JP2020002159A - Vasoprotective and cardioprotective antidiabetic therapy - Google Patents

Abstract

To provide a pharmaceutical composition for treating and/or preventing oxidative stress, vascular stress and/or endothelial dysfunction.SOLUTION: Disclosed is the use of linagliptin for preparation of a pharmaceutical composition for use in a method of treating and/or preventing oxidative stress, vascular stress and/or endothelial dysfunction, including the step of administering linagliptin.SELECTED DRAWING: None

Description

  The present invention relates to certain DPP-4 inhibitors for treating and / or preventing oxidative stress, vascular stress and / or endothelial dysfunction, and to diabetic or non-diabetic patients (for cardiovascular and / or renal diseases). Use of such DPP-4 inhibitors in the treatment and / or prevention of at-risk patient groups.

  The present invention relates to certain DPP-4 inhibitors for treating and / or preventing oxidative stress, vascular stress and / or endothelial dysfunction, and to diabetic or non-diabetic patients (for cardiovascular and / or renal diseases). (Including at-risk patient groups), pharmaceutical compositions, and methods of using DPP-4 inhibitors for use in preparing such pharmaceutical compositions.

The present invention relates to certain DPP-4 inhibitors for treating and / or preventing oxidative stress, vascular stress and / or endothelial dysfunction, and to diabetic or non-diabetic patients (for cardiovascular and / or renal diseases). Use of such DPP-4 inhibitors in the treatment and / or prevention of at-risk patient groups.
The invention further relates to the use of certain DPP-4 inhibitors for the treatment and / or prevention of endothelial dysfunction.
The invention further relates to certain DPP-4 inhibitors for use as antioxidants and / or anti-inflammatory agents.
The present invention also further treats and / or prevents oxidative stress, vascular stress and / or endothelial dysfunction (eg, in diabetic or non-diabetic patients), especially separately from or beyond blood glucose management. Certain DPP-4 inhibitors.
The present invention is further directed to certain DPP-4 inhibitors for treating and / or preventing (eg, beyond blood glucose control) oxidative stress induced by or associated with hyperglycemia. In addition to the use of such DPP-4 inhibitors in anti-diabetic therapy.
The present invention further provides for the treatment of metabolic disorders (eg diabetes, especially type 2 diabetes mellitus) and / or diseases related thereto (eg diabetes complications), especially oxidative stress, vascular stress and / or endothelial dysfunction, or Certain DPP-4 inhibitors for treating and / or preventing in a patient having or at risk for a disease or condition associated with or associated therewith.

The present invention further provides for the treatment of metabolic disorders (eg, diabetes, especially type 2 diabetes mellitus) and / or diseases related thereto (eg, diabetic complications) with cardiovascular and / or renal diseases, such as myocardial infarction, Certain DPPs to treat and / or prevent in patients with or at risk for stroke or peripheral arterial occlusive disease and / or diabetic nephropathy, microalbumin or macroalbuminuria, or acute or chronic renal impairment -4 inhibitors.
The invention further relates to metabolic disorders (eg diabetes, especially type 2 diabetes mellitus) and / or diseases associated therewith, including diabetic complications in microvessels or large vessels such as diabetic retinopathy, diabetic neuropathy, diabetes Certain types of DPP-4 inhibition that are treated and / or prevented in patients with or at risk for obstructive nephropathy or cardiovascular or cerebrovascular disease (eg, myocardial infarction, stroke or peripheral arterial occlusive disease) Agent.
The present invention further relates to certain DPP-4 inhibitors that modulate, block or alleviate the deleterious metabolic memory effects (of chronic or transient episodes) of hyperglycemia, especially against diabetic complications.
The invention further relates to certain DPP-4s that treat, prevent, or reduce the risk of microvascular or macrovascular disease that can be induced, memorized, or associated with exposure to oxidative stress. Related to inhibitors.

The present invention further relates to metabolic disorders (eg, diabetes, especially type 2 diabetes mellitus) and / or diseases related thereto (eg, diabetic complications) having or having a cardiovascular disease and / or renal disease. Patients at risk, especially those with type 2 diabetes at risk for cardiovascular or cerebrovascular events, e.g., one or more risk factors selected from A), B), C) and D) below. For certain DPP-4 inhibitors for treating and / or preventing in type 2 diabetics, the method comprises administering a therapeutically effective amount of a DPP-4 inhibitor, optionally with one or more other therapeutic agents. And administering together to said patient:
A) Previous or existing vascular disease (eg, myocardial infarction (eg, asymptomatic or symptomatic), coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure ( Eg NYHA class I or II, eg <40% left ventricular function or peripheral obstructive artery disease);
B) vascular related end-organ diseases (eg nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease and / or microalbumin or macroalbuminuria);
C) Elderly (eg ages 60-70); and
D) One or more cardiovascular risk factors selected from:
Advanced type 2 diabetes mellitus (eg for a period of more than 10 years),
Hypertension (eg> 130/80 mmHg, or systolic blood pressure> 140 mmHg, or at least one antihypertensive treatment),
-At this moment daily smoking,
-Dyslipidemia (atherogenic dyslipidemia, postprandial lipemia, or high levels of LDL cholesterol (e.g. LDL cholesterol is greater than 130-135 mg / dL), low levels of HDL cholesterol (e.g. <35-40 mg / dL, <45-50 mg / dL in women), and / or high levels of triglycerides in the blood (eg,> 200-400 mg / dL) or at least one treatment for lipid abnormalities),
Obesity (eg, abdominal obesity and / or visceral obesity, or a body volume index of 45 kg / m ² or more),
-Ages between 40 and under 80
-A metabolic syndrome, hyperinsulinemia or insulin resistance, and-a family history of hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or cardiomyopathy in first degree.

Furthermore, the present invention relates to cardiovascular or cerebrovascular events (eg, cardiovascular death, (fatal or non-fatal) myocardial infarction (eg, asymptomatic or symptomatic MI), (fatal or non-fatal). (Fatal) stroke, or the appearance of hospitalization (eg, for acute coronary syndrome, leg amputation, (emergency) revascularization, for heart failure, or for unstable angina), preferably in patients with type 2 diabetes Type 2 diabetics, especially at risk for cardiovascular or cerebrovascular events, for example, having one or more risk factors selected from A), B), C) and D) below For certain DPP-4 inhibitors used in a method for preventing, reducing the risk of their appearance, or delaying their appearance in a patient, the method comprises providing a therapeutically effective amount of a DPP-4 inhibitor. Administering to said patient together with one or more other therapeutic substances by:
A) Previous or existing vascular disease (eg, myocardial infarction (eg, asymptomatic or symptomatic), coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure ( Eg NYHA class I or II, eg left ventricular function less than 40%) or peripheral obstructive artery disease);
B) vascular related end-organ diseases (eg nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease and / or microalbumin or macroalbuminuria);
C) Elderly (eg ages 60-70); and
D) One or more cardiovascular risk factors selected from:
Advanced type 2 diabetes mellitus (eg for a period of more than 10 years),
Hypertension (eg> 130/80 mmHg, or systolic blood pressure> 140 mmHg, or at least one antihypertensive treatment),
-Daily smoking at the moment,
-Dyslipidemia (atherogenic dyslipidemia, postprandial lipemia, or high levels of LDL cholesterol (e.g. LDL cholesterol is greater than 130-135 mg / dL), low levels of HDL cholesterol (e.g. <35-40 mg / dL, <45-50 mg / dL in women), and / or high levels of triglycerides in the blood (eg,> 200-400 mg / dL), or at least one treatment for dyslipidemia).
Obesity (eg, abdominal obesity and / or visceral obesity, or a body volume index of 45 kg / m ² or more),
-Ages between 40 and under 80
-A metabolic syndrome, hyperinsulinemia or insulin resistance, and-a family history of hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or cardiomyopathy in first degree.

Furthermore, the present invention relates to cardiovascular or cerebrovascular events (eg, cardiovascular death, (fatal or non-fatal) myocardial infarction (eg, asymptomatic or symptomatic MI), (fatal or non-fatal). (Fatal) stroke, or the appearance of hospitalization (eg, acute coronary syndrome, leg amputation, (emergency) revascularization, due to heart failure or due to unstable angina), vascular-related end-organ disease, Certain DPPs used in methods to prevent, reduce the risk of, or delay the appearance of, especially in type 2 diabetic patients with nephropathy, renal dysfunction, chronic kidney disease, microalbumin or macroalbuminuria With respect to -4 inhibitors, the method comprises administering to the patient a therapeutically effective amount of a DPP-4 inhibitor, optionally with one or more other therapeutic agents.
Furthermore, the present invention provides improved cognitive function (eg, diminishes, reverses or treats cognitive decline), improved β-cell function (eg, improves insulin secretion rate from 3h dietary resistance, and improves long-term β-cell function. Ameliorate), improving circadian glucose patterns (eg, improving behavioral glucose profiles, glycemic variability, biomarkers of oxidation, inflammation or endothelial function), and / or improving sustained glucose management by β-cell autoantibody status For certain DPP-4 inhibitors used in a method for (e.g., glutamate decarboxylase (GAD)), the method comprises providing a therapeutically effective amount of a DPP-4 inhibitor, optionally with one or more Administering to the patient along with other therapeutic agents.
Furthermore, the present invention relates to certain DPP-types used in methods of preventing, reducing the risk of, delaying its progress, prolonging, attenuating, reversing or treating cognitive dysfunction or cognitive decline. With respect to four inhibitors, the method comprises administering to the patient a therapeutically effective amount of a DPP-4 inhibitor, optionally together with one or more other therapeutic agents.

Furthermore, the present invention is used in a method of preventing, reducing the risk of, delaying its progress, prolonging, attenuating, reversing or treating its latent autoimmune diabetes (LADA) in adults. For certain DPP-4 inhibitors, the method comprises administering to the patient a therapeutically effective amount of a DPP-4 inhibitor, optionally with one or more other therapeutic agents.
Still further, the invention provides for preventing, reducing the risk of, delaying its progression, prolonging its onset, weakening its cardiovascular or cerebrovascular diseases or events (eg, those described herein), Reverse or treat and further prevent diabetic nephropathy in a patient in need thereof (eg, the patients described herein, especially those with type 2 diabetes), reduce its risk, slow its progression, and start its onset Certain DPP-4 inhibitors for use in a method of prolonging, weakening, reversing, or treating, said method comprising the step of providing a therapeutically effective amount of a DPP-4 inhibitor and optionally one or more other Administering to said patient together with a therapeutic substance.

Furthermore, the present invention relates to one or more of the following methods, wherein an effective amount of certain DPP-4 inhibitors is optionally administered to a patient together with an effective amount of one or more other active agents. For methods involving:
A method of treating, alleviating, preventing and / or protecting against oxidative stress, such as non-diabetic or diabetic (hyperglycemic) -induced or non-diabetic or diabetic-associated oxidative stress;
-A method of treating, preventing, reducing the risk of, delaying its progress, prolonging, weakening, reversing its onset or improving endothelial function of endothelial dysfunction;
-A method of treating, preventing, reducing the risk, slowing its progression, prolonging, attenuating or reversing its disease or condition associated with oxidative stress (e.g. as described herein);
Treating, preventing, reducing the risk of, delaying its progress, prolonging, weakening or reversing its ischemia / reperfusion injury (of the kidney, heart, brain or liver) and / or ( How to reduce myocardial infarction size (after myocardial infarction / reperfusion);
-(Harmful) vascular remodeling, such as remodeling of the heart, especially after myocardial infarction, which is characterized by cardiomyocyte hypertrophy, interstitial fibrosis, ventricular dilation, asystole and / or cell death / apoptosis A method of treating, preventing, reducing the risk, delaying its progress, prolonging, weakening or reversing its onset;
-A method of treating, preventing, reducing the risk, slowing its progression, prolonging, weakening or reversing its chronic or acute renal failure and / or peripheral arterial occlusion;
Treating, preventing and reducing the risk of congestive heart failure (eg NYHA class I, II, III or IV) and / or cardiac hypertrophy (eg left ventricular hypertrophy) and / or nephropathy and / or albuminuria , Slowing its progress and prolonging, weakening or reversing its onset;
Treating, preventing and reducing the risk of uremic cardiomyopathy, gap dilation, and / or (cardiac) fibrosis (especially those found in patients with chronic kidney and heart disease often associated with type 2 diabetes) How to mitigate, slow its progress, prolong, weaken or reverse its onset;
-A method of modulating, blocking, preventing, alleviating or protecting against adverse metabolic memory effects of hyperglycemia (chronic, early or transient episodes), especially for diabetic complications;
-A method for preventing or protecting against oxidation of atherosclerotic or preatherogenic low density lipoproteins (especially small and dense LDL particles) and / or atherosclerotic plaque formation;
-A method for preventing or protecting against impairment of pancreatic beta cell function or viability induced by oxidative stress;
-A method of treating, preventing, mitigating or ameliorating inflammation of the pancreatic islets or lipotoxicity and sugar toxicity in the islets, or increasing the beta cell / alpha cell ratio, protecting the beta cells, or normalizing the morphology or function of the pancreatic islets And / or-complications of diabetes mellitus, such as diseases of the micro and large vessels, such as nephropathy, microalbumin or macroalbuminuria, proteinuria, retinopathy, cataract, neuropathy, learning or memory Disorders, neurodegenerative or cognitive abnormalities, cardiovascular or cerebrovascular diseases, endothelial dysfunction, tissue ischemia, diabetic foot or diabetic ulcer, atherosclerosis, hypertension, myocardial infarction, acute coronary syndrome , Unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy (including uremic cardiomyopathy), heart failure, cardiac rhythm abnormalities Prevent vascular restenosis, and / or stroke, especially in patients in need thereof (e.g., patients with type 1 diabetes, LADA or especially type 2 diabetes) separately or beyond blood glucose control; A method of reducing that risk, slowing its progress, prolonging, weakening, reversing or treating its onset.

Furthermore, the present invention provides for the prevention of diabetic nephropathy in patients (e.g., those described herein, especially Type 2 diabetic patients) that do not respond appropriately to methods of treatment with an angiotensin receptor blocker (ARB, e.g., telmisartan). For certain DPP-4 inhibitors used in a method of reducing its risk, delaying its progression, prolonging its life, attenuating it, reversing it or treating it, the method comprises administering a therapeutically effective amount of Administering a DPP-4 inhibitor to said patient, optionally together with one or more other therapeutic agents (eg, ARB, eg, Telmisartan).
Features of diabetic nephropathy include hyperfiltration (early stages), microalbumin or macroalbuminuria, nephrotic syndrome, proteinuria, hypertension, fluid retention, edema, and / or renal and renal filtration functions (eg, glomerular filtration Rate GFR), which may include a progressive impairment or decrease (which eventually leads to renal failure or end-stage renal disease). Still other features may include chronic or nodular glomerulosclerosis, import and export hyalinoid arteriosclerosis, and / or interstitial fibrosis and atrophy. Still other features may include abnormal albumin / creatinine or protein / creatinine ratios and / or abnormal glomerular filtration rates.

The invention further relates to certain DPP-4 inhibitors for use in a method of preventing or treating diabetic nephropathy in a patient who exhibits an inappropriate response to a method of treatment with an angiotensin receptor blocker (ARB, such as telmisartan). . The method comprises administering to the patient a therapeutically effective amount of a DPP-4 inhibitor and telmisartan.
Thus, in a specific embodiment, a preferred DPP-4 inhibitor within the intended scope of the invention is linagliptin.
Pharmaceutical compositions or combinations for use in these methods of treatment, comprising a DPP-4 inhibitor as defined herein, optionally together with one or more other active agents, are also contemplated.
Furthermore, the invention also relates to the combination of one, two or more further active agents, each of which is defined herein, optionally for use in a method of treatment as defined herein. DPP-4 inhibitors.
Furthermore, the invention also relates to the combination of one, two or more further active agents, each of which is defined herein, optionally for use in a method of treatment as defined herein. Of a DPP-4 inhibitor for the manufacture of a pharmaceutical composition, said composition being suitable for the therapeutic and / or prophylactic purposes of the present invention.
The present invention still further relates to the therapeutic (treatment and prophylaxis) methods described herein, wherein the method comprises an effective amount of a DPP-4 inhibitor described herein and optionally a 1D described herein. Administering one or more other active or therapeutic agents to a patient in need thereof.

Figure 2 shows the effect of linagliptin on thymosan A (ZymA) -induced ROS in human PMN (LPS = lipopolysaccharide, PMN = polymorphonuclear neutrophils, Bl356 = linagliptin, Nebi = nebivolol). Figure 3 shows the effect of linagliptin on human leukocyte (PMN) adhesion to human endothelial cells following LPS stimulation (Turks and CF-DA staining, BL1356 = linagliptin). FIG. 9 shows the effect of linagliptin on LPS (50 μg / mL) -induced adhesion of neutrophils to EA.hy cells (measured by oxidation of Amplex Red). Shows the effect of gliptin on the oxidative burst of isolated human neutrophils upon stimulation with LPS or thymosan A as measured by luminol / horseradish peroxidase (HRP) enhanced chemiluminescence (LPS = lipopolysaccharide, PMN = polymorphonuclear) Neutrophils, LG = Bl1356 = linagliptin, AG = alogliptin, VG = vildagliptin, SaG = saxagliptin, SiG = sitagliptin, Nebi = nebivolol). Shows the effect of gliptin on the oxidative burst of isolated human monocytes / lymphocytes upon stimulation with LPS or thymosan A, as measured by luminol / horseradish peroxidase (HRP) enhanced chemiluminescence (LPS = lipopolysaccharide, PMN = poly) Nucleated neutrophils, LG = Bl1356 = Linagliptin, AG = Alogliptin, VG = Vildagliptin, SaG = Saxagliptin, SiG = Sitagliptin, Nebi = Nebivolol). 2 is a table comparing gliptin for direct antioxidant activity in vitro. 9 shows the effect of linagliptin on LPS-activated neutrophil-driven oxidation of L-012 scavenging of peroxidase-induced ROS and inhibition of NADPH oxidase activity. Quantification of the oxidative burst of isolated human PMN (5 × 10 ⁵ cells / mL) with increasing concentrations of LPS and linagliptin was performed by enhanced chemiluminescence using the luminol analog L-012 (100 μM) (PBS = phosphate Buffered saline, LPS = lipopolysaccharide, PMN = polymorphonuclear neutrophils, LG = Bl1356 = linagliptin. Figure 2 shows the effect of linagliptin on whole blood oxidative burst / oxidative stress in nitroglycerin-induced nitrate tolerance (LPS = lipopolysaccharide, EtOH Ctr = ethanol control, GTN s.c. = trinitroglycerin-subcutaneous, Bl 1356 = linagliptin). Figure 2 shows the effect of linagliptin on whole blood oxidative burst / oxidative stress in nitroglycerin-induced nitrate tolerance (LPS = lipopolysaccharide, EtOH Ctr = ethanol control, GTN s.c. = trinitroglycerin-subcutaneous, Bl 1356 = linagliptin). Figure 3 shows the improvement of endothelial dysfunction in GTN or LPS treated rats by linagliptin (pretreatment with linagliptin (3-10 mg / kg), induction of endothelial dysfunction by nitrate or LPS (3 days)). FIG. 8A shows the effects of GTN-induced endothelial dysfunction and linagliptin on endothelium-dependent relaxation (EtOH Ctr = ethanol control, GTN s.c. = trinitroglycerin-subcutaneous, Bl1356 = linagliptin). FIG. 8B shows the effects of LPS (10 mg / kg / day i.p.) in vivo treatment and linagliptin treatment on endothelium-dependent relaxation (LPS = lipopolysaccharide, EtOH Ctr = ethanol control). Figure 3 shows the improvement of endothelial dysfunction in GTN or LPS treated rats by linagliptin (pretreatment with linagliptin (3-10 mg / kg), induction of endothelial dysfunction by nitrate or LPS (3 days)). FIG. 8A shows the effects of GTN-induced endothelial dysfunction and linagliptin on endothelium-dependent relaxation (EtOH Ctr = ethanol control, GTN s.c. = trinitroglycerin-subcutaneous, Bl1356 = linagliptin). FIG. 8B shows the effects of LPS (10 mg / kg / day i.p.) in vivo treatment and linagliptin treatment on endothelium-dependent relaxation (LPS = lipopolysaccharide, EtOH Ctr = ethanol control). Figure 2 shows the direct vasodilator effect of gliptin. Gliptin-induced vasodilation is determined by the recording of isotonic tone in isolated aortic ring segments and relaxation in response to increasing cumulative concentrations of linagliptin, sitagliptin or saxagliptin (1 nM to 32 μM) (FIG. 9A). In another set of experiments, aortic relaxation in response to increasing cumulative concentrations of linagliptin, alogliptin or vildagliptin (1 nM to 32 or 100 μM) is tested (FIG. 9B). Data are the mean ± SEM of 12 (FIG. 9A) or 4 (FIG. 9B) aortic rings of a total of 10 rats. *, P <0.05 vs DMSO (solvent control); ^# , p <0.05 vs sitagliptin / virdagliptin; superscript section symbol, p <0.05 vs saxagliptin / aggloliptin. Figure 9A continued. Figure 2 shows the direct vasodilator effect of gliptin. Gliptin-induced vasodilation is determined by the recording of isotonic tone in isolated aortic ring segments and relaxation in response to increasing cumulative concentrations of linagliptin, sitagliptin or saxagliptin (1 nM to 32 μM) (FIG. 9A). In another set of experiments, aortic relaxation in response to increasing cumulative concentrations of linagliptin, alogliptin or vildagliptin (1 nM to 32 or 100 μM) is tested (FIG. 9B). Data are the mean ± SEM of 12 (FIG. 9A) or 4 (FIG. 9B) aortic rings of a total of 10 rats. *, P <0.05 vs DMSO (solvent control); ^# , p <0.05 vs sitagliptin / virdagliptin; superscript section symbol, p <0.05 vs saxagliptin / aggloliptin. Shows renal function in STZ-treated animals based on linagliptin, telmisartan or a combination thereof or blood glucose detected after placebo treatment: 1) non-diabetic eNOS ko control mice, placebo (natrosol) (n = 14); 2) mock Treated diabetic eNOS ko mice, placebo (natrosol) (n = 17); 3) telmisartan (po 1 mg / kg) treated diabetic eNOS ko mice (n = 17); 4) Linagliptin (po 3 mg / kg) treated diabetic eNOS ko mice (N = 14); 5) Diabetic eNOS ko mice treated with telmisartan (po 1 mg / kg) + linagliptin (po 3 mg / kg) (n = 12). Shows the albumin / creatinine ratio between non-diabetic and diabetic animals: 1) non-diabetic eNOS ko control mice, placebo (natrosol) (n = 14); 2) mock-treated diabetic eNOS ko mice, placebo (natrosol) (n = 17); 3) diabetic eNOS ko mouse treated with telmisartan (po 1 mg / kg) (n = 17); 4) diabetic eNOS ko mouse treated with linagliptin (po 3 mg / kg) (n = 14); 5) telmisartan (po 1 mg / kg) kg) + linagliptin (po 3 mg / kg) treated diabetic eNOS ko mice (n = 12). Results of a rat experiment showing the effect of a combination of telmisartan (Telmi) and linagliptin (Bl1356) and treatment with telmisartan alone (Telmi solo) or linagliptin alone (Bl1356 solo) on blood pressure in a hypertension-induced cardiac hypertrophy (causing heart failure) model It is. From time point 3 to time point 6 in FIG. 12, the first line from the top indicates placebo 2K1C (highest RR systole), the second line from the top indicates linagliptin, and the center line indicates telmisartan , The second line from the bottom indicates a placebo mimic, the first line from the bottom indicates telmisartan + linagliptin (lowest RR systole). It is a table of the experimental result of the chronic renal failure model which shows the effect of linagliptin on the cardiac fibrosis marker and the left ventricular dysfunction marker in the heart tissue (TGF-β = transforming growth factor beta, TIMP = tissue inhibition of metalloproteinase). Factor, Col1α = collagen type 1 alpha, Col3α = collagen type 3 alpha, BNP = type B natriuretic peptide). FIG. 9 shows the experimental results in diabetic eNOS knockout C57BL / 6J mice as a diabetic nephropathy model (resistant to ARB treatment), and shows the effects of linagliptin and telmisartan on albuminuria.

DETAILED DESCRIPTION OF THE INVENTION Oxidative stress is an imbalance in the ability of a biological system to rapidly detoxify reactive oxygen species and reactive intermediates or repair the resulting damage (reactive oxygen species are free radicals). Which typically include an oxygen-based or nitrogen-based unpaired electron and peroxide in its outer electron orbital). Disruption of the normal redox state of tissue can cause deleterious effects by the production of peroxides and free radicals that damage all components within the cell, including proteins, lipids and nucleic acids / DNA. Oxidative stress targets many organs (eg, blood vessels, eyes, heart, skin, kidneys, joints, lungs, brain, immune system, liver, or multiple organs) and may be centrally involved in many diseases or conditions. Examples of diseases or conditions that are closely related to oxidative stress include atherosclerosis (eg, platelet activation and atheromatous plaque formation), endothelial dysfunction, restenosis, high blood pressure, peripheral obstructive vascular disease, Ischemia-reperfusion injury (eg, kidney, liver, heart or cerebral ischemia-reperfusion injury), fibrosis (eg, kidney, liver, heart or lung fibrosis); macular degeneration, retinal degeneration, cataract, retinopathy; coronary Arterial heart disease, ischemia, myocardial infarction; psoriasis, dermatitis; chronic kidney disease, nephritis, acute renal failure, glomerulonephritis, nephropathy; rheumatoid arthritis, osteoarthritis; asthma, COPD, respiratory distress syndrome; Degenerative diseases (eg Alzheimer's disease, Parkinson's disease, Huntington's disease), schizophrenia, bipolar disorder, obsessive-compulsive disorder; chronic systemic inflammation, perivascular inflammation, autoimmune diseases, multiple sclerosis, lupus erythematosus, inflammatory bowel disease, Ulcerative colitis; NAFLD / NASH; including chronic fatigue syndrome, polycystic ovary syndrome, sepsis, diabetes, metabolic syndrome, insulin resistance, hyperglycemia, hyperinsulinemia, dyslipidemia, hypercholesterolemia, hyperlipidemia, etc. It is. In addition to their natural pharmacological properties, certain drugs used clinically include, but are not limited to, antihypertensives, angiotensin receptor blockers and antihyperlipidemics (eg statins) ) Protects diverse organs through antioxidant stress mechanisms.

Patients having or at risk for oxidative stress and / or vascular stress include their oxidative stress markers (eg, oxidized LDL), inflammatory status markers (eg, proinflammatory interleukins), 8-OHdG, isoprostein ( For example, diagnosis can be made by determining F2-isoprostein, 8-isoprostein F2alpha), nitrotyrosine or N-carboxymethyllysine (CML).
Endothelial dysfunction (usually clinically determined as endothelium-dependent vasomotor dysfunction (eg, an imbalance between vasodilation and vasoconstriction)) is defined as endothelial cells (cells that line the inner surface of blood vessels, arteries, and veins). ) Is physiologically incapable of preventing the cells from performing their normal biochemical functions. Normal endothelial cells are required for control of coagulation, platelet adhesion, immune function, volume and electrolyte content of the inter- and extra-vascular spaces. Endothelial dysfunction is closely linked to pro-inflammatory, pro-oxidative and pro-thrombotic changes in the arterial wall. Endothelial dysfunction is thought to be a key event in the development and progression of atherosclerosis and arteriosclerosis, and precedes clinically distinct vascular complications. The prognosis of endothelial dysfunction is important for detecting vascular disease and predicting adverse vascular events. Risk factors for atherosclerosis and vascular diseases / events are closely related to endothelial dysfunction. Endothelial damage may also contribute to kidney injury and / or chronic or progressive kidney injury, such as interstitial fibrosis, glomerulonephritis, microalbumin or macroalbuminuria, nephropathy and / or chronic kidney disease or renal failure It becomes. There is evidence supporting that oxidative stress contributes to vascular disease as well as endothelial dysfunction or damage.

  Type 2 diabetes mellitus is a complex condition centrally responsible for the dual endocrine effects of insulin resistance and impaired insulin secretion, resulting in the failure to maintain the plasma glucose levels within normal limits. It is a common chronic and progressive disease arising from physiology. It results in hyperglycemia and its associated microvascular and macrovascular complications or chronic damage, such as diabetic nephropathy, retinopathy or neuropathy, or macrovascular (eg, cardiovascular or cerebrovascular) complications. . Although the components of vascular disease play an important role, they are not only factors in the diabetes-related disease area. Frequent complications lead to a marked reduction in life expectancy. Diabetes is currently the leading cause of adult-onset blindness, renal failure, and leg amputation in the industrialized world due to diabetes-induced complications, with a 2- to 5-fold increase in risk of cardiovascular death.

Thorough and strict glycemic control during early (from new diagnosis to 5 years) diabetes has sustained and beneficial effects and reduces the risk of diabetic complications (both microvascular and macrovascular) This has been established in a randomized large-scale trial. However, despite undergoing thorough glycemic control, many patients with diabetes still develop diabetic complications.
Epidemiological and predictive data support the long-term impact of early (up to 5 years from new diagnosis) metabolic management on clinical outcomes. Hyperglycemia has long-lasting adverse effects in both type 1 and type 2 diabetes, and glycemic control must be initiated very early in diabetes or provided thoroughly or rigorously. It has been found that it may not be enough to completely alleviate the complications.
Furthermore, transient episodes of hyperglycemia (eg, hyperglycemic events) can trigger molecular changes, and these changes can be persistent or irreversible after returning to euglycemia Was found.
Taken together, these data indicate that metabolic memory is preserved early in the diabetic process, and that in certain diabetic conditions, oxidative and / or vascular stress can persist after glucose normalization. Advocates. This phenomenon, in which even the initial glycemic environment and / or transient hyperglycemia is memorized with clinical consequences in target end organs (eg, blood vessels, retina, kidney, heart, limbs), has recently been described as "metabolic memory". It is called.

Potential mechanisms for transmitting this "memory" include certain epigenetic changes, non-enzymatic glycation of cellular proteins and lipids (eg, formation of additional glycation end products), oxidatively modified atherogenic Lipoproteins and / or excess intracellular reactive oxygen and nitrogen species (RONS), which occur especially at the glycated mitochondrial protein level and probably work in concert with each other to maintain stress signaling .
Mitochondria are one of the major sources of reactive oxygen species (ROS) in cells. Mitochondrial dysfunction increases electron leakage and ROS generation in the mitochondrial respiratory chain (MRC). High levels of glucose and lipids impair the activity of MRC complex enzymes. For example, the MRC enzyme NADPH oxidase generates superoxide from NADPH in cells. Increased NADPH oxidase activity can be detected in diabetic patients.
Furthermore, the overproduction of free radicals, such as reactive oxygen species (ROS), can result in the development and / or maintenance of oxidative and vascular stress and metabolic memory following glucose normalization, and thus, for example, endothelial dysfunction or other diabetic complications There is evidence to show that it contributes to the integration of hyperglycemia and cellular memory in E. coli.

Thus, normalization of blood glucose, whether induced by hyperglycemia (a chronic, early or transient episode of) or primarily associated with the persistent (long-term) oxidative stress associated therewith, There are certain metabolic conditions in that long-lasting activation of many pathways involved in the pathogenesis of diabetes can still exist. Thus, one of the major findings in the course of diabetes progression was the presentation that overproduction of free radicals may still be apparent, even at normoglycemic levels or separately from actual blood glucose levels. For example, endothelial dysfunction (a causative marker of diabetic vascular complications) can persist after blood glucose normalization. However, there is evidence that endothelial dysfunction can be largely blocked using a combination of antioxidant therapy and blood glucose normalization.
Thus, treatment of oxidative and / or vascular stress, particularly above glycemic control (eg, by reducing cellular reactive species and / or glycation (eg, by suppressing the production of free oxygen or nitrogen radicals)), is particularly useful for treating glycemic conditions. Independent treatment beneficially modulates, alleviates, blocks or protects against the memory effects of hyperglycemia, further reduces that risk, is associated with long-term diabetic complications, especially oxidative stress, or The onset of complications induced by the above can be prevented, treated or prolonged in patients in need thereof.

Treatment of type 2 diabetes is typically initiated by diet and exercise and subsequent oral antidiabetic monotherapy, although in some patients blood glucose is initially controllable, but the treatment is high, however. With a secondary failure rate. The limitations of monotherapy for glycemic control can be overcome for a limited period of time in at least some patients by combining multiple drugs to achieve blood glucose reduction that cannot be sustained during long-term monotherapy. The available data support the conclusion that, in most patients with type 2 diabetes, conventional monotherapy has failed, requiring multidrug therapy. However, since type 2 diabetes is a progressive disease, it is very difficult to maintain stable blood glucose levels for a long period of time even in patients who have a good initial response to usual combination therapy, May require increased dosage or another treatment with insulin. Although existing combination therapies have the potential to enhance glycemic control, they have limitations (especially with regard to long-term efficacy). Furthermore, conventional treatment methods may show an increased risk of side effects, such as hypoglycemia or weight gain, which may be a compromise of the efficacy and tolerability of the treatment method.
Thus, for many patients, these existing drug therapies result in progressive deterioration of metabolic control despite treatment, and in particular poor control of long-term metabolic status, and thus a progressive or late Type 2 diabetes (including diabetes that shows inadequate glycemic control despite conventional oral or parenteral antidiabetic treatment) fails to achieve and maintain glycemic control.

Thus, while thorough treatment of hyperglycemia reduces the incidence of chronic damage, many patients with type 2 diabetes are partially affected by the limitations, tolerability, and long-term efficacy of conventional anti-hyperglycemic therapy. Remains improperly treated due to inconvenient dosing.
The high incidence of this treatment failure may be due to the complications or chronic injury (microvascular and macrovascular complications such as diabetic nephropathy, retinopathy or neuropathy) or brain associated with a high rate of long-term hyperglycemia in type 2 diabetic patients It is a major contributor to vascular or cardiovascular complications, including myocardial infarction, stroke or vascular mortality or morbidity.
Oral antidiabetic drugs commonly used in therapy (eg, first or second and / or alone or (first or additional) combination therapy) include metformin, sulfonylureas, thiazolidinedione, glinide and α-glucosidase Inhibitors include, but are not limited to.
Parenteral (typically injectable) antidiabetic drugs commonly used in therapy (eg, first or second and / or alone or (first or additional) combination therapy) include GLP-1 or GLP -1 analogs and insulin or insulin analogs, but is not limited thereto.
However, the use of these conventional anti-diabetic or anti-hyperglycemic drugs can be associated with a variety of side effects. For example, metformin is associated with lactic acid or gastrointestinal side effects, sulfonylureas, glinides and insulin or insulin analogs are associated with hypoglycemia and weight gain, and thiazolidinedione is associated with edema, fractures, weight gain and heart failure / heart effects. In addition, alpha-glucosidase blockers and GLP-1 or GLP-1 analogs can be associated with gastrointestinal side effects (eg, dyspepsia, flatulence or diarrhea, or nausea or vomiting) and very seriously (but rarely) pancreatitis.
Therefore, there is still a need in the art for effective, safe and acceptable anti-diabetic treatments.

Furthermore, in the treatment of type 2 diabetes, it is necessary to avoid the inherent complications of the condition and to effectively treat the condition while delaying the progress of the disease in order to achieve a long-term therapeutic effect. Is done.
Furthermore, anti-diabetic treatment should not only prevent long-term complications often seen in advanced-stage diabetes, but also be a treatment option for diabetic patients who have developed or are at risk for developing complications (eg, renal impairment) Are still needed.
Furthermore, there is still a need to provide prevention or mitigation of the side effects or risks associated with conventional anti-diabetic treatments.
The enzyme DDP-4 (dipeptidyl peptidase IV), also known as CD26, is a serine known to cause cleavage of the N-terminal dipeptide of many proteins with a N-terminal proline or alanine residue. It is a protease. Because of this property, DPP-4 inhibitors interfere with plasma levels of bioactive peptides, including the peptide GLP-1, and are considered promising drugs for the treatment of diabetes mellitus.
For example, DDP-4 inhibitors and their uses are disclosed below: WO 2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO 2004/041820, WO 2004/046148, WO 2005/051950, WO 2005/082906, WO 2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769, WO2007 / 014886, WO 2004/050658, WO 2004/111051, WO 2005/058901, WO 2005 / 097798, WO 2006/068163, WO 2007/071738, WO 2008/017670, WO 2007/128721, WO 2007/128724, WO 2007/128761 or WO 2009/121945.

HbA1c levels (products of non-enzymatic glycation of hemoglobin B chain) are extremely important in monitoring diabetes mellitus. HbA1c reflects the average blood glucose level 4-12 weeks ago in the sense of "memory of blood glucose", since its production is essentially dependent on blood glucose levels and red blood cell life span. Diabetic patients whose HbA1c levels are well controlled by more intensive diabetes treatment (ie, less than 6.5% of the total hemoglobin in the sample) are very well protected from diabetic microangiopathy. Available treatments for diabetes can provide diabetic patients with an average improvement in HbA1c levels on the order of 1.0-1.5%. This reduction in HbA1c levels is not sufficient in all diabetics to achieve a desired target range of HbA1c of less than 7.0%, preferably less than 6.5%, more preferably less than 6%.
In the context of the present invention, inadequate or inadequate glycemic control means that the patient exhibits an HbA1c value of more than 6.5%, especially more than 7.0%, more preferably more than 7.5%, especially more than 8% Means state. Embodiments of patients with inadequate or inadequate glycemic control include, but are not limited to, patients with HbA1c levels of 7.5 to 10% (or in another embodiment, 7.5 to 11%). One particular embodiment of a poorly managed patient embodiment is a patient with poor glycemic control, including, but not limited to, a patient with an HbA1c value of 9% or more.

In glycemic control, in addition to improving HbA1c levels, other recommended therapeutic goals for patients with type 2 diabetes mellitus are normal or as normal as possible in fasting plasma glucose (FPG) and postprandial plasma glucose levels. It is a near improvement. The recommended desired target range of pre-prandial (starved) plasma glucose is 70-130 mg / dL (or 90-140 mg / dL) or less than 110 mg / dL, and 2 hours postprandial plasma glucose is less than 180 mg / dL or 140 mg / dL. Is less than.
In certain embodiments, diabetic patients within the meaning of the present invention may include patients who have not been previously treated with antidiabetic drugs (drug-naive patients). Thus, in certain embodiments, the treatment methods described herein can be used on naive patients. In another embodiment, diabetic patients within the meaning of the invention include those with advanced or late stage diabetes mellitus 2 (including those who have failed conventional antidiabetic drug treatment), such as 1 as defined herein. One, two or three or more conventional oral and / or parenteral antidiabetic drugs, patients whose blood glucose has been inappropriately controlled, such as metformin, thiazolidinedione (particularly pioglitazone), sulfonylurea, glinide, GLP-1 or GLP- 1 Despite (monotherapy) therapy with analogs, insulin or insulin analogs, or α-glucosidase inhibitors, or metformin / sulfonylurea, metformin / thiazolidinedione (especially pioglitazone), sulfonylurea / α-glucosidase inhibitors, pioglitazone / sulfonylurea, Metformin / insulin, pioglitazone / Glycemic control despite dual combination therapy with insulin or sulfonylurea / insulin may include poor patient. Thus, in certain embodiments, the treatment methods described herein may be used, for example, in the treatment of conventional oral and / or parenteral anti-diabetic monotherapy or dual or triple therapy as described herein. Can be used in some patients.

Yet another embodiment of a diabetic patient within the meaning of the present invention is a patient for whom metformin therapy is inappropriate, including:
-Patients for whom metformin therapy is contraindicated, e.g. patients with one or more contraindications to metformin therapy according to the tag, e.g. renal disease, renal impairment or dysfunction (according to the locally approved product information for metformin) Patients with at least one contraindication selected from dehydration; unstable or acute congestive heart failure; acute or chronic metabolic acidosis; and hereditary galactose intolerance.
-One or more unacceptable side effects due to metformin, in particular patients suffering from gastrointestinal side effects associated with metformin, e.g. at least one gastrointestinal tract selected from nausea, vomiting, diarrhea, intestinal gas and severe abdominal discomfort Patients suffering from vascular side effects.
Yet another embodiment of diabetic patients that may be amenable to the treatment methods of the present invention include diabetic patients for whom normal metformin therapy is not appropriate, e.g., reduced doses of metformin therapy may result in reduced, non-tolerant or contraindicated metformin resistance. Patients (including, but not limited to) elderly (eg, ages 60-65) due to or due to (mild) impairment / decrease in renal function.

Yet another embodiment of a diabetic patient within the meaning of the present invention is a patient having renal disease, renal insufficiency or insufficient or impaired renal function (including mild, moderate and severe renal impairment), This may include, for example, elevated serum creatinine levels (e.g., serum creatinine levels above the normal upper limit for the age of the patient, e.g., 130-150 [mu] mol / L or higher for males, or 1.5 mg / dL or higher, females 1.4 mg / dL or higher (124 μmol / L or more)) or abnormal creatinine clearance (eg, glomerular filtration rate (GFR) of 30-60 mL / min or less).
As a more detailed illustration of the foregoing, mild renal impairment is suggested by, for example, creatinine clearance of 50-80 mL / min (substantially consistent with serum creatinine levels of 1.7 mg / dL or less in men and 1.5 mg / dL or less in women). Moderate renal impairment is suggested, for example, by a creatinine clearance of 30-50 mL / min (approximately equal to serum creatinine levels of 1.7 <to 3.0 mg / dL in men and 1.5 <to 2.5 mg / dL in women) Severe renal impairment can be indicated, for example, by a creatinine clearance of less than 30 mL / min (approximately equal to serum creatinine levels of 3.0 mg / dL <in men and 2.5 mg / dL <in women). Patients with end-stage renal disease require dialysis (eg, hemodialysis or peritoneal dialysis).
As a more specific example, patients with renal disease, renal insufficiency or impairment include patients with chronic renal insufficiency or impairment, which include glomerular filtration rates (GFR, mL / min / 1.73 m ² ) can be stratified into the following five stages: stage 1 characterized by more than 90 normal GFR + persistent albuminuria or known structural or hereditary renal disease; mild kidney Phase 2 characterized by mild GFR decline (GFR 60-89) indicative of impairment; Phase 3 characterized by moderate GFR decline (GFR 30-59) indicative of moderate renal impairment; Severe Stage 4 characterized by a severe decline in GFR indicative of renal impairment (GFR 15-29); and Terminal 5 characterized by a GFR of less than 15 requiring dialysis or exhibiting complete renal failure (end-stage) Kidney disease, ESRD).

Yet another aspect of a diabetic patient within the meaning of the present invention is renal complications such as diabetic nephropathy (chronic and progressive renal dysfunction, albuminuria, proteinuria, fluid retention (edema) in the body and / or Hypertensive) or at risk of developing it.
Yet another embodiment of a diabetic patient that may be compatible with the treatment methods of the present invention may include a type 2 diabetic patient having or at risk for developing renal complications, such as diabetic retinopathy. Is not.)
Yet another aspect of diabetic patients that may be amenable to the treatment methods of the present invention include macrovascular complications such as myocardial infarction, coronary artery disease, ischemic or hemorrhagic stroke, and / or peripheral obstructive arterial disease. Or a type 2 diabetic patient at or at risk of developing it.
Yet another aspect of diabetic patients that may be amenable to the treatment methods of the present invention include type 2 diabetic patients having or at risk for cardiovascular or cerebrovascular disease or event (e.g., heart disease as described herein). Patients at vascular risk), but not limited to.
Still other embodiments of diabetic patients that may be compatible with the treatment methods of the present invention include diabetic patients with elderly and / or advanced diabetes (especially type 2 diabetes), for example, patients with insulin treatment, with triple anti-diabetic oral therapy Patients may include, but are not limited to, patients with pre-existing cardiovascular and / or cerebrovascular events, and / or patients with a long duration of disease (eg, from 5 years to 10 years).

Yet another embodiment of a diabetic patient that may be compatible with the treatment method of the present invention includes a diabetic having one or more cardiovascular risk factors selected from A), B), C) and D) below. Patients (particularly patients with type 2 diabetes) may include (but are not limited to):
A) Previous or existing vascular disease (eg, myocardial infarction (eg, asymptomatic or symptomatic), coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure) (Eg, NYHA class I or II, eg, less than 40% left ventricular function), or peripheral occlusive artery disease);
B) vascular related end-organ diseases (eg nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease and / or microalbumin or macroalbuminuria);
C) Elderly (eg, over 60-70); and
D) One or more cardiovascular risk factors selected from:
Advanced type 2 diabetes mellitus (eg for a period of more than 10 years),
Hypertension (eg> 130/80 mmHg, or systolic blood pressure> 140 mmHg, or at least one antihypertensive treatment;
-At this moment daily smoking,
-Dyslipidemia (e.g. atherogenic dyslipidemia, postprandial lipemia, or high levels of LDL cholesterol (e.g. LDL cholesterol of 130 or more -135 mg / dL), low levels of HDL cholesterol (e.g. <35-40 mg in men) / dL or <45-50 mg / dL in women) and / or high levels of triglycerides in the blood (eg> 200-400 mg / dL) or at least one treatment for lipid abnormalities),
Obesity (eg, abdominal obesity and / or visceral obesity, or a body volume index of 45 kg / m ² or more),
-Ages from 40 to 80,
-A metabolic syndrome, hyperinsulinemia or insulin resistance, and-a family history of hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or cardiomyopathy in first degree.

  In certain embodiments, a patient that may be compatible with the treatment methods of the present invention may have or be at risk for one or more of the following diseases, disorders, or conditions: type 1 diabetes, type 2 diabetes, glucose Impaired tolerance (IGT), starved blood glucose disorder (IGF), hyperglycemia, postprandial hyperglycemia, postabsorption hyperglycemia, latent autoimmune diabetes in adults (LADA), overweight, obesity, dyslipidemia Disease (including, for example, atherogenic dyslipidemia), hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFA, postprandial lipemia, hypertension, atherosclerosis, endothelial dysfunction, Osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome, hyperuricemia, metabolic syndrome, nephropathy, microalbumin or macroalbuminuria, proteinuria, retinopathy, cataract , Neuro C, learning or memory impairment, neurodegenerative or cognitive abnormalities, cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot or diabetic ulcer, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, Acute coronary syndrome, unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy (including, for example, uremic cardiomyopathy), heart failure, cardiac hypertrophy, abnormal heart rhythm, vascular restenosis, stroke, Ischemia / reperfusion injury (of kidney, heart, brain or liver), fibrosis (of kidney, heart, brain or liver), vascular remodeling (of kidney, heart, brain or liver); diabetes, especially type 2 diabetes (It is preferably intrinsic (eg, as an underlying disorder)).

In yet another embodiment, the patient that is amenable to the method of treatment of the present invention has diabetes (particularly type 2 diabetes mellitus) and may further include one or more other diseases, disorders or conditions (eg, from those just described). Selected) or have its risk.
Within the scope of the present invention, certain DPP-4 inhibitors as defined herein (optionally one or more other therapeutic agents (e.g. selected from those described herein)) or pharmaceutical combinations, Or a combination according to the invention of such a DPP-4 inhibitor as defined herein may be used for the purposes of the invention and / or to satisfy one or more of the above requirements. It has now been found to have properties that make these DPP-4 inhibitors suitable.
The present invention therefore relates to certain DPP-4 inhibitors as defined herein, preferably linagliptin (Bl1356), for use in the methods of treatment described herein.
The present invention still further relates to certain DPP-4 inhibitors as defined herein, preferably linagliptin (Bl1356), in combination with metformin for use in the treatment methods described herein.
The present invention further relates to certain DPP-4 inhibitors as defined herein, preferably linagliptin (Bl1356), in combination with pioglitazone for use in the methods of treatment described herein.
The present invention further relates to certain DPP-4 inhibitors as defined herein, preferably linagliptin (Bl1356), in combination with telmisartan for use in the methods of treatment described herein.

The present invention further relates to a pharmaceutical composition comprising certain DPP-4 inhibitors as defined herein, preferably linagliptin (Bl1356), for use in the treatment methods described herein.
The present invention further relates to pharmaceutical compositions comprising certain DPP-4 inhibitors as defined herein, preferably linagliptin (B1356) and metformin, for use in the treatment methods described herein.
The invention further relates to a pharmaceutical composition comprising certain DPP-4 inhibitors as defined herein, preferably linagliptin (B1356) and pioglitazone, for use in the treatment methods described herein.
The invention further relates to certain DPP-4 inhibitors (particularly Bl1356) and those described herein, which are used particularly simultaneously, separately or sequentially in the treatment methods described herein. The combination comprising one or more other active substances, wherein the other active substances are, for example, other antidiabetic substances, active substances that lower blood glucose levels, active substances that lower blood lipid levels, blood HDL. Active substances that increase levels, active substances that lower blood pressure, active substances indicated in the treatment of atherosclerosis or obesity, antiplatelet agents, anticoagulants, and vascular endothelial protective agents, for example, each of which is selected from the group consisting of: It is as described herein.

The present invention furthermore relates to certain DPP-4 inhibitors (especially Bl1356) and one or more of them which are used, particularly simultaneously, separately or sequentially, in the treatment methods described herein, optionally in combination with telmisartan. For combinations comprising other anti-diabetic drugs, the anti-diabetic drugs include metformin, sulfonylurea, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonist, alpha-glucosidase inhibitor, insulin or insulin analog, and GLP-1 or GLP. -1 selected from the group consisting of analogs.
The present invention still further relates to a method of treating and / or preventing a metabolic disease, particularly type 2 diabetes mellitus and / or a condition associated therewith (eg diabetic complications), said method comprising metformin, sulfonylurea, nateglinide, repaglinide And an effective amount of one or more other antidiabetic agents selected from the group consisting of thiazolidinedione, a PPAR-gamma agonist, an alpha-glucosidase inhibitor, insulin or an insulin analog, and GLP-1 or a GLP-1 analog. An effective amount of a DPP-4 inhibitor as specified herein (especially Bl1356), and optionally an effective amount of telmisartan, is administered to a patient in need thereof (especially a human patient), such as a patient described herein (risk patient). (Including a group) in combination (simultaneously, separately or sequentially).

The present invention still further relates to therapies or methods of treatment described herein, such as methods for treating and / or preventing metabolic disorders, particularly type 2 diabetes mellitus and / or conditions associated therewith (eg, diabetic complications). The method comprises treating a therapeutically effective amount of linagliptin (Bl1356) and optionally one or more other therapeutic agents, such as metformin, sulfonylurea, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonist, alpha-glucosidase inhibitor An antidiabetic drug selected from the group consisting of insulin, insulin or insulin analogs, and GLP-1 or GLP-1 analogs and / or telmisartan, to a patient in need thereof (especially a human patient), for example, as described herein. (E.g., the risk patients described herein).
The present invention still further relates to therapies or methods of treatment described herein, such as methods for treating and / or preventing metabolic disorders, particularly type 2 diabetes mellitus and / or conditions associated therewith (eg, diabetic complications). The method may further comprise providing a therapeutically effective amount of linagliptin (Bl1356) to a patient in need thereof (especially a human patient), such as a patient described herein (a patient at risk as described herein (especially a heart patient). A patient having or having a vascular or cerebrovascular disease or event and / or a patient having or having a renal disease).

The present invention still further relates to therapies or methods of treatment described herein, such as methods for treating and / or preventing metabolic disorders, particularly type 2 diabetes mellitus and / or conditions associated therewith (eg, diabetic complications). The method comprises administering to a patient in need thereof (particularly a human patient) a therapeutically effective amount of linagliptin (Bl1356) and metformin, for example, a patient as described herein (a risk patient as described herein). Especially patients with cardiovascular or cerebrovascular disease or events or at-risk patients).
The present invention still further relates to therapies or methods of treatment described herein, such as methods for treating and / or preventing metabolic disorders, particularly type 2 diabetes mellitus and / or conditions associated therewith (eg, diabetic complications). The method may comprise providing a therapeutically effective amount of linagliptin (Bl1356) and telmisartan to a patient in need thereof (particularly a human patient), such as a patient as described herein (a risk patient as described herein). Especially patients with cardiovascular or cerebrovascular disease or events or at risk patients and / or at risk for renal disease).
Examples of such metabolic disorders or diseases that can be compatible with the methods of treatment of the present invention, particularly those with or at risk for cardiovascular and / or renal disease, include type 1 diabetes, 2 Type diabetes, impaired glucose tolerance (IGT), fasting blood glucose disorder (IFG), hyperglycemia, postprandial hyperglycemia, postabsorption hyperglycemia, latent autoimmune diabetes in adults (LADA), overweight, obesity Dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFAemia, postprandial lipemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non This may include, but is not limited to, alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy, polycystic ovary syndrome, and / or metabolic syndrome.

The invention further comprises the step of administering a therapeutically effective amount of a certain DPP-4 inhibitor, optionally in combination with one or more other therapeutic agents described herein, comprising: On at least one of the methods:
A patient in need thereof (eg a patient as described herein, in particular a type 2 diabetic), especially oxidative stress, vascular stress and / or endothelial dysfunction, or a disease or condition associated with or associated therewith In or at risk for, or cardiovascular and / or renal disease (eg, myocardial infarction, stroke, or peripheral arterial occlusive disease, and / or diabetic nephropathy, microalbumin or macroalbuminuria) Or patients with or at risk for acute or chronic renal impairment), or
A) Previous or existing vascular disease (eg, myocardial infarction (eg, asymptomatic or symptomatic), coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure) (Eg, NYHA class I or II, eg, less than 40% left ventricular function), or peripheral occlusive artery disease);
B) vascular related end-organ diseases (eg nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease and / or microalbumin or macroalbuminuria);
C) Elderly (eg, over 60-70); and
D) One or more cardiovascular risk factors selected from:
Advanced type 2 diabetes mellitus (eg for a period of more than 10 years),
Hypertension (eg> 130/80 mmHg, or systolic blood pressure> 140 mmHg, or at least one antihypertensive treatment),
-At this moment daily smoking,
-Dyslipidemia (e.g. atherogenic dyslipidemia, postprandial lipemia, or high levels of LDL cholesterol (e.g. LDL cholesterol of 130 or more -135 mg / dL), low levels of HDL cholesterol (e.g. <35-40 mg in men) / dL, <45-50 mg / dL in women), and / or high levels of triglycerides in the blood (eg,> 200-400 mg / dL), or at least one treatment for lipid abnormalities),
Obesity (eg, abdominal obesity and / or visceral obesity, or a body volume index of 45 kg / m ² or more),
-Ages from 40 to 80,
-A metabolic syndrome, hyperinsulinemia or insulin resistance, and-a hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or a family history of vascular disease or cardiomyopathy in first degree,
A patient having one or more cardiovascular risk factors selected from A), B), C) and D) above,
-Metabolic disorders or diseases, such as type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, post-absorption hyperglycemia, adult Latent autoimmune diabetes mellitus (LADA), overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFA, postprandial lipemia, hypertension, atherosclerosis To prevent and slow the progression of endothelial dysfunction, osteoporosis, chronic systemic inflammation, nonalcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy, polycystic ovary syndrome, and / or metabolic syndrome How to prolong, prolong or treat;
-Methods for improving and / or maintaining glycemic control and / or for reducing fasting plasma glucose, postprandial plasma glucose, post-absorption plasma glucose and / or glycosylated hemoglobin HbA1c;
-Prevent, slow, prolong or slow progression from prediabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance, and / or metabolic syndrome to type 2 diabetes mellitus. How to reverse;
Complications of diabetes mellitus, e.g. microvascular or macrovascular diseases, e.g. nephropathy, microalbumin or macroalbuminuria, proteinuria, retinopathy, cataract, neuropathy, impaired learning or memory, neurodegenerative or cognitive abnormalities , Cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot or diabetic ulcer, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable stenosis Prevent, reduce, reduce the risk of, and slow the risk of heart disease, peripheral arterial occlusive disease, cardiomyopathy (including, for example, uremic cardiomyopathy), heart failure, abnormal heart rhythm, vascular restenosis, and / or stroke How to prolong, prolong or treat;
-A method of reducing body weight and / or body fat or preventing an increase in body weight and / or body fat, or promoting body weight and / or body fat reduction;
-For preventing, slowing down or treating pancreatic beta cell degeneration and / or loss of pancreatic beta cell functionality, and / or for improving, retaining and / or restoring pancreatic beta cell functionality. And / or a method of stimulating and / or restoring or protecting the function of pancreatic insulin secretion;
Methods of preventing, slowing down, prolonging or treating non-alcoholic steatohepatosis (NAFLD) (including hepatic steatosis), non-alcoholic steatohepatitis (NASH) and / or hepatic fibrosis (eg hepatic steatosis) Preventing, slowing, slowing down, weakening, treating or reversing inflammation (of the liver) and / or abnormal accumulation of liver fat);
-Methods of preventing, delaying, prolonging or treating type 2 diabetes in which normal anti-diabetic alone or in combination therapy has failed;
-How to achieve the required dose reduction of the usual antidiabetic drugs required for an adequate therapeutic effect;
-Methods to reduce the risk of side effects (e.g. hypoglycemia and / or weight gain) associated with conventional anti-diabetic drugs; and / or-methods to maintain and / or improve insulin sensitivity, and / or hyperinsulinemia. And / or a method for treating or preventing insulin resistance.

Other features of the present invention will be apparent to one skilled in the art from the foregoing and following teachings, including the examples and claims.
The features of the invention, in particular the pharmaceutical compounds, compositions, combinations, methods and uses, relate to DPP-4 inhibitors as defined above and below.
DPP-4 inhibitors contemplated by the present invention include, but are not limited to, any of the DPP-4 inhibitors described above and below, preferably orally active DPP-4 inhibitors. Not done.
Embodiments of the present invention find use in the treatment and / or prevention of metabolic disorders (particularly type 2 diabetes mellitus) in patients with type 2 diabetes and also suffering from renal disease, renal dysfunction or renal impairment. In particular, the DPP-4 inhibitor is administered to the patient at the same dose level as the patient with normal renal function, thus, for example, the DPP-4 inhibitor is used for renal dysfunction. It does not require dose down-regulation.
For example, the DPP-4 inhibitors of the present invention (especially those that may be suitable for patients with impaired renal function) may have a therapeutic window in which the DPP-4 inhibitor and its active metabolite are relatively wide (about> 100-fold). And / or may be an oral DPP-4 inhibitor that is primarily eliminated by hepatic metabolism or biliary excretion (preferably without additional addition to the kidneys).

In a more detailed example, the DPP-4 inhibitors of the present invention (especially those that may be appropriate for patients with impaired renal function) have a relatively wide (about> 100-fold) therapeutic window, preferably a safety comparable to placebo Or a DPP-4 inhibitor which has one or more of the following pharmacokinetic properties (preferably at its oral therapeutic dose level):
-The DPP-4 inhibitor is substantially or predominantly excreted via the liver (e.g. more than 80% or even more than 90% of the administered orally administered dose) and / or Renal elimination does not occupy a substantial or only a few elimination pathways (eg, of the oral dose measured by following the elimination of the oral dose of radiolabeled carbon ( ¹⁴ C) material, Less than 10%, preferably less than 7%);
The DPP-4 inhibitor is mainly excreted unchanged from the parent drug (eg, greater than 70% of the orally administered dose of radiolabeled carbon ( ¹⁴ C) material in urine and stool on average; Or more than 80%, or preferably 90%), and / or is not removed to a substantial or negligible extent by metabolism (eg, less than 30%, less than 20%, preferably 10%).
The (major) metabolite of the DPP-4 inhibitor is pharmacologically inactive. For example, the major metabolite does not bind to the target enzyme DPP-4 and, in some cases, is rapidly removed as compared to the parent compound (eg, the metabolite has a terminal half-life of 20 hours or less, or preferably about 16 hours or less). , For example, 15.9 hours).
In certain embodiments, the (major) metabolite (which may be pharmacologically inactive) in plasma of a DPP-4 inhibitor having a 3-amino-piperidin-1-yl substituent is 3-amino-piperidine The amino group of the -1-yl component is replaced by a hydroxyl group, and the 3-hydroxy-piperidin-1-yl component (eg, the 3- (S) -hydroxy-piperidin-1-yl component, by reversing the configuration of the chiral center) Is a derivative that forms

Yet another property of a DPP-4 inhibitor of the present invention may be one or more of the following: Rapid achievement of steady state (eg, steady state on days 2 to 5 of treatment with a therapeutic oral dose level). Plasma levels (reaching more than 90% of steady-state plasma concentration), little accumulation (eg mean accumulation rate _{RA, AUC} using therapeutic oral dose levels of less than 1.4), and / or DPP-4 inhibition Maintenance of long lasting effects on DPP-4 (preferably once daily) (eg, near complete (> 90%) DPP-4 inhibition at therapeutic oral dose levels, once daily therapeutic oral dose) > 80% inhibition during the 24 h after ingestion), markedly reduced blood glucose excursions 2 h postprandial at therapeutic dose levels (> 80% already on the first day of treatment) and excreted in urine Less than 1% of the administered dose of unchanged parent compound That no more than about 3-6%.
Thus, for example, a DPP-4 inhibitor of the present invention has a predominantly non-renal elimination route (ie, the DPP-4 inhibitor has a non-substantial or negligible extent (eg, an oral dose, preferably an oral therapeutic dose). Less than 10%, preferably less than 7%, eg, about 5%) is excreted from the kidney (eg, as measured by tracking the excretion of oral doses of radiolabeled carbon ( ¹⁴ C) material). .
Furthermore, the DPP-4 inhibitors of the present invention may be characterized as being substantially or predominantly excreted via the liver or feces (eg, to track the excretion of oral doses of radiolabeled carbon ( ¹⁴ C) material). By measuring).

Furthermore, the DPP-4 inhibitor of the present invention is mainly excreted unchanged as a parent drug (eg, excreted radioactivity in urine and feces after oral administration of radiolabeled carbon ( ¹⁴ C) substance). Said DPP-4 inhibitor is excreted little or only minimally via metabolism, with an average of more than 70%, or more than 80%, or preferably 90% of And / or the major metabolite of the DPP-4 inhibitor may be characterized as being pharmacologically inactive or having a relatively wide therapeutic window.
Furthermore, the DPP-4 inhibitors of the present invention may be used for glomerular function and / or tubule in type 2 diabetic patients with chronic renal dysfunction (eg mild, moderate or severe renal impairment or end stage renal disease) The troph level of the DPP-4 inhibitor in the plasma of type 2 diabetic patients with no significant impairment of function and / or mild or moderate renal impairment is similar to that of patients with normal renal function And / or said DPP-4 inhibitor is a type 2 diabetes having renal dysfunction (preferably unrelated to the stage of renal dysfunction, such as mild, moderate or severe renal dysfunction or end-stage renal disease) The patient may be characterized by no need for dose adjustment.
Furthermore, a DPP-4 inhibitor according to the present invention may be administered in a patient whose minimum effective dose results in more than 50% inhibition in a trough (24 hours after the last dose) in patients with more than 80% of DPP-4 activity. And / or its fully therapeutic dose is a dose that results in more than 80% inhibition of DPP-4 activity in trough (24 hours after last dose) in more than 80% of patients And
Furthermore, the DPP-4 inhibitors of the present invention may be used in type 2 diabetic patients who have been diagnosed with renal impairment and / or at risk of developing renal complications, such as diabetic nephropathy (chronic and progressive kidney disease). It may be characterized as being suitable for use in patients having or at risk for dysfunction, albuminuria, proteinuria, fluid retention in the body (edema) and / or hypertension).

  In a first embodiment (Embodiment A), the DPP-4 inhibitor of the present invention relates to any DPP-inhibitor of formula (I) or (II) or (III) or (IV): 4 is an inhibitor, or a pharmaceutically acceptable salt thereof:

Formula (I)

Formula (II)

Formula (III)

(Formula IV)

Where:
R1 is ([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, R2 is 3- (R) -amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino or (2- (S) -Amino-propyl) -methylamino.

With respect to the first embodiment (Embodiment A), preferred DPP-4 inhibitors are any or all of the following compounds and pharmaceutically acceptable salts thereof:
1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -Xanthin (WO 2004/018468, compare with 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 (compare WO 2004/018468, Example 2 (252)):

1-[(quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-((R) -3-amino-piperidin-1-yl) -xanthine (WO 2004/018468, compare with 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 (WO 2004/050658, compare with Example 136):

1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-[(2-amino-2-methyl-propyl) -methylamino ] -Xanthin (WO 2006/029769, compare with Example 2 (1)):

1-[(3-cyano-quinolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-((R) -3-amino-piperidin-1-yl) -Xanthin (WO 2005/085246, compare with Example 1 (30)):

1- (2-cyano-benzyl) -3-methyl-7- (2-butyn-1-yl) -8-((R) -3-amino-piperidin-1-ylxanthine (WO 2005/085246; (Compare with Example 1 (39)):

1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-[(S)-(2-amino-propyl) -methylamino ] -Xanthin (WO 2006/029769, compare with Example 2 (4)):

1-[(3-cyano-pyridin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-((R) -3-amino-piperidin-1-yl) -Xanthin (WO 2005/085246, compare with Example 1 (52)):

1-[(4-methyl-pyrimidin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-((R) -3-amino-piperidin-1-yl) -Xanthin (WO 2005/085246, compare with Example 1 (81)):

1-[(4,6-dimethyl-pyrimidin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-((R) -3-amino-piperidin-1- Ilxanthin (WO 2005/085246, compare with Example 1 (82)):

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

These DPP-4 inhibitors are distinguished from structurally similar DPP-4 inhibitors. Because, when combined with other pharmaceutically active substances, they combine very good potential and long-lasting action with favorable pharmacological properties, receptor selectivity and favorable side effect profiles, or have unexpected therapeutic effects. This is because it provides a strategic advantage or improvement. Their preparation is disclosed in the publications mentioned.
Among the aforementioned DPP-4 inhibitors of embodiment A of the present invention, a more preferred DPP-4 inhibitor is 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- ( 2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine, especially its free base (also known as linagliptin or Bl1356).
A particularly preferred DPP-4 inhibitor within the present invention is linagliptin. As used herein, the term linagliptin refers to linagliptin or its acceptable salts (including hydrates and solvates) and crystalline forms thereof, preferably linagliptin is 1-[(4-methyl-quinazoline- 2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine. Crystal forms are described in WO 2007/128721. Methods for producing linagliptin are described, for example, in patent applications WO 2004/018468 and WO 2006/048427. Linagliptin is distinguished from structurally similar DPP-4 inhibitors. Because linagliptin combines very good potential and long-lasting action with favorable pharmacological properties, receptor selectivity and favorable side-effect profile, or unexpected treatment with single or dual or triple therapy This is because it results in an advantage or improvement.

To avoid any doubt, the disclosures of each of the above and below-cited references cited above in connection with the specifically indicated DPP-4 inhibitors are hereby incorporated by reference in their entirety.
It is to be understood that, in the context of the present invention, the combination, composition or combination use of the present invention may contemplate the simultaneous, sequential or separate administration of the active ingredients or ingredients.
In this context, “combination” or “combined” as used in the present invention refers to both fixed and non-fixed (eg, free) forms (including kits) and uses (eg, simultaneous, sequential or separate of the active ingredients or components). Including but not limited to use).
The combination administration of the present invention may be carried out by administering the active ingredients or ingredients together, for example by administering them as one single formulation or simultaneously as two separate formulations or dosage forms. Alternatively, administration may be effected by administering the active ingredient or ingredient sequentially, for example as two separate formulations or dosage forms.
For the combination therapies of the invention, the active ingredients or ingredients may be administered separately (which suggests they are formulated separately) or may be formulated together (wherein they are To be formulated as the same preparation or as the same dosage form). Thus, administration of one component of the combination of the invention may be prior to, concurrent with, or subsequent to administration of the other component of the combination.
Unless otherwise stated, combination therapy may refer to first-, second-, or third-line treatment methods, or initial or additional combination therapy or replacement therapy.

  With respect to embodiment A, methods for synthesizing the DPP-4 inhibitor of embodiment A of the present invention are known to those skilled in the art. Advantageously, the DPP-4 inhibitors according to embodiment A of the present invention can be prepared using synthetic methods described in the literature. Thus, for example, the purine derivatives of the formula (I) may be of the formula WO 2002/068420, WO 2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006/048427, which are hereby incorporated by reference. Available as described. Purine derivatives of formula (II) can be obtained, for example, as described in WO 2004/050658 or WO 2005/110999, which is incorporated herein by reference. Purine derivatives of formulas (III) and (IV) are available, for example, as described in WO 2006/068163, WO 2007/071738 or WO 2008/017670, which are hereby incorporated by reference. In particular, the preparation of the DPP-4 inhibitors mentioned above is disclosed in the publications mentioned in connection therewith. Specific DPP-4 inhibitor polymorphic crystal modifications and formulations are disclosed in WO 2007/128721 and WO 2007/128724, respectively, the disclosures of which are incorporated herein by reference in their entirety. ing. Formulations of specific DPP-4 inhibitors with metformin or other combination partners are described in WO 2009/121945, which is incorporated by reference herein in its entirety.

Typical dispensing strengths of the two-component fixed combination (tablets) of linagliptin / metformin IR (immediate release) are 2.5 / 500 mg, 2.5 / 850 mg and 2.5 / 1000 mg, which are 1-3 times a day, especially twice a day Can be administered.
Typical dispensing strength of a two-component fixed combination (tablet) of linagliptin / metformin XR (extended release) is 5/500 mg, 5/1000 mg and 5/1500 mg (one tablet each) or 2.5 / 500 mg, 2.5 / 500 mg 750 mg and 2.5 / 1000 mg (two tablets each), which can be administered 1-2 times a day, especially once a day, preferably taken in the evening with a meal.
The invention is further used in combination therapy (additional or initial) with metformin (eg, 500 to 2000 mg of metformin hydrochloride for a total daily dose, eg, 500, 850 or 1000 mg once or twice daily). Provides a DPP-4 inhibitor as defined herein.
For pharmaceutical applications in warm-blooded vertebrates (especially humans), the compounds of the invention are usually formulated as preparations of 0.001 to 100 mg / kg body weight, preferably 0.01 to 15 mg / kg (in each case 1 day per day). Used 4 times). For this purpose, the compounds may optionally be combined with other active substances, in combination with one or more inert carriers and / or diluents, such as corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate. , Polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or a fatty substance (eg solid fat or a suitable mixture thereof) Together with the usual galenic preparations (eg plain or coated tablets, capsules, powders, suspensions or suppositories).

Pharmaceutical compositions of the invention comprising a DPP-4 inhibitor as defined herein are therefore described in the art and further comprise pharmaceutically acceptable prescription excipients suitable for the desired route of administration. And prepared by those skilled in the art. Examples of such excipients include diluents, binders, carriers, fillers, lubricants, dispersing aids, crystallization retarders, disintegrants, solubilizers, colorants, pH adjusters, It includes but is not limited to activators and emulsifiers.
Oral preparations or dosage forms of the DPP-4 inhibitors of the present invention can be prepared according to known techniques.
Examples of suitable diluents for the compound of embodiment A include cellulose powder, calcium hydrogen phosphate, erythritol, low substituted hydroxypropylcellulose, mannitol, pregelatinized starch or xylitol.
Examples of suitable lubricants for the compounds of embodiment A include talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate.
Examples of suitable binders for compounds of embodiment A include copovidone (copolymer of vinylpyrrolidone with other vinyl derivatives), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone ( Povidone), pregelatinized starch, or low-substituted hydroxypropylcellulose (L-HPC).
Suitable disintegrants for the compounds of embodiment A include corn starch or crospovidone.

A suitable method for preparing a pharmaceutical formulation of a DPP-4 inhibitor according to embodiment A of the present invention is as follows:
-Direct compression of the active substance in a powder mixture with suitable tableting excipients;
-Granulation with a suitable excipient and subsequent mixing with a suitable excipient and subsequent tableting as well as film coating; or-filling of the powder mixture or granules into capsules.
Suitable granulation methods are as follows:
Wet granulation in a high intensity mixer followed by fluid bed drying;
-One container granulation;
-Fluidized bed granulation; or-dry granulation with suitable excipients (for example by roller compaction) and subsequent compression or filling into capsules.
An exemplary composition of a DPP-4 inhibitor of embodiment A of the present invention (eg, tablet core) comprises a first diluent mannitol, a pre-gelatinized starch as a second diluent with additional binding properties, binding It includes the agent copovidone, the disintegrant corn starch, and magnesium stearate as a lubricant, where copovidone and corn starch can be optional.
The tablets of the DPP-4 inhibitor of embodiment A of the present invention can be film coated, preferably the film coat is hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and iron oxide (Eg, red and / or yellow).

The pharmaceutical composition (or formulation) can be packaged in various ways. Generally, the product to be delivered will include one or more containers containing the one or more pharmaceutical compositions in an appropriate form. Typically, tablets are bundled in suitable primary packaging for easy handling, delivery and storage, and for proper stability of the composition upon prolonged contact with the surroundings during storage. The primary container for tablets can be a bottle or a blister pack.
Suitable bottles, for example for a pharmaceutical composition or a combination (tablets) containing a DPP-4 inhibitor according to embodiment A of the present invention are glass or polymers (preferably polypropylene (PP) or high density polyethylene (HD- Manufactured from PE)) and can be sealed with a screw cap. The screw lid can be provided with a child-friendly safety closure (eg, a push-to-close) to prevent or prevent children from accessing the contents. If necessary (e.g. in areas of high humidity), the additional use of desiccants (e.g. bentonite clay, molecular sieves or preferably silica gel) can extend the shelf life of the packaging composition.
Suitable blister packs, for example for a pharmaceutical composition or combination (tablets), comprising a DPP-4 inhibitor according to embodiment A of the invention are a top foil (which can be broken by tablets) and a bottom (for tablets) Or having said pockets). The top foil may comprise a metal foil, especially an aluminum foil or an aluminum alloy foil (eg having a thickness of 20 μm to 45 μm, preferably 20 μm to 25 μm), the inside of which (sealing side) is coated with a heat-encapsulated polymer layer. it can. The bottom is a multilayer polymer foil (eg poly (vinylidene chloride) (PVDC) coated poly (vinyl chloride) (PVC); or poly (chlorotrifluoroethylene) (PCTFE) laminated PVC foil) or multilayer polymer-metal-polymer foil (Eg, a low temperature formable laminated PVC / aluminum / polyamide composition).

To ensure long shelf life, especially in hot and humid climatic conditions, additional overwraps or pouches made from multilayer polymer-metal-polymer foils (eg, laminated polyethylene / aluminum / polyester compositions) may be used in blister packs. Can be used for The replenishment desiccant (eg, bentonite clay, molecular sieve, or preferably silica gel) in the pouch package can further extend the shelf life under such harsh conditions.
The product can also include a label or packaging insert. They relate to the instructions conventionally included in the packaging of therapeutic products and should include information on the use, handling, dosage, administration, contraindications and / or warnings on the use of such therapeutic products. Can be. In some embodiments, the label or package insert indicates that the composition can be used for any of the purposes described herein.
With respect to the first embodiment (Embodiment A), the typically required dosage of the DPP-4 inhibitor described herein in Embodiment A is 0.1 mg to 10 mg, preferably 10 mg, when administered intravenously. 0.25 mg to 5 mg, for oral administration 0.5 mg to 100 mg, preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably 2.5 mg to 10 mg or 1 mg to 5 mg, in each case 1 day From 4 times. Thus, for example, 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1 The dosage of -yl) -xanthine is 0.5 mg to 10 mg / patient / day for oral administration, preferably 2.5 mg to 10 mg or 1 mg to 5 mg / patient / day.
A dosage form prepared with a pharmaceutical composition comprising a DPP-4 inhibitor as described herein in embodiment A contains the active ingredient in a dosage range of 0.1-100 mg. Thus, for example, 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1 Specific dosage strengths of -yl) -xanthine are 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg.

A particular embodiment of the DPP-4 inhibitors of the present invention relates to a therapeutically effective orally administered DPP-4 inhibitor at a low dose level, wherein said DPP-4 inhibitor is, for example, <100 mg or <70 mg / patient / Daily, preferably <50 mg, more preferably <30 mg or <20 mg, even more preferably 1 mg to 10 mg, especially 1 mg to 5 mg (particularly 5 mg) / patient / day at an oral dose level which is therapeutically effective, If necessary, it is divided into 1 to 4 single doses, in particular 1 or 2 single doses (which may be the same size), preferably orally once or twice daily (more preferably Is administered once daily), and is advantageously administered with or without food at any time of the day. Thus, for example, a 5 mg daily oral dose of Bl1356 may be administered on a once-daily dosing regimen (ie, 5 mg Bl1356 once daily) or a twice-daily dosing regimen (ie, 2.5 mg Bl1356 daily). Twice) with or without food at any time of the day.
The dosage of the components in the combinations and compositions of the present invention may be varied, provided that the amount of the active ingredient will be such that a suitable dosage form will be obtained. Thus, the selected dosage and the selected dosage form will depend on the desired therapeutic effect, on the route of administration, and on the duration of the treatment. A suitable dosage range for the combination is from the highest tolerated dose of the single agent to a lower dose, for example 1/10 of the highest tolerated dose.

A particularly preferred DPP-4 inhibitor to be emphasized within the meaning of the present invention is 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1- Yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine (also known as Bl1356 or linagliptin). Bl1356 exhibits high potency, 24 hour duration of action, and a wide therapeutic window. In patients with type 2 diabetes orally administered Bl1356 at multiple doses once daily for 12 days, Bl1356 exhibits favorable pharmacodynamic and drug fate profiles (see, eg, Table 1 below), and Rapid attainment (eg, reaching steady state plasma levels (<90% of predose plasma concentration at day 13) during treatment on days 2 and 5 in all dose groups), very little accumulation (eg, 1 mg Mean accumulation ratio R _{A, AUC} ≤1.4 at doses above and maintaining long lasting effects with DPP-4 inhibition (eg almost complete (> 90%) DPP-4 inhibition at dose levels of 5 mg and 10 mg) I.e., 92.3 and 97.3% inhibition at steady state, respectively, and more than 80% inhibition during the 24-hour interval after drug ingestion), and blood glucose amplitude 2 hours postprandial (already on day 1 at doses ≥2.5 mg). Marked (> 80%) decrease in urine and excretion in urine on day 1 That the cumulative amount does not exceed about 3-6% by day 12 increased less than 1% of the administered dose of unchanged parent compound (renal clearance C _{LR, SS} is about 70 mL / min to about 14 for oral administration dosage For example, for a 5 mg dose, renal clearance is about 70 mL / min). In people with type 2 diabetes, Bl1356 shows placebo-like safety and resistance. At doses as low as about 5 mg or more, Bl1356 functions as a once-a-day oral drug showing complete 24-hour DPP-4 inhibition. At therapeutic oral dose levels, Bl1356 is excreted primarily through the liver and to a very small extent via the kidney (less than about 7% of the oral dose). Bl1356 is excreted unchanged via bile in principle. The portion of Bl1356 removed via the kidneys increases very slightly over time and with increasing doses, so that it may not be necessary to modify the Bl1356 dose according to the patient's renal function. Non-renal elimination of B11356, in combination with its low accumulation capacity and wide margin of safety, can be a significant advantage in a population of patients with high rates of renal dysfunction and diabetic nephropathy.

Table 1: Geometric mean (gMean) and geometric coefficient of variation (gCV) of Bl1356 drug fate parameters at steady state (day 12)
* Median and range [min-max]
NC: Not calculated because most values are below the lower limit of quantification

Since different metabolic dysfunctions often occur simultaneously, it is very frequently indicated to combine a number of different principles of action. Thus, DPP-4 inhibitors reduce the blood pressure or blood lipid levels, increase blood HDL levels, and reduce blood pressure, which are conventional for the corresponding disorders, e.g., other anti-diabetic substances, especially for anti-diabetic substances. If combined with one or more active agents selected from those indicated in the treatment of atherosclerosis or obesity, an improved therapeutic outcome can be obtained in response to the diagnosed dysfunction. .
The above-mentioned DPP-4 inhibitors can also be used in conjunction with other active substances, in addition to their use in monotherapy, thereby obtaining improved therapeutic results. Such combination therapy may be provided in a free combination of the substances or in a fixed combination form (eg a tablet or capsule). Pharmaceutical formulations containing the combination partners required for the foregoing can be obtained commercially as pharmaceutical compositions or can be formulated by one skilled in the art using conventional methods. Actives commercially available as pharmaceutical formulations are available in a number of places in the prior art, such as the annually published drug list, the American Pharmaceutical Manufacturers Association "Rpte Liste (TM)", or as the "Physicians' Desk Reference". It is listed in the manufacturer's compilation, which is updated annually for known prescription drugs.

  Examples of antidiabetic drug combination partners are: metformin; sulfonylureas such as glubenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glibornuride and gliclazide; nateglinide; repaglinide; mitiglinide; Modulators, such as metaglidase; PPAR-gamma agonists, such as riboglitazone, mitoglitazone, INT-131 and vaglititazone; PPAR-gamma antagonists; And KRP297; PPAR-gamma / alpha / delta modulators, such as lobeglitazone; AMPK-activators, such as AICAR; (ACC1 and ACC2) inhibitors; diacylglycerol-acetyltransferase (DGAT) inhibitors; pancreatic beta cell GCRP agonists, such as SMT3-receptor-agonists and GPR119, such as GPR119 agonist 5-ethyl-2- {4- [4 -(4-tetrazol-1-yl-phenoxymethyl) -thiazol-2-yl] -piperidin-1-yl} -pyrimidine or 5- [1- (3-isopropyl- [1,2,4] oxadiazol-5) -Yl) -piperidin-4-ylmethoxy] -2- (4-methanesulfonyl-phenyl) -pyridine; 11β-HSD-inhibitor; FGF19 agonist or analog; alpha-glucosidase blockers such as acarbose, voglibose and miglitol; -Antagonists; insulin and insulin analogues such as human insulin, insulin lispro, insulin glucocillin, r-DNA-insulin aspart, NPH insulin GLP-1 and GLP-1; insulin detmir, insulin degludec, insulin tregopyl, insulin zinc suspension and insulin glargine; gastric inhibitory peptides (GIP); amylin and amylin analogs (eg, pramlintide or davarintide); 1 analog, for example Exendin-4, for example Exenatide, Exenatide LAR, Liraglitide, Taspoglitide, Lixisenatide (AVE-0010), LY-2428757 (PEGylated form of GLP-1), Duraglutide (LY-2189265), Semaglutide or Albiglutide; SGLT2 -Inhibitors, such as dapagliflozin, sergliflozin (KGT-1251), atigliflozin, canagliflozin, ipragliflozin or tofogliflozin; inhibitors of protein tyrosine phosphatases (eg troduskemin); inhibitors of glucose-6-phosphatase; Modulators of toose-1,6-bisphosphatase; modulators of glycogen phosphorylase; glucagon receptor antagonists; phosphoenol pyruvate carboxykinase (PEPCK) inhibitors; pyruvate dehydrogenase kinase (PDK) inhibitors; tyrosine kinase inhibitors (from 50 mg 600 mg), for example PDGF-receptor-kinase (see EP-A-564409, WO 98/35958, US 5093330, WO 2004/005281 and WO 2006/041976) or inhibitors of serine / threonine kinase; glucokinase / regulatory protein regulation Substances (including glucokinase activators); glycogen synthase kinase inhibitors; inhibitors of SH2-domain containing inositol 5-phosphatase type 2 (SHIP2); IKK inhibitors such as high dose salicylates; JNK1 inhibitors; Theta inhibitors; beta3 agonists, such as ritobeg Ron, YM178, solabegron, talibegron, N-5984, GRC-1087, rafabegulon, FMP825; aldose reductase inhibitors such as AS3201, zenarestat, fidarestat, epalrestat, ranirestat, NZ-314, CP-744809 and CT-112; SGLT-1 or SGLT-2 inhibitor; KV1.3 channel inhibitor; GPR40 modulator such as [(3S) -6-({2 ', 6'-dimethyl-4'-[3- (methylsulfonyl) propoxy ] Biphenyl-3-yl} methoxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid; SCD-1 inhibitor; CCR-2 antagonist; dopamine receptor agonist (bromocriptine mesylate [Cycloset]); -(3- (2,6-dimethylbenzyloxy) phenyl) -4-oxobutanoic acid; sirtuin stimulants; and other DPP IV inhibitors.

Metformin is usually administered at a dose of about 500 mg to 2000 mg, up to 2500 mg per day, using a variety of dosage regimens: about 100 mg to 500 mg, or 200 mg to 850 mg (1 to 3 times daily), or about 300 mg to 1000 mg once or twice daily, or sustained release metformin, about 100 mg to 1000 mg or preferably 500 mg to 1000 mg once or twice daily, or about 500 mg to 2000 mg once daily. Specific dosage strengths can be metformin hydrochloride 250, 500, 625, 750, 850 and 1000 mg.
For children aged 10 to 16 years, the recommended starting dose of metformin is 500 mg once daily. If this dose does not give adequate results, the dose can be increased to 500 mg twice daily. Further increases can increase the daily dose up to 2000 mg by 500 mg weekly and can be administered as divided doses (eg, 2 to 3 divided doses). Metformin can be administered with food to reduce nausea.
The dosage of pioglitazone is usually about 1-10 mg, 15 mg, 30 mg or 45 mg once a day.
Rosiglitazone is usually administered in doses of 4 to 8 mg once a day (or twice a day) (typical dosage strengths are 2, 4 and 8 mg).
Glibenclamide (glyburide) is usually administered at a dose of 2.5-20 mg once / day (or divided into two doses) (typical dosage strengths are 1.25, 2.5 and 5 mg) or micronized glibenclamide Is administered in doses of 0.75-3 to 12 mg once daily (or in two divided doses) (typical dosage strengths are 1.5, 3, 4.5 and 6 mg).
Glipizide is usually administered at a dose of 2.5 to 10-20 mg once daily (or up to 40 mg divided into two doses) (typical dosage strengths of 5 and 10 mg), or extended release glibenclamide It is administered in 5 to 10 mg (up to 20 mg) once daily doses (typical dosage strengths are 2.5, 5 and 10 mg).
Glimepiride is usually administered in a daily dose of 1-2 to 4 mg (up to 8 mg) (typical dosage strengths are 1, 2 and 4 mg).

The glibenclamide / metformin dual combination is usually administered at a dose of 1.25 / 250 once daily to 10/1000 mg twice daily (typical dosage strengths are 1.25 / 250, 2.5 / 500 and 5/50). / 500mg).
The glipizide / metformin dual combination is usually administered in 2.5 / 250 to 10/1000 mg twice daily doses (typical dosage strengths are 2.5 / 250, 2.5 / 500 and 5/500 mg) .
The glimepiride / metformin dual combination is usually administered at a dose of 1/250 to 4/1000 mg twice daily.
The rosiglitazone / glimepiride dual combination is usually administered at a dose of 4/1 once or twice a day to 4/2 mg twice a day (typical dosage strengths of 4/1, 4 / 2, 4/4, 8/2 and 8/4 mg).
The pioglitazone / glimepiride dual combination is usually administered in a once daily dose of 30/2 to 30/4 mg (typical dosage strengths are 30/4 and 45/4 mg).
The rosiglitazone / metformin dual combination is usually administered at a dose of 1/500 to 4/1000 mg twice daily (typical dosage strengths are 1/500, 2/500, 4/500, 2/500 / 1000 and 4/1000 mg).
The pioglitazone / metformin dual combination is usually administered at a dose of 15/500 once or twice daily to 15/850 mg three times daily (typical dosage strengths are 15/500 and 15/500 850 mg).

Nateglinide, a non-sulfonylurea insulin secretagogue, is usually administered with meals in doses of 60 to 120 mg (up to 360 mg / day, typical dosage strengths are 60 and 120 mg); repaglinide is usually 0.5 mg It is administered with meals at doses of up to 4 mg (up to 16 mg / day, typical dosage strengths are 0.5, 1 and 2 mg). The repaglinide / metformin dual combination is available in dosage strengths of 1/500 and 2/850 mg.
Acarbose is usually administered with a meal in a dose of 25 to 100 mg. Miglitol is usually administered with a meal in a dose of 25 to 100 mg.
Examples of combination partners that reduce blood lipid levels include HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin, lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin; fibrates such as bezafibrate, fenofibrate, clofibrate. Nicotinic acid and derivatives thereof, such as acipimox; PPAR-alpha agonists; PPAR-delta agonists, such as {4-[(R) -2-ethoxy-3- (4- Trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-henoxy} -acetic acid; acyl-coenzyme A; cholesterol acyltransferase (ACAT; EC 2.3.1.26) such as avasimib; cholesterol absorption inhibitors such as ezetimibe; Gall Acid-binding substances such as cholestyramine, colestipol and colesevelam; bile acid transport inhibitors; HDL-modulating active substances such as D4F, reverse D4F, LXR-modulating active substances and FXR-modulating active substances; CETP inhibitors such as torcetrapib, JTT-705 ( Darcetrapib) or the compounds of WO 2007/005572 (anasetrapib) or evasetrapib; LDL receptor modulators; MTP inhibitors (eg lomitapide); and ApoB100 antisense RNA.
The dose of atorvastatin is usually 1 mg to 40 mg or 10 mg to 80 mg once a day.

Examples of combination partners that lower blood pressure are beta blockers, such as atenolol, bisoprolol, ceriprolol, metoprolol, nebivolol and carvedilol; diuretics such as hydrochlorothiazide, chlorthalidone, xipamide, furosemide, piretanide, toracemide, spironolactone, eplerenone, amiloride and amiloride triam. Calcium channel blockers, such as amlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine, felodipine, lacidipine, lercanipidine, manidipine, isradipine, nilvadipine, verapamil, galopamil and diltiazem; , Benazepril, perindine Lil, fosinopril and trandolapril; and angiotensin II receptor blockers (ARB), e.g. telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan, a azilsartan and eprosartan.
The dosage of telmisartan is usually from 20 mg to 320 mg, or from 40 mg to 160 mg / day.
Examples of combination partners that increase HDL levels in the blood are cholesteryl ester transfer protein (CETP) inhibitors; inhibitors of endothelial lipase; modulators of ABC1; LXRalpha antagonists; LXRbeta agonists; / Beta modulators and substances that increase the expression and / or plasma concentration of apolipoprotein AI.

Examples of combination partners for the treatment of obesity are sibutramine; tetrahydrolipstatin (orlistat); alizayme (cetilistat); dexfenfluramine; acoxin; MC4 receptor agonists; NPY5, in addition to the above, NPY2 antagonists (eg berneperito); beta3-AR agonists such as SB-418790 and AD-9677; 5HT2C receptor agonists such as APD356 (Lorcaserin); Steroyl-CoA desaturase (SCD1) inhibitor; fatty acid synthase (FAS) inhibitor; CCK receptor agonist; gerrelin receptor modulator; Pyy3-36; orexin receptor antagonist; Fensin; in addition to the above, the two-drug combination bupropion / naltrexone, bupropion / zonisamide, topiramate / phentermine and pramlintide / metreleptin.
Examples of combination partners for the treatment of atherosclerosis are: phospholipase A2 inhibitors; inhibitors of tyrosine kinases (50 mg to 600 mg) such as PDGF-receptor kinase (EP-A-564409, WO 98/35958, US 5093330). OxLDL antibodies and oxLDL vaccines; Apo A-1 Milano; ASA; and VCAM-1 inhibitors.

Still further within the scope of the present invention, the DPP-4 inhibitor may optionally be combined with one or more antioxidants, anti-inflammatory agents and / or vascular endothelial protective agents.
Examples of antioxidant combination partners are selenium, betaine, vitamin C, vitamin E and beta-carotene.
An example of an anti-inflammatory drug combination partner is pentoxifylline, and another example of an anti-inflammatory drug combination partner is a PDE-4 inhibitor, such as tetomilast, roflumilast, or 3- [7-ethyl-2- (methoxymethyl)- 4- (5-methyl-3-pyridinyl) pyrrolo [1,2-b] pyridazin-3-yl] propanoic acid (or disclosed in US 7153854, WO 2004/063197, US 7459451 and / or WO 2006/004188) Other species).
Yet another example of an anti-inflammatory partner drug is a caspase inhibitor such as (3S) -5-fluoro-3-({[(5R) -5-isopropyl-3- (1-isoquinolinyl) -4,5-dihydro -5-isoxazolyl] carbonyl} amino-4-oxopentanoic acid (or other species disclosed in WO 2005/021516 and / or WO 2006/090997).
An example of a vascular endothelial protective agent is a PDE-5 inhibitor, such as sildenafil, verdenafil or tadalafil, and another example of a vascular endothelial protective agent is a nitric oxide donor or stimulant (eg, L-arginine or tetrahydrobiopterin).

Still further, and within the scope of the present invention, optionally, the DPP-4 inhibitor comprises one or more antiplatelet agents, such as (low dose) aspirin (acetylsalicylic acid), selective COX-2 or non-selective COX-1. / COX-2 inhibitors, or ADP receptor inhibitors, such as thienopyridines (eg, crepidogrel or prasugrel), erynogrels or ticagrelar, or thrombin receptor antagonists, such as bolapaxer.
Still further within the scope of the present invention, the DPP-4 inhibitor may be one or more anticoagulants, such as heparin, warfarin, or a direct thrombin inhibitor (eg, dabigatran), or a factor Xa inhibitor (eg, Rivaroxaban or apixaban or edoxaban or otamixaban).
Still further, within the scope of the present invention, optionally, a DPP-4 inhibitor may be combined with one or more agents for the treatment of heart failure.
Examples of combination partners for the treatment of heart failure include beta blockers such as atenolol, bisoprolol, celiprolol, metoprolol and nebivolol; diuretics such as hydrochlorothiazide, chlorthalidone, xipamide, furosemide, piretanide, toracemide, spironolactone, eplerenone, amiloride and triamterene. ACE inhibitors such as ramipril, lisinopril, cilazapril, quinapril, captopril, enalapril, benazepril, perindopril, fosinopril and trandolapril; Losartan; cardiac glycosides such as digoxin and di Toxin; binding alpha / beta blockers, for example carvedilol; or B-type natriuretic peptide (BNP) and BNP- derived peptides and BNP- fusion product; vasodilators; antiarrhythmics.
Still further within the scope of the present invention, the DPP-4 inhibitor may be one or more CCK-2 or gastrin agonists, such as proton pump inhibitors (reversible inhibitors in addition to reversible inhibitors of H + / K + -ATPase). Omeprazole, esomeprazole, pantoprazole, rabeprazole or lansoprazole.

The present invention should not be limited in scope by the specific embodiments described herein. Various modifications in addition to those described herein will be apparent to those skilled in the art from this disclosure. Such modifications are included within the scope of the present invention.
All patent applications cited herein are hereby incorporated by reference in their entirety.

Some specific embodiments of the present invention are illustratively described below.
(1) Use of linagliptin for the preparation of a pharmaceutical composition for use in any one or more of the following methods:
Type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), fasting blood glucose disorder (IFG), hyperglycemia, postprandial hyperglycemia, post-absorption hyperglycemia, latent autoimmune diabetes in adults (LADA), overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, nonalcoholic fatty liver disease (NAFLD) ), A method of preventing, slowing, prolonging or treating a metabolic disorder or disease selected from retinopathy, neuropathy, nephropathy, polycystic ovary syndrome, and / or metabolic syndrome;
-Methods for improving and / or maintaining glycemic control and / or for reducing fasting plasma glucose, postprandial plasma glucose, post-absorption plasma glucose and / or glycosylated hemoglobin HbA1c;
-Prevent, slow, prolong or slow progression from prediabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance, and / or metabolic syndrome to type 2 diabetes mellitus. How to reverse;
-Microvascular or macrovascular diseases, including nephropathy, microalbumin or macroalbuminuria, proteinuria, retinopathy, cataract, neuropathy, learning or memory impairment, neurodegenerative or cognitive abnormalities, cardiovascular system Or cerebrovascular disease, tissue ischemia, diabetic foot or diabetic ulcer, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral artery A method for preventing, reducing the risk of, delaying, prolonging, or treating the complications of diabetes mellitus, which is an occlusive disease, cardiomyopathy, heart failure, abnormal heart rhythm, vascular restenosis, and / or stroke ;
-A method of reducing body weight and / or body fat or preventing an increase in body weight and / or body fat, or promoting body weight and / or body fat reduction;
-For preventing, slowing down or treating pancreatic beta cell degeneration and / or loss of pancreatic beta cell functionality, and / or for improving, retaining and / or restoring pancreatic beta cell functionality. And / or a method of stimulating and / or restoring or protecting the function of pancreatic insulin secretion;
-A method for preventing, slowing down, prolonging or treating non-alcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH) and / or hepatic fibrosis;
-Methods of preventing, delaying, prolonging or treating type 2 diabetes in which normal anti-diabetic alone or in combination therapy has failed;
-How to achieve the required dose reduction of the usual antidiabetic drugs required for an adequate therapeutic effect;
-Methods to reduce the risk of side effects associated with conventional anti-diabetic drugs; and / or-methods to maintain and / or improve insulin sensitivity, and / or to treat or prevent hyperinsulinemia and / or insulin resistance. the method of;
In one or more of
Patients with or at risk for cardiovascular and / or renal disease or having one or more cardiovascular risk factors selected from A), B), C) and D) below In patients, using linagliptin,
A method for using said linagliptin, comprising: administering to the patient a therapeutically effective amount of linagliptin, optionally together with one or more other therapeutic agents:
A) Previous or existing pulses selected from, for example, myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass grafting, ischemic or hemorrhagic stroke, congestive heart failure, and peripheral occlusive artery disease Vascular disease;
B) a vascular-related end-organ disease selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease and microalbumin or macroalbuminuria;
C) Elderly (eg, over 60-70); and
D) One or more cardiovascular risk factors selected from:
Advanced type 2 diabetes mellitus (eg for a period of more than 10 years),
-Hypertension,
-At this moment daily smoking,
-Dyslipidemia,
-Obesity,
-Ages from 40 to 80,
-A metabolic syndrome, hyperinsulinemia or insulin resistance, and-a family history of hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or cardiomyopathy in first degree.
(2) The use according to (1), wherein the method comprises treating type 2 diabetes mellitus.
(3) Cardiac vein wherein the patient is selected from myocardial infarction, stroke, peripheral arterial occlusive disease, diabetic nephropathy, microalbumin or macroalbuminuria, acute or chronic renal failure, hyperuricemia, and / or hypertension The use according to (1) or (2), which is a type 2 diabetic patient having or at risk for vascular and / or renal diseases.
(4) any of (1) to (3), wherein the patient is a type 2 diabetic patient having one or more cardiovascular risk factors selected from the following A), B), C) and D) Use as described in Crab:
A) Previous or existing pulses selected from, for example, myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass grafting, ischemic or hemorrhagic stroke, congestive heart failure, and peripheral occlusive artery disease Vascular disease;
B) a vascular-related end-organ disease selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease, and microalbumin or macroalbuminuria;
C) Elderly (eg, over 60-70); and
D) One or more cardiovascular risk factors selected from:
Advanced type 2 diabetes mellitus (eg for a period of more than 10 years),
-Hypertension,
-At this moment daily smoking,
-Dyslipidemia,
-Obesity,
-Ages from 40 to 80,
-A metabolic syndrome, hyperinsulinemia or insulin resistance, and-a family history of hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or cardiomyopathy in first degree.
(5) cardiovascular or cerebral vessels selected from cardiovascular death, myocardial infarction, stroke and hospitalization (eg, due to acute coronary syndrome, leg amputation, revascularization, heart failure or unstable angina) A method of preventing the occurrence of a sexual event, preferably in a type 2 diabetic patient, reducing the risk of or prolonging the occurrence, said method optionally comprising administering a therapeutically effective amount of one or more linagliptin. Use of linagliptin for the preparation of a pharmaceutical composition for use in the above method, comprising administering to a patient in need thereof with another therapeutic agent.
(6) the patient with type 2 diabetes is at risk for a cardiovascular or cerebrovascular event, with one or more of the following risk factors selected from A), B), C) and D): Uses described in (5):
A) Previous or existing vessels selected from myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass grafting, ischemic or hemorrhagic stroke, congestive heart failure, and peripheral occlusive artery disease Systemic disease;
B) a vascular-related end-organ disease selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease, and microalbumin or macroalbuminuria;
C) Elderly (eg, over 60-70); and
D) One or more cardiovascular risk factors selected from:
Advanced type 2 diabetes mellitus (eg for a period of more than 10 years),
-Hypertension,
-At this moment daily smoking,
-Dyslipidemia,
-Obesity,
-Ages from 40 to 80,
-A metabolic syndrome, hyperinsulinemia or insulin resistance, and-a family history of hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or cardiomyopathy in first degree.
(7) the type 2 diabetic patient has a vascular-related end-organ disease selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease, and microalbumin or macroalbuminuria; Use according to (6).
(8) The occurrence of cardiovascular or cerebrovascular events selected from cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for unstable angina, A method of preventing, reducing the risk of, or prolonging the appearance of, a type 2 diabetic patient at risk for a vascular event, comprising administering a therapeutically effective amount of linagliptin, optionally with one or more other therapeutic agents. Use of linagliptin for the preparation of a pharmaceutical composition for use in the above method, comprising administering to a patient together with.
(9) The use according to any of (5) to (8), wherein the type 2 diabetic patient has nephropathy, renal dysfunction, chronic kidney disease, and / or microalbumin or macroalbuminuria.
(10) The use according to any of (5) to (9), wherein the type 2 diabetic patient has mild, moderate or severe renal impairment or end-stage renal disease.
(11) The use according to any one of (5) to (10), wherein the type 2 diabetic patient has microalbuminuria or diabetic nephropathy.
(12) one or more other therapeutic substances are other antidiabetic substances, active substances that lower blood glucose levels, active substances that lower blood lipid levels, active substances that raise blood HDL levels, and lower blood pressure Any one of (1) to (11), which is selected from an active substance to be activated, an active substance indicated in the treatment of atherosclerosis or obesity, an antiplatelet agent, an anticoagulant, and a vascular endothelial protective agent. use.
(13) The other antidiabetic substance is selected from metformin, sulfonylurea, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonist, alpha-glucosidase inhibitor, insulin and insulin analogs, and GLP-1 and GLP-1 analogs , (12).
(14) The use according to (12) or (13), wherein the active substance that lowers blood pressure is selected from an angiotensin receptor blocker (ARB), an angiotensin converting enzyme (ACE) inhibitor, and a beta-blocker.
(15) The method according to (14), wherein the angiotensin receptor blocker (ARB) is telmisartan, and / or the angiotensin converting enzyme (ACE) inhibitor is ramipril, and / or the beta-blocker is carvedilol, nebiball or metoprolol. Use of.
(16) the active substance that lowers blood lipid levels and / or increases blood HDL levels is selected from statins, nicotinic acid or a derivative thereof, fibrates, cholesterol absorption inhibitors, and bile acid sequestering agents; Use according to any one of (12) to (15).
(17) The statin is atorvastatin, simvastatin or rosuvastatin, and / or nicotinic acid or a derivative thereof is niacin, and / or fibrate is fenofibrate, and / or the cholesterol absorption inhibitor is ezetimibe, And / or the use of (16), wherein the bile acid sequestering agent is colesevelam.
(18) The use according to any of (12) to (17), wherein the antiplatelet agent is selected from low-dose aspirin, clopidogrel, prasugrel, bolapaxer, and ticagreler.
(19) The use according to any one of (12) to (18), wherein the anticoagulant is selected from heparin, warfarin, dabigatran, rivaroxaban, and apixaban.
(20) The method further comprises selecting linagliptin from metformin, sulfonylurea, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonist, alpha-glucosidase inhibitor, insulin or insulin analog, and GLP-1 or GLP-1 analog1 Use according to any of (1) to (19), comprising the step of administering together with one or more other antidiabetic substances, and optionally telmisartan.
(21) The use according to any of (1) to (20), wherein the method further comprises the step of administering linagliptin together with metformin.
(22) The use according to any one of (1) to 20, wherein the method further comprises the step of administering linagliptin together with telmisartan.
(23) The use according to any of (1) to (20), wherein the method comprises administering a pharmaceutical composition comprising linagliptin and metformin.
(24) The use according to any one of (1) to (23), wherein the linagliptin is orally administered in a total amount of 5 mg per day.
(25) In the patient,
Treating or preventing ischemic / reperfusion injury (of the kidney, heart, brain or liver), reducing its risk, slowing its progress, prolonging, weakening or reversing its onset and / or (Harmful) vascular remodeling, such as cardiac remodeling, which can be characterized by cardiomyocyte hypertrophy, interstitial fibrosis, ventricular dilation, asystole and / or cell death / apoptosis. Treat or prevent modeling, reduce its risk, slow its progress, prolong, weaken or reverse its onset; or-treat and prevent chronic or acute renal failure and / or peripheral arterial occlusion Reduce the risk, delay its progression, prolong, weaken or reverse its onset; or-reduce congestive heart failure and / or cardiac hypertrophy and / or nephropathy and / or albuminuria Treat, prevent, reduce its risk, slow its progression, prolong, weaken or reverse its onset; or-treat uremic cardiomyopathy, gap dilation, and / or (cardiac) fibrosis A method of treating, preventing, reducing the risk, delaying its progress, prolonging, weakening or reversing its onset, comprising the steps of: converting an effective amount of linagliptin into an effective amount of one or more other active substances. Use of linagliptin for the preparation of a pharmaceutical composition for use in the above method comprising administering to a patient together with.
(26) Preventing, reducing the risk of, delaying its progression, prolonging, attenuating, reversing or treating diabetic nephropathy in patients who do not respond appropriately to treatment with an angiotensin receptor blocker (ARB) A method of using a pharmaceutical composition for use in the method, wherein the method comprises administering to the patient a therapeutically effective amount of linagliptin, optionally together with one or more other therapeutic agents. Use of linagliptin for preparation.
(27) Preparation of a pharmaceutical composition for use in a method of using linagliptin with telmisartan to treat diabetic nephropathy, including albuminuria, in a patient that does not respond appropriately to angiotensin receptor blocker (ARB). Of linagliptin for the treatment.
(28) The use according to (26), wherein the method comprises administering a therapeutically effective amount of linagliptin in combination with the ARB.
(29) The use according to (28), wherein the ARB is telmisartan.
(30) The use according to (26) to (29), wherein linagliptin is orally administered in a total dose of 5 mg per day.
(31) Use of linagliptin for the preparation of a pharmaceutical composition for use in a method for treating and / or preventing oxidative stress, vascular stress and / or endothelial dysfunction in a patient with sepsis.
(32) The use according to (31), wherein the patient has non-diabetic sepsis or diabetic sepsis.
(33) Use of linagliptin for the preparation of a pharmaceutical composition for treating and / or preventing sepsis.

  Further embodiments, features and advantages of the present invention will become apparent from the following examples. The following examples are provided to illustrate the principles of the present invention by way of example without limiting it.

Antioxidant action :
Anti-inflammatory and vasodilator potential of linagliptin The direct antioxidant effects of gliptin (linagliptin, alogliptin, vildagliptin, saxagliptin, sitagliptin) are based on xanthine oxidase, peroxynitrite (intrinsic and Sin-1 inducible) or hydrogen peroxide. / Peroxidase-mediated 1-electron-oxidation as assessed by interference with superoxide formation. These oxidations are detected by phenol fluorescence, chemiluminescence and nitrification (traced by HPLC). The indirect antioxidant effect of gliptin is measured on isolated human leukocytes (PMN) by interfering with the oxidative burst (NADPH oxidase activation) induced by the phorbol esters PDBu, endotoxin LPS and thymosan A and the chemotactic peptide fMLP. You.
The direct vasodilator effect of gliptin is measured by the isotonic toning technique on isolated aortic ring segments. The indirect antioxidant effect of linagliptin was also demonstrated in nitroglycerin-induced nitrate tolerance and linagliptin treatment (3-10 mg / kg / day for 7 days on a special diet) in endothelial function (acetylcholine of phenylephrine precontracted aortic vascular fragments). -Dependent relaxation) and smooth muscle function (nitroglycerin-dependent relaxation) as measured by isometric tone recordings. Furthermore, reactive oxygen and nitrogen species (RONS) formation is measured in isolated cardiac mitochondria and in whole blood LPS or PDBu triggered oxidative bursts. Furthermore, the anti-inflammatory potential of linagliptin is tested in an experimental model of LPS (10 mg / kg, 24-hour ip) -induced septic shock in Wistar rats. The effects of sepsis and linagliptin co-therapy (3-10 mg / kg / day on a special diet for 7 days) are determined by isometric tone recordings, RONS formation in blood vessels, heart and blood vessels, and protein expression by Western blot.

Result :
(See Figure 1-6)
Direct antioxidant properties :
Only all gliptins showed poor direct antioxidant capacity. Slight (but significant) suppression of superoxide formation is observed for vildagliptin and linagliptin in response to peroxynitrite formation / -mediated nitrification. All but not saxagliptin show significant inhibition of 1-electron oxidation by the hydrogen peroxide / peroxidase system, with linagliptin being the most potent compound.
Indirect antioxidant properties in isolated human neutrophils : Linagliptin shows the best inhibition of oxidative burst of isolated human leukocytes in response to NADPH oxidase activation by LPS and thymosan A. When L-012 enhanced chemiluminescence was used, LPS (0.5, 5 and 50 μg / mL) increased the PMN-derived RONS signal in a concentration-dependent manner, and linagliptin suppressed this signal in a concentration-dependent manner.
In experiments with lumino / peroxidase that enhance chemiluminescence, linagliptin is much more effective at inhibiting LPS or thymosan A-triggered oxidative burst of isolated PMN than other gliptins. Linagliptin is as effective as nebivolol in this assay. This effectiveness in inhibiting LPS-dependent RONS formation is somewhat stronger than the inhibitory effect on zymosan A-triggered RONS. All of these measurements support the superior antioxidant effect of linagliptin on isolated neutrophils when compared to other gliptins.
Inhibition of activated neutrophil adhesion to endothelial cells : By examining the adhesion of LPS-stimulated human neutrophils to cultured endothelial cells (the number of adhered PMNs can be determined by PDBu-triggered oxidative burst (amplex red / peroxidase fluorescence measurement) Linagliptin suppresses the adhesion of leukocytes to endothelial cells in the presence of LPS.

Treatment of vascular dysfunction and / or oxidative stress :
Effects of Linagliptin Treatment on Vascular Dysfunction and Oxidative Stress in Nitrate-Tolerant Rats : Isotonic Tonic Experiments in Organ Baths Reveal That Nitroglycerin and LPS Treatment Induce Significant Endothelial Dysfunction and Nitrate Tolerance . Endothelial dysfunction caused by both factors is significantly improved by linagliptin therapy (FIGS. 8A and 8B), but nitrate tolerance remains unchanged. Nitroglycerin treatment causes cardiac mitochondrial ROS formation and whole blood LPS / thymosan A-triggered oxidative burst. All of these side effects are improved by linagliptin treatment (FIG. 7). Neither nitroglycerin nor linagliptin treatment affects the weight of the animals, but blood glucose levels are slightly increased in the nitroglycerin group, which is normalized by linagliptin treatment.
In summary, treatment with linagliptin in vivo reduced nitroglycerin-induced endothelial dysfunction and further showed a slight improvement in ROS formation of isolated cardiac mitochondria and oxidative burst of whole blood from nitrate-tolerant rats.
Effect of linagliptin on vascular dysfunction and oxidative stress in septic rats : A very similar protective effect of linagliptin is observed in experimental models of septic shock. Vascular function (Ach-, GTN-, and diethylamine NONOate-dependent relaxation) is greatly impaired by LPS, which is almost normalized by linagliptin treatment. Mitochondrial and whole blood (LPS, PDBu stimulated) RONS production is dramatically increased by LPS and improved by linagliptin treatment. Vascular oxidative stress (as measured by DHE-dependent fluorescence microscopy) and vascular inflammation markers (VCAM-1, Cox-2, and NOS-2) are dramatically increased by LPS treatment and markedly improved by linagliptin therapy. Similar effects are observed for aortic protein tyrosine nitrification and malondialdehyde content (both are markers of oxidative stress) and aortic NADPH oxidase subunit expression (Nox1 and Nox2). As proof of concept, DPP-4 activity and GLP-1 levels are detected in corresponding animals, revealing a strong inhibition of DPP-4 and an almost 10-fold increase in plasma GLP-1 levels.
Direct vasodilator effect of gliptin : Isotonic tonic recordings indicate that some gliptins show a direct vasodilator effect in the concentration range of 10-100 μM. Linagliptin is the most potent compound, followed by alogliptin and vildagliptin, while sitagliptin and saxagliptin are less effective at inducing vasodilation than the vehicle control (DMSO) (see FIGS. 9A and 9B).
These observations support the pleiotropic antioxidant and anti-inflammatory properties of linagliptin, which properties are not (or only to a small extent) shared with other gliptins. Furthermore, linagliptin reduces leukocyte adhesion to endothelial cells due to the presence of LPS, and also ameliorates nitroglycerin-induced and pro-inflammatory endothelial dysfunction and oxidative stress. This may contribute to improving endothelial function and supporting cardioprotective effects of linagliptin. Thus, there is evidence that linagliptin confers an antioxidant effect that beneficially affects cardiovascular disease, secondary to diabetic complications with high levels of morbidity and mortality.

Treatment of diabetic nephropathy and albuminuria :
Endothelial damage is a hallmark of type 2 diabetes and contributes to progression to end-stage renal disease. Furthermore, vascular endothelial NO synthase (eNOS) activity is altered in T2D, and genetic abnormalities in the corresponding gene (NOS3) are closely associated with the further progression of diabetic nephropathy in patients with type 1 and type 2 diabetes. Involved. The use of low doses of STZ to induce T2D in this genetic phenotype (eNOS-/-) has recently been reported (Brosius et al. JASN 2009), making it an effective experimental model for DN. 8-week old eNOS − / − mice are rendered diabetic by intraperitoneal injection of streptozotocin (100 mg / kg / day for 2 consecutive days). Diabetes onset (blood glucose defined as> 250 mg / dL) is established one week after streptozocin injection. Insulin is not given because it can prevent the development of diabetic nephropathy. Treat mice for 4 weeks with:
1) Non-diabetic control mouse, placebo (natrosol) (n = 14)
2) mock-treated diabetic eNOS ko mouse, placebo (natrosol) (n = 17)
3) Telmisartan (po 1 mg / kg) treated diabetic eNOS ko mice (n = 17)
4) Linagliptin inhibitor (po 3mg / kg) treated diabetic eNOS ko mice (n = 14)
5) Telmisartan (1 mg / kg) + Linagliptin (3 mg / kg) treated diabetic eNOS ko mice (n = 12)
Renal function (s-creatinine, albumin) and blood glucose levels are detected.
No significant differences in blood glucose in STZ-treated animals were detected between linagliptin, telmisartan or the combination described above and placebo (see FIG. 10).
Although no effect on blood glucose is detected, the albumin / creatinine ratio is significantly reduced in the linagliptin + telmisartan treatment group (middle bar, 5 in FIG. 11). The corresponding monotherapy also reduces the albumin / creatinine ratio but is not significant. The albumin / creatinine ratio in non-diabetic versus diabetic animals is also significantly reduced (see FIG. 11). These effects support the use of linagliptin and telmisartan in renal protection and treatment and / or prevention of diabetic nephropathy and albuminuria. The combination of linagliptin and telmisartan offers a novel therapeutic approach for patients with or at risk for diabetic nephropathy and albuminuria.

Treatment of congestive heart failure and cardiac hypertrophy :
We propose the hypothesis that glucose / energy supply is particularly important in cardiac dysfunction characterized by cardiac hypertrophy. Inadequate energy supply is thought to be one of the most important steps from compensatory to decompensated left ventricular hypertrophy leading to cardiac dysfunction. The classic model of hypertension-induced left ventricular hypertrophy resulting from long-lasting left ventricular failure and pathological remodeling is the 2 kidney 1 renal vasoconstriction hypertension (Goldbat) model (2K1C model).
Animals are treated with the following regimen for up to 3 months:
1.2K1C-rat, Telmisartan (10mg / kg KG) in drinking water (n = 14)
2. 2K1C-rat, linagliptin (Bl1356) in feed (89 ppm, comparable to 3-10 mg / kg oral gavage) (n = 15)
3.2K1C-rat, telmisartan (10 mg / kg) + linagliptin (Bl1356) (89 ppm) (n = 15)
4. 2K1C-rat, placebo (n = 17)
Five. SHAM-rat, placebo (n = 11)
Non-invasive, systolic blood pressure is measured in all groups at multiple time points (for each compound, 1. before treatment; 2. 1 week after treatment; 3. 4 weeks after treatment; 4. 6 weeks after treatment 5. after 12 weeks of treatment; and 6. after 6 weeks of treatment).
Prior to treatment, only sham-treated animals show significant differences from the other groups. From week 1 of treatment to the end of the experiment, telmisartan and the combination of telmisartan and linagliptin are always significant for vehicle-treated animals. The combination of telmisartan and linagliptin reaches the level of placebo sham-treated animals and shows additional effects in addition to telmisartan monotherapy (see FIG. 12). These effects support the use of linagliptin and telmisartan in the treatment and / or prevention of cardiac hypertrophy and / or congestive heart failure. The combination of linagliptin and telmisartan provides a novel therapeutic approach for patients with or at risk for cardiac hypertrophy and / or congestive heart failure.

Treatment of uremic cardiomyopathy :
Uremic cardiomyopathy is a substantial contributor to the morbidity and mortality of patients with chronic kidney disease, which is also a frequent complication of type 2 diabetes. Glucagon-like peptide-1 (GLP-1) can improve cardiac function, and GLP-1 is mainly degraded by dipeptidyl peptidase (DPP-4). Linagliptin is the only DPP-4 inhibitor that can be used clinically (e.g., in patients with type 2 diabetes and diabetic nephropathy) without performing titration at all stages of renal failure.
Scrutinize linagliptin in a rat model with chronic renal insufficiency (5/6 nephrectomy [5 / 6N]) : Eight weeks after 5 / 6N or sham surgery, rats are treated with 3.3 mg / kg linagliptin or The formulation is treated orally for 4 weeks, followed by sampling plasma for 72 hours for quantification of DPP-4 activity and GLP-1 levels. At the end of the experiment, heart tissue is collected for mRNA analysis.
5 / 6N had a significant (p <0.01) decrease in GFR (measured by creatinine clearance) (2510 ± 210 mU24h in sham surgery; 1665 ± 104.3 mU24h in 5 / 6N) and increased cystatin levels (700 in sham surgery). ± 35.7 ng / mL; 1434 ± 77.6 ng / mL at 5 / 6N). DPP-4 activity was significantly reduced at all time points and there is no difference between sham surgery and 5 / 6N animals. In contrast, active GLP-1 levels were measured at maximum plasma concentration (C _max ; 6.36 ± 2.58 pg / mL for 5 / 6N, 3.91 ± 1.86 pg / mL for sham surgery) and AUC _{(0-72 h)} (5 / 6N, and significantly increased in 5 / 6N animals as measured by sham surgery at 114 pg.h / mL; p <0.001). In addition to cardiac fibrosis markers (profibrotic factors) such as TGF-β, tissue inhibitors of matrix metalloproteinase 1 (TIMP-1) and collagen 1α1 and 3α1 as well as left ventricular dysfunction markers such as brain natriuretic peptides ( BNP) mRNA levels are all significantly increased at 5 / 6N relative to sham-operated animals and consequently are reduced or normalized by linagliptin treatment (all p <0.05, see FIG. 13).
Linagliptin increased the AUC of GLP-1 almost 2-fold in rat renal failure models, and in addition to BNP (a marker of left ventricular dysfunction) and cardiac fibrosis markers (TGF-β, It reduces the gene expression of TIMP-1, Col1α1 and Col3α1). These effects support the use of linagliptin in the treatment and / or prevention of uremic cardiomyopathy. Linagliptin offers a novel therapeutic approach for patients with uremic cardiomyopathy.

Effects on infarct size and cardiac function after myocardial ischemia / reperfusion :
The purpose of this experiment was to determine the cardiac effects (particularly the effects on myocardial ischemia / reperfusion, cardiac function or infarct size) of the xanthine-based DPP-4 inhibitors of the present invention, eg, stromal cell-derived factor-1 alpha (SDF- 1α) should be evaluated based on the symptoms involved.
Male Wistar rats are divided into three groups: sham surgery, ischemia / reperfusion (I / R), and I / R + DPP-4 inhibitor of the invention; n = 10 / group. DPP-4 inhibitors are administered once daily starting two days prior to I / R. The left ventral descending coronary artery is ligated for 30 minutes. Echocardiography is performed 5 days later and cardiac catheterization is performed 7 days later. DPP-4 inhibitors showed absolute infarct size (-27.8%; p <0.05), percentage of infarcted tissue relative to total risk area (-18.5%; p <0.05), and myocardial fibrosis range (-31.6%; p <0.05). DPP-4 inhibitors significantly increase the accumulation of stem / progenitor cells characterized by CD34-, CXCR4- and C-kit- expression and cardiac immunoreactivity of infarcted myocardium to active SDF-1α. Left ventricular ejection fraction is similar in all MI groups after 7 days, but DPP-4 inhibition reduces infarct size, reduces fibrotic remodeling, and blocks infarcted area by preventing SDF-1α degradation. Increase stem cell density.
The xanthine-based DPP-4 inhibitor of the present invention can reduce infarct size after myocardial infarction. Mechanisms of action can include reduced degradation of SDF-1α followed by increased recruitment of circulating CXCR-4 ⁺ stem cells and / or an incretin receptor-dependent pathway.
These data show that in the treatment or prevention of myocardial ischemia / reperfusion and / or cardioprotection, increased stem cell recruitment, improved tissue repair, activated myocardial regeneration, reduced infarct size, reduced fibrotic remodeling And / or enhances the utility of the xanthine-based DPP-4 inhibitors of the present invention in increasing the density of stem cells in the infarcted heart region.
According to the fact that infarct size is a predictor of future events (including mortality), the xanthine-based DPP-4 inhibitors of the present invention may be useful in treating cardiac (systolic) function, cardiac contractility and / or myocardial dysfunction. It may be further useful in improving mortality after blood / reperfusion.

Effects of linagliptin on infarct size and cardiac function after myocardial ischemia / reperfusion :
Materials and Methods : Male Wistar rats are divided into three groups: sham surgery, I / R, and I / R + linagliptin (n = 16-18 / group). Linagliptin is given once daily (3 mg / kg), starting 30 days before I / R. IR is induced by ligation of the left ventral descending coronary artery for 30 minutes, with echocardiography performed 58 days later and cardiac catheterization 60 days later.
Linagliptin reduces absolute infarct size (-18%; p <0.05) in this ischemia-reperfusion injury model, as well as the ratio of infarcted tissue to total risk area (-21%; p <0.001). Furthermore, glucagon-like peptide-1 (GLP-1) levels are increased 18-fold (p <0.0001), and DPP-4 activity is further reduced by 78% (p <0.0001). Echocardiographic parameters in addition to left ventricular left end diastolic and systolic pressures were similar between groups, with a marked improvement in isovolumetric contractility index (dP / dT _min ) (from -4771 ± 79 mmHg / s to -4957). ± 73 mmHg / s) or an improvement in the maximal rate of left ventricular pressure drop. These data further support the cardioprotective function of linagliptin at the onset of acute myocardial infarction.

Treatment of ARB resistant diabetic nephropathy :
The need for improved treatment for diabetic nephropathy is extremely high in patients who do not respond appropriately to angiotensin receptor blocker (ARB). In this experiment, the effects of linagliptin alone or in combination with ARB telmisartan on the progression of diabetic nephropathy in diabetic eNOS ko mice (a new model approximating human pathology) will be investigated.
Sixty-five male eNOS knockout C57BL / 6J mice were divided into four groups following intraperitoneal administration of high-dose streptozocin: telmisartan (1 mg / kg), linagliptin (3 mg / kg), linagliptin + telmisartan (3 + 1 mg / kg). kg), and excipients. Fourteen mice are used as non-diabetic controls. After 12 weeks, urine and blood are obtained and blood pressure is measured. Glucose levels increase, which is similar in all diabetic groups. Telmisartan alone reduced blood pressure mildly (5.9 mmHg) relative to diabetic controls (111.2 ± 2.3 mmHg vs 117.1 ± 2.2 mmHg; mean ± SEM; n = 14 each; p = 0.071), none of the other treatments Not significant. Combination treatment significantly alleviates albuminuria compared to diabetic controls (71.7 ± 15.3 μg / 24h vs 170.8 ± 34.2 μg / 24h; n = 12-13; p = 0.017), but telmisartan (97.8 ± 26.4 The effect of monotherapy with either μg / 24h; n = 14) or linagliptin (120.8 ± 37.7 μg / 24h; n = 11) is not statistically significant (see FIG. 14). Linagliptin (alone and in combination) results in significantly lower plasma osteopontin levels compared to telmisartan alone (values are similar to diabetic controls). Plasma TNF-α levels are significantly lower in all treatment groups than in the vehicle treatment group. Plasma neutrophil gelatinase-associated lipocalin (NGAL) levels are significantly increased after treatment with telmisartan compared to untreated diabetic controls, and this effect is prevented by combination treatment with linagliptin.
Furthermore, linagliptin (alone and in combination with telmisartan) significantly alleviates renal glomerulosclerosis compared to diabetic controls as measured by histological score (2.1 +/- 0.0 vs 2.4 + / -0.0; p <0.05), the relief achieved with telmisartan alone is not a significant difference. In conclusion, linagliptin significantly reduces urinary albumin excretion (eg, in a blood pressure-independent manner) in ARB-refractory diabetic eNOS knockout mice. These effects may support the use of linagliptin in renal protection and in the treatment and / or prevention of ARB resistant diabetic nephropathy. Linagliptin can provide a novel therapeutic approach for patients who are resistant to ARB treatment.

Delays onset of diabetes and preserves beta-cell function in nonobese type 1 diabetes :
Although reduced pancreatic T cell migration and altered cytokine production are considered important components of the development of insulitis, the exact mechanisms and actions in pancreatic cell pools are still not completely understood. In an attempt to assess the effects of linagliptin on pancreatic inflammation and beta-cell mass, diabetic progression of non-obese diabetic (NOD) mice over a 60-day experimental period was combined with terminal serological assessment of pancreatic cellular changes To investigate.
Sixty female NOD mice (10 weeks of age) were included in the study and were fed normal diet or diet containing linagliptin (0.083 g linagliptin / kg diet; corresponding to 3-10 mg / kg (po)) throughout the experiment. . Obtain plasma samples every two weeks to determine the onset of diabetes (BG> 11 mmol / L). At termination, the pancreas is removed and terminal blood samples are obtained for evaluation of active GLP-1 levels.
At the end of the experimental period, the incidence of diabetes is significantly reduced in linagliptin-treated mice (9 out of 30 mice) compared to the control group (18 out of 30 mice; p = 0.021). Subsequent serologic evaluation of beta cell mass (identified by insulin immunoreactivity) indicated significantly higher beta cell mass (vehicle 0.18 ± 0.03 mg; linagliptin 0.48 ± 0.09 mg, p <0.01) in linagliptin-treated mice. The total islet amount (excipient 0.40 ± 0.04 mg; linagliptin 0.70 ± 0.09 mg, p <0.01) is shown. Linagliptin has a propensity for peri-islet infiltrating lymphopenia (1.06 ± 0.15; linagliptin 0.79 ± 0.12 mg; p = 0.17). As expected, active plasma GLP-1 is high in linagliptin-treated mice.
In summary, the data indicate that linagliptin can delay the onset of diabetes in a type 1 diabetes model (NOD mice). The strong beta cell comforting effects observed in this animal model indicate that such DPP-4 inhibitors not only protect beta cells by increasing active GLP-1 levels, but also have direct or indirect anti-inflammatory effects. Can be shown. These effects may support the use of linagliptin in the treatment and / or prevention of type 1 diabetes or latent autoimmune diabetes in adults (LADA). Linagliptin may provide a novel therapeutic approach for patients with type 1 diabetes or LADA or those at risk for the above.

Effects of linagliptin on body weight, total fat, liver fat and muscle cell fat :
In yet another experiment, the effects of long-term treatment with linagliptin on body weight, total fat, muscle cell fat, and hepatic fat in a non-diabetic model of diet-induced obesity (DIO) are probed compared to anorectic subtramin.
Rats are fed a high-fat diet for 3 months and continue on a high-fat diet while receiving vehicle, linagliptin (10 mg / kg) or sibutramine (5 mg / kg) for another 6 weeks. Magnetic resonance spectroscopy (MRS) analysis of total fat, muscle fat and liver fat is performed before treatment and at the end of the experiment.
Sibutramine causes a significant weight loss (-12%) compared to controls, whereas linagliptin has no significant effect. Whole fat is also significantly reduced by sibutramine (-12%), but animals treated with linagliptin show no significant reduction (-5%). However, linagliptin and sibutramine result in a strong reduction in muscle cell fat (-24% and -34%, respectively). Furthermore, linagliptin treatment results in a severe decrease in hepatic fat (-39%), whereas the effect of sibutramine (-30%) is not significant (see table below). Thus, linagliptin improves muscle intracellular lipids and hepatic lipid accumulation, albeit unclear with respect to weight. Alleviation of hepatic steatosis, inflammation and fibrosis as measured by histological scoring is also observed with linagliptin treatment.

Table: Effect of linagliptin on body weight, total fat, liver fat and muscle cell fat
In conclusion, linagliptin treatment causes a strong decrease in intramuscular and hepatic lipids, both of which are distinct from weight loss. Linagliptin treatment offers additional benefits to diabetic patients who are still affected by hepatic steatosis (eg, NAFLD). The effect of sibutramine on muscle and liver fat is mainly due to the known weight loss induced by this compound.

Linagliptin has similar efficacy to glimepiride, but improves cardiovascular safety over 2 years in patients with type 2 diabetes poorly managed with metformin :
A two-year double-blind study scrutinizes the long-term efficacy and safety of adding linagliptin or glimepiride to metformin in use for the treatment of type 2 diabetes. T2DM patients with stable metformin (1500 mg / day) or more for 10 weeks or more are randomized for 2 years of linagliptin (5 mg / day, N = 764) or glimepiride (1-4 mg / day, N = 755) . The analysis of efficacy is based on the change from baseline in HbA1c in the Complete Analysis Set (FAS) population and each Protocol (PP) population. Safety assessment involves the capture of pre-specified, predictive, and further awarded cardiovascular (CV) events (CV death, nonfatal myocardial infarction or stroke, unstable angina with hospitalization) included. Baseline characteristics are well balanced in the two groups (HbA1c 7.7% for both groups). In the PP population, the adjusted mean (± SE) HbA1c change from baseline was -0.4% (± 0.04%) for linagliptin (5 mg / day) versus -0.5% (± 0.4%) for glimepiride (mean dose 3 mg / day). 0.04%). The average difference between groups is 0.17% (95% CI, 0.08-0.27%; p = 0.0001 for non-inferiority). Similar results are observed in the FAS population. Much less patients will use investigator-defined hypoglycemia when using linagliptin than glimepiride (7.5% vs 36.1%; p <0.0001). Body weight decreases with linagliptin and increases with glimepiride (-1.4 kg vs. +1.3 kg; adjusted mean difference, -2.7 kg; p <0.0001). CV events occurred in 13 linagliptin patients (1.7%) versus 26 glimepiride patients (3.4%), indicating a significant 50% reduction in the relative risk for the combined CV endpoint (RR, 0.50; 95% CI, 0.26-0.96; p = 0.04). In conclusion, when added to metformin monotherapy, linagliptin provides a similar HbA1c reduction as glimepiride, but linagliptin has low blood sugar, low relative weight loss, and a significant number of CV events for which arbitration was performed Few.

Cardiovascular Risk from Linagliptin in Patients with Type 2 Diabetes: Pre-specified Predictive and Further Rulings Based on a Phase III Broad Program :
The benefits of the cardiovascular system (CV) in lowering glucose in type 2 diabetes mellitus (T2DM) are currently controversial, especially if the blood glucose reduction is too severe. Some drug use has been reported to have unexpectedly worse CV results.
Linagliptin is the first once-a-day DPP-4 inhibitor that can be used as a single dose without the need for dose adjustments to reduce renal function. Linagliptin achieves glycemic control without the potential for weight gain or hypoglycemic risk (which can be a benefit of CV).
In order to review the CV profile of the DPP-4 inhibitor linagliptin, a pre-designated post-analysis is performed on all CV events from eight Phase III randomized double-blind control trials (≥12 weeks). CV events are proactively ruled by an unrelated expert panel that has not been given prior information. The primary endpoint of this analysis is the composite of CV death, nonfatal stroke, nonfatal myocardial infarction (MI) and hospitalization for unstable angina (UAP). Other secondary and tertiary endpoints, including FDA customary major CV event side effects (MACE), will also be evaluated.
Of the 5239 patients included (average baseline for HbA _1c 8.0%), 3319 received linagliptin once daily (5 mg: 3159, 10 mg: 160), and 1920 compared with a comparator (placebo 997, glimepiride: 781, voglibose: 162). Cumulative exposure (years per person) is 2060 for linagliptin and 1372 for comparison. As a result, the primary CV events for which arbitration was performed occur in 11 (0.3%) patients receiving linagliptin and 23 (1.2%) receiving comparators. The hazard ratio for the primary endpoint is significantly lower for linagliptin relative to the comparator, and the hazard ratio for the comparator for all other endpoints is similar or significantly lower for linagliptin (TABLE).
This is the first pre-specified, predictive, separately arbitrated post-CV analysis of DPP-4 inhibitors in an extensive Phase III program. Although post-analysis with obvious limitations, this data supports a reduction in potential CV events for linagliptin.

TABLE:
* Significantly lower hazard ratio (upper limit 95% CI <1.0; p <0.05)

Treatment of patients with type 2 diabetes mellitus at high cardiovascular risk :
The long-term effects of linagliptin treatment on cardiovascular morbidity and mortality and related efficacy parameters in a related population of type 2 diabetes mellitus are reviewed as follows:
Poor glycemic control (naive to treatment or currently treated with metformin and / or an alpha-glucosidase inhibitor (single or dual therapy) (eg, 6.5-8.5% HbA1c) or In the presence or absence of metformin or an alpha-glucosidase inhibitor, eg, with sulfonylurea or glinide (single or dual therapy) (eg, 7.5-8.5% HbA1c) and high cardiovascular system A type 2 diabetic patient having an event risk (e.g. as defined in one or more of the following risk factors A), B), C) and D) is treated with linagliptin (possibly one or more other active substances ( For a period of time (e.g., 2 years or more, 4-5 years or 1-6 years), as well as other anti-diabetic drugs (e.g. Lurea (eg, glimepiride) or placebo. Evidence of successful treatment compared to other anti-diabetic or placebo-treated patients is evidenced by the low number of single or multiple complications (complications include, for example, cardiovascular or cerebrovascular Sexual events such as cardiovascular death, myocardial infarction, stroke or hospitalization (eg, acute coronary syndrome, leg amputation, hospitalization for emergency revascularization or unstable angina)), or preferably The longer the time required for the first appearance of such complications (e.g. the following components of the primary composite endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and unstable angina) Hospitalization due to illness) can be known by prolonging the time of the first appearance).
Yet another therapeutic success is that a greater proportion of patients receiving study treatment have no need for emergency medical care at the end of the study and no weight gain (eg,> 2%) and glycemic control (eg, HbA1c <7%) ) Is maintained. Yet another therapeutic success is that a greater proportion of patients receiving study treatment have no need for emergency care at the end of the study and have no moderate / severe hypoglycemic episodes and gain weight (eg,> 2%) It can be known from the fact that blood sugar control (for example, HbA1c is 7% or less) is maintained without any problem.
Yet another therapeutic success can be seen in the CV excellence of treatment with linagliptin, which shows a reduced risk (eg, preferably a 20% risk reduction) compared to treatment with glimepiride.
Risk factors for cardiovascular events A), B), C) and D) are as follows:
A) Previous vascular disease (eg age 40-85):
-Myocardial infarction (eg 6 weeks or more),
Coronary artery disease (e.g., stenosis of the left main coronary artery or at least two major coronary arteries in the angiogram of more than 50% of the lumen diameter),
-Percutaneous coronary intervention (eg for more than 6 weeks),
-Coronary artery bypass grafting (eg showing recurrent angina after 4 years or after surgery),
-Ischemic or hemorrhagic stroke (eg 3 months or more),
-Peripheral occlusive artery disease (eg previous limb bypass surgery or percutaneous transluminal angioplasty; previous limb or leg amputation due to circulatory failure; major limb artery (total limb artery detected by angiography or ultrasound) Significant vascular stenosis (> 50% stenosis) of the iliac artery, internal iliac artery, external iliac artery, femoral artery, popliteal artery), history of intermittent claudication (for tarsal joints); at least one side Arm's blood pressure ratio is less than 0.90),
B) Vascular-related end organ diseases (eg ages 40-85):
- renal dysfunction (eGFRF30-59mL / min 1.73 m ² with renal dysfunction eg moderate defined by MDRD prescription),
Microalbumin or macroalbuminuria (eg microalbuminuria or random spot urinary albumin: creatine ratio of 30 μg / mg or more),
-Retinopathy (eg proliferative retinopathy, or retinal neovascularization or previous retinal laser coagulation),
C) Elderly (for example, 70 years or older):
D) At least two of the following cardiovascular risk factors (eg ages 40-85):
Advanced type 2 diabetes mellitus (eg for a period of more than 10 years),
Hypertension (eg systolic blood pressure> 140 mmHg or at least one blood pressure lowering treatment),
-At this moment daily smoking,
Treatment of (atherogenic) dyslipidemia or elevated blood levels of LDL cholesterol (eg LDL cholesterol of 135 mg / dL or more) or at least one dyslipidemia;
- (visceral and / or abdominal) obesity (for example body volume index 45 kg / m ² or more),
-Ages between 40 and 80.

  Cognitive function (eg, cognitive decline, changes in psychomotor speed, psychological stability), β-cell function (eg, insulin secretion rate for 3 h meal tolerance test, long-term β-cell function), renal function parameters, circadian glucose pattern (eg, behavior Glucose profile, glycemic variability, oxidation, inflammatory and endothelial function biomarkers, cognition, and CV prevalence / mortality), asymptomatic MI (eg, ECG parameters, CV prophylactic properties), LADA (eg, The beneficial effects (eg, improvement) of linagliptin treatment on the use or progression of disease in LADA) and / or the persistence of glucose management in β-cell autoantibody status (eg, GAD) will be probed in tributary studies.

Claims (31)

  A method for treating and / or preventing oxidative stress, vascular stress and / or endothelial dysfunction, comprising the step of administering linagliptin to a patient in need thereof.   2. The method of claim 1, wherein the patient is a non-diabetic patient or a diabetic selected from, for example, type 1 diabetes, adult latent autoimmune diabetes (LADA) and type 2 diabetes.   The method according to claim 1, for treating and / or preventing endothelial dysfunction in a type 2 diabetic patient. A method for using linagliptin, comprising:
-E.g. type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, post-absorption hyperglycemia, latent autoimmunity in adults Diabetes (LADA), overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease ( NAFLD), retinopathy, neuropathy, nephropathy, polycystic ovary syndrome, and / or a method of preventing, delaying, prolonging or treating the metabolic disorder or disease selected from metabolic syndrome;
-Methods for improving and / or maintaining glycemic control and / or for reducing fasting plasma glucose, postprandial plasma glucose, post-absorption plasma glucose and / or glycosylated hemoglobin HbA1c;
-Prevent, slow, prolong or slow progression from prediabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance, and / or metabolic syndrome to type 2 diabetes mellitus. How to reverse;
Complications of diabetes mellitus, for example microvascular or macrovascular diseases, including nephropathy, microalbumin or macroalbuminuria, proteinuria, retinopathy, cataract, neuropathy, impaired learning or memory, neurodegenerative or Cognitive abnormalities, cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot or diabetic ulcer, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, Prevent, reduce, reduce the risk of, slow or prolong the risk of stable angina, peripheral arterial occlusive disease, cardiomyopathy, heart failure, cardiac rhythm abnormalities, vascular restenosis, and / or stroke. Or a method of treating;
-A method of reducing body weight and / or body fat or preventing an increase in body weight and / or body fat, or promoting body weight and / or body fat reduction;
-For preventing, slowing down or treating pancreatic beta cell degeneration and / or loss of pancreatic beta cell functionality, and / or for improving, retaining and / or restoring pancreatic beta cell functionality. And / or a method of stimulating and / or restoring or protecting the function of pancreatic insulin secretion;
-A method for preventing, slowing down, prolonging or treating non-alcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH) and / or hepatic fibrosis;
-Methods of preventing, delaying, prolonging or treating type 2 diabetes in which normal anti-diabetic alone or in combination therapy has failed;
-How to achieve the required dose reduction of the usual antidiabetic drugs required for an adequate therapeutic effect;
-Methods to reduce the risk of side effects associated with conventional anti-diabetic drugs; and / or-methods to maintain and / or improve insulin sensitivity, and / or to treat or prevent hyperinsulinemia and / or insulin resistance. the method of;
In one or more of
In patients having or at risk for oxidative stress, vascular stress and / or endothelial dysfunction, or diseases or conditions associated with or associated therewith, or for example myocardial infarction, stroke, peripheral arterial occlusive disease, diabetes In patients with or at risk for cardiovascular and / or renal disease selected from nephropathy, microalbumin or macroalbuminuria, and acute or chronic renal impairment, or A), B) Using linagliptin in a patient with one or more cardiovascular risk factors selected from C) and D),
A method for using said linagliptin, comprising: administering to the patient a therapeutically effective amount of linagliptin, optionally together with one or more other therapeutic agents:
A) Previous or existing pulses selected from, for example, myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass grafting, ischemic or hemorrhagic stroke, congestive heart failure, and peripheral occlusive artery disease Vascular disease;
B) a vascular-related end-organ disease selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease and microalbumin or macroalbuminuria;
C) Elderly (eg, over 60-70); and
D) One or more cardiovascular risk factors selected from:
Advanced type 2 diabetes mellitus (eg for a period of more than 10 years),
-Hypertension,
-At this moment daily smoking,
-Dyslipidemia,
-Obesity,
-Ages from 40 to 80,
-A metabolic syndrome, hyperinsulinemia or insulin resistance, and-a family history of hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or cardiomyopathy in first degree.   5. The method of claim 4, comprising treating type 2 diabetes mellitus.   Cardiovascular system wherein the patient is selected from, for example, myocardial infarction, stroke, peripheral arterial occlusive disease, diabetic nephropathy, microalbumin or macroalbuminuria, acute or chronic renal impairment, hyperuricemia, and / or hypertension The method according to at least one of claims 1 to 5, which is a type 2 diabetic patient having or at risk for a disease and / or renal disease. 7. The at least one of claims 1 to 6, wherein the patient is a type 2 diabetic patient having one or more of the following cardiovascular risk factors selected from A), B), C) and D). Method:
A) Previous or existing pulses selected from, for example, myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass grafting, ischemic or hemorrhagic stroke, congestive heart failure, and peripheral occlusive artery disease Vascular disease;
B) a vascular-related end-organ disease selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease, and microalbumin or macroalbuminuria;
C) Elderly (eg, over 60-70); and
D) One or more cardiovascular risk factors selected from:
Advanced type 2 diabetes mellitus (eg for a period of more than 10 years),
-Hypertension,
-At this moment daily smoking,
-Dyslipidemia,
-Obesity,
-Ages from 40 to 80,
-A metabolic syndrome, hyperinsulinemia or insulin resistance, and-a family history of hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or cardiomyopathy in first degree.   Cardiovascular or cerebrovascular events selected from cardiovascular death, myocardial infarction, stroke and hospitalization (eg, due to acute coronary syndrome, leg amputation, revascularization, heart failure or unstable angina) A method of preventing the occurrence, preferably of reducing the risk of, or prolonging the occurrence, preferably in a type 2 diabetic patient, wherein said method optionally comprises administering to one or more other therapeutically effective amounts of linagliptin. Administering said therapeutic agent to a patient in need thereof. 9. The type 2 diabetic patient is at risk for a cardiovascular or cerebrovascular event, with one or more of the following risk factors selected from A), B), C) and D). The method described in:
A) Previous or existing vessels selected from myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass grafting, ischemic or hemorrhagic stroke, congestive heart failure, and peripheral occlusive artery disease Systemic disease;
B) a vascular-related end-organ disease selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease, and microalbumin or macroalbuminuria;
C) Elderly (eg, over 60-70); and
D) One or more cardiovascular risk factors selected from:
Advanced type 2 diabetes mellitus (eg for a period of more than 10 years),
-Hypertension,
-At this moment daily smoking,
-Dyslipidemia,
-Obesity,
-Ages from 40 to 80,
-A metabolic syndrome, hyperinsulinemia or insulin resistance, and-a family history of hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or cardiomyopathy in first degree.   10. The type 2 diabetes patient according to claim 8 or 9, wherein the patient has a vascular-related end-organ disease selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease, and microalbumin or macroalbuminuria. the method of.   The occurrence of cardiovascular or cerebrovascular events selected from cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and hospitalization for unstable angina, cardiovascular or cerebrovascular events A method of preventing, reducing the risk of, or prolonging the appearance of, a type 2 diabetic patient at risk of having a therapeutically effective amount of linagliptin, optionally with one or more other therapeutic agents. The above method, comprising the step of administering to the patient.   12. The method according to at least one of claims 8 to 11, wherein the type 2 diabetic patient has nephropathy, renal dysfunction, chronic kidney disease, and / or microalbumin or macroalbuminuria.   13. The method according to at least one of claims 8 to 12, wherein the type 2 diabetic patient has mild, moderate or severe renal impairment or end stage renal disease.   14. The method according to at least one of claims 8 to 13, wherein the type 2 diabetic patient has microalbuminuria or diabetic nephropathy.   One or more other therapeutic substances may be other anti-diabetic substances, active substances that lower blood glucose levels, active substances that lower blood lipid levels, active substances that raise blood HDL levels, active substances that lower blood pressure 15. The method according to at least one of claims 4 to 14, wherein the method is selected from active substances indicated in the treatment of atherosclerosis or obesity, antiplatelet agents, anticoagulants and vascular endothelial protective agents.   The other antidiabetic agent is selected from metformin, sulfonylurea, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonist, alpha-glucosidase inhibitor, insulin and insulin analogs, and GLP-1 and GLP-1 analogs. 15. The method according to 15.   17. The method according to claim 15 or 16, wherein the blood pressure lowering active substance is selected from an angiotensin receptor blocker (ARB), an angiotensin converting enzyme (ACE) inhibitor, and a beta-blocker.   18. The method according to claim 17, wherein the angiotensin receptor blocker (ARB) is telmisartan, and / or the angiotensin converting enzyme (ACE) inhibitor is ramipril, and / or the beta-blocker is carvedilol, nebiball or metoprolol.   16. The active substance that lowers blood lipid levels and / or increases blood HDL levels is selected from statins, nicotinic acid or derivatives thereof, fibrates, cholesterol absorption inhibitors, and bile acid sequestrants. 20. The method of at least one of claims 1 to 18.   The statin is atorvastatin, simvastatin or rosuvastatin, and / or the nicotinic acid or derivative thereof is niacin, and / or the fibrate is fenofibrate, and / or the cholesterol absorption inhibitor is ezetimibe, and / or 20. The method of claim 19, wherein the bile acid sequestering agent is colesevelam.   21. The method according to at least one of claims 15 to 20, wherein the antiplatelet agent is selected from low dose aspirin, clopidogrel, prasugrel, bolapaxer and ticagreler.   22. The method according to at least one of claims 15 to 21, wherein the anticoagulant is selected from heparin, warfarin, dabigatran, rivaroxaban and apixaban.   In addition, linagliptin is selected from metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonists, alpha-glucosidase inhibitors, insulin or insulin analogs, and one or more other GLP-1 or GLP-1 analogs. 23. The method of at least one of claims 1 to 22, comprising administering together with an antidiabetic agent, and optionally telmisartan.   24. The method of at least one of claims 1 to 23, further comprising the step of administering linagliptin together with metformin.   24. The method of at least one of claims 1 to 23, further comprising administering linagliptin together with telmisartan.   24. The method of at least one of claims 1 to 23, comprising administering a pharmaceutical composition comprising linagliptin and metformin.   27. The method of at least one of claims 1 to 26, wherein linagliptin is administered orally in a total of 5 mg daily. Especially in patients who need it separately or beyond the control of blood glucose, such as those with type 1 diabetes, LADA or especially type 2 diabetes,
-Treating, preventing, reducing the risk, delaying its progress, prolonging, weakening or reversing its ischemia / reperfusion injury (of the kidney, heart, brain or liver) and / or ( Reduce myocardial infarct size of the heart (e.g. after myocardial ischemia / reperfusion); or-may be characterized by cardiomyocyte hypertrophy, interstitial fibrosis, ventricular dilation, asystole and / or cell death / apoptosis, Treat and prevent (harmful) vascular remodeling, for example cardiac remodeling (especially after myocardial infarction), reduce its risk, slow its progression, prolong its onset, weaken or reverse it -Treating or preventing chronic or acute renal failure and / or peripheral arterial occlusion, reducing its risk, delaying its progression, prolonging its onset, weakening or reversing; or-congestive heart Treating (eg, NYHA class I, II, III or IV) and / or cardiac hypertrophy (eg, left ventricular hypertrophy) and / or nephropathy and / or albuminuria, reducing their risk, and progressing Delays, prolongs, weakens, or reverses its onset; or-in uremic cardiomyopathy, gap dilation, and / or (cardiac) fibrosis (especially chronic kidney and heart disease often associated with type 2 diabetes) Treating, preventing, reducing the risk, delaying its progress, prolonging, attenuating, or reversing its onset, wherein said method comprises an effective amount of a certain DPP Administering to the patient, optionally together with an effective amount of one or more other active agents, wherein the DPP-4 inhibitor is linagliptin.   Preventing diabetic nephropathy in patients (eg, patients with type 2 diabetes) that do not respond appropriately to treatment with an angiotensin receptor blocker (ARB, eg, telmisartan), reducing its risk, slowing its progression, prolonging its onset, A method of weakening, reversing or treating a subject, comprising administering to a patient a therapeutically effective amount of a DPP-4 inhibitor, optionally together with one or more other therapeutic agents (eg, ARB, eg, telmisartan). The above method, wherein the DPP-4 inhibitor is linagliptin.   A method of using linagliptin with telmisartan to treat diabetic nephropathy, including albuminuria, in patients who do not respond appropriately to angiotensin receptor blocker (ARB).   A DPP-4 inhibitor for use in a method of treatment substantially as described herein, wherein said method is linagliptin, wherein said method is any of the methods described herein, e.g., treating or preventing the examples thereof. The DPP-4 inhibitor, which comprises the method of claim 1.