Aromatic heterocyclic compounds as antiinflammatory agents

Abstract

Disclosed are novel aromatic heterocyclic compounds of the formula(I) wherein Ar 1 , Ar 2 , L, Q and X are described herein. The compounds are useful in pharmaceutic compositions for treating diseases or pathological conditions involving inflammation such as chronic inflammatory diseases. Also disclosed are processes of making such compounds.

What is claimed is:  
     
         1 . A compound of the formula (I) shown below, wherein said compound is a hydroxylated or oxidized metabolite compound of the formula (I);  
       
         
           
           
               
               
           
         
       
       wherein 
 Ar 1  is pyrazole optionally substituted by one or more R 1 , R 2  or R 3 ;  
 Ar 2  is: 
 phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with one to three R 2  groups;  
 
 L is a C 1-10  saturated or unsaturated branched or unbranched carbon chain; 
 wherein one or more methylene groups are optionally independently replaced by O, N or S; and  
 wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C 1-4  branched or unbranched alkyl which may be substituted by one or more halogen atoms;  
 
 Q is selected from the group consisting of: 
 a) pyridine, pyrimidine, pyridazine, imidazole, benzimidazole, oxazo[4,5-b]pyridine and imidazo[4,5-b]pyridine, which are optionally substituted with one to three groups selected from the group consisting of halogen, C 1-6  alkyl, C 1-6  alkoxy, hydroxy, mono- or di-(C 1-3  alkyl)amino, C 1-6  alkyl-S(O) m  and phenylamino wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C 1-6  alkyl and C 1-6  alkoxy;  
 b) morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, piperidine, piperidinone or tetrahydropyrimidone which are optionally substituted with one to three groups selected from the group consisting of C 1-6  alkyl, C 1-6  alkoxy, hydroxy, mono- or di-(C 1-3  alkyl)amino-C 1-3  alkyl, phenylamino-C 1-3  alkyl and C 1-3  alkoxy-C 1-3  alkyl;  
 
 R 1  is selected from the group consisting of: 
 a) C 3-10  branched or unbranched alkyl, which may optionally be partially or fully halogenated, and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle selected from the group hereinabove described, being substituted with 0 to 5 groups selected from the group consisting of halogen, C 1-6  branched or unbranched alkyl which is optionally partially or fully halogenated, C 3-8  cycloalkyl, C 5-8  cycloalkenyl, hydroxy, cyano, C 1-3  alkyloxy which is optionally partially or fully halogenated, NH 2 C(O) and di(C 1-3 )alkylaminocarbonyl;  
 b) C 3-7  cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which may optionally be partially or fully halogenated and which may optionally be substituted with one to three C 1-3  alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from O, S, CHOH, >C═O, >C═S and NH;  
 c) C 3-10  branched alkenyl which may optionally be partially or fully halogenated, and which is optionally substituted with one to three C 1-5  branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from halogen, C 1-6  branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, cyano, C 1-3  alkyloxy which is optionally partially or fully halogenated, NH 2 C(O), mono- or di(C 1-3 )alkylaminocarbonyl;  
 d) C 5-7  cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group may optionally be substituted with one to three C 1-3  alkyl groups;  
 e) cyano; and,  
 f) methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;  
 
 R 2  is selected from the group consisting of: 
 a C 1-6  branched or unbranched alkyl which may optionally be partially or fully halogenated, acetyl, aroyl, C 1-4  branched or unbranched alkoxy, which may optionally be partially or fully halogenated, halogen, methoxycarbonyl and phenylsulfonyl;  
 
 R 3  is selected from the group consisting of: 
 a) a phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl; wherein such phenyl, naphthyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a C 1-6  branched or unbranched alkyl, phenyl, naphthyl, heterocycle selected from the group hereinabove described, C 1-6  branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C 1-5  alkyl, naphthyl C 1-5  alkyl, halo, hydroxy, cyano, C 1-3  alkyloxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(C 1-3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH 2 C(O), a mono- or di-(C 1-3 )alkyl aminocarbonyl, C 1-5  alkyl-C(O)—C 1-4  alkyl, amino-C 1-5  alkyl, mono- or di-(C 1-3 )alkylamino-C 1-5  alkyl, amino-S(O) 2 , di-(C 1-3 )alkylamino-S(O) 2 , R 4 -C 1-5  alkyl, R 5  -C 1-5  alkoxy, R 6 -C(O)—C 1-5  alkyl and R 7 -C 1-5  alkyl(R 8 )N;  
 b) a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoirnidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from phenyl, naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C 1-6  branched or unbranched alkyl which is optionally partially or fully halogenated, halo, cyano, C 1-3  alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(C 1-3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH 2 C(O), a mono- or di-(C 1-3 )alkyl aminocarbonyl, C 1-4  alkyl-OC(O), C 1-5  alkyl-C(O)—C 1-4  branched or unbranched alkyl, an amino-C 1-5  alkyl, mono- or di-(C 1-3 )alkylamino-C 1-5  alkyl, R 9 -C 1-5  alkyl, R 10 -C 1-5  alkoxy, R 11 -C(O)—C 1-5  alkyl and R 12 -C 1-5 alkyl(R 13 )N;  
 c) cycloalkyl selected from the group consisting of cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which the cycloalkyl may optionally be partially or fully halogenated and which may optionally be substituted with one to three C 1-3  alkyl groups;  
 d) C 5-7  cycloalkenyl, selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group may optionally be substituted with one to three C 1-3  alkyl groups; and  
 e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl;  
 f) C 1-6  branched or unbranched alkyl which may optionally be partially or fully halogenated; wherein  
 or R 1  and R 2  taken together may optionally form a fused phenyl or pyridinyl ring,  
 
 each R 8 , R 13  is independently selected from the group consisting of: 
 hydrogen and C 1-4  branched or unbranched alkyl which may optionally be partially or fully halogenated;  
 
 each R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , and R 12  is independently selected from the group consisting of: 
 morpholine, piperidine, piperazine, imidazole and tetrazole;  
 m=0, 1, 2;  
 X=O or S and  
 physiologically acceptable acids or salts thereof.  
 
 
     
     
         2 . The metabolite compound according to  claim 1  where in the formula (I) Ar 2  is naphthyl, tetrahydronaphthyl, indanyl or indenyl.  
     
     
         3 . The metabolite compound according to  claim 2  where in the formula (I) Ar 2  is naphthyl.  
     
     
         4 . The metabolite compound according to  claim 3  where in the formula (I): 
 Ar 2  is 1-naphthyl;  
 L is C 1-6  saturated or unsaturated branched or unbranched carbon chain wherein 
 one or more methylene groups are optionally independently replaced by O, N or S; and  
 wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C 1-4  branched or unbranched alkyl which may be substituted by one or more halogen atoms;  
 R 1  is selected from the group consisting of C 3-10 alkyl branched or unbranched, cyclopropyl and cyclohexyl which may optionally be partially or fully halogenated and which may optionally be substituted with one to three C 1-3  alkyl groups;  
 R 3  is selected from the group consisting of C 1-4 alkyl branched or unbranched, cyclopropyl, phenyl, pyridinyl each being optionally substituted as described in  claim 1 , alkoxycarbonylalkyl, C 1-6 alkyl branched or unbranched, cyclopropyl and cyclopentyl optionally substituted as described in  claim 1 .  
 
 
     
     
         5 . The metabolite compound according to  claim 4  where in the formula (I) L is C 1-5  saturated carbon chain wherein one or more methylene groups are optionally independently replaced by O, N or S; 
 wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C 1-4  branched or unbranched alkyl which may be substituted by one or more halogen atoms; and X═O.  
 
     
     
         6 . The metabolite compound according to  claim 5  where in the formula (I) L is propoxy, ethoxy or methoxy each being optionally substituted with 0-2 oxo groups and one or more C 1-4  branched or unbranched alkyl which may be substituted by one or more halogen atoms.  
     
     
         7 . The metabolite compound according to  claim 6  where in the formula (I) L is ethoxy optionally substituted with 0-2 oxo groups and one or more C 1-4  branched or unbranched alkyl which may be substituted by one or more halogen atoms.  
     
     
         8 . The metabolite compound according to  claim 5  where in the formula (I) L is methyl or propyl each being optionally substituted with 0-2 oxo groups and one or more C 1-4  branched or unbranched alkyl which may be substituted by one or more halogen atoms.  
     
     
         9 . The metabolite compound according to  claim 5  where in the formula (I) L is C 3-5  acetylene optionally substituted with 0-2 oxo groups and one or more C 1-4  branched or unbranched alkyl which may be substituted by one or more halogen atoms.  
     
     
         10 . The metabolite compound according to  claim 5  where in the formula (I) L is methylamino optionally substituted with 0-2 oxo groups and one or more C 1-4  branched or unbranched alkyl which may be substituted by one or more halogen atoms.  
     
     
         11 . A compound selected from the group consisting of: 
 1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea;    1-[5-tert-butyl-2-(3 -hydroxy-4-methyl-phenyl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea;    1-[5-tert-butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3 -yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea;    1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-{4-[2-(3-oxo-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;    1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-{4-[2-(4-hydroxy-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;    1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea;    1-[5-tert-butyl)-2-(1-hydroxy-6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea;    1-[5-tert-butyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]- 3-{4-[2-(4-hydroxy-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;    1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)-naphthalen-1-yl]-urea;    1-[5-tert-butyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-hydroxy-2-pyridin-4-yl-ethoxy)-naphthalen-1-yl]-urea;    1-[5-tert-butyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-{4-[2-(1-hydroxy-pyridin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;    1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]- 3-{4-[2-(1 -oxo-thiomorpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;    1-[5-tert-butyl-2-(4-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]- 3-{4-[2-(1-oxo-thiomorpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;    1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]- 3-{4-[2-(1,3 dioxo-thiomorpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea;    1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea and    1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-{4-[2-(4-hydroxy-morpholin-4-yl)-ethoxy]-naphthalen-1-yl}-urea.    
     
     
         12 . A method of treating a cytokine mediated disease or condition which comprises administering to a patient in need of such treatment a therapeutically effective amount of a metabolite compound according to  claim 1 .  
     
     
         13 . The method according to  claim 12  wherein the cytokine mediated disease or condition is selected from the groups consisting of rheumatoid arthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus erythematosus and insulin-dependent diabetes mellitus, toxic shock syndrome, osteoarthritis, diabetes, inflammatory bowel diseases, acute and chronic pain, contact dermatitis, atherosclerosis, glomerulonephritis, reperfusion injury, bone resorption diseases, asthma, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, dermatoses with acute inflammatory components, acute purulent meningitis, necrotizing entrerocolitis and syndromes associated with hemodialysis, septic shock, leukopherisis and granulocyte transfusion  
     
     
         14 . The method according to  claim 13  wherein the cytokine mediated disease or condition is selected from the groups consisting of as rheumatoid arthritis, Crohn's disease and psoriasis.  
     
     
         15 . A pharmnaceutical composition comprising a metabolite compound according to  claim 1  or the pharmaceutically acceptable derivatives thereof.