Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-22
2002-10-22
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S376000, C544S392000, C544S394000, C544S403000
Reexamination Certificate
active
06469010
ABSTRACT:
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 piperazino-diphenylmethane 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 ionhomeostasis inside and outside the cell cause the accumulation of a large amount of intracellular divalent Ca ions (Ca
2+
) (Ca
2+
overload). It is believed that the Ca
2+
overload causes functional disorders in the mitochondria and randomly activates various enzyme reactions and invites further Ca
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
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
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
2+
channel and Na
+
channel reported to be involved in the mechanism of cause of the Ca
2+
overload. [P. J. Pauwels et al., Life Science, 48, 1881 (1991)].
As a result, we found that compounds of the general formula (I):
wherein, Q represents a group having the formula:
R—A—B—
in which R represents a hydrogen atom, substituted or unsubstituted phenyl 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;
a group having the formula.
in which R
1
represents a hydrogen atom, a halogen atom, an alkyl group which may be substituted by a halogen atom, an alkoxy group, or a hydroxyl group; or
a group having the formula:
in which R
2
represents a hydrogen atom, a halogen atom,: an alkyl group which may be substituted by a halogen atom, an alkoxy group, or a hydroxyl group;
X represents an oxygen atom or a methylene group,
the substitution of X for the benzene ring being in an ortho, meta, or para position,
E and Y may be the same or different from each other and represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxy group, or an alkyl group which may be substituted by a halogen atom,
the dotted line shows the presence or absence of a bond, when said dotted line shows the presence of a bond, Z represents a carbon atom, and when said dotted line shows the absence of a bond, Z represents CH or a nitrogen atom have powerful inhibitory actions on one type of the non-L type Ca
2+
channel, that is, the T-type Ca
2+
channel, and Na
+
channel and are effective in various types of animal disease models and thereby completed the present invention.
BEST MODE FOR CARRYING OUT THE INVENTION
Flunarizine which is used as an agent for improvement of the brain circulation [P. J. Pauwels et al.; Life Science, 48, 1881 (1991); G. E. 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
2
receptors. This is a major defect in its use. The compounds of the general formula (I) of the present invention, however, were found to have an extremely low affinity for the dopamine D
2
receptors causing the side effects of flunarizine.
In the present invention, ischemic diseases include cerebral 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 functional and organic diseases of the brain, ischemic cardiac diseases, for example, 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 also disorders of transplanted organs at the time of organ transplants, and temporary blockage of the blood flow in organs at the time of surgery.
The compounds having the general formula (I) of the present invention include compounds of the following general formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and (Ti).
In the general formula (Ia):
wherein, Q represents a group having the formula R—A—B—, the formula:
or the formula:
and A, B, E, R, R
1
, R
2
X, and Y are as defined above, preferable examples of substituents for the substituted or unsubstituted phenylgroup, substituted or unsubstituted phenoxy group, or substituted or unsubstituted benzoyl group represented by R include a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom, a hydroxyl group, a C
1
-C
5
alkokyl group which may be branched such as a methoxy group and an ethoxy group, and a C
1
-C
5
alkyl group which may be branched and may be substituted by a halogen atom, such as a methyl group, an ethyl group and a trifluoromethyl group. Examples of a halogen atom of the C
1
-C
5
alkyl group which may be branched and may be substituted by a halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.
Examples of the cycloalkylene group represented by A include a 1,1-cyclopropylene group, a 1,2-cyclopropylene group, a 1,1-cyclobutylene group, a 1,1-cyclopentylene-group, a 1,1-cyclohexylene group, etc., preferably a C
3
-C
6
cycloalkylene group, particularly preferably a 1,1-cyclopropylene group or a 1,2-cyclopropy
Annoura Hirokazu
Fukunaga Atsuko
Inomata Norio
Matsuki Shinsuke
Tamura Shigeki
Chang Ceila
Suntory Limited
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