Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-15
2002-02-19
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S236500, C514S247000, C514S252010, C514S252020, C544S114000, C544S238000, C544S239000
Reexamination Certificate
active
06348468
ABSTRACT:
DESCRIPTION
1. 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.
2. 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. 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. 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, a variety of 5,6-diphenylpyridazine derivatives are known to 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 against interleukin-1&bgr; production by these 5,6-diphenylpyridazine derivatives.
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 as medicines 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 substituted or unsubstituted aryl group, R
2
is a phenyl group substituted at least at 4-position by a lower alkoxyl group, a lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group, and optionally has one or more substituents at the remaining positions, R
3
represents a hydrogen atom, a lower alkoxyl group, a halogenated lower alkyl group, a lower cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted, nitrogen-containing heterocyclic ring residue, a substituted or unsubstituted aminocarbonyl group, or a lower alkylcarbonyl group, A represents a single bond or a linear or branched lower alkylene group or lower alkenylene group, X represents an oxygen atom or a sulfur atom, 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, with the proviso that A is a single bond when R
3
is a halogenated lower alkyl group and that the following combinations are excluded: R
1
and R
2
are 4-methoxyphenyl groups, X is an oxygen atom, the carbon-carbon bond at the 4-position and the 5-position is a double bond, A is a single bond, and R
3
is a hydrogen atom or a 2-chloroethyl group; 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.
As will be demonstrated in tests to be described subsequently herein, the inhibitory activity against interleukin-1&bgr; production by the pyridazine derivative (1) or the salt thereof is extremely strong and reaches 100 to 1,000 times as high as the action of the abovedescribed known 5,6-diphenylpyridazine derivatives (EUR. J. MED. CHEM. 14, 53-60, 1979).
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 aryl group represented by R
1
can be phenyl, naphthyl and pyridyl, with phenyl and pyridyl being particularly preferred. These aryl groups may contain 1 to 3 substituents. Examples of such substituents can include halogen atoms, lower alkyl groups, lower alkoxyl groups, lower alkylthio groups, lower alkylsulfinyl groups, lower alkylsulfonyl groups, carboxyl group, lower alkoxycarbonyl groups, nitro group, amino group, and lower alkylamino groups. Here, illustrative of the halogen atoms can be fluorine, chlorine, bromine and iodine. The lower alkyl groups are those containing 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl and n-butyl. Illustrative of the lower al
Habata Yuriko
Kitamura Takahiro
Koshi Tomoyuki
Kotaki Kyoko
Kumai Natsuyo
Bernhardt Emily
Kowa Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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