RU2783208C2 - Agent for inhibition of increase in intra-neural calcium concentration - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to inhibition of an increase in an intra-neural calcium concentration. The use of an agent for inhibition of an increase in an intra-neural calcium concentration is disclosed, where the agent includes a cyclic amine derivative of the formula (I) or its pharmaceutically acceptable salt, where A is a group of the formula (IIa), (IIb), or (IIc):

,

,

where R¹ is a hydroxyl group or a hydrogen atom, R² is a methyl group, an ethyl group, n-propyl group, an isopropyl group, n-butyl group, a difluoromethyl group, or 2,2,2-trifluoroethyl group, R³ is a hydrogen atom, a fluorine atom, a bromine atom, or a chlorine atom, each R⁴ is independently a methyl group or an ethyl group, n has a value of 1 or 2, when R¹ is a hydroxyl group, carbon marked with *, an asymmetrical carbon atom. The use of a cyclic amine derivative for the treatment or prevention of a disease related to neuron hyperexcitability is also disclosed.

EFFECT: group of inventions provides expansion of the arsenal of means of a specific purpose.

21 cl, 5 tbl, 4 ex

Description

The field of technology to which the invention belongs

[0001]

The present invention relates to an agent for inhibiting the increase in intraneuronal calcium concentration.

Prerequisites for the creation of the invention

[0002]

Intracellular calcium in neurons plays a very important role as a mediator of intracellular signal transduction in the regulation of cell functions such as differentiation, proliferation, growth, survival, apoptosis, gene transcription, membrane excitation, neurotransmitter release and synaptic plasticity (non-patent literature 1 and 2).

[0003]

The intracellular calcium concentration is maintained at a level of several tens to hundreds of nmol/l in the normal state, while the intracellular calcium concentration increases from several hundred nmol/l to several tens of µmol/l with various cell stimulation. This increase in intracellular calcium concentration causes various vital reactions. After the completion of the necessary vital reactions, the intracellular calcium concentration is restored to a normal level. Thus, for the normal implementation of cell functions, it is important to strictly control the intracellular concentration of calcium flowing into or out of cells through various receptors, ion channels, etc.

[0004]

In neurons, excitatory transmission, which is an important function of neurons, occurs when intracellular calcium concentration increases. If the intraneuronal calcium concentration goes out of strict control for any reason, an abnormal increase in the intraneuronal calcium concentration occurs, which, as a result, causes many nervous diseases and nervous disorders. This abnormal increase in intraneuronal calcium concentration is indicated, for example, by intraneuronal calcium concentration outside the normal range, the length of the period of increase in intraneuronal calcium concentration outside the normal range, or the number of increases in intraneuronal calcium concentration per unit of time outside the normal range. For example, epilepsy is considered as a disease caused by abnormal excitation of brain neurons, in particular, by an abnormal increase in the number of increases in intraneuronal calcium concentration per unit time. Gabapentin, a therapeutic agent for epilepsy, is known to bind to a voltage-gated calcium channel presynaptically present in excitatory neurons and inhibit excitatory synaptic transmission, thereby exerting an antiepileptic effect (Non-Patent Literature 3). Thus, agents for inhibiting the increase in intraneuronal calcium concentration are useful for the prevention or treatment of various neuronal diseases and disorders caused by neuronal hyperexcitability associated with an increase in intraneuronal calcium concentration.

[0005]

Patent Literature 1 and 2 disclose that cyclic amine derivatives have an analgesic effect, but do not disclose or suggest their effects of inhibiting the increase in intraneuronal calcium concentration.

Bibliography

Patent Literature

[0006]

Patent Literature 1: International Publication WO 2013/147160

Patent Literature 2: International Publication WO 2016/136944

Non-Patent Literature

[0007]

Non-Patent Literature 1: Berridge, Neuron, 1998, vol. 21, p. 13-26

Non-Patent Literature 2: Pchitskaya et al., Cell Calcium, 2018, vol. 70, p. 87-94

Non-Patent Literature 3: Fink et al., British Journal of Pharmacology, 2000, vol. 130, p. 900-906

The essence of the invention

Technical task

[0008]

The purpose of the present invention is to provide an agent for inhibiting the increase in intraneuronal calcium concentration.

The solution of the problem

[0009]

As a result of intensive research aimed at achieving the above object, the present inventors have found that a cyclic amine derivative or a pharmacologically acceptable salt thereof has a marked inhibitory effect on the increase in intraneuronal calcium concentration.

[0010]

Specifically, the present invention provides an agent for inhibiting the increase in intraneuronal calcium concentration, comprising a cyclic amine derivative represented by the following general formula (I), or a pharmacologically acceptable salt thereof, as an active ingredient:

[Formula 1]

where A is a group represented by the following general formula (IIa), (IIb) or (IIc):

[Formula 2]

where R ¹ represents a hydroxyl group or a hydrogen atom, R ² represents a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, difluoromethyl group or 2,2,2-trifluoroethyl group, R ³ represents a hydrogen atom, a fluorine atom, a bromine atom, or a chlorine atom, each R ⁴ is independently a methyl group or an ethyl group, n is 1 or 2, and when R ¹ is a hydroxyl group, the carbon marked with * represents an asymmetric atom carbon.

[0011]

In the above cyclic amine derivative, A is preferably a group represented by the general formula (IIa), in which R ² is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, or a 2,2,2- trifluoroethyl group, and R ³ preferably represents a hydrogen atom or a chlorine atom; when R ¹ is a hydroxyl group, the stereochemical configuration of the asymmetric carbon marked with * is preferably S. The inhibitory effect on the increase in intraneuronal calcium concentration can be enhanced by setting the values indicated above.

[0012]

In the above cyclic amine derivative, A is preferably a group represented by the general formula (IIb), in which R ² is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, or a 2,2,2- trifluoroethyl group, and R ³ preferably represents a hydrogen atom or a chlorine atom; when R ¹ is a hydroxyl group, the stereochemical configuration of the asymmetric carbon marked with * is preferably S. The inhibitory effect on the increase in intraneuronal calcium concentration can be enhanced by setting the values indicated above.

[0013]

In the above cyclic amine derivative, preferably when A is a group represented by the general formula (IIc) and n is 1 or 2, R ² is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n -butyl group or 2,2,2-trifluoroethyl group, and R ³ preferably represents a hydrogen atom or a chlorine atom; when R ¹ is a hydroxyl group, the stereochemical configuration of the asymmetric carbon marked with * is preferably S. The inhibitory effect on the increase in intraneuronal calcium concentration can be enhanced by setting the values indicated above.

[0014]

In the above cyclic amine derivative, R ¹ preferably represents a hydrogen atom; in this case, R ² is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or a 2,2,2-trifluoroethyl group, and R ³ is preferably a hydrogen atom or a chlorine atom. The inhibitory effect on the increase in intraneuronal calcium concentration can be further enhanced by setting the values indicated above.

[0015]

In the above cyclic amine derivative, R ¹ preferably represents a hydroxyl group; in this case, R ² is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or a 2,2,2-trifluoroethyl group, and R ³ is preferably a hydrogen atom or a chlorine atom. The stereochemical configuration of the asymmetric carbon marked with * is preferably S. The inhibitory effect on the increase in intraneuronal calcium concentration can be further enhanced by setting the values indicated above.

[0016]

The present invention also provides a pharmaceutical composition for treating or preventing a disease associated with neuronal hyperexcitability, comprising a cyclic amine derivative represented by the above general formula (I), or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient, and the like.

[0017]

The present invention also provides a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for use in the treatment or prevention of a disease associated with neuronal hyperexcitability.

[0018]

The present invention also provides the use of a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for the treatment or prevention of a disease associated with neuronal hyperexcitability.

[0019]

The present invention also provides the use of a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a disease associated with neuronal hyperexcitability.

[0020]

The present invention also provides a method for treating or preventing a disease associated with neuronal hyperexcitability, which comprises administering a therapeutically effective amount of a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof to a patient in need of treatment.

[0021]

The present invention also provides a method for inhibiting an increase in intraneuronal calcium concentration, which comprises contacting an effective amount of a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof with neurons.

[0022]

The present invention also provides a method for inhibiting an increase in intraneuronal calcium concentration, which comprises administering an effective amount of a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof to a subject in need thereof.

[0023]

Examples of the above disease associated with neuronal hyperexcitability include, but are not limited to: diseases of the central nervous system such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis (ALS), spinocerebellar degeneration, spinocerebellar ataxia, Down syndrome, multiple sclerosis, schizophrenia, depression, mania, anxiety neurosis, obsessive-compulsive disorder, panic disorder, bipolar disorder, corticobasal degeneration, progressive supranuclear palsy, dementia with Lewy bodies, frontotemporal lobar degeneration, mild cognitive impairment, that precede Alzheimer's disease, frontotemporal lobar dementia, epilepsy, alcoholism, drug addiction, anxiety symptoms, unpleasant mental states, dysthymia, cyclothymia, nervous erethism, autism, syncope, increase and loss of sexual desire; lesions of the central nervous system or peripheral nervous system, such as head trauma, spinal cord injury, cerebral edema, impaired perception, diabetic neuropathy, dysfunction of the autonomic nervous system, and whiplash; memory disorders such as senile dementia, cerebrovascular dementia and amnesia, intracerebral hemorrhage, cerebral infarction and its consequences and complications; cerebrovascular disorders such as asymptomatic cerebrovascular accident, transient ischemic attack, hypertensive encephalopathy and blood-brain barrier disorder, as well as relapses or sequelae of cerebrovascular disorders; decrease in central functions after cerebrovascular occlusion and disorders or anomalies of autoregulation of cerebral or renal circulation; metabolic syndromes such as normal pressure idiopathic hydrocephalus, obstructive hydrocephalus, and infectious or metabolic encephalopathy; autoimmune diseases such as neuromyelitis optica and limbic encephalitis; cancers such as neuroepithelial tissue tumors (glioma, neuronal tumor, etc.), neurilemmal tumors (neurilemmoma, neurofibromatosis, etc.), meningeal tumors (meningioma and other mesenchymal tumors), sellar tumor, and metastatic tumor; sleep disorder; and itching.

[0024]

The present description includes the contents disclosed in Japanese Patent Application No. 2018-066541, which is the priority literature of the present application.

Useful effects of the invention

[0025]

The cyclic amine derivative of the present invention, or a pharmacologically acceptable salt thereof, can inhibit the increase in intraneuronal calcium concentration.

Description of Embodiments

[0026]

The following terms used in the description, unless otherwise indicated, are defined as follows.

[0027]

The cyclic amine derivative according to one embodiment of the present invention is characterized in that it is represented by the following general formula (I):

[Formula 3]

where A is a group represented by the following general formulas (IIa), (IIb) or (IIc):

[Formula 4]

where R ¹ represents a hydroxyl group or a hydrogen atom, R ² represents a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, difluoromethyl group or 2,2,2-trifluoroethyl group, R ³ represents a hydrogen atom, a fluorine atom, a bromine atom, or a chlorine atom, each R ⁴ is independently a methyl group or an ethyl group, n is 1 or 2, and when R ¹ is a hydroxyl group, the carbon marked with * represents an asymmetric atom carbon.

[0028]

In the above cyclic amine derivative, A is preferably a group represented by the general formula (IIa), in which R ² is preferably a methyl group, an ethyl group, an isopropyl group, an n-butyl group, or a 2,2,2-trifluoroethyl group, and R ³ preferably represents a hydrogen atom or a chlorine atom. When R ¹ is a hydroxyl group, the stereochemical configuration of the asymmetric carbon marked with * is preferably S.

[0029]

In the above cyclic amine derivative, A is preferably a group represented by the general formula (IIa), in which R ² is preferably an n-propyl group and R ³ is preferably a hydrogen atom or a chlorine atom. When R ¹ is a hydroxyl group, the stereochemical configuration of the asymmetric carbon marked with * is preferably S.

[0030]

In the above cyclic amine derivative, A is preferably a group represented by the general formula (IIb), in which R ² is preferably a methyl group, an ethyl group, an isopropyl group, an n-butyl group, or a 2,2,2-trifluoroethyl group, and R ³ preferably represents a hydrogen atom or a chlorine atom. When R ¹ is a hydroxyl group, the stereochemical configuration of the asymmetric carbon marked with * is preferably S.

[0031]

In the above cyclic amine derivative, A is preferably a group represented by the general formula (IIb), in which R ² is preferably an n-propyl group and R ³ is preferably a hydrogen atom or a chlorine atom. When R ¹ is a hydroxyl group, the stereochemical configuration of the asymmetric carbon marked with * is preferably S.

[0032]

In the above cyclic amine derivative, preferably when A is a group represented by the general formula (IIc) and n is 1 or 2, R ² is preferably a methyl group, an ethyl group, an isopropyl group, an n-butyl group, or 2 ,2,2-trifluoroethyl group, and R ³ preferably represents a hydrogen atom or a chlorine atom. When R ¹ is a hydroxyl group, the stereochemical configuration of the asymmetric carbon marked with * is preferably S.

[0033]

In the above cyclic amine derivative, preferably when A is a group represented by the general formula (IIc) and n is 1 or 2, R ² is preferably an n-propyl group and R ³ is preferably a hydrogen atom or an atom chlorine. When R ¹ is a hydroxyl group, the stereochemical configuration of the asymmetric carbon marked with * is preferably S.

[0034]

In the above cyclic amine derivative, R ¹ is preferably a hydrogen atom, while R ² is preferably a methyl group, an ethyl group, an isopropyl group, an n-butyl group or a 2,2,2-trifluoroethyl group, and R ³ is preferably an atom hydrogen or chlorine atom.

[0035]

In the above cyclic amine derivative, R ¹ is preferably a hydrogen atom, while R ² is preferably an n-propyl group, and R ³ is preferably a hydrogen atom or a chlorine atom.

[0036]

In the above cyclic amine derivative, R ¹ is preferably a hydroxyl group, while R ² is preferably a methyl group, an ethyl group, an isopropyl group, an n-butyl group or a 2,2,2-trifluoroethyl group, and R ³ is preferably an atom hydrogen or chlorine atom. The stereochemical configuration of the asymmetric carbon marked with * is preferably S.

[0037]

In the above cyclic amine derivative, R ¹ is preferably a hydroxyl group, while R ² is preferably an n-propyl group, and R ³ is preferably a hydrogen atom or a chlorine atom. The stereochemical configuration of the asymmetric carbon marked with * is preferably S.

[0038]

In the cyclic amine derivative according to another embodiment of the present invention, A is a group represented by the general formula (IIa), R ¹ is a hydrogen atom, R ² is a methyl group, an ethyl group, an isopropyl group, an n-butyl group or a 2,2,2-trifluoroethyl group, R ³ is a hydrogen atom, a fluorine atom, a bromine atom or a chlorine atom, and each R ⁴ is independently a methyl group or an ethyl group. In this embodiment, it is preferred that R ² is a methyl group, an ethyl group, or a 2,2,2-trifluoroethyl group and R ³ is a hydrogen atom.

[0039]

In a cyclic amine derivative according to another embodiment of the present invention, A is a group represented by the general formula (IIa), R ¹ is a hydrogen atom, R ² is an n-propyl group, R ³ is a hydrogen atom, an atom a fluorine atom, a bromine atom or a chlorine atom, and each R ⁴ independently represents a methyl group or an ethyl group. In this embodiment, it is preferred that R ³ is a hydrogen atom.

[0040]

In a cyclic amine derivative according to another embodiment of the present invention, A is a group represented by the general formula (IIa), R ¹ is a hydroxyl group, R ² is a methyl group, an ethyl group, an isopropyl group, an n-butyl group or a 2,2,2-trifluoroethyl group, R ³ is a hydrogen atom, a fluorine atom, a bromine atom or a chlorine atom, and each R ⁴ is independently a methyl group or an ethyl group. In this embodiment, it is preferred that R ³ is a hydrogen atom or a chlorine atom. In this embodiment, it is preferred that R ² is a methyl group, an ethyl group, or a 2,2,2-trifluoroethyl group and R ³ is a hydrogen atom. In this embodiment, it is preferred that the stereochemical configuration of the asymmetric carbon marked with * is the S configuration.

[0041]

In a cyclic amine derivative according to another embodiment of the present invention, A is a group represented by the general formula (IIa), R ¹ is a hydroxyl group, R ² is an n-propyl group, R ³ is a hydrogen atom, an atom a fluorine atom, a bromine atom or a chlorine atom, and each R ⁴ independently represents a methyl group or an ethyl group. In this embodiment, it is preferred that R ³ is a hydrogen atom. In this embodiment, it is preferred that the stereochemical configuration of the asymmetric carbon marked with * is the S configuration.

[0042]

In a cyclic amine derivative according to another embodiment of the present invention, A is a group represented by the general formula (IIb), R ¹ is a hydroxyl group, R ² is a methyl group, an ethyl group, an isopropyl group, an n-butyl group or a 2,2,2-trifluoroethyl group, R ³ is a hydrogen atom, a fluorine atom, a bromine atom or a chlorine atom, and each R ⁴ is independently a methyl group or an ethyl group. In this embodiment, it is preferred that R ² is a methyl group, an ethyl group, or a 2,2,2-trifluoroethyl group, and R ³ is a hydrogen atom. In this embodiment, it is preferred that the stereochemical configuration of the asymmetric carbon marked with * is the S configuration.

[0043]

In a cyclic amine derivative according to another embodiment of the present invention, A is a group represented by the general formula (IIb), R ¹ is a hydroxyl group, R ² is an n-propyl group, R ³ is a hydrogen atom, an atom a fluorine atom, a bromine atom or a chlorine atom, and each R ⁴ independently represents a methyl group or an ethyl group. In this embodiment, it is preferred that R ³ is a hydrogen atom. In this embodiment, it is preferred that the stereochemical configuration of the asymmetric carbon marked with * is the S configuration.

[0044]

In a cyclic amine derivative according to another embodiment of the present invention, A is a group represented by the general formula (IIc), n is 1 or 2, R ¹ is a hydroxyl group, R ² is a methyl group, an ethyl group, an isopropyl group, an n-butyl group or a 2,2,2-trifluoroethyl group, R ³ is a hydrogen atom, a fluorine atom, a bromine atom or a chlorine atom, and each R ⁴ is independently a methyl group or an ethyl group. In this embodiment, it is preferred that R ² is a methyl group, an ethyl group, or a 2,2,2-trifluoroethyl group, and R ³ is a hydrogen atom. In this embodiment, it is preferred that the stereochemical configuration of the asymmetric carbon marked with * is the S configuration.

[0045]

In a cyclic amine derivative according to another embodiment of the present invention, A is a group represented by the general formula (IIc), n is 1 or 2, R ¹ is a hydroxyl group, R ² is an n-propyl group, R ³ represents a hydrogen atom, a fluorine atom, a bromine atom or a chlorine atom, and each R ⁴ independently represents a methyl group or an ethyl group. In this embodiment, it is preferred that R ³ is a hydrogen atom. In this embodiment, it is preferred that the stereochemical configuration of the asymmetric carbon marked with * is the S configuration.

[0046]

In a cyclic amine derivative according to another embodiment of the present invention, A is a group represented by the general formula (IIa), R ¹ is a hydroxyl group or a hydrogen atom, R ² is an n-propyl group, an isopropyl group, or n- a butyl group, R ³ represents a hydrogen atom, a fluorine atom, a bromine atom or a chlorine atom, and each R ⁴ independently represents a methyl group or an ethyl group; when R ¹ represents a hydroxyl group, the carbon marked with * represents an asymmetric carbon atom.

[0047]

In a cyclic amine derivative according to another embodiment of the present invention, A is a group represented by the general formula (IIb), R ¹ is a hydroxyl group or a hydrogen atom, R ² is an n-propyl group, an isopropyl group, or n- a butyl group, R ³ represents a hydrogen atom, a fluorine atom, a bromine atom or a chlorine atom, and each R ⁴ independently represents a methyl group or an ethyl group; when R ¹ represents a hydroxyl group, the carbon marked with * represents an asymmetric carbon atom.

[0048]

In a cyclic amine derivative according to another embodiment of the present invention, A is a group represented by the general formula (IIc), R ¹ is a hydroxyl group or a hydrogen atom, R ² is an n-propyl group, an isopropyl group, or n- a butyl group, R ³ is a hydrogen atom, a fluorine atom, a bromine atom or a chlorine atom, each R ⁴ is independently a methyl group or an ethyl group, and n is 1 or 2; when R ¹ represents a hydroxyl group, the carbon marked with * represents an asymmetric carbon atom.

[0049]

Specific examples of the preferred compound as the cyclic amine derivative represented by the above general formula (I) (hereinafter, the cyclic amine derivative (I)) will be shown in Tables 1-1, 1-2 and 1-3; however, the present invention is not limited to this.

[0050]

Table 1-1

[0051]

Table 1-2

[0052]

Table 1-3

[0053]

When the cyclic amine derivative (I) has an isomer such as an enantiomer and a stereoisomer, any of the isomers and mixtures thereof are included in the cyclic amine derivative (I). In addition, when the cyclic amine derivative (I) has an isomer such as an enantiomer and a stereoisomer, the cyclic amine derivative (I) may be a mixture containing any of the isomers or a mixture thereof. In addition, when the cyclic amine derivative (I) has conformational isomers, the cyclic amine derivative (I) includes any of the isomers and mixtures thereof. The desired isomer can be obtained by a known method or the like. For example, when an enantiomer of the cyclic amine derivative (I) is present, the enantiomer separated from the cyclic amine derivative (I) is also included in the cyclic amine derivative (I).

[0054]

The desired enantiomer can be obtained by known methods (for example, an optically active synthetic intermediate is used or the racemic mixture of the final product is subjected to a known method or a similar method (for example, optical separation)).

[0055]

Also included is a prodrug of a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof. A cyclic amine derivative (I) prodrug refers to a compound that is enzymatically or chemically converted to a cyclic amine derivative (I) in vivo . The active prodrug form of the cyclic amine derivative (I) is a cyclic amine derivative (I); however, the prodrug of the cyclic amine derivative (I) may itself be active.

[0056]

As a prodrug of the cyclic amine derivative (I), for example, a compound obtained by alkylation, phosphorylation or boration of the hydroxyl group of the cyclic amine derivative (I) can be mentioned. Each of these compounds can be synthesized from the cyclic amine derivative (I) according to a known method.

[0057]

The prodrug of the cyclic amine derivative (I) can be converted to the cyclic amine derivative (I) under the physiological conditions described in the known literature ("Development of pharmaceutical products", Hirokawa-Shoten Ltd., vol. 7, p. 163 to 198, 1990, and Progress in Medicine, vol. 5, pp. 2157 to 2161, 1985).

[0058]

The cyclic amine derivative (I) can be labeled with a radioisotope. Examples of radioisotopes used for labeling include ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁵ O and/or ¹⁸ O.

[0059]

As the pharmacologically acceptable salt of the cyclic amine derivative (I), for example, an inorganic salt such as hydrochloride, sulfate, phosphate and hydrobromide can be mentioned; or an organic salt such as oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, salicylate, xinafoate, pamoate, ascorbate, adipate, methanesulfonate, p-toluenesulfonate and cinnamate.

[0060]

A cyclic amine derivative (I) or a pharmacologically acceptable salt thereof includes a hydrate and a solvate thereof.

[0061]

When the cyclic amine derivative (I) or its pharmacologically acceptable salt has crystalline polymorphs, the cyclic amine derivative (I) or its pharmacologically acceptable salt includes all crystalline polymorphs and mixtures thereof.

[0062]

The cyclic amine derivative (I) or a pharmacologically acceptable salt thereof can be synthesized according to the method described in the known literature (International Publication WO 2013/147160) or the known literature (International Publication WO 2016/136944), for example.

[0063]

In the present description, the term "increased intracellular calcium concentration" means that the intracellular calcium concentration rises to such an extent that abnormal excitatory neuronal transmission occurs, and this is indicated, for example, by an intracellular calcium concentration outside the normal range, the duration of the period of increase in intracellular calcium concentration for outside the normal range, or the number of increases in intracellular calcium concentration per unit of time outside the normal range, as an indicator.

[0064]

In the present description, the term "inhibiting the increase in intracellular calcium concentration" means that the abnormal excitatory neuronal transmission that has occurred is suppressed or the state without abnormal excitatory neuronal transmission is maintained, and this is indicated by, for example, intracellular calcium concentration within the normal range, the duration of the period of increase in intracellular calcium concentration within the normal range, or the number of increases in intracellular calcium concentration per unit time within the normal range, as an indicator. The term "inhibition of the increase in intracellular calcium concentration" also means that the increase in intracellular calcium concentration is inhibited by 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 100% compared with the case where the increase in intracellular calcium concentration is not inhibited.

[0065]

Examples of the above disease associated with neuronal hyperexcitability include, but are not limited to: diseases of the central nervous system such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis (ALS), spinocerebellar degeneration, spinocerebellar ataxia, Down syndrome, multiple sclerosis, schizophrenia, depression, mania, anxiety neurosis, obsessive-compulsive disorder, panic disorder, bipolar disorder, corticobasal degeneration, progressive supranuclear palsy, dementia with Lewy bodies, frontotemporal lobar degeneration, mild cognitive impairment, that precede Alzheimer's disease, frontotemporal lobar dementia, epilepsy, alcoholism, drug addiction, anxiety symptoms, unpleasant mental states, dysthymia, cyclothymia, nervous erethism, autism, syncope, increase and loss of sexual desire; lesions of the central nervous system or peripheral nervous system, such as head trauma, spinal cord injury, cerebral edema, impaired perception, diabetic neuropathy, dysfunction of the autonomic nervous system, and whiplash; memory disorders such as senile dementia, cerebrovascular dementia and amnesia, intracerebral hemorrhage, cerebral infarction and its consequences and complications; cerebrovascular disorders such as asymptomatic cerebrovascular accident, transient ischemic attack, hypertensive encephalopathy and blood-brain barrier disorder, as well as relapses or sequelae of cerebrovascular disorders; decrease in central functions after cerebrovascular occlusion and disorders or anomalies of autoregulation of cerebral or renal circulation; metabolic syndromes such as normal pressure idiopathic hydrocephalus, obstructive hydrocephalus, and infectious or metabolic encephalopathy; autoimmune diseases such as neuromyelitis optica and limbic encephalitis; cancers such as neuroepithelial tissue tumors (glioma, neuronal tumor, etc.), neurilemmal tumors (neurilemmoma, neurofibromatosis, etc.), meningeal tumors (meningioma and other mesenchymal tumors), sellar tumor, and metastatic tumor; sleep disorder; and itching.

[0066]

The cyclic amine derivative (I) or a pharmacologically acceptable salt thereof can be used as a drug for the treatment or prevention of a disease associated with neuronal hyperexcitability in a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey or human), and especially in humans.

[0067]

When the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is used as a drug, the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, alone or in combination with a pharmaceutically acceptable carrier, may be administered orally or parenterally.

[0068]

As the dosage form, when a drug containing a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient is administered orally, for example, tablets (including sugar- or film-coated tablets), pills, granules, powders can be mentioned. , capsules (including soft capsules and microcapsules), syrups, emulsions and suspensions. As the dosage form, when a drug containing a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient is administered parenterally, injections, infusions, drops, suppositories, transdermal liniments and adhesive patches can be mentioned, for example. In addition, it is effective to prepare a sustained release composition using a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof in combination with a suitable base (for example, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, mixtures of butyric acid polymer and a polymer of glycolic acid or a fatty acid ester of polyglycerol).

[0069]

Compositions having the above dosage forms can be prepared according to preparation methods known in the art of drug formulation. In this case, if necessary, preparation can be carried out by adding an excipient, binder, lubricant, disintegrant, sweetener, surfactant, suspending agent or emulsifier, which are commonly used in the field of drug formulation.

[0070]

Tablets can be obtained, for example, by adding an excipient, binder, disintegrant or lubricant. Pills and granules can be obtained by adding, for example, an excipient, binder or disintegrant. Powders and capsules can be obtained by adding, for example, an excipient. Syrups can be obtained by adding, for example, a sweetener. Emulsions or suspensions can be obtained by adding, for example, a surfactant, a suspending agent or an emulsifier.

[0071]

As the excipient, for example, lactose, glucose, starch, sucrose, microcrystalline cellulose, licorice root powder, mannitol, sodium hydrogen carbonate, calcium phosphate and calcium sulfate can be mentioned.

[0072]

As the binder, for example, starch paste solution, gum arabic solution, gelatin solution, tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution and glycerin can be mentioned.

[0073]

As disintegrant, for example, starch and calcium carbonate can be mentioned.

As a lubricant, for example, magnesium stearate, stearic acid, calcium stearate and purified talc can be mentioned.

[0074]

As a sweetener, for example, glucose, fructose, invert sugar, sorbitol, xylitol, glycerol and simple syrup can be mentioned.

[0075]

As the surfactant, for example, sodium lauryl sulfate, polysorbate 80, fatty acid sorbitan monoester and polyoxyl 40 stearate can be mentioned.

[0076]

As a suspending agent, for example, gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose and bentonite can be mentioned.

[0077]

As an emulsifier, for example, gum arabic, tragacanth, gelatin and polysorbate 80 can be mentioned.

[0078]

When a drug containing a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient is prepared in the above dosage forms, a coloring agent, preservative, flavoring agent, flavoring agent, stabilizer or thickening agent commonly used in the field of drug formulation may be added.

[0079]

The daily dose of a drug containing a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient varies depending on, for example, the condition or body weight of the patient or the type or route of administration of the compound. For example, when administered orally to an adult (weight: about 60 kg), the amount of the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient is in the range of 1 to 1000 mg, and administration is preferably carried out in 1 to 3 doses. For example, when administered parenterally to an adult (weight: about 60 kg), the amount of the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient is in the range of 0.01 to 100 mg per body weight (1 kg), and the solution for injection is preferably administered intravenously.

[0080]

The cyclic amine derivative (I) or a pharmacologically acceptable salt thereof may be mixed with other drugs in an appropriate ratio, or may be used in combination with other drugs to supplement or enhance the therapeutic or prophylactic effect or reduce the dose. The cyclic amine derivative (I) or a pharmacologically acceptable salt thereof may be administered simultaneously with other drugs, or may be administered together with them continuously in an arbitrary order. As other drugs, you can specify, for example, but not limited to, therapeutic agents for the above disease associated with hyperexcitability of neurons. Examples of these include donepezil, memantine, galanthamine, rivastigmine, entacapone, levodopa, benserazide hydrochloride, carbidopa, zonisamide, amantadine hydrochloride, bromocriptine mesylate, pergolide mesylate, cabergoline, pramipexole hydrochloride, rotigotine, talipexole hydrochloride, ropinirole hydrochloride, apomorphine chloride hydrochloride hydrate, selegiline hydrochloride , trihexyphenidyl hydrochloride, biperidene hydrochloride, promethazine hydrochloride, istradephylline, droxidopa, riluzole, protirelin tartrate hydrate, taltirelin hydrate, chlorpromazine, haloperidol, sulpiride, risperidone, perospirone, olanzapine, quetiapine, paroxetine, fluvoxamine, sertraline, escitalopram, milnacipran, mirtacipran, duloxetine , amoxapine, amitriptyline, imipramine, clomipramine, dosulepin, trimipramine, nortriptyline, lofepramine, setiptyline, maprotiline, mianserin, lithium carbonate, carbamazepine, sodium valproate, lamotrigine, tofisopam, clothiazepam, etizolam, lorazepam, alprazolam, bromazepam, diazepam, , ethylloflazepat , Flutoprazepam, Tandospirone Citrate, Disulfiram, Cyanamide, Acamprosate, Valproic Acid, Ethosuximide, Phenobarbital, Carbamazepam, Phenytoin, Ambenonium Chloride, Edrophonium Chloride, Acetylcholine Chloride, Neostigmine Bromide, Sugammadex Sodium, Neostigmine Methyl Sulfate, Piracetam, Nebrogmine Chloride, Pyridostium Nestigmine Chloride, Pyridostium Nestigmine Chloride methyl sulfate, atropine sulfate hydrate, pregabalin, epalrestat, mexiletin, aspirin, ticlopidine hydrochloride, clopidogrel sulfate, cilostazol, warfarin potassium, dabigatran etexilate methanesulfonate, edoxaban tosylate hydrate, rivaroxaban, apixaban, amobarbital, esobarbitol, estazolam, sekubitexalam, sodium , zolpidem tartrate, dexmedetomidine hydrochloride, triazolam, triclophos sodium, nitrazepam, haloxazolam, sodium phenobarbital, flunitrazepam, flurazepam hydrochloride, brotizolam, bromovaleryl urea, calcium pentobarbital, chloral hydrate, midazolam, ramelteon, rilmazafone hydrochloride, and nalormetazepine hydrochloride

Examples

[0081]

Hereinafter, the present invention will be described in detail with reference to Examples; however, the present invention is not limited to them.

[0082]

The test compounds used were 1-(4-(dimethylamino)piperidin-1-yl)-3-(1-ethyl-1H-imidazol-2-yl)-3-hydroxypropan-1-one (hereinafter referred to as "compound 1" ), (S)-1-(4-(dimethylamino)piperidin-1-yl)-3-hydroxy-3-(1-methyl-1H-imidazol-2-yl)propan-1-one (hereinafter referred to as "compound 2"), 1-(4-(dimethylamino)piperidin-1-yl)-3-hydroxy-3-(1-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl)propan-1- he (hereinafter referred to as "compound 3") and 1-(4-(dimethylamino)piperidin-1-yl)-3-(1-methyl-1H-imidazol-2-yl)propan-1-one sulfate monohydrate (hereinafter referred to as "compound 4") shown in Table 2 and synthesized according to the methods described in the known literature (International publications WO 2013/147160 and WO 2016/136944).

[0083]

table 2

[0084]

In addition, 1-((R)-3-(3-(dimethylamino)piperidin-1-yl)-3-hydroxy-3-(1-methyl-1H-imidazol-2-yl)propane was used as test compounds -1-one (hereinafter referred to as "compound 5"), 3-hydroxy-3-(1-methyl-1H-imidazol-2-yl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1 -yl)propan-1-one (hereinafter referred to as "compound 6"), 1-(4-(dimethylamino)piperidin-1-yl)-3-(1-propyl-1H-imidazol-2-yl)-3- hydroxypropan-1-one (hereinafter referred to as "compound 7"), 1-((R)-3-(dimethylamino)pyrrolidin-1-yl)-3-hydroxy-3-(1-methyl-1H-imidazol-2- yl)propan-1-one (hereinafter referred to as "compound 8"), 3-(5-chloro-1-methyl-1H-imidazol-2-yl)-1-(4-(dimethylamino)piperidin-1-yl) -3-hydroxypropan-1-one (hereinafter referred to as "compound 9"), 1-(4-(dimethylamino)piperidin-1-yl)-3-(1-isopropyl-1H-imidazol-2-yl)-3- hydroxypropan-1-one (hereinafter referred to as "compound 10"), 1-(4-(dimethylamino)piperidin-1-yl)-3-(1-(2-methoxyethyl)-1H-imidazol-2-yl)-3 -hydroxypropan-1-one (hereinafter referred to as "Compound of Comparative Example 1") and 1-(4-(dimethylamino)piperidin-1-yl) -3-(1-(3,3,3-trifluoropropyl)-1H-imidazol-2-yl)-3-hydroxypropan-1-one (hereinafter referred to as a "Compound of Comparative Example 2") shown in Table 3.

[0085]

From the test compounds shown in Table 3, compound 5, compound 6 and compound 8 were synthesized according to the methods described in the known literature (International Publications WO 2013/147160 and WO 2016/136944). Compound 7, compound 9 and compound 10 were synthesized by the methods described in the Examples below. Compounds of Comparative Example 1 and Comparative Example 2 were synthesized by the methods described in the Reference Examples below. Their starting materials and intermediates were synthesized by the methods described in the Reference Examples below. It should be noted that commercially available products were used for the compounds that were used in the synthesis of the compounds of Reference Examples and whose synthesis methods are not described below.

[0086]

In the description below, the solvent names shown in the NMR data are the solvents used in the measurements. 400 MHz NMR spectra were measured using a JNM-AL 400 series nuclear magnetic resonance (NMR) spectrometer (JEOL, Ltd.). Chemical shifts are expressed with δ (unit: ppm) using tetramethylsilane as reference, and the corresponding signals respectively have the following meanings: s (singlet), d (doublet), t (triplet), sq. (quartet), quint. (quintet), sept. (septet), m (multiplet), br. (wide), dd (double doublet), dt (double triplet), ddd (double double doublet), dkv. (double quartet), td (triple doublet) and tt (triple triplet). ESI-MS spectra were measured using an Agilent Technologies 1200 Series, G6130A (from Agilent Technology). For all solvents used commercially available products. For flash column chromatography, YFLC W-Prep2XY (from YAMAZEN) was used.

[0087]

(Reference Example 1) Synthesis of 1-propyl-1H-imidazole-2-carbaldehyde:

[Formula 5]

1-Iodopropane (1.22 ml, 12.5 mmol) and potassium carbonate (2.16 g, 15.6 mmol) were added to a solution of 1H-imidazole-2-carbaldehyde (1.00 g, 10.4 mmol) in N,N-dimethylformamide (10.0 ml), and the reaction liquid was stirred at 60°C for 3 hours. Water was added to the reaction liquid, and then the reaction liquid was extracted with ethyl acetate. The organic layer was washed with 10% sodium chloride aqueous solution and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate) to give 1-propyl-1H-imidazole-2-carbaldehyde (0.786 g, 5.69 mmol, 55%) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.93 (3H, t, J=7.4 Hz), 1.77-1.85 (2H, m), 4.37 (2H, t, J=7.2 Hz), 7.16(1H, s), 7.28(1H, s), 9.82(1H, s).

[0088]

(Reference Example 2) Synthesis of 5-chloro-1-methyl-1H-imidazole-2-carbaldehyde:

[Formula 6]

Dess-Martin reagent (1.04 g, 2.46 mmol) was added to a solution of (5-chloro-1-methyl-1H-imidazol-2-yl) methanol (0.300 g, 2.05 mmol) in dichloromethane (20, 0 ml) at 0°C, and the reaction liquid was stirred at the same temperature for 3 hours. A 10% sodium thiosulfate aqueous solution and a saturated sodium hydrogencarbonate aqueous solution were added to the reaction liquid, and then the reaction liquid was extracted with chloroform. The organic layer was washed with 10% sodium chloride aqueous solution and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate) to give 5-chloro-1-methyl-1H-imidazole-2-carbaldehyde (0.235 g, 1.62 mmol, 79%) as a white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.98 (3H, s), 7.24 (1H, s), 9.70 (1H, s).

[0089]

(Reference Example 3) Synthesis of 1-isopropyl-1H-imidazole-2-carbaldehyde:

[Formula 7]

2-Iodopropane (1.26 ml, 12.5 mmol) and potassium carbonate (2.16 g, 15.6 mmol) were added to a solution of 1H-imidazole-2-carbaldehyde (1.00 g, 10.4 mmol) in N,N-dimethylformamide (10 ml) and the reaction liquid was stirred at 60°C for 3 hours. Water was added to the reaction liquid, and then the reaction liquid was extracted with ethyl acetate. The organic layer was washed with 10% sodium chloride aqueous solution and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate) to give 1-isopropyl-1H-imidazole-2-carbaldehyde (0.703 g, 5.09 mmol, 49%) as a yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47 (6H, t, J=6.6 Hz), 5.48 (1H, q, J=6.6 Hz), 7.30 (1H , s), 7.33 (1H, s), 9.83 (1H, s).

[0090]

(Reference Example 4) Synthesis of 1-(2-methoxyethyl)-1H-imidazole-2-carbaldehyde:

[Formula 8]

2-Bromoethyl methyl ether (1.20 ml, 12.5 mmol), potassium carbonate (2.16 g, 15.6 mmol) and sodium iodide (0.468 g, 3.12 mmol) were added to a solution of 1H-imidazole-2- carbaldehyde (1.00 g, 10.4 mmol) in N,N-dimethylformamide (10.0 ml) and the reaction liquid was stirred at 60° C. for 3 hours. Water was added to the reaction liquid, and then the reaction liquid was extracted with ethyl acetate. The organic layer was washed with 10% sodium chloride aqueous solution and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate) to give 1-(2-methoxyethyl)-1H-imidazole-2-carbaldehyde (0.535 g, 3.47 mmol, 33%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 3.32 (3H, s), 3.67 (2H, t, J=5.0 Hz), 4.59 (2H, t, J=5.0 Hz ), 7.23-7.30(2H, m), 9.81(1H, s).

[0091]

(Reference Example 5) Synthesis of 1-(3,3,3-trifluoropropyl)-1H-imidazole-2-carbaldehyde:

[Formula 9]

1,1,1-Trifluoro-3-iodopropane (0.710 ml, 6.24 mmol) and potassium carbonate (1.08 g, 7.81 mmol) were added to a solution of 1H-imidazole-2-carbaldehyde (0.500 g, 5. 20 mmol) in N,N-dimethylformamide (5.20 ml) and the reaction liquid was stirred at 60° C. for 5 hours. Water was added to the reaction liquid, and then the reaction liquid was extracted with ethyl acetate. The organic layer was washed with 10% sodium chloride aqueous solution and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate) to give 1-(3,3,3-trifluoropropyl)-1H-imidazole-2-carbaldehyde (0.0863 g, 0.449 mmol, 8.6%) as colorless oil.

1H-NMR (400 MHz, CDCl3) δ: 2.60-2.72 (2H, m), 4.61 (2H, t, J=6.8 Hz), 7.18 (1H, s), 7 .32 (1H, s), 9.83 (1H, s).

[0092]

(Reference Example 6) Synthesis of Compound of Comparative Example 1:

[Formula 10]

A solution of lithium diisopropylamide in tetrahydrofuran (2.0 M, 0.969 ml, 1.94 mmol) was added dropwise to a solution of 1-(4-dimethylaminopiperidin-1-yl)ethanone (0.300 g, 1.76 mmol) in tetrahydrofuran (6, 00 ml) at -78°C, and the reaction liquid was stirred at the same temperature for 1 hour. A solution of 1-(2-methoxyethyl)-1H-imidazole-2-carbaldehyde (0.292 g, 2.12 mmol) in tetrahydrofuran (2.80 ml) was added to the reaction liquid at the same temperature. The reaction liquid was stirred for 1 hour and stirred at 0° C. for another 1 hour. A saturated ammonium chloride aqueous solution and an aqueous potassium carbonate solution were successively added to the reaction liquid, and then the reaction liquid was extracted with chloroform. The organic layer was washed with 10% sodium chloride aqueous solution and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform/methanol) to give Comparative Example 1 (0.193 g, 0.594 mmol, 34%) as a colorless oil.

1H-NMR (400 MHz, DMSO-d6) δ: 1.04-1.40(2H, m), 1.62-1.80(2H, m), 2.10-2.35(7H, m ), 2.46-2.59(1H, m), 2.80-2.90(1H, m), 2.95-3.10(2H, m), 3.24(3H, s), 3.61 (2H, t, J=5.5 Hz), 3.90-4.00 (1H, m), 4.10-4.38 (3H, m), 5.05-5.11 ( 1H, m), 5.38-5.42(1H, m), 6.73(1H, s), 7.07(1H, s).

(Reference Example 7) Synthesis of Compound of Comparative Example 2:

[Formula 11]

A solution of lithium diisopropylamide in tetrahydrofuran (2.0 M, 0.246 ml, 0.492 mmol) was added dropwise to a solution of 1-(4-dimethylaminopiperidin-1-yl)ethanone (0.0760 g, 0.448 mmol) in tetrahydrofuran (1.80 ml ) at -78°C and the reaction liquid was stirred at the same temperature for 1 hour. A solution of 1-(3,3,3-trifluoropropyl)-1H-imidazole-2-carbaldehyde (0.0860 g, 0.448 mmol) in tetrahydrofuran (0.70 ml) was added to the reaction liquid at the same temperature. The reaction liquid was stirred for 1 hour and stirred at 0° C. for another 1 hour. A saturated ammonium chloride aqueous solution and an aqueous potassium carbonate solution were successively added to the reaction liquid, and then the reaction liquid was extracted with chloroform. The organic layer was washed with 10% sodium chloride aqueous solution and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform/methanol) to give Comparative Example 2 (0.0845 g, 0.233 mmol, 52%) as a colorless oil.

1H-NMR (400 MHz, DMSO-d6) δ: 1.03-1.40(2H, m), 1.63-1.79(2H, m), 2.10-2.33(7H, m ), 2.47-2.59(1H, m), 2.78-2.90(3H, m), 2.95-3.13(2H, m), 3.90-3.98(1H , m), 4.21-4.36 (3H, m), 5.03-5.10 (1H, m), 5.49-5.54 (1H, m), 6.77 (1H, s ), 7.17 (1H, s).

ESI-MS: m/z= 363 (M+H) ⁺ .

[0093]

(Example 1) Synthesis of Compound 7:

[Formula 12]

A solution of lithium diisopropylamide in tetrahydrofuran (2.0 M, 0.969 ml, 1.94 mmol) was added dropwise to a solution of 1-(4-dimethylaminopiperidin-1-yl)ethanone (0.300 g, 1.76 mmol) in tetrahydrofuran (6, 00 ml) at -78°C, and the reaction liquid was stirred at the same temperature for 1 hour. A solution of 1-propyl-1H-imidazole-2-carbaldehyde (0.292 g, 2.12 mmol) in tetrahydrofuran (2.8 ml) was added to the reaction liquid at the same temperature. The reaction liquid was stirred for 1 hour and stirred at 0° C. for another 1 hour. A saturated ammonium chloride aqueous solution and an aqueous potassium carbonate solution were successively added to the reaction liquid, and then the reaction liquid was extracted with chloroform. The organic layer was washed with 10% sodium chloride aqueous solution and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform/methanol) to give compound 7 (0.296 g, 0.960 mmol, 55%) as a colorless oil.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.85 (3H, t, J=7.4 Hz), 1.00-1.40 (2H, m), 1.61-1, 80(4H, m), 2.10-2.33(7H, m), 2.45-2.59(1H, m), 2.73-2.88(1H, m), 2.93- 3.13(2H, m), 3.86-4.00(3H, m), 4.25-4.35(1H, m), 4.98-5.05(1H, m), 5, 34-5.40(1H, m), 6.72(1H, s), 7.07(1H, s).

ESI-MS: m/z= 309 (M+H) ⁺ .

[0094]

(Example 2) Synthesis of Compound 9:

[Formula 13]

A solution of lithium diisopropylamide in tetrahydrofuran (2.0 M, 0.745 ml, 1.49 mmol) was added dropwise to a solution of 1-(4-dimethylaminopiperidin-1-yl)ethanone (0.231 g, 1.36 mmol) in tetrahydrofuran (5. 10 ml) at -78°C, and the reaction liquid was stirred at the same temperature for 1 hour. A solution of 5-chloro-1-methyl-1H-imidazole-2-carbaldehyde (0.235 g, 1.63 mmol) in tetrahydrofuran (1.70 ml) was added to the reaction liquid at the same temperature, and stirred for 1 hour. The reaction liquid was then stirred at 0°C for another 1 hour. A saturated ammonium chloride aqueous solution and an aqueous potassium carbonate solution were successively added to the reaction liquid, and then the reaction liquid was extracted with chloroform. The organic layer was washed with 10% sodium chloride aqueous solution and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform/methanol) to give compound 9 (0.159 g, 0.505 mmol, 37%) as a colorless oil.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.04-1.21 (1H, m), 1.28-1.40 (1H, m), 1.64-1.80 (2H , m), 2.15 (6H, s), 2.24-2.35 (1H, m), 2.44-2.60 (1H, m), 2.78-2.88 (1H, m ), 2.95-3.11(2H, m), 3.59(3H, s), 3.90-3.98(1H, m), 4.27-4.35(1H, m), 5.00-5.10(1H, m), 5.50-5.58(1H, m), 6.85(1H, s).

ESI-MS: m/z= 315 (M+H) ⁺ .

[0095]

(Example 3) Synthesis of Compound 10:

[Formula 14]

A solution of lithium diisopropylamide in tetrahydrofuran (2.0 M, 0.969 ml, 1.94 mmol) was added dropwise to a solution of 1-(4-dimethylaminopiperidin-1-yl)ethanone (0.300 g, 1.76 mmol) in tetrahydrofuran (6, 00 ml) at -78°C, and the reaction liquid was stirred at the same temperature for 1 hour. A solution of 1-isopropyl-1H-imidazole-2-carbaldehyde (0.292 g, 2.12 mmol) in tetrahydrofuran (2.8 ml) was added to the reaction liquid at the same temperature. The reaction liquid was stirred for 1 hour and stirred at 0° C. for another 1 hour. A saturated ammonium chloride aqueous solution and an aqueous potassium carbonate solution were successively added to the reaction liquid, and then the reaction liquid was extracted with chloroform. The organic layer was washed with 10% sodium chloride aqueous solution and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform/methanol) to give compound 10 (0.302 g, 0.979 mmol, 56%) as a colorless oil.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.04-1.41 (8H, m), 1.62-1.80 (2H, m), 2.16 (6H, s), 2.25-2.34(1H, m), 2.48-2.59(2H, m), 2.76-2.88(1H, m), 2.95-3.16(2H, m ), 3.90-4.00(1H, m), 4.27-4.38(1H, m), 5.05-5.12(1H, m), 5.36-5.42(1H , m), 6.77 (1H, s), 7.20 (1H, s).

ESI-MS: m/z= 309 (M+H) ⁺ .

[0096]

Table 3

[0097]

(Example 4) Effect of a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof on a high potassium-induced increase in intracellular calcium concentration in rat dorsal root (DRG) neurons.

A cyclic amine derivative (I) or a pharmacologically acceptable salt thereof was investigated for its inhibitory effect on the high potassium-induced increase in intracellular calcium concentration in DRG neurons.

[0098]

(1) DRG collection

SD rats (male, 4 to 6 weeks old; Charles River Laboratories Japan, Inc.) were anesthetized and euthanized by abdominal aortic bleed. After incision of the dorsal part, the spinal column was excised and cooled in ice. The posterior column was cut off and the spinal cord was removed from the ventral side of the spinal column. The DRG (from L4 to L6) with nerve fibers was then excised with tweezers. The dissected DRGs were immersed in ice-cold L-15 Leibovitz medium (Thermo Fisher Scientific) and the nerve fibers were removed under a stereoscopic microscope to separate the DRGs.

[0099]

(2) Dissociated culture of DRG neurons

Small incisions were made on the separated DRGs with ophthalmic scissors followed by incubation at 37° C. for 20 minutes with collagenase A (Roche Molecular Systems). After centrifugation at 200×g for 5 minutes, the supernatant was removed and 0.05% trypsin-EDTA (Thermo Fisher Scientific) was added, followed by incubation at 37°C for 5 minutes. To this mixture was added DMEM (Thermo Fisher Scientific) containing 1% penicillin-streptomycin (Thermo Fisher Scientific) and 10% fetal calf serum (Thermo Fisher Scientific). After centrifugation at 200×g for 5 minutes, the supernatant was removed. After removal of the supernatant, Neurobasal-A medium (Thermo Fisher Scientific) containing 1% penicillin-streptomycin and 2% B-27 (Thermo Fisher Scientific) was added, which was prepared as DRG nerve culture medium. The cells were then dissociated by micropipetting. The dissociated cells were passed through a 70 μm cell strainer (Greiner) and centrifuged at 200×g for 5 minutes. After centrifugation, the supernatant was removed and the cells were suspended in culture medium. This cell suspension was inoculated into a 35 mm polylysine-coated dish (Matsunami Glass Ind., Ltd.) pre-coated with laminin (Sigma-Aldrich), cultured overnight at 37° C. under 5% CO ₂ , and then used to measure the change intracellular calcium concentration.

[0100]

(3) Loading fluorescent calcium dye

Cal-520, AM (registered trademark) (AAT Bioquest) was used as the fluorescent calcium dye. The medium was removed from the cells cultured in the Cup, and the cells were washed twice with perfusate. Then added Cal-520, AM solution, adjusted to 4 μmol/l, and the cells were cultured at 37°C for 1-1.5 hours in an atmosphere of 5% CO ₂ . The perfusate was an aqueous solution containing NaCl (140 mmol/l), KCl (5 mmol/l), CaCl ₂ ⋅2H ₂ O (1.2 mmol/l), MgCl ₂ ⋅6H ₂ O (2 mmol/l) , D(+)-glucose (14 mmol/l) and HEPES (10 mmol/l) adjusted to pH 7.4. The dish was then washed by perfusion at 2 ml/min for 10 minutes.

[0101]

(4) Measurement of change in intracellular calcium concentration

The change in intracellular calcium concentration was measured by analyzing, using analysis software, the change in fluorescence intensity of cells loaded with fluorescent calcium dye in images obtained with a confocal laser microscope system (Nikon Instech Co., Ltd.). The laser wavelength was 488 nm and images were taken at intervals of 57-60 sheets per minute.

[0102]

To induce neuronal excitation, a treatment with a high potassium solution (hereinafter, "high potassium treatment") was carried out to cause an increase in intracellular calcium concentration by depolarization of cell membranes. High-potassium treatment and treatment with a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof (compounds 1-10, compound of Comparative Example 1 and compound of Comparative Example 2) (hereinafter, "compound treatment") of the cells was performed by perfusion and solution exchange. The perfusion rate was controlled to 2 ml/min using a tubing pump. Inducing an increase in intracellular calcium concentration by high potassium treatment was performed by treating cells for 1 minute with an aqueous solution containing NaCl (125 mmol/l or 115 mmol/l), KCl (32.5 mmol/l or 30 mmol/l). l), CaCl ₂ ⋅2H ₂ O (1.2 mmol/l), MgCl ₂ ⋅6H ₂ O (2 mmol/l), D(+)-glucose (14 mmol/l) and HEPES (10 mmol/l ) adjusted to pH 7.4. The high potassium treatment was performed 8 times at 5 minute intervals. Compounds 1 to 10, the compound of Comparative Example 1 and the compound of Comparative Example 2 were each dissolved in distilled water at a concentration of 100 mmol/L (Otsuka Pharmaceutical Factory), then the solution was diluted to 30 μmol/L with perfusate, and treatment with the compound was carried out by treating the cells with the resulting solution . The compound treatment was performed continuously from 3 minutes before the start of the third high potassium treatment cycle until after the end of the eighth high potassium treatment cycle (hereinafter, "compound treatment group"). As a control, treatment using a solution obtained by diluting distilled water with perfusate was carried out continuously from 3 minutes before the start of the third high potassium treatment cycle to after the end of the eighth high potassium treatment cycle (hereinafter, "vehicle treatment group"). However, with respect to Compounds 5-10, the compound of Comparative Example 1 and the compound of Comparative Example 2, inducing an increase in intracellular calcium concentration by high potassium treatment was performed by treating the cells for 1 minute with an aqueous solution containing NaCl (115 mmol/L), KCl (30 mmol/l), CaCl ₂ ⋅2H ₂ O (1.2 mmol/l), MgCl ₂ ⋅6H ₂ O (2 mmol/l), D(+)-glucose (14 mmol/l) and HEPES (10 mmol/l) adjusted to pH 7.4.

[0103]

(5) Image analysis and calculation of the degree of inhibition of the increase in intracellular calcium concentration

The resulting images were analyzed using ImageJ 1.51j8 (National Institutes of Health). The brightness value of each cell was measured over time to obtain a curve of change in the brightness value as a function of time. The area under the curve (AUC) of change in brightness value versus time was calculated for each high potassium treatment cycle. The response rate of each cell was calculated as the ratio of the total AUC of the seventh and eighth high potassium treatment cycles to the total AUC of the first and second high potassium treatment cycles according to Equation 1 below. Then, the degree of inhibition of the increase in intracellular calcium concentration of each cell was calculated according to Expression 2 below based on the response rate of each cell and the average response rate of all cells in the vehicle treatment group. The average value of the degree of inhibition for all cells in each group was considered as the degree of inhibition for each group, and the degree of inhibition of the increase in intracellular calcium concentration for the vehicle treatment group was determined to be 0%.

Response rate of each cell = (Total AUC of the seventh and eighth high potassium treatment cycles)/(Total AUC of the first and second high potassium treatment cycles) × 100 ... Expression 1

The degree of inhibition of the increase in intracellular calcium concentration of each cell (%) = [1 - (Response rate of each cell)/(Average value of the response rate of all cells in the vehicle treatment group)]) × 100 ... Expression 2

[0104]

The inhibitory effects of Compounds 1-4 on intracellular calcium elevation induced by high potassium treatment of DRG neurons are shown in Table 4. In this table, "Inhibition Rate" is the calculated degree of inhibition of intracellular calcium elevation (which is the mean value; the number of cells in each group was 106-262). In this table, Compound 1, Compound 2, Compound 3, and Compound 4 represent a compound processing group for each compound. In the table, "#" and "###" denote a statistically significant (#: p < 0.05, ###: p < 0.001, Dunnett's multiple comparison test) difference compared to the vehicle treatment group.

[0105]

Table 4 Connection under test Degree of inhibition (%) Compound 1 35.5 ^♯♯♯ Compound 2 19.3 ^♯♯♯ Compound 3 17.8 ^♯♯♯ Compound 4 ^11.9♯

[0106]

In all compound treatment groups, the increase in intracellular calcium concentration was significantly inhibited compared to the vehicle treatment group. This demonstrated that compounds 1-4 inhibit the high potassium-induced increase in intracellular calcium concentration in DRG neurons. The degree of inhibition of the increase in intraneuronal calcium concentration in the compound treatment group using compounds 1-3 of general formula (I), where R ¹ represents a hydroxyl group, was greater than in the compound treatment group using compound 4 of general formula (I), where R ¹ represents a hydrogen atom.

[0107]

The inhibitory effects of Compounds 5-10, Comparative Example 1 Compound, and Comparative Example 2 Compound tested in the same manner as above are shown in Table 5 (which represents the average value; the number of cells in each group was 60-250). In this table, "Compound 5", "Compound 6", "Compound 7", "Compound 8", "Compound 9", "Compound 10", "Compound of Comparative Example 1" and "Compound of Comparative Example 2" represent the compound processing group using each connection. In this table, "###" denotes a statistically significant (###: p < 0.001, Dunnett's multiple comparison test) difference compared to the vehicle treatment group.

[0108]

Table 5 Connection under test Degree of inhibition (%) Compound 5 39.0 ^♯♯♯ Compound 6 23.3 ^♯♯♯ Compound 7 15.4 ^♯♯♯ Compound 8 13.2 ^♯♯♯ Compound 9 7.1 Compound 10 5.9 Compound of Comparative Example 1 -3.3 Compound of Comparative Example 2 -1.1

[0109]

In compound 5-10 treatment groups, the increase in intracellular calcium concentration was inhibited. Of these, in compound 5-8 treatment groups, the increase in intracellular calcium concentration was significantly inhibited compared to the vehicle treatment group. On the other hand, the increase in intracellular calcium concentration was not inhibited by Comparative Example 1 and Comparative Example 2 in their respective treatment groups.

[0110]

These results demonstrate that the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof serves as an agent for inhibiting the increase in intraneuronal calcium concentration.

Industrial Applicability

[0111]

The cyclic amine derivative (I) or pharmacologically acceptable salt thereof of the present invention significantly inhibits the increase in intraneuronal calcium concentration, and thus can be used as a drug for a neuronal hyperexcitability disease.

[0112]

All publications, patents and patent applications cited in this application are incorporated herein by reference in their entirety.

Claims (33)

1. Use of an agent for inhibiting an increase in intraneuronal calcium concentration, wherein the agent comprises a cyclic amine derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient: [Formula 1]

, where A is a group represented by the following general formula (IIa), (IIb) or (IIc): [Formula 2]

, where R ¹ represents a hydroxyl group or a hydrogen atom, R ² represents a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, difluoromethyl group or 2,2,2-trifluoroethyl group, R ³ represents a hydrogen atom, a fluorine atom, a bromine atom, or a chlorine atom, each R ⁴ is independently a methyl group or an ethyl group, n is 1 or 2, and when R ¹ is a hydroxyl group, the carbon marked with * represents an asymmetric atom carbon. 2. Use according to claim 1, wherein A is a group represented by the general formula (IIa). 3. Use according to claim 1, wherein A is a group represented by the general formula (IIb). 4. Use according to claim 1, wherein A is a group represented by the general formula (IIc). 5. Use according to claim 1, where R ¹ represents a hydrogen atom. 6. Use according to claim 1, where R ¹ represents a hydroxyl group. 7. Application according to any one of paragraphs. 1-6, where R ² represents a methyl group, an ethyl group, an isopropyl group, an n-butyl group, or a 2,2,2-trifluoroethyl group. 8. Application according to any one of paragraphs. 1-6, where R ² represents an n-propyl group. 9. Application according to any one of paragraphs. 1-6, where R ³ represents a hydrogen atom or a chlorine atom. 10. Application according to any one of paragraphs. 1-4 and 6, where the stereochemical configuration of the asymmetric carbon marked with * is the S-configuration. 11. Use of a cyclic amine derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient: [Formula 1]

, where A is a group represented by the following general formula (IIa), (IIb) or (IIc): [Formula 2]

, where R ¹ represents a hydroxyl group or a hydrogen atom, R ² represents a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, difluoromethyl group or 2,2,2-trifluoroethyl group, R ³ represents a hydrogen atom, a fluorine atom, a bromine atom, or a chlorine atom, each R ⁴ is independently a methyl group or an ethyl group, n is 1 or 2, and when R ¹ is a hydroxyl group, the carbon marked with * represents an asymmetric atom carbon, for the treatment or prevention of a disease associated with hyperexcitability of neurons. 12. Use according to claim 11, wherein A is a group represented by the general formula (IIa). 13. Use according to claim 11, wherein A is a group represented by the general formula (IIb). 14. Use according to claim 11, wherein A is a group represented by the general formula (IIc). 15. Use according to claim 11, where R ¹ represents a hydrogen atom. 16. The use according to claim 11, where R ¹ represents a hydroxyl group. 17. Application according to any one of paragraphs. 11-16, where R ² represents a methyl group, an ethyl group, an isopropyl group, an n-butyl group, or a 2,2,2-trifluoroethyl group. 18. Application according to any one of paragraphs. 11-16, where R ² represents an n-propyl group. 19. Application according to any one of paragraphs. 11-16, where R ³ represents a hydrogen atom or a chlorine atom. 20. Application according to any one of paragraphs. 11-14 and 16, where the stereochemical configuration of the asymmetric carbon marked with * is the S-configuration. 21. The use according to claim 11, where the disease associated with hyperexcitability of neurons is associated with an increase in intraneuronal calcium concentration.