KR102042778B1 - Novel sodium channel inhibitor compound, preparation method thereof, and pharmaceutical composition for prevention or treatment of sodium channel related diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel sodium channel inhibiting compound, a method for producing the same, and a pharmaceutical composition for preventing or treating a sodium channel-related disease including the same. According to the present invention, the novel sodium channel inhibiting compound is capable of inhibiting sodium channels excellently and, in particular, is a compound having excellent inhibitory activity on Nav 1.7 channel. As a pharmaceutical composition or health functional food composition containing the above as active ingredients, the present invention has beneficial effects capable of preventing, alleviating or treating sodium channel-related diseases such as pain disorders associated with sodium channel activity like Nav 1.7 channel-related diseases, specifically, neuropathic pain, spontaneous provoked pain, paroxysmal extreme pain disorder, erythromelalgia or erythromelalgia pain. The compound is represented by chemical formula 1.

Description

Novel sodium channel inhibitor compound, preparation method according to the present invention, and pharmaceutical composition for prevention or treatment of sodium channel related diseases the same as an active ingredient}

The present invention relates to novel sodium channel inhibitory compounds, methods for their preparation, and pharmaceutical compositions for the prevention or treatment of sodium channel related diseases comprising the same.

Neuropathic pain is chronic pathologic pain caused by nerve damage or abnormal neurological function (post-herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, spinal cord injuries, etc.). It is known as one of the most severe pain. Axons and dehydration are caused by wounds and diseases affecting the peripheral nerves, resulting in neuropathic changes, initiating membrane remodeling in the damaged centripetal zone, and influencing to the intact, and in the central zone where neuropathic changes have occurred. Excessive ion release is induced to constitute an early neuropathic pain signal, excessively inducing spontaneous pain and continuously increasing dislocation to become chronic pain.

In order to treat such neuropathic pain, a method of inhibiting voltage-gated sodium channels (VGSCs) may be used. Neuropathy because VGSCs are ion channels that play a fundamental role in regulating cell stimulation and abnormal activity associated with several pathologies, including cardiac arrhythmias, epilepsy, neuropathic disease, ankylosing spasms, chronic and neuropathic pain It can be a good target for drugs for the treatment of sexual pain, and specifically, drugs that regulate the voltage-gated pore of VGSCs that selectively pass sodium ions to determine the electrical stimulation of sensory neurons. By controlling or inhibiting neuropathic afferent stimulation, it is possible to treat neuropathic pain (Non-Patent Document 1).

Sodium channels have nine variants from Nav1.1 to 1.9, which are classified based on the type of membrane protein they are made of. Diseases associated with each sodium channel from Nav1.1 to 1.9 are ivory, especially among sodium channels, Nav 1.7 is associated with neuropathic pain, genetic pain disease is associated with mutations in the SCN9A gene and is seizure It has been shown to be directly related to paroxysmal extreme pain disorder, erythromelal pain, and erythema pain, and the development of drugs targeting pain-related VGSCs is urgently needed.

Although local anesthetic, lidocaine, has been suggested in the clinic as a first-generation drug for the treatment of neuropathic pain, these first-generation drugs potentially affect sodium channels, but are non-selective sodium channel inhibitors, each of which is a subtype. There is no selectivity for Therefore, there may be systemic side effects due to CNS passage, and there are side effects that may indicate potential chronic symptoms.

Therefore, the present inventors are trying to develop a neuropathic pain treatment agent through the regulation and inhibition of VGSCs, the compound according to the present invention has a remarkably excellent inhibitory effect against Nav1.7, especially among VGSCs, central neuropathy The present invention was completed by confirming the excellent pain inhibition.

J.Pain 7 (15), Supplement 1, 2006, S3-S12

It is an object of the present invention to provide novel sodium channel inhibitory compounds.

Another object of the present invention is to provide a method for preparing the novel sodium channel inhibitory compound.

Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of sodium channel-related diseases containing the novel sodium channel inhibitory compound as an active ingredient.

Another object of the present invention to provide a dietary supplement for the prevention or improvement of sodium channel-related diseases containing the novel sodium channel inhibitory compound as an active ingredient.

In order to achieve the above object,

In one aspect of the invention,

A compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided.

[Formula 1]

(In Formula 1,

R ¹ is unsubstituted or substituted C _1-10 straight or branched alkyl, unsubstituted or substituted C _1-10 straight or branched alkoxy, unsubstituted or substituted C _3-10 cycloalkyl, N, O and Unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted C _6-10 aryl comprising one or more heteroatoms selected from the group consisting of S, or from the group consisting of N, O and S Unsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected,

Wherein the substituted alkyl, substituted alkoxy, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is halogen, C _1-10 straight or branched chain alkyl, C _1-10 Straight or branched alkoxy, —NO ₂ , —CN, oxo (═O), unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _6-10 aryl, (N, O and S Unsubstituted or substituted 3-10 membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of (unsubstituted or substituted comprising one or more heteroatoms selected from the group consisting of N, O and S) One or more substituents independently selected from the group consisting of 5-10 atoms heteroaryl), unsubstituted or substituted C _6-10 aryloxy, and unsubstituted or substituted C _6-10 arylC _1-3 alkoxy Is substituted,

Here again, the substituted cycloalkyl, substituted C _6-10 aryl, substituted 3-10 atom heterocycloalkyl, substituted 5-10 atom heteroaryl, substituted C _6-10 aryloxy, or Substituted C _6-10 arylC _1-3 alkoxy is a group consisting of C _1-5 straight or branched alkyl, unsubstituted or substituted with one or more halogens, C _1-5 straight or branched alkoxy, halogen and —CN. One or more substituents independently selected from

The substituted cycloalkyl, substituted C _6-10 aryl, substituted 3-10 atom heterocycloalkyl, or substituted 5-10 atom heteroaryl is unsubstituted or substituted C _3-10 alkyl Ring, unsubstituted or substituted C _6-10 aryl ring, unsubstituted or substituted 3-10 membered heterocycle comprising one or more heteroatoms selected from the group consisting of N, O and S, or N, O And an unsubstituted or substituted 5-10 atom heteroaryl ring including one or more heteroatoms selected from the group consisting of S, fused and substituted,

Here again, the substituted alkyl ring, substituted aryl ring, substituted heterocyclic ring, substituted heteroaryl ring is C _1-5 unsubstituted or substituted with one or more halogen, straight or branched chain alkyl, C _1-5 At least one substituent is independently selected from the group consisting of linear or branched alkoxy, halogen and -CN; And

R ² is unsubstituted or substituted C _1-10 straight or branched alkyl, unsubstituted or substituted C _1-10 straight or branched alkoxy, unsubstituted or substituted C _3-10 cycloalkyl, N, O and Unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted C _6-10 aryl comprising one or more heteroatoms selected from the group consisting of S, or from the group consisting of N, O and S Unsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected,

Wherein the substituted alkyl, substituted alkoxy, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is halogen, unsubstituted or substituted C _1-10 straight or branched alkyl, Unsubstituted or substituted C _1-10 straight or branched chain alkoxy, hydroxy, C _1-5 alkylthio, hydrothio, oxo (═O), —NO ₂ , —CN, —NR ³ R ⁴ ,- Boc, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _6-10 aryl, (unsubstituted or substituted comprising one or more heteroatoms selected from the group consisting of N, O and S) Independently heterocycloalkyl of 3-10 atoms), or (unsubstituted or substituted 5-10 atoms of heteroaryl including one or more heteroatoms selected from the group consisting of N, O and S) One or more substituents selected ,

Again wherein R ³ and R ⁴ are each independently H, C _1-10 straight or branched alkyl, or —Boc,

The substituted alkyl, substituted alkoxy, substituted cycloalkyl, substituted aryl, substituted heterocycloalkyl, substituted heteroaryl are substituted by C _1-5 alkylthio, hydrothio, unsubstituted or one or more halogens. C _1-5 straight or branched alkyl, C _1-5 straight or branched alkoxy, halogen and -CN are substituted with one or more substituents independently selected from the group consisting of).

In another aspect of the invention,

As shown in Scheme 1 below,

There is provided a method for preparing a compound represented by Chemical Formula 1, comprising the step of reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3 to prepare a compound represented by Chemical Formula 1.

Scheme 1

(In the above Reaction Scheme 1,

R ¹ , R ² , and R ³ are as defined in Chemical Formula 1).

Furthermore, in another aspect of the present invention,

Provided is a pharmaceutical composition for preventing or treating sodium channel-related diseases containing a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In another aspect of the invention,

Provided is a health functional food composition for preventing or ameliorating sodium channel related diseases containing a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

The novel sodium channel inhibitory compound according to the present invention can inhibit sodium channel excellently, and is particularly a compound having excellent Nav 1.7 channel inhibitory activity. As a pharmaceutical composition or health functional food composition containing the same as an active ingredient, sodium Channel-related diseases, such as pain disorders associated with sodium channel activity, such as Nav 1.7 channel-related diseases such as neuropathic pain, spontaneous provoked pain, seizure pain disorders ( There are useful effects that can prevent, ameliorate, or treat diseases such as paroxysmal extreme pain disorder, erythromelalgia, or erythema pain.

Figure 1 shows the quantified pain sensitivity of rats in Example 14 compound at a dose of 60 mg / kg.
Figure 2 shows the numerical value of the pain sensitivity of rats appearing in Example 15 compound dosed 2 mg / kg, or 6 mg / kg.
Figure 3 is a numerical representation of the pain sensitivity of rats appearing in Example 21 compound at a dose of 60 mg / kg.

Hereinafter, the present invention will be described in detail.

The following description is presented to aid in understanding the invention, and the present invention is not limited to the contents of the following description.

In one aspect of the invention,

In one aspect of the invention,

A compound represented by the following formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided.

[Formula 1]

(In Formula 1,

R ¹ is unsubstituted or substituted C _1-10 straight or branched alkyl, unsubstituted or substituted C _1-10 straight or branched alkoxy, unsubstituted or substituted C _3-10 cycloalkyl, N, O and Unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted C _6-10 aryl comprising one or more heteroatoms selected from the group consisting of S, or from the group consisting of N, O and S Unsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected,

Wherein the substituted alkyl, substituted alkoxy, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is halogen, C _1-10 straight or branched chain alkyl, C _1-10 Straight or branched alkoxy, —NO ₂ , —CN, oxo (═O), unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _6-10 aryl, (N, O and S Unsubstituted or substituted 3-10 membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of (unsubstituted or substituted comprising one or more heteroatoms selected from the group consisting of N, O and S) One or more substituents independently selected from the group consisting of 5-10 atoms heteroaryl), unsubstituted or substituted C _6-10 aryloxy, and unsubstituted or substituted C _6-10 arylC _1-3 alkoxy Is substituted,

Here again, the substituted cycloalkyl, substituted C _6-10 aryl, substituted 3-10 atom heterocycloalkyl, substituted 5-10 atom heteroaryl, substituted C _6-10 aryloxy, or Substituted C _6-10 arylC _1-3 alkoxy is a group consisting of C _1-5 straight or branched alkyl, unsubstituted or substituted with one or more halogens, C _1-5 straight or branched alkoxy, halogen and —CN. One or more substituents independently selected from

The substituted cycloalkyl, substituted C _6-10 aryl, substituted 3-10 atom heterocycloalkyl, or substituted 5-10 atom heteroaryl is unsubstituted or substituted C _3-10 alkyl Ring, unsubstituted or substituted C _6-10 aryl ring, unsubstituted or substituted 3-10 membered heterocycle comprising one or more heteroatoms selected from the group consisting of N, O and S, or N, O And an unsubstituted or substituted 5-10 atom heteroaryl ring including one or more heteroatoms selected from the group consisting of S, fused and substituted,

Here again, the substituted alkyl ring, substituted aryl ring, substituted heterocyclic ring, substituted heteroaryl ring is C _1-5 unsubstituted or substituted with one or more halogen, straight or branched chain alkyl, C _1-5 At least one substituent is independently selected from the group consisting of linear or branched alkoxy, halogen and -CN; And

R ² is unsubstituted or substituted C _1-10 straight or branched alkyl, unsubstituted or substituted C _1-10 straight or branched alkoxy, unsubstituted or substituted C _3-10 cycloalkyl, N, O and Unsubstituted or substituted 3-10 membered heterocycloalkyl, unsubstituted or substituted C _6-10 aryl comprising one or more heteroatoms selected from the group consisting of S, or from the group consisting of N, O and S Unsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected,

Wherein the substituted alkyl, substituted alkoxy, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is halogen, unsubstituted or substituted C _1-10 straight or branched alkyl, Unsubstituted or substituted C _1-10 straight or branched chain alkoxy, hydroxy, C _1-5 alkylthio, hydrothio, oxo (═O), —NO ₂ , —CN, —NR ³ R ⁴ ,- Boc, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _6-10 aryl, (unsubstituted or substituted comprising one or more heteroatoms selected from the group consisting of N, O and S) Independently heterocycloalkyl of 3-10 atoms), or (unsubstituted or substituted 5-10 atoms of heteroaryl including one or more heteroatoms selected from the group consisting of N, O and S) One or more substituents selected ,

Again wherein R ³ and R ⁴ are each independently H, C _1-10 straight or branched alkyl, or —Boc,

The substituted alkyl, substituted alkoxy, substituted cycloalkyl, substituted aryl, substituted heterocycloalkyl, substituted heteroaryl are substituted by C _1-5 alkylthio, hydrothio, unsubstituted or one or more halogens. C _1-5 straight or branched alkyl, C _1-5 straight or branched alkoxy, halogen and -CN are substituted with one or more substituents independently selected from the group consisting of).

In another aspect of the invention,

R ¹ is unsubstituted or substituted C _1-5 linear or branched alkyl,

Wherein the substituted alkyl is halogen, C _1-10 straight or branched alkoxy, —NO ₂ , —CN, oxo (═O), unsubstituted or substituted C _5-6 cycloalkyl, unsubstituted or substituted C _6-10 aryl, (unsubstituted or substituted 5-6 membered heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S), (N, O and S Unsubstituted or substituted 5-10 membered heteroaryl including one or more heteroatoms selected from the group), unsubstituted or substituted C _6-10 aryloxy, and unsubstituted or substituted C _6-10 aryl C One or more substituents independently selected from the group consisting of _1-3 alkoxy,

Here again, the substituted cycloalkyl, substituted aryl, substituted heterocycloalkyl, substituted heteroaryl, substituted C _6-10 aryloxy, or substituted C _6-10 arylC _1-3 alkoxy, One or more substituents independently selected from the group consisting of C _1-5 straight or branched alkyl, C _1-5 linear or branched alkoxy, halogen and —CN substituted with one or more halogens; or

Wherein said substituted cycloalkyl, substituted aryl, substituted heterocycloalkyl, or substituted heteroaryl is one or more heteroatoms selected from the group consisting of C _5-6 alkyl rings, phenyl rings, N, O and S Heterocycle of 5-6 atoms including, or 5-6 atoms heteroaryl ring containing one or more heteroatoms selected from the group consisting of N, O and S may be fused and substituted.

In another aspect of the invention,

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In another aspect of the invention,

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In one embodiment of the invention,

The compound represented by Formula 1 may be a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is one selected from the following compound groups.

(1) (S) -2-amino-1- (4- (2,3,4-trimethoxybenzyl) piperazin-1-yl) propan-1-one;

(2) (S) -2-amino-1- (4- (2,5-difluorobenzyl) piperazin-1-yl) propan-1-one;

(3) (S) -2-amino-1- (4- (naphthalen-2-ylmethyl) piperazin-1-yl) propan-1-one;

(4) (S) -2-amino-1- (4- (4-methoxybenzyl) piperazin-1-yl) propan-1-one;

(5) (2S) -2-amino-1- (4- (2,3-dihydrobenzo [b] [1,4] dioxine-2-carbonyl) piperazin-1-yl) propane-1 -On;

(6) (S) -2-amino-1- (4- (2-phenoxyacetyl) piperazin-1-yl) propan-1-one;

(7) (S) -2-amino-1- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) propan-1-one;

(8) (2S) -2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3-methylbutan-1-one;

(9) (2S) -2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3-phenylpropan-1-one;

(10) (2S, 3S) -2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3-methylpentan-1-one;

(11) (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) (pyrrolidin-2-yl) -methanone;

(12) 2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4- (methylthio) butan-1-one;

(13) (2R) -2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3,3-dimethylbutan-1-one;

(14) (2S) -2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4-methylpentan-1-one;

(15) 2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3- (1H-indol-3-yl) propan-1-one;

(16) 2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3- (4-hydroxyphenyl) propan-1-one;

(17) 4- (4-bromophenyl) 1-1 (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one;

(18) 1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4-p-tolylbutan-1-one;

(19) 1- (4-chlorophenyl) -4- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butane-1,4-dione;

(20) 1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -2-methyl-4-phenylbutan-1,4-dione; And

(21) 1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4- (4-methoxyphenyl) butan-1-one.

The compound represented by 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 inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobene Sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 Sulfonates, naphthalene-2-sulfonates, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and adding an organic or inorganic acid. The solvent may be prepared by filtration and drying, or the solvent and the excess acid may be distilled under reduced pressure, dried, and then crystallized under an organic solvent.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).

Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, stereoisomers, hydrates, and the like that can be prepared therefrom.

In one aspect of the invention,

The compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, solvate thereof, hydrate thereof and the like may be understood to be a sodium channel inhibiting compound.

In one embodiment of the invention,

The compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, solvate thereof, hydrate thereof and the like may be understood to be a sodium channel 1.7 (Nav 1.7) inhibiting compound.

In another embodiment of the invention,

The compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, solvates thereof, hydrates thereof, and the like, exhibit excellent inhibitory activity on sodium channel 1.7, and in particular, show better inhibitory activity on sodium channel 1.7 than other subtypes. Can be understood to be a compound.

As described above,

In one embodiment of the present invention, using the following example compound as an example, it was confirmed that the sodium channel inhibitory activity, as shown in the following experimental example, in particular, excellent inhibitory activity on sodium channel 1.7.

Thus, the compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, solvates thereof, hydrates thereof, and the like, provided in the present invention, are related to the disease associated with sodium channels, that is, to the present time, the activity of sodium channels. A disease identified as being associated with, or a disease identified as being related to the expression of sodium channels, or experimentally, with regard to the activity of sodium channels, it may or may not be effective to prevent, ameliorate, improve, treat, etc. It can be understood to include all expected diseases, compounds, and the like provided in the present invention can be understood to be an effective ingredient that can exhibit the effects of prevention, improvement, improvement, treatment and the like.

In another aspect of the invention,

As shown in Scheme 1 below,

There is provided a method for preparing a compound represented by Chemical Formula 1, comprising the step of reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3 to prepare a compound represented by Chemical Formula 1.

Scheme 1

(In the above Reaction Scheme 1,

R ¹ , R ² , and R ³ are as defined in Chemical Formula 1).

Hereinafter, a method for preparing a compound represented by Chemical Formula 1 according to the present invention will be described in detail step by step.

In the method for preparing a compound represented by Formula 1 according to the present invention,

The compound represented by Chemical Formula 2 may be used as a starting material, or may be changed to a form of various salts thereof, for example, a salt with an acid, to form the starting material, but is not limited thereto. Any changeable form of starting material that may be included is included in the present invention.

On the other hand, the compound represented by the formula (3) is not particularly limited as long as it has the carboxy group represented, and in particular, if the compound represented by the formula (1) can be prepared, by reacting as in Scheme 1, It is included in the present invention without limitation.

In addition, the range that can be changed / modified from the reaction scheme 1, for example, a range that can be easily changed / modified by those skilled in the art, can be understood to be included in the present invention, the present invention includes this.

On the other hand, the reaction conditions of the reaction can be changed / modified in consideration of the yield of the final target compound, and the like, the solvent, reaction time, reaction temperature, etc. can be easily understood that can be changed / modified, without being particularly limited. If it is a condition under which the compound represented by Formula 1 may be prepared, it should be understood to be included in the present invention.

The type of solvent that can be used is not limited, but, for example, dichloromethane (DCM), tetrahydrofuran, dioxane, ethyl ether, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) And dichloroethane, acetonitrile, toluene, chlorobenzene, and at least one selected from the group consisting of acetone.

The reaction time is not particularly limited, but may be set to, for example, 1 to 48 hours, 2 to 24 hours, 3 to 20 hours, or 4 hours, or 16 hours, or about 19 hours.

The reaction temperature is also not particularly limited, but as an example, room temperature, 10-50 ° C., 20-40 ° C., 20-35 ° C., or 30-35 ° C. may be set, but is not limited thereto.

As an embodiment of the present invention, it can be carried out as Preparation Example 1-3, Example 1-21.

Furthermore, in another aspect of the present invention,

Provided is a pharmaceutical composition for preventing or treating sodium channel-related diseases containing a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In another aspect of the invention,

Provided is a health functional food composition for preventing or ameliorating sodium channel related diseases containing a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the invention,

The sodium channel-related disease may be understood as a disease related to the activity of the sodium channel, or a disease related to the expression of the sodium channel.

In another embodiment of the invention,

The sodium channel-related diseases may be understood to be all diseases that can develop or develop abnormalities, overexpression of sodium channels, or over-expression of sodium channels.

In another embodiment of the invention,

The sodium channel-related disease may be understood to be particularly related to sodium channel 1.7 (Nav 1.7), and in particular, to the present time, the disease related to sodium channel 1.7 (Nav 1.7) may be identified, studied, or predicted. Includes all diseases.

In another embodiment of the invention,

The sodium channel related disorders include, for example, neuropathic pain, spontaneous provoked pain, paroxysmal extreme pain disorder, erythromelalgia, or erythema pain. The disease may be a disease, and in particular, the activity of the compound, stereoisomer, or pharmaceutically acceptable salt thereof provided in the present invention may be prevented, ameliorated, improved, or directly related to sodium channel 1.7. It is a disease that can be treated, and furthermore, the pharmaceutical composition and the nutraceutical composition provided in the present invention are diseases that can be prevented, improved, improved, or treated.

In another aspect of the invention,

Compounds provided herein, stereoisomers thereof, pharmaceutically acceptable salts thereof, pharmaceutical compositions, nutraceutical compositions particularly inhibit Nav 1.7, preferably selectively inhibit Nav 1.7, For example, it selectively inhibits Nav 1.7 with better inhibitory activity than at least one of the other sodium channel subtypes (Nav 1.1, Nav 1.2, Nav 1.3, Nav 1.4, Nav 1.5, Nav 1.6, Nav 1.8, Nav 1.9), Preferably, from the effect of selectively inhibiting Nav 1.7 relative to all other sodium channel subtypes, it can be understood that the effect of prevention, amelioration, improvement or treatment in the above-mentioned diseases is achieved.

In view of this, in particular, the side effects of conventional non-selective drugs can be significantly improved, and the compounds provided by the present invention, stereoisomers thereof, pharmaceutically acceptable salts thereof, pharmaceutical compositions, and nutraceutical compositions are useful. .

In the above-described pharmaceutical composition according to the present invention, the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be administered in various formulations, oral and parenteral, during clinical administration. If so, it may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and the like, optionally with bores such as starch, agar, alginic acid or its sodium salt and the like. Release or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.

Pharmaceutical compositions comprising the compound represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be performed by injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

In this case, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, and it is an ampule or vial unit dosage form. It can be prepared by. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

Examples of the formulation is related to the conventional formulation, it will be readily understood by those skilled in the art that the formulation of the present invention is not limited thereto.

Furthermore, the dosage of the compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the subject, Based on an adult subject of 70 kg, it is generally 0.1-1000 mg / day, preferably 1-500 mg / day, and is divided once or several times a day at regular time intervals according to the judgment of a doctor or pharmacist. It may also be administered.

Furthermore, the present invention provides a method for treating a sodium channel-related disease comprising administering to a subject a therapeutically effective amount of a compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. to provide.

At this time, the sodium channel-related diseases are as described herein.

The therapeutically effective amount refers to an amount that can treat, prevent or ameliorate the symptoms or conditions of the subject when administered into the body, depending on the method of administration. In addition, the amount may be different depending on the weight, age, sex, condition, family history of the subject to be administered, and in the present invention, the treatment method may determine a different amount of dosage according to different conditions for each subject.

The "effective amount" refers to sodium channel related disorders, such as sodium channel 1.7 related disorders such as neuropathic pain, spontaneous provoked pain, paroxysmal extreme pain disorder It is an amount effective for treating a disease such as erythromelalgia, or erythema pain. In another embodiment, an "effective amount" of a compound is an amount capable of inhibiting sodium channel activity or inhibiting sodium channel aberrant activity.

The compounds and compositions according to the methods of the invention can be administered using any amount and any route of administration effective for treating a disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds of the present invention are frequently formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dose unit form” as used herein refers to physically discrete units of the formulation appropriate for the subject to be treated. It will also be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The particular effective dosage level for any particular subject or organism depends on various factors, including: the disease to be treated and the severity of the disease; The activity of the specific compound employed; The specific composition employed; Age, weight, general health, sex and diet of the subject; Time of administration, route of administration, and rate of excretion of the specific compound employed; Duration of treatment; Certain compounds employed alone or coadministered with drugs, and other factors well known in medical technology.

The term “subject” refers to a subject in need of a compound provided herein, stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions, or nutraceutical compositions, otherwise relating to sodium channel Diseases, eg, sodium channel 1.7 related diseases, such as neuropathic pain, spontaneous provoked pain, paroxysmal extreme pain disorder, erythromelalgia, Or a subject in need of an effect of preventing, ameliorating, ameliorating, or treating a disease such as erythema pain, wherein the subject is for example an animal, preferably a non-mammalian, or a mammal, more preferably Livestock, human, most preferably human.

Hereinafter, the present invention will be described in detail by production examples, examples and experimental examples.

However, the following Preparation Examples, Examples and Experimental Examples are merely illustrative of the present invention, but the content of the present invention is not limited thereto.

Preparation Example 1 Preparation of (S) -2-amino-1- (piperazin-1-yl) propan-1-one Derivative

Step 1: To the dried flask, add N-Boc-protein (1eq), R ¹ -piperazine (1.1eq), and PyBop (1.1eq) in 3 ml of DMF and dissolve. After DIEA (2eq) was added and stirred for 16 hours at room temperature. After extraction with 20 mL of 10% HCl and 30 mL EtOAc, the organic layer was collected and then extracted twice with NaHCO ₃ solution. Finally, after washing twice with brine solution, MgSO ₄ is added to the collected organic layer and filtered under reduced pressure. The organic layer was concentrated under reduced pressure, and then purified by recrystallization in a ratio of EA: Hexane = 1:10 to obtain the target compound of Step 1.

Step 2: CHCl ₃ and 4-HCl dioxane were added in a 1: 1 ratio to the target compound of step 1 concentrated under reduced pressure, followed by stirring at room temperature for about 3 hours. After concentration under reduced pressure, EA: Hexane = 1:10 to recrystallization and purification, and then filtered under reduced pressure to give the final target compound.

Preparation Example 2 Preparation of 2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) ethanone derivative

Step 1: In a dried flask, add N-Boc-Protein-R ⁵ (1eq), 1-((4-chlorophenyl) (phenyl) methyl) piperazine (1.1eq), PyBop (1.1eq) in 3 ml of DMF. Put and melt Then DIEA (2eq) was added and stirred for 16 hours at room temperature. After extraction with 20 mL of 10% HCl and 30 mL EtOAc, the organic layer was collected and extracted twice with NaHCO ₃ solution. Finally, after washing twice with brine solution, MgSO ₄ was added to the combined organic layers and filtered under reduced pressure. The organic layer was concentrated under reduced pressure, and then purified by recrystallization in a ratio of EA: Hexane = 1:10 to obtain the target compound of Step 1.

Step 2: CHCl ₃ and 4-HCl dioxane were added in a 1: 1 ratio to the target compound of step 1 concentrated under reduced pressure, followed by stirring at room temperature for about 3 hours. After concentration under reduced pressure, EA: Hexane = 1:10 to recrystallization and purification, and then filtered under reduced pressure to give the final target compound.

Preparation Example 3 Preparation of 1-((4-chlorophenyl) (phenyl) methyl) piperazine Derivative

To the dried flask, dissolve 3 ml of DMF in R ² -COOH (1eq), 1-((4-chlorophenyl) (phenyl) methyl) piperazine (1.1eq), and PyBop (1.1eq). Then DIEA (2eq) was added and stirred for 16 hours at room temperature. After extraction with 20 mL of 10% HCl and 30 mL EtOAc, the organic layer was collected and extracted twice with NaHCO ₃ solution. Finally, after washing twice with brine solution, MgSO ₄ was added to the collected organic layers and filtered under reduced pressure. The organic layer was concentrated under reduced pressure, and then purified by recrystallization at a ratio of EA: Hexane = 1:10 to obtain a final target compound.

To carry out as in Preparation Example 1-3, to the following Example compound.

Example 1 Preparation of (S) -2-amino-1- (4- (2,3,4-trimethoxybenzyl) piperazin-1-yl) propan-1-one

Using R ¹ -piperazine of Preparation Example 1 as 1- (2,3,4-trimethoxybenzyl) piperazine, it was carried out as in Preparation Example 1 to obtain a final target compound as a brown oil ( 17.1%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (brs, 2H), 7.95 (s, 1H), 7.32-7.19 (m, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.25 (brs , 2H), 3.78-3.57 (m, 7H), 2.89 (s, 6H), 2.73 (s, 5H), 2.05 (dd, J = 2Hz, J = 2.4Hz, 3H) HR-FABMS Calcd for C ₁₇ H ₂₈ N ₃ O ₄ (M ⁺ + H): 338.2074 Found 338.2078

Example 2 Preparation of (S) -2-amino-1- (4- (2,5-difluorobenzyl) piperazin-1-yl) propan-1-one

Using R ¹ -piperazine of Preparation Example 1 as 1- (2,5-difluorobenzyl) piperazine, it was carried out as in Preparation Example 1 to obtain a final target compound as a brown oil (16.9% ).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.53 (brs, 1H), 7.34-7.31 (m, 2H), 4.36 (brs, 2H), 4.09 (s, 3H), 3.72-3.57 (m, 6H) , 3.08-2.89 (m, 6H), 1.31-1.23 (m, 3H) HR-FABMS Calcd for C ₁₄ H ₂₀ F ₂ N ₃ O (M ⁺ + H): 284.1569 Found 284.1568

Example 3 Preparation of (S) -2-amino-1- (4- (naphthalen-2-ylmethyl) piperazin-1-yl) propan-1-one

Using R ¹ -piperazine of Preparation Example 1 as 1- (naphthalen-2-ylmethyl) piperazine and performing as in Preparation Example 1, the final target compound was obtained as a pale brown powder (16.4%). .

mp 180 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (s, 1H), 8.11 (s, 3H), 7.97 (s, 3H), 7.57 (d, J = 7.6 Hz, 4H), 3.09 (s, 4H ), 3.023-2.89 (m, 3H), 1.85 (s, 1H), 1.74-1.71 (m, 1H), 1.31 (s, 3H) HR-FABMS Calcd for C ₁₈ H ₂₄ N ₃ O (M ⁺ + H ): 298.1914 Found 298.1916

Example 4 Preparation of (S) -2-amino-1- (4- (4-methoxybenzyl) piperazin-1-yl) propan-1-one

Using R ¹ -piperazine of Preparation Example 1 as 1- (4-methoxybenzyl) piperazine, it was carried out as in Preparation Example 1 to obtain a final target compound as a brown powder (17.0%).

mp 142 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (brs, 1H), 8.08 (s, 1H), 7.24 (s, 1H), 6.94 (s, 1H), 3.75 (s, 2H), 3.17 (s , 3H), 3.15-3.02 (m, 3H), 3.02-2.99 (m, 3H), 1.83 (s, 2H), 1.75-1.71 (m, 3H), 1.29-1.15 (m, 3H)

Example 5 (2S) -2-amino-1- (4- (2,3-dihydrobenzo [b] [1,4] dioxine-2-carbonyl) piperazin-1-yl) propane Preparation of -1-one

Using R ¹ -piperazine of Preparation Example 1 as 1- (2,3-dihydrobenzo [b] [1,4] dioxine-2-carbonyl) piperazine, it was carried out as in Preparation Example 1 above. This resulted in the final desired compound as a brown powder (10.2%).

mp 204 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (brs, 2H), 6.92 (s, 1H), 6.86-6.84 (m, 4H), 5.28 (s, 1H), 4.20 (dd, J = 6.8 Hz , J = 5.6 Hz, 1H), 3.71-3.67 (m, 3H), 3.59-3.46 (m, 5H), 1.71-1.31 (m, 3H) HR-FABMS Calcd for C ₁₆ H ₂₂ N ₃ O ₄ (M ⁺ + H): 320.1605 found 320.1610

Example 6 Preparation of (S) -2-amino-1- (4- (2-phenoxyacetyl) piperazin-1-yl) propan-1-one

Using R ¹ -piperazine of Preparation Example 1 as 1- (2-phenoxyacetyl) piperazine, it was carried out as in Preparation Example 1 to obtain a final target compound as a brown powder (41.9%).

mp 191 ° C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.12 (s, 3H), 7.37 (s, 4H), 4.37 (s, 1H), 3.76 (s, 2H), 3.60-3.50 (m, 4H), 1.30 (d, J = 6.4 Hz, 3H) HR-FABMS Calcd for C ₁₅ H ₂₂ N ₃ O ₃ (M ⁺ + H): 292.1656 found 292.1660

Example 7 Preparation of (S) -2-amino-1- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) propan-1-one

Using R ¹ -piperazine of Preparation Example 1 as 1- (bis (4-fluorophenyl) methyl) piperazine, it was carried out as in Preparation Example 1 to obtain a final desired compound as a yellow oil (31.1 %).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (brs, 2H), 7.45 (s, 3H), 7.16 (s, 3H), 4.46 (brs, 1H), 4.30 (brs, 1H), 4.03 (q , J = 6.8 Hz, 1H), 3.04-2.99 (m, 5H), 1.99 (s, 1H), 1.75-1.72 (m, 1H), 0.86-0.82 (m, 3H) HR-FABMS Calcd for C ₂₀ H ₂₄ F ₂ N ₃ O (M ⁺ + H): 360.4129

Example 8 Preparation of (2S) -2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3-methylbutan-1-one

Using N-Boc-Protein-R ⁵ of Preparation Example 2 as (R) -2- (tert-butoxycarbonylamino) -3-methylbutanoic acid, the preparation was carried out as in Preparation Example 2, and the final object was The compound was obtained as a brown oil (87.5%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (s, 2H), 7.38-7.32 (m, 7H), 7.20 (brs, 2H), 4.56 (brs, 1H), 4.03 (q, J = 4.8 Hz , 4H), 3.04-2.99 (m, 7H), 1.77-1.70 (m, 5H) HR-FABMS Calcd for C ₂₂ H ₂₉ ClN ₃ O (M ++ H): 386.1994 Found: 386.1997.

Example 9 Preparation of (2S) -2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3-phenylpropan-1-one

Using N-Boc-Protein-R ⁵ of Preparation Example 2 as (R) -2- (tert-butoxycarbonylamino) -3-phenylpropanoic acid, the preparation was carried out as in Preparation Example 2, and the final object The compound was obtained as a brown oil (85.1%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.20 (s, 2H), 7.98 (s, 2H), 7.32 (d, J = 3.2 Hz, 8H), 7.21 (s, 2H), 4.58 (brs, 1H ), 4.03 (q, J = 7.2 Hz, 2H), 3.04-2.99 (m, 8H), 1.73 (p, J = 3.2 Hz, 3H) HR-FABMS Calcd for C ₂₆ H ₂₉ ClN ₃ O 434.1994 Found: 434.1991

Example 10 Preparation of (2S, 3S) -2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3-methylpentan-1-one

Using N-Boc-Protein-R ⁵ of Preparation Example 2 as (2S, 3S) -2- (tert-butoxycarbonylamino) -3-methylpentanoic acid, the preparation was carried out as in Preparation Example 2, The final desired compound was obtained as a yellow powder (80.9%).

mp 92 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (s, 2H), 7.45-7.33 (m, 6H), 7.23 (brs, 1H), 4.42 (s, 1H), 4.15 (s, 1H), 4.038 (q, J = 7.2 Hz, 1H), 3.17-2.99 (m, 3H), 1.99 (s, 1H), 1.73 (p, J = 3.2 Hz, 1H), 1.19 (s, 1H), 1.16 (t, J = 3.6, 1H), 1.07-0.97 (m, 5H) HR-FABMS Calcd for C ₂₃ H ₃₁ ClN ₃ O (M ⁺ + H): 400.2150 Found: 400.2149

Example 11 Preparation of (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) (pyrrolidin-2-yl) -methanone

Using N-Boc-Protein-R ⁵ of Preparation Example 2 as 1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid, the preparation was carried out as in Preparation Example 2, and the final target compound was changed to green. Obtained as a powder (43.8%).

mp 82 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.26 (brs, 1H), 7.45-7.23 (m, 9H), 4.51 (brs, 1H), 4.42 (s, 1H), 3.04-2.99 (3H), 2.33 -2.32 (m, 5H), 1.87-1.82 (m, 2H), 1.76-1.71 (m, 1H), 1.26 (t, J = 6.4 Hz, 1H), 1.19-1.15 (m, 1H) HR-FABMS Calcd for C ₂₂ H ₂₇ ClN ₃ O (M ⁺ + H): 384.1837 Found: 384.1883.

Example 12 Preparation of 2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4- (methylthio) butan-1-one

Using N-Boc-Protein-R ⁵ of Preparation Example 2 as 2- (tert-butoxycarbonylamino) -4- (methylthio) butanoic acid, the preparation was carried out as in Preparation Example 2, and the final object The compound was obtained as a yellow powder (43.2%).

mp 73 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (brs, 2H), 7.47-7.39 (m, 4H), 7.37-7.22 (m, 3H), 4.43 (s, 1H), 3.57-3.46 (m, 3H), 3.02-2.99 (m, 6H), 1.75-1.71 (m, 3H), 1.11 (d, J = 2 Hz, 4H) HR-FABMS Calcd for C ₂₂ H ₂₉ ClN ₃ OS (M ⁺ + H): 418.1714 Found: 418.1718.

Example 13 Preparation of (2R) -2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3,3-dimethylbutan-1-one

Using N-Boc-Protein-R ⁵ of Preparation Example 2 as (R) -2- (tert-butoxycarbonylamino) -3,3-dimethylbutanoic acid, the preparation was carried out as in Preparation Example 2, The final desired compound was obtained as a yellow powder (86.2%).

mp 183 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 13.34 (brs, 1H), 8.49 (s, 2H), 7.86 (s, 3H), 7.52-7.36 (m, 4H), 5.18 (brs, 1H), 4.54 (brs , 2H), 4.11 (brs, 1H), 4.10 (brs, 1H), 3.91 (brs, 1H), 3.41 (s, 1H), 3.65-3.47 (m, 3H), 3.44 (s, 1H), 3.22- 3.18 (m, 2H), 1.92-1.83 (m, 9H) HR-FABMS Calcd for C ₂₃ H ₃₁ ClN ₃ O (M ⁺ + H): 400.2150 Found: 400.2159.

Example 14 Preparation of (2R) -2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4-methylpentan-1-one

Using N-Boc-Protein-R ⁵ of Preparation Example 2 as (S) -2- (tert-butoxycarbonylamino) -4-methylbutenoic acid, the preparation was carried out as in Preparation Example 2, and the final object The compound was obtained as a yellow powder (46.3%).

mp 183 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.26 (brs, 2H), 7.90-7.86 (m, 3H), 7.52-7.44 (m, 4H), 3.22 (d, J = 3.6 Hz, 3H), 1.87-1.71 (m, 8H), 0.97-0.90 ( m, 9H) HR-FABMS Calcd for C 18 H 17 ClN 3 O (M + + H): 400.215 Found: 400.2151.

Example 15 2-Amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3- (1H-indol-3-yl) propan-1-one Manufacture

N-Boc-Protein-R ⁵ of Preparation Example 2 was used as 2- (tert-butoxycarbonylamino) -3- (1H-indol-3-yl) propanoic acid, and the preparation was carried out as in Preparation Example 2. The final desired compound was obtained as a light brown powder (88.0%).

mp 202 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 8.17 (s, 3H), 7.82 (brs, 1H), 7.45-7.22 (m, 8H), 6.99 (s, 2H), 4.50 (brs, 1H), 3.96 (brs, 1H), 3.73-3.65 (m, 3H), 3.12-3.04 (m, 3H), 3.03-2.99 (m, 5H) HR-FABMS Calcd for C ₂₇ H ₃₀ ClN ₅ O (M ⁺ + NH ₄ ): 475.2133 Found: 475.2146.

Example 16 Preparation of 2-Amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3- (4-hydroxyphenyl) propan-1-one

Using N-Boc-Protein-R ⁵ of Preparation Example 2 as 2- (tert-butoxycarbonylamino) -3- (4-hydroxyphenyl) propanoic acid, it was carried out as in Preparation Example 2, The final desired compound was obtained as a yellow powder (51.2%).

mp 198 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 8.09 (brs, 2H), 7.40-7.36 (m, 5H), 7.32-7.22 (m, 3H), 6.98 (d, J = 4.4 Hz, 2H), 6.72 (d, J = 4.4 Hz, 2H), 4.47 (brs, 1H), 4.21 (s, 1H), 3.57-3.38 (m, 4H), 3.04-2.89 (m, 5H) HR -FABMS Calcd for C ₂₆ H ₂₉ ClN ₃ O ₂ (M ⁺ + H): 450.1943 Found: 450.1944.

Example 17 Preparation of 4- (4-bromophenyl) 1-1 (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one

Using R ² -COOH of Preparation Example 3 as 4- (4-bromophenyl) butanoic acid, the preparation was carried out as in Preparation Example 3 to obtain the final target compound as a yellow oil (11.4%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.45-7.43 (m, 3H), 7.41-7.37 (m, 2H), 7.35-7.29 (m, 4H), 7.21 (d, J = 7.2 Hz, 1H) , 7.15 (s, 1H), 7.13 (s, 1H), 4.85 (d, J = 5.2Hz, 1H), 4.62 (s, 1H), 4.36 (s, 1H), 4.10-4.01 (m, 2H), 3.91-3.87 (m, 1H), 1.91-1.23 (m, 2H), 1.15 (s, 2H) HR-FABMS Calcd for C 27 H 29 BrClN 2O (M + + H): 511.1146 Found: 511.1140.

Example 18 Preparation of 1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4-p-tolylbutan-1-one

Using R ² -COOH of Preparation Example 3 as 4-p-tolylbutanoic acid, the preparation was carried out as in Preparation Example 3, whereby a final desired compound was obtained as a reddish brown oil (11.3%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.49-7.29 (m, 8H), 7.21 (t, J = 7.2 Hz, 1H), 7.05 (q, J = 8 Hz, 4H), 4.36 (s, 1H) , 3.45-3.41 (m, 4H), 3.04-2.99 (m, 5H), 1.76-1.70 (m, 6H), 1.24-1.15 (m, 2H), HR-FABMS Calcd for C ₂₈ H ₃₂ ClN ₂ O ( M ⁺ + H): 447.2198 Found: 447.2201

Example 19 Preparation of 1- (4-chlorophenyl) -4- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butane-1,4-dione

Using R ² -COOH of Preparation Example 3 as 4- (4-chlorophenyl) -4-oxobutanoic acid, the preparation was carried out in the same manner as in Preparation Example 3, whereby the final desired compound was obtained as a yellow powder (13.1%). .

mp 176 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (dd, J = 1.6 Hz, J = 4.8 Hz, 2H), 7.61-7.58 (m, 3H), 7.58-7.43 (m, 8H), 3.35-3.17 (m, 4H), 3.04-2.99 (m, 3H), 2.67 (dd, J = 1.6 Hz, J = 2 Hz, 2H), 1.75-1.71 (m, 2H), 1.26-1.23 (m, 2H) HR- FABMS Calcd for C ₂₇ H ₂₇ Cl ₂ N ₂ O ₂ (M ⁺ + H): 481.1444 Found: 481.1446

Example 20 Preparation of 1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -2-methyl-4-phenylbutane-1,4-dione

Using R ² -COOH of Preparation Example 3 as 4- (4-chlorophenyl) -2-methyl-4-oxobutanoic acid, the preparation was carried out in the same manner as in Preparation Example 3 to obtain the final target compound as a yellow powder. (13.6%).

mp 156 ° C .; ¹ H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 7.2 Hz, 2H), 7.63 (t, J = 7.2 Hz, 4H), 7.57 (s, 2H), 7.53-7.41 (m, 6H) , 3.03-2.99 (m, 5H), 1.74-1.71 (m, 3H), 1.27-1.23 (m, 3H), 1.15-1.05 (m, 4H) HR-FABMS Calcd for C ₂₈ H ₃₀ ClN ₂ O ₂ ( M ⁺ + H): 461.1990 Found: 461.1992

Example 21 Preparation of 1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4- (4-methoxyphenyl) butan-1-one

Using R ² -COOH of Preparation Example 3 as 4- (4-methoxyphenyl) butanoic acid, the preparation was carried out in the same manner as in Preparation Example 3 to obtain the final target compound as a yellow oil (11.5%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (s, 3H), 7.42 (brs, 6H), 7.12-7.08 (m, 2H), 6.84-6.80 (m, 2H), 3.76-3.75 (m, 3H), 3.23-3.19 (m, 3H), 2.56 (t, J = 7.6 Hz, 3H), 2.36 (t, J = 6.4 Hz, 3H), 1.88-1.82 (m, 6H) HR-FABMS Calcd for C ₂₈ H ₃₂ ClN ₂ O ₂ (M ⁺ + H): 463.2147 Found: 463.2149

The chemical structure of the compound prepared in Example 1-21 is shown in Table 1 below.

Example constitutional formula Example constitutional formula One

12

2

13

3

14

4

15

5

16

6

17

7

18

8

19

9

20

10

21

11

Experimental Example 1 Evaluation of Sodium Channel Inhibition Effect

In order to evaluate the inhibitory effect on the sodium channel of the compound according to the present invention, the following voltage / ion probe reader (VIPR) assay was performed.

In vitro experiments were sent to SB Drug Discovery Company (Glasgow, UK) for VIPR assay of the synthetic material of this experiment.

Specifically, HEK cells expressing hNav1.5, hNav1.7, and hNav1.8 ion channels were planted in poly-D-lysine-coated black-walled, white-bottomed 96 well biocoated plates prior to analysis. Incubated for 24 hours in 100 μL culture. The next day, membrane potential staining was performed according to the manufacturer's instructions. That is, the contents of one bottle of the dye was dissolved in 10 ml of Hepes-HBSS buffer (pH7.4) or a large bottle of the dye (component A) dye buffer in 100 ml of buffer. Hepes-HBSS and dye solution were preheated to 37 ° C. in advance, 90 μl dye was added to the wells (190 μl total) and incubated at 37 ° C. for 60 minutes. Standard inhibitors (TTX) were tested with each assay. 10 μl of compound was added 10 minutes before the plate was read. Flexstation was set to add 50 μl of channel activator and veratridine and fluorescence was read at 530 nm excitation and 565 nm emission. Each well was read at 1.52 second intervals for 120 seconds, and the degree of sodium channel inhibition of each compound is shown in Table 2 as a percentage (% ingibition).

Example Nav1.7
10 uM
% inhibition Nav1.8
10 uM
% inhibition Nav1.5
10 uM
% inhibition One 63.4 2 28.4 NI 3 51.6 1.48 4 25.7 1.50 5 5.42 6 21.7 7 52.7 8 39.2 17.9 9 54.2 14.7 10 95.9 18.6 11 77.4 12 100 13 79.2 14 59.2 15 90.1 16 56.7 17 68.6 18 62.8 19 32.3 NI 20 48.2 NI 21 48.2 NI

Looking at Table 2, the example compound according to the present invention was found to be excellent Nav 1.7 channel inhibitory activity. In particular, the compounds of Examples 10, 12, and 15 were found to have a Nav 1.7 channel inhibitory activity of 80% or more, indicating a very good inhibitory activity.

In addition, in terms of sodium channel selectivity of the compound of the present invention, it was confirmed that the inhibitory activity against Nav 1.7 is significantly higher than that of Nav 1.5 or Nav 1.8, and the compound of the present invention exhibits selective inhibitory activity against Nav 1.7 channel. Confirmed.

Accordingly, the compound according to the present invention has excellent sodium channel inhibitory activity, and may be usefully used for sodium channel-related diseases as a pharmaceutical composition or a health food composition containing the same as an active ingredient, and in particular, a selection for Nav 1.7 channel. As a result of its inhibitory activity, Nav 1.7 can be particularly useful for the treatment of pathological pain such as dermatitis, paroxysmal pain and erythema pain, which are related to 1.7 channel.

Experimental Example 2 Analyzing Analgesic Effect

In order to evaluate the specific pain inhibitory activity (analgesic effect) of the compound according to the present invention, the in vivo experiment was carried out as follows.

The in vivo experiment was conducted in the biochemistry laboratory of Professor Yoon Tae-young of Kyung Hee University School of Medicine, and behavioral test was conducted to confirm the inhibitory effect of the central neuropathic pain of the compound on spinal cord-induced central neuropathic pain rat (animal model). It was.

<2-1> Preparation of Central Neuropathic Pain Animal Model

Chloral hydrate (500 mg / kg) was intraperitoneally injected into rats, followed by anesthesia, and the spinal cord T8-T10 was exposed. The spinal cord injury animal model was given a trauma similar to human spinal cord injury by dropping a 10 g weight from a certain height and using a NYU impactor designed to quantify the trauma intensity on a computer. Specifically, the rat was fixed to the clamp of the NYU impactor, and the weight of the spinal cord T9 was damaged by freely dropping the weight of 10g at 25mm height. The wound site was closed after confirming that a certain damage was applied within a predetermined error range through data on the damage intensity displayed on the computer. Wounds were disinfected with povidone solution and bred in cages (cages) two times, and artificially massaged bladder three times a day to help with urination.

<2-2> Evaluation of central neuropathic pain inhibitory effect

Behavioral response tests were conducted to determine the central neuropathic pain inhibitory effects of the compounds of Examples 14, 15, and 21 on spinal cord injury neurons.

Specifically, the BBB locomoter test and pain response induced after injury were observed until 28 days after spinal cord injury. Rats were placed under a transparent plastic box (10 cm × 10 cm) on a wire mesh (3 mm × 3 mm) to acclimate for 20 minutes and von-Frey filaments were applied to both paws of the rat. Tactile (mechanical) sensitivity increases to a logarithmic series of stiff nylon bone-prey single filaments (Stoelting, WoodDale, IL, USA sizes: 0.4 g (3.61 mN), 0.6 g (3.84 mN), 1.0 g (4.08 mN), 2.0 g (4.31 mN), 4.0 g (4.56 mN), 6.0 g (4.74 mN), 8.0 g (4.93 mN) and 15.0 g (5.18 mN)) were used to assess the avoidance response of the foot with increasing mechanical stimulation. Bonfre filaments were applied to each foot for 3-4 seconds to bend completely, and stimulation was performed at 2 second intervals. The 50% threshold was determined using the up-down method (Chaplan et al. 1994). The experiments began with the identification of the most sensitive sites at several sites using 0.4-15 g of 8 bone filaments sequentially. When the avoidance reaction of the foot did not appear, the experiment was repeated with the filament of the next thickness, and when there was a reaction, the experiment was performed by applying a weaker filament, and the results are shown in FIGS. 1, 2, and 3, respectively.

Figure 1 shows the quantified pain sensitivity of rats in Example 14 compound at a dose of 60 mg / kg.

Figure 2 shows the numerical value of the pain sensitivity of rats appearing in Example 15 compound dosed 2 mg / kg, or 6 mg / kg.

Figure 3 is a numerical representation of the pain sensitivity of rats appearing in Example 21 compound at a dose of 60 mg / kg.

Looking at Figure 1-3, Examples 14, 15, 21 compounds of the present invention are all confirmed a rapid and significant analgesic inhibitory effect compared to the control Gabapentin.

Of these, in particular, the fastest analgesic effects were seen in Examples 15 and 21, and the most potent analgesic effects were seen in Examples 14 and 15 at 60-90 minutes later. As a whole, it was confirmed in Example 15 that the long-lasting and excellent analgesic effect appeared.

In addition, it was confirmed that Example 15 showed the best effect even at the smallest dose.

Therefore, the compound according to the present invention is excellent in neuropathic pain inhibitory activity, it can be usefully used as a pharmaceutical composition for the prevention and treatment of neuropathic pain containing it.

Claims (11)

A compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

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delete delete delete The method of claim 1,
The compound represented by Formula 1 is any one selected from the following compound group, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
(8) (2S) -2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3-methylbutan-1-one;
(9) (2S) -2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3-phenylpropan-1-one;
(10) (2S, 3S) -2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3-methylpentan-1-one;
(13) (2R) -2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3,3-dimethylbutan-1-one;
(14) (2S) -2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4-methylpentan-1-one;
(15) 2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3- (1H-indol-3-yl) propan-1-one;
(16) 2-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -3- (4-hydroxyphenyl) propan-1-one;
(17) 4- (4-bromophenyl) 1-1 (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one;
(18) 1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4-p-tolylbutan-1-one;
(19) 1- (4-chlorophenyl) -4- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butane-1,4-dione;
(20) 1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -2-methyl-4-phenylbutan-1,4-dione; And
(21) 1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4- (4-methoxyphenyl) butan-1-one.
delete (1) (S) -2-amino-1- (4- (2,3,4-trimethoxybenzyl) piperazin-1-yl) propan-1-one;
(3) (S) -2-amino-1- (4- (naphthalen-2-ylmethyl) piperazin-1-yl) propan-1-one;
(7) (S) -2-amino-1- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) propan-1-one; or
A compound represented by Formula 1;
Or neuropathic pain, spontaneous provoked pain, paroxysmal extreme pain disorder, or red limb pain, containing stereoisomers thereof or pharmaceutically acceptable salts thereof as an active ingredient. erythromelalgia), or a pharmaceutical composition for the prevention or treatment of erythema pain disease:
[Formula 1]

(In Formula 1,
R ¹ is

or

ego; And

R ² is

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The method of claim 7, wherein
The disease is characterized in that the disease being prevented or treated from sodium channel 1.7 (Nav 1.7) inhibitory activity, pharmaceutical composition.
delete (1) (S) -2-amino-1- (4- (2,3,4-trimethoxybenzyl) piperazin-1-yl) propan-1-one;
(3) (S) -2-amino-1- (4- (naphthalen-2-ylmethyl) piperazin-1-yl) propan-1-one;
(7) (S) -2-amino-1- (4- (bis (4-fluorophenyl) methyl) piperazin-1-yl) propan-1-one; or
A compound represented by Formula 1;
Or neuropathic pain, spontaneous provoked pain, paroxysmal extreme pain disorder, or red limb pain, containing stereoisomers thereof or pharmaceutically acceptable salts thereof as an active ingredient. erythromelalgia), or nutraceutical composition for the prevention or improvement of erythema pain disease:
[Formula 1]

(In Formula 1,
R ¹ is

or

ego; And

R ² is

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delete

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