Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to certain DPP-4 inhibitors for improving glycemic control, such as e.g. improving hemoglobin A1 c (HbA1 c) and/or fasting plasma glucose (FPG), in type 2 diabetes patients with inadequate glycemic control despite therapy with metformin, as well as to the use of these DPP-4 inhibitors in antidiabetic therapy.
• DPP-4 inhibitors for improving glycemic control such as e.g. improving hemoglobin A1 c (HbA1 c) and/or fasting plasma glucose (FPG), in type 2 diabetes patients with inadequate glycemic control despite therapy with metformin, as well as to the use of these DPP-4 inhibitors in antidiabetic therapy.
• Pharmaceutical compositions for treating and/or preventing metabolic diseases (particularly diabetes, especially type 2 diabetes mellitus, and diseases related thereto) in these patients comprising a DPP-4 inhibitor as defined herein optionally together with one or more other active substances are also contemplated.
• Type 2 diabetes mellitus is a common chronic and progressive disease arising from a complex pathophysiology involving the dual endocrine effects of insulin resistance and impaired insulin secretion.
• the treatment of type 2 diabetes typically begins with diet and exercise, followed by oral antidiabetic monotherapy, and although conventional monotherapy may initially control blood glucose in some patients, it is however associated with a high secondary failure rate.
• the limitations of single-agent therapy for maintaining glycemic control may be overcome, at least in some patients, and for a limited period of time by combining multiple oral drugs to achieve reductions in blood glucose that cannot be sustained during long-term therapy with single agents. Available data support the conclusion that in most patients with type 2 diabetes monotherapy will fail and treatment with multiple drugs will be required.
• these existing drug therapies result in progressive deterioriation in glycemic control despite treatment and do not sufficiently control glycemia especially over long-term and thus fail to achieve and to maintain metabolic control e.g. in advanced or late stage type 2 diabetes and/or in diabetes with secondary drug failure.
• This high incidence of therapeutic failure is a major contributor to the high rate of long-term hyperglycemia-associated complications or chronic damages (including micro- and makrovascular complications such as e.g. diabetic nephrophathy, retinopathy or neuropathy, or cardiovascular complications) in patients with type 2 diabetes.
• chronic damages including micro- and makrovascular complications such as e.g. diabetic nephrophathy, retinopathy or neuropathy, or cardiovascular complications
• Oral antidiabetic drugs conventionally used in therapy include, without being restricted thereto, metformin, sulphonylureas, thiazolidinediones, glinides and ⁇ -glucosidase inhibitors.
• Metformin is the drug of choice for beginning or first-line antidiabetic therapy (especially for overweight patients), unless there is risk of renal impairment, contraindication or intolerance to metformin.
• metformin alone fails to control glucose concentrations to target levels
• multiple other medications e.g. dual or triple combination treatments
• become stepwise necessary to improve glycemic control at least for a certain time such as e.g. as follows:
• metformin monotherapy fails to control glucose concentrations to target levels (e.g. HbAIc > 6.5%)
• a sulfonylurea or a glinide
• a thiazolidinedione may be used as add-on therapy to metformin.
• a thiazolidinedione may be used additionally to the metformin/sulfonylurea combination.
• a sulfonylurea and a thiazolidinedione fails to control glucose concentrations to target levels (e.g.
• metformin/sulfonylurea combination may be used with once daily basal insulin, or, in case of still yet further deterioration, metformin may be used with twice daily premix insulin, or, finally, multiple daily insulin may be used.
• a recommended standard medication for type 2 diabets patients with suboptiomal glycemic control despite therapy with metformin alone, is a combination therapy taking a sulfonylurea and metformin, particularly as add-on medication of the sulfonylurea to metformin background therapy.
• Sulphonylureas stimulate insulin secretion from pancreatic beta- cells in a non-glucose-dependent manner and are generally and frequentially used as a first- or second-line (mono- or combination) treatment in type 2 diabetes (especially indicated for non-obese patients and/or for patients ineligible for or with failure in metformin therapy).
• SU Sulphonylureas
• glinides stimulate insulin secretion from pancreatic beta- cells in a non-glucose-dependent manner and are generally and frequentially used as a first- or second-line (mono- or combination) treatment in type 2 diabetes (especially indicated for non-obese patients and/or for patients ineligible for or with failure in metformin therapy).
• some patients do not always respond well to these conventional oral antidiabetic agents especially in long-term treatment and may show insufficient or deterioration in glycemic control despite treatment with a sulphonylurea drug (secondary SU
• sulfonylureas increase plasma levels of insulin and may cause hypoglycaemia, which is - besides weight gain - one of their major adverse effects, particularly in association with renal impairment and/or in elderly patients.
• hypoglycaemia which is - besides weight gain - one of their major adverse effects, particularly in association with renal impairment and/or in elderly patients.
• an increased sulfonylurea dose may be required, whereas, on the other side, with regard to safety/tolerability, sometimes a decreased sulfonylurea dose may be required, thus requiring often an unsatisfying compromise in SU medication.
• antidiabetic combination therapies e.g. combined metformin/sulfonylurea therapy
• metformin alone has their limitations, such as e.g. by their inability to prevent progressive beta-cell dysfunction and/or progressive loss of glycemic control, by the risk of secondary failure and/or by the risk or incidence of adverse effects associated with the medications such as e.g. hypoglycemic episodes and/or weight gain.
• type 2 diabetes is a progressive chronic condition which frequently requires long-term treatment
• physicians treating patients with type 2 diabetes need to have a range of treatment and combination regimens so they can tailor the therapy to the individual needs.
• HbAI c and FPG levels are key diagnostic measures of the effective management of type 2 diabetes.
• the HbA1 c value In the monitoring of the treatment of diabetes mellitus the HbA1 c value, the product of a non- enzymatic glycation of the haemoglobin B chain, is of exceptional importance. As its formation depends essentially on the blood sugar level and the life time of the erythrocytes the HbAIc in the sense of a "blood sugar memory" reflects the average blood sugar level of the preceding 4-12 weeks. Diabetic patients whose HbAI c level has been well controlled over a long time by more intensive diabetes treatment (i.e. ⁇ 6.5 % of the total haemoglobin in the sample) are significantly better protected from diabetic microangiopathy.
• the available treatments for diabetes can give the diabetic an average improvement in their HbAI c level of the order of 1.0 - 1.5 %. This reduction in the HbAI C level is not sufficient in all diabetics to bring them into the desired target range of ⁇ 7.0 %, preferably ⁇ 6.5 % and more preferably ⁇ 6 % HbAIc.
• FPG fasting plasma glucose
• PPG postprandial plasma glucose
• patients with inadequate or insufficient glycemic control despite a therapy with metformin include, without being limited to, patients having a HbAIc value from 7.5 to 10% (or, in another embodiment, from 7.5 to 11 %) at baseline despite treatment with metformin, particularly despite medication with ⁇ 1 g metformin per day.
• a special sub-embodiment of inadequately controlled patients within the meaning of this invention refers to patients in advanced or late stage type 2 diabetes patients and/or with poor glycemic control including, without being limited, patients having a HbAIc value ⁇ 9% at baseline.
• DPP-4 dipeptidyl peptidase IV
• CD26 The enzyme DPP-4 (dipeptidyl peptidase IV) also known as CD26 is a serine protease known to lead to the cleavage of a dipeptide from the N-terminal end of a number of proteins having at their N-terminal end a prolin or alanin residue. Due to this property DPP-4 inhibitors interfere with the plasma level of bioactive peptides including the peptide GLP-1 and are considered to be promising drugs for the treatment of diabetes mellitus.
• DPP-4 inhibitors and their uses are disclosed in WO 2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO 2004/041820, WO 2004/046148, WO 2005/051950, WO 2005/082906, WO 2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769 or WO2007/014886; or in WO 2004/050658, WO 2004/1 11051 , WO 2005/058901 or WO 2005/097798; or in WO 2006/068163, WO 2007/071738 or WO 2008/017670; or in WO 2007/128721 or WO 2007/128761.
• DPP-4 inhibitors As further DPP-4 inhibitors the following compounds can be mentioned:
• sitagliptin is in the form of its dihydrogenphosphate salt, i.e. sitagliptin phosphate.
• sitagliptin phosphate is in the form of a crystalline anhydrate or monohydrate.
• a class of this embodiment refers to sitagliptin phosphate monohydrate.
• Sitagliptin free base and pharmaceutically acceptable salts thereof are disclosed in US Patent No. 6,699,871 and in Example 7 of WO 03/004498. Crystalline sitagliptin phosphate monohydrate is disclosed in WO 2005/003135 and in WO 2007/050485.
• a tablet formulation for sitagliptin is commercially available under the trade name Januvia ® .
• a tablet formulation for sitagliptin/metformin combination is commercially available under the trade name Janumet ® .
• Vildagliptin is specifically disclosed in US Patent No. 6,166,063 and in Example 1 of WO 00/34241. Specific salts of vildagliptin are disclosed in WO 2007/019255. A crystalline form of vildagliptin as well as a vildagliptin tablet formulation are disclosed in WO 2006/078593. Vildagliptin can be formulated as described in WO 00/34241 or in WO 2005/067976. A modified release vildagliptin formulation is described in WO 2006/135723. For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents.
• a tablet formulation for vildagliptin is commercially available under the trade name Galvus ® .
• a tablet formulation for vildagliptin/metformin combination is commercially available under the trade name Eucreas ® .
• Saxagliptin is specifically disclosed in US Patent No. 6,395,767 and in Example 60 of WO
• saxagliptin is in the form of its HCI salt or its mono-benzoate salt as disclosed in WO 2004/052850.
• saxagliptin is in the form of the free base.
• saxagliptin is in the form of the monohydrate of the free base as disclosed in WO 2004/052850.
• Crystalline forms of the HCI salt and the free base of saxagliptin are disclosed in WO 2008/131 149.
• a process for preparing saxagliptin is also disclosed in WO 2005/10601 1 and WO 2005/115982. Saxagliptin can be formulated in a tablet as described in WO 2005/1 17841.
• 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
• Alogliptin is specifically disclosed in US 2005/261271 , EP 1586571 and in WO 2005/095381.
• alogliptin is in the form of its benzoate salt, its hydrochloride salt or its tosylate salt each as disclosed in WO 2007/035629.
• a class of this embodiment refers to alogliptin benzoate.
• Polymorphs of alogliptin benzoate are disclosed in WO 2007/035372.
• a process for preparing alogliptin is disclosed in WO 2007/1 12368 and, specifically, in WO 2007/035629.
• Alogliptin (namely its benzoate salt) can be formulated in a tablet and administered as described in WO 2007/033266.
• Formulations of Aloglipitin with pioglitazone or metformin are described in WO 2008/093882 or WO 2009/011451 , respectively.
• WO 2008/093882 for details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents.
• (2S)-1 - ⁇ [2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl ⁇ -pyrrolidine-2-carbonitrile or a pharmaceutically 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 pharmaceutically acceptable salt thereof:
• This compound and methods for its preparation are disclosed in WO 2005/000848.
• a process for preparing this compound is also disclosed in WO 2008/031749, WO 2008/031750 and WO 2008/055814.
• This compound can be formulated in a pharmaceutical composition as described in WO 2007/017423.
• WO 2007/017423 For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents.
• DPP-4 inhibitors as defined herein have unexpected and particularly advantageous properties, which make them particularly suitable for improving glycemic control in patients with type 2 diabetes mellitus inadequately controlled on metformin alone.
• 5 mg BI 1356 daily provides in the patients the maximum glycemic effect with up to greatest percentage of patients achieving the targets of a HbAIc lowering of at least 0.5% from baseline (>0.5%: 53.2%, >1.0%: 27.4%) and of a HbAI c value of ⁇ 7.0% (14.5%).
• a dose of a DPP-4 inhibitor resulting in >80% DPP-4 inhibition in >80% of the patients at trough is a therapeutic dose.
• the present invention provides a DPP-4 inhibitor as defined herein for use in improving glycemic control in type 2 diabetes patients with inadequate glycemic control despite metformin therapy, particularly despite monotherapy with metformin, for example despite maximal tolerated dose of oral therapy with metformin.
• a special embodiment of this invention refers to a DPP-4 inhibitor as defined herein for use in improving glycemic control in type 2 diabetes patients with inadequate glycemic control despite metformin therapy, wherein said DPP-4 inhibitor reduces significantly glycosylated haemoglobin HbAIc and/or fasting plasma glucose.
• Another special embodiment of this invention refers to a DPP-4 inhibitor as defined herein for use in improving glycemic control in type 2 diabetes patients with inadequate glycemic control despite metformin therapy, wherein said DPP-4 inhibitor may be used as add-on or initial combination therapy with metformin, particularly as add-on combination therapy with metformin.
• Another special embodiment of this invention refers to a DPP-4 inhibitor as defined herein for use in reducing significantly glycosylated haemoglobin HbAIc and/or fasting plasma glucose in type 2 diabetes patients with inadequate glycemic control on metformin alone, wherein said DPP-4 inhibitor is administered to said patients in an amount from 1 mg to 10 mg once daily, particularly 5 mg once daily, over 12 weeks as add-on to metformin background therapy.
• the present invention further provides a DPP-4 inhibitor as defined herein for resulting in >80% DPP-4 inhibition at trough in >80% of type 2 diabetes patients with inadequate glycemic control having HbAIc at baseline from 7.5 to 10% despite mono-medication with ⁇ 1 g metformin per day, wherein said DPP-4 inhibitor is administered over 12 weeks in an amount of 5 mg orally once daily as add-on to metformin background therapy.
• the present invention further provides a DPP-4 inhibitor as defined herein for use in the treatment and/or prevention (including preventing or slowing the progression or delaying the onset) of metabolic diseases, particularly diabetes (especially type 2 diabetes mellitus) and diseases related thereto (e.g. diabetic complications), in patients with inadequate glycemic control despite therapy with metformin, particularly despite monotherapy with metformin.
• metabolic diseases particularly diabetes (especially type 2 diabetes mellitus) and diseases related thereto (e.g. diabetic complications)
• the present invention further provides a pharmaceutical composition for use in the therapies described herein in patients with insufficient glycemic control despite treatment with metformin, said pharmaceutical composition comprising a DPP-4 inhibitor as defined herein and optionally one or more pharmaceutically acceptable carriers and/or diluents.
• the present invention further provides a fixed or non-fixed combination including a kit-of- parts for use in the therapies described herein in patients with insufficient glycemic control despite therapy with metformin, said combination comprising a DPP-4 inhibitor as defined herein and one or more other active substances, e.g. any of those mentioned herein.
• the present invention further provides the use of a DPP-4 inhibitor as defined herein optionally in combination with one or more other active substances, such as e.g. any of those mentioned herein, for the manufacture of a pharmaceutical composition for the therapies described herein, in patients with insufficient glycemic control despite therapy with metformin.
• the present invention further provides a pharmaceutical composition for use in the therapies described herein in patients with insufficient glycemic control despite therapy with metformin, said pharmaceutical composition comprising a DPP-4 inhibitor as defined herein and optionally one or more other active substances, such as e.g. any of those mentioned herein.
• the present invention further provides a method of treating and/or preventing metabolic diseases, particularly type 2 diabetes mellitus, in patients with insufficient glycemic control despite therapy with metformin, said method comprising administering to a subject in need thereof (particularly a human patient) an effective amount of a DPP-4 inhibitor as defined herein, optionally separately, sequentially, simultaneously, concurrently or chronologically staggered with an effective amount of one or more other active substances, such as e.g. any of those mentioned herein.
• DPP-4 inhibitors as defined herein may be useful in one or more of the following methods
• a condition or disorder selected from the group consisting of complications of diabetes mellitus
• pancreatic beta cells for preventing or treating the degeneration of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells and/or stimulating and/or restoring the functionality of pancreatic insulin secretion;
• Examples of such metabolic diseases or disorders amenable by the therapy of this invention in patients with insufficient glycemic control despite metformin therapy may include, without being restricted 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.
• the present invention further provides a DPP-4 inhibitor as defined herein, optionally in combination with one or more other active substances, such as e.g. any of those mentioned herein, for use in one or more of the following methods: - preventing, slowing the progression of, delaying or treating a metabolic disorder or disease, such as e.g.
• type 1 diabetes mellitus type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy and/or metabolic syndrome;
• ITT impaired glucose tolerance
• IGF impaired fasting blood glucose
• hyperglycemia postprandial hyperglycemia, overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy and/or metabolic syndrome;
• diabetes mellitus such as micro- and macrovascular diseases, such as nephropathy, micro- or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative or cognitive disorders, cardio- or cerebrovascular diseases, tissue ischaemia, diabetic foot or ulcus, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders, vascular restenosis, and/or stroke;
• micro- and macrovascular diseases such as nephropathy, micro- or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative or cognitive disorders, cardio- or cerebrovascular diseases, tissue ischaemia, diabetic foot or ulcus, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome,
• pancreatic beta cells - preventing, slowing, delaying or treating the degeneration of pancreatic beta cells and/or the decline of the functionality of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells and/or stimulating and/or restoring the functionality of pancreatic insulin secretion;
• NAFLD non alcoholic fatty liver disease
• NASH non-alcoholic steatohepatitis
• liver fibrosis liver fibrosis
• a DPP-4 inhibitor within the meaning of the present invention includes, without being limited to, any of those DPP-4 inhibitors mentioned hereinabove and hereinbelow, preferably orally active DPP-4 inhibitors.
• a DPP-4 inhibitor according to this invention may be such an oral DPP-4 inhibitor, which and whose active metabolites have preferably a relatively wide (e.g. about > 100 fold) therapeutic window and/or, especially, that are primarily eliminated via hepatic metabolism or biliary excretion.
• a DPP-4 inhibitor according to this invention may be such an orally administered DPP-4 inhibitor, which has a relatively wide (e.g. > 100 fold) therapeutic window and/or which fulfils one or more of the following pharmacokinetic properties (preferably at its therapeutic oral dose levels):
• the DPP-4 inhibitor is substantially or mainly excreted via the liver (e.g. > 80 % or even > 90 % of the administered oral dose), and/or for which renal excretion represents no substantial or only a minor elimination pathway (e.g. ⁇ 10 %, preferably ⁇ 7 %, of the administered oral dose measured, for example, by following elimination of a radiolabeled carbon ( 14 C) substance oral dose);
• the DPP-4 inhibitor is excreted mainly unchanged as parent drug (e.g. with a mean of > 70%, or > 80%, or, preferably, 90% of excreted radioactivity in urine and faeces after oral dosing of radiolabeled carbon ( 14 C) substance), and/or which is eliminated to a non- substantial or only to a minor extent via metabolism (e.g. ⁇ 30%, or ⁇ 20%, or, preferably, 10%);
• the (main) metabolite(s) of the DPP-4 inhibitor is/are pharmacologically inactive.
• the main metabolite does not bind to the target enzyme DPP-4 and, optionally, it is rapidly eliminated compared to the parent compound (e.g. with a terminal half-life of the metabolite of ⁇ 20 h, or, preferably, ⁇ about 16 h, such as e.g. 15.9 h).
• the (main) metabolite in plasma (which may be pharmacologically inactive) of a DPP-4 inhibitor having a 3-amino-piperidin-1-yl substituent is such a derivative where the amino group of the 3-amino-piperidin-1-yl moiety is replaced by a hydroxyl group to form the 3-hydroxy-piperidin-1-yl moiety (e.g. the 3-(S)-hydroxy-piperidin-1-yl moiety, which is formed by inversion of the configuration of the chiral center).
• Further properties of a DPP-4 inhibitor according to this invention may be one or more of the following: Rapid attainment of steady state (e.g.
• a DPP-4 inhibitor according to this invention may be characterized in that said DPP-4 inhibitor is excreted to a non-substantial or only to a minor extent (e.g. ⁇ 10 %, preferably ⁇ 7 % of administered oral dose) via the kidney (measured, for example, by following elimination of a radiolabeled carbon ( 14 C) substance oral dose).
• a minor extent e.g. ⁇ 10 %, preferably ⁇ 7 % of administered oral dose
• a DPP-4 inhibitor according to this invention may be characterized in that said DPP- 4 inhibitor is excreted substantially or mainly via the liver (measured, for example, by following elimination of a radiolabeled carbon ( 14 C) substance oral dose).
• a DPP-4 inhibitor according to this invention may be characterized in that said DPP-4 inhibitor is excreted mainly unchanged as parent drug (e.g. with a mean of >
• said DPP-4 inhibitor is eliminated to a non-substantial or only to a minor extent via metabolism, and/or the main metabolite of said DPP-4 inhibitor is pharmacologically inactive or has a relatively wide therapeutic window.
• a DPP-4 inhibitor in the context of the present invention is any DPP-4 inhibitor of formula (I)
• R1 denotes ([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 denotes 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino or (2-(S)-amino-propyl)-methylamino, or its pharmaceutically acceptable salt.
• a DPP-4 inhibitor in the context of the present invention is a DPP-4 inhibitor selected from the group consisting of sitagliptin, vildagliptin, saxagliptin, alogliptin,
• preferred DPP-4 inhibitors are any or all of the following compounds and their pharmaceutically acceptable salts:
• DPP-4 inhibitors are distinguished from structurally comparable DPP-4 inhibitors, as they combine exceptional potency and a long-lasting effect with favourable pharmacological properties, receptor selectivity and a favourable side-effect profile or bring about unexpected therapeutic advantages or improvements when combined with other pharmaceutical active substances.
• Their preparation is disclosed in the publications mentioned.
• a more preferred DPP-4 inhibitor among the abovementioned DPP-4 inhibitors of embodiment A of this invention is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1- yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, particularly the free base thereof (which is also known as BI 1356).
• the definitions of the active compounds (including the DPP-4 inhibitors) mentioned hereinabove and hereinbelow also comprise their pharmaceutically acceptable salts as well as hydrates, solvates and polymorphic forms thereof. With respect to salts, hydrates and polymorphic forms thereof, particular reference is made to those which are referred to herein.
• the methods of synthesis for the DPP-4 inhibitors according to embodiment A of this invention are known to the skilled person.
• the DPP- 4 inhibitors according to embodiment A of this invention can be prepared using synthetic methods as described in the literature.
• purine derivatives of formula (I) can be obtained as described in WO 2002/068420, WO 2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006/048427, the disclosures of which are incorporated herein.
• Purine derivatives of formula (II) can be obtained as described, for example, in WO 2004/050658 or WO 2005/110999, the disclosures of which are incorporated herein.
• Purine derivatives of formula (III) and (IV) can be obtained as described, for example, in WO 2006/068163, WO 2007/071738 or WO 2008/017670, the disclosures of which are incorporated herein.
• the preparation of those DPP-4 inhibitors, which are specifically mentioned hereinabove, is disclosed in the publications mentioned in connection therewith.
• Polymorphous crystal modifications and formulations of particular DPP-4 inhibitors are disclosed in WO 2007/128721 and WO 2007/128724, respectively, the disclosures of which are incorporated herein in their entireties.
• Formulations of particular DPP-4 inhibitors with metformin or other combination partners are described in WO 2009/121945, the disclosure of which is incorporated herein in its entirety.
• Typical dosage strengths of the dual fixed combination of BI 1356 / metformin are 2.5/500 mg, 2.5/850 mg and 2.5/1000 mg, which may be administered 1-3 times a day, particularly twice a day.
• the compounds of this invention are usually used in dosages from 0.001 to 100 mg/kg body weight, preferably at 0.1-15 mg/kg, in each case 1 to 4 times a day.
• the compounds, optionally combined with other active substances may be incorporated together with one or more inert conventional carriers and/or diluents, e.g.
• compositions according to this invention comprising the DPP-4 inhibitors as defined herein are thus prepared by the skilled person using pharmaceutically acceptable formulation excipients as described in the art.
• excipients include, without being restricted to diluents, binders, carriers, fillers, lubricants, flow promoters, crystallisation retardants, disintegrants, solubilizers, colorants, pH regulators, surfactants and emulsifiers.
• Suitable diluents for compounds according to embodiment A include cellulose powder, calcium hydrogen phosphate, erythritol, low substituted hydroxypropyl cellulose, mannitol, pregelatinized starch or xylitol.
• Suitable lubricants for compounds according to embodiment A include talc, polyethyleneglycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate.
• Suitable binders for compounds according to embodiment A include copovidone (copolymerisates of vinylpyrrolidon with other vinylderivates), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidon (povidone), pregelatinized starch, or low-substituted hydroxypropylcellulose (L-HPC).
• Suitable disintegrants for compounds according to embodiment A include corn starch or crospovidone.
• An exemplary composition of a DPP-4 inhibitor according to embodiment A of the invention comprises the first diluent mannitol, pregelatinized starch as a second diluent with additional binder properties, the binder copovidone, the disintegrant corn starch, and magnesium stearate as lubricant; wherein copovidone and/or corn starch may be optional.
• compositions may be packaged in a variety of ways.
• an article for distribution includes a container that contains the pharmaceutical composition in an appropriate form. Tablets are typically packed in an appropriate primary package for easy handling, distribution and storage and for assurance of proper stability of the composition at prolonged contact with the environment during storage.
• Primary containers for tablets may be bottles or blister packs.
• a suitable bottle e.g. for a pharmaceutical composition or combination comprising a DPP-4 inhibitor according to embodiment A of the invention, may be made from glass or polymer (preferably polypropylene (PP) or high density polyethylene (HD-PE)) and sealed with a screw cap.
• the screw cap may be provided with a child resistant safety closure (e.g. press- and-twist closure) for preventing or hampering access to the contents by children.
• a desiccant such as e.g. bentonite clay, molecular sieves, or, preferably, silica gel
• the shelf life of the packaged composition can be prolonged.
• a suitable blister pack e.g. for a pharmaceutical composition or combination comprising a DPP-4 inhibitor according to embodiment A of the invention, comprises or is formed of a top foil (which is breachable by the tablets) and a bottom part (which contains pockets for the tablets).
• the top foil may contain a metalic foil, particularly an aluminium or aluminium alloy foil (e.g. having a thickness of 20 ⁇ m to 45 ⁇ m, preferably 20 ⁇ m to 25 ⁇ m) that is coated with a heat-sealing polymer layer on its inner side (sealing side).
• the bottom part may contain a multi-layer polymer foil (such as e.g.
• PVDC polyvinyl choride coated with poly(vinylidene choride)
• PCTFE poly(chlorotriflouroethylene)
• multi-layer polymer-metal-polymer foil such as e.g. a cold-formable laminated PVC/aluminium/polyamide composition
• the article may further comprise a label or package insert, which refer to instructions customarily included in commercial packages of therapeutic products, that may contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.
• the label or package inserts indicates that the composition can be used for any of the purposes described herein.
• the dosage typically required of the DPP-4 inhibitors mentioned herein in embodiment A when administered intravenously is 0.1 mg to 10 mg, preferably 0.25 mg to 5 mg, and when administered orally is 0.5 mg to 100 mg, preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably 2.5 mg to 10 mg or 1 mg to 5 mg, in each case 1 to 4 times a day.
• 0.1 mg to 10 mg preferably 0.25 mg to 5 mg
• 0.5 mg to 100 mg preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably 2.5 mg to 10 mg or 1 mg to 5 mg, in each case 1 to 4 times a day.
• the dosage of 1-[(4-methyl- quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine when administered orally 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.
• a dosage form prepared with a pharmaceutical composition comprising a DPP-4 inhibitor mentioned herein in embodiment A contain the active ingredient in a dosage range of 0.1- 100 mg.
• dosage strengths 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.
• the doses of DPP-4 inhibitors mentioned herein in embodiment B to be administered to mammals may be generally from about 0.5 mg to about 350 mg, for example from about 10 mg to about 250 mg, preferably 20-200 mg, more preferably 20-100 mg, of the active moiety per person per day, or from about 0.5 mg to about 20 mg, preferably 2.5-10 mg, per person per day, divided preferably into 1 to 4 single doses which may, for example, be of the same size.
• Single dosage strengths comprise, for example, 10, 25, 40, 50, 75, 100, 150 and 200 mg of the DPP-4 inhibitor active moiety.
• a dosage strength of the DPP-4 inhibitor sitagliptin is usually between 25 and 200 mg of the active moiety.
• a recommended dose of sitagliptin is 100 mg calculated for the active moiety (free base anhydrate) once daily.
• Unit dosage strengths of sitagliptin free base anhydrate (active moiety) are 25, 50, 75, 100, 150 and 200 mg.
• Particular unit dosage strengths of sitagliptin (e.g. per tablet) are 25, 50 and 100 mg.
• An equivalent amount of sitagliptin phosphate monohydrate to the sitagliptin free base anhydrate is used in the pharmaceutical compositions, namely, 32.13, 64.25, 96.38, 128.5, 192.75, and 257 mg, respectively. Adjusted dosages of 25 and 50 mg sitagliptin are used for patients with renal failure.
• Typical dosage strengths of the dual combination of sitagliptin / metformin are 50/500 mg and 50/1000 mg.
• a dosage range of the DPP-4 inhibitor vildagliptin is usually between 10 and 150 mg daily, in particular between 25 and 150 mg, 25 and 100 mg or 25 and 50 mg or 50 and 100 mg daily.
• Particular examples of daily oral dosage are 25, 30, 35, 45, 50, 55, 60, 80, 100 or 150 mg.
• the daily administration of vildagliptin may be between 25 and 150 mg or between 50 and 100 mg.
• 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 one or two times a day.
• Particular dosage strengths are 50 mg or 100 mg vildagliptin.
• Typical dosage strengths of the dual combination of vildagliptin / metformin are 50/850 mg and 50/1000 mg.
• Alogliptin may be administered to a patient at a daily dose of between 5 mg/day and 250 mg/day, optionally between 10 mg and 200 mg, optionally between 10 mg and 150 mg, and optionally between 10 mg and 100 mg of alogliptin (in each instance based on the molecular weight of the free base form of alogliptin).
• specific dosage amounts 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 pharmaceutically acceptable salt form.
• Saxagliptin may be administered to a patient at a daily dose of between 2.5 mg/day and 100 mg/day, optionally between 2.5 mg and 50 mg.
• Specific dosage amounts that may be used include, but are not limited to 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg , 40 mg, 50 mg and 100 mg of saxagliptin per day.
• Typical dosage strengths of the dual combination of saxagliptin / metformin are 2.5/500 mg and 2.5/1000 mg.
• DPP-4 inhibitors of this invention refers to those orally administered DPP-4 inhibitors which are therapeutically efficacious at low dose levels, e.g. at oral dose levels ⁇ 100 mg or ⁇ 70 mg per patient per day, preferably ⁇ 50 mg, more preferably ⁇ 30 mg or ⁇ 20 mg, even more preferably from 1 mg to 10 mg, particularly from 1 mg to 5 mg (more particularly 5 mg), per patient per day (if required, divided into 1 to 4 single doses, particularly 1 or 2 single doses, which may be of the same size, preferentially, administered orally once- or twice daily (more preferentially once-daily), advantageously, administered at any time of day, with or without food.
• the daily oral amount 5 mg BI 1356 can be given 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), at any time of day, with or without food.
• a particularly preferred DPP-4 inhibitor to be emphasized within the meaning of this 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, 24h duration of action, and a wide therapeutic window.
• BI 1356 shows favourable pharmacodynamic and pharmacokinetic profile (see e.g. Table 1 below) with rapid attainment of steady state (e.g.
• BI 1356 acts as a true once-daily oral drug with a full 24 h duration of DPP-4 inhibition.
• BI 1356 is mainly excreted via the liver and only to a minor extent (about ⁇ 7% of the administered oral dose) via the kidney.
• BI 1356 is primarily excreted unchanged via the bile.
• the fraction of BI 1356 eliminated via the kidneys increases only very slightly over time and with increasing dose, so that there will likely be no need to modify the dose of BI 1356 based on the patients' renal function.
• the non-renal elimination of BI 1356 in combination with its low accumulation potential and broad safety margin may be of significant benefit in a patient population that has a high prevalence of renal insufficiency and diabetic nephropathy.
• a DPP-4 inhibitor is combined with active substances customary for the respective disorders, such as e.g. one or more active substances selected from among the other antidiabetic substances, especially active substances that lower the blood sugar level or the lipid level in the blood, raise the HDL level in the blood, lower blood pressure or are indicated in the treatment of atherosclerosis or obesity.
• the DPP-4 inhibitors mentioned above - besides their use in mono-therapy - may also be used in conjunction with other active substances, by means of which improved treatment results can be obtained.
• Such a combined treatment may be given as a free combination of the substances or in the form of a fixed combination, for example in a tablet or capsule.
• Pharmaceutical formulations of the combination partner needed for this may either be obtained commercially as pharmaceutical compositions or may be formulated by the skilled man using conventional methods.
• the active substances which may be obtained commercially as pharmaceutical compositions are described in numerous places in the prior art, for example in the list of drugs that appears annually, the "Rote Liste ®" of the federal association of the pharmaceutical industry, or in the annually updated compilation of manufacturers' information on prescription drugs known as the "Physicians' Desk Reference".
• Examples of antidiabetic combination partners are metformin; sulphonylureas such as glibenclamide, tolbutamide, glimepiride, glipizide, gliquidon, glibornuride and gliclazide; nateglinide; repaglinide; thiazolidinediones such as rosiglitazone and pioglitazone; PPAR gamma modulators such as metaglidases; PPAR-gamma agonists such as Gl 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-ace
• GLP-1 and GLP-1 analogues such as Exendin-4, e.g. exenatide, exenatide LAR, liraglutide, taspoglutide, lixisenatide (AVE-0010), LY-2428757 (a PEGylated version of GLP-1 ), LY-2189265 (GLP-1 analogue linked to lgG4-Fc heavy chain), semaglutide or albiglutide; SGLT2-inhibitors such as KGT-1251 ; inhibitors of protein tyrosine-phosphatase (e.g.
• trodusquemine inhibitors of glucose-6-phosphatase; fructose-1 ,6-bisphosphatase modulators; glycogen phosphorylase modulators; glucagon receptor antagonists; phosphoenolpyruvatecarboxykinase (PEPCK) inhibitors; pyruvate dehydrogenasekinase (PDK) inhibitors; inhibitors of tyrosine-kinases (50 mg to 600 mg) such as PDGF-receptor- kinase (cf. EP-A-564409, WO 98/35958, US 5093330, WO 2004/005281 , and
• glucokinase/regulatory protein modulators incl. glucokinase activators; glycogen synthase kinase inhibitors; inhibitors of the SH2-domain-containing inositol 5- phosphatase type 2 (SHIP2) ; IKK inhibitors such as high-dose salicylate ; JNK1 inhibitors ; protein kinase C-theta inhibitors; beta 3 agonists such as ritobegron, YM 178, solabegron, talibegron, N-5984, GRC-1087, rafabegron, FMP825; aldosereductase inhibitors such as AS 3201 , zenarestat, fidarestat, epalrestat, ranirestat, NZ-314, CP-744809, and CT-1 12; SGLT-1 or SGLT-2 inhibitors, such as e.g.
• Metformin is usually given in doses varying from about 500 mg to 2000 mg up to 2500 mg per day using various dosing regimens from about 100 mg to 500 mg or 200 mg to 850 mg (1 -3 times a day), or about 300 mg to 1000 mg once or twice a day, or delayed-release metformin in doses of about 100 mg to 1000 mg or preferably 500 mg to 1000 mg once or twice a day or about 500 mg to 2000 mg once a day.
• Particular dosage strengths may be 250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride.
• a maximal tolerated dose with regard to metformin is for example 2000 mg per day, 1500 mg per day (for example in asian countries) or 850 mg three times a day or any equivalent thereof.
• a dosage of pioglitazone is usually of about 1 -10 mg, 15 mg, 30 mg, or 45 mg once a day.
• Rosiglitazone is usually given in doses from 4 to 8 mg once (or divided twice) a day (typical dosage strengths are 2, 4 and 8 mg).
• Glibenclamide is usually given in doses from 2.5-5 to 20 mg once (or divided twice) a day (typical dosage strengths are 1.25, 2.5 and 5 mg), or micronized glibenclamide in doses from 0.75-3 to 12 mg once (or divided twice) a day (typical dosage strengths are 1.5, 3, 4.5 and 6 mg).
• Glipizide is usually given in doses from 2.5 to 10-20 mg once (or up to 40 mg divided twice) a day (typical dosage strengths are 5 and 10 mg), or extended-release glipizide in doses from 5 to 10 mg (up to 20 mg) once a day (typical dosage strengths are 2.5, 5 and 10 mg).
• Glimepiride is usually given in doses from 1-2 to 4 mg (up to 8 mg) once a day (typical dosage strengths are 1 , 2 and 4 mg).
• a dual combination of glibenclamide/metformin is usually given in doses from 1.25/250 once daily to 10/1000 mg twice daily (typical dosage strengths are 1.25/250, 2.5/500 and 5/500 mg).
• a dual combination of glipizide/metformin is usually given in doses from 2.5/250 to 10/1000 mg twice daily (typical dosage strengths are 2.5/250, 2.5/500 and 5/500 mg).
• a dual combination of glimepiride/metformin is usually given in doses from 1/250 to 4/1000 mg twice daily.
• a dual combination of rosiglitazone/glimepiride is usually given in doses from 4/1 once or twice daily to 4/2 mg twice daily (typical dosage strengths are 4/1 , 4/2, 4/4, 8/2 and 8/4 mg).
• a dual combination of pioglitazone/glimepiride is usually given in doses from 30/2 to 30/4 mg once daily (typical dosage strengths are 30/4 and 45/4 mg).
• a dual combination of rosiglitazone/metformin is usually given in doses from 1/500 to 4/1000 mg twice daily (typical dosage strengths are 1/500, 2/500, 4/500, 2/1000 and 4/1000 mg).
• a dual combination of pioglitazone/metformin is usually given in doses from 15/500 once or twice daily to 15/850 mg thrice daily (typical dosage strengths are 15/500 and 15/850 mg).
• the non-sulphonylurea insulin secretagogue nateglinide is usually given in doses from 60 to 120 mg with meals (up to 360 mg/day, typical dosage strengths are 60 and 120 mg); repaglinide is usually given in doses from 0.5 to 4 mg with meals (up to 16 mg/day, typical dosage strengths are 0.5, 1 and 2 mg).
• a dual combination of repaglinide/metformin is available in dosage strengths of 1/500 and 2/850 mg.
• Acarbose is usually given in doses from 25 to 100 mg with meals.
• Miglitol is usually given in doses from 25 to 100 mg with meals.
• HMG-CoA- reductase inhibitors such as simvastatin, atorvastatin, lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin; fibrates such as bezafibrate, fenofibrate, clofibrate, gemfibrozil, etofibrate and etofyllinclofibrate; nicotinic acid and the derivatives thereof such as acipimox; PPAR-alpha agonists; PPAR-delta agonists; inhibitors of acyl-coenzyme
• A:cholesterolacyltransferase such as avasimibe; cholesterol resorption inhibitors such as ezetimib; substances that bind to bile acid, 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; MTP inhibitors (e.g. lomitapide); and ApoBI OO antisense RNA.
• ACAT cholesterolacyltransferase
• avasimibe such as avasimibe
• cholesterol resorption inhibitors such as ezetimib
• substances that bind to bile acid such as cholestyramine, colestipol and colesevelam
• a dosage of atorvastatin is usually from 1 mg to 40 mg or 10 mg to 80 mg once a day
• beta-blockers such as atenolol, bisoprolol, celiprolol, metoprolol and carvedilol
• diuretics such as hydrochlorothiazide, chlortalidon, 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,
• a dosage of telmisartan is usually from 20 mg to 320 mg or 40 mg to 160 mg per day.
• combination partners which increase the HDL level in the blood are Cholesteryl Ester Transfer Protein (CETP) inhibitors; inhibitors of endothelial lipase; regulators of ABC1 ; LXRalpha antagonists; LXRbeta agonists; PPAR-delta agonists; LXRalpha/beta regulators, and substances that increase the expression and/or plasma concentration of apolipoprotein A-I.
• CETP Cholesteryl Ester Transfer Protein
• combination partners for the treatment of obesity are sibutramine; tetrahydrolipstatin (orlistat); alizyme (cetilistat); dexfenfluramine; axokine; cannabinoid receptor 1 antagonists such as the CB1 antagonist rimonobant; MCH-1 receptor antagonists; MC4 receptor agonists; NPY5 as well as NPY2 antagonists (e.g.
• 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 desaturase (SCD1 ) inhibitors; fatty acid synthase (FAS) inhibitors; CCK receptor agonists; Ghrelin receptor modulators; Pyy 3-36; orexin receptor antagonists; and tesofensine; as well as the dual combinations bupropion/naltrexone, bupropion/zonisamide, topiramate/phentermine and pramlintide/metreleptin.
• combination partners for the treatment of atherosclerosis are phospholipase A2 inhibitors; inhibitors of tyrosine-kinases (50 mg to 600 mg) such as PDGF-receptor-kinase (cf. 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.
• phospholipase A2 inhibitors inhibitors of tyrosine-kinases (50 mg to 600 mg) such as PDGF-receptor-kinase (cf. 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 is
• BI 1356 (1 , 5, or 10 mg qd), a potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor
• DPP-4 dipeptidyl peptidase-4
• MET metformin-treated type 2 diabetic patients
• HbAI c type 2 diabetic patients
• Antidiabetic medication other than metformin was washed out for 6 weeks (34.7% of the patients).
• the primary endpoint was change from baseline in HbAIc, adjusted for prior antidiabetic medication.
• 333 patients (mean baseline HbAI c 8.3%; fasting plasma glucose [FPG] 185 mg/dL) were randomized to BI 1356, PBO or open-label GLIM.
• gMean concentration after single oral administration was 7.05 nM (28.5% gCV) for 5 mg BI 1356, and 267 nM (66.6% gCV) for 100 mg BI 1356.
• the upper limits of the one-sided 95% confidence intervals of the adjusted mean QTcI change from baseline (1-4 h) of BI 1356 compared with placebo were 0.5 ms (5 mg) and -0.9 ms (100 mg) with mean estimates of -1.1 and -2.5 ms, respectively.
• the maximum upper limits of the one-sided 95% confidence intervals for the adjusted QTcI changes from baseline compared with placebo were below 2.5 ms for both doses and thus well below the non-inferiority margin of 10 ms.
• BI 1356 single dose administration of therapeutic (5 mg) and supratherapeutic (100 mg) doses of BI 1356 did not prolong the QT interval.
• the supratherapeutic dose resulted in maximum plasma concentrations that were about 38-fold higher than those obtained after the administration of the therapeutic dose of 5 mg, providing further support for the unique safety profile of BI 1356 within the class of DPP-4 inhibitors.

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