Treatment for diabetes in patients inappropriate for metformin therapy

Abstract

To treat and / or prevent metabolic diseases, particularly diabetes, in patients for whom metformin therapy is inappropriate due to intolerability or contraindication against metformin.SOLUTION: Certain DPP-4 inhibitors are particularly suitable, such as 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)-xanthine.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to certain DPP-4 inhibitors for the treatment and / or prevention of metabolic disorders, in particular diabetes (especially type 2 diabetes) and conditions associated therewith, in patients for whom standard metformin treatment is not appropriate (due to intolerance or contraindications to metformin), and to the use of said DPP-4 inhibitors in said treatment and / or prevention. Pharmaceutical compositions and combinations comprising a DPP-4 inhibitor as defined herein, optionally together with one or more other active substances, for the treatment and / or prevention of metabolic disorders (especially diabetes) in these patients are also contemplated. [Background technology]

[0002] Type 2 diabetes is a common disease with increasing prevalence worldwide and can be associated with macrovascular complications such as cardiovascular disease, and / or microvascular complications such as blindness, neuropathy and / or renal impairment or failure. There are various reasons why kidney dysfunction can occur in people with diabetes. One typical long-term complication of diabetes is diabetic nephropathy, which in some cases can progress to kidney failure. Although intensive treatment of hyperglycemia can reduce the incidence of chronic damage, many type 2 diabetes patients remain undertreated, in part due to limited long-term efficacy, tolerability and inconvenience of dosing of conventional hyperglycemic therapies.

[0003] Dietary therapy and exercise therapy are essential for the treatment of diabetes. When these therapies do not adequately control the patient's condition (especially blood glucose level), oral or parenteral antidiabetic drugs are further used to treat diabetes. Conventional antidiabetic or hyperglycemic drugs include, but are not limited to, metformin, sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1, GLP-1 analogs, insulin, and insulin analogs. However, the use of these conventional antidiabetic or hyperglycemic drugs may be accompanied by various side effects. For example, metformin may be associated with lactic acidosis or gastrointestinal side effects; sulfonylureas, glinides, insulin or insulin analogues may be associated with hypoglycemia or weight gain; thiazolidinediones may be associated with edema, bone fractures, weight gain or heart failure / cardiac effects; and alpha-glucosidase blockers, GLP-1 or GLP-1 analogues may be associated with gastrointestinal side effects (e.g., dyspepsia, bloating or diarrhea, or nausea or vomiting).

[0004] Metformin is a hyperglycemic drug that improves glucose tolerance in patients with type 2 diabetes. Metformin can be used alone or combined with other hyperglycemic drugs that improve glycemic control in patients with type 2 diabetes who respond to metformin. Metformin may also be of value in the treatment of obese or overweight diabetic patients or in patients with polycystic ovarian syndrome. However, metformin treatment may be accompanied by side effects such as gastrointestinal symptoms or, occasionally, as a serious side effect, lactic acidosis (which may be fatal), one putative risk factor being reduced renal function. Furthermore, metformin is mainly excreted unchanged from the kidney by renal glomerular filtration and tubular secretion, and is therefore contraindicated in patients with renal disease or impaired renal function. Thus, conventional metformin treatment may be inappropriate for certain patients, for example, due to intolerance or contraindication to metformin. Thus, the number of patients who are metformin ineligible is very large and includes a significant proportion of patients who would benefit from the drug. Therefore, there remains a need in the art to provide an effective, safe and acceptable antidiabetic treatment for these diabetic patients who are ineligible for metformin treatment.

[0005] In monitoring the treatment of diabetes, the value of HbA1c, a product of nonenzymatic glycation of the hemoglobin B chain, is of exceptional importance. Since its formation depends essentially on the blood glucose level and on the life span of red blood cells, HbA1c reflects the average blood glucose level 4-12 weeks prior in the sense of "glycemic memory". Diabetic patients whose HbA1c levels are well controlled over time by more intensive diabetes treatment (i.e. total hemoglobin in the sample <6.5%) are significantly better protected from diabetic microangiopathy. The available treatments for diabetes can give diabetics an average improvement in HbA1c levels of about 1.0 - 1.5%. This reduction in HbA1c levels is not enough to bring all diabetic patients into the desired target range of <7.0%, preferably <6.5%, more preferably <6% HbA1c.

[0006] Within the scope of glycemic control, in addition to improving HbA1c levels, other recommended treatment goals for patients with type 2 diabetes are to improve fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels to normal or as close to normal as possible. The recommended desired target ranges for preprandial (fasting) plasma glucose are 90-130 mg / dL or <110 mg / dL, and 2-hour postprandial plasma glucose is <180 mg / dL or <140 mg / dL. Within the meaning of the present invention, inadequate or insufficient glycemic control refers in particular to a condition in which the patient has an HbA1c value of more than 6.5%, in particular more than 7.0%, even more preferably more than 7.5%, in particular more than 8%. The embodiment of the patient with inadequate or insufficient glycemic control includes, but is not limited to, patients with an HbA1c value of 7.5-10% (or in another embodiment, 7.5-11%). A special subembodiment of the inadequately controlled patient relates to patients with poor glycemic control, including, but not limited to, patients with an HbA1c value of ≧9%.

[0007] Patients who are ineligible for metformin treatment within the meaning of the present invention include: - Patients for whom metformin treatment is contraindicated, e.g. patients who have one or more contraindications to metformin treatment according to the classification label, e.g. patients who have at least one contraindication selected from the following: renal disease, renal impairment, or renal insufficiency (e.g., as specified by the locally approved product information for metformin); dehydration, unstable or acute congestive heart failure, Acute or chronic metabolic acidosis, and Hereditary galactose intolerance; and - Patients experiencing one or more intolerable side effects due to metformin, in particular gastrointestinal side effects associated with metformin, for example patients experiencing one or more gastrointestinal side effects selected from the following: nausea, vomiting, diarrhea, Intestinal gas, Severe abdominal discomfort.

[0008] Furthermore, due to increased susceptibility to side effects, treatment of elderly patients (e.g., ≧60-70 years old) must often be accompanied by careful monitoring of renal function. Metformin is not usually recommended for elderly individuals, particularly ≧80 years old, unless creatinine clearance measurements indicate that renal function is not declining. Thus, patients who are ineligible for metformin treatment may include, but are not limited to, elderly patients, e.g., ≧60-65 years old, or particularly ≧80 years old.

[0009] A particular embodiment of patients ineligible for metformin treatment within the meaning of the present invention relates to patients with renal disease, renal impairment, or renal insufficiency or impairment (including mild, moderate and severe renal impairment), e.g. as indicated by high serum creatinine levels (e.g. serum creatinine levels above the upper normal limit for age, e.g. ≧130-150 μmol / l, or ≧1.5 mg / dl (≧136 μmol / l) in men and ≧1.4 mg / dl (≧124 μmol / l) in women) or abnormal creatinine clearance (e.g. glomerular filtration rate (GFR) ≦30-60 ml / min, e.g. including moderate or severe renal impairment including ESRD).

[0010] In this context, as a more detailed example, mild renal impairment may be indicated, for example, by a creatinine clearance of 50-80 ml / min (approximately corresponding to a serum creatinine level of ≦1.7 mg / dL in men and ≦1.5 mg / dL in women); moderate renal impairment may be indicated, for example, by a creatinine clearance of 30-50 ml / min (approximately corresponding to a serum creatinine level 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 indicated, for example, by a creatinine clearance of <30 ml / min (approximately corresponding to a serum creatinine level of >3.0 mg / dL in men and >2.5 mg / dL in women). Patients with end-stage renal disease require dialysis (e.g., hemodialysis or peritoneal dialysis).

[0011] As another more detailed example, patients with renal disease, renal insufficiency or impairment may be treated with a glomerular filtration rate (GFR, ml / min / 1.73 m 2 ) into 5 stages: stage 1 is characterized by a normal GFR > 90 and persistent proteinuria or known structural or genetic renal disease; stage 2 is characterized by a mild decrease in GFR (GFR 60-89) describing mild renal impairment; stage 3 is characterized by a moderate decrease in GFR (GFR 30-59) describing moderate renal impairment; stage 4 is characterized by a severe decrease in GFR (GFR 15-30) describing severe renal impairment; and end stage 5 is characterized by a GFR < 15 describing the need for dialysis or established renal failure (end stage renal disease, ESRD).

[0012] Other intolerable (gastrointestinal) side effects caused by metformin (such as nausea, vomiting, gas, diarrhea) can be associated with the dosage of the drug, and therefore can be minimized when the dosage of metformin is reduced.Because there are many patients within the scope of the present invention who should not or cannot use metformin, and who can only use metformin at reduced dosages, the dosing of metformin must be highly individually adjusted (e.g., by dose escalation) based on efficacy, safety and tolerance, often as a compromise between efficacy and safety / tolerance.Therefore, there is also a need in the art to provide better (e.g., more effective) antidiabetic treatment to diabetic patients who need reduced-dose metformin treatment due to reduced tolerance, intolerance, or contraindication to metformin.

[0013] Metformin is usually administered at a dose of about 500mg to 2000mg, up to 2500mg, about 100mg to 500mg or 200mg to 850mg (1-3 times a day), or about 300mg to 1000mg once or twice a day using various dosage regimens, or delayed release metformin at a dose of about 100mg to 1000mg or preferably 500mg to 1000mg once or twice a day or about 500mg to 2000mg once a day. Specific doses can be 250, 500, 625, 750, 850 and 1000mg of metformin hydrochloride.

[0014] The enzyme DPP-4 (dipeptidyl peptidase IV), also known as CD26, is a serine protease known to lead to the cleavage of dipeptides from the N-terminus of many proteins that have proline or alanine residues at their N-terminus. Due to this property, DPP-4 inhibitors interfere with the plasma levels of bioactive peptides, including the peptide GLP-1, and are considered to be promising drugs for the treatment of diabetes.

[0015] For example, DPP-4 inhibitors and their uses, in particular in metabolic (especially diabetic) diseases, are described in WO 2002 / 068420, WO 2004 / 018467, WO 2004 / 018468, WO 2004 / 018469, WO 2004 / 041820, WO 2004 / 046148, WO 2005 / 051950, WO 2005 / 082906, WO 2005 / 063750, WO 2005 / 085246, WO 2006 / 027204, WO 2006 / 029769 or WO2007 / 014886; or in WO 2004 / 050658, WO 2004 / 111051, WO 2005 / 058901 or WO 2005 / 097798; or in WO 2006 / 068163, WO 2007 / 071738 or WO 2008 / 017670; or in WO 2007 / 128721 or WO 2007 / 128761.

[0016] Further DPP-4 inhibitors can include the following compounds: - Sitagliptin (MK-0431), having the following structural formula A, is (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one, also called (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine;

[0017] [ka]

[0018] In one embodiment, sitagliptin is in the form of dihydrogen phosphate, i.e., sitagliptin phosphate. In a further embodiment, sitagliptin phosphate is in the form of crystalline anhydrate or monohydrate. One of the embodiments relates to sitagliptin phosphate monohydrate. Sitagliptin free base and its pharma-ceutically acceptable salts are disclosed in U.S. Pat. No. 6,699,871 and in Example 7 of WO 03 / 004498. Crystalline sitagliptin phosphate monohydrate is disclosed in WO 2005 / 003135 and WO 2007 / 050485. More specifically, for example, how to make, formulate or use the compounds or their salts are described in these references.

[0019] A tablet formulation of sitagliptin is commercially available under the trade name Januvia®. A tablet formulation of sitagliptin / metformin combination is commercially available under the trade name Janumet®. - Vildagliptin (LAF-237), having the following structural formula B, is (2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}pyrrolidine-2-carbonitrile, also known as (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine

[0020] [ka]

[0021] Vildagliptin is disclosed in detail in U.S. Patent No. 6,166,063 and in Example 1 of WO 00 / 34241. Certain salts of vildagliptin are disclosed in WO 2007 / 019255. Vildagliptin tablet formulations as well as vildagliptin crystalline forms are disclosed in WO 2006 / 078593. Vildagliptin can be formulated as described in WO 00 / 34241 or WO 2005 / 067976. Modified release vildagliptin formulations are described in WO 2006 / 135723. More specifically, for example, how to make, formulate or use the compounds or their salts are described in these references.

[0022] A tablet formulation of vildagliptin is commercially available under the trade name Galvus®. A tablet formulation of vildagliptin / metformin combination is commercially available under the trade name Eucreas®. - Saxagliptin (BMS-477118), which has the following structural formula C, is (1S,3S,5S)-2-{(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl}-2-azabicyclo[3.1.0]hexane-3-carbonitrile, also known as (S)-3-hydroxyadamantylglycine-L-cis-4,5-methanoproline nitrile;

[0023] [ka]

[0024] Saxagliptin is disclosed in detail in U.S. Pat. No. 6,395,767 and Example 60 of WO 01 / 68603. In one embodiment, saxagliptin is in the form of an HCl salt or a monobenzoate salt as disclosed in WO 2004 / 052850. In further embodiments, saxagliptin is in the form of a free base. In yet further embodiments, saxagliptin is in the form of a monohydrate of the free base as disclosed in WO 2004 / 052850. Crystalline forms of the HCl salt and free base of saxagliptin are disclosed in WO 2008 / 131149. Methods for preparing saxagliptin are also disclosed in WO 2005 / 106011 and WO 2005 / 115982. Saxagliptin can be formulated into tablets as described in WO 2005 / 117841. More specifically, for example, how to make, formulate or use the compounds or their salts are described in these references.

[0025] - Alogliptin (SYR-322), having the following structural formula E, is 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl}methyl)benzonitrile

[0026] [ka]

[0027] Alogliptin is disclosed in detail in US 2005 / 261271, EP 1586571 and WO 2005 / 095381. In one embodiment, alogliptin is in the form of a benzoate, hydrochloride or tosylate, respectively, as disclosed in WO 2007 / 035629. One of the embodiments relates to alogliptin benzoate. Polymorphs of alogliptin benzoate are disclosed in WO 2007 / 035372. Methods for preparing alogliptin are disclosed in WO 2007 / 112368, in particular in WO 2007 / 035629. Alogliptin (i.e., its benzoate) can be formulated and administered in tablets as described in WO 2007 / 033266. Combinations of alogliptin with metformin or pioglitazone are described in WO 2008 / 093882 or WO 2009 / 011451, respectively. More specifically, for example, how to make, formulate or use the compounds or their salts are described in these references.

[0028] - (2S)-1-{[2-(5-methyl-2-phenyloxazol-4-yl)ethylamino]acetyl}pyrrolidine-2-carbonitrile or a pharma- ceutically acceptable salt thereof, preferably the mesylate, or (2S)-1-{[1,1,-dimethyl-3-(4-pyridin-3-ylimidazol-1-yl)propylamino]acetyl}pyrrolidine-2-carbonitrile or a pharma-ceutically acceptable salt thereof:

[0029] These compounds and their preparation methods are disclosed in WO 03 / 037327. The mesylate salt of the former compound, as well as its crystalline polymorphs, is disclosed in WO 2006 / 100181. The fumarate salt of the latter compound, as well as its crystalline polymorphs, is disclosed in WO 2007 / 071576. These compounds may be formulated into pharmaceutical compositions as described in WO 2007 / 017423. More specifically, for example, how to make, formulate or use the compounds or their salts are described in these references.

[0030] - (S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethylpyrrolidin-2-one or a pharma- ceutical acceptable salt thereof:

[0031] [ka]

[0032] This compound and its preparation are disclosed in WO 2005 / 000848. Methods for the preparation of this compound, particularly its dihydrochloride salt, are also disclosed in WO 2008 / 031749, WO 2008 / 031750 and WO 2008 / 055814. This compound may be formulated into pharmaceutical compositions as described in WO 2007 / 017423. More specifically, for example, how to make, formulate or use the compounds or their salts are described in these references.

[0033] - (3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone (also called gosogliptin) or a pharma- ceutical acceptable salt thereof: This compound and methods for its preparation are disclosed in WO 2005 / 116014 and US 7,291618. More specifically, for example, how to make, formulate or use the compounds or their salts are described in these references.

[0034] - (1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one or a pharma- ceutical acceptable salt thereof:

[0035] [ka]

[0036] This compound and methods of preparation are disclosed in WO 2007 / 148185 and US 20070299076. More specifically, for example, how to make, formulate or use the compounds or their salts are described in these references.

[0037] - (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl}-4-fluoropyrrolidine-2-carbonitrile (also called merogliptin) or a pharma- ceutical acceptable salt thereof:

[0038] [ka]

[0039] This compound and methods for its preparation are disclosed in WO 2006 / 040625 and WO 2008 / 001195. Specifically claimed salts include the methanesulfonate and p-toluenesulfonate salts. More specifically, for example, how to make, formulate or use the compounds or their salts are described in these references.

[0040] - (R)-2-[6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluorobenzonitrile or a pharma- ceutical acceptable salt thereof:

[0041] [ka]

[0042] This compound and its preparation and use are disclosed in WO 2005 / 095381, US 2007060530, WO 2007 / 033350, WO 2007 / 035629, WO 2007 / 074884, WO 2007 / 112368, WO 2008 / 114807, WO 2008 / 114800 and WO 2008 / 033851. In particular, the claimed salts include succinate (WO 2008 / 067465), benzoate, benzenesulfonate, p-toluenesulfonate, (R)-mandelate and hydrochloride. In particular, for example, the method of producing, formulating or using this compound or its salt is described in these references.

[0043] - 5-{(S)-2-[2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethylamino]propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bisdimethylamide or a pharma- ceutical acceptable salt thereof:

[0044] [ka]

[0045] This compound and methods of preparation are disclosed in WO 2006 / 116157 and US 2006 / 270701. More detailed information, such as how to make, formulate or use this compound or a salt thereof, is set forth in these references.

[0046] - 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine (also called teneligliptin) or a pharma- ceutical acceptable salt thereof: The compound and its preparation are disclosed in WO 02 / 14271. Individual salts are disclosed in WO 2006 / 088129 and WO 2006 / 118127 (including, inter alia, the hydrochloride and hydrobromide salts). Combination therapy with the compound is described in WO 2006 / 129785. More details, for example, on how to prepare, formulate or use the compound or its salts, are described in these references.

[0047] - [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic acid (also called dutogliptin) or a pharma- ceutical acceptable salt thereof: The compound and its preparation are disclosed in WO 2005 / 047297, WO 2008 / 109681 and WO 2009 / 009751. Individual salts are disclosed in WO 2008 / 027273 (including citrate, tartrate). Formulations of the compound are described in WO 2008 / 144730. More details, for example, on how to make, formulate or use the compound or its salts, are set forth in these references.

[0048] - (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile or a pharma- ceutical acceptable salt thereof: This compound and methods for its preparation are disclosed in WO 2005 / 075421, US 2008 / 146818 and WO 2008 / 114857. More detailed information, for example about how to make, formulate or use this compound or its salts, is set forth in these references. - 2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile or a pharma- ceutically acceptable salt thereof, or 6-[(3R)-3-aminopiperidin-1-yl]-5-(2-chloro-5-fluorobenzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione or a pharma-ceutically acceptable salt thereof: These compounds and methods for their preparation are disclosed in WO 2009 / 084497 and WO 2006 / 068163, respectively, and more particularly, for example, as to how to make, formulate or use the compounds or salts thereof, are set forth in these references. For the avoidance of doubt, the disclosures of each of the above cited references are hereby expressly incorporated herein in their entireties. Summary of the Invention [Problem to be solved by the invention]

[0049] Within the scope of the present invention, it has surprisingly been found that DPP-4 inhibitors as defined herein have surprising, particularly advantageous properties which make them particularly suitable for treating and / or preventing (including arresting or slowing the progression of) metabolic diseases, in particular diabetes (especially type 2 diabetes) and conditions related thereto (e.g. diabetic complications), in particular in patients in whom metformin treatment is unsuitable due to intolerance or contraindications to metformin, e.g. patients who are ineligible for metformin therapy due to intolerance or contraindications to metformin or patients who require a reduced metformin dose. [Means for solving the problem]

[0050] Thus, the present invention provides a DPP-4 inhibitor as defined herein for use in the treatment and / or prevention of metabolic diseases, in particular type 2 diabetes, in patients in whom metformin treatment is inappropriate due to intolerance to or contraindications to metformin. The present invention further provides the use of a DPP-4 inhibitor as defined herein for the preparation of a pharmaceutical composition for the treatment and / or prevention of metabolic diseases, in particular type 2 diabetes, in patients in whom metformin treatment is inappropriate due to intolerance to or contraindications to metformin. The present invention further provides a pharmaceutical composition for use in the treatment and / or prevention of metabolic diseases, in particular type 2 diabetes, in patients in whom metformin treatment is inappropriate due to intolerance to or contraindications to metformin, said pharmaceutical composition comprising a DPP-4 inhibitor as defined herein and optionally one or more pharma- ceutically acceptable carriers and / or diluents.

[0051] The present invention further provides fixed or non-fixed combinations comprising a kit-of-parts for use in the treatment and / or prevention of metabolic diseases, in particular type 2 diabetes, in patients in whom metformin treatment is inappropriate due to intolerance to or contraindications to metformin, said combinations comprising a DPP-4 inhibitor as defined herein and optionally one or more other active substances, such as any of those listed herein. The present invention further provides the use of a DPP-4 inhibitor as defined herein in combination with one or more other active substances, such as any of those mentioned herein, for the manufacture of a pharmaceutical composition for the treatment and / or prevention of metabolic diseases, in particular type 2 diabetes, in patients in whom metformin treatment is inappropriate due to intolerance to or contraindications to metformin. The present invention further provides a pharmaceutical composition for use in the treatment and / or prevention of metabolic diseases, in particular type 2 diabetes, in patients in whom metformin treatment is unsuitable due to intolerance or contraindications to metformin, comprising a DPP-4 inhibitor as defined herein and optionally one or more other active substances, such as any of those mentioned herein, e.g. for separate, sequential, simultaneous, parallel or alternating sequential use of the active ingredients.

[0052] The present invention further provides a method for the treatment and / or prevention of metabolic diseases, in particular type 2 diabetes, in patients in whom metformin treatment is inappropriate due to intolerance or contraindications to metformin, comprising administering to a subject (in particular a human patient) in need thereof an effective amount of a DPP-4 inhibitor as defined herein, optionally alone or in separate, sequential, simultaneous, parallel or alternating sequence combination with an effective amount of one, two or more other active substances, such as any of those mentioned herein.

[0053] Additionally, DPP-4 inhibitors as defined herein may be effective in one or more of the following ways in patients in whom metformin treatment is inappropriate due to intolerance or contraindications to metformin: - Preventing, retarding, slowing or treating metabolic diseases; - Improve glycemic control and / or reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; - preventing, slowing, retarding or treating a condition or disorder selected from the group consisting of complications of diabetes; - Lose weight or prevent weight gain or promote weight loss; - preventing or treating the degeneration of pancreatic beta cells and / or restoring and / or improving the function of pancreatic beta cells and / or stimulating and / or restoring the function of pancreatic insulin secretion; and / or - maintaining and / or improving insulin sensitivity and / or treating or preventing hyperinsulinemia and / or insulin resistance.

[0054] Examples of such metabolic diseases or disorders suitable for treatment according to the invention in patients ineligible for metformin treatment include, but are not limited to, type 1 diabetes, type 2 diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, metabolic syndrome X, obesity, hypertension, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, endothelial dysfunction and osteoporosis. The present invention further provides the use of a DPP-4 inhibitor as defined herein for the manufacture of a medicament for one or more of the following purposes, optionally in combination with one or more other active substances, such as any of those listed herein, in particular in patients for whom metformin treatment is inappropriate due to intolerance or contraindications to metformin and / or in patients with renal disease, renal insufficiency or impaired or impaired renal function (including patients with chronic renal failure): - preventing, slowing the progression, retarding or treating a metabolic disease or disorder, such as type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy and / or metabolic syndrome; - improving glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; - Prevent, delay, slow or reverse the progression of Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), insulin resistance and / or metabolic syndrome to type 2 diabetes; - prevent, reduce the risk of, slow the progression, delay or treat complications of diabetes, such as microvascular and macrovascular diseases, e.g. nephropathy, microalbuminuria, macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning disabilities, memory impairment, neurodegenerative disorders, cognitive impairment, cardiovascular disorders, cerebrovascular disorders, tissue ischemia, diabetic foot, diabetic ulcers, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders, vascular restenosis, and / or stroke; - reducing weight or preventing weight gain or promoting weight loss; - preventing, slowing, retarding or treating the degeneration of pancreatic beta cells and / or the decline of pancreatic beta cell function and / or improving and / or restoring pancreatic beta cell function and / or stimulating and / or restoring pancreatic insulin secretion function; - Prevent, slow, delay or treat non-alcoholic fatty liver disease (NAFLD), including hepatic steatosis, non-alcoholic steatohepatitis (NASH) and / or liver fibrosis; - Prevent, slow, delay or treat type 2 diabetes mellitus due to primary or secondary failure to conventional (oral) antihyperglycemic monotherapy or combination therapy; - Achieving a reduction in the dosage of conventional antihyperglycemic agents required for adequate therapeutic effect; - reducing the risk of side effects associated with traditional antihyperglycemic agents; and / or - maintaining and / or improving insulin sensitivity and / or treating or preventing hyperinsulinemia and / or insulin resistance.

[0055] Further, according to an embodiment of the present invention there is provided a DPP-4 inhibitor as defined herein for treating and / or preventing (including reducing the risk of onset or progression of) a metabolic disorder or disease, in particular diabetes (in particular type 2 diabetes), in patients with renal disease, renal insufficiency or insufficiency or impairment of renal function (including patients with chronic renal failure), optionally in combination with one or more other active substances, for example selected from those listed herein.

[0056] In an embodiment of the invention, patients as described herein who are suitable for treatment with a DPP-4 inhibitor as defined herein, optionally in combination (additionally or initially) with one or two conventional antihyperglycemic agents selected from sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and insulin or insulin analogues, include drug-naive and pre-treated diabetic patients, e.g. patients with inadequate glycemic control despite conventional antidiabetic treatment (e.g. primary or secondary drug failure), e.g. metformin, sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and insulin or insulin analogues. These may include, but are not limited to, patients who have inadequate glycemic control despite treatment (and, where applicable, treatment with maximal tolerated oral doses) with one, two or three conventional antihyperglycemic agents selected from: an insulin or insulin analogue, an alpha-glucosidase blocker, a GLP-1 or GLP-1 analogue, and an insulin or insulin analogue (e.g., despite monotherapy with a sulfonylurea, pioglitazone or (basal) insulin, or despite dual therapy with a sulfonylurea / pioglitazone, sulfonylurea / (basal) insulin or pioglitazone / (basal) insulin combination).

[0057] In a further embodiment of the invention, there is provided a DPP-4 inhibitor as defined herein for use in the (first line) treatment of patients with type 2 diabetes mellitus for which metformin treatment is not appropriate (due to intolerance to or contraindications to metformin), optionally in combination with one or more conventional antihyperglycemic agents selected from sulfonylureas, thiazolidinediones (e.g. pioglitazone), glinides, alpha-glucosidase blockers, GLP-1, GLP-1 analogues, insulin, and insulin analogues.

[0058] In a further embodiment of the invention, there is provided a DPP-4 inhibitor as defined herein for use in the (second or third line) treatment of patients with type 2 diabetes mellitus in which metformin treatment is not appropriate (due to intolerance to or contraindications to metformin) and who are inadequately controlled with one or more of said conventional antihyperglycemic agents, optionally in combination with one or more conventional antihyperglycemic agents selected from sulfonylureas, thiazolidinediones (e.g. pioglitazone), glinides, alpha-glucosidase blockers, GLP-1, GLP-1 analogues, insulin, and insulin analogues.

[0059] In a further embodiment of the invention there is provided a DPP-4 inhibitor as defined herein in combination with pioglitazone for use in type 2 diabetes patients for whom metformin treatment is according to the invention not suitable (due to intolerance to or contraindications to metformin), in particular patients who are overweight. Other aspects of the invention will be apparent to those skilled in the art from the remarks above and below. DPP-4 inhibitors within the meaning of the present invention include, but are not limited to, any of the DPP-4 inhibitors listed above and below, preferably orally active DPP-4 inhibitors.

[0060] A particular embodiment of the invention relates to DPP-4 inhibitors for use in the treatment of type 2 diabetes in patients with inadequate glycemic control in whom metformin treatment is inappropriate due to intolerance to or contraindications to metformin. Another particular embodiment of the invention relates to a DPP-4 inhibitor for use in the treatment and / or prevention of metabolic diseases, in particular type 2 diabetes, in patients (in particular in patients with renal disease, renal insufficiency or renal impairment) for which metformin treatment is inappropriate due to intolerance or contraindications to metformin, characterized in that said DPP-4 inhibitor is administered to said patients at low dosage levels or, advantageously, at the same dosage levels as in patients with normal renal function, such that, for example, said DPP-4 inhibitor does not require downward dosage adjustments due to reduced renal function.

[0061] A particular embodiment of the invention relates to a DPP-4 inhibitor for use in the treatment of type 2 diabetes in patients who are ineligible for metformin treatment due to intolerance or contraindication to metformin, e.g. any of the intolerance or contraindications defined hereinbefore or hereinafter. Within the meaning of the present invention, a special subgroup of patients to which the inventive treatment relates concerns those with chronic renal failure or disorder (especially of moderate, severe or end stage). Patients with renal disease, renal insufficiency, or impairment require careful evaluation, especially for appropriate selection of medication and dosing regimen, based on the type and properties (e.g., pharmacokinetics, pharmacodynamics, metabolism, excretion route) of the individual medication and the patient's grade of renal impairment. DPP-4 inhibitors that may be indicated for the present invention (especially for patients with reduced renal function) may be oral DPP-4 inhibitors whose active metabolites preferably have a relatively wide (e.g., about >100-fold) therapeutic window and / or are, in particular, primarily eliminated by hepatic metabolism or biliary excretion.

[0062] More specifically, a particularly suitable DPP-4 inhibitor for the purposes of the present invention (especially for patients with reduced renal function) may be an orally administered DPP-4 inhibitor that has a relatively wide (e.g., >100-fold) therapeutic window and / or meets one or more of the following pharmacokinetic properties (preferably at therapeutic oral dose levels): - DPP-4 inhibitors are substantially or predominantly excreted via the liver (e.g., >80% or >90% of an administered oral dose) and / or renal excretion is little or only a minor route of elimination (e.g., radiolabeled carbon ( 14 C) the amount measured by tracing the excretion of an oral dose of the substance is, for example, <10%, preferably <7% of the measured administered oral dose; - DPP-4 inhibitors are excreted largely unchanged as the parent drug (e.g., radiolabeled carbon ( 14C) on average >70%, or >80%, or preferably 90% of the radioactivity excreted in urine and feces after oral administration of the substance) and / or is barely excreted or eliminated to only a small extent by metabolism (e.g., <30%, or <20%, or preferably 10%); - one or more (major) metabolites of a DPP-4 inhibitor are pharmacologically inactive, e.g., the major metabolites do not bind to or inhibit the activity of the target enzyme DPP-4 and, optionally, are rapidly excreted compared to the parent compound (e.g., have an elimination half-life of 15.9 hours, ≦20 hours, or preferably ≦about 16 hours).

[0063] In one embodiment, a (major) metabolite (which may be pharmacologically inactive) of a DPP-4 inhibitor having a 3-aminopiperidin-1-yl substituent is a derivative in which the amino group of the 3-aminopiperidin-1-yl moiety is replaced by a hydroxyl group to form a 3-hydroxypiperidin-1-yl moiety.

[0064] Properties of DPP-4 inhibitors that may be attractive for the present invention may further include one or more of the following: rapid achievement of steady state (e.g., reaching steady state plasma levels (>90% of steady state plasma concentration) between the second and fifth days of treatment with therapeutic oral dose levels), small accumulation (e.g., mean accumulation ratio R A,AUC ≦1.4), and / or maintains a prolonged effect on DPP-4 inhibition, preferably when used once daily (e.g., near complete (>90%) DPP-4 inhibition at therapeutic oral dosage levels, >80% inhibition over a 24 hour interval following once daily ingestion of a therapeutic oral drug dose), a significant reduction in 2 hour postprandial blood glucose excursion of >80% at therapeutic dosage levels (already on the first day of treatment), and a cumulative amount of unchanged parent compound excreted in the urine of less than 1% of the administered dose on the first day, increasing to no more than about 3-6% at steady state.

[0065] The present invention therefore also relates to a DPP-4 inhibitor for use in the treatment and / or prevention of metabolic diseases (in particular type 2 diabetes in patients for whom metformin treatment is inappropriate due to intolerance or contraindications to metformin, in particular in patients with renal disease, renal insufficiency or renal impairment), wherein said DPP-4 inhibitor is hardly excreted or is excreted only to a small extent via the kidney (e.g. <10%, preferably <7% of the administered oral dose) (e.g. radiolabeled carbon ( 14 C) measured by tracing the excretion of an oral dose of the substance. The present invention further relates to a DPP-4 inhibitor for use in the treatment and / or prevention of metabolic disorders (particularly type 2 diabetes in patients for whom metformin treatment is inappropriate due to intolerance or contraindications to metformin, in particular in patients with renal disease, renal insufficiency or renal impairment), wherein said DPP-4 inhibitor is substantially or predominantly excreted via the liver (e.g., a radiolabeled carbon ( 14 C) measured by tracing the excretion of an oral dose of the substance. The present invention further relates to a DPP-4 inhibitor for use in the treatment and / or prevention of metabolic disorders, in particular type 2 diabetes in patients for whom metformin treatment is inappropriate due to intolerance or contraindications to metformin, in particular in patients with renal disease, renal insufficiency or renal impairment, The DPP-4 inhibitors are excreted largely unchanged as the parent drug (e.g., radiolabeled carbon ( 14 C) The radioactivity excreted in the urine and feces after oral administration of the substance is on average >70%, or >80%, or preferably 90%, characterized in that the DPP-4 inhibitor is hardly eliminated or is excreted only to a small extent by metabolism, and / or the main metabolites of the DPP-4 inhibitor are pharmacologically inactive or have a relatively wide therapeutic window. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0066] In a first embodiment (embodiment A), the DPP-4 inhibitor in the context of the present invention is a DPP-4 inhibitor of the formula The following formula (I)

[0067] [ka]

[0068] Or the following formula (II)

[0069] [ka]

[0070] Or formula (III)

[0071] [ka]

[0072] Or formula (IV)

[0073] [ka]

[0074] (wherein R1 represents ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methylquinazolin-2-yl)methyl, 2-cyanobenzyl, (3-cyanoquinolin-2-yl)methyl, (3-cyanopyridin-2-yl)methyl, (4-methylpyrimidin-2-yl)methyl or (4,6-dimethylpyrimidin-2-yl)methyl; and R2 represents 3-(R)-aminopiperidin-1-yl, (2-amino-2-methylpropyl)methylamino or (2-(S)-aminopropyl)methylamino, or a pharma-ceutically acceptable salt thereof.

[0075] In a second embodiment (embodiment B), the DPP-4 inhibitor in the context of the present invention is a DPP-4 inhibitor selected from the group consisting of: Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, (2S)-1-{[2-(5-methyl-2-phenyloxazol-4-yl)ethylamino]acetyl}pyrrolidine-2-carbonitrile, (2S)-1-{[1,1,-dimethyl-3-(4-pyridin-3-ylimidazol-1-yl)propylamino]acetyl}pyrrolidine-2-carbonitrile, (S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethylpyrrolidin-2-one, (3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone, (1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one, (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl}-4-fluoropyrrolidine-2-carbonitrile, (R)-2-[6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluorobenzonitrile, 5-{(S)-2-[2-((S)-2-cyanopyrrolidin-1-yl)-2-oxo-ethylamino]propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bisdimethylamide, 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine, [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic acid, (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile, 2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile, and 6-[(3R)-3-aminopiperidin-1-yl]-5-(2-chloro-5-fluorobenzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione, or A pharma- ceutically acceptable salt thereof.

[0076] Regarding the first embodiment (embodiment A), preferred DPP-4 inhibitors are any or all of the following compounds and pharma- ceutically acceptable salts thereof: 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine (corresponding to WO 2004 / 018468, Example 2 (142)):

[0077] [ka]

[0078] 1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine (corresponding to WO 2004 / 018468, Example 2 (252)):

[0079] [ka]

[0080] 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine (corresponding to WO 2004 / 018468, Example 2(80)):

[0081] [ka]

[0082] 2-((R)-3-aminopiperidin-1-yl)-3-(but-2-ynyl)-5-(4-methylquinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one (corresponding to WO 2004 / 050658, Example 136):

[0083] [ka]

[0084] 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(2-amino-2-methylpropyl)methylamino]xanthine (corresponding to WO 2006 / 029769, Example 2(1)):

[0085] [ka]

[0086] 1-[(3-cyanoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine (corresponding to WO 2005 / 085246, Example 1(30)):

[0087] [ka]

[0088] 1-(2-cyanobenzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine (corresponding to WO 2005 / 085246, Example 1(39)):

[0089] [ka]

[0090] 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-aminopropyl)methylamino]xanthine (corresponding to WO 2006 / 029769, Example 2(4)):

[0091] [ka]

[0092] 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine (corresponding to WO 2005 / 085246, Example 1(52)):

[0093] [ka]

[0094] 1-[(4-methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine (corresponding to WO 2005 / 085246, Example 1(81)):

[0095] [ka]

[0096] 1-[(4,6-dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine (corresponding to WO 2005 / 085246, Example 1(82)):

[0097] [ka]

[0098] 1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine (corresponding to WO 2005 / 085246, Example 1(83)):

[0099] [ka]

[0100] These DPP-4 inhibitors are distinguished from structurally comparable DPP-4 inhibitors because they combine exceptional potency and long duration of action with favorable pharmacological properties, receptor selectivity and favorable side effect profiles or provide unexpected therapeutic benefits or improvements when combined with other pharmacoactive substances, the preparations of which are disclosed in the cited references. Among the above-mentioned DPP-4 inhibitors of embodiment A of the present invention, a more preferred DPP-4 inhibitor is 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine, in particular the free base thereof (also known as BI 1356).

[0101] Unless otherwise specified, according to the present invention, the definitions of active compounds (including DPP-4 inhibitors) referred to above and below are to be understood to include pharma- ceutically acceptable salts, as well as hydrates, solvates and polymorphs thereof. With regard to the salts, hydrates and polymorphs thereof, particular mention is made of those shown herein.

[0102] With regard to embodiment A, the synthetic method for the DPP-4 inhibitor of embodiment A of the present invention is known to those skilled in the art. Advantageously, the DPP-4 inhibitor of embodiment A of the present invention can be prepared using synthetic methods described in the literature. Thus, for example, the purine derivative of formula (I) can be obtained as described in WO 2002 / 068420, WO 2004 / 018468, WO 2005 / 085246, WO 2006 / 029769 or WO 2006 / 048427, the disclosures of which are incorporated herein by reference. The purine derivative of formula (II) can be obtained as described in WO 2004 / 050658 or WO 2005 / 110999, the disclosures of which are incorporated herein by reference. The purine derivatives of formula (III) and (IV) can be obtained, for example, as described in WO 2006 / 068163, WO 2007 / 071738 or WO 2008 / 017670, the disclosures of which are incorporated herein by reference. The preparation of these DPP-4 inhibitors is described in detail above and in the references cited 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 incorporated herein by reference. Formulations of specific DPP-4 inhibitors with metformin or other combination partners are described in PCT / EP2009053978, the disclosures of which are incorporated herein by reference in their entirety. Typical doses for the BI 1356 / metformin dual combination are 2.5 / 500 mg, 2.5 / 850 mg and 2.5 / 1000 mg.

[0103] With respect to embodiment B, synthetic methods for the DPP-4 inhibitors of embodiment B are described in the scientific literature and / or published patent documents, particularly those cited herein. For pharmaceutical application in warm-blooded vertebrates, especially humans, the compounds of the present invention are usually used at a dose of 0.001-100 mg / kg body weight, preferably 0.1-15 mg / kg, in any case 1-4 times / day. The compounds for this purpose may be combined with other active substances as necessary and may be incorporated into conventional galenic preparations such as plain tablets, coated tablets, capsules, powders, suspensions or suppositories together with one or more conventional inert carriers and / or diluents, such as corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances, such as hard fats or suitable mixtures thereof.

[0104] Thus, the pharmaceutical compositions of the present invention comprising the DPP-4 inhibitors defined herein are prepared by those skilled in the art using pharma- ceutical acceptable formulation excipients described in the art, examples of which include, but are not limited to, diluents, binders, carriers, fillers, lubricants, glidants, crystallization retardants, disintegrants, solubilizers, colorants, pH adjusters, surfactants and emulsifiers. Examples of suitable diluents for the compounds of embodiment A include cellulose powder, calcium hydrogen phosphate, erythritol, low-substituted hydroxypropylcellulose, mannitol, pregelatinized starch or xylitol. Among these diluents, mannitol, low-substituted hydroxypropylcellulose and pregelatinized starch should be highlighted.

[0105] Examples of lubricants suitable for the compounds of embodiment A include talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate. Among these lubricants, magnesium stearate should be highlighted. Examples of suitable binders for the compounds of embodiment A include copovidone (a copolymer of vinylpyrrolidone and other vinyl derivatives), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (povidone), pregelatinized starch, or low-substituted hydroxypropylcellulose (L-HPC). Among these binders, copovidone and pregelatinized starch should be highlighted.

[0106] Examples of suitable disintegrants for the compounds of embodiment A include corn starch or crospovidone. Among these disintegrants, corn starch should be highlighted. A suitable method for preparing a pharmaceutical formulation of a DPP-4 inhibitor according to embodiment A of the present invention comprises Direct tableting of the active substance in a powder mixture with suitable tableting excipients; Granulating with suitable excipients, then mixing with suitable excipients, then tableting and film coating; or Loading the powder mixture or granules into capsules. The appropriate granulation method is: Wet granulation in an intensive mixer followed by fluid bed drying; ·One-pot granulation; Fluid bed granulation; or Dry granulation (e.g. roller compaction) with suitable excipients and then compressed into tablets or filled into capsules.

[0107] An exemplary composition of the DPP-4 inhibitor of embodiment A of the present invention comprises a first diluent mannitol, pregelatinized starch as a second diluent with additional binding properties, a binder copovidone, a disintegrant cornstarch, and magnesium stearate as a lubricant; wherein copovidone and / or cornstarch may be optional. Details regarding dosage forms, formulation and administration of the DPP-4 inhibitors of the present invention are set forth in the scientific literature and / or published patent documents, particularly those cited herein.

[0108] With regard to the first embodiment (embodiment A), the dose typically required for the DPP-4 inhibitors listed herein in embodiment A is 0.1 mg to 10 mg, preferably 0.25 mg to 5 mg, when administered intravenously, and 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, when administered orally, in each case 1 to 4 times a day. Thus, for example, the dose of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine, when administered orally, is 0.5 mg to 10 mg / patient / day, preferably 2.5 mg to 10 mg or 1 mg to 5 mg / patient / day.

[0109] Dosage forms prepared with pharmaceutical compositions containing DPP-4 inhibitors as set forth herein in embodiment A contain the active ingredient in a dosage range of 0.1-100 mg. Thus, for example, specific dosages of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine are 0.5 mg, 1 mg, 2.5 mg, 5 mg, and 10 mg.

[0110] With regard to the second embodiment (embodiment B), the dose of the DPP-4 inhibitor mentioned herein in embodiment B administered to a mammal, e.g., a human, weighing, for example, about 70 kg, may generally be about 0.5 mg to about 350 mg, e.g., about 10 mg to about 250 mg, preferably 20-200 mg, more preferably 20-100 mg of active moiety / person / day, or about 0.5 mg to about 20 mg, preferably 2.5-10 mg / person / day, divided, for example, into equal sized, preferably 1 to 4 single doses. The single doses may contain, for example, 10, 25, 40, 50, 75, 100, 150 and 200 mg of the DPP-4 inhibitor active moiety.

[0111] The dose of the DPP-4 inhibitor sitagliptin is usually 25-200 mg of active moiety. The recommended dosage of sitagliptin is 100 mg calculated for the active moiety (free base anhydrate) once a day. The unit doses of sitagliptin free base anhydrate (active ingredient) are 25, 50, 75, 100, 150 and 200 mg. The specific unit doses of sitagliptin (e.g. per tablet) are 25, 50 and 100 mg. An equivalent amount of sitagliptin phosphate monohydrate to sitagliptin free base anhydrate, i.e. 32.13, 64.25, 96.38, 128.5, 192.75 and 257 mg, respectively, is used in the pharmaceutical composition. Adjusted doses of sitagliptin of 25 and 50 mg are used in patients with renal failure. Typical doses for the sitagliptin / metformin dual combination are 50 / 500 mg and 50 / 1000 mg. The dose range of the DPP-4 inhibitor vildagliptin is usually 10-150 mg per day, in particular 25-150 mg, 25-100 mg or 25-50 mg or 50-100 mg per day. Specific examples of daily oral doses are 25, 30, 35, 45, 50, 55, 60, 80, 100 or 150 mg. In a more specific embodiment, the daily administration of vildagliptin may be 25-150 mg or 50-100 mg. In another more specific embodiment, the daily administration of vildagliptin may be 50 or 100 mg. The application of the active ingredient may be performed up to three times per day, preferably once or twice per day. A specific dose is 50 mg or 100 mg of vildagliptin. Typical doses of the vildagliptin / metformin dual combination are 50 / 850 mg and 50 / 1000 mg.

[0112] Alogliptin may be administered to a patient in a daily dose of 5mg / day to 250mg / day, optionally 10mg to 200mg, optionally 10mg and 150mg, optionally 10mg and 100mg of alogliptin (in each case based on the molecular weight of alogliptin free base).Accordingly, individual dosages that can be used include, but are not limited to, 10mg, 12.5mg, 20mg, 25mg, 50mg, 75mg and 100mg / day of alogliptin.Alogliptin may be administered in free base form or as a pharma- ceutically acceptable salt.

[0113] Saxagliptin may be administered to a patient in a daily dose of 2.5 mg / day to 100 mg / day, optionally 2.5 mg to 50 mg. Individual dosage amounts that may be used include, but are not limited to, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, and 100 mg of saxagliptin. Exemplary doses for the dual combination of saxagliptin / metformin are 2.5 / 500 mg and 2.5 / 1000 mg.

[0114] Particular embodiments of the DPP-4 inhibitors of the present invention relate to those orally administered DPP-4 inhibitors which are therapeutically effective at low dosage levels, for example at dosage levels of <100 mg or <70 mg / patient / day, preferably <50 mg, more preferably <30 mg or <20 mg, even more preferably 1 mg to 10 mg / patient / day (divided, if necessary, into 1 to 4 single doses, especially 1 or 2 single doses, which may be of equal size), especially 1 mg to 5 mg (more especially 5 mg), administered with or without food, preferentially orally once daily, more preferentially at any time during the day.

[0115] A particularly preferred DPP-4 inhibitor to be highlighted within the meaning of the present invention is 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine (also known as BI 1356). BI 1356 is highly potent, has a 24-hour duration of action, and has a wide therapeutic window. In type 2 diabetes patients receiving repeated oral doses of 1, 2.5, 5, or 10 mg of BI 1356 once daily for 12 days, BI 1356 has been shown to exhibit rapid attainment of steady state (e.g., steady-state plasma levels (>90% of pre-dose plasma levels on day 13) were reached between days 2 and 15 of treatment in all dose groups), little accumulation (e.g., mean accumulation ratios of R 100 to R 100 at doses above 1 mg). A,AUC ≤ 1.4) and sustained long-term effect on DPP-4 inhibition (e.g., nearly complete (>90%) DPP-4 inhibition at the 5 mg and 10 mg dose levels, i.e., 92.3 and 97.3% inhibition at steady state, respectively, and >80% inhibition over 24 hours after drug ingestion), as well as a significant reduction in 2-hour postprandial blood glucose excursions by ≥ 80% (already on day 1) at doses ≥ 2.5 mg, and a cumulative amount of unchanged parent compound excreted in urine of < 1% of the dose on day 1, increasing to approximately 3-6% or less on day 12 (renal clearance CL R,ssBI 1356 exhibits favorable pharmacodynamic and pharmacokinetic profiles (e.g., see Table 1 below) with renal clearance of about 14 to about 70 mL / min for oral dosages, e.g., for a 5 mg dose, renal clearance is about 70 ml / min. In people with type 2 diabetes, BI 1356 exhibits placebo-like safety and tolerability. At low doses of ≥ about 5 mg, BI 1356 acts as a true once-daily oral agent with DPP-4 inhibition of full duration of 24 hours. At therapeutic oral dose levels, BI 1356 is excreted mostly via the liver and to a small extent via the kidney (about <7% of the administered oral dose). BI 1356 is primarily excreted unchanged via the bile. The fraction of BI 1356 excreted via the kidney increases very little over time and with increasing dose, so there is likely no need to modify the dose of BI 1356 based on the patient's renal function. The non-renal elimination of BI 1356 combined with the low accumulation potential and wide safety margin may be significantly advantageous in patient populations with a high prevalence of renal insufficiency and diabetic nephropathy.

[0116] Table 1: Geometric mean (gMean) and geometric coefficient of variation (gCV) of pharmacokinetic parameters of BI 1356 at steady state (day 12) TIFF2025023114000026.tif160160

[0117] Since different metabolic dysfunctions often occur simultaneously, it is quite often necessary to combine many different active ingredients with each other.Therefore, depending on the dysfunction diagnosed, when DPP-4 inhibitor is combined with one or more active substances that are customary for each disorder, such as other antidiabetic substances, in particular, the active substances that are required to reduce blood glucose or lipid levels, increase blood HDL levels, reduce blood pressure, or treat atherosclerosis or obesity, improved therapeutic results can be obtained.

[0118] The above-mentioned DPP-4 inhibitors can also be used - apart from their use in monotherapy - together with other active substances, which can result in improved therapeutic results. Such combined treatments can be administered as free combinations of substances or in the form of fixed combinations, for example in tablets or capsules. The pharmaceutical preparations of one or more combination partners required for this can be commercially obtained as pharmaceutical compositions or can be formulated by those skilled in the art using conventional methods. The active substances that can be commercially obtained as pharmaceutical compositions are described in numerous places in the prior art, for example in the list of drugs listed annually, in the "Rote Liste" of the Federal Pharmaceutical Association, or in the annually updated compilation of manufacturers' information on prescription drugs known as the "Physician's Desk Reference".

[0119] Examples of antidiabetic combination partners are sulfonylureas, e.g., glibenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glibornuride, gliclazide; nateglinide; repaglinide; thiazolidinediones, e.g., rosiglitazone, pioglutazone; PPAR gamma modulators, e.g., metaglytidase; PPAR gamma agonists, e.g., GI 262570; PPAR gamma antagonists; PPAR gamma / alpha modulators, e.g., tesaglitazar, muraglitazar, aleglitazar, indeglitazar, AVE0897, KRP297; PPAR gamma / alpha / delta modulators; AMPK activators, e.g., AICAR; acetyl-CoA carboxylase (ACC1 and ACC2) inhibitors; diacylglycerol-acetyltransferase (DGAT) inhibitors; Pancreatic beta cell GCRP agonists, e.g. SMT3-receptor-agonists, GPR119; 11β-HSD inhibitors; FGF19 agonists or analogues; alpha-glucosidase blockers, e.g. acarbose, voglibose, miglitol; alpha2-antagonists; insulin and insulin analogues, e.g. human insulin, insulin lispro, insulin glycirin, r-DNA-insulin aspart, NPH insulin, insulin detemir, insulin zinc suspension, insulin glargine; gastric inhibitory peptide (GIP); pramlintide, davalintide; amylin or amylin analogues or GLP-1 or GLP-1 analogues, for example exendin-4, for example exenatide, exenatide LAR, liraglutide, taspoglutide, AVE-0010, LY-2428757, LY-2189265, semaglutide or albiglutide; SGLT2 inhibitors, for example KGT-1251; protein tyrosine phosphatase inhibitors (for example trodasquemine); glucose-6-phosphatase inhibitors; fructose-1,6-bisphosphatase modulators; glycogen phosphorylase modulators; glucagon receptor antagonists; phosphoenolpyruvate carboxykinase (PEPCK) inhibitors; pyruvate dehydrogenase kinase (PDK) inhibitors;Tyrosine kinase inhibitors (50mg to 600mg), e.g., PDGF receptor kinase (see EP-A-564409, WO 98 / 35958, US 5093330, WO 2004 / 005281 and WO 2006 / 041976); regulatory protein modulators including glucokinase / glucokinase activators; glycogen synthase kinase inhibitors; SH2-domain containing inositol 5-phosphatase type 2 (SHIP2) inhibitors; IKK inhibitors, e.g., high dose salicylate; JNK1 inhibitors; protein kinase C-theta inhibitors; β3 agonists, e.g., ritobegron, YM 178, solabegron, talibegron, N-5984, GRC-1087, rafabegron, FMP825; aldose reductase inhibitors, e.g., AS 3201, zenarestat, fidarestat, epalrestat, ranirestat, NZ-314, CP-744809, CT-112; SGLT-1 or SGLT-2 inhibitors, such as dapagliflozin, sergliflozin, atigliflozin, larnagliflozin or canagliflozin (or compounds of formula (IS) or (IK) from WO 2009 / 035969); KV 1.3 channel inhibitors; GPR40 modulators; SCD-1 inhibitors; CCR-2 antagonists; dopamine receptor agonists (bromocriptine mesylate [Cycloset]); or other DPP IV inhibitors.

[0120] The dose of the partner drug pioglitazone is usually about 1-10 mg, 15 mg, 30 mg or 45 mg once daily. Rosiglitazone is usually administered in a dose of 4 to 8 mg once daily (or in two divided doses) (typical doses are 2, 4 and 8 mg). Glibenclamide (glyburide) is usually administered at a dose of 2.5-5 to 20 mg once daily (or divided into 2 doses) (typical doses are 1.25, 2.5, and 5 mg), or micronized glibenclamide at a dose of 0.75-3 to 12 mg once daily (or divided into 2 doses) (typical doses are 1.5, 3, 4.5, and 6 mg). Glipizide is usually administered in doses of 2.5 to 10-20 mg once daily (up to 40 mg divided into two doses) (typical doses are 5 to 10 mg) or extended release glipizide in doses of 5 to 10 mg (up to 20 mg) once daily (typical doses are 2.5, 5, and 10 mg). Glimepiride is usually administered in a dose of 1-2 to 4 mg (up to 8 mg) once daily (typical doses are 1, 2 and 4 mg). The dual glibenclamide / metformin combination is usually administered in doses ranging from 1.25 / 250 mg once daily to 10 / 1000 mg twice daily (typical doses 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 doses are 2.5 / 250, 2.5 / 500 and 5 / 500 mg). The glimepiride / metformin dual combination is usually administered at a dose of 1 / 250 to 4 / 1000 mg twice daily.

[0121] The dual combination of rosiglitazone / glimepiride is usually administered in doses of 4 / 1 mg once or twice daily to 4 / 2 mg twice daily (typical doses are 4 / 1, 4 / 2, 4 / 4, 8 / 2 and 8 / 4 mg). The pioglitazone / glimepiride dual combination is usually administered at doses of 30 / 2 to 30 / 4 mg once daily (typical doses are 30 / 4 and 45 / 4 mg). The dual combination of rosiglitazone / metformin is usually administered in doses of 1 / 500 to 4 / 1000 mg twice daily (typical doses 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 mg once or twice daily to 15 / 850 mg three times daily (typical doses are 15 / 500 and 15 / 850 mg). The nonsulfonylurea insulin secretagogue nateglinide is usually given at a dose of 60-120 mg with meals (up to 360 mg / day, typical doses are 60-120 mg); repaglinide is usually given at a dose of 0.5-4 mg with meals (up to 16 mg / day, typical doses are 0.5, 1 and 2 mg). The repaglinide / metformin dual combination is available in doses of 1 / 500 and 2 / 850 mg. Acarbose is usually given at a dose of 25-100 mg with meals (up to 300 mg / day, typical doses are 25, 50, and 100 mg). Miglitol is usually given at a dose of 25-100 mg with meals (up to 300 mg / day, typical doses are 25, 50, and 100 mg). Conventional antidiabetic and antihyperglycemic agents typically used in single or dual or triple (add-on or initial) combination therapy may include, but are not limited to, metformin, sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1, GLP-1 analogs, insulin, and insulin analogs, including, by way of example, those agents set forth herein, combinations thereof.

[0122] For purposes of the present invention, specific antidiabetic partner agents for use in combination with the DPP-4 inhibitors of the present invention may include, but are not limited to, glibenclamide (low dose), glimepiride (low dose), gliquidone (low dose), glipizide, repaglinide, acarbose, miglitol, rosiglitazone and pioglitazone, particularly for patients with moderate renal impairment; repaglinide (low dose), pioglitazone, insulin and insulin analogues, particularly for patients with severe renal impairment. Examples of combination partners which lower blood lipid levels are simvastatin, atorvastatin, lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin; fibrates, such as bezafibrate, fenofibrate, clofibrate, gemfibrozil, etofibrate and etofylline clofibrate; nicotinic acid and its derivatives, such as acipimox; PPAR alpha agonists; PPAR delta agonists; Acyl-coenzyme A: cholesterol transferase inhibitors (ACAT; EC 2.3.1.26), such as avasimibe; cholesterol absorption inhibitors, such as ezetimibe; substances which bind to bile acids, such as cholestyramine, colestipol, colesevelam; bile acid transport inhibitors; HDL modulating active substances, such as D4F, reverse D4F, LXR modulating active substances, FXR modulating active substances; CETP inhibitors, such as torcetrapib, JTT-705 (dalcetrapib) or compound 12 from WO 2007 / 005572 (anacetrapib); LDL receptor modulators; ApoB100 antisense RNA. The dose of the partner drug atorvastatin is usually 1 mg to 40 mg or 10 mg to 80 mg once a day.

[0123] Exemplary lipid-lowering partner agents may include, but are not limited to, statins (e.g., atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, or rosuvastatin), ezetimibe, fibrates (e.g., fenofibrate or gemfibrozil), CETP inhibitors, bile acid sequestrants (e.g., cholestyramine or colesevelam), and nicotinic acid or nicotinic acid derivatives (which increase HDL levels in the blood), as well as combinations thereof (e.g., statin / ezetimibe or statin / fibrate combinations). Exemplary lipid-lowering drugs, particularly for patients with moderate or severe renal impairment, may include, but are not limited to, atorvastatin, fluvastatin, gemfibrozil, ezetemibe and fenofibrate, and combinations thereof (e.g., atorvastatin / ezetemibe; fluvastatin / ezetemibe; statin / fenofibrate or fluvastatin / gemfibrozil, each optionally with ezetemibe; combinations thereof). Exemplary lipid-lowering drugs, particularly for patients with ESRD, may include, but are not limited to, atorvastatin, fluvastatin, gemfibrozil, and ezetemibe, and combinations thereof (e.g., atorvastatin / ezetemibe or fluvastatin / ezetemibe combinations).

[0124] Examples of combination partners that lower blood pressure are beta-blockers, e.g. atenolol, bisoprolol, celiprolol, metoprolol, carvedilol; diuretics, e.g. hydrochlorothiazide, chlorthalidone, xipamide, furosemide, piretanide, torasemide, spironolactone, eplerenone, amiloride, triamterene; calcium channel blockers (e.g. amlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine, felodipine, lacidipine, lercanipidine, manidipine, isradipine, nilvadipine, verapamil, gallopamil, diltiazem); ACE inhibitors, e.g. ramipril, lisinopril, cilazapril, quinapril, captopril, enalapril, benazepril, perindopril, fosinopril, trandolapril; and angiotensin II receptor blockers (ARBs), such as telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan, and eprosartan.

[0125] The dose of the partner drug telmisartan is usually 20 mg to 320 mg or 40 mg to 160 mg per day. Typical blood pressure lowering partner drugs include ACE inhibitors (ACEi) (e.g., ramipril, lisinopril, quinapril, captopril, enalapril, benazepril, perindopril, trandolapril, fosinopril or moexipril), ARBs (e.g., telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan or epolosartan), calcium channel blockers (CCBs) (e.g., non-dihydropyridine CCBs, e.g., diltiazem or verapamil, or di ... These may include, but are not limited to, thiazide-type diuretics (e.g., hydrochlorothiazide or chlorthiaridone), alpha-blockers and beta-blockers (e.g., atenolol, carvedilol or metoprolol), and combinations thereof (e.g., ACEi / ARB, ACEi / beta-blocker, ARB / beta-blocker, ACEi / diuretic, ARB / diuretic, ACEi / CCB or ARB / CCB combinations). Examples of combination partners that increase HDL levels in the blood are cholesteryl ester transfer protein (CETP) inhibitors; endothelial lipase inhibitors; ABC1 regulators; LXR alpha antagonists; LXR beta agonists; PPAR delta agonists; LXR alpha / beta regulators, agents that increase the expression and / or plasma concentration of apolipoprotein AI.

[0126] Examples of combination partners for the treatment of obesity are: sibutramine; tetrahydrolipstatin (orlistat), cetilistat; alizyme; dexfenfluramine; axoxoquin; cannabinoid receptor 1 antagonists, such as the CB1 antagonist limonobant; MCH-1 receptor antagonists; MC4 receptor agonists; NPY5, NPY2 antagonists; beta3-AR agonists, such as SB-418790, AD-9677; 5HT2c receptor agonists, such as APD 356 (lorcaserin); myostatin inhibitors; Acrp30, adiponectin; steroyl-CoA desaturase (SCD1) inhibitors; fatty acid synthase (FAS) inhibitors; CCK receptor agonists; ghrelin receptor modulators; Pyy 3-36; orexin receptor antagonists; tesofensine; These are the dual combinations bupropion / naltrexone, bupropion / zonisamide, topiramate / phentermine, and pramlintide / metreleptin.

[0127] Examples of combination partners for the treatment of atherosclerosis are phospholipase A2 inhibitors; tyrosine kinase inhibitors (50 mg to 600 mg), e.g. PDGF receptor kinase (see EP-A-564409, WO 98 / 35958, US 5093330, WO 2004 / 005281, and WO 2006 / 041976); oxLDL antibodies, oxLDL vaccines; apoA-1 Milano; ASA; VCAM-1 inhibitors. For use of the agents listed herein in patients with renal disease, impaired renal function or renal failure, in some cases - depending on the individual agent (e.g., pharmacokinetics, pharmacodynamics, metabolism, excretion route) and the patient's grade of renal impairment - it may be necessary to adjust or reduce the dosage due to the patient's declining renal function. The present invention should not be limited in scope by the specific embodiments described herein. Various modifications of the invention in addition to those described herein may become apparent to those skilled in the art from this disclosure. Such modifications are intended to be encompassed within the scope of the appended claims. All patent applications cited herein are hereby incorporated by reference in their entirety. Further embodiments, features and advantages of the present invention may become apparent from the following examples, which serve, by way of example, to illustrate the principles of the present invention without limiting it thereto. EXAMPLES

[0128] The usefulness of the DPP-4 inhibitors of the present invention for the present invention can be examined using clinical trials: For example, in a randomized, double-blind, parallel group study, the safety and efficacy of a DPP-4 inhibitor of the present invention (e.g., 5 mg of BI 1356 administered orally once daily) will be compared to placebo (wherein the placebo is replaced by glimepiride) over an 18-week treatment period, followed by a 34-week double-blind extension period, in patients with type 2 diabetes and inadequate glycemic control (e.g., HbA1c 7%-10%) who are ineligible for metformin treatment due to intolerance or contraindications to metformin. Patients who are ineligible for metformin treatment are defined as follows: Contraindications to metformin treatment according to classification, for example: renal disease or renal insufficiency (e.g., as specified by the product information for locally approved metformin); Dehydration according to the investigator's clinical judgment; unstable or acute congestive heart failure, acute or chronic metabolic acidosis (conditions indicated in the patient's history); Hereditary galactose intolerance; or Observed intolerable side effects caused by metformin include: nausea, vomiting, diarrhea, Intestinal gas, Severe abdominal discomfort.

[0129] In this study, the efficacy of a DPP-4 inhibitor of the present invention in this patient population is examined over a shorter treatment period of 18 weeks, and the safety / tolerability is compared to a sulfonylurea drug (glimepiride) over a longer treatment period of up to 52 weeks. The success of the treatment is tested by determining the HbA1c value by comparing it with the initial value and / or with the value of the placebo group. A significant change in the HbA1c value compared with the initial value and / or with the placebo value indicates the effectiveness of the DPP-4 inhibitor for treatment. The success of the treatment can also be tested by determining the fasting plasma glucose value by comparing it with the initial value and / or with the value of the placebo group. A significant decrease in the fasting blood glucose value indicates the effectiveness of the treatment. The presence of the treatment to target response (i.e., HbA1c<7% or <6.5% with treatment) also indicates the effectiveness of the treatment.

[0130] Safety and tolerability of treatment will be examined by assessing patient condition and relevant changes from baseline, such as the occurrence and intensity of side effects (e.g., renal adverse events, hypoglycemic episodes, etc.) or weight gain with glimepiride treatment compared to DPP-4 inhibitor treatment. As another example, in a randomized, double-blind, parallel group study, the safety, efficacy and tolerability of a DPP-4 inhibitor of the present invention (e.g., 5 mg BI 1356) is compared to placebo over a 52 week treatment period in male and female patients with type 2 diabetes and severe chronic renal impairment (GFR<30 ml / min, not on chronic dialysis), including patients on insulin and / or sulfonylurea background medication. Safety and tolerability of the treatment will be determined by assessing the patient's condition. Efficacy can be determined by change from baseline in HbA1c after 12 weeks of treatment, by change in fasting plasma glucose parameters, or by change in insulin and / or sulfonylurea dose over time compared to baseline at 52 weeks.

[0131] Metabolism and excretion profile of DPP-4 inhibitors for the present invention: Oral radiolabeling (e.g.,14 [C]-labeled) DPP-4 inhibitors can be used, for example, to investigate the excretion pathway, mass balance, and metabolism of the DPP-4 inhibitors of the present invention in human subjects as follows for compounds determined to be suitable for the present invention: 10mg[ 14 After oral administration of [C]BI 1356 / subject (e.g., healthy male volunteers), total radioactivity is primarily excreted via the feces, with an average of 83.8% of the administered dose being excreted within 16 days. Renal excretion accounts for 6.6% of the administered dose 9 days after administration. Recovery of total radioactivity ranges from 86.1%-95.1% (average: 90.4%) of the administered dose. [ 14 After oral administration of [C]BI 1356, the parent compound was the most abundant radioactive substance in all matrices examined. 14 C]BI 1356 accounts for an average of 74% of the sample radioactivity after oral dosing (sample pool: 1.5+3+6 hours). An inactive major metabolite is identified in plasma with 16.9% of the sample radioactivity in the pooled samples. The parent compound [ 14 [C]BI 1356 is excreted unchanged in urine and feces, with an average of 90% of the radioactivity excreted after oral dosing. Metabolites, including the major metabolite, individually accounted for <10% of the excretion.

Claims

1. A DPP-4 inhibitor for oral administration for treating and / or preventing metabolic disease in patients for whom metformin treatment is inappropriate due to intolerance or contraindications to metformin.

2. 2. The DPP-4 inhibitor according to claim 1, for use in the treatment and / or prevention of metabolic diseases in patients who are ineligible for metformin therapy due to intolerance or contraindications to metformin.

3. 2. The DPP-4 inhibitor according to claim 1, for use in the treatment and / or prevention of metabolic disorders in patients who require low-dose metformin therapy due to poor tolerance, intolerance or contraindications to metformin.

4. The DPP-4 inhibitor according to any one of claims 1 to 3, for use in the treatment and / or prevention of type 2 diabetes in at least one patient with contraindications selected from the following: Renal disease, renal impairment or renal insufficiency, dehydration, unstable or acute congestive heart failure, Acute or chronic metabolic acidosis, and Hereditary galactose intolerance.

5. The DPP-4 inhibitor according to claim 4, for use in the treatment and / or prevention of type 2 diabetes in patients with renal disease, renal impairment or renal insufficiency.

6. In the first embodiment (embodiment A), Formula (I) 【Chemistry 1】 Or formula (II) 【Chemistry 2】 Or formula (III) 【Chemistry 3】 Or formula (IV) 【Chemistry 4】 (In the formula, R1 represents ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methylquinazolin-2-yl)methyl, 2-cyanobenzyl, (3-cyanoquinolin-2-yl)methyl, (3-cyanopyridin-2-yl)methyl, (4-methylpyrimidin-2-yl)methyl, or (4,6-dimethylpyrimidin-2-yl)methyl; and R2 represents 3-(R)-aminopiperidin-1-yl, (2-amino-2-methylpropyl)methylamino, or (2-(S)-aminopropyl)methylamino. or a pharma- ceutically acceptable salt thereof; or In a second embodiment (embodiment B), Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, (2S)-1-{[2-(5-methyl-2-phenyloxazol-4-yl)ethylamino]acetyl}pyrrolidine-2-carbonitrile, (2S)-1-{[1,1,-dimethyl-3-(4-pyridin-3-ylimidazol-1-yl)propylamino]acetyl}pyrrolidine-2-carbonitrile, (S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethylpyrrolidin-2-one, (3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone, (1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one, (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl}-4-fluoropyrrolidine-2-carbonitrile, (R)-2-[6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluorobenzonitrile, 5-{(S)-2-[2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethylamino]propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bisdimethylamide, 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine, [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic acid, (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile, 2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile, and 6-[(3R)-3-aminopiperidin-1-yl]-5-(2-chloro-5-fluorobenzyl)-1,3-dimethyl-1,5-dihydropyrrolo[3,2-d]pyrimidine-2,4-dione, or Pharmaceutically acceptable salts thereof The DPP-4 inhibitor according to any one of claims 1 to 5, selected from the group consisting of

7. The DPP-4 inhibitor is 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine, 1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine, 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine, 2-((R)-3-aminopiperidin-1-yl)-3-(but-2-ynyl)-5-(4-methylquinazolin-2-ylmethyl)-3,5-dihydroimidazo[4,5-d]pyridazin-4-one, 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(2-amino-2-methylpropyl)methylamino]xanthine, 1-[(3-cyanoquinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine, 1-(2-cyanobenzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine, 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-aminopropyl)methylamino]xanthine, 1-[(3-cyanopyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine, 1-[(4-methylpyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine, 1-[(4,6-dimethylpyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine and 1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-aminopiperidin-1-yl)xanthine, or Pharmaceutically acceptable salts thereof The DPP-4 inhibitor according to any one of claims 1 to 6, selected from the group consisting of:

8. The DPP-4 inhibitor according to any one of claims 1 to 7, wherein the DPP-4 inhibitor is 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-aminopiperidin-1-yl)xanthine.

9. The DPP-4 inhibitor Saxagliptin, Alogliptin, (2S)-1-{[2-(5-methyl-2-phenyloxazol-4-yl)ethylamino]acetyl}pyrrolidine-2-carbonitrile, (2S)-1-{[1,1,-dimethyl-3-(4-pyridin-3-ylimidazol-1-yl)propylamino]acetyl}pyrrolidine-2-carbonitrile, (S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethylpyrrolidin-2-one, (3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone, (1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one, (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl}-4-fluoropyrrolidine-2-carbonitrile, (R)-2-[6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluorobenzonitrile, 5-{(S)-2-[2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethylamino]propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bisdimethylamide, 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine, [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic acid, (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile, 2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile, and 6-[(3R)-3-aminopiperidin-1-yl]-5-(2-chloro-5-fluorobenzyl)-1,3-dimethyl-1,5-dihydropyrrolo[3,2-d]pyrimidine-2,4-dione, or Pharmaceutically acceptable salts thereof The DPP-4 inhibitor according to any one of claims 1 to 6, selected from the group consisting of:

10. 10. The DPP-4 inhibitor according to any one of claims 1 to 9, for use in the treatment and / or prevention of type 2 diabetes in patients with renal disease, renal impairment or renal insufficiency, wherein said DPP-4 inhibitor is used in said patients in the same dosage as in patients with normal renal function.

11. The DPP-4 inhibitor according to any one of claims 1 to 10, characterized in that the DPP-4 inhibitor and one or more of its major active metabolites have a relatively wide therapeutic window and / or are excreted mainly via hepatic metabolism or biliary excretion.

12. The DPP-4 inhibitor according to any one of claims 1 to 11, wherein the DPP-4 inhibitor is primarily excreted via the liver.

13. The DPP-4 inhibitor according to any one of claims 1 to 12, wherein excretion via the kidney is a minor excretion route.

14. The DPP-4 inhibitor according to any one of claims 1 to 13, wherein the DPP-4 inhibitor is excreted largely unchanged.

15. The DPP-4 inhibitor according to any one of claims 1 to 14, wherein excretion by metabolism is a minor excretion pathway.

16. 16. The DPP-4 inhibitor of any one of claims 1 to 15, wherein the DPP-4 inhibitor has placebo-like safety / tolerability and / or is primarily excreted as the parent drug via the liver.

17. The DPP-4 inhibitor according to any one of claims 1 to 16, wherein the main metabolite of the DPP-4 inhibitor is pharmacologically inactive or has a relatively wide therapeutic window.

18. The DPP-4 inhibitor according to any one of claims 1 to 17, for use in patients with mild, moderate or severe renal impairment or end stage renal disease.

19. 19. The DPP-4 inhibitor according to any one of claims 1 to 18, further used in combination with an active substance selected from one or more antidiabetic drugs, an active substance that lowers blood glucose levels, an active substance that lowers blood lipid levels, an active substance that increases blood HDL levels, an active substance that lowers blood pressure, an active substance required for the treatment of atherosclerosis, and an active substance required for the treatment of obesity.

20. 20. The DPP-4 inhibitor according to any one of claims 1 to 19, further in combination with one or more active substances selected from sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1, GLP-1 analogues, insulin, and insulin analogues.

21. The DPP-4 inhibitor according to any one of claims 1 to 20, further in combination with one or more active substances selected from repaglinide, pioglitazone, insulin, and insulin analogues.

22. The DPP-4 inhibitor according to any one of claims 1 to 21, in combination with pioglitazone.

23. A DPP-4 inhibitor according to any one of claims 1 to 3 for use in the treatment and / or prevention of type 2 diabetes in patients suffering from gastrointestinal side effects associated with metformin, such as at least one gastrointestinal side effect selected from the following: nausea, vomiting, diarrhea, Intestinal gas, and Severe abdominal discomfort.

24. 1. A DPP-4 inhibitor for oral therapeutic use in diabetic patients, characterized in that <10%, preferably ≦7%, of the administered oral dose is excreted via the kidney.

25. 25. The DPP-4 inhibitor according to claim 24, characterized in that it is excreted unchanged mainly via the bile.

26. 26. The DPP-4 inhibitor according to claim 24 or 25, characterized in that >80%, preferably ≥90%, of an administered oral dose is excreted unchanged as the parent drug.

27. 27. The DPP-4 inhibitor according to any one of claims 24 to 26, characterized in that its main metabolites are pharmacologically inactive.

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