Carbamate compounds and processes for preparing the same

Details Carbamate compounds and processes for preparing the same Carbamate compounds and processes for preparing the same

1996-06-17

1998-12-15

Davis, Zinna Northington

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514538, 546335, 560157, C07D21330, C07D27108, A61K 3144, A61K 31165

Patent

active

058497722

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/KR95/00124 Sep. 21, 1995.


BACKGROUND OF THE INVENTION

1. Field of the Invention
The present invention relates, in general, to novel enantiomeric carbamate compounds pharmaceutically useful for central nervous disorders and, more particularly, to (S)-2-aryl-1,3-propanediol monocarbamate derived from (R)-3-acetoxy-2-arylpropanol carbamate and to (S)-3-acetoxy-2-arylpropanol carbamate, its intermediate. Also, the present invention is concerned with processes for preparing the novel carbamate compounds.
2. Description of the Prior Art
Carbamates have been effectively used for controlling central nervous system (hereinafter referred to as "CNS") disorders, especially, as an antiepiletic and a centrally acting muscle relaxant. For example, 2-methyl-2-propyl-1,3-propanediol dicarbamate was reported in J. Am. Chem. Soc., 73, 5779 (1951), and the pharmaceutical activity thereof was ascertained in J. Pharmacol. Exp. Ther., 104, 229 (1952).
U.S. Pat. No. 3,256,728 discloses that the compounds, represented by the following general formula A, are pharmaceutically useful therapeutics for CNS disorders: ##STR3## wherein, R.sub.1 is a carbamate or methylene carbamate; R.sub.2 is an alkyl group containing one or two carbon atoms, a hydroxy alkyl group containing one or two carbon atoms, hydroxy or hydrogen; R.sub.3 is hydrogen or an alkyl group containing one or two carbon atoms; and Z represents a halogen such as fluorine, chlorine, bromine or iodine, a methylmethoxy group, a phenyl group, a nitro group or an amine group.
Besides, other carbamate compounds which are very useful therapeutic medicines against CNS disorders, in particular, as antiepiletic and centrally acting muscle relaxant, are disclosed, including 2-phenyl-1,3-propanediol dicarbamate in U.S. Pat. No. 2,884,444 and isopropyl meprobamate in U.S. Pat. No. 2,937,119. At present, various researches for such carbamate compounds are being actively continued in the art.


SUMMARY OF THE INVENTION

Based on intensive and thorough study and research by the present inventors, it was found that the carbamate compounds represented by the following structural formulas I and II are useful for the treatment and prevention of CNS diseases including nervous myalgia, epilepsy and cerebral apoplexy: ##STR4## wherein, R is ##STR5## wherein X is an oxygen atom or a sulfur atom; and Y represents a halogen element, trifluoromethyl, or a lower alkyl group containing one to three carbon atoms.
In addition, taking advantage of the far superior activity of single enantiomeric isomer to racemic mixture in biological systems, the present inventors developed the enantiomers of Formulas I and II, which had never been found, and applied them as pharmaceutically active ingredients against CNS diseases.
The carbamate compounds of Formulas I and II are chiral molecules with a chiral center of carbon at 2-propyl and may have either an (S) or (R)-configuration.
Accordingly, it is an object of the present invention to provide novel (S)-enantiomeric compounds represented by Formulas I and II, which have pharmaceutically useful activity against central nervous system diseases.
It is another object of the present invention to provide a method for preparing the compounds of Formulas I and II at high yield and high purity within a short time.


DETAILED DESCRIPTION OF THE INVENTION

The compound of Formula II can be prepared by treating (R)-3-acetoxy-2-aryl-propanol, represented by the following formula III: ##STR6## wherein, R is as defined above, with phosgene in a mixture of aromatic hydrocarbon and halogenohydrocarbon in the presence of amine base, and followed by anhydrous ammonia.
Available aromatic hydrocarbons include benzene, toluene and xylene and a halogenohydrocarbon is selected from the group consisting of chloroform, dicholomethane, 1,2-dichloroethane and trichloroethane. The preferred solvent is a mixture of toluene and dichloromethane.
As the amine base, antipyrine, diisopropylethylamine, diethylamine, triethylamine or pyridine is available, with

REFERENCES:
patent: 2884444 (1959-04-01), Berger et al.
patent: 2937119 (1960-05-01), Berger et al.
patent: 3265728 (1966-08-01), Bossinger
patent: 4221582 (1980-09-01), Garrod et al.
Chemical Abstracts, vol. 119, No. 21, Abstract 216, 700b, Nov. 22, 1993, p. 14 (Advsomalle et al.).
Choi et al, J. of Org. Chem, vol. 57, No. 21, 1992 pp. 5764-5766.
Ludwig et al, J. of Med. Chem, vol. 12, No. 3, 1969, pp. 462-472.
Ludwig et al., J.A.C.S., 73, 5799 (1951).
Berger, J. Pharm. Exp. Ther., 104, 229 (1952).

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