Use of carbamate compounds for prevention, alleviation or treatment of bipolar disorder

Abstract

The present invention relates to a use for the purpose of preventing, alleviating, or treating bipolar disorder by administering a pharmaceutical composition comprising a carbamate compound of the following chemical formula 1.

Claims

1. A method for alleviating or treating mania in a subject suffering from bipolar disorder, comprising administering to the subject a therapeutically effective amount of a carbamate compound of the following Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof: ##STR00005## wherein, R.sub.1 and R.sub.2 are each independently selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.8 alkyl, halo-C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 thioalkoxy and C.sub.1-C.sub.8 alkoxy; 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 R.sub.1 and R.sub.2 are each independently selected from the group consisting of hydrogen, halogen and C.sub.1-C.sub.8 alkyl.

3. 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##

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

5. The method according to claim 4, wherein the mammal is a human.

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

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows behavioral changes compared with the vehicle-administered negative control group after administration of carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl)ethyl ester prepared in the Preparation Example (the compound of Formula 2, hereinafter referred to as “the test compound”) to normal mice and bipolar mania-induced mice.

(2) FIG. 2 shows behavioral changes compared with the vehicle-administered negative control group after administration of the positive control compound valproic acid to normal mice and bipolar mania-induced mice.

DETAILED DESCRIPTION

(3) 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

(4) Carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl)ethyl ester was prepared according to the method described in Preparation Example 50 of PCT Publication No. WO 2010/150946.

Example: Experiment of Pharmacological Effect for Treatment of Mania in Mouse Bipolar Mania Model

(5) Male ICR mice weighing 20 to 25 g were purchased from Orient Bio and used in this experiment. Animals were stabilized for more than 4 days under conditions of standard temperature (19 to 25° C.), humidity (40 to 60%), free access to food and water, and controlled light (illuminated from 7 am to 7 pm), and then used. 158 mice were divided into the following groups. Compounds to be administered to mice in each group were prepared by dissolving them in 30% polyethylene glycol 400 (Sigma), and orally administered to mice at a volume of 10 ml/kg.

(6) Normal Mouse Group (7 to 8 Mice Per Group) Mice as a negative control group, once orally administered with 30% PEG400 as a vehicle at a dose of 10 ml/kg Mice once orally administered with the test compound at a dose of 5, 10 and 20 mg/kg Mice as a positive control group, once orally administered with valproic acid at a dose of 300 mg/kg

(7) Bipolar Mania-Induced Mouse Group (10 to 14 Mice Per Group, Administered with the Combination of Amphetamine and Chlordiazepoxide after Administration of the Following Control Compound and the Test Compound) Mice as a negative control group, once orally administered with 30% PEG400 as a vehicle at a dose of 10 ml/kg Mice once orally administered with the test compound at a dose of 5, 10 and 20 mg/kg Mice as a positive control group, once orally administered with valproic acid at a dose of 300 mg/kg

(8) To determine the concentration of the positive control compound and the test compound, valproic acid 300 mg/kg and the test compound 5, 10 and 20 mg/kg were each orally administered to normal mice. After 1 hour, an open field test was conducted for 30 minutes using Opto-Varimax® (Columbus Instruments, Ohio, USA) equipment, and it was confirmed that the behavior in these groups did not significantly decrease compared with the vehicle-administered negative control group [FIGS. 1 and 2: normal m ice].

(9) The combined preparation of Amphetamine 2.5 mg/kg and Chlordiazepoxide 2.5 mg/kg was intraperitoneally administered to mice to induce mania, and 30 minutes after administration the behavior was measured in the open field test for 30 minutes. Analysis of the measured behavior by one-tailed student's t test compared with the negative control group administered with only the vehicle indicated that the behavior significantly increased (p<0.05) [FIGS. 1 and 2: normal mouse control group vs. bipolar mania-induced mouse control group]. Hence, this was used as the bipolar mania induction condition (Arban et al., 2005).

(10) In order to confirm the effect of the positive control compound and the test compound to prevent mania in mania-induced models (inhibition of increased behavior), valproic acid 300 mg/kg, and the test compound 5, 10 and 20 mg/kg were each orally administered to mice in each group. After 30 minutes, the combined preparation of Amphetamine and Chlordiazepoxide was intraperitoneally administered. 30 minutes after intraperitoneal administration, the open field test was conducted for 30 minutes. The behavioral changes in the test group compared to the negative control group (100%) was analyzed by one-way ANOVA, which confirmed the efficacy (p<0.05), and the results are shown in FIGS. 1 and 2.

(11) Administration of the test compound in the mania-induced mice reduced the behavior in the open field test versus the vehicle-treated group (negative control group) (FIG. 1), and especially at doses of 10 mg/kg or more of the test compound the efficacy was similar or better than that of valproic acid at 300 mg/kg (FIG. 2). The test compound did not affect the behavior of the normal mice up to doses of 20 mg/kg, whereas it significantly reduced mania in the mania-induced mice, indicating that the test compound can treat bipolar mania without affecting normal behavior (FIG. 1).

(12) From the above results, it was confirmed that the present compounds showed sufficient pharmacological effect to inhibit an increase in behavior in the bipolar mania models and no effect on behavior of normal mice, and thus the present compounds can be effectively used as a drug for treating bipolar mania.