KR20090028239A - Novel compounds, process for preparing the same, and composition comprising the same for inhibiting pain - Google Patents

Abstract

A compound is provided to suppress effectively chronic neuropathic pain and inflammatory pain by suppressing T-type calcium channel activity. A compound is indicated as a chemical formula 1. In the chemical formula 1: R1 is hydrogen; cycloalkyl of CH2-C3~C10; benzyl substituted or non-substituted to one or more radicals selected from a group consisting of linear or branched alkyl of C1~C10, alkoxy of C1~C4, halogen, nitro and N(CH3)2. In the chemical formula 1: R2 is NR5R6; R3 and R4 are aryl of C6~C20 or aryl of C6~C20 substituted to halogen; R5 and R6 are hydrogen, p- tolyloxy or C6~C20 of aryl; n is integer of 1 to 5.

Description

Novel compounds, process for preparing the same, and composition comprising the same for inhibiting pain}

The present invention relates to a novel compound, a method for preparing the same, and a composition for inhibiting pain, including the same.

Pain is defined as a sensory and emotional unpleasant experience that is or is expressed in connection with a substantial or potential tissue injury. Pain is a major symptom in various diseases, but its perception is very subjective and is one of the most difficult pathologies to effectively diagnose and treat. Pain leads to severe impairment of functional capacity and endangers the patient's work, social and family life.

Pain is largely classified into acute pain and chronic pain, and chronic pain includes neuropathic pain.

Acute pain is usually caused by inflammation or soft tissue damage, and its neuronal mechanism is well known and can be treated with general analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opiate preparations.

Chronic neuropathic pain is caused by damage to the peripheral sensory nerves, the pain is very severe, and often relapses even with conventional painkillers, including opiate agents, effective treatment is difficult.

In addition to peripheral nerve trauma, neuropathic pain can be caused by herpes virus infection, diabetes, burning pain, plexus avulsion, neuroma, limb amputation, vasculitis, chronic alcoholism, human immunodeficiency virus infection, thyroid function This can include nerve damage caused by hypothyroidism, uremia or vitamin deficiency.

Neuropathic pain is largely classified into three types: hyperalgesia, allodynia, and spontaneous pain. The cause of excessive pain above normal levels is called "pain pain", and the case of pain caused by being sensitive to a weak stimulus that is normally not able to cause pain is called "allodynia". Pain even when absent is called "voluntary pain". For example, allodynia may be painful even by a weak mechanical stimulus (mechanical allodynia), or pain in a range of temperature changes that are normally unpleasant (cooling / warming allodynia).

Painkillers currently in use are divided into two types. The first is a group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs) and related COX-2 inhibitors, and the second is an opiate such as morphine. These analgesics are effective in suppressing the usual response but have little effect on some types, such as neuropathic pain. However, administration of opiate in high doses can provide some analgesic effects, but there is a possibility of serious side effects or poisoning due to increased dose. NSAIDs, which have lower analgesic effects than opiate agents, may not only benefit from higher doses but also cause gastrointestinal side effects specific to NSAIDs.

Therefore, there is an urgent need to study new compounds or their use which can suppress neuropathic pain by a mechanism different from the known analgesics.

A representative example of the target material of such a study is an ion channel blocker. In particular, the potential-gated calcium channel regulates the excitability of the pain sensory nerves in the dorsal horn of the spinal cord and is known to be deeply involved in the development and persistence of neuropathic pain. N-type and T-type are well known. Gabapentin and pregabalin, which are currently used as a treatment for neuropathic pain, are also known to be of this class. Sodium channel blockers such as carbamazepine also exhibit analgesic effects by blocking the initiation and propagation of action potentials of neurons.

Thus, the inventors of the present invention while studying a compound capable of inhibiting pain by blocking the calcium channel, a compound that effectively inhibits T-type calcium channel activity was prepared, the compound is used for chronic neuropathic pain and inflammatory pain It was confirmed that the inhibitory effect is excellent and completed the present invention.

The present invention is to provide a compound having an excellent inhibitory effect on pain by blocking the calcium channel, a preparation method thereof and a composition for inhibiting pain comprising the same.

The present invention provides a compound represented by the following formula (1).

In Chemical Formula 1,

R ₁ is hydrogen; C ₁ -C ₁₀ straight or branched alkyl; Cycloalkyl of CH ₂ -C ₃ -C ₁₀ ; Or benzyl unsubstituted or substituted with one or more groups selected from the group consisting of C ₁ to C ₁₀ straight or branched alkyl, C ₁ to C ₄ alkoxy, halogen, nitro and N (CH ₃ ) ₂ ,

또는 NR₅R₆ 이고,R ₂ is

Or NR ₅ R ₆ ,

R ₃ and R ₄ are each independently an aryl group of C ₆ ~ C ₂₀ aryl substituted by halogen or C ₆ ~ C ₂₀ of,

R ₅ and R ₆ are each independently hydrogen; C ₆ -C ₂₀ aryl substituted with one or more groups selected from p-tolyloxy or C ₁ -C ₄ alkyl; Or CH (C ₆ -C ₂₀ aryl) (C ₆ -C ₂₀ aryl substituted with halogen),

n is an integer of 1-5.

Preferably, in Formula 1

R ₁ is hydrogen; ethyl; Isobutyl; 2-ethylbutyl; CH ₂ -cyclohexyl; Or benzyl unsubstituted or substituted with one or more groups selected from the group consisting of isopropyl, methoxy, Cl, nitro and N (CH ₃ ) ₂ ,

또는 NR₅R₆ 이고,R ₂ is

Or NR ₅ R ₆ ,

R ₃ and R ₄ are each independently phenyl or 4-chlorophenyl,

R ₅ and R ₆ are each independently hydrogen, (p-tolyloxy) -phenyl, CH (phenyl) (4-chlorophenyl), or 2,6-dimethylphenyl,

n is an integer of 3.

Preferred compounds of the compound of formula 1 of the present invention are specifically as follows:

1) 4-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one,

2) 4-amino-N- (4-p-tolyloxy) phenyl) butanamide,

3) 4-amino-N-((4-chlorophenyl) (phenyl) methyl) butanamide,

4) 4-amino-N- (2,6-dimethylphenyl) butanamide,

5) 1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4- (ethylamino) butan-1-one,

6) 1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4- (cyclohexylmethylamino) butan-1-one,

7) 4- (4- (dimethylamino) benzylamino) -1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one,

8) 1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4- (isobutylamino) butan-1-one,

9) 4- (2-ethylbutylamino) -1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one,

10) 4- (benzylamino) -1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one,

11) 4- (4-methoxybenzylamino) -1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one,

12) 4- (4-nitrobenzylamino) -1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one,

13) 4- (4-isopropylbenzylamino) -1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one, and

14) 4- (2,6-dichlorobenzylamino) -1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one.

The compound of formula 1 of the present invention may be prepared and used in the form of pharmaceutically acceptable salts, solvates and hydrates according to methods conventional in the art. Pharmaceutically acceptable salts are acid addition salts formed by free acid. The inorganic acid and organic acid may be used as the free acid, and hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, and trifluoric acid may be used as the organic acid. Roacetic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholine ethanesulfonic acid, camphorsulfonic acid, 4-nitrobenzenesulfonic acid, hydroxy-O-sulfonic acid, 4-toluenesulfonic acid, cal Luteuronic acid, emboic acid, glutamic acid, aspartic acid and the like can be used.

In addition, the present invention

1) preparing a compound represented by the following Chemical Formula 4 by condensing the amine compound represented by the following Chemical Formula 2 with the compound represented by the following Chemical Formula 3;

2) preparing a compound represented by the following Chemical Formula 5 by deprotecting the compound represented by the following Chemical Formula 4 prepared in step 1) with HCl-dioxane and chloroform; And

3) providing a method of preparing a compound represented by Chemical Formula 1 by reducing amination reaction of the compound represented by Chemical Formula 5 prepared in step 2) with an aldehyde compound represented by Chemical Formula 6; It is represented by Scheme 1.

In Reaction Scheme 1, R ₁ , R ₂ and n are as defined in Formula 1.

Referring to the manufacturing method of the present invention in detail step by step as follows.

The amine compound represented by the formula (2) used in the preparation method is preferably a benzylamine derivative or aniline derivative, and the benzylamine derivative is 1-((4-chlorophenyl) (phenyl) methyl) piperazine or (4-chlorophenyl) (Phenyl) methanamine and the like, and aniline derivatives include 4- (p-tolyloxy) benzeneamine or 2,6-dimethylaniline.

The compound of Formula 3 is preferably an amino acid in which nitrogen is protected by t-butyloxycarbonyl (BOC) group.

The aldehyde compound of Formula 6 is acetaldehyde, cyclohexane carboxaldehyde, 4- (dimethylamino) benzaldehyde, isobutyraldehyde, 2-ethylbutyraldehyde, benzaldehyde, 4-methoxybenzaldehyde, 4-nitrobenzaldehyde, 4- Preference is given to isopropylbenzaldehyde or 2,6-dichlorobenzaldehyde.

In step 1), the condensation reaction conditions may be carried out under conventional peptide binding reaction conditions well known in the art. Reaction solvents used in the reaction include ethyl ether, ethyl hydrochloride (THF), dichloromethane, chloroform, dimethyl sulfonyloxide (DMSO), dimethylformamide (DMF), and the like. Coupling of peptide binding reactions known to those skilled in the art in the presence or absence of a base such as TEA (triethylamine), DIEA (N, N-diisopropylethylamine) or NMM (N-methyl morpholine) to promote the reaction. agent) can be used as a catalyst. Examples of the coupling agent include DIC (diisopropyl carbodiimide), EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide), TBTU (2- (1-H-benzotriazole-1-yl) -1,1,3,3 -tetramethyluromium tetrafluoro borate), DCC (dicyclohexyl carbodiimide), HATU (dimethylamino-([1,2,3] triazolo [4,5-b] pyridin-3-yloxy) -methylene) -dimethyl-ammonium hexafluorophosphate), PyBOP ( benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate). In the present invention, it is preferable to use PyBOP as a reaction catalyst in the presence of DIEA.

Step 2) is a step of deprotecting the t-butyloxycarbonyl (BOC) group protected in nitrogen by reacting the compound represented by the formula (4) with HCl-dioxane and chloroform.

Step 3) is a reductive amination reaction, which may be performed in an inert solvent in the presence of a reducing agent. The reducing agent used above is not particularly limited, but may be selected from sodium borohydride (NaBH ₄ ), sodium cyanoborohydride (NaBH ₃ CN), and sodium triacetoxyborohydride (NaBH (OAc) ₃ ). Preferably, sodium triacetoxyborohydride is most preferred.

The present invention also provides a composition for inhibiting pain, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The compound of the present invention is excellent in inhibiting T-type calcium channel activity, and excellent in inhibiting chronic neuropathic pain and inflammatory pain, and thus can be usefully used for pain suppression.

The composition of the present invention may contain at least one known active ingredient having a pain inhibitory effect together with the compound of Formula 1.

The composition of the present invention may be prepared by including one or more pharmaceutically acceptable carriers in addition to the above-described active ingredients for administration. Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components, as necessary. And other conventional additives such as bacteriostatic agents can be added. Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Furthermore, it may be preferably formulated according to each disease or component by an appropriate method in the art or using a method disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA.

The composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the weight, age, sex and health of the patient. The range varies depending on the diet, the time of administration, the method of administration, the rate of excretion and the severity of the disease. The daily dosage of the compound of Formula 1 is about 5 to 250 mg / kg, preferably about 8 to 60 mg / kg, and more preferably administered once to several times a day.

The composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug therapy and biological response modifiers for pain inhibition.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

A. t- Butyl  Substituted Carbamate  Produce

Production Example  One  t-butyl 4- (4-((4- Chlorophenyl ) ( Phenyl ) methyl Piperazin-1-yl) -4- Oxo Preparation of Butyl Carbamate

2.46 mmol of 4- (Boc-amino) butanoic acid, 2.71 mmol of 1-((4-chlorophenyl) (phenyl) methyl) piperazine, 2.71 mmol of benzotriazole-1 in 20 mL of dimethylformamide (DMF) -Iloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) was added and dissolved, and 4.92 mmol of N, N-diisopropylethylamine (DIEA) was added thereto and stirred at room temperature for 16 hours. 20 mL of 10% HCl was added to the reaction solution, and extracted with 30 mL of ethyl acetate (EtOAc). The organic layer was washed with 20 mL of 10% HCl, washed twice with 20 mL of saturated NaHCO ₃ solution, and twice with 20 mL of saturated NaCl solution. The organic layer was collected, dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the organic solvent of the filtrate was removed under reduced pressure to obtain a target compound (yield: 80%).

¹ H NMR (Acd ₆ ) δ 7.42-7.5 (m, 4H), 7.25-7.32 (m, 4H), 7.2-7.22 (m, 1H), 6.0 (brs, 1H), 4.4 (s, 1H), 3.5 -3.6 (m, 4H), 3.1 (q, J = 6.4 Hz, 2H), 2.3-2.4 (m, 6H), 1.7-1.8 (m, 2H), 1.4 (s, 9H)

Production Example  2  t-butyl 3- (4- (p- Tolyloxy ) Phenylcarbamoyl ) Profile of carbamate  Produce

Except for using 4- (p-tolyloxy) benzeneamine instead of 1-((4-chlorophenyl) (phenyl) methyl) piperazine in Preparation Example 1 in the same manner as in Preparation Example 1 Was obtained (yield: 42%).

¹ H NMR (Acd ₆ ) δ 9.4 (brs, 1H), 7.7 (d, J = 9.2 Hz, 2H), 7.2 (d, J = 9.2 Hz, 2H), 6.9 (d, J = 9.2 Hz, 2H) , 6.85 (d, J = 9.2 Hz, 2H), 6.0 (brs, 1H), 3.15 (q, J = 6.4 Hz, 2H), 2.4 (t, J = 7.2 Hz, 2H), 2.3 (s, 3H) , 1.8-1.84 (m, 2H), 1.4 (s, 9H)

Production Example  3  t-butyl 3-((4- Chlorophenyl ) ( Phenyl ) methyl ) Cabamo ) Profile carbamate Manufacture

In the same manner as in Preparation Example 1, except that (4-chlorophenyl) (phenyl) methanamine was used instead of 1-((4-chlorophenyl) (phenyl) methyl) piperazine in Preparation Example 1 The target compound was obtained (yield: 51%).

¹ H NMR (Acd ₆ ) δ 8.0 (brs, 1H), 7.24-7.38 (m, 9H), 6.24 (d, J = 8.4 Hz, 1H), 6.0 (brs, 1H), 3.1 (q, J = 6.4 Hz, 2H), 2.32 (t, J = 7.4 Hz, 2H), 1.74-1.82 (m, 2H), 1.4 (s, 9H)

Production Example  4  t-butyl 3- (2,6- Dimethylphenylcarbamoyl ) Profile of carbamate  Produce

A target compound was obtained in the same manner as in Preparation Example 1, except that 2,6-dimethylaniline was used instead of 1-((4-chlorophenyl) (phenyl) methyl) piperazine in Preparation Example 1 (yield) : 72%).

¹ H NMR (Acd ₆ ) δ 8.5 (brs, 1H), 7.0 (s, 3H), 6.0 (brs, 1H), 3.2 (q, J = 6.6 Hz, 2H), 2.4 (t, J = 7.2 Hz, 2H), 2.2 (s, 6H), 1.8-1.85 (m, 2H), 1.4 (s, 9H)

B. 4-amino-N-substituted Butanamide  Produce

Production Example  5  4-amino-1- (4-((4- Chlorophenyl ) ( Phenyl ) methyl Preparation of Piperazin-1-yl) butan-1-one

0.76 mmol of chloroform (5 mL) of t-butyl 4- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4-oxobutylcarbamate prepared in Preparation Example 1 above And 4 M HCl-dioxane (5 mL) and then stirred for 3 hours. The solvent was removed under reduced pressure to give the target compound (yield: 100%).

¹ H NMR (D ₂ O) δ 7.56-7.62 (m, 4H), 7.4-7.54 (m, 5H), 3.72-3.8 (m, 5H), 2.7-3.16 (m, 6H), 2.58 (t, J = 7.4 Hz, 2H), 1.9-2.0 (m, 2H);

HR-FABMS Calcd for C ₂₁ H ₂₇ ON ₃ Cl: (M ⁺ +1): 372.1843, Found: 372.1838

Production Example  6  : 4-amino-N- (4-p- Tolyloxy ) Phenyl ) Butanamide  Produce

T-butyl prepared in Preparation Example 2 instead of t-butyl 4- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4-oxobutylcarbamate in Preparation Example 5 A target compound was obtained in the same manner as in Production Example 5 except that 3- (4- (p-tolyloxy) phenylcarbamoyl) propylcarbamate was used (yield: 91%).

¹ H NMR (DMSO-d ₆ ) δ 7.7 (brs, 3H), 7.55 (d, J = 9.2 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.9 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 2.84 (t, J = 7.8 Hz, 2H), 2.4 (t, J = 7.2 Hz, 2H), 2.28 (s, 3H), 1.8-1.88 ( m, 2H)

Production Example  7  : 4-amino-N-((4- Chlorophenyl ) ( Phenyl ) methyl ) Butanamide  Produce

T-butyl prepared in Preparation Example 3 instead of t-butyl 4- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4-oxobutylcarbamate in Preparation Example 5 A target compound was obtained in the same manner as in Production Example 5 except that 3-((4-chlorophenyl) (phenyl) methyl) carbamoyl) propylcarbamate was used (yield: 96%).

¹ H NMR (DMSO-d ₆ ) δ 7.7 (brs, 3H), 7.2-7.4 (m, 9H), 6.1 (d, J = 8.4 Hz, 1H), 2.76 (t, J = 7.8 Hz, 2H), 2.32 (t, J = 7.2 Hz, 2H), 1.74-1.82 (m, 2H)

Production Example  8  : 4-amino-N- (2,6- Dimethylphenyl ) Butanamide  Produce

T-butyl prepared in Preparation Example 4 instead of t-butyl 4- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4-oxobutylcarbamate in Preparation Example 5 A target compound was obtained in the same manner as in Production Example 5 except that 3- (2,6-dimethylphenylcarbamoyl) propylcarbamate was used (yield: 100%).

¹ H NMR (DMSO-d ₆ ) δ 7.8 (brs, 3H), 7.0 (s, 3H), 2.85 (q, J = 7.6 Hz, 2H), 2.44 (t, J = 7.2 Hz, 2H), 2.1 ( s, 6H), 1.84-1.9 (m, 2H)

C. 4-Substituted-1- (4-((4- Chlorophenyl ) ( Phenyl ) methyl Preparation of Piperazin-1-yl) butan-1-one

Example  One  : 1- (4-((4- Chlorophenyl ) ( Phenyl ) methyl Piperazin-1-yl) -4- ( Ethylamino Preparation of Butan-1-one

0.5 mmol of 4-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one and acetaldehyde prepared in Preparation Example 5 above 1,2 -Dichloroethane (9 mL), to which 0.7 mmol of sodium triacetoxyborohydride (NaBH (OAc) ₃ ) and 0.5 mmol of triethylamine were added. After reacting overnight under nitrogen at room temperature, the reaction was terminated with a saturated NaHCO ₃ solution. The reaction was extracted with ethyl acetate (EtOAc), dried over MgSO ₄ and filtered under reduced pressure. The organic solvent of the filtrate was removed under reduced pressure to obtain the target compound (yield: 79%).

¹ H NMR (CDCl ₃ ) δ 7.34-7.38 (m, 4H), 7.2-7.3 (m, 5H), 4.2 (s, 1H), 3.58-3.63 (m, 2H), 3.44-3.48 (m, 2H) , 2.65 (q, J = 6.8 Hz, 2H), 2.44-2.56 (m, 2H), 2.3-2.4 (m, 6H), 1.74-1.82 (m, 2H), 1.0-1.1 (m, 3H)

Example  2  : 1- (4-((4- Chlorophenyl ) ( Phenyl ) methyl Piperazin-1-yl) -4- ( Cyclohexyl Preparation of Methylamino) butan-1-one

A target compound was obtained in the same manner as in Example 1, except that cyclohexanecarboxaldehyde was used instead of acetaldehyde in Example 1 (yield: 20%).

¹ H NMR (CDCl ₃ ) δ 7.34-7.38 (m, 4H), 7.2-7.3 (m, 5H), 4.2 (s, 1H), 3.58-3.62 (m, 2H), 3.44-3.48 (m, 2H) , 2.74-2.8 (t, J = 6.8 Hz, 2H), 2.5-2.54 (d, J = 6.4 Hz, 2H), 2.42 (t, J = 7.0 Hz, 2H), 2.3-2.4 (m, 4H), 1.84-1.9 (m, 2H), 1.62-1.8 (m, 4H), 1.1-1.3 (m, 4H), 0.84-0.96 (m, 3H);

HR-FABMS Calcd for C ₂₈ H ₃₇ ON ₃ Cl: (M ⁺ +1): 468.2782, Found: 468.2778.

Example  3  4- (4- (dimethylamino) Benzylamino ) -1- (4-((4- Chlorophenyl ) ( Phenyl ) Me Preparation of Tyl) piperazin-1-yl) butan-1-one

The target compound was obtained in the same manner as in Example 1, except that 4- (dimethylamino) benzaldehyde was used instead of acetaldehyde in Example 1 (yield: 33%).

¹ H NMR (Acd ₆ ) δ 7.45-7.7 (m, 5H), 7.15-7.35 (m, 5H), 6.7-6.8 (m, 3H), 4.3 (s, 1H), 3.5-3.58 (m, 6H) , 3.0 (s, 6H), 2.88-2.9 (m, 2H), 2.38 (t, J = 7.4 Hz, 2H), 2.3-2.36 (m, 4H), 1.86-1.93 (m, 2H)

Example  4  : 1- (4-((4- Chlorophenyl ) ( Phenyl ) methyl Piperazin-1-yl) -4- ( Isobutyl Preparation of Mino) butan-1-one

Except for using isobutyraldehyde instead of acetaldehyde in Example 1, the target compound was obtained in the same manner as in Example 1 (yield: 43%).

¹ H NMR (CDCl ₃ ) δ 7.34-7.38 (m, 4H), 7.2-7.3 (m, 5H), 4.2 (s, 1H), 3.58-3.64 (m, 2H), 3.44-3.48 (m, 2H) , 2.62-2.66 (t, J = 6.8 Hz, 2H), 2.3-2.42 (m, 6H), 1.7-1.84 (m, 4H), 1.24-1.28 (t, J = 7.2 Hz, 1H), 0.88-0.92 (d, J = 6.8 Hz, 6H)

Example  5  4- (2- Ethylbutylamino ) -1- (4-((4- Chlorophenyl ) ( Phenyl ) methyl Preparation of Piperazin-1-yl) butan-1-one

A target compound was obtained in the same manner as in Example 1, except that 2-ethylbutyaldehyde was used instead of acetaldehyde in Example 1 (yield: 25%).

¹ H NMR (CDCl ₃ ) δ 7.34-7.4 (m, 4H), 7.2-7.3 (m, 5H), 4.2 (m, 1H), 3.4-3.66 (m, 6H), 2.3-2.4 (m, 6H) , 1.88-2.0 (m, 2H), 1.8-1.82 (m, 1H), 1.6-1.7 (m, 4H), 1.4-1.5 (m, 2H), 0.78-0.96 (m, 6H)

Example  6  : 4-( Benzylamino ) -1- (4-((4- Chlorophenyl ) ( Phenyl ) methyl Preparation of Piperazin-1-yl) butan-1-one

A target compound was obtained in the same manner as in Example 1, except that benzaldehyde was used instead of acetaldehyde in Example 1 (yield: 3%).

¹ H NMR (CDCl ₃ ) δ 7.2-7.4 (m, 14H), 4.2 (s, 1H), 3.9 (s, 2H), 3.56-3.62 (m, 2H), 3.42-3.46 (m, 2H), 2.8 (t, J = 6.4 Hz, 2H), 2.4 (t, J = 6.8 Hz, 2H), 2.3-2.38 (m, 4H), 1.88-1.94 (m, 2H)

Example  7  : 4- (4- Methoxybenzylamino ) -1- (4-((4- Chlorophenyl ) ( Phenyl ) methyl Preparation of Piperazin-1-yl) butan-1-one

A target compound was obtained in the same manner as in Example 1, except that 4-methoxybenzaldehyde was used instead of acetaldehyde in Example 1 (yield: 19%).

¹ H NMR (CDCl ₃ ) δ 7.2-7.38 (m, 11H), 6.84-6.9 (m, 2H), 4.2 (s, 1H), 3.9 (s, 2H), 3.8 (s, 3H), 3.55-3.6 (m, 2H), 3.4-3.5 (m, 2H), 2.8 (m, 2H), 2.3-2.5 (m, 6H), 1.9-2.0 (m, 2H)

Example  8  : 4- (4- Nitrobenzylamino ) -1- (4-((4- Chlorophenyl ) ( Phenyl ) methyl Preparation of Piperazin-1-yl) butan-1-one

A target compound was obtained in the same manner as in Example 1, except that 4-nitrobenzaldehyde was used instead of acetaldehyde in Example 1 (yield: 76%).

¹ H NMR (CDCl ₃ ) δ 8.24 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.5 (d, J = 8.4 Hz, 1H), 7.2-7.4 (m, 9H), 4.2 (s, 1H), 3.9 (s, 2H), 3.6-3.65 (m, 2H), 3.4-3.5 (m, 2H), 2.6 (t , J = 6.8 Hz, 2H) 2.3-2.4 (m, 6H), 1.8-1.88 (m, 2H)

Example  9  : 4- (4- Isopropylbenzylamino ) -1- (4-((4- Chlorophenyl ) ( Phenyl ) methyl Preparation of Piperazin-1-yl) butan-1-one

A target compound was obtained in the same manner as in Example 1, except that 4-isopropylbenzaldehyde was used instead of acetaldehyde in Example 1 (yield: 7%).

¹ H NMR (CDCl ₃ ) δ 7.6 (d, J = 8.0 Hz, 1H), 7.2-7.4 (m, 11H), 7.18 (d, J = 8.0 Hz, 1H) 4.2 (d, J = 6.4 Hz, 1H ), 3.74 (s, 2H), 3.58-3.64 (m, 2H), 3.44-3.48 (m, 2H), 2.86-2.96 (m, 1H), 2.68 (t, J = 6.8 Hz, 2H), 2.3- 2.4 (m, 6H), 1.98-2.04 (m, 2H), 1.2-1.3 (m, 6H)

Example  10  4- (2,6- Dichlorobenzylamino ) -1- (4-((4- Chlorophenyl ) ( Phenyl ) methyl Preparation of Piperazin-1-yl) butan-1-one

A target compound was obtained in the same manner as in Example 1, except that 2,6-dichlorobenzaldehyde was used instead of acetaldehyde in Example 1 (yield: 25%).

¹ H NMR (CDCl ₃ ) δ 7.2-7.38 (m, 12H), 4.2 (s, 1H), 3.74-3.78 (m, 2H), 3.58-3.64 (m, 2H), 3.44-3.5 (m, 2H) , 2.44 (t, J = 7.6 Hz, 2H), 2.3-2.4 (m, 4H), 2.04-2.12 (m, 2H), 1.8-1.84 (m, 2H)

Experimental Example  One  Of the compounds of the present invention Whole cell  Patch clamp method whole - cell patch -type calcium channel activity measurement

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 incubated at a temperature of 36.5 ° C. in a humidified incubator of 95% O ₂ /5% CO ₂ . Change the culture solution every 3 to 4 days, cells were sub-cultured every week, and only HEK293 cells expressing α _1G T-type calcium channel using G-418 (0.5 mg / ml) solution To grow. Cells used for T-type calcium channel activity assay were recorded 2-4 days after incubation on a cover slip coated with poly-L-lysine (0.5 mg / ml) at each dispense. Current measurements of T-type calcium channels at the single cell level were measured by an electrophysiological whole cell patch clamp method using an EPC-9 amplifier (HEKA, German). For the composition of T-type calcium channel activity measurement, 140 mM NaCl, 2 mM CaCl ₂ , 10 mM HEPES (pH 7.4) was used as the extracellular solution, and KCl 130 mM, HEPES 10 mM, EGTA as the intracellular solution. 11 mM, MgATP 5 mM (pH 7.4) was used. The T-type calcium channel activation protocol activated at low voltage is performed by inserting a 3-4 MΩ-resistance microglass electrode containing the intracellular solution prepared above into a single cell to enter whole-cell recording mode. The drug effect on the peak magnitude of inward current due to T-type calcium channel activity when the cell membrane potential was fixed at -100 mV and then low polarized at -30 mV (50 ms duration) every 15 seconds was measured.

The results are shown in Table 1.

compound IC ₅₀ (μM) Preparation Example 5 3.71 ± 0.67 Example 1 0.42 ± 0.04 Example 2 0.19 ± 0.01 Example 3 2.32 ± 0.04 Example 4 0.36 ± 0.01 Example 5 1.54 ± 0.16 Example 6 1.67 ± 0.13 Example 7 16.10 ± 0.41 Example 8 0.60 ± 0.08 Example 9 0.28 ± 0.03 Example 10 1.02 ± 0.16

As shown in Table 1, it can be seen that the compound according to the present invention effectively inhibits T-type calcium channel activity.

Experimental Example  2  : Chronic of Compounds of the Invention Neuropathic  Inhibitory effect of pain

In order to confirm the inhibitory effect of chronic neuropathic pain of the compound of the present invention, the following experiment was performed.

1. Chronic Neuropathic  Induction of Pain-Preparation of Tail Nerve Injury Model

Sprague-Dawley rats, 8 weeks old, are provided freely with food and water at 12 to 25 degrees Celsius with a 12-hour light-dark cycle (light starts at 7 am). Breeding by.

To induce chronic neuropathic pain, rats are anesthetized with 0.5-2% enflurane, and the inferior / superior caudal trunks distributed over the tail of the rats are subjected to S1 and S2 spinal nerves. Cut in between. The proximal portion was further cut 1 mm to prevent reconnection between the proximal and distal ends of the cut stem. In this model, the S1 spinal cord nerves that dominate the nerves in the tail region are damaged, resulting in chronic neuropathic pain.

2. Chronic Neuropathic  Measurement of pain inhibitory effect-mechanical, cooling and Whole angle Allodynia  inspection

In order to conduct chronic neuropathic pain tests (mechanical, cooling and warm allodynia tests) in the tails of experimental animals, behavioral tests were performed 1 day before surgery and 1, 7 and 14 days after surgery. In order to give mechanical, cold and warm stimuli to the tails, the experimental animals were put down in a transparent plastic tube (4.5 × 12, 5.5 × 5, 6.5 × 18 cm; diameter × length). The animals were acclimated to the experimental environment for 1 hour before behavioral testing.

After 14 days of nerve injury, which is the time when allodynia of the experimental animal model prepared in 1 reached its peak, the compounds prepared in Preparation Example 5 and Example 2 were injected into the abdominal cavity of the experimental animal by 60 mg / kg, respectively. 1, 3, 5 hours after the compound was injected, behavioral tests were performed to determine the anti-allodynia effect of the compound of the present invention. At this time, a solvent control group (vehicle) was used.

1) Mechanical Allodynia  inspection

In order to evaluate the mechanical sensitivity in the tail of the test animal, the withdrawal threshold was measured using an up-down method. Using eight different von Frey filaments (0.4, 0.6, 1.0, 2.0, 4.0, 6.0, 8.0, 15.0 g, Stoelting, Wood Dale, IL, USA) The case was evaluated as avoidance response. When the first stimulus was 2.0 g and the avoidance response appeared, the weak filament was used the next time. If no response, the stronger filament was used. 50% threshold interpolation according to Dixon method.

2) cooling and Whole angle Allodynia  inspection

In order to evaluate the sensitivity to cooling and warmth in the tail of the experimental animal, withdrawal latency was measured. After dipping the tail of the test animal in the water bath of 4 ℃ (cold) and 40 ℃ (temperature), respectively, the time until the avoidance reaction was measured. . This was performed 5 times at 5 minute intervals to calculate the average of these values. The shorter the reaction time, the more severe the cooling and warming allodynia.

The inhibitory effect of chronic neuropathic pain of the compounds of Preparation Examples 5 and 2 of the present invention is shown in FIGS. 1 and 2 (A: mechanical allodynia, B: cooling allodynia, C: warm allodynia) . In Fig. 1 and Fig. 2, the injection time of the drug is indicated by a vertical dotted line, and n value means the number of rats used in the experiment.

As shown in Figure 1 and 2, the compound of the present invention can be seen that the chronic neuropathic pain inhibitory effect is superior to the experimental group treated with the solvent control group. Compounds of the present invention showed a statistically significant analgesic effect at 1 hour post-injection for stimuli causing mechanical allodynia, cold allodynia, and warm allodynia (P <0.05).

Experimental Example  3  : Inhibitory Effect of Inflammatory Pain of Compound of the Present Invention

In order to confirm the inhibitory effect of the inflammatory pain of the compound of the present invention, the following experiments were performed using formalin, an inflammation-inducing substance.

Rats were injected subcutaneously with 50 μl of 5% formalin and the compounds prepared in Preparation Examples 5 and 60 to 60 μg / kg in one hind paw. Subcutaneous injection of only 50 μl of 5% formalin into one hind paw of the rat was used as a control. Thereafter, the rats were placed in an observation chamber (horizontal, 16 cm × 14 cm) for 60 minutes in 5 minute increments, and the rats licked or bited their feet. After injecting formalin, the results were divided into phase 1 up to 10 minutes and phase 2 up to 60 minutes from 10 minutes.

Inhibitory effect of inflammatory pain of Preparation Example 5 of the present invention and the compounds of Examples 1 to 3 are shown in FIGS. 3 to 6, respectively.

As shown in Figures 3 to 6, the compound of the present invention showed an excellent analgesic effect on inflammatory pain in the first and second stages compared to the control.

Examples of preparations for the compositions of the present invention are illustrated below.

Formulation example  One  : Preparation of Injection Solution

Injection solution containing 10 mg of the active ingredient was prepared by the following method.

1 g of Compound 1, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. The solution was bottled and sterilized by heating at 20 ° C. for 30 minutes.

The components of the injection solution are as follows.

1 g of compound of Formula 1

0.6 g sodium chloride

0.1 g of ascorbic acid

Distilled Water Determination

Formulation example  2  : Preparation of Syrup

Syrup containing the compound of Formula 1 as an active ingredient 2% (weight / volume) was prepared by the following method.

Compound 1, saccharin and sugars were dissolved in 80 g of warm water. After the solution was cooled, a solution consisting of glycerin, saccharin, spices, ethanol, sorbic acid and distilled water was prepared and mixed thereto. Water was added to this mixture to 100 ml.

The components of the syrup are as follows.

2 g of a compound of formula 1

Saccharin 0.8 g

25.4 g per

Glycerin 8.0 g

0.04 g of spices

Ethanol 4.0 g

0.4 g of sorbic acid

Distilled Water Determination

Formulation example  3  : Preparation of Tablet

A tablet containing 15 mg of the active ingredient was prepared by the following method.

250 g of compound 1 was mixed with 175.9 g lactose, 180 g potato starch, and 32 g colloidal silicic acid. 10% gelatin solution was added to the mixture, which was then ground and passed through a 14 mesh sieve. It was dried and the mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into a tablet.

The components of the tablet are as follows.

250 g of compound of Formula 1

Lactose 175.9 g

180 g potato starch

32 g of colloidal silicic acid

10% gelatin solution

Potato Starch 160 g

50 g of talc

5 g of magnesium stearate

The compound of the present invention is excellent in inhibiting T-type calcium channel activity, and excellent in inhibiting chronic neuropathic pain and inflammatory pain, and thus can be usefully used for pain suppression.

1 is a diagram showing the inhibitory effect of chronic neuropathic pain of the compound of the present invention (Production Example 5) (A: mechanical allodynia, B: cooling allodynia, C: warm allodynia).

Figure 2 is a diagram showing the inhibitory effect of chronic neuropathic pain of the compound of the present invention (Example 2) (A: mechanical allodynia, B: cooling allodynia, C: warm allodynia).

Figure 3 is a diagram showing the inhibitory effect of inflammatory pain of the compound of the present invention (Preparation Example 5).

Figure 4 is a diagram showing the inhibitory effect of inflammatory pain of the compound of the present invention (Example 1).

5 is a view showing the inhibitory effect of inflammatory pain of the compound of the present invention (Example 2).

6 is a view showing the inhibitory effect of inflammatory pain of the compound of the present invention (Example 3).

Claims (6)

Compound represented by the following formula (1): <Formula 1>

In Chemical Formula 1, R ₁ is hydrogen; C ₁ -C ₁₀ straight or branched alkyl; Cycloalkyl of CH ₂ -C ₃ -C ₁₀ ; Or benzyl unsubstituted or substituted with one or more groups selected from the group consisting of C ₁ to C ₁₀ straight or branched alkyl, C ₁ to C ₄ alkoxy, halogen, nitro and N (CH ₃ ) ₂ , R ₂ is

Or NR ₅ R ₆ , R ₃ and R ₄ are each independently an aryl group of C ₆ ~ C ₂₀ aryl substituted by halogen or C ₆ ~ C ₂₀ of, R ₅ and R ₆ are each independently hydrogen; C ₆ -C ₂₀ aryl substituted with one or more groups selected from p-tolyloxy or C ₁ -C ₄ alkyl; Or CH (C ₆ -C ₂₀ aryl) (C ₆ -C ₂₀ aryl substituted with halogen), n is an integer of 1-5. The compound of claim 1, wherein R ₁ is hydrogen; ethyl; Isobutyl; 2-ethylbutyl; CH ₂ -cyclohexyl; Or benzyl unsubstituted or substituted with one or more groups selected from the group consisting of isopropyl, methoxy, Cl, nitro and N (CH ₃ ) ₂ , R ₂ is

Or NR ₅ R ₆ , R ₃ and R ₄ are each independently phenyl or 4-chlorophenyl, R ₅ and R ₆ are each independently hydrogen, (p-tolyloxy) -phenyl, CH (phenyl) (4-chlorophenyl), or 2,6-dimethylphenyl, n is an integer of 3; The compound of claim 1, wherein the compound is 1) 4-amino-1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one, 2) 4-amino-N- (4-p-tolyloxy) phenyl) butanamide, 3) 4-amino-N-((4-chlorophenyl) (phenyl) methyl) butanamide, 4) 4-amino-N- (2,6-dimethylphenyl) butanamide, 5) 1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4- (ethylamino) butan-1-one, 6) 1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4- (cyclohexylmethylamino) butan-1-one, 7) 4- (4- (dimethylamino) benzylamino) -1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one, 8) 1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) -4- (isobutylamino) butan-1-one, 9) 4- (2-ethylbutylamino) -1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one, 10) 4- (benzylamino) -1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one, 11) 4- (4-methoxybenzylamino) -1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one, 12) 4- (4-nitrobenzylamino) -1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one, 13) 4- (4-isopropylbenzylamino) -1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one, and 14) 4- (2,6-dichlorobenzylamino) -1- (4-((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl) butan-1-one Characterized by a compound. 1) preparing a compound represented by the following Chemical Formula 4 by condensing the amine compound represented by the following Chemical Formula 2 with the compound represented by the following Chemical Formula 3; 2) preparing a compound represented by the following Chemical Formula 5 by deprotecting the compound represented by the following Chemical Formula 4 prepared in step 1) with HCl-dioxane and chloroform; And 3) reacting the compound represented by the following Chemical Formula 5 prepared in step 2) with an aldehyde compound represented by the following Chemical Formula 6 and reducing amination to prepare a compound represented by Chemical Formula 1; Method for producing a compound of claim 1 represented by. <Scheme 1>

In Scheme 1, R ₁ is hydrogen; C ₁ -C ₁₀ straight or branched alkyl; Cycloalkyl of CH ₂ -C ₃ -C ₁₀ ; Or C ₁ ~ C ₁₀ straight-chain or branched alkyl, one or more selected from alkoxy, halogen, nitro and N (CH ₃₎ made eojin group ₂ of C ₁ ~ C ₄ group is a substituted or unsubstituted benzyl, R ₂ is

Or NR ₅ R ₆ , R ₃ and R ₄ are each independently an aryl group of C ₆ ~ C ₂₀ aryl substituted by halogen or C ₆ ~ C ₂₀ of, R ₅ and R ₆ are each independently hydrogen; C ₆ -C ₂₀ aryl substituted with one or more groups selected from p-tolyloxy or C ₁ -C ₄ alkyl; Or CH (C ₆ -C ₂₀ aryl) (C ₆ -C ₂₀ aryl substituted with halogen), n is an integer of 1-5. A composition for inhibiting pain, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof. The composition of claim 5, wherein the pain is chronic neuropathic pain or inflammatory pain.

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