Patent EA-005210-B1 (EA)
Title: Hydroxy diphenyl urea sulfonamides as il-8 receptor antagonists
Inventor: JIN QI
IPC: C07C311/43
Filed: 1999-12-15
Abstract: 1. A compound of the formula (I): wherein Rb is independently hydrogen, OC1-5alkyl, C1-5alkyl, C3alkenyl, benzyl, C3-5cycloalkyl, C3-5cycloalkyl-C1-5alkyl, pyridyl, 5-6-membered heterocyclyl or 5-6-membered heterocyclyl-C1-4alkyl, containing in the ring a nitrogen atom and/or an oxygen atom, wherein all of moieties may be optionally substituted one to three times with a group independently selected from halogen, C1-4alkyl, amino, mono- or di-C1-4alkyl-substituted amino, hydroxy, OC1-4alkyl, benzyloxy, C(O)OH, C(O)OC1-4alkyl, NHC(O)OC1-4alkyl, S(O)m' C1-4alkyl and C(O)NH(halo-substituted phenyl); or the two Rb substituents taken with the nitrogen atom to which they are joined, may form 4-6-membered ring, optionally containing in the ring, in addition to the nitrogen atom, NH, NC(O)OC1-4alkyl, O, S, SO or SO2 moieties and optionally substituted with a group independently selected from hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, C(O)OH and C(O)OC1-4alkyl; m is 1; m' is 0, 1 or 2; n is 1 or 2; R1 is independently selected from halogen or C1-4alkoxy; Y is halogen, C1-4alkoxy, C1-4alkylendioxy, phenyloxy or benzyloxy; or a pharmaceutically acceptable salt thereof. 2. The compound according to Claim 1 wherein R1 is halogen. 3. The compound according to Claim 2 wherein R1 is independently fluorine, chlorine, or bromine. 4. The compound according to Claim 1 wherein Y is halogen. 5. The compound according to Claim 4 wherein Y is independently fluorine, chlorine, or bromine. 6. The compound according to Claim 1 wherein Rb is hydrogen, C1-4alkyl, or C1-4alkyl substituted with C(O)OH or C(O)ORa. 7. The compound according to Claim 1 wherein Y is halogen, n is 1 or 2, R1 is halogen, and Rb is independently hydrogen, C1-4alkyl, or C1-4alkyl substituted with C(O)OH or C(O)ORa. 8. The compound according to Claim 1 which is selected from the group consisting of: N-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl)-N'-(2-bromophenyl)urea; N-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl)-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-(N"-benzylaminosulfonyl)-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-(N"-benzylaminosulfonyl)-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-(N",N"-dimethylaminosulfonyl)-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-(N",N"-dimethylaminosulfonyl)-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-(N"-methylaminosulfonyl)-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-(N"-methylaminosulfonyl)-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-[N"-(methoxycarbonylmethyl)aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[N"-(methoxycarbonylmethyl)aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-[N"-(carboxymethyl)aminosulfonyl-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[N"-(carboxymethyl)aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl)-N'-(2-chlorophenyl)urea; N-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl)-N'-phenylurea; N-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl)-N'-(2-phenoxyphenyl)urea; N-[2-hydroxy-3-[N"-(2-carboxyethyl)aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-(isopropylaminosulfonyl)-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-(isopropylaminosulfonyl)-4-chlorophenyl]-N'-(2-chlorophenyl)urea; N-[2-hydroxy-3-(isopropylaminosulfonyl)-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl)-N'-(2-methoxyphenyl)urea; N-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl)-N'-(2,3-methylenedioxyphenyl)urea; N-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl)-N'-(2-benzyloxyphenyl)-urea; N-[2-hydroxy-3-(N"-allylaminosulfonyl)-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-[N"-(2-trifluoroethyl)aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-(N"-phenylaminosulfonyl)-4-methoxyphenyl]-N-(2,3-dichlorophenyl)-urea; N-[2-hydroxy-3-(N"-phenylaminosulfonyl)-4-methoxyphenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[N"-(2-methoxyethyl)aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-[N"-(2-methoxyethyl)aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-(4-morpholinylsulfonyl)-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-(4-morpholinylsulfonyl)-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-[N"-[3-(tert-butoxycarbonylamino)propyl]aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-[N"-[3-(tert-butoxycarbonylamino)propyl]aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[N"-(3-aminopropyl)aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea trifluoroacetate; N-[2-hydroxy-3-[N"-(3-aminopropyl)aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea hydrochloride; N-[2-hydroxy-3-[N"-(3-aminopropyl)aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea trifluoroacetate; N-[2-hydroxy-3-[N"-[2-(tert-butoxycarbonylamino)ethyl]aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[N"-(2-aminoethyl)aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-(1-piperazinylsulfonyl)-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea trifluoroacetate; N-[2-hydroxy-3-(piperazin-1-ylsulfonyl)-4-chlorophenyl]-N'-(2-bromophenyl)urea trifluoroacetate; N-[2-hydroxy-3-[N"-(3-methylthiopropyl)aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-[N"-(3-methylthiopropyl)aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl)-N'-(2,3-dichlorophenyl)urea potassium salt; N-(2-hydroxy-3-aminosulfonyl-4-chlorophenyl)-N'-(2,3-dichlorophenyl)urea sodium salt; N-[2-hydroxy-3-[N",N"-di-(2-methoxyethyl)aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[N",N"-di-(2-methoxyethyl)aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-[N"-[2-(dimethylamino)ethyl]aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea hydrochloride; N-[2-hydroxy-3-[N"-[2-(dimethylamino)ethyl]aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea hydrochloride; N-[2-hydroxy-3-[N"-[3-(methylsulfonyl)propyl]aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-[N"-[3-(methylsulfonyl)propyl]aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[N"-[2-(morpholinyl)ethyl]aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea hydrochloride; N-[2-hydroxy-3-[N"-[2-(morpholinyl)ethyl]aminosulfonyl]-4-chlorophenyl]-N'-(2-chlorophenyl)urea hydrochloride; N-[2-hydroxy-3-[N"-[2-(4-morpholinyl)ethyl]aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-(4-thiomorpholinylsulfonyl)-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-(4-thiomorpholinylsulfonyl)-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[N",N"-di-(2-hydroxyethyl)aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[N",N"-di-(2-hydroxyethyl)aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea, N-[2-hydroxy-3-[N"-[3-(methylsulfinyl)propyl]aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-[N"-[3-(methylsulfinyl)propyl]aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[N"-[(1-tert-butoxycarbonylpiperidin-4-yl)methyl]aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)-urea, N-[2-hydroxy-3-[N"-[(1-tert-butoxycarbonylpiperidin-4-yl)methyl]aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[N"-[(piperidin-4-yl)methyl]aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea trifluroacetate; N-[2-hydroxy-3-[N"-[(piperidin-4-yl)methyl]aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea hydrochloride; N-[2-hydroxy-3-(1-azetidinylsulfonyl)-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-(1-azetidinylsulfonyl)-4-chlorophenyl]-N'-(2-chlorophenyl)urea; N-[2-hydroxy-3-(1-azetidinylsulfonyl)-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-(N",N"-dimethylaminosulfonyl)-4-chlorophenyl]-N'-(2-bromophenyl)urea potassium salt; N-[2-hydroxy-3-(N",N"-dimethylaminosulfonyl)-4-chlorophenyl]-N'-(2-bromophenyl)urea sodium salt; N-[2-hydroxy-3-(N"-cyclopropylaminosulfonyl)-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-(N"-cyclopropylaminosulfonyl)-4-chlorophenyl]-N'-(2-chlorophenyl)urea; N-[2-hydroxy-3-(N"-cyclopropylaminosulfonyl)-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-(N"-propylaminosulfonyl)-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-(N"-propylaminosulfonyl)-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-(N"-propylaminosulfonyl)-4-chlorophenyl]-N'-(2-chlorophenyl)urea; N-[2-hydroxy-3-(N"-ethylaminosulfonyl])-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-(N"-ethylaminosulfonyl)-4-chlorophenyl]-N'-(2-chlorophenyl)urea; N-[2-hydroxy-3-(N"-ethylaminosulfonyl)-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-[N"-[5-(tert-butoxycarbonylamino)-5-carboxylpentyl]aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[N"-[5-(tert-butoxycarbonylamino)-5-carboxypentyl]aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-[N"-[5-(tert-butoxycarbonylamino)-5-carboxypentyl]aminosulfonyl]-4-chlorophenyl]-N'-(2-chlorophenyl)urea; N-[2-hydroxy-3-[N"-(2-hydroxyethyl)aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[N"-(2-hydroxyethyl)aminosulfonyl]-4-chlorophenyl]-N'-(2,3-dichlorophenyl)urea; N-[2-hydroxy-3-[N"-[[(2-bromophenylamino)carboxy]ethyl]aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)urea; N-[2-hydroxy-3-[N"-(2-benzyloxyethyl)aminosulfonyl]-4-chlorophenyl]-N'-(2-bromophenyl)ur