Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-11-17
2000-04-04
Seaman, D. Margaret
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514314, 514367, 514375, 514414, 514419, 546174, 548180, 548219, 5483047, 5483101, C07D21512, C07D27760, C07D26362, C07D23504, C07D23512
Patent
active
060462124
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to chalcone derivatives having excellent antagonism to cys-leukotriene receptors and drugs containing the same.
BACKGROUND ART
Peptidoleukotrienes (LT) are a group of physiologically-active substances synthesized from eicosapolyenoic acids such as arachidonic acid in animal tissues. Among these, LTC.sub.4, LTD.sub.4 and LTE.sub.4 are known to act as important causal substances for bronchial asthma both in vitro and in vivo (Henderson, W. R., Jr. Ann. Intern. Med., 121, 684-697, 1994). As morbid conditions caused by these leukotrienes, there are airway constriction, mucosal oversecretion and pulmonary edema. They eventually induce an airway disorder which is a characteristic of asthma. Effects of LTC.sub.4 or LTD.sub.4 on airway constriction when inhaled reach 1,000 times as much as those of histamine. LTE.sub.4 has lower activities compared with the other leukotrienes, but airway constriction induced by LTE.sub.4 is long lasting compared with that caused by the other leukotrienes (Larsen, J. S., Acosta, E. P. Ann. Pharmacother, 27, 898-903, 1993).
Keeping in step with discovery of roles of leukotrienes in biosynthesis pathways and diseases as mentioned above, there are increasing activities for the development of synthesis inhibitors for leukotrienes, antagonists to cys-leukotriene (cys-LT) receptors and the like with a view to inhibiting leukotrienes (Metters, K. M., J. Lipid Mediators Cell Signalling, 12, 413-427, 1995). According to some recent reports in clinical aspects, it has been indicated that cys-LT receptor antagonists are extremely effective for various types of asthma (Taylor, I. K., Thorax, 50, 1005-1010, 1995; Pauwels, R. A., Joos, G. F., Kips. J. C. Allergy, 30, 615-622, 1995).
It is however the current situation that no compound has been found to have fully satisfactory cys-LT receptor antagonism.
An object of the present invention is therefore to provide a compound having a high cys-LT receptor antagonism and a drug containing the compound.
DISCLOSURE OF THE INVENTION
With the foregoing circumstances in view, the present inventors have proceeded with extensive research in attempts to obtain a compound having a high cys-LT receptor antagonism. As a result, a novel compound represented by the below-described formula (1) has been found to have a high cys-LT receptor antagonism and hence to be useful as a drug, leading to the completion of the present invention.
The present invention therefore provides a chalcone derivative represented by the following formula (1): ##STR1## wherein
A represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a group ##STR2## in which X represents a hydrogen or halogen atom or a hydroxyl, lower alkyl or lower alkoxyl group and B represents --CH.dbd.CH--, --N(R.sup.6)--, R.sup.6 being a lower alkyl group or a lower alkoxyalkyl group, --O-- or --S--,
W represents --CH.dbd.CH-- or --CH.sub.2 O--, and
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 may be the same or different and each independently represent a hydrogen or halogen atom, a hydroxyl, a lower alkyl, lower alkoxyl, carboxyl, cyano, alkyloxycarbonyl or tetrazolyl group, a group --CONHR.sup.7 in which R.sup.7 represents a hydrogen atom or a lower alkyl group, or a group --O(CH.sub.2).sub.n R.sup.8 in which R.sup.8 represents a carboxyl, alkyloxycarbonyl or tetrazolyl group and n stands for a number of from 1 to 4,
with the proviso that at least one of the groups R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 represents a carboxyl, cyano, alkyloxycarbonyl or tetrazolyl group, the group --CONHR.sup.7 or the group --O(CH.sub.2).sub.n R.sup.8 ; or
a salt or solvate thereof.
This invention also provides a drug comprising as an effective ingredient the chalcone derivative (1) or its salt or solvate.
Further, this invention also provides a cys-LT receptor antagonist comprising the chalcone derivative (1) or its salt or solvate as an effective ingredient.
In addition, this invention also provides an antiallergic agent co
REFERENCES:
Chemical Abstracts 125:275456, 1995.
Chemical Abstracts 122:133214, 1994.
Chemical Abstracts 124:8860, 1995.
Mauriel e. Zwaagstra et al, "Synthesis and Structure--Activity Relationships of Carboxylated Chalcones: A Novel Series of CysLT.sub.1 (LTD.sub.4) Receptor Antagonists", J. Med. Chem., vol. 40, pp. 1075-1089 (1997).
Onogi Kazuhiro
Tamura Masahiro
Timmerman Henk
Toma Tsutomu
Wada Yasushi
Kowa Co. Ltd.
Seaman D. Margaret
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