Use of a carbamate compound to prevent, alleviate or treat visceralgia or pain arising from visceral disease

Abstract

The present invention relates to use of a carbonate compound of chemical formula 1, or a pharmaceutically permissible salt, solvate or hydrate thereof, for prevention, alleviation or treatment of visceralgia, or pain arising from visceral disease.

Claims

1. A method for alleviating or treating visceral pain or pain caused by visceral diseases in a subject, comprising administering a therapeutically effective amount of a carbamate compound of the following Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof to the subject: ##STR00005## wherein, R.sub.1 and R2 are each independently selected from the group consisting of hydrogen, halogen, and C.sub.1-C.sub.8 alkyl; and one of A.sub.1 and A.sub.2 is CH, and the other is N.

2. The method according to claim 1, wherein the carbamate compound of Formula 1 is carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of the following Formula 2: ##STR00006##

3. The method according to claim 1, wherein the visceral disease is a disease related to internal organs caused by tumors, inflammation, ischemia or mechanical obstruction.

4. The method according to claim 1, wherein the visceral pain or pain caused by visceral diseases is a pain caused by cholecystitis, cholangitis, pancreatitis, pneumonia, pneumothorax, pleurisy, pleural pain, diaphragmatic abscess, hepatitis, Budd-Chiari syndrome, splenic infarction, splenic rupture, spleen abscess, gastritis, gastric ulcer, appendicitis, salpingitis, oophoritis, inguinal hernia, ectopic pregnancy, kidney stones, nephritis, cystitis, inflammatory colitis, mesenteric lymphadenitis, diverticulitis, irritable bowel syndrome, Crohn's disease, digestive ulcers, non-ulcerative dyspepsia, gastroesophageal reflux disease, abdominal aortic aneurysm rupture, abdominal aortic dissection, angina, myocardial infarction, myocarditis, endocarditis, esophagitis, pulmonary embolism, other heart and lung diseases, gastroenteritis, intestinal obstruction, aortic aneurysm rupture, peritonitis, very severe hyperlipidemia, hyperparathyroidism, acute adrenal insufficiency, porphyria, lead poisoning, heat stroke, shingles, visceral membrane tumors, childbirth or severe menstruation.

5. The method according to claim 1, wherein the subject is a mammal.

6. The method according to claim 5, wherein the mammal is a human.

7. The method according to claim 1, wherein the therapeutically effective amount of the carbamate compound of Formula 1 is 50 to 500 mg based on the free form once-daily administration.

Description

DETAILED DESCRIPTION

(1) Hereinafter, the present invention will be explained in more detail through working examples. However, the following working examples are only intended to illustrate one or more embodiments and are not intended to limit the scope of the invention.

PREPARATION EXAMPLE

Synthesis of Carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester

(2) Carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester (hereinafter referred to as “Test Compound”) was prepared according to the method described in Preparation Example 50 of International Publication No. WO 2010/150946.

EXAMPLE

Analgesic Effect in Acetic Acid-Induced Writhing Test

(3) Experimental Animals

(4) Male ICR mice (body weight: 24 to 30 g) were used in this experiment. The experimental animals were maintained at a light-and-darkness cycle of 12 hours, a temperature of 22 to 25° C., a relative humidity of 40 to 60%, and free access to water and food. For stabilization of animal behavior, the experimental animals were allowed to acclimate to the laboratory conditions for at least 1 hour before the test.

(5) Drug Administration, Acetic Acid Injection and Measurement of Pain Behavior

(6) As a vehicle serving as the negative control, 30% PEG400 (v/v) was used, and Test Compound was dissolved in the vehicle and administered orally at doses of 3, 10 and 30 mg/kg. Morphine which is the positive control was dissolved in saline and administered subcutaneously at a dose of 10 mg/kg. The final dose of solution was 10 ml/kg.

(7) After 1 hour of oral administration of the vehicle and Test Compound or 30 minutes after subcutaneous administration of morphine, the mice were gently restrained, and 0.8% (v/v) acetic acid solution was administered intraperitoneally to the abdomen of the mice. The mice were immediately returned to the observation box, and the number of writhing pain behaviors of the mice for 10 minutes was recorded.

(8) Statistics

(9) The effect of the compound was expressed as the mean±standard error, and statistical significance was recognized when data differed by p<0.05 using one-way ANOVA and Dunnett's test.

(10) Experiment Result

(11) As can be seen from Table 1, when Test Compound was administered orally, a statistically significant decrease in pain behavior was observed compared to the vehicle administration group. This reduction in pain behavior was observed in a dose-dependent manner, showing a pain suppression rate of 25.8% in the 3 mg/kg group, 66.1% in the 10 mg/kg group and a perfect pain suppression rate of 100% in the 30 mg/kg group. In addition, in the positive control (morphine) group, a significant reduction in pain behavior of 98.2% was observed by subcutaneous administration of 10 mg/kg.

(12) TABLE-US-00001 TABLE 1 Acetic acid-induced writhing test Suppression Dosage Number Number of rate compared Treatment (mg/kg, of writhing to negative drug p.o.) animals (writes/10 minutes) control.sup.2) Vehicle  0 8 23.3 ± 1.9 — Morphine 10 (s.c) 7  0.4 ± 0.3.sup.1)  98.2% Test  3 8 17.3 ± 2.6  25.8% Compound 10 8  7.9 ± 2.4.sup.1)  66.1% 30 8  0.0 ± 0.0.sup.1) 100.0% .sup.1)Significance of pain behavior time in comparison with negative; p < 0.01 .sup.2)Suppression rate compared to negetive control = [(vehicle group average of writhing number − morphine or Test Compound group average)/vehicle group average of writhing number] × 100

(13) From the above results of the pain model experiments, it was confirmed that

(14) Test Compound has a significant effect on visceral pain or pain caused by visceral diseases. In addition, it was confirmed that Test Compound exhibits a pharmacological effect at a level comparable to the narcotic analgesic, morphine which has already been used as a therapeutic agent for patients suffering from visceral pain or pain caused by visceral diseases.