Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-17
2004-03-16
Desai, Rita (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S192000
Reexamination Certificate
active
06706734
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a pharmaceutical composition for the alleviation or treatment of symptoms due to 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 (percutaneous transluminal coronary angioplasty)/PTCR (percutaneous transluminal coronary revascularization)/CABG (coronary artery bypass grafting) 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 Ca
2+
overload suppressants. The present invention further relates to a novel arylpiperidinol and arylpiperidine derivatives having an action in suppressing Ca
2+
overload and useful for the alleviation or treatment of symptoms due to the above ischemic diseases and also symptoms derived from seizures, epilepsy, migraine, etc., their pharmaceutically acceptable salts, and synthetic intermediates for the preparation of the 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
2+
). 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)].
Pharmaceuticals which suppress cytotoxic Ca
2+
overload are considered to be these 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.
DISCLOSURE OF THE INVENTION
Under the above circumstances, the objective of the present invention is to provide a pharmaceutical composition having an action of suppressing cytotoxic Ca
2+
overload, with high safety, and useful for the alleviation or treatment of symptoms due to ischemic diseases or symptoms derived from seizures, epilepsy, and migraine.
Another objective of the present invention is to provide a novel arylpiperidinol and arylpiperidine derivatives useful as pharmaceutical ingredients, their pharmaceutically acceptable salts, and synthetic intermediates of the same.
In accordance with the present invention, there is provided a pharmaceutical composition for the alleviation or treatment of symptoms due to ischemic diseases or symptoms derived from seizures, epilepsy, and migraine containing, as an effective ingredient, a compound having the formula (I):
wherein, R is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted benzoyl group, A is a connecting bond, a cycloalkylene group, or an alkenylene group optionally substituted with a lower alkyl group, B is an alkylene group optionally substituted with a hydroxyl group or an alkoxy group or a group —NHCO(CH
2
)
n
—, where n is an integer of 1 to 5, E is a connecting bond, an oxygen atom, or a methylene group, X is a hydroxyl group or a hydrogen atom provided that, when E is an oxygen atom or a methylene group, X is not a hydrogen atom, and Y and Z may be the same or different from each other and represent a hydrogen atom, a halogen atom, an alkoxy group, or an alkyl group optionally substituted with a halogen atom or its pharmaceutically acceptable salt.
BEST MODE FOR CARRYING OUT THE INVENTION
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 Ca
2+
overload [P. J. Pauwels et al.; Life Science, 48, 1881 (1991)]. As a result, it was found that the compounds having the formula (I) have a powerful action in suppressing one type of the non-L-type Ca
2+
channel, that is, the T-type Ca
2+
channel, and Na
+
channel and was effective in various types of animal disease models as well, whereby the present invention was completed.
In the present invention, as ischemic diseases, 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 may be mentioned.
The compounds having the formula (I) according to the present invention include compounds having the formulas (Ia) and (Ib):
In the formula (Ia)
wherein, R, A, B, E, Y, and Z are as the same defined above, examples of the preferable substituent of the optionally substituted phenyl group, the optionally substituted phenoxy group, or the optionally substituted 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
to C
5
optionally branched alkoxy group such as a methoxy group and an ethoxy group, and a C
1
to C
5
optionally branched alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group and a trifluoromethyl group. Examples of the halogen atom of the C
1
to C
5
optionally branched alkyl group optionally substituted with a halogen atom include a fluorine atom, a chlorine atom, a bromine atom, etc.
Examples of the cycloalkylene group represented by A in formula (Ia) include preferably a C
3
to C
6
cycloalkylene group such as a 1,1-cyclopropylene group, a 1,2-cyclopropylene group, a 1,1-cyclobutylene group, a 1,1-cyclopentylene group, and a 1,1-cyclohexylene group, more preferably a 1,1-cyclopropylene group or a 1,2-cyclopropylene group. Preferable examples of the alkenylene group of the alkenylene group optionally substituted with a lower alkyl group include preferably a C
2
to C
4
alkenylene group such as a vinylene group and a butadiene group, more preferably a butadiene group. Examples of the alkyl groups of the alkenylene group optionally substituted with a lower alkyl group include a methyl group, an ethyl group, a propyl group, and an isopropyl group.
Preferable examples of the alkylene group of the alkylene group optionally substituted with a hydroxy group or an alkoxy group represented by B in formula (Ia) include preferably a C
1
to C
6
optionally branched alkylene group such as a methylene group, a dimethylene group, a trimethylene group, a tetramethylene group, a methyl
Annoura Hirokazu
Nakanishi Kyoko
Tamura Shigeki
Burns Doane Swecker & Mathis L.L.P.
Daiichi Suntory Pharma Co., Ltd.
Desai Rita
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