Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-07
2002-02-19
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S127000
Reexamination Certificate
active
06348480
ABSTRACT:
TECHNICAL FIELD
This invention relates to a medicament, particularly a pyrazole derivative having an action to inhibit calcium release-activated calcium channel, and a pharmaceutical composition containing the same as an active ingredient, particularly a calcium release-activated calcium channel inhibitor.
BACKGROUND ART
It has been known for a long time that calcium ion (Ca
2+
) is important for an intracellular second messenger in the activation of various cells. Intracellular Ca
2+
also acts as an important regulatory factor in inflammatory cells. It has been suggested, however, that voltage-operated Ca
2+
channel (to be referred to as “VOCC” hereinafter) inhibitors such as nifedipine does not show inhibitory activity against the activation of inflammatory cells and that a Ca
2+
influx mechanism other than VOCC exist in inflammatory cells.
Hoth et al. have cenorted that Ca
2+
-selecive and Ca
2+
store depletion-activated Ca
2+
channel, namely Ca
2+
released-activated Ca
2+
channel (to be referred to as “CRACC” hereinafter; also called store-dependent Ca
2+
channel), is present in mast cells and lymphocytes, and these cells are insensitive to membrane potential (
Pflugers Arch.,
430, pp. 315-322 (1995)). It is known that CRACC is present in several inflammatory cells such as mast cells, lymphocytes, astrocytes (
J. Biol. Chem.,
270, pp. 29-32 (1995)) and the like, and that it is deeply concerned in, for example, cytokine production and lipid mediator release (
J. Immunol.,
155, pp. 285-296 (1995) and
Br. J. Pharmacol.,
114, pp. 598-601 (1995)).
Recently, it has been revealed that tenidap, an agent for treating rheumatoid arthritis, has a potency of CRACC inhibitor (
Cell Calcium,
14, pp. 1-16 (1993)). Therefore, a CRACC inhibitor has a possibility of therapeutic potency on chronic inflammatory diseases including rheumatoid arthritis.
It is known that CRACC is also present in endothelial cells (
Am. J. Physiol.,
269, C 733-738 (1995)) and epithelial cells (
J. Biol. Chem.,
270, pp.29169-175 (1995)). Since it has been reported that sustained calcium influx takes a role in the radical affection of endothelial cells (
Am. J. Physiol.,
261, C 889-896 (1991)), it is suggested that a CRACC inhibitor should have protective efficacy on endothelial cell-concerned tissue damage.
In addition, it has been reported that blockades of calcium influx inhibit cell proliferation and interleukin 2 (IL-2) production (
Br. J. Pharmacol.,
113 , pp. 861-868 (1994)). Therefore, a CRACC inhibitor is useful as an agent for the prevention and treatment of proliferative or progressive diseases (e.g., malignant tumor and the like) and autoimmune diseases, and also as a suppresser for tissue rejection in transplantation.
On the other hand, it is known that in excitable cells such as smooth muscle cells and nerve cells, intracellular calcium is mainly regulated with VOCC not with CRACC. Therefore, it is expected that a calcium channel blocker having CRACC selectivity against VOCC should be an useful agent for the prevention or treatment of various inflammatory diseases, allergic diseases, autoimmune diseases, tissue damages, proliferative diseases and the like without undesirable actions on cardiovascular and central nervous system.
Recently, some compounds showing CRACC inhibitory activity have been reported, such as a cycloalkyl-piperazinylethanol derivative disclosed in a published German patent application 4404249 and a 2-(3,4-dihydro-1-isoquinolyl)acetamide derivative disclosed in WO 94/00435. It has also reported that 5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide inhibits CRACC (
J. Pharm. Exp. Ther.,
257, pp. 967-971 (1991)). However, there are no reports on a compound whose CRACC selectivity over VOCC has been confirmed.
On the other hand, a published German patent application 2525024 discloses a 5-(heterocycloylaminophenyl)-1-phenylpyrazole derivative which shows an anti-inflammatory activity. However, this patent does not disclose or suggest about its inhibitory activities against CRACC and IL-2 production.
WO 95/18097 discloses an anthranilic acid derivative represented by the following formula, which inhibits a cyclic GMP phosphodiesterase. In the formula, R
1
to R
4
represent H, a halogen atom, . . . , pyrazolyl which may be substituted, . . . ; n is 0 to 6, W represents N or CH, Y represents O or S, . . . (see said published patent application for details).
An unexamined published Japanese patent application 9-59236 discloses an R
1
, R
2
-di-substituted benzamide derivative represented by the following formula, which is useful for the prevention and treatment of rheumatic, allergic and other inflammatory diseases. In the formula, R
1
represents a substituted or unsubstituted aromatic heterocyclic ring, . . . , R
2
represents a halogen, a nitro, —NR
5
R
6
, . . . , A represents —C(═Z) NR
3
R
4
or —NR
4
C(═Z)R
3
, R
3
represents a substituted or unsubstituted aromatic hydrocarbon ring, a substituted or unsubstituted aromatic heterocyclic ring . . . (see said published patent application for details). However, there is no illustrative disclosure about pyrazolyl as the aromatic heterocyclic ring group. In addition, there is no disclosure about inhibitory activities against CRACC and/or IL-2 production.
DISCLOSURE OF THE INVENTION
The inventors of the present invention have conducted extensive studies on the screening of compounds having excellent CRACC inhibitory activity. As a result of the efforts, certain pyrazole derivatives which possess entirely different structures from those of the reported CRACC inhibitors have been found to show excellent CRACC inhibitory activity. The present invention has been accomplished by further finding that these compounds have high CRACC selectivity over VOCC.
Accordingly, the invention relates to a novel pyrazole derivative represented by the following general formula (I) which is characterized in that it has a pyrazolyl group unsubstituted or substituted with a specified group, or a pharmaceutically acceptable salt thereof. In the specification of this application, lower alkyl and halogen atom are abbreviated as Alk and Hal, respectively.
(In the formula, each symbol has the following meaning:
D: pyrazolyl which may have 1 to 3 substituents selected rom the group consisting of -Alk, -lower alkenyl, -lower alkynyl, -halogeno-lower alkyl, -Alk-cycloalkyl, -Alk-O-Alk, -cycloalkyl, —O-Alk, —COOH, —COO-Alk and -Hal,
n: 0 or 1,
B: phenylene, a nitrogen-containing, divalent, saturated ring group, or a monocyclic, divalent heteroaromatic ring group which may be substituted with Alk,
X: —NR
1
—CR
2
R
3
—, —CR
2
R
3
—NR
1
—, —NR
1
—SO
2
—, —SO
2
—NR
1
— or —CR
4
═CR
5
—,
R
1
: —H, —OH, -Alk, —O-Alk or —CO-Alk,
R
2
and R
3
: the same or different from each other and each represents —H or -Alk, or R
2
and R
3
together form ═O or ═S,
R
4
and R
5
: the same or different from each other and each represents —H, -Hal, -halogeno-lower alkyl or -Alk, and
A: benzene ring which may have one or more substituents; mono-, di- or tricyclic fused heteroaryl which may have one or more substituents; cycloalkyl which may have one or more substituents; a nitrogen-containing, saturated ring group which may have one or more substituents; lower alkenyl which may have one or more substituents; lower alkynyl which may have one or more substituents; or Alk which may have one or more substituents, or A and X may together form a group represented by a formula
(wherein A
2
is a nitrogen-obtaining hetero ring selected from the group consisting of 1-pyrrolidinyl, pyrazolidinyl, piperidino, piperazinyl, morpholino, 3,4-dihydro-2H-1,4-benzoxazin-4-yl and indolinyl, wherein the hetero ring may have one or more subsuituents), with the proviso that
(1) when D is 3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl, n is 0, B is 1,4-phenylene and X is NHCO, A is a group other than 4-methyl-1,2,3-thiadiazol-5-yl,
(2) when D is 1-methyl-5-trifluo
Funatsu Masashi
Ishikawa Jun
Kawazoe Souichirou
Kubota Hirokazu
Okamoto Yoshinori
Rao Deepak R.
Raymond Richard L.
Sughrue & Mion, PLLC
Yamanouchi Pharmaceutical Co. Ltd.
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