Hydroxy diphenyl urea sulfonamides as IL-8 receptor antagonists

• US 20030109527A1
• Filed: 11/18/2002
• Published: 06/12/2003
• Est. Priority Date: 12/16/1998
• Status: Abandoned Application

• Current Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Original Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Inventors: McCleland, Brent W., Palovich, Michael R., Jin, Qi, Widdowson, Katherine L.
• Application Number:
  US10/299,503
• Publication Number:
  US 20030109527A1
• Time in Patent Office: Days
• US Class Current: 514/238.2
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/26 : Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07C 2601/02 : with a three-membered ring
• CPC Class Codes: C07C 2601/08 : the ring being saturated
• CPC Class Codes: C07C 311/47 : Y being a hetero atom
• CPC Class Codes: C07C 317/28 : with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
• CPC Class Codes: C07C 323/49 : to sulfur atoms
• CPC Class Codes: C07D 205/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 207/48 : Sulfur atoms
• CPC Class Codes: C07D 211/28 : to which a second hetero atom is attached
• CPC Class Codes: C07D 213/76 : to which a second hetero atom is attached nitro radicals C07D213/61
• CPC Class Codes: C07D 241/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 261/02 : not condensed with other rings
• CPC Class Codes: C07D 295/26 : Sulfur atoms
• CPC Class Codes: C07D 307/14 : Radicals substituted by nitrogen atoms not forming part of a nitro radical

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.

Claims

1. A compound of the formula (I):

2. The compound according to claim 1 wherein R₁ is substituted in the 4-position by an electron withdrawing moiety.

3. The compound according to claim 2 wherein R₁ is halogen, cyano or nitro.

4. The compound according to claim 3 wherein R₁ is halogen.

5. The compound according to claim 4 wherein R₁ 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, R₁ 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.

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.

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 R₁ is as in claim 1, above.

18. A compound selected from the group consisting of formulas (II), (III), (IV), (V) and (VI) hereinbelow:

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