Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-02-26
2000-01-04
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514249, 514252, 514253, 514256, 514259, 514307, 514314, 514342, 514365, 544235, 544238, 544284, 544333, 544353, 544405, 546144, 546148, 546167, 546152, 5462697, 5462704, 548202, 548203, C07D40114, C07D30786, C07D41704, A61K 31425
Patent
active
060110376
DESCRIPTION:
BRIEF SUMMARY
FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel thiazole derivatives which are used in the pharmaceutical industry for the production of medicaments.
KNOWN TECHNICAL BACKGROUND
Japanese Patent Specification JP 46-15935 describes substituted 4-(carboxyphenyl)thiazoles and their use for the treatment of thrombosis, arteriosclerosis, gastric ulcers and hypersecretion. European Patent Applications EP 0 513 387 and EP 0 600 092 describe, inter alia, 2-(substituted phenyl)thiazole derivatives, 2-(substituted 2, 3-dihydrobenzofuran) thiazole derivatives and their use as inhibitors of oxygen free radical release by neutrophils. The compounds are therefore described as suitable for the treatment of acute inflammatory processes such as ischemias and reperfusion damage.
DESCRIPTION OF THE INVENTION
It has now surprisingly been found that the novel thiazole derivatives described in greater detail below, which differ from the previously published thiazoles, in particular by the subtituents on the 2-(2,3-dihydrobenzofuran) ring, are selective inhibitors of phosphodiesterase IV.
The invention thus relates to compounds of the formula I, in which 1-4C-alkoxy which is completely or mainly substituted by fluorine, bonded, are a 5-, 6- or 7-membered hydrocarbon ring, if desired interrupted by an oxygen atom, heterocycle substituted by R44, R45 and R46, which is selected from the group consisting of pyridine, pyrrole, quinoline, isoquinoline, indole, isoindole, indolizine, pyrimidine, pyrazine, pyridazine, quinoxaline, quinazoline, cinnoline, benzimidazole, thiophene and furan or a heterocycle substituted by R44 and R45, which is selected from the group consisting of pyrazole, imidazole, oxazole, isoxazole, thiazole and isothiazole, where sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonyl, 1-4C-alkoxysulfonyl, hydroxy-1-4C-alkyl, hydroxyl, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, halogen, cyano or nitro, 1-4C-alkylcarbonylamino, nitro, halogen, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonyl, carboxyl, 1-4C-alkyl or 1-4C-alkoxy, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, hydroxy-1-4C-alkyl, hydroxyl, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, halogen, cyano or nitro, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonyl or 1-4C-alkoxy and isoquinolines, pyrimidines, pyrazines, imidazoles, quinoxalines, quinazolines and benzimidazoles and their salts.
1-4C-alkoxy represents a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Alkyl radicals having 1 to 4 carbon atoms which may be mentioned here are, for example, the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl 2-radicals.
3-7C-cycloalkoxy represents the cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy radical. The 3-5C-cycloalkoxy radicals cyclopropyloxy, cyclobutyloxy and cyclopentyloxy may preferably be mentioned.
3-7C-cycloalkylmethoxy is, for example, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy or cycloheptylmethoxy. The 3-5C-cycloalkylmethoxy radicals, cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy may preferably be mentioned.
1-4C-alkoxy completely or mainly substituted by fluorine which may be mentioned is, for example, the 1,2,2,-trifluoroethoxy, the 2,2,3,3,3-pentafluoro-ethoxy, the perfluoroethoxy and in particular the 1,1,2,2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethoxy and preferably the difluoro-methoxy radicals.
1-4C-alkyl represents straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. The examples which may be mentioned are the butyl, the isobutyl, the sec-butyl, the tert-butyl, the propyl, the isopropyl, the ethyl and in particular the methyl radi
REFERENCES:
Palfreyman et al., Phosphodiesterase Type IV Inhibitors, Progress in Medicinal Chemistry, vol. 33, pp. 1-52, 1996.
Dumaitre et al., Synthesis and Cyclic GMP Phosphodiesterase Inhibitory Activity of a series of 6-phenylpyrazolo[3,4-d]pyrimidones, J. Med. Chem. 1996, 39, pp. 1635-1644.
Chihiro et al., Novel thiazole derivatives aas inhibitors of Superoxide production by human neurophils, J. Med. Chem., 38, pp. 353-358, 1995.
Bar Thomas
Ulrich Wolf-Rudiger
ByK Gulden Lomberg Chemische Fabrik GmbH
Rao Deepak R.
Shah Mukund J.
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