Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-10-28
1998-03-03
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514211, 5142305, 514255, 514253, 514320, 514337, 514357, 540552, 544105, 544376, 544393, 544394, 546196, 546232, 546234, 5462817, 546337, 546338, A61K 31445, A61K 31495, C07D21126, C07D24104
Patent
active
057234752
DESCRIPTION:
BRIEF SUMMARY
This application is a PCT/JP 96/00469, Feb. 28, 1996.
TECHNICAL FIELD
The present invention relates to novel arylpiperidine and arylpiperazine derivatives. More specifically it relates to novel arylpiperidine and arylpiperazine derivatives useful for the medicaments having a powerful action in suppressing cytotoxic Ca.sup.2+ overload and used for the alleviation or treatment of, 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, and also symptoms derived from seizures, epilepsy, migraine, etc. and pharmaceutical compositions containing these compounds are effective ingredients, medicaments for the alleviation or treatment of symptoms derived from ischemic diseases, and Ca.sup.2+ overload suppressants.
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 (1989); E. Boddeke et al.: Trends Pharmacol. Sci., 10,397 (1989)!. Therefore, drugs which suppress cytotoxic Ca.sup.2+ overload are effective agents for the alleviation or treatment of various ischemic diseases.
Flunarizine which is used as an agent for improvement of the brain Billman; Eur. J. Pharmacol., 212, 231 (1992)! suffers from the problem that it causes as a side effect the onset of symptoms of Parkinson's disease due to its action of blocking dopamine D.sub.2 receptors. This is a major defect in its use.
DISCLOSURE OF THE INVENTION
Consequently, the objective of the present invention is to provide novel arylpiperidine and arylpiperazine derivatives, and their salts, useful as medicaments having a powerful action in suppressing cytotoxic Ca.sup.2+ overload and used for the alleviation or treatment of ischemic diseases with no substantial side effects.
The another objective of the present invention is to provide a pharmaceutical composition, a medicament for the alleviation or treatment of ischemic diseases, and a Ca.sup.2+ overload suppressant containing an arylpiperidine or arylpiperazine derivative or its pharmaceutically acceptable salt, as an effective ingredients.
According to the present invention, there are provided an arylpiperidine and arylpiperazine derivatives having the general formula (I): ##STR2## wherein, A and B represent a carbonyl group or sulfonyl group, m and p are different and represent 0 or 1, represent a hydrogen atom, an unsubstituted or substituted alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted aralkyl group, an unsubstituted or substituted heterocyclic group containing nitrogen, an unsubstituted or substituted heterocyclic group containing oxygen or R.sup.1 and R.sup.2, taken together with the nitrogen atom to which they are linked, may form an unsubstituted or substituted heterocyclic group, provided that when B is a sulfonyl group, R.sup.2 does not represent a hydrogen atom, hydrogen atom, a halogen atom, an alkoxy group, or an alkyl group which may be substituted by a halogen atom, atom, and when said dotted line shows the absence of a bond, Z represents CH or a nitrogen atom,
REFERENCES:
patent: 5084456 (1992-01-01), Guillaumet et al.
Flouzat et al, "Novel Nonopioid Non-Antiinflammatory Analgesics: 3-(Aminoalkyl)-and of Medicinal Chemistry, vol. 36, No. 4, pp. 497-503 (1993).
Kurokawa et al, "A new Class of Calcium Antagonists. 2..sup.1 Synthesis and Biological Activity of Chemistry, vol. 34, pp. 927-934 (1991).
Kurokawa et al, "A New Class of Calcium Antagonists. Synthesis and Biological Activity of e!thiepin Derivatives," Journal of Medicinal Chemistry, vol. 34, pp. 593-599 (1991).
Beaulieu et al, "Liquid Chromatographic Method for Determination of Trazodone and Related Compounds in Drug Raw Materials," Journal of AOAC International, vol. 77, No. 4, pp. 857-861 (1994).
Annoura Hirokazu
Fukunaga Atsuko
Tamura Shigeki
Uesugi Mayumi
Dahlen Garth M.
Dentz Bernard
Suntory Limited
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