Patent NZ-329178-A (NZ)
Title: 2,5-dioxo-imidazolidine derivatives as inhibitors leucocyte adhesion and as VLA-4 antagonists
Inventor: STILZ HANS ULRICH
IPC: C07K5/023
Filed: 1997-11-13
Abstract: A compound of formula (I) wherein: W is R1-A-C(R13) or R1-A-CH=C; Y is a carbonyl, thiocarbonyl or methylene group; Z is N(RO), oxygen, sulfur or a methylene group; A is a bivalent radical from the group consisting of alkylene, cycloalkylene, phenylene, phenylenealkyl, alkylenephenyl, phenylenealkenyl or a bivalent radical of a 5- or 6-membered saturated or unsaturated ring which can contain 1 or 2 nitrogen atoms and can be mono- or disubstituted by alkyl or doubly bonded oxygen or sulfur; B is a bivalent radical from the group consisting of alkylene, alkenylene, phenylene, phenylenealkyl, alkylenephenyl, where the bivalent alkylene radical can be unsubstituted or substituted by a radical from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, optionally substituted aryl, aryl-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl and heteroaryl-alkyl optionally substituted in the heteroaryl radical; D is C(R2)(R3), N(R3) or CH=C(R3); E is tetrazolyl, (RSO)2P(O), HOS(O)2' R9NHS(O)2 or R10CO; R is hydrogen, alkyl, cycloalkyl, optionally substituted aryl or aryl-alkyl optionally substituted in the aryl radical; RO is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, bicycloalkylalkyl, tricycloalkyl, tricycloalkyl-alkyl, optionally substituted aryl, aryl-alkyl optionally substituted in the aryl radical, optionally substituted heteroaryl, heteroaryl-alkyl optionally substituted in the heteroaryl radical, CHO, alkyl-CO, cycloalkyl-CO, cycloalkyl-alkyl-CO, bicycloalkyl-CO, bicycloalkylalkyl-CO, tricycloalkyl-CO, tricycloalkylalkyl-CO, optionally substituted aryl-CO, arylalkyl-CO optionally substituted in the aryl radical, optionally substituted heteroaryl-CO, heteroaryl-alkyl-CO optionally substituted in the heteroaryl radical, alkyl-S(O)n' cycloalkyl-S(O)n' cycloalkyl-alkyl-S(O)n' bicycloalkyl-S(O)n' bicycloalkyl-alkyl-S(O)n' tricycloalkyl-S(O)n' tricycloalkyl-alkyl-S(O)n' optionally substituted aryl-S(O)n'aryl-alkyl-S(O)n optionally substituted in the aryl radical, optionally substituted heteroaryl-S(O)n or heteroaryl-alkyl-S(O)n optionally substituted in the heteroaryl radical, where n is 1 or 2; R1 is X-NH-C(=NH)-(CH2)p or X1-NH-(CH2)P' where p is 0, 1, 2 or 3; X is hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonyl, optionally substituted arylcarbonyl, optionally substituted aryloxycarbonyl, aryl-alkoxycarbonyl which can also be substituted in the aryl radical, (RSO)2P(O), cyano, hydroxyl, alkoxy, aryl-alkoxy which can also be substituted in the aryl radical, or amino; X1 is X or is R'-NH-C(=N-R"), where R' and R" independently of one another have the meanings of X; R2 is hydrogen, alkyl, optionally substituted aryl, aryl, alkyl optionally substituted in the aryl radical or cycloalkyl; R3 is hydrogen, alkyl, optionally substituted aryl, aryl, alkyl optionally substituted in the aryl radical, cycloalkyl, alkenyl, alkynyl, alkenylcarbonyl, alkynylcarbonyl, pyridyl, R11NH, R4CO, COOR4, CON(CH3)R14, CONHR14, CSNHR14, COOR15, CON(CH3)R15 or CONHR15; R4 is hydrogen or alkyl which can optionally be mono- or polysubstituted by identical or different radicals R4'; R4' is hydroxyl, hydroxycarbonyl, aminocarbonyl, mono- or di alkyl)aminocarbonyl, aminoalkylaminocarbonyl, aminoalkylpheny-lalkylaminocarbonyl, alkylcarbonylaminoalky-lphenylalkylaminocarbonyl, alkylcarbonylamino alkylaminocarbonyl,  aryl-alkoxycarbonyl which can also be substituted in the aryl radical, amino, mercapto, alkoxy, alkoxycarbonyl, optionally substituted cycloalkyl, halogen, nitro, trifluoromethyl or the radical R5; R5 is optionally substituted aryl, aryl-alkyl optionally substituted in the aryl radical, a mono- or bicyclic 5- to 12-membered heterocyclic ring which can be aromatic, partially hydrogenated or completely hydrogenated and which can contain one, two or three identical or different heteroatoms from the group consisting of nitrogen, oxygen and sulfur, a radical RS or a radical RSCO-, where the aryl radical and, independently thereof, the heterocyclic radical can be mono- or polysubstituted by identical or different radicals from the group consisting of alkyl, alkoxy, halogen, nitro, amino and trifluoromethyl; R6 is R7R5N, R7-O or R7S or an amino acid side chain, a natural or unnatural amino acid, imino acid, optionally N-alkylated or N-(aryl-alkylated) azaamino acid or a dipeptide radical which can also be substituted in the aryl radical and/or in which the peptide bond can be reduced to -NH-CH2-, and their esters and amides, where hydrogen or hydroxymethyl can optionally stand in place of free functional groups and/or where free functional groups can be protected by protective groups customary in peptide chemistry; R7 is hydrogen, alkyl, aryl-alkyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, arylalkylcarbonyl or arylalkyloxycarbonyl, where the alkyl groups can optionally be substituted by an amino group and/or where the aryl radicals can be mono- or polysubstituted, preferably monosubstituted, by identical or different radicals from the group consisting of alkyl, alkoxy, halogen, nitro, amino and trif/uoromethyl, or is a natural or unnatural amino acid, imino acid, optionally N-alkylated or N-aryl-alkylated azaamino acid or a dipeptide radical which can also be substituted in the aryl radical and/or in which the peptide bond can be reduced to -NH-CH2-; R8 is hydrogen, alkyl, optionally substituted aryl or aryl, alkyl which can also be substituted in the aryl radical; R9 is hydrogen, aminocarbonyl, alkylaminocarbonyl, cycloalkylamino-carbonyl, optionally substituted arylaminocarbonyl, alkyl optionally substituted aryl or cycloalkyl; R10 is hydroxyl, alkoxy, aryl-alkoxy which can also be substituted in the aryl radical, optionally substituted aryloxy, amino or mono- or di-{alkyl)amino; R11 is hydrogen, alkyl, R12CO, optionally substituted aryl-S(O)2, alkyl-S(O)2, arylalkyl optionally substituted in the aryl radical or R9NHS(O)2; R12 is hydrogen, alkyl, alkenyl, alkynyl, optionally substituted aryl, alkoxy, aryl-alkoxy which can also be substituted in the aryl radical, optionally substituted aryloxy, amino or mono- or di-(alkyl)amino; R13 is hydrogen, alkyl, arylalkyl optionally substituted in the aryl radical or cycloalkyl; R14 is hydrogen or alkyl which can optionally be mono- or polysubstituted by identical or different radicals from the group consisting of hydroxyl, hydroxycarbonyl, aminocarbonyl, mono- or di-{alkyl)aminocarbonyl, amino-alkylaminocarbonyl, aminoalkylphenylalkylaminocarbonyl, alkylcarbonylaminoalkylphenylalkylaminocarbonyl, alkylcarbonyl-aminoalkylaminocarbonyl, arylalkoxycarbonyl which can also be substituted in the aryl radical, amino, mercapto, alkoxy, alkoxycarbonyl, optionally substituted cycloalkyl, HOS(O)2alkyl, R9NHS(O)2alkyl, (RSO)2P(O)alkyl, tetrazolylalkyl, halogen, nitro, trifluoromethyl and R5; R15 is R16-alkyl or R16; R16 is a 6- to 24-membered bicyclic or tricyclic radical which is saturated or partially unsaturated and which can also contain one to four identical or different heteroatoms from the group consisting of nitrogen, oxygen and sulfur and which can also be substituted by one or more identical or different substituents from the group consisting of alkyl and oxo; b, c, d and f independently of one another are 0 or 1, but cannot all simultaneously be O, e, g and h independently of one another are 0, 1, 2, 3, 4, 5 or 6; in all their stereoisomeric forms and mixtures thereof in any ratio, and of their physiologically tolerable salts for the production of pharmaceuticals for inhibition of the adhesion and/or migration of leucocytes or for inhibition of the VLA-4 receptor.