Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-20
2004-01-20
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252030, C514S252060, C544S238000, C544S239000
Reexamination Certificate
active
06680316
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel pyridazin-3-one derivatives, which have excellent inhibitory activity against interleukin-1&bgr; production and are useful for the prevention and treatment of immune system diseases, inflammatory diseases, ischemic diseases and the like, and also to medicines containing them as effective ingredients.
BACKGROUND ART
In many diseases, for example, rheumatism, arthritis, osteoporosis, inflammatory colitis, immune deficiency syndrome, ichorrhemia, hepatitis, nephritis, ischemic diseases, insulin-dependent diabetes mellitus, arterial sclerosis, Parkinson's disease, Alzheimer's disease, leukemia and the like, stimulation of interleukin-1&bgr; production, an inflammatory cytokine, is observed. This interleukin-1&bgr; serves to induce synthesis of an enzyme which is considered to take part in inflammation like collagenase and PLA2 and, when intra-articularly injected to animals, causes multi-articular destruction highly resembling rheumatoid arthritis. In the normal living body, on the other hand, interleukin-1&bgr; is controlled in activity by interleukin-1 receptor, soluble interleukin-1 receptor and interleukin-1 receptor antagonist.
From research conducted making use of recombinants of these bioactivity-inhibiting substances, anti-interleukin-1&bgr; antibodies and anti-receptor antibodies against various disease models, interleukin-1&bgr; has been found to play an important role in the body, leading to an increasing potential of substances having interleukin-1&bgr; inhibitory activity as therapeutics for such diseases.
For example, immunosuppressors and steroids which are used for the treatment of rheumatism out of such many diseases have been reported to inhibit the production of interleukin-1&bgr;. Even among medicaments currently under development, KE298, a benzoylpropionic acid derivative [The Japanese Society of Inflammation (11th), 1990], for example, has been reported to,have inhibitory activity against interleukin-1&bgr; production although it is an immunoregulator. Inhibitory activity against interleukin-1&bgr; production is also observed on a group of compounds which are called “COX-2 selective inhibitors”, for example, nimesulide as a phenoxysulfonanilide derivative (DE 2333643), T-614 as a phenoxybenzopyran derivative (U.S. Pat. No. 4,954,518), and tenidap (hydroxyindole derivative) as a dual inhibitor (COX-1/5-LO).
For all of these compounds, however, interleukin-1&bgr; production inhibitory activity is not their primary action so that their inhibitory activity against interleukin-1&bgr; production is lower than their primary action.
In recent years, increasingly active synthesis research is under way with a focus placed on inhibitory activity against interleukin-1&bgr; production. Production inhibitors can be classified into a group of compounds which inhibit the transfer process of an inflammatory signal to a cell nucleus and another group of compounds which inhibit an enzyme ICE that functions in the processing of a precursor of interleukin-1&bgr;. Known examples of compounds presumed to have the former action include SB203580 [Japanese Language Laid-Open (Kokai) Publication (PCT) No. HEI 7-503017], FR167653 (Eur. J. Pharm., 327, 169-175, 1997), E-5090 (EP 376288), CGP47969A (Gastroenterology, 109, 812-828, 1995), hydroxyindole derivatives (Eur. J. Med. Chem. 31, 187-198, 1996), and triarylpyrrole derivatives (WO 97/05878), while known examples of compounds presumed to have the latter action include VE-13,045 which is a peptide compound (Cytokine, 8(5), 377-386, 1996).
None of these compounds can however exhibit sufficient inhibitory activity against interleukin-1&bgr; production.
On the other hand, it is known that a variety of 5,6-diphenylpyridazine derivatives have analgesic and anti-inflammatory action (Eur. J. Med. Chem., 14, 53-60, 1979). Absolutely nothing has however been known with respect to inhibitory activity of these 5,6-diphenylpyridazine derivatives against interleukin-1&bgr; production.
Accordingly, an object of the present invention is to provide a compound having excellent inhibitory activity against interleukin-1&bgr; production and also a medicine containing it as an effective ingredient.
DISCLOSURE OF THE INVENTION
Under such circumstances, the present inventors have proceeded with an extensive investigation. As a result, it has been found that pyridazin-3-one derivatives represented by the below-described formula (1) have excellent inhibitory activity against interleukin-1&bgr; production and are useful as medicines for the prevention and treatment of immune system diseases, inflammatory diseases and ischemic diseases, leading to the completion of the present invention.
Namely, the present invention provides a pyridazin-3-one derivative represented by the following formula (1):
wherein Ar
1
represents a substituted or unsubstituted aromatic group, Ar
2
represents a phenyl group having a substituent at least at the 4-position thereof, R
1
represents a linear or branched alkyl group, an alkyl group having a cyclic structure, a substituted or unsubstituted phenyl group or a substituted or unsubstituted phenyl(lower alkyl) group, and R
2
represents a cyano group, a carboxyl group, a (lower alkoxy)carbonyl group, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted carbamoyl group; or a salt thereof.
The present invention also provides a medicine comprising the pyridazin-3-one derivative (1) or the salt thereof as an effective ingredient.
Further, the present invention also provides an inhibitor of interleukin-1&bgr; production comprising the pyridazin-3-one derivative (1) or the salt thereof as an effective ingredient.
Furthermore, the present invention also provides a pharmaceutical composition comprising the pyridazin-3-one derivative (1) or the salt thereof and a pharmaceutically acceptable carrier.
Moreover, the present invention also provides use of the pyridazin-3-one derivative (1) or the salt thereof as a medicine.
In addition, the present invention also provides a method for treating a disease caused by stimulation of interleukin-1&bgr; production, which comprises administering the pyridazin-3-one derivative (1) or the salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
The pyridazin-3-one derivative according to the present invention is represented by the formula (1).
In the formula (1), examples of the aromatic group represented by Ar
1
can include all aromatic hydrocarbon groups and heterocyclic aromatic groups, such as phenyl, naphthyl, pyridyl and quinolyl groups, with a phenyl group being particularly preferred. Illustrative of one or more substituents which the aromatic group may have are halogen atoms, lower alkoxy group,s lower alkylthio groups, lower alkylsulfinyl groups, and lower alkylsulfonyl groups. Examples of the halogen atoms can include fluorine, chlorine, bromine and iodine atoms. Examples of the lower alkyl moieties in the lower alkoxy, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl groups can include linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl groups. Among these substituents, lower alkoxy groups are preferred with a methoxy group being particularly preferred.
Illustrative of the substituent which the substituted phenyl group represented by Ar
2
has at the 4-position thereof are lower alkoxy, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl groups. More specifically, groups similar to those exemplified above in connection with Ar
1
can be mentioned, with lower alkoxy groups, especially a methoxy group being preferred. Further, the substituted phenyl group may be substituted at other position or positions by halogen atoms, lower alkoxy groups or the like. Examples of these halogen atoms and lower alkoxy groups can be similar to those exemplified above in connection with Ar
1
can be mentioned.
Illustrative of the linear or branched alkyl group represented by R
1
are those h
Furuyama Tomoko
Kitamura Takahiro
Koshi Tomoyuki
Kyotani Yoshinori
Matsuda Takayuki
Kowa Co. Ltd.
Rao Deepak
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