PDE IV inhibiting 2-cyanoiminoimidazole derivatives

Details PDE IV inhibiting 2-cyanoiminoimidazole derivatives PDE IV inhibiting 2-cyanoiminoimidazole derivatives

1999-03-19

2000-04-18

Higel, Floyd D.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

514299, 514393, 514398, 546112, 5483315, C07D23332, C07D23336, C07D23338, C07D23370, C07D22102, A61R 314168, A61R 31438

Patent

active

060517182

DESCRIPTION:

BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage application under 35 U.S.C. 371 of PCT/EP97/05322 filed Sep. 24, 1997, which claims priority from EP 96.202.749.6, filed Oct. 2, 1996.
The present invention concerns 2-cyanoiminoimidazole derivatives having phosphodiesterase IV (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 95/05386, published on Feb. 23, 1995 by Smithkline Beecham Corporation, discloses phenethylamine derivatives, such as N-[2-(3-cyclopentyloxy-3-methoxyphenyl)ethyl]imidodicarbamide and N'-cyano-1-[2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl]carboximidamide, useful for treating phosphodiesterase IV related disease states. It also generically discloses phenethylamine derivatives containing a cyanoguanidine moiety.
The compounds of the present invention differ structurally from art-known PDE IV inhibitors by the fact that they invariably contain a 2-cyanoiminoimidazole moiety. They 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 compounds also have few gastro-intestinal side-effects which are often associated with PDE IV inhibitors.
The present invention concerns 2-cyanoiminoimidazole derivatives having the formula ##STR2## 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 oxygen, sulfur or nitrogen; indanyl; 6,7-dihydro-5H-cyclopentapyridinyl; 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, indanyl, 6,7-dihydro-5H-cyclopentapyridinyl, 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 R.sup.4 is a radical of formula: with 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; or p-toluenesulfonyl; --(CH.sub.2).sub.m --; 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 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 alkoxy-C.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

REFERENCES:
patent: 4880933 (1989-11-01), Shiokawa et al.

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