US20060052456A1 - Kynurenine 3-hydroxylase inhibitors for the treatment of diabetes by increasing the number of islets of langerhans cells - Google Patents

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

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US20060052456A1
US20060052456A1 US10/541,493 US54149305A US2006052456A1 US 20060052456 A1 US20060052456 A1 US 20060052456A1 US 54149305 A US54149305 A US 54149305A US 2006052456 A1 US2006052456 A1 US 2006052456A1
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radical
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kynurenine
insulin
alkyl
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Valerie Autier
Annick Arbellot De Vacqueur
Micheline Kergoat
Gerard Moinet
Dominique Marais
Catherine Kargar
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Merck Patent GmbH
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Definitions

  • the present invention relates to compounds with inhibitory activity on kynurenine 3-hydroxylase and in particular to their use as products for pharmaceutical use by increasing the number of islets of Langerhans cells in the case of patients in need thereof, especially for the prevention and treatment of diabetes and related its complications and/or related pathologies (obesity, hypertension, etc.).
  • Diabetes mellitus represents a very heterogeneous group of diseases all having a certain number of characteristics in common: elevation of glycaemia and increased long-term risk of developing cardiovascular complications.
  • insulin-dependent diabetes which involves the manifestation of immunological phenomena
  • non-insulin-dependent diabetes NIDD
  • the diabetes is said to be insulin-dependent if its symptoms (thirst, polyuria, coma, etc.) are associated with hyperglycaemia and ketosis: the administration of insulin is then vital from the early stages of the disease.
  • the diabetes is considered as non-insulin-dependent and is treated in general using oral antidiabetic agents.
  • Non-insulin-dependent diabetes currently affects 110 million people worldwide. This number shows no sign of decreasing, since it is forecast that 216 million people will be affected by 2010.
  • Maintaining a sugar balance requires strict coordination between the organs (brain, liver, pancreas, muscles and adipose tissue mainly) involved in energy metabolism.
  • the liver and the pancreas are the main participants. Specifically, it has been clearly demonstrated that excessive production of glucose by the liver is responsible for fasted hyperglycaemia in diabetics (Consoli et al., Diabetes, Vol. 38 (1989), 550-557). Similarly, impairment in pancreatic function (number of islets of Langerhans cells, secretion of insulin and glucagon in response to glucose) contributes to the development of postprandial hyperglycaemia (Polonsky et al., N. Engl. J. Med., 318 (1988), 1231-39).
  • Insulin-dependent diabetes is an autoimmune disease that destroys the beta cells of the pancreas. This disease involves genetic factors (genes of the HLA (human leukocyte antigen) system and of insulin itself) and also environmental factors of nutritional and/or viral origin.
  • HLA human leukocyte antigen
  • the pancreas is a mixed organ comprising exocrine tissue, the role of which is the synthesis and secretion of the enzymes required for digestion, and an endocrine tissue composed of several types of cells, the role of which is to synthesis and secrete the hormones involved in maintaining carbohydrate homeostasis.
  • the endocrine cells are grouped together in the exocrine pancreas in the form of small structures of complex cellular organisation known as islets of Langerhans. These islets are composed of four major cell types:
  • alpha cells which secrete glucagon
  • the amount of circulating insulin is controlled by rapid changes in the amount of hormone released by individual beta cells as a function of the variations in plasmatic glucose.
  • a longer-term regulation also exists, which makes it possible to adapt the production of insulin by means of changes in the total mass of beta cells.
  • the pancreas is capable of adapting its mass of beta cells when the demand for insulin increases. The increase in this demand is observed in physiological and physiopathological situations in which there is a reduction in the biological efficacy of insulin (insulin resistance).
  • an insufficiency in the number of islets of Langerhans cells and more particularly of beta cells may also contribute towards the secretory deficit and thus towards the establishment of hyperglycaemia in the case of type I and 11 diabetics (Klöppel G. et al. Surv. Synth. Path. Res (1985), 4:110125).
  • Several studies performed on animal models of diabetes show that the genetic terrain is an important parameter in the growth of beta cells (Andersson A., Diabetologia (1983); 25: 269-272; Swenne I. Diabetes, (1984), 32:14-19).
  • the main treatment for type I diabetes consists of the subcutaneous injection of insulin.
  • the clinical manifestation of diabetes is always preceded by a longer or shorter asymptomatic period known as prediabetes, during which organs can, however, become affected long before the diabetes is diagnosed.
  • the American Diabetes Association suggested a new definition of prediabetes, namely a condition characterised by blood glucose concentrations that are higher normal, but lower than those corresponding to the predefined criteria of diabetes.
  • a normal glycaemic equilibrium is characterised by a fasting glycaemia of less than 1.10 g/l and a glycaemia after meals of less than 1.40 g/l. If the fasting glycaemia is 1.26 g/l or greater and/or increases to more than 2 g/l after meals, diabetes is diagnosed.
  • the prediabetic condition corresponding to type I diabetes may be defined by the presence of immunological markers, such as those described by Buysschaert et al, Louvain Med. 119, S251-S258, 2000, especially including 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.
  • immunological markers such as those described by Buysschaert et al, Louvain Med. 119, S251-S258, 2000, especially including 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
  • the type II prediabetic condition is characterised mainly by a disappearance of the early peak of insulin secretion, the consequence of which is glucose intolerance (also known as IGT, for “impaired glucose tolerance”) or impaired fasting glycaemia (also known as IFG, for “impaired fasting glucose”).
  • IGT glucose intolerance
  • IFG impaired fasting glycaemia
  • Type II diabetes No medicament exists for effectively preventing diabetes. It is thus desirable to provide novel routes for the prevention and/or treatment of prediabetes or diabetes.
  • the main treatment of type I diabetes consists of the subcutaneous injection of insulin.
  • A1c glycated haemoglobin
  • Type II diabetes it is legitimate to propose a medicinal treatment when the level of glycated haemoglobin (A1c) remains higher than 7% after 3 to 6 months of the only hygieno-dietetic measurements. It is necessary to do this if the A1c remains higher than 8% (Nathan, N.E.J.M., (2002), 17: 1342-1349).
  • Type II diabetes is generally treated using oral active medicaments.
  • Sulfonylureas in particular present a major risk of hypoglycaemia, which demands that the dosage of these medicaments be scrupulously defined and complied with from patient to patient. Simultaneous correction of the two defects mentioned above without risks of associated hypoglycaemia would constitute a fundamental breakthrough in the treatment of type II diabetes and its complications. The prevention of the associated cardiovascular risk, which represents one of the major complications, would also be of important benefit to diabetic patients.
  • Tryptophan is an amino acid whose involvement in controlling carbohydrate metabolism has previously been reported (Tsiolakis D. and V. Marks, Horm. Metabol. Res., 16 (1964), 226-229). Its complex metabolisation via kynurenine leads to the production of NAD+. Some of the intermediate metabolites have also been described as possibly being involved in glycaemia control (Connick J.
  • the concentration of these metabolites is controlled by three enzymes: kynurenine 3-hydroxylase, kynureninase and kynurenine aminotransferase.
  • Kynurenine aminotransferase has also been suspected of being involved in the hypertension physiopathology of SHR rats (Spontaneously Hypertensive Rat; Kwok et al., JBC, 35779-35782, September 2002) which are otherwise insulin-resistant.
  • SHR rats Sertaneously Hypertensive Rat; Kwok et al., JBC, 35779-35782, September 2002
  • the research conducted with the aim of meeting the objectives of the present invention has made it possible to demonstrate, surprisingly, that the modulation of tryptophan metabolism in the kynurenine pathway via the pancreatic inhibition of kynurenine 3-hydroxylase allows an increase in the number of islets of Langerhans cells and thus plays an important role especially in the prevention and treatment of diabetic diseases, its complications and/or its related pathologies (obesity, hypertension, etc.).
  • One of the objectives of the present invention consequently consists in providing novel therapeutic means which have curative and/or preventive activity for the prevention of diabetes, its complications and/or its related pathologies, by increasing the number of islets of Langerhans cells, and which are free of the risk of hypoglycaemia.
  • the present invention also proposes, as another objective, a process for the treatment of diabetes that makes it possible to avoid the side effects and especially hypoglycaemia, the said process using therapeutic means whose mechanism of action for this type of pathology is not described or suggested in the prior art.
  • Certain compounds are known (see patents U.S. Pat. No. 6,048,896 and U.S. Pat. No. 6,323,240), which have inhibitory activity on the kynurenine 3-hydroxylase and which are useful in the treatment of neurodegenerative diseases, including diseases of the central nervous system, sclerosis and glaucoma-related retinopathy. Such compounds were already known as having analgesic and anti-inflammatory properties.
  • the research conducted with the aim of meeting the objectives of the present invention has made it possible to demonstrate, surprisingly, that the inhibition of kynurenine 3-hydroxylase plays an important role in the prevention and treatment of diabetic diseases, in particular non-insulin-dependent diabetes, its complications and/or its related pathologies.
  • kynurenine 3-hydroxylase inhibitors show activity towards pancreatic beta cells.
  • the kynurenine 3-hydroxylase inhibitors increase the number of islets of Langerhans cells and in particular the beta cells.
  • kynurenine 3-hydroxylase inhibitors should thus make it possible to compensate for the reduction in the number of pancreatic islets of Langerhans cells in the course of the diabetic condition, in addition to their effect on the function of these cells.
  • kynurenine 3-hydroxylase inhibitors thus make it possible to prevent diabetes and its effects.
  • kynurenine 3-hydroxylase inhibitors thus make it possible to specifically target the treatment of hyperglycaemia as a function of the type of diabetes, its degree of progress and/or the population concerned.
  • kynurenine 3-hydroxylase inhibitors makes it possible to act selectively on the increase in the number of islets of Langerhans cells. This therefore makes it possible to selectively target patients with an anomaly of insulin secretion of the islets of Langerhans cells in response to glucose and/or an impairment in their number.
  • kynurenine 3-hydroxylase inhibitors makes it possible to treat and/or prevent insulin-dependent diabetes, by increasing the mass of insulin-secreting islets of Langerhans cells.
  • kynurenine 3-hydroxylase inhibitors make it possible to prevent insulin-dependent diabetes by increasing the number of insulin-secreting islets of Langerhans cells before the disease has been declared, more particularly during prediabetes.
  • kynurenine 3-hydroxylase inhibitors makes it possible to treat and/or prevent early non-insulin-dependent diabetes, by increasing the number of functional cells. This is particularly advantageous insofar as this use makes it possible to avoid increasing the number of non-functional beta cells and reducing the mass of beta cells, respectively, above or below the normal value, which thus makes it possible to advantageously avoid the appearance of diabetes, its symptoms and/or its complications.
  • kynurenine 3-hydroxylase inhibitors makes it possible to treat and/or prevent non-insulin-dependent diabetes at an advanced stage, known as a late stage, by replacing the non-functional beta cells with functional beta cells.
  • kynurenine 3-hydroxylase inhibitors makes it possible to treat and/or prevent late non-insulin-dependent diabetes by regenerating the number of beta cells, following the failure and/or a reduction in the number of the beta cells.
  • the kynurenine 3-hydroxylase inhibitors may be administered orally, in monotherapy, to prevent and/or treat non-insulin-dependent diabetes.
  • the kynurenine 3-hydroxylase inhibitors can be used in vitro for the treatment of pancreatic stem cells; the said treated cells may be transplanted into a patient to prevent and/or treat non-insulin-dependent diabetes.
  • the kynurenine 3-hydroxylase inhibitors can be used in vitro for the treatment of pancreatic stem cells; the said treated cells may be transplanted into a patient to prevent and/or treat insulin-dependent diabetes.
  • the kynurenine 3-hydroxylase inhibitors may be administered in combination with one or more agents for reducing the body's immune response, to prevent and/or treat insulin-dependent diabetes.
  • the present invention thus relates to the use of a kynurenine 3-hydroxylase inhibitor for the manufacture of a medicament for increasing the number of islets of Langerhans cells.
  • the present invention relates to the use of a kynurenine 3-hydroxylase inhibitor for the manufacture of a medicament for the treatment and/or prevention of insulin-dependent diabetes.
  • the present invention relates to the use of a kynurenine 3-hydroxylase inhibitor for the manufacture of a medicament for the prevention and/or treatment of insulin-dependent prediabetes.
  • the present invention relates to the use of a kynurenine 3-hydroxylase inhibitor for the manufacture of a medicament for the prevention of non-insulin-dependent diabetes.
  • the present invention relates to the use of a kynurenine 3-hydroxylase inhibitor for the manufacture of a medicament for the treatment of early non-insulin-dependent diabetes.
  • the present invention relates to the use of a kynurenine 3-hydroxylase inhibitor for the manufacture of a medicament for the treatment of late non-insulin-dependent diabetes.
  • the present invention relates to pharmaceutical compositions comprising a kynurenine 3-hydroxylase inhibitor in combination with one or more immunosuppressants.
  • the present invention also relates to the 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.
  • the present invention relates to any of the uses mentioned above in the case of a patient with an impairment in the number of islets of Langerhans cells.
  • the impairment in the number of islets of Langerhans cells represents a decrease of at least 40% in the number of cells, more preferably a decrease of between 50% and 90%, and even more preferably between 60% and 85%.
  • the present invention relates to any of the uses mentioned above in the case of a patient presenting anti-islets of Langerhans cells immunological markers.
  • the present invention relates to any of the uses mentioned above in the case of a patient presenting any diabetic risk factor.
  • the present invention relates to any of the uses mentioned above in the case of a patient with insulin resistance.
  • the present invention relates to any of the uses mentioned above in the case of a patient presenting markers, such as glycated haemoglobin at concentrations higher than 7%.
  • the present invention relates to any of the uses mentioned above in the case of a patient whose islets of Langerhans cells show an anomaly of insulin secretion in response to glucose.
  • the present invention relates to any of the uses mentioned above in the case of a patient with related hyperglycaemia and obesity.
  • the present invention relates to any of the uses mentioned above, comprising the in vitro treatment of isolated islets of Langerhans cells with a kynurenine 3-hydroxylase inhibitor.
  • the present invention also relates to the method for the in vitro treatment of isolated islets of Langerhans cells with a kynurenine 3-hydroxylase inhibitor.
  • the culturing and transplantation of the said islets of Langerhans cells may especially be performed by application or adaptation of the methods described by Jardinerty et al., Current Opinion in Pharmacology.2001, 1 :641-650.
  • prediabetes means a condition characterised by one or more of the following factors: the presence of anti-islets of Langerhans cells immunological markers, an impairment in the number of islets of Langerhans cells, suppression of the early peak of insulin secretion, glucose intolerance, an impairment tin fasting glycaemia and/or any diabetic risk factor.
  • the expression “impairment in fasting glycaemia and/or glucose intolerance” means 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.
  • the expression “anti-islets of Langerhans cells immunological markers” means any immunological marker indicating the existence of an autoimmune response of the body directed against the antigenic markers of the body's islets of Langerhans cells.
  • markers include auto-antibodies, such as those described by Buysschaert et al., Louvain Med. 119, S251-S258, 2000.
  • These antibodies 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.
  • the expression “impairment in the number of islets of Langerhans cells” means a decrease of at least 40% in the number of cells.
  • the impairment in the number of islets of Langerhans cells represents a decrease of at least 40% in the number of cells, more preferably a decrease of between 50% and 90% and even more preferably between 60% and 85%.
  • the expression “anomaly of insulin secretion in response to glucose” means any impairment in the normal capacity of the islets of Langerhans cells to secrete insulin in response to glucose.
  • the expression “diabetic risk factor” means any complaint directly or indirectly associated with the appearance of diabetes. These especially comprise familial history, gestational diabetes, excess weight, obesity, insufficient physical exercise, high blood pressure, a high level of triglycerides, inflammation, hyperlipidaemia, etc.
  • the term “immunosuppressant” means any physical agent (for example x-rays) chemical agent (for example azathioprine or mercaptopurine) or biological agent (for example anti-lymphocyte serum) for reducing or inhibiting the stimulation of an immune response of the body with an antigen.
  • physical agent for example x-rays
  • chemical agent for example azathioprine or mercaptopurine
  • biological agent for example anti-lymphocyte serum
  • the term “islets of Langerhans cells” means the alpha, beta, delta and PP cells mentioned above; more preferably, the islets of Langerhans cells represent the beta cells.
  • the compounds corresponding to the general formula (I) or to the general formula (II) described hereinbelow generally have inhibitory activity on kynurenine 3-hydroxylase.
  • some families of compounds are known to have activity that is useful in the treatment of diabetes, and especially the families of compounds corresponding to patent application WO-A-98/07681 and the families corresponding to patent application EP-A-0 885 869.
  • the compounds with substantial activity on kynurenine 3-hydroxylase are especially preferred.
  • the term “substantial activity” means any inhibitory activity on the enzyme by the in vitro test process defined below, thus making it possible to obtain an effective therapeutic action on the enzyme.
  • an enzymatic activity of less than or equal to 70%, advantageously less than or equal to 50% and even more preferably less than or equal to 30% relative to the control, is preferred.
  • the compounds of family Ih are found to be noteworthy kynurenine 3-hydroxylase inhibitors and agents for increasing the mass of beta cells, especially antidiabetic agents.
  • Confirmation of the existence of inhibitory activity on kynurenine 3-hydroxylase may be made by any known means and especially, in a particularly simple manner, by subjecting the compound to an in vitro test that will be defined hereinbelow.
  • the compounds with inhibitory activity on kynurenine 3-hydroxylase belong to the general formula (I) or to the general formula (II) below: in which:
  • W represents a divalent radical chosen from the following radicals:
  • R 1 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;
  • R 2 is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl and a heterocyclic radical;
  • R 3 is chosen from hydrogen, a halogen atom, hydroxyl, thiol, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, cycloalkyl and a heterocyclic radical;
  • R 2 and R 3 together also possibly forming a group ⁇ CR 16 R 17 ; or alternatively together forming, with the carbon atom that bears them, a cycloalkyl radical or a heterocyclic radical;
  • R 4 is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —N(R 12 R 12′ ), —N(R 12 )OR 13 , linear or branched alkyl containing from 1 to 14 carbon atoms and optionally substituted, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and a heterocyclic radical;
  • R 5 , R 6 , R 7 and R 8 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;
  • radicals R 5 and R 6 on the one hand, or R 6 and R 7 , 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;
  • R 9 represents hydrogen organ alkyl radical
  • R 10 is chosen from an alkyl, an aryl and a heteroaryl radical
  • R 12 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 R 12 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;
  • R 13 is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, heteroaryl, —N(R 12 R 12′ ) or —N(R 12 )OR 13 radical;
  • R 14 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; R 14 may also form a bond with R 2 , thus forming a double bond between the carbon atoms respectively bearing the substituents R 14 and R 2 ; or alternatively R 14 forms, with R 2 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,
  • R 15 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;
  • R 14 and R 15 also possibly forming, together with the carbon atom that bears them, a cycloalkyl radical or a heterocyclic radical;
  • R 16 and R 17 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
  • R 16 and R 17 form, together with the carbon atom that bears them, a cycloalkyl radical or a heterocyclic radical;
  • R 11 is chosen from hydrogen and an alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl radical, and any protecting group for is an amine function;
  • halogen atom denotes a fluorine, chlorine, bromine or iodine atom.
  • alkyl denotes a linear or branched alkyl radical containing from 1 to 6 carbon atoms, optionally substituted by one or more chemical groups chosen from hydroxyl, carboxyl, cyano, nitro, —N(R 12 R 12′ ), —N(R 12 )OR 13 , aryl, heteroaryl, cycloalkyl, heterocyclic radical, alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, halogen atom, trifluoromethyl, thiol, —SR 13′ , —S(O)R 13′ and —S(O 2 )R 13′ , with R 13′ having the same definition as R 13 , with the exception of hydrogen.
  • the possible substituents on the alkyl radical containing from 1 to 14 carbon atoms may be identical to those described above.
  • alkenyl denotes an alkenyl radical containing one or more double bonds; the said radical, which is linear or branched, and which contains from 2 to 6 carbon atoms, is optionally substituted by one or more chemical groups chosen from hydroxyl, carboxyl, cyano, nitro, —N(R 12 R 12′ ), —N(R 12 )OR 13 , aryl, heteroaryl, cycloalkyl, heterocyclic radical, alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, halogen atom, trifluoromethyl, thiol, —SR 13′ , —S(O)R 13′ and —S(O 2 )R 13′ , with R 13′ having the same definition as R 13 , with the exception of hydrogen.
  • alkynyl denotes an alkynyl radical containing one or more triple bonds; the said radical, which is linear or branched, and which contains from 2 to 6 carbon atoms, is optionally substituted by one or more chemical groups chosen from hydroxyl, carboxyl, cyano, nitro, —N(R 12 R 12′ ), —N(R 12 )OR 13 , aryl, heteroaryl, cycloalkyl, heterocyclic radical, alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, halogen atom, trifluoromethyl, thiol, —SR 13′ , —S(O)R 13′ and —S(O 2 )R 13′ , with R 13′ having the same definition as R 13 , with the exception of hydrogen.
  • alkoxy should be understood as being “alkyl”+“oxy”, in which the term “alkyl” is as defined above.
  • the substituents of the alkoxy radical are identical to those defined for the alkyl radical.
  • cycloalkyl denotes a bridged or non-bridged monocyclic, bicyclic or tricyclic cycloalkyl radical containing from 3 to 13 carbon atoms, optionally substituted by one or more chemical groups, which may be identical or different, chosen from hydroxyl, carboxyl, cyano, nitro, —N(R 12 R 12′ ), —N(R 12 )OR 13 , aryl, heteroaryl, cycloalkyl, heterocyclic radical, alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, halogen atom, trifluoromethyl, thiol, —SR 13′ , —S(O)R 13′ and —S(O 2 )R 13′ , with R 13′ having the same definition as R 13 , with the exception of hydrogen.
  • cycloalkenyl denotes a cycloalkyl radical as defined above comprising at least one double bond.
  • heterocyclic radical denotes a monocyclic or bicyclic radical 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 being optionally substituted by one or more chemical groups, which may be identical or different, chosen from hydroxyl, carboxyl, cyano, nitro, —N(R 12 R 12′ ), —N(R 12 )OR 13 , aryl, heteroaryl, cycloalkyl, heterocyclic radical, alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, halogen atom, trifluoromethyl, thiol, —SR 13′ , —S(O)R 13′ and —S(O 2 )R 13′ , with R 13′ having the same definition as R
  • aryl denotes a monocyclic, bicyclic or tricyclic aryl radical containing from 6 to 14 carbon atoms, optionally substituted by one or more chemical groups, which may be identical or different, chosen from hydroxyl, carboxyl, cyano, nitro, —N(R 12 R 12′ ) —N(R 12 )OR 13 ; aryl, heteroaryl, cycloalkyl; heterocyclic: radical, alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, halogen atom, trifluoromethyl, thiol, —SR 13′ , —S(O)R 13′ and —S(O 2 )R 13′ , with R 13′ having the same definition as R 13 , with the exception of hydrogen.
  • heteroaryl denotes a monocyclic or bicyclic heteroaryl radical 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 heteroaryl radical being optionally substituted by one or more chemical groups, which may be identical or different, chosen from hydroxyl, carboxyl, cyano, nitro, —N(R 12 R 12′ ), —N(R 12 )OR 13 , aryl, heteroaryl, cycloalkyl, heterocyclic radical, alkyl, alkenyl, alkynyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, halogen atom, trifluoromethyl, thiol, —SR 13′ , —S(O)R 13′ and —S(O 2 )R 13′ , with R 13′ having the same definition as R 13 , with the exception of hydrogen.
  • a preferred aryl radical is the phenyl radical or the 1-naphthyl, 2-naphthyl or fluorenyl radical.
  • alkyl and alkoxy radicals substituted by an aryl radical the benzyl, benzyloxy, phenethyl, phenylethoxy, naphthylmethyl and naphthylmethoxy radicals are particularly preferred.
  • cycloalkyl radicals that are preferred are cyclopropyl, cyclopentyl, cyclohexyl, the adamantyl radical and radicals derived from tetralin and from decalin.
  • heteroaryl radical and “heterocyclic radical” preferably mean a pyridyl, furyl, thienyl, 1-quinolyl, 2-quinolyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, morpholino, piperazinyl, piperidyl, pyranyl, thiopyranyl, indanyl, benzothienyl or benzofuryl radical.
  • the term “geometrical isomer” means a cis/trans or E/Z isomerism. More particularly, for the compounds of the formula (I) and when R 14 forms a bond with R 2 , thus forming a double bond between the carbon atoms respectively bearing the substituents R 14 and R 2 , this double bond may be of E or Z configuration.
  • geometrical isomers which may or may not be pure, alone or as a mixture, form an integral part of the compounds of the formula (I).
  • optical isomer includes all the forms of isomers, alone or as mixtures, arising from the presence of one or more axes and/or centres of symmetry in the molecule, and resulting in the rotation of a beam of polarised light.
  • optical isomer more particularly includes the enantiomers and diastereoisomers, in pure form or as a mixture.
  • acids capable of forming pharmaceutically acceptable salts with the compounds of the formula (I) or of the formula (II) above include hydrochloric acid, phosphoric acid, sulfuric acid, tartaric acid, citric acid, maleic acid, acetic acid, fumaric acid, alkylsulfonic acid and camphoric acid.
  • bases capable of forming pharmaceutically acceptable salts with the compounds of the formula (I) or of the formula (II) above include sodium hydroxide, potassium hydroxide, diethylamine, triethylamine, ethanolamine, diethanolamine, arginine and lysine.
  • the compounds of the formulae (I) and (II) above also comprise the prodrugs of these compounds.
  • prodrugs means compounds which, once administered to the patient, are chemically and/or biologically transformed by the living body, into compounds of the formula (I) or (II).
  • prodrugs of compounds of the formula (I) above are those for which R 4 represents a radical —OP, in which P is a leaving group, for example a sugar residue, such as sucrose, which can thus lead to compounds in which R 4 represents —OH.
  • P is a leaving group
  • Such prodrugs are included in the field of the present invention.
  • the compounds of the formula (I) that are preferred are those having the following characteristics, taken separately or in combination:
  • W represents a divalent radical chosen from the following radicals:
  • R 1 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;
  • R 2 is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl, alkyl, alkenyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl and aryl;
  • R 3 is chosen from hydrogen, a halogen atom, hydroxyl, thiol, alkyl, alkenyl, alkoxy, alkylthio and aryl;
  • R 2 and R 3 together also possibly forming a group ⁇ CR 16 R 17 ;
  • R 4 is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —N(R 12 R 12′ ), —N(R 12 )OR 13 , linear or branched alkyl containing from 1 to 14 carbon atoms and optionally substituted, cycloalkyl, cycloalkenyl, aryl, heteroaryl and a heterocyclic radical;
  • R 12 and R 12′ which may be identical or different, are chosen, is independently of each other, from hydrogen and an alkyl, alkenyl, alkynyl, alkylcarbonyl, aryl or heteroaryl radical;
  • R 13 is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, —N(R 12 R 12′ ) or —N(R 12 )OR 13 radical;
  • R 14 is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl, alkyl, alkenyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, aryl and arylalkyl; R 14 may also form a bond with R 2 , thus forming a double bond between the carbon atoms respectively bearing the substituents R 14 and R 2 ; or alternatively R 14 forms, with R 2 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;
  • R 15 is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl, alkyl, alkenyl, alkylcarbonyl, alkoxycarbonyl, alkoxy, alkylthio and aryl;
  • R 16 is chosen from hydrogen and an alkyl or aryl radical
  • R 17 represents a hydrogen atom
  • R 11 is chosen from hydrogen and any protecting group for an amine function
  • this invention relates to the use of compounds of the, formula (Ia) that have inhibitory activity on kynurenine 3-hydroxylase, for the preparation of a medicament for the prevention and/or treatment of diabetes.
  • These compounds of the formula (Ia) have the general structure (I) as defined above, in which:
  • W represents a divalent radical chosen from the following radicals:
  • R 1 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;
  • R 2 is chosen from hydrogen, a halogen atom, hydroxyl, thiol, carboxyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl and a heterocyclic radical;
  • R 3 is chosen from hydrogen, a halogen atom, hydroxyl, thiol, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, cycloalkyl and a heterocyclic radical;
  • R 2 and R 3 together also possibly forming a group ⁇ CR 16 R 17 , or alternatively forming, together with the carbon atom that bears them, a cycloalkyl radical or a heterocyclic radical;
  • R 4 is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —N(R 12 R 12′ ), —N(R 12 )OR 13 , linear or branched alkyl containing from 1 to 14 carbon atoms and optionally substituted, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and a heterocyclic radical;
  • R 12 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 R 12 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;
  • R 13 is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, heteroaryl, —N(R 12 R 12′ ) or —N(R 12 )OR 13 radical;
  • R 14 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; R 14 may also form a bond with R 2 , thus forming a double bond between the carbon atoms respectively bearing the substituents R 14 and R 2 ; or alternatively R 14 forms, with R 2 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,
  • R 15 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;
  • R 14 and R 15 also possibly forming, together with the carbon atom that bears them, a cycloalkyl radical or a heterocyclic radical;
  • R 16 and R 17 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 R 16 and R 17 form, together with the carbon atom that bears them, a cycloalkyl radical or a heterocyclic radical; and
  • R 11 is chosen from hydrogen and an alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl radical, and any protecting group for an amine function;
  • R 15 is other than an alkyl radical, optionally substituted by aryl, heteroaryl, cycloalkyl and a heterocyclic radical;
  • W represents a divalent radical chosen from the radicals:
  • R 1 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 —SR 13′ , —S(O)R 13′ and —S(O 2 )R 13′ , and a halogen atom;
  • R 2 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;
  • R 3 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;
  • R 2 and R 3 together also possibly forming a group ⁇ CR 16 R 17 ;
  • R 4 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(R 12 R 12′ ) and —N(R 12 )OR 13 ;
  • R 12 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;
  • R 13 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;
  • R13′ 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(R 12 R 12′ );
  • R 14 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; R 14 may also form a bond with R 2 , thus forming a double bond between the carbon atoms respectively bearing the substituents R 14 and R 2 ;
  • R 15 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;
  • R 16 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
  • R 17 represents a hydrogen atom
  • R 15 is other than an alkyl radical, optionally substituted by aryl, heteroaryl, cycloalkyl and a heterocyclic radical;
  • the compounds (Ib) defined above show entirely advantageous inhibitory activity on kynurenine 3-hydroxylase.
  • these compounds are most particularly preferred and simple to use for any of the abovementioned uses according to the invention.
  • this invention relates to the use of compounds of the family (Ic) as kynurenine 3-hydroxylase inhibitors in any of the abovementioned uses according to the invention.
  • These compounds of family (Ic) have the general structure (I) as defined above, in which:
  • W represents the divalent radical:
  • R 1 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;
  • R 2 represents hydrogen
  • R 3 represents hydrogen
  • R 4 is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —N(R 12 R 12′ ) and —N(R 12 )OR 13 ;
  • R 12 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 R 12 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;
  • R 13 is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, heteroaryl, —N(R 12 R 12′ ) or —N(R 12 )OR 13 radical;
  • R 14 represents hydrogen
  • R 15 represents hydrogen
  • the invention relates to the use of compounds of the family (Id) as kynurenine 3-hydroxylase inhibitors in any of the above-mentioned uses according to the invention, the said compounds (Id) having the general structure (I) as defined above, in which:
  • W represents the divalent radical:
  • R 1 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;
  • R 2 represents hydrogen
  • R 3 represents hydrogen
  • R 4 is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —N(R 12 R 12′ ) and —N(R 12 )OR 13 ;
  • R 12 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 R 12 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;
  • R 13 is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, heteroaryl, —N(R 12 R 12′ ) or —N(R 12 )OR 13 radical;
  • R 14 represents hydrogen
  • R 15 is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, cycloalkyloxy, heteroaryloxy and heterocyclyloxy;
  • Another preferred group of compounds consists of the compounds of family (Ie) as kynurenine 3-hydroxylase inhibitors in any of the abovementioned uses according to the invention, the said compounds (Ie) belonging to the general formula (I) as defined above, in which:
  • W represents the divalent radical:
  • R 1 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;
  • R 2 and R 14 together form a bond, thus forming a double bond between the carbon atoms respectively bearing R 2 and R 14 ;
  • R 3 represents hydrogen
  • R 4 is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —N(R 12 R 12′ ) and —N(R 12 )OR 13 ;
  • R 12 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 R 12 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;
  • R 13 is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, heteroaryl, —N(R 12 R 12′ ) or —N(R 12 )OR 13 radical;
  • R 15 represents hydrogen
  • this invention relates to the use of compounds of family (If) as kynurenine 3-hydroxylase inhibitors in any of the abovementioned uses according to the invention, the said compounds (If) belonging to the general formula (I) as defined above, in which:
  • W represents the divalent radical:
  • R 1 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;
  • R 2 and R 14 together form a bond, thus forming a double bond between the carbon atoms respectively bearing R 2 and R 14 ;
  • R 3 represents hydrogen
  • R 4 is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —N(R 2 R 2 ′) and —N(R 2 )OR 13 ;
  • R 12 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 R 12 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;
  • R 13 is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, heteroaryl, —N(R 12 R 12′ ) or —N(R 12 )OR 13 radical;
  • R 15 is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, cycloalkyloxy, heteroaryloxy and heterocyclyloxy;
  • the compounds are chosen from the family of compounds (Ig) consisting of:
  • W represents the divalent radical:
  • R 15 is chosen from a thiol, alkylthio, alkenylthio, alkynylthio, arylthio, cycloalkylthio, heteroarylthio or heterocyclylthio radical;
  • R 15 cannot represent a thiol or alkylthio radical
  • the compounds of family (Ih) form a particularly preferred aspect of the present invention.
  • the compounds of family (Ih) have entirely noteworthy hypoglycaemiant properties and, in this respect, are useful as kynurenine 3-hydroxylase inhibitors in any of the abovementioned uses according to the invention.
  • the compounds of family (Ih) show inhibitory activity on kynurenine 3-hydroxylase that may be linked to the observed effect on the increase in the mass of beta cells, especially in the case of diabetes.
  • a preferred subfamily of the compounds of the family (Ih) consists of the compounds of the family (Ii) belonging to the general formula (I) in which:
  • W represents the divalent radical:
  • R 1 represents an aryl radical
  • R 2 represent hydrogen, or forms a bond with R 14 ;
  • R 3 represents hydrogen
  • R 4 is chosen from hydroxyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, —N(R 12 R 12′ ) and —N(R 12 )OR 13 ;
  • R 12 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 R 12 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;
  • R 13 is chosen from hydrogen and an alkyl, alkenyl, alkynyl, aryl, heteroaryl, —N(R 12 R 12′ ) or —N(R 12 )OR 13 radical;
  • R 14 represents hydrogen, or forms a bond with R 2 ;
  • R 15 represents an arylthio radical
  • W represents the divalent radical:
  • R 1 represents a phenyl radical
  • R 2 represents hydrogen
  • R 3 represents hydrogen
  • R 4 is chosen from hydroxyl and an alkoxy radical
  • R 14 represents hydrogen
  • R 15 represents a phenylthio radical
  • examples of compounds of family (Ih) are:
  • the compounds of the formula (I) are different from:
  • R 5 , R 6 , R 7 and R 8 are as defined above;
  • R 9 represents hydrogen
  • R 10 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;
  • R 5 , R 6 , R 7 and R 8 which may be identical or different, are chosen, independently of each other, from hydrogen, a halogen atom, a nitro radical and a trifluoromethyl radical;
  • radicals R 6 and R 7 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
  • R 9 and R 10 are as defined above;
  • the compounds of the formula (II) are chosen from the list consisting of:
  • the compounds that are preferred according to the invention are those with substantial inhibitory activity on kynurenine 3-hydroxylase as defined above.
  • compositions according to the invention thus comprise as active principle a pharmacologically effective amount of at least one kynurenine 3-hydroxylase inhibitor, preferably a compound of the formula (I) or of the formula (II), alone or in combination with one or more fillers, vehicles, colorants or sweeteners, i.e. any suitable and pharmaceutically acceptable non-toxic, inert excipient usually used in the production of pharmaceutical compositions.
  • compositions are administered to patients in need thereof, i.e. to individuals whose condition might be prevented or improved by increasing the number of islets of Langerhans cells.
  • the kynurenine 3-hydroxylase inhibitors may be useful in combination with an active agent usually used in the treatment of diabetes, as a main active principle or as an adjuvant and/or potentiator of the said agent.
  • compositions thus obtained will be in various forms, the most advantageous being gel capsules, suppositories, injectable or drinkable solutions, patches, plain, sugar-coated, film-coated or sublingual tablets, sachets, packets, lozenges, creams, ointments, dermal gels, aerosols, etc.
  • the working dose may be adapted according to the nature and severity of the pathology to be treated, the administration route and also the patient's age and weight.
  • the unit dose will range between 5 mg and 2000 mg per day, in one or more dosage intakes, advantageously between 10 mg and 1000 mg, for example between 50 mg and 800 mg.
  • the kynurenine 3-hydroxylase inhibitors have the twofold activity of controlling the secretion of both glucagon and insulin. Specifically, in the absence of glucose, the secretion of glucagon is stimulated whereas that of insulin is not. In the presence of glucose, the secretion of insulin is potentiated whereas the secretion of glucagon remains normally inhibited.
  • the invention also relates to a process for increasing the number of islets of Langerhans cells, comprising the administration, to a patient requiring it, of a dose of one or more compounds that inhibit kynurenine 3-hydroxylase of the formula (I) or of the formula (II) defined above, such that it produces a substantial inhibition of kynurenine 3-hydroxylase in the patient.
  • the process defined above allows the prevention or treatment of diabetes and/or its complications, especially in the case of patients presenting the characteristics of the diabetes pathology, without this pathology yet having been declared.
  • the criteria for diagnosing this pathology are defined, for example, in Diabetes Care, vol. 25, suppl. 1, January 2002.
  • the compounds of the formulae (I) and (II) defined above have been found to be useful in the prevention and/or treatment of diabetes and its complications, by increasing the number of islets of Langerhans cells, according to a mode of action that is hitherto unknown in this therapeutic field.
  • the invention also relates to a process for manufacturing medicaments for increasing the number of islets of Langerhans cells, especially for the the treatment and/or prevention of diabetes and its complications, by inhibiting kynurenine 3-hydroxylase, in which at least one compound of the formula (I) or (II) 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.
  • the invention also relates to a process for screening candidate compounds for activity in increasing the number of islets of Langerhans cells, especially for the the treatment and/or prevention of diabetes or its complications, by inhibiting kynurenine 3-hydroxylase, the said candidates not corresponding to formula (I) or (II), 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.
  • Infrared spectrometry (cm ⁇ 1 ): 1702.8; 1680.7; 1595.0; 1435.2; 1326.6; 1217.6.
  • silica, eluent methylcyclohexane, ethyl acetate, acetic acid (50/45/5): Rf: 0.53.
  • the reaction medium is left at 20° C. for 72 hours and then concentrated under vacuum.
  • the crude oil isolated is then purified on a column of silica (eluent: 90/10 cyclohexane/ethyl acetate).
  • Infrared spectrometry (cm ⁇ 1 ): 1730.6; 1685.1; 1493.9; 1448.8; 1287.6; 1248.21; 1213.6.
  • Rat livers are homogenised (1:8 weight/volume) in a buffer solution comprising: 0.25 M sucrose; 50 mM pH 7.4 Tris; 1 mM EDTA; and 1 mM DTT.
  • the homogenates are centrifuged for 10 minutes at 12000 rpm.
  • the pellets are resuspended in the buffer solution described above (1:2 weight/volume).
  • the kynurenine 3-hydroxylase inhibition is determined by incubating 10 ⁇ L of the homogenate with NADPH (2 mM), kynurenine (100 ⁇ M) and various concentrations of the test compounds in a final volume of 100 ⁇ L at 37° C. for 5 minutes.
  • (R)-2-benzyl-4-(4-fluorophenyl)-4-oxobutanoic acid (compound i) has an IC 50 value of 1 ⁇ 0.2 ⁇ mol/L
  • 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide (compound k) has an IC 50 value of 10 ⁇ 2.1 ⁇ mol/L.
  • the antidiabetic activity of the compounds of the formulae (I) and (II) orally was determined on an experimental model of non-insulin-dependent diabetes, induced in rats with steptozotocin.
  • the model of non-insulin-dependent diabetes is obtained in the rats by means of a neonatal injection (on the day of birth) of steptozotocin.
  • the diabetic rats used are eight weeks old.
  • the animals are housed, from the day of birth to the day of the experiment, in an animal house at a regulated temperature of 21 to 22° C. and subjected to a fixed cycle of light (from 7 a.m. to 7 p.m.) and darkness (from 7 p.m. to 7 a.m.).
  • Their food consisted of a maintenance diet, and water and food were given “ad libitum”, with the exception of fasting two hours before the tests, during which period the food is removed (post-absorptive state).
  • the rats are treated orally for one (D1) or four (D4) days with the test product. Two hours after the final administration of the product and 30 minutes after anaesthetising the animals with pentobarbital sodium (Nembutal®), a 300 ⁇ L blood sample is taken from the end of the tail.
  • D1 or D4 days Two hours after the final administration of the product and 30 minutes after anaesthetising the animals with pentobarbital sodium (Nembutal®), a 300 ⁇ L blood sample is taken from the end of the tail.
  • the compounds of the family (Ih), especially the compounds of the subfamily (Ii), in particular compound Ih-1 defined previously (2-(2′-naphthylthio)-4-phenyl-4-oxobutanoic acid) and compound Ih-3 of the subfamily (Ij) (2-(4′-fluorophenylthio)-4-phenyl-4-oxobutanoic acid) were evaluated according to the experimental protocol described above.
  • This antidiabetic activity is correlated with an inhibitory effect of this family of molecules on kynurenine 3-hydroxylase.
  • the hepatocytes are isolated from the liver of Wistar rats fasted for 24 hours, according to the method described in Methods Cell Biol., 13 (1975), 29-83.
  • the hepatocytes are cultured for 16 to 18 hours in DMEM medium in the presence of AMP cyclase/dexamethasone at respective concentrations of 5 ⁇ 10 ⁇ 5 M and 5 ⁇ 10 ⁇ 7 M, with preincubation of the products at the test doses. After washing in pH 7.4 PBS buffer, the cells are incubated for three hours at 37° C. in a Krebs/AMPc/DEX buffer at the abovementioned concentrations. 0.1 ⁇ M insulin is used as reference substance. Two identical experiments are performed (Table III-1).
  • the hepatocytes are cultured for 16 to 18 hours in RPMI 1640 medium free of glucose but supplemented with 1% glutamine, 100 U/mL penicillin, 100 mg/mL streptomycin and 7 ⁇ 10 ⁇ 5 M hydrocortisone hemisuccinate.
  • Quantification of the glucose is performed via a calorimetric method using glucose oxidase (IL testTM Glucose, Monarch 181633-80).
  • the protein assay is performed on the rest of the incubation medium via the Lowry method (BIO-RAD Dc protein assay, BIO-RAD 5000116).
  • the results are expressed as nmoles of glucose produced per ng of proteins.
  • the statistical test used is the t test.
  • tryptophan and kynurenine are powerful inhibitors of hepatic glucose production in vitro.
  • pancreas is taken from animals rendered diabetic by injection of streptozotocin on the day of birth (Portha et al., Diabetes, 23: 889-895; (1974)) and anaesthetised with pentobarbital (Nembutal: 45 mg/kg; intraperitoneal route).
  • pancreas The isolation and perfusion of the pancreas were performed according to a modification (Assan et al., Nature, 239 (1972), 125-126) of the protocol described by Sussman et al. ( Diabetes, 15 (1966), 466-472).
  • the concentration of the hormones, insulin and glucagon, secreted into the medium is measured via a competitive radioimmunoassay using the kits: Insulin-CT Cis Bio-International, Schering and Glucagon-10904-Biochem immuno system, respectively.
  • results are expressed as the mean ⁇ SEM (standard error of mean) of several experiments.
  • the statistical test used is the Scheffé test.
  • FIG. 1 shows that tryptophan stimulates insulin secretion in a glucose-dependent manner in a diabetic rat pancreas.
  • FIG. 2 shows that tryptophan stimulates glucagon secretion in a glucose-dependent manner in a diabetic rat pancreas.
  • Kynurenic acid like tryptophan, stimulates the secretion of insulin ( FIG. 3 ) and of glucagon ( FIG. 4 ) in a glucose-dependent manner in a diabetic rat pancreas.
  • FIG. 5 and FIG. 6 show the secretion profile for insulin and glucagon, respectively, stimulated with kynurenine (at 10 ⁇ 4 M and 10 ⁇ 5 M) in a glucose-dependent manner in a diabetic rat pancreas. This stimulation is similar to that obtained with tryptophan and kynurenic acid.
  • the kynurenine 3-hydroxylase inhibitors show the same insulin and glucagon secretion profile as for tryptophan, kynurenine and kynurenic acid. This observation may be seen in FIGS. 7 and 8 (stimulation of insulin and of glucagon, respectively, with compound i) and in FIGS. 9 and 10 (stimulation of insulin and of glucagon, respectively, with compound k).
  • the insulin secretion is assayed by RIA in the incubation medium.
  • the potential of the various chemical compounds to stimulate insulin secretion is estimated by calculating the stimulation factor*.
  • a compound stimulates the secretion of insulin if this factor is greater than or equal to 130% for a given dose of insulin.
  • ⁇ NB ⁇ : ⁇ ⁇ stimulation ⁇ ⁇ factor ( G + Product ) * 100 G
  • FIG. 11 shows the insulin secretion for compounds Ih-18 and (i) at 10 ⁇ 5 M at glucose concentrations of 2.8 mM and 8 mM.
  • Embryonic pancreases are collected on day 12.5 of gestation from gestating females of the Wistar strain, which have received an overdose of sodium pentobarbital.
  • the embryos are extracted from the uterus and placed in phosphate-buffered saline (PBS).
  • PBS phosphate-buffered saline
  • the dorsal pancreatic bud is dissected under stereomicroscopy.
  • the separation of the mesenchyme, which inhibits the development of the endocrine pancreas, is performed via an enzymatic reaction with 0.05% concentrated collagenase A in the synthetic culture medium RPMI 1640.
  • pancreatic epithelia thus isolated are inserted into a collagen gel, which allows three-dimensional culturing to be performed.
  • the pancreases are cultured in the RPMI 1640 culture medium supplemented with 10% foetal calf serum and 5.5 mM glucose and in the absence (control) or in the presence of the test compounds.
  • the cultures are maintained at 37° C. in the presence of 5% CO 2 for seven days.
  • the culture medium is renewed every day.
  • pancreases are isolated from the collagen gels and dissociated into individual cells by means of a trypsin digestion (0.05% trypsin-EDTA) for three minutes at 37° C.
  • the enzymatic reaction is quenched by adding RPMI 1640 medium containing 20% foetal calf serum.
  • the cells are washed with the same medium and then fixed to glass slides using a cytocentrifuge for five minutes at 125 ⁇ g.
  • the cells are then treated with 4% paraformaldehyde, and then incubated overnight at 4° C. with guinea pig anti-insulin antibody (1:1 500 dilution).
  • FIGS. 12, 13 , 14 and 15 represent the amount of beta cells expressing insulin in the cultured rat foetal pancreatic buds over seven days, with or without test compound.
  • the increase in the number of beta cells is mainly due to stimulation of the neogenesis of these cells from the stems cells.

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FR03-00-107 2003-01-07
FR0300107A FR2849599B1 (fr) 2003-01-07 2003-01-07 Utilisation d'inhibiteurs de la kynurenine-3-hydroxylase pour le traitement du diabete
FR03-14-0263 2003-12-04
FR0314263A FR2849598B1 (fr) 2003-01-07 2003-12-04 Utilisation d'inhibiteurs de la kynurenine-3-hydroxylase pour le traitement du diabete, par augmentation du nombre de cellules des ilots de langerhans
PCT/EP2003/014538 WO2004060368A1 (en) 2003-01-07 2003-12-18 Kynurenine 3-hydroxylase inhibitors for the treatment of diabetes by increasing the number of islets of langerhans cells

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US20080070905A1 (en) * 2006-08-16 2008-03-20 J. David Gladstone Institutes Small molecule inhibitors of kynurenine-3-monooxygenase
US20080070937A1 (en) * 2006-08-16 2008-03-20 J. David Gladstone Institutes Small molecule inhibitors of kynurenine-3-monooxygenase
US20100273872A1 (en) * 2007-12-03 2010-10-28 Valerie Autier Use of 4-oxobutanoic acid derivatives in the treatment of pathologies associated with immunological disorders

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FR2849598B1 (fr) * 2003-01-07 2006-09-22 Merck Sante Sas Utilisation d'inhibiteurs de la kynurenine-3-hydroxylase pour le traitement du diabete, par augmentation du nombre de cellules des ilots de langerhans
KR20110042026A (ko) * 2008-03-12 2011-04-22 유니버시티 오브 마이애미 저혈당증의 치료 및 검출을 위한 분석 및 방법
PL228037B1 (pl) * 2009-03-23 2018-02-28 Marciniak Agnieszka Maria Zastosowanie kwasu kynureninowego w zapobieganiu lub leczeniu chorób trzustki
US8329149B2 (en) 2009-12-30 2012-12-11 Avon Products, Inc. Topical lightening composition and uses thereof
US8609717B2 (en) 2010-08-18 2013-12-17 Samumed, Llc β- and γ-diketones and γ-hydroxyketones as WNT/β-catenin signaling pathway activators
ES2709824T3 (es) 2013-02-22 2019-04-17 Samumed Llc Gamma-dicetonas como activadores de la ruta de señalización Wnt/beta-catenina
RU2727039C2 (ru) 2014-08-20 2020-07-17 СЭМЬЮМЕД, ЭлЭлСи Гамма-дикетоны для лечения и профилактики старения кожи и морщин
US20170209401A1 (en) * 2014-09-26 2017-07-27 The University Of British Columbia A combination of kynurenine and antigen presenting cells (apc) as therapeutics and methods for their use in immune modulation

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US20080070905A1 (en) * 2006-08-16 2008-03-20 J. David Gladstone Institutes Small molecule inhibitors of kynurenine-3-monooxygenase
US20080070937A1 (en) * 2006-08-16 2008-03-20 J. David Gladstone Institutes Small molecule inhibitors of kynurenine-3-monooxygenase
US7994338B2 (en) 2006-08-16 2011-08-09 The J. David Gladstone Institutes Small molecule inhibitors of kynurenine-3-monooxygenase
US8071631B2 (en) 2006-08-16 2011-12-06 The J. David Gladstone Institutes, A Testamentary Trust Established Under The Will Of J. David Gladstone Small molecule inhibitors of kynurenine-3-monooxygenase
US8466182B2 (en) 2006-08-16 2013-06-18 The J. David Gladstone Institutes, A Testamentary Trust Established Under The Will Of J. David Gladstone Small molecule inhibitors of kynurenine-3-monooxygenase
US8710237B2 (en) 2006-08-16 2014-04-29 The J. David Gladstone Institute Small molecule inhibitors of kynurenine-3-monooxygenase
US20100273872A1 (en) * 2007-12-03 2010-10-28 Valerie Autier Use of 4-oxobutanoic acid derivatives in the treatment of pathologies associated with immunological disorders

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