Kynurenine 3-hydroxylase inhibitors for the treatment of diabetes by increasing the number of islets of langerhans cells

• US 20060052456A1
• Filed: 12/18/2003
• Published: 03/09/2006
• Est. Priority Date: 01/07/2003
• Status: Abandoned Application

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Marais, Dominique, Kergoat, Micheline, Kargar, Catherine, Moinet, Gerard, Arbellot De Vacqueur, Annick, Autier, Valerie
• Application Number:
  US10/541,493
• Publication Number:
  US 20060052456A1
• Time in Patent Office: Days
• US Class Current: 514/570
• 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 medica ment for increasing the number of islets of Langerhans cells, which is intended especially for the prevention and/or treatment of diabetes.

Claims

1. Use of a kynurenine 3-hydroxylase inhibitor for the manufacture of a medicament for increasing the number of islets of Langerhans cells.

2. Use of a kynurenine 3-hydroxylase inhibitor according to claim 1, in the context of the treatment and/or prevention of diabetes, its complications and/or its related pathologies.

11. Use according to claim 1, which is suitable for the said treatment and/or the said prevention in the case of a patient with an impairment in the number of islets of Langerhans cells.

12. Use according to claim 11, for which the said patient shows a decrease in the number of islets of Langerhans cells of at least 40%.

13. Use according to claim 11, for which the said patient shows a decrease in the number of islets of Langerhans cells of between 50% and 90%.

14. Use according to claim 1, which is suitable for the said treatment and/or the said prevention in the case of a patient with glucose intolerance.

15. Use according to claim 14, for which the said patient presents a fasting glycaemia of between 1.10 g/l and 1.26 g/l and a glycaemia after meals of between 1.40 g/l and 2 g/l after meals.

16. Use according to claim 1, which is suitable for the said treatment and/or the said prevention in the case of a patient with one or more anti-islets of Langerhans cells immunological markers.

17. Use according to claim 16, for which the said marker(s) indicate(s) the existence of an autoimmune response of the body directed against the antigenic markers of the body'"'"'s islets of Langerhans cells.

18. Use according to claim 16, for which the said marker(s) is (are) chosen from the anti-islet (ICA), anti-glutamic acid decarboxylase (GAD), anti-tyrosine phosphatase (IA-2) and anti-(pro)insulin (AIA) auto-antibodies, or the anti-carboxypeptidase H, anti-64 kD and anti-heat shock protein antibodies.

19. Use according to claim 1, which is suitable for the said treatment and/or the said prevention in the case of a patient with insulin resistance.

20. Use according to claim 19, for which the said patient responds partially or not at all to insulin secreted by the beta cells or injected.

21. Use according to claim 1, for which the said patient presents a level of glycated haemoglobin of higher than 7%.

22. Use according to claim 1, for which the said patient has islets of Langerhans cells showing an anomaly of insulin secretion in response to glucose.

23. Use according to claim 1, for which the said patient presents a suppression of the early peak of insulin secretion.

24. Use according to claim 1, for which the said patient shows related hyperglycaemia and obesity.

25. Use according to claim 24, for which the said patient suffers from paediatric obesity.

26. Use according to claim 1, which is suitable for the said treatment and/or the said prevention in the case of a patient presenting any diabetic risk factor.

27. Use according to claim 25, for which the said risk factor is chosen from familial history, gestational diabetes, excess weight, obesity, insufficient physical exercise, high blood pressure, a high level of triglycerides, hyperlipidaemia and inflammation.

28. Use according to claim 1, comprising the in vitro treatment of isolated islets of Langerhans cells with the said kynurenine 3-hydroxylase inhibitor.

33. Use according to claim 1, for which the said kynurenine 3-hydroxylase inhibitor is a compound of the general formula (I) or (II):

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 together forming, 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;

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

the radicals R⁵ and R⁶, on the one hand, or R⁶ and R⁷, on the other hand, may also form, 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, a trifluoromethyl, cyano or nitro radical, an alkyl radical and an alkoxy radical;

R⁹ represents hydrogen or an alkyl radical;

R¹⁰ is chosen from an alkyl, an aryl and a heteroaryl 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;

and also the possible geometrical and/or optical isomers thereof, and 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.

53. Process for manufacturing a medicament for the the treatment and/or prevention of diabetes, its complications and/or its related pathologies, by increasing the number of islets of Langerhans cells, in which at least one compound of the formula (I) or (II) as defined in one of 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.

54. Process for screening candidate compounds for activity in the prevention or treatment of diabetes, its complications and/or its related pathologies, by increasing the number of islets of Langerhans cells by inhibiting kynurenine 3-hydroxylase, the said candidates not corresponding to formula (I) or (II) as defined in one of claim 33, 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.

3. Use of a kynurenine 3-hydroxylase inhibitor for the manufacture of a medicament for the treatment of prediabetes.

4. Use according to claim 3, for which the said prediabetes is an insulin-dependent prediabetes.

5. Use according to claim 3, for which the said prediabetes is a non-insulin-dependent prediabetes.

9. Use according to claim 3, for which the said treatment or prevention is by increasing the number of islets of Langerhans cells.

6. Use of a kynurenine 3-hydroxylase inhibitor for the manufacture of a medicament for the the treatment and/or prevention of insulin-dependent diabetes.

7. Use of a kynurenine 3-hydroxylase inhibitor for the manufacture of a medicament for the prevention of non-insulin-dependent diabetes.

8. Use of a kynurenine 3-hydroxylase inhibitor for the manufacture of a medicament for the treatment of early non-insulin-dependent diabetes.

10. Use of a kynurenine 3-hydroxylase inhibitor in combination with one or more immunosuppressants, for the manufacture of a medicament for the prevention and/or treatment of insulin-dependent diabetes.

29. Process for increasing the number or the insulin-secreting capacity of islets of Langerhans cells, comprising the in vitro application of a kynurenine 3-hydroxylase inhibitor to the said cells.

30. Pharmaceutical composition comprising a kynurenine 3-hydroxylase inhibitor in combination with one or more immunosuppressants.

31-32. -32. (canceled)

34-52. -52. (canceled)