Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-10
2003-12-16
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S247000, C514S252030, C544S238000, C544S239000, C544S114000, C544S224000
Reexamination Certificate
active
06664256
ABSTRACT:
TECHNICAL FIELD
The present invention relates to phenylpyridazine compounds having excellent inhibitory activity against interleukin-1&bgr; production and methods for the prevention and treatment of immune system diseases, inflammatory diseases, ischemic diseases and the like using the compounds, and medicines containing them as active ingredients.
BACKGROUND ART
In many diseases, such as rheumatism, arthritis, osteoporosis, inflammatory colitis, immune deficiency syndrome, ichoremia, hepatitis, nephritis, ischemic diseases, insulin-dependent diabetes mellitus, arterial sclerosis, Parkinson's disease, Alzheimer's disease, and leukemia, stimulation of the production of an inflammatory cytokine known as interleukin-1&bgr; is observed. Interleukin-1&bgr; serves to induce synthesis of an enzyme which is considered to take part in inflammation, such as collagenase and PLA2, and, when intra-articularly injected into animals, causes multiarticular destruction highly resembling rheumatoid arthritis. In the normal living body, on the other hand, interleukin-1&bgr; is controlled in activity by interleukin-1 receptors, soluble interleukin-1 receptor and interleukin-1 receptor antagonists.
From research conducted using recombinants of these bioactivity-inhibiting substances, anti-interleukin-1&bgr; antibodies, anti-receptor antibodies and knockout mice on various disease models, interleukin-1&bgr; has been found to play a pivotal 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 used for the treatment of rheumatism have been reported to inhibit the production of interleukin-1&bgr;. Even among medicines 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 in a group of compounds called “COX-2 selective inhibitors”, including for example, nimesulide as a phenoxysulfonanilide derivative (DE 2333643), T-614 as a phenoxybenzopyran derivative (U.S. Pat. No. 4,954,518), and tenidap (oxyindole 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 research has been 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 transmission process of an inflammatory signal to a cell nucleus and the transcription and translation process, 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).
However, none of these compounds 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). However, absolutely nothing has been known with respect to inhibitory activity of these 5,6-diphenylpyridazine derivatives against interleukin-1&bgr; production.
As pyridazine derivatives having inhibitory activity against interleukin-1&bgr; production, some pyridazine derivatives have been published recently in JP 7-69894, WO 9841511, WO 9910331, WO 9910332, WO 9925697 and WO 9944995. They are, however, different in chemical structure from the compounds according to the present invention.
There is thus a need for compounds capable of inhibiting interleukin-1&bgr; production.
SUMMARY OF THE PRESENT INVENTION
Accordingly, one object of the present invention is to provide a compound having excellent inhibitory activity against interleukin-1&bgr; production.
A further object of the present invention is to provide a method for the treatment of diseases and conditions caused by stimulation of interleukin-1&bgr; production.
A further object of the present invention is to provide a pharmaceutical composition useful in treatment of diseases and conditions caused by stimulation of interleukin-1&bgr; production.
These and other objects of the present invention have been satisfied by the discovery of phenylpyridazine compounds of formula (I):
wherein
R1, R2, R3, R4 and n have the meanings disclosed herein, which has excellent inhibitory activity against interleukin-1&bgr; production, and their use in pharmaceutical compositions and methods for treating diseases caused by stimulation of interleukin-1&bgr; production.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention relates to pyridazine compounds represented by formula (I) having excellent inhibitory activity against interleukin-1&bgr; production and useful as medicines for the prevention and treatment of immune system diseases, inflammatory diseases and ischemic diseases.
The phenylpyridazine compound of the present invention is represented by the following formula (I):
wherein
R
1
represents a substituted or unsubstituted phenyl group or a substituted or unsubstituted pyridyl group,
R
2
represents a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group;
R
3
represents a hydrogen atom or a lower alkoxy group,
or R
2
and R
3
may be fused together to form an alkylenedioxy group,
R
4
represents hydrogen, halogen, cyano, carboxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkylthio, substituted or unsubstituted lower alkylsulfinyl, substituted or unsubstituted lower alkylsulfonyl, substituted or unsubstituted lower alkylsulfonyloxy, substituted or unsubstituted aryl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylthio, substituted or unsubstituted phenylsulfinyl, substituted or unsubstituted phenylsulfonyl, substituted or unsubstituted pyridyloxy, substituted or unsubstituted morpholino, substituted or unsubstituted morpholinocarbonyl, substituted or unsubstituted piperidinocarbonyl, substituted or unsubstituted 1-piperazinylcarbonyl or substituted or unsubstituted amino, and
n is 0 or 1,
with the proviso that when R
1
is 4-methoxyphenyl group, R
2
is a methoxy group and R
3
is a hydrogen atom, R
4
can not be hydrogen or halogen, and also R
1
can not be 4-(methylsulfonyl)phenyl or 4-(aminosulfonyl)phenyl;
or a salt thereof.
The present invention also provides a composition comprising the phenylpyridazine compound (I) or the salt thereof as an effective ingredient, in a suitable pharmaceutically acceptable carrier.
Moreover, the present invention also provides a method for treating a disease caused by stimulation of interleukin-1&bgr; production, which comprises administering to a subject in need thereof, an effective amount of the phenylpyridazine compound (I) or the salt thereof, either alone or as a composition in a pharmacologically acceptable carrier.
Within the context of the present invention, the term “lower alkyl” represents alkyl groups having from 1 to 6 carbons and being either linear, branched or cyclic.
Illustrative of the lower alkyl group and the lower alkyl moieties in the lower alkoxy group, lower alkylth
Koshi Tomoyuki
Kotaki Kyoko
Kumai Natsuyo
Kyotani Yoshinori
Matsuda Takayuki
Bernhardt Emily
Kowa Co. Ltd.
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