Patent NZ-334971-A (NZ)
Title: 2-cyanoiminoimidazole derivatives for use as phosphodiesterase (PDE) IV inhibitors
Inventor: FREYNE EDDY JEAN EDGARD
IPC: A61K31/415
Filed: 1997-09-24
Abstract: 2-cyanoiminoimidazole derivatives of the above formula, wherein: R1 and R2 each independently are hydrogen; C1-6 alkyl; difluoromethyl; trifluoromethyl; C3-6 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; C1-6 alkylsulfonyl; arylsulfonyl; or C1-10 alkyl substituted with one or two substituents each independently selected from aryl, pyridinyl, thienyl, furanyl, indanyl, 6,7-dihydro-5H-cyclopentapyridinyl, C3-7 cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; R3 is hydrogen, halo or C1-6 alkyloxy; R4 is hydrogen; halo; C1-6 alkyl; trifluoromethyl; C3-6 cycloalkyl; carboxyl; C1-4 alkyloxycarbonyl; C3-6 cycloalkylaminocarbonyl; aryl; Het1 ; or C1-6 alkyl substituted with cyano, amino, hydroxy, C1-4 alkylcarbonylamino, aryl or Het1 ; or R4 is a radical of formula: --O--R7 (a- 1); or --NH--R8 (a- 2);  Wherein R7 is hydrogen; C1-6 alkyl; C1-6 alkyl substituted with hydroxy, carboxyl, C1-4 alkyloxycarbonyl, amino, mono- or di(C1-4 alkyl)amino, Het1 or aryl;  R8 is hydrogen; C1-6 alkyl; C1-4 alkylcarbonyl; C1-6 alkyl substituted with hydroxy, carboxyl, C1-4 alkyloxycarbonyl, amino, mono- or di(C1-4 alkyl)amino, Het1 or aryl;  R5 is hydrogen, halo, hydroxy, C1-6 alkyl or C1-6 alkyloxy; or R4 and R5 taken together may form a bivalent radical of formula: --(CH2)n -- (b-1); --CH2 --CH2 --O--CH2 --CH2 -- (b-2); --CH2 --CH2 --N(R9)--CH2 --CH2 -- (b-3); or --CH2 -CH=CH--CH2 -- (b-4); wherein n is 2, 3, 4 or 5; R9 is hydrogen, C1-6 alkyl, C1-6 alkylsulfonyl or p-toluenesulfonyl; R6 is a hydrogen or C1-4 alkyl; or R4 and R6 taken together may form a bivalent radical of formula - (CH2)m --; wherein m is 1, 2, 3 or 4; --A--B-- is a bivalent radical of formula: --CR10=CR11 -- (c-1); or --CHR10 --CHR11 -- (c-2); wherein each R10 and R11 independently is hydrogen or C1-4 alkyl; L is hydrogen; C1-6 alkyl; C1-6 alkylcarbonyl; C1-6 alkyloxycarbonyl; C1-6 alkyl substituted with one or two substituents selected from the group consisting of hydroxy, C1-4 alkyloxy, C1-4 alkyloxycarbonyl, mono- and di(C1-4 alkyl)amino, aryl and Het2 ; C3-6 alkenyl; C3-6 alkenyl substituted with aryl; piperidinyl; piperidinyl substituted with C1-4 alkyl or arylC1-4 alkyl; C1-6 alkylsulfonyl or arylsulfonyl; aryl is phenyl or phenyl substituted with one, two or three substituents selected from halo, hydroxy, C1-4 alkyl, C1-4 alkyloxy, C3-6 cycloalkyl, trifluoromethyl, amino, nitro, carboxyl, C1-4 alkyloxycarbonyl and C1-4 alkylcarbonylamino; Het1 is pyridinyl; pyridinyl substituted with C1-4 alkyl; furanyl; furanyl substituted with C1-4 alkyl; thienyl; thienyl substituted with C1-4 alkylcarbonylamino; hydroxypyridinyl, hydroxypyridinyl substituted with C1-4 alkyl or C1-4 alkoxy-C1-4 alkyl; imidazolyl; imidazolyl substituted with C1-4 alkyl; thiazolyl; thiazolyl substituted with C1-4 alkyl; oxazolyl; oxazolyl substituted with C1-4 alkyl; isoquinolinyl; isoquinolinyl substituted with C1-4 alkyl; quinolinonyl, quinolinonyl substituted with C1-4 alkyl; morpholinyl; piperidinyl; piperidinyl substituted with C1-4 alkyl, C1-4 alkyloxycarbonyl or arylC1-4 alkyl; piperazinyl; piperazinyl substituted with C1-4 alkyl, C1-4 alkyloxycarbonyl or arylC1-4 alkyl; and Het2 is morpholinyl; piperidinyl; piperidinyl substituted with C1-4 alkyl or arylC1-4 alkyl; piperazinyl; piperazinyl substituted with C1-4 alkyl or arylC1-4 alkyl; pyridinyl; pyridinyl substituted with C1-4 alkyl; furanyl; furanyl substituted with C1-4 alkyl; thienyl or thienyl substituted with C1-4 alkyl or C1-4 alkylcarbonylamino.  Also disclosed are the N-oxide forms, the pharmaceutically acceptable acid or base addition salts, the stereochemically isomeric forms, the compositions and process of manufacturing the above formula.