Aryl 5-thio-β-d-glucopyranoside derivatives and therapeutic agents for diabetes containing the same

1. A 5-thio-β-D-glucopyranoside compound of the following formula or a pharmaceutically acceptable salt thereof or a hydrate thereof:

wherein

Y represents —O— or —NH—,

R 1 , R 2 , R 3 and R 4 , which may be the same or different, each represent a hydrogen atom, a C 2-10 acyl group, a C 7-10 aralkyl group, a C 2-6 alkoxycarbonyl group, a C 1-6 alkoxy-C 2-10 acyl group or a C 1-6 alkoxy-C 2-6 alkoxycarbonyl group,

Ar represents an aryl group substituted with —X-A 1 , in which the aryl group may further be substituted with the same or different 1 to 4 substituents selected from:

a halogen atom;

a hydroxyl group;

a C 1-6 alkyl group which may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a hydroxyl group;

a group represented by the formula:

—(CH 2 ) m -Q

wherein m represents an integer of 0 to 4 and Q represents a formyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a sulfonic acid group, a C 1-6 alkoxy group which may be substituted with 1 to 4 halogen atoms, a C 1-6 alkoxy-C 1-6 alkoxy group, a C 2-10 acyloxy group, a C 2-10 acyl group, a C 2-6 alkoxycarbonyl group, a C 1-6 alkylthio group, a C 1-6 alkylsulfinyl group, a C 1-6 alkylsulfonyl group, —NHC(═O)H, a C 2-10 acylamino group, a C 1-6 alkylsulfonylamino group, a C 1-6 alkylamino group, an N,N-di(C 1-6 alkyl)amino group, a carbamoyl group, an N—(C 1-6 alkyl)aminocarbonyl group, or an N,N-di(C 1-6 alkyl)aminocarbonyl group; or

a C 3-7 cycloalkyl group, a C 3-7 cycloalkyloxy group, an aryl group, a C 7-10 aralkyl group, an aryloxy group, a C 7-10 aralkyloxy group, a C 7-10 aralkylamino group, a heteroaryl group, or a 4- to 6-membered heterocycloalkyl group, provided that each of these groups may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C 1-6 alkyl group and a C 1-6 alkoxy group,

X represents —(CH 2 )n-, —CO(CH 2 )n-, —CH(OH)(CH 2 )n-, —O—(CH 2 )n-, —CONH(CH 2 )n-, —NHCO(CH 2 )n-, wherein n represents an integer of 0 to 3, —COCH═CH—, —S— or —NH—, and

A 1 represents an aryl group, a heteroaryl group or a 4- to 6-membered heterocycloalkyl group, each of which may be substituted with the same or different 1 to 4 substituents selected from:

a halogen atom;

a hydroxyl group;

a C 1-6 alkyl group which may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a hydroxyl group;

a group represented by the formula:

—(CH 2 ) m ′-Q′

wherein m′ represents an integer of 0 to 4 and Q′ represents a formyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a sulfonic acid group, a C 1-6 alkoxy group which may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a hydroxyl group, a C 1-6 alkoxy-C 1-6 alkoxy group, a C 2-10 acyloxy group, a C 2-10 acyl group, a C 2-6 alkoxycarbonyl group, a C 1-6 alkylthio group, a C 1-6 alkylsulfinyl group, a C 1-6 alkylsulfonyl group, —NHC(═O)H, a C 2-10 acylamino group, a C 1-6 alkylsulfonylamino group, a C 1-6 alkylamino group, an N,N-di(C 1-6 alkyl)amino group, a carbamoyl group, an N—(C 1-6 alkyl)aminocarbonyl group, or an N,N-di(C 1-6 alkyl)aminocarbonyl group; or

a C 3-7 cycloalkyl group, a C 3-7 cycloalkyloxy group, an aryl group, a C 7-10 aralkyl group, an aryloxy group, a C 7-10 aralkyloxy group, a C 7-10 aralkylamino group, a heteroaryl group, or a 4- to 6-membered heterocycloalkyl group, provided that each of these groups may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C 1-6 alkyl group and a C 1-6 alkoxy group.

2. A 5-thio-β-D-glucopyranoside compound of the following formula or a pharmaceutically acceptable salt thereof or a hydrate thereof:

wherein

Y represents —O— or —NH—,

R 1 , R 2 , R 3 and R 4 , which may be the same or different, each represent a hydrogen atom, a C 2-10 acyl group, a C 7-10 aralkyl group, a C 2-6 alkoxycarbonyl group, a C 1-6 alkoxy-C 2-10 acyl group or a C 1-6 alkoxy-C 2-6 alkoxycarbonyl group, and

at least one of R 5 , R 6 , R 7 , R 8 and R 9 represents —X-A 1 and the other, which may be the same or different, each represent:

a hydrogen atom;

a halogen atom;

a hydroxyl group;

a C 1-6 alkyl group which may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a hydroxyl group;

a group represented by the formula:

—(CH 2 ) m -Q

wherein m represents an integer of 0 to 4 and Q represents a formyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a sulfonic acid group, a C 1-6 alkoxy group which may be substituted with 1 to 4 halogen atoms, a C 1-6 alkoxy-C 1-6 alkoxy group, a C 2-10 acyloxy group, a C 2-10 acyl group, a C 2-6 alkoxycarbonyl group, a C 1-6 alkylthio group, a C 1-6 alkylsulfinyl group, a C 1-6 alkylsulfonyl group, —NHC(═O)H, a C 2-10 acylamino group, a C 1-6 alkylsulfonylamino group, a C 1-6 alkylamino group, an N,N-di(C 1-6 alkyl)amino group, a carbamoyl group, an N—(C 1-6 alkyl)aminocarbonyl group, or an N,N-di(C 1-6 alkyl)aminocarbonyl group; or

a C 3-7 cycloalkyl group, a C 3-7 cycloalkyloxy group, an aryl group, a C 7-10 aralkyl group, an aryloxy group, a C 7-10 aralkyloxy group, a C 7-10 aralkylamino group, a heteroaryl group, or a 4- to 6-membered heterocycloalkyl group, provided that each of these groups may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C 1-6 alkyl group and a C 1-6 alkoxy group,

X represents —(CH 2 )n-, —CO(CH 2 )n-, —CH(OH)(CH 2 )n-, —O—(CH 2 )n-, —CONH(CH 2 )n-, —NHCO(CH 2 )n-, wherein n represents an integer of 0 to 3, —COCH═CH—, —S— or —NH—, and

A 1 represents an aryl group, a heteroaryl group or a 4- to 6-membered heterocycloalkyl group, each of which may be substituted with the same or different 1 to 4 substituents selected from:

a halogen atom;

a hydroxyl group;

a C 1-6 alkyl group which may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a hydroxyl group;

a group represented by the formula:

—(CH 2 ) m ′-Q′

wherein m′ represents an integer of 0 to 4 and Q′ represents a formyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a sulfonic acid group, a C 1-6 alkoxy group which may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a hydroxyl group, a C 1-6 alkoxy-C 1-6 alkoxy group, a C 2-10 acyloxy group, a C 2-10 acyl group, a C 2-6 alkoxycarbonyl group, a C 1-6 alkylthio group, a C 1-6 alkylsulfinyl group, a C 1-6 alkylsulfonyl group, —NHC(═O)H, a C 2-10 acylamino group, a C 1-6 alkylsulfonylamino group, a C 1-6 alkylamino group, an N,N-di(C 1-6 alkyl)amino group, a carbamoyl group, an N—(C 1-6 alkyl)aminocarbonyl group, or an N,N-di(C 1-6 alkyl)aminocarbonyl group; or

a C 3-7 cycloalkyl group, a C 3-7 cycloalkyloxy group, an aryl group, a C 7-10 aralkyl group, an aryloxy group, a C 7-10 aralkyloxy group, a C 7-10 aralkylamino group, a heteroaryl group, or a 4- to 6-membered heterocycloalkyl group, provided that each of these groups may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C 1-6 alkyl group and a C 1-6 alkoxy group.

3. The 5-thio-β-D-glucopyranoside compound according to claim 2 , wherein Y is —O—, or a pharmaceutically acceptable salt thereof or a hydrate thereof.

4. The 5-thio-β-D-glucopyranoside compound according to claim 2 , wherein R 5 is —X-A 1 , or a pharmaceutically acceptable salt thereof or a hydrate thereof.

5. The 5-thio-β-D-glucopyranoside compound according to claim 4 , wherein X is —(CH 2 )n-, wherein n represents an integer of 0 to 3, or a pharmaceutically acceptable salt thereof or a hydrate thereof.

6. The 5-thio-β-D-glucopyranoside compound according to claim 4 , wherein X is —CO(CH 2 )n-, wherein n represents an integer of 0 to 3, or a pharmaceutically acceptable salt thereof or a hydrate thereof.

7. A 5-thio-β-D-glucopyranoside compound of the following formula or a pharmaceutically acceptable salt thereof or a hydrate thereof:

wherein

X represents —(CH 2 )n-, —CO(CH 2 )n-, —CH(OH)(CH 2 )n-, —O—(CH 2 )n-, —CONH(CH 2 )n-, —NHCO(CH 2 )n-, wherein n represents an integer of 0 to 3, —COCH═CH—, —S— or —NH—,

R 1 , R 2 , R 3 and R 4 , which may be the same or different, each represent a hydrogen atom, a C 2-10 acyl group, a C 7-10 aralkyl group, a C 2-6 alkoxycarbonyl group, a C 1-6 alkoxy-C 2-10 acyl group or a C 1-6 alkoxy-C 2-6 alkoxycarbonyl group,

R 6 , R 7 , R 8 and R 9 , which may be the same or different, each represent:

a hydrogen atom;

a halogen atom;

a hydroxyl group;

a C 1-6 alkyl group which may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a hydroxyl group;

a group represented by the formula:

—(CH 2 ) m -Q

wherein m represents an integer of 0 to 4 and Q represents a formyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a sulfonic acid group, a C 1-6 alkoxy group which may be substituted with 1 to 4 halogen atoms, a C 1-6 alkoxy-C 1-6 alkoxy group, a C 2-10 acyloxy group, a C 2-10 acyl group, a C 2-6 alkoxycarbonyl group, a C 1-6 alkylthio group, a C 1-6 alkylsulfinyl group, a C 1-6 alkylsulfonyl group, —NHC(═O)H, a C 2-10 acylamino group, a C 1-6 alkylsulfonylamino group, a C 1-6 alkylamino group, an N,N-di(C 1-6 alkyl)amino group, a carbamoyl group, an N—(C 1-6 alkyl)aminocarbonyl group, or an N,N-di(C 1-6 alkyl)aminocarbonyl group; or

a C 3-7 cycloalkyl group, a C 3-7 cycloalkyloxy group, an aryl group, a C 7-10 aralkyl group, an aryloxy group, a C 7-10 aralkyloxy group, a C 7-10 aralkylamino group, a heteroaryl group, or a 4- to 6-membered heterocycloalkyl group, provided that each of these groups may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C 1-6 alkyl group and a C 1-6 alkoxy group, and

R 10 , R 11 , R 12 , R 13 and R 14 , which may be the same or different, each represent:

a hydrogen atom;

a halogen atom;

a hydroxyl group;

a C 1-6 alkyl group which may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a hydroxyl group;

a group represented by the formula:

—(CH 2 ) m ′-Q′

wherein m′ represents an integer of 0 to 4 and Q′ represents a formyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a sulfonic acid group, a C 1-6 alkoxy group which may be substituted with 1 to 4 halogen atoms, a C 1-6 alkoxy-C 1-6 alkoxy group, a C 2-10 acyloxy group, a C 2-10 acyl group, a C 2-6 alkoxycarbonyl group, a C 1-6 alkylthio group, a C 1-6 alkylsulfinyl group, a C 1-6 alkylsulfonyl group, —NHC(═O)H, a C 2-10 acylamino group, a C 1-6 alkylsulfonylamino group, a C 1-6 alkylamino group, an N,N-di(C 1-6 alkyl)amino group, a carbamoyl group, an N—(C 1-6 alkyl)aminocarbonyl group, or an N,N-di(C 1-6 alkyl)aminocarbonyl group; or

a C 3-7 cycloalkyl group, a C 3-7 cycloalkyloxy group, an aryl group, a C 7-10 aralkyl group, an aryloxy group, a C 7-10 aralkyloxy group, a C 7-10 aralkylamino group, a heteroaryl group, or a 4- to 6-membered heterocycloalkyl group, provided that each of these groups may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C 1-6 alkyl group and a C 1-6 alkoxy group.

8. The 5-thio-β-D-glucopyranoside compound according to claim 7 , wherein X is —CH 2 —, or a pharmaceutically acceptable salt thereof or a hydrate thereof.

9. The 5-thio-β-D-glucopyranoside compound according to claim 7 , wherein X is —O— or —NH—, or a pharmaceutically acceptable salt thereof or a hydrate thereof.

10. A 5-thio-β-D-glucopyranoside compound of the following formula or a pharmaceutically acceptable salt thereof:

wherein R 6A to R 9A , which may be the same or different, each represent a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy-C 1-6 alkoxy group, a carboxyl group, a C 2-6 alkoxycarbonyl group, a hydroxyl group or a hydroxy-C 1-4 alkyl group, R C represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a hydroxy-C 1-4 alkyl group, a halogen-substituted C 1-6 alkyl group or a C 1-6 alkylthio group, R 4A represents a hydrogen atom, a C 2-6 alkoxycarbonyl group or a C 2-6 alkanoyl group, and R 1A to R 3A , which may be the same or different, each represent a hydrogen atom, a C 2-8 alkanoyl group or a benzoyl group.

11. A 5-thio-β-D-glucopyranoside compound of the following formula or a pharmaceutically acceptable salt thereof:

wherein R D represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a hydroxy-C l-4 alkyl group, and R E represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a hydroxy-C 1-4 alkyl group.

12. A 5-thio-β-D-glucopyranoside compound of the following formula or a pharmaceutically acceptable salt thereof or a hydrate thereof:

wherein R 1 , R 2 , R 3 and R 4 , which may be the same or different, each represent a hydrogen atom, a C 2-10 acyl group, a C 7-10 aralkyl group, a C 2-6 alkoxycarbonyl group, a C 1-6 alkoxy-C 2-10 acyl group or a C 1-6 alkoxy-C 2-6 alkoxycarbonyl group, R 6B represents a hydrogen atom, a halogen atom, a hydroxyl group, a C 2-10 acyloxy group, or a C 1-6 alkyl or C 1-6 alkoxy group which may be substituted with 1 to 4 halogen atoms, and R 8B represents a hydrogen atom, a halogen atom or a C 1-6 alkyl group which may be substituted with 1 to 4 halogen atoms.

13. A pharmaceutical preparation, which comprises the 5-thio-β-D-glucopyranoside compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

14. A method of treating a condition treatable by inhibiting sodium-dependent glucose transporter 2 activity said method comprising administering to a subject in need of treatment a pharmaceutically effective amount of the 5-thio-β-D-glucopyranoside compound according to claim 1 , a pharmaceutically acceptable salt thereof or a hydrate thereof.

15. The method according to claim 14 , wherein the condition is diabetes, diabetes-related diseases or diabetic complications.

16. A pharmaceutical preparation, which comprises the 5-thio-β-D-glucopyranoside compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a hydrate thereof, in combination with at least one drug selected from the group consisting of an insulin sensitizer selected from the group consisting of a PPARγ agonist; a PPARα/γ agonist; a PPARδ agonist; and a PPARα/γ/δ agonist, a glycosidase inhibitor, a biguanide, an insulin secretagogue, an insulin formulation and a dipeptidyl peptidase IV inhibitor.

17. A pharmaceutical preparation, which comprises the 5-thio-β-D-glucopyranoside compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a hydrate thereof, in combination with at least one drug selected from the group consisting of a hydroxymethylglutaryl coenzyme A reductase inhibitor, a fibrate, a squalene synthase inhibitor, an acyl-coenzyme A:cholesterol acyltransferase inhibitor, a low-density lipoprotein receptor promoter, a microsomal triglyceride transfer protein inhibitor and an anorectic.

18. A 5-thio-β-D-glucopyranoside compound of the following formula or a pharmaceutically acceptable salt thereof or a hydrate thereof:

wherein

R 21 , R 22 , R 23 and R 24 , which may be the same or different, each represent a hydrogen atom or a C 2-10 acyl group,

R 25 represents an amino group, a C 2-6 alkanoyl group, a carboxyl group, a formyl group, a C 2-6 alkoxycarbonyl group or a hydroxyl group, and

R 26 and R 27 , which may be the same or different, each represent a hydrogen atom, a halogen atom, a hydroxyl group, a C 1-6 alkyl group which may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a hydroxyl group, or a C 1-6 alkoxy group which may be substituted with 1 to 4 halogen atoms.