HK1245148A - Uses of dpp iv inhibitors - Google Patents

Description

Use of DPP IV inhibitors

The application is a divisional application of an invention application with the application date of 2007, 5 and 3 months, China application number of 201410295522.9 and the invention name of 'application of DPP IV inhibitor'; the application with the Chinese application number of 201410295522.9 is a divisional application of the invention with the application date of 2007, 5, 3 and 200780020753.7, and the invention name of the invention is the application of the DPP IV inhibitor.

The present specification describes the use of selected DPP IV inhibitors in the treatment of physiological functional disorders and in reducing the risk of developing these functional disorders in a patient group at risk. Furthermore, the present specification describes the use of the above mentioned DPP IV inhibitors in combination with other active substances, whereby improved therapeutic results may be achieved. These applications can be used to prepare corresponding medicaments.

The enzyme DPP-IV, also known as CD26, is a serine protease that promotes cleavage of dipeptides in proteins having a proline or alanine group at the N-terminus. DPP-IV inhibitors thus affect the plasma content of biologically active peptides, including the peptide GPG-1, and are extremely valuable molecules for the treatment of diabetes.

Type I diabetes, which occurs predominantly in adolescents under 30 years of age, is classified as an autoimmune disease. Under the influence of the corresponding genetic factors and of a number of factors, insulitis occurs, with subsequent destruction of the B cells, so that the pancreas can no longer produce large amounts of insulin (if at all).

Type II diabetes is not classified as an autoimmune disease and manifests itself as fasting glucose levels in excess of 125mg glucose per deciliter of plasma; measurement of blood glucose values is a standard procedure in conventional medical analysis. Prediabetes is suspected if the fasting plasma glucose level exceeds the maximum normal level of 99mg glucose per deciliter of plasma, but does not exceed a threshold of 125mg glucose per deciliter of plasma, which is associated with diabetes. This is also known as pathological fasting glucose (fasting glucose abnormality). Another indication of prediabetes is abnormal glucose tolerance, i.e., blood glucose levels of 140 mg/dl plasma and 199 mg/hr glucose 2 hours after a fasting intake of 75mg glucose in the context of an oral glucose tolerance test.

If glucose tolerance tests are performed, the blood glucose level of a diabetic patient will exceed 199mg glucose per deciliter of plasma 2 hours after a 75 g glucose intake on an empty stomach. In the glucose tolerance test, 75 grams of glucose was orally administered to test patients after 10-12 hours of fasting and blood glucose levels were recorded immediately before and 1 and 2 hours after glucose ingestion. In a healthy subject, the blood glucose level should be between 60mg to 99mg per deciliter of plasma prior to glucose ingestion, less than 200mg per deciliter 1 hour after glucose ingestion and less than 140 mg per deciliter 2 hours after. If after 2 hours, the value is between 140 mg and 199mg, it is considered as glucose intolerance or in some cases as glucose intolerance.

The non-enzymatic glycation product of the B chain of hemoglobin, the HbA1c value, is particularly important when monitoring the treatment of diabetes. Since its formation depends mainly on blood glucose level and erythrocyte longevity, HbA1c reflects the average blood glucose level of the previous 4-12 weeks in the sense of "glycemic memory". HbA1c levels have been well controlled for longer periods of time (i.e., < 6.5% total hemoglobin in the sample) than intensive diabetes therapy and are significantly better protected from diabetic microangiopathy. Effective treatment of diabetes can give diabetic patients a mean improvement in HbA1c levels of about 1.0% to 1.5%. This reduction in HbA1c levels is not sufficient to bring all diabetic patients within the desired target range of < 6.5% and preferably < 6% HbA1 c.

If insulin resistance is detectable, this is a particularly powerful indicator of the presence of a complex metabolic disorder of pre-diabetes. Thus, to maintain glucose homeostasis, one person may need 2-3 times as much insulin as another. The most reliable method for determining insulin resistance is the normal glucose-hyperinsulinemic clamp test (euglycemic-hyperinsulinemic clamp test). The ratio of insulin to glucose is determined within the scope of a combined insulin-glucose infusion technique. If glucose uptake is below 25% of the probed background population, insulin resistance is present (WHO definition). What is convenient compared to the clamp test is the so-called minimum model, in which during the venous glucose tolerance test the insulin and glucose concentrations in the blood are measured at fixed time intervals and the insulin resistance is calculated therefrom. Another measurement method is the mathematical HOMA model. Insulin resistance is calculated from the fasting plasma glucose concentration and the fasting insulin concentration. In this method, it is not possible to distinguish between hepatic insulin resistance and peripheral insulin resistance. These methods are not really suitable for assessing insulin resistance in daily practice. Other parameters are commonly used in daily clinical practice to assess insulin resistance. Preferably, for example, the triglyceride concentration of the patient is used, since an increased triglyceride content is significantly correlated with the presence of insulin resistance.

For a slight simplification, it is assumed in practice that a person has insulin resistance if it has at least 2 of the following characteristics:

1) overweight or obese

2) Hypertension (hypertension)

3) Dyslipidemia (altered total lipid content in blood)

4) At least one close relative has identified impaired glucose tolerance or type II diabetes.

Overweight means a Body Mass Index (BMI) of between 25kg/m²And 30kg/m²In between, BMI is the quotient of weight (kg) and height (m) squared. In overt obesity, BMI is 30kg/m²Or higher.

According to the above definition of insulin resistance, it is clear that if a patient is found to suffer from hypertension, hypotensive agents are suitable and indicated for the treatment of insulin resistance.

A similar indication of prediabetes is the satisfaction of the pathology of metabolic syndrome, which is mainly characterized by insulin resistance. According to the ATP IHINCEP criteria (Journal of the American Medical Association 285: 2486-:

1) abdominal obesity, defined as waist circumference > 40 inches or 102 cm for men and > 35 inches or 94 cm for women

2) Triglyceride content > 150 mg/dl

3) The HDL-cholesterol level in men is less than 40 mg/dl

4) Hypertension > 130/> 85mm Hg

5) Fasting blood glucose is more than 110 mg/dl.

This definition of metabolic syndrome directly indicates that hypotensive agents are suitable for treating metabolic syndrome if the patient is found to have hypertension.

A triglyceride blood level of more than 150 mg/dl is also indicative of prediabetes. This speculation is evidenced by the low blood levels of HDL cholesterol. In females, a content of less than 55 mg per dl of plasma is considered too low, whereas in males a content of less than 45mg per dl of plasma is considered too low. Triglycerides and HDL cholesterol in blood can also be determined by standard methods in medical analysis and are described, for example, in Thomas L (editor): "Labor und Diagnose", TH-BooksmbH, Frankfurt Main 2000. Prediabetes is further confirmed if fasting blood glucose levels also exceed 99mg glucose per deciliter of plasma.

Term(s) forGestational diabetes mellitus(gestational diabetes) refers to a form of sugar disease that develops during pregnancy and usually stops immediately after delivery. Gestational diabetes was confirmed by screening tests performed between weeks 24 to 28 of gestation. It is typically a simple test that measures blood glucose levels one hour after administration of 50 grams of glucose solution. If the content of the extract exceeds 140 mg/dl in 1 hour, gestational diabetes is suspected. The final confirmation can be obtained by a standard glucose tolerance test with 75 grams of glucose.

HyperglycemiaFunctional disorders with very high glucose levels measured in the blood in the fasting state (high glucose levels of 100-125 mg/dl or diabetes-hyperglycemia levels of > 125mg/dl compared to normal levels of < 100 mg/dl) or in the non-fasting state (> high glucose levels of 180 mg/dl) are described.

The clinician is atPostprandial syndrome of adrenergic(reactive hypoglycemia) refers to a functional condition in which disproportionately high insulin levels result in a decrease in blood glucose levels (hypoglycemia) caused by an imbalance between rapidly digested carbohydrates and sustained high insulin levels after a meal.

Term(s) forDiabetic footRefers to foot damage caused by diabetes, the main cause of which is polyneuropathy attributable to inadequate metabolic control. Diabetic feet are diagnosed by the appearance of common lesions (e.g., ulcers) in the existing diabetic setting.

Term(s) forDiabetes mellitusAssociated ulcerRefers to ulcerative inflammatory skin defect of diabetic patients. Diabetes-related ulcers are diagnosed by typical anamnesis (anamnesis) and physical examination (e.g., examining the feet).

The term is used if a diabetic patient experiences an increase in total cholesterol or more commonly an increase in plasma triglycerides with or without a decrease in HDL cholesterol in diabetic hyperlipidemiaDiabetic hyperlipidemia。

The term is used when total cholesterol is not elevated, but the distribution of HDL-cholesterol and LDL-cholesterol is altered, i.e., the patient's HDL cholesterol level is too low (e.g., < 55 mg/dl for females and < 45 mg/dl for males)Diabetic dyslipidemia A block。

The term is used if subjective symptoms or objective examination indicate that the heart is not capable of delivering the necessary ejection outputHeart failure Exhausted wine. Subjective symptoms may be, for example, dyspnea under stress or under rest. Objective examination includes a reduction in ejection output of the heart (reduction in ejection volume) based on ultrasound, pulmonary congestion based on X-rays, and/or a reduction in walking distance.

Some selected DPP IV inhibitors are particularly suitable for the preparation of a medicament for the therapeutic treatment of patients already diagnosed with a medical or physiologically functional disorder selected from the following: prediabetes, glucose intolerance (glucose intolerance), pathologic fasting glucose (fasting glucose abnormality), diabetic foot, diabetes-related ulcers, diabetic hyperlipidemia, diabetic dyslipidemia, newly diagnosed type I diabetes (to maintain residual secretion of insulin from the pancreas), gestational diabetes (gestational diabetes), hyperglycemia, adrenergic postprandial syndrome (reactive hypoglycemia), or heart failure.

These drugs can also be used to reduce the following risks: despite treatment, patients experience impaired glucose metabolism, elevated HbA1c values, abnormal fasting glucose values, dominant type II diabetes (diabetes), diabetic foot, diabetic-related ulcer, diabetic hyperlipidemia, or diabetic dyslipidemia, and despite treatment, insulin treatment may become necessary or major vascular complications may occur.

Examples of such macrovascular complications are myocardial infarction, acute coronary syndrome, unstable angina, stable angina, hemorrhagic or ischemic stroke, peripheral arterial occlusive disease, cardiomyopathy, left heart insufficiency, right heart insufficiency, total heart failure, arrhythmia and vascular restenosis. These macrovascular complications are known to those skilled in the art and are described in detail in standard textbooks.

Furthermore, these substances are suitable for enhancing the viability and secretory capacity of the cells after transplantation of islets of Langerhans or beta cells and thereby ensuring favorable results after transplantation. These substances can also be used during isolation and transplantation of pancreatic islets or beta cells by adding the specific substance to a conventional isolation or storage medium at a suitable concentration of 1nmol/l to 1. mu. mol/l, preferably at a concentration of 1nmol/l to 100 nmol/l. This leads to an increase in the quality of the plant material to be transplanted. The increased quality is especially obtained in combination with an increased amount of GLP-1 (glucagon-like peptide 1), preferably at a concentration of 1-100 nmol/l. Another object of the invention is a corresponding isolation or storage medium and a corresponding method for enhancing the viability and secretory capacity of pancreatic islets or beta cells by adding a DPP IV inhibitor to the used medium.

Finally, the above-mentioned inhibitors are suitable for the treatment of various forms of arthritis, but especially rheumatoid arthritis.

Selected DPP IV inhibitors of the present invention can be described by formula (I) or formula (II)

Wherein R1 represents ([1, 5] naphthyridin-2-yl) methyl, (quinazolin-2-yl) methyl, (quinoxalin-6-yl) methyl, (4-methyl-quinazolin-2-yl) methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl) methyl, (3-cyano-pyridin-2-yl) methyl, (4-methyl-pyrimidin-2-yl) methyl or (4, 6-dimethyl-pyrimidin-2-yl) methyl and R2 represents 3- (R) -amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino or (2- (S) -amino-propyl) -methylamino.

Particularly preferred DPP IV inhibitors are the following compounds and their therapeutically active salts:

1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine (see WO 2004/018468, example 2 (142)):

1- [ ([1, 5] naphthyridin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (see WO 2004/018468, example 2 (252)):

1- [ (quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -amino-piperidin-1-yl) -xanthine (see WO 2004/018468, example 2 (80)):

2- ((R) -3-amino-piperidin-1-yl) -3- (but-2-ynyl) -5- (4-methyl-quinazolin-2-ylmethyl) -3, 5-dihydro-imidazo [4, 5-d ] pyridazin-4-one (see WO 2004/050658, example 136):

1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (2-amino-2-methyl-propyl) -methylamino ] -xanthine (see WO 2006/029769, example 2 (1)):

1- [ (3-cyano-quinolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (see WO 2005/085246, example 1 (30)):

1- (2-cyano-benzyl) -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (see WO 2005/085246, example 1 (39)):

1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (S) - (2-amino-propyl) -methylamino ] -xanthine (see WO 2006/029769, example 2 (4)):

1- [ (3-cyano-quinolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (see WO 2005/085246, example 1 (52)):

1- [ (4-methyl-pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (see WO 2005/085246, example 1 (81)):

1- [ (4, 6-dimethyl-pyrimidin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (see WO 2005/085246, example 1 (82)):

1- [ (quinoxalin-6-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- ((R) -3-amino-piperidin-1-yl) -xanthine (cf. WO 2005/085246, example 1 (83)):

these DPP IV inhibitors differ from structurally similar DPP IV inhibitors in that they, when combined with other pharmaceutically active substances, combine a specific potency and sustained action with a favourable pharmacological profile, receptor selectivity and a favourable side-effect profile, or give rise to unexpected therapeutic advantages or improvements. Their preparation is disclosed in said publication.

Since different metabolic functional disorders often occur simultaneously, it is often prescribed to combine a number of active ingredients which differ from one another. Thus, depending on the functional disorder diagnosed, increased therapeutic results are obtained if a DPP IV inhibitor is combined with an active substance selected from other antidiabetic substances, in particular an active substance which reduces the blood glucose level or the lipid level in the blood, increases the HDL level in the blood, reduces blood pressure or is indicated for the treatment of atherosclerosis or obesity.

The required dose of the DPP IV inhibitor is from 0.1mg to 10mg, preferably from 0.25mg to 5mg, when administered intravenously, and from 0.5mg to 100mg, preferably from 2.5mg to 50mg, when administered orally, in each case from 1 to 4 times per day. To this end, the compounds, preferably in combination with other active substances, can be formulated with one or more customary inert carriers and/or diluents, for example with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetostearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or suitable mixtures thereof, to form customary galenical preparations, such as tablets, coated tablets, capsules, powders, suspensions or suppositories.

The DPP IV inhibitors of the present invention are therefore prepared by those skilled in the art using excipients allowing formulation as described in the prior art. Examples of such excipients are diluents, binders, carriers, fillers, lubricants, glidants, crystallization retarders, disintegrants, cosolvents, colorants, pH adjusters, surfactants and emulsifiers.

Examples of suitable diluents include cellulose powder, dibasic calcium phosphate, erythritol, (low-substituted) hydroxypropyl cellulose, mannitol, pregelatinized starch, or xylitol.

Examples of suitable binders include copolymers of vinylpyrrolidone and other vinyl derivatives (copovidone), Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), polyvinylpyrrolidone (povidone), pregelatinized starch, or low-substituted hydroxypropylcellulose.

Examples of suitable lubricants include talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil, or magnesium stearate.

Examples of suitable disintegrants include corn starch or cross-linked polyvinylpyrrolidone.

Suitable methods for preparing pharmaceutical formulations of the DPP IV inhibitors of the present invention are:

● tableting the active substance in powder mixture directly with suitable tableting excipients;

● are granulated with suitable excipients and then mixed with suitable excipients and then tabletted and film coated; or

● the powder mixture or granules are filled into capsules.

Suitable granulation methods are:

● wet granulation in an intensive mixer followed by fluid bed drying;

● granulating in one pot;

● fluidized bed granulation; or

● are dry granulated with suitable excipients (e.g., by roller compaction) and subsequently tableted or filled into capsules.

The above mentioned DPP IV inhibitors may also be used in combination with other active substances, whereby improved therapeutic results may be obtained. The combination therapy can be administered in the form of a free combination of these substances or in the form of a fixed combination, for example in the form of tablets or capsules. Pharmaceutical preparations of the combination partners required for this purpose are commercially available in the form of pharmaceutical compositions or can be prepared by the person skilled in the art using customary methods. The active substances available in the form of pharmaceutical compositions are described in a number of places in the prior art, for example in the annually published drug catalogue, "Rote" of the pharmaceutical industry association"middle, or yearly updated compilation of prescription drug related manufacturer information called" Physicians' Desk Reference ".

Examples of antidiabetic combination partners are metformin; sulfonylureas, such as glibenclamide (glibenclamide), tolbutamide (tolbutamide), glimepiride (glimepiride), glipizide (glipizide), gliquidone (gliquidon), glibenclamide (glibornuride), and gliclazide (gliclazide); nateglinide (nateglinide); repaglinide (repaglinide); thiazolidinediones such as rosiglitazone (rosiglitazone) and pioglitazone (pioglitazone); PPAR γ modulators, such as meglitinide (metaglidase); PPAR-gamma agonists such as GI 262570; a PPAR γ antagonist; PPAR-gamma/alpha modulators such as texaprazole (tesaglitazar), moglicazole (muraglitazar) and KRP 297; PPAR-gamma/alpha/modulators; AMPK-activators such as AICAR; inhibitors of acetyl-coa carboxylase (ACC1 and ACC 2); diacylglycerol-acetyltransferase (DGAT) inhibitors; pancreatic beta cell GCRP agonists such as SMT 3-receptor agonists and GPR 119; 11 β -HSD inhibitors; an FGF19 agonist or analog; alpha-glucosidase blockers such as acarbose, voglibose and miglitol; an alpha 2-antagonist; insulin and insulin analogs such as human insulin, insulin lispro (insulin lispro), insulin glargine (insulin glusilin), r-DNA-insulin aspart (insulin aspart), NPH insulin, insulin dime (insulin destemir), insulin zinc suspension, and insulin gold (insulin glargin); gastric Inhibitory Peptide (GIP); pramlintide (pramlintide); amylin (amylin) or GLP-1 and GPL-1 analogs such as Exendin-4; SGLT2 inhibitors, such as KGT-1251; inhibitors of protein tyrosine-phosphatases; inhibitors of glucose-6-phosphatase; fructose-1, 6-bisphosphatase modulators; glycogen phosphatase modulators (glycogen phosphatase modulators); a glucagon receptor antagonist; inhibitors of phosphoenolpyruvate carboxykinase (PEPCK); inhibitors of Pyruvate Dehydrogenase Kinase (PDK); inhibitors of tyrosine-kinases (50mg to 600mg), such as PDGF receptor-kinases (see EP-A-564409, WO98/35958, US5093330, WO 2004/005281 and WO 2006/041976); glucokinase/regulatory protein modulators, including glucokinase activators; glycogen synthase kinase inhibitors; an SH 2-domain containing type 2 inositol 5-phosphatase (SHIP 2); IKK inhibitors such as high dose salicylates; JNK1 inhibitors; protein kinase C-theta inhibitors; beta 3 agonists such as ritobiron (ritobiegron), YM 178, solabegron (solabegron), taliebron (taliebron), N-5984, GRC-1087, lafaxine (rafabegren), FMP 825; aldose reductase inhibitors such AS AS 3201, zenarestat (zenarestat), fadesistat (fidarestat), epalrestat (epalrestat), Ranitistat (ranirest), NZ-314, CP-744809 and CT-112; SGLT-1 or SGLT-2 inhibitors; KV 1.3 channel inhibitors; GPR40 modulators; an SCD-1 inhibitor; a CCR-2 antagonist; and other DPP IV inhibitors.

Examples of 11 β -HSD1 inhibitors are described in:

WO 2007/013929, WO 2007/007688, WO 2007/003521, WO 2006/138508, WO 2006/135795, WO 2006/135667, WO 2006/134481, WO 2006/134467, WO 2006/132436, WO 2006/132197, WO 2006/113261, WO 2006/106423, WO 2006/106052, WO 2006/105127, WO 2006/104280, WO 2006/100502, WO 2006/097337, WO 2006/095822, WO 2006/094633, WO 2006/080533, WO 2006/074330, WO 2006/074244, WO 2006/068992, WO 2006/068991, WO 2006/068199, WO 2006/066109, WO 2006/055752, WO 2006/053024, WO 2006/051662, WO 2006/050908, WO 2006/049952, WO 2006/048750, WO 2006/048331, WO 2006/048330, WO 2006/040329, WO 2006/037501, WO 2006/030805, WO 2006/030804, WO 2006/017542, WO 2006/024628, WO 2006/024627, WO 2006/020598, WO 2006/010546, WO 2006/002349, WO 2006/002350, WO 2006/012173, WO 2006/012227, WO 2006/012226, WO 2006/000371, WO 2005/118538, WO 2005/116002, WO 2005/110992, WO 2005/110980, WO 2005/108359, WO 2005/108361, WO 2005/108360, WO 2005/108368, WO 2005/103023, WO 2005/097764, WO 2005/097759, WO 2005/095350, WO 2005/075471, WO 2005/063247, WO 2005/060963, WO 2005/047250, WO 2005/046685, WO 2005/044192, WO 2005/042513, WO 2005/016877, WO 2004/113310, WO 2004/106294, WO 2004/103980, WO 2004/089896, WO 2004/089380, WO 2004/089471, WO 2004/089470, WO 2004/089367, WO 2004/073200, WO 2004/065351, WO 2004/058741, WO 2004/056745, WO 2004/056744, WO 2004/041264, WO 2004/037251, WO 2004/033427, WO 2004/011410, WO 2003/104208, WO 2003/104207, WO 2003/065983, WO 2003/059267, WO 2003/044009, WO 2003/044000, WO 2003/043999, WO 2002/076435, WO 2001/090094, WO 2001/090093, WO 2001/090092, WO 2001/090091, WO 2001/090090, US 2007/049632, US 2006/148871, US 2006/025445, US 2006/004049, US 2005/277647, US 2005/261302, US 2005/245534, US 2005/245532, US 2005/245533 and JP 2005/170939. Representative examples of 11 β -HSD1 inhibitors are the following compounds:

and salts thereof.

Examples of glycogen phosphatase modulators are described in:

WO 2006/126695, WO 2006/082401, WO 2006/082400, WO 2006/059165, WO 2006/059164, WO 2006/059163, WO 2006/056815, WO 2006/055463, WO 2006/055462, WO 2006/055435, WO 2006/053274, WO 2006/052722, WO 2005/085245, WO 2005/085194, WO 2005/073231, WO 2005/073230, WO 2005/073229, WO 2005/067932, WO 2005/020987, WO 2005/020986, WO 2005/020985, WO 2005/019172, WO 2005/018637, WO 2005/013981, WO 2005/013975, WO 2005/012244, WO 2004/113345, WO 2004/104001, WO 2004/096768, WO 2004/092158, WO 2004/078743, WO 2004/072060, WO 2004/065356, WO 2004/041780, WO 2004/037233, WO 2004/033416, WO 2004/007455, WO 2004/007437, WO 2003/104188, WO 2003/091213, WO 2003/084923, WO 2003/084922, WO 2003/074532, WO 2003/074531, WO 2003/074517, WO 2003/074513, WO 2003/074485, WO 2003/074484, WO 2003/072570, WO 2003/059910, WO 2003/037864, WO 2002/096864, WO 2002/020530, WO 2001/094300, WO 2000/123347, WO 1996/39384, WO 1996/39385, EP 1391460, EP 1136071, EP 1125580, EP1088824, EP 0978279, JP 2004196702, US 2004/002495, US 2003/195243 and US 5998463.

Examples of glucokinase activators are described in: WO 2007/017649, WO 2007/007910, WO 2007/007886, WO 2007/007042, WO 2007/007041, WO 2007/007040, WO 2007/006814, WO 2007/006761, WO 2007/006760, WO 2006/125972, WO 2006/125958, WO 2006/112549, WO 2006/059163, WO 2006/058923, WO 2006/049304, WO 2006/040529, WO 2006/040528, WO 2006/016194, WO 2006/016178, WO 2006/016174, WO 2005/121110, WO 2005/103021, WO 2005/095418, WO 2005/095417, WO 2005/090332, WO 2005/080360, WO 2005/080359, WO 2005/066145, WO 2005/063738, WO 2005/056530, WO 2005/054233, WO 2005/054200, WO 2005/049019, WO 2005/046139, WO 2005/045614, WO 2005/044801, WO 2004/081001, WO 2004/076420, WO 2004/072066, WO 2004/072031, WO 2004/063194, WO 2004/063179, WO 2004/052869, WO 2004/050645, WO 2004/031179, WO 2004/002481, WO 2003/095438, WO 2003/080585, WO 2003/055482, WO 2003/047626, WO 2003/015774, WO 2003/000267, WO 2003/000262, WO 2002/048106, WO 2002/046173, WO 2002/014312, WO 2002/008209, WO 2001/085707, WO 2001/085706, WO 2001/083478, WO 2001/083465, WO 2001/044216 and WO 2000/058293.

Representative examples of glucokinase activators are the following compounds:

wherein G is₁Represents cyclopropyl or cyclobutyl and G₂Represents 5-fluoro-thiazol-2-yl, 1-methyl-1H-pyrazol-3-yl or pyrazin-2-yl; and

wherein G is₃Represents methyl or ethyl and G₄Represents thiazol-2-yl, 4-methyl-thiazol-2-yl, 5-methyl-thiazol-2-yl or pyrazin-2-yl, and salts thereof.

Examples of SGLT1 or SGLT2 inhibitors are described in: WO 2006/108842, WO 2006/087997, WO 2006/080577, WO 2006/080421, WO 2006/073197, WO 2006/064033, WO 2006/062224, WO 2006/054629, WO 2006/037537, WO 2006/035796, WO 2006/018150, WO 2006/008038, WO 2006/002912, WO 2006/010557, WO 2006/011502, WO 2006/011469, WO 2005/121161, WO 2005/012326, WO 2005/095429, WO 2005/095372, WO 2005/095373, WO 2005/092877, WO 2005/085267, WO 2005/085265, WO 2005/085237, WO 2005/063785, WO 2005/021566, WO 2005/012243, WO 2005/012242, WO 2005/012326, WO 2005/012318, WO 2005/011592, WO 2004/113359, WO 2004/099230, WO 2004/089967, WO 2004/089966, WO 2004/087727, WO 2004/080990, WO 2004/058790, WO 2004/052903, WO 2004/052902, WO 2004/019958, WO 2004/018491, WO 2004/014932, WO 2004/014931, WO 2004/013118, WO 2003/099836, WO 2003/080635, WO 2003/020737, WO 2003/011880, WO 2003/000712, WO 2002/099893, WO 2002/088157, WO 2002/083066, WO 2002/068440, WO 2002/068439, WO 2002/064606, WO 2002/053573, WO 2002/044192, WO 2002/036602, WO 2002/028872, WO 2001/074835, WO 200I/074834, WO 2001/068660, WO 2001/027128, WO 3974, WO 2001/016147, JP 2005247834, JP2004359630, JP 2004196788, JP 2003012686 and US 2006/063722.

Representative examples of SGLT1 or SGLT2 inhibitors are the following compounds and their salts or complexes with natural amino acids:

wherein G is₅And G₈Independently of one another, represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, ethynyl, prop-1-yn-1-yl, but-1-yn-1-yl, hydroxy, methoxy, ethoxy, difluoromethoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy or cyclohexyloxy; and is

G₆Represents fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trimethylsilylethyl, ethynyl, 2-hydroxy-prop-2-ylethynyl, 2-methoxyprop-2-ylethynyl, 3-hydroxy-1-prop-1-ynyl, 3-methoxy-1-prop-1-ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxyPentyloxy, cyclohexyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy and N-acetylpiperidin-4-yloxy; and is

G₇Represents hydrogen or fluorine;

wherein G represents fluorine, chlorine, methyl, ethyl, ethynyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclobutoxy, cyclopentyloxy, 3-tetrahydrofuryloxy or 4-tetrahydropyranyloxy;

wherein G represents fluorine, chlorine, methyl, ethyl, ethynyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclobutoxy, cyclopentyloxy, 3-tetrahydrofuryloxy or 4-tetrahydropyranyloxy;

wherein G is₈Represents hydrogen, methoxycarbonyl or ethoxycarbonyl, and

G₉represents fluorine, chlorine, methyl, ethyl, ethynyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclobutoxy, cyclopentyloxy, 3-tetrahydrofuryloxy or 4-tetrahydropyranyloxy; and

wherein:

G₁₀is represented by C_1-3Alkyl radicalOr perfluoro-C_1-3An alkyl group;

G₁₁represents hydrogen, C_1-3Alkyl or perfluoro-C_1-3An alkyl group;

G₁₂represents fluorine, chlorine, bromine, C_1-6Alkyl, C substituted by 1 to 3 fluorine atoms_1-6Alkyl radical, C_1-6Alkoxy, C substituted by 1 to 3 fluorine atoms_1-6Alkoxy radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, perfluoro-C_1-3Alkyl, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuryloxy or 4-tetrahydropyranyloxy; and is

G₁₃And G₁₄Independently of one another, hydrogen, fluorine, chlorine, bromine, C_1-6Alkyl, C substituted by 1 to 3 fluorine atoms_1-6Alkyl radical, C_1-6Alkoxy, C substituted by 1 to 3 fluorine atoms_1-6Alkoxy radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, perfluoro-C_1-3An alkyl group; and is

G₁₅Represents hydrogen, C_2-20Alkanoyl radical, C_1-6Alkoxycarbonyl or benzoyl.

A particularly preferred example of an antidiabetic combination partner is metformin, in a dose from about 100mg to 500mg or from 200mg to 850mg (one to three times a day), or from about 300mg to 1000mg once or twice a day; or sustained-release (delayed-release) metformin in a dosage of about 100mg to 1000mg or preferably 500mg to 1000mg once or twice a day or about 500mg to 2000mg once a day. Another particularly preferred example is pioglitazone, which is administered in a dose of about 1-10mg, 15mg, 30mg or 45mg once a day. Another particularly preferred example is miglitol in a dose of about 10mg to 50mg or up to 100mg one to three times a day.

Examples of combination partners that lower the lipid content in the blood are HMG-CoA reductase inhibitors such as simvastatin (simvastatin), atorvastatin (atorvastatin), lovastatin (lovastatin), fluvastatin (fluvastatin), pravastatin (pravastatin) and rosuvastatin (rosuvastatin); fibrates such as bezafibrate, fenofibrate, clofibrate, gemfibrozil, etofibrate, and etoxytheophylline clofibrate; nicotinic acid and its derivatives, such as acipimox (acipimox); PPAR-alpha agonists; a PPAR-agonist; acyl-coenzyme A: cholesterol acyltransferase (ACAT; EC 2.3.1.26) inhibitors, such as avasimibe (avasimibe); cholesterol reuptake inhibitors such as ezetimibe (ezetimib); substances that bind bile acids, such as cholestyramine (cholestyramine), colestipol (colestipol), and colesevelam (colesevelam); a bile acid metastasis inhibitor; HDL modulating actives such as D4F, retro D4F, LXR modulating actives and FXR modulating actives; CETP inhibitors such as Tochester (torcetrapib), JTT-705, or Compound 12 from WO 2007/005572; a LDL receptor modulator; and ApoB100 antisense RNA. An especially preferred example is atorvastatin in a dose of about 1mg to 40mg or 10mg to 80mg once a day.

Examples of blood pressure lowering combination partners are beta-blockers such as atenolol (atenolol), bisoprolol (bisoprolol), celiprolol (celiprolol), metoprolol (metoprolol) and carvedilol (carvedilol); diuretics such as hydrochlorothiazide, chlorothiazide (chlorotalidon), xipamide (xipamide), furosemide (furosemide), piretanide (piretanide), torasemide (torasemide), spironolactone (spironolactone), eplerenone (eplerenone), amiloride (amiloride) and triamterene (triamterene); calcium channel blockers such as amlodipine (amlodipine), nifedipine (nifedipine), nitrendipine (nitrendipine), nisoldipine (nisoldipine), nicardipine (nicardipine), felodipine (felodipine), lacidipine (lacidipine), lercanidipine (lercanidipine), manidipine (manidipine), isradipine (isradipine), nilvadipine (nilvadipine), verapamil (verapamil), galopamid (gallopamil) and diltiazem (diltiazem); ACE inhibitors such as ramipril (ramipril), lisinopril (lisinopril), cilazapril (cilazapril), quinapril (quinapril), captopril (captopril), enalapril (enalapril), benazepril (benazepril), perindopril (perindopril), fosinopril (fosinopril) and trandolapril (traolampril); and angiotensin II receptor blockers (ARBs) such as telmisartan (telmisartan), candesartan (candesartan), valsartan (valsartan), losartan (losartan), irbesartan (irbesartan), olmesartan (olmesartan), and eprosartan (eprosartan). Particularly preferred examples are metoprolol at a dose of 50mg to 200mg per day, amlodipine at a dose of 2.5mg to 10mg per day, ramipril at a dose of 2.5mg to 15mg per day, valsartan at a dose of 80mg to 160mg per day and telmisartan at a dose of 20mg to 320mg or 40mg to 160mg per day.

Examples of combination partners that increase HDL levels in the blood are Cholesteryl Ester Transfer Protein (CETP) inhibitors; an endothelial lipase inhibitor; ABC1 modulators; an LXR α antagonist; LXR β agonists; a PPAR-agonist; LXR alpha/beta modulators, and agents that increase the expression and/or plasma concentration of the apolipoprotein A-I.

Examples of combination partners for the treatment of obesity are sibutramine (sibutramine); tetrahydrolipstatin (orlistat); allixame (alizyme); dexfenfluramine (dexfenfluramine); axokine (axokine); cannabinoid receptor 1 antagonists, such as CB1 antagonist rimontant; an MCH-1 receptor antagonist; MC4 receptor agonists; NPY5 and NPY2 antagonists; beta 3-AR agonists such as SB-418790 and AD-9677; 5HT2c receptor agonists, such as APD 356; inhibitors of tubocurarine (myostatin); acrp30 and adiponectin (adiponectin); inhibitors of stearoyl-coa desaturase (SCD 1); fatty Acid Synthase (FAS) inhibitors; a CCK receptor agonist; modulators of the intragastric hormone (Ghrelin) receptor; pyy 3-36; orexin receptor antagonists; and tesofensine (tesofensine).

Examples of combination partners for the treatment of atherosclerosis are phospholipase a2 inhibitors; inhibitors of tyrosine-kinases (50mg to 600mg), such as PDGF-receptor-kinase inhibitors (see EP- ｃA-564409, WO98/35958, US5093330, WO 2004/005281 and WO 2006/041976); oxLDL antibodies and oxLDL vaccines; apoA-1 Milano; ASA; and VCAM-1 inhibitors.

Examples of combination partners for the treatment of heart failure are beta-blockers such as atenolol, bisoprolol, celiprolol and metoprolol; diuretics such as hydrochlorothiazide, chlorthalidone, xipamide, furosemide, piretanide, torasemide, spironolactone, eplerenone, amiloride and triamterene; ACE inhibitors such as ramipril, lisinopril, cilazapril, quinapril, captopril, enalapril, benazepril, perindopril, fosinopril and trandolapril; and angiotensin II receptor blockers (ARBs) such as telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan and eprosartan; cardiac glycosides, such as digoxin (digoxin) and digitoxin (digitoxin); combination α/β blockers such as carvedilol (carvedilol); b-type natriuretic peptide (BNP), BNP-derived peptides, and BNP-fusion products. Particularly preferred examples are a dose of metoprolol of 50 to 200mg per day, a dose of ramipril of 2.5 to 15mg per day, a dose of valsartan of 80 to 160mg per day, a dose of telmisartan of 20 to 320mg or 40 to 160mg per day, a dose of eplerenone (eplerenone) of 25 to 100mg, a dose of digoxin of 0.25 to 0.6mg per day, a dose of carvedilol of 3.25 to 100mg, a bolus injection of 2 μ g/kg followed by a dose of 0.01 μ g/kg/min of BNP (e.g. nesiritide).

Pharmaceutical combinations comprising selected DPP IV inhibitors contain, for example, 1.75 to 10.5mg glibenclamide, 500 to 3000mg tolbutamide, 0.5 to 6g glimepiride, 2.5 to 40mg glipizide, 1-4 x 30mg gliquidone, to 3 x 25mg gliboside, 80 to 160mg gliclazide; 500mg to 1000mg, preferably 500mg, 850mg or 1000mg of metformin; 60mg to 180mg nateglinide; 0.25mg to 4mg repaglinide; 2mg to 45mg thiazolidinedione; 200mg to 600mg of meglitinide; 2.5mg to 5mg PPAR γ/α modulator; 0.1mg to 100mg alpha glucosidase blocker; 1-250IU insulin; 15 μ g to 120 μ g pramlintide; 5mg to 80mg statins (statins); 50mg to 1000mg of a fibrate; 1000mg to 3000mg niacin or a derivative; about 250mg acipimox (acipimox); about 10mg cholesterol resorption inhibitor; 0.5g to 30g of a bile acid binding substance; 10mg to 600mg and preferably 10mg to 120mg of a CETP inhibitor; 2.5mg to 100mg beta-blocker; 3mg to 200mg diuretic; 2.5mg to 500mg of a calcium channel blocker; 1mg to 4mg ACE inhibitor; 5mg to 600mg angiotensin II receptor blocker; 10mg to 15mg sibutramine; about 120mg orlistat; 15mg to 30mg dexfenfluramine; or 5mg to 20mg cannabinoid receptor antagonist, a dosage of 25mg to 100mg eplerenone; digoxin at a dose of 0.25mg to 0.6mg per day; carvedilol in a dosage of 3.25mg to 100 mg; BNP (e.g. nesiritide) is injected rapidly at a dose of 2 μ g/kg followed by 0.01 μ g/kg/min.

To sum up, the present invention relates to the following:

item 1 use of a DPP IV inhibitor of formula (I) or formula (II) and one of its salts for the preparation of a medicament for the therapeutic treatment of a patient already diagnosed with a physiologically functional disorder selected from pre-diabetes, glucose intolerance, pathological fasting glucose, diabetic foot, a diabetes related ulcer, diabetic hyperlipidemia, diabetic dyslipidemia, newly diagnosed type I diabetes, gestational diabetes, hyperglycemia, adrenergic postprandial syndrome and heart failure, or for the therapeutic treatment of a patient transplanted pancreatic islets or beta cells,

it is characterized in that

R1 represents ([1, 5] naphthyridin-2-yl) methyl, (quinazolin-2-yl) methyl, (quinoxalin-6-yl) methyl, (4-methyl-quinazolin-2-yl) methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl) methyl, (3-cyano-pyridin-2-yl) methyl, (4-methyl-pyrimidin-2-yl) methyl or (4, 6-dimethyl-pyrimidin-2-yl) methyl, and

r2 represents 3- (R) -amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino or (2- (S) -amino-propyl) -methylamino.

Use of a DPP IV inhibitor of formula (I) or formula (II) and one of its salts for the preparation of a medicament for the treatment of a patient already diagnosed with pre-diabetes or dominant type II diabetes, characterized in that by using the medicament the following risk is reduced: despite the impaired glucose metabolism that still exists in the treatment, the elevated HbA1c values that still exist despite the treatment, the impaired fasting glucose values that still exist despite the treatment, the need for insulin treatment, overt type II diabetes, diabetic foot, diabetic-related ulcer, diabetic hyperlipidemia, diabetic dyslipidemia or macrovascular complications,

it is characterized in that

R1 represents ([1, 5] naphthyridin-2-yl) methyl, (quinazolin-2-yl) methyl, (quinoxalin-6-yl) methyl, (4-methyl-quinazolin-2-yl) methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl) methyl, (3-cyano-pyridin-2-yl) methyl, (4-methyl-pyrimidin-2-yl) methyl or (4, 6-dimethyl-pyrimidin-2-yl) methyl, and

r2 represents 3- (R) -amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino or (2- (S) -amino-propyl) -methylamino.

Item 3. the use according to item 2, characterized in that the macrovascular complication is selected from the group consisting of myocardial infarction, acute coronary syndrome, unstable angina, stable angina, hemorrhagic or ischemic stroke, peripheral arterial occlusive disease, cardiomyopathy, left heart insufficiency, right heart insufficiency, whole heart failure, arrhythmia and vascular restenosis.

Item 4. the use according to item 1, characterized in that the pharmaceutical composition is used for the therapeutic treatment of patients who have been diagnosed with pre-diabetes, glucose intolerance or pathologic fasting glucose.

The use according to item 1, characterized in that the pharmaceutical composition is for the therapeutic treatment of patients who have been diagnosed with diabetic hyperlipidemia or diabetic dyslipidemia.

Item 6. the use according to item 1, characterized in that the pharmaceutical composition is for the therapeutic treatment of gestational diabetes.

Item 7. the use according to item 1, characterized in that the pharmaceutical composition is for the therapeutic treatment of hyperglycemia or adrenergic postprandial syndrome.

Use according to item 1, characterized in that the pharmaceutical composition is for the therapeutic treatment of heart failure.

Item 9 use according to item 2, characterized in that the risk of further elevated HbA1c values, worsening fasting glucose and the need for insulin treatment is reduced by the use of a pharmaceutical composition.

Item 10 use of a DPP IV inhibitor of formula (I) or formula (II) and one of its salts for the preparation of a pharmaceutical combination with an active substance selected from the group consisting of: other antidiabetic actives; an active substance that lowers blood glucose levels; an active substance that lowers the level of lipids in the blood; an active substance that raises the level of HDL in blood; a blood pressure lowering active; and active substances for the treatment of atherosclerosis or obesity,

it is characterized in that

R1 represents ([1, 5] naphthyridin-2-yl) methyl, (quinazolin-2-yl) methyl, (quinoxalin-6-yl) methyl, (4-methyl-quinazolin-2-yl) methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl) methyl, (3-cyano-pyridin-2-yl) methyl, (4-methyl-pyrimidin-2-yl) methyl or (4, 6-dimethyl-pyrimidin-2-yl) methyl, and

r2 represents 3- (R) -amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino or (2- (S) -amino-propyl) -methylamino.

Item 11 use according to item 10 for the preparation of a pharmaceutical combination of a DPP IV inhibitor with another antidiabetic or hypotensive active substance.

Item 12 use according to item 10, characterized in that a pharmaceutical combination of a DPP IV inhibitor and metformin, miglitol, atorvastatin, valsartan or telmisartan is prepared.

Item 13. the use according to item 10, characterized in that the pharmaceutical combination is for the therapeutic treatment of a patient for whom a physiologically functional disorder has been diagnosed, said physiologically functional disorder being selected from the group consisting of pre-diabetes, glucose intolerance, pathologic fasting glucose, diabetic foot, diabetes-related ulcer, diabetic hyperlipidemia, diabetic dyslipidemia, newly diagnosed type I diabetes, gestational diabetes, heart failure, hyperglycemia and adrenergic postprandial syndrome.

Item 14. a culture medium for the isolation or storage of pancreatic islets or beta cells, characterized in that the culture medium contains 1nmol/l to 1 μmol/l of DPPIV inhibitor for enhancing the viability and secretory capacity of these cells.

Item 15 medium of item 14, characterized in that the DPP IV inhibitor has the structure of formula (I) or formula (II) and one of its salts,

it is characterized in that

R1 represents ([1, 5] naphthyridin-2-yl) methyl, (quinazolin-2-yl) methyl, (quinoxalin-6-yl) methyl, (4-methyl-quinazolin-2-yl) methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl) methyl, (3-cyano-pyridin-2-yl) methyl, (4-methyl-pyrimidin-2-yl) methyl or (4, 6-dimethyl-pyrimidin-2-yl) methyl, and

r2 represents 3- (R) -amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino or (2- (S) -amino-propyl) -methylamino.

Item 16. method of enhancing the viability and secretory capacity of islets or β cells, characterized in that during the isolation and transplantation of these islets or β cells, a DPP IV inhibitor is added to the isolation and storage medium at a concentration of 1nmol/l to 1 μmol/l.

A method of treating a patient with a DPP IV inhibitor, characterized in that said patient is diagnosed with a physiological functional disorder selected from the group consisting of prediabetes, glucose intolerance, pathologic fasting glucose, diabetic foot, diabetes related ulcer, diabetic hyperlipidemia, diabetic dyslipidemia, newly diagnosed type I diabetes, gestational diabetes, heart failure, hyperglycemia, and adrenergic postprandial syndrome, or treating a patient with transplanted islets or beta cells.

Item 18. a method of treating a pre-diabetic or type II diabetes patient with a DPP IV inhibitor, characterized in that the treatment reduces the risk of impaired glucose metabolism despite the treatment, the risk of an elevated HbA1c value despite the treatment, the risk of impaired fasting glucose values despite the treatment, the need for insulin treatment, overt type II diabetes, diabetic foot, diabetes-related ulcer, diabetic hyperlipidemia, diabetic dyslipidemia, or macrovascular complications.

A method of treating a patient with a DPP IV inhibitor, characterized in that said patient suffers from heart failure.

Examples

Example 1: treatment of prediabetes

The efficacy of the DPP IV inhibitors of the present invention for treating prediabetes characterized by pathological fasting glucose and/or abnormal glucose tolerance was tested using clinical studies. In studies over a shorter period of time (e.g., 2-4 weeks), the success of treatment was verified by determining fasting glucose values after the end of the study treatment period and/or postprandial or post-stress test (oral glucose tolerance test or food tolerance test after a specified meal), and comparing them to values prior to the start of the study and/or to those of the placebo group. Furthermore, fructosamine values were determined before and after treatment and compared to initial values and/or placebo values. A significant decrease in fasting glucose levels or non-fasting glucose levels demonstrates the efficacy of the treatment. In studies over a longer period of time (12 weeks or more), the success of treatment was tested by measuring HbA1c values, comparing to initial values and/or to placebo values. A significant change in HbA1c values compared to initial and/or placebo values demonstrates the efficacy of DPPIV inhibitors for the treatment of pre-diabetes.

Example 2: prevention of overt type II diabetes

Treatment of patients with pathological fasting glucose and/or glucose tolerance abnormalities (prediabetes) is also intended to prevent the shift to overt type II diabetes. The efficacy of the treatment can be investigated in comparative clinical studies of prediabetic patients on active substances or combinations of active substances, or on placebo or on non-drug treatment or on other drugs for a longer period of time (e.g. 1-5 years). During and at the end of treatment, it was tested how many patients developed overt type II diabetes by determining fasting glucose and/or loading test (e.g., oGTT), i.e., fasting glucose levels > 125mg/dl and/or 2 hour values > 199mg/dl according to oGTT. The number of patients presenting with overt type II diabetes is significantly reduced when treated with the active substance or combination of active substances compared to one of the other forms of treatment, demonstrating the efficacy of the active substance or combination of active substances in preventing the transition from pre-diabetes to overt diabetes.

Example 3: treatment of type II diabetes

The treatment of type II diabetic patients with the active substances according to the invention, in addition to an immediate improvement of the glucose metabolism status, prevents the metabolic status from worsening in the long run. The patients are treated with the active substance or combination of active substances according to the invention for a longer period of time, for example 1 to 6 years, this result being observed in comparison with patients treated with other antidiabetic drugs. If no or only a slight increase in fasting glucose and/or HbA1c values is observed, the success of the treatment compared to patients treated with other antidiabetic drugs is demonstrated. Treatment success is further demonstrated if patients treated with the active substance of the invention or the combination of active substances of the invention produce a worsening in glucose metabolism (e.g. an increase in the HbA1c value to > 6.5% or > 7%) compared to patients treated with other drugs, to a significantly lesser extent to the extent of treatment with another oral antidiabetic drug or with insulin or with an insulin analogue or with other antidiabetic agent (e.g. a GLP-1 analogue).

Example 4: treatment of insulin resistance

In clinical studies conducted for varying durations (e.g., 2 weeks to 12 months), treatment success was checked using a hyperinsulinemic euglycemic clamp study. At the end of the study, a significant increase in the rate of glucose infusion compared to the initial value or compared to the placebo combination or the group given different treatments demonstrates the efficacy of the active substance or combination of active substances for the treatment of insulin resistance.

Example 5: treatment of diabetic hyperlipidemia or dyslipidemia

In clinical studies of type II diabetic patients of varying duration (e.g. 2 weeks to 60 months), treatment success was examined by measuring total cholesterol, LDL-cholesterol, HDL-cholesterol and plasma triglycerides. The significant decrease in total cholesterol, LDL-cholesterol or plasma triglycerides and/or the increase in HDL-cholesterol levels, during or at the end of the study, compared to the starting values or compared to the placebo group or the group given different treatments, demonstrates the efficacy of the active or combination of actives for the treatment of diabetic dyslipidemia or hyperlipidemia.

Example 6: treatment of hyperglycemia

In clinical studies conducted for varying durations (e.g., 1 day to 24 months), patients with hyperglycemia were examined for treatment success by determining fasting glucose or non-fasting glucose (e.g., after a meal or after oGTT or a meal-specific stress test). These significant decreases in glucose values, either during the study or at the end of the study, compared to the initial values or compared to the placebo group or the group given different treatments demonstrate the efficacy of the active substance or combination of active substances for the treatment of hyperglycemia.

Example 7: treatment of gestational diabetes

In clinical studies conducted for a shorter period of time (e.g., 2-4 weeks), treatment success was checked by determining the fasting glucose value at the end of the treatment period of the study and/or the glucose value after a meal or after a stress test (oral glucose tolerance test or food tolerance test determined after a meal) and comparing it to the value before the study was started and/or to the value of the placebo group. In addition, fructosamine values can be determined before and after treatment and compared to initial values and/or placebo values. The efficacy of the active or combination of actives is demonstrated by a significant decrease in fasting glucose levels or non-fasting glucose levels.

In a longer study (12 weeks or longer), treatment success was checked by measuring HbA1c values (compared to the initial value and placebo). A significant change in the HbA1c value compared to the initial value and/or placebo value demonstrates the efficacy of the active substance or combination of active substances for the treatment of gestational diabetes.

Example 8: treatment of women already suffering from gestational diabetes

Patients with gestational diabetes have a significantly increased risk of developing overt type II diabetes after pregnancy. Treatment can prevent the shift to overt type II diabetes. To this end, women with a history of gestational diabetes are treated for a longer period (e.g. 1-4 years) with an active substance according to the invention or a combination of active substances according to the invention or with a placebo or with a non-drug treatment or with another drug. During and at the end of treatment, a check is made to determine how many patients have developed overt type II diabetes (fasting glucose content > 125mg/dl and/or 2 hour value > 199mg/dl after oGTT) by measuring fasting glucose and/or by a stress test (e.g., oGTT). The number of patients who developed overt type II diabetes is significantly reduced when treated with the active substance according to the invention or the combination of active substances according to the invention compared to different types of treatment, demonstrating the efficacy of the active substance or the combination of active substances for the prevention of overt diabetes in women with a history of gestational diabetes.

Example 9: prevention of microvascular or macrovascular complications

Treatment of type II diabetes or pre-diabetic patients with an active substance of the invention or a combination of active substances of the invention prevents or reduces microvascular complications (e.g. diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic foot, diabetic ulcers) or macrovascular complications (e.g. myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, arrhythmia, vascular restenosis). Patients with type II diabetes or pre-diabetes are treated chronically, e.g. for 1-6 years, with the active substance or the combination of active substances of the invention and compared to patients treated with other antidiabetic drugs or with placebo. A lower number of single or multiple complications demonstrate successful treatment compared to patients treated with other antidiabetic drugs or with placebo. In the case of macrovascular events, diabetic feet and/or diabetic ulcers, they are counted by anamnesis and various test methods. In the case of diabetic retinopathy, treatment success is determined by computer controlled illumination and evaluation of the eye background or other ophthalmic methods. In the case of diabetic neuropathy, nerve conductivity is measured, for example, using a calibrated tuning fork, in addition to anamnesis and clinical examinations. For diabetic nephropathy, the following parameters were investigated before the start of the study, during the study and at the end of the study: albumin secretion, creatinine clearance, serum creatinine value, time elapsed for serum creatinine value doubling, time elapsed until dialysis is required.

Example 10: treatment of metabolic syndrome

The efficacy of an active or combination of actives of the invention can be tested in clinical studies with different running times (e.g. 12 weeks to 6 years) by determining fasting glucose or non-fasting glucose (e.g. after a meal or after oGTT or a meal-determining stress test) or HbA1c values. These significant decreases in glucose values or HbA1c values, compared to the initial values or compared to placebo or to groups given different treatments, demonstrate the efficacy of the active substance or combination of active substances for the treatment of metabolic syndrome during or at the end of the study. A reduction in systolic and/or diastolic blood pressure, a reduction in plasma triglycerides, a reduction in total or LDL cholesterol, an increase in HDL cholesterol or a weight loss compared to the starting value at the start of the study or compared to a group of patients treated with placebo or with different therapies.

Example 11: film-coated tablets of DPP IV inhibitor

To prepare the granulation solution, copovidone (copovidone) was dissolved in pure water at ambient temperature. The DPP IV inhibitor, mannitol, pregelatinized starch, and corn starch are mixed in a suitable mixer to prepare a premix. The premix is wetted with the granulation solution and subsequently granulated in a mixer at a high shear rate. The wet granules were screened through a sieve having a mesh size of 1.6 mm. The granules were dried in a fluid bed dryer at about 60 ℃ until a dry weight loss value of 2-4% was obtained. Compressing the processed mixture to form the tablet core.

Hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide and iron oxide are suspended in purified water at ambient temperature in a suitable mixer to prepare a suspension for tablet coating. The tablet cores were coated with this suspension until a 3% weight gain was obtained. By way of example, the following tablet compositions can be obtained in this way:

example 12: enhancing the vitality and the secretion capability of the islet or beta cell

This experiment is performed after successful isolation of pancreatic islets or pancreatic beta cells by storing, transferring or culturing them in a medium containing a DPP IV inhibitor at a concentration of 1nmol/l to 1 μmol/l, preferably 1nmol/l to 100nmol/l, for future transplantation.

Furthermore, following islet or pancreatic beta cell transplantation, the patient (and these may also be animals) is treated with a DPP IV inhibitor at a daily dose between 1mg to 200mg, preferably at a dose between 5mg to 100mg to enhance the viability and secretory capacity of these transplants. This was tested by analyzing insulin secretion after stimulation with glucose or other drugs that increase insulin secretion. Furthermore, the quality improvement can also be achieved using Diabetologia 42: 566, 1999 or Diabetes 48: 7381999 (entrapment of apoptosis and inhibition therof).

Example 13: combination therapy of DPP IV inhibitor and metformin

For the treatment of type II diabetes or pre-diabetes, the DPP IV inhibitor of the present invention may be combined with the antidiabetic active substance metformin in free or fixed combination in a tablet. A therapeutically effective dose of a DPP IV inhibitor (e.g. a dose between 0.1mg and 100 mg) may be combined with different doses of metformin, e.g. with a single dose of 500mg, 850mg or 1000mg of metformin, a total daily dose of 500-2850mg of metformin, or with 500mg, 1000mg, 1500mg or 2000mg of metformin in sustained release form. The clinical efficacy of this combination with metformin can be tested in clinical studies. In this regard, type II diabetic or pre-diabetic patients are treated with a DPP IV inhibitor alone or with metformin alone or with a combination of a DPP IV inhibitor and metformin. Treatment lasts for a period between 2 weeks and 6 years. The combination of a DPP-IV inhibitor and metformin causes a significantly greater reduction in fasting glucose and/or non-fasting glucose and/or HbA1c values compared to either the DPP IV inhibitor alone or metformin alone demonstrates that the combination is suitable and effective.

Example 14: combination therapy of DPP IV inhibitor-glitazone (glitazone)

For the treatment of type II diabetes or pre-diabetes, the DPP IV inhibitors of the present invention may be combined in a tablet with an antidiabetic active substance comprising glitazones or thiazolidinediones, such as pioglitazone or rosiglitazone, in free combination or in fixed combination. A therapeutically effective dose of a DPP IV inhibitor (e.g., a dose between 0.1mg to 100 mg) may be combined with a different dose of pioglitazone (15mg, 30mg or 45mg) or rosiglitazone (2mg, 4mg or 8mg, administered once or twice a day). The clinical efficacy of this combination with rosiglitazone or pioglitazone can be tested in clinical studies. In this regard, type II diabetic or pre-diabetic patients are treated with a DPP IV inhibitor alone or with rosiglitazone or pioglitazone alone or with a combination of a DPPIV inhibitor and rosiglitazone or pioglitazone. Treatment lasts for a period between 2 weeks and 6 years. The combination of a DPP-IV inhibitor with rosiglitazone or pioglitazone that results in a significantly greater reduction in fasting glucose and/or non-fasting glucose and/or HbA1c values compared to the DPP IV inhibitor alone or rosiglitazone or pioglitazone alone demonstrates that the combination is suitable and effective.

Example 15: combination therapy of DPP IV inhibitor-SGLT 2 inhibitor

For the treatment of type II diabetes or pre-diabetes, the DPP IV inhibitor of the present invention may be combined in a tablet with an antidiabetic active comprising an SGLT-2 inhibitor in a free combination or in a fixed combination. A therapeutically effective dose of DPPIV inhibitor (e.g., a dose between 0.1mg and 100 mg) may be combined with a different dose of SGLT-2 inhibitor (0.5mg to 1000 mg). The clinical efficacy of this combination with an SGLT-2 inhibitor can be tested in clinical studies. In this regard, patients with type II diabetes or pre-diabetes are treated with a DPP IV inhibitor alone or with an SGLT-2 inhibitor alone or in combination with a DPP IV inhibitor and an SGLT-2 inhibitor. Treatment lasts for a period between 2 weeks and 6 years. The combination of a DPP-IV inhibitor and an SGLT-2 inhibitor resulting in a significantly greater reduction in fasting glucose and/or non-fasting glucose and/or HbA1c values compared to either the DPP IV inhibitor alone or the SGLT-2 inhibitor alone demonstrates that the combination is suitable and effective.

Example 16: combination therapy of DPP IV inhibitor-antihypertensive agent

For the treatment of patients with type II diabetes or pre-diabetes or metabolic syndrome, the DPP IV inhibitor of the present invention may be combined with an antihypertensive active in a tablet in a free or fixed combination. A therapeutically effective dose of a DPPIV inhibitor (e.g., a dose between 0.1mg and 100 mg) may be combined with different doses of an ACE-inhibitor (e.g., 2.5mg to 15mg ramipril), an AT 1-receptor antagonist (e.g., 20mg to 160mg telmisartan), a beta-blocker (e.g., 50mg to 200mg metoprolol), or a diuretic (e.g., 12.5mg to 25mg hydrochlorothiazide). The clinical efficacy of this combination with an antihypertensive agent can be tested in clinical studies. In this regard, patients with type II diabetes or pre-diabetes or metabolic syndrome are treated with either a DPP IV inhibitor alone or an antihypertensive agent alone or a combination of a DPP IV inhibitor and an antihypertensive agent. Treatment lasts for a period between 2 weeks and 6 years. The combination of a DPP-IV inhibitor and an antihypertensive agent reduces fasting glucose and/or non-fasting glucose and/or HbA1c values to at least as much as the DPP IV inhibitor alone, and the combination of a DPP-IV inhibitor and an antihypertensive agent reduces systolic and/or diastolic blood pressure to at least as much as the antihypertensive agent alone, demonstrating that the combination is suitable and effective.

Example 17: combination therapy with DPP IV inhibitor-lipid lowering agents

For the treatment of patients with type II diabetes or pre-diabetes or metabolic syndrome or diabetic dyslipidemia or hyperlipidemia, the DPP IV inhibitor of the present invention may be combined with a lipid lowering agent/HDL-raising agent in a tablet in a free or fixed combination. A therapeutically effective dose of a DPP IV inhibitor (e.g., a dose between 0.1mg and 100 mg) may be combined with various doses of a statin (e.g., 10mg to 80mg atorvastatin or 10mg to 80mg simvastatin), a fibrate (e.g., fenofibrate), a cholesterol absorption inhibitor, or with an HDL-raising substance such as a CETP-inhibitor (e.g., tocarpep 10mg to 120mg once a day or twice a day 120 mg). The clinical efficacy of this combination with a lipid lowering/HDL-raising agent can be tested in clinical studies. In this regard, patients with type II diabetes or pre-diabetes or metabolic syndrome or diabetic dyslipidemia or hyperlipidemia are treated with either a DPP IV inhibitor alone or a lipid lowering agent/HDL-raising agent alone or a combination of a DPP IV inhibitor and a lipid lowering agent/HDL-raising agent. Treatment lasts for a period between 2 weeks and 6 years. The combination of DPP-IV inhibitor with lipid lowering agent/HDL-raising agent reduces fasting glucose and/or non-fasting glucose and/or HbA1c values to at least as much as DPP IV inhibitor alone, and the combination of DPP-IV inhibitor with lipid lowering agent/HDL-raising agent reduces total cholesterol or LDL-cholesterol or plasma triglycerides or increases HDL-cholesterol values to at least as much as lipid lowering agent/HDL-raising agent alone, proving that the combination is suitable and effective.

Example 18: combination therapy of DPP IV inhibitor-BNP/BNP-derived peptides or BNP-fusion peptides on heart failure patients

For the treatment of patients with acute heart failure, the DPP IV inhibitors of the present invention may be combined in tablets in free or fixed combination with substances that favorably influence heart failure. A therapeutically effective dose of a DPP IV inhibitor (e.g. a dose between 0.1mg and 100 mg) may be combined with different doses of ACE-inhibitors (e.g. 2.5mg to 15mg ramipril), AT 1-receptor antagonists (e.g. 20mg to 160mg telmisartan), beta-blockers (e.g. 50mg to 200mg metoprolol), combined alpha/beta-blockers (e.g. 3.25mg to 100mg carvedilol), diuretics (e.g. 12.5mg to 25mg hydrochlorothiazide), mineralocorticoid receptor antagonists (e.g. 25mg to 100mg eplerenone; and/or B-type natriuretic peptide (BNP)) (e.g. a2 μ g/kg bolus followed by 0.01 μ g/kg/min nesiritide), BNP derived peptides or BNP-fusion products. The combination of BNP with a DPP-IV inhibitor results in higher concentrations of full-length BNP (1-32) in vivo. The clinical efficacy of a particular combination can be tested in clinical studies. Treatment lasts between 1 day and 6 years. The combination results in a significant improvement in clinical condition (higher cardiac ejection output and/or reversal of pulmonary congestion, and/or reversal of pulmonary wedge pressure, and/or decreased mortality due to acute heart failure) compared to other therapies, demonstrating that the combination is effective in treating acute heart failure.

Example 19: DPP-IV inhibitor for treating patients with heart failure

The DPP IV inhibitors of the present invention may be used to treat patients with chronic heart failure. This treatment results in higher concentrations of endogenous full-length BNP (1-32) in vivo. The clinical efficacy of this treatment can be tested in clinical studies. Treatment lasts for a period between 2 weeks and 6 years. The significant improvement in clinical condition caused by the DPP-IV inhibitors of the present invention (due to lower frequency of hospitalization for acute heart failure, ability to travel longer distances, higher human power (ergometrics) load capacity, higher cardiac ejection output and/or reversal of pulmonary congestion, and/or decreased mortality due to heart failure) compared to different treatments or placebo demonstrates that this combination is effective in treating chronic heart failure.

Claims (10)

1. Use of a DPP IV inhibitor of formula (I) or formula (II) and one of its salts for the preparation of a medicament for the therapeutic treatment of a patient who has been diagnosed with a physiologically functional disorder selected from the group consisting of pre-diabetes, glucose intolerance, pathological fasting glucose, diabetic foot, diabetes related ulcers, diabetic hyperlipidemia, diabetic dyslipidemia, newly diagnosed type I diabetes, gestational diabetes, hyperglycemia, adrenergic postprandial syndrome and heart failure, or for the therapeutic treatment of a patient with transplanted islets of Langerhans or beta cells,

it is characterized in that

R1 represents ([1, 5] naphthyridin-2-yl) methyl, (quinazolin-2-yl) methyl, (quinoxalin-6-yl) methyl, (4-methyl-quinazolin-2-yl) methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl) methyl, (3-cyano-pyridin-2-yl) methyl, (4-methyl-pyrimidin-2-yl) methyl or (4, 6-dimethyl-pyrimidin-2-yl) methyl, and

r2 represents 3- (R) -amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino or (2- (S) -amino-propyl) -methylamino.

2. Use of a DPP IV inhibitor of formula (I) or formula (II) and one of its salts for the preparation of a medicament for the treatment of patients already diagnosed with pre-diabetes or dominant type II diabetes, characterized in that by using the medicament the following risks are reduced: despite the impaired glucose metabolism that still exists in the treatment, the elevated HbA1c values that still exist despite the treatment, the impaired fasting glucose values that still exist despite the treatment, the need for insulin treatment, overt type II diabetes, diabetic foot, diabetic-related ulcer, diabetic hyperlipidemia, diabetic dyslipidemia or macrovascular complications,

it is characterized in that

R1 represents ([1, 5] naphthyridin-2-yl) methyl, (quinazolin-2-yl) methyl, (quinoxalin-6-yl) methyl, (4-methyl-quinazolin-2-yl) methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl) methyl, (3-cyano-pyridin-2-yl) methyl, (4-methyl-pyrimidin-2-yl) methyl or (4, 6-dimethyl-pyrimidin-2-yl) methyl, and

r2 represents 3- (R) -amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino or (2- (S) -amino-propyl) -methylamino.

3. Use according to claim 2, characterized in that the macrovascular complication is selected from the group consisting of myocardial infarction, acute coronary syndrome, unstable angina, stable angina, hemorrhagic or ischemic stroke, peripheral arterial occlusive disease, cardiomyopathy, left heart insufficiency, right heart insufficiency, whole heart failure, arrhythmia and vascular restenosis.

4. Use according to claim 1, characterized in that the pharmaceutical composition is used for the therapeutic treatment of patients who have been diagnosed with pre-diabetes, glucose intolerance or pathologic fasting glucose.

5. The use according to claim 1, characterized in that the pharmaceutical composition is for the therapeutic treatment of patients who have been diagnosed with diabetic hyperlipidemia or diabetic dyslipidemia.

6. Use according to claim 1, characterized in that the pharmaceutical composition is for the therapeutic treatment of gestational diabetes.

7. Use according to claim 1, characterized in that the pharmaceutical composition is for the therapeutic treatment of hyperglycemia or of the adrenergic postprandial syndrome.

8. Use according to claim 1, characterized in that the pharmaceutical composition is for the therapeutic treatment of heart failure.

9. Use according to claim 2, characterized in that the risk of further elevated HbA1c values, worsening fasting glucose and the need for insulin treatment is reduced by the use of the pharmaceutical composition.

10. Use of a DPP IV inhibitor of formula (I) or formula (II) and one of its salts for the preparation of a pharmaceutical combination with an active substance selected from the group consisting of: other antidiabetic actives; an active substance that lowers blood glucose levels; an active substance that lowers the level of lipids in the blood; an active substance that raises the level of HDL in blood; a blood pressure lowering active; and active substances for the treatment of atherosclerosis or obesity,

it is characterized in that

R1 represents ([1, 5] naphthyridin-2-yl) methyl, (quinazolin-2-yl) methyl, (quinoxalin-6-yl) methyl, (4-methyl-quinazolin-2-yl) methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl) methyl, (3-cyano-pyridin-2-yl) methyl, (4-methyl-pyrimidin-2-yl) methyl or (4, 6-dimethyl-pyrimidin-2-yl) methyl, and

r2 represents 3- (R) -amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino or (2- (S) -amino-propyl) -methylamino.