Morphinane derivatives and medicinal use thereof

Details Morphinane derivatives and medicinal use thereof Morphinane derivatives and medicinal use thereof

1998-11-25

2001-02-13

Kight, John (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S041000, C546S046000, C546S039000

Reexamination Certificate

active

06187782

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel morphinan derivatives and compounds having abilities to bind to opioid &egr;-receptor containing the same as effective components as well as to medical uses thereof.
BACKGROUND ART
As the receptor relating to analgesic action on central nerve, opioid receptors have been revealed, and the opioid receptors are classified into three types &mgr;, &dgr; and &kgr;. &bgr;-endorphin which is one of the endogeneous opioid peptides showing strong analgesic action, has been considered as a non-selective agonist having affinities to both &mgr; and &dgr; receptors. However, detailed study using antagonists each of which is selective to each type of the opioid receptors has revealed that &bgr;-endorphin has an additional site on which it acts, in addition to the known three types of receptors. As the action site, &egr;-type receptor is drawing attention recently.
Morphine having morphinan skeleton is known as a strong analgesic for a long time, and is widely used now. However, this drug has serious side effects which are clinically problematic, such as addiction, respiratory depression and smooth muscle-depressomotor action (constipation), and it has been clarified that these side effects are exhibited through &mgr; receptors. Since use of the drug requires strict control, a strong analgesic acting on the central nerve, which may be safely used, is desired.
On the other hand, the above-mentioned &bgr;-endorphin has been reported not to show cross tolerance to morphine which is &mgr;-agonist. Agonists at &egr;-receptor are expected as analgesics free from the side effects which the &mgr;-agonists have, and are thought to be applicable not only to a pain such as postoperative pain or cancer pain, but also widely to general pains, so that it is thought to be highly useful. Further, since it does not have the cross tolerance, it is expected that the drug is effective to patients having tolerance to an analgesic such as morphine.
As is apparent from the above-mentioned study of the opioid receptors, it is known that antagonists play important roles in the pharmacological studies of receptors, and antagonists at &egr;-receptor are expected to be important tools in the pharmacological study of this receptor.
DISCLOSURE OF THE INVENTION
That is, an object of the present invention is to provide a compound which binds to opioid &egr;-receptor, more specifically, to provide an opioid &egr;-receptor agonist or antagonist.
The present inventors intensively studied to discover that the morphinan derivatives represented by the formula (I) are compounds having abilities to bind to opioid &egr;-receptor, and have &egr;-receptor agonist activity or antagonist activity, thereby completing the present invention.
That is, the present invention provides a morphinan derivative of the formula (I):
{wherein
Y is single bond or double bond;
R
1
is hydrogen, hydroxy, C
1
-C
5
alkoxy, C
1
-C
5
alkanoyloxy or C
7
-C
13
aralkyloxy;
R
2
is hydrogen or C
1
-C
5
alkyl;
R
3
and R
4
independently are hydrogen, fluorine, chlorine, bromine, iodine, C
1
-C
5
alkyl or phenyl;
A is —X(═O)—NR
6
— or —NR
6
—X(═O)—, wherein X is carbon or S═O, R
6
is hydrogen, C
1
-C
5
alkyl, C
3
-C
7
alkenyl, C
3
-C
7
alkynyl, C
6
-C
12
aryl or C
7
-C
13
aralkyl;
B is valence bond, C
1
-C
14
straight or branched alkylene (wherein said C
1
-C
14
straight or branched alkylene may be substituted with at least one substituent selected from the group consisting of C
1
-C
5
alkoxy, C
1
-C
5
alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl, phenyl and phenoxy, and that 1 to 3 methylene groups therein may be substituted by carbonyl group), C
2
-C
14
linear or branched acyclic unsaturated hydrocarbon containing 1 to 3 double bonds and/or triple bonds (wherein said C
2
-C
14
linear or branched acyclic unsaturated hydrocarbon may be substituted with at least one substituent selected from the group consisting of C
1
-C
5
alkoxy, C
1
-C
5
alkanoyloxy, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl, phenyl and phenoxy, and that 1 to 3 methylene groups therein may be substituted by carbonyl group), C
1
-C
14
straight or branched saturated or unsaturated hydrocarbon containing 1 to 5 thioether bonds, ether bonds and/or amino bonds (wherein 1 to 3 methylene groups in said C
1
-C
14
straight or branched saturated or unsaturated hydrocarbon may be substituted by carbonyl group);
R
5
is hydrogen, cyano, or an organic group having the following skeleton:
 (wherein Q is —NH—, —S— or —O—, T is —CH
2
—, —NH—, —S— or —O—, d is a number from 0 to 5, e and f independently are numbers of not less than 0 whereas the total of e and f is not more than 5)
(wherein said organic group may be substituted with at least one substituent selected from the group consisting of C
1
-C
5
alkyl, C
1
-C
5
alkoxy, C
1
-C
5
alkanoyloxy, hydroxy, C
1
-C
5
alkoxycarbonyl, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, phenyl, phenoxy and methylenedioxy), wherein —B—R
5
, R
6
and nitrogen to which —B—R
5
and R
6
are bound may cooperatively form a heterocyclic ring selected from the group consisting of morpholine, piperidine, pyrrolidine, piperazine, N-methylpiperazine, N-phenylpiperazine, indoline, tetrahydroquinoline and tetrahydroisoquinoline
when A is —X(═O)—NR
6
—, or —B—R
5
and R
6
may cooperatively form C
2
-C
6
alkylene or
 (wherein a and b independently are numbers of not less than 0, the total of a and b being not more than 4) when
A is —NR
6
—X(═O)—;
R
8
is C
4
-C
7
cycloalkylalkyl or C
7
-C
13
aralkyl} or a pharmaceutically acceptable acid addition salt thereof.
The present invention also provides a pharmaceutical which has ability to bind to opioid &egr;-receptor, more specifically, an opioid &egr;-receptor agonist or antagonist, comprising as an effective component said morphinan derivative or the pharmaceutically acceptable acid addition salt thereof according to the present invention.
BEST MODE FOR CARRYING OUT THE INVENTION
As mentioned above, the morphinan derivatives according to the present invention are represented by the above-described formula (I). In formula (I), R
1
may preferably be hydrogen, hydroxy, methoxy, ethoxy, acetoxy, propionyloxy or benzyloxy, more preferably hydrogen, hydroxy, methoxy or acetoxy.
R
2
may preferably be hydrogen or methyl.
R
3
and R
4
may be the same or different, and may preferably be hydrogen, chlorine, bromine, iodine, methyl, ethyl or phenyl, more preferably hydrogen, methyl or phenyl. “A” may preferably be carbamoyl, acylamino or sulfonylamino, more prefeably carbamoyl or acylamino. B may preferably be valence bond, —(CH
2
)
n
— (n is a number from 0 to 6, hereinafter indicated as “n=0-6”), —(CH
2
)
n
—CH═CH—(CH
2
)
m
— (n=1-2, m=0-2), —(CH
2
)
n
—CH═CH—CH═CH—(CH
2
)
m
— (n and m are independently numbers of 0 to 2 (hereinafter indicated as “n,m=0-2”), —(CH
2
)
n
—C≡C—(CH
2
)
m
— (n,m=0-2), —(CH
2
)
n
—C(═O)— (n=1-4), —(CH
2
)
n
—O—(CH
2
)
m
— (n=1-3, m=0-3), —(CH
2
)
n
—S—(CH
2
)
m
— (n=1-3, m=0-3), or —(CH
2
)
n
—NH—(CH
2
)
m
— (n=1-3, m=0-3), more preferably —(CH
2
)
n
— (n=0-6), —(CH
2
)
n
—CH═CH— (n=1-2), —(CH
2
)
n
—CH═CH—CH═CH— (n=0-2), —(CH
2
)
n
—C≡C— (n=0-2), —CH
2
—C(═O)—, —(CH
2
)
n
—O—(CH
2
)
m
— (n≠0,n+m=1-3), —(CH
2
)
n
—S—(CH
2
)
m
— (n≠0,n+m=1-3), or —(CH
2
)
n
—NH—(CH
2
)
m
— (n≠0, n+m=1-3). R
5
may preferably be hydrogen or an organic group having the following skeleton:
(wherein Q is —NH—, —S— or —O—, T is —CH
2
—, —NH—, —S— or —O—, d is a number from 0 to 5, e and f independently are numbers of not less than 0 whereas the total of e and f is not more than 5)
(wherein said organic group may be substituted with at least one substituent selected fro

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