Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-09-23
2000-04-11
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514320, 546196, 546217, 546236, A61K 31445, C07D21120, C07D40506
Patent
active
06048876&
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to medicaments for the alleviation or treatment of symptoms based on ischemic diseases, for example, cerebral infarction, intracerebral hemorrhage, transient ischemic attack, subarachnoid hemorrhage, head trauma, after effects of brain surgery, after effects of cerebral arteriosclerosis and other cerebrovascular disorders, or variant angina, unstable angina, myocardial infarction, cardiovascular system disorders accompanying surgery for revascularization by PTCA/PTCR/CABG etc., malignant arrhythmia, and other myocardial ischemia-reperfusion injury, and further symptoms due to disorders of transplanted organs at the time of organ transplants, temporary blockage of the blood flow in organs at the time of surgery, etc. or symptoms derived from seizures, epilepsy, migraine, etc.
The present invention further relates to novel piperidine derivatives, tetrahydropyridine derivatives, piperazinodiphenylether derivatives, and piperazinodiphenylmethane derivatives useful for the alleviation or treatment of symptoms based on aforementioned ischemic diseases and intermediates for the synthesis of aforementioned compounds.
BACKGROUND ART
In cellular disorders caused by advanced ischemia, the depletion of ATP, the fall in the pH in the cells, and the destruction of the mechanism for maintenance of the energy-dependent ion homeostasis inside and outside the cell cause the accumulation of a large amount of intracellular divalent Ca ions (Ca.sup.2+) (Ca.sup.2+ overload). It is believed that the Ca.sup.2+ overload causes functional disorders in the mitochondria and randomly activates various enzyme reactions and invites further Ca.sup.2+ overload to cause a repeated vicious cycle and in the end causes irreparable damage to the cell wall and cell death [F. B. Meyer: Brain Res. Rev., 14, 227 (1989); E. Boddeke et al.: Trends Pharmacol. Sci., 10, 397 (1989)].
Medicament for suppressing cytotoxic Ca.sup.2+ overload are considered useful for the alleviation or treatment of various ischemic diseases, for example, cerebral infarction, intracerebral hemorrhage, transient ischemic attack, subarachnoid hemorrhage, head trauma, after effects of brain surgery, after effects of cerebral arteriosclerosis and other cerebrovascular disorders, or variant angina, unstable angina, myocardial infarction, cardiovascular system disorders accompanying surgery for revascularization by PTCA/PTCR/CABG etc., malignant arrhythmia and myocardial ischemia-reperfusion injury, and further disorders of transplanted organs at the time of organ transplants and temporary blockage of the blood flow in organs at the time of surgery, however, no medicament with sufficient activity has yet been obtained.
DISCLOSURE OF INVENTION
In consideration of the state of the prior art, the objective of the present invention is to provide medicaments which have the powerful action of suppressing cytotoxic Ca.sup.2+ overload for the alleviation and treatment without side effects of symptoms based on ischemic diseases or symptoms derived from seizures, epilepsy, migraine, etc.
Another objective of the present invention is to provide novel compounds and their salts useful as the medicaments and intermediates for synthesizing the same.
The present inventors screened compounds by evaluating the inhibitory effects on the non-L type Ca.sup.2+ channel and Na.sup.+ channel reported to be involved in the mechanism of cause of the Ca.sup.2+ overload [P. J. Pauwels et al., Life Science, 48, 1881 (1991)].
As a result, we found that compounds of the general formula (I): ##STR2## wherein, Q represents a group having the formula: group, substituted or unsubstituted phenoxy group, or substituted or unsubstituted benzoyl group,
A represents a connecting bond, a cycloalkylene group, an alkenylene group which may be substituted by a lower alkyl group, a dialkoxymethylene group, or a hydroxyiminomethylene group, and
B represents an alkylene group which may be substituted by a hydroxyl group or an alkoxy group; ##STR3## in which R.sup.1 represen
REFERENCES:
patent: 4241071 (1980-12-01), Martin et al.
patent: 5110816 (1992-05-01), Houziaux et al.
Journal of Medicinal Chemistry, Laurence L. Martin et al., 1979, vol. 22, No. 11, pp. 1347-1354.
Foguet Ambros et al, "Improvements in the object of patent 8,702,460 regarding a `process for preparation of new 1-[2-(phenylmethyl)phenyl]piperazines,` useful as antidepressants", Chemical Abstracts, 116: 106319q (1992).
Scarpelli et al. "Cell injury" p. 44, 1986.
Webster dictionary, pp. 438, 1057, 1984.
Annoura Hirokazu
Fukunaga Atsuko
Inomata Norio
Matsuki Shinsuke
Tamura Shigeki
Chang Ceila
Suntory Limited
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