Genipin derivatives and uses thereof

1. A method of treating a disorder selected from deficient first-phase insulin secretion, non-insulin dependent diabetes mellitus, or a combination of deficient first-phase insulin secretion and non-insulin dependent diabetes mellitus in a mammal, comprising:

i) administering to the mammal a compound represented by the following structural formula:

or pharmaceutically acceptable salts thereof, wherein:

— — — — is a single or double bond;

X 1 is ═CR 18 —, X 2 is ═CR 12 —, and X 3 is CR 13 R 14 ; X 2 is ═CR 18 —, X 3 is ═CR 12 —, and X 1 is CR 13 R 14 ; or X 1 is CR 6 R 7 , X 2 is CR 8 R 9 and X 3 is CR 10 R 11 ;

X 4 is —O— or —NR′—;

R′ is H or a C1-C5 alkyl;

R 1 is —H, —OH, ═O, —OSi(R 19 ) 3 , a hexose or pentose; or R 1 , taken together with a substituent of X 3 selected from R 10 , R 11 , R 12 , R 13 , R 14 , and R 18 , together with C7a, the carbon to which R 1 is attached, and the carbon represented by X 3 , form a cyclic ether;

R 2 is —OR, or —NR 4 R 5 ; or when X 1 is CR 13 R 14 , R 2 and R 13 , together with C4, C4a, the carbon to which R 13 is attached and the carbonyl group to which R 2 is attached, form a lactone ring;

R is H or a C1-C5 alkyl;

R 3 is —H, —OH, or —OR, or, optionally when — — — — is a single bond, ═O;

R 4 and R 5 are each, independently, —H or a C1-C5 alkyl; or R 4 and R 5 together with the nitrogen to which they are attached form a heterocyclic ring, wherein the C1-C5 alkyl or the heterocyclic ring are optionally substituted with one or more of hydroxy, a halo, a C1-C5 alkyl, phenyl, or cyano;

R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 13 , R 14 and R 99 are independently —H, —OH, —F, —Cl, —Br, —I, —NO 2 , —NR 2 , —C(O)NR 2 , a C1-C5 alkyl, a hydroxyalkyl, —CH 2 OC(O)NR 15 R 16 , or —CH 2 OC(O)R 17 ; or R 13 and R 14 together are ═O; or R 8 and R 10 together with two adjacent carbons to which they are attached, form an epoxy ring; or R 6 and R 8 together with two adjacent carbons to which they are attached, form an epoxy ring;

R 12 and R 18 are each, independently, —H, a C1-C5 alkyl, hydroxyalkyl, —CH 2 OC(O)NR 15 R 16 , —CH 2 OC(O)R 17 , or —CH 2 OH;

R 15 and R 16 are each, independently, —H or a C1-C5 alkyl;

R 17 is a C1-C5 alkyl; and

R 19 for each occurrence is, independently, a C1-C5 alkyl or an aryl, provided that

when X 4 is —O—, R 2 is —OCH 3 , and R 1 is ═O, —OH, —OC(O)CH 3 , glucosyl, O-tetraacetylglucosyl, O-tetramethylglucosyl, or t-butyldimethylsiloxy, and X 3 is ═CR 12 or CR 10 R 11 , then none of R 10 , R 11 , or R 12 is —CH 2 OH, —CH 2 OC(O)CH 3 , or —CH 3 ;

when X 4 is —O—, R 2 is —OCH 3 , and R 1 is —H, ═O, —OH or t-butyldimethylsiloxy, and X 3 is CR 10 R 11 , then none of R 10 and R 11 is —CH 2 OH, and R 10 and R 11 are not both —H; and

the compound is not

ii) administering to the mammal a compound represented a structural formula selected from:

or pharmaceutically acceptable salts thereof, wherein:

ring A is optionally substituted with one or more of —OH, a halo, nitro, cyano, or carboxy;

X 4 is —O— or —NR—;

R is H or a C1-C5 alkyl;

R 1 is —OH, ═O, —OSi(R 19 ) 3 , a hexose or pentose;

R 20 is —OR, or —NR 4 R 5 ; and

R 4 and R 5 are each, independently, —H or a C1-C5 alkyl; or R 4 and R 5 together with the nitrogen to which they are attached form a heterocyclic ring, wherein the C1-C5 alkyl or the heterocyclic ring are optionally substituted with one or more of hydroxy, a halo, a C1-C5 alkyl, phenyl, or cyano.

2. The method of claim 1 , wherein the compound is represented by the following structural formula:

wherein:

X 1 is ═CR 18 —, X 2 is ═CR 12 —, and X 3 is CR 13 R 14 ; X 2 is ═CR 18 —, X 3 is ═CR 12 —, and X 1 is CR 13 R 14 ; or X 1 is CR 6 R 7 , X 2 is CR 8 R 9 and X 3 is CR 10 R 11 ;

X 4 is —O— or —NR—;

R is H or a C1-C5 alkyl;

R 1 is —OH, ═O, —OSi(R 19 ) 3 , a hexose or pentose;

R 2 is —OR, or —NR 4 R 5 ; or when X 1 is CR 13 R 14 , R 2 and R 13 , together with C4, C4a, C5, the carbon to which R 13 is attached and the carbonyl group to which R 2 is attached, form a five membered lactone ring;

R 4 and R 5 are each, independently, —H or a C1-C5 alkyl; or R 4 and R 5 together with the nitrogen to which they are attached form a heterocyclic ring, wherein the C1-C5 alkyl or the heterocyclic ring are optionally substituted with one or more of hydroxy, a halo, a C1-C5 alkyl, phenyl, or cyano;

R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 13 and R 14 are independently —H, —OH, a C1-C5 alkyl, a hydroxyalkyl, —CH 2 OC(O)NR 15 R 16 , —CH 2 OC(O)R 17 , or —CH 2 OH; or R 13 and R 14 together are ═O; or R 8 and R 10 together with two adjacent carbons to which they are attached, form an epoxy ring;

R 12 and R 18 are each, independently, —H, a C1-C5 alkyl, hydroxyalkyl, —CH 2 OC(O)NR 15 R 16 , —CH 2 OC(O)R 17 , or —CH 2 OH;

R 15 and R 16 are each, independently, —H or a C1-C5 alkyl;

R 17 is a C1-C5 alkyl; and

R 19 for each occurrence is, independently, a C1-C5 alkyl or an aryl.

3. The method of claim 1 , wherein the compound is represented by the following structural formula:

4. The method of claim 1 , wherein the compound is represented by the following structural formula:

wherein:

X 5 is ═CR 18 —, X 2 is ═CR 12 —, and X 3 is CR 13 R 14 ; X 2 is ═CR 18 —, X 3 is ═CR 12 —, and X 5 is CR 21 R 22 ; or X 1 is CR 6 R 7 , X 2 is CR 8 R 9 and X 3 is CR 10 R 11 ; and

R 21 and R 22 are independently —H, —OH, a C1-C5 alkyl, a hydroxyalkyl, —CH 2 OC(O)NR 15 R 16 , —CH 2 OC(O)R 17 , or —CH 2 OH; or R 21 and R 22 together are ═O.

5. The method of claim 1 , wherein the compound is represented by the following structural formula:

wherein:

R 2 is —OR, or —NR 4 R 5 ; and

R 23 , R 24 , R 25 , R 26 are independently —H, —OH, a C1-C5 alkyl, a hydroxyalkyl, —CH 2 OC(O)NR 15 R 16 , —CH 2 OC(O)R 17 , or —CH 2 OH, provided that when R 1 is glucosyl and R 25 is —H, R 26 is not methyl.

6. The method of claim 2 , wherein the non-insulin dependent diabetes mellitus is the early stages of non-insulin dependent diabetes mellitus.

7. The method of claim 1 , wherein the compound is represented by a structural formula selected from:

8. The method of claim 1 , wherein the compound is represented by a structural formula selected from

9. The method of claim 1 , wherein the compound is represented by the following structural formula:

10. The method of claim 1 , wherein the compound is represented by the following structural formula:

11. The method of claim 1 , wherein the compound is represented by the following structural formula:

12. A method of treating a disorder selected from deficient first-phase insulin secretion, non-insulin dependent diabetes mellitus, or a combination of deficient first-phase insulin secretion and non-insulin dependent diabetes mellitus in a mammal, comprising administering to the mammal a compound represented by:

or pharmaceutically acceptable salts thereof, wherein:

— — — — is a single or double bond;

X 1 is CR 6 R 7 , X 2 is CR 8 R 9 and X 3 is CR 10 R 11 ;

X 4 is —O—;

R 1 taken together with a substituent of X 3 selected from R 10 , R 11 , together with C7a, the carbon to which R 1 is attached, and the carbon represented by X 3 , form a cyclic ether; and R 2 is —OR or —NR 4 R 5 ;

R is independently H or a C1-C5 alkyl;

R 3 is —H, —OH, or —OR, or, optionally when — — — — is a single bond, ═O;

R 4 and R 5 are each, independently, —H or a C1-C5 alkyl; or R 4 and R 5 together with the nitrogen to which they are attached form a heterocyclic ring, wherein the C1-C5 alkyl or the heterocyclic ring are optionally substituted with one or more of hydroxy, a halo, a C1-C5 alkyl, phenyl, or cyano;

R 6 , R 7 , and R 10 are independently selected from the group consisting of —H, —OH, —F, —Cl, —Br, —I, —NO 2 , —NR 2 , —C(O)NR 2 , a C1-C5 alkyl, a hydroxyalkyl, —CH 2 OC(O)NR 15 R 16 , and —CH 2 OC(O)R 17 ; or R 8 and R 10 together with two adjacent carbons to which they are attached, form an epoxy ring; or R 6 and R 8 together with two adjacent carbons to which they are attached, form an epoxy ring;

R 8 , R 9 and R 11 are independently selected from the group consisting of —H, —OH, —F, —Cl, —Br, —I, a C1-C5 alkyl and a hydroxyalkyl;

R 15 and R 16 are each, independently, —H or a C1-C5 alkyl; and

R 17 is a C1-C5 alkyl, provided that the compound is not

13. A method of treating a disorder selected from deficient first-phase insulin secretion, non-insulin dependent diabetes mellitus, or a combination of deficient first-phase insulin secretion and non-insulin dependent diabetes mellitus in a mammal, comprising administering to the mammal a compound represented by a structural formula selected from:

14. The method of claim 13 , wherein the compound is represented by a compound represented by a structural formula selected from: