KR20110075842A - Therapeutic use of ethylamino-benzoic acid derivative - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing ethyl amino benzoic acid derivatives is provided to remove reactive oxygen and prevent or treat pain with high stability. CONSTITUTION: A pharmaceutical composition for preventing or treating pain contains 2-acetoxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid of chemical formula 1, 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid of chemical formula 2, or pharmaceutically acceptable salt thereof.

Description

Therapeutic use of ethylamino-benzoic acid derivative

The present invention relates to a pharmaceutical composition for treating or preventing pain, comprising as an active ingredient a compound having a specific formula or a pharmaceutically acceptable salt thereof. That is, the present invention relates to a novel medical use of the compound or a pharmaceutically acceptable salt thereof.

Pain refers to the experience of unpleasant feelings and emotions associated with or caused by actual or potential tissue damage. Pain is classified by cause and duration. The causes are classified as invasive pain and neuropathic pain. Invasive pain is pain caused by tissue damage, and neuropathic pain is defined as pain caused by abnormalities or psychological problems of the nervous system. The classification by period includes acute pain such as postoperative pain and chronic pain such as low back pain. Chronic pain is defined as pain lasting more than 6 months, and less than 6 months as acute pain. Representative examples of acute pain include toothache, menstrual pain and visceral pain including acute abdominal pain, postoperative pain, and pain due to fracture, and representative examples of chronic pain include osteoarthritis pain, rheumatoid arthritis pain, back pain and cancerous pain.

Current treatment regimens for pain can be broadly divided into two types. One is a narcotic analgesic that is generally used when the size of the pain the patient feels is severe or severe or the other is a non-narcotic analgesic that is used when the size of the pain the patient feels is mild or severe. Narcotic analgesics have a significant analgesic effect by stimulating the endogenous endorphin system. These narcotic analgesics have the advantage of great analgesic effects, but have disadvantages of limited use due to side effects on vomiting, constipation, and respiratory abilities, and in particular addictive.

In contrast, non-narcotic analgesics are generally used because they are almost non-addictive, and include nonsteroidal anti-inflammatory drugs (NSAIDs) such as acetaminophen and aspirin. They are mainly used for pain, headache, neuralgia, muscle pain, dysmenorrhea, sprains, toothache, joint pain. These non-narcotic drugs have common features of anti-inflammatory, analgesic and antipyretic effects, and are currently widely used for acute and chronic pain management.

The fundamental mechanism of action of these anti-inflammatory drugs is the inhibition of the production of prostaglandins, which are produced from arachidonic acid via an enzyme called cyclooxygenase (COX). There are two subtypes of COX-1 and COX-2 in our body. COX-1 is found in blood vessels, stomach and kidneys, and COX-2 is induced in inflammatory sites. Since most NSAIDs act non-selectively on both COX-1 and COX-2, they cause severe gastrointestinal disorders, since NSAIDs also inhibit COX-1, which has the ability to protect and maintain the stomach wall. Accordingly, although COX-2 selective inhibitors have been developed and used in the spotlight, side effects causing cardiovascular disease may occur due to the strong inhibition of vasodilation due to COX-2 inhibition.

Free radicals are known to cause pain due to excessive generation in tissue damage as well as neuropathy diseases. Indeed, it has been reported that free radicals are involved in the process of hyperalgesia and allodynia caused by physical stimuli in neuropathic animal models. Thus, drugs that simultaneously inhibit the production of prostaglandins and free radicals can be developed as safe analgesics that reduce inflammatory pain and non-inflammatory pain (eg neuropathic pain).

Accordingly, the technical problem to be achieved by the present invention is to provide a method for the treatment or prevention of pain using a compound having a low side effect and high safety, and a pharmaceutical use for treating or preventing the pain of such a compound.

In order to achieve the above technical problem, the present invention provides a pharmaceutical composition for the treatment or prevention of pain, characterized in that it comprises an ethylamino benzoic acid derivative represented by the following formula (1) and (2) or a pharmaceutically acceptable salt thereof as an active ingredient to provide.

That is, the present invention provides a therapeutic or preventive use of the pain of the ethylamino benzoic acid derivatives represented by Formulas 1 and 2 or pharmaceutically acceptable salts thereof. In addition, the present invention is represented by 2-acetoxy-5- [2- (4-trifluoromethyl-phenyl) -ethylamino] -benzoic acid represented by Chemical Formula 1 (hereinafter referred to as "Compound 1") and Chemical Formula 2 An ethylamino benzoic acid derivative comprising 2-hydroxy-5- [2- (4-trifluoromethyl-phenyl) -ethylamino] -benzoic acid (hereinafter referred to as "Compound 2"), or a pharmaceutically acceptable Provided are methods of treating or preventing pain in an animal, including a human, comprising administering a therapeutically effective amount of a salt.

The inventors prepared various compounds to inhibit prostaglandin production, remove free radicals, and evaluate the pharmacological action without damage to the gastrointestinal tract, wherein the ethylamino benzoic acid derivatives represented by Formulas 1 and 2, or pharmaceutically thereof The present invention has been completed and found that not only acceptable salts are safe but also very useful for the treatment or prevention of pain diseases.

"Pharmaceutically acceptable salts" of the present invention refer to salts that are made from non-toxic or less acid or base. When the compounds of the present invention are relatively acidic, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base and a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, salts consisting of sodium, potassium, calcium, ammonium, magnesium or organic amino. When the compounds of the present invention are relatively basic, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid and a suitable inert solvent. Pharmaceutically acceptable acid addition salts include propionic acid, isobutyl acid, oxalic acid, malic acid, malonic acid, benzoic acid, succinic acid, suberic, fumaric acid, manderic acid, phthalic acid, benzenesulfonic acid, p-torylsul Phonic acid, citric acid, tartaric acid, methanesulfonic acid, hydrochloric acid, bromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogen phosphate, sulfuric acid, monohydrosulfuric acid, hydrogen iodide, phosphorous acid Salts formed of, and the like, but are not limited thereto. It also includes, but is not limited to, salts of amino acids such as arginate and analogs of organic acids such as glucuronic or galactunoric acids.

The compounds of the present invention may exist in unsolvated as well as solvated forms, including hydrate forms. The compounds of the present invention may exist in crystalline or amorphous form, and all such physical forms are included within the scope of the present invention.

The present invention also provides a pharmaceutical composition comprising an ethylamino benzoic acid derivative represented by Chemical Formulas 1 and 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or additive. The ethylamino benzoic acid derivatives or pharmaceutically acceptable salts thereof of the present invention may be administered alone or in admixture with any convenient carrier, excipient, etc., and such dosage forms may be single or repeated dose formulations.

The pharmaceutical composition of the present invention may be a solid preparation or a liquid preparation. Solid preparations include, but are not limited to, powders, granules, tablets, capsules, suppositories, and the like. Solid form preparations may include, but are not limited to, excipients, flavors, binders, preservatives, disintegrants, lubricants, fillers and the like. Liquid formulations include, but are not limited to, solutions such as water, propylene glycol solutions, suspensions, emulsions, and the like, and may be prepared by adding suitable colorants, flavors, stabilizers, viscosity agents, and the like.

For example, powders may be prepared by simply mixing the ethylamino benzoic acid derivatives of the present invention with suitable pharmaceutically acceptable excipients such as lactose, starch, microcrystalline cellulose. Granules are compounds of the present invention or pharmaceutically acceptable salts thereof; Pharmaceutically acceptable excipients; And a pharmaceutically acceptable binder such as polyvinylpyrrolidone and hydroxypropyl cellulose, and then prepared by using a wet granulation method using a solvent such as water, ethanol, isopropanol, or a dry granulation method using a compressive force. Can be. Tablets may also be prepared by mixing the granules with a suitable pharmaceutically acceptable glidant such as magnesium stearate and then tableting using a tableting machine.

The pharmaceutical composition of the present invention may be administered orally, by injection (eg, intramuscular injection, intraperitoneal injection, intravenous injection, infusion, subcutaneous injection, implant), inhalant, nasal administration, depending on the condition and condition of the individual to be treated. It may be administered as a vaginal agent, rectal agent, sublingual agent, transdermal agent, topical agent, and the like, but is not limited thereto. It may be formulated into a suitable dosage unit dosage form comprising a pharmaceutically acceptable carrier, excipient, vehicle, commonly used and nontoxic, depending on the route of administration. Depot formulations capable of continually releasing the drug for a period of time are also within the scope of the present invention.

The present invention also provides a method for treating or preventing pain, comprising administering to a subject in need thereof a therapeutically effective amount of an ethylamino benzoic acid derivative represented by Formulas 1 and 2 or a pharmaceutically acceptable salt thereof. . That is, the present invention provides a medicinal use of treating or preventing pain of an ethylamino benzoic acid derivative or a pharmaceutically acceptable salt thereof.

More specifically, the ethylamino benzoic acid derivatives or pharmaceutically acceptable salts thereof of the present invention are insoluble water pain. (Including moderate to severe acute nociceptive pain); Cancer pain (Tumor related pains such as bone pain, headache, facial pain, visceral pain, pain associated with chemotherapy, such as pain syndrome after chemotherapy, pain syndrome after chronic surgery, syndrome after radiation therapy, and cancer Acute pain syndromes, including those due to therapeutic interactions such as chemotherapy toxicity, immunotherapy, hormonal therapy and radiation therapy); lumbago (Including low back pain due to disc herniation or rupture, or abnormalities in the posterior lumbar, sacroiliac, vertebral or posterior ligament); Inflammatory pain (including joint pain, rheumatoid disease, rheumatoid arthritis and osteoarthritis causing symptoms); Musculoskeletal disorder pain (including muscle pain, spondylitis pain, serum-negative (non-rheumatic) arthrosis pain, non-articular rheumatoid pain, dystrophin-deficient muscular dystrophy pain, glycogen breakdown pain, multiple myositis pain and purulent myositis pain); Visceral pain, such as heart and vascular pain (including angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleroderma and skeletal muscle ischemia); Pain due to gastrointestinal disorders (Digestive organ visceral pain, non-digestive visceral pain, functional bowel disorders (FBD), inflammatory bowel disease (IBD), gastroesophageal reflux, indigestion, irritable bowel syndrome (IBS), functional abdominal pain syndrome (FAPS), Crohn's disease, ileum) Pain associated with saline and ulcerative colitis, dysmenorrhea, pelvic pain, cystitis and pancreatitis); Pain due to tension / sprains; Postoperative pain (pain after any type of surgery); Post-traumatic pain; Pain after burns; Acute pain; Headache (including cluster headaches); Neuropathic pain (diabetic neuropathy, postherpetic neuralgia, cancer neuropathy, HIV neuropathy, trigeminal neuralgia, ring pain, carpal tunnel syndrome, chronic alcoholism, hypothyroidism, uremia or vitamin deficiency neuropathic pain, central Pain as a result of lesions or dysfunction of the nervous system, including pain after sexual stroke, and pain due to multiple sclerosis, spinal cord injury, Perkins disease, and epilepsy); And maxillofacial pain (including toothache and temporomandibular fascia pain).

Therefore, the present invention is not tolerated pain, cancer pain, back pain, inflammatory pain, musculoskeletal disorder pain, visceral pain, pain caused by tension or sprain, postoperative pain, post traumatic pain, post burn pain, acute pain, headache, neuropathic It provides a pharmaceutical composition for the treatment or prevention of pain selected from the group consisting of pain and maxillofacial pain.

In use for the treatment of pain, the ethylamino benzoic acid derivatives and pharmaceutically acceptable salts of the present invention may be administered from about 0.01 mg / kg to about 100 g / kg daily, from about 0.1 mg / kg to about 10 g A daily dose of / kg is preferred. However, the dosage may vary depending on the condition of the patient (age, sex, weight, etc.), the severity of the condition being treated, the compound used and the like. If desired, the total daily dose may be divided for convenience and divided several times throughout the day.

The present invention provides a pharmaceutical composition for the prevention and / or treatment of pain, comprising an ethylamino benzoic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention also provides a method for the prevention and / or treatment of pain, characterized in that a therapeutically effective amount of an ethylamino benzoic acid derivative or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

<Example 1-1> Preparation of Compound 2

In addition, 2-hydroxy-5- [2- (4-trifluoromethyl-phenyl) -ethylamino] -benzoic acid (Compound 2), which is a preferred embodiment of the present invention, may be prepared through the following Scheme 1, but It is not limited.

<Scheme 1>

Reaction conditions: (a) 4- (trifluoromethyl) hydrocinnamic acid, PCl ₅ , xylene, reflux, 12 hours; (b) acetyl chloride, DMF / K ₂ CO ₃ , room temperature, 2 hours; (c) NaBH _{4 ,} acetic acid / 1,4-dioxane, about 95, 50 minutes; (d) HCl / H ₂ O, acetic acid.

Example 1-2 Preparation of Compound 1

Compound 1 was prepared similar to the following scheme.

Compound a: Na ₂ CO ₃ (32.6 g, 307 mmol) and di-tert-butyl dicarbonate in a 200 mL H 2 O: 1,4-dioxane (1: 1) mixed solution of compound 2 (50.0 g, 154 mmol) (40.3 g, 185 mmol) was added at room temperature. After stirring for 8 hours, di-tert-butyl dicarbonate (16.8 g, 76.9 mmol) was further added. After an additional 8 hours of stirring at room temperature, the reaction mixture was neutralized with 2N HCl (pH-6). The resulting mixture was extracted with ethyl acetate (200 mL, twice). The organic phases were combined, washed with brine (100 mL), dried over MgSO ₄ and filtered. As a result, Compound a, a concentrate in yellow foam, was obtained, and crude Compound a was used in the subsequent reaction without further purification.

1 H NMR (400 MHz, CDCl 3) 10.52 (1H, br S), 7.53 (d, 2H, J = 8 Hz), 7.53 (br, 1H), 7.28 (d, 2H, J = 8 Hz), 7.26 (br , 1H), 6.94 (d, 1H, J = 8.8 Hz), 3.85 (t, 2H, J = 7.2 Hz), 2.94 (t, 2H, J = 7.2 Hz), 1.43 (br s, 9H).

Compound b: N, N-diisopropylethylamine (80.3 mL, 461 mmol) and acetyl chloride (21.9 mL, 307 mmol) were added to a dichloromethane (200 mL) solution of compound a at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 5 hours. 1N HCl (100 mL) aqueous solution was added to the reaction mixture. The reaction was separated into layers and the aqueous layer was extracted with dichloromethane (100 mL). The organic phases were mixed and washed with brine (100 mL). Dried over MgSO ₄ , filtered and concentrated. The crude product was recrystallized in diethyl ether to give compound b (51.5 g, 71.7%) as a white solid.

1 H NMR (400 MHz, CDCl 3) 7.82 (br s, 1 H), 7.54 (d, 2H, J = 8 Hz), 7.38-7.24 (m, 1H), 7.28 (d, 1H, J = 8 Hz), 7.08 (d, 1H, J = 7.6 Hz), 3.91 (t, 2H, J = 7.2 Hz), 2.98 (t, 2H, J = 7.2 Hz), 2.34 (s, 3H), 1.42 (br s, 9H).

Compound 1: A solution of dichloromethane (200 mL) of compound b (51.5 g, 110 mmol) was treated with a 1,4-dioxane solution (200 mL) of 4 N HCl at 0 ° C. The reaction mixture was warmed to room temperature. After stirring for 5 hours, the suspension was concentrated. The residue was triturated in diethyl ether (500 mL). Filtration and washing with dichloromethane (500 mL) and diethyl ether (500 mL) gave ND-07 (46.0 g, 82.5 mmol, 92.3%) as a white solid.

1 H NMR (400 MHz, DMSO-d6) 7.66 (d, 2H, J = 7.6 Hz), 7.52 (d, 2H, J = 7.6 Hz), 7.15 (s, 1H), 6.91 (d, 1H, J = 8.6 Hz), 6.85 (d, 1H, J = 8.6 Hz), 3.32 (t, 2H, J = 7 Hz), 2.95 (t, 2H, J = 7 Hz), 2.18 (s, 3H)) LCMS calc. for C ₁₈ H ₁₆ F ₃ NO ₄ (M + H +): 368, found 368.

Example 2 Effect Evaluation Using Acetic Acid Pain Model

end. Experiment Content

(1) experimental animals

Eighteen to 20 g of ICR mice were used in each group. The animals were housed in groups of four in a cage and were free to eat and drink. They were taken to the lab at least two hours before the day of the pain test so they could adjust to the test setting.

(2) drug injection

Compound 1 was homogenized with 1% Lutrol ™ to use doses of 10, 25, 50 and 100 mg / kg in the experiment.

(3) Experimental procedure

Thirty minutes after oral administration of Compound 1, 1% acetic acid was administered at a dose of 10 ml / kg into the mouse abdominal cavity using a syringe with a 26-gauge needle. Visceral pain was induced by leaving for 5 minutes after administering 1% acetic acid. The pain behavior of the mice was recorded for 15 minutes after visceral pain was induced. The test items for pain behavior were body torsion and licking. After the pain behavior test, the number of twists and licks of the body was quantified, respectively.

I. Experiment result

1 and 2 show the number of twists and licks in the body after administration of acetic acid in the abdominal cavity of mice. As shown in Figures 1 and 2, the group administered with Compound 1 was confirmed that the pain is suppressed compared to the group administered with the excipient alone. The pain relief effect was shown to be drug concentration dependent, and was significantly inhibited in the group of Compound 1 50 and 100 mg / kg dose ( p <0.05).

Example 3 Evaluation of Effect Using Formalin Pain Model

end. Experiment Content

(1) experimental animals

25-30 g of ICR mice were used in each group six. Animals were housed in groups of six in a cage and were free to eat and drink. They were taken to the lab at least two hours before the day of the pain test so they could adjust to the test setting.

(2) drug injection

Compound 1 was homogenized with 1% Lutrol ™ to use doses of 10, 25, 50 and 100 mg / kg in the experiment.

(3) Experimental procedure

Thirty minutes after oral administration of Compound 1, 50 microliters of 2.5% formalin was injected subcutaneously into the hind paw of a mouse using a syringe with a 30-gauge needle. The pain behavior test time was observed by dividing 0-5 minutes into the first reactor (phase I) and 20-25 minutes into the second reactor (phase II) immediately after injection. The first reactor is known to cause acute pain in which formalin acts directly on the receptor, and the second reactor is known to cause inflammatory pain as persistent pain. The test item for pain behavior was to lick the sole of the formalin injection. The total time to lick the sole after pain behavior test was quantified and presented as a result.

I. Experiment result

As a result of injecting formalin into the mice, the pain response of the characteristic primary and secondary reactors was observed, and the results are shown in FIGS. 3 and 4. The primary reactor represents the average of the sum of reactions from 5 minutes after formalin injection, and the secondary reactor represents the sum of the reactions occurring between 20 and 25 minutes after formalin injection. As can be seen in Figures 3 and 4, in the first reactor (acute pain) and the second reactor (inflammatory pain), the compound 1 administration group showed a significant pain relief effect compared to the excipient group, significant It was confirmed that the pain was suppressed ( p <0.05). These results suggest that Compound 1 is effective in alleviating inflammatory pain as well as acute pain.

Example 4 Evaluation of Effect Using Heat Pain Model

end. Experiment Content

(1) experimental animals

20-25 g of ICR mice were used in each group of 5 mice. The animals were housed in groups of five in a cage and were free to eat and drink. They were taken to the lab at least two hours before the day of the pain test so they could adjust to the test setting.

(2) drug injection

Compound 1 was homogenized with 1% Lutrol ™ to use doses of 25 and 100 mg / kg in the experiment.

(3) Experimental procedure

Thirty minutes after oral administration of Compound 1, 3 cm of the tail of the mouse was soaked in a bath at 55 ± 1 ° C. The test item for pain behavior was the time of tail recovery and the stopwatch was used for time measurement. The time to retrieve the tail after the pain behavior test was quantified and presented as a result.

I. Experiment result

5 shows the time to recover the tail after soaking the tail of the mouse in hot water in order to determine the pain relief effect of Compound 1 against heat pain. As can be seen in Figure 5, the group administered with Compound 1 was confirmed to reduce the heat pain compared to the group administered with excipients only, the pain relief effect was shown to be concentration-dependent drug. Compound 1 showed more than 25 mg / kg of comparable pain relief compared to the comparative drugs.

Example  4 Drug Evaluation of Compound 1 in Diabetic Neuropathy Pain Model

end. Experiment Content

(1) Induction of Diabetes in Rats

Forty-two male Sprague-Dawley rats weighing about 250 g were used as experimental animals. Night and day cycles were controlled at 12-hour intervals in the nursery, and three animals were kept in cages. Water and food were freely ingested and used for experiments after adapting in a laboratory environment for 7 days after purchase.

Diabetes was induced by intraperitoneal injection of 60 mg of streptozotocin per kg of body weight, and after 3 days of administration, venous blood was taken from the tail vein, and it was determined that diabetes was induced when fasting blood glucose was 250 mg / dL or more. The normal control group was injected with the same volume of citrate buffer. The experimental animals were divided into 12 normal controls without diabetes, 15 diabetic controls with diabetes, and 15 groups with Compound 1 after diabetes.

(2) Drug administration

Compound 1 was orally administered twice daily for 8 weeks after homogenizing 12.5 mg / kg body weight with 10% lutrol (excipient) to confirm that diabetes was induced. Normal control and diabetic controls received the same volume of 10% lutrol (excipient). Behavioral tests for mechanical allodynia were performed at 4, 6, and 8 weeks after drug administration, respectively.

(3) mechanical allodynia measurement

Mechanical allodynia was measured using von Frey hair. The rats were placed in a transparent acrylic box with a wire mesh at the bottom and open at the top and bottom. After the rats were stabilized, von Frey hair, which was able to apply 6 g of pressure, was used to apply pressure to the rats' feet and kept for 3 seconds. A total of 10 stimuli were applied to record the number of times the rat exhibited an avoidance response to lifting or avoiding paws. The average value was used as a result by repeating twice for each individual 15 minutes apart.

I. Experiment result

Compound 1 showed antiallodynic effect in diabetic neuropathy model. As a result of von Frey's test, there was a statistically significant mechanical allodynia in diabetic control group at 38.8 ± 5.5% at 4 weeks, 42.3 ± 6.3% at 6 weeks, and 35.8 ± 4.6% at 8 weeks. In the diabetic group treated with Compound 1, allergic dysfunction was reduced, and 21.3 ± 2.6%, 23.9 ± 3.7%, and 21.1 ± 2.9% at 4, 6, and 8 weeks after Compound 1 administration, respectively. In comparison, it was confirmed that the mechanical allodynia significantly decreased (FIG. 6).

Example 5 Drug Evaluation of Compound 1 in Diabetic Neuropathy Pain Model

end. Experiment Content

(1) Induction of Diabetes in Rats

 As an experimental animal (Oriental Bio), 30 mature male ICR mice at around 20 g of body weight were used. Night and day cycles were controlled at 12-hour intervals in the nursery, and water and food were freely consumed. Adapted in a lab environment for 7 days after purchase and used for experiments.

 Diabetes was induced by intraperitoneal injection of 200 mg of streptozotocin per kg of body weight, and 3 days after administration, venous blood was taken from the tail vein, and it was determined that diabetes was induced when fasting blood glucose was 250 mg / dL or more. The normal control group was injected with the same volume of citrate buffer. The experimental animals were divided into 10 normal control groups that did not cause diabetes, 10 diabetic control groups that induced diabetes, and 10 group treated with Compound 2 after inducing diabetes.

I. Experiment result

Compound 2 showed hyperalgesia effect on hyperalgesia in response to heat stimulation in diabetic neuropathy model (FIG. 7). As a result of the tail-flick test, it was observed that hyperalgesia with statistically significant heat stimulation was 16.9% at 3 weeks in the diabetic control group compared to the normal control group. In the diabetic group administered with Compound 2, it was confirmed that such hyperalgesia is reduced.

1 and 2 is a graph showing the analgesic effect of Compound 1 of the present invention in the acetic acid pain model.

3 and 4 are graphs showing the analgesic effect of Compound 1, a compound of the present invention, in a formalin pain model.

5 is a graph showing the analgesic effect of Compound 1 of the present invention in a heat pain model.

6 is a graph showing the antiallodynic effect of Compound 1, a compound of the present invention, in diabetic neuropathic pain model.

Figure 7 is a graph showing the reduction effect on hyperalgesia of compound 2 of the present invention in diabetic neuropathic pain model.

Claims (2)

2-acetoxy-5- [2- (4-trifluoromethyl-phenyl) -ethylamino] -benzoic acid represented by the following formula (1) and 2-hydroxy-5- [2- (4 represented by the formula (2) -Trifluoromethyl-phenyl) -ethylamino] -benzoic acid or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating or preventing pain. <Formula 1>

<Formula 2>

The method of claim 1, wherein the pain is nociceptive pain, cancer pain, back pain, inflammatory pain, musculoskeletal disorder pain, visceral pain, pain due to tension or sprains, post-operative pain, post-traumatic pain, post-burn pain, acute pain, Pharmaceutical composition, characterized in that the pain selected from the group consisting of headache, neuropathic pain and maxillofacial pain.

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