Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-01-13
2001-01-09
Davis, Zinna Northington (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S037000
Reexamination Certificate
active
06172078
ABSTRACT:
TECHNICAL FIELD
The present invention relates to quinolinomorphinan derivatives or pharmacologically acceptable acid addition salts thereof, and an agent for curing or preventing worsening of cerebral disorders comprising one of the derivatives or salts thereof, and particularly to a medicine useful for ameliorating various cerebral diseases and aftereffects thereof, and preventing the recurrence thereof.
BACKGROUND ART
In recent years, cases of diseases in the cerebral region such as various cerebrovascular diseases have increased with the arrival of the aging society. Cerebrovascular diseases are possibly caused by aging, hypertension, arterial sclerosis, hyperlipidemia, and the like, and are generally referred to as “cerebral stroke”. In a broad sense, cerebral vascular diseases possibly include functional disorders of the brain due to head trauma.
Cerebral stroke is roughly classified into ischemic (infarcted) diseases and hemorrhagic diseases. Examples of the former include cerebral infarction (cerebral thrombosis, cerebral embolism), and the like, and examples of the latter include cerebral hemorrhage, subarachnoid hemorrhage, and the like. In these diseases, the blood flow is clogged due to a cerebrovascular disorder, and thus glucose and oxygen, which are energy sources of the action of the cerebral nerve cells, are insufficiently supplied, resulting in various damages of the nerve cells. These diseases are fundamentally caused by death of the cerebral nerve cells of a damage area and the periphery thereof. Such cerebrovascular diseases cause occurrence of various aftereffects such as cerebrovascular dementia, which are critical medical and social problems at present.
Medicines which have been developed as agents for curing such cerebrovascular diseases in Japan are mainly used for ameliorating aftereffects such as psychoneurosis and the like, and main medicines have the function to increase the amount of the blood flow to the brain to promote the supply of glucose and oxygen to an ischemic area. From the viewpoint of the functional mechanism, these medicines are expressed by vague terms such as medicines for ameliorating the cerebral blood flow, medicines for activating cerebral metabolism, and medicines for ameliorating cerebral function. However, almost all of these medicines are effective in ameliorating marginal symptoms such as volition disorders, affective disorders, behavioral abnormality, and the like, while the activity to the nucleus symptoms of dementia such as memory disorders and the like is considered as doubtful. Also some anti cerebral edema agents, antithrombotic agents, and thrombolytic agents are clinically used, particularly, in the acute stage of a cerebrovascular disease. These agents also have no direct action on the cerebral nerve cells, but are used only for symptomatic therapy. In any case, the above present medicines have substantially no effect on damage of the cerebral nerve cells in cerebrovascular diseases, and have no action to inhibit directly the death of the cerebral nerve cells.
As described above, there is now no medicine effective against damage of the cerebral nerve cells which are fundamental causes of cerebrovascular diseases. It is known that the degree of such damage has correlation to the ischemia time the cerebral blood flow is clogged, and a long ischemia time causes organic damage of the cerebral nerve cells which are not ameliorated even by recovery of the blood flow. For such cerebrovascular disorders, it is important to cure the disorders in the acute stage within 24 hours from the occurrence of the diseases. Therefore, there is now demand for developing, as early as possible, a safe medicine which has a secure protective effect on damages of the cerebral nerve cells and which is easy to use.
In addition to such cerebrovascular disorders, an increase in cerebral neurodegenerative diseases such as Alzheimer's disease is also a problem, and approach for elucidating causes and developing a therapeutic method is actively carried out in various fields. Although the main object of the approach is to activate, particularly, the acetylcholine nervous system, approach is also carried out by employing the neuroprotective action by a substance related to a nerve growth factor, a neurotrophic factor for the death of the nerve cells due to cerebral neurodegenerative diseases. Also the effect of a medicine having the cerebral neuroprotective action is expected.
The present invention relates to an agent for curing or preventing worsening of cerebral disorders, and an object of the present invention is to provide a medicine useful for ameliorating various cerebral diseases and aftereffects thereof, and preventing the recurrence thereof. Particularly, the present invention provides a medicine useful for curing or preventing worsening of cerebral stroke, traumatic cerebral diseases, cerebral edema, and cerebral neurodegenerative diseases by inhibiting various ischemic, hemorrhagic or traumatic cerebral disorders and damage of the cerebral nerve cells caused by various nerve degeneration, to protect the cerebral nerve cells.
DISCLOSURE OF INVENTION
The object can be achieved by the present invention described below.
The present invention relates to an agent for curing or preventing worsening of cerebral disorders comprising a quinolinomorphinan derivative or a pharmacologically acceptable acid addition salt thereof, which is represented by the following formula (I):
wherein R
1
represents hydrogen, alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aryl having 6 to 12 carbon atoms, aralkyl having 7 to 13 carbon atoms, alkenyl having 2 to 7 carbon atoms, alkanoyl having 1 to 5 carbon atoms, furan-2-ylalkyl (wherein an alkyl moiety has 1 to 5 carbon atoms), or thiophene-2-ylalkyl (wherein an alkyl moiety has 1 to 5 carbon atoms);
R
2
and R
3
independently represent hydrogen, hydroxy, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, aralkyloxy having 7 to 13 carbon atoms, or arylcarbonyloxy having 7 to 13 carbon atoms;
m represents an integer of 0 to 4;
R
5
is each of m substituents on the benzene ring, which independently represent R
18
, or two R
5
substituted at adjacent carbons form together a fused ring structure A (wherein residual 0 to 2 substituents R
5
each represent R
18
or form another fused ring structure A);
the fused ring structure A is benzo, indeno, naphtho, pyrido, or cycloalkeno having 5 to 7 carbon atoms, which is substituted by 0 to 4 substituents R
9
, or unsubstituted dioxoleno;
R
9
and R
18
(1) independently represent fluoro, chloro, bromo, iodo, nitro, hydroxy, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, isothiocyanato, trifluoromethyl, trifluoromethoxy, cyano, phenyl, hydroxyalkyl having 1 to 3 carbon atoms, SR
6
, SOR
6
, SO
2
R
6
, (CH
2
)
k
CO
2
R
7
, SO
2
NR
7
R
8
, CONR
7
R
8
, (CH
2
)
k
NR
7
R
8
, or (CH
2
)
k
N(R
7
)COR
8
(wherein k represents an integer of 0 to 5, R
6
represents alkyl having 1 to 5 carbon atoms, and R
7
and R
8
independently represent hydrogen, alkyl having 1 to 5 carbon atoms, or cycloalkylalkyl having 4 to 6 carbon atoms), and/or (2) R
9
and R
18
substituted at adjacent carbons with a ring junction therebetween form together any one of ethano, propano and o-benzeno bridged structures R
9
—R
18
; and
R
4
represents hydrogen, alkyl having 1 to 5 carbon atoms, hydroxyalkyl having 1 to 5 carbon atoms, aryl having 6 to 12 carbon atoms (which may be substituted by at least one substituent R
17
), NR
10
R
11
, OR
12
, COOR
13
or CONR
14
R
15
, or any one of bridged structures R
4
—R
5
of N(R
16
)CO, N(R
16
)C(═NH), N(R
16
)CH
2
, o-benzeno, ethano, propano, and butano, which are formed together by R
4
and R
5
substituted at the peri position;
R
17
represents fluoro, chloro, bromo, iodo, nitro, amino, hydroxy, alkyl having 1 to 5 carbon atoms, alkoxy 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, trifluoromethyl, trifluoromethoxy
Imamura Yoshifumi
Kaneeda Masanobu
Matsuda Susumu
Miyauchi Yasushi
Nagase Hiroshi
Birch & Stewart Kolasch & Birch, LLP
Davis Zinna Northington
Toray Industries Inc.
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