Medicaments and pharmaceutical compositions comprising carbamate compound for use in the prevention, alleviation or treatment of diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy

Abstract

The present invention relates to a use to be used for the purpose of preventing, alleviating or treating diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy by administering a pharmaceutical composition containing a carbamate compound of chemical formula 1.

Description

Use of carbamate compounds for the prevention, alleviation or treatment of diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy

[0001] The present invention relates to a use for the purpose of preventing, alleviating or treating diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy by administering a pharmaceutical composition comprising a carbamate compound of the following chemical formula 1:

[0002] [Chemical Formula 1]

[0003]

[0004] In the above chemical formula 1, R1, R2, A1 and A2 are as defined herein.

[0005] Peripheral neuropathy refers to the structural and functional disorders of the peripheral nerves, which consist of motor, sensory, and autonomic nerves. Depending on the type of nerve affected, various symptoms may appear. Peripheral neuropathy may be a standalone condition, caused by other conditions such as ischemia or diabetes, or as a side effect of chemotherapy or radiation therapy. Symptoms include a variety of combinations, including lethargy, changes in the autonomic nervous system, and sensory changes. Sensory neuropathy, in particular, manifests as benign symptoms, including loss of sensation, tingling, and pain, depending on the affected nerve or organ.

[0006] Among peripheral neuropathy, neuropathy resulting from complications of diabetes is the most common, and approximately 34% of diabetic patients suffer from diabetic peripheral neuropathy (DPN). However, it is known that 50% of diabetic peripheral neuropathy is asymptomatic, which is known to worsen the disease. Diabetic peripheral neuropathy is characterized by paresthesia, pain, allodynia, hyperalgesia, numbness, muscle weakness, and cramps. Paresthesia, which is a decrease in sensation, can cause an inability to feel temperature changes or injuries, and pain that feels like tingling, prickling, stabbing, or burning. Muscle weakness also reduces reflexes, balance, and coordination. Painful diabetic peripheral neuropathy is a major factor in lowering the quality of life due to pathologically severe pain, and can also be accompanied by depression.

[0007] In order to fundamentally prevent or delay the progression of diabetic peripheral neuropathy, blood sugar control is essential to prevent damage to peripheral nerves, and treatment includes treatment of the cause and symptomatic treatment.

[0008] Common treatments include low-dose tricyclic antidepressants such as nortriptyline or amitriptyline, serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine, and anticonvulsants such as gabapentin or pregabalin. Additionally, pain relievers such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are used. However, current treatments are insufficient to demonstrate sufficient efficacy, with pain reduction effects of less than 30% in 20-40% of patients. (Lancet Neurol. 2015; 14: 162-173)

[0009] Chemotherapy has increased the survival rate of many cancer patients, but it also causes various side effects. Among these, chemotherapy-induced peripheral neuropathy (CIPN) is a representative side effect of chemotherapy, with a prevalence of 68%. Symptoms persist for weeks to months after treatment, and in some cases, even years, resulting in pain syndrome. Chemotherapy agents such as platinum, taxane, and vinca alkaloids are known to be the primary inducers of CIPN, and these agents are commonly used in patients with colorectal, gastric, breast, and hematological cancers. Chemotherapy damages the myelin sheath surrounding nerve axons, leading to nerve cell degeneration. Key symptoms include sensory disturbances such as pain, paresthesia, allodynia, hyperalgesia, and numbness; motor disturbances such as muscle weakness, cramps, and decreased muscle tone; and autonomic dysfunction such as hypotension, sweating, and gastrointestinal symptoms. In anticancer chemotherapy, the probability of occurrence increases as the dose increases, the drug administration cycle becomes shorter, and many types of drugs are administered together. It is also known that the probability of occurrence is higher if there is a previous experience with other neuropathy.

[0010] When CIPN occurs, various attempts are made to enhance the autogenous capacity of peripheral nerves, such as discontinuing or reducing the dose of chemotherapy, as suggested by the integrated cancer treatment guidelines. Duloxetine is recommended as a moderate treatment for CIPN, and other possible treatments include tricyclic antidepressants, gabapentin plus opioids, and the triple combination of baclofen, amitriptyline, and ketamine. Furthermore, various drug combinations, such as alpha-lipoic acid, amifostine, amitriptyline, and calcium and magnesium, are being used, although their efficacy has not been proven.

[0011] The present invention seeks to provide a method for preventing, alleviating or treating diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy.

[0012] In addition, the present invention provides a use of a carbamate compound of the following chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in the prevention, alleviation or treatment of diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy:

[0013] [Chemical Formula 1]

[0014]

[0015] In the above chemical formula 1, R1, R2, A1 and A2 are as defined herein.

[0016] The present invention provides a medicament for preventing, alleviating or treating diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy, comprising a therapeutically effective amount of a carbamate compound of the following chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0017] [Chemical Formula 1]

[0018]

[0019]

[0020] In the above chemical formula 1,

[0021] R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 thioalkoxy and C1-C8 alkoxy,

[0022] In A1 and A2, one is CH and the other is N.

[0023] In addition, the present invention provides a pharmaceutical composition for preventing, alleviating or treating diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy, comprising a therapeutically effective amount of a carbamate compound of the above chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and further comprising at least one pharmaceutically acceptable carrier.

[0024] In addition, the present invention provides a method for preventing, alleviating or treating diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy, comprising administering to a subject a therapeutically effective amount of a carbamate compound of the above chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0025] In addition, the present invention provides a use of the carbamate compound of the above chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for preventing or treating diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy, or for improving symptoms related thereto.

[0026]

[0027] According to one specific example of the present invention, in the above chemical formula 1, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen and C1-C8 alkyl.

[0028] In one specific embodiment, C1-C8 haloalkyl is perfluoroalkyl.

[0029]

[0030] According to another specific example of the present invention, the carbamate compound of the above formula 1 is carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl)ethyl ester of the following formula 2:

[0031] [Chemical Formula 2]

[0032]

[0033]

[0034] The carbamate compounds of the above chemical formulas 1 and 2 can be prepared by those skilled in the art using known compounds or compounds that can be easily prepared therefrom. In particular, the method for preparing the compound of the above chemical formula 1 is described in detail in International Patent Publication Nos. WO 2006 / 112685 A1, WO 2010 / 150946 A1, and WO 2011 / 046380 A2, which are incorporated herein by reference. The compound of the above chemical formula 1 can be chemically synthesized by the methods described in the above documents, but these are merely exemplary methods, and the order of unit operations, etc. can be selectively changed as needed, and are not intended to limit the scope of the invention.

[0035]

[0036] The carbamate compound of the above chemical formula 1 can be used for the prevention, alleviation or treatment of diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy.

[0037] Diabetic peripheral neuropathy is a type of chronic sensorimotor neuropathy, and is a concept that includes painful diabetic peripheral neuropathy and diabetic autonomic neuropathy.

[0038] Chemotherapy-induced peripheral neuropathy (CIPN) occurs in approximately 40% of patients receiving chemotherapy, and symptoms vary depending on the chemotherapy agent used, including its mechanism of action, dosage, and duration of administration. The main chemotherapy agents that cause CIPN include platinum, taxane, and vinca alkaloids.

[0039] The dosage of the carbamate compound of formula 1 for the prevention, alleviation, or treatment of the above disease will typically vary depending on the severity of the disease, the body weight, and the metabolic state of the subject to be treated. A "therapeutically effective amount" for an individual patient means an amount sufficient to achieve the above-mentioned pharmacological effect, i.e., a therapeutic effect. A therapeutically effective amount of the compound of formula 1, when administered to a human, is 50 to 500 mg, 50 to 400 mg, 50 to 300 mg, 100 to 400 mg, 100 to 300 mg, 50 to 200 mg, or 100 to 200 mg once daily on a free basis. Preferably, it is 50 to 300 mg, and more preferably, it is 50 to 200 mg.

[0040] The compound of the present invention can be administered by conventional methods used for administering therapeutic agents, such as oral, parenteral, intravenous, intramuscular, subcutaneous, or rectal administration.

[0041] The therapeutically effective amount of the compound of formula 1 can be achieved by an appropriate titration method. In one embodiment, the titration method may include: (1) administering 12.5 mg of the compound of formula 1 to the patient once daily for two weeks; (2) thereafter administering 25 mg of the compound of formula 1 to the patient once daily for two weeks; (3) thereafter administering 50 mg of the compound of formula 1 to the patient once daily for two weeks; and (4) thereafter increasing the dose by up to 50 mg of the compound of formula 1 once daily at two-week intervals until a therapeutically effective amount is reached. In another embodiment, the titration method may include: (1) administering 50 mg of the compound of formula 1 to the patient once daily for two weeks; (2) a step of increasing the dosage of 50 mg of the compound of formula 1 once a day at two-week intervals until 200 mg of the compound of formula 1 is administered once a day, wherein the compound of formula 1 is administered for six weeks and the therapeutically effective amount is 200 mg / day. In another specific example, the dosing regimen may include a step of (1) administering 50 mg of the compound of formula 1 to the patient once a day, increasing the dosage by 50 mg every week until the dosage becomes 100 mg / day, and further a step of (2) increasing the dosage by 50 mg every week until the dosage becomes 200 mg / day after step (1); Or (3) it may include a step of increasing the dosage by 100 mg every week to reach a dosage of 400 mg / day, and at this time, it may be a method of administering for 2 weeks, 4 weeks, or 6 weeks depending on the required therapeutically effective amount of the compound of chemical formula 1 (100 mg / day, 200 mg / day, or 400 mg / day).

[0042] In addition to the methods described above, an appropriate dosage regimen may be used to achieve a therapeutically effective amount of the compound of formula 1.

[0043] According to another embodiment of the present invention, a medicament for preventing, alleviating or treating symptoms of diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy is provided, comprising a therapeutically effective amount of a carbamate compound of the above chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0044] Symptoms of the above diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy may include, but are not limited to, paresthesia, hyperalgesia, allodynia, numbness, loss of vibration or position sense, muscle weakness, muscle tone, cramps, hypotension, sweating, or gastrointestinal abnormalities.

[0045]

[0046] A pharmaceutical or pharmaceutical composition according to a specific embodiment of the present invention may comprise a therapeutically effective amount of a compound selected from the group consisting of a carbamate compound of the present invention, a pharmaceutically acceptable salt, solvate, hydrate thereof, and combinations thereof.

[0047] Pharmaceutically acceptable salts of the carbamate compound of the above chemical formula 1 include, for example, independently, acetate, benzenesulfonate, benzoate, bitartrate, calcium acetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydrogencarbonate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, Polygalacturonate. Salicylate, stearate, subacetate, succinate or hemisuccinate, sulfate or hemisulfate, tannate, tartrate, oxalate or hemitartrate, teoclate, triethiodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, ammonium, tetramethylammonium, calcium, lithium, magnesium, potassium, sodium, and zinc.

[0048] A pharmaceutical or pharmaceutical composition according to one embodiment of the present invention may be administered orally or parenterally. In the case of parenteral administration, it may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intradermal administration, topical administration, intranasal administration, intravaginal administration, intrapulmonary administration, and rectal administration. In the case of oral administration, the pharmaceutical composition according to one embodiment may be formulated as a tablet, or the active agent may be coated or protected from degradation in the stomach. In addition, the composition may be administered by any device that allows the active agent to travel to the target cell. The route of administration may vary depending on the general condition and age of the subject to be treated, the nature of the treatment condition, and the active ingredient selected.

[0049] The appropriate dosage of a drug or pharmaceutical composition according to one embodiment of the present invention varies depending on factors such as the formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity, and a skilled physician can easily determine and prescribe a dosage effective for the desired treatment or prevention. The pharmaceutical composition according to one embodiment may be administered in one or multiple doses, for example, may be administered once to four times a day. According to one specific example, the pharmaceutical composition may contain 50 to 500 mg, 50 to 400 mg, 50 to 300 mg, 100 to 400 mg, 100 to 300 mg, 50 to 200 mg, or 100 to 200 mg of the compound of formula 1 in free form, preferably 50 to 300 mg, more preferably 50 to 200 mg.

[0050] A pharmaceutical or pharmaceutical composition according to one embodiment of the present invention may be manufactured in a unit dosage form or may be manufactured by placing it in a multi-dose container by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains, and thereby. In this case, the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or in the form of an extract, powder, granules, tablet or capsule, and may additionally include a dispersing agent or stabilizer. In addition, the pharmaceutical composition may be administered in the form of a suppository, spray, ointment, cream, gel, inhalant or skin patch. In addition, the pharmaceutical composition may be manufactured for administration to mammals, more preferably for administration to humans.

[0051] The pharmaceutically acceptable carrier may be solid or liquid and may be one or more selected from excipients, antioxidants, buffers, bacteriostatic agents, dispersants, adsorbents, surfactants, binders, preservatives, disintegrants, sweeteners, flavoring agents, glidants, release-controlling agents, wetting agents, stabilizers, suspending agents, and lubricants. In addition, the pharmaceutically acceptable carrier may be selected from saline solution, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and mixtures thereof.

[0052] In one embodiment, suitable fillers include, but are not limited to, sugars (e.g., dextrose, sucrose, maltose, and lactose), starches (e.g., corn starch), sugar-alcohols (e.g., mannitol, sorbitol, maltitol, erythritol, and xylitol), starch hydrolysates (e.g., dextrin and maltodextrin), cellulose or cellulose derivatives (e.g., microcrystalline cellulose), or mixtures thereof.

[0053] In one specific embodiment, suitable binders include, but are not limited to, povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, gums, sucrose, starch, or mixtures thereof.

[0054] In one specific example, suitable preservatives include, but are not limited to, benzoic acid, sodium benzoate, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorbutol, gallate, hydroxybenzoate, EDTA or mixtures thereof.

[0055] In one specific example, suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked carboxymethylcellulose, starch, microcrystalline cellulose, or mixtures thereof.

[0056] In one embodiment, suitable sweeteners include, but are not limited to, sucralose, saccharin, sodium or potassium or calcium saccharin, acesulfame potassium or sodium cyclamate, mannitol, fructose, sucrose, maltose or mixtures thereof.

[0057] In one specific example, suitable glidants include, but are not limited to, silica, colloidal silicon dioxide, talc, and the like.

[0058] In one specific embodiment, suitable lubricants include, but are not limited to, long-chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glyceride waxes, or mixtures thereof.

[0059]

[0060] The carbamate compound of the above chemical formula 1 can be used together with an additional drug for the prevention, alleviation or treatment of diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy.

[0061] In one specific embodiment according to the present invention, the pharmaceutical or pharmaceutical composition of the present invention may be a combination preparation comprising a carbamate compound of the above chemical formula 1 and such an additional drug as a therapeutically effective amount of an active ingredient.

[0062] In one specific example, examples of additional drugs include, but are not limited to, painkillers such as acetaminophen or nonsteroidal anti-inflammatory drugs for diabetic peripheral neuropathy, antidepressants such as tricyclic antidepressants such as nortriptyline or amitriptyline or MAO inhibitors, anticonvulsants such as gabapentin or pregabalin, and combination drugs of baclofen + amitriptyline + ketamine, and CIPN includes, but is not limited to, painkillers such as acetaminophen or nonsteroidal anti-inflammatory drugs, antidepressants such as tricyclic antidepressants such as nortriptyline or amitriptyline or MAO inhibitors, anticonvulsants such as gabapentin or pregabalin, opioids, capsaicin, and the like.

[0063] In one specific example, when the pharmaceutical or pharmaceutical composition of the present invention is the above-mentioned combination preparation, the weight ratio (a:b) of the carbamate compound of the above-mentioned chemical formula 1 [component (a)] and the additional drug [component (b)] in the combination preparation may be, for example, within the range of 1,000:1 to 1:1,000, or 500:1 to 1:500, or 100:1 to 1:100, or 50:1 to 1:50, or 10:1 to 1:10, but is not limited thereto.

[0064]

[0065] The terms "prevent," "preventing," and "prevention" as used herein mean reducing the likelihood of or eliminating the possibility of contracting a disease.

[0066] The terms "alleviate," "alleviating," and "alleviation," as used herein, mean alleviating all or part of a disease and / or its accompanying symptoms.

[0067] The terms “treat,” “treating,” and “treatment” as used herein mean eliminating all or part of a disease and / or its accompanying symptoms.

[0068] The term "subject" as used herein means an animal, preferably a mammal (e.g., primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc.), and most preferably humans, that is the object of treatment, observation or experiment.

[0069] The term "therapeutically effective amount" as used herein means that amount of an active compound or pharmaceutical preparation that is sought by a researcher, veterinarian, physician, or other clinician to induce a biological or medical response in a tissue system, animal, or human, including alleviating the symptoms of the disease or disorder being treated.

[0070] The term "composition" as used herein includes a product comprising a specified ingredient in a specified amount and any product resulting directly or indirectly from a combination of specified ingredients in specified amounts.

[0071] The drug or composition according to the present invention can effectively prevent, alleviate or treat diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy.

[0072] Figure 1 shows the average blood glucose level (BGL) measured in all animals to confirm the induction of diabetes in rats by streptozotocin. The average BGL at baseline was 102.52 ± 0.93 mg / dl, but increased to 385.33 ± 7.28 mg / dl 3 days after streptozotocin administration. The elevated BGL was maintained throughout the experimental period, reaching 405.05 ± 12.74 mg / dl on day 14, and 412.52 ± 10.77 mg / dl by day 23, confirming that diabetes was induced and maintained throughout the experimental period.

[0073] Figure 2 shows the results of comparing the preventive and therapeutic effects of mechanical allodynia induced by streptozotocin in rats by administering carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl)ethyl ester (hereinafter referred to as “test compound”) prepared in the manufacturing example and the positive control compound gabapentin to the negative control group administered a vehicle through the von Frey test.

[0074] Figure 3 shows the results of comparing the effects of test compounds and a positive control group on suppressing the development of mechanical allodynia in rats induced by Taxol, as measured by the von Frey test, with those of the negative control group administered a vehicle. Taxol-induced peripheral neuropathy was induced by intraperitoneal (IP) administration of 2 mg / kg Taxol at a dose of 0.5 ml / kg to rats on days 1, 3, 5, 7, and 9.

[0075] The present invention is described in more detail below through examples. However, these examples are merely intended to illustrate one or more specific examples and are not intended to limit the scope of the invention.

[0076]

[0077] Manufacturing example: Preparation of carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl)ethyl ester

[0078] Carbamate (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl)ethyl ester (used herein with the same meaning as “test compound”) was prepared according to the method described in Preparation Example 50 of International Publication No. WO 2010 / 150946.

[0079] Example 1: Experimental model of diabetic peripheral neuropathy

[0080] The effect of the test compound on alleviating diabetic peripheral neuropathy was confirmed using a streptozotocin (STZ)-induced rat model, which is widely known as a model for diabetes and diabetic peripheral neuropathy.

[0081] laboratory animals

[0082] Male rats (Sprague-Dawley, 160-180 g, Harlan Laboratories, Israel) were purchased and acclimated to the animal laboratory for more than 1 week. The experimental animals were allowed free access to water and food under an environment with a 12-h day / night cycle, a temperature of 20-24°C, and a relative humidity of 40-60%.

[0083] Measurement of mechanical allodynia (von Frey test)

[0084] The severity of pain was assessed by the withdrawal response using a von Frey filament. The mechanical stimulus was applied to the right hind paw using the up-down method, and the minimum force of flexion that elicited a withdrawal response was defined as the paw withdrawal threshold (J Neurosci Methods, 1994; 53 (1): 55-63). First, the rats were placed in an acrylic box (13 × 25 × 13 cm3) with a wire mesh floor installed approximately 35 cm above the floor and allowed to stabilize for at least 20 minutes. Among the filaments with various bending forces (0.008, 0.02, 0.04, 0.07, 0.16, 0.4, 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0, 26.0, 60.0, 100, 180, and 300 g), stimulation was applied starting with a 2.0 g filament to the extent that it slightly bent in the vertical direction to the sole surface, and stimulation was performed with a filament with lower or higher bending force depending on the presence or absence of a response.

[0085] Induction of diabetic peripheral neuropathic pain

[0086] This experiment investigated the analgesic effect of compound treatment at two different doses (10 mg / kg and 30 mg / kg) in a streptozotocin (STZ)-induced diabetic peripheral neuropathic pain model in rats.

[0087] Diabetes was induced by injecting 0.5 ml of streptozotocin (60 mg / kg) dissolved in sodium citrate buffer (pH = 6) into the tail vein of rats. Animals were placed under a red lamp before injection and then restrained in a restraint device.

[0088] The rat model of streptozotocin (STZ)-induced diabetic peripheral neuropathy is induced between days 14 and 24 following intra-caudal injection of STZ. Blood glucose levels (BGL) were measured in all animals on day 3 of the experiment to determine whether diabetes had been induced. Animals showing signs of mechanical allodynia by the von Frey test on day 14 were evaluated for BGL on days 14 and 23 of the experiment (Fig. 1).

[0089] The test compound and the positive and negative control groups were administered daily from experimental days 14 to 24 (administration route: negative control and test compound-PO, positive control-IP). Pain tests were performed on experimental days 14 and 24, 2 hours after administration of the negative control group, test compound, and positive control. After the experiment, all animals were euthanized with CO2.

[0090] result

[0091] 1) Results of the von Frey test at 10 mg / kg and 30 mg / kg of test compound: The mean flexion force required to induce an avoidance response in the negative control treated animals at baseline was 60.00 ± 0.00 g compared to the vehicle-treated group on days 14 and 24. On day 14 of the experiment, the avoidance flexion force (18.55 ± 2.47 g) due to mechanical allodynia before drug administration was significantly lower, and on day 24, the mechanical allodynia before drug administration was still present (23.00 ± 5.35 g).

[0092] On day 14 of the experiment, administration of the positive control gabapentin at a dose of 150 mg / kg IP did not significantly inhibit allodynia (51.85 ± 4.91 g vs. 34.50 ± 6.61 g for the vehicle). Administration of the test compound at 10 mg / kg PO also showed a tendency to inhibit allodynia (46.09 ± 4.48 g vs. 34.50 ± 6.61 g for the vehicle). Administration of the test compound at 30 mg / kg PO also showed a tendency to inhibit allodynia (50.23 ± 3.89 g for the test compound at 30 mg / kg vs. 34.50 ± 6.61 g for the vehicle).

[0093] On the 24th day of the experiment, gabapentin at a dose of 150 mg / kg IP showed a significant inhibitory effect on the induction of pain (45.30 ± 4.63 g) compared to the vehicle (22.85 ± 3.86 g). Administration of the test compound at a dose of 10 mg / kg PO showed a significant inhibitory effect on the induction of pain (44.36 ± 3.63 g) compared to the vehicle-administered group (22.85 ± 3.86 g). Administration of the test compound at a dose of 30 mg / kg PO also showed a significant effect on the induction of pain (46.91 ± 4.46 g) compared to the vehicle-administered group (22.85 ± 3.86 g) (Fig. 2).

[0094] 2) Results of the von Frey test at 10 mg / kg and 30 mg / kg of the test compound on days 14 and 24: Pretreatment vs. posttreatment:

[0095] On the 14th day of the experiment, the flexion force, which was 18.15 ± 2.07 g before gabapentin 150 mg / kg IP administration as a positive control, significantly suppressed allodynia induction to 51.85 ± 4.91 g after administration. The test compound 10 mg / kg PO administration showed a significant allodynia-inducing suppression effect from 18.23 ± 2.66 g before administration to 46.09 ± 4.48 g after administration. In addition, 30 mg / kg PO administration showed a significant allodynia-inducing suppression effect from 18.23 ± 2.17 g before administration to 50.23 ± 3.89 g after administration.

[0096] On the 24th day of the experiment, the flexion force, which was 25.50 ± 3.95 g before gabapentin 150 mg / kg IP administration, significantly suppressed allodynia induction to 45.30 ± 4.63 g after administration. The test compound 10 mg / kg PO showed a significant allodynia-inducing suppression effect from 25.18 ± 2.96 g before administration to 44.36 ± 3.63 g after administration, and 30 mg / kg PO also showed a significant allodynia-inducing suppression effect from 23.55 ± 2.52 g before administration to 46.91 ± 4.46 g after administration (Fig. 2).

[0097] conclusion

[0098] In the present invention, when compared with the highest dose of gabapentin (150 mg / kg), which is a positive control used for the treatment of DPN in a streptozotocin-induced rat model of DPN, a low dose of the test compound (10 mg / kg) showed ~75% pain reduction compared to the negative control, showing similar efficacy to gabapentin 150 mg / kg. From these results, it was confirmed that administration of the test compound at 10 mg / kg and 30 mg / kg was effective in suppressing mechanical allodynia. From this, it was found that administration of the test compound was effective in treating diabetic peripheral neuropathy.

[0099]

[0100] Example 2: Experimental model of chemotherapy-induced peripheral neuropathy

[0101] laboratory animals

[0102] Male rats (Sprague-Dawley, 160-180 g, Harlan Laboratories, Israel) were purchased and acclimated to the animal laboratory for more than 1 week. The experimental animals were allowed free access to water and food under an environment with a 12-h day / night cycle, a temperature of 20-24°C, and a relative humidity of 40-60%.

[0103] Measurement of mechanical allodynia (von Frey test)

[0104] The degree of pain was assessed by the withdrawal response using von Frey filaments. The mechanical stimulus was applied to the right hind paw using the up-down method, and the minimum force of flexion that showed the withdrawal response was defined as the paw withdrawal threshold (J Neurosci Methods, 1994; 53 (1): 55-63). First, the rats were placed in an acrylic box (13 x 25 x 13 cm) with a wire mesh floor installed approximately 35 cm above the floor. 3 ) and stabilization was performed for at least 20 minutes. Among the filaments with various flexural forces (0.008, 0.02, 0.04, 0.07, 0.16, 0.4, 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0, 26.0, 60.0, 100, 180, and 300 g), stimulation was applied starting with a 2.0 g filament to the extent that it slightly bent in the vertical direction to the sole surface, and stimulation was performed with a filament with a lower or higher flexural force depending on the presence or absence of a response.

[0105] Taxol-induced pain neuropathy

[0106] Peripheral neuropathy was induced by intravenous administration of 0.5 ml / kg of Taxol (2 mg / kg), a commonly used anticancer drug for the treatment of solid tumors, on days 1, 3, 5, 7, and 9. The von Frey test was used to confirm the induction of allodynia. Only animals with a mean pain threshold of 43 g or less in the hind paw were included in the study.

[0107] On day 13 of the experiment, only animals that demonstrated allodynia by the von Frey test were selected for the experimental group. The test compounds (10 mg / kg and 30 mg / kg) and the vehicle as a negative control were administered orally 2 hours before the pain test on days 13 and 14. The positive control, morphine (5 mg / kg), was administered intraperitoneally 30 minutes before the pain test on days 13 and 14. After the study, all animals were euthanized with CO2.

[0108] result

[0109] The rat model of pain induction through Taxol administration is a well-known model of chemotherapy-induced peripheral neuropathy. Hyperalgesia was induced by Taxol administration on days 1, 3, 5, 7, and 9 of the study. This was confirmed through the von Frey test before drug treatment on day 13 of the experiment. The maintenance of hyperalgesia throughout the experimental period was confirmed through data from the vehicle-administered group after drug treatment on days 13 and 14.

[0110] On the 13th day of the experiment, the morphine group administered at a dose of 5 mg / kg IP showed a significant allodynia-induced suppression effect compared to the vehicle-administered group. The test compound-administered group at a dose of 10 mg / kg showed a tendency to suppress allodynia-induced pain compared to the vehicle-administered group, and the test compound-administered group at a dose of 30 mg / kg showed a significant allodynia-induced suppression effect compared to the vehicle-administered group.

[0111] On the 14th day of the experiment, the morphine group administered at a dose of 5 mg / kg IP showed a significant allodynia-induced suppression effect compared to the vehicle-administered group. The group administered at a dose of 10 mg / kg of the test compound showed a tendency to suppress allodynia-induced pain compared to the vehicle-administered group, and the group administered at a dose of 30 mg / kg showed a significant allodynia-induced suppression effect (Fig. 3).

[0112] conclusion

[0113] Considering the results obtained under the conditions of this study and the limited results in lifestyle data, the administration of the test compound at a dose of 10 mg / kg tended to suppress mechanical allodynia in a peripheral neuropathy model, and the administration of the test compound at a dose of 30 mg / kg showed significant efficacy in suppressing mechanical allodynia in a Taxol-induced peripheral neuropathy model. From this, it was found that the administration of the test compound was effective in treating chemotherapy-induced peripheral neuropathy.

[0114]

[0115] statistics

[0116] Each experimental group was compared with the negative control group using one-way ANOVA and Turkey post-test (Prism®GraphPad).

Claims

1. A drug for preventing, alleviating or treating diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy, comprising a therapeutically effective amount of a carbamate compound of the following chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof: [Chemical Formula 1] In the above chemical formula 1, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 thioalkoxy and C1-C8 alkoxy, In A1 and A2, one is CH and the other is N.

2. In paragraph 1, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, and C1-C8 alkyl.

3. In the first paragraph, the carbamate compound of the chemical formula 1 is a carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl)ethyl ester of the following chemical formula 2: [Chemical Formula 2] 4. A drug according to any one of claims 1 to 3, which is manufactured for administration to mammals.

5. A drug according to any one of claims 1 to 3, wherein the therapeutically effective amount of the carbamate compound of formula 1 is 50 to 500 mg in free form when administered once a day.

6. A drug according to claim 1, wherein the diabetic peripheral neuropathy is diabetic painful peripheral neuropathy, diabetic autonomic neuropathy, or both.

7. In paragraph 1, the chemotherapeutic agent causing chemotherapy-induced peripheral neuropathy is at least one drug selected from the group consisting of platinum series, taxane series, and vinca-alkaloid series.

8. A pharmaceutical composition for preventing, alleviating or treating diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy, comprising a therapeutically effective amount of a carbamate compound of the following chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and further comprising at least one pharmaceutically acceptable carrier: [Chemical Formula 1] In the above chemical formula 1, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, halo C1-C8 alkyl, C1-C8 thioalkoxy and C1-C8 alkoxy, In A1 and A2, one is CH and the other is N.

9. A pharmaceutical composition in claim 8, wherein R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, and C1-C8 alkyl.

10. In paragraph 8, a pharmaceutical composition wherein the carbamate compound of chemical formula 1 is carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl)ethyl ester of chemical formula 2 below: [Chemical Formula 2] 11. A pharmaceutical composition prepared for administration to a mammal according to any one of claims 8 to 10.

12. A pharmaceutical composition according to any one of claims 8 to 10, wherein the therapeutically effective amount of the carbamate compound of formula 1 is 50 to 500 mg in free form when administered once a day.

13. A pharmaceutical composition according to claim 8, wherein the diabetic peripheral neuropathy is diabetic painful peripheral neuropathy, diabetic autonomic neuropathy, or both.

14. A pharmaceutical composition according to claim 8, wherein the chemotherapeutic agent causing chemotherapy-induced peripheral neuropathy is at least one selected from the group consisting of platinum series, taxane series, and vinca-alkaloid series.

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