Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-29
2003-01-21
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S154000, C546S155000, C546S157000
Reexamination Certificate
active
06509352
ABSTRACT:
This application is a 371 of PCT/JP99/07398, filed Dec. 28, 1999.
TECHNICAL FIELD
The present invention relates to novel 2-oxoquinoline compounds and pharmaceutical uses thereof. In addition, the invention relates to novel uses of some types of 2-oxoquinoline compounds. More specifically, the invention relates to novel 2-oxoquinoline compounds that selectively act on cannabinoid receptors, particularly on peripheral cannabinoid receptors, and that have immunomodulating action, anti-inflammatory action, and antiallergic action with fewer side effects on the central nervous system and to pharmaceutical uses thereof.
BACKGROUND ART
So far, a series of compounds named cannabinoids, which comprise C, H, and O, are known as constituents of cannabis. It has also been known that, among them, tetrahydrocannabinol (THC) is a major hallucinogen, and that a principal ingredient contained in the cannabis plant is &Dgr;9-THC. It has been reported that &Dgr;9-THC has actions including ataxia, increased sensitivity to stimulation, antiemetic action, analgesic action, hypothermic action, respiratory depression, catalepsy-inducing action, vasodilator action, immunosuppressive action, etc.
The sites of these actions of &Dgr;9-THC are roughly categorized into the central nervous system (Devane et al., Mol Pharmacol. 1988, 34, 605-613; Hollister et al., Pharmacol. Rev., 1986, 38, 1-20; Renu et al., Prog. Drug Res., 1991, 36, 71-114) and the peripheral tissues (Nye et al., J. Pharmacol. Exp. Ther., 1985, 234, 784-791; Flynn et al., Mol Pharmacol. 1992, 41, 736-742). There are reports suggesting that some of the actions on the central nervous system are medically applicable.
On the other hand, it has been found that there exists the peripheral type receptor, for example, the receptor on macrophages (Munnro et al., Nature, 1993, 365, 61-65). Based on this finding, research and development are being carried out with the objective of designing peripheral type receptor agonists capable of modulating immune reaction and having anti-inflammatory action, antiallergic action, as well as the original immunomodulating action.
Further, agents selectively acting on peripheral type cannabinoid receptors can be safe agents that have no side effects on the central nervous system such as hypothermic action, catalepsy, and such, and therefore modulators selective for the peripheral type receptor are expected to be developed in particular.
Known cannabinoid receptor agonists include pyrazole derivatives (Unexamined Published Japanese Patent Application (JP-A) No. Hei 6-73014; EP Nos. 656354 and 658546), THC derivatives (JP-A Hei 3-209377), benzoxazine derivatives (U.S. Pat. No. 5,112,820), indole derivatives (U.S. Pat. No. 5,081,122), and aliphatic acid derivatives (WO 94/12466). However, there have previously been no findings on 2-oxoquinoline compounds by which the compounds of the present invention are characterized.
On the other hand, a variety of quinoline derivatives have been reported in terms of chemical structure.
For example, a reference of J. Pharm. Sci., 73, 11, 1652-1653 (1984) describes 6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid benzylamide (compound A shown below), which is useful as a stimulant for the central nervous system. Another reference, Khim. Geterotsikl. Soedin., 8, 1101-1104 (1993), describes 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (pyridine-2-yl)amide (compound B shown below), which is useful as an anti-inflammatory agent. In Pharmaproject and others, it has been reported that 4-hydroxy-2-oxo-1-methyl-1,2-dihydroquinoline-3-carboxylic acid N-methyl-N-phenylamide (compound C shown below) that is also called “roquinimex” can be used as agents for a variety of diseases, e.g., anti-inflammatory agent, immunosuppressant, and antirheumatic agent.
Further, Examined Japanese Patent Publication No. Sho 47-14107 discloses a method for synthesizing 3-benzoylamino-6,7-dimethoxy-2-(1H)quinolone (compound D shown below) that can be used as an agent acting on the central nervous system.
In addition, 2-oxo-1,2-dihydroquinoline-3-carboxylic acid cyclohexylamide has been disclosed in Synthesis, 11, 1362-1364 (1995). Quinoline compounds which are useful as immunomodulators have been disclosed in Published Japanese Translation of International Publication No. Hei 4-500373. Quinoline compounds which are useful as analgesic agents have been disclosed in French Patent Publication No. 2377400. Quinoline compounds which are useful as 5-HT
4
receptor agonists have been disclosed in republished patent publication WO 96/05166.
Further, one of 2-oxoquinoline compounds having 3,4-methylenedioxyphenyl group, which is one of specific features of the compounds of the present invention, is N-(3,4-methylenedioxyphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxamide (compound E shown below), which is a compound capable of enhancing immunological activities and has been disclosed in JP-A Sho 57-171975 (EP No. 59698). Yet further, 1-methyl-2-oxo-3-{N-(1,3-benzodioxole-5-yl)-N-methylcarbamoyl}-4-hydroxy-6-methylthio-1,2-dihydroquinoline (compound F shown below), which has immunomodulating action, anti-inflammatory action, and analgesic action, has been disclosed in Published Japanese Translation of International Publication No. Hei 6-506925 (WO 92/18483).
However, these references have no description suggesting the existence of 2-oxoquinoline compounds of the present invention nor suggestion of pharmacological action based on the cannabinoid receptor-mediated mechanism.
On the other hand, description found in the publication of WO 97/29079 is that some compounds having quinoline structure, functioning as cannabinoid receptor agonist or antagonist, are useful as immunomodulators, anti-inflammatory agents, antiallergic agents, or the like.
However, the quinoline compounds disclosed in the reference are merely quinolines that have been substituted with a hydroxy, and in the reference, there is no description suggesting the existence of the 2-oxoquinoline compounds of the present invention.
A reference of JP-A Hei 11-80124 (WO 99/02499) also describes immunomodulator, anti-inflammatory agent, and antiallergic agent comprising cannabinoid receptor agonist or antagonist as an active ingredient. The patent publication has also disclosed 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-aminophenyl)amide (compound G) and such, which is one of compounds having the 2-oxoquinoline structure that is one of specific features of the compounds of the present invention.
In more detail, in the above-mentioned patent publication, for example, just merely the above-mentioned compound G and three other compounds are specifically disclosed, and the reference has no description of the inventive compounds that disclosed herein, which is represented by general formula (I), including compounds of which R
a
is alkyl; compounds of which X is —COOR
b
, —CONH
2
, —(CH
2
)
p
—OC(═Y)—NR
d
—(Alk
b
)
s
—R, —(CH
2
)
q
—NR
e
—C(═Z)—(NR
f
)
w
—(Alk
c
)
v
—R, —(CH
2
)
p
—OH, or —(CH
2
)
q
—NR
e
R
e
′ (where each symbol is as defined herein); compounds of which X is —CONR
c
—(Alk
a
)
r
—R and R
c
is alkyl; or compounds of which R is represented by:
where each symbol is as defined herein.
It should be noted that, while the above-mentioned patent application was first laid open to public inspection on Jan. 21, 1999 (WO 99/02499), the priority date of the present application is Jan. 8, 1999, which is therefore earlier than the above publication date.
DISCLOSURE OF THE INVENTION
An objective of the present invention is to provide novel compounds selectively acting on cannabinoid receptors, particularly on peripheral cannabinoid receptors and to provide pharmaceutical compositions thereof.
More specifically, the objective of the present invention is to provide novel compounds and pharmaceutical compositions thereof that are capable of selectively acting on cannabinoid receptors, particularly on the receptors of peripheral tissues, and that hav
Inaba Takashi
Iwamura Hiroyuki
Kaya Tetsudo
Bozicevic Field & Francis LLP
Japan Tobacco Inc.
Keddie James S.
Seaman D. Margaret
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