration such as intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, local administration, nasal administration, vaginal administration, intrapulmonary administration or rectal administration. In the case of oral administration, the drug or pharmaceutical composition of the present invention can be prepared in the form of powders, granules, tablets, pills, sugar-coated tablets, capsules, liquids, gels, syrups, suspensions, wafers and the like according to methods known in the art. The pharmaceutical composition in one embodiment can be prepared without a coating or with a coating of an active agent or protected from degradation in the stomach. The composition may be administered by any device capable of transporting the active agent to the target cell. The route of administration may vary depending on the general health and age of the subject being treated, the nature of the treatment conditions, and the active agent selected.

A suitable dose of the drug or pharmaceutical composition in one embodiment of the present invention varies depending on factors such as the method of preparation, the mode of administration, and the age, body weight, sex, pathological condition, diet, time of administration, route of administration, rate of excretion and sensitivity of the patient. A physician of general training can readily determine and prescribe a dosage effective for the desired treatment or prophylaxis. The pharmaceutical composition in one embodiment can be administered in single or multiple doses, for example, can be administered in divided doses from 1 to 4 times per day. The pharmaceutical composition in one embodiment can contain from 0.1 to 500 mg/kg (body weight), preferably from 0.5 to 100 mg/kg (body weight) of the compound of chemical formula 1.

The drug or pharmaceutical composition in one embodiment of the present invention can be prepared in the form of a single dose by preparation using a pharmaceutically acceptable carrier and/or excipient or by placing in a multi-dose container according to a technique that can be easily performed by a person with general training in the art to which the present invention pertains. In this case, the preparation can be in the form of a solution, suspension or emulsion in an oily or aqueous medium, can be in the form of an extract, powder, granule, tablet or capsule, and can further contain a dispersing agent or a stabilizing agent. The pharmaceutical composition can be administered in the form of a suppository, spray, ointment, cream, gel, inhalant or skin patch. The pharmaceutical composition can be prepared for administration to a mammal, more preferably for administration to a human.

The pharmaceutically acceptable carrier may be solid or liquid and may be one or more selected from the group consisting of a filler, an antioxidant, a buffer, a bacteriostatic, a dispersing agent, an adsorbent, a surfactant, a binder, a preservative, a disintegrating agent, a sweetener, a flavoring agent, a glidant, a mold release agent, a wetting agent, a stabilizing agent, a suspending agent, and a lubricant. The pharmaceutically acceptable carrier may be selected from the group consisting of saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and any mixture thereof.

In one embodiment, suitable excipients may include, but are not limited to, sugars (e.g., dextrose, sucrose, maltose, and lactose), starch (e.g., corn starch), hydroxy sugars (e.g., mannitol, sorbitol, maltitol, erythritol, and xylitol), starch hydrolysates (e.g., dextrin and maltodextrin), cellulose or cellulose derivatives (e.g., microcrystalline cellulose), or any mixture thereof.

In one embodiment, a suitable binder may include, but is not limited to, magnesium aluminum silicate, povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, acacia, sucrose, starch paste, or any mixture thereof.

In one embodiment, a suitable preservative may include, but is not limited to, benzoic acid, sodium benzoate, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, gallate, hydroxybenzoate, EDTA, or any mixture thereof.

In one embodiment, a suitable disintegrant may be sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starch, microcrystalline cellulose, or any mixture thereof, but is not limited to these.

In one embodiment, a suitable sweetener may include, but is not limited to, sucralose, saccharin, sodium or potassium or calcium salt of saccharin, acesulfame potassium or sodium cyclamate, mannitol, fructose, sucrose, maltose, or any mixture thereof.

In one embodiment, silicon dioxide, colloidal silicon dioxide, talc, etc. can be used as a suitable glidant, but the glidant is not limited to them.

In one embodiment, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glyceride wax, or any mixture thereof, can be used as a suitable lubricant, but the lubricant is not limited to them.

An imidazopyrimidine or imidazotriazine of chemical formula 1 may be used in combination with an additional drug to prevent, alleviate, or treat cognitive impairment, or to improve cognitive function.

Accordingly, the drug or pharmaceutical composition proposed in the present invention may be a combination preparation containing an imidazopyrimidine or imidazotriazine of chemical formula 1 and such an additional drug as an active ingredient in a therapeutically effective amount.

As such an additional medicinal product, one or more selected from the group consisting of the following can be used, for example: dimethylamylamine, methylphenidate, amphetamine, tacrine, rivastigmine, galantamine, donepezil, memantine, tolcapone, levodopa, atomoxetine, clonidine, pramipexole, guanfacine and fexofenadine.

Therefore, the medicament or pharmaceutical composition in one embodiment of the present invention may further comprise one or more medicaments selected from the group consisting of dimethylamylamine, methylphenidate, amphetamine, tacrine, rivastigmine, galantamine, donepezil, memantine, tolcapone, levodopa, atomoxetine, clonidine, pramipexole, guanfacine and fexofenadine.

In one embodiment, if the medicament or pharmaceutical composition according to the present invention is a combination preparation, the ratio in the mixture (a:b) of the weight of the imidazopyrimidine or imidazotriazine of chemical formula 1 [component (a)] to the weight of the additional medicament [component (b)] in the combination preparation may be, for example, in the range of from 1,000:1 to 1:1000, or from 500:1 to 1:500, or from 100:1 to 1:100, or from 50:1 to 1:50, or from 10:1 to 1:10, but is not limited thereto.

As used in the present invention, the terms "prevent" and "prevention" mean reducing or eliminating the likelihood of a disease occurring.

When used in the present invention, the terms "alleviate" and "alleviate" mean alleviating a disease and/or all or part of its symptoms.

When used in the present invention, the terms "treat" and "treatment" mean eliminating a disease and/or all or part of its symptoms.

As used herein, the term "subject" means animals, preferably mammals (e.g., primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc.), most preferably humans, who are the objects of treatment, observation, or study.

As used herein, the term "therapeutically effective amount" means an amount of an active compound or pharmaceutical agent that produces a biological or medical response in an animal or human tissue system that is desired by a researcher, veterinarian, physician or other clinician, and includes alleviation of the symptoms of the disease or disorder being treated.

As used herein, the term "composition" includes products containing specified ingredients in specified amounts and arbitrary products that are directly or indirectly formed from combinations of specified ingredients in specified amounts.

As used herein, the term "cognitive impairment" means an impairment that exhibits atrophy in a cognitive function or cognitive domain of an animal, such as working memory, attention and arousal, language learning and memory, visual learning and memory, reasoning and problem solving, such as executive function, task processing speed, and/or social cognition. In particular, it is known that cognitive impairment can exhibit a lack of attention, disorganized thinking, slow thinking, difficulty in understanding, poor concentration, loss of problem solving ability, unstable memory, difficulty expressing thoughts, and/or difficulty integrating thoughts, sensations, and behavior, or difficulty eliminating inappropriate thoughts, and can be used interchangeably with the term "cognitive impairment."

[Beneficial effects of the invention]

The drug and pharmaceutical composition provided in the present invention can effectively prevent, alleviate or treat cognitive impairment, or improve cognitive function.

[Brief description of the drawings]

Fig. 1 shows the result showing the effect of the test compound (0.03, 0.1, and 0.3 mg/kg) in the cognitive impairment model of rats by administering dizocilpine in an object recognition study.

Fig. 2 shows the result showing the effect of the test compound (0.1, 0.3, and 1 mg/kg) in the cognitive impairment model of rats by administering dizocilpine in a Y-maze study.

Fig. 3 shows the result showing the effect of the test compound (0.1 and 0.3 mg/kg) in the natural forgetting model in rats in the object recognition study.

Fig. 4 shows the result showing the effect of the test compound (1 and 3 mg/kg) in the natural forgetting model in rats in the object recognition study.

[Description of embodiments]

The present invention is described in more detail below using examples. However, these examples are provided only to illustrate one or more embodiments and the scope of the present invention is not limited to them.

Example of obtaining: Obtaining the studied compound

According to the procedure 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 (the test compound) was obtained.

Example 1: Effect on cognitive impairment in rat models by administration of dizocilpine in an object recognition study

An animal model of cognitive impairment was used in which cognitive ability was reduced by administration of dizocilpine, a cognitive inhibitor.

Experimental animals

Male rats (Wistar, 4 weeks old, Orient Bio Co., Ltd.) were purchased and acclimatized for 1 week or more in an animal cage. The experimental animals were maintained in a light-controlled environment (light for 12 h/no light for 12 h) and stored and used in accordance with the standards for the care and use of laboratory animals established by the Institutional Animal Care and Use Committee (IACUC), and were maintained in an environment with a temperature of 19°C to 25°C and a relative humidity of 30% to 70%, and were given ad libitum access to water and food. The rats were stabilized for 1 week or more and then used in the object recognition study. The rats were randomly divided into groups, and the study was conducted under light.

Medicine

To generate a symptom-inducing cognitive decline animal model, experimental animals were administered dizocilpine, an N-methyl-D-aspartate (NMDA) receptor inhibitor.

Dizocilpine (purchased from Sigma) was dissolved in freshly prepared saline solution used as a diluent and administered subcutaneously at a dose of 0.1 mg/kg in a volume of 1 ml per 1 kg of rat body weight 30 min before training. The control group received only saline solution.

The test compound was dissolved in 5% DMSO (dimethyl sulfoxide) in 10% cremophor and administered orally 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 1 h before training. The control group was administered only the diluent (5% DMSO in 10% cremophor).

Object recognition research

Each rat was restrained by the experimenter for 3 min or more and acclimated to the box for 3 min twice in an empty box before the experiment. After administration of vehicle or test compound intraperitoneally at a dose of 1 mg/kg 1 h before training and vehicle or dizocilpine subcutaneously 30 min before training, the rats were placed in the training boxes. Training was performed by placing the rats in a box in which two identical plastic cylinders or two square stainless steel pyramids were placed. One hour after training, testing was performed in a box in which one plastic cylinder and one square stainless steel pyramid were placed. During the testing, the time it took the rat to find each object was determined. The results of the study were analyzed using a stainless steel square pyramid as a novel object for rats trained in a box containing two plastic cylinders, and a plastic cylinder as a novel object for rats trained in a box containing two stainless steel square pyramids.

Statistical analysis of experimental results

The recognition index was calculated based on the time it took to detect the object, the recognition index data between groups were analyzed using one-way analysis of variance (ANOVA) and Dunnett's multiple comparison test, and then the effect was determined to be significant if p<0.05. All results are presented as mean ± SEM.

Research results

The recognition index for the negative control group which was administered dizocilpine only was 49.77±1.03 sec and there was a significant decrease in cognitive function compared with the vehicle only group which was the positive control group and had a recognition index of 63.29±1.56 sec (P<0.001). When dizocilpine and the test compound were administered together, the recognition indices for the 0.1 mg/kg group and the 0.3 mg/kg group were 57.95±1.8 sec and 57.62±1.89 sec, respectively, and there was a significant recovery in cognitive function compared with the negative control group which had a decreased cognitive function (both P<0.01).

The results of the recognition index analysis for the cognitively impaired rat model with dizocilpine administration in the object recognition study using the test compound are shown in Table 1.

[Table 1] Results of recognition index analysis for the cognitively impaired rat model by dizocilpine administration in an object recognition study using the test compound The medicine used for treatment Dose Recognition index ¹⁾ (mean±SEM) Dizocilpine (mg/kg, sc ²⁾ ) Test compound (mg/kg, po ³⁾ ) Diluent NT ⁴⁾ NT 63.29±1.56 Dizocilpine 0,1 NT 49.77±1.03 Dizocilpine and test compound 0,1 0.03 51.95±1.79 Dizocilpine and test compound 0,1 0,1 57.95±1.8 Dizocilpine and test compound 0,1 0.3 57.62±1.89 ¹⁾ Recognition index = time of detection of a new object/total detection time (identical object + new object) × 100;
²⁾ sc = Subcutaneous;
³⁾ po = Oral administration (per os);
⁴⁾ NT = Not entered.

These data confirmed a synergistic increase in the effect of restoring impaired cognitive function as a result of the administration of the test compound.

Example 2: Effect on a rat model of cognitive impairment by administration of dizocilpine in a Y-maze study

Experimental animals

Male rats (Wistar, 4 weeks old, Orient Bio Co., Ltd.) were purchased and acclimatized for 1 week or more in an animal cage. The experimental animals were maintained in a light-controlled environment (light for 12 h/no light for 12 h) and stored and used in accordance with the standards for the care and use of laboratory animals established by the Institutional Animal Care and Use Committee and were maintained in an environment with a temperature of 19°C to 25°C and a relative humidity of 30% to 70% and were given ad libitum access to water and food. The rats were stabilized for 1 week or more and then used in the Y-maze study. The rats were randomly divided into groups and the study was conducted under light.

Medicine

To generate a symptom-inducing animal model of cognitive decline, experimental animals were administered dizocilpine, an NMDA receptor inhibitor.

Dizocilpine (purchased from Sigma) was dissolved in freshly prepared saline solution used as a diluent and administered subcutaneously at a dose of 0.1 mg/kg in a volume of 1 ml per 1 kg of rat body weight 30 min before training. The control group received only saline solution.

The test compound was dissolved in 5% DMSO in 9.5% cremophor and administered orally at doses of 0.1, 0.3, and 1 mg/kg in a volume of 5 ml per 1 kg of rat body weight 1 h before training. The control group was administered only the diluent (5% DMSO in 9.5% cremophor).

Exploration with the Y-maze

Rats were restrained by the experimenter for 3 min for 2 days and the Y-maze trial was conducted the following day. After administration of vehicle or test compound intraperitoneally 1 h before the trial and vehicle or dizocilpine subcutaneously 30 min before the trial, the Y-maze trial was conducted for 5 min by placing the rat at the end of one arm of the Y-maze and allowing the rat to move freely. The three arms, positioned at equal angles in the Y-maze, had the same length of 45 cm, the same width of 10 cm and the same height of 20 cm. An instance in which a rat visited three different arms in succession was defined as alternating behavior.

Statistical analysis of experimental results

Alternation frequency was determined by identifying the rat's alternating behavior from the recorded visit to each arm in the Y-maze trial, alternation frequency data between groups were analyzed using one-way ANOVA and Dunnett's multiple comparison test, and the effect was considered significant if p<0.05. All results are presented as mean ± SEM.

Research results

The alternation frequency for the negative control group, which was given dizocilpine only, was 49.2±5.3 sec, and there was a significant decrease in cognitive function compared with the vehicle group, which was the positive control group, which had an alternation frequency of 70.1±2.8 sec (P<0.001). When dizocilpine and the test compound were administered together, the alternation frequency for the 0.1 mg/kg group was 67.3±3.5 sec, and there was a significant recovery in cognitive function compared with the negative control group, which had decreased cognitive function (P<0.001).

The alternation frequency for the group of animals administered 0.3 mg/kg of the test compound was 57.3±5.7 s and there was a tendency towards restoration of cognitive function compared to the control group with reduced cognitive function.

The results of the alternation frequency analysis in a rat model in which cognitive ability was reduced by dizocilpine administration in a Y-maze study using the test compound are shown in Table 2.

[Table 2] Results of alternation frequency analysis for a rat model with cognitive impairment due to dizocilpine administration in a Y-maze study using the test compound The medicine used for treatment Dose Alternation frequency ¹⁾ (mean±SEM) Dizocilpine (mg/kg, sc ²⁾ ) Test compound (mg/kg, po ³⁾ ) Diluent NT ⁴⁾ NT 70.1±2.8 Dizocilpine 0,1 NT 49.2±5.3 Dizocilpine and test compound 0,1 0,1 67.3±3.5 Dizocilpine and test compound 0,1 0.3 57.3±5.7 Dizocilpine and test compound 0,1 1 49.9±7.2 ¹⁾ Frequency of alternation = number of actual instances of alternating behavior/maximum possible number of instances of alternating behavior × 100;
[maximum possible number of alternating behavior cases = total number of studies - 2]
²⁾ sc = Subcutaneous;
³⁾ po = Oral administration (per os);
⁴⁾ NT = Not entered.

These data confirmed a synergistic increase in the effect of restoring impaired cognitive function as a result of the administration of the test compound.

Example 3: Effect on natural forgetting model in rats in object recognition study

A natural forgetting model, in which natural forgetting occurs over time, was used as an animal model of cognitive impairment.

Experimental animals

Male rats (Wistar, 4 weeks old, Orient Bio Co., Ltd.) were purchased and acclimatized for 1 week or more in an animal cage. The experimental animals were maintained in a light-controlled environment (light for 12 h/no light for 12 h) and stored and used in accordance with the standards for the care and use of laboratory animals established by the Institutional Animal Care and Use Committee and were maintained in an environment with a temperature of 19°C to 25°C and a relative humidity of 30% to 70% and were given ad libitum access to water and food. The rats were stabilized for 1 week or more and then used in the object recognition study. The rats were randomly divided into groups and the study was conducted under light.

Medicine

The test compound was dissolved in 5% DMSO in 10% cremophor and administered orally at a dose of 1 mg/kg 1 h before training. The control group received only the vehicle (5% DMSO in 10% cremophor).

Object recognition research

Each rat was restrained by the experimenter for 3 min or more and acclimatized twice in an empty box for 3 min before the experiment. After intraperitoneal administration of the diluent or test compound at a dose of 1 mg/kg 1 h before training, the rats were placed in the boxes for training. Training was performed by placing the rats in a box containing two identical plastic cylinders or two square stainless steel pyramids. Twenty-four hours after training, a study was performed in a box containing one plastic cylinder and one square stainless steel pyramid. During the study, the time it took the rat to find each object was determined. The results of the study were analyzed using the square stainless steel pyramid as a novel object for rats trained in a box containing two plastic cylinders and the plastic cylinder as a novel object for rats trained in a box containing two square stainless steel pyramids.

Statistical analysis of experimental results

The recognition index was calculated based on the time it took to detect the object, the recognition index data between groups were analyzed using one-way ANOVA and Dunnett's multiple comparison test, and then the effect was determined to be significant if p<0.05. All results are presented as mean ± SEM.

Research results

The experiment was performed twice according to the dose of the test compound. In the first experiment, the recognition index for the group of animals that were administered the diluent, which was the control group, was 48.61±1.87 s and was not statistically different from 50, which was the recognition index when the animals of the group could not distinguish an identical object from a new object, but observed it for exactly the same time, and thus confirmed that sufficient natural forgetting occurred within 24 hours.

When the test compound was administered at 0.1 mg/kg and 0.3 mg/kg, the recognition indices were 56.57±2.37 s and 59.77±2.64 s, respectively, and were significantly different from the values for the control group, in which natural forgetting occurred (P<0.05, P<0.01, respectively).

The results of the recognition index analysis in the natural forgetting model in rats in the object recognition study using the test compound (0.1 mg/kg and 0.3 mg/kg) are shown in Table 3.

[Table 3] Results of recognition index analysis in rat natural forgetting model in object recognition study using test compound (0.1 mg/kg and 0.3 mg/kg) The medicine used for treatment Dose of the test compound (mg/kg, po ²⁾ ) Recognition index ¹⁾ (mean±SEM) Diluent NT ³⁾ 48.61±1.87 Compound under study 0,1 56.57±2.37 Compound under study 0.3 59.77±2.64 ¹⁾ Recognition index = time of detection of a new object/total detection time (identical object + new object) × 100;
²⁾ po = Oral administration (per os);
³⁾ NT = Not entered.

And in the second experiment, the recognition index for the group of animals that were injected with the diluent, which was the control group, was 51.20±2.61 s and was not statistically different from 50, which was the recognition index when the animals of the group could not distinguish an identical object from a new object, but observed it for exactly the same amount of time, and thus confirmed that sufficient natural forgetting occurred within 24 hours.

When the test compound was administered at 1 mg/kg, the recognition index was 60.91±2.72 s and was significantly different from the value of the control group in which natural forgetting occurred (P<0.01). The recognition index for the group in which the animals were administered 3 mg/kg of the test compound was 56.20±2.27 s, indicating that natural forgetting was reduced compared with the control group in which natural forgetting occurred.

The results of the recognition index analysis in the natural forgetting model in rats in the object recognition study using the test compound (1 mg/kg and 3 mg/kg) are shown in Table 4.

[Table 4] Results of recognition index analysis in rat natural forgetting model in object recognition study using test compound (1 mg/kg and 3 mg/kg) The medicine used for treatment Dose of the test compound
(mg/kg, po ²⁾ ) Recognition index ¹⁾ (mean±SEM) Diluent NT ³⁾ 51.20±2.61 Compound under study 1 60.91±2.72 The medicine used for treatment 3 56.20±2.27 ¹⁾ Recognition index = time of detection of a new object/total detection time (identical object + new object) × 100;
²⁾ po = Oral administration (per os);
³⁾ NT = Not entered.

Using experimental data in such a natural forgetting model, the effect of the test compound on natural forgetting was confirmed by improving cognitive function in a normal cognitive state.

Claims (18)

1. A method for preventing, alleviating or treating cognitive impairment or improving cognitive function in a subject, which comprises administering to the subject a therapeutically effective amount of 6-[4-fluoro-2-(trifluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine or a pharmaceutically acceptable salt, solvate or hydrate thereof. 2. The method according to claim 1, which is intended for the prevention, relief or treatment of symptoms of cognitive impairment. 3. The method according to claim 1, wherein the symptoms of cognitive impairment are decreased attention, decreased language proficiency, decreased spatiotemporal ability, decreased ability to comprehend, or decreased judgment. 4. The method according to claim 1, which is intended to alleviate or treat a disease associated with cognitive impairment. 5. The method of claim 4, wherein the disorder associated with cognitive impairment is selected from the group consisting of the following: mild cognitive impairment, Alzheimer's disease, Alzheimer's type dementia, presenile dementia, early onset Alzheimer's disease, senile dementia, dementia with Lewy bodies, microinfarction dementia, AIDS-associated dementia, HIV dementia, Lewy body-associated dementia, Down syndrome-associated dementia, Pick's disease, early short-term memory impairment, age-associated cognitive impairment, age-associated memory impairment, drug-associated cognitive impairment, immunodeficiency syndrome-associated cognitive impairment, vascular disease-associated cognitive impairment, schizophrenia-associated cognitive impairment, Parkinson's disease-associated cognitive impairment, epilepsy-associated cognitive impairment, depression-associated cognitive impairment cognitive impairment, cognitive impairment associated with bipolar disorder, cognitive impairment associated with obsessive-compulsive disorder, post-traumatic stress disorder, attention deficit disorder, attention deficit hyperactivity disorder, and learning disorder. 6. The method of claim 5, wherein the cognitive impairment disorder is selected from the group consisting of: mild cognitive impairment, Alzheimer's disease, Alzheimer's type dementia, presenile dementia, early onset Alzheimer's disease, senile dementia, early short-term memory impairment, age-related cognitive impairment, age-related memory impairment, drug-related cognitive impairment, and schizophrenia-related cognitive impairment. 7. The method according to claim 1, wherein the subject is a mammal. 8. The method according to claim 1, wherein 0.1 to 500 mg/kg of body weight of 6-[4-fluoro-2-(trifluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine is administered. 9. The method of claim 1, wherein one or more drugs selected from the group consisting of the following are additionally administered: dimethylamylamine, tacrine, rivastigmine, galantamine, donepezil, memantine, tolcapone, levodopa, atomoxetine, clonidine, pramipexole, guanfacine, and fexofenadine. 10. Use of 6-[4-fluoro-2-(trifluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine or a pharmaceutically acceptable salt, solvate or hydrate thereof for the prevention, alleviation or treatment of cognitive impairment, or for improving cognitive function. 11. The use according to item 10, which is intended for the prevention, relief or treatment of symptoms of cognitive impairment. 12. Use according to claim 11, where the symptoms of cognitive impairment were decreased attention, decreased language proficiency, decreased spatiotemporal ability, decreased ability to comprehend, or decreased judgment. 13. The use according to paragraph 10, which is intended for the alleviation or treatment of a disorder associated with cognitive impairment. 14. The use according to claim 13, wherein the disorder associated with cognitive impairment is selected from the group consisting of the following: mild cognitive impairment, Alzheimer's disease, Alzheimer's type dementia, presenile dementia, early onset Alzheimer's disease, senile dementia, dementia with Lewy bodies, microinfarction dementia, AIDS-associated dementia, HIV dementia, Lewy body-associated dementia, Down syndrome-associated dementia, Pick's disease, early short-term memory impairment, age-associated cognitive impairment, age-associated memory impairment associated with a drug, cognitive impairment associated with immunodeficiency syndrome, cognitive impairment associated with vascular disease, cognitive impairment associated with schizophrenia, cognitive impairment associated with Parkinson's disease, cognitive impairment associated with epilepsy, cognitive impairment associated with depression-related cognitive impairment, bipolar disorder-related cognitive impairment, obsessive-compulsive disorder-related cognitive impairment, post-traumatic stress disorder, attention deficit disorder, attention deficit hyperactivity disorder, and learning disorder. 15. The use according to claim 14, wherein the disorder associated with cognitive impairment is selected from the group consisting of the following: mild cognitive impairment, Alzheimer's disease, dementia of the Alzheimer's type, presenile dementia, early onset Alzheimer's disease, senile dementia, early short-term memory impairment, age-related cognitive impairment, age-related memory impairment, drug-related cognitive impairment, and schizophrenia-related cognitive impairment. 16. The use according to paragraph 10, which is intended for administration to a mammal. 17. Use according to paragraph 10, where from 0.1 to 500 mg/kg body weight of 6-[4-fluoro-2-(trifluoromethyl)phenyl]-2-(2-pyridyloxymethyl)imidazo[1,2-a]pyrimidine is used. 18. The use according to claim 10, wherein one or more drugs selected from the group consisting of the following are additionally used: dimethylamylamine, tacrine, rivastigmine, galantamine, donepezil, memantine, tolcapone, levodopa, atomoxetine, clonidine, pramipexole, guanfacine and fexofenadine.

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