JP7227107B2 - Angioprotective and Cardioprotective Antidiabetic Therapy - Google Patents

Description

The present invention provides certain DPP-4 inhibitors that treat and/or prevent oxidative stress, vascular stress and/or endothelial dysfunction and diabetic or non-diabetic patients (with cardiovascular and/or renal disease). The use of such DPP-4 inhibitors in the treatment and/or prophylaxis of patients, including at-risk patient groups.

The present invention provides certain DPP-4 inhibitors that treat and/or prevent oxidative stress, vascular stress and/or endothelial dysfunction and diabetic or non-diabetic patients (with cardiovascular and/or renal disease). Methods for the treatment and/or prophylaxis of patients, including at-risk patient groups, pharmaceutical compositions, and methods of using DPP-4 inhibitors for the preparation of such pharmaceutical compositions.

The present invention provides certain DPP-4 inhibitors that treat and/or prevent oxidative stress, vascular stress and/or endothelial dysfunction and diabetic or non-diabetic patients (with cardiovascular and/or renal disease). The use of such DPP-4 inhibitors in the treatment and/or prophylaxis of patients, including 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 present invention also relates to certain DPP-4 inhibitors used as antioxidants and/or anti-inflammatory agents.
The present invention furthermore treats and/or prevents oxidative stress, vascular stress and/or endothelial dysfunction (e.g. in diabetic or non-diabetic patients), particularly separately or beyond glycemic control. of certain DPP-4 inhibitors for
The present invention further provides certain DPP-4 inhibitors for treating and/or preventing oxidative stress (e.g. beyond control of blood sugar) induced by or associated with hyperglycemia. In addition to the use of such DPP-4 inhibitors in antidiabetic therapy.
The present invention furthermore provides metabolic diseases (e.g. diabetes, especially type 2 diabetes mellitus) and/or diseases associated therewith (e.g. diabetic complications), in particular oxidative stress, vascular stress and/or endothelial dysfunction, or Certain DPP-4 inhibitors for the treatment and/or prophylaxis of patients having or at risk of having a disease or condition associated with or associated with .

The present invention furthermore provides metabolic diseases (e.g. diabetes, especially type 2 diabetes mellitus) and/or diseases associated therewith (e.g. diabetic complications), cardiovascular diseases and/or renal diseases such as myocardial infarction, Certain DPPs to treat and/or prevent in patients with or at risk of stroke or peripheral arterial occlusive disease and/or diabetic nephropathy, microalbumin or macroalbuminuria, or acute or chronic renal impairment -4 inhibitors.
The present invention furthermore provides metabolic diseases (e.g. diabetes, in particular type 2 diabetes mellitus) and/or diseases associated therewith, in microvascular or macrovascular diabetic complications such as diabetic retinopathy, diabetic neuropathy, diabetes mellitus. certain DPP-4 inhibitions to treat and/or prevent patients with or at risk of having or having cardiovascular or cerebrovascular disease (e.g., myocardial infarction, stroke, or peripheral arterial occlusive disease) or nephropathy Regarding agents.
The present invention further relates to certain DPP-4 inhibitors that modulate, block or alleviate the adverse metabolic memory effects of hyperglycemia (chronic or transient episodes), particularly for diabetic complications.
The present invention further provides certain DPP-4 compounds for treating, preventing or reducing the risk of microvascular or macrovascular disease that may be induced, remembered or associated with exposure to oxidative stress. Regarding inhibitors.

The present invention furthermore provides metabolic diseases (e.g. diabetes, especially type 2 diabetes mellitus) and/or diseases associated therewith (e.g. diabetic complications) having or having cardiovascular disease and/or renal disease. At-risk patients, particularly those with type 2 diabetes who are 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 to treat and/or prevent in patients with type 2 diabetes mellitus, the method comprises administering a therapeutically effective amount of a DPP-4 inhibitor, optionally with one or more other therapeutic agents. administering to said patient together:
A) previous or existing vascular disease (e.g. myocardial infarction (e.g. asymptomatic or symptomatic), coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure ( e.g. NYHA class I or II e.g. left ventricular function <40%) or peripheral occlusive arterial disease);
B) vascular-related end-organ diseases (e.g. nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease and/or microalbumin or macroalbuminuria);
C) old age (eg, age 60-70); and
D) One or more cardiovascular risk factors selected from:
- advanced type 2 diabetes mellitus (eg for more than 10 years),
- hypertension (eg >130/80 mmHg, or systolic blood pressure >140 mmHg, or at least one antihypertensive therapy),
- current daily smoking,
- Dyslipidemia (atherogenic dyslipidemia, postprandial lipidemia, or high LDL cholesterol (e.g., LDL cholesterol ≥ 130 - 135 mg/dL), low HDL cholesterol (e.g., <35-40 mg/dL 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 dyslipidemia),
- obesity (e.g. abdominal and/or visceral obesity or body mass index ≥ 45 kg/ ^m2 ),
- aged 40 or over but under 80,
- metabolic syndrome, hyperinsulinemia or insulin resistance, and - hyperuricemia, erectile dysfunction, polycystic ovarian syndrome, sleep apnea, or a family history of vascular disease or cardiomyopathy in the first degree.

Furthermore, the present invention also includes cardiovascular or cerebrovascular events (e.g. cardiovascular death, (fatal or non-fatal) myocardial infarction (e.g. asymptomatic or symptomatic MI), (fatal or non-fatal) fatal) stroke, or hospitalization (e.g. for acute coronary syndrome, leg amputation, (emergency) revascularization, heart failure, or for unstable angina)), preferably in patients with type 2 diabetes Type 2 diabetes mellitus, particularly those with type 2 diabetes at risk for cardiovascular or cerebrovascular events, e.g. with one or more risk factors selected from A), B), C) and D) below With respect to certain DPP-4 inhibitors for use in methods to prevent, reduce the risk of their development, or delay their development in a patient, said methods optionally comprise a therapeutically effective amount of a DPP-4 inhibitor. administering to said patient together with one or more other therapeutic agents by:
A) previous or existing vascular disease (e.g. myocardial infarction (e.g. asymptomatic or symptomatic), coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure ( e.g. NYHA class I or II, e.g. left ventricular function <40%) or peripheral occlusive arterial disease);
B) vascular-related end-organ diseases (e.g. nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease and/or microalbumin or macroalbuminuria);
C) old age (eg, age 60-70); and
D) One or more cardiovascular risk factors selected from:
- advanced type 2 diabetes mellitus (eg for more than 10 years),
- hypertension (eg >130/80 mmHg, or systolic blood pressure >140 mmHg, or at least one antihypertensive therapy),
- current daily smoking,
- Dyslipidemia (atherogenic dyslipidemia, postprandial lipidemia, or high LDL cholesterol (e.g., LDL cholesterol ≥ 130 - 135 mg/dL), low HDL cholesterol (e.g., <35-40 mg/dL 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 dyslipidemia).
- obesity (e.g. abdominal and/or visceral obesity or body mass index ≥ 45 kg/ ^m2 ),
- aged 40 or over but under 80,
- metabolic syndrome, hyperinsulinemia or insulin resistance, and - hyperuricemia, erectile dysfunction, polycystic ovarian syndrome, sleep apnea, or a family history of vascular disease or cardiomyopathy in the first degree.

Furthermore, the present invention also includes cardiovascular or cerebrovascular events (e.g. cardiovascular death, (fatal or non-fatal) myocardial infarction (e.g. asymptomatic or symptomatic MI), (fatal or non-fatal) fatal) stroke, or hospitalization (e.g. for acute coronary syndrome, leg amputation, (emergency) revascularization, heart failure, or for unstable angina)), vascular-associated end-organ disease, Certain DPPs used in methods of prophylaxis, reducing the risk of their development, or delaying their development, especially in patients with type 2 diabetes who have nephropathy, renal dysfunction, chronic renal 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 together with one or more other therapeutic agents.
Furthermore, the present invention is directed to improving cognitive function (e.g. attenuating, reversing or treating cognitive decline), improving beta-cell function (e.g. improving insulin secretion rate from 3h diet tolerance, improving long-term beta-cell function). improve circadian glucose patterns (e.g. improve behavioral glucose profile, glycemic variability, oxidative, inflammatory or endothelial function biomarkers), and/or sustained improvement in glucose control due to beta-cell autoantibody status. For certain DPP-4 inhibitors used in the method (e.g., for glutamic acid decarboxylase (GAD)), the method comprises adding a therapeutically effective amount of the DPP-4 inhibitor to optionally one or more administering to said patient along with other therapeutic agents.
Furthermore, the present invention provides certain DPP-DPPs for use in methods of preventing, reducing the risk of, slowing the progression of, delaying the onset of, attenuating, reversing or treating cognitive dysfunction or decline. With respect to DPP-4 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 finds use in methods of preventing, reducing the risk of, slowing progression of, delaying onset of, attenuating, reversing or treating adult latent autoimmune diabetes (LADA). With respect to DPP-4 inhibitors of the species, 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 prevents, reduces the risk of, delays the progression of, delays the onset of, attenuates the cardiovascular or cerebrovascular diseases or events (such as those described herein), reversing or treating and also preventing, reducing the risk of, slowing the progression of, and initiating diabetic nephropathy in patients in need thereof (e.g., patients described herein, particularly patients with type 2 diabetes) of certain DPP-4 inhibitors for use in methods of prolonging, attenuating, reversing or treating administering to said patient with a therapeutic substance.

Furthermore, the present invention also provides one or more of the following methods, wherein an effective amount of certain DPP-4 inhibitors, optionally together with an effective amount of one or more other active agents, is administered to a patient: Regarding methods involving:
- a method of treating, alleviating, preventing and/or protecting against oxidative stress, such as non-diabetic or diabetic (hyperglycemia)-induced or non-diabetic or diabetes-associated oxidative stress;
- methods of treating, preventing, reducing the risk of, slowing the progression of, delaying the onset of, attenuating, reversing endothelial dysfunction or improving endothelial function;
- methods of treating, preventing, reducing the risk of, slowing progression of, delaying onset of, attenuating or reversing diseases or conditions associated with oxidative stress (such as those described herein);
- treat, prevent, reduce the risk of, delay the progression of, delay the onset of, attenuate or reverse ischemia/reperfusion injury (of the kidney, heart, brain or liver) and/or ( methods of reducing myocardial infarct size in the heart (after myocardial infarction/reperfusion);
- (detrimental) vascular remodeling, such as remodeling of the heart (especially remodeling after myocardial infarction, characterized by cardiomyocyte hypertrophy, interstitial fibrosis, ventricular dilatation, contractile dysfunction and/or cell death/apoptosis) methods of treating, preventing, reducing the risk of, slowing the progression of, delaying onset of, attenuating or reversing the onset of
- methods of treating, preventing, reducing the risk of, slowing the progression of, delaying the onset of, attenuating or reversing chronic or acute renal failure and/or peripheral arterial occlusion;
- treat, prevent or reduce the risk of congestive heart failure (e.g. NYHA class I, II, III or IV) and/or cardiac hypertrophy (e.g. left ventricular hypertrophy) and/or nephropathy and/or albuminuria , methods of slowing its progress, prolonging its onset, weakening or reversing it;
- treat, prevent and reduce the risk of uremic cardiomyopathy, space dilation and/or (cardiac) fibrosis, especially in patients with chronic kidney disease and heart disease often associated with type 2 diabetes methods of alleviating, slowing its progression, prolonging its onset, attenuating or reversing it;
- 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 of preventing or protecting against oxidation and/or atherosclerotic plaque formation of atherogenic or proatherogenic low-density lipoproteins (particularly small and dense LDL particles);
- a method of preventing or protecting against oxidative stress-induced impairment of pancreatic beta-cell function or viability;
- A method of treating, preventing, alleviating or ameliorating pancreatic islet inflammation or islet lipotoxicity and glycotoxicity, or increasing the beta-cell/alpha-cell ratio, protecting beta-cells, or normalizing pancreatic islet morphology or function. and/or - complications of diabetes mellitus, such as micro- and macrovascular diseases such as nephropathy, microalbumin or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory. Disorders, neurodegenerative or cognitive abnormalities, cardiovascular or cerebrovascular disease, 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, for example, uremic cardiomyopathy), heart failure, cardiac rhythm abnormalities, vascular restenosis, and/or stroke, especially blood sugar To prevent, reduce the risk of, slow the progression of, or initiate its initiation in patients in need thereof (e.g. type 1 diabetes, LADA or especially type 2 diabetes), separately from control or beyond control of blood glucose. A method of stretching, weakening, reversing or treating.

Furthermore, the present invention prevents diabetic nephropathy in patients (e.g., patients described herein, particularly type 2 diabetics) who do not respond adequately to treatment regimens with angiotensin receptor blockers (ARBs, e.g., telmisartan). , to reduce the risk of, delay the progression of, delay the onset of, attenuate, reverse or treat, the method comprising a therapeutically effective amount of administering to said patient a DPP-4 inhibitor optionally together with one or more other therapeutic agents (eg ARBs such as 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 function (e.g. glomerular filtration rate (GFR) progressive impairment or decline, eventually leading to renal failure or end-stage renal disease. Still other features may include diffuse or nodular glomerulosclerosis, afferent and efferent hyaline-like arteriosclerosis, and/or interluminal fibrosis and atrophy. Still other features may include abnormal albumin/creatinine or protein/creatinine ratios and/or abnormal glomerular filtration rate.

The present invention further relates to certain DPP-4 inhibitors for use in methods of preventing or treating diabetic nephropathy in patients who show an inadequate response to treatment regimens with angiotensin receptor blockers (ARBs such as telmisartan). . The method comprises administering to the patient a therapeutically effective amount of a DPP-4 inhibitor and telmisartan.
Accordingly, in a specific embodiment, a preferred DPP-4 inhibitor within the contemplation of the present invention is linagliptin.
Also contemplated are pharmaceutical compositions or combinations comprising a DPP-4 inhibitor as defined herein, optionally together with one or more other active agents, for use in these methods of treatment.
Furthermore, the present invention also provides a therapeutic agent, optionally in combination with one, two or more additional active agents (each of which is defined herein), for use in the therapeutic methods defined herein. related to DPP-4 inhibitors.
Furthermore, the present invention also provides a therapeutic agent, optionally in combination with one, two or more additional active agents (each of which is defined herein), for use in the therapeutic methods defined herein. and the use 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 invention.
Furthermore, the present invention relates to therapeutic (therapeutic and prophylactic) methods as described herein, said methods comprising an effective amount of a DPP-4 inhibitor as described herein and optionally 1 as described herein. This includes administering one or more other active or therapeutic agents to the patient in need thereof.

Effect of linagliptin on zymosan A (ZymA)-induced ROS in human PMNs (LPS = lipopolysaccharide, PMN = polymorphonuclear neutrophils, Bl1356 = linagliptin, Nebi = nebivolol). Effect of linagliptin on human leukocyte (PMN) adhesion to human endothelial cells following LPS stimulation (Turks and CF-DA staining, BL1356=linagliptin). Effect of linagliptin on LPS (50 μg/mL)-induced adhesion of neutrophils to EA.hy cells (measured by amplex red oxidation). Shows the effect of gliptin on the oxidative burst of isolated human neutrophils upon LPS or zymosan A stimulation, as measured by luminol/horseradish peroxidase (HRP)-enhanced chemiluminescence (LPS = lipopolysaccharide, PMN = polymorphonuclear Neutrophils, LG = B11356 = 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 LPS or zymosan A stimulation, as measured by luminol/horseradish peroxidase (HRP)-enhanced chemiluminescence (LPS = lipopolysaccharide, PMN = polysaccharide). morphonuclear neutrophils, LG = B11356 = linagliptin, AG = alogliptin, VG = vildagliptin, SaG = saxagliptin, SiG = sitagliptin, Nebi = nebivolol). Table comparing gliptin with respect to direct antioxidant effects in vitro. 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 oxidative burst of isolated human PMNs (5×10 ⁵ cells/mL) with increasing concentrations of LPS and linagliptin was performed by enhanced chemiluminescence with the luminol analogue L-012 (100 μM) (PBS=phosphate buffered saline, LPS=lipopolysaccharide, PMN=polymorphonuclear neutrophils, LG=B11356=linagliptin). 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, Bl1356 = linagliptin). 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, Bl1356 = linagliptin). Linagliptin amelioration of endothelial dysfunction in GTN or LPS treated rats (pretreatment with linagliptin (3-10 mg/kg), induction of endothelial dysfunction with nitrate or LPS (3 days)). FIG. 8A shows the effect of GTN-induced endothelial dysfunction and linagliptin on endothelium-dependent relaxation (EtOH Ctr=ethanol control, GTN s.c.=trinitroglycerin-subcutaneous, B11356=linagliptin). Figure 8B shows the effect of LPS (10 mg/kg/day i.p.) in vivo treatment and linagliptin treatment on endothelium-dependent relaxation (LPS = lipopolysaccharide, EtOH Ctr = ethanol control). Linagliptin amelioration of endothelial dysfunction in GTN or LPS treated rats (pretreatment with linagliptin (3-10 mg/kg), induction of endothelial dysfunction with nitrate or LPS (3 days)). FIG. 8A shows the effect of GTN-induced endothelial dysfunction and linagliptin on endothelium-dependent relaxation (EtOH Ctr=ethanol control, GTN s.c.=trinitroglycerin-subcutaneous, B11356=linagliptin). Figure 8B shows the effect of LPS (10 mg/kg/day i.p.) in vivo treatment and linagliptin treatment on endothelium-dependent relaxation (LPS = lipopolysaccharide, EtOH Ctr = ethanol control). A direct vasodilatory effect of gliptin is shown. Gliptin-induced vasodilation is determined by isometric tension recordings in isolated aortic ring segments and relaxation in response to increasing cumulative concentrations of linagliptin, sitagliptin or saxagliptin (from 1 nM to 32 μM) (FIG. 9A). In another set of experiments, aortic relaxation is examined in response to increasing cumulative concentrations of linagliptin, alogliptin or vildagliptin (from 1 nM to 32 or 100 μM) (FIG. 9B). Data are the mean±SEM of 12 (FIG. 9A) or 4 (FIG. 9B) aortic rings from a total of 10 rats. *, p<0.05 vs. DMSO (vehicle control); ^# , p<0.05 vs. sitagliptin/vildagliptin; superscripted section symbols, p<0.05 vs. saxagliptin/aglogliptin. Figure 9A continued. A direct vasodilatory effect of gliptin is shown. Gliptin-induced vasodilation is determined by isometric tension recordings in isolated aortic ring segments and relaxation in response to increasing cumulative concentrations of linagliptin, sitagliptin or saxagliptin (from 1 nM to 32 μM) (FIG. 9A). In another set of experiments, aortic relaxation is examined in response to increasing cumulative concentrations of linagliptin, alogliptin or vildagliptin (from 1 nM to 32 or 100 μM) (FIG. 9B). Data are the mean±SEM of 12 (FIG. 9A) or 4 (FIG. 9B) aortic rings from a total of 10 rats. *, p<0.05 vs. DMSO (vehicle control); ^# , p<0.05 vs. sitagliptin/vildagliptin; superscripted section symbols, p<0.05 vs. saxagliptin/aglogliptin. Renal function relative to detected blood glucose after linagliptin, telmisartan or their combination or placebo treatment in STZ-treated animals is shown: 1) non-diabetic eNOS ko control mice, placebo (natrosol) (n=14); 2) sham. 3) Telmisartan (p.o. 1 mg/kg) treated diabetic eNOS ko mice (n=17); 4) Linagliptin (p.o. 3 mg/kg) treated diabetic eNOS ko mice. (n=14); 5) telmisartan (p.o. 1 mg/kg) + linagliptin (p.o. 3 mg/kg) treated diabetic eNOS ko mice (n=12). Shown are the albumin/creatinine ratios of non-diabetic and diabetic animals: 1) non-diabetic eNOS ko control mice, placebo (natrosol) (n=14); 2) sham-treated diabetic eNOS ko mice, placebo (natrosol) (n=14); 17); 3) telmisartan (p.o. 1 mg/kg) treated diabetic eNOS ko mice (n=17); 4) linagliptin (p.o. 3 mg/kg) treated diabetic eNOS ko mice (n=14); kg) + linagliptin (p.o. 3 mg/kg) treated diabetic eNOS ko mice (n=12). Results of rat experiments showing the effect of 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. is. Between timepoints 3 and 6 in Figure 12, the first line from the top shows placebo 2K1C (maximum RR systolic), the second line from the top shows linagliptin, and the middle line shows telmisartan. , second bottom line shows placebo sham and first bottom line shows telmisartan + linagliptin (lowest RR systolic). Table of experimental results from a chronic renal failure model showing the effects of linagliptin on markers of cardiac fibrosis and left ventricular dysfunction in cardiac tissue (TGF-β = transforming growth factor beta, TIMP = tissue inhibition of metalloproteinases). factor, Col1α=collagen type 1 alpha, Col3α=collagen type 3 alpha, BNP=B-type natriuretic peptide). Experimental results in diabetic eNOS knockout C57BL/6J mice as a diabetic nephropathy model (resistant to ARB treatment) are shown showing the effects of linagliptin and telmisartan on albuminuria.

DETAILED DESCRIPTION OF THE INVENTION Oxidative stress is an imbalance in the ability of biological systems to rapidly detoxify reactive oxygen species and reactive intermediates or to repair the damage caused (reactive oxygen species are free radicals , which typically includes oxygen-based or nitrogen-based unpaired electrons and peroxides of its outer electron orbitals). Perturbation of the normal redox state of tissues can cause deleterious effects through the generation of peroxides and free radicals that damage all intracellular components, 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 can be centrally involved in many diseases or conditions. Examples of diseases or conditions closely associated with oxidative stress include atherosclerosis (e.g., platelet activation and atheromatous plaque formation), endothelial dysfunction, restenosis, hypertension, peripheral occlusive vascular disease, Ischemia-reperfusion injury (e.g. renal, hepatic, cardiac or cerebral ischemia-reperfusion injury), fibrosis (e.g. renal, hepatic, cardiac or pulmonary 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 (e.g. 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; chronic fatigue syndrome, polycystic ovarian syndrome, sepsis, diabetes, metabolic syndrome, insulin resistance, hyperglycemia, hyperinsulinemia, dyslipidemia, hypercholesterolemia, hyperlipidemia Including blood. In addition to their natural pharmacological properties, certain drugs in clinical use include, but are not limited to, antihypertensive agents, angiotensin receptor blockers and antihyperlipidemic agents (e.g. statins). ) protect diverse organs through antioxidant stress mechanisms.

Patients with or at risk of oxidative stress and/or vascular stress should be tested for their oxidative stress markers (e.g. oxidized LDL), inflammatory state markers (e.g. proinflammatory interleukins), 8-OHdG, isoprosteine ( For example, diagnosis can be made by determining F2-isoprosteine, 8-isoprosteine F2 alpha), nitrotyrosine or N-carboxymethyllysine (CML).
Endothelial dysfunction (usually clinically determined as an endothelium-dependent vasomotor disorder (e.g., imbalance between vasodilation and vasoconstriction)) affects endothelial cells (cells that line the inner surface of blood vessels, arteries and veins). ), preventing them from performing their normal biochemical functions. Normal endothelial cells are required for coagulation, platelet adhesion, immune function, volume and regulation of the electrolyte content of the intravascular space. Endothelial dysfunction is closely associated with pro-inflammatory, pro-oxidative and pro-thrombotic changes within arterial walls. 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 detection of vascular disease and prediction of adverse vascular events. Risk factors for atherosclerosis and vascular diseases/events are closely associated with endothelial dysfunction. Endothelial damage also contributes to renal damage and/or chronic or progressive renal damage such as intertubular fibrosis, glomerulonephritis, microalbumin or macroalbuminuria, nephropathy and/or chronic renal disease or renal failure. becomes. Evidence exists to support that oxidative stress contributes not only to endothelial dysfunction or injury but also to vascular disease.

Type 2 diabetes mellitus is a complex condition that centrally involves the dual endocrine effects of insulin resistance and impaired insulin secretion, resulting in failure to meet the requirements necessary to maintain plasma glucose levels within the normal range. It is a common chronic and progressive disease arising from physiology. Said results in hyperglycemia and associated microvascular and macrovascular complications or chronic damage such as diabetic nephropathy, retinopathy or neuropathy, or macrovascular (e.g. cardiovascular or cerebrovascular) complications . Although factors in vascular disease play an important role, they are not the only factors in the diabetes-related disease spectrum. Complications that occur frequently result in 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-related death.

Thorough and rigorous glycemic control during early stage (up to 5 years from new diagnosis) diabetes has durable beneficial effects and reduces the risk of diabetic complications (both microvascular and macrovascular) was established in a large randomized trial. However, despite receiving intensive glycemic control, many patients with diabetes still develop diabetic complications.
Epidemiologic and prognostic data support a long-term impact of early (up to 5 years from new diagnosis) metabolic management on clinical outcome. Hyperglycemia has long-lasting detrimental effects in both type 1 and type 2 diabetes, and glycemic control must be initiated very early in diabetes or provided intensively or strictly. , may not be sufficient to completely alleviate the complications.
Furthermore, transient episodes of hyperglycemia (e.g., hyperglycemic events) can induce molecular changes, and these changes can persist or be irreversible after return to normoglycemia. It was found that
Taken together, these data demonstrate that metabolic memory is preserved early in the course of diabetes and that in certain diabetic conditions, oxidative and/or vascular stress can persist after glucose normalization. advocated. This phenomenon that the initial glycemic environment and/or even transient hyperglycemia is remembered with clinical consequences in target end-organs (e.g. blood vessels, retina, kidneys, heart, extremities) has recently been termed "metabolic memory". It is called

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

Therefore, it is possible to normalize blood glucose by primarily implicating sustained (long-term) oxidative stress induced by (chronic, early or transient episodes of) or associated with hyperglycemia. However, there is a certain metabolic condition in that there may still be long-lasting activation of many pathways involved in the pathogenesis of diabetes. Thus, one of the major discoveries in the progression of diabetes was the indication that overproduction of free radicals can still be evident even at normoglycemic levels or independently of actual blood glucose levels. For example, endothelial dysfunction, a causative marker of diabetic vascular complications, can persist after normalization of blood sugar. However, there is evidence that endothelial dysfunction can be largely blocked using a combination of antioxidant therapy and normalization of blood sugar.
Thus, treatment of oxidative stress and/or vascular stress, especially beyond glycemic control (e.g., by reducing cellular reactive species and/or glycation (e.g., by inhibiting the production of free oxygen or nitrogen radicals)), is particularly useful in glycemic conditions. A treatment independent of and beneficially modulates, modulates, blocks or protects against the memory effects of hyperglycemia and further reduces the risk associated with long-term diabetic complications, particularly oxidative stress, or The onset of complications induced by the foregoing can be prevented, treated or delayed in patients in need thereof.

Treatment of type 2 diabetes is typically initiated with diet and exercise followed by oral antidiabetic monotherapy, although in some patients blood glucose is initially controllable, the treatment is however high. With a secondary failure rate. The limitations of monotherapy for glycemic control can be overcome in at least some patients for a limited period of time by combining multiple agents to achieve a reduction in blood glucose that is not sustained during long-term monotherapy. Available data support the conclusion that in most patients with type 2 diabetes, conventional monotherapy fails and multidrug therapy is required. However, because 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 show a good initial response to conventional combination therapy, and ultimately may require increased dosage or alternative treatment with insulin. Although existing combination therapies have the potential to enhance glycemic control, the therapies have limitations, particularly with regard to long-term efficacy. Furthermore, conventional treatment methods may present an increased risk of side effects, such as hypoglycemia or weight gain, which may be the result of compromised efficacy and tolerability of the treatment method.
Thus, for many patients, these existing drug therapies result in progressive deterioration of metabolic control despite treatment, particularly in the long-term, when the metabolic state is not adequately controlled and thus progressive or late-stage. Type diabetics (including diabetics who exhibit inadequate glycemic control despite conventional oral or parenteral antidiabetic drug therapy) fail to achieve and maintain glycemic control.

Thus, while intensive treatment of hyperglycemia reduces the incidence of chronic damage, many patients with type 2 diabetes are in part due to the limitations, tolerance, and long-term efficacy of conventional antihyperglycemic therapy. Remains inadequately treated due to the inconvenience of medication.
This high incidence of treatment failure is associated with high rates of long-term hyperglycemia in patients with type 2 diabetes or chronic injury (microvascular and macrovascular complications such as diabetic nephropathy, retinopathy or neuropathy) or brain disease. It is a major contributor to vascular or cardiovascular complications, including myocardial infarction, stroke or vascular-related mortality or morbidity.
Oral anti-diabetic agents commonly used in therapy (e.g., first-line or second-line and/or single or (initial or add-on) combination therapy) include metformin, sulfonylureas, thiazolidinediones, glinides and α-glucosidase. Including but not limited to inhibitors.
Parenteral (typically injectable) antidiabetic agents commonly used in therapy (e.g. first or second and/or single or (primary or additional) combination therapy) include GLP-1 or GLP Including but not limited to -1 analogues and insulin or insulin analogues.
However, the use of these conventional anti-diabetic or anti-hyperglycemic agents can be associated with various side effects. For example, metformin is associated with lactic acid or gastrointestinal side effects, sulfonylureas, glinides and insulin or insulin analogues are associated with hypoglycemia and weight gain, thiazolidinediones are associated with edema, fractures, weight gain and heart failure/cardiac 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 most importantly (but rarely) pancreatitis.
Therefore, there is still a need in the art for effective, safe and acceptable anti-diabetic treatment methods.

Furthermore, in the treatment of type 2 diabetes, in order to achieve a long-term therapeutic effect, it is required to effectively treat the symptoms while avoiding the complications inherent in the symptoms and delaying the progression of the disease. be done.
Furthermore, anti-diabetic treatment not only prevents the long-term complications often seen in advanced diabetes, but is also a treatment option for diabetics who have developed or are at risk for complications (e.g., renal damage). is still in demand.
Furthermore, there is still a need to provide prevention or alleviation of the side effects or risks associated with conventional anti-diabetic treatments.
The enzyme DDP-4 (dipeptidyl peptidase IV), also known as CD26, is known to produce N-terminal dipeptide cleavage of many proteins with N-terminal proline or alanine residues. 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 agents for the treatment of diabetes mellitus.
For example, DDP-4 inhibitors and their uses are disclosed in: WO 2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO 2004/041820, WO 2004/046148, WO WO 2005/051950, WO 2005/082906, WO 2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769, WO2007/014886, WO 2004/050658, WO 2004/11105050502, WO2 /097798, WO 2006/068163, WO 2007/071738, WO 2008/017670, WO 2007/128721, WO 2007/128724, WO 2007/128761 or WO 2009/121945.

HbA1c (a product of nonenzymatic glycation of the hemoglobin B chain) is of critical importance in monitoring diabetes mellitus. HbA1c reflects average blood glucose levels 4-12 weeks ago in the sense of "glycemic memory" because its production is essentially dependent on blood glucose levels and red blood cell lifespan. Diabetics whose HbA1c levels are well controlled with more intensive diabetes treatment (ie less than 6.5% of total hemoglobin in the sample) are very well protected from diabetic microangiopathy. The available treatments for diabetes can provide diabetics with an average improvement on the scale of 1.0-1.5% in their HbA1c levels. This reduction in HbA1c levels is not sufficient in all diabetics to bring the desired target range of HbA1c below 7.0%, preferably below 6.5%, more preferably below 6%.
For the purposes of the present invention, inadequate or inadequate glycemic control means that the patient exhibits an HbA1c value above 6.5%, especially above 7.0%, more preferably above 7.5%, especially above 8%. means state. Embodiments of patients with inadequate or poor glycemic control include (but are not limited to) those with HbA1c values of 7.5 to 10% (or 7.5 to 11% in another embodiment). One particular aspect of the poorly controlled patient aspect is patients with poor glycemic control, including, but not limited to, patients with HbA1c values of 9% or greater.

Among glycemic control, in addition to improving HbA1c levels, other recommended treatment goals for patients with type 2 diabetes mellitus are normal or as normal as possible fasting plasma glucose (FPG) and postprandial plasma glucose levels. It's a near improvement. Recommended desired target range for preprandial (fasting) plasma glucose is 70-130 mg/dL (or 90-140 mg/dL) or less than 110 mg/dL and 2-hour 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 anti-diabetic drugs (drug-naive patients). Thus, in some embodiments, the treatment methods described herein can be used in naive patients. In another embodiment, diabetic patients within the meaning of the present invention include patients with advanced or late stage type 2 diabetes mellitus (including patients who have failed conventional antidiabetic drug therapy), e.g. Patients with inadequate glycemic control with one, two or more conventional oral and/or parenteral antidiabetic drugs, such as metformin, thiazolidinediones (especially pioglitazone), sulfonylureas, glinides, GLP-1 or GLP- 1 analogues, insulin or insulin analogues, or despite (monotherapy) therapy with alpha-glucosidase inhibitors, or metformin/sulfonylureas, metformin/thiazolidinediones (particularly pioglitazone), sulfonylureas/alpha-glucosidase inhibitors, pioglitazone/sulfonylureas, Patients with poor glycemic control despite dual therapy with metformin/insulin, pioglitazone/insulin or sulfonylurea/insulin may be included. Thus, in certain embodiments, the methods of treatment described herein are combined with prior experience with treatment, e.g., with conventional oral and/or parenteral anti-diabetic monopharmaceutical agents or dual or triple combination agents described herein. It can be used in patients with

Yet another embodiment of a diabetic patient within the meaning of the present invention is a patient who is unsuitable for metformin therapy, including:
- Patients with contraindications to metformin therapy, e.g. patients with one or more contraindications to metformin therapy according to the label, e.g. unstable or acute congestive heart failure; acute or chronic metabolic acidosis; and hereditary galactose intolerance.
- patients suffering from one or more unacceptable side effects attributed to metformin, in particular gastrointestinal side effects associated with metformin, such as at least one gastrointestinal selected from nausea, vomiting, diarrhea, intestinal gas and severe abdominal discomfort Patients suffering from vascular side effects.
Yet another embodiment of patients with diabetes who may be amenable to the methods of treatment of the present invention include patients with diabetes who are not suitable for regular metformin therapy, e.g. or due to (mild) impairment/decline in renal function (including but not limited to elderly patients (eg 60-65 years old)).

Yet another embodiment of a diabetic patient within the meaning of the present invention is a patient with renal disease, renal insufficiency or insufficient or impaired renal function (including mild, moderate and severe renal impairment), This includes, for example, elevated serum creatinine levels (e.g., serum creatinine levels above the upper normal limit for the patient's age, e.g., 130-150 μmol/L or higher, or 1.5 mg/dL or higher in men, or 1.4 mg/dL or higher in women). (>124 μmol/L)), or by abnormal creatinine clearance (eg glomerular filtration rate (GFR) <30-60 mL/min).
As a further illustration of the above, mild renal impairment is suggested by, for example, a creatinine clearance of 50-80 mL/min (approximately corresponding to 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 corresponding 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 may be suggested, for example, by a creatinine clearance of less than 30 mL/min (approximately corresponding 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, said glomerular filtration rate (GFR, mL/min/1.73m ² ) can be stratified into 5 stages: normal GFR ≥90 + persistent albuminuria or stage 1 characterized by known structural or hereditary renal disease; Stage 2, characterized by mildly decreased GFR (GFR 60-89) indicating impairment; stage 3, characterized by moderately decreased GFR (GFR 30-59) indicating moderate renal impairment; severe Stage 4, characterized by severely decreased GFR (GFR 15-29) indicating renal impairment; kidney disease, ESRD).

Yet another aspect of the diabetic patient within the meaning of the present invention is renal complications such as diabetic nephropathy (chronic and progressive renal insufficiency, albuminuria, proteinuria, body fluid retention (edema) and/or have or are at risk of developing type 2 diabetes.
Yet another embodiment of a diabetic patient amenable to the treatment methods of the present invention may include a type 2 diabetic patient who has or is at risk of developing renal complications such as diabetic retinopathy (but not limited to the foregoing). not).
Yet another embodiment of a diabetic patient amenable to the treatment methods of the present invention has macrovascular complications such as myocardial infarction, coronary artery disease, ischemic or hemorrhagic stroke, and/or peripheral occlusive arterial disease. or at risk of developing type 2 diabetes (but not limited to the foregoing).
Yet another embodiment of a diabetic patient amenable to the methods of treatment of the present invention is a type 2 diabetic patient having or at risk of having a cardiovascular or cerebrovascular disease or event (e.g., a cardiovascular disease described herein). patients at vascular risk), including but not limited to the foregoing.
Still other embodiments of diabetic patients amenable to the treatment methods of the present invention include diabetic patients (particularly type 2 diabetes) who are elderly and/or have advanced diabetes, e.g. patients on insulin therapy, patients on triple anti-diabetic oral therapy Patients may include (but are not limited to) patients, patients with pre-existing cardiovascular and/or cerebrovascular events, and/or patients with long duration of disease (eg, 5 to 10 years).

Yet another embodiment of a diabetic patient amenable to the treatment methods of the present invention includes diabetes mellitus with one or more cardiovascular risk factors selected from A), B), C) and D) below Patients (particularly those with type 2 diabetes) may include (but are not limited to):
A) previous or existing vascular disease (e.g. myocardial infarction (e.g. asymptomatic or symptomatic), coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure) (e.g. NYHA class I or II, e.g. left ventricular function <40%), or peripheral occlusive arterial disease);
B) vascular-related end-organ diseases (e.g. nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease and/or microalbumin or macroalbuminuria);
C) old age (e.g. 60+-70 years); and
D) One or more cardiovascular risk factors selected from:
- advanced type 2 diabetes mellitus (eg for more than 10 years),
- hypertension (eg >130/80 mmHg, or systolic blood pressure >140 mmHg, or at least one antihypertensive therapy,
- current daily smoking,
- Dyslipidemia (e.g. atherogenic dyslipidemia, postprandial lipidemia, or high LDL cholesterol (e.g. LDL cholesterol >130-135 mg/dL), low 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 dyslipidemia),
- obesity (e.g. abdominal and/or visceral obesity or body mass index ≥ 45 kg/ ^m2 ),
- aged between 40 and 80,
- metabolic syndrome, hyperinsulinemia or insulin resistance, and - hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or a family history of vascular disease or cardiomyopathy in the first degree.

In certain embodiments, a patient amenable to treatment methods of the invention may have or be at risk of one or more of the following diseases, disorders or conditions: type 1 diabetes, type 2 diabetes, glucose Impaired tolerance (IGT), fasting blood glucose impairment (IGF), hyperglycemia, postprandial hyperglycemia, postabsorption hyperglycemia, latent autoimmune diabetes in adults (LADA), overweight, obesity, dyslipidemia disease (including, for example, atherogenic dyslipidemia), hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFAemia, postprandial lipidemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome, hyperuricemia, metabolic syndrome, nephropathy, microalbumin or macroalbuminuria, proteinuria, retinopathy, cataract , neuropathy, 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, cardiac rhythm abnormality, vascular restenosis, stroke , ischemia/reperfusion injury (of the kidney, heart, brain or liver), fibrosis (of the kidney, heart, brain or liver), vascular remodeling (of the kidney, heart, brain or liver); diabetes, especially type 2 Diabetes (preferably true (eg as an underlying disease)).

In yet another embodiment, a patient amenable to treatment methods of the present invention has diabetes (particularly type 2 diabetes mellitus) and one or more other diseases, disorders or conditions (e.g., those listed immediately above). selected).
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, pharmaceutical compositions) or the combined use according to the invention of such DPP-4 inhibitors as defined herein meet the objects of the invention and/or fulfill one or more of the above needs. have now been found to have properties that make them suitable for DPP-4 inhibitors.
The present invention therefore relates to certain DPP-4 inhibitors as defined herein, preferably linagliptin (Bl1356), for use in the therapeutic methods described herein.
The present invention further relates to certain DPP-4 inhibitors as defined herein, preferably linagliptin (Bl1356), in combination with metformin for use in the therapeutic 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 therapeutic methods 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 therapeutic methods described herein.

The present invention furthermore relates to pharmaceutical compositions comprising certain DPP-4 inhibitors as defined herein, preferably linagliptin (Bl1356), for use in the methods of treatment described herein.
The present invention furthermore relates to pharmaceutical compositions comprising certain DPP-4 inhibitors as defined herein, preferably linagliptin (B11356) and metformin, for use in the methods of treatment described herein.
The present invention furthermore relates to pharmaceutical compositions comprising certain DPP-4 inhibitors as defined herein, preferably linagliptin (B11356) and pioglitazone, for use in the therapeutic methods described herein.
The present invention also provides certain DPP-4 inhibitors (especially Bl1356) and selected from those described herein, particularly for simultaneous, separate or sequential use in the therapeutic methods described herein. with one or more other active substances, said other active substances are e.g. other antidiabetic substances, blood sugar level lowering active substances, blood lipid level lowering active substances, blood HDL selected from level-increasing active substances, blood pressure-lowering active substances, active substances indicated in the treatment of atherosclerosis or obesity, antiplatelet agents, anticoagulants, and vascular endothelial protective agents, for example each of It is described herein.

The present invention furthermore provides certain DPP-4 inhibitors (especially Bl1356) and one or more, particularly used concurrently, separately or sequentially in the therapeutic methods described herein, optionally in combination with telmisartan. wherein said antidiabetic agent is metformin, sulfonylurea, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonist, alpha-glucosidase inhibitor, insulin or insulin analogue, and GLP-1 or GLP -1 is selected from the group consisting of analogues.
The present invention furthermore relates to a method of treating and/or preventing metabolic diseases, in particular type 2 diabetes mellitus and/or symptoms associated therewith (e.g. diabetic complications), said method comprising metformin, sulfonylureas, nateglinide, repaglinide , thiazolidinediones, PPAR-gamma agonists, alpha-glucosidase inhibitors, insulin or insulin analogues, and GLP-1 or GLP-1 analogues. An effective amount of a DPP-4 inhibitor (particularly Bl1356) as defined herein, and optionally an effective amount of telmisartan, to a patient (especially a human patient) in need thereof, e.g. (including groups) in combination (simultaneously, separately or sequentially).

The present invention further relates to a therapy or method of treatment as described herein, such as a method of treating and/or preventing a metabolic disease, particularly type 2 diabetes mellitus and/or conditions associated therewith (e.g. diabetic complications). , the method includes a therapeutically effective amount of linagliptin (Bl1356) and optionally one or more other therapeutic agents such as metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-gamma agonists, alpha-glucosidase inhibitors. , insulin or an insulin analogue, and GLP-1 or a GLP-1 analogue, and/or telmisartan to a patient (especially a human patient) in need thereof, e.g. (eg, at-risk patients described herein).
The present invention further relates to a therapy or method of treatment as described herein, such as a method of treating and/or preventing a metabolic disease, particularly type 2 diabetes mellitus and/or conditions associated therewith (e.g. diabetic complications). , the method includes administering a therapeutically effective amount of linagliptin (B11356) to a patient (especially a human patient) in need thereof, e.g. patients with or at risk of vascular or cerebrovascular disease or events and/or patients with or at risk of renal disease)).

The present invention furthermore relates to a therapy or method of treatment as described herein, such as a method of treating and/or preventing a metabolic disease, in particular diabetes mellitus type 2 and/or conditions associated therewith (e.g. diabetic complications). , the method comprises administering therapeutically effective amounts of linagliptin (B11356) and metformin to a patient (especially a human patient) in need thereof, e.g. particularly to patients with or at risk of having a cardiovascular or cerebrovascular disease or event).
The present invention furthermore relates to a therapy or method of treatment as described herein, such as a method of treating and/or preventing a metabolic disease, in particular diabetes mellitus type 2 and/or conditions associated therewith (e.g. diabetic complications). , the method provides a therapeutically effective amount of linagliptin (B11356) and telmisartan to a patient (especially a human patient) in need thereof, e.g. particularly to patients with cardiovascular or cerebrovascular disease or events or patients at risk and/or patients at risk of renal disease).
Examples of such metabolic disorders or diseases that may be amenable to the methods of treatment of the present invention, particularly in patients with or at risk of cardiovascular and/or renal disease include type 1 diabetes, 2 type diabetes, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, postabsorption hyperglycemia, latent autoimmune diabetes in adults (LADA), overweight, obesity , dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFAemia, postprandial lipidemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non Alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy, polycystic ovary syndrome, and/or metabolic syndrome may include, but are not limited to.

The present invention further includes administering a therapeutically effective amount of certain DPP-4 inhibitors, optionally in combination with one or more other therapeutic agents described herein, comprising: For at least one of the methods:
A patient in need thereof (e.g. a patient as described herein, especially a patient with type 2 diabetes), in particular oxidative stress, vascular stress and/or endothelial dysfunction, or a disease or condition associated with or associated with said or cardiovascular and/or renal disease (e.g., myocardial infarction, stroke, or peripheral arterial occlusive disease, and/or diabetic nephropathy, microalbumin or macroalbuminuria) , or acute or chronic renal impairment), or
A) previous or existing vascular disease (e.g. myocardial infarction (e.g. asymptomatic or symptomatic), coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure) (e.g. NYHA class I or II, e.g. left ventricular function <40%), or peripheral occlusive arterial disease);
B) vascular-related end-organ diseases (e.g. nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease and/or microalbumin or macroalbuminuria);
C) old age (e.g. 60+-70 years); and
D) One or more cardiovascular risk factors selected from:
- advanced type 2 diabetes mellitus (eg for more than 10 years),
- hypertension (eg >130/80 mmHg, or systolic blood pressure >140 mmHg, or at least one antihypertensive therapy),
- current daily smoking,
- Dyslipidemia (e.g. atherogenic dyslipidemia, postprandial lipidemia, or high LDL cholesterol (e.g. LDL cholesterol >130-135 mg/dL), low 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 dyslipidemia),
- obesity (e.g. abdominal and/or visceral obesity or body mass index ≥ 45 kg/ ^m2 ),
- aged between 40 and 80,
- metabolic syndrome, hyperinsulinemia or insulin resistance, and - hyperuricemia, erectile dysfunction, polycystic ovarian syndrome, sleep apnea, or a family history of vascular disease or cardiomyopathy in the first degree,
Patients with 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 blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, postabsorption hyperglycemia, adults latent autoimmune diabetes (LADA), overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFAemia, postprandial lipidemia, hypertension, and atherosclerosis endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy, polycystic ovarian syndrome, and/or metabolic syndrome. , lengthening or treating methods;
- methods for improving and/or maintaining glycemic control and/or for lowering fasting plasma glucose, postprandial plasma glucose, postabsorptive plasma glucose and/or glycosylated hemoglobin HbA1c;
- prevent, slow, prolong, or slow progression of prediabetes, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance, and/or progression from metabolic syndrome to type 2 diabetes mellitus how to reverse;
- Complications of diabetes mellitus, such as microvascular or macrovascular disease, such as nephropathy, microalbumin or macroalbuminuria, proteinuria, retinopathy, cataract, neuropathy, 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 stenosis. prevent, reduce the risk of, or slow the progression of cardiopathy, peripheral arterial occlusive disease, cardiomyopathy (including, for example, uremic cardiomyopathy), heart failure, cardiac rhythm abnormalities, vascular restenosis, and/or stroke , lengthening or treating methods;
- a method of reducing body weight and/or body fat, or preventing weight and/or body fat gain, or promoting weight and/or body fat loss;
- methods for preventing, slowing or treating pancreatic beta-cell degeneration and/or decline in pancreatic beta-cell functionality and/or for improving, maintaining and/or restoring pancreatic beta-cell functionality and/or a method of stimulating and/or restoring or protecting the functionality of pancreatic insulin secretion;
- a method for preventing, slowing, prolonging or treating nonalcoholic fatty liver disease (NAFLD) (including hepatic steatosis), nonalcoholic steatohepatitis (NASH) and/or liver fibrosis (e.g. hepatic steatosis) , methods of preventing, retarding, slowing, attenuating, treating or reversing (hepatic) inflammation and/or abnormal accumulation of hepatic fat);
- methods of preventing, slowing progression, prolonging or treating type 2 diabetes in which conventional antidiabetic mono- or combination therapy has failed;
- methods of achieving a reduction in the dose of conventional antidiabetic drugs required for adequate therapeutic effect;
- methods of reducing the risk of side effects associated with conventional antidiabetic drugs (e.g. hypoglycemia and/or weight gain); and/or - methods of maintaining and/or improving 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 those skilled in the art from consideration of the above and following, including the examples and claims.
Aspects of the present invention, particularly 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.
Embodiments of the present invention are used in the treatment and/or prevention of metabolic disease (particularly type 2 diabetes mellitus) in patients with type 2 diabetes and also in patients suffering from renal disease, renal insufficiency or renal impairment. In particular, said DPP-4 inhibitor is administered to said patient at the same dose level as a patient with normal renal function, thus for example said DPP-4 inhibitor is for renal dysfunction. It is characterized by the fact that it does not require dose downward adjustment.
For example, the DPP-4 inhibitors of the present invention (which may be particularly suitable for patients with renal impairment) have a relatively broad (approximately >100-fold) therapeutic window for the DPP-4 inhibitor and its active metabolites. and/or such an oral DPP-4 inhibitor that is cleared primarily by hepatic metabolism or biliary excretion (preferably without further addition to the kidney).

In a more detailed example, the DPP-4 inhibitors of the present invention (which may be particularly suitable for patients with renal impairment) provide a relatively wide (approximately >100-fold) therapeutic window (preferably safety comparable to placebo). profile) and/or (preferably at its oral therapeutic dose levels) such that it satisfies one or more of the following pharmacokinetic properties:
- the DPP-4 inhibitor is substantially or mainly (e.g. greater than 80% or even greater than 90% of the administered orally administered dose) excreted via the liver and/or for which Renal excretion occupies no substantial or only a minor elimination route (e.g., an orally administered dose measured by following the excretion of an orally administered dose of radiolabeled carbon ( ¹⁴ C) material, e.g. less than 10%, preferably less than 7%);
- The DPP-4 inhibitor is excreted predominantly unchanged from the parent drug (e.g. >70% of the orally administered dose of radiolabeled carbon ( ¹⁴ C) material on average in urine and feces, or more than 80%, or preferably 90%), and/or are removed by metabolism to an insubstantial or negligible extent (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 it is rapidly cleared compared to the parent compound (e.g. the terminal half-life of the metabolite is 20 hours or less, or preferably about 16 hours or less). , for example 15.9 hours).
In certain embodiments, the (major) plasma metabolite (which may be pharmacologically inactive) of a DPP-4 inhibitor having a 3-amino-piperidin-1-yl substituent is 3-amino-piperidine The amino group of the -1-yl moiety is replaced by a hydroxyl group and the 3-hydroxy-piperidin-1-yl moiety (e.g. the 3-(S)-hydroxy-piperidin-1-yl moiety, by reversing the configuration of the chiral center It is a derivative such that it forms

Yet another property of the DPP-4 inhibitors of the present invention can be one or more of the following: rapid achievement of steady state (e.g. plasma levels (greater than 90% of steady-state plasma concentration), little accumulation (e.g. mean accumulation rate _{RA, AUC} ≤ 1.4 using therapeutic oral dose levels), and/or DPP-4 inhibition (preferably when using once-daily) (e.g., nearly complete (greater than 90%) DPP-4 inhibition at therapeutic oral dose levels, once-daily therapeutic oral doses) >80% inhibition over 24 hours after ingestion), marked reduction in blood glucose excursion 2 hours postprandial at therapeutic dose levels (>80% already on the first day of treatment), and excretion in urine Accumulation of the unchanged parent compound should be less than 1% of the administered dose and should not increase by more than about 3-6% at steady state.
Thus, for example, a DPP-4 inhibitor of the present invention has a predominantly non-renal elimination route (i.e., said DPP-4 inhibitor has a non-substantial or minor degree (e.g., oral administration dose, preferably oral therapeutic dose). less than 10%, preferably less than 7%, e.g. about 5%) is excreted by the kidney (e.g. measured by tracking excretion of an oral dose of radiolabeled carbon ( ¹⁴ C) substance). .
Furthermore, the DPP-4 inhibitors of the present invention may be characterized in that they are substantially or predominantly excreted via the liver or feces (e.g. following excretion of oral doses of radiolabeled carbon ( ¹⁴ C) substances). (measured by

Furthermore, the DPP-4 inhibitor of the present invention should be excreted mainly unchanged as a parent drug (e.g. excreted radioactivity in urine and feces after oral administration of a radiolabeled carbon ( ¹⁴ C) substance). on average greater than 70%, or greater than 80%, or preferably 90% unchanged), said DPP-4 inhibitor is excreted very little or only very little via metabolism; and/or the major metabolite of said DPP-4 inhibitor may be characterized as being pharmacologically inactive or having a relatively broad therapeutic window.
Furthermore, the DPP-4 inhibitors of the present invention may also improve glomerular function and/or renal tubular function in patients with type 2 diabetes with chronic renal insufficiency (e.g., mild, moderate, or severe renal impairment or end-stage renal disease). Trough levels of said DPP-4 inhibitors in plasma of type 2 diabetic patients who do not significantly impair function and/or who have mild or moderate renal impairment are similar to those of patients with normal renal function and/or said DPP-4 inhibitor is type 2 diabetes mellitus with renal impairment (preferably irrespective of stage of renal impairment, e.g. mild, moderate or severe renal impairment or end stage renal disease) It can be characterized by no need for dose adjustment in patients.
Furthermore, the DPP-4 inhibitors of the present invention are doses whose minimal effective dose results in greater than 50% inhibition of DPP-4 activity in the trough (24 hours after the last dose) in more than 80% of patients and/or that the fully therapeutic dose is the dose that produces greater than 80% inhibition of DPP-4 activity in the trough (24 hours after the last dose) in more than 80% of patients can be
Furthermore, the DPP-4 inhibitors of the present invention may be used in patients with type 2 diabetes who have been diagnosed with renal impairment and/or are at risk of developing renal complications, such as diabetic nephropathy (chronic and progressive renal It may be characterized as being suitable for use in patients who have or are at risk of having dysfunction, albuminuria, proteinuria, body fluid retention (edema) and/or hypertension.

In a first embodiment (embodiment A), the DPP-4 inhibitor of the context of the present invention is any DPP- 4 inhibitor, or a pharmaceutically acceptable salt thereof:

式（I）

Formula (I)

式（II）

Formula (II)

式（III）

Formula (III)

（式IV）

(Formula IV)

During the ceremony,
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) -Xanthines (cf. WO 2004/018468, Example 2 (142)):

1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl )-xanthine (cf. 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, 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 (cf. WO 2004/050658, Example 136):

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

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

1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-ylxanthine (WO 2005/085246, implemented (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 ]-xanthine (cf. WO 2006/029769, Example 2(4)):

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

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

1-[(4,6-dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidine-1- Ilkanthin (cf. WO 2005/085246, Example 1 (82)):

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

These DPP-4 inhibitors are distinct from structurally similar DPP-4 inhibitors. This is because, when combined with other pharmaceutically active substances, they combine a very good potency and long lasting action with favorable pharmacological properties, receptor selectivity and a favorable side effect profile or unexpected therapeutic effects. because it provides a commercial advantage or improvement. Their preparation is disclosed in the publications mentioned.
A more preferred DPP-4 inhibitor among the above-mentioned DPP-4 inhibitors of embodiment A 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, especially its free base (also known as linagliptin or B11356).
A particularly preferred DPP-4 inhibitor within the present invention is linagliptin. The term linagliptin as used herein refers to linagliptin or acceptable salts thereof (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 the production of linagliptin are described, for example, in patent applications WO 2004/018468 and WO 2006/048427. Linagliptin is distinct from structurally similar DPP-4 inhibitors. This is because linagliptin combines exceptional potency and long-lasting action with favorable pharmacological properties, receptor selectivity and a favorable side effect profile, or unexpected treatment in single- or double- or triple-drug combination therapy. because it yields an economic advantage or improvement.

For the avoidance of any doubt, the disclosure of each of the documents cited above and below in connection with the specifically indicated DPP-4 inhibitors is hereby incorporated by reference in its entirety.
In accordance with the present invention, it is to be understood that the combination, composition or combined use of the invention may contemplate simultaneous, sequential or separate administration of the active ingredients or components.
In this connection, "combination" or "combined" within the meaning of the invention includes fixed or non-fixed (e.g. free) forms (including kits) and uses (e.g. simultaneous, sequential or separate use), including but not limited to:
Administration of the combination of the invention can be carried out by administering the active ingredients or components together, for example by administering them simultaneously in one single formulation or in two separate formulations or dosage forms. Alternatively, administration may be effected by administering the active ingredients or ingredients sequentially, eg, as two separate formulations or dosage forms.
For combination therapy of the present invention, the active ingredients or components can be administered separately (the foregoing implies that they are formulated separately) or can be formulated together (the foregoing implies that they are be formulated as the same preparation or as the same dosage form). Thus, administration of one component of the combination of the invention may precede, be simultaneous with, or follow administration of the other component of the combination.
Unless otherwise specified, combination therapy can refer to primary, secondary or tertiary treatment modalities, or primary or adjunctive combination therapy or replacement therapy.

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

Typical dosage strengths for the linagliptin/metformin IR (immediate release) dual fixed combination (tablets) are 2.5/500 mg, 2.5/850 mg and 2.5/1000 mg 1-3 times a day, especially twice a day. can be administered.
Typical dosage strengths for the linagliptin/metformin XR (long-term release) binary fixed combination (tablets) are 5/500 mg, 5/1000 mg and 5/1500 mg (one tablet each), or 2.5/500 mg, 2.5/ 750 mg and 2.5/1000 mg (2 tablets each), which can be administered 1-2 times a day, especially once a day, preferably in the evening with meals.
The present invention further finds use in (add-on or initial) combination therapy with metformin (e.g. a total daily dose of 500 to 2000 mg metformin hydrochloride, e.g. 500 mg, 850 mg or 1000 mg once or twice daily). , provides DPP-4 inhibitors as defined herein.
For pharmaceutical application in warm-blooded vertebrates (especially humans), the compounds of the invention will normally be given as a dosage of 0.001 to 100 mg/kg body weight, preferably 0.01-15 mg/kg (one daily dose in each case). 4 times from). For this purpose, the compounds are combined with one or more inert carriers and/or diluents such as corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, optionally in combination with other active substances. , polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as solid fats or suitable mixtures thereof. Together, they can be incorporated into conventional galenic preparations such as 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 contain pharmaceutically acceptable formulation excipients suitable for the desired route of administration. prepared by those skilled in the art using Examples of such excipients include diluents, binders, carriers, fillers, lubricants, dispersing agents, crystallization retardants, disintegrants, solubilizers, colorants, pH modifiers, interfacial Including but not limited to active agents and emulsifiers.
Oral preparations or dosage forms of the DPP-4 inhibitors of this invention can be prepared according to known techniques.
Examples of suitable diluents for compounds of embodiment A include cellulose powder, calcium hydrogen phosphate, erythritol, low-substituted hydroxypropylcellulose, mannitol, pregelatinized starch or xylitol.
Examples of suitable lubricants for 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 (a copolymer of vinylpyrrolidone with other vinyl derivatives), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone ( povidone), pregelatinized starch, or low-substituted hydroxypropyl cellulose (L-HPC).
Suitable disintegrants for 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 invention is as follows:
- direct compression of the active substance in a powder mixture containing suitable compression excipients;
- granulation with suitable excipients and subsequent mixing with suitable excipients and subsequent tableting plus film coating; or - filling of powder mixtures or granules into capsules.
Suitable granulation methods are:
- Wet granulation in an intensive mixer followed by fluid bed drying;
- one-pot granulation;
- fluid bed granulation; or - dry granulation (eg by roller compaction) with suitable excipients and subsequent tableting or filling into capsules.
An exemplary composition (e.g., tablet core) of a DPP-4 inhibitor of embodiment A of the present invention comprises mannitol as a first diluent, pregelatinized starch as a second diluent with additional binding properties, binding copovidone as an agent, corn starch as a disintegrant, and magnesium stearate as a lubricant, where the copovidone and corn starch can be optional.
The DPP-4 inhibitor tablet of embodiment A of the present invention may be film coated, preferably said film coat comprises hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and iron oxide. (eg red and/or yellow).

Pharmaceutical compositions (or formulations) can be packaged in a variety of ways. Generally, the product to be delivered will comprise one or more containers containing one or more pharmaceutical compositions in suitable form. Typically, tablets are bundled in suitable primary packaging for easy handling, shipping and storage, and for adequate stability of the composition upon prolonged contact with the environment during storage. For tablets the primary container can be a bottle or a blister pack.
Suitable bottles for e.g. pharmaceutical compositions or combinations (tablets) containing a DPP-4 inhibitor according to embodiment A of the invention are glass or polymer (preferably polypropylene (PP) or high density polyethylene (HD- Manufactured from PE)) and can be closed with a screw cap. Screw caps can be provided with child-safe closures (eg, push-and-turn closures) to prevent or prevent children from accessing the contents. If necessary (eg in areas of high humidity) the shelf life of the packaged composition can be extended by the additional use of desiccants (eg bentonite clay, molecular sieves or preferably silica gel).
Suitable blister packs, e.g. for pharmaceutical compositions or combinations (tablets), comprising a DPP-4 inhibitor according to embodiment A of the invention comprise a top foil (breakable by the tablet) and a bottom foil (for tablets). (having a pocket of ). The top foil may comprise a metal foil, in particular an aluminum or aluminum alloy foil (eg having a thickness of 20 μm to 45 μm, preferably 20 μm to 25 μm) coated on its inside (sealing side) with a heat encapsulating polymer layer. can. The bottom is a multi-layer polymer foil (e.g. poly(vinylidene chloride) (PVDC) coated poly(vinyl chloride) (PVC); or poly(chlorotrifluoroethylene) (PCTFE) laminated PVC foil) or a multi-layer polymer-metal-polymer foil (eg cold-formable laminated PVC/aluminum/polyamide compositions).

Additional overwraps or pouches made from multi-layer polymer-metal-polymer foils (e.g. laminated polyethylene/aluminum/polyester compositions) are added to the blister packs to ensure a long shelf life, especially under hot and humid climatic conditions. can be used for A supplemental desiccant (eg, bentonite clay, molecular sieves, or preferably silica gel) within the pouch packaging can further extend the shelf life under such extreme conditions.
The product may also include a label or packaging insert. They shall refer to the instructions customarily included in the commercial packaging of therapeutic products and shall contain information on instructions, care, dosage, administration, contraindications and/or warnings regarding the use of such therapeutic products. can be done. 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), typically required dosages of the DPP-4 inhibitors described herein in embodiment A are 0.1 mg to 10 mg when administered intravenously, preferably 0.25 mg to 5 mg, when orally administered 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 once daily 4 times from Thus for example 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidine-1 The dosage of -yl)-xanthine is 0.5 mg to 10 mg/patient/day, preferably 2.5 mg to 10 mg or 1 mg to 5 mg/patient/day when administered orally.
A dosage form prepared with a pharmaceutical composition comprising a DPP-4 inhibitor as described herein in embodiment A contains the active ingredient in the 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-piperidine-1 -yl)-xanthine specific dosage strengths 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 orally administered DPP-4 inhibitors that are therapeutically effective at low dose levels, said DPP-4 inhibitors for example <100 mg or <70 mg/patient/ is therapeutically effective at oral dosage levels preferably <50 mg, more preferably <30 mg or <20 mg, more preferably 1 mg to 10 mg, especially 1 mg to 5 mg (especially 5 mg) per patient per day, said If necessary, divided into 1 to 4 single doses, especially 1 or 2 single doses (which may be of the same size), preferably orally once or twice daily (more preferably is administered once daily), advantageously at any time of the day with or without food. Thus, for example, a daily oral dose of 5 mg of Bl1356 can be administered in a once daily dosing regimen (i.e. 5 mg Bl1356 once daily) or in a twice daily dosing regimen (i.e. 2.5 mg Bl1356 daily). twice) at any time of the day with or without food.
The dosages of the ingredients in the combinations and compositions of the invention may vary provided that the amount of said active ingredient is such that a suitable dosage form will be obtained. Accordingly, the selected dosage and selected dosage form will depend on the desired therapeutic effect, route of administration and duration of treatment. A suitable dosage range for the combination is from the maximum tolerated dose of the single agents to a lower dose, eg 1/10 of the maximum 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-butyne-1- yl)-8-(3-(R)-Amino-piperidin-1-yl)-xanthine (also known as Bl1356 or linagliptin). B11356 exhibits high potency, 24-hour duration of action, and a wide therapeutic window. In patients with type 2 diabetes who received multiple doses of Bl1356 orally once daily for 12 days, Bl1356 exhibited a favorable pharmacodynamic and drug profile (see, for example, Table 1 below), showing a Rapid reaching (e.g. reaching steady-state plasma levels (<90% of day 13 pre-dose plasma concentration) between days 2 and 5 of treatment in all dose groups), negligible accumulation (e.g. 1 mg mean accumulation ratio _{RA, AUC} ≤ 1.4 at doses exceeding (i.e., 92.3 and 97.3% inhibition at steady state, respectively, and greater than 80% inhibition during the 24-hour interval after drug intake), and the 2-hour postprandial blood glucose amplitude (already on day 1 at doses of 2.5 mg and above). a significant (>80%) reduction in urinary urinary excretion on day 1 and an increase of less than 1% of the administered dose and an increase of more than about 3-6% on day 12 (renal clearance C _LR,SS is about 14 to about 70 mL/min for an orally administered dose, eg renal clearance is about 70 mL/min for a 5 mg dose). In people with type 2 diabetes, Bl1356 exhibits placebo-like safety and tolerability. At low doses of about 5 mg and above, B11356 functions as a true once-daily oral drug that exhibits full 24-hour sustained DPP-4 inhibition. At therapeutic oral dose levels, B11356 is excreted primarily via the liver and only to a very minor extent via the kidney (less than about 7% of the oral dose). Bl1356 is essentially excreted unchanged via the bile. The portion of Bl1356 that is cleared via the kidney increases very slightly over time and with increasing dose, so that it is probably not necessary to modify the dose of Bl1356 according to the patient's renal function. Non-renal elimination of Bl1356, combined with its low accumulation capacity and wide margin of safety, may be of significant benefit in patient populations with high rates of renal insufficiency and diabetic nephropathy.

*中央値及び範囲[最小－最大]
NC：ほとんどの値が定量の下限未満であるので計算していない Table 1: Geometric Mean (gMean) and Geometric Coefficient of Variation (gCV) of Bl1356 Drug-Lapse Parameters at Steady State (Day 12)

*Median and range [minimum-maximum]
NC: not calculated as most values are below the lower limit of quantitation

Since various metabolic dysfunctions often occur simultaneously, it is very often indicated to combine a number of different principles of action. Therefore, DPP-4 inhibitors are commonly used against disorders to which conventional active agents such as other anti-diabetic agents, in particular lower blood sugar levels or blood lipid levels, raise blood HDL levels and lower blood pressure. or in combination with one or more active agents selected from active agents indicated in the treatment of atherosclerosis or obesity, an improved therapeutic outcome can be obtained depending on the diagnosed dysfunction. .
In addition to being used in monotherapy, the DPP-4 inhibitors described above can also be used in conjunction with other active agents to obtain improved therapeutic results. Such combination therapies may be provided in free combination of the substances or in fixed combination form (eg tablets or capsules). Pharmaceutical formulations containing the combination partners required for the foregoing are available on the market as pharmaceutical compositions or can be formulated by those skilled in the art using routine methods. Active substances available on the market as pharmaceutical formulations can be found in numerous places in the prior art, for example in the annual drug list, the Pharmaceutical Manufacturers Association's "Rpte Liste" or as the "Physicians' Desk Reference". Listed in annually updated manufacturers' compilations of known prescription drugs.

Examples of antidiabetic combination partners are: metformin; sulfonylureas such as glucenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glibornuride and gliclazide; nateglinide; repaglinide; mitiglinide; thiazolidinediones such as rosiglitazone and pioglitazone; modulators such as metaglitases; PPAR-gamma agonists such as riboglitazone, mitoglitazone, INT-131 and varaglitazone; PPAR-gamma antagonists; PPAR-gamma/alpha modulators such as tesaglitazar, muraglitazar, alleglitazar, indeglitazar and KRP297; PPAR-gamma/alpha/delta modulators such as robeglitazone; AMPK-activators such as AICAR; acetyl-CoA carboxylase (ACC1 and ACC2) inhibitors; diacylglycerol-acetyltransferase (DGAT) inhibitors; GCRP agonists such as SMT3-receptor-agonists and GPR119, such as GPR119 agonists 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine-1 -yl}-pyrimidine or 5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-2-(4-methanesulfonyl-phenyl)-pyridine; 11β-HSD-inhibitors; FGF19 agonists or analogues; alpha-glucosidase blockers such as acarbose, voglibose and miglitol; alpha2-antagonists; insulin and insulin analogues such as human insulin, insulin lispro, insulin glucose, r-DNA-insulin aspert, NPH insulin, insulin detemir, insulin degludec, insulin tregopyr, insulin zinc suspension and insulin glargine; gastric inhibitory peptide (GIP); amylin and amylin analogues (e.g. pramlintide or davalintide); GLP- 1 and GLP-1 analogues such as Exendin-4, e.g. churaglutide (LY-2189265), semaglutide or albiglutide; SGLT2-inhibitors such as dapagliflozin, sergliflozin (KGT-1251), atigliflozin, canagliflozin, ipragliflozin or tofogliflozin; inhibitors of protein tyrosine phosphatases (e.g. troduskemin) inhibitors of glucose-6-phosphatase; fructose-1,6-bisphosphatase modulators; glycogen phosphorylase modulators; glucagon receptor antagonists; inhibitors of tyrosine kinases (50 mg to 600 mg), e.g. PDGF-receptor-kinases (see EP-A-564409, WO 98/35958, US 5093330, WO 2004/005281 and WO 2006/041976) or serine/threonine kinases glucokinase/regulatory protein modulators (including glucokinase activators); glycogen synthase kinase inhibitors; inhibitors of SH2-domain containing inositol 5-phosphatase type 2 (SHIP2); IKK inhibitors, e.g. salicylates; JNK1 inhibitors; protein kinase C-theta inhibitors; beta3 agonists such as ritobegron, YM178, solabegron, talibegron, N-5984, GRC-1087, rafabegron, FMP825; darestat, epalrestat, ranirestat, NZ-314, CP-744809 and CT-112; SGLT-1 or SGLT-2 inhibitors; KV1.3 channel inhibitors; GPR40 modulators 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 antagonists; dopamine receptor agonists (bromocriptine mesylate [Cycloset]); 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutanoic acid; sirtuin stimulators; and other DPP IV inhibitors agent.

Metformin is usually administered in doses of about 500 mg to 2000 mg up to 2500 mg per day using various dosage regimens: about 100 mg to 500 mg, or 200 mg to 850 mg (1-3 times per day), or about 300 mg to 1000 mg once or twice daily, or extended 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 provide adequate results, the dose can be increased to 500 mg twice daily. Further increments may be made by weekly increments of 500 mg up to a maximum daily dose of 2000 mg, 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 (or divided into two) daily (typical dosage strengths are 2, 4 and 8 mg).
Glibenclamide (glyburide) is usually given in doses of 2.5-20 mg once daily (or divided into two doses) (typical dosage strengths are 1.25, 2.5 and 5 mg) or finely divided glibenclamide is administered in doses of 0.75-3 to 12 mg once daily (or divided into two doses) (typical dosage strengths are 1.5, 3, 4.5 and 6 mg).
Glipizide is usually given in doses of 2.5 to 10-20 mg once daily (or divided into two doses up to 40 mg) (typical dosage strengths are 5 and 10 mg), or extended-release glibenclamide Dosages of 5 to 10 mg (up to 20 mg) are administered once daily (typical dosage strengths are 2.5, 5 and 10 mg).
Glimepiride is usually administered in doses of 1-2 to 4 mg (up to 8 mg) once daily (typical dosage strengths are 1, 2 and 4 mg).

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

Nateglinide, a nonsulfonylurea insulin secretagogue, is usually given 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. to 4 mg with meals (up to 16 mg/day, typical dosage strengths are 0.5, 1 and 2 mg). Repaglinide/metformin dual combinations are available in dosage strengths of 1/500 and 2/850 mg.
Acarbose is usually given with food in doses of 25 to 100 mg. Miglitol is usually given with meals in doses of 25 to 100 mg.
Examples of combination partners that lower blood lipid levels are HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin, lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin; fibrates such as bezafibrate, fenofibrate, clofibrate , gemfibrozil, ethofibrate and ethophyllinclofibrate; nicotinic acid and its derivatives 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 avasimibe; cholesterol absorption inhibitors such as ezetimibe; bile acid binding agents such as cholestyramine, colestipol and colesevelam; bile acid transport inhibitors; HDL modulating actives such as D4F, reverse D4F, LXR modulating and FXR modulating actives; CETP inhibitors such as torcetrapib, JTT-705 (dalcetrapib) or compounds of WO 2007/005572 (anacetrapib) or evacetrapib; LDL receptor modulators; MTP inhibitors (eg lomitapide); and ApoB100 antisense RNA.
The dosage of atorvastatin is usually 1 mg to 40 mg or 10 mg to 80 mg once daily.

Examples of blood pressure lowering combination partners are beta blockers such as atenolol, bisoprolol, celiprolol, metoprolol, nebivolol and carvedilol; diuretics such as hydrochlorothiazide, chlorthalidone, xipamide, furosemide, piretanide, torasemide, spironolactone, eplerenone, amiloride and triamterene. calcium channel blockers such as amlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine, felodipine, lacidipine, lercanipidine, manidipine, isradipine, nilvadipine, verapamil, gallopamil and diltiazem; ACE inhibitors such as ramipril, lisinopril, cilazapril, quinapril, captopril, enalapril , benazepril, perindopril, fosinopril and trandolapril; and angiotensin II receptor blockers (ARBs) such as telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan, azilsartan and eprosartan.
The dosage of telmisartan is usually 20 mg to 320 mg, or 40 mg to 160 mg/day.
Examples of combination partners that increase blood HDL levels are cholesteryl ester transfer protein (CETP) inhibitors; inhibitors of endothelial lipase; modulators of ABC1; LXR alpha antagonists; LXR beta agonists; PPAR-delta agonists; /beta modulators and substances that increase the expression and/or plasma concentration of apolipoprotein AI.

dexfenfluramine; acoxin; cannabinoid receptor 1 antagonists such as the CB1 antagonist trimonobant; MCH-1 receptor antagonists; NPY5, in addition to NPY2 antagonists (e.g. verneperit); beta3-AR agonists such as SB-418790 and AD-9677; 5HT2C receptor agonists such as APD356 (lorcaserin); myostatin inhibitors; Acrp30 and adiponectin; fatty acid synthase (FAS) inhibitors; CCK receptor agonists; galerin receptor modulators; Pyy3-36; orexin receptor antagonists; bupropion/zonisamide, topiramate/phentamine 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 , WO 2004/005281 and WO 2006/041976); oxLDL antibodies and oxLDL vaccines; Apo A-1 Milano; ASA;

Furthermore, still within the scope of the present invention, the DPP-4 inhibitor can optionally be combined with one or more antioxidants, anti-inflammatory agents and/or endothelial protective agents.
Examples of antioxidant combination partners are selenium, betaine, vitamin C, vitamin E and beta carotene.
An example of an anti-inflammatory combination partner is pentoxifylline, another example of an anti-inflammatory 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]pyrizazin-3-yl]propanoic acid (or 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).
Examples of endothelial protective agents are PDE-5 inhibitors such as sildenafil, verdenafil or tadalafil, further examples of endothelial protective agents are nitric oxide donors or stimulants such as L-arginine or tetrahydrobiopterin.

Also within the scope of the present invention, the DPP-4 inhibitor is also optionally 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), elinogrel or ticagler, or thrombin receptor antagonists such as vorapaxor.
Also within the scope of the present invention, the DPP-4 inhibitor further optionally comprises one or more anticoagulants such as heparin, warfarin, or direct thrombin inhibitors (e.g. dabigatran), or factor Xa inhibitors (e.g. rivaroxaban or apixaban or edoxaban or otamixaban).
Furthermore, still within the scope of the present invention, DPP-4 inhibitors may also optionally be combined with one or more agents for the treatment of heart failure.
Examples of combination partners for the treatment of heart failure are beta blockers such as atenolol, bisoprolol, celiprolol, metoprolol and nebivolol; diuretics such as hydrochlorothiazide, chlorthalidone, xipamide, furosemide, piretanide, torasemide, spironolactone, eplerenone, amiloride and triamterene. ACE inhibitors such as ramipril, lisinopril, cilazapril, quinapril, captopril, enalapril, benazepril, perindopril, fosinopril and trandolapril; angiotensin II receptor blockers (ARBs) such as telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan and epsartan; cardiac glycosides such as digoxin and digitoxin; binding alpha/beta blockers such as carvediol; vasodilators; be.
Further still within the scope of the present invention, the DPP-4 inhibitor further optionally comprises one or more CCK-2 or gastrin agonists such as proton pump inhibitors (reversible inhibitors of H+/K+-ATPase as well as irreversible (including sex inhibitors), for example omeprazole, esomeprazole, pantoprazole, rabeprazole or lansoprazole.

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

Some specific aspects of the invention are described below by way of example.
(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), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, postabsorption hyperglycemia, latent autoimmune diabetes in adults (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 metabolic syndrome for preventing, slowing progression of, prolonging or treating a metabolic disorder or disease;
- methods for improving and/or maintaining glycemic control and/or for lowering fasting plasma glucose, postprandial plasma glucose, postabsorptive plasma glucose and/or glycosylated hemoglobin HbA1c;
- prevent, slow, prolong, or slow progression of prediabetes, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance, and/or progression from metabolic syndrome to type 2 diabetes mellitus how to reverse;
- Microvascular or macrovascular disease, 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 Methods of preventing, reducing the risk of, slowing, prolonging, or treating complications of diabetes mellitus that are obstructive disease, cardiomyopathy, heart failure, cardiac rhythm abnormalities, vascular restenosis, and/or stroke ;
- a method of reducing body weight and/or body fat, or preventing weight and/or body fat gain, or promoting weight and/or body fat loss;
- methods for preventing, slowing or treating pancreatic beta-cell degeneration and/or decline in pancreatic beta-cell functionality and/or for improving, maintaining and/or restoring pancreatic beta-cell functionality and/or a method of stimulating and/or restoring or protecting the functionality of pancreatic insulin secretion;
- a method of preventing, slowing, prolonging or treating non-alcoholic fatty liver disease (NAFLD), liver steatosis, non-alcoholic steatohepatitis (NASH) and/or liver fibrosis;
- methods of preventing, slowing progression, prolonging or treating type 2 diabetes in which conventional anti-diabetic mono- or combination therapy has failed;
- methods of achieving a reduction in the dose of conventional antidiabetic drugs required for adequate therapeutic effect;
- methods of reducing the risk of side effects associated with conventional antidiabetic drugs; and/or - methods of maintaining and/or improving 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 of cardiovascular and/or renal disease or with one or more cardiovascular risk factors selected from A), B), C) and D) below Patients using linagliptin,
A method for using linagliptin, wherein said method comprises administering to a patient a therapeutically effective amount of linagliptin, optionally together with one or more other therapeutic agents:
A) previous or existing pulse, e.g. selected from myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure, and peripheral occlusive artery disease vascular disease;
B) a vessel-related end-organ disease selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease and microalbumin or macroalbuminuria;
C) old age (e.g. 60+-70 years); and
D) One or more cardiovascular risk factors selected from:
- advanced type 2 diabetes mellitus (eg for more than 10 years),
- hypertension,
- current daily smoking,
- dyslipidemia,
-obesity,
- aged between 40 and 80,
- metabolic syndrome, hyperinsulinemia or insulin resistance, and - hyperuricemia, erectile dysfunction, polycystic ovarian syndrome, sleep apnea, or a family history of vascular disease or cardiomyopathy in the first degree.
(2) Use according to (1), wherein the method comprises treatment of type 2 diabetes mellitus.
(3) cardiac infarction in which the patient is selected from myocardial infarction, stroke, peripheral arterial occlusive disease, diabetic nephropathy, microalbumin or macroalbuminuria, acute or chronic renal impairment, hyperuricemia, and/or hypertension Use according to (1) or (2), wherein the patient is a type 2 diabetic with or at risk of having vascular disease and/or renal disease.
(4) Any of (1) to (3), wherein the patient is a type 2 diabetes patient with one or more cardiovascular risk factors selected from A), B), C) and D) below. Uses described in:
A) previous or existing pulse, e.g. selected from myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure, and peripheral occlusive artery disease vascular disease;
B) a vessel-related end-organ disease selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease, and microalbumin or macroalbuminuria;
C) old age (e.g. 60+-70 years); and
D) One or more cardiovascular risk factors selected from:
- advanced type 2 diabetes mellitus (eg for more than 10 years),
- hypertension,
- current daily smoking,
- dyslipidemia,
-obesity,
- aged between 40 and 80,
- metabolic syndrome, hyperinsulinemia or insulin resistance, and - hyperuricemia, erectile dysfunction, polycystic ovarian syndrome, sleep apnea, or a family history of vascular disease or cardiomyopathy in the first degree.
(5) cardiovascular or cerebrovascular selected from cardiovascular-related death, myocardial infarction, stroke and hospitalization (e.g. due to acute coronary syndrome, leg amputation, revascularization, heart failure or unstable angina) A method of preventing, reducing the risk of developing, or prolonging the development of a sexual event, preferably in a patient with type 2 diabetes, said method comprising a therapeutically effective amount of linagliptin, optionally one or more The use of linagliptin for the preparation of a pharmaceutical composition for use in said method, comprising the step of administering to a patient in need thereof together with another therapeutic agent of linagliptin.
(6) patients with type 2 diabetes at risk for cardiovascular or cerebrovascular events with one or more of the risk factors selected from A), B), C) and D) below; Use according to (5):
A) Prior or existing vessel selected from myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure, and peripheral occlusive arterial disease system diseases;
B) a vessel-related end-organ disease selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease, and microalbumin or macroalbuminuria;
C) old age (e.g. 60+-70 years); and
D) One or more cardiovascular risk factors selected from:
- advanced type 2 diabetes mellitus (eg for more than 10 years),
- hypertension,
- current daily smoking,
- dyslipidemia,
-obesity,
- aged between 40 and 80,
- metabolic syndrome, hyperinsulinemia or insulin resistance, and - hyperuricemia, erectile dysfunction, polycystic ovarian syndrome, sleep apnea, or a family history of vascular disease or cardiomyopathy in the first degree.
(7) the type 2 diabetic has a vessel-related end-organ disease selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease, and microalbumin or macroalbuminuria, (5) or Use according to (6).
(8) the occurrence of a cardiovascular or cerebrovascular event selected from cardiovascular-related death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for unstable angina pectoris; A method of preventing, reducing the risk of developing, or prolonging development in a patient with type 2 diabetes at risk for a vascular event, comprising a therapeutically effective amount of linagliptin, optionally one or more other therapeutic agents. Use of linagliptin for the preparation of a pharmaceutical composition for use in said method, comprising the step of administering to a patient in combination with linagliptin.
(9) The use according to any one of (5) to (8), wherein the type 2 diabetes patient has nephropathy, renal dysfunction, chronic renal disease, and/or microalbumin or macroalbuminuria.
(10) The use according to any one of (5) to (9), in which the type 2 diabetes patient has mild, moderate or severe renal impairment or end-stage renal disease.
(11) Use according to any one of (5) to (10), wherein the type 2 diabetes patient has microalbuminuria or diabetic nephropathy.
(12) the one or more other therapeutic agents are other antidiabetic agents, active agents that lower blood sugar levels, active agents that lower blood lipid levels, active agents that raise blood HDL levels, lower blood pressure active agents indicated in the treatment of atherosclerosis or obesity, antiplatelet agents, anticoagulants, and vascular endothelial protective agents. use.
(13) other antidiabetic agents selected from metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-gamma agonists, alpha-glucosidase inhibitors, insulin and insulin analogues, and GLP-1 and GLP-1 analogues , (12).
(14) Use according to (12) or (13), wherein the blood pressure-lowering active substance is selected from angiotensin receptor blockers (ARBs), angiotensin converting enzyme (ACE) inhibitors, and beta-blockers.
(15) 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, nebivor or metoprolol Use of.
(16) active substances that lower blood lipid levels and/or raise blood HDL levels are selected from statins, nicotinic acid or derivatives thereof, fibrates, cholesterol absorption inhibitors, and bile acid sequestrants; Use according to any one of (12) to (15).
(17) 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 the use according to (16), wherein the bile acid sequestrant is colesevelam.
(18) Use according to any one of (12) to (17), wherein the antiplatelet agent is selected from low-dose aspirin, clopidogrel, prasugrel, borapaxer and ticagler.
(19) 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 linagliptin selected from metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-gamma agonists, alpha-glucosidase inhibitors, insulin or insulin analogs, and GLP-1 or GLP-1 analogs Use according to any one of (1) to (19), comprising administering together with one or more other antidiabetic agents, and optionally telmisartan.
(21) Use according to any one of (1) to (20), wherein the method further comprises administering linagliptin together with metformin.
(22) Use according to any one of (1) to 20, wherein the method further comprises administering linagliptin together with telmisartan.
(23) Use according to any one of (1) to (20), wherein the method comprises administering a pharmaceutical composition comprising linagliptin and metformin.
(24) Use according to any one of (1) to (23), wherein linagliptin is orally administered in a total daily dose of 5 mg.
(25) in a patient,
- treat, prevent, reduce the risk of, delay the progression of, delay the onset of, attenuate or reverse ischemia/reperfusion injury (of the kidney, heart, brain or liver) and/or the heart or - (detrimental) vascular remodeling, such as cardiac remodeling, which may be characterized by cardiomyocyte hypertrophy, interstitial fibrosis, ventricular dilatation, contractile dysfunction and/or cell death/apoptosis. treat, prevent, reduce the risk of, slow progression of, delay the onset of, attenuate or reverse modelling; or - treat and prevent chronic or acute renal failure and/or peripheral arterial occlusion. , reduce its risk, slow its progression, delay its onset, attenuate or reverse it; or - treat and prevent congestive heart failure and/or cardiac hypertrophy and/or nephropathy and/or albuminuria. reduce its risk, slow its progression, delay its onset, attenuate or reverse its onset; , reducing its risk, slowing its progression, delaying its onset, attenuating or reversing its onset, comprising administering an effective amount of linagliptin optionally together with an effective amount of one or more other active agents to a patient Use of linagliptin for the preparation of a pharmaceutical composition for use in said method comprising the step of administering to.
(26) preventing, reducing the risk of, slowing the progression of, delaying the onset of, attenuating, reversing or treating diabetic nephropathy in patients who do not respond adequately to treatment regimens with angiotensin receptor blockers (ARBs); A pharmaceutical composition for use in a method, said method comprising administering to a patient a therapeutically effective amount of linagliptin, optionally together with one or more other therapeutic agents. Use of linagliptin for preparation.
(27) Preparation of pharmaceutical compositions for use in methods of using linagliptin together with telmisartan to treat diabetic nephropathy, including albuminuria, in patients who do not respond adequately to angiotensin receptor blockers (ARBs) Use of linagliptin for
(28) The use according to (26), wherein the method comprises administering a therapeutically effective amount of linagliptin in combination with an ARB.
(29) The use according to (28), wherein the ARB is telmisartan.
(30) 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 of treating and/or preventing oxidative stress, vascular stress and/or endothelial dysfunction in patients 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 invention will become apparent from the following examples. The following examples serve to further illustrate the principles of the present invention by way of illustration without limiting the invention.

Antioxidant action :
Anti-inflammatory and Vasodilator Potential of Linagliptin
The direct antioxidant effects of gliptins (linagliptin, alogliptin, vildagliptin, saxagliptin, sitagliptin) are mediated by xanthine oxidase, peroxynitrite (intrinsic and Sin-1-induced), or by hydrogen peroxide/peroxidase-mediated 1-electron-oxidation. Assessed by interference with product production. These oxidations are detected by phenol fluorescence, chemiluminescence and nitrification (trace by HPLC). The indirect antioxidant effect of gliptin was measured in isolated human leukocytes (PMN) by blocking the oxidative burst (NADPH oxidase activation) induced by the phorbol ester PDBu, the endotoxin LPS and zymosan A, and the chemotactic peptide fMLP. be.
The direct vasodilatory effect of gliptin is measured by the isometric tension technique on isolated aortic ring segments. The indirect antioxidant effects of linagliptin have also been demonstrated in a rat model of nitroglycerin-induced nitrate tolerance and linagliptin treatment (3-10 mg/kg/day for 7 days with a special diet) in endothelial function (phenylephrine precontractile aortic vessel fragment acetylcholine). -dependent relaxation), measured by isometric tension recordings of smooth muscle function (nitroglycerin-dependent relaxation). Furthermore, reactive oxygen and nitrogen species (RONS) formation is measured in isolated cardiac mitochondria and in whole blood LPS- or PDBu-initiated oxidative bursts. Furthermore, the anti-inflammatory potential of linagliptin is tested in an experimental model of LPS (10 mg/kg ip for 24 hours)-induced septic shock in Wistar rats. The effects of sepsis and linagliptin cotherapy (special diet 3-10 mg/kg/day for 7 days) are determined by isometric strain recordings, vascular, cardiac and vascular RONS formation and protein expression by Western blot.

Result :
(See Figure 1-6)
Direct antioxidant properties :
Only all gliptins showed insufficient direct antioxidant capacity. A slight (but significant) suppression of superoxide formation is observed for vildagliptin and linagliptin in response to peroxynitrite formation/-mediated nitrification. All gliptins except saxagliptin show significant interference with 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 zymosan-A. Using L-012-enhanced chemiluminescence, LPS (0.5, 5 and 50 μg/mL) increases the PMN-derived RONS signal in a concentration-dependent manner, and linagliptin suppresses this signal in a concentration-dependent manner.
In experiments with lumino/peroxidase enhancing chemiluminescence, linagliptin is much more effective than other gliptins in suppressing the LPS- or zymosan-A-triggered oxidative burst of isolated PMNs. Linagliptin is as effective as nebivolol in this assay. This efficacy to inhibit LPS-dependent RONS formation is somewhat stronger than the inhibitory effect on zymosan A-initiated RONS. All of these measurements support the superior antioxidant activity of linagliptin in isolated neutrophils when compared to other gliptins.
Inhibition of Adhesion of Activated Neutrophils to Endothelial Cells : By examining the adhesion of LPS-stimulated human neutrophils to cultured endothelial cells (the number of adherent PMNs was measured by PDBu-initiated oxidative burst (amplplex red/peroxidase fluorescence ), linagliptin suppresses leukocyte adhesion 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 : Isometric Tension Experiments in Organ Baths Reveal that Nitroglycerin and LPS Treatment Induces Marked Endothelial Dysfunction and Nitrate Tolerance . Endothelial dysfunction caused by both factors is markedly ameliorated by linagliptin therapy (FIGS. 8A and 8B), but nitrate tolerance is unchanged. Nitroglycerin treatment causes cardiac mitochondrial ROS formation and whole blood LPS/Thymosan A-triggered oxidative burst. Both of these side effects are ameliorated by linagliptin treatment (Figure 7). Neither nitroglycerin nor linagliptin treatment affects the body weight of the animals, but blood glucose levels are slightly increased in the nitroglycerin group, which is normalized by linagliptin treatment.
In summary, in vivo treatment with linagliptin attenuates nitroglycerin-induced endothelial dysfunction and shows modest improvement in ROS formation in isolated cardiac mitochondria and oxidative burst in whole blood from nitrate-tolerant rats.
Effects 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 nearly normalized by linagliptin treatment. Mitochondrial and whole blood (LPS, PDBu-stimulated) RONS production is dramatically increased by LPS and ameliorated by linagliptin treatment. Vascular oxidative stress (measured by DHE-dependent fluorescence microscopy) and vascular inflammatory markers (VCAM-1, Cox-2, and NOS-2) are dramatically increased by LPS treatment and markedly ameliorated by linagliptin therapy. Similar effects are observed for aortic protein tyrosine nitrification and malondialdehyde content (both markers of oxidative stress) and aortic NADPH oxidase subunit expression (Nox1 and Nox2). As proof of concept, DPP-4 activity and GLP-1 levels were detected in corresponding animals, demonstrating potent inhibition of DPP-4 and an almost 10-fold increase in plasma GLP-1 levels.
Direct Vasodilatory Effects of Glyptins : Isometric tension recordings demonstrate that some gliptins exhibit direct vasodilatory effects in the concentration range of 10-100 μM. Linagliptin was the most potent compound, followed by alogliptin and vildagliptin, while sitagliptin and saxagliptin were less effective than vehicle control (DMSO) in inducing vasodilation (see Figures 9A and 9B).
These observations support the pleiotropic antioxidant and anti-inflammatory properties of linagliptin, which are not shared (or shared to a lesser extent) with other gliptins. Furthermore, linagliptin reduces leukocyte adhesion to endothelial cells due to the presence of LPS and further ameliorates nitroglycerin-induced and inflammation-induced 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 antioxidant effects that have a beneficial impact on 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, endothelial NO synthase (eNOS) activity is altered in T2D, and genetic abnormalities in the corresponding gene (NOS3) are closely associated with the progression of further 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-/-) was recently reported (Brosius et al. JASN 2009), providing a valid experimental model for DN. Eight-week-old eNOS−/− mice are rendered diabetic by intraperitoneal injection of streptozotocin (100 mg/kg/day for two consecutive days). Diabetes onset (defined as blood glucose >250 mg/dL) is documented 1 week after streptozocin injection. Insulin is not administered as it may prevent the development of diabetic nephropathy. Mice are treated for 4 weeks with:
1) Non-diabetic control mice, placebo (natrosol) (n=14)
2) Sham-operated diabetic eNOS ko mice, 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 are detected between linagliptin, telmisartan or the above combinations and placebo (see Figure 10).
The albumin/creatinine ratio is significantly decreased in the linagliptin + telmisartan treated group (middle bar, Figure 11, 5) despite no detectable effect on blood glucose. Corresponding single-drug therapy also reduces the albumin/creatinine ratio, but not significantly. The albumin/creatinine ratio in nondiabetic versus diabetic animals is also significantly reduced (see Figure 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 of diabetic nephropathy and albuminuria.

Treatment of congestive heart failure and cardiac hypertrophy :
We hypothesize that glucose/energy supply is particularly important in cardiac dysfunction characterized by cardiac hypertrophy. Inadequate energy delivery is considered 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 caused by 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 regimens for 3 months:
1. 2K1C-rats, telmisartan (10 mg/kg KG) in drinking water (n=14)
2. 2K1C-rats, linagliptin (Bl1356) in diet (89 ppm, comparable to 3-10 mg/kg oral gavage) (n=15)
3. 2K1C- rats, telmisartan (10 mg/kg) + linagliptin (Bl1356) (89 ppm) in diet (n=15)
4. 2K1C- rats, placebo (n=17)
Five. SHAM-rats, placebo (n=11)
Non-invasive, systolic blood pressure is measured in all groups at multiple time points (for each compound: 1. pretreatment; 2. 1 week after treatment; 3. 4 weeks after treatment; 4. 6 weeks after treatment). 5. 12 weeks after treatment; and 6. 6 weeks after treatment).
Only sham-treated animals show significant differences to other groups before treatment. From the first week of treatment to the end of the experiment, telmisartan and the combination of telmisartan and linagliptin are consistently significant relative to vehicle-treated animals. The combination of telmisartan and linagliptin reaches the level of placebo sham-treated animals and shows an additive effect on top of telmisartan single treatment (see Figure 12). These effects support the use of linagliptin and telmisartan for 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 of cardiac hypertrophy and/or congestive heart failure.

Treatment of uremic cardiomyopathy :
Uremic cardiomyopathy contributes substantially 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 (eg in patients with type 2 diabetes and diabetic nephropathy) in all stages of renal failure without dose adjustments.
To probe linagliptin in a rat model with chronic renal insufficiency (5/6 nephrectomy [5/6N]): Eight weeks after 5/ 6N or sham surgery, rats were treated with 3.3 mg/kg linagliptin or The formulation is treated orally for 4 weeks, followed by sampling of plasma for 72 hours for quantification of DPP-4 activity and GLP-1 levels. Heart tissue is collected for mRNA analysis at the end of the experiment.
5/6N had a marked (p<0.01) decrease in GFR (measured by creatinine clearance) (2510±210 mU24h at sham; 1665±104.3 mU24h at 5/6N) and increased cystatin levels (700 at sham). ±35.7 ng/mL; 1434 ±77.6 ng/mL at 5/6N). DPP-4 activity decreased significantly at all time points and was not different between sham-operated and 5/6N animals. In contrast, active GLP-1 levels were higher than the maximum plasma concentration (C _max ; 6.36±2.58 pg/mL for 5/6N and 3.91±1.86 pg/mL for sham surgery) and AUC _(0-72h) (5 201 pg.h/mL for /6N and 114 pg.h/mL for sham surgery; p<0.001) significantly increased in 5/6N animals. Cardiac fibrosis markers (profibrotic factors) such as TGF-β, tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) and collagen 1α1 and 3α1 plus left ventricular dysfunction markers such as brain natriuretic peptide ( BNP) mRNA levels are both significantly increased in 5/6N vs. sham-operated animals and consequently decreased or normalized by linagliptin treatment (all p<0.05, see FIG. 13).
Linagliptin almost doubled the AUC of GLP-1 in a rat model of renal failure and also increased BNP (a marker of left ventricular dysfunction) as well as markers of cardiac fibrosis (TGF-β, TGF-β) in uremic rat hearts. 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 is to investigate the cardiac effects of the xanthine-based DPP-4 inhibitors of the invention, particularly their effects on myocardial ischemia/reperfusion, cardiac function or infarct size, e.g., 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-operated, ischemia/reperfusion (I/R), and I/R plus DPP-4 inhibitors of the invention; n=10/group. DPP-4 inhibitors are administered once daily starting 2 days before 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 reduced absolute infarct size (−27.8%; p<0.05), percentage of infarcted tissue to total area at risk (−18.5%; p<0.05), and extent of myocardial fibrosis (−31.6%; p < 0.05). DPP-4 inhibitors markedly increase stem/progenitor cell accumulation characterized by CD34-, CXCR4- and C-kit-expression and cardiac immunoreactivity to active SDF-1α in infarcted myocardium. Although left ventricular ejection fractions were similar in all MI groups after 7 days, DPP-4 inhibition reduced infarct size, decreased fibrotic remodeling, and further reduced infarct area by preventing degradation of SDF-1α. increase the stem cell density of
The xanthine-based DPP-4 inhibitors of the present invention can reduce infarct size after myocardial infarction. Mechanisms of action may involve reduced degradation of SDF-1α followed by increased recruitment of circulating CXCR-4 ⁺ stem cells and/or incretin receptor dependent pathways.
These data suggest 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, and decreased fibrous remodeling. and/or enhance the usefulness of the xanthine-based DPP-4 inhibitors of the invention in increasing the density of stem cells in infarcted heart regions.
Given that infarct size is a predictor of future events (including mortality), the xanthine-based DPP-4 inhibitors of the present invention may improve cardiac (systolic) function, cardiac contractility and/or myocardial ischemia. It may further be 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-operated, I/R, and I/R plus 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, followed by echocardiography after 58 days and cardiac catheterization after 60 days.
Linagliptin reduces absolute infarct size (-18%; p<0.05) as well as the percentage of infarcted tissue to total area at risk (-21%; p<0.001) in this model of ischemia-reperfusion injury. Furthermore, glucagon-like peptide-1 (GLP-1) levels are increased 18-fold (p<0.0001) and DPP-4 activity is decreased by 78% (p<0.0001). Left ventricular left end diastolic and systolic pressures as well as echocardiographic parameters were similar between groups, with a marked improvement in isovolumic contractility index (dP/dT _min ) (from -4771 ± 79 mmHg/s to -4957 mmHg/s). ±73 mmHg/s) or improvement in maximal rate of drop in left ventricular pressure. These data further support a cardioprotective function of linagliptin in the onset of acute myocardial infarction.

Treatment of ARB-resistant diabetic nephropathy :
The need for ameliorative treatment for diabetic nephropathy is extremely high in patients who do not respond adequately to angiotensin receptor blockers (ARBs). This experiment probes the effect of linagliptin alone or in combination with ARBs telmisartan on the progression of diabetic nephropathy in diabetic eNOS ko mice (a novel model resembling human pathology).
Sixty-five male eNOS knockout C57BL/6J mice were divided into four groups after high-dose streptozocin intraperitoneal administration: telmisartan (1 mg/kg), linagliptin (3 mg/kg), linagliptin plus telmisartan (3+1 mg/kg). kg), and excipients. 14 mice are used as non-diabetic controls. After 12 weeks, urine and blood are obtained and blood pressure is measured. Glucose levels are increased, and this is the same in all diabetic groups. Telmisartan alone reduced blood pressure modestly (5.9 mmHg) versus diabetic controls (111.2 ± 2.3 mmHg vs 117.1 ± 2.2 mmHg; mean ± SEM; each n = 14; p = 0.071); Not significant. Combined treatment significantly alleviated albuminuria compared with diabetic controls (71.7±15.3 μg/24h vs 170.8±34.2 μg/24h; n=12−13; p=0.017), whereas 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 Figure 14). Linagliptin (alone and in combination) results in significantly lower plasma osteopontin levels compared to telmisartan alone (values similar to diabetic controls). Plasma TNF-α concentrations 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 concomitant treatment with linagliptin.
Furthermore, linagliptin (alone and in combination with telmisartan) significantly attenuates 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 significantly different. In conclusion, linagliptin significantly reduces urinary albumin excretion (eg, in a blood pressure-independent manner) in ARB-refractory diabetic eNOS knockout mice. These actions may support the use of linagliptin in renal protection and in the treatment and/or prevention of ARB-resistant diabetic nephropathy. Linagliptin may provide a novel therapeutic approach for patients resistant to ARB therapy.

Delaying diabetes onset and preserving beta-cell function in non-obese type 1 diabetes :
Decreased pancreatic T-cell migration and altered cytokine production are thought to be important factors in the development of insulitis, but the exact mechanisms and actions on the pancreatic cell pool are still not fully understood. In an attempt to assess the effects of linagliptin on pancreatic inflammation and beta-cell mass, diabetes progression in non-obese diabetic (NOD) mice over an experimental period of 60 days was combined with terminal serological assessment of pancreatic cellular changes. to investigate.
60 female NOD mice (10 weeks old) are included in the experiment and are fed normal chow or chow containing linagliptin (0.083 g linagliptin/kg feed; corresponding to 3-10 mg/kg (po)) throughout the experimental period. . Plasma samples are obtained every 2 weeks to determine the onset of diabetes (BG>11 mmol/L). At termination, the pancreas is removed and a terminal blood sample is obtained for assessment of active GLP-1 levels.
At the end of the experimental period, diabetes incidence 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 serological assessment of beta-cell mass (identified by insulin immunoreactivity) showed significantly higher beta-cell mass in linagliptin-treated mice (0.18±0.03 mg vehicle; 0.48±0.09 mg linagliptin, p<0.01) and Total islet dose (vehicle 0.40±0.04 mg; linagliptin 0.70±0.09 mg, p<0.01) is shown. Linagliptin was associated with a trend towards perislet infiltrating lymphocyte depletion (1.06±0.15; linagliptin 0.79±0.12 mg; p=0.17). As expected, active plasma GLP-1 is elevated in linagliptin-treated mice.
In summary, the present data show that linagliptin can delay the onset of diabetes in a type 1 diabetes model (NOD mice). The strong beta cell soothing effect observable in this animal model suggests 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. It shows that it is possible to show 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 offer a novel therapeutic approach for patients with or at risk of type 1 diabetes or LADA.

Effects of linagliptin on body weight, total fat, liver fat and intramuscular fat :
In yet another experiment, the effects of long-term treatment with linagliptin compared to the anorectic subtramin on body weight, total body fat, intramuscular fat and liver fat in a non-diabetic model of diet-induced obesity (DIO) are probed.
Rats are fed a high-fat diet for 3 months and continue on the high-fat diet while receiving vehicle, linagliptin (10 mg/kg) or sibutramine (5 mg/kg) for an additional 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 significant weight loss (-12%) compared to controls, whereas linagliptin shows no significant effect. Total fat is also significantly reduced by sibutramine (-12%), whereas linagliptin-treated animals show no significant reduction (-5%). However, linagliptin and sibutramine lead to strong reductions in intramuscular fat (-24% and -34%, respectively). Furthermore, linagliptin treatment results in a strong reduction in liver fat (-39%), whereas the effect of sibutramine (-30%) is not significant (see table below). Thus, linagliptin ameliorates muscle cell lipid and hepatic lipid accumulation, albeit imprecisely in terms of weight. A reduction in liver steatosis, inflammation and fibrosis as measured by histological scoring is also observed with linagliptin treatment.

結論すれば、リナグリプチン処置は、筋細胞内脂質及び肝脂質の強い低下を惹起し、前記は両方とも体重低下とは別個である。リナグリプチン処置は、さらに別に肝脂肪症（例えばNAFLD）の影響を受ける糖尿病患者に対し更なる利益を提供する。シブトラミンの筋肉脂肪及び肝臓脂肪に対する影響は、主としてこの化合物によって誘発される既知の体重低下による。 Table: Effects of linagliptin on body weight, total fat, liver fat and intramuscular fat

In conclusion, linagliptin treatment caused a strong reduction in intramuscular and hepatic lipids, both of which were distinct from weight loss. Linagliptin treatment offers additional benefits to diabetic patients who are also otherwise affected by hepatic steatosis (eg NAFLD). Sibutramine's effects on muscle fat and liver fat are primarily due to the known weight loss induced by this compound.

Linagliptin has efficacy similar to glimepiride but improves cardiovascular safety over 2 years in patients with type 2 diabetes inadequately controlled with metformin:
A two-year double-blind study will examine the long-term efficacy and safety of adding linagliptin or glimepiride to metformin in use for the treatment of type 2 diabetes. Patients with T2DM on stable metformin (≥1500 mg/day) for ≥10 weeks will be randomized for linagliptin (5 mg/day, N=764) or glimepiride (1-4 mg/day, N=755) for 2 years . Efficacy analyzes will be based on change from baseline in HbA1c in the complete analysis set (FAS) and each protocol (PP) populations. Safety assessments included capture of prespecified, predictive, and adjudicated cardiovascular (CV) events (CV death, nonfatal myocardial infarction or stroke, hospitalized unstable angina). included. Baseline characteristics are well balanced in the 2 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% (±0.04%) for glimepiride (mean dose 3 mg/day) (± 0.04%). The mean 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. Far fewer patients experience investigator-defined drug-related hypoglycemia when using linagliptin than glimepiride (7.5% vs. 36.1%; p<0.0001). Body weight is decreased with linagliptin and increased 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%), representing a significant 50% reduction in 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 provided similar HbA1c reductions as glimepiride, but linagliptin was associated with less hypoglycemia, less relative weight loss, and significantly fewer adjudicated CV events. few.

Cardiovascular Risk from Linagliptin in Patients with Type 2 Diabetes: Prespecified Predictive and Further Adjudicated Post-Analysis Based on the Phase III Extensive Program:
The benefits of the cardiovascular system (CV) in lowering glucose in type 2 diabetes mellitus (T2DM) are currently controversial, especially when hypoglycemia is too strong. Several drug uses have been reported to be associated with unexpectedly worse CV outcomes.
Linagliptin is the first once-daily DPP-4 inhibitor available as a single dose that does not require dose adjustment for renal impairment. Linagliptin achieves glycemic control without weight gain or increased risk of hypoglycemia, which may be of benefit to CV.
To probe the CV profile of the DPP-4 inhibitor linagliptin, a prespecified post-analysis will be performed on all CV events from eight Phase III randomized double-blind controlled trials (over 12 weeks). CV events are adjudicated prospectively by an uninformed and unrelated panel of experts. The primary endpoint for this analysis is a composite of CV death, non-fatal stroke, non-fatal myocardial infarction (MI) and hospitalization for unstable angina (UAP). Other secondary and tertiary endpoints, including FDA's conventional major CV event side effects (MACE), will also be evaluated.
Of the 5239 patients included (mean baseline HbA _1c of 8.0%), 3319 received once-daily linagliptin (5 mg: 3159; 10 mg: 160) and 1920 received a comparator (placebo). : 997, glimepiride: 781, voglibose: 162). Cumulative exposure (in person-years) is 2060 for linagliptin and 1372 for the comparator. As a result, adjudicated primary CV events occurred in 11 (0.3%) linagliptin-treated patients and 23 (1.2%) comparator-treated patients. Hazard ratios for the primary endpoint are significantly lower for linagliptin versus comparator, and hazard ratios for all other endpoints are similar or significantly lower for linagliptin (TABLE).
This is the first pre-specified, predictive, separately adjudicated post-CV analysis of a DPP-4 inhibitor in a broad-spectrum Phase III program. Although a post-analysis with obvious limitations, the data support a potential reduction of CV events for linagliptin.

*有意に低いハザード比（上限95％CI＜1.0；p＜0.05） TABLE:

*Significantly lower hazard ratio (upper 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 relevant population of patients with type 2 diabetes mellitus are probed as follows:
Inadequate glycemic control (treatment naive or currently being treated with e.g. metformin and/or alpha-glucosidase inhibitors (single or dual therapy) e.g. HbA1c 6.5-8.5%) or (e.g. HbA1c 7.5-8.5%)) in the presence or absence of metformin or alpha-glucosidase inhibitors, e.g. Type 2 diabetes patients with event risk (e.g., as defined by one or more of risk factors A), B), C) and D) listed below) are treated with linagliptin (optionally with one or more other active agents ( for a period of time (eg, 2 years or more, 4-5 years, or 1-6 years), and other antidiabetic medications (eg, sulfonylureas, such as glimepiride) or placebo-treated patients. Evidence of successful treatment compared to other antidiabetic medications or placebo-treated patients is a low number of single or multiple complications (complications include, for example, cardiovascular or cerebrovascular disease). sexual events, e.g. cardiovascular death, myocardial infarction, stroke or hospitalization (e.g. acute coronary syndrome, leg amputation, hospitalization for emergency revascularization or unstable angina)), or preferably thereof (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)) by prolonging the time of the first appearance of either).
Yet another therapeutic success is a greater proportion of patients undergoing study treatment, with no need for emergency medical care and no weight gain (e.g., >2%) and glycemic control (e.g., HbA1c <7%) at the end of the study. ) is maintained. Yet another therapeutic success is a greater proportion of patients undergoing study treatment, no need for emergency medical care and no moderate/severe hypoglycemic episodes and weight gain (e.g., 2% or more) at the end of the study. Blood sugar control (e.g., HbA1c < 7%) is maintained without
Yet another therapeutic success can be seen in the CV superiority of treatment with linagliptin showing a risk reduction (eg preferably a 20% risk reduction) compared to treatment with glimepiride.
Risk factors A), B), C) and D) for cardiovascular events are:
A) Previous vascular disease (eg age 40-85 years):
- myocardial infarction (eg 6 weeks or longer),
- coronary artery disease (e.g. stenosis of 50% or more of the lumen diameter in the left main coronary artery or at least two major coronary arteries on angiogram),
- percutaneous coronary intervention (eg 6 weeks or longer),
- coronary artery bypass graft (for example >4 years or showing recurrent angina after surgery),
- ischemic or hemorrhagic stroke (eg 3 months or longer),
- Peripheral occlusive arterial disease (e.g. previous limb bypass surgery or percutaneous transluminal angioplasty; previous limb or leg amputation due to circulatory failure; major limb arteries (total arteries) detected by angiography or ultrasound; history of significant vascular stenosis (>50% stenosis) of the iliac artery, internal iliac artery, external iliac artery, femoral artery, popliteal artery), intermittent claudication (related to the tarsal joint); arm blood pressure ratio less than 0.90),
B) Vascular-related end-organ disease (eg age 40-85 years):
- renal impairment (e.g. eGFRF 30 - 59 mL/min/1.73 m ² with moderate renal impairment as prescribed by MDRD prescription),
- microalbuminuria or macroalbuminuria (e.g. microalbuminuria or random spot urinary albumin:creatine ratio ≥ 30 μg/mg),
- retinopathy (e.g. proliferative retinopathy, or retinal neovascularization or prior retinal laser coagulation therapy),
C) Elderly (e.g. age 70+):
D) At least 2 of the following cardiovascular risk factors (eg age 40-85 years):
- advanced type 2 diabetes mellitus (eg for more than 10 years),
- hypertension (e.g. systolic blood pressure >140 mmHg or at least one blood pressure lowering therapy),
- current daily smoking,
- treatment of (atherogenic) dyslipidemia or elevated blood levels of LDL-cholesterol (e.g. LDL-cholesterol greater than or equal to 135 mg/dL) or at least one lipid abnormality,
- (visceral and/or abdominal) obesity (e.g. body mass index ≥ 45 kg/ ^m2 ),
- Age over 40 and under 80.

Cognitive function (e.g. cognitive decline, changes in psychomotor speed, psychological stability), β-cell function (e.g. insulin secretion rate for 3h food tolerance test, long-term β-cell function), renal function parameters, circadian glucose patterns (e.g. behavioral time glucose profile, glycemic variability, biomarkers of oxidation, inflammation and endothelial function, cognition, and CV prevalence/mortality), asymptomatic MI (e.g. ECG parameters, CV prophylaxis characteristics), LADA (e.g. emergency treatment regimens) Use or disease progression in LADA), and/or the beneficial effects (eg, improvement) of linagliptin treatment on the persistence of glucose control in beta-cell autoantibody conditions (eg, GAD) are probed in tributary studies.

Claims (4)

A pharmaceutical composition comprising linagliptin for use in a method of treating diabetes mellitus type 2 , wherein one or more cardiovascular risks selected from A), B), C) and D) below used in patients with factors,
The pharmaceutical composition, wherein the method comprises administering to the patient a therapeutically effective amount of linagliptin, optionally together with one or more other therapeutic agents:
A) Prior or existing vessel selected from myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure, and peripheral occlusive arterial disease system diseases;
B) a vessel-related end-organ disease selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic kidney disease and microalbumin or macroalbuminuria;
C) old age ( 70 years and older); and
D) At least 2 cardiovascular risk factors selected from:
- advanced type 2 diabetes mellitus (duration >10 years),
- hypertension,
- current daily smoking,
- dyslipidemia, and
-obesity. the patient has cardiovascular and/or renal disease selected from myocardial infarction, stroke, peripheral arterial occlusive disease, diabetic nephropathy, microalbumin or macroalbuminuria, acute or chronic renal impairment and /or hypertension 2. The composition of claim 1 , wherein a patient with type 2 diabetes has or is at risk of having it. the method is
In addition, linagliptin plus one or more other antidiabetic agents selected from metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-gamma agonists, alpha-glucosidase inhibitors, insulin, and GLP-1, and optionally telmisartan or
further comprising administering linagliptin together with metformin, or
further comprising administering linagliptin together with telmisartan;
3. A composition according to claim 1 or 2 . 4. The composition of any one of claims 1-3 , wherein linagliptin is administered orally in a total daily dose of 5 mg.

Images