KR101171953B1 - 2-4-Subsituted-1,4-diazepan-1-ylethanone compounds having activity for T-type calcium channel - Google Patents

Abstract

The present invention comprises a 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound having activity against a T-type calcium channel, a method for preparing the compound, and the compound as an active ingredient It relates to a pharmaceutical composition. The novel 1- (4-substituted-1,4-diazepan-1-yl) ethanone compounds or pharmaceutically acceptable salts thereof of the present invention have an antagonistic action against T-type calcium channels, so that epilepsy, hypertension, etc. It is useful as a treatment for brain diseases, treatment for heart diseases such as angina pectoris, treatment for pain diseases such as chronic pain and neuropathic pain, or as an anticancer agent.

Description

{2- (4-Subsituted-1,4-diazepan-1-yl) ethanone compounds with activity on T-type calcium channels having activity for T-type calcium channel}

The present invention comprises a 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound having activity against a T-type calcium channel, a method for preparing the compound, and the compound as an active ingredient It relates to a pharmaceutical composition. The novel 1- (4-substituted-1,4-diazepan-1-yl) ethanone compounds or pharmaceutically acceptable salts thereof of the present invention have an antagonistic action against T-type calcium channels, so that epilepsy, hypertension, etc. It is useful as a treatment for brain diseases, treatment for heart diseases such as angina pectoris, treatment for pain diseases such as chronic pain and neuropathic pain, or as an anticancer agent.

Calcium channels play an important role in intracellular signal transduction by increasing the concentration of calcium by stimulation of nerve cells. The calcium channel is divided into a high-voltage activated calcium channel and a low-voltage activated calcium channel. A representative low voltage activated calcium channel is a T-type calcium channel.

T-type calcium channels are present in the central muscles, adrenal glands, isotopes, and the heart, and antagonists of T-type calcium channels are known to be effective in treating brain diseases such as epilepsy and hypertension and heart diseases such as angina. [1) Hosravani, Houman et al., "Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy", Annals of Neurology (2005), 57 (5) , 745-749; 2) Vitko, Iuliia et al., "Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel", Journal of Neuroscience (2005), 25 (19) , 4844-4855; 3) Clozel, Cardiovas Drugs Ther . (1990), 4 , pp. 731-736; 4) Hefti, Arzneimittel forschung (1990), 40 , 417-421; 5) Moosmang, Sven et al., "Antihypertensive Effects of the Putative T-Type Calcium Channel Antagonist Mibefradil Are Mediated by the L-Type Calcium Channel Cav1.2", Circulation Research (2006), 98 (1) , 105-110 ]

Recently, antagonists of T-type calcium channels have been shown to be effective in treating chronic pain [ Drugs of the Future (2005), 40 , 573-580], and spinal nerve ligation in a1G knock-out mice. It has been reported that nerve pain can be relieved as a result of causing spinal nerve ligation. [ Molecules & Cells , 2008, 25 , 242-246] In addition, mibefradil and ethosuximide as antagonists of T-type calcium channels induce mechanical and thermal in animal models of spinal nerve ligation. The degree of inhibition was reported to be dependent on the drug dose, indicating that antagonists of T-type calcium channels are effective in treating neurological pain. [ Pain , 2003, 105 , 159-168]

Other reports suggest that calcium is known to be involved in cell growth, suggesting that antagonists of T-type calcium channels may have anticancer effects. Nat. Rev. Mol. Cell Biol. 2003 , 4 , 517-529]

Mibefradil, a commercially available antagonist of T-type calcium channels, was used to treat hypertension and angina, but mibepradil was banned due to its interaction with various other drugs. There is an urgent need for the development of antagonists of T-type calcium channels. To date, there have been many efforts to develop antagonists of T-type calcium channels, but the antagonists of selective T-type calcium channels are not well known.

As described above, the antagonist of T-type calcium channel is effective as an anti-cancer agent for treating brain diseases such as epilepsy and hypertension, for treating heart diseases such as angina pectoris, for treating chronic pain, neuropathic pain, etc. Ham has already been revealed in several papers. It is also a new T-type calcium channel that is selective for T-type calcium channels, has a good pharmacokinetic profile, good ADME (absorption, distribution, metabolism, and excretion) and is effective in heart disease, cancer, epilepsy, neurological pain and related diseases. Antagonist development is required.

An object of the present invention is to provide a 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound having a novel structure.

The present invention includes a novel 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound or a pharmaceutically acceptable salt as an active ingredient and has a selective antagonism against T-type calcium channels. It is another object to provide a pharmaceutical composition.

The present invention is a novel 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound or a pharmaceutically acceptable salt containing as an active ingredient, brain disease treatment agents such as epilepsy, hypertension, angina, etc. It is another object of the present invention to provide a therapeutic agent for pain diseases such as heart disease, chronic pain, neuropathic pain, or an anticancer agent.

In order to realize the above object, the present invention provides a 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound represented by the following Chemical Formula 1 showing selective antagonistic activity on T-type calcium channel And a method for producing the compound and a pharmaceutical composition containing the compound.

In Chemical Formula 1,

R ¹ is a C ₁ to C ₆ alkyl group; Or a heteroaryl group selected from imidazole, benzimidazole and oxazole, wherein the heteroaryl group may be substituted or unsubstituted with 1 to 3 substituents selected from C ₁ to C ₆ alkyl and phenyl,

R ² is a phenyl amino group having 1 to 3 substituted or unsubstituted substituents selected from halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ haloalkyl; Or a heterocycloalkyl group selected from piperidine, piperazine and morpholine, wherein the heterocycloalkyl group may be substituted or unsubstituted with 1 to 3 substituents selected from C ₁ to C ₆ alkyl and benzyl.

Since the 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound of the present invention or a pharmaceutically acceptable salt thereof has an antagonistic action against T-type calcium channel, epilepsy, hypertension, etc. It is useful as an agent for treating brain diseases, treatment for heart diseases such as angina pectoris, treatment for pain diseases such as chronic pain and neuropathic pain, or anticancer agents.

Pharmaceutically acceptable salts of the 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound represented by the formula (1) include, for example, metal salts, salts with organic bases, inorganic acids and Salts, salts with organic acids, salts with basic or acidic amino acids, and the like. Suitable metal salts include, for example, alkali metal salts such as sodium salts, potassium salts and the like; Alkaline earth metal salts such as calcium salts, magnesium salts, barium salts and the like; Aluminum salts and the like. Salts with organic bases are, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N Salts with , N -dibenzylethylenediamine and the like. Salts with inorganic acids may include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Salts with organic acids may include, for example, salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p -toluenesulfonic acid, and the like. . Salts with basic amino acids may include, for example, salts with arginine, lysine, ornithine and the like. Salts with acidic amino acids may include, for example, salts with aspartic acid, glutamic acid and the like.

The substituents used in the definition of the 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound represented by Chemical Formula 1 according to the present invention will be described in more detail as follows.

'Halo' or 'halogen' is used interchangeably with each other, and means the elements fluoro, chloro, bromo, iodo. 'Alkyl group' includes all linear, pulverized and cyclic carbon chains having 1 to 6 carbon atoms, with preferred alkyl groups being methyl, ethyl, n -propyl, isopropyl, n -butyl and isobutyl Groups , tert -butyl groups, neopentyl groups, cyclopentyl groups, 3,3-dimethylbutyl groups, cyclohexyl groups and the like. 'Haloalkyl group' includes 1 to 13 halogen atoms such as fluoro, chloro, bromo and iodo, and includes all linear, pulverized and cyclic carbon chains having 1 to 6 carbon atoms, and preferred halo. The alkyl group includes a fluoromethyl, trifluoromethyl, 1,2-dichloroethyl group, 1,1-dichloroethyl group, pentafluoroethyl group and the like. "Alkoxy group" means an alkyl group of carbon connected to oxygen, wherein alkyl is as defined above. "Heteroaryl group" includes 5 to 10 atoms of aromatic heterohydrocarbon group in the form of a monocyclic or conjugated ring containing one or more preferably 1 to 4 heteroatoms selected from N, O and S. The heteroaryl groups described above may specifically be pyrrolyl, furyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxdiazolyl, thidiazolyl, tetrazolyl, Pyridinyl, pyrazinyl, triazinyl, pyridazinyl, pyrimidinyl, triazolyl, indolyl, indolinyl, isoindolyl, benzfuryl, benzfurazanyl, dibenzfuryl, isobenzfuryl, indazolyl, Benzimidazolyl, imidazopyridinyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, dibenzthiophenyl, naphthyridyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, frino Thalazinyl, chinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenthiathiazinyl, acridinyl, and the like. The heteroaryl group may be substituted with one or more substituents selected from halo, C ₁ -C ₆ alkyl, amine, C ₁ -C ₆ alkylamino, phenyl and the like. 'Heterocycloalkyl group' is an aliphatic heterohydrocarbon group having 5 to 10 carbon atoms containing 1 to 4 heteroatoms selected from N, O, and S, consisting of a single ring, a bicyclic ring, or a cyclic ring, which may include an unsaturated carbon chain. Include. The heterocycle group is specifically tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, pyrrolidinoneyl, piperidinyl, isoindoledioneyl, dioxanyl, Dioxoranyl, benzdioxyyl, chromanyl and the like.

In the 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound represented by Formula 1, preferably, R ¹ is a methyl group, an ethyl group, an isopropyl group, a tert -butyl group, Imidazol-1-yl group, imidazol-2-yl group, imidazol-5-yl group, 2-phenyl-imidazol-5-yl group, 1H -benz [ d ] imidazol-2-yl group, oxazole-2 -Yl group, oxazol-4-yl group, oxazol-5-yl group, or 4-phenyl-5-propyl-oxazol-2-yl group; R ² is 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group , 2,3-dimethylphenyl group, 2,4-dimethylphenyl group, 2,5-dimethylphenyl group, 2,6-dimethylphenyl group, 3,4-dimethylphenyl group, 2,3-diethylphenyl group, 2,4-diethyl Phenyl group, 2,5-diethylphenyl group, 2,6-diethylphenyl group, 3,4-diethylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2- (trifluoro Methyl) phenyl group, 3- (trifluoromethyl) phenyl group, or 4- (trifluoromethyl) phenyl group, piperidinyl group, 4-methylpiperidinyl group, 2-ethylpiperidinyl group, 4-benzylpiperidinyl group, It is a compound which shows a piperazinyl group, a 4-methyl piperazinyl group, a 4-methyl piperazinyl group, or a morpholino group.

Particularly preferred examples of the 1- (4-substituted-1,4-diazepane-1-yl) ethanone compound represented by Chemical Formula 1 are as follows:

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (2,6-diethylphenylamino) ethanone ;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (2,4-dimethylphenylamino) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (3,4-dimethylphenylamino) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (2,6-dimethylphenylamino) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (2-fluorophenylamino) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (3-fluorophenylamino) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (4-fluorophenylamino) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (2-chlorophenylamino) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (3-chlorophenylamino) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (4-chlorophenylamino) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- ( o- tolylamino) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- ( m- tolylamino) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- ( p- tolylamino) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (2-methoxyphenylamino) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (3-methoxyphenylamino) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (4-methoxyphenylamino) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (2- (trifluoromethyl) phenylamino) Ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (3- (trifluoromethyl) phenylamino) Ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (4- (trifluoromethyl) phenylamino) Ethanone;

2- (3-chlorophenylamino) -1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepan-1-yl) ethanone;

2- (3-chlorophenylamino) -1- (4-neopentyl-1,4-diazepan-1-yl) ethanone;

2- (3-chlorophenylamino) -1- (4- (3,3-dimethylbutyl) -1,4-diazepan-1-yl) ethanone;

1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepan-1-yl) -2- (piperidin-1-yl) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (piperidin-1-yl) ethanone;

2-morpholino-1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepan-1-yl) ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl))-2-morpholinoethanone;

2- (4-methylpiperidin-1-yl) -1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepan-1-yl) Ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl))-2- (4-methylpiperidin-1-yl Ethanone;

2- (2-ethylpiperidin-1-yl) -1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepan-1-yl) Ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl))-2- (2-ethylpiperidin-1-yl Ethanone;

2- (4-benzylpiperidin-1-yl) -1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepan-1-yl) Ethanone;

1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl))-2- (2-ethylpiperidin-1-yl Ethanone;

2- (2,6-diethylphenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepan-1-yl) ethanone ;

2- (2,6-dimethylphenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepan-1-yl) ethanone;

2- (2-methoxyphenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepan-1-yl) ethanone;

2- (3-methoxyphenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepan-1-yl) ethanone;

2- (4-methoxyphenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepan-1-yl) ethanone;

2- (4-fluorophenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepan-1-yl) ethanone;

2- (3-fluorophenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepan-1-yl) ethanone;

2- (2-fluorophenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepan-1-yl) ethanone;

1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (2- (trifluoromethyl) phenylamino) Ethanon.

On the other hand, the present invention includes a method for producing a 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound represented by the formula (1).

The preparation method according to the present invention comprises a (1,4-azpan-1-yl) ethanone compound represented by the following Chemical Formula 2, an aldehyde compound represented by the following Chemical Formula 3a, or the following Chemical Formula 3b, as shown in Scheme 1 below. And a process of preparing the 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound represented by the following Chemical Formula 1 by reacting the represented halide compound.

[Reaction Scheme 1]

In Scheme 1, n, R ¹ , and R ² are each as defined above, and X represents a halogen atom.

The reaction according to Scheme 1 may be performed by reductive amination with an aldehyde compound represented by Chemical Formula 3a as a kind of alkylation reaction or by a coupling reaction with a halide compound represented by Chemical Formula 3b. have.

The reductive amination reaction is carried out in the presence of a reducing agent. In the reaction, molecular sieves (molecular sieve, 4 A, beads, 4-8 mesh) were used. As the reducing agent, NaBH (OAc) ₃ , NaBH ₃ CN, NaBH _4, etc. may be used. The amount of the reducing agent is slightly different depending on the reactivity, and is about 2 to 10 equivalents, preferably NaBH (OAc) ₃ 2 to 4 Use equivalents. The reaction temperature is about 20 ℃ to 50 ℃, the reaction can be carried out smoothly even around room temperature.

In addition, the coupling reaction may be performed under conditions using a suitable binder and an organic solvent. Examples of the binder include inorganic bases such as carbonates, sulfates, and hydroxides of alkali or alkaline earth metals, or mono (C ₁ -C ₅ alkyl) amines, di (C ₁ -C ₅ alkyl) amines, and tri (C ₁ -C ₅ alkyls). Organic bases, such as an amine, etc. can be used, Especially preferably, ethyl diisopropylamine (EDIPA) is used. The reaction temperature may be carried out in the range of -30 ℃ to the reflux temperature of the solvent used, more specifically in the temperature range of room temperature to 120 ℃, more specifically may be carried out within 30 ℃ to 80 ℃.

The solvent used in the reductive amination reaction and the coupling reaction described above may be an inert organic solvent which does not affect the reaction as an organic solvent commonly used in the art. Specific examples of organic solvents that may be used in the present invention include diethyl ether, lower alcohols having 1 to 6 carbon atoms such as methanol, ethanol and propanol, ethers such as tetrahydrofuran, or halogenated hydrocarbons such as chloroform and dichloromethane. Nitriles such as acetonitrile, and amides such as N, N- dimethylformamide (DMF) and the like can be used. Preferably, dichloromethane, N, N -dimethylformamide (DMF) is used.

In addition, the preparation method of the compound represented by Formula 2 used as a raw material in the preparation method according to Scheme 1 may be prepared by varying the preparation method according to the type of substituent R ² .

For example, the (1,4-azpan-1-yl) ethanone compound represented by the following Chemical Formula 2a, in which the substituent R ² is a substituted or unsubstituted phenylamino group, is represented by the following Chemical Formula 3 as shown in Scheme 2 below. It can be manufactured and used by making it react with the 1, 4- azepane compound shown, and the phenylamino ethanoate represented by following formula (4).

Scheme 2

In Scheme 2, Y represents a hydrogen atom or a tert -butoxycarbonyl group (t-Boc); R ³ represents a hydrogen atom or 1 to 3 substituents selected from halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkyl.

The preparation process of Scheme 2 is carried out using a microwave in the presence of 2,3,4,6,7,8-hexahydro-1 H -pyrimido [1,2-a] pyrimidine (TBD) at 30 ℃ to 90 ℃ It can be carried out in the temperature range. Deprotection of t-Boc protecting groups can also be carried out by techniques well known in Protective Groups in Organic Synthesis , TW Green and RGM Wuts, 3rd Ed. Wiely. Specifically, dichloromethane, chloroform, ethyl acetate, benzene, toluene in the presence of an inorganic acid (e.g. hydrochloric acid, bromic acid, sulfuric acid) or an organic acid (e.g. acetic acid, acetic acid, trifluoroacetic acid, methanesulfonyl acid). Optionally at 0 ° C. to 100 ° C. in a solvent such as tetrahydrofuran, dioxane.

And, as shown in Scheme 2 below (1,4-azpan-1-yl) ethanone compound represented by the following formula (2b) wherein R ² is a heterocycloalkyl group,

Iii) 2-chloro-1- (1,4-azepan-1- represented by the following formula (6) by reacting with a 1,4-diazepane represented by the following formula (3) and chloroacetyl chloride represented by the following formula (5) (1) preparing an ethanone compound; And

Ii) A 2-chloro-1- (1,4-azpan-1-yl) ethanone compound represented by the following Chemical Formula 6 may be prepared by reacting with a heterocycloalkyl compound represented by the following Chemical Formula 7.

Scheme 3

In Scheme 3, Y represents a hydrogen atom or tert -butoxycarbonyl (t-Boc); Q is selected from C, N or O; R ⁴ represents a hydrogen atom or 1 to 3 substituents selected from C ₁ to C ₆ alkyl and benzyl.

The iii) process according to Scheme 3 may be carried out at -20 ° C to 40 ° C in the presence of an organic base such as triethylamine as an amidation reaction, or with a base without stirring in a diethyl ether solvent. Ii) The binding reaction is carried out under reductive amination reaction conditions under suitable binders and organic solvents such as dichloromethane as defined in Scheme 1 above, or ethyl diisopropylamine under N, N -dimethylformamide solvent conditions. It may be carried out under alkylation reaction conditions using a base such as (EDIPA).

On the other hand, the present invention includes a pharmaceutical composition comprising a 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. .

The pharmaceutical composition of the present invention is suitable for oral or parenteral administration by formulating in a conventional formulation method including other conventional carriers, adjuvants or diluents together with the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. It may be prepared in the form. In the case of oral administration, it may be prepared in the form of tablets, capsules, solutions, syrups, suspensions, etc., and in the case of parenteral administration, it may be prepared in the form of injections for intraperitoneal, subcutaneous, muscle, and transdermal.

The effective daily dose of T-type calcium channel antagonist of the pharmaceutical composition of the present invention is 0.01 to 1000 mg / day based on an adult, but the dosage is the age, weight, sex, dosage form, health condition and disease level of the patient. Depending on the judgment of the doctor or pharmacist may be divided doses once a day to several times a day.

Accordingly, the present invention provides a pharmaceutical use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same for the purpose of treating and preventing a disease.

That is, the present invention has an activity against T-type calcium channels, and thus diseases treatable by T-type calcium channel antagonism, such as brain diseases such as epilepsy and hypertension, heart diseases such as angina pectoris, chronic pain, and neuropathy It includes medicinal uses used for the treatment of pain diseases such as pain or cancer diseases.

The present invention as described above will be described in more detail through the following Examples and Experimental Examples, but the present invention is not limited to these Examples and Experimental Examples.

[Example]

Representative Synthesis Example 1 Synthesis of Methyl 2- (2,6-diethylphenylamino) acetate (Formula 4)

2,6-diethylaniline, methyl bromoacetate, and ethyl diisopropylamine (EDIPA) were added to N, N -dimethylformamide, and the mixture was stirred under reflux at 60 ° C. for 12 hours to obtain methyl 2- (2,6). -Diethylphenylamino) acetate was obtained in 99% yield.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.05 (d, 2H, J = 7.49 Hz), 6.96 (q, 2H, J = 6.92 Hz), 3.95 (bs, 1H), 3.79 (s, 3H), 2.71 (q, 4H, J = 7.56 Hz), 1.27 (q, 6H, J = 4.31 Hz).

Representative Synthesis Example 2. Synthesis of 1- (1,4-diazepan-1-yl) -2- (2,6-diethylphenylamino) ethanone (Formula 2a)

In a closed vessel for microwave (75 ° C., 100 w), tetrahydrofuran, tert -butyl 1,4-diazepane-1-carboxylate, methyl 2- (2,6-diethylphenylamino) acetate, and 2,3,4,6,7,8-hexahydro-1 H -pyrimido [1,2-a] pyrimidine (TBD) was added, followed by stirring for 3 hours using ultrasonic waves (75 ° C, 100 w). Tert - butyl4- (2- (2,6-diethylphenylamino) acetyl) -1,4-diazepane-1-carboxylate was obtained in 99% yield.

Deprotection of tert - butyl4- (2- (2,6-diethylphenylamino) acetyl) -1,4-diazepane-1-carboxylate obtained above with stirring in trifluoroacetic acid (TFA) The reaction was carried out to obtain 1- (1,4-diazepan-1-yl) -2- (2,6-diethylphenylamino) ethanone in 77% yield.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.04 (d, 2H, J = 7.16 Hz), 6.95-6.90 (m, 1H), 4.73 (bs, 1H), 3.79 (d, 2H, J = 14.08 Hz) , 3.72-3.36 (m, 4H), 2.99-2.86 (m, 4H), 2.87 (q, 4H, J = 7.54 Hz), 1.87-1.79 (m, 2H), 1.27 (t, 6H, J = 7.54 Hz ).

Representative Synthesis Example 3. Synthesis of 1- (1,4-diazepane-1-yl) -2- (phenylamino) ethanone (Formula 2a)

In a closed vessel for microwave (75 ° C., 100 w), tetrahydrofuran, methyl 2- (phenylamino) acetate, and 1,4-diazepane-1-carboxylate were added for 3 hours using ultrasound. Stirring gave 1- (1,4-diazepane-1-yl) -2- (phenylamino) ethanone directly in a yield of 64%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.04 (d, 2H, J = 7.16 Hz), 6.95-6.90 (m, 1H), 4.73 (bs, 1H), 3.79 (d, 2H, J = 14.08 Hz) , 3.72-3.36 (m, 4H), 2.99-2.86 (m, 4H), 2.87 (q, 4H, J = 7.54 Hz), 1.87-1.79 (m, 2H), 1.27 (t, 6H, J = 7.54 Hz ).

Representative Synthesis Example 4 Synthesis of tert -Butyl 4- (2-chloroacetyl) -1,4-diazepane-1-carboxylate (Formula 6)

Dichloromethane to tert - butyl-1,4-diazepane-1-carboxylate and triethylamine back into the (TEA), was added dropwise chloroacetyl chloride at 0 ℃ conditions slowly and stirred for 1 hour at room temperature After 10 minutes, tert - Butyl 4- (2-chloroacetyl) -1,4-diazepane-1-carboxylate (yield 87%) was prepared.

¹ H NMR (CDCl ₃ , 300 MHz) δ 4.14-4.09 (m, 2H), 3.66-3.38 (m, 6H), 1.94-1.85 (m, 2H), 1.45 (s, 9H)

Representative Synthesis Example 5. Synthesis of 1- (1,4-diazepane-1-yl) -2- (piperidin-1-yl) ethanone (Formula 2b)

To tert -butyl 4- (2-chloroacetyl) -1,4-diazepane-1-carboxylate, piperidine, and ethyl diisopropylamine (EDIPA) were added to N, N -dimethylformamide at 70 ° C. stirred under reflux for 12 hours and tert - butyl-4- (2- (piperidin-1-yl) acetyl) to give the 1,4-diazepan-1-carboxylate in 64% yield.

tert -butyl 4- (2- (piperidin-1-yl) acetyl) -1,4-diazepane-1-carboxylate was dissolved in dichloromethane and deprotected by stirring in 1M HCl methanol solution for 12 hours. 1- (1,4-diazepane-1-yl) -2- (piperidin-1-yl) ethanone was obtained in 88% yield.

¹ H NMR (CDCl ₃ , 400 MHz) δ 3.69-3.61 (m, 4H), 3.14 (d, 1H, J = 7.44 Hz) 3.05-2.88 (m, 4H), 2.45 (s, 4H), 2.06 (bs , 1H), 1.95-1.81 (m, 2H), 1.64-1.26 (m, 6H)

The following examples are examples of the compound represented by Formula 1 synthesized using the above-described representative synthesis example.

Example 1. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (2,6-diethylphenyl Amino) ethanone (Compound No. 1)

2- (chloromethyl) -1 H- benzimidazole (89 mg, 0.53 mmol) and 1- (1,4-diazepane-1-yl) -2- (2 in 5 mL of N, N -dimethylformamide , 6-Diethylphenylamino) ethanone (200 mg, 0.69 mmol) and EDIPA (185 μL, 1.06 mmol) were added thereto, and the mixture was stirred under reflux at 70 ° C. for 8 hours to obtain 157 mg (70%) of the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.56 (s, 2H), 7.26-7.22 (m, 2H), 7.04 (t, 2H, J = 6.05 Hz), 7.00-6.93 (m, 1H), 3.99 ( d, 2H, J = 14.97 Hz), 3.81-3.71 (m, 4H), 3.41 (t, 2H, J = 5.84 Hz), 2.89-2.67 (m, 8H), 1.90 (d, 2H, J = 4.21 Hz ), 1.28-1.21 (m, 6 H).

Example 2. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (2,4-dimethylphenylamino Ethanone (Compound No. 2)

The target compound was obtained in the same manner as in Example 1, with a yield of 76%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.56 (s, 2H), 7.26-7.23 (m, 2H), 6.92 (t, 2H, J = 7.72 Hz), 6.40 (q, 1H, J = 8.18 Hz) , 4.00-3.50 (m, 8H), 2.80-2.77 (m, 4H), 2.28-2.21 (m, 6H), 1.94-1.90 (m, 2H).

Example 3. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (3,4-dimethylphenylamino Ethanone (Compound No. 3)

The target compound was obtained in the same manner as in Example 1, with a yield of 45%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.55 (s, 2H), 7.25-7.20 (m, 2H), 6.93 (t, 1H, J = 7.61 Hz), 6.49-6.39 (m, 2H), 3.94 ( d, 2H, J = 3.59 Hz), 3.82 (d, 2H, J = 20.53 Hz), 3.70-3.46 (m, 4H), 2.84-2.69 (m, 4H), 2.17 (t, 6H, J = 7.75 Hz ), 1.88-1.83 (m, 2 H).

Example 4. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (2,6-dimethylphenylamino Ethanone (Compound No. 4)

The target compound was obtained in the same manner as in Example 1, with a yield of 70%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.57 (t, 2H, J = 2.44 Hz), 7.25-7.23 (m, 2H), 6.99 (t, 2H, J = 6.04 Hz), 6.83-6.80 (m, 1H), 3.99 (d, 2H, J = 11.27 Hz), 3.84-3.70 (m, 4H), 3.43 (t, 2H, J = 6.17 Hz), 2.87-2.74 (m, 4H), 2.34 (t, 6H , J = 4.04 Hz). 1.92-1.88 (m, 2 H).

Example 5. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (2-fluorophenylamino) Ethanone (Compound No. 5)

The target compound was obtained in the same manner as in Example 1, with a yield of 67%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.55 (s, 2H), 7.25-7.21 (m, 2H), 7.01-6.93 (m, 2H), 6.66-6.54 (m, 2H), 5.13 (bs, 1H ), 3.96 (d, 2H, J = 5.22 Hz), 3.87 (d, 2H, J = 20.48 Hz), 3.76-3.49 (m, 4H), 2.83 (ddd, 2H, J = 8.33, 5.29, 5.29 Hz) , 2.72 (t, 2H, J = 5.25 Hz), 1.92-1.83 (m, 2H).

Example 6. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (3-fluorophenylamino) Ethanone (Compound No. 6)

The target compound was obtained in the same manner as in Example 1, with a yield of 73%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.53 (s, 2H), 7.22-7.01 (m, 3H), 6.39-6.19 (m, 3H), 5.69 (bs, 1H), 3.92 (d, 2H, J = 6.18 Hz), 3.74 (d, 2H, J = 19.86 Hz), 3.40 (q, 2H, J = 6.24 Hz), 2.80-2.66 (m, 4H), 1.86-1.79 (m, 2H).

Example 7. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (4-fluorophenylamino) Ethanone (Compound No. 7)

The target compound was obtained in the same manner as in Example 1, with a yield of 65%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.53 (bs, 2H), 7.26-7.20 (m, 2H), 6.92-6.86 (m, 2H), 6.57-6.50 (m, 2H), 4.85 (bs, 1H ), 3.95 (d, 2H, J = 4.57 Hz), 3.82 (d, 2H, J = 22.66 Hz), 3.74-3.49 (m, 4H), 2.87-2.71 (m, 4H), 1.93-1.84 (m, 2H).

Example 8. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (2-chlorophenylamino) ethane On (Compound No. 8)

The target compound was obtained in the same manner as in Example 1, with a yield of 75%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.55 (s, 2H), 7.28-7.08 (m, 4H), 6.68-6.44 (m, 2H), 5.60 (bs, 1H), 3.97-3.47 (m, 8H ), 2.87-2.70 (m, 4H), 1.92-1.84 (m, 2H).

Example 9. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (3-chlorophenylamino) ethane On (Compound No. 9)

The target compound was obtained in the same manner as in Example 1, with a yield of 70%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.55 (d, 2H, J = 2.32 Hz), 7.26-7.21 (m, 2H), 7.09-7.04 (m, 2H), 6.69-6.49 (m, 3H), 3.95 (d, 2H, J = 5.18 Hz), 3.83-3.46 (m, 6H), 2.87-2.71 (m, 4H), 1.94-1.85 (m, 2H).

Example 10. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (4-chlorophenylamino) ethane On (Compound No. 10)

The target compound was obtained in the same manner as in Example 1, with a yield of 68%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.56 (s, 2H), 7.26-7.22 (m, 2H), 7.12 (t, 2H, J = 8.32 Hz), 6.53 (q, 2H, J = 8.64 Hz) , 4.99 (bs, 1H), 3.96 (d, 2H, J = 2.67 Hz), 3.85-3.70 (m, 4H), 3.51 (q, 2H, J = 6.06 Hz), 2.87-2.73 (m, 4H), 1.96-1.85 (m, 2 H).

Example 11. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- ( o- tolylamino) ethanone (Compound No. 11)

The target compound was obtained in the same manner as in Example 1, with a yield of 60%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.56 (bs, 2H), 7.26-7.21 (m, 4H), 6.72-6.44 (m, 4H), 4.92 (bs, 1H), 3.96-3.51 (m, 8H ), 2.88-2.73 (m, 4H), 2.23 (d, 3H, J = 4.62 Hz), 1.895-1.88 (m, 2H).

Example 12. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- ( m- tolylamino) ethanone (Compound No. 12)

The target compound was obtained in the same manner as in Example 1, with a yield of 60%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.55 (bs, 2H), 7.23-7.05 (m, 3H), 6.56 (d, 1H, J = 6.60 Hz), 6.42 (d, 2H, J = 12.12 Hz) , 4.84 (bs, 1H), 3.94 (d, 2H, J = 3.50 Hz), 3.84 (d, 2H, J = 21.77 Hz), 3.70 (d, 2H, J = 5.17 Hz), 3.49 (t, 2H, J = 6.15 Hz), 2.84-2.70 (m, 4H), 2.27 (d, 3H, J = 5.45 Hz), 1.89-1.85 (m, 2H).

Example 13. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- ( p- tolylamino) ethanone (Compound No. 13)

The target compound was obtained in the same manner as in Example 1, with a yield of 60%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.54 (s, 2H), 7.24-7.21 (m, 2H), 6.99 (t, 2H, J = 8.04 Hz), 6.54 (q, 2H, J = 8.28 Hz) , 3.93 (d, 2H, J = 3.91 Hz), 3.82 (d, 2H, J = 21.10 Hz), 3.70-3.45 (m, 4H), 2.83-2.69 (m, 4H), 2.23 (d, 3H, J = 3.06 Hz), 1.86-1.84 (m, 2 H).

Example 14. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (2-methoxyphenylamino) Ethanone (Compound No. 14)

The target compound was obtained in the same manner as in Example 1, with a yield of 37%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.55 (s, 2H), 7.24-7.22 (m, 2H), 6.88-6.49 (m, 4H), 5.44 (bs, 1H), 3.95 (t, 3H, J = 11.84 Hz), 3.84 (t, 4H, J = 5.11 Hz), 3.73 (q, 2H, J = 4.48 Hz), 3.53 (q, 2H, J = 6.01 Hz), 2.87-2.72 (m, 4H), 1.93-1.86 (m, 2 H).

Example 15. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (3-methoxyphenylamino) Ethanone (Compound No. 15)

The target compound was obtained in the same manner as in Example 1, with a yield of 62%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.54 (s, 2H), 7.26-7.19 (m, 2H), 7.06 (q, 2H, J = 7.92 Hz), 6.29-6.12 (m, 3H), 5.10 ( bs, 1H), 3.92-3.40 (m, 11H), 2.81-2.60 (m, 4H), 1.97-1.81 (m, 2H).

Example 16. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (4-methoxyphenylamino) Ethanone (Compound No. 16)

The target compound was obtained in the same manner as in Example 1, with a yield of 33%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.55 (s, 2H), 7.24-7.21 (m, 2H), 6.80-6.76 (m, 2H), 6.62-6.57 (m, 2H), 3.96-3.68 (m , 8H), 3.53 (q, 2H, J = 6.19 Hz), 2.86-2.74 (m, 4H), 1.91-1.87 (m, 2H).

Example 17. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (2- (trifluoromethyl ) Phenylamino) ethanone (Compound No. 17)

The target compound was obtained in the same manner as in Example 1, with a yield of 86%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.58-7.47 (m, 3H), 7.35 (t, 2H, J = 7.86 Hz), 7.30-7.23 (m, 2H), 6.78-6.52 (m, 2H), 5.83 (bs, 1H), 4.01 (s, 2H), 3.90 (dd, 2H, J = 12.50, 3.41 Hz), 3.80-3.47 (m, 4H), 2.93-2.77 (m, 4H), 1.98-1.91 ( m, 2H).

Example 18. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (3- (trifluoromethyl ) Phenylamino) ethanone (Compound No. 18)

The target compound was obtained in the same manner as in Example 1, with a yield of 85%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.54 (s, 2H), 7.23-7.19 (m, 3H), 6.93 (d, 1H, J = 7.13 Hz), 6.73 (t, 2H, J = 7.76 Hz) , 5.20 (bs, 1H), 3.95-3.46 (m, 8H), 2.93-2.71 (m, 4H), 1.88-1.83 (m, 2H).

Example 19. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (4- (trifluoromethyl ) Phenylamino) ethanone (Compound No. 19)

The target compound was obtained in the same manner as in Example 1, with a yield of 78%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.53 (t, 2H, J = 2.96 Hz), 7.34 (t, 2H, J = 8.43 Hz), 7.22-7.20 (m, 2H), 6.69 (t, 2H, J = 7.33 Hz), 4.01 (d, 2H, J = 7.46 Hz), 3.94 (d, 2H, J = 11.80 Hz), 3.71-3.62 (m, 4H), 2.87-2.73 (m, 4H), 1.99- 1.88 (m, 2 H).

Example 20. 2- (3-Chlorophenylamino) -1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepan-1-yl) ethane On (Compound No. 20)

The target compound was obtained in the same manner as in Example 1, with a yield of 41%.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.85 (d, 2H, J = 6.71 Hz), 7.32 (q, 3H, J = 6.29 Hz), 7.08-7.01 (m, 1H), 6.94 (d, 2H, J = 6.81 Hz), 6.67-6.44 (m, 3H), 5.04 (s, 1H), 3.77 (dd, 2H, J = 13.12, 3.87 Hz), 3.63 (d, 2H, J = 7.09 Hz), 3.43 ( q, 2H, J = 6.10 Hz), 2.76-2.62 (m, 4H), 1.88-1.81 (m, 2H).

Example 21. 2- (3-Chlorophenylamino) -1- (4-neopentyl-1,4-diazepan-1-yl) ethanone (Compound No. 21)

2- (3-chlorophenylamino) -1- (1,4-diazepane-1-yl) ethanone (127 mg, 0.47) synthesized with commercial reagent trimethylacetaldehyde (40 μL, 0.36 mmol) in 5 mL of DCM mmol), NaBH (OAc) ₃ (231 mg, 1.09 mmol) and a molecular sieve were added and stirred for 20 minutes to obtain the target compound (yield 25%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.09 (ddd, 1H, J = 8.01, 1.05, 1.05 Hz), 6.67 (d, 1H, J = 7.84 Hz), 6.57-6.51 (m, 2H), 3.84 ( q, 2H, J = 3.51 Hz), 3.69 (t, 2H, J = 5.40 Hz) 3.54-3.46 (m, 2H), 2.91-2.73 (m, 8H), 2.27 (d, 2H, J = 7.21 Hz) , 1.90-1.71 (m, 2H), 0.87 (s, 9H),

Example 22. 2- (3-Chlorophenylamino) -1- (4- (3,3-dimethylbutyl) -1,4-diazepan-1-yl) ethanone (Compound No. 22)

In the same manner as in Example 21, 3,3-dimethylbutyraldehyde was used to obtain a target compound in a yield of 81%.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.07 (t, 1H, J = 8.04 Hz), 7.64 (ddd, 1H, J = 7.88, 0.81 Hz), 6.55-6.17 (m, 2H), 3.81-3.47 ( m, 6H), 2.81-2.52 (m, 6H), 2.09-1.89 (m, 2H), 1.43-1.24 (m, 2H), 0.88 (s, 9H).

Example 23. 1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepan-1-yl) -2- (piperidin-1-yl Ethanone (Compound No. 23)

43% of the title compound was obtained in the same manner as in Example 1.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.90 (d, 2H, J = 6.98 Hz), 7.34-7.28 (m, 3H), 6.93 (d, 2H, J = 9.95 Hz), 3.70-3.47 (m, 6H), 3.07 (d, 2H, J = 8.53 Hz), 2.73-2.38 (m, 8H), 1.82-1.78 (m, 2H), 1.52-1.22 (m, 6H).

Example 24. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (piperidin-1-yl Ethanone (Compound No. 24)

The target compound was obtained in the same manner as in Example 1, with a yield of 53%.

¹ H NMR (CDCl ₃ , 300 MHz) δ 11.12 (d, 2H, J = 26.40 Hz), 7.69 (bs, 1H), 7.41 (bs, 1H), 7.23-7.18 (m, 2H), 3.93 (d, 2H, J = 3.89 Hz), 3.68-3.58 (m, 4H), 3.08 (d, 2H, J = 11.22 Hz), 2.79-2.69 (m, 4H), 2.39 (bs, 4H), 1.83 (bs, 2H ), 1.52-1.38 (m, 6 H).

Example 25. 2-morpholino-1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepan-1-yl) ethanone (Compound No. 25)

The target compound was obtained in the same manner as in Example 1, with a yield of 23%.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.87 (d, 2H, J = 7.10 Hz), 7.39-7.35 (m, 3H), 6.97 (t, 1H, J = 8.16 Hz), 3.70-3.58 (m, 10H), 3.14 (d, 2H, J = 19.89 Hz), 2.81-2.52 (m, 8H), 2.39 (bs, 4H), 1.99-1.84 (m, 2H).

Example 26. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl))-2-morpholinoethanone (compound Number 26)

The target compound was obtained in the same manner as in Example 1, with a yield of 20%.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.74-7.68 (m, 1H), 7.45-7.43 (m, 1H), 7.29-7.20 (m, 2H), 3.95 (d, 1H, J = 3.06 Hz), 3.73-3.61 (m, 8H), 3.16 (d, 2H, J = 12.82 Hz), 2.83-2.72 (m, 4H), 2.55-2.51 (m, 4H), 1.93-1.83 (m, 2H).

Example 27. 2- (4-Methylpiperidin-1-yl) -1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepane- 1-yl) ethanone (Compound No. 27)

The target compound was obtained in the same manner as in Example 1, with a yield of 46%.

¹ H NMR (CDCl ₃ , 300 MHz) δ 11.90 (bs, 1H), 7.91 (t, 2H, J = 6.99 Hz), 7.30 (bs, 3H), 6.95 (bs, 1H), 3.76-3.54 (m, 6H), 3.10 (d, 2H, J = 9.44 Hz), 2.83-5.54 (m, 6H), 2.03-1.12 (m, 9H), 0.86 (d, 2H, J = 5.83 Hz).

Example 28. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl))-2- (4-methylpiperidine -1-yl) ethanone (Compound No. 28)

The target compound was obtained in the same manner as in Example 1, with a yield of 32%.

¹ H NMR (CDCl ₃ , 300 MHz) δ 10.42 (bs, 1H), 7.71 (bs, 1H), 7.43 (bs, 1H), 7.27-7.21 (m, 2H), 3.97-3.61 (m, 6H), 3.15-2.70 (m, 8H), 2.05-1.19 (m, 9H), 0.90 (d, 2H, J = 5.92 Hz).

Example 29. 2- (2-ethylpiperidin-1-yl) -1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepane- 1-yl) ethanone (Compound No. 29)

The target compound was obtained in the same manner as in Example 1, with a yield of 75%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.91-7.89 (m, 2H), 7.27-7.21 (m, 3H), 6.90 (d, 1H, J = 11.70 Hz), 3.62-3.48 (m, 7H), 2.99-2.19 (m, 8H), 1.78-1.91 (m, 10H), 0.81-0.74 (m, 3H).

Example 30. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl))-2- (2-ethylpiperidine -1-yl) ethanone (Compound No. 30)

The target compound was obtained in the same manner as in Example 1, with a yield of 68%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 10.93 (bs, 1H), 7.68 (bs, 1H), 7.40 (bs, 1H), 7.22-7.16 (m, 2H), 3.92 (d, 2H, J = 1.95 Hz), 3.70-3.52 (m, 5H), 3.03-2.11 (m, 8H), 1.84-1.81 (m, 2H), 1.61-1.21 (m, 8H), 0.83-0.76 (m, 3H).

Example 31. 2- (4-benzylpiperidin-1-yl) -1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepane- 1-yl) ethanone (Compound No. 31)

The target compound was obtained in the same manner as in Example 1, with a yield of 83%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.95-7.91 (m, 2H), 7.28-7.04 (m, 8H), 6.93 (d, 1H, J = 12.91 Hz), 3.63-3.51 (m, 6H), 3.07 (d, 2H, J = 9.93 Hz), 2.84-2.19 (m, 6H), 2.45 (d, 2H, J = 6.96 Hz), 1.97-1.44 (m, 7H).

Example 32. 1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl))-2- (2-ethylpiperidine -1-yl) ethanone (Compound No. 32) (please remove)

The target compound was obtained in the same manner as in Example 1, with a yield of 68%.

¹ H NMR (CDCl ₃ , 400 MHz) δ 10.46 (bs, 1H), 7.57 (bs, 2H), 7.35-7.10 (m, 7H), 3.95 (d, 2H, J = 6.16 Hz), 3.12 (d, 2H, J = 17.73 Hz), 2.90-3.70 (m, 6H), 2.50 (d, 2H, J = 6.82 Hz), 1.98-1.24 (m, 9H).

Example 33. 2- (2,6-diethylphenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepane-1- Ethanone (Compound No. 33)

The target compound was obtained in the same manner as in Example 1, with a yield of 73%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64-7.61 (m, 2H), 7.43 (t, 2H, J = 7.45 Hz), 7.32-7.28 (m, H), 7.05 (d, 2H, J = 7.46 Hz), 6.94-6.90 (m, 1H), 3.92-3.78 (m, 6H), 3.43-3.41 (m, 2H) 2.87-2.71 (m, 10H), 2.0-1.67 (m, 4H), 1.28- 1.24 (m, 7H), 0.98 (t, 3H, J = 5.40 Hz)

Example 34. 2- (2,6-dimethylphenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepane-1-yl Ethanone (Compound No. 34)

The target compound was obtained in the same manner as in Example 1, with a yield of 62%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 765 (d, 2H, J = 8.14 Hz), 7.44 (t, 2H, J = 7.46 Hz), 7.34 (d, 1H, J = 1.47 Hz), 7.31-7.27 (m, 2H), 7.00 (t, 1H, J = 7.33 Hz), 3.85-3.42 (m, 8H), 2.88-2.77 (m, 6H), 2.34 (s, 6H), 1.95 (b, 2H), 1.77-1.75 (m, 2H), 1.02 (t, 3H , J = 7.34 Hz).

Example 35. 2- (2-methoxyphenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepane-1-yl) Ethanone (Compound No. 35)

The target compound was obtained in the same manner as in Example 1, with a yield of 93%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64-7.08 (m, 5H), 6.29-6.25 (m, 2H), 6.17 (b, 1H), 5.01 (b, 1H), 3.85-3.50 (m, 11 H), 2.90-2.77 (m, 6H), 2.04 (b, 2H), 1.76-1.74 (m, 2H), 1.00 (t, 3H, J = 7.35 Hz).

Example 36. 2- (3-methoxyphenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepane-1-yl) Ethanone (Compound No. 36)

The target compound was obtained in the same manner as in Example 1, with a yield of 49%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65 (d, 2H, J = 7.45 Hz), 7.44 (t, 2H, J = 8.05 Hz) 7.31 (m, 1 H), 7.09 (t, 1 H, J = 8.07 Hz), 6.30 (t, 2H, J = 1.92 Hz), 6.17 (b, 1H), 4.97 (b, 1H), 3.86-3.50 (m, 11H), 2.91-2.78 (m, 6H), 1.99 (b, 2H), 1.80-1.72 ( m, 2H), 1.02 (t, 3H, 7.36 Hz).

Example 37. 2- (4-methoxyphenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepan-1-yl) Ethanone (Compound No. 37)

The target compound was obtained in the same manner as in Example 1, with a yield of 69%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.05-7.97 (m, 2H), 7.63-7.27 (m, 3H), 6.78-6.56 (m, 4H), 3.83-3.67 (m, 11H), 2.89- 2.75 (m, 6H), 201-1.80 (b, 2H), 1.76 (q, 2H, J = 7.46 Hz), 0.99 (t, 3H, J = 7.36 Hz).

Example 38. 2- (4-fluorophenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepane-1-yl) Ethanone (Compound No. 38)

Performing the same method as in Example 1, the target compound was obtained in a yield of 56%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.64-7.61 (m, 2H), 7.42-7.38 (m, 3H), 6.90 (t, 2H, J = 6.69 Hz), 6.56-6.51 (m, 2H), 3.85-3.49 (m, 8H), 2.90-2.77 (m, 6H), 1.78-1.71 (m, 4H), 1.00 (t, 3H, J = 7.33 Hz).

Example 39. 2- (3-fluorophenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepane-1-yl) Ethanone (Compound No. 39)

The target compound was obtained in the same manner as in Example 1, with a yield of 58%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.36 (m, 2H), 7.81-7.07 (m, 4H), 6.40 (d, 2H, J = 8.14 Hz), 6.29 (d, 1H, J = 11.52 Hz), 5.01 (b, 1H), 3.85-3.50 (m, 8H), 2.86-2.77 (m, 6H), 2.00-1.80 (bd, 2H), 1.77 (q, 2H, J = 7.22 Hz), 1.00 (t, 3H, J = 7.35 Hz).

Example 40. 2- (2-fluorophenylamino) -1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepane-1-yl) Ethanone (Compound No. 40)

The target compound was obtained in the same manner as in Example 1, with a yield of 58%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.64-7.62 (m, 2H), 7.42-7.36 (m, 3H), 6.98-6.92 (m, 2H), 6.60-6.50 (m, 2H), 5.01 (b , 1H), 3.86-3.45 (m, 8H), 2.89-2.74 (m, 6H), 1.77-1.70 (m, 4H), 0.99 (t, 3H, J = 7.35 Hz).

Example 41. 1- (4-((4-phenyl-5-propyloxazol-2-yl) methyl) -1,4-diazepane-1-yl) -2- (2 (trifluoromethyl) Phenylamino) ethanone (Compound No. 41)

The target compound was obtained in the same manner as in Example 1, with a yield of 58%.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.64 (d, 2H, j = 8.10 Hz), 7.47-7.26 (m, 5H), 6.72-6.58 (m, 2H), 5.08 (b, 1H), 3.91 -3.54 (m, 8H), 2.94-2.80 (m, 6H), 2.0 (b, 2H), 1.78 (m, 2H), 1.00 (t, 3H, J = 7.36 Hz).

[Example]

On the other hand, the novel compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following is a description of some formulations containing the compound of Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation 1: tablet (direct pressure)

After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

Formulation 2: Tablet (Wet Granulation)

After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

Formulation 3: Powders and Capsules

5.0 mg of the active ingredient was sieved, followed by mixing with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. Filled in 5 gelatin capsules.

Formulation 4: Injection

Injectables were prepared by containing 100 mg as the active ingredient, as well as 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ -12H ₂ O and 2974 mg of distilled water.

[Experimental Example]

On the other hand, for the novel compound represented by the formula (1) according to the present invention was tested for the antagonism of the T-type calcium channel by the method as shown in the following experimental example. The synthesized compound was obtained by using the FDSS6000 as a method of the following experimental example to determine the percent inhibition of the T-type calcium channel.

Experimental Example: T-type calcium channel activity detection method using FDSS6000

Stable α1G T-type calcium channel and Kir2.1 using 96-well cell distributor (Titertek) in 96-well plates treated with poly-L-lysine (0.05 mg / ml) 12-24 hours before activity detection The cells of HEK293 cell line (α1G cell line: KCTC 10519BP, Genetic Bank of Korea Research Institute of Bioscience and Biotechnology), which were expressed as, were dispensed at a density of 4 × 10 ⁴ per well. On the day of the experiment, the cells attached to the 96-well plate were subjected to HEPES buffer (unit mM: 150 NaCl, 5 KCl, 1 MgCl ₂ , 2 CaCl ₂ , 10 HEPES, 10) using a 96-well plate auto washing machine (Bio Tek). After washing three times with glucose, pH 7.4) and reacting for 1 hour at room temperature in HEPES buffer solution containing 5 μM Fluoro-3 / AM and 0.001% Pluronic F-127, it was labeled with fluorescent dye. Washed again with HEPES buffer twice. It was then washed once with HEPES buffer containing 10 mM CaCl ₂ and adjusted to a final volume of 81 μL 10 minutes before measuring the FDSS6000 instrument. Apart from the 96-well plates in which the cells were prepared, two 96-well drug plates were prepared to contain KCl (final concentration 75 mM) and blocker drug to activate T-type calcium channels. Since most cell-based HTS instruments have a liquid application system for drug injection but no liquid inhalation system, 27 μL of blocking drug and KCl in 10 mM CaCl ₂ HEPES buffer at 5 times higher concentration are prepared. Diluted by 1/5 in 135 μL, the final volume of the plate, is measured. Specific FDSS6000 measurement conditions were to measure the change in intracellular calcium concentration changed by KCl administration after 75 seconds of drug pretreatment after recording 20 seconds of reference value. It was set at 100% and the percentage (%) inhibitory effect on the inhibitory effect of the test substance was obtained, and 10 μM of mibepradil was always used as a control drug.

As a detailed calcium imaging technique, the excitation wavelengths (340 nm and 380 nm) were selectively exposed to cells by a computer-controlled filter wheel in view of four light sources of xenon lamps mounted on the FDSS6000. Data were obtained every 1.23 seconds, and the emitter fluorescence light entering through a 515 nm long-pass filter was passed through a cooling CCD camera built into the instrument and then 96-well by a digital fluorescence analyzer. Average values of 340/380 were obtained for each well in the phase. All image data and analysis was done using the FDSS6000 dedicated program provided by Hamamatsu Photonics.

The% inhibition rate of calcium migration of T-type calcium channels of the novel compounds according to the present invention is shown in Table 1 below.

Test compound % Inhibition of FDSS (10 μM) Test compound % Inhibition of FDSS (10 μM) Compound number 1 62.27 Compound number 31 33.51 Compound number 8 32.22 Compound number 32 42.15 Compound number 9 40.87 Compound number 33 41.68 Compound number 10 36.85 Compound number 34 63.32 Compound number 17 66.00 Compound number 35 37.91 Compound no.18 27.29 Compound number 37 28.73 Compound number 19 28.19 Compound number 38 37.33 Compound number 20 59.86 Compound number 40 41.65 Compound number 21 29.22 Compound number 41 38.87 Compound number 22 44.73 Mibepradil 79.29

Since the novel 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound represented by the general formula (1) of the present invention has an antagonistic action on the T-type calcium channel, brain diseases such as epilepsy and hypertension It can be usefully used as a preventive or therapeutic agent for pain diseases such as heart disease such as angina pectoris, chronic pain, neuropathic pain, or cancer-related diseases.

Claims (7)

1- (4-substituted-1,4-diazepan-1-yl) ethanone compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[Formula 1]

In Chemical Formula 1,
R ¹ is a C ₁ to C ₆ alkyl group; Imidazole group; Benzimidazole groups; Or an oxazole group, wherein an imidazole group, a benzimidazole group, or an oxazole group may be substituted or unsubstituted with 1 to 3 substituents selected from C ₁ -C ₆ alkyl and phenyl
R ² represents a heterocycloalkyl group selected from piperidine, piperazine and morpholine, wherein the heterocycloalkyl group may be substituted or unsubstituted with 1 to 3 substituents selected from C ₁ to C ₆ alkyl and benzyl.
The method according to claim 1,
R ¹ is a methyl group, an ethyl group, isopropyl group, tert -butyl group, imidazol-1-yl group, imidazol-2-yl group, imidazol-5-yl group, 2-phenyl-imidazol-5-yl group, 1 H -benz [ d ] imidazol-2-yl group, oxazol-2-yl group, oxazol-4-yl group, oxazol-5-yl group, or 4-phenyl-5-propyl-oxazol-2-yl group Indicate,
R ² is a piperidinyl group, 4-methylpiperidinyl group, 2-ethylpiperidinyl group, 4-benzylpiperidinyl group, piperazinyl group, 4-methylpiperazinyl group, 4-methylpiperazinyl group, or A compound characterized by showing a morpholino group.
The method according to claim 1,
1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepan-1-yl) -2- (piperidin-1-yl) ethanone;
1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl) -2- (piperidin-1-yl) ethanone;
2-morpholino-1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepan-1-yl) ethanone;
1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepane-1-yl))-2-morpholinoethanone;
2- (4-methylpiperidin-1-yl) -1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepan-1-yl) Ethanone;
1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl))-2- (4-methylpiperidin-1-yl Ethanone;
2- (2-ethylpiperidin-1-yl) -1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepan-1-yl) Ethanone;
1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl))-2- (2-ethylpiperidin-1-yl Ethanone;
2- (4-benzylpiperidin-1-yl) -1- (4-((2-phenyl-1 H -imidazol-5-yl) methyl) -1,4-diazepan-1-yl) Ethanone;
1- (4-((1H - benz [ d ] imidazol-2-yl) methyl) -1,4-diazepan-1-yl))-2- (2-ethylpiperidin-1-yl Ethanone; And
Compound selected from pharmaceutically acceptable salts thereof.
The pharmaceutical composition for the treatment and prevention of diseases selected from epilepsy, hypertension, angina pectoris, chronic pain, neurological pain, and cancer, wherein the compound of any one selected from claims 1 to 3 is included as an active ingredient.
delete delete Iii) 2-chloro-1- (1,4-diazepane-1- represented by the following formula (6) by reacting with a 1,4-diazepane represented by the following formula (3) and chloroacetyl chloride represented by the following formula (5): (1) preparing an ethanone compound;

Wherein Y is a hydrogen atom or tert -butoxycarbonyl
Ii) a 2-cyclo-1- (1,4-diazepan-1-yl) ethanone compound represented by the following formula (6) is reacted with a heterocycloalkyl compound represented by the following formula (7), and is represented by the following formula (2b) Preparing a (1,4-diazepan-1-yl) ethanone compound; And

Wherein Y is a hydrogen atom or tert -butoxycarbonyl, Q is C, N or O and R ⁴ is a hydrogen atom or 1 to 3 substituents selected from C ₁ -C ₆ alkyl and benzyl )
Iii) a reductive amination reaction of the (1,4-diazepane-1-yl) ethanone compound represented by Formula 2b with an aldehyde compound represented by Formula 3a, or a halide compound represented by Formula 3b Preparing a 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound represented by the following Chemical Formula 1b;

(In the above scheme, Y, Q and R ⁴ are each as defined above, R ¹ is as defined in claim 1, and X represents a halogen atom.)
Method for producing a 1- (4-substituted-1,4-diazepan-1-yl) ethanone compound comprising a.