Pharmaceutical combinations for the treatment of metabolic disorders   

Abstract: The invention relates to a pharmaceutical composition comprising 1.a and/or 1.b according to claim 1 in combination with at least one second therapeutic agent 2 which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance and hyperglycemia. In addition the present invention relates to methods for preventing or treating of metabolic disorders and related conditions.

FIELD OF THE INVENTION

The invention is directed to pharmaceutical combinations comprising an inhibitor of 11-beta-hydroxysteroid dehydrogenase 1 of formula 1.a or 1.b as one active ingredient in combination with at least one additional active ingredient 2 which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, dyslipidemia/hyperlipidemia.

Furthermore the invention relates to methods for preventing, slowing progression of, delaying, or treating a metabolic disorder; for improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of glycosylated hemoglobin HbA1c; for preventing, slowing, delaying or reversing progression from impaired glucose tolerance, impaired fasting blood glucose, insulin resistance and/or from metabolic syndrome to type 2 diabetes mellitus; for preventing, slowing progression of, delaying or treating of a condition or disorder selected from the group consisting of complications of diabetes mellitus; for reducing the weight or preventing an increase of the weight or facilitating a reduction of the weight; for preventing or treating the degeneration of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells and/or restoring the functionality of pancreatic insulin secretion; for preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat; maintaining and/or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and/or insulin resistance; or preventing, slowing progression of delaying or treating athersclerosis and complications of atherosclerosis; preventing, slowing progression of delaying or treating glaucoma and complications of glaucoma; preventing, slowing progression of delaying or treating dyslipidemia/hyperlipidemia and complications of dyslipidemia/hyperlipidemia; improving glycemic control in patients with type 2 diabetes as an adjunct to diet and exercise; or improving glycemic control in patients with type 2 diabetes

in patients in need thereof characterized in that an inhibitor of 11-beta-hydroxysteroid dehydrogenase 1 of formula 1.a or 1.b as defined hereinafter is administered in combination or alternation with at least one second therapeutic agent 2 as defined hereinafter.

Furthermore the invention relates to methods preventing, slowing progression of delaying or treating athersclerosis and complications of atherosclerosis; or preventing, slowing progression of delaying or treating glaucoma and complications of glaucoma; or preventing, slowing progression of delaying or treating dyslipidemia/hyperlipidemia and complications of dyslipidemia/hyperlipidemia

in patients in need thereof characterized in that an inhibitor of 11-beta-hydroxysteroid dehydrogenase 1 of formula 1.a or 1.b as defined hereinafter is administered to a patient in need thereof.

In addition the present invention relates to the use of an inhibitor of 11-beta-hydroxysteroid dehydrogenase 1 of formula 1.a or 1.b as defined hereinafter for the manufacture of a medicament for use in a method as described hereinbefore and hereinafter.

In addition the present invention relates to the use of at least one second therapeutic agent 2 as defined hereinafter for the manufacture of a medicament for use in a method as described hereinbefore and hereinafter.

The invention also relates to a use of a pharmaceutical composition according to this invention for use in a method as described hereinbefore and hereinafter.

BACKGROUND OF THE INVENTION

The compounds (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (compound 1.a) and 3-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (compound 1.b), solvates, hydrates and pharmaceutically acceptable salts have been disclosed in WO 09/134400 and WO 10/011314 and have the following structure:

Compounds 1.a and 1.b are effective inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 and are therefore promising therapeutic agents for ameliorating or treating disorders or diseases in which decreasing the level of cortisol is effective in treating a disease state.

Type 2 diabetes is an increasingly prevalent disease that due to a high frequency of complications leads to a significant reduction of life expectancy. Because of diabetes-associated microvascular complications, type 2 diabetes is currently the most frequent cause of adult-onset loss of vision, renal failure, and amputations in the industrialized world. In addition, the presence of type 2 diabetes is associated with a two to five fold increase in cardiovascular disease risk.

After long duration of disease, most patients with type 2 diabetes will eventually fail on oral therapy and become insulin dependent with the necessity for daily injections and multiple daily glucose measurements.

The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated that intensive treatment with metformin, sulfonylureas or insulin resulted in only a limited improvement of glycemic control (difference in HbA1c ˜0.9%). In addition, even in patients within the intensive treatment arm glycemic control deteriorated significantly over time and this was attributed to deterioration of β-cell function. Importantly, intensive treatment was not associated with a significant reduction in macrovascular complications, i.e. cardiovascular events.

Therefore there is an unmet medical need for methods, medicaments and pharmaceutical compositions with a good efficacy with regard to glycemic control, with regard to disease-modifying properties and with regard to reduction of cardiovascular morbidity and mortality while at the same time showing an improved safety profile.

The aim of the present invention is to provide a pharmaceutical composition and method for preventing, slowing progression of, delaying or treating a metabolic disorder.

A further aim of the present invention is to provide a pharmaceutical composition and method for improving glycemic control in a patient in need thereof.

Another aim of the present invention is to provide a pharmaceutical composition and method for preventing, slowing or delaying progression from impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or metabolic syndrome to type 2 diabetes mellitus.

Yet another aim of the present invention is to provide a pharmaceutical composition and method for preventing, slowing progression of, delaying or treating of a condition or disorder from the group consisting of complications of diabetes mellitus.

A further aim of the present invention is to provide a pharmaceutical composition and method for reducing the weight or preventing an increase of the weight in a patient in need thereof.

Another aim of the present invention is to provide a new pharmaceutical composition with a high efficacy for the treatment of metabolic disorders, in particular of diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), and/or hyperglycemia, which has good to very good pharmacological and/or pharmacokinetic and/or physicochemical properties.

A further aim of the present invention is to provide a pharmaceutical composition and method for preventing, slowing progression of delaying or treating athersclerosis and complications of atherosclerosis.

A further aim of the present invention is to provide a pharmaceutical composition and method for preventing, slowing progression of delaying or treating glaucoma and complications of glaucoma.

A further aim of the present invention is to provide a pharmaceutical composition and method for preventing, slowing progression of delaying or treating dyslipidemia/hyperlipidemia and complications of dyslipidemia/hyperlipidemia.

Further aims of the present invention become apparent to the one skilled in the art by description hereinbefore and in the following and by the examples.

SUMMARY

Within the scope of the present invention it has now surprisingly been found that a pharmaceutical composition comprising compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof can advantageously be used in combination with at least one second therapeutic agent 2 which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG) and hyperglycemia for preventing, slowing progression of, delaying or treating a metabolic disorder, in particular in improving glycemic control in patients. This opens up new therapeutic possibilities in the treatment and prevention of type 2 diabetes mellitus, overweight, obesity, complications of diabetes mellitus and of neighboring disease states.

Further also within the scope of the present invention is a pharmaceutical composition comprising compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof which can advantageously be used for preventing, slowing progression of delaying or treating athersclerosis and complications of atherosclerosis.

Further also within the scope of the present invention is a pharmaceutical composition comprising compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof which can advantageously be used for preventing, slowing progression of delaying or treating glaucoma and complications of glaucoma.

Further also within the scope of the present invention is a pharmaceutical composition comprising compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof which can advantageously be used for preventing, slowing progression of delaying or treating dyslipidemia/hyperlipidemia and complications of dyslipidemia/hyperlipidemia.

Further also within the scope of the present invention is a pharmaceutical composition comprising compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof which can advantageously be used in combination with at least one second therapeutic agent 2 for preventing, slowing progression of delaying or treating athersclerosis and complications of atherosclerosis.

Further also within the scope of the present invention is a pharmaceutical composition comprising compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof which can advantageously be used in combination with at least one second therapeutic agent 2 for preventing, slowing progression of delaying or treating glaucoma.

Further also within the scope of the present invention is a pharmaceutical composition comprising compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof which can advantageously be used in combination with at least one second therapeutic agent 2 for preventing, slowing progression of delaying or treating dyslipidemia/hyperlipidemia and complications of dyslipidemia/hyperlipidemia.

Further also within the scope of the present invention is a pharmaceutical composition comprising compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof which can advantageously be used in combination with at least one second therapeutic agent 2 as defined below and above, for improving glycemic control in patients with type 2 diabetes.

Further also within the scope of the present invention is a pharmaceutical composition comprising compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof which can advantageously be used in combination with at least one second therapeutic agent 2 as defined below and above, as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

Therefore in a first aspect the present invention provides a pharmaceutical composition comprising a compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof in combination with at least one second therapeutic agent 2 which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, dyslipidemia/hyperlipidemia.

According to another aspect of the invention there is provided a method for preventing, slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, atherosclerosis, glaucoma, dyslipidemia/hyperlipidemia in a patient in need thereof characterized in that a compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof is/are administered in combination or alternation with at least one second therapeutic agent 2 as defined hereinbefore and hereinafter.

According to another aspect of the invention there is provided a method for improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of glycosylated hemoglobin HbA1c in a patient in need thereof characterized in that a compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof is/are administered in combination or alternation with at least one second therapeutic agent 2 as defined hereinbefore and hereinafter.

According to another aspect of the invention there is provided a method for improving glycemic control in patients with type 2 diabetes in a patient in need thereof characterized in that a compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof is/are administered in combination or alternation with at least one second therapeutic agent 2 as defined hereinbefore and hereinafter.

According to another aspect of the invention there is provided a method for improving glycemic control in patients with type 2 diabetes as an adjunct to diet and exercise in a patient in need thereof characterized in that a compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof is/are administered in combination or alternation with at least one second therapeutic agent 2 as defined hereinbefore and hereinafter.

According to another aspect of the invention there is provided a method for slowing progression of delaying or treating athersclerosis and complications of atherosclerosis in a patient in need thereof characterized in that a compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof is/are administered to a patient in need thereof.

According to another aspect of the invention there is provided a method for slowing progression of delaying or treating glaucoma and complications of glaucoma in a patient in need thereof characterized in that a compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof is/are administered to a patient in need thereof.

According to another aspect of the invention there is provided a method for slowing progression of delaying or treating dyslipidemia/hyperlipidemia and complications of dyslipidemia/hyperlipidemia to a patient in need thereof.

The pharmaceutical composition according to this invention may also have valuable disease-modifying properties with respect to diseases or conditions related to impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance, atherosclerosis, glaucoma, dyslipidemia/hyperlipidemia and/or metabolic syndrome.

According to another aspect of the invention there is provided a method for preventing, slowing, delaying or reversing progression from impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or from metabolic syndrome to type 2 diabetes mellitus in a patient in need thereof characterized in that a compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof is/are administered in combination or alternation with at least one second therapeutic agent 2 as defined hereinbefore and hereinafter.

As by the use of a pharmaceutical composition according to this invention an improvement of the glycemic control in patients in need thereof is obtainable, also those conditions and/or diseases related to or caused by an increased blood glucose level may be treated.

According to another aspect of the invention there is provided a method for preventing, slowing the progression of, delaying or treating of a condition or disorder selected from the group consisting of complications of diabetes mellitus such as glaucoma, cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischaemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease, in a patient in need thereof characterized in that a compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof is/are administered in combination or alternation with at least one second therapeutic agent 2 as defined hereinbefore and hereinafter. The term “tissue ischaemia” particularly comprises diabetic macroangiopathy, diabetic microangiopathy, impaired wound healing and diabetic ulcer.

According to another aspect of the invention there is provided a method for reducing the weight or preventing an increase of the weight or facilitating a reduction of the weight in a patient in need thereof characterized in that a compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof is/are administered in combination or alternation with at least one second therapeutic agent 2 as defined hereinbefore and hereinafter.

According to another aspect of the invention there is provided a method for preventing, slowing, delaying or treating the degeneration of pancreatic beta cells and/or the decline of the functionality of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells and/or restoring the functionality of pancreatic insulin secretion in a patient in need thereof characterized in that a compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof is/are administered in combination or alternation with at least one second therapeutic agent 2 as defined hereinbefore and hereinafter.

By the administration of a combination or pharmaceutical composition according to the present invention an abnormal accumulation of fat in the liver may be reduced or inhibited. Therefore according to another aspect of the present invention there is provided a method for preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat in a patient in need thereof c characterized in that a compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof is/are administered in combination or alternation with at least one second therapeutic agent 2 as defined hereinbefore and hereinafter. Diseases or conditions which are attributed to an abnormal accumulation of liver fat are particularly selected from the group consisting of general fatty liver, non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), hyperalimentation-induced fatty liver, diabetic fatty liver, alcoholic-induced fatty liver or toxic fatty liver.

As a result thereof another aspect of the invention provides a method for maintaining and/or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and/or insulin resistance in a patient in need thereof characterized in that a compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof is/are administered in combination or alternation with at least one second therapeutic agent 2 as defined hereinbefore and hereinafter.

According to another aspect of the invention there is provided a compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof for the use in preventing, slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome; or improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of glycosylated hemoglobin HbA1c; or preventing, slowing, delaying or reversing progression from impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or from metabolic syndrome to type 2 diabetes mellitus; or preventing, slowing the progression of, delaying or treating of a condition or disorder selected from the group consisting of complications of diabetes mellitus such as cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischaemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease; or reducing the weight or preventing an increase of the weight or facilitating a reduction of the weight; or preventing, slowing, delaying or treating the degeneration of pancreatic beta cells and/or the decline of the functionality of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells and/or restoring the functionality of pancreatic insulin secretion; or preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat; or maintaining and/or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and/or insulin resistance; or preventing, slowing progression of delaying or treating athersclerosis and complications of atherosclerosis; or preventing, slowing progression of delaying or treating glaucoma and complications of glaucoma; preventing, slowing progression of delaying or treating dyslipidemia/hyperlipidemia and complications of dyslipidemia/hyperlipidemia; or improving glycemic control in patients with type 2 diabetes as an adjunct to diet and exercise; or improving glycemic control in patients with type 2 diabetes

in a patient in need thereof characterized in that the compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof is administered in combination or alternation with at least one second therapeutic agent 2 as defined hereinbefore and hereinafter.

According to another aspect of the invention there is provided least one second therapeutic agent 2 as defined hereinbefore and hereinafter for the use in preventing, slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome; or improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of glycosylated hemoglobin HbA1c; or preventing, slowing, delaying or reversing progression from impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or from metabolic syndrome to type 2 diabetes mellitus; or preventing, slowing the progression of, delaying or treating of a condition or disorder selected from the group consisting of complications of diabetes mellitus such as cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischaemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease; or reducing the weight or preventing an increase of the weight or facilitating a reduction of the weight; or preventing, slowing, delaying or treating the degeneration of pancreatic beta cells and/or the decline of the functionality of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells and/or restoring the functionality of pancreatic insulin secretion; or preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat; or maintaining and/or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and/or insulin resistance; or preventing, slowing progression of delaying or treating athersclerosis and complications of atherosclerosis; or preventing, slowing progression of delaying or treating glaucoma and complications of glaucoma; preventing, slowing progression of delaying or treating dyslipidemia/hyperlipidemia and complications of dyslipidemia/hyperlipidemia; improving glycemic control in patients with type 2 diabetes as an adjunct to diet and exercise; or improving glycemic control in patients with type 2 diabetes

in a patient in need thereof characterized in that the least one second therapeutic agent 2 is administered in combination or alternation with compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof.

According to another aspect of the invention there is provided a pharmaceutical composition according to the present invention for the use for a therapeutic and preventive method as described hereinbefore and hereinafter.

The term “active ingredient” of a pharmaceutical composition according to the present invention means the compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof and/or the second therapeutic ingredient 2.

The term “body mass index” or “BMI” of a human patient is defined as the weight in kilograms divided by the square of the height in meters, such that BMI has units of kg/m2.

The term “overweight” is defined as the condition wherein the individual has a BMI greater than or 25 kg/m2 and less than 30 kg/m2. The terms “overweight” and “pre-obese” are used interchangeably.

The term “obesity” is defined as the condition wherein the individual has a BMI equal to or greater than 30 kg/m2. According to a WHO definition the term obesity may be categorized as follows: the term “class I obesity” is the condition wherein the BMI is equal to or greater than 30 kg/m2 but lower than 35 kg/m2; the term “class II obesity” is the condition wherein the BMI is equal to or greater than 35 kg/m2 but lower than 40 kg/m2; the term “class III obesity” is the condition wherein the BMI is equal to or greater than 40 kg/m2.

The term “visceral obesity” is defined as the condition wherein a waist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 in women is measured. It defines the risk for insulin resistance and the development of pre-diabetes.

The term “abdominal obesity” is usually defined as the condition wherein the waist circumference is >40 inches or 102 cm in men, and is >35 inches or 94 cm in women. With regard to a Japanese ethnicity or Japanese patients abdominal obesity may be defined as waist circumference ≧85 cm in men and ≧90 cm in women (see e.g. investigating committee for the diagnosis of metabolic syndrome in Japan).

The term “euglycemia” is defined as the condition in which a subject has a fasting blood glucose concentration within the normal range, greater than 70 mg/dL (3.89 mmol/L) and less than 110 mg/dL (6.11 mmol/L). The word “fasting” has the usual meaning as a medical term.

The term “hyperglycemia” is defined as the condition in which a subject has a fasting blood glucose concentration above the normal range, greater than 110 mg/dL (6.11 mmol/L). The word “fasting” has the usual meaning as a medical term.

The term “hypoglycemia” is typically defined as a condition in which a subject has symptoms known to be caused by hypoglycaemia, i.e. low blood glucose concentration at the time the symptoms occur and reversal or improvement of symptoms or problems when the blood glucose concentration is restored to normal. Typically, plasma glucose levels below 70 mg/dl (3.9 mmol/L), in particular below 60 mg/dl (3.3 mmol/L), are considered hypoglycaemic.

The term “postprandial hyperglycemia” is defined as the condition in which a subject has a 2 hour postprandial blood glucose or serum glucose concentration greater than 200 mg/dL (11.11 mmol/L).

The term “impaired fasting blood glucose” or “IFG” is defined as the condition in which a subject has a fasting blood glucose concentration or fasting serum glucose concentration greater than 110 mg/dL and less than 126 mg/dl (7.00 mmol/L).

The term “impaired glucose tolerance” or “IGT” is defined as the condition in which a subject has a 2 hour postprandial blood glucose or serum glucose concentration greater than 140 mg/dl (7.78 mmol/L) and less than 200 mg/dL (11.11 mmol/L). The abnormal glucose tolerance, i.e. the 2 hour postprandial blood glucose or serum glucose concentration can be measured as the blood sugar level in mg of glucose per dL of plasma 2 hours after taking 75 g of glucose after a fast.

The term “hyperinsulinemia” is defined as the condition in which a subject with insulin resistance, with or without euglycemia, in which the fasting or postprandial serum or plasma insulin concentration is elevated above that of normal, lean individuals without insulin resistance, having a waist-to-hip ration <1.0 (for men) or <0.8 (for women).

The terms “insulin-sensitizing”, “insulin resistance-improving” or “insulin resistance-lowering” are synonymous and used interchangeably.

The term “insulin resistance” is defined as a state in which circulating insulin levels in excess of the normal response to a glucose load are required to maintain the euglycemic state (Ford E S, et al. JAMA. (2002) 287:356-9). A method of determining insulin resistance is the euglycaemic-hyperinsulinaemic clamp test. The ratio of insulin to glucose is determined within the scope of a combined insulin-glucose infusion technique. There is found to be insulin resistance if the glucose absorption is below the 25th percentile of the background population investigated (WHO definition). Rather less laborious than the clamp test are so called minimal models in which, during an intravenous glucose tolerance test, the insulin and glucose concentrations in the blood are measured at fixed time intervals and from these the insulin resistance is calculated. In this method it is not possible to distinguish between hepatic and peripheral insulin resistance.

Furthermore insulin resistance, the response of a patient with insulin resistance to therapy, insulin sensitivity and hyperinsulinemia may be quantified by assessing the “homeostasis model assessment to insulin resistance (HOMA-IR)” score, a reliable indicator of insulin resistance (Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Further reference is made to methods for the determination of the HOMA-index for insulin sensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), of the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl. 1): A459) and to an euglycemic clamp study. In addition, plasma adiponectin levels can be monitored as a potential surrogate of insulin sensitivity. The estimate of insulin resistance by the homeostasis assessment model (HOMA)-IR score is calculated with the formula (Galvin P, et al. Diabet Med 1992;9:921-8):

HOMA-IR=[fasting serum insulin (μU/mL)]×[fasting plasma glucose(mmol/L)/22.5]

As a rule, other parameters are used in everyday clinical practice to assess insulin resistance. Preferably, the patient\'s triglyceride concentration is used, for example, as increased triglyceride levels correlate significantly with the presence of insulin resistance.

Patients with a predisposition for the development of IGT or IFG or type 2 diabetes are those having euglycemia with hyperinsulinemia and are by definition, insulin resistant. A typical patient with insulin resistance is usually overweight or obese. If insulin resistance can be detected this is a particularly strong indication of the presence of prediabetes. Thus, it may be that in order to maintain glucose homoeostasis a person needs 2-3 times as much insulin as another person, without this having any direct pathological significance.

The methods to investigate the function of pancreatic beta-cells are similar to the above methods with regard to insulin sensitivity, hyperinsulinemia or insulin resistance: An improvement of the beta-cell function can be measured for example by determining a HOMA-index for beta-cell function (Matthews et al., Diabetologia 1985, 28: 412-19), the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl. 1): A459), the insulin/C-peptide secretion after an oral glucose tolerance test or a meal tolerance test, or by employing a hyperglycemic clamp study and/or minimal modeling after a frequently sampled intravenous glucose tolerance test (Stumvoll et al., Eur J Clin Invest 2001, 31: 380-81).

The term “pre-diabetes” is the condition wherein an individual is pre-disposed to the development of type 2 diabetes. Pre-diabetes extends the definition of impaired glucose tolerance to include individuals with a fasting blood glucose within the high normal range ≧100 mg/dL (J. B. Meigs, et al. Diabetes 2003; 52:1475-1484) and fasting hyperinsulinemia (elevated plasma insulin concentration). The scientific and medical basis for identifying pre-diabetes as a serious health threat is laid out in a Position Statement entitled “The Prevention or Delay of Type 2 Diabetes” issued jointly by the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases (Diabetes Care 2002; 25:742-749).

Individuals likely to have insulin resistance are those who have two or more of the following attributes: 1) overweight or obese, 2) high blood pressure, 3) hyperlipidemia, 4) one or more 1st degree relative with a diagnosis of IGT or IFG or type 2 diabetes. Insulin resistance can be confirmed in these individuals by calculating HOMA-IR score. For the purpose of this invention, insulin resistance is defined as the clinical condition in which an individual has a HOMA-IR score>4.0 or a HOMA-IR score above the upper limit of normal as defined for the laboratory performing the glucose and insulin assays.

The term “type 2 diabetes” is defined as the condition in which a subject has a fasting blood glucose or serum glucose concentration greater than 125 mg/dL (6.94 mmol/L). The measurement of blood glucose values is a standard procedure in routine medical analysis. If a glucose tolerance test is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of glucose per dL of plasma 2 hours after 75 g of glucose have been taken on an empty stomach. In a glucose tolerance test 75 g of glucose are administered orally to the patient being tested after 10-12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after taking it. In a healthy subject the blood sugar level before taking the glucose will be between 60 and 110 mg per dL of plasma, less than 200 mg per dL 1 hour after taking the glucose and less than 140 mg per dL after 2 hours. If after 2 hours the value is between 140 and 200 mg this is regarded as abnormal glucose tolerance.

The term “late stage type 2 diabetes mellitus” includes patients with a secondary drug failure, indication for insulin therapy and progression to micro- and macrovascular complications e.g. diabetic nephropathy, coronary heart disease (CHD).

The term “HbA1c” refers to the product of a non-enzymatic glycation of the haemoglobin B chain. Its determination is well known to one skilled in the art. In monitoring the treatment of diabetes mellitus the HbA1c value is of exceptional importance. As its production depends essentially on the blood sugar level and the life of the erythrocytes, the HbA1c in the sense of a “blood sugar memory” reflects the average blood sugar levels of the preceding 4-6 weeks. Diabetic patients whose HbA1c value is consistently well adjusted by intensive diabetes treatment (i.e. <6.5% of the total haemoglobin in the sample), are significantly better protected against diabetic microangiopathy. For example metformin on its own achieves an average improvement in the HbA1c value in the diabetic of the order of 1.0-1.5%. This reduction of the HbA1 C value is not sufficient in all diabetics to achieve the desired target range of <6.5% and preferably <6% HbA1c.

The “metabolic syndrome”, also called “syndrome X” (when used in the context of a metabolic disorder), also called the “dysmetabolic syndrome” is a syndrome complex with the cardinal feature being insulin resistance (Laaksonen D E, et al. Am J Epidemiol 2002;156:1070-7). According to the ATP III/NCEP guidelines (Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) JAMA: Journal of the American Medical Association (2001) 285:2486-2497), diagnosis of the metabolic syndrome is made when three or more of the following risk factors are present: 1. Abdominal obesity, defined as waist circumference >40 inches or 102 cm in men, and >35 inches or 94 cm in women; or with regard to a Japanese ethnicity or Japanese patients defined as waist circumference 85 cm in men and 90 cm in women; 2. Triglycerides: ≧150 mg/dL 3. HDL-cholesterol <40 mg/dL in men 4. Blood pressure ≧130/85 mm Hg (SBP ≧130 or DBP ≧85) 5. Fasting blood glucose ≧110 mg/dL

The NCEP definitions have been validated (Laaksonen D E, et al. Am J Epidemiol. (2002) 156:1070-7). Triglycerides and HDL cholesterol in the blood can also be determined by standard methods in medical analysis and are described for example in Thomas L (Editor): “Labor and Diagnose”, TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.

According to a commonly used definition hypertension is diagnosed if the systolic blood pressure (SBP) exceeds a value of 140 mm Hg and diastolic blood pressure (DBP) exceeds a value of 90 mm Hg. If a patient is suffering from manifest diabetes it is currently recommended that the systolic blood pressure be reduced to a level below 130 mm Hg and the diastolic blood pressure be lowered to below 80 mm Hg.

Within the meaning of the present invention glaucoma is a disease in which the optic nerve is damaged, leading to progressive, irreversible loss of vision. It is often, but not always, associated with increased pressure of the fluid in the eye. The nerve damage involves loss of retinal ganglion cells in a characteristic pattern. There are many different sub-types of glaucoma but they can all be considered a type of optic neuropathy. Raised intraocular pressure is a significant risk factor for developing glaucoma (above 21 mmHg or 2.8 kPa). One person may develop nerve damage at a relatively low pressure, while another person may have high eye pressure for years and yet never develop damage. Untreated glaucoma leads to permanent damage of the optic nerve and resultant visual field loss, which can progress to blindness.

Within the meaning of the present invention atherosclerosis (also known as arteriosclerotic vascular disease or ASVD) is a condition in which an artery wall thickens as the result of a build-up of fatty materials such as cholesterol. It is a syndrome affecting arterial blood vessels, a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of macrophage white blood cells and promoted by low-density lipoproteins (plasma proteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the macrophages by functional high density lipoproteins (HDL),

With the term “dyslipidemia/hyperlipidemia” a disorder of lipoprotein metabolism, including lipoprotein overproduction or deficiency is defined. Dyslipidemias may be manifested by elevation of the total cholesterol, the low-density lipoprotein (LDL) cholesterol and the triglyceride concentrations, and a decrease in the “good” high-density lipoprotein (HDL) cholesterol concentration in the blood. Dyslipidemia/hyperlipidemia within the meaning of the present invention is indicated when LDL cholesterol levels for adults more than 100 mg/dL (2.60 mmol/L), HDL cholesterol levels are equal to or lower than 40 mg/dL (1.02 mmol/L), and triglyceride levels are more than 150 mg/dL (1.7 mmol/L).

The terms “prophylactically treating” and “preventing” are used interchangeably.

DETAILED DESCRIPTION

The aspects according to the present invention, in particular the pharmaceutical compositions, methods and uses, refer to compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof.

The aspects according to the present invention, in particular the pharmaceutical compositions, methods and uses, refer to an at least one therapeutic agent 2 which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), atherosclerosis, glaucoma, dyslipidemia/hyperlipidemia and hyperglycemia.

Preferably the at least one second therapeutic agent 2 is selected from the groups 2.a) to 2.m) consisting of:

2.a) biguanides,

2.b) sulfonylureas,

2.c) metiglinides,

2.d) thiazolidindiones,

2.e) alpha-glucosidase inhibitors,

2.f) insulins and insulin analogues,

2.g) dipeptidyl peptidase IV inhibitors (DPP IV inhibitors)

2.h) SGLT 2 inhibitors,

2.i) PPAR gamma/alpha modulators,

2.j) glucose-dependent insulinotropic polypeptide agonists,

2.k) beta-3 agonists,

2.l) GLP1 and GLP1 analogues,

2.m) PPAR gamma modulators, and

2.n) HMG-CoA reductase inhibitors

2.o) PPAR delta modulators.

More preferably the at least one second therapeutic agent 2 is selected from the groups 2.a), 2.g) and 2.h) as described hereinbefore and hereinafter.

Examples of biguanides are metformin (2.a1), phenformin (2.a2) and buformin (2.a3). Compound 1.a and/or a compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof in combination with a biguanide, for example with metformin, can improve glycemic control and may act synergistically with the biguanide, for example to reduce weight that has overall beneficial effects on the metabolic syndrome which is commonly associated with type 2 diabetes mellitus.

Examples of sulfonylureas are chlorpropamide (2.b1), acetohexamide (2.b2), tolazamide (2.b3), glibenclamide (2.b4), tolbutamide (2.b5), glimepiride (2.b6), glipizide (2.b7), gliquidone (2.b8), glibornurid (2.b9), glyburide (2.b10) and gliclazide (2.b11). As the efficacy of sulfonylureas wears off over the course of treatment, a combination of compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof with a sulfonylurea may offer additional benefit to the patient in terms of better glycemic control. This combination may also allow a reduction in the dose of sulfonylureas which may translate into less hypoglycemia which is an undesirable side effect of sulfonylureas.

Examples of meglitinides are nateglinide (2.c1), repaglinide (2.c2) and mitiglinide (2.c3). As the efficacy of meglitinides wears off over the course of treatment, a combination of compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof with a meglitinide may offer additional benefit to the patient in terms of better glycemic control. This combination may also allow a reduction in the dose of meglitinides which may translate into less hypoglycemia which is an undesirable side effect of meglitinides.

Examples of thiazolidindiones are pioglitazone (2.d1), rosiglitazone (2.d2), troglitazone (2.d3) and ciglitazone (2.d4). Additional benefits from the combination of compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof and a thiazolidindione may relate to synergistic reduction in blood glucose, an improved glycemic control, an improvement of fluid retention caused by thiazolidindiones and reducing or nullifying weight gain associated with the use of thiazolidindiones.

Examples of alpha-glucosidase inhibitors are miglitol (2.e1), acarbose (2.e2) and voglibose (2.e3). A combination of compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof and an alpha-glucosidase inhibitor will add to their blood glucose lowering effect and may allow a reduction in the dose of the alpha-glucosidase inhibitor that are commonly associated with unpleasant gastro-intestinal side effects, thereby making it more tolerable and improve the patients compliance with the treatment.

Examples of insulins and insulin analogues are short acting insulins like insulin lispro (Humalog®) (2.f1), insulin aspartat (Novorapid®) (2.f2), insulin glulisine (Apidra®) (2.f3), regular insulin (2.f4), intermediate acting insulins like NPH-insulins and long acting insulins like lente (2.f5) and ultralente insulin (2.f6), insulin glargine (Lantus®) (2.f7), insulin detemir (Levemir®) (2.f8). The term insulins includes recombinant insulins. The use of insulin is commonly associated with weight gain as a result of the anabolic effects of insulin as well as fluid retention. Combining compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof with insulin or an insulin analogue will achieve a better glycemic control with lower doses of insulin.

Examples of DPP IV inhibitors are denagliptin (2.g1), carmegliptin (2.g2), melogliptin (2.g3) sitagliptin (2.g4), vildagliptin (2.g5), saxagliptin (2.g6), linagliptin (2.g7), dutogliptin (2.g8), gemigliptin (2.g9) and alogliptin (2.g10). Combining compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof with a DPP IV inhibitor is expected to improve glycemic control.

Examples of SGLT 2 inhibitors are 6-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile (2.h1), 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile (2.h2), 1-cyano-2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methyl-benzene (2.h3), 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile (2.h4), 2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile (2.h5), 2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile (2.h6), 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene (2.h7), 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene (2.h8), 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene (2.h9), 1-methyl-244-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene (2.h10), 1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene (2.h11), dapagliflozin (2.h12), atigliflozin (2.h13), remogliflozin (2.h14), sergliflozin (2.h15) and canagliflozin (2.h16). Combining compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof with a SGLT 2 inhibitor is expected to improve glycemic control.

Compounds (2.h1) to (2.h11) and methods of their synthesis are described for example in the following patent applications: WO 2005/092877, WO 2006/117360, WO 2006/117359, WO 2006/120208, WO 2006/064033, WO 2007/031548, WO 2007/093610, WO 2008/020011, WO 2008/055870.

Examples of PPAR gamma/alpha modulators are tesaglitazar (2.i1), muraglitazar (2.i2) and KRP297 (2.i3). Combining compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof with a PPAR gamma/alpha modulator is expected to improve glycemic control.

Examples of glucose-dependent insulinotropic polypeptide agonists are pramlintide (2.j1) and amlyin (2.j2). Combinations with such second therapeutic agents 2 are expected to improve glycemic control.

Examples of beta-3 agonists are ritobegron (2.k1), YM 178 (2.k2), solabegron (2.k3), talibegronb (2.k4), N-5984 (2.k5), GRC-1087 (2.k6), rafabegron (2.k7) and FMP825 (2.k8). Combining compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof with a beta-3 agonist is expected to improve glycemic control.

An example of GLP1 and GLP1 analogues is exenatide (2.l1), liraglutide (2.l2) and taspoglutide (2.l3). Combining compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof with a GLP-1 analogue is expected to improve glycemic control and add to GLP-1 analogue weight reducing effect.

An example of PPAR gamma modulators is metaglidasen (2.m1). Combining a compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof with a PPAR gamma modulator is expected to improve glycemic control.

Examples of HMG-CoA reductase inhibitors are simvastatin (2.n1), lovastatin (2.n2), and provastatin (2.n3). Combining compound 1.a and/or compound 1.b, solvates, hydrates or pharmaceutically acceptable salts thereof with a HMG-CoA reductase inhibitor is expected to improve glycemic control.

Examples of PPAR delta modulators are GW 501516 (2.o1), GW 0742 (2.o2), L165041(2.o3), LY 465608 (2.o4), and L-796449 (2.o5).

Even more preferably the at least one second therapeutic agent 2 is selected from the group consisting of (2.a1), (2.d1), (2.g7) and (2.h9).

Most preferably the at least one second therapeutic agent 2 is selected from the group consisting of consisting of (2.a1), (2.g7), (2.h9).

In addition, therapeutic agents 2 can also be selected from GPR119 agonists.

According to this invention it is to be understood that the definitions of the above listed second therapeutic agents 2 also comprise their pharmaceutically acceptable salts as well as hydrates, solvates and polymorphic forms thereof.

Therefore the pharmaceutical compositions, methods and uses according to this invention relate to combinations which are selected from the Table 1.

TABLE 1 Second Composition therapeutic

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