Quinazolinone derivatives and their use as cb agonists

Abstract

Novel quinazolinone derivatives of formula (I) wherein R 1 -R 9 are as defined in the description, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them.

1 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , R 3 , R 4  and R 5  independently are hydrogen; halogen; C 1 -C 4 alkyl; C 2 -C 4 alkenyl; C 3 -C 7 cycloalkyl; C 3 -C 7 cycloalkylC 1 -C 4 alkyl; C 1 -C 4 alkoxyC 1 -C 4 alkyl; C 1 -C 4 alkylcarboxy; hydroxyC 1 -C 4 alkoxyC 1 -C 4 alkyl; ydroxyl; hydroxyC 1 -C 4 alkyl; phenylC 1 -C 4 alkyl which is optionally substituted by ydroxyl, C 1 -C 4 alkoxy, carboxy, C 1 -C 4 alkoxycarbonylC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, cyano; SO 2 R 10 ; cyano; —SO 2 N(R 10 )R 11 ; —S—R 10  or —SOR 10 ; or R 1  and R 2  or R 2  and R 3  denote, together with the carbon atoms to which they are attached, an aromatic or aliphatic carbocyclic group having 5 to 10 ring atoms or an aromatic or aliphatic heterocyclic group having 5 to 10 ring atoms of which one, two or three are hetero atoms selected from nitrogen, oxygen and sulfur;  
 R 6  is —CH 2 —O—C(O)—N(R 12 )R 13 , —CH 2 —X—C(O)—R 14 , C 1 -C 4 alkyl or hydroxyC 1 -C 4 alkyl;  
 R 7 , R 8  and R 9  independently are C 1 -C 4 alkyl;  
 R 10  and R 11  independently are hydrogen, C 1 -C 4 alkyl; C 2 -C 4 alkenyl; C 3 -C 7 cycloalkyl; C 3 -C 7 cycloalkylC 1 -C 4 alkyl; C 1 -C 4 alkoxyC 1 -C 4 alkyl; C 1 -C 4 alkylcarboxy; hydroxyC 1 -C 4 alkoxyC 1 -C 4 alkyl; ydroxyl; hydroxyC 1 -C 4 alkyl; phenylC 1 -C 4 alkyl which is optionally substituted by ydroxyl, C 1 -C 4 alkoxy, carboxy, C 1 -C 4 alkoxycarbonylC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, cyano; or R 10  and R 11  form together an aliphatic heterocyclic group having 5 to 10 ring atoms of which one, two or three are hetero atoms selected from nitrogen, oxygen and sulfur;  
 R 12  and R 13  independently are hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylC 1 -C 4 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkoxyC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, dihydroxyC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonylC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, cyano, —SO 2 R 10 , —SO 2 N(R 10 )R 11 , —S—R 10 , —SOR 10 , —C 1 -C 4 -alkylene-SO 2 R 10 , —C 1 -C 4 -alkylene-SOR 10 , —C 1 -C 4 -alkylene-NH—SO 2 R 10 , —C 1 -C 4 -alkylene-CON(R 10 )R 11 , —CON(R 10 )R 11 , —C 1 -C 4 -alkylene-C(O)OR 10 ,fluoroalkyl, or R 6a  and R 6b  form a substituted or unsubstituted aliphatic heterocyclic group having 5 to 10 ring atoms;  
 R 14  is NH, C 1 -C 4 alkyl-NH—, C 2 -C 4 alkenyl-NH—, C 3 -C 7 cycloalkyl-NH—, C 7 -C 7 cycloalkylC 1 -C 4 alkyl-NH—, C 1 -C 4 alkoxyC 1 -C 4 alkyl-NH—, hydroxyC 1 -C 4 alkoxyC 1 -C 4 alkyl-NH—, hydroxyC 1 -C 4 alkyl-NH—, dihydroxyC 1 -C 4 alkyl-NH—, C 1 -C 4 alkoxycarbonylC 1 -C 4 alkyl-NH—, C 1 -C 4 alkoxycarbonyl-NH—, —NH—C 1 -C 4 -alkylene-CN, —NH—SO 2 R 10 , —NH—SO 2 (R 10 )R 11 , —NH—C 1 -C 4 -alkylene-S—R 10 , —NH—SOR 10 , —NH—C 1 -C 4 -alkylene-SO 2 R 10 , —NH—C 1 -C 4 -alkylene-SOR 10 , —NH—C 1 -C 4 -alkylene-NH—SO 2 R 10 , —NH—C 1 -C 4 -alkylene-CON(R 10 )R 11 —NH—CON(R 10 )R 11 , —NH—C 1 -C 4 -alkylene-C(O)OR 10 , —NH-fluoroalkyl, or a substituted or unsubstituted aliphatic heterocyclic group having 5 to 10 ring atoms;  
 X is O or CH 2 ;  
 with the proviso that when R 1  is either halogen, methyl, ethyl, methoxy, trifluromethyl or hydrogen and R 2 , R 3 , R 4  are either hydrogen, methyl or methoxy and R 5  is hydrogen or methyl, R 12  is neither hydrogen, C 2 -C 4 alkyl, C 2 -C 4 alkenyl, hydroxyC 1 -C 4 alkyl, —C 1 -C 4 -alkylene-SO 2 R 10 , nor-C 1 -C 4 -alkylene-SOR 10 ;  
 in free base or acid addition salt form.  
 
     
     
         2 . A compound of formula I according to  claim 1   
       wherein 
 R 1  R 2 , R 3 , R 4  and R 5  independently are hydrogen; halogen; C 1 -C 4 alkyl; C 2 -C 4 alkenyl; C 3 -C 7 cycloalkyl; C 3 -C 7 cycloalkylC 1 -C 4 alkyl; C 1 -C 4 alkoxyC 1 -C 4 alkyl; C 1 -C 4 alkylcarboxy; hydroxyC 1 -C 4 alkoxyC 1 -C 4 alkyl; ydroxyl; hydroxyC 1 -C 4 alkyl; phenylC 1 -C 4 alkyl which is optionally substituted by ydroxyl, C 1 -C 4 alkoxy, carboxy, C 1 -C 4 alkoxycarbonylC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, cyano; —SO 2 R 10 ; cyano; —SO 2 N(R 10 )R 11 ; —S—R 10  or —SOR 10 ; or R 1  and R 2  or R 2  and R 3  denote, together with the carbon atoms to which they are attached, an aromatic or aliphatic carbocyclic group having 5 to 10 ring atoms or an aromatic or aliphatic heterocyclic group having to 10 ring atoms of which one, two or three are hetero atoms selected from nitrogen, oxygen and sulfur;  
 R 5  is C 1 -C 4 alkyl or hydroxyC 1 -C 4 alkyl;  
 R 7 , R 8  and R 9  independently are C 1 -C 4 alkyl;  
 R 10  and R 11  independently are hydrogen, C 1 -C 4 alkyl; C 2 -C 4 alkenyl; C 3 -C 7 cycloalkyl; C 3 -C 7 cycloalkylC 1 -C 4 alkyl; C 1 -C 4 alkoxyC 1 -C 4 alkyl; C 1 -C 4 alkylcarboxy; hydroxyC 1 -C 4 alkoxyC 1 -C 4 alkyl; ydroxyl; hydroxyC 1 -C 4 alkyl; phenylC 1 -C 4 alkyl which is optionally substituted by ydroxyl, C 1 -C 4 alkoxy, carboxy, C 1 -C 4 alkoxycarbonylC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, cyano; or R 10  and R 11  form together an aliphatic heterocyclic group having 5 to 10 ring atoms of which one, two or three are hetero atoms selected from nitrogen, oxygen and sulfur;  
 R 12  and R 13  independently are hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylC 1 -C 4 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkoxyC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, dihydroxyC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonylC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, cyano, —SO 2 R 10 , —SO 2 N(R 10 )R 11 , —S—R 10 , —SOR 10 , —C 1 -C 4 -alkylene-SO 2 R 10 , —C 1 -C 4 -alkylene-SOR 10 , —C 1 -C 4 -alkylene-NH—SO 2 R 10 , —C 1 -C 4 -alkylene-CON(R 10 )R 11 , —CON(R 10 )R 11 , —C 1 -C 4 -alkylene-C(O)OR 10 ,fluoroalkyl, or R 6a  and R 6b  form a substituted or unsubstituted aliphatic heterocyclic group having 5 to 10 ring atoms;  
 R 14  is NH, C 1 -C 4 alkyl-NH—, C 2 -C 4 alkenyl-NH—, C 3 -C 7 cycloalkyl-NH—, C 3 -C 7 cycloalkylC 1 -C 4 alkyl-NH—, C 1 -C 4 alkoxyC 1 -C 4 alkyl-NH—, hydroxyC 1 -C 4 alkoxyC 1 -C 4 alkyl-NH—, hydroxyC 1 -C 4 alkyl-NH—, dihydroxyC 1 -C 4 alkyl-NH—, C 1 -C 4 alkoxycarbonylC 1 -C 4 alkyl-NH—, C 1 -C 4 alkoxycarbonyl-NH—, —NH—C 1 -C 4 -alkylene-CN, —NH—SO 2 R 10 , —NH—SO 2 N(R 10 )R 11 , NH—C 1 -C 4 -alkylene-S—R 10 , —NH—SOR 10 , —NH—C 1 -C 4 -alkylene-SO 2 R 10 , —NH—C 1 -C 4 -alkylene-SOR 10 , —NH—C 1 -C 4 -alkylene-NH—SO 2 R 10 , —NH—C 1 -C 4 -alkylene-CON(R 10 )R 11 , —NH—CON(R 10 )R 11 , —NH—C 1 -C 4 -alkylene-C(O)OR 10 , —NH-fluoroalkyl, or a substituted or unsubstituted aliphatic heterocyclic group having 5 to 10 ring atoms;  
 X is O or CH 2 ;  
 with the proviso that when R 1  is either halogen, methyl, ethyl, methoxy, trifluromethyl or hydrogen and R 2 , R 3 , R 4  are either hydrogen, methyl or methoxy and R 5  is hydrogen or methyl, R 12  is neither hydrogen, C 2 -C 4 alkyl, C 2 -C 4 alkenyl, hydroxyC 1 -C 4 alkyl, —C 1 -C 4 -alkylene-SO 2 R 10 , nor —C 1 -C 4 -alkylene-SOR 10 ;  
 in free base or acid addition salt form.  
 
     
     
         3 . A compound of formula I according to  claim 1 , wherein R 1  represents —SO 2 NHCH 3  and the remaining radicals and symbols have the meanings as defined under  claim 1 .  
     
     
         4 . A compound of  claim 1  selected from the group of 2-ethylcarbamoyloxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl) 4 -oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester and 2-(2-hydroxy-ethylcarbamoyloxymethyl)-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester, in free base or acid addition salt form.  
     
     
         5 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is hydrogen, —CH 2 C(O)OCH 3 , —CH 2 CH 2 C(O)OCH 3 , —C(O)N(CH 3 ) 2 , —C(O)OCH 3 , cyano, —SO 2 -1-pyrrolidinyl, —SO 2 CH 3 , —SO 2 NHCH 3 , —SO 2 N(CH 3 ) 2 , —SO 2 N(CH 3 )CH 2 COOH, —S—CH 3 , —SOCH 3  or R 1  forms with R 2  a —NH—CH 2 —CH 2 —CH 2 — or —CH═CH—CH═CH— ring;  
 R 2 , R 3 , R 4  and R 5  independently are hydrogen; halogen; C 1 -C 4 alkyl; C 2 -C 4 alkenyl; C 3 -C 7 cycloalkyl; C 3 -C 7 cycloalkylC 1 -C 4 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl; C 1 -C 4 alkylcarboxy; hydroxyC 1 -C 4 alkoxyC 1 -C 4 alkyl; ydroxyl; hydroxyC 1 -C 4 alkyl; phenylC 1 -C 4 alkyl which is optionally substituted by ydroxyl, C 1 -C 4 alkoxy, carboxy, C 1 -C 4 alkoxycarbonylC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, cyano; —SO 2 R 10 ; cyano; —SO 2 N(R 10 )R 11 , —S—R 10  or —SOR 10 , or R 1  and R 2  or R 2  and R 3  denote, together with the carbon atoms to which they are attached, an aromatic or aliphatic carbocyclic group having 5 to 10 ring atoms or an aromatic or aliphatic heterocyclic group having 5 to 10 ring atoms of which one, two or three are hetero atoms selected from nitrogen, oxygen and sulfur;  
 R 6  is —CH 2 —O—C(0>N(R 12 )R 13 , —CH 2 —X—C(O)—R 14 , C 1 -C 4 alkyl or hydroxyC 1 -C 4 alkyl;  
 R 7 , R 8  and R 9  independently are C 1 -C 4 alkyl;  
 R 10  and R 11  independently are hydrogen, C 1 -C 4 alkyl; C 2 -C 4 alkenyl; C 3 -C 7 cycloalkyl; C 3 -C 7 cycloalkylC 1 -C 4 alkyl; C 1 -C 4 alkoxyC 1 -C 4 alkyl; C 1 -C 4 alkylcarboxy; hydroxyC 1 -C 4 alkoxyC 1 -C 4 alkyl; ydroxyl; hydroxyC 1 -C 4 alkyl; phenylC 1 -C 4 alkyl which is optionally substituted by ydroxyl, C 1 -C 4 alkoxy, carboxy, C 1 -C 4 alkoxycarbonylC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, cyano; or R 10  and R 11  form together an aliphatic heterocyclic group having 5 to 10 ring atoms of which one, two or three are hetero atoms selected from nitrogen, oxygen and sulfur;  
 R 12  and R 13  independently are hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylC 1 -C 4 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkoxyC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, dihydroxyC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonylC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, cyano, —SO 2 R 10 , —SO 2 N(R 10 )R 11 , —S—R 10 , —SOR 10 , —C 1 -C 4 -alkylene-SO 2 R 10 , —C 1 -C 4 -alkylene-SOR 11 , C 1 -C 4 -alkylene-NH—SO 2 R 10 , —C 1 -C 4 -alkylene-CON(R 10 )R 11 , —CON(R 10 )R 11 , —C 1 -C 4 -alkylene-C(O)OR 10 ,fluoroalkyl, or R 6a  and R 6b  form a substituted or unsubstituted aliphatic heterocyclic group having 5 to 10 ring atoms;  
 R 14  is NH, C 1 -C 4 alkyl-NH—, C 2 -C 4 alkenyl-NH—, C 3 -C 7 cycloalkyl-NH—, C 3 -C 7 cycloalkylC 1 -C 4 alkyl-NH—, C 1 -C 4 alkoxyC 1 -C 4 alkyl-NH—, hydroxyC 1 -C 4 alkoxyC 1 -C 4 alkyl-NH—, hydroxyC 1 -C 4 alkyl-NH—, dihydroxyC 1 -C 4 alkyl-NH—, C 1 -C 4 alkoxycarbonylC 1 -C 4 alkyl-NH—, C 1 -C 4 alkoxycarbonyl-NH—, —NH—C 1 -C 4 -alkylene-CN, —NH—SO 2 R 10 , —NH—SO 2 N(R 10 )R 11 , —NH—C 1 -C 4 -alkylene-S—R 11 , —NH—SOR 10 , —NH—C 1 -C 4 -alkylene-SO 2 R 10 , —NH—C 1 -C 4 -alkylene-SOR 11 , —NH—C 1 -C 4 -alkylene-NH—SO 2 R 10 , —NH—C 1 -C 4 -alkylene-CON(R 10 )R 11 , —NH—CON(R 10 )R 11 , —NH—C 1 -C 4 -alkylene-C(O)OR 10 , —NH-fluoroalkyl, or a substituted or unsubstituted aliphatic heterocyclic group; having 5 to 10 ring atoms;  
 X is O or CH 2 ;  
 with the proviso that when R 1  is either halogen, methyl, ethyl, methoxy, trifluromethyl or hydrogen and R 2 , R 3 , R 4  are either hydrogen, methyl or methoxy and R 5  is hydrogen or methyl, R 12  is neither hydrogen, C 2 -C 4 alkyl, C 2 -C 4 alkenyl, hydroxyC 1 -C 4 alkyl, —C 1 -C 4 -alkylene-SO 2 R 10 , nor —C—C 4 -alkylene-SOR 10 ;  
 in free base or acid addition salt form.  
 
     
     
         6 . (canceled).  
     
     
         7 . A process for the production of a compound of formula I or an acid addition salt thereof, comprising 
 (i) for the production of a compound of formula I wherein R 6  is —CH 2 —O—C(O)—N(R 12 )R 13  and R 13  is hydrogen, the step of reacting a compound of formula II                          wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8  and R 9  are as defined in  claim 1;     with a compound of formula III                          wherein R 12  is as defined in  claim 1;  or    (ii) alternatively to (i) for the production of a compound of formula I wherein R 6  is —CH 2 —O—C(O)—N(R 12 )R 13  and R 13  is hydrogen, the step of reacting a compound of formula IV                          wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8  and R 9  are as defined in  claim 1;     with a compound of formula V      H 2 N—R 12   (V)    wherein R 12  is as defined in  claim 1;  or    (iii) for the production of a compound of formula I wherein R 6 =—CH 2 —X—C(O)—R 14  and X=CH 2 , the step of reacting a compound of formula VI                          wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 9  are as defined in  claim 1;     with a compound of formula VII      H—R 14   (VII)    wherein R 14  is as defined in  claim 1;  or    (iv) for the production of a compound of formula I wherein R 6 =—CH 2 —X—C(O)—R 14  and X=O, reacting a compound of formula VIII                          wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 9  are as defined in  claim 1;     with a compound of formula VII      H—R 14   (VII)    wherein R 14  is as defined in  claim 1;  or    (v) for the production of a compound of formula I wherein R 5  is C 1 -C 4 alkyl or hydroxyC 1 -C 4 alkyl, the step of reacting a compound of formula IX                          wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 9  are as defined in  claim 1  and R 6  is C 1 -C 4 alkyl or hydroxyC 1 -C 4 alkyl, with a compound of formula X      Y—R 9   (X)    wherein R 9  is as defined in  claim 1  and Y is a leaving group; and    recovering the so obtained compound of formula I in free base or in acid addition salt form.    
     
     
         8 . (canceled)  
     
     
         9 . (canceled)  
     
     
         10 . A pharmaceutical composition comprising a compound of  claim 1  in free base or pharmaceutically acceptable acid salt form, in association with a pharmaceutical carries or diluent.  
     
     
         11 . (canceled)  
     
     
         12 . (canceled)  
     
     
         13 . (canceled)  
     
     
         14 . A method for treating or preventing of ocular disorders selected from the group consisting of glaucoma, normal tension glaucoma and neurodegenerative diseases conditions of the retina and the optic nerve in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form.  
     
     
         15 . A combination which comprises (a) a therapeutically effective amount of a compound of  claim 1  in free base or pharmaceutically acceptable acid salt form and (b) a second drug substance, said second drug substance being for example for use in the treatment and prevention of chronic pain, osteo and rheumatoid arthritis, teno-synovitis and gout, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.  
     
     
         16 . A method for treating or preventing a disease or condition in which cannabinoid receptor activation plays a role or is implicated, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form.  
     
     
         17 . A method of treating a mammal having a disease or condition in which cannabinoid receptor activation plays a role or is implicated comprising administering to the animal a combination which comprises (a) a therapeutically effective amount of a compound of  claim 1  in free base or pharmaceutically acceptable acid salt form and (b) a second drug substance, said second drug substance being for use in the treatment and prevention of chronic pain, osteo and rheumatoid arthritis, teno-synovitis and gout.  
     
     
         18 . A compound of  claim 5  in free base or pharmaceutically acceptable acid addition salt form, for use in the treatment or prevention of a disease or condition in which cannabinoid receptor activation plays a role or is implicated.  
     
     
         19 . A pharmaceutical composition comprising a compound of  claim 5  in free base or pharmaceutically acceptable acid salt form, in association with a pharmaceutical carries or diluent.  
     
     
         20 . A method of treatment comprising administering to a subject, in need thereof, a compound of  claim 5  in free base or pharmaceutically acceptable acid addition salt form, for the treatment or prevention of a disease or condition in which cannabinoid receptor activation plays a role or is implicated.  
     
     
         21 . A method of treatment comprising administering to a subject, in need thereof, a compound of  claim 5  in free base or pharmaceutically acceptable acid addition salt form, for the treatment or prevention of ocular disorders selected from the group consisting of glaucoma, normal tension glaucoma and neurodegenerative diseases conditions of the retina and the optic nerve.  
     
     
         22 . A combination which comprises (a) a therapeutically effective amount of a compound of  claim 5  in free base or pharmaceutically acceptable acid salt form and (b) a second drug substance, said second drug substance being for example for use in the treatment and prevention of chronic pain, osteo and rheumatoid arthritis, teno-synovitis and gout, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.  
     
     
         23 . A method for treating or preventing a disease or condition in which cannabinoid receptor activation plays a role or is implicated, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound of  claim 5  in free base or pharmaceutically acceptable acid addition salt form.  
     
     
         24 . A method of treating a mammal having a disease or condition in which cannabinoid receptor activation plays a role or is implicated comprising administering to the animal a combination which comprises (a) a therapeutically effective amount of a compound of  claim 5  in free base or pharmaceutically acceptable acid salt form and (b) a second drug substance, said second drug substance being for use in the treatment and prevention of chronic pain, osteo and rheumatoid arthritis, teno-synovitis and gout.