INDENE DERIVATIVES AS PHARMACEUTICAL AGENTS
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.
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) 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 , 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.