Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-14
2002-10-22
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S248000, C514S252020, C514S252030, C514S252040, C514S252050, C544S235000, C544S238000, C544S240000
Reexamination Certificate
active
06469003
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a pyridazinone derivative having a cell adhesion inhibiting activity and useful for the treatment or prevention of inflammation, asthma, chronic articular rheumatism, arteriosclerosis, allergy, cancer metastasis, inflammatory disorder accompanying operation or treatment, ischemic reperfusion injury, rejection at organ transplantation, psoriasis, acute pulmonary injury, inflammatory intestinal disease, burn and the like, or pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising as an active ingredient the derivative or a pharmaceutically acceptable salt thereof.
BACKGROUND OF THE INVENTION
An inflammatory reaction is a sort of defense reaction which occurs at the time when a living body has received a stimulus caused by an alien substance, microbism or the like from the outside. At an inflammatory site, leukocytes which have infiltrated from blood vessels are observed, and the overresponse of the leukocytes causes tissue injury. The infiltration of leukocytes into tissues from blood vessels proceeds through several steps (
Cell,
67, 1033-1036 (1991);
Immunol Today,
14, 99-102 (1993);
Cell,
76, 301-314 (1994)). For example, the infiltration of leukocytes into tissues at an inflammatory site observed mainly at early stage of inflammation is begun with the occurrence of adhesion of leukocytes circulating in blood vessels at physiological state to vascular endothelial cells. Since the phenomena of the adhesion of leukocytes to vascular endothelial cells and the infiltration into tissues are observed at chronic articular rheumatism, asthma, inflammatory intestinal disease, arteriosclerosis, and the like, the adhesion of leukocytes to vascular endothelial cells is considered to be an important step for the progress of these various diseases. (
Arthritis Rheum.,
36, 147-157 (1993);
J. Clin. Invest.,
93: 1411-1421 (1994);
The Journal of the Japanese Society of Internal Medicine,
82: 1480-1485 (1993);
Nature,
362: 801-809 (1993)).
Therefore, preventive or therapeutic effects on the above diseases including inflammation can be expected by inhibiting the adhesion of leukocytes to vascular endothelial cells. In fact, it has been reported that an antibody against an adhesion molecule of leukocytes such as LFA-1 or Mac-1, an antibody against ICAM-1 of a vascular endothelial cell or the like, suppresses the tissue infiltration of leukocytes in various laboratory animal models (
Science,
255: 1125-1127 (1992);
Am. Rev. Respir. Dis.,
147: 435-441 (1993)).
In addition, it has been revealed that derivatives of sialyl Lewis X which is sugar chain ligands of E-selectin are effective for inflammatory diseases as selectin inhibitors (Japan Society of Chest Disease (37th), 210 (1997)). However, these are used only limitedly owing to their antigenicity and low oral bioavailability. Therefore, some low molecular weight compounds have been reported for the purpose of overcoming these defects. For example,
The Year's Drug News
(p. 506, Prous Science (1995)) describes various low molecular weight compounds which exhibit a cell adhesion inhibiting activity. Furthermore, since cell adhesion of cancer cells acts an important role in their metastasis, inhibition of cell adhesion has been also thought to be effective in the cancer therapy (
Cancer Res.,
82: 1120-1129 (1991);
Cancer Res.,
53: 354-361 (1993)). In conclusion, the agents inhibiting cell adhesion are useful for the diseases mentioned above which are intractable and/or sufficient therapeutic methods are not established, because they have a different mode of action from that of pharmaceuticals hitherto employed.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a pyridazinone derivative having a strong cell adhesion inhibiting activity and possessing an antiinflammatory activity, an antiasthmatic activity, an antirheumatic activity, an antiarteriosclerotic activity, an antiallergic activity, a suppressive activity of cancer metastasis, a suppressive activity of inflammatory disorder accompanying operation or treatment, a suppressive activity of ischemic reperfusion injury, a suppressive activity of rejection at organ transplantation, an antipsoriatic activity, a suppressive activity of acute pulmonary injury, a therapeutic activity of inflammatory intestinal disease, a therapeutic activity of burn and the like, or pharmaceutically acceptable salt thereof, and a medicament comprising as an active ingredient the derivative or a pharmaceutically acceptable salt thereof.
The present invention relates to a pyridazinone derivative represented by formula (I):
{wherein
R
1
represents a phenyl group, a substituted phenyl group, an aromatic heterocyclic group or a substituted aromatic heterocyclic group;
R
2
represents a (C
1
-C
8
)alkyl group, a substituted (C
1
-C
8
)alkyl group, a phenyl group, a substituted phenyl group, an aralkyl group, a substituted aralkyl group, an aromatic heterocyclic group, a substituted aromatic heterocyclic group, an amino group, an amino group substituted with one or two (C
1
-C
8
)alkyl groups which are the same or different, a 4- to 10-membered cyclic amino group, a cyano group, a carboxyl group, a (C
1
-C
8
)alkoxycarbonyl group, a carbamoyl group, a thiocarbamoyl group, an aminocarbonyl group, an aminocarbonyl group substituted with one or two (C
1
-C
8
)alkyl groups or substituted (C
1
-C
8
)alkyl groups which are the same or different, a 4- to 10-membered cyclic aminocarbonyl group, a phenylaminocarbonyl group, a substituted phenylaminocarbonyl group, an aromatic heterocyle-aminocarbonyl group or a substituted aromatic heterocyle-aminocarbonyl group;
R
3
represents a hydrogen atom, a (C
1
-C
8
)alkyl group, a substituted (C
1
-C
8
)alkyl group, a phenyl group, a substituted phenyl group, an aromatic heterocyclic group or a substituted aromatic heterocyclic group;
R
4
represents a cyano group,
(wherein
R
5
represents a hydrogen atom, a (C
1
-C
8
)alkyl group, a substituted (C
1
-C
8
)alkyl group, a (C
1
-C
8
)alkoxy group, a hydroxyl group, amino group, an amino group substituted with one or two (C
1
-C
8
)alkyl groups which are the same or different, a 4- to 10-membered cyclic amino group, phenyl group, a substituted phenyl group, an aromatic heterocyclic group or a substituted aromatic heterocyclic group, or R
5
may form (CR
7
2
)
m
(wherein R
7
are the same or different and represents hydrogen atom, a (C
1
-C
8
)alkyl group, a substituted (C
1
-C
8
)alkyl group, a phenyl group, a substituted phenyl group, an aromatic heterocyclic group or a substituted aromatic heterocyclic group, and m represent an integer of 2 to 7) together with R
3
to form a ring; and
Y represents NH, O or S),
(wherein
R
6
represents a hydrogen atom, a (C
1
-C
8
)alkyl group, a substituted (C
1
-C
8
)alkyl group, a phenyl group, a substituted phenyl group, an aromatic heterocyclic group or a substituted aromatic heterocyclic group, or R
6
may form (CR
7
2
)
m
(wherein R
7
and m have the same meanings as described above) together with R
3
to form a ring; and
R
8
represents a hydrogen atom or a (C
1
-C
8
)alkylcarbonyl group), or
(wherein
R
6
has the same meaning as described above; and
R
9
and R
10
are the same or different and represent a (C
1
-C
8
)alkyl group or a substituted (C
1
-C
8
)alkyl group, or R
9
and R
10
together form a (C
2
-C
4
)alkylene chain and may form a ring together with the atoms attached thereto); and
X represents a single bond, O or S(O)
n
(wherein n represents an integer of 0, 1 or 2)},
or a pharmaceutically acceptable salt thereof.
Further, the present invention relates to a pharmaceutical composition comprising as an active ingredient the derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
Furthermore, the present invention relates to use of the derivative or a pharmaceutically acceptable salt thereof as a cell adhesion inhibitor.
Moreover, the present invention relates to use of the
Gotoh Makoto
Nagamine Masashi
Onishi Masanobu
Oshita Yoshitami
Satoh Akiyuki
Nihon Nohyaku Co. Ltd.
Raymond Richard L.
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