Substituted pyrazole compounds

Details Substituted pyrazole compounds Substituted pyrazole compounds

2001-12-03

2003-12-23

Fan, Jane (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S333000, C546S275400, C546S256000

Reexamination Certificate

active

06667325

ABSTRACT:

TECHNICAL FIELD
This invention relates to novel aminopyrazole derivatives or salts thereof. More particularly, it relates to substituted pyrazole compounds represented by the following formula, or salts thereof.
wherein:
R
1
represents a group of any one of the following formulae i) to viii):
i) —CH(OH)—CH(R
4
)—(A)
n
—Y
ii) —CH═C(R
4
)—(A)
n
—Y
iii) —CH
2
—CH(R
4
)—(A)
n
—Y
iv) —CO—B
1
—A—Y
v) —A—B
2
—CH(R
4
)—Y
vi) —A—CH(R
4
)—B
2
—Y
vii) —CH(OH)—CH═C(R
4
)—Y
in which A is a lower alkylene group, Y is an aryl group (this aryl group may optionally be substituted by halogen, lower alkyl, lower alkoxy, amino or nitro), a cycloalkyl group or a heteroaryl group, R
4
is a hydrogen atom or a lower alkyl group, B
1
is —CH(R
4
)— or —N(R
4
)—, B
2
is —CH(OH)—, —CO— or —O—, and n is 0 or 1;
R
2
represents a hydrogen atom, a lower alkyl group [this lower alkyl group may optionally be substituted by hydroxyl, amino, or mono- or di-(lower alkyl)amino] or an aralkyl group;
R
3
represents a phenyl group (this phenyl group may optionally be substituted by halogen, trifluoromethyl or lower alkylenedioxy) or a pyridyl group; and
Q represents a pyridyl or quinolyl group.
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 effect 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 the Pamphlet of PCT International Publication WO93/14081).
It is expected that these TNF-&agr; production inhibitors, IL-1 production inhibitors, IL-6 production inhibitors and COX-II production inhibitors will be effective in the treatment or prevention of TNF-&agr;-related diseases, IL-1-related diseases, IL-6-related diseases and COX-II-related diseases, 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, Behcet'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, some types of pyrazole derivatives having a p38MAP kinase inhibiting effect have recently been proposed (see the Pamphlets of PCT International Publications WO98/52940 and WO98/52941).
The present inventors have now found that, among a series of pyrazole compounds in which the 5- and 3-position of the pyrazole ring is substituted by a phenyl or pyridyl group and the 4-position thereof is substituted by a pyridyl or quinolyl group, the compounds further having a certain substituent comprising an aryl, cycloalkyl or heteroaryl group attached to the 3- or 5-position of the pyrazole ring through the medium of a principal chain composed of at least two carbon, oxygen and/or nitrogen atoms have an excellent p38MAP kinase inhibiting effect and are hence exhibit an inhibitory effect on the production of TNF-&agr;, IL-1, IL-6, COX-II and the like.
Thus, the present invention provides substituted pyrazole compounds 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, tert-butyl, n-pentyl and n-hexyl, and examples of the “lower alkoxy group” include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and n-hexyloxy. Moreover, examples of the “lower alkylene group” include —CH
2
—, —CH(CH
3
)—, —CH(C
2
H
5
)—, —(CH
2
)
2
—, —CH
2
—CH(CH
3
)—, —CH
2
—CH(C
2
H
5
)—, —(CH
2
)
3
—, —CH
2
—CH
2
—CH(CH
3
)—, —(CH
2
)
4
— and —(CH
2
)
6
—, and examples of the “lower alkylenedioxy group” include methylenedioxy, ethylenedioxy and propylenedioxy.
The “aryl group” is a monocyclic or polycyclic aromatic hydrocarbon group, and examples thereof include phenyl, indenyl and naphthyl. The “aralkyl group” is an alkyl group substituted by an aryl group as defined above and preferably an aryl-substituted lower alkyl group, and examples thereof include benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenypropyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthymethyl and diphenylmethyl.
The “aryl group (this aryl group may optionally be substituted by halogen, lower alkyl, lower alkoxy, amino or nitro)” represented by the symbol Y may preferably be an unsubstituted phenyl group; a phenyl group substituted by 1 or 2 substituents selected from halogen, lower alkyl, lower alkoxy, amino and nitro; or a phenyl group substituted by 3 to 5 halogen atoms.
Thus, these substituted aryl groups include, for example, 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-aminophenyl, 4-aminophenyl, 2-nitrophenyl, 4-nitrophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-chloro-4-fluorophenyl, 2,5-dimethylphenyl, 2,4-dimethoxyphenyl, 4-amino-3-methylphenyl, 3-methyl-4-nitrophenyl and 2,3,4,5,6-pentafluorophenyl.
The term “cycloalkyl group” generally comprehends cycloalkyl groups having 3 to 10 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Affiliated with

Also associated with

Rating

Substituted pyrazole compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Substituted pyrazole compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted pyrazole compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3162953