Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1988-10-18
1990-10-23
Hollrah, Glennon H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514252, 514300, 514312, 514318, 544360, 544362, 544363, 546123, 546156, 546193, A61K 31495, C07D40114
Patent
active
049652664
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel and useful heteroarylcarboxamide derivatives which have an antiallergic activity based on 5-lipoxygenase inhibitory activity and the like.
BACKGROUND ART
British Patent No. 1,433,774 and U.S. Pat. No. 3,943,141 disclose 1,4-dihydro-4-oxo-N(1H-tetrazol-5-yl)-3quinolinecarboxamide derivatives and 1,4-dihydro-4-oxo-N-(1H-tetrazol-5-yl)-1,8-naphthyridine-3-carboxamide derivatives, respectively, as a useful antiallergic agent. DT-OS 3242344 discloses that alkylenediamine derivatives such as N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-2-hydroxy-6-methyl pyridine-3-carboxamide are useful for treatment of sinus tachycardia and ischemic heart diseases.
The mechanism of the development of allergic diseases such as bronchial asthma and allergic rhinitis have been generally thought as follows. In genetically specific individuals who are exposed to allergens such as pollen or mite, B-lymphocytes produce antigen-specific IgE in cooperation with macrophages and T-lymphocyte. The antigen-specific IgE binds to IgE receptors on the membrane of mast cells or basophiles. The bridging of IgE molecules by the re-invading antigen triggers the change of structure of cell membrane, the increment of membrane fluidity and the activation of various enzymes (including 5-lipoxygenase). Consequently, chemical mediators such as leukotrienes C4.sub.4, D.sub.4, E.sub.4 and B.sub.4, histamine and prostaglandins are released from these cells, and cause the syndromes in allergic disease.
Among these chemical mediators, leukotrienes C.sub.4, D.sub.4 and E.sub.4 cause strongly the contraction of bronchial smooth muscle [P. Hedqvist et al., Acta Physiol. Scand., 110, 331 (1980)], increased vascular permeability [A. Ueno et al., Prostaglandins, 21, 637 (1981)], and secretion of mucus [S. J. Coles et al., Prostaglandins, 25, 155 (1983)], and leukotriene B.sub.4 does leukocyte emigration [A. W. Ford-Hutchinson et al., Nature, 286, 264 (1980)], playing an important role in the development of allergic diseases. Compounds that inhibit the biosynthesis and release of leukotrienes or inhibit the binding of leukotrienes to their receptors may be useful for the prophylaxis or treatment of allergic diseases. 5-Lipoxygenase is an enzyme which catalyzes an early step of biosynthesis of leukotrienes, that is, the conversion of arachidonic acid into 5-hydroperoxyeicosatetraenoic acid.
The present inventors have intensively studied to find out a compound which can inhibit the 5-lipoxygenase and, as a result, have found that the aromatic heterocyclic carboxylic acid derivatives represented by the following formula (I) are fit for the above purpose and thus completed the present invention.
DISCLOSURE OF THE INVENTION
The present invention provides heteroarylcarboxamide derivatives of the formula (I): ##STR3## wherein A means an alkylene group having 3 to 5 carbon atoms, X means <NCHPh.sub.2 or <C.dbd.CPh.sub.2 in which Ph means phenyl and .circle.Het means the formulas: ##STR4## in which Y means nitrogen atom or .dbd.CH--, R.sub.1 means hydroxy, an alkoxy group having 1 to 6 carbon atoms or mercapto, R.sub.2 means hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, nitro or cyano, R.sub.3 means an alkyl group having 1 to 6 carbon atoms, provided that R.sub.2 is attached at the 7-position when Y means nitrogen atom, and physiologically acceptable salts thereof, a process for preparation thereof and a pharmaceutical composition containing the same as an active ingredient.
The physiologically acceptable salts of the compounds represented by the formula (I) include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and the like, and organic acid salts such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate and the like. Since the compounds of the present invention may exist in the form of hydrate or solvate, these hydrate and sol
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Ishii Katsumi
Kon Tatsuya
Nakamura Hideo
Nishikawa Yoshinori
Shindo Tokuhiko
Dainippon Pharmaceutical Co., Ltd.
Hollrah Glennon H.
Turnipseed James H.
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