Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-22
2001-09-18
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S031000
Reexamination Certificate
active
06291470
ABSTRACT:
TECHNICAL FIELD
The present invention relates to compounds having affinities to &dgr;-opioid receptor. &dgr;-opioid receptor relates to analgetic, immune and circulatory systems (especially blood pressure) and ligands having high selectivities to this receptor can be used as analgesics, immunosuppressive agents (employed in organ transplantation (kidney, liver and heart), skin transplantation, treatment of autoimmune diseases (rheumatism, various allergies and collagen diseases) and the like], immunopotentiating agents (anti-tumor agents and anti-virus agents), blood pressure-lowering agents and the like.
PRIOR ART
Opioid receptors include three types called &mgr;, &dgr; and &kgr;. Among these, &dgr;-opioid receptor relates various pharmacological effects as mentioned above. However, the number of agonists and antagonists having high selectivities to this receptor is small and the mechanism has not yet been clarified. Recently, a non-peptidic antagonist NTI was discovered by Portoghese (Portoghese, P. S. et al., J. Med. Chem., 31, 281 (1988); 33, 1714 (1990)). Subsequently, synthesis of an antagonist (5′-NTII) which can irreversibly bind to the receptor was reported (Portoghese, P. S. et al., J. Med. Chem. 33, 1547 (1990)). Since a ligand which irreversibly binds to the receptor is very useful in studying the receptor, researchers are paying more and more attention to 5′-NTII. However, its antagonist activity and selectivity to &dgr;-opioid receptor are low. Therefore, as a probe for studying the receptor, a ligand having higher activity and selectivity is demanded.
On the other hand, participation of endogenous opioid peptides such as enkephalin, and morphine in immune system has been pointed out and it is known that opioids may possibly be immunopotentiating agents and immunosuppressive agents. Paying attention to this, the present inventors studied the influence on the immune system by NTI. As a result, it was shown that this compound exhibits immunosuppressive action in vitro and in vivo (Japanese Laid-open Patent Application (Kokai) No. 3-223288). Since currently used immunosuppressive agents have problems in toxicities and side effects, an agent having a low toxicity or having a different mechanism of action is demanded. It is expected that &dgr;-opioid antagonist is one of the candidates thereof.
It has recently been discovered that opioids relate to flow of calcium ion into cells, which has a relationship with ischemia in brain, and that opioids have brain cell-protecting action. Thus, use of opioids as a brain cell-protecting agent is increasingly expected.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a &bgr;-opioid antagonist having high antagonist activity and receptor selectivity.
Another object of the present invention is to provide a &bgr;-opioid antagonist having high immunosuppressive action and brain cell-protecting action.
To attain the above-mentioned objects, the present inventors intensively studied to discover that the compound represented by the formula (I) below has the above-mentioned characteristics, thereby completing the present invention. That is, the present invention provides an indole derivative represented by the formula (I):
[wherein R
1
represents C
1
-C
5
alkyl, C
4
-C
6
cycloalkylalkyl, C
5
-C
7
cycloalkenylalkyl, aryl, C
1
-C
3
aralkyl, C
4
-C
5
trans-alkenyl, allyl, C
1
-C
3
furan-2-ylalkyl or C
1
-C
3
thiophene-2-ylalkyl;
R
2
represents hydrogen, hydroxy, C
1
-C
5
alkanoyloxy or C
1
-C
5
alkoxy;
R
3
represents hydrogen, C
1
-C
5
alkyl, C
1
-C
5
alkanoyl or benzyl;
R
4
represents hydrogen, C
1
-C
5
alkyl or benzyl;
R
5
and R
6
, the same or different, represent hydrogen, iodine, trifluoromethyl, trifluoromethoxy, cyano, phenyl, C
1
-C
3
hydroxyalkyl, SR
7
, SOR
7
, SO
2
R
7
, (CH
2
)
m
CO
2
R
7
(wherein m represents an integer of 0-3, R
7
represents C
1
-C
5
alkyl), SO
2
NR
8
R
9
, CONR
8
R
9
, (CH
2
)
n
NR
8
R
9
(wherein n represents an integer of 1-3, R
8
and R
9
, the same or different, represent C
1
-C
5
alkyl, or C
4
-C
6
cycloalkylalkyl), isothiocyanato (NCS; bonded to one of 4′-, 6′- and 7′-positions) or nitro (bonded to one of 4′-, 6′- and 7′-positions), with the proviso that R
5
and R
6
are not simultaneously hydrogen atoms) or R
5
and R
6
are bonded and cooperatively represent C
3
-C
6
alkylene (with the proviso that one or more hydrogen atoms in the alkylene moiety may be substituted with R
10
(wherein R
10
represents C
1
-C
5
alkyl, C
1
-C
5
alkoxy, C
1
-C
5
alkanoyl, C
1
-C
5
hydroxyalkyl, SR
7
, SOR
7
, SO
2
R
7
(CH
2
)
m
CO
2
R
7
, SO
2
NR
8
R
9
, CONR
8
R
9
, (CH
2
)
n
NR
8
R
9
(wherein m, n, R
7
, R
8
and R
9
represent the same meanings as described above, respectively), and with the proviso that said alkylene is bonded to carbon atoms adjacent to each other on the benzene ring to form a ring) or R
5
and R
6
cooperatively represent —S=T—U=V— (wherein at least one of S, T, U and V represents nitrogen and the remainders represent CH (with the proviso that the hydrogen may be substituted with said R
10
) which is bonded to carbon atoms adjacent to each other on the benzene ring to form a ring);
the formula (I) includes (+) isomers, (−) isomers and racemates]
and pharmaceutically acceptable acid addition salts thereof.
The present invention also provides an immunosuppressive agent, a brain cell-protecting agent, an antiallergic agent and an anti-inflammatory agent comprising as an effective ingredient the indole derivative or the pharmaceutically acceptable acid addition salt thereof according to the present invention.
The present invention further provides a process for producing the indole derivative or the pharmaceutically acceptable acid addition salt thereof according to the present invention, comprising the step of reaction of a compound of the formula (III):
(wherein R
1
, R
2
and R
3
represent the same meanings as described above, respectively) with a phenylhydrazine derivative of the formula (IV):
(wherein R
4
, R
5
and R
6
represent the same meanings as described above, respectively) in the presence of an acid catalyst.
By the present invention, novel indole derivatives which are &dgr;-opioid antagonists having high selectivities and activities, and phamaceutically acceptable acid addition salts thereof, as well as a process for producing the same, were provided. The indole derivatives according to the present invention have excellent immunosuppressive actions, brain cell-protecting actions, antiallergic actions and anti-inflammatory actions.
REFERENCES:
patent: 4816586 (1989-03-01), Portughese et al.
patent: 5225417 (1993-07-01), Dappen et al.
patent: 5332818 (1994-07-01), Nagase et al.
patent: 5352680 (1994-10-01), Portoghese et al.
patent: 5354863 (1994-10-01), Dappen et al.
patent: 5457208 (1995-10-01), Portughese et al.
patent: 5849731 (1998-12-01), Nagase et al.
patent: 9107966 (1990-11-01), None
patent: 4342529A (1992-11-01), None
patent: WO 8900995A1 (1989-02-01), None
patent: WO9407896 (1994-04-01), None
Portoghese et al.,J. Med. Chem., vol. 33, No. 6, 1714-1720 (1990).
Portoghese et al.,J. Med. Chem,. 33, 1547-1548 (1990).
Portoghese et al.,J. Med. Chem., 35, 4086-4091 (1992).
Olmsted et al.,J. Med. Chem.36, 179-180 (1993).
Nagase et al.,Chem. Abstr.vol. 119, Entry 95503 (1992).
Nagase et al.,Chem Abstr.vol. 115 Entry 174658 (1990).
Kawai Koji
Mizusuna Akira
Nagase Hiroshi
Nakatani Izumi
Birch & Stewart Kolasch & Birch, LLP
Raymond Richard L.
Toray Industries Inc.
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