Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1988-02-17
1989-12-26
Hollrah, Glennon H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544364, 544375, 549354, A61K 31495, C07D40504
Patent
active
048898589
DESCRIPTION:
BRIEF SUMMARY
FEATURES OF THE INVENTION
The present invention relates to novel dibenz[b,e]oxepin derivatives useful for prevention and treatment of cerebral diseases caused by hypoxia.
TECHNICAL BACKGROUND
The brain, different from other organs, exists under particular environment such that it is dipped in cerebrospinal fluid within rigid bodies such as the skull and pachymenix and is one of such organs as showing most active energy metabolism. The oxygen consumption rate of the brain is the highest among all of the organs. Most of energy required for cranial nerves cells are supplied with oxygen and glucose. Since these energy sources are scarcely stored in the brain, they are always supplied from blood. Therefore, mechanism for controlling cerebral blood flow in the cerebral blood vessel itself is well developed in order to stably supply energy source for the brain tissue and to keep the outer environment constant in the cranial nerves cells.
However, when the homeostatic mechanism is damaged in the brain by physical oppression such as cerebrovascular disorders, cerebral tumor or cerebral injury, the cranial nerves cells are exposed to hypoxic condition (cerebral anoxia/cerebral hypoxia) and cannot fulfill the normal function. Such condition of cerebral anoxia increases the production of various toxic active oxygen species. These activated oxygen species peroxidize membrane lipid of the cerebral mitochondria and it results in functional disturbance of the cranial nerves cells and finally a breakdown of the brain cells themselves. This gives such a vicious circle that the functional disturbance of the cranial nerves cells and the breakdown of the brain cells in turn induce severe cerebral anoxia This is the reason why the cerebral anoxia is called a common denominator of most disorders based on cerebral circulatory disturbances [Eur. Neurol., 17 (Supple. 1), 113 (1978)].
Under such circumstances, the present inventors have continuously studied to find compounds having an excellent protective effect against cerebral anoxia and preferably with an inhibitory effect on lipid peroxidation of brain mitochondria. The present inventors have finally succeeded in selection of novel dibenz[b,e]oxepin derivatives of the present invention and completed the present invention.
Prior arts relevant to the present invention include U.S Pat. No 4,144,337 and South African Pat. No. 85/3053.
In the above U.S. Pat. No. 4,144,337, the compounds having the following general formula (A) are disclosed. ##STR2## wherein each of R.sub.1 and R.sub.4, which may be the same or different, is hydrogen, halogen of atomic number from 9 to 35, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, either each of R.sub.2 and R.sub.3 is hydrogen or R.sub.2 and R.sub.3 together are oxygen, either B and D together with the carbon atoms to which they are bound form a benzene ring, or B is sulphur and B and D together with the carbon atoms to which they are bound form a thiophene ring which may be substituted in the position .alpha. to the sulphur atom with halogen of atomic number from 9 to 35 or alkoxy of 1 to 4 carbon atoms, and when B and D together with the carbon atoms to which they are bound form a benzene ring, A is oxygen, sulphur, --CH.sub.2 --O-- or --CH.sub.2 --S-- in either orientation, or a group of formula ##STR3## wherein each of R.sub.5 and R.sub.6, which may be the same or different, is alkyl of 1 to 4 carbon atoms, or when B is sulphur and B and D together with the carbon atoms to which they are bound form a substituted or unsubstituted thiophene ring, A is a group of formula ##STR4## wherein each of R.sub.7 and R.sub.8, which may be the same or different, is hydrogen or alkyl of 1 to 4 carbon atoms and either each of E and F is hydrogen or E and F together form a bond.
Bearing in mind the structure of the compounds of the present invention, which will be fully explained hereinafter, detailed investigation of the very complicated substituents of the general formula (A) indicates that the general formula (A) covers an extremely sm
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Kurokawa Mikio
Masuda Yoshinobu
Naruto Shunsuke
Sato Fuminori
Uno Hitoshi
Dainippon Pharmaceutical Co., Ltd.
Hollrah Glennon H.
Turnipseed James H.
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