Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-11
2004-09-14
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253030, C514S307000, C514S309000, C514S310000, C544S358000, C544S363000, C546S139000, C546S143000
Reexamination Certificate
active
06790844
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a clinically useful medicament having a serotonin antagonism, in particular, that for treating, ameliorating and preventing spastic paralysis or central muscle relaxants for ameliorating myotonia.
BACKGROUND OF THE INVENTION
Myotonia, which seriously restrains daily life, is induced by any of a number of factors or a combination thereof, for example, cervico-omo-brachial syndromes accompanying stiffness or pain in the neck, shoulder, arm, lumbar and dorsal skeletal muscles due to abnormal posture, fatigue, changes in the backbone with ageing etc., shoulder periarthritis accompanying inflammation in the tissues constituting the shoulder joint due to changes in the shoulder joint caused by trauma, etc., and spastic paralysis wherein accelerated limb muscle tonus hinders voluntary movements.
In particular, spastic paralysis is a disease which accompanies limb muscle tonus, stiffening, walking difficulty, etc. and thus seriously restrains daily life.
PRIOR ART
It has been a practice to treat these diseases mainly with the use of medicaments. At the present stage, central muscle relaxants or peripheral muscle relaxants are administered to patients with these diseases.
Particular examples of used central muscle relaxants include Tolperisone hydrochloride, Baclofen, Tizanidine hydrochloride, Chlorzoxazone and Diazepam.
On the other hand, particular examples of used peripheral muscle relaxants include suxamethonium chloride, Pancuronium bromide and dantrolene sodium.
Central muscle relaxants act selectively on the central nervous system so as to relax muscles. Therefore, it is expected that those action on the upper center would exhibit a more potent muscle relaxant effect. However, there arise at the same time someproblems including extrapyramidal symptoms and neurologic manifestations such as sleepiness, sluggishness and atony. Namely, there has been known hitherto no medicament capable of achieving well-balanced principal action and side effects.
Diazepam, which is inherently a minor tranquilizer, is efficacious against diseases accompanying mental symptoms such as anxiety, tension and depression. However, its effect is too potent to merely ameliorate myotonia. With the use of diazepam, therefore, spastic paralysis can be relieved but there arise some problems such as dizziness.
On the other hand, suxamethonium chloride and Pancuronium bromide which are peripheral muscle relaxants are marketed exclusively as injections, which makes the chronic administration thereof difficult.
Dantrolene sodium is processed into injections and preparations for oral use and has a relatively potent muscle relaxant effect. However, it suffers from problems of having only a low margin of safety and frequently inducing muscular atony. Accordingly, it is difficult for those other than medical specialists to administer this medicine.
As discussed above, there has been known hitherto no medicaments for treating and ameliorating myotonia in spastic paralysis etc., which is clinically useful and has a high safety.
DISCLOSURE OF THE INVENTION
Under these circumstances, the present inventors have conducted extensive studies to develop medicaments for treating, ameliorating and preventing spastic paralysis or central muscle relaxants which have a potent effect of ameliorating myotonia while sustaining a high safety and newly paid their attention to compounds having a serotonin antagonism. As a result, they have successfully found that a novel condensed pyridine compound represented by the following formula or a pharmacologically acceptable salt thereof has an excellent central muscle relaxant effect and a high safety and thus makes it possible to solve the above problems, thus completing the present invention.
Accordingly, the present invention aims at providing clinically useful novel medicaments which have well-balanced principal action and side effects and make it possible to overcome the problem encountering in the prior art that those acting on the upper center would exhibit a more potent muscle relaxant effect but at the same time suffer from some problems including extrapyramidal symptoms and neurologic manifestations such as sleepiness, sluggishness and weakness.
Because of the anti-serotonin effect, it is expected that the condensed pyridine compound of the present invention is moreover usable in preventing, treating and ameliorating depression, emotional disorders, schizophrenia, sleep disturbance, anxiety, spinal cord injury, thrombosis, hypertension, brain circulatory disturbances, peripheral circulatory disturbances, drug addiction, etc.
In addition to the condensed pyridine compound, the present invention provides medicinal composition which comprises a pharmaceutically effective dose of the condensed pyridine compound, its pharmaceutically acceptable salt or hydrates thereof and pharmaceutically acceptable carriers. Further, it provides an agent for treating, ameliorating or preventing diseases against which serotonin antagonism is efficacious, an agent for treating, ameliorating or preventing spastic paralysis and a muscle relaxant, which comprise the above-mentioned active ingredient.
Further, it provides a treating, ameliorating or prophylactic agent comprising the above-mentioned effective ingredient for diseases for which the serotonin antagonism is efficacious or, a therapeutic, ameliorating and prophylactic agents of spastic paralysis and a muscle relaxation agent.
Furthermore, it provides a method for treating diseases against which the serotonin antagonism is efficacious or spastic paralysis, or ameliorating myotonia, which comprising the step of administering a pharmacologically effective dose of the condensed pyridine compound, its pharmacologically acceptable salt or hydrates thereof to a patient. Additionally, it provides the use of the effective ingredient for producing the above-mentioned medicaments.
Herein, the condensed pyridine compound (I) of the present invention is represented by the following formula:
wherein, ring A represents benzene ring, pyridine ring, thiophene ring or furan ring;
R
1
represents hydrogen atom, halogen atom, a lower alkyl group or a lower alkoxyl group;
R
2
represents 4-morpholinyl group, 1-imidazolyl group, 1-lower alkyl homopiperazin-4-yl group or any one selected from the groups represented by the following formulae:
(wherein, T represents nitrogen atom or methine group;
R
3
represents hydrogen atom, halogen atom, a lower alkyl group or a lower alkoxyl group;
R
4
represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, a halogenated lower alkyl group, a lower cycloalkyl group, an aryl group, an aralkyl group, 1-piperidyl group, an alkenyl group, a cyano lower alkyl group, a carbamoyl lower alkyl group, a lower acyl group, an aromatic acyl group, a lower alkoxyl carbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl group;
R
5
and R
6
are the same as or different from each other and each represents hydrogen atom, a lower alkyl group, a di lower alkyl aminoalkyl group, an optionally substituted heteroaryl lower alkyl group);
n represents 0 or an integer of 1 to 6; and
B represents an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyloxy group, an aryl (hydroxy)alkyl group, an aromatic acyl amino group, an arylsulfonylamino group, a lower alkoxyl arylsulfonylamino group, a hydroxy lower alkoxyl styryl group, a lower alkoxyl aryloxy group, 4-phenylpiperidin-1-yl group, 4-pyridylpiperidin-1-yl group, an optionally substituted arylalkenyl group, an optionally substituted arylalkynyl group, an optionally substituted heteroarylalkenyl group, an optionally substituted heteroarylalkynyl group, an aromatic acyl alkynyl group, an optionally N-substituted amino lower alkyl group, an optionally substituted arylamino group, an optionally substituted aralkylamino group or any one selected from the groups represented by the following formulae:
(wherein z represents 0 or 1;
Q represents nitrogen atom or methine g
Kawano Koki
Kitazawa Noritaka
Kubota Atsuhiko
Matsunaga Manabu
Okabe Tadashi
Birch & Stewart Kolasch & Birch, LLP
Eisai Co., Ltd
Patel Sudhaker B.
Shah Mukund J.
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