Kynurenine 3-hydroxylase inhibitors for the treatment of diabetes

• US 7,727,977 B2
• Filed: 12/18/2003
• Issued: 06/01/2010
• Est. Priority Date: 01/07/2003
• Status: Expired due to Fees

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Mariais, Dominique, Autier, Valerie, Kargar, Catherine, Kergoat, Micheline, Arbellot De Vacqueur, Annick, Moinet, Gérard
• Primary Examiner(s): Marschel; Ardin
• Assistant Examiner(s): Hughes; Alicia R
• Application Number:
  US10/541,377
• Publication Number:
  US 20060142358A1
• Time in Patent Office: 2,357 Days
• Field of Search: 514/183
• US Class Current: 514/183
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/06 the aromatic ring being substituted by nitro groups
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/235 having an aromatic ring attached to a carboxyl group
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The present invention relates to the use of at least one compound with inhibitory activity on kynurenine 3-hydroxylase for the preparation of a medicament for the prevention and/or treatment of diabetes.

Claims

1. A method for treating diabetes or a complication thereof comprising administering to a patient in need thereof an effective amount of one of the following compounds

2-benzylthio-4-phenyl-4-oxobutanoic acid;

2-(4′

-methylphenylthio)-4phenyl-4-oxobutanoic acid;

2-(4′

-chlorophenylthio)-4phenyl-4-oxobutanoic acid;

2-(4′

-fluorophenylthio)-4phenyl-4-oxobutanoic acid;

2-(4′

-methoxyphenylthio)4phenyl-4-oxobutanoic acid;

2-phenylthio-4-phenyl-4-oxobutanoic acid;

2-carboxymethylthio-4-phenyl-4-oxobutanoic acid;

2-cyclohexylthio-4-phenyl-4-oxobutanoic acid;

2-(2′

-naphthylthio)-4-phenyl-4-oxobutanoic acid;

ethyl 2-phenylthio-4-phenyl-4-oxobutanoate;

ethyl 2-(4′

-fluorophenylithio)-4-phenyl-4-oxobutanoate;

ethyl 2-(4′

-chlorophenylthio)-4-phenyl-4-oxobutanoate;

ethyl 2-(4′

-methylphenylthio)-4-phenyl-4- oxobutanoate;

ethyl 2-(4′

-methoxyphenylthio)-4-phenyl-4- oxobutanoate;

ethyl 2-(2′

-naphthylthio)-4phenyl-4-oxobutanoate;

ethyl 2-cyclohexylthio-4-phenyl-4-oxobutanoate;

ethyl 2-benzylthio-4-phenyl-4-oxobutanoate;

2-phenylthio-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(4′

-fluorophenylthio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(4′

-chlorophenylthio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(4′

-methylphenylithio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(4′

-methoxyphenylthio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(2′

-naphthylthio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-cyclohexylthio-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-benzylthio-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-phenylthio-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

2-(4′

-fluorophenylthio)-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

2-(4′

-methylphenylthio)-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

2-(4′

-methoxyphenylithio)-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

2-(2′

-naphthylthio)4(4′

-chlorophenyl)-4-oxobutanoic acid;

or

2. A method according to claim 1, wherein the risk of hypoglycaemia is reduced.

3. A method according to claim 1, wherein non-insulin-dependent diabetes or a complication thereof is treated.

4. A method according to claim 1, wherein diabetes is treated.

5. A method according to claim 1, wherein a complication of diabetes is treated.

7. A method according to claim 1, comprising administering to a patient in need thereof an effective amount of one of the following compounds

2-benzylthio-4-phenyl-4-oxobutanoic acid;

2-(4′

-methylphenylthio)-4-phenyl-4-oxobutanoic acid;

2-(4′

-chlorophenylthio)-4-phenyl-4-oxobutanoic acid;

2-(4′

-fluorophenylthio)-4-phenyl-4-oxobutanoic acid;

2-(4′

-methoxyphenylthio)-4-phenyl-4-oxobutanoic acid;

2-phenylthio-4-phenyl-4-oxobutanoic acid;

2-carboxymethylthio-4-phenyl-4-oxobutanoic acid;

2-cyclohexylthio-4-phenyl-4-oxobutanoic acid;

2-(2′

-naphthylthio)-4-phenyl-4-oxobutanoic acid;

ethyl 2-phenylthio-4-phenyl-4-oxobutanoate;

ethyl 2-(4′

-fluorophenylthio)-4-phenyl-4- oxobutanoate;

ethyl 2-(4′

-chlorophenylthio)-4-phenyl4- oxobutanoate;

ethyl 2-(4′

-methylphenylthio)-4-phenyl-4- oxobutanoate;

ethyl 2-(4′

-methoxyphenylthio)-4-phenyl-4- oxobutanoate;

ethyl 2-(2′

-naphthylthio)-4phenyl-4-oxobutanoate;

ethyl 2-cyclohexylthio-4-phenyl-4-oxobutanoate;

ethyl 2-benzylthio-4-phenyl-4-oxobutanoate;

2-phenylthio-4(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(4′

-fluorophenylthio)-4-(4′

-methoxyphenyl)- 4-oxobutanoic acid;

2-(4′

-chlorophenylthio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(4′

-methylphenylthio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(4′

-methoxyphenylthio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(2′

-naphthylthio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-cyclohexylthio-4-(4′

-methoxyphenyl)-4- oxobutanoic acid;

2-benzylthio-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-phenylthio-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

2-(4′

-fluorophenylthio)-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

2-(4′

-methylphenylthio)-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

2-(4′

-methoxyphenylthio)-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

2-(2′

-naphthylthio)-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

or

6. A compound, which is

2-benzylthio-4-phenyl-4-oxobutanoic acid;

2-(4′

-methylphenylthio)-4phenyl-4-oxobutanoic acid;

2-(4′

-chlorophenylthio)-4-phenyl-4-oxobutanoic acid;

2-(4′

-fluorophenylthio)-4-phenyl-4-oxobutanoic acid;

2-(4′

-methoxyphenylthio)-4-phenyl-4-oxobutanoic acid;

2-phenylthio-4-phenyl-4-oxobutanoic acid;

2-carboxymethylthio-4-phenyl-4-oxobutanoic acid;

2-cyclohexylthio-4-phenyl-4-oxobutanoic acid;

2-(2′

-naphthylthio)-4-phenyl-4-oxobutanoic acid;

ethyl 2-phenylithio-4-phenyl-4-oxobutanoate;

ethyl 2-(4′

-fluorophenylthio)-4-phenyl-4- oxobutanoate;

ethyl 2-(4′

-chlorophenylthio)-4-phenyl-4- oxobutanoate;

ethyl 2-(4′

-methylphenylthio)-4-phenyl-4- oxobutanoate;

ethyl 2-(4′

-methoxyphenylthio)-4-phenyl-4- oxobutanoate;

ethyl 2-(2′

-naphthylthio)-4-phenyl-4-oxobutanoate;

ethyl 2-cyclohexylthio-4-phenyl-4-oxobutanoate;

ethyl 2-benzylthio-4-phenyl-4-oxobutanoate;

2-phenylthio-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(4′

-fluorophenylthio)-4-(4′

-methoxyphenyl)-4- oxobutanoic acid;

2-(4′

-chlorophenylthio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(4′

-methylphenylthio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(4′

-methoxyphenylthio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(2′

-naphthylthio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-cyclohexylthio-4-(4′

-methoxyphenyl)-4- oxobutanoic acid;

2-benzylthio-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-phenylthio-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

2-(4-fluorophenylthio)-4-(4′

-chlorophenyl)-4- oxobutanoic acid;

2-(4′

-methylphenylthio)-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

2-(4′

-methoxyphenylthio)-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

2-(2′

-naphthylthio)-4-(4′

-chlorophenyl)-4- oxobutanoic acid;

or

8. A method according to claim 6, wherein the risk of hypoglycaemia is reduced.

9. A method according to claim 6, wherein non-insulin-dependent diabetes or a complication thereof is treated.

10. A method according to claim 6, wherein diabetes is treated.

11. A method according to claim 6, wherein a complication of diabetes is treated.

12. A method according to claim 6, comprising administering to a patient in need thereof an effective amount of one of the following compounds

2-benzylthio-4phenyl-4-oxobutanoic acid;

2-(4′

-methylphenylthio)-4-phenyl-4-oxobutanoic acid;

2-(4′

-chlorophenylthio)-4-phenyl-4-oxobutanoic acid;

2-(4′

-fluorophenylthio)-4-phenyl-4-oxobutanoic acid;

2-(4′

-methoxyphenylthio)-4-phenyl-4-oxobutanoic acid;

2-phenylthio-4-phenyl-4-oxobutanoic acid;

2-(2′

-naphthylthio)-4-phenyl-4-oxobutanoic acid;

ethyl 2-phenylthio-4phenyl-4-oxobutanoate;

ethyl 2-(4′

-fluorophenylthio)-4-phenyl-4- oxobutanoate;

ethyl 2-(4′

-chlorophenylthio)-4-phenyl-4- oxobutanoate;

ethyl 2-(4′

-methylphenylthio)-4-phenyl-4- oxobutanoate;

ethyl 2-(4′

-methoxyphenylthio)-4-phenyl-4- oxobutanoate;

ethyl 2-(2′

-naphthylthio)4-phenyl-4-oxobutanoate;

ethyl 2-benzylthio-4-phenyl-4-oxobutanoate;

2-phenylthio-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(4′

-fluorophenylthio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(4′

-chlorophenylthio)-4(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(4′

-methylphenylthio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-(4′

-methoxyphenylthio)-4-(4′

-methoxyphenyl)4oxobutanoic acid;

2-(2′

-naphthylthio)-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-benzylthio-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

2-phenylthio-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

2-(4′

-fluorophenylthio)-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

2-(4′

-methylphenylthio)-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

2-(4′

-methoxyphenylthio)-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

2-(2 ′

-naphthylthio)-4-(4′

-chlorophenyl)-4-oxobutanoic acid;

or

13. A method according to claim 6, comprising administering to a patient in need thereof an effective amount of one of the following compounds

2-carboxymethylthio-4phenyl-4-oxobutanoic acid;

or a salt thereof with a pharmaceutically acceptable acid or base.

14. A method according to claim 6, comprising administering to a patient in need thereof an effective amount of one of the following compounds

2-cyclohexylthio-4-phenyl-4-oxobutanoic acid;

ethyl 2-cyclohexylthio-4-phenyl-4-oxobutanoate;

or

2-cyclohexylthio-4-(4′

-methoxyphenyl)-4-oxobutanoic acid;

or a salt thereof with a pharmaceutically acceptable acid or base.