Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1996-11-21
2001-01-23
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S044000, C546S045000, C546S046000
Reexamination Certificate
active
06177438
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an analgesic, diuretic, antitussive, or new preventive or therapeutic drug for ischemic brain disorders, cerebral nerve cell disorders and dementia having for its active ingredient a morphinan derivative or pharmacologically acceptable acid addition salt thereof.
Background Art
Morphine has long been known as a powerful analgesic having a morphinan skeleton, and is widely used even at present. However, this drug has serious side effects that present clinical problems, including drug dependence and respiratory suppression and inhibitory action of smooth muscle movement (constipation). Thus, its use is required to be carefully monitored. There is therefore a need for a powerful analgesic that acts on the central nervous system and that also can be used safely.
In addition, it has also been reported that drugs that act on opioid receptors effect urination (J. D. Leander, J. Pharmacol. Exp. Ther., 227, 35 (1983)), and thus the effective use of that action is also desired.
On the other hand, known examples of powerful antitussives that act on the central nervous system include codeine and dextromethorphan. Although these drugs are used not only for medical purposes, but are also widely used as one ingredient of comprehensive cold medications, they too essentially have serious side effects that present clinical problems, including drug dependency, respiratory suppression and inhibitory action of smooth muscle movement (constipation) and psychotomimetics. In particular, in view of the seriousness of the abuse of antitussives containing codeine and the psychotomimetics of dextromethorphan, a powerful yet safe antitussive is desired that acts on the central nervous system.
Aside from the above, there has been an increase in recent years in various types of ischemic diseases of the cerebroiuasciilar and cardiovascular system accompanying increasing of aged people. Cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis and cerebral phlebothrombosis, cerebrovascular disorders caused by intracerebral hemorrhage and intracerebral thrombus, and functional brain damage caused by head injury and so forth bring about a shortage of glucose and oxygen used as energy sources for nerve cell activity. Due to the resulting necrosis of nerve cells at the ischemic site, various symptoms are manifest as sequela of this necrosis, including cerebrovascular dementia and other disorders. In addition, accompanying the increasing proportion of elderly persons in society resulting from prolongation of the average life span, the problem of such diseases as Alzheimer's disease is becoming a serious problem both medically and socially. In the past, drugs that were developed against these ischemic cerebrovascular disorders and psychoneurotic symptoms accompanying senile dementia consisted primarily of those that mainly increased blood flow to the brain to promote the supply of glucose, oxygen and so forth to the ischemic site. Although these drugs are referred with obscure expressions such as cerebral circulatory improvers, cerebral metabolic activators and cerebral function improvers in terms of their action and mechanism, despite being considered to be effective in improving peripheral symptoms such as volitional disorders, emotional disorders and behavioral abnormalities, their effects are not clear with respect to improvement of the core symptoms of dementia such as memory disorders. Thus, at present, since there is no drug which is able to effectively treat these diseases, the development of a therapeutic drug is desired that demonstrates more reliable action and effects while also being safe and easy to use.
DISCLOSURE OF THE INVENTION
The existence of opioid receptors has been clearly established as receptors involved in analgesic action on the central nervous system. Moreover, these receptors are known to be able to be classified into the three types &mgr;, &dgr; and &kgr;. In addition, &sgr; receptors are also known to demonstrate psychotomimetics. Those agonists having affinity for &kgr;-receptors or &sgr;-receptors have been shown to have strong analgesic activity, while not demonstrating serious side effects that present clinical problems such as drug dependence, respiratory suppression and inhibitory action of smooth muscle movement, that are observed in the case of morphine and so forth, which are &mgr;-receptor agonists. In addition, the psychotomimetics observed in existing &kgr;-receptor agonists is reported to be caused by affinity to &sgr; receptors. Moreover, &kgr;-receptor agonists do not demonstrate cross tolerance with &mgr;-receptor agonists such as morphine. Analgesics free of such side effects have a high degree of usefulness since they can be applied in not only the control of pain in patients having post-operative pain and cancer patients, but can also be widely applied for general pain. In addition, the absence of cross tolerance indicates that these analgesics are effective even in patients that have developed tolerance to analgesics such as morphine. Namely, the object of the present invention is to provide a &kgr;-receptor agonist or &sgr;-receptor agonist that has powerful analgesic action while not having serious side effects like those of morphine, not having cross tolerance with morphine and so forth, and not demonstrating any affinity whatsoever for a receptors.
In addition, a second object of the present invention is to provide a useful diuretic that takes advantage of the effects of opioid action drugs on urination.
On the other hand, although antitussives such as morphine and codeine, which act on &mgr; receptors, and dextromethorphan, which acts on &sgr; receptors, have been long known, it has not been possible to avoid serious side effects such as drug dependency, respiratory suppression, inhibitory action of smooth muscle movement (constipation) and psychotomimetics. However, those agonists that have affinity for &kgr; receptors have been shown not to demonstrate serious side effects that present clinical problems, such as drug dependency, respiratory suppression, inhibitory action of smooth muscle movement and so forth observed in morphine and so forth, which are &mgr;-receptor agonists. In addition, the psychotomimetics observed in existing &kgr;-receptor agonists is reported to be caused by affinity to &sgr; receptors. Namely, a third object of the present invention is to provide a &kgr;-receptor agonist having powerful antitussive activity that is free of the serious side effects observed in &mgr;-receptor agonists and &sgr;-receptor agonists.
Moreover, aside from the above, a fourth object of the present invention is to provide a new preventive and therapeutic drug for ischemic brain disorders, cerebroneuronal disorders and dementia.
As a result of earnest studies to solve the above-mentioned problems, the inventors of the present invention found that the morphinan derivative indicated with general formula (I) is a compound that demonstrates analgesic action, diuretic action, antitussive action and new preventive or therapeutic effects against ischemic brain disorders, cerebroneuronal disorders and dementia while also having the excellent characteristics described above, thus leading to completion of the present invention.
Namely, the present invention relates to a morphinan derivative represented with general formula (I) below or pharmacologically acceptable acid salt thereof, its production process, as well as its pharmaceutical applications:
[wherein,
. . . . .
represents a single or double bond;
R
1
represents an alkyl group having 1-5 carbon atoms, a cycloalkylalkyl group having 4-7 carbon atoms, a cycloalkenylalkyl group having 5-7 carbon atoms, an aryl group having 6-12 carbon atoms, an aralkyl group having 7-13 carbon atoms, an alkenyl group having 4-7 carbon atoms, an allyl group, a furan-2-ylalkyl group having 1-5 carbon atoms or a thiophen-2-ylalkyl group having 1-5 carbon atoms;
R
2
represents —A—B—R
11
(wherein, A is a valence bond, —C(═O)—, —XC(═Y)—, —XC(═Y)Z—,
Endoh Takashi
Hayakawa Jun
Kawai Koji
Kawamura Kuniaki
Nagase Hiroshi
Birch & Stewart Kolasch & Birch, LLP
Ford John M.
Toray Industries Inc.
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