KR101591772B1 - Novel amine compound or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for prevention or treatment of diseases induced by activation of T-type or N-type calcium ion channel containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel amine compound or a pharmaceutically acceptable salt thereof, a process for preparing the same, and a pharmaceutical composition for preventing or treating T-type or N-type calcium channel activity-related diseases comprising the same, Or a pharmaceutically acceptable salt thereof according to the present invention inhibits T-type or N-type calcium channel activity, thereby inhibiting T-type or N-type calcium channel-induced epilepsy, depression, Parkinson's disease, Dementia, sleep disorders, hypertension, cardiac arrhythmia, angina pectoris, myocardial infarction, congestive heart failure, neurogenic pain, cancer and the like.

Description

TECHNICAL FIELD The present invention relates to a novel amine compound or a pharmaceutically acceptable salt thereof, a process for preparing the same, and a pharmaceutical composition for preventing or treating T-type or N-type calcium channel activity- preparation method and pharmaceutical composition for prevention or treatment of diseases induced by activation of T-type or N-type calcium ion channel containing the same active ingredient}

The present invention relates to a novel amine compound or a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating T-type or N-type calcium channel activity-related diseases.

Calcium in neurons plays an important role in neuronal signal transduction. There are several channels of calcium, but voltage-dependent calcium channels play an important role in the delivery of terminal stimuli. Voltage-dependent calcium channels are characterized by high voltage-activated calcium channels (hereinafter abbreviated as " HVA ") which are activated at a higher voltage than the resting mebrane potential and low- And low voltage-activated calcium channels (LVA). The HVA calcium channel is further subdivided into L, P / Q, N, and R-type according to the pharmacological properties of the induced current and the LVA calcium channel is further divided into T-type.

HVA calcium channels are well known to play an important role in the transmission and reflexes of pain, ranging from sensory end cells to the central nervous system, and inhibitors of these channels have already been commercialized as analgesics for various pain Non-Patent Document 1). However, the pain-regulating function of the LVA calcium channel, which produces T-type calcium currents, is still uncertain. The reason for classifying T-type calcium currents as functions of the LVA calcium channel is that these calcium currents are generated when the excitability of neurons is lowered, and play a role in enhancing excitability again. Thus, neuronal cells excited by T-type calcium channel induce multiple excitation, resulting in a tense ignition involving T-type calcium channel and other forms of excitability. The T-type calcium channel pathway proteins are encoded by three genes, designated α _1G , α _1H and α _1I , respectively.

 Recently, the fact that the function of T-type calcium currents in the peripheral nervous system is related to the hyperalgesia response to mechanical or thermal stimuli by reductants has been shown in experiments using the T-type calcium current inhibitor mibefradil (Non-Patent Document 2), it is not known which T-type calcium channel is involved. Mibefradil (RO40-5967) is known to have an initial blood pressure lowering effect, and several calcium channel inhibitory effects including T-type calcium channel have been reported. However, recently, the most selective inhibitory effect on T- .

The mibefradil drug is effective for hypertension, angina pectoris and stroke. It is mainly used for the treatment of hypertension. It is a side effect due to drug-drug interactions due to inhibition of CYP3A4 enzyme in the liver. It has been withdrawn from the pharmaceutical market in June.

In addition, calcium plays an important role as an intracellular signaling substance and regulates various cellular actions. Since calcium is known to be involved in cell growth during cell action, it is predicted that an inhibitor of T-type calcium channel activity will have an anticancer effect (Non-Patent Document 3).

Voltage-sensitive calcium channels regulate intracellular calcium concentrations that affect a variety of important neuronal functions such as cell sensitivity, neurotransmitter release, hormone secretion, intracellular metabolism, neuroleptic activity, and gene expression. N-type channels are found primarily in central and peripheral neurons located first in the anterior synaptic nerve endings. These channels regulate the calcium flow required for depolarization-induced release of the transmitter from the synaptic terminals. Delivery of pain signals from the periphery to the central nervous system (CNS) is mediated by N-type calcium channels located in the spinal cord (Non-Patent Document 4).

N-type calcium channel activity inhibitors are useful for neuroprotection and analgesia. The selective N-type calcium channel activity inhibitor, ziconotide, has been found to have analgesic activity in animal models and neuroprotective activity in local and ischemic ischemic models. Examples of known calcium channel activity inhibitors include flunarizine, fluspirilene, cilnipide, PD 157767, SB-201823, SB-206284, NNCO9-0026, and PD 151307 (Hu et al., supra).

Recently, Pfizer researchers have published studies of substituted oxadiazole analogs with calcium channel blocking activity. Such compounds are predicted to have analgesic action and are also useful for the treatment of diseases such as hypertension, congestive heart failure, stroke, ischemic heart disease and angina pectoris (Patent Document 1).

Selective calcium channel, good pharmacokinetic profile, good epilepsy with good absorption, distribution, metabolism, and excretion; cancer; Heart disease such as hypertensive, deep arrhythmia, angina pectoris, myocardial infarction, congestive heart failure; There is a need for inhibitors of calcium channel activity that are effective in the treatment of pain disorders such as neuropathic pain, chronic and acute pain.

Accordingly, the present inventors have made efforts to develop a compound exhibiting a T-type or N-type calcium channel inhibitory effect, so that the amine compound according to the present invention has excellent inhibitory activity against T-type or N-type calcium channel , T-type or N-type calcium channel-related diseases, and completed the present invention.

International Publication No. WO 2008117148

Schaible, Prog. Brain Res. , ≪ / RTI > 2000, 129: 173-190 Todorovic, Neuron, 2001, 31: 75-85 Nat. Rev. Mol. Cell Biol. 2003, 4, 517-529 Song et al., J. Med. Chem. 43: 3474-3477 (2000)

It is an object of the present invention to provide a novel amine compound or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for producing the novel amine compound.

Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating T-type or N-type calcium channel activity-related diseases containing the novel amine compound or a pharmaceutically acceptable salt thereof as an active ingredient .

Another object of the present invention is to provide a health food composition for preventing or ameliorating T-type or N-type calcium channel activity-related diseases containing the novel amine compound or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, the present invention provides an amine compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

R ¹ is C _{6 - 10} aryl or a nitrogen atom (N), oxygen atoms (O) and sulfur atoms of 5 to 8 at a single ring containing a hetero atom, at least one selected from the group consisting of (S) heteroaryl, or Heteroaryl of 8 to 11 atomic ring,

Wherein R < ¹ > is an unsubstituted or halogen, C _{6 - 10} aryl, C _{6 - 10} aryloxy, and nitrogen atoms (N), oxygen atoms (O) and from 5 to 8 at a single ring containing a hetero atom, at least one selected from the group consisting of a sulfur atom (S) a heteroaryl or heterocycloalkyl may be optionally substituted by one or more substituents selected from the group consisting of alkyl, wherein the substituent is C ₁ unsubstituted or halogen, a straight-chain or _branched-4 alkyl, straight or branched C _{1 - 4} alkoxy, straight or branched C _{1 - 4} haloalkyl and cyano may be further substituted with at least one member selected from the group consisting of a furnace; And

And ₄ alkoxy C _6-10 alkyl substituted with aryl, wherein A is _{-CH (CH 3) - - R} 2 is -A (C = O) NH ₂ or unsubstituted or straight or branched C _1, or - C ₆ H ₆ -.

The present invention also provides a process for preparing the novel amine compound.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating T-type or N-type calcium channel activity-related diseases containing the novel amine compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a health food composition for preventing or ameliorating T-type or N-type calcium channel activity-related diseases containing the novel amine compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The novel amine compound or a pharmaceutically acceptable salt thereof according to the present invention inhibits T-type or N-type calcium channel activity, thereby inhibiting T-type or N-type calcium channel-induced epilepsy, depression, It can be useful for preventing or treating diseases such as heart disease, dementia, sleeping disorder, hypertension, heart arrhythmia, angina pectoris, myocardial infarction, congestive heart failure, neurogenic pain, cancer and the like.

Hereinafter, the present invention will be described in detail.

The present invention provides an amine compound represented by the following formula (1): < EMI ID =

[Chemical Formula 1]

R ¹ is C _{6 - 10} aryl or a nitrogen atom (N), oxygen atoms (O) and sulfur atoms of 5 to 8 at a single ring containing a hetero atom, at least one selected from the group consisting of (S) heteroaryl, or Heteroaryl of 8 to 11 atomic ring,

Wherein R < ¹ > is an unsubstituted or halogen, C _{6 - 10} aryl, C _{6 - 10} aryloxy, and nitrogen atoms (N), oxygen atoms (O) and from 5 to 8 at a single ring containing a hetero atom, at least one selected from the group consisting of a sulfur atom (S) a heteroaryl or heterocycloalkyl may be optionally substituted by one or more substituents selected from the group consisting of alkyl, wherein the substituent is C ₁ unsubstituted or halogen, a straight-chain or _branched-4 alkyl, straight or branched C _{1 - 4} alkoxy, straight or branched C _{1 - 4} haloalkyl and cyano may be further substituted with at least one member selected from the group consisting of a furnace; And

And a C _{6 -10} aryl-alkyl substituted by _4-alkoxy, wherein A is _{-CH (CH 3) - - R} 2 is -A (C = O) NH ₂ or unsubstituted or straight or branched C _1, or - C ₆ H ₆ -.

Preferably, in Formula 1,

R ¹ is phenyl, furanyl, isoxazole or indole unsubstituted or substituted with one member selected from the group consisting of chlorine, phenyl, phenoxy, pyridine, pyrimidine, piperazine and morpholine, Which may be further substituted with one or more unsubstituted or at least one member selected from the group consisting of chlorine, methyl, methoxy, trifluoromethyl and cyano; And

R ² is -A (C = O) NH ₂ or unsubstituted or C _{1 -,} and benzyl substituted with _two alkoxy, wherein A is -CH (CH ₃₎ - wherein the - or -C ₆ H ₆ .

More preferably, in Formula 1,

^,

^,

^,

^,

,

,

,

,

및

으로 이루어진 군으로부터 선택되는 1종이고; 및R ¹ is

^,

^,

^,

^,

,

,

,

,

And

One species selected from the group consisting of; And

,

및

으로 이루어진 군으로부터 선택되는 1종인 화합물이다.
R ² is

,

And

≪ / RTI >

The present invention also provides a compound of the formula (1), or a pharmaceutically acceptable salt thereof, represented by the following formula (2), (3) or (4)

(2)

(3)

[Chemical Formula 4]

In the above formulas 2 to 4, R ¹ is as defined above.

Preferably, in the above formulas 2 to 4,

R ¹ is phenyl, furanyl, isoxazole or indole unsubstituted or substituted with one member selected from the group consisting of chlorine, phenyl, phenoxy, pyridine, pyrimidine, piperazine and morpholine, Which is unsubstituted or substituted with at least one member selected from the group consisting of chlorine, methyl, methoxy, trifluoromethyl and cyano.

More preferably, in the above Chemical Formulas 2 to 4,

^,

^,

^,

^,

,

,

,

,

및

으로 이루어진 군으로부터 선택되는 1종이고; 및R ¹ is

^,

^,

^,

^,

,

,

,

,

And

One species selected from the group consisting of; And

,

및

으로 이루어진 군으로부터 선택되는 1종인 화합물이다.
R ² is

,

And

≪ / RTI >

Further, the amine compound represented by Formula 1 may be more specifically exemplified as follows:

(S) -2 - ((5- (3- (Trifluoromethyl) phenyl) furan-2-yl) methylamino) propanamide;

(S) -2 - ((5- (3-chloro-4-methoxyphenyl) furan-2-yl) methylamino) propanamide;

(S) -2 - ((5- (4-chlorophenyl) furan-2-yl) methylamino) propanamide;

(S) -2 - ((5- (4-chlorophenyl) isoxazol-3-yl) methylamino) propanamide;

(S) -2- (4- (4-cyanophenoxy) benzylamino) propanamide;

(S) -2 - ((5-chloro-1 H-indol-3-yl) methylamino) propanamide;

(S) -2- (4-morpholinobenzylamino) propanamide;

(S) -2- (4- (Pyridin-4-yl) benzylamino) propanamide;

(S) -2- (4- (Pyrimidin-5-yl) benzylamino) propanamide;

(S) -2- (4- (4-methylpiperazin-1-yl) benzylamino) propanamide;

3 - ((5- (3- (trifluoromethyl) phenyl) furan-2-yl) methylamino) benzamide;

3 - ((5- (3-Chloro-4-methoxyphenyl) furan-2-yl) methylamino) benzamide;

3 - ((5- (4-Chlorophenyl) furan-2-yl) methylamino) benzamide;

3 - ((5- (4-chlorophenyl) isoxazol-3-yl) methylamino) benzamide;

3- (4- (4-cyanophenoxy) benzylamino) benzamide;

3 - ((5-Chloro-lH-indol-3-yl) methylamino) benzamide;

3- (4-morpholinobenzylamino) benzamide;

N - ((5- (3- (trifluoromethyl) phenyl) furan-2-yl) methyl) (3,4,5-trimethoxyphenyl) methanamine;

N - ((5- (3-chloro-4-methoxyphenyl) furan-2-yl) methyl) (3,4,5-trimethoxyphenyl)

Methane amine;

N - ((5- (4-chlorophenyl) furan-2-yl) methyl) (3,4,5-trimethoxyphenyl) methanamine;

N - ((5- (4-chlorophenyl) isoxazol-3-yl) methyl) (3,4,5-trimethoxyphenyl) methanamine;

4- (4 - ((3,4,5-trimethoxybenzylamino) methyl) phenoxy) benzonitrile;

N - ((5-chloro-1 H-indol-3-yl) methyl) (3,4,5-trimethoxyphenyl) methanamine;

N- (4-morpholinobenzyl) (3,4,5-trimethoxyphenyl) methanamine;

N- (4- (pyridin-4-yl) benzyl) (3,4,5-trimethoxyphenyl) methanamine; And

N- (4- (Pyrimidin-5-yl) benzyl) (3,4,5-trimethoxyphenyl) methanamine.

The preferred structures of the amine compounds represented by Formula 1 according to the present invention are shown in Table 1 below.

Example constitutional formula Example constitutional formula One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

- -

The amine compound represented by the general formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like, which are non-toxic organic acids such as hydrochloric acid, hydrobromic acid, Examples of such pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphate chlorides, bromides, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-diate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, Such as benzene sulfonate, benzene sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene -1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method. For example, the amine compound represented by Chemical Formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., The precipitate formed by adding the inorganic acid may be filtered and dried. Alternatively, the precipitate may be dried by evaporating the solvent and excess acid under reduced pressure, followed by crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

Furthermore, the present invention encompasses not only the amine compound represented by Formula 1 above and pharmaceutically acceptable salts thereof, but also solvates and hydrates thereof which can be prepared therefrom.

The present invention also relates to a process for producing a compound represented by the formula (1)

Reacting a compound represented by the formula (5) with a compound represented by the formula (6) to produce a compound represented by the formula (1): < EMI ID =

[Reaction Scheme 1]

In the above Reaction Scheme 1, R ¹ And R < ² >

Specifically, as shown in the following Reaction Scheme 2, 3 or 4,

(2), (3) or (4), characterized by comprising the step of reacting a compound represented by the formula (5) with a compound represented by the formula (7) ≪ / RTI >

[Reaction Scheme 2]

[Reaction Scheme 3]

[Reaction Scheme 4]

In the above Reaction Scheme 2, 3 or 4, R ¹ And R < ² > are as defined above.

Hereinafter, the production method according to the present invention will be described in detail.

Specifically, the aldehyde group of the compound represented by the formula (5) may be subjected to a reductive amination reaction with an amine group of the compound represented by the formula (7), (8) or (9) in the presence of a reducing agent to prepare a compound represented by the formula (2)

At this time, the compound represented by Formula 5 is preferably in the form of an acid salt to maintain a pH of 7 to 8, and more preferably in a hydrochloride form.

The reducing agent that can be used is sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride, pyridine boro complex, zinc borohydride, etc., and sodium cyanoborohydride, sodium borohydride, Rid, sodium triacetoxyborohydride or the like is preferably used.

Further, usable solvents include alcohol solvents such as methanol, ethanol, propanol and butanol, ether solvents such as tetrahydrofuran, dioxane, methylene chloride and 1,2-dimethoxyethane, dimethylformamide, dimethylsulfoxide and the like Can be used alone or in combination.

The reaction may be carried out, followed by extraction with an organic solvent, drying, filtration and vacuum distillation, and further subjecting to column chromatography or recrystallization.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating T-type or N-type calcium channel activity-related diseases containing the novel amine compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Wherein said T-type or N-type calcium channel activity related diseases are selected from the group consisting of epilepsy, depression, Parkinson's disease, dementia, sleep disorders, hypertension, cardiac arrhythmia, angina pectoris, myocardial infarction, congestive heart failure, neurogenic pain, Colon cancer, and the like.

Calcium plays an important role as an intracellular signaling substance and regulates various cellular actions. Among cellular activities, calcium is known to be involved in cell growth. Thus, the T-type calcium channel activity inhibitor may be used as an anticancer agent. In addition, N-type calcium channel activity inhibitors are useful for neuroprotection and analgesia. It is known that selective N-type calcium channel activity inhibitors have analgesic activity in animal models and neuroprotective activity in local and broad-based ischemia models. The N-type calcium channel activity inhibitors of the present invention are useful for neuroprotection and analgesia Can be usefully used.

Further, conventional mivafradil, chiconotide, flunarizine, fluspirilene, cilnipide, PD 157767, SB-201823, SB-206284, NNCO9-0026, PD 151307 (Hu Various types of T-type or N-type calcium channel activity inhibitors are known, such as epilepsy, depression, Parkinson's disease, dementia, sleep disorders, hypertension, cardiac arrhythmia, angina pectoris, myocardial infarction, Congestive heart failure, neurogenic pain, cancer, and the like. Therefore, the compounds according to the present invention can also be useful for diseases such as epilepsy, depression, Parkinson's disease, dementia, sleeping disorder, hypertension, heart arrhythmia, angina pectoris, myocardial infarction, congestive heart failure, neuropathic pain and cancer.

The inhibition of the T-type or N-type calcium channel activity of the amine compound represented by Formula 1 according to the present invention was measured. As a result, the compounds of Examples 15, 18, 19, 20, 21, calcium channel inhibitory activity% is not less than 50%, and an IC ₅₀ value of less than 10 μM, in particular examples 18 and 19 and the compound 20 is more than 75% of the% inhibition of the calcium channel activity T- type, IC ₅₀ values of 3 and the compounds of Examples 18, 19, 20, 21, and 22 exhibited N-type calcium channel activity inhibition percentages of 50% or more and IC ₅₀ values of 10 μM or less, , 20 and 22 exhibited an inhibition of N-type calcium channel activity by 70% or more, indicating excellent effects in inhibiting T-type or N-type calcium channel activity (see Experimental Example 1).

Accordingly, the novel amine compound or its pharmaceutically acceptable salt according to the present invention inhibits T-type or N-type calcium channel activity, thereby inhibiting T-type or N-type calcium channel-induced epilepsy, depression, Can be useful for preventing or treating Parkinson's disease, dementia, sleeping disorder, hypertension, heart arrhythmia, angina pectoris, myocardial infarction, congestive heart failure, neuropathic pain, cancer, especially breast cancer, liver cancer and colon cancer.

In the pharmaceutical composition according to the present invention, the amine compound represented by the formula (1) or a pharmaceutically acceptable salt thereof can be administered in various formulations for oral administration and parenteral administration at the time of clinical administration. Such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like.

Solid formulations for oral administration include tablets, pills, powders, granules, capsules, troches, etc. These solid preparations may contain one or more of the amine compounds of formula 1, or pharmaceutically acceptable salts thereof, The salt may be formulated by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included in addition to commonly used simple diluents such as water and liquid paraffin. .

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.

The dose of the amine compound of the present invention represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof to the human body may vary depending on the age, body weight, sex, dosage form, health condition and disease severity of the patient, Is generally 0.1-1000 mg / day, preferably 1-500 mg / day on the basis of an adult patient of 70 Kg, and may also be administered once a day, It may be divided into several doses.

The pharmaceutical composition of the present invention can be used alone or in combination with methods for the prevention or treatment of T-type or N-type calcium channel activity-related diseases or using surgery, hormone therapy, chemotherapy and biological response modifiers have.

The present invention also provides a health food composition for preventing or ameliorating T-type or N-type calcium channel activity-related diseases containing the amine compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Herein, the T-type or N-type calcium channel activity-related diseases are characterized by inhibiting-type or N-type calcium channel activity, thereby inhibiting T-type or N-type calcium channel-induced epilepsy, depression, Parkinson's disease, Dementia, sleep disorders, hypertension, cardiac arrhythmia, angina pectoris, myocardial infarction, congestive heart failure, neurogenic pain, cancer, and the like.

The amine compound represented by the formula (1) according to the present invention inhibits T-type or N-type calcium channel activity, thereby inhibiting T-type or N-type calcium channel-induced epilepsy, depression, Parkinson's disease, dementia, And can be added to health supplements such as food, beverages, etc. as a health food composition for preventing or ameliorating sleep disorders, hypertension, cardiac arrhythmia, angina pectoris, myocardial infarction, congestive heart failure, neuropathic pain and cancer.

There is no particular limitation on the kind of the food. Examples of the foods to which the above substances can be added include dairy products including dairy products, meat, sausage, bread, biscuits, rice cakes, chocolate, candies, snacks, confectionery, pizza, ramen and other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, all of which include health functional foods in a conventional sense.

The amine compound represented by the formula (1) according to the present invention can be added directly to food or used together with other food or food ingredients, and can be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of the compound in the health food may be 0.1 to 90 parts by weight of the total food. However, in the case of long-term intake intended for health and hygiene purposes or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.

In addition, the health functional beverage composition of the present invention has no particular limitation on other components other than the above-mentioned compounds as essential components in the indicated ratios, and may contain various flavoring agents or natural carbohydrates as additional components such as ordinary beverages have. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.

In addition to the above, the amine compound represented by the formula (1) according to the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and thickening agents (cheese, Organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the amine compounds of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the present invention is not limited to the following Examples and Experimental Examples.

< Example  1 (S) -2 - ((5- (3- ( Trifluoromethyl ) Phenyl ) Furan -2 days) Methyl amino ) Pro Phenamide

Under nitrogen gas substitution, l-alanine amide hydrochloride (0.5 mmol) and 4A molecular sieve (0.1 g) of powder were mixed in dry methanol. Of NaBH ₃ CN was added (0.33 mmol), stirred for 15 minutes at room temperature, 5- (3- (trifluoromethyl) furfural (0.4 mmol) was added to the mixture. The reaction mixture was 30-35 ℃ After completion of the reaction, the reaction mixture was filtered through Celite 545, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: methanol = 4: 1) The objective compound (51%) of white powder was obtained.

mp 130-132 [deg.] C;

[?] _D ²⁵ -15 ( c 1.02, methanol);

^{1 H NMR (400 MHz, CDCl} 3) δ 7.87 (s, 1H), 7.80 (t, J = 4.4Hz, 1H), 7.50-7.49 (m, 2H), 7.06 (brs, 1H), 6.67 (d, J = 3.6Hz, 1H), 6.30 (d, J = 3.6Hz, 1H), 5.30 (brs, 1H), 3.85 (dd, J = 25, 14.6Hz, 2H), 1.37 (d, J = 7.2Hz, 3H);

_{HR-FABMS Calcd for C 15 H} 16 F 3 N 2 O 2 (M + + H): 313.1164, Found: 313.1167.

< Example  2> (S) -2 - ((5- (3- Chloro -4- Methoxyphenyl ) Furan -2 days) Methyl amino ) Propane amides

The procedure of Example 1 was repeated except for using 5- (3-chloro-4-methoxy-phenyl) furfural in place of 5- (3- (trifluoromethyl) And purified by column chromatography (ethyl acetate: methanol: hexane = 7: 1: 1) to obtain the target compound (59%) as a white powder.

mp 101-102 [deg.] C; [?] _D ²⁵ -14.7 ( c 0.99, methanol);

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.65 (d, J = 2.4Hz, 1H), 7.49 (dd, J = 8.6,4Hz, 1H), 7.08 (brs, 1H), 6.94 (d, J = 8.4Hz , 1H), 6.46 (d, J = 3.2Hz, 1H), 6.25 (d, J = 3.2Hz, 1H), 5.28 (brs, 1H), 3.93 (s, 3H), 3.82 (dd, J = 24.6, 14.4 Hz, 2H), 3.30 (q, J = 6.8 Hz, 1H), 1.36 (d, J = 6.8 Hz, 3H);

_{HR-FABMS Calcd for C 15 H} 18 ClN 2 O 3 (M + + H): 309.1006, Found: 309.1009.

< Example  3> (S) -2 - ((5- (4- Chlorophenyl ) Furan -2 days) Methyl amino ) Propanamide

In the same manner as in Example 1, except for using 5- (4-chlorophenyl) furfural instead of 5- (3- (trifluoromethyl) furfural in Example 1, the reaction was conducted and column chromatography Ethyl acetate: methanol = 7: 1) to obtain the title compound (56%) as a white powder.

mp 102-104 [deg.] C;

[?] _D ²⁵ -14.3 ( c 1.03, methanol);

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.56 (d, J = 8.8Hz, 2H), 7.34 (d, J = 8.8Hz, 2H), 7.07 (brs, 1H), 6.56 (d, J = 3.2Hz, 1H), 6.28 (d, J = 3.2Hz, 1H), 5.36 (brs, 1H), 3.83 (dd, J = 23.4,14.8Hz, 2H), 3.32 (q, J = 7.2Hz, 1H), 1.36 ( d, J = 6.8 Hz, 3H);

_{HR-FABMS Calcd for C 14 H} 16 ClN 2 O 2 (M + + H): 279.0900, Found: 279.0902.

< Example  4 >. (S) -2 - ((5- (4- Chlorophenyl ) Isoxazol -3 days) Methyl amino ) Propanamide De

In the same manner as in Example 1, except that 5- (4-chlorophenyl) isoxazole-3-carboxaldehyde was used instead of 5- (3- (trifluoromethyl) And purified by column chromatography (ethyl acetate: methanol = 7: 1) to obtain the target compound (62%) as a white powder.

mp 113 [deg.] C;

[?] _D ²⁵ -9.1 ( c 1.00, methanol);

_{^{1 HNMR (400MHz, CDCl 3)}} δ 7.71 (d, J = 8.8Hz, 2H), 7.45 (d, J = 9.2Hz, 2H), 6.92 (brs, 1H), 6.47 (s, 1H), 5.33 (brs 1H), 3.92 (s, 2H), 3.32 (q, J = 7.2 Hz, 1H), 1.39 (d, J = 6.8 Hz, 3H);

_{HR-FABMS Calcd for C 13 H} 15 ClN 3 O 2 (M + + H): 280.0853, Found: 280.0849.

< Example  5 >. (S) -2- (4- (4- Cyanophenoxy ) Benzylamino ) Propanamide

The procedure of Example 1 was repeated except for using 4- (4-formylphenoxy) benzonitrile instead of 5- (3- (trifluoromethyl) furfural, and the reaction was conducted by column chromatography The residue was purified by chromatography (ethyl acetate: methanol = 1: 1) to obtain the target compound (62%) as a transparent oil.

[?] _D ²⁵ -8.6 ( c 1.03, methanol);

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.60 (d, J = 8.8Hz, 2H), 7.35 (d, J = 8.8Hz, 2H), 7.04 (d, J = 8.4Hz, 2H), 7.00 (d, J = 6.8Hz, 2H), 5.34 (brs, 1H), 3.80 (dd, J = 21.4,13.2Hz, 2H), 3.28 (q, J = 7.2Hz, 1H), 1.38 (d, J = 7.2Hz, 3H);

_{HR-FABMS Calcd for C 17 H} 18 N 3 O 2 (M + + H): 296.1399, Found: 296.1397.

< Example  6> (S) -2 - ((5- Chloro -1 H-indol-3-yl) Methyl amino ) Propanamide

The procedure of Example 1 was repeated except that 5-chloroindole-3-carboxaldehyde was used instead of 5- (3- (trifluoromethyl) furfural in Example 1 and the reaction was carried out for 24 hours with stirring under reflux. , And purified by column chromatography (ethyl acetate: methanol = 2: 1) to obtain the desired compound (65%) as a pale brown product;

mp 112 [deg.] C; [?] _D ²⁵ -9.0 ( c 1.01, methanol);

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.16 (brs, 1H), 7.61 (d, J = 1.6Hz, 1H), 7.30 (d, J = 8.4Hz, 1H), 7.18-7.15 (m, 2H), 7.06 (brs, 1H), 5.29 (brs, 1H), 3.94 (dd, J = 18.8,13.2Hz, 2H), 3.29 (q, J = 6.8Hz, 1H), 1.35 (d, J = 6.8Hz, 3H );

_{HR-FABMS Calcd for C 12 H} 15 ClN 3 O (M + + H): 252.0904, Found: 252.0900.

< Example  7 >. (S) -2- (4- Morpholino benzylamino ) Propanamide

The procedure of Example 1 was repeated except that 4- (4-formylphenyl) morpholine was used in place of 5- (3- (trifluoromethyl) furfural in Example 1, and the resultant was purified by column chromatography (Ethyl acetate: methanol = 1: 1) to obtain the target compound (91%) as a white powder.

mp 192-194 [deg.] C;

[?] _D ²⁵ -7.2 ( c 0.99, methanol);

_{^{1 H NMR (400MHz, D 2}} O) δ 7.37 (d, J = 8.8Hz, 2H), 7.14 (d, J = 8.4Hz, 2H), 3.94 (t, J = 4.8Hz, 4H), 3.78 (dd J = 32.8 Hz, 2H), 3.47 (q, J = 6.8 Hz, 1H), 3.21 (t, J = 4.8 Hz, 4H), 1.33 (d, J = 6.8 Hz, 3H);

_{HR-FABMS Calcd for C 14 H} 22 N 3 O 2 (M + + H): 264.1712, Found: 264.1710.

< Example  8> (S) -2- (4- (Pyridin-4-yl) Benzylamino ) Propanamide

The reaction was conducted in the same manner as in Example 1, except that 4- (4-formylphenyl) pyridine was used instead of 5- (3- (trifluoromethyl) furfural in Example 1 and purified by column chromatography Ethyl acetate: methanol = 1: 1) to obtain the aimed compound (58%) as a white powder.

mp 172-175 [deg.] C;

[?] _D ²⁵ -9.9 ( c 0.99, methanol);

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.66 (dd, J = 4.4,1.6Hz, 2H), 7.62 (dd, J = 6.4,1.6Hz, 2H), 7.50 (dd, J = 4.4,1.6Hz, 2H), 7.43 (dd, J = 6.4,1.6Hz, 2H), 7.02 (brs, 1H), 5.31 (brs, 1H), 3.85 (dd, J = 23.2,13.6Hz, 2H), 3.29 (q, J = 6.8 Hz, 1 H), 1.38 (d, J = 6.8 Hz, 3 H);

_{HR-FABMS Calcd for C 15 H} 18 N 3 O (M + + H): 256.1450, Found: 256.1447.

< Example  9> (S) -2- (4- (Pyrimidin-5-yl) Benzylamino ) Propanamide

The procedure of Example 1 was repeated except that 4- (pyrimidin-5-yl) benzaldehyde was used instead of 5- (3- (trifluoromethyl) furfural in Example 1, The residue was purified by flash chromatography (ethyl acetate: methanol: hexane = 4: 1: 1) to obtain the target compound (80%) as a white powder.

mp 147-149 [deg.] C;

[?] _D ²⁵ -9.4 ( c 1.03, methanol);

_{^{1 H NMR (400MHz, CDCl 3}} ) δ9.21 (s, 1H), 8.95 (s, 2H), 7.57 (d, J = 8.4Hz, 2H), 7.47 (d, J = 8.4Hz, 2H), 7.00 (br s, 1H), 5.30 (brs, 1H), 3.86 (dd, J = 22.8,14 Hz, 2H), 3.29 (q, J = 6.8 Hz, 1H), 1.39 (d, J = 6.8 Hz, 3H);

_{HR-FABMS Calcd for C 14 H} 17 N 4 O (M + + H): 257.1402, Found: 257.1404.

< Example  10 (S) -2- (4- (4- Methylpiperazine -1 day) Benzylamino ) Propanamide

The procedure of Example 1 was repeated except that 4- (4-methylpiperazinyl) benzaldehyde was used instead of 5- (3- (trifluoromethyl) furfural in Example 1, and the reaction was carried out by column chromatography The residue was purified by flash chromatography (ethyl acetate: methanol = 1: 1) to obtain the target compound (25%) as a white powder.

mp 134-136 [deg.] C;

[?] _D ²⁵ -6.5 ( c 1.00, methanol);

_{^{1 H NMR (400MHz, D 2}} O) δ 7.34 (d, J = 8.8Hz, 2H), 7.13 (d, J = 8.8Hz, 2H), 3.67 (dd, J = 39.4,12.8Hz, 2H), 3.33 (q, J = 6.8 Hz, 1H), 3.20 (brs, 4H), 2.68 (brs, 4H), 2.33 (s, 3H), 1.27 (d, J = 7.2 Hz, 3H);

_{HR-FABMS Calcd for C 15 H} 25 N 4 O (M + + H): 277.2028, Found: 277.2030.

< Example  11 > 3 - ((5- (3- ( Trifluoromethyl ) Phenyl ) Furan -2 days) Methyl amino ) Benzamide

3-Aminobenzamide (0.4 mmol) and 5- (3- (trifluoromethyl) furfural (0.4 mmol) were mixed in dry methylene chloride and stirred for about 30 minutes under nitrogen gas substitution. Cetoxyborohydride (0.6 mmol) was added and the mixture was stirred at room temperature for 16 hours. The methylene chloride solvent of the reaction mixture was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate) to obtain the desired compound (13%) as a yellow powder .

mp 116-118 [deg.] C;

^{1 H NMR (400MHz, Acetone-} d 6) δ 7.98-7.96 (m, 2H), 7.64 (t, J = 8.0Hz, 1H), 7.60 (t, J = 8.0Hz, 1H), 7.35 (s, 1H ), 7.19-7.18 (m, 2H) , 6.98 (d, J = 3.2Hz, 1H), 6.93-6.90 (m, 1H), 6.46 (d, J = 3.2Hz, 1H), 5.68 (brs, 1H) , 4.50 (d, J = 5.6 Hz, 2H);

_{HR-EIMS Calcd for C 19 H} 15 F 3 N 2 O 2 (M +): 360.1086, Found: 360.1086.

< Example  12 > 3 - ((5- (3- Chloro -4- Methoxyphenyl ) Furan -2 days) Methyl amino ) Benzamide

In a manner similar to that of Example 11, except for using 5- (3-chloro-4-methoxy-phenyl) furfural in place of 5- (3- (trifluoromethyl) And the residue was purified by column chromatography (ethyl acetate) to obtain the aimed compound (27%) as a yellow powder.

mp 159 [deg.] C;

^{1 H NMR (400MHz, DMSO-} d 6) δ 7.70 (d, J = 2Hz, 1H),

7.61 (dd, J = 8.8,2Hz, 1H), 7.35 (s, 1H), 7.19-7.17 (m, 2H), 7.15 (d, J = 8.8Hz, 1H), 6.92-6.89 (m, 1H), 6.70 (d, J = 3.6 Hz, 1H), 6.39 (d, J = 3.2 Hz, 1H), 5.64 (brs, 1H), 4.45 (d, J = 6 Hz, 2H), 3.92

_{HR-EIMS Calcd for C 19 H} 17 ClN 2 O 3 (M +): 356.0928, Found: 356.0926.

< Example  13 > 3 - ((5- (4- Chlorophenyl ) Furan -2 days) Methyl amino ) Benzamide

According to the same manner as that in Example 11, except for using 5- (4-chlorophenyl) furfural and 3-aminobenzamide in place of 5- (3- (trifluoromethyl) furfural in Example 11 And purified by column chromatography (ethyl acetate) to obtain the desired compound (62%) as a yellow powder.

mp 145-147 [deg.] C; ^{1 HNMR (400MHz, Acetone-d} 6) δ 7.70 (d, J = 8.8Hz, 2H), 7.42 (d, J = 8.8Hz, 2H), 7.36 (s, 1H), 7.19-7.17 (m, 2H) , 6.92-6.89 (m, 1H), 6.81 (d, J = 3.6Hz, 1H), 6.41 (d, J = 3.6Hz, 1H), 5.65 (brs, 1H), 6.47 (d, J = 5.6Hz, 2H);

_{HR-EIMS Calcd for C 18 H} 15 ClN 2 O 2 (M +): 326.0822, Found: 326.0822.

< Example  14 > 3 - ((5- (4- Chlorophenyl ) Isoxazol -3 days) Methyl amino ) Benzamide

Step 1: 3 - ((5- (4- Chlorophenyl ) Isoxazol -3 days) Methyleneamino ) Benzamide

3-Aminobenzamide (0.4 mmol) and 5- (4-chlorophenyl) isoxazole-3-carboxaldehyde (0.4 mmol) were mixed in dry methylene chloride under nitrogen gas substitution and stirred for about 30 minutes. After completion of the reaction, the precipitated precipitate was washed with methanol and then dried to obtain the desired compound (41.3%) as a yellow powder.

^{1 H NMR (400MHz, DMSO-} d 6) δ 8.86 (s, 1H), 8.07 (brs, 1H), 8.04 (d, J = 6.8Hz, 2H), 7.89-7.88 (m, 1H), 7.85-7.83 (m, 1H), 7.66 ( d, J = 8.8,2H), 7.62 (s, 1H), 7.55 (d, J = 5.2,2H), 7.46 (brs, 1H)

Step 2: 3 - ((5- (4- Chlorophenyl ) Isoxazol -3 days) Methyl amino ) Benzamide

3 - ((5- (4-chlorophenyl) isoxazol-3-yl) methyleneamino) benzamide obtained in the above Step 1 was dissolved in dimethylformamide under nitrogen substitution. The powder was quenched and stirred. Sodium borohydride (NaBH _4, 0.6 mmol) was added to the reaction, followed by stirring at room temperature for 24 hours. The mixture was filtered using Celite 545, and the filtrate was concentrated under reduced pressure. The residue was extracted with ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (ethyl acetate: methanol = 9: 1) to obtain the target compound (23%) as a white powder.

mp 184-186 [deg.] C;

^{1 H NMR (400 MHz, DMSO} -d 6) δ 7.87 (d, J = 8.8Hz, 2H), 7.77 (brs, 1H), 7.58 (d, J = 9.2, Hz, 2H), 7.18 (brs, 1H ), 7.16 (t, J = 2Hz, 1H), 7.13 (d, J = 7.6Hz, 1H), 7.08-7.06 (m, 1H), 6.98 (s, 1H), 6.79 (d, J = 8Hz, 1H ), 4.40 (d, J = 4.8 Hz, 2H);

_{HR-EIMS Calcd for C 17 H} 14 ClN 3 O 2 (M +): 327.0775, Found: 327.0772.

< Example  15> 3- (4- (4- Cyanophenoxy ) Benzylideneamino ) Benzamide

Step 1: 3- (4- (4- Cyanophenoxy ) Benzylideneamino ) Benzamide

The procedure of Step 14 of Example 14 was repeated except for using 4- (4-formylphenoxy) benzonitrile instead of 5- (4-chlorophenyl) isoxazole-3-carboxaldehyde in Step 1 of Example 14. 1, and the resulting precipitate was washed with methanol and dried to obtain the target compound (65%) as a white powder.

^{1 H NMR (400MHz, DMSO-} d 6) δ 8.70 (s, 1H), 8.04 (d, J = 8.8Hz, 2H), 8.03 (brs, 1H), 7.90 (d, J = 8.8Hz, 2H), J = 8.8 Hz, 2H), 7.50 (t, J = 8 Hz, 1H), 7.43-7.40 (m, 2H)

Step 2: 3- (4- (4- Cyanophenoxy ) Benzylamino ) Benzamide

(4- (4-cyanophenoxy) isoxazol-3-yl) methyleneamino) benzamide obtained in Step 1 was used instead of 3 - ( Benzylideneamino) benzamide was used instead of 2-ethoxy-benzyloxy) benzaldehyde to obtain the desired compound (16%) as a pale brown powder.

mp 108-110 [deg.] C;

^{1 H NMR (400MHz, DMSO-} d 6) δ 7.83 (d, J = 9.2Hz, 2H), 7.77 (brs, 1H), 7.45 (d, J = 8.4Hz, 2H), 7.19 (brs, 1H), 7.11 (d, J = 8.4Hz, 2H), 7.10-7.08 (m, 1H), 7.06 (d, J = 8.8Hz, 2H), 7.02 (d, J = 8Hz, 1H), 6.71 (d, J = 6.8 Hz, 1H), 6.44 (t, J = 6.2 Hz, 1H), 4.32 (d, J = 6.0 Hz, 2H);

_{HR-EIMS Calcd for C 21 H} 17 N 3 O 2 (M +): 343.1321, Found: 343.1324.

< Example  16 > 3 - ((5- Chloro -1 H-indol-3-yl) Methyl amino ) Benzamide

In a similar manner to that described in Example 11, except for using 5-chloroindole-3-carboxaldehyde instead of 5- (3- (trifluoromethyl) furfural in Example 11, the title compound The target compound (63%) was obtained;

^{1 H NMR (400MHz, DMSO-} d 6) δ 11.08 (brs, 1H), 7.74 (brs, 1H), 7.69 (d, J = 2.4Hz, 1H), 7.40 (d, J = 2.4Hz, 1H), 7.36 (d, J = 8.8Hz, 1H), 7.16-7.15 (m, 1H), 7.09-7.05 (m, 2H), 7.00 (d, J = 8.0Hz, 1H), 6.79 (dd, J = 8.0, 2.4 Hz, 1 H), 6.13 (brs, 1 H), 4.37 (d, J = 5.6 Hz, 2 H);

_{HR-EIMS Calcd for C 16 H} 14 ClN 3 O (M +): 299.0825, Found: 299.0823.

< Example  17> 3- (4- Morpholino benzylamino ) Benzamide

The procedure of Example 11 was repeated except that 4- (4-formylphenyl) morpholine was used instead of 5- (3- (trifluoromethyl) furfural in Example 11 to obtain yellow powder 33%) of the desired compound.

mp 167-168 [deg.] C;

^{1 H NMR (400 MHz, Acetone} -d 6) δ 7.28 (d, J = 8.8Hz, 2H), 7.25 (s, 1H), 7.14-7.12 (m, 2H), 6.92 (d, J = 8.8Hz, 2H), 6.80 (dt, J = 6.0,2.8Hz, 1H), 6.39 (brs, 1H), 5.48 (brs, 1H), 4.29 (d, J = 5.6Hz, 2H), 3.76 (t, J = 4.8 Hz, 4H), 3.10 (t, J = 4.8 Hz, 4H);

_{HR-EIMS Calcd for C 19 H} 17 ClN 2 O 3 (M +): 311.1634, Found: 311.1631.

< Example  18 > N - ((5- (3- ( Trifluoromethyl ) Phenyl ) Furan -2 days) methyl ) (3,4,5- tree Methoxyphenyl) Methanamine

3,4,5-trimethoxybenzylamine (0.4 mmol) and 5- (3- (trifluoromethyl) furfural (0.4 mmol) were mixed in dry methylene chloride under nitrogen gas substitution and stirred for about 30 minutes. The residue was purified by column chromatography (ethyl acetate: methanol = 5: 1) to give the title compound as a colorless oil. &Lt; 1 &gt; 1) to obtain the desired compound (32%) as a red oil.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.90 (s, 1H), 7.81 (td, J = 4.8,1.6Hz, 1H), 7.50-7.48 (m, 2H), 6.69 (d, J = 3.2Hz, 1H ), 6.59 (s, 2H), 6.32 (d, J = 3.2 Hz, 1H), 3.89 (s, 2H), 3.85 (d, J = 10.8 Hz, 9H), 3.80

_{HR-FABMS Calcd for C 22 H} 23 F 3 NO 4 (M + + H): 422.1579, Found: 422.1579.

< Example  19> N - ((5- (3- Chloro -4- Methoxyphenyl ) Furan -2 days) methyl ) (3,4,5- Trimethoxyphenyl ) Methanamine

According to the same manner as that in Example 18, except for using 5- (3-chloro-4-methoxy-phenyl) furfural instead of 5- (3- (trifluoromethyl) And purified by column chromatography (ethyl acetate: methanol = 9: 1) to obtain the desired compound (50%) as a red oil;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.68 (d, J = 2Hz, 1H), 7.50 (dd, J = 8.4,2.0Hz, 1H), 6.93 (d, J = 8.4Hz, 1H), 6.59 (s , 2H), 6.48 (d, J = 3.2Hz, 1H), 6.26 (d, J = 3.2Hz, 1H), 3.93 (s, 3H), 3.85 (d, J = 11.2Hz, 9H), 3.86 (s , &Lt; / RTI &gt; 2H), 3.79 (s, 2H);

_{HR-FABMS Calcd for C 22 H} 25 ClNO 5 (M + + H): 418.1421, Found: 418.1420.

< Example  20 > N - ((5- (4- Chlorophenyl ) Furan -2 days) methyl ) (3,4,5- Trimethoxyphenyl ) Methanamine

The reaction was carried out in the same manner as in Example 18, except that 5- (4-chlorophenyl) furfural was used instead of 5- (3- (trifluoromethyl) furfural in Example 18, and subjected to column chromatography Ethyl acetate: methanol = 5: 1) to obtain the desired compound (37%) as a red oil.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.58 (d, J = 8.8Hz, 2H), 7.34 (d, J = 8.4Hz, 2H), 6.59-6.58 (m, 3H), 6.28 (d, J = 3.2 Hz, 1H), 3.86 (s, 2H), 3.85 (d, J = 9.6 Hz, 9H), 3.79 (s, 2H);

HR-FABMS Calcd for C ₂₁ H ₂₃ ClNO ₄ (M ⁺ + H): 388.1316, Found: 388.1313.

< Example  21> 4- (4 - ((3,4,5- Trimethoxybenzylamino ) methyl ) Phenoxy ) Benzonitrile

The reaction was conducted in the same manner as in Example 18, except that 4- (4-formylphenoxy) benzonitrile was used instead of 5- (3- (trifluoromethyl) furfural in Example 18, The residue was purified by chromatography (ethyl acetate: methanol = 2: 1) to obtain the desired compound (56%) as a red oil.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.60 (dd, J = 6.8,2.0Hz, 2H), 7.39 (dd, J = 6.4,2.0Hz, 2H), 7.03 (dd, J = 6.8,2.0Hz, 2H ), 7.00 (dd, J = 6.8, 2.0 Hz, 2H), 6.59 (s, 2H), 3.86 (d, J = 10 Hz, 9H), 3.84 (s, 2H), 3.80

HR-FABMS Calcd for C ₂₄ H ₂₅ N ₂ O ₄ (M ⁺ + H): 405.1814, Found: 405.1813.

< Example  22 > N - ((5- Chloro -1 H-indol-3-yl) methyl ) (3,4,5- Trimethoxyphenyl ) Methanamine

The reaction was conducted in a similar manner to Example 18, except that 5-chloroindole-3-carboxaldehyde was used instead of 5- (3- (trifluoromethyl) furfural in Example 18, and the residue was subjected to column chromatography Ethyl acetate: methanol = 2: 1) to obtain a red solid (43%).

mp 108-111 [deg.] C;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.08 (brs, 1H), 7.65 (s, 1H), 7.29 (d, J = 8.8Hz, 1H), 7.20 (s, 1H), 7.16 (dd, J = 8.8 , 2.0 Hz, 1H), 6.60 (s, 2H), 3.98 (s, 2H), 3.86 (d, J = 8.4 Hz, 9H), 3.82

_{HR-FABMS Calcd for C 19 H} 22 ClN 2 O 3 (M + + H): 361.1319, Found: 361.1316.

< Example  23 > N- (4- Morpholino benzyl ) (3,4,5- Trimethoxyphenyl ) Methanamine

The reaction was conducted in a similar manner to Example 18, except that 4- (4-formylphenyl) morpholine was used instead of 5- (3- (trifluoromethyl) furfural in Example 18 and purified by column chromatography (Ethyl acetate: methanol = 1: 1) to obtain the desired compound (35%) as a red powder.

mp 90-94 [deg.] C;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.25 (d, J = 8.4Hz, 2H), 6.90 (d, J = 8.8Hz, 2H), 6.57 (s, 2H), 3.88-3.84 (m, 13H), 3.75 (d, J = 4.8 Hz, 4H), 3.15 (t, J = 4.8 Hz, 4H);

_{HR-FABMS Calcd for C 21 H} 29 N 2 O 4 (M + + H): 373.2127, Found: 373.2126.

< Example  24> N- (4- (Pyridin-4-yl) benzyl) (3,4,5- Trimethoxyphenyl ) Methanamine

The reaction was conducted in the same manner as in Example 18, except that 4- (4-formylphenyl) pyridine was used instead of 5- (3- (trifluoromethyl) furfural in Example 18, and the resultant was purified by column chromatography Ethyl acetate: methanol = 2: 1) to obtain the desired compound (40%) as a black oil.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.66 (dd, J = 4.8,1.6Hz, 2H), 7.63 (d, J = 8.4Hz, 2H), 7.52 (dd, J = 4.8,1.6Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 6.59 (s, 2H), 3.89 (s, 2H), 3.86 (d, J = 11.2 Hz, 9H), 3.79

_{HR-FABMS Calcd for C 22 H} 25 N 2 O 3 (M + + H): 365.1865, Found: 365.1864.

< Example  25> N- (4- (Pyrimidin-5-yl) benzyl) (3,4,5- Trimethoxyphenyl ) Methanamine

The procedure of Example 18 was repeated except that 4- (pyrimidin-5-yl) benzaldehyde was used instead of 5- (3- (trifluoromethyl) furfural in Example 18, Purification by chromatography (ethyl acetate: methanol = 9: 1) afforded the desired compound (29%) as a red solid.

mp 66-68 [deg.] C;

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 9.21 (s, 1H), 8.96 (s, 2H), 7.57 (d, J = 8.4Hz, 2H), 7.51 (d, J = 8.4Hz, 2H), 6.60 ( s, 2H), 3.91 (s, 2H), 3.86 (d, J = 11.2 Hz, 9H), 3.80 (s, 2H);

_{HR-FABMS Calcd for C 21 H} 24 N 3 O 3 (M + + H): 366.1818, Found: 366.1819.

< Experimental Example  1> Assessment of calcium channel activity inhibition

To investigate the effects of the compounds of Examples 1 to 25 on T-type and N-type calcium channel activity inhibition, T-type and N-type Calcium channel activity was measured.

Specifically, the culture solution was prepared by adding 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin (v / v) to DMEM (Dulbecco's modified Eagle's medium). Cells were cultured at 36.5 ° C in a humidified incubator at 95% O ₂ /5% CO ₂ . The culture solution was changed once every 3-4 days and the cells were sub-cultured once a week. Using the G-418 (0.5 mg / ml) solution, α _{1G T-type} and α _1B N- Only HEK293 cells expressing the channel were grown. Cells used for T-type calcium channel activity assays were recorded 2-4 days after incubation on cover slips coated with poly-L-lysine (0.5 mg / ml) at each dispensing. To measure the current of T-type calcium channel at a single cell level, electrophysiological whole-cell patch clamp method was measured using an EPC-9 amplifier (HEKA, German). For the T-type calcium channel activity measurement, 140 mM NaCl, 2 mM CaCl ₂ , and 10 mM HEPES (pH 7.4) were used as the extracellular solution, and KCl 130 mM, HEPES 10 mM, EGTA 11 mM, and MgATP 5 mM (pH 7.4) were used. The T-type calcium channel activation protocol, which is activated at a low voltage, was performed by punching a micro-glass electrode having a resistance of 3-4 MΩ into a single cell into a whole-cell recording mode , The drug effect on the peak magnitude of the inward current due to the T-type calcium channel activity was measured when the cell membrane potential was fixed at -100 mV and then depolarized to -30 mV (50 ms duration) every 15 seconds. The results are shown in Table 2.

Example HEK 293 cells (T-type:? _1G ) HEK 293 cells (N-type:? _1B ) % Inhibition (10 μM) IC ₅₀ ([mu] M) % Inhibition (10 μM) IC ₅₀ ([mu] M) One 12.9 ± 2.5 - - - 2 13.3 ± 1.6 - - - 3 8.0 ± 3.3 - - - 4 1.6 ± 2.2 - - - 5 6.9 ± 1.5 - - - 6 25.1 ± 3.7 - - - 7 4.8 ± 0.4 - - - 8 5.9 ± 1.0 - - - 9 7.6 ± 3.9 - - - 10 4.9 ± 0.8 - - - 11 39.3 ± 11.9 - - - 12 41.6 ± 4.0 - - - 13 14.5 ± 3.8 - - - 14 25.2 ± 2.7 - - - 15 53.0 + - 8.3 7.4 ± 1.6 21.6 ± 4.7 - 16 39.9 ± 1.4 - - - 17 4.1 ± 0.4 - - - 18 86.6 ± 4.8 2.5 ± 0.3 81.6 ± 5.5 6.7 ± 1.1 19 77.6 ± 0.8 2.4 ± 0.2 70.6 ± 2.9 5.9 ± 0.4 20 91.3 ± 8.8 1.9 ± 0.3 80.2 ± 2.5 4.3 ± 0.4 21 60.4 ± 1.0 6.4 ± 0.3 54.9 ± 4.3 9.4 ± 0.8 22 64.2 ± 5.9 5.2 ± 0.5 75.2 ± 12.7 9.5 ± 1.3 23 9.8 ± 0.5 - - - 24 21.9 ± 3.0 - - - 25 38.3 ± 1.5 - - -

As shown in Table 2, the compounds of Examples 15, 18, 19, 20, 21, and 22 among the compounds according to the present invention exhibited T-type calcium channel activity inhibition percentages of 50% or more and IC ₅₀ values of 10 μM. In particular, the compounds of Examples 18, 19 and 20 exhibited a T-type calcium channel activity inhibition percentage of 75% or more and an IC ₅₀ value of 3 μM or less.

In addition, the compounds of Examples 18, 19, 20, 21 and 22 among the compounds according to the present invention exhibited N-type calcium channel activity inhibition percentages of 50% or more and IC ₅₀ values of 10 μM or less, 19, 20 and 22 showed that the% inhibition of N-type calcium channel activity was above 70%.

Accordingly, the amine compound represented by Formula 1 or its pharmaceutically acceptable salt according to the present invention inhibits T-type or N-type calcium channel activity, thereby inhibiting T-type or N-type calcium channel-induced Hypertension, cancer, epilepsy, or neuropathic pain.

< Formulation example  1> Preparation of pharmaceutical preparations

<1-1> Sanje  Produce

2 g of the amine compound represented by the formula (1)

Lactose 1 g

After mixing the above components, the mixture was packed in an airtight container to prepare a powder.

<1-2> Preparation of tablets

100 mg of the amine compound represented by the formula (1)

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

&Lt; 1-3 > Preparation of capsules

100 mg of the amine compound represented by the formula (1)

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

<1-4> Preparation of Injection Solution

10 &lt; RTI ID = 0.0 &gt; pg / ml &lt;

Until dilute hydrochloric acid BP pH 3.5

Sodium chloride BP injected up to 1 ml

The compound according to the invention was dissolved in a suitable volume of injected sodium chloride BP and the pH of the resulting solution was adjusted to pH 3.5 using dilute hydrochloric acid BP and the volume was adjusted using injectable sodium chloride BP and mixed thoroughly. The solution was filled in a 5 ml type I ampoule made of transparent glass, sealed in an upper lattice of air by dissolving the glass, sterilized by autoclaving at 120 DEG C for 15 minutes or longer, and an injection solution was prepared.

< Manufacturing example  2> Manufacture of health food

An amine compound represented by the formula (1): 500 ng

Vitamin mixture quantity

70 [mu] g of vitamin A acetate

Vitamin E 1.0 mg

0.13 mg of vitamin

0.15 mg of vitamin B2

0.5 mg vitamin B6

0.2 [mu] g vitamin B12

10 mg vitamin C

Biotin 10 μg

Nicotinic acid amide 1.7 mg

50 mg of folic acid

Calcium pantothenate 0.5 mg

Mineral mixture quantity

1.75 mg of ferrous sulfate

0.82 mg of zinc oxide

Magnesium carbonate 25.3 mg

15 mg of potassium phosphate monobasic

Secondary calcium phosphate 55 mg

Potassium citrate 90 mg

100 mg of calcium carbonate

24.8 mg of magnesium chloride

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

< Formulation example  3> Health drink  Produce

An amine compound represented by the formula (1): 500 ng

Citric acid 1000 mg

100 g of oligosaccharide

Plum concentrate 2 g

Taurine 1 g

Purified water was added to a total of 900 ml

The above components were mixed according to a conventional health drink manufacturing method, and the mixture was stirred and heated at 85 DEG C for about 1 hour. The resulting solution was filtered to obtain a sterilized container, which was sealed and sterilized, And used for manufacturing.

Although the composition ratio is relatively mixed with the ingredient suitable for the favorite drink, it is also possible to arbitrarily modify the blending ratio according to the regional or national preference such as the demand class, the demanded country, and the use purpose.

Claims (15)

delete delete delete delete delete delete Or a pharmaceutically acceptable salt thereof, wherein the compound is any one selected from the group consisting of the following compounds:
(6) (S) -2 - ((5-Chloro-lH-indol-3-yl) methylamino) propanamide;
(11) 3 - ((5- (3- (Trifluoromethyl) phenyl) furan-2-yl) methylamino) benzamide;
(12) 3 - ((5- (3-Chloro-4-methoxyphenyl) furan-2-yl) methylamino) benzamide;
(13) 3 - ((5- (4-Chlorophenyl) furan-2-yl) methylamino) benzamide;
(14) 3 - ((5- (4-Chlorophenyl) isoxazol-3-yl) methylamino) benzamide;
(15) 3- (4- (4-Cyanophenoxy) benzylamino) benzamide;
(16) 3 - ((5-chloro-1 H-indol-3-yl) methylamino) benzamide;
(17) 3- (4-morpholinobenzylamino) benzamide;
(18) N - ((5- (3- (trifluoromethyl) phenyl) furan-2-yl) methyl) (3,4,5-trimethoxyphenyl) methanamine;
(19) N - ((5- (3-Chloro-4-methoxyphenyl) furan-2- yl) methyl) (3,4,5-trimethoxyphenyl)
Methane amine;
(20) N - ((5- (4-chlorophenyl) furan-2-yl) methyl) (3,4,5-trimethoxyphenyl) methanamine;
(21) 4- (4 - ((3,4,5-trimethoxybenzylamino) methyl) phenoxy) benzonitrile;
(22) N - ((5-chloro-1H-indol-3-yl) methyl) (3,4,5-trimethoxyphenyl) methanamine;
(23) N- (4-morpholinobenzyl) (3,4,5-trimethoxyphenyl) methanamine;
(24) N- (4- (Pyridin-4-yl) benzyl) (3,4,5-trimethoxyphenyl) methanamine; And
(25) N- (4- (Pyrimidin-5-yl) benzyl) (3,4,5-trimethoxyphenyl) methanamine.
As shown in Scheme 1 below,
(5) which is dissolved in at least one solvent selected from the group consisting of methanol, ethanol, propanol, butanol, tetrahydrofuran, dioxane, methylene chloride, 1,2-dimethoxyethane, dimethylformamide and dimethylsulfoxide And a compound represented by the formula (6)
In the presence of at least one reducing agent selected from the group consisting of sodium cyanoborohydride, sodium borohydride, and sodium triacetoxyborohydride,
Or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of claim 7 or a pharmaceutically acceptable salt thereof represented by the formula (1) (step 1) by reacting the compound of formula (1) at a temperature of from room temperature to 35 ° C for 15 minutes to 24 hours, Method of preparing acceptable salts:
[Reaction Scheme 1]

(In the above Reaction Scheme 1,
R ¹ is

^,

^,

^,

^,

,

,

,

or

ego;
R ² is

,

or

to be).
delete The pharmaceutical composition of claim 7 or a pharmaceutically acceptable salt thereof as an active ingredient is selected from the group consisting of epilepsy, depression, Parkinson's disease, dementia, sleep disorder, hypertension, cardiac arrhythmia, angina pectoris, myocardial infarction, congestive heart failure, A pharmaceutical composition for preventing or treating diseases caused by the activity of a T-type or N-type calcium ion channel selected from the group consisting of liver cancer and colon cancer.
delete delete The pharmaceutical composition of claim 7 or a pharmaceutically acceptable salt thereof as an active ingredient is selected from the group consisting of epilepsy, depression, Parkinson's disease, dementia, sleep disorder, hypertension, cardiac arrhythmia, angina pectoris, myocardial infarction, congestive heart failure, Type or N-type calcium ion channel selected from the group consisting of liver cancer, colon cancer, liver cancer, and colon cancer. delete delete