Treatment for diabetes in patients with insufficient glycemic control despite therapy with oral or non-oral antidiabetic drug

Abstract

To provide DPP-4 inhibitors for treating and / or preventing metabolic diseases, particularly diabetes, in patients with insufficient glycemic control despite a therapy with an oral and / or non-oral antidiabetic drug.SOLUTION: The present invention provides the use of a DPP-4 inhibitor represented by formula (I) and the like.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to certain DPP-4 inhibitors for the treatment and / or prevention of metabolic diseases, in particular diabetes (especially type 2 diabetes mellitus) and diseases related thereto, in patients with inadequate glycemic control despite treatment with oral and / or parenteral antidiabetic drugs (especially insulin secretagogues such as sulfonylureas or glinide drugs), as well as the use of these DPP-4 inhibitors in said treatment and / or prevention. Pharmaceutical compositions for the treatment and / or prevention of metabolic diseases, in particular diabetes, in these patients, comprising a DPP-4 inhibitor as specified herein, optionally together with one or more other active substances, are also contemplated. [Background technology]

[0002] Type 2 diabetes mellitus is a common chronic and progressive disease resulting from a complex pathophysiology involving the dual endocrine actions of insulin resistance and impaired insulin secretion. Treatment of type 2 diabetes typically begins with diet and exercise, followed by oral antidiabetic monotherapy, and although conventional monotherapy can initially control blood glucose in some patients, it is associated with a high rate of secondary failure. The limitations of monotherapy in maintaining glycemic control may be overcome, at least in some patients, and for a limited period of time, by combining multiple oral drugs to obtain a reduction in blood glucose, which cannot be sustained during long-term treatment with a single drug. Available data support the conclusion that in most patients with type 2 diabetes, monotherapy will be ineffective and multiple drug treatment will be required. However, because type 2 diabetes is a progressive disease, even patients who have a good initial response to combination therapy will eventually require increased doses or further treatment with insulin, because blood glucose levels are very difficult to maintain stable over time. Thus, existing combination therapies have the potential to improve glycemic control, but are not without limitations, especially with regard to long-term efficacy. Furthermore, many results indicate that the risk of hypoglycemia may increase with conventional combination therapies, and the need for multiple drugs may also reduce patient compliance. In addition, taking multiple antihyperglycemic drugs increases the potential for pharmacokinetic interactions with other drugs the patient may be taking.

[0003] Thus, for many patients, these existing drug therapies result in a progressive deterioration of glycemic control despite treatment, and in particular do not adequately control blood glucose over the long term, resulting in an inability to obtain and maintain metabolic control in advanced or late stage type 2 diabetes (including diabetes with inadequate glycemic control despite conventional oral or parenteral antidiabetic agents, secondary drug failure and / or diabetes with indications for insulin). Therefore, although intensive treatment of hyperglycemia may reduce the development of chronic damage, many patients with type 2 diabetes remain inadequately treated, in part due to limitations in the long-term efficacy, tolerance, and inconvenience of dosing of conventional antihyperglycemic medications. This high incidence of therapeutic failure is a significant contributing factor to the high rate of long-term hyperglycemia-related complications or chronic damage in patients with type 2 diabetes, including micro- and macrovascular complications, such as diabetic nephropathy, retinopathy or neuropathy, or cardiovascular complications. Oral antidiabetic drugs commonly used in treatment (e.g., first or second line, and / or monotherapy or (initial or add-on) combination therapy) include, but are not limited to, metformin, sulfonylureas, thiazolidinediones, glinides, and α-glucosidase inhibitors. Parenteral antidiabetic drugs commonly used in treatment (e.g., first or second line, and / or monotherapy or (initial or add-on) combination therapy) include, but are not limited to, GLP-1 or GLP-1 analogs, and insulin or insulin analogs.

[0004] However, the use of these conventional antidiabetic or antihyperglycemic drugs may be associated with various adverse effects (side effects). For example, metformin may be associated with lactic acidosis or gastrointestinal side effects. Sulfonylureas, glinides and insulin or insulin analogs may be associated with hypoglycemia and weight gain. Thiazolidinediones may be associated with edema, bone fractures, weight gain and heart failure / cardiac effects. Also, alpha-glucosidase blockers and GLP-1 or GLP-1 analogs may be associated with gastrointestinal adverse effects (e.g., dyspepsia, flatus or diarrhea, or nausea or vomiting). Sulfonylureas (SUs) as well as glinides stimulate insulin secretion from pancreatic beta cells in a non-glucose-dependent manner and are commonly and frequently used as first- or second-line (single or combined) treatments for type 2 diabetes (especially indicated for non-obese patients and / or patients who are unsuitable for or have become ineffective on metformin treatment). However, as mentioned above, some patients do not always respond well to these conventional oral antidiabetic drugs, especially in long-term treatment, and may show insufficient or worsening glycemic control despite treatment with sulfonylureas. Patients on long-term sulfonylurea treatment also experience a decline or attrition of pancreatic beta cell function over time. For those patients whose condition is such that sulfonylureas alone (monotherapy) are ineffective in regulating blood glucose levels, a change to other oral agents (e.g. metformin / thiazolidinedione) or SU combination therapy (add-on and initial double and triple SU combination therapy), especially a combination of sulfonylureas with metformin and / or thiazolidinedione, may be indicated depending on the disease stage, and / or a combination with insulin or (eventually) a transition to insulin (e.g. once daily basal insulin, twice daily premix insulin or multiple daily insulin depending on the disease stage). However, even with combination therapy, some patients may show insufficient glycemic control or a deterioration of glycemic control, especially over time, despite combination therapy.

[0005] Thus, the continuous loss of efficacy over time is a major concern with the use of insulin secretagogues, including glinides and sulfonylureas (secondary SU ineffectiveness). Furthermore, sulfonylureas increase the plasma level of insulin and may cause hypoglycemia (which is one of their major adverse effects, especially in association with renal impairment and / or in elderly patients, besides weight gain). Thus, with SU drugs, on the one hand, an increased sulfonylurea dose may often be required for efficacy, and on the other hand, a decreased sulfonylurea dose may often be required for safety / tolerability, thus often requiring an unsatisfactory compromise with SU drugs. Therefore, there is a need in the art to provide effective, safe and tolerable antidiabetic treatments for these patients with advanced or late stage type 2 diabetes mellitus (including patients with inadequate glycemic control with conventional oral and / or parenteral antidiabetic drugs, e.g., metformin, sulfonylureas, thiazolidinediones, glinides and / or α-glucosidase inhibitors, and / or GLP-1 or GLP-1 analogues, and / or insulin or insulin analogues). Additionally, there is a need in the art to provide adequate glycemic control for diabetic patients with secondary failure of oral antidiabetic therapy. Further, there remains a need in the art to provide prevention (including prevention or delay of progression) of secondary failure of oral antidiabetic treatment. Furthermore, there is a need in the art to provide methods for preventing or reducing the risk of adverse effects associated with (conventional) antidiabetic treatments. In monitoring the treatment of diabetes mellitus, the value of HbA1c, a product of nonenzymatic glycosylation of the hemoglobin B chain, is of particular importance. Its production depends substantially on the blood glucose level and on the life span of red blood cells, so HbA1c in the sense of "glycemic memory" reflects the average blood glucose level of the previous 4-12 weeks. Diabetic patients whose HbA1c levels have been better controlled over time by more intensive diabetes treatment (i.e., < 6.5 % of the total hemoglobin in the sample) are significantly better protected from diabetic microangiopathy. The available treatments for diabetes can give diabetic patients an average improvement in their HbA1c levels of the order of 1.0-1.5%. This reduction in HbA1c levels is not sufficient in all diabetic patients to bring them into the desired target range of HbA1c of < 7.0 %, preferably < 6.5 %, and even more preferably < 6 %.

[0006] During glycemic control, in addition to improving HbA1c levels, other treatment goals recommended for patients with type 2 diabetes mellitus are the improvement of 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 70-130 mg / dL) or <110 mg / dL, and for 2-hour postprandial plasma glucose are <180 mg / dL or <140 mg / dL. Within the meaning of the present invention, patients with inadequate glycemic control despite treatment with oral or parenteral antidiabetic drugs include, but are not limited to, patients with HbA1C values ​​of 7.0-10% (or 7.5-11%, or 7.5-10%) despite treatment with said drugs. Examples of diabetic patients with secondary failure of oral antidiabetic treatment within the meaning of the present invention are - Patients for whom metformin treatment is contraindicated, e.g., patients who have one or more contraindications to metformin treatment per label, e.g., renal disease, impairment or failure (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 Patients with at least one of the following contraindications: - Patients who suffer from one or more intolerable side effects due to metformin, in particular gastrointestinal side effects associated with metformin, e.g. Nausea, vomiting, diarrhea, Intestinal gas, and Severe abdominal discomfort Patients suffering from at least one gastrointestinal side effect selected from the following: These patients are unsuitable for metformin treatment.

[0007] Specific examples of patients who may be amenable to the treatment of the present invention include, but are not limited to, diabetic patients for whom conventional metformin treatment is not appropriate, e.g., diabetic patients who require reduced doses of metformin treatment due to reduced tolerance, intolerance or contraindications to metformin or due to (mildly) impaired / decreased renal function (including, for example, elderly patients aged 60-65 years or older). Furthermore, due to increased susceptibility to adverse effects, treatment of elderly patients (over 60-70 years of age) should often be accompanied by careful monitoring of renal function. Metformin is not usually recommended for elderly individuals, particularly those over 80 years of age, unless creatinine clearance measurements indicate that renal function is not impaired. Thus, patients unsuitable for metformin therapy may also include, for example, but are not limited to, elderly patients over 60-65 years of age, and particularly those over 80 years of age. Further specific examples of diabetic patients with secondary failure of oral antidiabetic treatment within the meaning of the present invention refer to patients with renal disease, renal failure or insufficient or impaired renal function (including mild, moderate and severe renal impairment) as indicated, for example, by elevated serum creatinine levels (e.g. serum creatinine levels above the upper limit of normal for their age, e.g. 130-150 μmol / l or more, or 1.5 mg / dl or more (136 μmol / l or more) in men and 1.4 mg / dl or more (124 μmol / l or more) in women) or abnormal creatinine clearance (e.g. glomerular filtration rate (GFR) below 30-60 ml / min).

[0008] In this context, for further example, mild renal impairment may be indicated by, for example, a creatinine clearance of 50-80 ml / min (approximately corresponding to a serum creatine level of 1.7 mg / dL or less in men and 1.5 mg / dL or less in women), moderate renal impairment may be indicated by, for example, a creatinine clearance of 30-50 ml / min (approximately corresponding to a serum creatine level of greater than 1.7 mg / dL to 3.0 mg / dL in men and greater than 1.5 mg / dL to 2.5 mg / dL in women), and severe renal impairment may be indicated by, for example, a creatinine clearance of less than 30 ml / min (approximately corresponding to a serum creatine level of greater than 3.0 mg / dL in men and greater than 2.5 mg / dL in women). Patients with end-stage renal disease require dialysis. The enzyme DPP-4 (dipeptidyl peptidase IV) (also known as CD26) is a serine protease known to effect the cleavage of dipeptides from the N-terminus of several 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 promising drugs for the treatment of diabetes mellitus. For example, DPP-4 inhibitors and their uses, in particular in metabolic (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 WO 2004 / 050658, WO 2004 / 111051, WO 2005 / 058901 or WO 2005 / 097798; or WO 2006 / 068163, WO 2007 / 071738 or WO 2008 / 017670; or WO 2007 / 128721 or WO 2007 / 128761. Further DPP-4 inhibitors 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 referred to as (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).

[0009] [ka]

[0010] In one embodiment, sitagliptin is in the form of its dihydrogen phosphate salt, i.e., sitagliptin phosphate. In a further embodiment, sitagliptin phosphate is in the form of a crystalline anhydrate or monohydrate. A class of this embodiment represents sitagliptin phosphate monohydrate. Sitagliptin free base and its pharma- ceutically acceptable salts are disclosed in U.S. Patent 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. These documents are hereby incorporated by reference for details, for example, on how to make, formulate, or use the compound or its salts. 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 called (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine).

[0011] [ka]

[0012] Vildagliptin is disclosed in detail in U.S. Patent No. 6,166,063 and in Example 1 of WO 00 / 34241. Particular salts of vildagliptin are disclosed in WO 2007 / 019255. Vildagliptin tablet formulations as well as crystalline forms of vildagliptin are disclosed in WO 2006 / 078593. Vildagliptin may be formulated as described in WO 00 / 34241 or WO 2005 / 067976. Modified release vildagliptin formulations are described in WO 2006 / 135723. These documents are hereby incorporated by reference for details, for example, on how to make, formulate, or use the compound or its salts. A tablet formulation of vildagliptin is expected to be marketed under the trade name Galvus®. A tablet formulation of the vildagliptin / metformin combination is marketed under the trade name Eucreas®. Saxagliptin (BMS-477118), having the structural formula C below, is (1S,3S,5S)-2-{(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl}-2-azabicyclo[3.1.0]hexane-3-carbonitrile (also referred to as (S)-3-hydroxyadamantylglycine-L-cis-4,5-methanoproline nitrile).

[0013] [ka]

[0014] 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 its HCl salt or its mono-benzoate salt as disclosed in WO 2004 / 052850. In a further embodiment, saxagliptin is in the form of the free base. In yet another embodiment, saxagliptin is in the form of the 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 may be formulated into tablets as described in WO 2005 / 117841. These documents are hereby incorporated by reference for details, for example, on how to make, formulate, or use the compound or its salts. Alogliptin (SYR-322), having the structural formula E below, is 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl}methyl)benzonitrile.

[0015] [ka]

[0016] Alogliptin is disclosed in detail in US 2005 / 261271, EP 1586571 and WO 2005 / 095381. In one embodiment, alogliptin is in the form of its benzoate, its hydrochloride or its tosylate salt, respectively, as disclosed in WO 2007 / 035629. A class of this embodiment represents alogliptin benzoate. Polymorphs of alogliptin benzoate are disclosed in WO 2007 / 035372. Methods for preparing alogliptin are disclosed in WO 2007 / 112368 and in detail in WO 2007 / 035629. Alogliptin (i.e., its benzoate) can be formulated and administered in tablets as described in WO 2007 / 033266. Formulations of alogliptin with metformin or pioglitazone are described in WO 2008 / 093882 or WO 2009 / 011451, respectively. These documents are hereby incorporated by reference for details, for example, on how to make, formulate, or use the compound or its salts. -(2S)-1-{[2-(5-methyl-2-phenyl-oxazol-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-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile or a pharma-ceutically acceptable salt thereof. These compounds and their preparation are described in WO 03 / 037327. The mesylate salt of the former compound as well as crystalline polymorphs thereof are disclosed in WO 2006 / 100181. The fumarate salt of the latter compound as well as crystalline polymorphs thereof are disclosed in WO 2007 / 071576. These compounds may be formulated in pharmaceutical compositions as described in WO 2007 / 017423. These documents are hereby incorporated by reference for details, for example, on how to make, formulate, or use these compounds or their salts. -(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-fluoromethyl-pyrrolidin-2-one or a pharma- ceutically acceptable salt thereof:

[0017] [ka]

[0018] 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 a pharmaceutical composition as described in WO 2007 / 017423. These documents are hereby incorporated by reference for details, for example, on how to make, formulate, or use the compound or its salts. -(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- ceutically acceptable salt thereof: This compound and methods for its preparation are disclosed in WO 2005 / 116014 and US 7,291,618. These documents are hereby incorporated by reference for details, for example, on how to make, formulate, or use the compound or its salts. -(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- ceutically acceptable salt thereof:

[0019] [ka]

[0020] This compound and methods for its preparation are disclosed in WO 2007 / 148185 and US 20070299076. Reference is hereby made to these documents for details on how to make, formulate or use this compound or its salts. -(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- ceutically acceptable salt thereof

[0021] [ka]

[0022] This compound and its preparation methods are disclosed in WO 2006 / 040625 and WO 2008 / 001195. In particular, the claimed salts include methanesulfonate and toluenesulfonate. For example, these documents are hereby referenced for details on how to manufacture, formulate or use this compound or its salts. -(R)-2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile or a pharma- ceutically acceptable salt thereof:

[0023] [ka]

[0024] This compound and its preparation method 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. For example, these documents are hereby referred to for details on the method of producing, formulating or using this compound or its salts. -5-{(S)-2-[2-((S)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide or a pharma- ceutically acceptable salt thereof:

[0025] [ka]

[0026] This compound and methods for its preparation are disclosed in WO 2006 / 116157 and US 2006 / 270701. Reference is hereby made to these documents for details on how to make, formulate or use this compound or its salts. -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- ceutically acceptable salt thereof: This compound and its preparation methods are disclosed in WO 02 / 14271. Particular salts are disclosed in WO 2006 / 088129 and WO 2006 / 118127 (including, inter alia, hydrochloride, hydrobromide). Combination therapy using this compound is described in WO 2006 / 129785. These documents are hereby incorporated by reference for details on, for example, how to prepare, formulate, or use this compound or its salts.

[0027] -[(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic acid (also called jutogliptin) or a pharma- ceutical acceptable salt thereof: This compound and methods for its preparation are disclosed in WO 2005 / 047297, WO 2008 / 109681 and WO 2009 / 009751. Particular salts are disclosed in WO 2008 / 027273 (including citrate, tartrate). Formulations of this compound are described in WO 2008 / 144730. Reference is hereby made to these documents for details regarding, for example, how to make, formulate or use this compound or its salts. -(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. Reference is hereby made to these documents for details on how to make, formulate or use this compound or its salts, for example. -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-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-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 reference is hereby made to these documents for details on how to make, formulate or use the compounds or salts thereof. For the avoidance of doubt, the disclosure of each of the above documents cited above is hereby expressly incorporated by reference. Summary of the Invention [Means for solving the problem]

[0028] Within the scope of the present invention, it has now surprisingly been found that the DPP-4 inhibitors specified herein possess unexpected, particularly advantageous, properties which make them particularly suitable for treating and / or preventing (including preventing or slowing the progression, or slowing the onset) metabolic diseases, in particular diabetes (in particular type 2 diabetes mellitus) and conditions associated therewith (e.g. diabetic complications), in patients with advanced or late stage type 2 diabetes (including patients with inadequate glycemic control despite oral and / or parenteral antidiabetic drugs and / or patients with an indication for insulin). Thus, the present invention provides a DPP-4 inhibitor as defined herein for use in the treatment of patients with inadequate glycemic control despite treatment with one or more conventional oral antidiabetic drugs (including single drug, dual or triple drug) selected from metformin, sulfonylureas, thiazolidinediones, glinides and α-glucosidase inhibitors. [Brief description of the drawings]

[0029] [Figure 1] HbA1c and glucose levels are shown after 54 days of treatment of 5-week-old female db / db mice with the indicated compounds (left bar: vehicle; middle bar: BI 1356; right bar: glibenclamide). [Diagram 2] HbA1c and glucose levels after 54 days of treatment of 5-week-old female db / db mice with the indicated compounds are shown (left bar: vehicle; middle bar: BI 1356; right bar: glibenclamide). [Diagram 3] The increase in insulin during an OGTT test (oral glucose tolerance test) is shown (left bar: vehicle; middle bar: BI 1356; right bar: glibenclamide). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] In another embodiment, the present invention provides a DPP-4 inhibitor as specified herein for use in the treatment of a patient with inadequate glycemic control despite treatment with one, two or three conventional oral or parenteral antidiabetic drugs (including single drug, double or triple drug) selected from metformin, sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, and insulin and insulin analogues, e.g. despite monotherapy with metformin, sulfonylurea, pioglitazone or (basal) insulin, or despite dual combination treatment with metformin / pioglitazone, metformin / sulfonylurea, metformin / (basal) insulin, sulfonylurea / pioglitazone, sulfonylurea / (basal) insulin or pioglitazone / (basal) insulin combinations. Furthermore, the present invention provides a DPP-4 inhibitor as defined herein for use in the treatment of patients with inadequate glycemic control despite monotherapy with a sulfonylurea or despite dual combination therapy with metformin / sulfonylurea, sulfonylurea / pioglitazone or sulfonylurea / (basal) insulin combinations. In particular, the present invention provides a DPP-4 inhibitor as defined herein for use in treating patients with inadequate glycemic control despite treatment with a sulfonylurea drug. Furthermore, the present invention provides a DPP-4 inhibitor as defined herein for use in the treatment and / or prevention of metabolic disorders, in particular type 2 diabetes mellitus, in patients with inadequate glycemic control despite treatment with a sulfonylurea drug. Furthermore, the present invention provides a DPP-4 inhibitor as defined herein for use in the treatment and / or prevention of diabetes with secondary sulfonylurea failure. Furthermore, the present invention 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 disorders, in particular type 2 diabetes mellitus, in patients with inadequate glycemic control despite treatment with a sulfonylurea drug.

[0031] Furthermore, the present invention provides a pharmaceutical composition for use in the treatment and / or prevention of metabolic disorders, in particular type 2 diabetes mellitus, in patients with poor glycemic control despite sulfonylurea treatment, said pharmaceutical composition comprising a DPP-4 inhibitor as specified herein and optionally one or more pharma- ceutically acceptable carriers and / or diluents. Furthermore, the present invention provides fixed or non-fixed combinations, including kit-of-parts, for use in the treatment and / or prevention of metabolic disorders, in particular type 2 diabetes mellitus, in patients with inadequate glycemic control despite treatment with a sulfonylurea drug, said combination comprising a DPP-4 inhibitor as specified herein and optionally one or more other active substances, such as any of those listed herein. Furthermore, the present invention provides the use of a DPP-4 inhibitor as specified herein in combination with one or more other active substances, such as any of those mentioned herein, for the preparation of a pharmaceutical composition for the treatment and / or prevention of metabolic disorders, in particular type 2 diabetes mellitus, in patients with inadequate glycemic control despite treatment with sulfonylureas. Furthermore, the present invention provides a pharmaceutical composition for use in the treatment and / or prevention of metabolic disorders, in particular type 2 diabetes mellitus, in patients with inadequate glycemic control despite treatment with a sulfonylurea drug, said pharmaceutical composition comprising a DPP-4 inhibitor as specified herein and optionally one or more other active substances, such as any of those listed herein, e.g. active ingredients for separate, sequential, simultaneous, concurrent or chronological use. Furthermore, the present invention provides a method for the treatment and / or prevention of metabolic disorders, in particular type 2 diabetes mellitus, in patients with inadequate glycemic control despite treatment with sulfonylureas, which method comprises administering to a subject (in particular a human patient) in need thereof an effective amount of a DPP-4 inhibitor as specified herein, optionally alone or, for example, separately, sequentially, simultaneously, concurrently or sequentially, in combination with an effective amount of one or more other active substances, such as any of those listed herein.

[0032] In addition, the present invention relates to a method for the treatment of one, two or three conventional antihyperglycemic agents selected from metformin, a sulfonylurea, a thiazolidinedione, a glinide, an alpha-glucosidase blocker, GLP-1 or a GLP-1 analogue, and insulin or an insulin analogue, for use in patients with inadequate glycemic control despite treatment (e.g., where applicable, despite treatment with the maximal tolerated oral dose) (e.g., despite monotherapy with metformin, sulfonylurea, pioglitazone or (basal) insulin, or despite dual combination treatment with metformin / pioglitazone, metformin / sulfonylurea, metformin / (basal) insulin, sulfonylurea / pioglitazone, sulfonylurea / (basal) insulin or pioglitazone / (basal) insulin combinations), optionally comprising administering to the patient a therapeutically effective amount of metformin, a sulfonylurea, a thiazolidinedione (e.g., pioglitazone), a glinide, an alpha-glucosidase blocker, a GLP-1 or a GLP-1 analogue, and insulin or an insulin analogue. or a DPP-4 inhibitor as specified herein in combination (additionally or initially) with a GLP-1 analogue and one or two conventional antihyperglycemic agents selected from insulin or an insulin analogue. In a further embodiment of the invention there is provided a DPP-4 inhibitor as specified herein, optionally in combination with one of the conventional antihyperglycemic agents selected from metformin, sulfonylureas, thiazolidinediones (e.g. pioglitazone), glinides, alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, and insulin and insulin analogues, for use in the (second line) treatment of type 2 diabetes patients who are inadequately controlled with said conventional antihyperglycemic agents alone. In a further embodiment of the invention there is provided a DPP-4 inhibitor as specified herein, optionally in combination with two conventional antihyperglycemic agents selected from metformin, sulfonylureas, thiazolidinediones (e.g. pioglitazone), glinides, alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, and insulin and insulin analogues, for use in the (third line) treatment of type 2 diabetes patients who are inadequately controlled with said dual combination of conventional antihyperglycemic agents.

[0033] In a further embodiment of the invention there is provided a DPP-4 inhibitor as specified herein in combination with a conventional antihyperglycemic agent selected from the group consisting of metformin, pioglitazone, a sulfonylurea, and insulin for use in the treatment of type 2 diabetes patients with inadequate glycemic control with conventional antihyperglycemic agents alone. In a further embodiment of the invention there is provided a DPP-4 inhibitor as specified herein in combination with two conventional antihyperglycemic agents selected from the group consisting of the following combinations: metformin and pioglitazone, metformin and a sulfonylurea, metformin and insulin, a sulfonylurea and pioglitazone, a sulfonylurea and insulin, and pioglitazone and insulin, for use in the treatment of a type 2 diabetes patient with inadequate glycemic control by two conventional antihyperglycemic agents. In particular, the present invention provides a DPP-4 inhibitor as defined herein in combination with a sulfonylurea for use in treating type 2 diabetes patients with inadequate glycemic control despite monotherapy with a maximal tolerated dose of a sulfonylurea. Further, the present invention provides a DPP-4 inhibitor as defined herein in combination with a sulfonylurea and metformin for use in treating type 2 diabetes patients with inadequate glycemic control despite dual combination therapy with a sulfonylurea and metformin. Further, the present invention provides a DPP-4 inhibitor as defined herein in combination with a sulfonylurea and pioglitazone for use in treating type 2 diabetes patients with inadequate glycemic control despite dual combination therapy with a sulfonylurea and pioglitazone. Further, the present invention provides a DPP-4 inhibitor as defined herein in combination with a sulfonylurea and insulin for use in treating type 2 diabetes patients with inadequate glycemic control despite dual combination therapy with a sulfonylurea and insulin. Additionally, the DPP-4 inhibitors identified herein may be beneficial in one or more of the following ways in diabetic patients with inadequate glycemic control despite treatment with oral antidiabetic agents, particularly sulfonylureas (secondary SU failure): - to prevent, slow, retard or treat metabolic disorders; - To improve glycemic control and / or reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c, - for preventing, slowing, retarding or treating a condition or disease selected from the group consisting of complications of diabetes mellitus; To reduce weight or prevent weight gain or promote weight loss, - to prevent or treat the degeneration of pancreatic beta cells and / or to improve and / or restore the function of pancreatic beta cells and / or to stimulate and / or restore the insulin secretory function of the pancreas and / or - To maintain and / or improve insulin sensitivity and / or treat or prevent hyperinsulinemia and / or insulin resistance.

[0034] Examples of such metabolic diseases or disorders amenable to treatment according to the invention in patients with secondary failure of oral antidiabetic treatment include, but are not limited to, type 1 diabetes, type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, metabolic syndrome X, obesity, hypertension, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, endothelial dysfunction and osteoporosis. Furthermore, the present invention provides the use of a DPP-4 inhibitor as specified herein, optionally in combination with one or more other active substances, such as any of those mentioned herein, for the manufacture of a medicament for one or more of the following purposes in patients with inadequate glycemic control despite single or double or triple treatment with one or more of the conventional oral or parenteral antidiabetic drugs selected in particular from metformin, sulfonylureas, thiazolidinediones (e.g. pioglitazone), glinides, alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, and insulin and insulin analogues: - preventing, slowing, retarding or treating 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, excess body weight, 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; - To improve glycemic control and / or reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c, - preventing, slowing or reversing the progression of impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and / or metabolic syndrome to type 2 diabetes mellitus; - preventing, reducing the risk of, slowing the progression, retarding or treating complications of diabetes mellitus, such as microvascular and macrovascular diseases, e.g. nephropathy, micro- or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory disorders, neurodegenerative or cognitive disorders, cardiovascular or cerebrovascular diseases, tissue ischemia, diabetic foot or ulcers, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndromes, unstable angina pectoris, stable angina pectoris, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders, vascular restenosis and / or stroke, - reduce weight or prevent weight gain or promote weight loss; - preventing, delaying or combating the degeneration of pancreatic beta cells and / or the decline in 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 hepatic steatosis (NASH) and / or liver fibrosis; - to prevent, slow, delay or treat type 2 diabetes mellitus which is primarily or secondarily refractory to conventional (oral) antihyperglycemic drugs, either alone or in combination; - obtaining a reduction in the dose of conventional antihyperglycemic drugs required for an adequate therapeutic effect; - Reduce the risk of adverse effects associated with conventional antihyperglycemic agents, and / or - Maintaining and / or improving insulin sensitivity and / or treating or preventing hyperinsulinemia and / or insulin resistance.

[0035] A particular embodiment of the present invention relates to DPP-4 inhibitors as defined herein for obtaining and / or maintaining glycemic control in type 2 diabetes patients with secondary sulfonylurea failure. Another particular embodiment of the present invention relates to a DPP-4 inhibitor as defined herein for use in the prevention (including preventing or delaying the progression) of diabetes secondary to SU failure. Another particular embodiment of the invention relates to a DPP-4 inhibitor as specified herein for use in preventing or reducing the risk of adverse effects associated with SU antidiabetic treatment, such as hypoglycemia and / or weight gain (or even for use in achieving weight loss). Another particular embodiment of the present invention relates to a DPP-4 inhibitor as specified herein for use in the treatment of diabetes with secondary sulfonylurea failure, wherein said DPP-4 inhibitor is used in add-on or initial combination therapy with a sulfonylurea single drug or dual drug (e.g. as adjunct therapy to a SU drug with or without metformin) or as a replacement for a sulfonylurea drug, optionally in combination with one or more other therapeutic agents, such as metformin and / or a thiazolidinedione (e.g. pioglitazone). Another specific embodiment of the invention relates to a DPP-4 inhibitor for use in improving HbA1c and / or FPG (e.g., mean reduction from baseline), reducing glucose excursion, and / or improving insulin secretion in patients with inadequate glycemic control (e.g., having an HbA1c of 7.5% to 10%, or 7.5% to 11%) despite treatment with a sulfonylurea drug (e.g., glibenclamide, glipizide or glimepride, with or without metformin).

[0036] Other aspects of the present invention will become apparent from the foregoing and following descriptions. DPP-4 inhibitors within the meaning of the present invention include, but are not limited to, any of those DPP-4 inhibitors listed above and below, preferably orally active DPP-4 inhibitors. An embodiment of the present invention relates to a DPP-4 inhibitor for use in the treatment and / or prevention of metabolic diseases (e.g. type 2 diabetes mellitus) in type 2 diabetic patients with secondary failure of oral antidiabetic treatment, said patient further suffering from renal disease, renal failure or renal impairment, characterized in particular in that said DPP-4 inhibitor is administered to said patient at the same dosage levels as for patients with normal renal function, thus, for example, said DPP-4 inhibitor does not require downward dosage adjustment due to impaired renal function. Another embodiment of the invention relates to a DPP-4 inhibitor for use in the treatment and / or prevention of metabolic disorders (in particular type 2 diabetes mellitus) in type 2 diabetic patients with secondary failure of oral antidiabetic treatment, said patients also being refractory or unsuitable for metformin treatment or requiring a metformin dose reduction due to intolerance or contraindications to metformin, such as any of the intolerance or contraindications identified above or below. DPP-4 inhibitors which may be suggested for the above purposes of the present invention (especially for patients with impaired renal function) may be such DPP-4 inhibitors, the active metabolites of which have a relatively wide therapeutic window (e.g., more than 100-fold) and / or are preferably primarily excreted, in particular by hepatic metabolism or biliary excretion. More specifically, DPP-4 inhibitors that are particularly suitable for the above-mentioned purposes of the present invention (especially in patients with impaired renal function) may be such orally administered DPP-4 inhibitors that have a relatively wide (e.g., >100-fold) therapeutic window and / or satisfy one or more of the following pharmacokinetic properties (preferably at their therapeutic oral dosage levels): -DPP-4 inhibitors are substantially or primarily excreted via the liver (e.g., >80% or even >90% of an administered oral dose) and / or renal excretion does not represent a substantial or only minor elimination route (e.g., elimination is followed by radioactive carbon ( 14 C) < 10% of the administered oral dose as measured by the oral dose of the substance, preferably < 7%; -DPP-4 inhibitors are excreted primarily unchanged as the parent drug (e.g., radiolabeled carbon ( 14 C) on average > 70%, or > 80%, or preferably 90% of the radioactivity excreted in urine and feces following oral administration of the substance, and / or is eliminated to a substantially non-existent or only insignificant extent by metabolism (e.g., < 30%, or < 20%, or preferably 10%); One or more (major) metabolites of the DPP-4 inhibitor are pharmacologically inactive, for example because they do not bind to the target enzyme DPP-4 and, optionally, because they are rapidly eliminated compared to the parent compound (e.g., with a terminal half-life of ≦20 hours, or preferably ≦about 16 hours, e.g., 15.9 hours).

[0037] Further properties of DPP-4 inhibitors, which may be attractive for the above-mentioned purposes of the present invention, may be one or more of the following: rapid attainment of steady state (e.g., reaching steady-state plasma levels (e.g., >90% of steady-state plasma concentrations) on days 2-4 of treatment at therapeutic oral dose levels), little accumulation (e.g., a mean accumulation ratio R A,AUC ≦ 1.4), and / or preferably preserving a long duration of action on DPP-4 inhibition when administered once daily (e.g., near complete (> 90%) DPP-4 inhibition at therapeutic oral dose levels, > 80% inhibition over a 24 hour interval following once daily ingestion of a therapeutic oral drug dose), a significant reduction in the 2 hour postprandial blood glucose excursion of ≧ 80% (already on the first day of treatment) at therapeutic dose levels, and a cumulative amount of unchanged parent compound excreted in urine on the first day that is less than 1% of the administered dose and does not increase by more than 3-6% at steady state. Thus, the present invention also relates to DPP-4 inhibitors for use in the treatment and / or prevention of metabolic diseases (in particular type 2 diabetes mellitus in patients for whom metformin treatment is unsuitable due to intolerance or contraindications to metformin, more particularly in patients with renal disease, renal failure or renal impairment), wherein said DPP-4 inhibitors are not excreted to a substantial extent by the kidney or are excreted to only a small extent (e.g. < 10%, preferably < 7% of the administered oral dose) (e.g. after elimination they are converted to radioactive carbon ( 14 C) is characterized by (as measured by oral dose of the substance). Furthermore, the present invention also relates to DPP-4 inhibitors for use in the treatment and / or prevention of metabolic disorders (particularly type 2 diabetes mellitus in patients for whom metformin treatment is unsuitable due to intolerance or contraindications to metformin, more particularly in patients with renal disease, renal failure or renal impairment), wherein said DPP-4 inhibitors are substantially or mainly excreted by the liver (e.g. after elimination they are converted to radioactive carbon ( 14 C) Characterized by: (as measured by oral dose of the substance).

[0038] Furthermore, the present invention also relates to DPP-4 inhibitors for use in the treatment and / or prevention of metabolic disorders, in particular type 2 diabetes mellitus in patients for whom metformin treatment is unsuitable due to intolerance or contraindications to metformin, more particularly in patients with renal disease, renal failure or renal impairment, The DPP-4 inhibitors are primarily excreted unchanged as the parent compound (e.g., radiolabeled carbon ( 14 C) >70%, or >80%, or preferably >90%, of the radioactivity excreted in urine and feces following oral administration of the substance; the DPP-4 inhibitor is not eliminated to a substantial extent by metabolism or is eliminated to only a small extent, and / or The main metabolites of the DPP-4 inhibitors are pharmacologically inactive or have a relatively wide therapeutic window. In a first embodiment (embodiment A), a DPP-4 inhibitor in the context of the present invention is any DPP-4 inhibitor of the formula below or a pharma- ceutically acceptable salt thereof. Formula (I)

[0039] [ka] Or formula (II) [ka] or formula (III) [ka] Or formula (IV) [ka]

[0040] In the formula, R1 represents ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyl, and R2 represents 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino, or (2-(S)-amino-propyl)-methylamino.

[0041] In a second embodiment (embodiment B), the DPP-4 inhibitor in the context of the present invention is Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, (2S)-1-{[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile, (2S)-1-{[1,1,-dimethyl-3-(4-pyridin-3-yl-imidazol-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-fluoromethyl-pyrrolidin-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-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile, 5-{(S)-2-[2-((S)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide, 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-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione or a pharma- ceutical acceptable salt thereof.

[0042] Regarding the first embodiment (embodiment A), preferred DPP-4 inhibitors are any or all of the following compounds and their pharma- ceutically acceptable salts: 1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (compare WO 2004 / 018468, Example 2(142)):

[0043] [ka]

[0044] 1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2004 / 018468, Example 2(252)): [ka]

[0045] 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2004 / 018468, Example 2(80)): [ka]

[0046] 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 (compare WO 2004 / 050658, Example 136): [ka]

[0047] 1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine (compare WO 2006 / 029769, Example 2(1)): [ka]

[0048] 1-[(3-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005 / 085246, Example 1(30)): [ka]

[0049] 1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005 / 085246, Example 1(39)): [ka]

[0050] 1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine (compare WO 2006 / 029769, Example 2(4)): [ka]

[0051] 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005 / 085246, Example 1(52)): [ka]

[0052] 1-[(4-Methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005 / 085246, Example 1(81)): [ka]

[0053] 1-[(4,6-Dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005 / 085246, Example 1(82)): [ka]

[0054] 1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005 / 085246, Example 1(83)): [ka]

[0055] These DPP-4 inhibitors are distinguished from structurally comparable DPP-4 inhibitors because they combine exceptional potency and advantageous pharmacological properties with long duration of action, receptor selectivity and favorable side effect profile, or provide unexpected therapeutic benefits or improvements when combined with other pharmacoactive substances, and their preparation is disclosed in the cited publications. A more preferred DPP-4 inhibitor among the above DPP-4 inhibitors according to 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, in particular the free base thereof (which is also known as BI 1356). Unless otherwise indicated, according to the present invention, the definitions of active compounds (including DPP-4 inhibitors) given above and below are to be understood to include not only their pharma- ceutically acceptable salts, but also their hydrates, solvates and polymorphs, with particular reference to those salts, hydrates and polymorphs mentioned herein. With regard to embodiment A, the method of synthesis of 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 the synthesis 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 included herein. The purine derivative of formula (II) can be obtained as described in WO 2004 / 050658 or WO 2005 / 110999, the disclosures of which are included herein. The purine derivatives of formulae (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. The preparation of these DPP-4 inhibitors, as detailed above, is disclosed in the publications mentioned in connection therewith. Polymorphic crystal variations 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 in their entirety. Formulations of specific DPP-4 inhibitors with metformin or other combination partners are described in PCT / EP2009053978, the disclosures of which are incorporated herein in their entirety. Typical doses of the BI 1356 / metformin dual combination are 2.5 / 500 mg, 2.5 / 850 mg and 2.5 / 1000 mg. With regard to embodiment B, methods of synthesis of the DPP-4 inhibitors of embodiment B are described in the scientific literature and / or published patent documents, particularly those cited herein.

[0056] For pharmaceutical application in warm-blooded vertebrates, especially humans, the compounds of the present invention are usually used in a dose of 0.001-100 mg / kg body weight, preferably 0.1-15 mg / kg body weight, in each case 1-4 times a day.For this purpose, the compounds, optionally combined with other active substances, can be incorporated into a conventional galenic preparation, such as plain or coated tablets, capsules, powders, suspensions or suppositories, together with one or more inert conventional 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 fat or suitable mixtures thereof. The pharmaceutical compositions of the present invention containing the DPP-4 inhibitors identified herein can thus be prepared by one skilled in the art using pharma- ceutically acceptable formulation excipients described in the art, including, but 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. 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.

[0057] Examples of binders suitable 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. Examples of disintegrants suitable 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 is Direct tableting of the active substance in the powder mixture with suitable tableting excipients; Granulation with suitable excipients and subsequent mixing with suitable excipients and subsequent tablet formation as well as film coating; or Filling capsules with powder mixtures or granules It is. The preferred 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. by roll compression) with suitable excipients and subsequent tablet formation or capsule filling It is.

[0058] An exemplary composition of the DPP-4 inhibitor of embodiment A of the present invention includes a first diluent mannitol, a pregelatinized starch as a second diluent having additional binding properties, a binder copovidone, a disintegrant corn starch, and magnesium stearate as a lubricant, where copovidone and / or corn starch are optional. For details regarding dosage forms, formulation and administration of the DPP-4 inhibitors of the present invention, reference is made to the scientific literature and / or published patent documents, particularly those cited herein. With regard to the first embodiment (embodiment A), the typically required dose of the DPP-4 inhibitors mentioned 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 per day. Thus, for example, the dose of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is 0.5 mg to 10 mg per patient per day, preferably 2.5 mg to 10 mg or 1 mg to 5 mg per patient per day, when administered orally. Dosage forms prepared with pharmaceutical compositions containing DPP-4 inhibitors as set forth herein in embodiment A contain active ingredient in the dose range of 0.1-100 mg. Thus, for example, specific doses of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine are 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg.

[0059] With regard to the second embodiment (embodiment B), the dose of the DPP-4 inhibitors listed herein in embodiment B to be administered to a mammal, e.g., a human of about 70 kg body weight, may generally be from about 0.5 mg to about 350 mg of active moiety per human per day, e.g., from about 10 mg to about 250 mg, preferably 20-200 mg, more preferably 20-100 mg, or preferably from about 0.5 mg to about 20 mg, preferably 2.5-10 mg, per human per day, divided into 1 to 4 single doses (which may, for example, be of equal size). Single doses include, for example, 10, 25, 40, 50, 75, 100, 150 and 200 mg of the DPP-4 inhibitor active moiety. The dose of the DPP-4 inhibitor sitagliptin is usually 25-200 mg of active moiety. The recommended dose of sitagliptin is 100 mg calculated on the active moiety (free base anhydrate) once daily. The unit doses of sitagliptin free base anhydrate (active moiety) are 25, 50, 75, 100, 150 and 200 mg. The specific unit doses (e.g. per tablet) of sitagliptin are 25, 50 and 100 mg. The equivalent amounts 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, are used in the pharmaceutical composition. Adjusted doses of sitagliptin 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 daily, in particular 25-150 mg, 25-100 mg or 25-50 mg or 50-100 mg daily. Particular examples of daily oral doses are 25, 30, 35, 45, 50, 55, 60, 80, 100 or 150 mg. In a more particular aspect, the daily administration of vildagliptin may be 25-150 mg or 50-100 mg. In another more particular aspect, the daily administration of vildagliptin may be 50 or 100 mg. The application of the active ingredient may occur up to three times a day, preferably once or twice a day. Particular doses are 50 mg or 100 mg of vildagliptin. Typical doses of the dual combination of vildagliptin / metformin are 50 / 850 mg and 50 / 1000 mg.

[0060] Alogliptin may be administered to a patient at a daily dose of 5 mg / day to 250 mg / day, optionally 10 mg to 200 mg, optionally 10 mg to 150 mg, and optionally 10 mg to 100 mg (based on the molecular weight of the free base form of alogliptin in each case). Thus, specific dosages that may be used include, but are not limited to, 10 mg, 12.5 mg, 20 mg, 25 mg, 50 mg, 75 mg, and 100 mg of alogliptin per day. Alogliptin may be administered in its free base form or as a pharma- ceutically acceptable salt. Saxagliptin may be administered to patients in a daily dose of 2.5 mg / day to 100 mg / day, optionally 2.5 mg to 50 mg. Specific dosages 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 per day. Exemplary dosages for the dual combination of saxagliptin / metformin are 2.5 / 500 mg and 2.5 / 1000 mg. 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 dosage levels of < 100 mg or < 70 mg per patient per day, preferably < 50 mg per patient per day, more preferably < 30 mg or < 20 mg, even more preferably 1 mg to 10 mg (divided, if required, into 1 to 4 single doses, especially 1 or 2 single doses, which may be of the same size), especially 1 mg to 5 mg (more especially 5 mg), preferably orally administered once daily, more preferably at any time of the day with or without food. Thus, for example, a daily oral dose of 5 mg BI 1356 may be administered in a once daily dosing regimen (i.e., 5 mg BI 1356 once daily) or in a twice daily dosing regimen (i.e., 2.5 mg BI 1356 twice daily) with or without food at any time of the day.

[0061] A particularly preferred DPP-4 inhibitor to be highlighted within the meaning of the present invention is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (also known as BI 1356). BI 1356 exhibits high potency, a 24-hour duration of action, and a wide therapeutic window. In patients with type 2 diabetes receiving multiple oral doses of 1, 2.5, 5 or 10 mg of BI 1356 once daily for 12 days, BI 1356 exhibits favorable pharmacodynamic and pharmacokinetic profiles (see Table 1 below) along with rapid attainment of steady state (e.g., steady state plasma levels (>90% of pre-dose plasma concentrations on day 13) were reached on days 2-5 of treatment in all dose groups), little accumulation (e.g., mean accumulation ratios R 1 - 100 at doses above 1 mg). A,AUC≦ 1.4) and preserved a long-lasting effect on DPP-4 inhibition (e.g., almost 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 at 24-h intervals after drug intake), as well as showing a significant reduction in the 2-h postprandial blood glucose excursion of ≧ 80% (already on day 1) at doses of ≧ 2.5 mg, with the cumulative amount of unchanged parent compound excreted in the urine on day 1 being less than 1% of the administered dose, increasing to ≦ 3-6% on day 12 (renal clearance CL R,ss is about 14 to about 70 mL / min for an administered oral dose, e.g., for a 5 mg dose, renal clearance is about 70 ml / min). In humans 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 drug with a full 24 hour period of DPP-4 inhibition. At therapeutic oral dose levels, BI 1356 is primarily excreted by the liver and to a small extent by the kidney (< 7% of the administered oral dose). BI 1356 is primarily excreted unchanged via the bile. The proportion of BI 1356 eliminated by the kidney increases only very slightly over time with increasing dose, so that it would probably not be necessary to modify the dose of BI 1356 based on the patient's renal function. The non-renal elimination of BI 1356, combined with its low accumulation potential and wide safety margin, may be of considerable benefit in patient populations with a high prevalence of renal failure and diabetic nephropathy. Table 1: Geometric mean (gMean) and geometric percent change (gCV) of pharmacokinetic parameters of BI 1356 at steady state (day 12)

[0062] [Table 1]

[0063] Since different metabolic dysfunctions often occur simultaneously, it is quite often appropriate to combine several different active ingredients with each other. Thus, depending on the diagnosed dysfunction, improved therapeutic results may be obtained when DPP-4 inhibitors are combined with one or more active substances customary for the respective disorder, for example other antidiabetic substances, in particular active substances that lower blood glucose levels or blood lipid levels, increase blood HDL levels, lower blood pressure, or are indicated for the treatment of atherosclerosis or obesity. Besides their use in monotherapy, the above DPP-4 inhibitors may also be used in conjunction with other active substances, which may result in improved therapeutic results. Such combined treatments may be given as free combinations of substances or in the form of fixed combinations, for example in tablets or capsules. The pharmaceutical preparations of the combination partners required for this may be commercially available as pharmaceutical compositions or may be formulated by those skilled in the art using conventional methods. Active substances that may be commercially available as pharmaceutical compositions are described in many places in the prior art, for example in the list of drugs appearing annually, the "Rote Liste" of the Federal Institute of the Pharmaceutical Industry, or in the annually updated compilation of manufacturers' information on prescription drugs known as the "Physicians' Desk Reference".

[0064] Examples of antidiabetic combination partners are metformin; sulfonylureas, such as glibenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glibornuride and gliclazide; nateglinide; repaglinide; thiazolidinediones, such as rosiglitazone and pioglitazone; PPAR gamma modulators, such as metaglydase; PPAR-gamma agonists, such as GI 262570; PPAR-gamma antagonists; PPAR-gamma / alpha modulators, such as tesaglitazar, muraglitazar, aleglitazar, indeglitazar and KRP297; PPAR-gamma / alpha / delta modulators; AMPK-activators, such as AICAR; acetyl-CoA carboxylase (ACC1 and ACC2) inhibitors; diacylglycerol-acetyltransferase (DGAT) inhibitors; pancreatic beta cell GCRP agonists, such as SMT3-receptor-agonists and GPR119; 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 glycirin, r-DNA-insulin aspart, NPH insulin, insulin detemir, insulin zinc suspension and insulin glargine; gastric acid inhibitory peptide (GIP); pramlintide, davalintide; amylin and amylin analogues or GLP-1 and GLP-1 analogues, such as exendin-4, such as exenatide, exenatide LAR , liraglutide, taspoglutide, AVE-0010, LY-2428757, LY-2189265, semaglutide or albiglutide;SGLT2-inhibitors, for example KGT-1251;inhibitors of protein tyrosine-phosphatase;inhibitors of glucose-6-phosphatase;fructose-1,6-bisphosphatase modulators;glycogen phosphorylase modulators;glucagon receptor antagonists;phosphoenolpyruvate carboxylase (PEPCK) inhibitors;pyruvate dehydrogenase kinase (PDK) inhibitors;Inhibitors of tyrosine kinases (50mg-600mg), e.g. PDGF-receptor-kinase (see EP-A-564409, WO 98 / 35958, US 5093330, WO 2004 / 005281, and WO 2006 / 041976); glucokinase / regulatory protein moxilators (including glucokinase activators); glycogen synthase kinase inhibitors; inhibitors of SH2-domain containing inositol 5-phosphatase type 2 (SHIP2); IKK inhibitors, e.g. high dose salicylate; JNK1 inhibitors; protein kinase C-theta inhibitors; beta3 agonists, e.g. ritobegron, YM 178, solabegron, talibegron, N-5984, GRC-1087, rafabegron, FMP825; aldose reductase inhibitors such as AS 3201, zenarestat, fidarestat, epalrestat, ranirestat, NZ-314, CP-744809 and CT-112; SGLT-1 or SGLT-2 inhibitors such as dapagliflozin, sergliflozin, atigliflozin, larunagliflozin 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 [Cyclocet]); and other DPP IV inhibitors. ;

[0065] Metformin is usually given in doses varying from about 500 mg to 2000 mg, up to 2500 mg per day using various dosing regimens of delayed release metformin at doses of 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 per day, or about 100 mg to 1000 mg, or preferably 500 mg to 1000 mg once or twice per day, or about 500 mg to 2000 mg once per day. Particular doses may be 250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride. Doses of pioglitazone are usually about 1-10 mg, 15 mg, 30 mg, or 45 mg once daily. Rosiglitazone is usually given in a dose of 4 to 8 mg once daily (or divided into two doses) (typical doses are 2, 4 and 8 mg). Glibenclamide (glyburide) is usually given in doses of 2.5-5 mg to 20 mg once daily (or 2 divided doses) (typical doses are 1.25, 2.5 and 5 mg), or micronized glibenclamide is given in doses of 0.75-3 mg to 12 mg once daily (or 2 divided doses) (typical doses are 1.5, 3, 4.5 and 6 mg). Glipizide is usually given in doses of 2.5 mg to 10-20 mg (up to 40 mg in two divided doses) once daily (typical doses are 5 mg and 10 mg) or extended-release glipizide is given in doses of 5 mg to 10 mg (up to 20 mg) once daily (typical doses are 2.5, 5, and 10 mg). Glimepiride is usually given in doses of 1-2 mg up to 4 mg (up to 8 mg) once daily (typical doses are 1, 2 and 4 mg). The glibenclamide / metformin dual combination is usually given 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 given in doses ranging from 2.5 / 250 mg 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 given in doses from 1 / 250 mg to 4 / 1000 mg twice daily. The dual combination of rosiglitazone / glimepiride is usually given in doses ranging from 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 dual pioglutazone / glimepiride combination is usually given in doses ranging from 30 / 2 mg to 30 / 4 mg once daily (typical doses are 30 / 4 and 45 / 4 mg). The rosiglitazone / metformin dual combination is usually given in doses ranging from 1 / 500 mg 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 given in doses ranging from 15 / 500 mg once or twice daily to 15 / 850 mg three times daily (typical doses are 15 / 500 and 15 / 850 mg).

[0066] The nonsulfonylurea insulin secretagogue nateglinide is usually given in doses from 60 mg to 120 mg with a meal (up to 360 mg / day, typical doses are 60 and 120 mg), and repaglinide is usually given in doses from 0.5 mg to 4 mg with a meal (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 in doses of 25 mg to 100 mg (up to 300 mg / day, typical doses are 25, 50, and 100 mg) with meals. Miglitol is usually given in doses of 25 mg to 100 mg (up to 300 mg / day, typical doses are 25, 50, and 100 mg) with meals. Conventional antidiabetic and antihyperglycemic agents typically used in monotherapy or dual or triple (add-on or initial) combination therapy include, but are not limited to, metformin, sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, as well as insulin and insulin analogues, such as those agents (including combinations thereof) exemplified herein.

[0067] Examples of combination partners which lower the lipid level in the blood are HMG-CoA-reductase inhibitors, such as simvastatin, atorvastatin, lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin; fibrates, such as bezafibrate, fenofibrate, clofibrate, gemfibrate, etofibrate and etofylline clofibrate; nicotinic acid and its derivatives, such as acipimox; PPAR-alpha agonists; PPAR-delta agonists; inhibitors of acyl-coenzyme A; cholesterol acyltransferase (ACAT; EC 2.3.1.26), such as avasimibe; cholesterol absorption inhibitors, such as ezetimibe; substances which bind bile acids, such as cholestyramine, colestipol and colesevelam; inhibitors of bile acid transport; HDL modulating active substances, such as D4F, reverse D4F. , LXR modulating active substances and FXR modulating active substances; CETP inhibitors, such as torcetrapib, JTT-705 (dalcetrapib) or compound 12 from WO 2007 / 005572 (anacetrapib); LDL receptor modulators; and ApoB100 antisense RNA. Doses of atorvastatin are usually from 1 mg to 40 mg, or from 10 mg to 80 mg, once daily. Examples of blood pressure lowering combination partners are beta-blockers, such as atenolol, bisoprolol, celiprolol, metoprolol 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, as well as angiotensin II receptor blockers. (ARBs), such as telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan, and eprosartan. Doses of telmisartan are usually from 20 mg to 320 mg, or from 40 mg to 160 mg per day.

[0068] Examples of combination partners that increase HDL levels in the blood are cholesteryl ester transfer protein (CETP) inhibitors; inhibitors of endothelial lipase; regulators of ABC1; LXR alpha antagonists; LXR beta agonists; PPAR-delta agonists; LXR alpha / beta regulators, and agents that increase the expression and / or plasma concentration of apolipoprotein AI. Examples of combination partners for the treatment of obesity are sibutramine; tetrahydrolipstatin (orlistat); alizyme; dexfenfluramine; axokine; cannabinoid receptor 1 antagonists, such as the CB1 antagonist trimobant; MCH-1 receptor antagonists; MC4 receptor agonists; NPY5 antagonists as well as NPY2 antagonists; beta3-AR agonists, such as SB-418790 and AD-9677; 5HT2c receptor agonists, such as APD 356 (lorcaserin); myostatin inhibitors; Acrp30 and adiponectin; steroyl-CoA desaturate (SCD1) inhibitors; fatty acid synthase (FAS) inhibitors; CCK receptor agonists; ghrelin receptor modulators; Pyy 3-36; an orexin receptor antagonist; and tesofensine, as well as dual combinations of bupropion / naltrexone, bupropion / zonisamide, topiramate / phentermine, and pramlintide / metreleptin.

[0069] 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-kinases (see EP-A-564409, WO 98 / 35958, US 5093330, WO 2004 / 005281, and WO 2006 / 041976); oxLDL antibodies and oxLDL vaccines; apoA-1 Milano; ASA; and VCAM-1 inhibitors. 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 fall 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 to illustrate the principles of the present invention by way of example and not by way of limitation. EXAMPLES

[0070] Animal models: Sulfonylureas (SUs), such as glibenclamide, are one of the most frequently used drugs for the treatment of diabetes. Long-term treatment with SUs results in elevated basal insulin secretion and decreased glucose-stimulated insulin secretion. These properties may play an important role in the occurrence of hypoglycemia and secondary treatment failure. Db / db mice represent an animal model of type 2 diabetes that exhibits insulin resistance and high levels of plasma glucose. In addition, in correlation with the age of the animals, pancreatic β-cells of aged db / db mice are unable to compensate for high glucose excursions with enhanced insulin secretion. Therefore, this model is suitable to study glibenclamide-induced secondary treatment failure in comparison with DPP-4 inhibitors (e.g., BI 1356). <Method> <Animals and Housing> Five-week-old female db / db mice are obtained from Charles River, Germany. Animals are housed in groups of 5-6 animals in a temperature- and humidity-controlled room with a 12:12 L / D cycle (lights on at 04:00 AM and off at 04:00 PM). All animals have free access to regular rodent food (Altromin standard #1324 food, Denmark) and water ad libitum. <In vivo experiment> 3 ml syringe (luer-lock TM, a gastric tube connected to a Vecton) is used to administer the compound solution orally by forced feeding every day at 08.00 AM on experimental days 0 - 59. A group of 12 animals is used: vehicle, 0.5% natrosol; BI 1356 3 mg / kg; glyburide 3 mg / kg. Body weight, food intake, and water intake are recorded daily for the first 2 weeks and twice a week for the remaining period. Blood glucose levels and HbA1c levels are measured in a semi - fed state at the time of the experiment on day 54, and an OGTT (2 g / kg) is performed on day 59. <Monitoring of HbA1c, Insulin, and Blood Glucose> Blood sampling for the measurement of "fed" blood glucose levels and HbA1c levels is performed at 10.00 AM on day 54. Before that blood sampling, the animals are transferred to a clean cage without food 2 hours before blood sampling. On day 59, an OGTT (2 g / kg) is performed after an overnight fast of the animals, and insulin is detected at t = 15 minutes. Blood Glucose: For each data point, 10 μl of blood is withdrawn from the tip of the tail into a microcapillary tube and measured using a Biosen S line glucose analyzer. Insulin: For each data point, 100 μl of blood is withdrawn from the tail vein and collected in an EDTA tube. Mouse endocrine immunoassay panel (LINCOplex TM ) is used to measure insulin and analyzed using a Luminex100TM system (LincoResearch, Missouri, USA). HbA1c: is measured using a standard enzyme assay kit (Bayer) on a fully automated analyzer.

[0071] <Results> Figures 1 and 2 show HbA1c and glucose levels after 54 days of treatment of 5-week-old female db / db mice with the indicated compounds. The DPP-4 inhibitor BI 1356 improves glucose levels as well as HbA1c levels compared to controls. In contrast, the sulfonylurea glibenclamide at a concentration of 3 mg / kg impairs HbA1c levels as well as glucose levels compared to controls and BI 1356. Figure 3 shows the increase in insulin during an OGTT test (oral glucose tolerance test). Only animals treated with BI 1356 are able to respond to increased glucose levels with an upregulation of insulin. FIG1 (left bar: vehicle; middle bar: BI 1356; right bar: glibenclamide): FIG2 (left bar: vehicle; middle bar: BI 1356; right bar: glibenclamide): FIG3 (left bar: vehicle; middle bar: BI 1356; right bar: glibenclamide):

[0072] Thus, in animals corresponding to β-cell and secondary failure of SU-induced treatment, the DPP-4 inhibitor BI 1356 is superior to glibenclamide in lowering insulin secretion as well as HbA1c and glucose. <Clinical:> Clinical trials may be used to test the feasibility of using the DPP-4 inhibitors of the present invention for the purposes of the present invention. For example, in a randomized, double-blind, placebo-controlled, parallel group study, the safety and efficacy of a DPP-4 inhibitor of the present invention (e.g., BI 1356 5 mg administered orally once daily) is tested in patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c 7.0% to 10%, or 7.5% to 10% or 11%) despite treatment with one or two conventional antihyperglycemic agents, e.g., sulfonylureas. The sulfonylurea study examines the efficacy and safety of a DPP-4 inhibitor of the present invention versus a placebo added to background sulfonylurea therapy (2-week placebo run-in phase; 18 weeks of double-blind treatment followed by 1-week follow-up after completion of study dosing; background treatment with sulfonylurea is administered during the entire study period (including the placebo run-in phase, at the unchanged dose)). Successful treatment is determined by determining HbA1c values ​​compared to initial values ​​and / or values ​​of the placebo group. A significant change in HbA1c values ​​compared to initial values ​​and / or values ​​of the placebo group demonstrates efficacy of the DPP-4 inhibitor for the treatment. Successful treatment is also determined by determining fasting plasma glucose values ​​compared to initial values ​​and / or values ​​of the placebo group. Efficacy of the treatment is demonstrated by a significant reduction in fasting glucose levels. Efficacy of the treatment is also demonstrated by the occurrence of treatment to target response (i.e., HbA1c < 7% under treatment). Safety and tolerability of treatment are assessed by analyzing patient status and relevant changes from baseline, such as the occurrence and intensity of adverse events (eg, hypoglycemic episodes, etc.) or weight gain.

Claims

1. A DPP-4 inhibitor represented by any one of the following formulae (I) to (IV) or a pharma- ceutical acceptable salt thereof for the treatment and / or prevention of metabolic disorders in patients with insufficient glycemic control despite treatment with one or more conventional oral or parenteral antidiabetic drugs selected from metformin, sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and insulin or insulin analogues: Formula (I) 【Chemistry 1】 Or formula (II) 【Chemistry 2】 or formula (III) 【Chemistry 3】 Or formula (IV) 【Chemistry 4】 wherein R1 represents ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyl; and R2 represents 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino, or (2-(S)-amino-propyl)-methylamino.

2. 2. The DPP-4 inhibitor according to claim 1 for the treatment and / or prevention of metabolic disorders in patients with inadequate glycemic control despite treatment with one or more oral antidiabetic drugs selected from metformin, sulfonylureas, thiazolidinediones, glinides and alpha-glucosidase inhibitors.

3. The DPP-4 inhibitor according to claim 1 or 2 for the treatment and / or prevention of metabolic diseases in patients with inadequate glycemic control despite treatment with sulfonylureas.

4. The DPP-4 inhibitor according to claim 1 or 2 for the treatment and / or prevention of metabolic diseases in patients with inadequate glycemic control despite treatment with a sulfonylurea drug alone.

5. A DPP-4 inhibitor according to claim 1 or 2 for the treatment and / or prevention of metabolic diseases in patients with inadequate glycemic control despite combination treatment with a sulfonylurea drug and metformin.

6. The DPP-4 inhibitor according to any one of claims 1 to 5, which is used for obtaining and / or maintaining glycemic control in a type 2 diabetes patient with secondary sulfonylurea failure.

7. A DPP-4 inhibitor according to any one of claims 1 to 6, used in combination with one or more conventional antidiabetic drugs.

8. 8. A DPP-4 inhibitor according to any one of claims 1 to 7, used in combination with said sulfonylurea, and optionally in combination with one or more other therapeutic agents, such as metformin and / or a thiazolidinedione (e.g. pioglitazone).

9. A DPP-4 inhibitor according to any one of claims 1 to 6, wherein the DPP-4 inhibitor is used as an alternative to the sulfonylurea and optionally in combination with one or more other therapeutic agents, such as metformin and / or a thiazolidinedione (e.g. pioglitazone).

10. The DPP-4 inhibitor according to any one of claims 1 to 9, wherein the sulfonylurea is selected from glibenclamide, glipizide and glimepiride.

11. 9. The DPP-4 inhibitor according to any one of claims 1 to 8, wherein the DPP-4 inhibitor is used in an add-on or initial combination therapy with a sulfonylurea selected from glibenclamide, glipizide and glimepiride, with or without metformin.

12. A DPP-4 inhibitor according to any one of claims 1 to 11, for use in improving HbA1c, FPG and / or PPG, reducing glucose excursion and / or improving insulin secretion in said patient.

13. A DPP-4 inhibitor according to any one of claims 1 to 12, used for the treatment of diabetes, such as lowering HbA1c and improving insulin secretion, in patients with indications for first- or second-line sulfonylurea therapy.

14. 13. A DPP-4 inhibitor according to any one of claims 1 to 12 for use in the treatment of diabetes in patients with indications for dual sulfonylurea combination therapy, such as a sulfonylurea plus metformin or a sulfonylurea plus thiazolidinedione or a sulfonylurea plus insulin.

15. 13. The DPP-4 inhibitor according to any one of claims 1 to 12, for use in the treatment of diabetes in patients with indications for triple combination therapy of metformin, a sulfonylurea and a thiazolidinedione, or metformin, a sulfonylurea and insulin, or a sulfonylurea, a thiazolidinedione and insulin.

16. The DPP-4 inhibitor according to any one of claims 1 to 12, which is used for the treatment of diabetes in patients who are suitable for insulin treatment.

17. 17. The DPP-4 inhibitor according to any one of claims 1 to 16, wherein the patient suffers from inadequate HbA1c values ​​of 7.5 to 11%, or 7.0 to 10%, or 7.5 to 10% despite treatment with a sulfonylurea drug.

18. A DPP-4 inhibitor according to any one of claims 1 to 17, for use in preventing or reducing the risk of side effects associated with SU antidiabetic treatment, such as hypoglycemia and / or weight gain, in said patient.

19. A DPP-4 inhibitor according to any one of claims 1 to 18, for use in preventing or delaying the progression of diabetes due to secondary SU failure in said patient.

20. A DPP-4 inhibitor according to any one of claims 1 to 19, wherein the patient is unsuitable for metformin treatment or requires reduced doses of metformin treatment due to intolerance or contraindications to metformin, e.g., a patient with renal impairment and / or an elderly patient.

21. 21. A DPP-4 inhibitor according to any one of claims 1 to 20 for use in combination with pioglitazone or metformin.

22. The DPP-4 inhibitor according to any one of claims 1 to 21, selected from the group consisting of: 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, 1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine, 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine, 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, 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine, 1-[(3-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine, 1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine, 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine, 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine, 1-[(4-methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine, 1-[(4,6-dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine and 1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine.

23. 23. The DPP-4 inhibitor according to any one of claims 1 to 22, which is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine.

24. A DPP-4 inhibitor for the oral treatment of diabetes mellitus patients, characterized in that less than 10%, preferably not more than 7%, of the administered oral dose is excreted via the kidney.

25. 25. The DPP-4 inhibitor according to claim 24, which is excreted unchanged primarily via the bile.

26. 26. The DPP-4 inhibitor according to claim 24 or 25, characterized in that more than 80%, preferably more than 90%, of the 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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