Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-09-29
1999-02-09
Higel, Floyd D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514397, 5483241, 5483245, 5483235, 5483111, A61K 31415, C07D23370, C07D23332, C07D40504
Patent
active
058695150
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a 371 of PCT application Ser. No. PCT/EP96/01393, filed Mar. 28, 1996, which claims priority from European Patent Application Serial No. 95.200.870.4, filed on Apr. 6, 1995.
The present invention concerns 1,3-dihydro-2H-imidazol-2-one derivatives having PDE IV and cytokine inhibiting activity and their preparation; it further relates to compositions comprising them, as well as their use as a medicine.
WO 94/12461 generically discloses a number of 1-(benzoylalkyl)-2-hydroxy-imidazole derivatives as selective inhibitors of phosphodiesterase type IV (PDE IV).
Unexpectedly, particular 1,3-dihydro-2H-imidazol-2-one derivatives show improved PDE IV inhibiting activity over the art compounds. In addition, the compounds of the present invention were found to display cytokine inhibiting activity. In view of these pharmacological properties, the present compounds have therapeutical utility in the treatment of disease states related to an abnormal enzymatic or catalytic activity of PDE IV, and/or disease states related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases.
The present invention concerns 1,3-dihydro-2H-imidazol-2-one derivatives having the formula ##STR4## the N-oxide forms, the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein: R.sup.1 and R.sup.2 each independently are hydrogen; C.sub.1-6 alkyl; difluoromethyl; trifluoromethyl; C.sub.3-6 cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from C.sub.1-10 alkyl substituted with one or two substituents each independently selected from aryl, pyridinyl, thienyl, furanyl, C.sub.3-7 cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; ##STR5## is a bivalent radical of formula ##STR6## wherein: R.sup.4 is hydrogen; cyano; C.sub.1-6 alkyl; C.sub.1-4 alkyloxycarbonyl; C.sub.1-6 alkyl substituted with hydroxy, carboxyl, C.sub.1-4 alkyloxycarbonyl, amino, mono- or di(C.sub.1-4 alkyl)amino, Het.sup.1 or aryl; hydroxy, carboxyl, C.sub.1-4 alkyloxycarbonyl, amino, aminocarbonyl, mono- or di(C.sub.1-4 alkyl)amino, mono- or di(C.sub.1-4 alkyl)aminocarbonyl, Het.sup.1 or aryl; ##STR7## wherein each R.sup.6 and R.sup.7 independently is hydrogen or C.sub.1-4 alkyl; alkyloxycarbonyl; C.sub.1-6 alkyl substituted with one or two substituents selected from the group consisting of hydroxy, C.sub.1-4 alkyloxy, C.sub.1-4 alkyloxycarbonyl, mono- and di(C.sub.1-4 alkyl)amino, aryl and Het.sup.2 ; C.sub.3-6 alkenyl, C.sub.3-6 alkenyl substituted with aryl; piperidinyl: piperidinyl substituted with C.sub.1-4 alkyl or arylC.sub.1-4 alkyl; C.sub.1-6 alkylsulfonyl or arylsulfonyl; selected from halo, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkyloxy, C.sub.3-6 cycloalkyl, trifluoromethyl, amino, nitro, carboxyl, C.sub.1-4 alkyloxycarbonyl and C.sub.1-4 alkylcarbonylamino; furanyl; furanyl substituted with C.sub.1-4 alkyl; thienyl; thienyl substituted with C.sub.1-4 alkylcarbonylamino; hydroxypyridinyl, hydroxypyridinyl substituted with C.sub.1-4 alkyl or C.sub.1-4 alkoxyC.sub.1-4 alkyl; imidazolyl; imidazolyl substituted with C.sub.1-4 alkyl; thiazolyl; thiazolyl substituted with C.sub.1-4 alkyl; oxazolyl; oxazolyl substituted with C.sub.1-4 alkyl; isoquinolinyl; isoquinolinyl substituted with C.sub.1-4 alkyl; quinolinonyl, quinolinonyl substituted with C.sub.1-4 alkyl; morpholinyl; piperidinyl; piperidinyl substituted with C.sub.1-4 alkyl, C.sub.1-4 alkyloxycarbonyl or arylC.sub.1-4 alkyl; piperazinyl; piperazinyl substituted with C.sub.1-4 alkyl, C.sub.1-4 alkyloxycarbonyl or arylC.sub.1-4 alkyl; and C.sub.1-4 alkyl or arylC.sub.1-4 alkyl; piperazinyl; piperazinyl substituted with C.sub.1-4 alkyl or arylC.sub.1-4 alkyl; pyridinyl; pyridinyl substituted with C.sub.1-4 alkyl; furanyl; furanyl substituted with C.sub.1-4 alkyl; thienyl or thienyl substituted with C.sub.1-4 alkyl or
REFERENCES:
patent: 4636516 (1987-01-01), Kubo et al.
patent: 4845233 (1989-07-01), Higuchi et al.
patent: 5059237 (1991-10-01), Kohsaka et al.
patent: 5401851 (1995-03-01), Boyd et al.
International Search Report Application Number PCT/EP96/01393 dated Mar.28,1996.
Andrés-Gil José Ignacio
Diels Gaston Stanislas Marcella
Fernandez-Gadea Francisco Javier
Freyne Eddy Jean Edgard
Higel Floyd D.
Janssen Pharmaceutica N.V.
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