Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1988-02-10
1990-02-27
Chan, Nicky
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549436, A61K 3136, C07D31768
Patent
active
049046942
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention is related to a novel biphenyl derivative having a liver ailment-moderating action and effective for the remedy of acute hepatitis and chronic hepatitis, a process for the preparation thereof, and a liver ailment-moderating agent comprising the novel derivative as an effective ingredient.
It is said that there are 2,000,000 patients suffering from liver diseases such as acute hepatitis and chronic hepatitis in Japan at present, and it is known that dibenzocyclo-octadiene type lignans contained in fruits of Schisandra chinesis BAILL belonging to the genus Schisadraceae are valuable for the remedy of these liver diseases (Japanese Patent Application No. 60-122560). However, the development of a medicine having a greater liver ailment-moderating action is desired.
Research was made with a view to discovering a substance having a more effective liver ailment-moderating action, and we have already proposed several compounds (Japanese Patent Application No. 60-136261). We continued this research, and found a novel compound represented by the formula (I) given below.
More specifically, in accordance with the present invention, there is provided a novel biphenyl derivative represented by the following formula (I): ##STR1## wherein R.sub.1 and R.sub.2 stand for a hydrogen atom or a methyl group.
BEST MODE FOR CARRYING OUT THE INVENTION
The compound of the formula (I) is prepared, for example, by subjecting a compound represented by the following formula (II): ##STR2## to at least one operation selected from hydrolysis and methylation.
The compound of the formula (II) as the starting compound can be obtained, for example, through the following steps (1) through (5).
(1) A commercially available alkyl ester of gallic acid is reacted with anhydrous potassium carbonate by using a methylating agent selected from iodomethane, dichloromethane and bromochloromethane in an organic solvent such as acetone or DMSO (dimethylsulfoxide) at 20.degree. to 60.degree. C. for 20 to 40 hours under an anhydrous condition, for example, in a nitrogen current to obtain a compound represented by the following formula (III): ##STR3## wherein R.sub.3 stands for a hydrogen atom, a methyl group, an ethyl group or a propyl group.
(2) The compound of the formula (III) is halogenated to obtain a compound represented by the following formula (IV): ##STR4## wherein R.sub.3 is as defined above and X stands for a halogen atom.
The halogenation is easily achieved by customary procedures. As specific examples of the halogen, there can be mentioned chlorine, bromine and iodine. As the reaction solvent, there can be mentioned acetic acid and chloroform, and a dissolution assistant such as DMF (dimethylformamide) may be used according to need. The reaction is completed within about 10 to 20 hours at a reaction temperature in the range of from -10.degree. C. to room temperature. After termination of the reaction, the reaction mixture is poured into ice water and extracted with ether, 10% potassium carbonate or the like to obtain a compound of the formula (IV).
(3) The compound of the formula (IV) is reacted with zinc in the presence of a base to obtain a compound represented by the following formula (V): ##STR5## wherein X is as defined above.
As specific examples of the base, there can be mentioned sodium hydroxide and potassium hydroxide. The reaction temperature is 0 to about 30.degree. C. and the reaction time is about 1 to 8 hours. By this reaction, the alkyl ester is hydrolyzed to form a carboxylic acid. Since the reaction product is precipitated in the reaction liquid, purification can be accomplished by such simple means as filtration and recrystallization.
Since the above reaction is a halogen substitution reaction at the 2- and 6-positions, the reaction is similarly advanced irrespective of the kinds of X and R.sub.3.
(4) Then, the compound of the formula (V) is methylated and coupling is effected by utilizing the Ullmann reaction to obtain a compound represented by the following formula (VI): ##STR6##
Th
REFERENCES:
Rapp et al., Chem. Ber., 105(1), 217-233 (1972).
Hosaka Kunio
Matsuoka Yoshiyuki
Mitsuhashi Hiroshi
Takeda Shigefumi
Chan Nicky
Tsumura & Co.
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