Methods of derivatives of probucol for the treatment of type II diabetes

1. A method for the treatment or prophylaxis of type II diabetes, a pre-diabetes condition or a diabetes related disorder in a host, comprising administering a compound of formula (B):

wherein

R a , R b , R c , and R d are independently hydrogen, straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl or substituted aralkyl; substituents on the R a , R b , R c and R d groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, and acyloxy;

Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, a carbohydrate group, —(CH 2 ) n —R e , —C(O)—R g , and —C(O)—(CH 2 ) a —R h , wherein when each of R a , R b , R c , and R d are t-butyl, Z cannot be hydrogen, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

R e is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, —CH(OH)R k , hydroxy, C(O)NH 2 , C(O)NHR, C(O)NR 2 , and epoxy;

R g is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R h is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, —CH(OH)R k , hydroxy, O-phosphate, C(O)NH 2 , C(O)NHR, C(O)NR 2 , C(O)-heteroaryl, C(O)-(glycine), C(O)-(arginine), C(O)-(glutamic acid), and C(O)-(lysine);

R k is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, —CH(OH)R, hydroxy, C(O)NH 2 , C(O)NHR, and C(O)NR 2 ;

R is alkyl, alkenyl, alkynyl, aryl, alkyl-C(O)OH, alkyl-C(O)O-alkyl, alkyl-C(O)O-aryl, heteroaryl, wherein any of these groups are optionally substituted, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; and substitutents on the groups defined above in Formula B are selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, halo, nitro, amino, alkylamino, dialkylamino, carboxy, aryl, heteroaryl, COOR, CONH 2 , CONHR, CONR 2 , haloalkyl, alkoxyalkyl, mono- or polyhydroxyalkyl, CH 2 —OR, CH 2 —OH, OCOR, O-phosphate, SO 2 —NH 2 , SO 2 —NHR, SO 2 —NR 2 , sulfonic acid and phosphonic acid, any of which can be further substituted

wherein the diabetes related disorder is not a diabetic vascular disease, diabetic nephropathy, or a diabetic retinopathy.

2. The method of claim 1 , wherein R a , R b , R c and R d are alkyl.

3. The method of claim 1 wherein Z is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a carbohydrate group, —(CH 2 ) n —R e , —C(O)—R g , and —C(O)—(CH 2 ) n —R h , and pharmaceutically acceptable salts thereof.

4. The method of claim 1 wherein Z is selected from the group consisting of alkyl, substituted alkyl, —C(O)—R g , and —C(O)—(CH 2 ) n —R h , and pharmaceutically acceptable salts thereof.

5. The method of claim 1 wherein the host has been diagnosed with diabetes.

6. The method of claim 1 wherein the host is at risk of or diagnosed with diabetes is at risk of or diagnosed with type 2 diabetes or a pre-diabetes condition.

7. The method of claim 1 wherein the method improves insulin sensitivity in a host.

8. The method of claim 1 , wherein the compound is a compound of Formula I:

wherein x is selected from 1, 2, 3 or 4;

or a pharmaceutically acceptable salt, ester, pharmaceutically acceptable derivative, or prodrug thereof.

9. The method of claim 8 wherein x is 2 or 3.

10. The method of claim 8 wherein the host has been diagnosed with diabetes.

11. The method of claim 8 wherein the host is at risk of or diagnosed with diabetes is at risk of or diagnosed with type 2 diabetes or a pre-diabetes condition.

12. The method of claim 8 wherein the method improves insulin sensitivity in a host.

13. The method of claim 1 , wherein the compound is a monosuccinic acid ester of probucol of the structure:

or a salt thereof.

14. The method of claim 1 , wherein the compound is a compound of Formula II:

wherein x is selected from 1, 2, 3 or 4;

or a pharmaceutically acceptable salt, ester, pharmaceutically acceptable derivative, or prodrug thereof.

15. The method of claim 14 wherein x is 1.

16. The method of claim 14 wherein the host has been diagnosed with diabetes.

17. The method of claim 14 wherein the host is at risk of or diagnosed with diabetes is at risk of or diagnosed with type 2 diabetes or a pre-diabetes condition.

18. The method of claim 14 wherein the method improves insulin sensitivity in a host.

19. A method of glycemic control in a host in need thereof is provided, including administering an effective amount of a compound of Formula (B):

wherein

R a , R b , R c , and R d are independently hydrogen, straight chained, branched, or cyclic alkyl which may be substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl or substituted aralkyl; substituents on the R a , R b , R c and R d groups are selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, haloalkyl, alkylamino, dialkylamino, acyl, and acyloxy;

Z is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, aralkyl, alkaryl, heteroaryl, heteroaralkyl, a carbohydrate group, —(CH 2 ) n —R e , —C(O)—R g , and —C(O)—(CH 2 ) n —R h , wherein when each of R a , R b , R c , and R d are t-butyl, Z cannot be hydrogen;

n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

R e is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, —CH(OH)R k , hydroxy, C(O)NH 2 , C(O)NHR, C(O)NR 2 , and epoxy;

R g is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R h is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, —CH(OH)R k , hydroxy, O-phosphate, C(O)NH 2 , C(O)NHR, C(O)NR 2 , C(O)-heteroaryl, C(O)-(glycine), C(O)-(arginine), C(O)-(glutamic acid), and C(O)-(lysine);

R k is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH 2 , NHR, NR 2 , mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH, COOR, —CH(OH)R, hydroxy, C(O)NH 2 , C(O)NHR, and C(O)NR 2 ;

R is alkyl, alkenyl, alkynyl, aryl, alkyl-C(O)OH, alkyl-C(O)O-alkyl, alkyl-C(O)O-aryl, heteroaryl, wherein any of these groups are optionally substituted, or when attached to a nitrogen atom, two adjacent R groups may combine to form a ring of 5 to 7 members; and substitutents on the groups defined above in Formula B are selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, halo, nitro, amino, alkylamino, dialkylamino, carboxy, aryl, heteroaryl, COOR, CONH 2 , CONHR, CONR 2 , haloalkyl, alkoxyalkyl, mono- or polyhydroxyalkyl, CH 2 —OR, CH 2 —OH, OCOR, O-phosphate, SO 2 —NH 2 , SO 2 —NHR, SO 2 —NR 2 , sulfonic acid and phosphonic acid, any of which can be further substituted.

20. The method of claim 19 , wherein R a , R b , R c and R d are alkyl.

21. The method of claim 19 wherein Z is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, a carbohydrate group, —(CH 2 ) n —R e , —C(O)—R g , and —C(O)—(CH 2 ) n —R h , and pharmaceutically acceptable salts thereof.

22. The method of claim 19 wherein Z is selected from the group consisting of alkyl, substituted alkyl, —C(O)—R g , and —C(O)—(CH 2 ) n —R h , and pharmaceutically acceptable salts thereof.

23. The method of claim 19 , wherein the compound is a compound of Formula I:

wherein x is selected from 1, 2, 3 or 4;

or a pharmaceutically acceptable salt, ester, pharmaceutically acceptable derivative, or prodrug thereof.

24. The method of claim 23 wherein x is 2 or 3.

25. The method of claim 19 , wherein the compound is a monosuccinic acid ester of probucol of the structure:

or a salt thereof.

26. The method of claim 19 , wherein the compound is a compound of Formula II:

wherein x is selected from 1, 2, 3 or 4;

or a pharmaceutically acceptable salt, ester, pharmaceutically acceptable derivative, or prodrug thereof.

27. The method of claim 26 wherein x is 1.