KR20080094010A - Pain-relieving composition - Google Patents

Abstract

A composition for relieving pain is provided to relieve pain, particularly neuropathic pain and inflammatory pain and be useful for preventing or treating pain not controlled by previous analgesics. A composition for relieving pain such as neuropathic pain comprises a compound represented by a formula(1) or a pharmaceutically acceptable salt thereof as an effective ingredient, wherein R^1 is isopropyl, benzyl, 4-methylbenzyl, 4-methoxybenzyl, l-methyl-3-phenyl propyl, 3,4,5-trimethoxybenzyl, 2-(4-(4-chlorophenyl)thiazole), 3-(5-t-butylisoxazole), 2-(4-(4-bromophenyl)thiazole), cyclohexyl, 5-(3-methylisoxazole) or 3,4-dibenzyloxypenethyl; R^2 is H or R^3CO; and R^3 is methyl, phenyl, benzyl, naphthyl(C10H7) or C10H7CH2. A method for relieving pain comprises a step of administering the compound of the formula(I) or the pharmaceutically acceptable salt thereof to a subject.

Description

Pain-inhibiting composition {PAIN-RELIEVING COMPOSITION}

The present invention relates to a composition for inhibiting pain.

Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. 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 divided into chronic pain such as acute pain and neuropathic pain.

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

Neuropathic pain is caused by damage to peripheral sensory nerves, and the pain is very severe and recurring frequently using conventional painkillers, including opiates, is difficult to treat effectively.

Causes of neuropathic pain are not only peripheral nerve trauma, but also herpes virus infection, diabetes, burning pain, plexus avulsion, neuroma, limb amputation, vasculitis, chronic alcoholism, human immunodeficiency virus infection, hypothyroidism And nerve damage caused by 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 do not normally cause discomfort (cooling / warming allodynia). Research into a substance that can prevent, suppress and cure such a variety of pain continues to be made.

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 inhibiting conventional reactions. However, they have little effect on some types, such as neuropathic pain. However, the analgesic effect can be obtained by administering a high dose of opiate, but there is a possibility of serious side effects or poisoning due to the increased dose. NSAIDs, which have lower analgesic effects than opiates, may not only benefit from higher doses but also cause gastrointestinal side effects specific to NSAIDs.

Therefore, there is an urgent need for the invention of a novel compound or a use thereof capable of inhibiting neuropathic pain by a mechanism different from the known analgesics.

A representative example of the target material of such a study is bradykinin, a bioactive substance that causes pain, increased vascular permeability and vasodilation.

Bradykinin is a 9 amino acid endogenous peptide hormone produced from the precursor kininogen by a group of proteolytic enzymes called kallikrein. Bradykinin is secreted by inflammation, trauma, burns, shock, allergies, and certain cardiovascular diseases, and once secreted initiates or increases the secretion of mediators that stimulate the nociceptive afferent nerve endings from white blood cells. The various pathophysiological reactions caused by bradykinin include septic shock, hemorrhagic shock, hypersensitivity, arthritis, rhinitis, asthma, inflammatory bowel disease, acute pancreatitis, gastric resection, carcinoidosis, migraine, hereditary Angioedema.

The receptors of bradykinin are mainly classified into B1 and B2 types according to the efficacy of various bradykinin analogs. The action of bradykinin at the B1 receptor mainly involves contracting arteries and veins, but may also relax peripheral resistance vessels. However, many of the more important functions of bradykinin are modulated by the B2 receptor. Since bradykinin at the B2 receptor causes hypotension and inflammation and increases capillary permeability, leading to edema and pain, it is known to play an important role in many diseases such as inflammation, cardiovascular disease, pain and colds. Nevertheless, bradykinin antagonists have never been used as pain relief agents.

On the other hand, the inventors have invented a novel nonpeptide compound having an antagonistic action against bradykinin (Korean Patent Registration No. 10-0446711). However, only the inhibitory effect of visceral muscle contraction activity by bradykinin was reported also in the above patent registration No. 10-0446711 of the present inventors, there was no confirmed analgesic effect.

The inventors of the present invention have completed the present invention by confirming the analgesic use of bradykinin antagonists that can be applied to the prevention or treatment of various pains.

Technical challenge

The present invention is to provide a composition for inhibiting pain, a method for preparing a composition and a method for alleviating pain using the same, comprising a non-peptide compound as an active ingredient.

Technical solution

The present invention provides a composition for inhibiting pain containing the compound of Formula 1 and / or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

In Formula 1, R ¹ is isopropyl, benzyl, 4-methylbenzyl, 4-methoxybenzyl, 1-methyl-3-phenylpropyl, 3,4,5-trimethoxybenzyl, 2- (4- (4 -Chlorophenyl) thiazole), 3- (5-t-butylisoxazole), 2- (4- (4-bromophenyl) thiazole), cyclohexyl, 5- (3-methylisoxazole), 3 , 4-dibenzyloxyphenethyl, R ² is H or R ³ CO, R ³ represents methyl, phenyl, benzyl, naphthyl (C ₁₀ H ₇ ), C ₁₀ H ₇ CH ₂ .

The compounds in the composition of this invention is N - (3,4,5- trimethoxy-benzyl) - N '-1- (4- chloro-benzhydryl) piperazin-iminodiacetic acid diamide (N - (3,4 , 5-trimethoxybenzyl) - N ' -1- (4-chlorobenzhydryl) piperazine iminodiacetic acid diamide) or N- or phenylacetyl -N' - (4- methoxybenzyl) -N "-1- (4- chloro-benzamide high Drill) piperazine iminodiacetic triamide ((N-phenylacetyl-N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) -piperazine iminodiacetic triamide) is preferred.

The composition of the present invention suppresses a variety of pains, in particular neuropathic pain, such as cooling allodynia, warming allodynia.

The composition of the present invention inhibits inflammatory pain in particular among pains.

Therefore, the composition of the present invention can be usefully used for the relief of pain which is not well controlled by existing painkillers.

Hereinafter will be described a method for producing a composition of the present invention.

The compound contained in the composition of this invention is manufactured using a well-known method. That is, it manufactures using the liquid combinatorial chemical method which uses imino diacetic anhydride as a template, and combines amines, 1- (4-chlorobenzhydryl) piperazine, and carboxylic acid sequentially.

Using the compound obtained above or a pharmaceutically acceptable salt thereof as an active ingredient, the composition for pain inhibition is prepared by mixing with a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers are well known to those skilled in the art. Acceptable carriers for compositions formulated into liquid solutions include saline and sterile water, and antioxidants, buffers, bacteriostatics, and other conventional additives may be added as needed. In addition, diluents, dispersants, surfactants, binders, and lubricants may be added to the compositions of the present invention to formulate into pills, capsules, granules, or tablets. One of ordinary skill in the art can formulate the compounds of the present invention in an appropriate manner or in a recognized manner as described in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA 1990. Alternatively, the composition of the present invention may be formulated into a patch for transdermal administration.

The present invention also provides a method for alleviating pain by using the pharmaceutical composition.

Pharmaceutical compounds prepared according to the invention can be prepared and administered in a wide variety of dosage forms by oral or parenteral route of administration. For example, these pharmaceutical compositions can be prepared in an inert, pharmaceutically acceptable carrier that is either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, patches and suppositories. Other solid and liquid formulations can be prepared according to methods known in the art. Appropriate formulations may be administered by the oral route, or as liquid formulations by parenteral routes such as intravenous, intramuscular or subcutaneous injection, or as solid formulations by parenteral routes such as patch preparations.

In unit doses of the preparations, the amount of the active ingredient according to the invention can be administered at a dose of 1-100 mg / kg per patient, per day, and can vary directly with the requirements of the patient, the severity of the condition to be treated and the compound used. . Appropriate concentrations and doses can thus be varied by those skilled in the art. In addition, it can be administered topically transdermally with a single patch with an amount of the active ingredient of 1-100 µg.

Hereinafter, preferred examples are provided to help understanding of 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.

1 is a diagram showing the manufacturing process of animal models of chronic neuropathic pain.

2a, 2b and 3b is a diagram showing the effect of inhibiting mechanical allodynia by the composition of the present invention.

Figure 3a and Figure 3b is a view showing the inhibitory effect of cooling allodynia by the composition of the present invention.

Figure 4 is a view showing the inhibitory effect of warm allodynia by the composition of the present invention.

Figure 5 is a diagram showing the inhibitory effect of inflammatory pain upon intraperitoneal injection of the composition of the present invention.

Figure 6 is a diagram showing the inhibitory effect of inflammatory pain upon transdermal administration of the composition of the present invention.

Embodiment for Invention

[Production Example 1] N -(3,4,5-trimethoxybenzyl)- N ' -1- (4-chlorobenzhydryl) piperazine Preparation of Compositions of the Invention Containing Iminodiacetic Diamide

1) Preparation of N-((t-butyloxy) carbonyl) iminodiacetic acid

In order to obtain N-phenylacetyl-N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide, first, its template N-((t- Butyloxy) carbonyl) iminodiacetic acid was prepared as follows: 1 mL flask of iminodiacetic acid (13.3 g, 100 mmol), dioxane (200 mL) and sodium hydroxide (8 g, 200 mmol) dissolved in 200 mL of water. A small amount of di-t-butyldicarbonate (25 mL, 110 mmol) was added to the solution and stirred at room temperature for 72 hours before the reaction mixture was ether (2 x 100 mL). The aqueous layer was acidified with 10% hydrochloric acid (100 mL) and extracted with ethyl acetate (3 × 150 mL) The combined organic layers were washed with saturated brine (2 × 150 mL) and Na ₂ SO ₄ After water was removed, the mixture was recrystallized (ethyl acetate: hexane = 1: 2) to obtain colorless crystals.

Yield: 10.33 g (44%)

¹ H-NMR (Acetone-d ₆ , 400 MHz): 4.12 and 4.08 (two s, 4H), 1.4 (s, 9H)

2) Preparation of N-((t-butyloxy) carbonyl) -N '-(3,4,5-trimethoxybenzyl) iminodiacetic acid monoamide

The title compound was prepared by binding 3,4,5-trimethoxybenzylamine to the first functional group of N-((t-butyloxy) carbonyl) iminodiacetic acid prepared in 1) above. Into the flask, 6.4 ml of DMF dissolved in N-((t-butyloxy) carbonyl) iminodiacetic acid (0.5 g, 2.14 mmol) and EDCI (0.41 g, 2.14 mmol) prepared in 1 above was added to room temperature. Stirred for 1 h. To this was slowly added dropwise 3,4,5-trimethoxybenzylamine (0.42 g, 2.14 mmol) through a syringe, followed by stirring at room temperature for 20 hours. Dilute the reaction with ethyl acetate (60 mL), wash with 10% aqueous hydrochloric acid solution (2 x 40 mL), saturated brine (40 mL), remove moisture with Na ₂ SO ₄ , and remove solvent under reduced pressure. To give an off-white oil.

Yield: 0.66 g (75%)

¹ H-NMR (Acetone-d ₆ , 400 MHz) 6.5 (2H, d), 4.4 (2H, dd), 4.0 (4H, d), 3.8 (9H, dd), 1.4 (9H, s)

FABMS m / z 413.18

3) N-((t-butyloxy) carbonyl) -N '-(3,4,5-trimethoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid dia Preparation of mead

The title compound was prepared by binding 1- (4-chlorobenzhydryl) piperazine to the compound prepared in 2).

Compound (0.5g, 1.21mmol), 4-chloro-benzhydrylpiperazine (0.35g, 1.21mmol) prepared in 2) and Benzotriazol-1-yl-oxy-trispyrrolidino phosphonium hexa Fluorophosphate (PyBOP) (0.72 g, 1.33 mmol) was added to 15 ml of DMF and N, N -diisopropylethylamine (0.62 mL, 2.42 mmol) was added. The reaction mixture was stirred at 25 ° C. for 16 h and then placed in a 250 mL separatory funnel. The reaction was diluted with 100 mL of ethyl acetate, washed three times with 50 mL of 10% hydrochloric acid, and then washed twice with NaHCO ₃ (50 mL). Thereafter, the mixture was washed successively with saturated brine, dried with Na ₂ SO ₄ , and the solvent was removed by a vacuum evaporator to obtain a pale yellow solid.

Yield: 0.67 g (81%)

¹ H-NMR (Acetone-d ₆ , 400 MHz) 7.2-7.5 (9H, m), 6.6 (2H, d), 4.4 (1H, d), 4.3 (2H, d), 4.2 (2H, d), 4.1 (2H, d), 3.8 (9H, d), 3.6 (4H, d), 1.3 (9H, d)

FABMS m / z 681.30

4) N -(3,4,5-trimethoxybenzyl)- N ' Preparation of -1- (4-chlorobenzhydryl) piperazine iminodiacetic diamide

The material (0.3 g, 0.44 mmol) prepared in 3) was dissolved in chloroform (5 mL) and 4 M HCl-dioxane (5 mL), and stirred for 3 hours. After the reaction was completed, the solvent and excess acid was removed by vacuum evaporator and washed with NaHCO ₃ solution with a weak base. Thereafter, the solvent was removed, and then chromatographed with EtOAc and MeOH 10: 1 to obtain the title compound as a yellow solid.

Yield: 138 mg (54%)

¹ H-NMR (Acetone-d ₆ , 400 MHz) 7.2-7.5 (9H, m), 6.6 (2H, d), 4.4 (1H, d), 4.3 (2H, d), 4.2 (2H, d), 4.1 (2H, d), 3.8 (9H, d), 3.6 (4H, d), 2.4 (4H, d)

FABMS m / z 581.30.

5) Preparation of Composition 1 of the Invention

One was prepared in N - (3,4,5-trimethoxy-benzyl) - N '-1- (4- chloro-benzhydryl) piperazin-iminodiacetic acid diamide for Tween 80: 100% ethanol: saline 8 It was dissolved in a solution mixed in 1: 1 to prepare the composition 1 (represented by sub1 in each case) of the present invention.

Preparation Example 2 Preparation of a Composition of the Invention Containing N-phenylacetyl-N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine-iminodiacetic acid triamide

1) Preparation of N-((t-butyloxy) carbonyl) iminodiacetic acid

In order to obtain N-phenylacetyl-N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide, first, its template N-((t- Butyloxy) carbonyl) iminodiacetic acid was prepared as follows.

Into a 1 L flask was placed imino diacetic acid (13.3 g, 100 mmol), dioxane (200 mL) and sodium hydroxide (8 g, 200 mmol) dissolved in 200 mL of water and stirred until the solution became uniform. A small amount of di-t-butyldicarbonate (25 mL, 110 mmol) was added to the solution, stirred at room temperature for 72 hours, and then the reaction mixture was washed with ether (2 x 100 mL). The aqueous layer was acidified with 10% hydrochloric acid (100 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with saturated brine (2 × 150 mL), water was removed with Na ₂ SO ₄ , and then recrystallized (ethyl acetate: hexane = 1: 2) to obtain colorless crystals.

Yield: 10.33 g (44%)

¹ H-NMR (Acetone-d ₆ , 400 MHz): 4.12 and 4.08 (two s, 4H), 1.4 (s, 9H)

2) Preparation of N-((t-butyloxy) carbonyl) -N '-(4-methoxybenzyl) iminodiacetic acid monoamide

The title compound was prepared by binding an amine to the first functional group of N-((t-butyloxy) carbonyl) iminodiacetic acid prepared in 1).

Into the flask, 6.4 ml of DMF dissolved in N-((t-butyloxy) carbonyl) iminodiacetic acid (0.5 g, 2.14 mmol) and EDCI (0.41 g, 2.14 mmol) prepared in 1 above was added to room temperature. Stirred for 1 h. 4-methoxybenzylamine (0.23 g, 2.14 mmol) was slowly added dropwise thereto through a syringe, followed by stirring at room temperature for 20 hours. Dilute the reaction with ethyl acetate (60 mL), wash with 10% aqueous hydrochloric acid solution (2 x 40 mL), saturated brine (40 mL), remove moisture with Na ₂ SO ₄ , and remove solvent under reduced pressure. To give an off-white oil.

Yield: 0.43 g (55%)

¹ H-NMR (Acetone-d ₆ , 400MHz): 6.8 (2H, dt), 7.2 and 7.3 (2H, t), 4.4 (2H, d), 4.2 (2H, d), 4.0 (2H, d) , 3.8 (3H, s), 1.4 (9H, two s)

FABMS m / z : 353.16

3) Preparation of N-((t-butyloxy) carbonyl) -N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid diamide

The title compound was prepared by binding 1- (4-chlorobenzhydryl) piperazine to the compound prepared in 2).

N-((t-butyloxy) carbonyl) -iminodiacetic monoamide (0.48 g, 1.31 mmol), 1- (4-chlorobenzhydryl) piperazine (0.41 g, 1.441 mmol) in a 30 ml vial ), Benzotriazol-1-yl-oxy-trispyrrolidino phosphonium hexafluorophosphate (PyBOP) (0.75 g, 1.44 mmol), and then DMF (15 mL), N, N-diiso Propylethylamine (i-Pr ₂ NEt; 0.5 ml, 2.62 mmol) was added and stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (100 mL), washed sequentially with 10% aqueous hydrochloric acid solution (100 mL), saturated aqueous NaHCO ₃ solution (2 x 50 mL), saturated brine (50 mL), and washed with Na ₂ SO ₄ . After removal, the solvent was removed under reduced pressure to give an orange solid.

Yield: 0.67 g (89%)

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.6 (11H, m), 6.8 (2H, t), 4.4 (1H, s), 4.3 (2H, d), 4.2 (2H, d) , 3.8 (2H, d), 3.7 (3H, s), 3.6 (4H, m), 2.4 (4H, m), 1.4 (9H, d)

FABMS m / z : 621.28

4) Preparation of N-phenylacetyl-N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide

The title compound was prepared by reacting a compound prepared in 3) with a carboxylic acid.

Into a 4 mL vial was added chloroform (1 mL), 4M hydrochloric acid-dioxane (1 mL), and 0.031 g (0.050 mmol) of the compound prepared in 3 above, followed by stirring for 3 hours. Solvent and excess acid were removed by evaporation, the residue was dissolved in 1 ml of DMF, 26.1 μl (0.15 mmol) of i-Pr ₂ NEt was added, 7.49 mg (0.055 mmol) of phenylacetic acid, and 25.64 mg (0.055 mg) of PyBrOP. mmol) was added and stirred for 16 hours. After stirring, the reaction mixture was diluted with ethyl acetate (40 mL), washed with 10% aqueous hydrochloric acid solution (3 x 30 mL), saturated aqueous NaHCO ₃ solution (2 x 30 mL), and saturated brine (30 mL). Water was removed with Na ₂ SO ₄ and concentrated to give a brownish yellow oil.

Yield: 25 mg (77%)

¹ H-NMR (Acetone-d ₆ , 400MHz): 7.2-7.6 (11H, m), 7.0-7.2 (5H, m) 6.8 (2H, t), 4.4 (1H, s), 4.3 (2H, d ), 4.2 (2H, d), 3.8 (2H, d), 3.7 (3H, s), 3.6 (4H, m), 3.4 (2H, s), 2.4 (4H, m)

FABMS m / z : 639.10

5) Preparation of Composition 2 of the Invention

N-phenylacetyl-N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide prepared in the above Tween 80: 100% ethanol: saline It was dissolved in a solution mixed at 8: 1: 1 to prepare a composition 2 (shown as sub2 in each case) of the present invention.

Example 1 Confirming the Analgesic Effect of the Composition of the Present Invention on Chronic Neuropathic Pain

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

A chronic neuropathic pain model was constructed as follows.

Four 8-week-old Sprague-Dawley rats are placed per cage, maintained at 22-25 degrees Celsius for 12-hour light-dark cycles (from 7 am). Food and water were given freely to raise.

To induce neuropathic pain, the rats were anesthetized with 0.5-2% enflurane and the inferior / superior caudal trunks distributed in the rat tail were shown in the left figure of the right figure of FIG. Cleavage between visible S1 and S2 spinal nerves (FIG. 1). The proximal portion was cut 1 mm further 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. Inhibitory effect of neuropathic pain by the composition of the present invention

1) Administration and Behavioral Tests of Compositions of the Invention

In order to investigate the inhibitory effect of neuropathic pain by the composition of the present invention, each of the compositions of the present invention was injected intraperitoneally 14 days after the nerve injury, which is the time when allodynia of the experimental animal model prepared in 1 reaches its peak. .

The above prepared N prepared in Example 1 - (3,4,5-trimethoxy-benzyl) - N '-1- (4- chloro-benzhydryl) piperazine already 6 or the composition containing 1 nodi acid diamide 60 mg / kg, containing N-phenylacetyl-N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide prepared in Preparation Example 2 3 mg / kg of each composition 2 was injected intraperitoneally, and 60 µg of the composition 1 was injected subcutaneously, and the solvent solution used for preparing the composition was used as a control.

To test for neuropathic pain in the tail, behavioral tests were performed 1 day before surgery and 1, 7 and 14 days after surgery. In order to give mechanical, cold and warm stimulation to the tail, 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.

Each drug was injected 14 days after surgery, and behavioral tests were performed after 1, 3, and 5 hours to determine the anti-allodynia effect of the composition of the present invention.

The result is shown in each figure, and the time of injecting the drug in each figure is shown by the vertical dashed line (n value in the figure means the number of rats used in the experiment).

2) mechanical allodynia testing

In order to confirm the inhibitory effect of mechanical allodynia with the composition of the present invention, a mechanical allodynia test was performed as follows.

In order to measure 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. The first stimulus was 20 g and the weak filament was used the next time the avoidance response appeared, and the stronger filament was used if no response was found. The 50% threshold was interpolated according to the Dixon method.

As shown in Figure 2, Composition 1 (sub1) and Composition 2 (sub2) of the present invention showed a tendency of analgesia compared to the animal group treated with the control (vehicle).

3) cooling and warming allodynia examination

In order to confirm the inhibitory effect of cooling and warming allodynia with the composition of the present invention, the sensitivity to cooling and warming in the tail was evaluated by measuring withdrawal latency as follows.

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.

As shown in Figures 3a and 3b, composition 1 (sub 1) of the present invention showed a statistically significant analgesic effect at 1 hour after injection for the stimulus that causes cooling allodynia.

As shown in FIG. 4, the composition 1 (sub 1) of the present invention showed a significant analgesic effect at 1 hour after injection for stimulation for warm-allodynia.

Example 2 Inhibitory Effect of Inflammatory Pain by Composition of the Present Invention

1) When injected into the abdominal cavity

In order to confirm the inhibitory effect of inflammatory pain by the composition of the present invention, an experiment was performed using formalin, an inflammation-inducing substance.

10 minutes prior to formalin injection, Composition 1 of the present invention was injected intraperitoneally of the experimental animal at a dose of 60 mg / kg. 50 μl of 5% formalin was subcutaneously injected into one hind paw of the rat, and the rat was licked or bited for 60 minutes in an observation chamber (horizontal, 16 cm × 14 cm) for 5 minutes. After injecting formalin, the results were divided into phase I up to 10 minutes and phase II up to 60 minutes from 10 minutes.

As shown in Figure 5, the composition 1 of the present invention was observed analgesic effect in the second phase (10 minutes to 60 minutes after drug administration) compared to the control. No analgesic effect was observed in the first phase (from 10 minutes immediately after administration).

2) In case of subcutaneous injection

In order to confirm the inhibitory effect of inflammatory pain by the composition of the present invention, an experiment was performed using formalin, an inflammation-inducing substance.

Rats were injected subcutaneously with a dose of 60 μg / kg of 50% of 5% popformin and Composition 1 of the present invention in one hind paw. Subcutaneous injection of only 50 μl of 5% formalin in one hind paw of the rat was used as a control. Afterwards, the rats licked or bited their feet for 60 minutes in 5 minute increments in an observation chamber (horizontal, 16 cm x 14 cm). After injecting formalin, the results were divided into phase I up to 10 minutes and phase II up to 60 minutes from 10 minutes.

As shown in Figure 6, the composition 1 of the present invention showed an excellent analgesic effect in the first and second period compared to the control.

Experiments as described above can be seen that the composition of the present invention inhibits inflammatory pain.

The composition of the present invention is effective in alleviating pain, and particularly has the effect of inhibiting neuropathic pain, such as cooling allodynia and warming allodynia.

The compositions of the present invention also effectively inhibited inflammatory pain, particularly among pains.

Therefore, the composition of the present invention can be usefully used for the prevention and treatment of pain that is not well controlled by the existing painkillers.

Claims (13)

A composition for inhibiting pain containing the compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. <Formula 1>

In Chemical Formula 1 R ¹ is isopropyl, benzyl, 4-methylbenzyl, 4-methoxybenzyl, 1-methyl-3-phenyl propyl, 3,4,5-trimethoxybenzyl, 2- (4- (4-chlorophenyl) Thiazole), 3- (5-t-butylisoxazole), 2- (4- (4-bromophenyl) thiazole), cyclohexyl, 5- (3-methylisoxazole) and 3,4-di 1 type selected from the group which consists of benzyloxy phenethyl, R <^2> is H or R <^3> CO, R ³ represents one kind selected from the group consisting of methyl, phenyl, benzyl, naphthyl (C ₁₀ H ₇ ) and C ₁₀ H ₇ CH ₂ . The method of claim 1 wherein the compound of formula N 1 - (3,4,5- trimethoxy-benzyl) - N '-1- (4- chloro-benzhydryl) piperazin-iminodiacetic acid diamide or a pharmaceutically Composition which is an acceptable salt. The compound of claim 1 wherein N-phenylacetyl-N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide or a pharmaceutically acceptable salt thereof. The composition of claim 1, wherein the pain is neuropathic pain. The composition of claim 4 wherein the neuropathic pain is cold allodynia or warm allodynia. The composition of claim 1, wherein the pain is inflammatory pain. A patch preparation comprising the composition of any one of claims 1 to 3 as an active ingredient. A method of alleviating pain by administering a pharmaceutical composition containing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. <Formula 1>

In Chemical Formula 1 R ¹ is isopropyl, benzyl, 4-methylbenzyl, 4-methoxybenzyl, 1-methyl-3-phenyl propyl, 3,4,5-trimethoxybenzyl, 2- (4- (4-chlorophenyl) Thiazole), 3- (5-t-butylisoxazole), 2- (4- (4-bromophenyl) thiazole), cyclohexyl, 5- (3-methylisoxazole) and 3,4-di 1 type selected from the group which consists of benzyloxy phenethyl, R <^2> is H or R <^3> CO, R ³ represents one kind selected from the group consisting of methyl, phenyl, benzyl, naphthyl (C ₁₀ H ₇ ) and C ₁₀ H ₇ CH ₂ . 10. The method of claim 8 wherein the compound of formula 1 N - (3,4,5- trimethoxy-benzyl) - N '-1- (4- chloro-benzhydryl) piperazin-iminodiacetic acid diamide or a pharmaceutically Which is an acceptable salt. A compound according to claim 8 wherein N-phenylacetyl-N '-(4-methoxybenzyl) -N "-1- (4-chlorobenzhydryl) piperazine iminodiacetic acid triamide or a pharmaceutically acceptable salt thereof. The method of claim 8, wherein the pain is neuropathic pain. The method of claim 11, wherein the neuropathic pain is cold allodynia or warm allodynia. The method of claim 8, wherein the pain is inflammatory pain.

Images