Indene derivatives as pharmaceutical agents

Abstract

Processes for making and using compounds of formula (I): wherein R 1 , R 2 , R 3 , R 4a , R 4b , R 5 and R 6 are defined herein, as well as other indene derivatives are disclosed herein. These compounds are disclosed as being useful in treating inflammatory conditions or diseases.

What is claimed is: 
     
         1 . A method of preparing a compound of formula (78): 
       
         
           
           
               
               
           
         
       
       wherein the method comprises treating a compound of formula (77): 
       
         
           
           
               
               
           
         
       
       under suitable conditions to yield the compound of formula (78). 
     
     
         2 . The method of  claim 1  wherein the suitable conditions comprise treating the compound of formula (77) with 80% acetic acid. 
     
     
         3 . The method of  claim 1  further comprising a preparation of the compound of formula (77), wherein the preparation comprises treating a compound of formula (76): 
       
         
           
           
               
               
           
         
       
       where each Ac is —C(O)CH 3 , under suitable conditions to yield the compound of formula (77). 
     
     
         4 . The method of  claim 3  wherein the suitable conditions comprise reacting the compound of formula (76) with lithium aluminum hydride in tetrahydrofuran. 
     
     
         5 . The method of  claim 3  further comprising a preparation of the compound of formula (76), wherein the preparation comprises treating a compound of formula (75): 
       
         
           
           
               
               
           
         
       
       where each Ac is —C(O)CH 3  and Ms is —S(O) 2 CH 3 , under suitable conditions to yield the compound of formula (76). 
     
     
         6 . The method of  claim 5  wherein the suitable conditions comprise reacting the compound of formula (75) with sodium azide in dimethylformamide. 
     
     
         7 . The method of  claim 5  further comprising a preparation of the compound of formula (75), wherein the preparation comprises treating a compound of formula (74): 
       
         
           
           
               
               
           
         
       
       where each Ac is —C(O)CH 3 , under suitable conditions to yield the compound of formula (75). 
     
     
         8 . The method of  claim 7  wherein the suitable conditions comprise treating the compound of formula (74) with mesyl chloride in the presence of a base. 
     
     
         9 . The method of  claim 7  further comprising a preparation of the compound of formula (74), wherein the preparation comprises treating a compound of formula (73): 
       
         
           
           
               
               
           
         
       
       where Ac is —C(O)CH 3 , under suitable conditions to yield the compound of formula (74). 
     
     
         10 . The method of  claim 9  wherein the suitable conditions comprise reacting the compound of formula (73) with acetic anhydride and 4-dimethylaminopyridine in pyridine. 
     
     
         11 . The method of  claim 9  further comprising a preparation of the compound of formula (73), wherein the preparation comprises treating a compound of formula (72): 
       
         
           
           
               
               
           
         
       
       where Ac is —C(O)CH 3 , under suitable conditions to yield the compound of formula (73). 
     
     
         12 . The method of  claim 11  wherein the suitable conditions comprise reducing the compound of formula (72) with sodium borohydride. 
     
     
         13 . The method of  claim 11  further comprising a preparation of the compound of formula (72), wherein the preparation comprises treating a compound of formula (71): 
       
         
           
           
               
               
           
         
       
       where Ac is —C(O)CH 3 , under suitable conditions to yield the compound of formula (72). 
     
     
         14 . The method of  claim 13  wherein the suitable conditions comprise reacting the compound of formula (71) with sodium periodate in tetrahydrofuran. 
     
     
         15 . The method of  claim 13  further comprising a preparation of the compound of formula (71), wherein the preparation comprises treating a compound of formula (70): 
       
         
           
           
               
               
           
         
       
       where Ac is —C(O)CH 3 , under suitable conditions to yield the compound of formula (71). 
     
     
         16 . The method of  claim 15  wherein the suitable conditions comprise treating the compound of formula (70) with 80% acetic acid. 
     
     
         17 . The method of  claim 15  further comprising a preparation of the compound of formula (70), wherein the preparation comprises treating a compound of formula (69): 
       
         
           
           
               
               
           
         
       
       under suitable conditions to yield the compound of formula (70). 
     
     
         18 . The method of  claim 17  wherein the suitable conditions comprise reacting the compound of formula (69) with acetic anhydride and 4-dimethylaminopyridine in pyridine. 
     
     
         19 . The method of  claim 1  further comprising treating the compound of formula (78) under suitable conditions to yield the compound of formula (79): 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 19  wherein the suitable conditions comprise treating the compound of formula (78) with hydrochloric acid in water and methanol. 
     
     
         21 . The method of  claim 3  further comprising treating the compound of formula (77) under suitable conditions to yield the compound of formula (80): 
       
         
           
           
               
               
           
         
       
     
     
         22 . The method of  claim 21  wherein the suitable conditions comprise treating the compound of formula (77) in acetonitrile with hydrochloric acid. 
     
     
         23 . A method of preparing a compound of formula (78): 
       
         
           
           
               
               
           
         
       
       wherein the method comprises:
 (a). treating a compound of formula (69): 
 
       
         
           
           
               
               
           
         
         
           under suitable conditions to yield a compound of formula (70): 
         
       
       
         
           
           
               
               
           
         
         
           where Ac is —C(O)CH 3 ; 
         
         (b). treating the compound of formula (70) under suitable conditions to yield a compound of formula (71): 
       
       
         
           
           
               
               
           
         
         
           where Ac is —C(O)CH 3 ; 
         
         (c). treating the compound of formula (71) under suitable conditions to yield a compound of formula (72): 
       
       
         
           
           
               
               
           
         
         
           where Ac is —C(O)CH 3 ; 
         
         (d). treating the compound of formula (72) under suitable conditions to yield a compound of formula (73): 
       
       
         
           
           
               
               
           
         
         
           where Ac is —C(O)CH 3 ; 
         
         (e). treating the compound of formula (73) under suitable conditions to yield a compound of formula (74): 
       
       
         
           
           
               
               
           
         
         
           where each Ac is —C(O)CH 3 ; 
         
         (f). treating the compound of formula (74) under suitable conditions to yield a compound of formula (75): 
       
       
         
           
           
               
               
           
         
         
           where each Ac is —C(O)CH 3  and Ms is —S(O) 2 CH 3 ; 
         
         (g). treating the compound of formula (75) under suitable conditions to yield a compound of formula (76): 
       
       
         
           
           
               
               
           
         
         
           where each Ac is —C(O)CH 3 ; 
         
         (h) treating the compound of formula (76) under suitable conditions to yield a compound of formula (77): 
       
       
         
           
           
               
               
           
         
       
       and
 (i). treating the compound of formula (77) under suitable conditions to yield the compound of formula (78). 
 
     
     
         24 . The method of  claim 23  further comprising treating the compound of formula (78) under suitable conditions to yield the compound of formula (79): 
       
         
           
           
               
               
           
         
       
     
     
         25 . A method of treating an inflammatory condition or disease in a mammal, which method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 the A, C or D ring is independently fully saturated, partially saturated or fully unsaturated; 
 C1, C4, C11, C12, C15 and C16 are each independently optionally substituted with one or two of the following, which are independently selected: hydrogen, alkyl, —R 8 —OR 7 , or —R 8 —N(R 7 ) 2 , provided that C4 is not substituted by two methyl groups; 
 C9 and C14 are each independently optionally substituted with hydrogen, alkyl, —R 8 —OR 7 , or —R 8 —N(R 7 ) 2 ; 
 R 1  is —OR 7 or —N(R 7 ) 2 ; 
 R 2  and R 3  are each independently selected from the group consisting of —R 8 —OR 7 , —R 8 —OC(O)R 9 , —R 10 —N(R 7 ) 2 , —R 10 —N(R 9 )C(O)R 9 , —R 10 —N(R 9 )S(O) t R 9  (where t is 1 or 2), —R 10 —N(R 9 )C(NR 9 )N(R 9 ) 2 , alkyl, alkenyl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl and optionally substituted heteroarylalkenyl; 
 R 4a  is hydrogen and R 4b  is alkenyl or alkynyl; 
 or R 4a  and R 4b  are each alkyl; 
 R 5  is alkyl or a direct bond to the carbon at C14, provided that when R 4a  is hydrogen and R 4b  is alkenyl or alkynyl, R 5  is alkyl and when R 4a  and R 4b  are both alkyl, R 5  is a direct bond to the carbon at C14; 
 R 6  is hydrogen, —R 8 —OR 7  or —R 8 —N(R 7 ) 2 ; 
 each R 7  is independently selected from the group consisting of hydrogen, —R 10 —OR 9 , —R 10 —N(R 9 ) 2 , alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; 
 each R 8  is independently selected from the group consisting of a direct bond, a straight or branched alkylene chain, and a straight or branched alkenylene chain; 
 each R 9  is independently selected from the group consisting of hydrogen, alkyl, aryl and aralkyl; and 
 each R 10  is independently selected from the group consisting of a straight or branched alkylene and a straight or branched alkenylene chain; 
 as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers; 
 or a pharmaceutically acceptable salt, solvate or prodrug thereof, in isolation or in a mixture.