Intermediates for the preparation of lipoxin A
View Patent ↗This invention is directed to compounds useful as intermediates in the synthesis of lipoxin A 4 analogs of the following formulas (I) and (II): wherein R 1 , R 2 , R 3 , R 4 and R 5 are described herein. These analogs are useful in treating inflammatory and autoimmune disorders in humans. These analogs are also useful in treating pulmonary or respiratory tract inflammation in humans.
1. A compound of the following formula:
wherein,
R 7a is hydrogen, alkyl, aryl, or aralkyl;
R 10 is a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain, or cycloalkylene; and
each of R 14 and R 14a is independently hydrogen or alkyl;
as a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers.
2. The compound according to claim 1 wherein R 14 is methyl and R 14a is hydrogen.
3. The compound according to claim 2 wherein R 10 is methylene and R 7a is alkyl.
4. The compound according to claim 3 wherein R 7a is methyl or tert-butyl.
5. A compound of the following formula:
wherein,
R 7a is hydrogen, alkyl, aryl, or aralkyl;
R 10 is a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain, or cycloalkylene; and
each of R 14 and R 14a is independently hydrogen or alkyl;
as a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers.
6. The compound according to claim 5 wherein R 14 is methyl and R 14a is hydrogen.
7. The compound according to claim 6 wherein R 10 is methylene and R 7a is alkyl.
8. The compound according to claim 7 wherein R 7a is methyl or tert-butyl.
9. A compound of the following formula (1) or (2):
wherein,
XX is hydrogen or a suitable protecting group;
R 7a is hydrogen, alkyl, aryl, or aralkyl;
R 10 is a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain, or cycloalkylene; and
each of R 14 and R 14a is independently hydrogen or alkyl;
as a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers.
10. The compound according to claim 9 wherein R 14 is methyl and R 14a is hydrogen.
11. The compound according to claim 10 wherein R 10 is methylene and R 7a is alkyl.
12. The compound according to claim 11 wherein R 7a is methyl or tert-butyl.
13. A compound having the following formula:
wherein,
R 3 is halo, —OR 6 , —SR 6 , —S(O) t R 7 (where t is 1 or 2) or —N(R 7 )R 8 ;
R 5 is aryl (optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy);
each R 6 is independently hydrogen, alkyl, aryl, aralkyl, —C(O)R 7 , —C(S)R 7 , —C(O)OR 14 ,
—C(S)OR 14 ,
—C(O)N(R 7 )R 8 , or —C(S)N(R 7 )R 8 ;
each R 7 is independently hydrogen, alkyl, cycloalkyl, aryl, or aralkyl;
R 7a is hydrogen, alkyl, aryl, or aralkyl;
each R 8 is independently hydrogen, alkyl, aryl, aralkyl, —C(O)R 7 , —C(O)OR 14 , or cycloalkyl (optionally substituted with one more substituents selected from alkyl, —N(R 7 ) 2 , and —C(O)OR 7 );
R 10 is a straight or branched alkylene chain, a straight or branched alkenylene chain, a straight or branched alkynylene chain, or cycloalkylene; and
each of R 14 and R 14a is independently hydrogen or alkyl;
as a single stereoisomer, a mixture of stereoisomers, or a racemic mixture of stereoisomers.
14. The compound according to claim 13 wherein
R 3 is —OR 6 ;
R 5 is aryl (optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, and haloalkoxy);
R 6 is hydrogen, alkyl, aryl, or aralkyl;
R 7a is alkyl;
R 10 is a straight or branched alkylene chain;
R 14 is methyl; and
R 14a is hydrogen.
15. The compound according to claim 14 wherein
R 3 is —OH;
R 5 is optionally-substituted phenyl; and
R 10 is methylene.
16. The compound according to claim 15 wherein
R 5 is 4-fluorophenyl; and
R 7a is methyl or tert-butyl.
17. The compound according to claim 16 , which is
methyl 2-({(4S,5R)-5-[(1E,3E,7E)-(S)-10-(4-fluorophenoxy)-9-hydroxydeca-1,3,7-trien-5-yn-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl}methoxy)acetate, or
tert-butyl 2-({(4S,5R)-5-[(1E,3E,7E)-(S)-10-(4-fluorophenoxy)-9-hydroxydeca-1,3,7-trien-5-yn-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl}methoxy)acetate.