Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-31
2001-08-21
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...
C540S481000, C540S597000, C546S044000, C546S045000, C546S046000
Reexamination Certificate
active
06277859
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an analgesic and diuretic having as its active ingredient a morphinan derivative or a pharmacologically acceptable acid 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, action that suppresses respiration and action that suppresses smooth muscle movement (constipation). Thus, there is 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.
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 classified into the three types, &mgr;, &dgr; and &kgr;. In addition, &sgr; receptors are also known to demonstrate psychotomimetics. Those agonists having affinity for these &kgr;-receptors or &dgr;-receptors have been shown to have strong analgesic activity, while not demonstrating serious side effects that present clinical problems, such as drug dependence, action that suppresses respiration and action that suppresses smooth muscle movement, that are observed in the case of morphin and so forth, which are &mgr;-receptor agonists. In addition, the psychotomimetics observed in existing &kgr;-receptor agonists are reported to be caused by the affinity to &sgr;-receptors. Moreover, &kgr;-receptor agonists do not demonstrate cross tolerance with &mgr;-receptor agonists such as morphin. Analgesics free of such side effects having 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 suffering from cancer, 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 morphin. Therefore, the object of the present invention is to provide a &kgr;-receptor agonist or &dgr;-receptor agonist that has powerful analgesic action while not having serious side effects like those of morphin, not having cross tolerance with morphin and so forth, and not demonstrating any affinity whatsoever for &sgr;-receptors. In addition, another object of the present invention is to provide a useful diuretic that takes advantage of the effects of opioid action drugs on urination.
As a result of earnest studies to solve the above-mentioned problems, the inventors of the present invention found that the morphinan derivatives indicated by the below formula (I) is a compound that demonstrates analgesic action and diuretic action 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 hydrogen atoms, a hydroxy group, a nitro group, an alkanoyloxy group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkyl group having 1-5 carbon atoms, or —NR
9
R
10
wherein R
9
represents a hydrogen atom or an alkyl group having 1-5 carbon atoms, and R
10
represents a hydrogen atom, an alkyl group having 1-5 carbon atoms, or —C(═O)R
11
wherein R
11
represents a hydrogen atom, a phenyl group or an alkyl group having 1-5 carbon atoms; R
3
represents a hydrogen atom, a hydroxy group, an alkanoyloxy group having 1-5 carbon atoms, or an alkoxy group having 1-5 carbon atoms; A represents —XC(═Y)—, —XC(═Y)Z—, —X—, —XSO
2
—, or —OC(OR
4
)R
4
— (where, X, Y and Z each independently represent NR
4
, S or O wherein R
4
represents a hydrogen atom, a straight-chain or branched chain alkyl group having 1-5 carbon atoms or an aryl group having 6-12 carbon atoms, and wherein R
4
may be identical or different); B represents a valence bond, a straight-chain or branched chain alkylene group having 1-14 carbon atoms (which may be substituted with at least one type of substituent groups selected from the group consisting of an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, a trifluoromethyl group and a phenoxy group, and wherein 1 to 3 methylene groups may be replaced with carbonyl groups), an acyclic unsaturated hydrocarbon containing from 1 to 3 double bonds and/or triple bonds and having 2-14 carbon atoms (which may be substituted with at least one substituent group selected from the group consisting of an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, a trifluoromethyl group and a phenoxy group, and wherein from 1 to 3 methylene groups may be replaced with carbonyl groups), or a straight-chain or branched chain saturated or unsaturated hydrocarbon group containing from 1 to 5 thioether, ether and/or amino bonds and having 1-14 carbon atoms (wherein hetero atoms are not bonded directly to A, and 1 to 3 methylene groups may be replaced with carbonyl groups); R
5
represents a hydrogen atom or an organic group having the basic skeleton of (formula 1) (which may be substituted with at least one or more substituent groups selected from the group consisting of an alkyl group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, an isothiocyanate group, a trifluoromethyl group and a methylenedioxy group),
(Formula 1) Organic Group Represented by R
5
(Formula 1—1)
R
6
represents a hydrogen atom; R
7
represents a hydrogen atom, a hydroxy group, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, or R
6
and R
7
together represent —O—, —CH
2
— or —S—; R
8
represents a hydrogen atom, an alkyl group having 1-5 carbon atoms, or an alkanoyl group having 1-5 carbon atoms, and the general formula (I) includes the (+) form, (−) form and (±) form].
DETAILED DESCRIPTION
Here, preferable examples of R
1
include an alkyl group having 1-5 carbon atoms, a cycloalkylmethyl group having 4-7 carbon atoms, a cycloalkenylmethyl group having 5-7 carbon atoms, a phenylalkyl group having 7-13 carbon atoms, an alkenyl group having 4-7 carbon atoms, an allyl group, a furan-2-yl-alkyl group having 1-5 carbon atoms and a thiophen-2-yl-alkyl group having 1-5 carbon atoms, while particularly preferable examples of R
1
include methyl, ethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentenylmethyl, cyclohexenylmethyl, benzyl, phenethyl, trans-2-butenyl, 2-methyl-2-butenyl, allyl, furan-2-yl-methyl and thiophen-2-yl-methyl groups.
Preferable examples of R
2
include a hydrogen atom, and hydroxy, nitro, acetoxy, methoxy, methyl, ethyl, propyl, amino, dimethylamino, acetylamino and benzoylamino groups, while particularly preferable examples include a hydrogen atom, and hydroxy, nitro, acetoxy, methyl and dimethylamino g
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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