Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-18
2003-06-17
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S256000, C514S277000, C514S291000, C514S312000, C514S318000, C514S320000, C514S321000, C514S322000, C514S323000, C544S127000, C544S362000, C544S383000, C544S384000, C544S392000, C544S398000, C544S401000, C544S403000, C546S090000, C546S153000, C546S155000, C546S193000, C546S196000, C546S197000, C546S198000, C546S199000, C546S200000, C546S201000, C546S202000, C546S205000, C546S277400, C546S342000, C546S344000
Reexamination Certificate
active
06579881
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
This 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.
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, and the like, 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.
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 such central muscle relaxants include Tolperisone hydrochloride, Baclofen, Tizanidine hydrochloride, Chlorzoxazone, and Diazepam. Particular examples of such 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 some problems including extrapyramidal symptoms and neurologic manifestations such as sleepiness, sluggishness, and atony. No medicament capable of achieving well-balanced principal action and side effects has been known hitherto.
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. 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 has only a low margin of safety and frequently induces muscularatony. Accordingly, it is difficult for those other than medical specialists to administer this medicine.
SUMMARY OF THE INVENTION
In view of the lack of a clinically useful, highly safe medicament for treating and amelioriating mytonia in spastic paralysis and the like, as discussed above, the present inventors have developed 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 profile. It has been found that a novel class of 1,4-substituted cyclic amine derivatives represented by the following formula, and pharmacologically acceptable salts thereof, have an excellent central muscle relaxant effect while maintaining a high safety safety profile. This discovery 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 1,4-substituted cyclic amine derivative (I) 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.
The 1,4-substituted cyclic amine derivative (I) according to the present invention is represented by the following formula:
wherein A, B, C and D are the same or different from one another and each represents methine or nitrogen, provided at least two of them are methine;
the bond represented by the following formula:
represents a single or double bond;
T represents methine or nitrogen;
Y and Z are the same or different from each other and each represents methine, nitrogen, a group represented by the following formula:
or a group represented by the following formula:
provided at least one of them represents nitrogen;
R
1
and R
2
are the same or different from each other and each represents hydrogen, halogeno, hydroxy, lower alkylsulfonylaminoalkyl, lower halogenated-alkylsulfonylaminoalkyl, 2-pyrrolidinon-1-yl, 1-hydroxy-1-(methoxypyridyl)methyl, methoxypyridylcarbonyl, 1,3-propanesultum-2-yl, lower hydroxypiperidylcarbonylalkyl, lower hydroxyalkylamidoalkyl, lower halogenated-alkylamidoalkyl, lower dihalogenated-alkylamidoalkyl, lower heteroarylamidoalkyl, lower hydroxyalkylamidoalkyl, optionally substituted amino, nitro, lower alkyl, lower alkoxy, lower acyl, lower alkoxyalkoxy, cyano, lower alkylsulfonyl, sulfonylamido, hydroxy-lower alkyl, hydroxy-lower alkoxy, lower alkoxycarbonylamino, lower alkylsulfonylamino, N-lower alkylalkylsulfonylamino, lower acylamino, optionally substituted aminoalkyl, optionally N-substituted lower acylaminoalkyl, optionally substituted aryl, optionally substituted arylsulfonylamino, lower alkylsulfonyloxy, hydroxyiminomethyl, (2-pyrrolidon-1-yl)methyl, (2-piperidon-1-yl)methyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, cycloalkylcarbonylaminoalkyl, optionally substituted ureido, optionally substituted ureido-lower alkyl, succinimido, (succinimido-1-yl)-lower alkyl, amido, optionally substituted carbamoyl, optionally substituted carbamoyl-lower alkyl, optionally substituted thiocarbamoyl-lower alkyl, formyl, aromatic acyl, heteroarylcarbonyl, halogenated lower alkyl, (2-imidazolidinon-1-yl)methyl, (2,4-imidazolidinedion-3-yl)methyl, (2-oxazolidon-3-yl)methyl, (glutarimido-1-yl)methyl, optionally substituted heteroarylhydroxyalkyl, cyano-lower alkyl, 1-hydroxy lower cycloalkyl, (2,4-thiazolidinedion-3-yl)methyl, optionally substituted 4-piperidylmethyl, heteroarylacyl, pyrrolidinylcarbonyl-lower alkyl, optionally substituted aminosulfonylalkyl, carboxy-lower alkyl or lower alkylamidoalkyl; or alternatively R
1
and R
2
together may form optionally substituted alicycle, optionally substituted heterocycle or alkylenedioxy, provided these rings may be substituted;
R
3
represents hydrogen, halogeno, lower alkyl, hydroxy, hydroxy-lower alkyl, lower alkoxy, formyl, optionally substituted aralkyloxy, hydroxy-lower alkoxy, optionally substituted sulfamoyl or optionally N-substituted sulfamoyl-lower alkyl;
R
4
represents hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxyalkyl, optionally aryl-substituted aryloxyalkyl or optionally aryl-substituted aralkyloxyalkyl;
R
5
represents lower alkyl, lower acyl, lower alkoxycarbonyl, aromatic acyl or a group represented by the following formula:
—Q
1
—(CH
2
)
s
—Q
2
—R
6
[wherein
Q
1
and Q
2
are both single bonds, or one of them is a single bond while the other represents oxygen, carbonyl, a group represented by —NHCO—, a group represented by —NHSO
2
— or a group represented by >CH—R
7
(wherein R
7
represents hydroxy, lower alkyl or halogeno):
s represents 0 or an integer of 1 to 6; and
R
6
represents optionally substituted
Kawano Koki
Kimura Teiji
Kitazawa Noritaka
Komatsu Makoto
Kubota Atsuhiko
Covington Raymond
Eisai Co. Ltd.
Rotman Alan L.
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