Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-22
2003-01-28
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S255030, C546S268400, C546S275400
Reexamination Certificate
active
06511997
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel aminopyrazole derivatives or salts thereof. More particularly, it relates to aminopyrazole derivatives represented by the following formula, or salts thereof.
wherein:
X
1
and X
2
each independently represent a hydrogen atom or a halogen atom, or when X
1
and X
2
are attached to positions adjacent to each other, they may be united together to form a lower alkylenedioxy group;
Q represents a pyridyl group or a quinolyl group;
R
1
represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted aryl group;
R
2
represents a hydrogen atom, a lower alkyl group, or an aralkyl group in which the aryl moiety may optionally be substituted;
R
3
represents a hydrogen atom, an organic sulfonyl group, or —C(═Y)—R
4
in which R
4
is a hydrogen atom or an organic residue and Y is an oxygen or sulfur atom;
provided that, when R
3
is a hydrogen atom, R
1
is a group other than a hydrogen atom and R
2
is a hydrogen atom.
BACKGROUND ART
TNF-&agr;, IL-1, IL-6 and COX-II are proteins which are predominantly produced by immunocompetent cells such as macrophages and neutrophilic leukocytes, and constitute important factors participating, for example, in immunoregulatory functions and inflammatory symptoms. TNF-&agr; and the like are also known as factors participating in many biological reactions in the hematopoietic system, the endocrine system, the nervous system and the like. Accordingly, the excessive or uncontrolled production of TNF-&agr; and the like in the living body are believed to be closely related to the onset and aggravation of diseases associated with TNF-&agr; and the like.
On the other hand, p38MAP kinase found within various types of cells in the living body are known to activate, in particular, some types of transcription factors. Specifically, transcription factors such as NF-&kgr;B, AP-1 and CREB bind to a certain DNA sequence common to TNF-&agr;, IL-1, IL-6, COX-II and the like, and thereby promote transcription. Within the cell nucleus, these transcription factors are activated by the action of p38MAP kinase, so that proteins such as TNF-&agr; are synthesized from the transcribed mRNA The mRNA which has gone out of the nucleus in the presence of calcium is inactivated by binding to a protein having a specific sequence, and decomposed rapidly. However, in the presence of p38MAP kinase activated by phosphorylation, the mRNA is released from the protein and thereby activated. Consequently, it is believed that the synthesis of proteins such as TNF-&agr;, IL-1, IL-6 and COX-II is also promoted along this pathway.
Accordingly, it is believed that the production of TNF-&agr;, IL-1, IL-6, COX-II and the like can be hindered by inhibiting p38MAP kinase. On the basis of this concept, there have been proposed a number of compounds which have a p38MAP kinase inhibiting activity and thereby hinder the production of TNF-&agr;, IL-1, IL-6, COX-II and the like (see, for example, Bioorganic & Medicinal Chemistry, Vol. 5, No. 1, pp. 49-64, 1997; and Japanese Patent Laid-Open No. 503017/'95).
It is expected that these TNF-&agr;, IL-1, IL-6 or COX-II production inhibitors will be effective in the treatment or prevention of diseases associated with TNF-&agr;, IL-1, IL-6 or COX-II, such as rheumatoid arthritis, multiple sclerosis, osteoarthritis, psoriasis, viral and bacterial infections, asthma, septic shock, IBD, Crohn's disease, Alzheimer's disease, diabetes, cachexia, osteoporosis, graft versus host disease, adult RDS, arteriosclerosis, gout, glomerulonephritis, congestive heart failure, ulcerative colitis, sepsis, cerebral malaria, restenosis, hepatitis, SLE, thrombosis, born resorption disease, chronic pulmonary inflammation disease, cardiac reperfusion injury, renal reperfusion injury, cancer, Reiter's syndrome, preterm labor, eczema, allograft rejection, stroke, fever, Behçet's disease, neuralgia, meningitis, sunburn, contact dermatitis, acute synovitis, spondylitis, muscle degeneration, angiogenesis, conjunctivitis, psoriatic arthritis, viral myocarditis, pancreatitis, glioblastoma, bleeding, joint inflammation, endotoxic shock, parasitic infections, tuberculosis, myocardial infarction, leprosy, diabetic retinopathy, IBS, transplant rejection, burns, bronchitis, ischemic heart disease, eclampsia, pneumonia, remission of swelling, low back pain, laryngopharyngitis, Kawasaki disease, myelopathy and atopic dermatitis.
Meanwhile, as to aminopyrazole derivatives, there have been known some aminopyrazole derivatives in which the 3- or 5-position of the pyrazole ring is substituted by a pyridyl group or an optionally substituted amino group, the 5- or 3-position is substituted by a pyridyl group, and the 4-position is substituted by a pyridyl group or an optionally substituted phenyl group (Japanese Patent Laid-Open No. 17470/'93). However, neither description nor suggestion is found therein about their p38MAP kinase inhibiting activities.
Very recently, certain aminopyrazole derivatives having p38MAP kinase inhibiting activities have been proposed (see the pamphlets of PCT International Publications WO98/52940 and WO98/52941).
The present inventors have now found that aminopyrazole derivatives in which one of the 3- and 5-positions of the pyrazole ring is substituted by an optionally substituted amino group, the other of the 3- and 5-positions thereof is substituted by a phenyl group that may be substituted by a halogen atom or a lower alkylenedioxy group, and the 4-position thereof is substituted by a pyridyl or quinolyl group have excellent p38MAP kinase inhibiting activities and are hence effective in hindering the production of TNF-&agr;, IL-1, IL-6, COX-II and the like.
Thus, the present invention provides aminopyrazole derivatives represented by the above formula (I), or salts thereof
DISCLOSURE OF THE INVENTION
The term “lower” as used herein means that the group or compound modified by this term has 6 or less carbon atoms and preferably 4 or less carbon atoms.
Thus, examples of the “lower alkyl group” include methyl, ethyl, n-propyl isopropyl, n-butyl, isobutyl sec-butyl, t-butyl, n-pentyl and n-hexyl, and examples of the “lower alkylenedioxy group” include methylenedioxy, ethylenedioxy and propylenedioxy.
The “aryl group” or the aryl moiety of the “aralkyl group” may be a monocyclic or polycyclic aromatic ring, and examples thereof include phenyl and naphthyl.
The “organic sulfonyl group” is a residue obtained by eliminating a hydroxyl group from an organic sulfonic acid, and examples thereof include methanesulfonyl ethanesulfonyl, benzenesulfonyl and p-toluenesulfonyl. On the other hand, the term “halogen atom” comprehends fluorine, chlorine, bromine and iodine atoms.
The “pyridyl group or quinolyl group” represented by the symbol Q may preferably be a 4-pyridyl group or a 4-quinolyl group.
The substituents which can be present in the “substituted or unsubstituted lower alkyl group” represented by the symbol R
1
include, for example, halogen, hydroxyl, lower alkoxy, lower alkanoyloxy, aralkyloxy, amino, lower alkylamino, di(lower alkyl)amino, aralkyloxycarbonylamino and lower alkoxycarbonylamino. The lower alkyl group may be substituted by one or two substituents selected from the foregoing. The substituents which can be present in the “substituted or unsubstituted aryl group” represented by the symbol R
1
include, for example, halogen, lower alkyl, halogeno(lower alkyl), lower alkoxy, lower alkylenedioxy, hydroxyl, aralkyloxy, lower alkanoyloxy, mercapto, lower alkylthio, amino, lower alkoxycarbonylamino and nitro. The aryl group may be substituted by one or two substituents selected from the foregoing.
The substituents which can be present in the aryl moiety of the “aralkyl group in which the aryl moiety may optionally be substituted” represented by the symbol R
2
may be the same as described above for the substituent(s) present in the aryl group represented by the symbol R
1
.
The “organic residue” represented by the symbol R
4
may be any
Asagarasu Akira
Asano Hajime
Doi Satoshi
Hasumi Koichi
Kanada Arihiro
Desai Rita
Rotman Alan L.
Teikoku Hormone Mfg. Co. Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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