Isoxazoles and oxadiazoles as anti-inflammatory inhibitors of IL-8

Abstract

The invention relates to isoxazole and oxadiazole compounds of Formulae I and II, pharmaceutical compositions containing the compounds, and methods for their production and use. These compounds are effective in inhibiting the action of IL-8 and are thus useful as anti-inflammatory agents for a variety of diseases.

We claim:  
     
         1 . A compound of Formula (I) or (II),  
       
         
           
           
               
               
           
         
       
       wherein 
 R is one or two independent members selected from hydrogen, halogen, C 1-6  alkyl, C 1-6  alkoxy, alkoxycarbonyl, aryl, aryloxy, hydroxy, nitro, sulfonylamino, trifluoromethyl, cyano, methylenedioxy, and ethylenedioxy;  
 X is nitrogen or CR 1  wherein R 1  is selected from hydrogen, alkyl, aryl, halogen, CH 2 OH, carbomethoxy, and carboethoxy;  
 Y is CR or nitrogen;  
 L is selected from oxygen, sulfur, —N(R 2 )-, —C(O)NR 2 -, -R 2 NC(O)—, —C(O)O—, and —OC(O)—, wherein R 2  is hydrogen or C 1-6  alkyl; and  
 Z is NR 3 R 4  or saturated heterocyclyl having one or two nitrogen as heteroatom, wherein R 3  and R 4  are independently selected from hydrogen, C 1-6  alkyl, and phenyl and the heterocyclyl group may be substituted with one or more independent substituents selected from halogen, oxo, OH, alkyl, amino and alkoxy;  
 Alk is a branched or unbranched alkyl group;  
 n is an integer from 0-6 representing the number of carbons in the alkylene group, with the proviso that when L is oxygen, sulfur, or nitrogen, n is an integer from 2-6;  
 or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound of  claim 1  wherein Z is saturated heterocyclyl having one or two nitrogens as heteroatom.  
     
     
         3 . The compound of  claim 1  wherein Z is NR 3 R 4 , R 3  and R 4  being alkyl or substituted alkyl.  
     
     
         4 . The compound of  claim 1  wherein R is one or two independent members selected from hydrogen, halogen, C 1-6  alkyl, C 1-6  alkoxy, alkoxycarbonyl, phenyl, phenyloxy, hydroxy, nitro, sulfonylamino, trifluoromethyl, cyano, methylenedioxy, and ethylenedioxy.  
     
     
         5 . The compound of  claim 1  wherein X is CH.  
     
     
         6 . The compound of  claim 5  wherein Z is  
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1  which is represented by Formula (II),  
       
         
           
           
               
               
           
         
       
       wherein Z, L, X, Y, R, and n are as claimed in  claim 1 .  
     
     
         8 . The compound of  claim 7  wherein X is CH and Z is  
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 8  wherein R is halogen.  
     
     
         10 . The compound of  claim 9  wherein R is 4-Cl.  
     
     
         11 . A compound of  claim 1  or a pharmaceutically acceptable salt thereof, which is piperazine, 1-[3-[4-[5-(4-chlorophenyl)-3-isoxazolyl]phenoxy]propyl]-4-methyl-.  
     
     
         12 . A compound of  claim 1  or a pharmaceutically acceptable salt thereof, which is piperazine, 1-[3-[4-[3-(4-chlorophenyl)-5-isoxazolyl]phenoxy]propyl]-4-methyl-.  
     
     
         13 . A compound of  claim 1  or a pharmaceutically acceptable salt thereof, which is piperazine, 1-[3-[4-[3-[4-(1,1-dimethylethyl)phenyl]-5-isoxazolyl]phenoxy]propyl]4-methyl-.  
     
     
         14 . A compound of  claim 1  or a pharmaceutically acceptable salt thereof, which is piperazine, 1-[3-[4-[3-[4-chloro-3-(trifluoromethyl)phenyl]-5-isoxazolyl]phenoxy]propyl]4-methyl-.  
     
     
         15 . A compound of  claim 1  or a pharmaceutically acceptable salt thereof, which is piperazine, 1-[3-[4-[3-(4-fluorophenyl)-5-isoxazolyl]phenoxy]propyl]4-methyl-.  
     
     
         16 . A compound of  claim 1  of a pharmaceutically acceptable salt thereof, which is piperazine, 1-[3-[4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]phenoxy]propyl]4-methyl-.  
     
     
         17 . A compound of  claim 1  or a pharmaceutically acceptable salt thereof, which is piperazine, 1-[3-[4-[3-(4-chlorophenyl)-1,2,4oxadiazol-5-yl]phenoxy]propyl]-.  
     
     
         18 . A compound of  claim 1  or a pharmaceutically acceptable salt thereof, which is 1-propanamine, 3-[4-[5-(4-chlorophenyl)-3-isoxazolyl]phenoxy]-N,N-dimethyl-.  
     
     
         19 . A compound of  claim 1  or a pharmaceutically acceptable salt thereof, which is 1,3-propanediamine, N 1 -[5-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-pyridinyl]-N 3 ,N 3 -dimethyl-.  
     
     
         20 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         21 . A method of treating a subject having a condition caused by or contributed to by action of IL-8, which comprises administering to said subject a therapeutically effective amount of the compound of Formula (I) or (II) as defined in  claim 1 .  
     
     
         22 . A method of preventing a subject from suffering from a condition caused by or contributed to by action of IL-8, which comprises administering to the subject a prophylactically effective amount of the compound of Formula (I) or (II) as defined in  claim 1 .  
     
     
         23 . The method of  claim 21  or  22  wherein said condition is inflammation.  
     
     
         24 . The method of  claim 21  or  22  wherein said condition is selected from adult respiratory distress syndrome (ARDS), rheumatoid arthritis (RA), myocardial perfusion injury, ulcerative colitis, psoriasis, chronic obstructive lung disease (COPD), cystic fibrosis (CF), and cancers.  
     
     
         25 . A process for preparing a compound of Formula (Ia),  
       
         
           
           
               
               
           
         
       
       wherein R, Z, and Y are as claimed in  claim 1 , which process comprises: 
 (a) converting a compound of Formula 1 to an oxime in the presence of NH 2 OH/HCl and pyridine in CH 2 Cl 2 ;  
                     
 (b) converting the oxime to the corresponding compound of Formula 2;  
                     
 (c) reacting the compound of Formula 2 with methoxyphenyl acetylene to form a compound of Formula 4;  
                     
 and  
 (d) converting the compound of Formula 4 to the corresponding compound of Formula 5 
                     
 and  
 (e) converting the compound of Formula 5 to the corresponding compound of Formula Ia.