Kynurenine 3-hydroxylase inhibitors for the treatment of diabetes

• US 20060142358A1
• Filed: 12/18/2003
• Published: 06/29/2006
• Est. Priority Date: 01/07/2003
• Status: Active Grant

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Autier, Valerie, Arbellot De Vacqueur, Annick, Marais, Dominique, Kergoat, Micheline, Kargar, Catherine, Moinet, Gerard
• Granted Patent: US 7,727,977 B2
• Time in Patent Office: Days
• US Class Current: 514/370
• 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. Use of at least one compound that inhibits kynurenine 3-hydroxylase, for the preparation of a medicament for the prevention and/or treatment of diabetes and its complications, by inhibition of kynurenine 3-hydroxylase.

2. Use according to claim 1, in which the medicament is for the prevention and/or treatment of non-insulin-dependent diabetes and its complications.

3. Use according to claim 1, in which the compound corresponds to the general formula (I) or to the general formula (II):

4. Use according to claim 3, in which the compound belongs to the general formula (I).

5. Use according to claim 1, in which the compound of the general formula (I) has the following characteristics, taken separately or in combination:

W represents a divalent radical chosen from the following radicals;

R¹ represents a radical chosen from linear or branched alkyl containing from 1 to 14 carbon atoms and optionally substituted, alkenyl, cycloalkyl, cycloalkenyl, a heterocyclic radical, an aryl radical and a heteroaryl radical;

R² is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl, alkyl, alkenyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl and aryl;

R³ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, alkyl, alkenyl, alkoxy, alkylthio and aryl;

R² and R³ together also possibly forming a group ═

CR¹⁶R¹⁷;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —

N(R¹²R^12′

), —

N(R¹²)OR¹³, linear or branched alkyl containing from 1 to 14 carbon atoms and optionally substituted, cycloalkyl, cycloalkenyl, aryl, heteroaryl and a heterocyclic radical;

R¹² and R^12′

, which may be identical or different, are chosen, independently of each other, from hydrogen and an alkyl, alkenyl, alkynyl, alkylcarbonyl, aryl or heteroaryl radical;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, —

N(R¹²R^12′

) or —

N(R¹²)OR¹³ radical;

R¹⁴ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl, alkyl, alkenyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, aryl and arylalkyl;

R¹⁴ may also form a bond with R², thus forming a double bond between the carbon atoms respectively bearing the substituents R¹⁴ and R²;

or alternatively R¹⁴ forms, with R² and with the carbon atoms that bear them, a ring containing a total of 3, 4, 5 or 6 carbon atoms, among which 1, 2 or 3 may be replaced with an atom chosen from nitrogen and oxygen, the said ring possibly comprising one or more unsaturations in the form of (a) double bond(s), and being optionally substituted by one or more radicals, which may be identical or different, chosen from oxo, alkoxy, alkoxycarbonyl and alkylcarbonyloxy;

R¹⁵ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl, alkyl, alkenyl, alkylcarbonyl, alkoxycarbonyl, alkoxy, alkylthio and aryl;

R¹⁶ is chosen from hydrogen and an alkyl or aryl radical;

R¹⁷ represents a hydrogen atom; and

R¹¹ is chosen from hydrogen and any protecting group for an amine function;

and also the possible geometrical and/or optical isomers thereof, and possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

6. Use according to claim 1, in which the compound belongs to the family (Ia) of the general formula (I) in which:

W represents a divalent radical chosen from the following radicals;

R¹ represents a radical chosen from linear or branched alkyl containing from 1 to 14 carbon atoms and optionally substituted, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, a heterocyclic radical, an aryl radical and a heteroaryl radical;

R² is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl and a heterocyclic radical;

R³ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, cycloalkyl and a heterocyclic radical;

R² and R³ together also possibly forming a group ═

CR¹⁶R¹⁷, or alternatively forming, together with the carbon atom that bears them, a cycloalkyl radical or a heterocyclic radical;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —

N(R¹²R^12′

), —

N(R¹²)OR¹³, linear or branched alkyl containing from 1 to 14 carbon atoms and optionally substituted, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and a heterocyclic radical;

R¹² and R^12′

, which may be identical or different, are chosen, independently of each other, from hydrogen and an alkyl, alkenyl, alkynyl, alkylcarbonyl, aryl or heteroaryl radical;

or alternatively R¹² and R^12′

may form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic group containing a total of 5 to 10 atoms, among which 1, 2, 3 or 4 are chosen, independently of each other, from nitrogen, oxygen and sulfur, the said heterocyclic radical also optionally comprising 1, 2, 3 or 4 double bonds and optionally being substituted by one or more chemical groups, which may be identical or different, chosen from hydroxyl, halogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, heterocyclic radical and trifluoromethyl;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, heteroaryl, —

N(R¹²R^12′

) or —

N(R¹²)OR¹³ radical;

R¹⁴ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, aryl, arylalkyl, heteroaryl, cycloalkyl and a heterocyclic radical;

R¹⁴ may also form a bond with R², thus forming a double bond between the carbon atoms respectively bearing the substituents R¹⁴ and R²;

or alternatively R¹⁴ forms, with R² and with the carbon atoms that bear them, a ring containing a total of 3, 4, 5, 6 or 7 carbon atoms, among which 1, 2 or 3 may be replaced with an atom chosen from nitrogen, oxygen and sulfur, the said ring possibly comprising one or more unsaturations in the form of (a) double bond(s), and being optionally substituted by one or more radicals, which may be identical or different, chosen from oxo, alkoxy, alkoxycarbonyl and alkylcarbonyloxy;

R¹⁵ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkoxycarbonyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, cycloalkyloxy, heteroaryloxy, heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, cycloalkylthio, heteroarylthio, heterocyclylthio, aryl, heteroaryl, cycloalkyl and a heterocyclic radical;

R¹⁴ and R¹⁵ also possibly forming, together with the carbon atom that bears them, a cycloalkyl radical or a heterocyclic radical;

R¹⁶ and R¹⁷, which may be identical or different, are chosen, independently of each other, from hydrogen, a halogen atom, an alkyl, aryl, heteroaryl or cycloalkyl radical and a heterocyclic radical;

or alternatively R¹⁶ and R¹⁷ form, together with the carbon atom that bears them, a cycloalkyl radical or a heterocyclic radical; and

R¹¹ is chosen from hydrogen and an alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl radical, and any protecting group for an amine function;

with the restriction that when R³, R² and R¹⁴ each represent hydrogen, then R¹⁵ is other than an alkyl radical, optionally substituted by aryl, heteroaryl, cycloalkyl and a heterocyclic radical;

and also the possible geometrical and/or optical isomers thereof, and possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

7. Use according to claim 6, in which the compound belongs to the family (Ib) of the general formula (I) in which:

W represents a divalent radical chosen from the radicals;

R¹ represents a phenyl radical, optionally substituted by 1, 2 or 3 groups chosen from cyano, nitro, phenyl, benzyl, alkyl, alkenyl containing from 2 to 4 carbon atoms, alkynyl containing from 2 to 4 carbon atoms, alkoxy, thiol —

SR¹³, —

S(O)R^13′

and —

S(O₂)R^13′

, and a halogen atom;

R² is chosen from hydrogen, a halogen atom, hydroxyl, thiol, optionally substituted alkyl, in particular benzyl, alkenyl containing from 2 to 4 carbon atoms, alkoxy, alkylthio and phenyl;

R³ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, optionally substituted alkyl, in particular benzyl, alkenyl containing from 2 to 4 carbon atoms, alkoxy, alkylthio and phenyl;

R² and R³ together also possibly forming a group ═

CR¹⁶R¹⁷;

R⁴ is chosen from hydroxyl, optionally substituted alkoxy, in particular benzyloxy, alkenyloxy containing from 2 to 4 carbon atoms, alkynyloxy containing from 2 to 4 carbon atoms, phenoxy, —

N(R¹²R^12′

) and —

N(R¹²)OR¹³;

R¹² and R^12′

, which may be identical or different, are chosen, independently of each other, from hydrogen, an optionally substituted alkyl radical, in particular benzyl, alkenyl containing from 2 to 4 carbon atoms, alkynyl containing from 2 to 4 carbon atoms, and phenyl;

R¹³ is chosen from hydrogen, an optionally substituted alkyl radical, in particular benzyl, alkenyl containing from 2 to 4 carbon atoms, alkynyl containing from 2 to 4 carbon atoms, and phenyl;

R^13′

is chosen from an optionally substituted alkyl radical, in particular benzyl, alkenyl containing from 2 to 4 carbon atoms, alkynyl containing from 2 to 4 carbon atoms, phenyl and —

N(R¹²R^12′

);

R¹⁴ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, optionally substituted alkyl, in particular benzyl, alkenyl containing from 2 to 4 carbon atoms, alkoxy, alkylthio and phenyl;

R¹⁴ may also form a bond with R², thus forming a double bond between the carbon atoms respectively bearing the substituents R¹⁴ and R²;

R¹⁵ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, optionally substituted alkyl, in particular benzyl, alkenyl containing from 2 to 4 carbon atoms, alkoxy, alkylthio and phenyl;

R¹⁶ is chosen from hydrogen, a halogen atom, hydroxyl, thiol, optionally substituted alkyl, in particular benzyl, alkenyl containing from 2 to 4 carbon atoms, alkoxy, alkylthio and phenyl; and

R¹⁷ represents a hydrogen atom;

with the restriction that when R³, R² and R¹⁴ each represent hydrogen, then R¹⁵ is other than an alkyl radical, optionally substituted by aryl, heteroaryl, cycloalkyl and a heterocyclic radical;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

8. Use according to claim 1, in which the compound is chosen from the family (Ic) of the general formula (I), in which:

W represents the divalent radical;

R¹ represents a radical chosen from linear or branched alkyl containing from 1 to 14 carbon atoms and optionally substituted, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, a heterocyclic radical, an aryl radical and a heteroaryl radical;

R² represents hydrogen;

R³ represents hydrogen;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —

N(R¹²R^12′

) and —

N(R¹²)OR¹³;

R¹² and R^12′

, which may be identical or different, are chosen, independently of each other, from hydrogen and an alkyl, alkenyl, alkynyl, alkylcarbonyl, aryl or heteroaryl radical;

or alternatively R¹² and R^12′

may form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic group containing a total of 5 to 10 atoms, among which 1, 2, 3 or 4 are chosen, independently of each other, from nitrogen, oxygen and sulfur, the said heterocyclic radical also optionally comprising 1, 2, 3 or 4 double bonds and optionally being substituted by one or more chemical groups, which may be identical or different, chosen from hydroxyl, halogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, heterocyclic radical and trifluoromethyl;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, heteroaryl, —

N(R¹²R¹²′

) or —

N(R¹²)OR¹³ radical;

R¹⁴ represents hydrogen;

R¹⁵ represents hydrogen;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

9. Use according to claim 1, in which the compound is chosen from the family (Id) of the general formula (I), in which:

W represents the divalent radical;

R¹ represents a radical chosen from linear or branched alkyl containing from 1 to 14 carbon atoms and optionally substituted, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, a heterocyclic radical, an aryl radical and a heteroaryl radical;

R² represents hydrogen;

R³ represents hydrogen;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —

N(R¹²R^12′

) and —

N(R¹²)OR¹³;

R¹² and R^12′

, which may be identical or different, are chosen, independently of each other, from hydrogen and an alkyl, alkenyl, alkynyl, alkylcarbonyl, aryl or heteroaryl radical;

or alternatively R¹² and R^12′

may form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic group containing a total of 5 to 10 atoms, among which 1, 2, 3 or 4 are chosen, independently of each other, from nitrogen, oxygen and sulfur, the said heterocyclic radical also optionally comprising 1, 2, 3 or 4 double bonds and optionally being substituted by one or more chemical groups, which may be identical or different, chosen from hydroxyl, halogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, heterocyclic radical and trifluoromethyl;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, heteroaryl, —

N(R¹²R^12′

) or —

N(R¹²)OR¹³ radical;

R¹⁴ represents hydrogen; and

R¹⁵ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, cycloalkyloxy, heteroaryloxy and heterocyclyloxy;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

10. Use according to claim 1, in which the compound is chosen from the family (Ie) of the general formula (I), in which:

W represents the divalent radical;

R¹ represents a radical chosen from linear or branched alkyl containing from 1 to 14 carbon atoms and optionally substituted, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, a heterocyclic radical, an aryl radical and a heteroaryl radical;

R² and R¹⁴ together form a bond, thus forming a double bond between the carbon atoms respectively bearing R² and R¹⁴;

R³ represents hydrogen;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —

N(R¹²R^12′

) and —

N(R¹²)OR¹³;

R¹² and R^12′

, which may be identical or different, are chosen, independently of each other, from hydrogen and an alkyl, alkenyl, alkynyl, alkylcarbonyl, aryl or heteroaryl radical;

or alternatively R¹² and R^12′

may form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic group containing a total of 5 to 10 atoms, among which 1, 2, 3 or 4 are chosen, independently of each other, from nitrogen, oxygen and sulfur, the said heterocyclic radical also optionally comprising 1, 2, 3 or 4 double bonds and optionally being substituted by one or more chemical groups, which may be identical or different, chosen from hydroxyl, halogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, heterocyclic radical and trifluoromethyl;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, heteroaryl, —

N(R¹²R^12′

) or —

N(R¹²)OR¹³ radical; and

R¹⁵ represents hydrogen;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

11. Use according to claim 1, in which the compound is chosen from the family (If) of the general formula (I), in which:

W represents the divalent radical;

R¹ represents a radical chosen from linear or branched alkyl containing from 1 to 14 carbon atoms and optionally substituted, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, a heterocyclic radical, an aryl radical and a heteroaryl radical;

R² and R¹⁴ together form a bond, thus forming a double bond between the carbon atoms respectively bearing R² and R¹⁴;

R³ represents hydrogen;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —

N(R¹²R^12′

) and —

N(R¹²)OR¹³;

R¹² and R^12′

, which may be identical or different, are chosen, independently of each other, from hydrogen and an alkyl, alkenyl, alkynyl, alkylcarbonyl, aryl or heteroaryl radical;

or alternatively R¹² and R^12′

may form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic group containing a total of 5 to 10 atoms, among which 1, 2, 3 or 4 are chosen, independently of each other, from nitrogen, oxygen and sulfur, the said heterocyclic radical also optionally comprising 1, 2, 3 or 4 double bonds and optionally being substituted by one or more chemical groups, which may be identical or different, chosen from hydroxyl, halogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, heterocyclic radical and trifluoromethyl;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, heteroaryl, —

N(R¹²R^12′

) or —

N(R¹²)OR¹³ radical; and

R¹⁵ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, cycloalkyloxy, heteroaryloxy and heterocyclyloxy;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

12. Use according to claim 1, in which the compound is chosen from the family (Ig) of the general formula (I), in which the compound is chosen from:

4-(4′

-methylcyclohexyl)-4-oxobutanoic acid;

2-hydroxy-4-(3′

,4′

-difluorophenyl)-4-oxobutanoic acid;

2-methoxy-4-(3′

,4′

-difluorophenyl)-4-oxobutanoic acid;

2-hydroxy-3-methyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

2-hydroxy-3-phenyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

2-hydroxy-3-benzyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

2-methyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

2-methyl-4-(3′

,4′

-difluorophenyl)-4-oxobutanoic acid;

2-chloro-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

2-chloro-4-(3′

,4′

-difluorophenyl)-4-oxobutanoic acid;

2-fluoro-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

2-fluoro-4-(3′

,4′

-difluorophenyl)-4-oxobutanoic acid;

2-thiomethyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

2-methylidene-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

2-phenyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

2-benzyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

3-methyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

3-phenyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

3-benzyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

methyl (R,S)-2-hydroxy-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoate;

methyl (R,S)-2-benzyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoate;

4-(3′

-fluorophenyl)-4-oxo-2-butenoic acid;

4-(3′

-chlorophenyl)-4-oxo-2-butenoic acid;

4-(3′

-nitrophenyl)-4-oxo-2-butenoic acid;

4-(3′

-fluoro-4′

-methoxyphenyl)-4-oxo-2-butenoic acid;

2-methyl-4-(3′

,4′

-dichlorophenyl)-4-oxo-2-butenoic acid;

3-methyl-4-(3′

,4′

-dichlorophenyl)-4-oxo-2-butenoic acid;

3-phenyl-4-(3′

,4′

-dichlorophenyl)-4-oxo-2-butenoic acid;

3-benzyl-4-(3′

,4′

-dichlorophenyl)-4-oxo-2-butenoic acid;

2,3-dimethyl-4-(3′

,4′

-dichlorophenyl)-4-oxo-2-butenoic acid;

2-hydroxy-4-(3′

-chlorophenyl)-4-oxo-2-butenoic acid;

2-hydroxy-4-(3′

-fluorophenyl)-4-oxo-2-butenoic acid;

2-hydroxy-4-(3′

,4′

-dichlorophenyl)-4-oxo-2-butenoic acid;

2-hydroxy-4-(3′

,4′

-difluorophenyl)-4-oxo-2-butenoic acid; and

2-hydroxy-4-(3′

-chloro-4′

-methoxyphenyl)-4-oxo-2-butenoic acid;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

13. Use according to claim 1, in which the compound is chosen from the family (Ih) of the general formula (I), in which:

W represents the divalent radical;

R¹, R², R³, R⁴, R¹², R^12′

, R¹³ and R¹⁴ are as defined above; and

R¹⁵ is chosen from a thiol, alkylthio, alkenylthio, alkynylthio, arylthio, cycloalkylthio, heteroarylthio or heterocyclylthio radical;

with the restriction that when R², R³ and R¹⁴ each represent hydrogen, then R¹⁵ cannot represent a thiol or alkylthio radical;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

14. Use according to claim 13, in which the compound is chosen from the family (Ii) of the general formula (I), in which:

W represents the divalent radical;

R¹ represents an aryl radical;

R² represent hydrogen, or forms a bond with R¹⁴;

R³ represents hydrogen;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —

N(R¹²R^12′

) and —

N(R¹²)OR¹³;

R¹² and R^12′

, which may be identical or different, are chosen, independently of each other, from hydrogen and an alkyl, alkenyl, alkynyl, alkylcarbonyl, aryl or heteroaryl radical;

or alternatively R¹² and R^12′

may form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic group containing a total of 5 to 10 atoms, among which 1, 2, 3 or 4 are chosen, independently of each other, from nitrogen, oxygen and sulfur, the said heterocyclic radical also optionally comprising 1, 2, 3 or 4 double bonds and optionally being substituted by one or more chemical groups, which may be identical or different, chosen from hydroxyl, halogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, heterocyclic radical and trifluoromethyl;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, heteroaryl, —

N(R¹²R^12′

) or —

N(R¹²)OR¹³ radical;

R¹⁴ represents hydrogen, or forms a bond with R²; and

R¹⁵ represents an arylthio radical;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

15. Use according to claim 14, in which the compound is chosen from the family (Ij) of the general formula (I), in which:

W represents the divalent radical;

R¹ represents a phenyl radical;

R² represents hydrogen;

R³ represents hydrogen;

R⁴ is chosen from hydroxyl and an alkoxy radical;

R¹⁴ represents hydrogen; and

R¹⁵ represents a phenylthio radical;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

16. Use according to claim 13, in which the compound is chosen from:

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-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′

-chlorophenyl)-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;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

17. Use according to any one of claims 1 to I claim 1, in which the compound is chosen from:

4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

4-(3′

,4′

-difluorophenyl)-4-oxobutanoic acid;

methyl 4-(3′

,4′

-dichlorophenyl)-4-oxobutanoate;

(R,S)-2-hydroxy-4-(3′

-chlorophenyl)-4-oxobutanoic acid;

(R,S)-2-hydroxy-4-(3′

-fluorophenyl)-4-oxobutanoic acid;

(R,S)-2-hydroxy-4-(3′

-nitrophenyl)-4-oxobutanoic acid;

(R,S)-2-hydroxy-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

(S)-2-hydroxy-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

(R)-2-hydroxy-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

methyl (R,S)-2-hydroxy-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoate;

(R,S)-2-hydroxy-4-(3′

,4′

-difluorophenyl)-4-oxobutanoic acid;

(R,S)-2-methoxy-4-(3′

,4′

-difluorophenyl)-4-oxobutanoic acid;

(R,S)-2-methoxy-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

(R,S)-2-methyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

(R,S)-3-methyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

2-hydroxy-3-benzyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

(R,S)-2-methyl-4-(3′

,4′

-difluorophenyl)-4-oxobutanoic acid;

(R,S)-2-chloro-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

(R,S)-2-methylidene-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

(R,S)-3-phenyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

methyl (R,S)-2-benzyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoate;

(R,S)-2-phenyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

(R,S)-2-benzyl-4-(3′

,4′

-dichlorophenyl)-4-oxobutanoic acid;

(E)-4-(3′

,4′

-dichlorophenyl)-4-oxo-2-butenoic acid;

(E)-4-(3′

,4′

-difluorophenyl)-4-oxo-2-butenoic acid;

(E)-4-(3′

-fluorophenyl)-4-oxo-2-butenoic acid;

(E)-4-(3′

-chlorophenyl)-4-oxo-2-butenoic acid;

(E)-4-(3′

-nitrophenyl)-4-oxo-2-butenoic acid;

(E)-2-methyl-4-(3′

,4′

-dichlorophenyl)-4-oxo-2-butenoic acid;

3-methyl-4-(3′

,4′

-dichlorophenyl)-4-oxo-2-butenoic acid;

3-benzyl-4-(3′

,4′

-dichlorophenyl)-4-oxo-2-butenoic acid;

(E)-2-hydroxy-4-(3′

-chlorophenyl)-4-oxo-2-butenoic acid;

(E)-2-hydroxy-4-(3′

-fluorophenyl)-4-oxo-2-butenoic acid;

(E)-2-hydroxy-4-(4′

-chlorophenyl)-4-oxo-2-butenoic acid;

(E)-2-hydroxy-4-(3′

,4′

-dichlorophenyl)-4-oxo-2-butenoic acid;

(E)-2-hydroxy-4-(3′

,4′

-difluorophenyl)-4-oxo-2-butenoic acid;

methyl (E)-2-hydroxy-4-(3′

,4′

-dichlorophenyl)-4-oxo-2-butenoate; and

ethyl (E)-2-hydroxy-4-(3′

,4′

-dichlorophenyl)-4-oxo-2-butenoate;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

18. Use according to claim 1, in which the compound belongs to the general formula (II).

19. Use according to claim 3, in which the compound belongs to the family (IIa) of the general formula (II) in which:

R⁵, R⁶, R⁷ and R⁸ are as defined above;

R⁹ represents hydrogen; and

R¹⁰ is chosen from a phenyl radical, optionally substituted in position 3 and/or 4 with an alkyl or alkoxy radical, preferably methyl or methoxy, and a naphthyl radical;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

20. Use according to claim 3, in which the compound belongs to the family (IIb) of the general formula (II) in which:

R⁵, R⁶, R⁷ and R⁸, which may be identical or different, are chosen, independently of each other, from hydrogen, a halogen atom, a nitro radical and a trifluoromethyl radical;

the radicals R⁶ and R⁷ also possibly forming, together with the carbon atoms to which they are attached, a benzene ring, optionally substituted by one or more groups, which may be identical or different, chosen from a halogen atom and a trifluoromethyl, nitro or alkoxy radical; and

R⁹ and R¹⁰ are as defined above;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

21. Use according to claim 1, in which the compound is chosen from the list consisting of:

4-methoxy-N-(4-naphthalen-2-ylthiazol-2-yl)benzenesulfonamide;

4-amino-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide;

4-methyl-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide;

3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide;

4-methoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide;

2-naphthalenesulfonic acid [4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide;

N-[4-(2-fluoro-5-trifluoromethylphenyl)thiazol-2-yl]-4-methylbenzenesulfonamide;

N-[4-(3-fluoro-5-trifluoromethylphenyl)thiazol-2-yl]-4-methylbenzenesulfonamide;

4-methyl-N-[4-(4-nitrophenyl)thiazol-2-yl]benzenesulfonamide;

4-amino-N-[4-(2-fluoro-5-trifluoromethylphenyl)thiazol-2-yl]benzenesulfonamide; and

3,4-dimethoxy-N-[4-(2-fluoro-5-trifluoromethylphenyl)thiazol-2-yl]benzenesulfenamide;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

22. Compound belonging to the family (Ih) of general structure (I) in which:

W represents the divalent radical;

R¹, R², R³, R⁴, R¹², R^12′

, R¹³ and R¹⁴ are as defined in claim 4;

and

R¹⁵ is chosen from a thiol, alkylthio, alkenylthio, alkynylthio, arylthio, cycloalkylthio, heteroarylthio or heterocyclylthio radical;

with the restriction that when R², R³ and R¹⁴ each represent hydrogen, then R¹⁵ cannot represent a thiol or alkylthio radical;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

23. Compound according to claim 22, belonging to the family (Ii) of general structure (I) in which:

W represents the divalent radical;

R¹ represents an aryl radical;

R² represent hydrogen, or forms a bond with R¹⁴;

R³ represents hydrogen;

R⁴ is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —

N(R¹²R^12′

) and —

N(R¹²)OR¹³;

R¹² and R^12′

, which may be identical or different, are chosen, independently of each other, from hydrogen and an alkyl, alkenyl, alkynyl, alkylcarbonyl, aryl or heteroaryl radical;

or alternatively R¹² and R^12′

may form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic group containing a total of 5 to 10 atoms, among which 1, 2, 3 or 4 are chosen, independently of each other, from nitrogen, oxygen and sulfur, the said heterocyclic radical also optionally comprising 1, 2, 3 or 4 double bonds and optionally being substituted by one or more chemical groups, which may be identical or different, chosen from hydroxyl, halogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, heterocyclic radical and trifluoromethyl;

R¹³ is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, heteroaryl, —

N(R¹²R^12′

) or —

N(R¹²)OR¹³ radical;

R¹⁴ represents hydrogen, or forms a bond with R²; and

R¹⁵ represents an arylthio radical;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

24. Compound according to claim 22, belonging to the family (Ij) of the general formula (I) in which:

W represents the divalent radical;

R¹ represents a phenyl radical;

R² represents hydrogen;

R³ represents hydrogen;

R⁴ is chosen from hydroxyl and an alkoxy radical;

R¹⁴ represents hydrogen; and

R¹⁵ represents a phenylthio radical;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

25. Compound according to claim 21, belonging to the family (Ih), chosen from:

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-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′

-chlorophenyl)-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;

and also the possible geometrical and/or optical isomers thereof, and the possible tautomeric forms thereof;

the solvates and hydrates of these compounds;

and also the possible salts thereof with a pharmaceutically acceptable acid or base, or alternatively the pharmaceutically acceptable prodrugs of these compounds.

26. Pharmaceutical composition comprising, as active principle, a pharmacologically effective amount of at least one compound defined in claim 1, alone or in combination with one or more pharmaceutically acceptable, suitable, non-toxic inert excipients.

27. Use of a compound as defined in claim 1, for the preparation of a medicament for the prevention and/or treatment of diabetes and its complications, by reducing the risk of hypoglycaemia.

28. Process for manufacturing a medicament for the treatment and/or prevention of diabetes, in particular non-insulin-dependent diabetes and its complications, in which at least one compound of the formula (I) or (II) as defined in claim 1 is subjected to an in vitro test of inhibition of kynurenine 3-hydroxylase, and the molecules responding positively to the said tests are then conditioned in the form of a pharmaceutical composition, optionally with addition of a pharmaceutically acceptable filler or vehicle.

29. Process for screening candidate compounds for activity in the prevention or treatment of diabetes, and especially non-insulin-dependent diabetes or its complications, by inhibiting kynurenine 3-hydroxylase, the said candidates not corresponding to formula (I) or (II) as defined in claim 1, in which process the candidate compounds are subjected to an in vitro test of inhibition of kynurenine 3-hydroxylase, and the candidate that has responded positively to this test is selected.