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
1999-11-30
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, 514399, 514400, 5483154, 5483235, 5483251, 5483255, A61K 31415, A61K 3144, C07D23332, C07D40106, C07D23336, C07D23370
Patent
active
059943769
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns the use of 1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-one derivatives for the manufacture of a medicament for treating warm-blooded animals suffering from disease states related to an abnormal enzymatic or catalytic activity of phosphodiesterase IV (PDE IV), and/or disease states related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases. The present invention also relates to new compounds having PDE IV and cytokine inhibiting activity, processes for their preparation and compositions comprising said new compounds.
1-[2-(3,4-diethoxyphenyl)ethyl]-1,2-dihydro-2H-imidazol-2-one and a number of (1,3-dihydro- and 1,3,4,5-tetrahydro-)(1-[2-(3,4-dimethoxyphenyl)propyl]- and 1-[2-(3,4-dimethoxyphenyl)ethyl])-2H-imidazol-2-one derivatives are specifically disclosed in U.S. Pat. No. 3,184,460 as therapeutic agents acting on the central nervous system, in particular, as tranquilizers. Synthetic Communications (1985) 15(10), 883-889, discloses a synthetic pathway for the preparation of 1,3,4,5-tetrahydro-1-[2-(3,4-dimethoxy-phenyl)ethyl]-3-phenylmethyl-2H-imi dazol-2-one. In the Chemical and Pharmaceutical Bulletin (1980), 28(6), 1810-1813, 1,3,4,5-tetrahydro-1,3-bis[2-(3,4-dimethoxyphenyl)ethyl]-2H-imidazol-2-one and 1,3,4,5-tetrahydro-1-[2-(3,4-dimethoxyphenyl)ethyl]-2H-imidazol-2-one are disclosed as intermediates in the synthesis of a diazasteroid system. WO 94/12461, WO 94/14742 and WO 94/20446 generically describe a number of 1-(phenylalkyl)-2-hydroxy-imidazole derivatives as selective PDE IV inhibitors.
Unexpectedly, particular 1,3-dihydro-1-(phenylalkyl)-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, or disease states related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases.
The present invention concerns the use of compounds of formula (I) for the manufacture of a medicament for treating warm-blooded animals suffering from disease states related to an abnormal enzymatic or catalytic activity of phosphodiesterase IV (PDE IV), and/or disease states related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases, said compounds having the formula ##STR1## the N-oxide forms, the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein: difluoromethyl; trifluoromethyl; C.sub.3-6 cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C.sub.1-6 alkylsulfonyl; arylsulfonyl; or 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; cycloalkyl; carboxyl; C.sub.1-4 alkyloxycarbonyl; C.sub.3-6 cycloalkylaminocarbonyl; aryl; Het.sup.1 ; or C.sub.1-6 alkyl substituted with cyano, amino, hydroxy, C.sub.1-4 alkylcarbonylamino, aryl or Het.sup.1 ; or hydroxy, carboxyl, C.sub.1-4 alkyloxycarbonyl, amino, mono- or di(C.sub.1-4 alkyl)amino, Het.sup.1 or aryl; 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; p-toluenesulfonyl; alkyl; and 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 subst
REFERENCES:
patent: 3184460 (1965-05-01), Akkerman et al.
Matoba et al., Chem. Pharm. Bull. Synthesis in the Diazasteroid Group . . . 28(6), 1810-1813 (1980).
Kano et al., Synthetic Communications, A Synthesis of Fused Heterocyclic Isoquinolines . . . , 15(10), 883-889 (1985).
Andrés-Gil José Ignacio
Diels Gaston Stanislas Marcella
Fernandez-Gadea Francisco Javier
Freyne Eddy Jean Edgard
Appollina Mary A.
Higel Floyd D.
Janssen Pharmaceutica N.V.
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