Methods and compositions for treatment of diabetes and dyslipidemia
The invention is directed to novel compounds of Formula I: as well as its stereoisomers and/or pharmaceutically acceptable salts, for the treatment of diabetes and diabetes associated dyslipidemia.
1. A composition comprising at least one compound according to Formula I:
its stereoisomers and/or pharmaceutically acceptable salts, wherein:
R 1 is selected from a group consisting of hydroxy, alkoxy, amine, alkyl, haloalkyl, NHSO 2 R, or NHCOR wherein R is selected from alkyl or cycloalkyl, NHR′ wherein R′ is alkyl or cycloalkyl optionally substituted by hydroxy or alkoxy;
n 1 and n 2 are independently selected from 0, 1, and 2;
at least one of R 3 and R 4 and/or R 5 and R 6 form a cyclic ring of 3-8 carbon atoms optionally containing alkyl groups, hetero atoms, or functional groups such as O, N, SO 2 ;
R 3 and R 4 or R 5 and R 6 , when they do not form a cyclic ring, are independently selected from hydrogen, alkyl, branched alkyl, and cycloalkyl;
L 1 is a linear aliphatic chain optionally containing from 4 to 16 carbon atoms, optionally substituted one or more times by alkyl, branched alkyl, cycloalkyl, or aryl;
R 2 is independently selected from hydrogen, alkoxy, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, cyano, or COR 7 , wherein R 7 is selected from hydroxy, alkyl, alkoxy, or amine, NHR′, NHSO 2 R, or NHCOR;
Y 1 is oxygen or hydrogen;
Y 2 is optional, and wherein when Y 2 is present, Y 1 and Y 2 are hydrogen and when Y 2 is not present, Y 1 forms a carbonyl group.
2. A composition according to claim 1 , wherein the compound is according to Formula II:
its stereoisomers and/or pharmaceutically acceptable, wherein:
R 1 and R 7 are independently selected from a group consisting of hydroxy, alkoxy, alkyl, amine, NHR′ wherein R′ is alkyl or cycloalkyl optionally substituted by hydroxy or alkoxy, NHSO 2 R or NHCOR, wherein R is selected from alkyl or cycloalkyl;
n 1 and n 2 are independently selected from 0, 1, and 2;
at least one of R 3 and R 4 and/or R 5 and R 6 form a cyclic ring of 3-8 carbon atoms optionally containing alkyl groups, hetero atoms, or functional groups such as O, N, SO 2 ;
R 3 and R 4 or R 5 and R 6 , when they do not form a cyclic ring, are independently selected from hydrogen, alkyl, branched alkyl, and cycloalkyl;
L 1 is independently a linear aliphatic chain optionally containing from 6 to 16 carbon-atoms and L 1 may optionally be substituted one or more times by alkyl, branched alkyl, cycloalkyl, or aryl.
3. A composition according to claim 1 , wherein the compound is according to Formula III:
its stereoisomers and/or pharmaceutically acceptable salts for the treatment of diabetes and diabetes-associated dyslipidemia, wherein:
R 1 is selected from a group consisting of hydroxy, alkoxy, amine, alkyl, haloalkyl, NHR′ wherein R′ is alkyl or cycloalkyl optionally substituted by hydroxy or alkoxy, NHSO 2 R or NHCOR, wherein R is selected from alkyl or cycloalkyl;
n 1 and n 2 are independently selected from 0, 1, and 2;
at least one of R 3 and R 4 and/or R 5 and R 6 form a cyclic ring of 3-8 carbon atoms optionally containing alkyl groups, hetero atoms, or functional groups such as O, N, SO 2 ;
R 3 and R 4 or R 5 and R 6 , when they do not form a cyclic ring, are independently selected from hydrogen, alkyl, branched alkyl, and cycloalkyl; and
L 1 is a linear aliphatic chain optionally containing from 4 to 16 carbon-atoms and L 1 may optionally be substituted one or more times by alkyl, branched alkyl, cycloalkyl, or aryl. R 2 is independently selected from hydrogen, alkoxy, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, cyano or COR 7 ; wherein R 7 is selected from a group consisting of hydroxy, alkyl, alkoxy, amine, NHR′, or NHSO 2 R.
4. The composition according to claim 1 , wherein the compound is selected from one or more of:
their stereoisomers, pharmaceutically acceptable salts, tautomers, and mixtures thereof.
5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound according to claim 1 .
6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound according to claim 2 .
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound according to claim 3 .
8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound according to claim 4 .
9. A method for the treatment of insulin resistance, diabetes, and/or cardiovascular disease in a subject, the method comprising administering to the subject at least one compound according to Formula I:
its stereoisomers and/or pharmaceutically acceptable salts, wherein:
R 1 is selected from a group consisting of hydroxy, alkoxy, amine, alkyl, haloalkyl, NHSO 2 R, or NHCOR wherein R is selected from alkyl or cycloalkyl, NHR′ wherein R′ is alkyl or cycloalkyl optionally substituted by hydroxy or alkoxy;
n 1 and n 2 are independently selected from 0, 1, and 2;
at least one of R 3 and R 4 and/or R 5 and R 6 form a cyclic ring of 3-8 carbon atoms optionally containing alkyl groups, hetero atoms, or functional groups such as O, N, SO 2 ;
R 3 and R 4 or R 5 and R 6 , when they do not form a cyclic ring, are independently selected from hydrogen, alkyl, branched alkyl, and cycloalkyl;
L 1 is a linear aliphatic chain optionally containing from 4 to 16 carbon atoms, optionally substituted one or more times by alkyl, branched alkyl, cycloalkyl, or aryl;
R 2 is independently selected from hydrogen, alkoxy, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, cyano, or COR 7 , wherein R 7 is selected from hydroxy, alkyl, alkoxy, or amine, NHR′, NHSO 2 R, or NHCOR;
Y 1 is oxygen or hydrogen;
Y 2 is optional, and wherein when Y 2 is present, Y 1 and Y 2 are hydrogen and when Y 2 is not present, Y 1 is a carbonyl group.
10. The method according to claim 9 , wherein the method comprises administering to the subject a compound according to Formula II:
its stereoisomers and/or pharmaceutically acceptable, wherein:
R 1 and R 7 are independently selected from a group consisting of hydroxy, alkoxy, alkyl, amine, NHR′ wherein R′ is alkyl or cycloalkyl optionally substituted by hydroxy or alkoxy, NHSO 2 R or NHCOR, wherein R is selected from alkyl or cycloalkyl;
n 1 and n 2 are independently selected from 0, 1, and 2;
at least one of R 3 and R 4 and/or R 5 and R 6 form a cyclic ring of 3-8 carbon atoms optionally containing alkyl groups, hetero atoms, or functional groups such as O, N, SO 2 ;
R 3 and R 4 or R 5 and R 6 , when they do not form a cyclic ring, are independently selected from hydrogen, alkyl, branched alkyl, and cycloalkyl;
L 1 is independently a linear aliphatic chain optionally containing from 6 to 16 carbon-atoms and L 1 may optionally be substituted one or more times by alkyl, branched alkyl, cycloalkyl, or aryl.
11. The method according to claim 9 , wherein the method comprises administering to the subject a compound according to Formula III:
its stereoisomers and/or pharmaceutically acceptable salts for the treatment of diabetes and diabetes-associated dyslipidemia, wherein:
R 1 is selected from a group consisting of hydroxy, alkoxy, amine, alkyl, haloalkyl, NHR′ wherein R′ is alkyl or cycloalkyl optionally substituted by hydroxy or alkoxy, NHSO 2 R or NHCOR, wherein R is selected from alkyl or cycloalkyl;
n 1 and n 2 are independently selected from 0, 1, and 2;
at least one of R 3 and R 4 and/or R 5 and R 6 form a cyclic ring of 3-8 carbon atoms optionally containing alkyl groups, hetero atoms, or functional groups such as O, N, SO 2 ;
R 3 and R 4 or R 5 and R 6 , when they do not form a cyclic ring, are independently selected from hydrogen, alkyl, branched alkyl, and cycloalkyl; and
L 1 is a linear aliphatic chain optionally containing from 4 to 16 carbon-atoms and L 1 may optionally be substituted one or more times by alkyl, branched alkyl, cycloalkyl, or aryl. R 2 is independently selected from hydrogen, alkoxy, hydroxy, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, cyano or COR 7 ; wherein R 7 is selected from a group consisting of hydroxy, alkyl, alkoxy, amine, NHR′, or NHSO 2 R.
12. The method according to claim 9 , wherein the method comprises administering to the subject a compound selected from one or more of:
their stereoisomers, pharmaceutically acceptable salts, tautomers, and mixtures thereof.