Hydroxy diphenyl urea sulfonamides as IL-8 receptor antagonists

Abstract

The invention relates to novel hydroxy diphenylurea sulfonamides, compositions and intermediates thereof. The hydroxy diphenylurea sulfonamides are useful in the treatment of disease states mediated by the chemokine, Interleukin-8.

What is claimed is:  
     
         1 . A compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R b  is independently hydrogen, NR 6 R 7 , OH, OR a , C 1-5 alkyl, aryl, arylC 1-4 alkyl, aryl C 2-4 alkenyl; cycloalkyl, cycloalkyl C 1-5  alkyl, heteroaryl, heteroarylC 1-4 alkyl, heteroarylC 2-4  alkenyl, heterocyclic, heterocyclic C 1-4 alkyl, or a heterocyclic C 2-4 alkenyl moiety, all of which moieties may be optionally substituted one to three times independently by halogen; nitro; halosubstituted C 1-4  alkyl; C 1-4  alkyl; amino, mono or di-C 1-4  alkyl substituted amine; OR a ; C(O)R a ; NR a C(O)OR a ; OC(O)NR 6 R 7 ; hydroxy; NR 9 C(O)R a ; S(O) m′ , R a ; C(O)NR 6 R 7 ; C(O)OH; C(O)OR a ; S(O) t NR 6 R 7 ; NHS(O) t R a ; or the two R b  substituents join to form a 3-10 membered ring, optionally substituted and containing, in addition to optionally substituted C 1-4  alkyl, independently, 1 to 3 NR a , O, S, SO, or SO 2  moities which can be optionally unsaturated;  
 R a  is an alkyl, aryl, arylC 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic, COOR a ′, or a heterocyclic C 1-4 alkyl moiety, all of which moieties may be optionally substituted;  
 R a ′ is an alkyl, aryl, arylC 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic or a heterocyclic C 1-4 alkyl moiety, all of which moieties may be optionally substituted;  
 m is an integer having a value of 1 to 3;  
 m′ is 0, or an integer having a value of 1 or 2;  
 n is an integer having a value of 1 to 3;  
 q is 0, or an integer having a value of 1 to 10;  
 t is 0, or an integer having a value of 1 or 2;  
 s is an integer having a value of 1 to 3;  
 R 1  is independently selected from hydrogen, halogen, nitro, cyano, C 1-10  alkyl, halosubstituted C 1-10  alkyl, C 2-10  alkenyl, C 1-10  alkoxy, halosubstituted C 1-10 alkoxy, azide, S(O) t R 4 , (CR 8 R 8 )q S(O) t R 4 , hydroxy, hydroxy substituted C 1-4 alkyl, aryl, aryl C 1-4  alkyl, aryl C 2-10  alkenyl, aryloxy, aryl C 1-4  alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C 2-10  alkenyl, heteroaryl C 1-4  alkyloxy, heterocyclic, heterocyclic C 1-4 alkyl, heterocyclicC 1-4 alkyloxy, heterocyclicC 2-10  alkenyl, (CR 8 R 8 )q NR 4 R 5 , (CR 8 R 8 )qC(O)NR 4 R 5 , C 2-10  alkenyl C(O)NR 4 R 5 , (CR 8 R 8 )q C(O)NR 4 R 10 , S(O) 3 R 8 , (CR 8 R 8 )q C(O)R 11 , C 2-10  alkenyl C(O)R 11 , C 2-10  alkenyl C(O)OR 11 , (CR 8 R 8 )q C(O)OR 11 , (CR 8 R 8 )q OC(O)R 11 , (CR 8 R 8 )qNR 4 C(O)R 11 , (CR 8 R 8 )q C(NR 4 )NR 4 R 5 , (CR 8 R 8 )q NR 4 C(NR 5 )R 11  (CR 8 R 8 )q NHS(O) t R 13 , (CR 8 R 8 )q S(O) t NR 4 R 5 , or two R 1  moieties together may form O—(CH 2 ) s O or a 5 to 6 membered saturated or unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moieties may be optionally substituted;  
 R 4  and R 5  are independently hydrogen, optionally substituted C 1-4  alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1-4 alkyl, heterocyclic, heterocyclicC 1-4  alkyl, or R 4  and R 5  together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O, N and S;  
 R 6  and R 7  are independently hydrogen, or a C 1-4  alkyl, heteroaryl, aryl, aklyl aryl, alkyl C 1-4  heteroalkyl, which may all be optionally substituted or R 6  and R 7  together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom is selected from oxygen, nitrogen or sulfur, and which ring may be optionally substituted;  
 Y is hydrogen, halogen, nitro, cyano, halosubstituted C 1 -10  alkyl, C 1-10  alkyl, C 2-10  alkenyl, C 1-10  alkoxy, halosubstituted C 1-10  alkoxy, azide, (CR 8 R 8 )qS(O) t R a , (CR 8 R 8 )qOR a , hydroxy, hydroxy substituted C 1-4 alkyl, aryl; aryl C 1-4  alkyl, aryloxy, arylC 1-4  alkyloxy, aryl C 2-10  alkenyl, heteroaryl, heteroarylalkyl, heteroaryl C 1-4  alkyloxy, heteroaryl C 2-10  alkenyl, heterocyclic, heterocyclic C 1-4 alkyl, heterocyclicC 2-10  alkenyl, (CR 8 R 8 )qNR 4 R 5 , C 2-10  alkenyl C(O)NR 4 R 5 , (CR 8 R 8 )qC(O)NR 4 R 5 , (CR 8 R 8 )q C(O)NR 4 R 10 , S(O) 3 R 8 , (CR 8 R 8 )qC(O)R 11 , C 2-10  alkenylC(O)R 11 , (CR 8 R 8 )qC(O)OR 11 , C 2-10 alkenylC(O)OR 11 , (CR 8 R 8 )qOC(O)R 11 , (CR 8 R 8 )qNR 4 C(O)R 11 , (CR 8 R 8 )q NHS(O) t R 13 , (CR 8 R 8 )q S(O) t NR 4 R 5 , (CR 8 R 8 )qC(NR 4 )NR 4 R 5 , (CR 8 R 8 )q NR 4 C(NR 5 )R 11 , or two Y moieties together may form O—(CH 2 ) s —O or a 5 to 6 membered saturated or unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;  
 R 8  is hydrogen or C 1-4  alkyl;  
 R 9  is hydrogen or a C 1-4  alkyl;  
 R 10  is C 1-10  alkyl C(O) 2 R 8 ;  
 R 11  is hydrogen, optionally substituted C 1-4  alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1-4 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1-4 alkyl;  
 R 13  is suitably C 1-4  alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclic, or heterocyclicC 1-4 alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound according to  claim 1  wherein R 1  is substituted in the 4-position by an electron withdrawing moiety.  
     
     
         3 . The compound according to  claim 2  wherein R 1  is halogen, cyano or nitro.  
     
     
         4 . The compound according to  claim 3  wherein R 1  is halogen.  
     
     
         5 . The compound according to  claim 4  wherein R 1  is independently, fluorine, chlorine, or bromine.  
     
     
         6 . The compound according to  claim 1  wherein Y is mono-substituted in the 2′-position or 3′-position, or is disubstituted in the 2′- or 3′-position of a monocyclic ring.  
     
     
         7 . The compound according to  claim 6  wherein Y is halogen.  
     
     
         8 . The compound according to  claim 4  wherein Y is independently fluorine, chlorine, or bromine.  
     
     
         9 . The compound according to  claim 1  wherein R b  is hydrogen, C 1-4  alkyl, or C 1-4  alkyl substituted with C(O)OH, or C(O)OR a .  
     
     
         10 . The compound according to  claim 1  wherein Y is halogen, n is 1 or 2, R 1  is halogen, m is 1 or 2, and R b  is, independently, hydrogen, C 1-4  alkyl, C 1-4  alkyl substituted with C(O)OH, or C(O)OR a .  
     
     
         11 . The compound according to  claim 1  which is selected from the group consisting of: 
 N-(2-Hydroxyl-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″-dimethyl)-aminosulfonyl-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″-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′-(2,3-dichlorophenyl) urea;  
 N-[2-Hydroxy-3-(N″-(2-methoxylcarbonyl)-methyl)-aminosulfonyl-4-chlorophenyl]-N′-(2-bromophenyl) urea;  
 N-[2-Hydroxy-3-[(N″-2-carboxymethyl)-aminosulfonyl]-4-chlorophenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[2-Hydroxy-3-(N″-2-carboxymethyl)-aminosulfonyl-4-chlorophenyl ]-N′-(2-bromophenyl) urea;  
 N-[2-Hydroxy-3-aminosulfonyl-4-chlorophenyl]-N′-(2-chlorophenyl) urea;  
 N-[2-Hydroxy-3-aminosulfonyl-4-chlorophenyl]-N′-phenyl urea;  
 N-(2-Hydroxy-3-aminosulfonyl-4-chlorophenyl)-N′-(2-phenoxyphenyl) urea;  
 N-(2-Hydroxy-3-[N′-(3-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-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-N′-(2-methoxyphenyl) urea;  
 N-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-N′-(2,3-methylenedioxy phenyl) urea;  
 N-(2-benzyloxyphenyl)-N′-(4-chloro-2-hydroxy-3-aminosulfonylphenyl) urea;  
 N-[3-(N″-allylaminosulfonyl)-4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[4-chloro-2-hydroxy-3-[N″-(2-trifluoroethyl)aminosulfonyl]phenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-(2,3-dichlorophenyl)-N′-[2-hydroxy-4-methoxy-3-N″-(phenylaminosulfonyl)phenyl] urea;  
 N-(2-bromophenyl)-N′-[2-hydroxy-4-methoxy-3-N″-(phenylaminosulfonyl)phenyl] urea;  
 N-[4-chloro-2-hydroxy-3-[N″-(2-methoxyethyl)aminosulfonyl]phenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[N″-(2-methoxyethyl)aminosulfonyl]phenyl] urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-(4-morpholinylsulfonyl)phenyl]urea;  
 N-[4-chloro-2-hydroxy-3-(4-morpholinylsulfonyl)phenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[3-[N′-[3-(tert-butoxycarbonylamino)propyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[3-[N″-[3-(tert-butoxycarbonylamino)propyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl] urea;  
 N-[3-[N″-(3-aminopropyl)aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2-bromophenyl) urea trifluoroacetate;  
 N-[3-[N″-(3-aminopropyl)aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2-bromophenyl) urea hydrochloride;  
 N-[3-[N″-(3-aminopropyl)aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea trifluoroacetate;  
 N-(2-bromophenyl)-N′-[3-[N″-[2-(tert-butoxycarbonylamino)ethyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl] urea;  
 N-[3-[N″-(2-aminoethyl)aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2-bromophenyl) urea;  
 N-(2-bromophenyl)-N′-[3-[[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl]-4-chloro-2-hydroxyphenyl] urea;  
 N-[3-[[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[4-chloro-2-hydroxy-3-(1-piperazinylsulfonyl)phenyl]-N′-(2,3-dichlorophenyl) urea trifluoroacetate;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-(piperazin-1-yl]sulfonyl)phenyl] urea trifluoroacetate;  
 N-[4-chloro-2-hydroxy-3-[N″-(3-methylthiopropyl)aminosulfonyl]phenyl ]-N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[N″-(3-methylthiopropyl)aminosulfonyl]phenyl] urea;  
 N-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-N′-(2,3-dichlorophenyl) urea potasium salt;  
 N-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-N′-(2,3-dichlorophenyl) urea sodium salt;  
 N-(2-bromophenyl)-N′-[4-chloro-3-[N″,N″-di-(2-methoxyethyl)aminosulfonyl]-2-hydroxyphenyl] urea;  
 N-[4-chloro-3-[N″,N″-di-(2-methoxyethyl)aminosulfonyl]-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-3-[N″-[2-(dimethylamino)ethyl]aminosulfonyl]-2-hydroxyphenyl] urea hydrochloride;  
 N-[4-chloro-3-[N″-[2-(dimethylamino)ethyl]aminosulfonyl]-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea hydrochloride;  
 N-[4-chloro-2-hydroxy-3-[N″-[3-(methylsulfonyl)propyl]aminosulfonyl]phenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[N″-[3-(methylsulfonyl)propyl]aminosulfonyl]phenyl] urea;  
 N-[4-chloro-2-hydroxy-3-[N″-[2-(morpholinyl)ethyl]aminosulfonyl]phenyl]-N′-(2,3-dichlorophenyl) urea hydrochloride;  
 N-[4-chloro-2-hydroxy-3-[N″-[2-(morpholinyl)ethyl]aminosulfonyl]phenyl]-N′-(2-chlorophenyl) urea hydrochloride;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[N ″-[2-(4-morpholinyl)ethyl]aminosulfonyl]phenyl] urea;  
 N-[4-chloro-2-hydroxy-3-(4-thiomorpholinylsulfonyl)phenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-(4-thiomorpholinylsulfonyl)phenyl] urea;  
 N-(2-bromophenyl)-N′-[4-chloro-3-[N″,N″-di-(2-hydroxyethyl)aminosulfonyl]-2-hydroxyphenyl] urea;  
 N-[4-chloro-3-[N″,N″-di-(2-hydroxyethyl)aminosulfonyl]-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea,  
 N-[4-chloro-2-hydroxy-3-[N″-[3-(methylsulfinyl)propyl]aminosulfonyl]phenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[N″-[3-(methylsulfinyl)propyl]aminosulfonyl]phenyl] urea;  
 N-(2-bromophenyl)-N′-[3-[N″-[(1-tert-butoxycarbonylpiperidin-4-yl)methyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl] urea,  
 N-[3-[N″-[(-tert-butoxycarbonylpiperidin-4-yl)methyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[4-chloro-2-hydroxy-3-(-oxidothiomorpholinosulfonyl)phenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)phenyl] urea;  
 N-[4-chloro-2-hydroxy-3-[N″-[(piperidin-4-yl)methyl]aminosulfonyl]phenyl]-N′-(2,3-dichlorophenyl) urea trifluroacetate;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[N″-[(piperidin-4-yl)methyl]aminosulfonyl]phenyl] urea hydrochloride;  
 N-[3-(1-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′-(2-bromophenyl) urea;  
 N-[3-(1-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N ′-(2-chlorophenyl) urea;  
 N-[3-(1-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′[4-chloro-3-(N″,N″-dimethylaminosulfonyl)-2-hydroxyphenyl] urea potassium salt;  
 N-(2-bromophenyl)-N′-[4-chloro-3-(N″,N″-dimethylaminosulfonyl)-2-hydroxyphenyl] urea sodium salt;  
 N-(2-bromophenyl)-N′-[4-chloro-3-(N″-cyclopropylaminosulfonyl)-2-hydroxyphenyl) urea;  
 N-[4-chloro-3-(N″-cyclopropylaminosulfonyl)-2-hydroxyphenyl]-N′-(2-chlorophenyl) urea;  
 N-[4-chloro-3-(N″-cyclopropylaminosulfonyl)-2-hydroxphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-(N″-propylaminosulfonyl)phenyl] urea;  
 N-[4-chloro-2-hydroxyl-3-(N″-propylaminosulfonyl)phenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[4-chloro-2-hydroxyl-3-(N″-propylaminosulfonyl)phenyl]-N′-(2-chlorophenyl) urea;  
 N-(2-bromophenyl)-N′[4-chloro-3-(N″-ethylaminosulfonyl])-2-hydroxyphenyl] urea;  
 N-[4-chloro-3-(N ″-ethylaminosulfonyl)-2-hydroxyphenyl]-N′-(2-chlorophenyl) urea;  
 N-[4-chloro-3-(N″-ethylaminosulfonyl)-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[3-[N″-[5-(tert-butoxycarbonylamino)-5-carboxylpentyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl] urea;  
 N-[3-[N″-[5-(tert-butoxycarbonylamino)-5-carboxylpentyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[3-[N″-[5-(tert-butoxycarbonylamino)-5-carboxylpentyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2-chlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[N″-(2-hydroxyethyl)aminosulfonyl] urea;  
 N-(2,3-dichlorophenyl)-N′-[4-chloro-2-hydroxy-3-[N″-(2-hydroxyethyl)aminosulfonyl] urea;  
 N-(2-bromophenyl)-N′[3-[N″-[[(2-bromophenylamino)carboxyl]ethyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl] urea;  
 N-[3-[N″-(2-benzyloxyethyl)aminosulfonyl]-4-chloro-2-hydroxyphenyl ]-N′-(2 bromophenyl) urea;  
 N-[2-Hydroxy-3-(N″-cyclopropylmethylaminosulfonyl)-4-chlorophenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[2-Hydroxy-3-(N″-cyclopropylmethylaminosulfonyl)-4-chlorophenyl]-N′-(2 chlorophenyl) urea;  
 N-[2-Hydroxy-3-(N″-cyclopropylmethylaminosulfonyl)-4-chlorophenyl]-N′-(2 bromophenyl) urea;  
 N-[2-Hydroxy-3-(N″-methoxy-N″-methylaminosulfonyl)-4-chlorophenyl]-N′-(2-bromophenyl) urea;  
 N-[2-Hydroxy-3-(N″-methoxy-N″-methylaminosulfonyl)-4-chlorophenyl]-N′-(2 chlorophenyl) urea;  
 N-[2-Hydroxy-3-(N″-methoxy-N″-methylaminosulfonyl)-4-chlorophenyl]-N′-(2,3 dichlorophenyl) urea;  
 N-[2-Hydroxy-3-(N″-pyrrolidinylsulfonyl)-4-chlorophenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[2-Hydroxy-3-(N″-pyrrolidinylsulfonyl)-4-chlorophenyl]-N′-(2-bromophenyl) urea;  
 N-[2-Hydroxy-3-(N″-pyrrolidinylsulfonyl)-4-chlorophenyl]-N′-(2-chlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[(4-pyridinylaminosulfonyl]phenyl] urea;  
 N-[4-chloro-2-hydroxy-3-[(4-pyridinylaminosulfonyl]phenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[[[2-(tetrahydro-2-furanyl)methyl]aminosulfonyl]phenyl] urea;  
 N-[4-chloro-2-hydroxy-3-[[[2-(tetrahydro-2-furanyl)methyl]aminosulfonyl]phenyl] -N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[[[(2R)-(tetrahydro-2-furanyl)methyl]aminosulfonyl]phenyl] urea; and  
 N-[4-chloro-2-hydroxy-3-[[[(2R)-(tetrahydro-2-furanyl)methyl]aminosulfonyl]phenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[[[(2S)-(tetrahydro-2-furanyl)methyl]aminosulfonyl]phenyl] urea;  
 N-[4-chloro-2-hydroxy-3-[[[(2S)-(tetrahydro-2-furanyl)methyl]aminosulfonyl]phenyl]-N-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′[4-chloro-2-hydroxy-3-(N″-cyclopentylaminosulfonyl)phenyl]urea;  
 N-[4-chloro-2-hydroxy-3-(N″-cyclopentylaminosulfonyl)phenyl]-N′-(2,3-dichlorophenyl)urea;  
 N-(2-chlorophenyl)-N′-[4-chloro-2-hydroxy-3-(N″-cyclopentylaminosulfonyl)phenyl]urea;  
 N-(2-bromophenyl)-N′[4-chloro-2-hydroxy-3-(N″-isoxazolidinylaminosulfonyl) phenyl]urea;  
 N-[4-chloro-2-hydroxy-3-(N″-isoxazolidinylaminosulfonyl)phenyl]-N′-(2,3-dichlorophenyl)urea;  
 N-(2-chlorophenyl)-N′-[4-chloro-2-hydroxy-3-(N″-isoxazolidinylaminosulfonyl) phenyl]urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-(N″-tetrahydroisoxazylaminosulfonyl) phenyl]urea;  
 N-[4-chloro-2-hydroxy-3-(N″-tetrahydroisoxazylaminosulfonyl)phenyl]-N′-(2,3-dichlorophenyl)urea;  
 N-(2-chlorophenyl)-N′-[4-chloro-2-hydroxy-3-N″-(tetrahydroisoxazylaminosulfonyl) phenyl]urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3[(2-isopropoxyethyl)aminosulfonyl]phenyl] urea;  
 N-[4-chloro-2-hydroxy-3-[(2-isopropoxyethyl)aminosulfonyl]phenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[4-chloro-2-hydroxy-3-[(2-isopropoxyethyl)aminosulfonyl]phenyl]-N′-(2-chlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[(2-ethoxyethyl)aminosulfonyl]phenyl] urea;  
 N-[4-chloro-2-hydroxy-3-[(2-ethoxyethyl)aminosulfonyl]phenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[4-chloro-2-hydroxy-3-[(2-ethoxyethyl)aminosulfonyl]phenyl]-N′-(2-chlorophenyl) urea;  
 N-(2-bromophenyl)-N′[4-chloro-2-hydroxy-3-[(2-methoxycarbonyl)azetidin-1-yl]sulfonylphenyl] urea;  
 N-[4-chloro-2-hydroxy-3-[(2-methoxycarbonyl)azetidin-1-yl]sulfonylphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[4-chloro-2-hydroxy-3-[(2-carboxy)-azetidin-1-yl]sulfonylphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[N″-[3-(4-morpholinyl)propyl]aminosulfonyl]phenyl] urea hydrochloride;  
 N-[4-chloro-2-hydroxy-3-[N″-[3-(4-morpholinyl)propyl]-aminosulfonyl]phenyl]-N′-(2,3-dichlorophenyl) urea hydrochloride;  
 N-[4-chloro-2-hydroxy-3-[N″-[3-(4-morpholinyl)propyl]aminosulfonyl]phenyl]-N′-(2-chlorophenyl) urea hydrochloride;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[S-(-)-(2-methoxymethyl)pyrrolidin-1-yl]sulfonylphenyl] urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[S-(-)-(2-hydroxymethyl)pyrrolidin-1-yl]sulfonylphenyl] urea;  
 N-[4-chloro-2-hydroxy-3-[S-(-)-(2-methoxymethyl)pyrrolidin-1-yl]sulfonylphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[4-chloro-2-hydroxy-3-[S-(-)-(2-hydroxymethyl)-pyrrolidin-1-ylsulfonyl]phenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[4-chloro-2-hydroxy-3-[S-(-)-(2-methoxymethyl)-pyrrolidin-1-yl]sulfonylphenyl]-N′-(2-chlorophenyl) urea;  
 N-[4-chloro-2-hydroxy-3-[S-(-)-(2-hydroxymethyl)-pyrrolidin-1-yl]sulfonylphenyl]-N′-(2-chlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[S-(2-methoxycarbonyl)pyrrolidin-1-yl]sulfonylphenyl] urea;  
 N-(2-bromophenyl)-N′-[4-chloro-2-hydroxy-3-[S-(2-carboxy)pyrrolidin-1-yl]sulfonylphenyl] urea;  
 N-(2-bromophenyl)-N′[3-[N″-(tert-butyl)aminosulfonyl]-4-chloro-2-hydroxyphenyl] urea;  
 N-[3-[N ″-(tert-butyl )aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[3-[N″-(tert-butyl)aminosulfonyl]-4-chloro-2-hydroxylphenyl]-N′-(2-chlorophenyl) urea;  
 N-[3-[N″-[5-(tert-butoxycarbonylamino)-5-carboxypentyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2-chlorophenyl) urea;  
 N-[3-[N″-(5-amino-5-carboxypentyl)aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2-chlorophenyl) urea hydrochloride;  
 N-[3-[N″-(5-amino-5-carboxypentyl)aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea hydrochloride;  
 N-[3-[N″-(5-amino-5-carboxypentyl)aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2-bromophenyl) urea hydrochloride;  
 N-[4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyphenyl]urea;  
 N-[4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyphenyl]-N′-(2-chlorophenyl) urea;  
 N-[3-[N″-[2-(tert-butoxycarbonylamino)ethyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[3-[N″-(2-aminoethyl)aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea trifluoroacetate;  
 N-[3-[N″-[2-(tert-butoxycarbonylamino)ethyl]aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2-chlorophenyl) urea;  
 N-[3-[N″-(2-aminoethyl)aminosulfonyl]-4-chloro-2-hydroxyphenyl]-N′-(2-chlorophenyl) urea trifluoroacetate;  
 N-[4-chloro-2-hydroxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-chlorophenyl) urea.;  
 N-[4-chloro-2-hydroxy-3-(aminosulfonyl)phenyl]-N′-(2-bromo-3-fluorophenyl) urea;  
 N-[4-chloro-2-hydroxy-3-(aminosulfonyl)phenyl]-N′-(2-chloro-3-fluorophenyl) urea;  
 N-(2-bromophenyl)-N′-[4chloro-3-[(1-ethyl-pyrrolidin-2-yl)methylaminosulfonyl]-2-hydroxyphenyl] urea hydrochloride;  
 N-[4-chloro-3-[(1-ethyl-pyrrolidin-2-yl)methylaminosulfonyl]-2-hydroxyphenyl] N′-(2,3-dichlorophenyl) urea hydrochloride; and  
 N-[4-chloro-3-[(1-ethyl-pyrrolidin-2-yl)methylaminosulfonyl]-2-hydroxyphenyl]-N′-(2-chlorophenyl) urea hydrochloride;  
 or a pharmaceutically acceptable salt thereof.  
 pharmaceutically acceptable salt thereof.  
 
     
     
         12 . A compound according to  claim 11  which is selected from the group consisting of: 
 N-(4-chloro-2-hydroxy-3-aminosulfonylphenyl)-N′-(2,3-dichlorophenyl) urea;  
 N-[4-chloro-2-hydroxy-3-[S-(-)-(2-methoxymethyl)pyrrolidin-1-yl ]sulfonylphenyl]-N′-(2,3-dichlorophenyl) urea;  
 N-[4-chloro-2-hydroxy-3-(N″-isoxazolidinylaminosulfonyl)phenyl]-N′-(2,3-dichlorophenyl)urea;  
 N-[4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)phenyl]-N′-(2,3-dichlorophenyl) urea; and  
 N-[4-chloro-3-[N″,N″-di-(2-methoxyethyl)aminosulfonyl ]-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea.  
 
     
     
         13 . A compound according to  claim 12  wherein the compound is in its sodium salt form.  
     
     
         14 . A compound according to  claim 13  wherein the compound is in its potassium salt form.  
     
     
         15 . A pharmaceutical composition comprising a compound according to any of  claims 1  to  14  and a pharmaceutically acceptable carrier or diluent.  
     
     
         16 . A method of treating a chemokine mediated disease, wherein the chemokine binds to an IL-8 a or b receptor in a mammal, which method comprises administering to said mammal an effective amount of a compound of the formula according to any one of  claims 1  to  14 .  
     
     
         17 . The method according to  claim 16  wherein the mammal is afflicted with a chemokine mediated disease selected from atopic dermatitis, osteo arthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke, septic shock, multiple sclerosis, endotoxic shock, psoriasis, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft vs. host reaction, alzheimers disease, allograft rejections, malaria, restinosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis and undesired hematopoietic stem cells release, diseases caused by respiratory viruses, herpesviruses, and hepatitis viruses, meningitis, herpes encephalitis, CNS vasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post surgical trauma, cystic fibrosis, pre-term labour, cough, pruritus, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, lyme arthritis, fibrodysplasia ossificans progressiva, acute and chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, uveitis, polymyositis, vasculitis, acne, gastric and duodenal ulcers, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness, bronchiolitis obliterans organizing pneumonia, bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor pulmonae, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hypoxia, surgerical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertropy, sarcoidosis, small airway disease, ventilation-perfusion mismatching, wheeze and lupus.  
     
     
         18 . A compound selected from the group consisting of formulas (II), (III), (IV), (V) and (VI) hereinbelow:  
       
         
           
                 
                 
                 
               
                     
                 
                     
                 
                   (V) 
                   (VI) 
                   (VII) 
                 
                     
                 
                     
                 
             
                
                
               
               
                
                
                
               
            
           
         
         wherein R 1  is not hydrogen.  
       
     
     
         19 . A method of converting a chloro compound of formula (VII) to a phenol of formula (III) by reacting with sodium acetate and 18-C-6 followed by hydrolysis with sulfuric acid and methanol.  
       
         
           
           
               
               
           
         
         wherein R represents H or Na; and  
         R 1  is as in  claim 1 , above.  
       
     
     
         20 . A method of converting a chloro compound of formula (VII) to a phenol of formula (III) by reacting to the chloro compound with sodium hydride and water in THF. 
 R=H or Na                          wherein R represents H or Na and R 1  is as in  claim 1 , above.    
     
     
         21 . A method of converting a compound of formula (VIII) to a nitro compound of formula (IX) by reacting the, sulfonic acid compound with nitric acid in sulfuric acid 
 R=H or Na