A hydroquinonylphenyl butyric acid amide derivative having the formula (I): ##STR1## wherein R.sup.1 represents an aromatic or heterocyclic group which may be substituted, R.sup.2 represents a hydrogen atom, a lower alkylcarbonyl group, an aromatic carbonyl or heterocyclic carbonyl group which may be substituted, and X represents an oxygen atom or sulfur atom or a pharmaceutically acceptable salt thereof, which has a cerebral insufficiency improving activity.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to novel hydroquinonylphenyl butyric acid 
amide derivatives and pharmaceutically acceptable salts thereof and 
pharmaceutical compositions having a cerebral insufficiency improving 
activity containing the same as an active ingredient. 
These compounds can be widely utilized because they are effective for 
ameliorating and curing various symptoms based on cerebral organic 
disorders and pathergasia. 
The term "cerebral organic disorders" used herein means various symptoms 
derived from cerebral ischemic diseases such as cerebral infarct sequela, 
cerebral hemorrhage sequela, and cerebral arteriosclerosis sequela and 
various organic disorders derived from senile dementia, dementia 
presenilis, amnesia, cephalic traumatic sequela, and cerebral operation 
sequela. Furthermore, the term pathergasia used herein means psychogender 
organic diseases derived from mania, melancholia, neurosis, Parkinson's 
disease, schizophrenia, schizophrenia-like disorders, and chorea 
(Huntington's chorea) as well as medicines and alcoholic beverages. 
2. Description of the Related Art 
Cerebral cells retain their own intracellular environments which are 
completely different from the surrounding environments, i.e., 
extracellular fluids, and while this difference is maintained, the 
cerebral cells are alive. Accordingly, energy must be always generated and 
supplied to cerebral cells, and most of the energy required by cerebral 
nerve cells is supplied by oxygen and glucose. These energy sources are 
not substantially stored in the brain, however, and therefore, are always 
supplied from the blood. 
If certain cerebral disturbances or disorders occur, and if the supply of 
oxygen and glucose to the brain is stopped, generally a gradual or 
stepwise degression in energy metabolism occurs, and as a result, the 
functions of the cells are lost with the elapse of time and the cells are 
soon organically disrupted, and, thus the normal functions of the cerebral 
cells cannot be effected. Therefore, a mechanism for adjusting cerebral 
bloodstreams in the cerebral blood vessels, per se, has been fully 
developed to ensure a stable supply of these energy sources to the 
cerebral tissues and to maintain the outer environments of the cerebral 
nerve cells. 
Various cerebral circulating improvers, cerebral vasodilators, and cerebral 
excitometabolites have been heretofore used for the medical treatment of 
cerebral blood vessel disorders, but although these medicines are 
effective for ameliorating subjective symptoms, no substantial 
amelioration of neural symptoms and mental symptoms thereby has been 
observed. 
In this connection, Japanese Unexamined Patent Publication (Kokai) No. 
61-44840 discloses various derivatives of benzoquinonyl alkanoic acids, 
which are described as effective as an antiasthmatic agent, an 
antiallergic agent or a cerebral circulating improver. 
SUMMARY OF THE INVENTION 
An object of the present invention is to provide a novel compound having 
effective activities for ameliorating and curing (or treating) cerebral 
organic disorders, by oral administration. 
Other objects and advantages of the present invention will be apparent from 
the following description. 
In accordance with the present invention, there is provided a 
hydroquinonylphenyl butyric acid amide derivative having the formula (I): 
##STR2## 
wherein R.sup.1 represents an aromatic or heterocyclic group which may be 
substituted, R.sup.2 represents hydrogen atom, a lower alkylcarbonyl 
group, an aromatic carbonyl or heterocyclic carbonyl group which may be 
substituted, and X represents oxygen atom or sulfur atom. 
In accordance with the present invention, there is also provided a 
pharmaceutical composition having a cerebral insufficiency improving 
activity comprising, as an active ingredient, a pharmaceutical effective 
amount of a hydroquinonylphenyl butyric acid amide derivative having the 
above-mentioned formula (I) or a pharmaceutically acceptable salt thereof. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The present inventors have found that various derivatives of hydroxyphenyl 
butyric acid amide having the above-mentioned formula (I) are extremely 
effective against cerebral anoxia of test animals, at a low dosage, and 
therefore, are an effective improver of, or remedy for, cerebral organic 
disorders. 
In the above-mentioned formula (I) according to the present invention, the 
aromatic group R.sup.1 may include, for example, aryl groups such as 
phenyl and naphthyl, and the heterocyclic group may include, for example, 
pyridyl groups (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), dihydropyridyl 
groups, N-methylhydropyridyl groups, thienyl groups, furyl groups, and 
these groups may be substituted with, for example, a hydroxyl group, 
alkoxy group, alkyl group, halogen atom. 
The lower alkylcarbonyl group R.sup.2 may include, for example, lower 
alkanoic acid acyl groups such as acetyl, propionyl, and butyryl groups 
and the aromatic carbonyl groups may include, for example, a benzoyl group 
and naphthoyl groups, the heterocyclic carbonyl groups may include, for 
example, furolyl, thenoyl, nicotinoyl, isonicotinoyl, pyridine-2-carbonyl, 
and dihydropyridinecarbonyl groups, and all of these may be also 
substituted with, for example, an alkyl group, hydroxyl group, alkoxy 
group, and halogen atom. 
The compounds according to the present invention having the above-mentioned 
formula (I) can be synthesized, for example, as described below. 
Namely, 
8,9-dimethoxy-7-hydroxy-6-methyl-5-phenyl-2-oxo-2,3,4,5-tetrahydrobenzoxep 
in obtained by the reaction between the known compounds .sub.-- 
-phenyl-.sub.-- -butyrolactone and 2,3-dimethoxy-5-methyl-1,4-hydroquinone 
in the presence of an acid such as polyphosphoric acid or sulfuric acid is 
reacted with a carboxylic acid having the formula (II): 
EQU R.sup.1 COOH (II) 
wherein R.sup.1 is as defined above or an acid anhydride or acid halide 
thereof, according to any conventional esterification method, a benzoxepin 
derivative having the formula (III): 
##STR3## 
wherein R.sup.1 is as defined above can be obtained. 
The compound (III) obtained above and morpholine or thiomorpholine can be 
reacted by heating in an inert solvent such as benzene or toluene, or the 
product is further allowed to react with a carboxylic acid having the 
formula (IV): 
EQU R.sup.3 COOH (IV) 
wherein R.sup.3 represents a lower alkyl group, aromatic group or 
heterocyclic group, which may be substituted or an acid anhydride or acid 
halide thereof, to give the hydroquinonylphenyl butyric acid amide 
derivative of the present invention having the formula (I). 
As mentioned above, the derivatives of hydroquinonylphenyl butyric acid 
amide having the formula (I) according to the present invention are 
effective for ameliorating and curing various symptoms based on cerebral 
organic disorders. This is clear from the later described Evaluation 
Examples showing that the present compounds (I) have an excellent 
antihypoxia activity against test animals. 
When the present derivatives are used as a medicine, there are no critical 
limitations to the administration methods thereof. 
The compounds having the general formula (I) according to the present 
invention can be administered alone or in combination with 
pharmaceutically acceptable conventional carriers, excipients, and fillers 
in a variety of dosage forms such as tablets, troches, pills, granules, 
powders, capsules, ampules, suppositories and the like. The excipients 
include, for example, starch, dextrin, sucrose, lactose, silic acid, 
carboxymethylcellulose, cellulose, gelatin, polyvinylpyrrolidone, 
glycerin, agar, calcium carbonate, sodium dicarbonate, paraffin, cetyl 
alcohol, stearic acid esters, kaolin, bentonite, talc, calcium stearate, 
magnesium stearate, polyethyleneglycol, water, ethanol, isopropyl alcohol 
and propyleneglycol. The present compounds may be, for example, 
parenterally administered, in the form of, for example, injections or 
suppositories. 
Although there are no critical limitations to the dosage range of the 
present cerebral insufficiency improver, the optimum dosage range of the 
compound (I) of the present invention is 0.1 to 1000 mg, preferably 10 to 
500 mg, per day. This dosage range can be suitably changed depending upon, 
for example, the characteristics of the subjects, including age, response, 
weight, severity of disease and the like, the administration methods, the 
dosage forms, and the dosing frequency.