Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-05-19
2004-08-03
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S035000, C546S031000, C546S028000
Reexamination Certificate
active
06770654
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel indole derivative and medical applications thereof.
BACKGROUND ART
Nowadays, opioid receptors are classified into three types: &mgr;, &dgr;, and &kgr;. Among these, research on the &dgr; opioid receptor was behind that regarding receptors of other types. Recently, however, several ligands selective to the &dgr; opioid receptor have been developed, and pharmacological actions relating to the &dgr; opioid receptor have become elucidated. Examples of known pharmacological actions relating to the &dgr; opioid receptor include analgesic, antitussive, immunosuppressive, and brain-cell-protecting actions.
Although &mgr; opioid agonists, represented by morphine, have been used as analgesics, &mgr; agonists have serious &mgr; opioidergic side effects such as drug dependence, suppression of the CNS, respiratory depression, or constipation. Also, since codeine, which is known as a typical antitussive, is related to the &mgr; opioid receptor, the aforementioned side effects are of serious concern. Antitussive actions of &kgr; opioid agonists are also known, although the &kgr; opioid agonists have side effects such as drug aversion or psychotomimetic effects. Although analgesic actions of the &dgr; opioid agonists have been reported, they are highly unlikely to show serious side effects compared to those of &mgr; and &kgr; opioid agonists.
As mentioned above, there are several known pharmacological actions relating to the &dgr; opioid receptor. With the use of the &dgr; receptor ligands as therapeutic agents for various diseases, separation from side effects such as drug dependence or psychotomimetic effects relating to &mgr; and &kgr; opioid receptors can be expected. Under these circumstances, the development of ligands selective to &dgr; opioid receptors has been proceeding, and agents that act on the &dgr; opioid receptor with higher affinity and higher selectivity are desired.
Known &dgr; ligand compounds are those described in WO 97/11948, etc. For example, WO 97/11948 describes a compound represented by general formula (I) according to the present invention, wherein R
1
represents cyclopropylmethyl, R
2
represents a hydroxy group, R
3
represents a methoxy group, R
10
and R
11
are bound to each other to form —O—, —Z—represents — CH
2
CH
2
CH
2
—, and m and n are each 0. In the present invention, the introduction of hydroxy and/or oxo as R
4
and/or R
5
can lower metabolic rate. This enables excellent drug efficacy to be sustained for a long period of time, and thus, frequency of administration can be reduced.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a &dgr; opioid receptor-selective ligand that can be used as an analgesic, antitussive, immunosuppressive, or brain-cell-protecting agent without serious side effects such as drug dependence, suppression of the CNS, or drug aversion relating to the &mgr; and &kgr; opioid receptors.
The present inventors have conducted concentrated studies in order to attain the above object. As a result, we have found an indole derivative that acts with high selectivity on the &dgr; opioid receptor, thereby completing the present invention. More specifically, the present invention provides an indole derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical comprising the same:
wherein R
1
is hydrogen, C
1-5
alkyl, C
4-7
cycloalkylalkyl, C
5-7
cycloalkenylalkyl, C
6-12
aryl, C
7-13
aralkyl, C
3-7
alkenyl, furan-2-yl-alkyl (wherein the alkyl moiety is C
1-5
), or thiophen-2-yl-alkyl (wherein the alkyl moiety is C
1-5
);
R
2
is hydrogen, hydroxy, C
1-5
alkoxy, or C
1-5
aliphatic acyloxy;
R
3
is hydrogen, hydroxy, C
2-5
alkoxy, C
1-5
aliphatic acyloxy, or C
7-13
aralkyloxy;
—Z— is a crosslinkage having 2 to 5 carbon atoms;
m is an integer from 0 to 3;
n is an integer from 0 to 10;
m number of R
4
groups and n number of R
5
groups are independently fluoro, chloro, bromo, iodo, nitro, C
1-5
alkyl, hydroxy, C
1-5
alkoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR
6
, SOR
6
, SO
2
R
6
, (CH
2
)
p
OR
6
, (CH
2
)
p
CO
2
R
6
, SO
2
NR
7
R
8
, CONR
7
R
8
, (CH
2
)
p
NR
7
R
8
, or (CH
2
)
p
N(R
7
)COR
8
, (wherein p is an integer from 0 to 5; R
6
is hydrogen or C
1-5
alkyl; and R
7
and R
8
are independently hydrogen, C
1-5
alkyl, or C
4-7
cycloalkylalkyl), among the above n number of R
5
groups, two R
5
groups bound to the same carbon atom become an oxygen atom to form oxo, or among the above m number of R
4
groups and n number of R
5
groups, two adjacent R
4
groups, two adjacent R
5
groups, or one R
4
and one R
5
groups may be bound to each other to form a benzene, pyridine, cyclopentane, cyclohexane, or cycloheptane fused ring (wherein at least one of m number of R
4
groups and n number of R
5
groups should be hydroxy, or two R
5
groups bound to the same carbon atom should become an oxygen atom to form oxo);
R
9
is hydrogen, C
1-5
alkyl, C
2-5
alkenyl, C
7-13
aralkyl, C
1-3
hydroxyalkyl, (CH
2
)
p
OR
6
, or (CH
2
)
p
CO
2
R
6
, wherein p and R
6
are as defined above; and
R
10
and R
11
are bound to each other to form —O—, —S—, or —CH
2
—, or R
10
is hydrogen while R
11
is independently hydrogen, hydroxy, C
1-5
alkoxy, or C
1-5
aliphatic acyloxy.
The present invention also provides a drug acting on &dgr; opioid receptor that comprises, as an active ingredient, an indole derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof. The “drug acting on &dgr; opioid receptor” used herein refers to a &dgr; opioid agonist or &dgr; opioid antagonist.
Examples of C
1-5
alkyl used herein include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, and pentyl. Examples of C
4-7
cycloalkylalkyl include cyclopropylmethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl, cyclobutylmethyl, and cyclohexylmethyl. Examples of C
5-7
cycloalkenylalkyl include cyclobutenylmethyl, 2-cyclobutenylethyl, and 3-cyclobutenylpropyl. Examples of C
6-12
aryl include phenyl, naphthyl, and tolyl. Examples of C
7-13
aralkyl include benzyl, phenethyl, naphthylmethyl, and 3-phenylpropyl. Examples of C
3-7
alkenyl include allyl, 3-butynyl, and phenyl. Examples of furan-2-yl-alkyl (wherein the alkyl moiety is C
1-5
) include 2-furylmethyl, 2-(2-furyl)ethyl, 1-(2-furyl)ethyl, and 3-(2-furyl)propyl. Examples of thiophen-2-yl-alkyl (wherein the alkyl moiety is C
1-5
) include 2-thienylmethyl, 2-(2-thienyl)ethyl, 1-(2-thienyl)ethyl, and 3-(2-thienyl)propyl. Examples of C
1-5
alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, and pentyloxy. Examples of C
2-5
alkoxy are the examples of C
1-5
alkoxy except for methoxy. Examples of C
1-5
aliphatic acyloxy include formyloxy, acetoxy, propionoxy, and pentanoyloxy. Examples of C
7-13
aralkyloxy include benzyloxy, phenethyloxy, and naphthylmethoxy.
According to a preferred embodiment of the compound represented by general formula (I), R
1
is C
4-7
cycloalkylalkyl and C
3-7
alkenyl, and C
4-7
cycloalkylalkyl is more preferable. As another embodiment, R
1
is hydrogen, C
1-5
alkyl, C
7-13
aralkyl, furan-2-yl-alkyl (wherein the alkyl moiety is C
1-5
), or thiophen-2-yl-alkyl (wherein the alkyl moiety is C
1-5
).
Among these preferred examples, hydrogen, C
1-5
alkyl, C
4-7
cycloalkylmethyl, C
3-7
alkenyl, C
7-13
aralkyl, furan-2-yl-alkyl (wherein the alkyl moiety is C
1-5
), or thiophen-2-yl-alkyl (wherein the alkyl moiety is C
1-5
) is more preferable. Hydrogen, methyl, phenethyl, 2-(2-furyl)ethyl (furan-2-yl-ethyl), or 2-(2-thienyl)ethyl (thiophen-2-yl-ethyl) is particularly preferred, and cyclopropylmethyl is also particularly preferable.
R
2
is preferably hydrogen, hydroxy, acetoxy, propionoxy, methoxy, or ethoxy, and hydrogen, hydroxy, acetoxy, or methoxy is particularly preferred.
R
3
is preferably hydrogen, hydroxy, or acetoxy, and hydroxy is particularly preferred.
—Z— is preferably C
2-5
alkylene.
R
4
and R
Aoki Takumi
Kawai Koji
Maeda Masayuki
Sakami Satoshi
Ueno Shinya
Aulakh Charanjit S.
Toray Industries Inc.
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