Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-31
2002-06-11
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252030, C544S238000, C544S239000
Reexamination Certificate
active
06403586
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel pyridazine 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 multiarticular destruction highly resembling rheumatoid arthritis. On the other hand, interleukin-1&bgr; is controlled in activity by interleukin-1&bgr; 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 research is under way for the synthesis of compounds with a focus placed on inhibitory activity against interleukin-1&bgr; production. Inhibitors synthesized in such research 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) and also that 3,4,5,6-substituted pyridazine derivatives have inhibitory activity against interleukin-1&bgr; converting enzymes [Japanese Patent Application Laid-Open (Kokai) No. HEI 7-69894]. Absolutely nothing has however been known with respect to inhibitory activity of 2,4,6-substituted pyridazin-3-one 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 pyridazine derivatives represented by the below-described formula (1) 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, leading to the completion of the present invention.
Namely, the present invention provides a pyridazine derivative represented by the following formula (1):
wherein R
1
represents a lower alkoxyl group, a lower alkylthio group or a halogen atom; R
2
represents a hydrogen atom, a lower alkoxyl group, a lower alkylthio group or a halogen atom; R
3
represents a linear or branched lower alkyl or lower alkenyl group, which may have one or more substituents each independently selected from a hydroxyl group, a halogen atom, a cyano group, a lower cycloalkyl group, a substituted or unsubstituted aromatic group or a substituted or unsubstituted carbamoyl group; R
4
represents a carboxyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted thiocarbamoyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted ureido group; and the dashed line indicates that the carbon-carbon bond between the 4-position and the 5-position is a single bond or a double bond; or a salt thereof.
Further, the present invention also provides a medicine comprising the pyridazine derivative (1) or the salt thereof as an effective ingredient.
Furthermore, the present invention also provides a pharmaceutical composition comprising the pyridazine derivative (1) or the salt thereof and a pharmaceutically acceptable carrier.
Moreover, the present invention also provides use of the pyridazine 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 pyridazine derivative (1) or the salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
The pyridazine derivative according to the present invention is represented by the formula (1). In the formula, illustrative of the lower alkoxyl groups represented by R
1
and R
2
can be those having 1 to 6 carbon atoms, for example, methoxy, ethoxy and propoxy. Illustrative of the lower alkylthio groups can be those having 1 to 6 carbon atoms, for example, methylthio, ethylthio and propylthio. Illustrative of the halogen atoms can be fluorine, chlorine, bromine and iodine.
Preferred as R
1
is a fluorine atom, a lower alkoxyl group or a lower alkylthio group, while preferred as R
2
is a hydrogen atom, a halogen atom or a lower alkoxyl group.
Examples of the lower alkyl group out of those represented by R
3
can include linear or branched lower alkyl groups having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl and n-butyl. Examples of the lower alkenyl group can include linear or branched lower alkenyl groups having 2 to 9 carbon atoms, more preferably 2 to 6 carbon atoms and 1 to 3 double bonds, for example, ethenyl, propenyl and butenyl.
These lower alkyl groups and lower alkenyl groups may have one or more substituents each independently selected from a hydroxyl group, a halogen atom, a cyano group, a lower cycloalkyl group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted carbamoyl group.
Examples of the lower cycloalkyl group can include those having 3 to 8 carbon atoms, for example, cyclo
Habata Yuriko
Kitamura Takahiro
Koshi Tomoyuki
Kotaki Kyoko
Kyotani Yoshinori
Bernhardt Emily
Kowa Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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