US008O17633B2

(12) United States Patent (10) Patent No.: US 8,017,633 B2 Kley et al. (45) Date of Patent: Sep. 13, 2011

(54) ROFLUMILAST FOR THE TREATMENT OF 2003. O186974 A1 10/2003 Marfat et al. DABETES MELLITUS 2004/OO87591 A1 5/2004 Garvey et al. 2004/0235845 A1 11/2004 Eggenweiler et al. (75) Inventors: Hans-Peter Kley, Allensbach (DE): 2005.0049258 A1 3/2005 Marfat et al. Guido Hanauer, Constance (DE); 2005/013O891 A1 6/2005 Forssmann et al. Daniela Hauser, Singen (DE); Beate 2006/0281745 A1 12/2006 Kley Schmidt, Allensbach (DE); Dirk FOREIGN PATENT DOCUMENTS Bredenbroeker, Constance (DE); DE 101.50517 A1 4/2003 EP O300726 B1 9, 1993 Wilhelm Wurst, Constance (DE); Joerg JP 5869812 4f1983 Kemkowski, Hamburg (DE) WO 9.402150 A1 2, 1994 WO 94O2465 A1 2, 1994 (73) Assignee: Nycomed GmbH, Constance (DE) WO 95O1338 A1 1, 1995 WO 97281,31 A1 8, 1997 WO 9914239 A1 3, 1999 (*) Notice: Subject to any disclaimer, the term of this WO 0042020 A1 T 2000 patent is extended or adjusted under 35 WO 0042034 A1 T 2000 U.S.C. 154(b) by 737 days. WO O135979 A2 5, 2001 WO 0.142244 A1 6, 2001 (21) Appl. No.: 11/885,450 WO O 170746 A1 9, 2001 WO O190076 A1 11 2001 WO O213798 A2 2, 2002 (22) PCT Filed: Mar. 3, 2006 WO O214280 A1 2, 2002 WO O264584 A1 8, 2002 (86). PCT No.: PCT/EP2006/06O418 WO 02074726 A2 9, 2002 WO O3O32993 A1 4/2003 S371 (c)(1), WO O3061638 A2 T 2003 (2), (4) Date: Sep. 5, 2007 WO 2004/O16596 A1 2, 2004 WO 2004067006 A1 8, 2004 (87) PCT Pub. No.: WO2006/094933 WO 2004/101752 A2 11/2004 WO 2004O98595 A1 11 2004 PCT Pub. Date: Sep. 14, 2006 WO 2004O98596 A1 11, 2004 WO 2004O98597 A1 11, 2004 (65) Prior Publication Data WO 2004O98598 A1 11 2004 US 2008/0214625A1 Sep. 4, 2008 WO 2004103407 A2 12/2004 WO 2005020926 A2 3, 2005 (30) Foreign Application Priority Data WO 2005.116653 A2 12/2005 Mar. 8, 2005 (EP) ...... 05101772 OTHER PUBLICATIONS (51) Int. Cl. Liang, et al., “The Phosphodiesterase Inhibitors Pentoxifylline and A6 IK3I/44 (2006.01) Rolipram Prevent Diabetes in NOD Mice”. Diabetes, 47:570-575, A6 IK3I/495 (2006.01) 1998. Leibowitz et al., “A Novel Secretagogue Is a A6 IK3I/40 (2006.01) Phosphodiesterase Inhibitor, Diabetes, 44:67-74, 1995. (52) U.S. Cl...... 514/352: 514/249; 514/412: 514/423; Ceriello et al., “Postprandial Glucose Regulation and Diabetic Com 514/428: 514/866 plications”, Arch. Intern. Med., 164:2090-2095, 2004. (58) Field of Classification Search ...... 514/352, Gerich, “Postprandial Hyperglycemia and Cardiovascular Disease'. 514/249, 617, 635, 866, 412,423, 428 Endocrine Practice, vol. 12, Suppl. 1, pp. 47-51, (2006). See application file for complete search history. * cited by examiner (56) References Cited Primary Examiner — Kevin E Weddington U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm — The Nath Law Group; 3,174,901 A * 3/1965 Sterne ...... 514,635 5,712.298 A 1/1998 Amschler Joshua B. Goldberg; Sheldon M. McGee 5,730,975 A 3/1998 Hotamisligil et al. 5,817,670 A 10/1998 Takayama et al. 6,011,060 A 1/2000 Laurent et al. (57) ABSTRACT 6, 191,138 B1 2/2001 Gutterer 6.255,326 B1 7/2001 Ashton et al. The invention relates to the use of Roflumilast and/or Roflu 6,331.543 B1 12/2001 Garvey et al. milast N-Oxide for the treatment of diabetes mellitus and 6,699,871 B2 * 3/2004 Edmondson et al...... 514,249 6,924,292 B2 8/2005 Kawano et al. accompanying disorders thereof. The invention additionally 7,109,342 B2 9, 2006 Nakai et al. relates to combinations of Roflumilast and/or Roflumilast 7,776,893 B2 * 8/2010 Kley ...... 514,352 2002fOOO2191 A1 1/2002 Friesen et al. N-Oxide with other active agents for the treatment of diabetes 2002fOOO2.192 A1 1/2002 Chen et al. mellitus. 2003, OO23087 A1 1/2003 Garvey et al. 2003, OO691.69 A1 4/2003 Macor et al. 2003.01.00563 A1 5/2003 Edmondson et al. 2 Claims, No Drawings US 8,017,633 B2 1. 2 ROFLUMLAST FOR THE TREATMENT OF originally diagnosed with type 2 diabetes evolve with time to DABETES MELLITUS a type 1 state, which is defined as exhibiting anti-B-cell autoimmunity. This application was filed under 35 U.S.C. 371 as a Because genetic factors contribute to the development of national stage of PCT/EP2006/060418, filed Mar. 3, 2006. 5 diabetes, the disease displays a strong familial aggregation. Although there are monogenic syndromes of insulin resis TECHNICAL FIELD tance, in which a definite gene has been identified as the cause of insulin resistance, these are relative rare. The more com The invention relates to the use of Roflumilast, its pharma mon presentation of diabetes appears to be polygenic. Addi cologically acceptable salts, its N-Oxide and the pharmaco 10 tionally, behavioural- and lifestyle-related risk factors exist. logically acceptable salts of the latter for the treatment of Type 2 diabetes is increasingly common primarily because of diabetes mellitus type 2, diabetes mellitus type 1 and for the increases in the prevalence of a sedentary lifestyle and obe prevention and/or inhibition of the progression of disorders sity. One of the major arguments for the role of behavioural which are related to diabetes mellitus. factors in the etiology of diabetes has been the rapid increase 15 in the prevalence and incidence of the disease in populations The invention furthermore relates to combinations of Rof undergoing rapid westernization. The westernization transi lumilast, its pharmacologically acceptable salts, its N-Oxide tion is usually accompanied by increases in obesity, decreases and the pharmacologically acceptable salts of the latter with in physical activity and alterations in dietary intake toward one or more other active compounds which are used in the more calories, fat and non-complex carbohydrates. treatment of diabetes mellitus type 2 and/or diabetes mellitus Plasma glucose concentrations are normally maintained type 1; as well as to pharmaceutical compositions, combina within a fairly narrow range despite wide fluctuations in the tion products and kits containing these combinations and uses body's Supply (e.g. meals) and demand (e.g. exercise) for of such combinations in the treatment of diabetes mellitus nutrients. After an overnight fast, insulin-independent tissues, type 2 and/or diabetes mellitus type 1. the brain (50%) and splancnic organs (25%), account for most 25 of the total body glucose disposal. Insulin-dependent tissues, BACKGROUND OF THE INVENTION adipose tissue and primarily skeletal muscles, are responsible for the remaining 25% of glucose utilization. This basal glu In the International Patent Application WO99/14239 com cose uptake is precisely matched by the release of glucose positions for treating diabetes mellitus and obesity are dis from the liver. In response to hyperglycemia after a meal, closed. The compositions contain at least two of the active 30 pancreatic insulin secretion is stimulated and the combination agents A, B and C, wherein A is at least one hormone which of hyperinsulinemia plus hyperglycemia promotes glucose stimulates the production of cAMP, B is at least one substance uptake (by splancnic and peripheral, primarily muscle, tis which inhibits the breakdown of a cyclic nucleotide, and C is Sues) and Suppresses hepatic glucose production. It follows, at least one hormone which stimulates the production of therefore, that defects at the level of the B-cell, muscle and cGMP. In the International Patent Application WO01/35979 35 liver can lead to the development of glucose intolerance and the combined use of a PDE3 and a PDE4 inhibitor for the diabetes mellitus. All the abnormalities in diabetes basically result from animbalance between insulin sensitivity and insu treatment of obesity is disclosed. In the International Patent lin secretion. The initial stage of diabetes is characterised by Application WO02/13798 the use of a selective c(GMP PDE5 impaired glucose tolerance and postprandial hyperglycemia. inhibitor for the treatment of Insulin Resistance Syndrome is 40 As the disease progresses, fasting hyperglycemia is observed. disclosed, wherein the Insulin Resistance Syndrome is The earliest detectable abnormality in NIDDM is an defined as the concomitant existence of two or more disease impairment in the body's ability to respond to insulin. states selected from dyslipidemia, hypertension, type 2 dia Because the pancreas is able to appropriately augment its betes mellitus, impaired glucose tolerance, a family history of secretion of insulin to offset the insulin resistance, glucose diabetes, hyperuricaemia and/or gout, a pro-coagulant state, 45 tolerance remains normal. With time, however, the beta-cell atherosclerosis and truncal obesity. In the unexamined Ger fails to maintain its high rate of insulin secretion and the man application DE 10150517 tetrahydropyridazine-3-one insulin resistance leads to the development of impaired glu derivatives are described which may be useful inter alia for cose tolerance and eventually overt diabetes mellitus. The the treatment of diabetes mellitus. In Diabetes 47, pp. 570 cause of pancreatic “exhaustion” remains unknown. Insulin 575, 1998 is disclosed that pentoxifylline and rolipram may 50 resistance in NIDDM involves both hepatic and peripheral be effective in the treatment of autoimmune diabetes or other tissues. In response to both endogenously secreted or exog conditions characterized by excessive production of inflam enously administered insulin, hepatic glucose production matory cytokines. fails to Suppress normally and muscle glucose uptake is Diabetes mellitus is on the rise worldwide and is consid diminished. The accelerated rate of hepatic glucose output is ered to be at an epidemic level by the World Health Organi 55 due mainly to augmented gluconeogenesis. In muscle many Zation. The clinical manifestation and progression of diabetes cellular defects in insulin action have been described includ often vary considerably between countries and commonly ing impaired insulin-receptor tyrosine kinase activity, dimin between ethnic groups in the same country. Currently diabe ished glucose transport, and reduced glycogen synthase and tes affects 151 million people worldwide and an estimate 300 pyruvate dehydrogenase activities. The abnormalities million people in 2025. There are two main forms of diabetes. 60 account for disturbances in the two major intracellular path Type 1 (insulin-dependent diabetes mellitus, IDDM) is due ways of glucose disposal, glycogen synthesis and glucose primarily to autoimmune-mediated destruction of pancreatic oxidation. In the earliest stages of NIDDM, the major defect B-cells, resulting in absolute insulin deficiency. It is the sec involves the inability of insulin to promote glucose uptake ond most common chronic disease of children. By contrast, and storage as glycogen. Other potential mechanisms that type 2 diabetes (non-insulin-dependent diabetes mellitus, 65 have been put forward to explain the glucose intolerance NIDDM) is characterized by insulin-resistance and inad include increased levels of free fatty acids, chronic low-grade equate insulin secretion. A significant fraction of individuals activation of the immune system (increased levels of TNFC. US 8,017,633 B2 3 4 and IL6), altered skeletal muscle blood flow, increased con and adipose tissues to insulin. Improvements in glucose version of to its insoluble amyloid form and glucose metabolism with treatment are closely corre toxicity. lated with decreased plasma free fatty acid metabolism. The Diabetes is associated with a variety of physiologic disor stimulation by rosiglitazone of PPARY in adipose tissue and ders such as hypertension and dyslipidemia. Diabetes also Subsequent adipocyte differentiation results in the generation increases the risk of macrovascular (coronary artery disease, of more, but Smaller, adipocytes which are more insulin sen stroke, amputation) and microvascular (blindness, renal fail sitive and produce less free fatty acid, TNFC. and leptin. ure, neuropathies) diseases. Myocardial infarction, stroke or Common adverse effects of rosiglitaZone are anemia, oedema renal failure are the cause of death for more than 70% of and increased body weight. diabetes patients. The huge mortality and debilitating neuro 10 pathies associated with diabetes underline the importance of DESCRIPTION OF THE INVENTION active medical intervention. There are several ways to counteract diabetes. The first is It is one object of the present invention to make available a lifestyle adjustments aimed at improving endogenous insulin pharmaceutical composition for the treatment of diabetes sensitivity. This can be achieved by increased physical activ 15 ity and bodyweight reduction with diet and behavioural mellitus, in particular diabetes mellitus type 2 which over modification. Unfortunately, most people with non-insulin comes Some or all of the above-mentioned disadvantages. dependent diabetes mellitus never receive sufficient nutri Treatment of diabetes mellitus is surprisingly achieved by tional education or are not capable of complying with a strict the use of a compound of formula 1.1 diet regimen. Another therapeutic way involves increasing insulin avail (1.1) ability by the administration of exogenous insulin, insulin F F analogues and insulin secretagogues such as Sulphonylureas. The primary mode of action of Sulphonylureas is through the depolarization of the pancreatic f-cells by blocking the ATP 25 r dependent potassium channels and causing an influx of cal C cium ions, which stimulate insulin secretion. The most fre quently encountered adverse effect of insulin, insulin O N analogues and insulin secretagogues is hypoglycemia. Body weight gain can also be a concern, because insulin not only 30 O C 2N increases uptake of blood glucose but also promotes the Syn thesis and storage of lipids. , of which is the most commonly used, also have proven to be effective anti-hyperglycemic or a pharmaceutically acceptable salt thereof and/or a com agents. Metformin reduces hepatic gluconeogenesis and 35 pound of formula 1.2 basal hepatic glucose output. Its most serious adverse effect is lactic acidosis. Other common adverse effects of metformin are nausea and anorexia. Oral antidiabetics such as Sulpho (1.2) nylureas and metformin as monotherapy or in combination F F have been shown to decrease fasting plasma glucose levels, 40 but postprandial hyperglycemia persists in more than 60% of r patients and probably accounts for Sustained increases of C hemoglobin A levels. C-Glucosidase inhibitors, e.g. and , pri O N marily target postprandial hyperglycemia. The therapy of 45 O N diabetes mellitus with C-glucosidase inhibitors is based on a C ano delayed intestinal degradation of starch and Sucrose. These carbohydrates must be hydrolysed by C-glucosidases to monosaccharides before they can be transported through the mucosa of the small intestine. The reversible inhibition of the 50 or a pharmaceutically acceptable salt thereof. brush border glucosidases results in redistribution of carbo The compound of formula 1.1 has the international non hydrate absorption from the upper portion of the gut to a more proprietary name (INN) Roflumilast 3-cyclopropyl extended surface area covering the whole length of the Small methoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl) intestine. This is accompanied by a delayed absorption of benzamide. monosaccharides and a decrease in the postprandial elevation 55 of blood glucose. Common adverse effects of C.-Glucosidase The compound of formula 1.2 is Roflumilast-N-Oxide inhibitors are symptoms of carbohydrate malabsorption and 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3.5- gastrointestinal discomfort. dichloro-1-oxido-pyridin-4-yl)benzamide. Another class of antidiabetic drugs are , The preparation of Roflumilast, its pharmaceutically Such as rosiglitaZone and , which are insulin 60 acceptable salts and its N-Oxide as well as the use of these sensitizers and act through activation of peroxisome prolif compounds as PDE4-inhibitors is described in the interna erator-activated receptor Y (PPARY). PPARY is mainly tional patent application WO95/01338. expressed in adipose tissues, plays an important role in adi Salts encompassed within the term “pharmaceutically pogenesis and modifies fatty acid synthesis and storage. acceptable salts' refer to non-toxic salts of the compounds of Binding of rosiglitazone to PPARY results in reduced endog 65 formulae 1.1 or 1.2 which are generally prepared by reacting enous glucose production and increased blood glucose a free base with a Suitable organic or inorganic acid or by uptake. It increases the sensitivity of skeletal muscle, liver reacting an acid with a Suitable organic or inorganic base. US 8,017,633 B2 5 6 Particular mention may be made of the pharmaceutically salt thereof and/or a compound of formula 1.2 or a pharma acceptable inorganic and organic acids customarily used in ceutically acceptable salt thereof for the production of a phar pharmacy. Those Suitable are in particular water-soluble and maceutical composition for the treatment of diabetes mellitus water-insoluble acid addition salts with acids such as, for type 2 and/or diabetes mellitus type 1 and for the prevention example, hydrochloric acid, hydrobromic acid, phosphoric 5 and/or inhibition of the progression of disorders which are acid, nitric acid, Sulfuric acid, acetic acid, citric acid, D-glu related to diabetes mellitus. conic acid, benzoic acid, 2-(4-hydroxybenzoyl)-benzoic Another aspect of the present invention is the use of a acid, butyric acid, Sulfosalicylic acid, maleic acid, lauric acid, compound of formula 1.1 or a pharmaceutically acceptable malic acid, fumaric acid, Succinic acid, oxalic acid, tartaric salt thereof and/or a compound of formula 1.2 or a pharma acid, embonic acid, Stearic acid, toluenesulfonic acid, meth 10 anesulfonic acid or 1-hydroxy-2-naphthoic acid. As ceutically acceptable salt thereof for the production of a phar examples of pharmaceutically acceptable salts with bases maceutical composition for the treatment of a disorder may be mentioned the lithium, sodium, potassium, calcium, selected from the group of metabolic syndrome, obesity, insu aluminium, , titanium, ammonium, meglumine or lin resistance, dyslipidemia and pathological glucose toler guanidinium salts. 15 aCC. It is understood that the compounds of formulae 1.1 and 1.2 The invention further relates to a method for treating dia and their pharmaceutically acceptable salts can also be betes mellitus type 2 and/or type 1 comprising administering present in the form of their pharmaceutically acceptable sol to a patient in need thereofan effective amount of a compound vates and in particular in the form of their hydrates. of formula 1.1 or a pharmaceutically acceptable salt thereof In the expression “diabetes mellitus type 2 and/or type 1 and/or a compound of formula 1.2 or a pharmaceutically and disorders which are related to diabetes mellitus’, diabetes acceptable salt thereof. mellitus type 2 stands for non-insulin-dependent diabetes The invention as well relates to a method for treating dia mellitus (NIDDM) and diabetes mellitus type 1 stands for betes mellitus type 2 and/or type 1 and for pre-venting and/or insulin-dependent diabetes mellitus (IDDM). Frequently cor inhibiting the progression of disorders which are related to related with diabetes mellitus type 2 are one or more of the 25 diabetes mellitus, comprising administering to a patient in metabolic syndrome, obesity, insulin resistance, dyslipi need thereof an effective amount of a compound of formula demia and a pathological glucose tolerance. Subjects with 1.1 or a pharmaceutically acceptable salt thereof and/or a diabetes mellitus type 2 and/or type 1 manifest varying compound of formula 1.2 or a pharmaceutically acceptable degrees of increased blood pressure, increased levels of cho salt thereof. lesterol and/or triglycerides, increased levels of uric acid and 30 The invention additionally relates to a method for treating increased levels of factors that promote coagulation. There a disorder selected from the group consisting of metabolic fore disorders which are related to diabetes mellitus are syndrome, obesity, insulin resistance, dyslipidemia and hypertension, hyperlipidemia, hyperuricemia, gout and pathological glucose tolerance comprising administering to a hypercoagulability, i.e. an abnormal, increased tendency to patient in need thereof an effective amount of a compound of form clots inside blood vessels. These disorders are well 35 formula 1.1 or a pharmaceutically acceptable salt thereof recognized risk factors for atherosclerotic macrovascular as and/or a compound of formula 1.2 or a pharmaceutically well as microvascular diseases. Atherosclerotic macrovascu acceptable salt thereof. lar diseases include myocardial infarction, stroke and limb Another aspect of the present invention is a method for amputation. Microvascular complications involve blindness, reducing postprandial hyperglycemia comprising administer renal diseases and debilitating neuropathies. 40 ing to a patient in need thereof for a prolonged period of time The term “effective amount” refers to a therapeutically an effective amount of a compound of formula 1.1 or a phar effective amount for treating diabetes mellitus type 2 and/or maceutically acceptable salt thereof and/or a compound of type 1 or to a therapeutically effective amount for treating formula 1.2 or a pharmaceutically acceptable salt thereof. diabetes mellitus type 2 and/or type 1 and for the prevention Still another aspect of the present invention is a method for and/or inhibition of the progression of disorders which are 45 reducing fasting hyperglycemia, comprising administering to related to diabetes mellitus. In case of a combination therapy a patient in need thereof for a prolonged period of time an the term “effective amount” refers to the sum of the amounts effective amount of a compound of formula 1.1 or a pharma of the combination partners, which is therapeutically effec ceutically acceptable salt thereof and/or a compound of for tive for treating diabetes mellitus type 2 and/or type 1. mula 1.2 or a pharmaceutically acceptable salt thereof. “Patient includes both human and other mammals. 50 The invention also relates to a method for reducing post It has now been found that the compound of formula 1.1 prandial hyperglycemia and fasting hyperglycemia, compris and/or the compound of formula 1.2 reduce postprandial ing administering to a patient in need thereof for a prolonged hyperglycemia and also fasting hyperglycemia. period of time an effective amount of a compound of formula This is an advantage over insulin secretagogues, bigu 1.1 or a pharmaceutically acceptable salt thereof and/or a anides and O-Glucosidase inhibitors which improve only one 55 compound of formula 1.2 or a pharmaceutically acceptable of fasting or postprandial hyperglycemia. In contrast to insu salt thereof. lin and insulin secretagogues, the compound of formula 1.1 The expression “for a prolonged period of time stands for and/or the compound of formula 1.2 do not induce hypogly the repeated administration of the active compound(s) for at cemia. least 3 days, more preferably for at least 5 days and most Thus, a first aspect of the present invention is the use of a 60 preferably for at least 10 days. compound of formula 1.1 or a pharmaceutically acceptable The invention further relates to a ready-to-use pharmaceu salt thereof and/or a compound of formula 1.2 or a pharma tical composition, comprising a compound of formula 1.1 or ceutically acceptable salt thereof for the production of a phar a pharmaceutically acceptable salt thereof and/or a com maceutical composition for the treatment of diabetes mellitus pound of formula 1.2 or a pharmaceutically acceptable salt type 2 and/or diabetes mellitus type 1. 65 thereofas active compound(s) therapeutic agent(s), which A further aspect of the present invention is the use of a additionally contains a reference to the fact that this ready to compound of formula 1.1 or a pharmaceutically acceptable use pharmaceutical composition can be employed in the treat US 8,017,633 B2 7 8 ment of diabetes mellitus type 2 and/or type 1 and disorders tion of the active compound can easily be fixed by any person which are related to diabetes mellitus. skilled in the art on the basis of his expert knowledge. Mode of administration, dosage forms and dosage for the In the case of oral administration of 3-cyclopropyl mono-therapy with Roflumilast, Roflumilast-N-oxide or a methoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl) pharmaceutically acceptable salt of either: 5 benzamide (Roflumilast) the daily dose (for an adult patient) Roflumilast, Roflumilast-N-oxide or a pharmaceutically is in the range from 50 to 1000 ug per day, preferably 50 to 500 acceptable salt of either may be administered in a variety of ug per day, preferably by once daily administration. forms. These include, for example, liquid, semi-solid and In the case of intravenous administration of 3-cyclopropy Solid dosage forms, such as liquid solutions (e.g., injectable lmethoxy-4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl) and infusible solutions), dispersions or Suspensions, tablets, 10 pills, powders, liposomes or Suppositories. The preferred benzamide (Roflumilast) the daily dose (for an adult patient) form depends on the intended mode of administration and is in the range from 50 to 500 ug per day, preferably 150 to 300 therapeutic application. ug per day. The most preferred mode of administration of Roflumilast, The compound of formula 1.1 or a pharmaceutically Roflumilast-N-oxide or a pharmaceutically acceptable salt of 15 acceptable salt thereofand/or the compound of formula 1.2 or either is oral. In another preferred embodiment Roflumilast, a pharmaceutically acceptable salt thereof may be adminis Roflumilast-N-oxide or a pharmaceutically acceptable salt of tered together with one or more other active compounds either is administered by intravenous infusion or injection. In which are used in the treatment of diabetes mellitus type 2 a further embodiment the Roflumilast, Roflumilast-N-oxide and/or diabetes mellitus type 1. “One or more other active ora pharmaceutically acceptable salt of either is administered compounds in this connection means preferably 1 or 2 other by intramuscular or subcutaneous injection. Other routes of active compounds. administration are also contemplated, including for example Non-limiting examples of other active compounds which intranasal and transdermal routes, and by inhalation. are used in the treatment of diabetes mellitus type 2 and/or Typically, the Roflumilast, Roflumilast-N-oxide or a phar type 1 are provided in the following list: maceutically acceptable salt of either will be administered in 25 Insulin and insulin analogues the form of a pharmaceutical composition comprising Roflu Glucagon-Like-Peptide-1 (GLP-1) receptor agonists milast, Roflumilast-N-oxide or a pharmaceutically accept agents able salt of either in conjunction with at least one pharmaceu agents tically acceptable auxiliary. Alpha-glucosidase inhibitors The pharmaceutical compositions are prepared by pro 30 PPAR-Agonists cesses which are known per se and familiar to the person agents skilled in the art. As pharmaceutical compositions Roflumi Dipeptidyl-peptidase (DPP) IV inhibitors last, Roflumilast-N-oxide or a pharmaceutically acceptable PDE1, PDE5, PDE9, PDE10 or PDE11 inhibitors salt of either is either employed as such, or preferably in Amylin agonists combination with at least one pharmaceutically acceptable 35 CoEnzym A inhibitors auxiliary, e.g. in the form of tablets, coated tablets, capsules, Anti-obesity drugs such as appetite Suppressors, Satiety caplets, Suppositories, emulsions, Suspensions, gels or solu increasing Substances, and energy expenditure increas tions, the active compound content advantageously being ing drugs between 0.1 to 99.9 wt %, preferably 5 to 95 wt %, more and pharmaceutically acceptable salts thereof. preferably 20 to 80 wt % and where, by the appropriate choice 40 Further aspects of the present invention are therefore: of the auxiliaries, a pharmaceutical administration form (e.g. Compositions comprising an amount of the compound of a Sustained-release form or an enteric form) exactly Suited to formula 1.1 or a pharmaceutically acceptable salt thereof the active compound and/or to the desired onset of action can and/or the compound of formula 1.2 or a pharmaceutically be achieved. acceptable salt thereof, and an amount of one or more other The person skilled in the art is familiar on the basis of 45 active compounds or pharmaceutically acceptable salts his/her expert knowledge with auxiliaries, which are suitable thereof which are used in the treatment of diabetes mellitus for the desired pharmaceutical formulations. As pharmaceu type 2 and/or type 1, wherein the first amount and the second tically acceptable auxiliaries, any auxiliaries known to be amount together comprise an effective amount for the treat Suitable for preparing pharmaceutical compositions can be ment of diabetes mellitus type 2 and/or type 1; and the above used. Examples thereof include, but are not limited to, sol 50 mentioned compositions for use in the treatment of diabetes vents, excipients, dispersants, emulsifiers, solubilizers, gel mellitus type 2 and/or type 1. formers, ointment bases, antioxidants, preservatives, stabiliz In another aspect the present invention provides the use of ers, carriers, fillers, binders, thickeners, complexing agents, the compound of formula 1.1 or a pharmaceutically accept disintegrating agents, buffers, permeation promoters, poly able salt thereof and/or the compound of formula 1.2 or a mers, lubricants, coating agents, propellants, tonicity adjust 55 pharmaceutically acceptable salt thereof in combination with ing agents, Surfactants, colorants, flavorings, Sweeteners and one or more other active compounds or pharmaceutically dyes. In particular, auxiliaries of a type appropriate to the acceptable salts thereof which are used in the treatment of desired formulation and the desired mode of administration diabetes mellitus type 2 and/or type 1 for the production of a are used. pharmaceutical composition, combination product or kit for Suitable oral formulations for Roflumilast and Roflumi 60 the treatment of diabetes mellitus type 2 and/or type 1. last-N-Oxide are disclosed in the international patent appli The compound of formula 1.1 or a pharmaceutically cation WOO3/70279. acceptable salt thereofand/or the compound of formula 1.2 or It is known to the person skilled in the art that the optimum a pharmaceutically acceptable salt thereof and the one or dose of an active compound can vary as a function of the body more other active compound(s) which is (are) used in the weight, the age and the general condition of the patient, and 65 treatment of diabetes mellitus type 2 and/or diabetes mellitus his/her response behavior to the active compound. The opti type 1 can be administered simultaneously, sequentially or mum dose necessary in each case and manner of administra separately. To this effect, the active compounds of the com

US 8,017,633 B2 11 12 As used herein, the term “synergistic' refers to the combi wherein each of the components (A), (B) and the optionally nation of the compound of formula 1.1 or a pharmaceutically existing component (C) is formulated in admixture with at acceptable salt thereofand/or the compound of formula 1.2 or least one pharmaceutically acceptable auxiliary: a pharmaceutically acceptable salt thereof with one or more and wherein the components (A), (B) and the optionally other active compounds or pharmaceutically acceptable salts existing component (C) are administered sequentially or thereof which are used in the treatment of diabetes mellitus separately. type 2 and/or type 1 either in form of the pharmaceutical As already mentioned above examples of other anti-dia composition, combination product or kit according to the betic compounds useful in the pharmaceutical compositions, invention having an efficacy for the treatment of diabetes combination products and kits according to the invention are 10 selected from the group consisting of: mellitus type 2 and/or type 1 that is greater than would be Insulin and insulin analogues expected from the sum of their individuals effects. The syn Glucagon-Like-Peptide-1 (GLP-1) receptor agonists ergistic effects of the embodiments of the present invention Sulfonylurea agents encompass additional unexpected advantages for the treat Biguanide agents ment of diabetes mellitus type 2 and/or type 1. Such addi 15 Alpha-glucosidase inhibitors tional advantages may include, but are not limited to, lower PPAR-Agonists ing the required dose of one or more of the active compounds Meglitinide agents of the combination, reducing the side effects of one or more of Dipeptidyl-peptidase (DPP) IV inhibitors the active compounds of the combination or rendering one or PDE1, PDE5, PDE9, PDE10 or PDE11 inhibitors more of the active compounds more tolerable to the patient in Amylin agonists need of diabetes mellitus type 2 and/or type 1 therapy. CoEnzym A inhibitors The combined administration of the compound of formula Anti-obesity drugs such as appetite Suppressors, Satiety 1.1 or a pharmaceutically acceptable salt thereof and/or the increasing Substances, and energy expenditure increas compound of formula 1.2 or a pharmaceutically acceptable ing drugs salt thereof and one or more other active compounds or phar 25 and pharmaceutically acceptable salts thereof. maceutically acceptable derivatives thereof which are used in In one embodiment of the invention, the other active com the treatment of diabetes mellitus type 2 and/or type 1 may pound(s) which is (are) used in the treatment of diabetes also be useful for decreasing the required number of separate mellitus type 2 and/or type 1 is (are) selected from the group dosages, thus, potentially improving compliance of the consisting of patient in need of diabetes mellitus type 2 and/or type 1 30 Insulin and insulin analogues therapy. Glucagon-Like-Peptide-1 (GLP-1) receptor agonists A further aspect of the present invention is the use of a Sulfonylurea agents pharmaceutical composition, a pharmaceutical combination Biguanide agents or a kit according to the invention for the production of a Alpha-glucosidase inhibitors medicament for the treatment of diabetes mellitus type 2 35 PPAR-Agonists and/or type 1. Meglitinide agents Still a further aspect of the present invention is a method for Dipeptidyl-peptidase (DPP) IV inhibitors treating diabetes mellitus type 2 and/or type 1 comprising PDE1, PDE5, PDE9, PDE10 or PDE11 inhibitors administering to a patient in need thereof a pharmaceutical Amylin agonists composition comprising a pharmaceutical formulation 40 CoEnzym A inhibitors including an amount of a compound of formula 1.1 or a Anti-obesity drugs such as appetite Suppressors, Satiety pharmaceutically acceptable salt thereof and/or a compound increasing Substances, and energy expenditure increas of formula 1.2 or a pharmaceutically acceptable salt thereof, ing drugs an amount of one or more other active compound(s) or a and pharmaceutically acceptable salts thereof. pharmaceutically acceptable salt(s) thereof which is (are) 45 In another embodiment of the present invention the other used in the treatment of diabetes mellitus type 2 and/or type 1, active compound which is used in the treatment of diabetes wherein the first amount and the second amount together mellitus type 2 and/or type 1 is insulin. Specific examples of comprise an effective amount for the treatment of diabetes insulin include, but are not limited to Humulin(R) human mellitus type 2 and/or type 1, and at least one pharmaceuti insulin, (rDNA origin), Novolin R. human insulin, (rDNA cally acceptable auxiliary. 50 origin), Velosulin(R) BR human buffered , Another aspect of the present invention is a method for (rDNA origin) and Exubera R. human insulin, inhaled. treating diabetes mellitus type 2 and/or type 1 comprising In another embodiment of the present invention the other administering to a patient in need thereofa combination prod active compound which is used in the treatment of diabetes uct comprising the components: mellitus type 2 and/or type 1 is an insulin analogue or a (A) an amount of the compound of formula 1.1 or a pharma 55 pharmaceutically acceptable salt thereof. Specific examples ceutically acceptable salt thereof and/or the compound of of insulin analogues include, but are not limited to, novarapid, formula 1.2 or a pharmaceutically acceptable Salt thereof; , , , insulin Zinc (B) an amount of one other active compound or a pharmaceu Suspension and Lys-Pro insulin. tically acceptable salt thereof which is used in the treat In another embodiment of the present invention the other ment of diabetes mellitus type 2 and/or type 1; and option 60 active compound which is used in the treatment of diabetes ally mellitus type 2 and/or type 1 is a Glucagon-Like-Peptide-1 (C) an amount of a further active compound or a pharmaceu receptor agonist or a pharmaceutically acceptable salt tically acceptable salt thereof which is used in the treat thereof. Specific examples of Glucagon-Like-Peptide-1 ment of diabetes mellitus type 2 and/or type 1, receptor agonists include, but are not limited to BIM-51077 wherein the first, the second and the optionally existing third 65 (CAS-No. 275371-94-3), (CAS-No. 141758 amount together comprise an effective amount for the 74-9), CJC-1131 (CAS-No. 532951-64-7), treatment of diabetes mellitus type 2 and/or type 1: (CAS-No. 20656-20-2) and ZP-10 (CAS-No. 320367-13-3). US 8,017,633 B2 13 14 A preferred Glucagon-Like-Peptide-1 receptor agonist is mellitus type 2 and/or type 1 is a meglitinide agent or a EXENATIDE. pharmaceutically acceptable salt thereof. Specific examples In another embodiment of the present invention the other of meglitinide agents include, but are not limited to REPA active compound which is used in the treatment of diabetes GLINIDE (CAS-No. 135062-02-1), (CAS mellitus type 2 and/or type 1 is a sulfonylurea agent or a 5 No. 105816-04-4) and (CAS-No. 145375 pharmaceutically acceptable salt thereof. Specific examples 43-5). of sulfonylurea agents include, but are not limited to, TOLB In another embodiment of the present invention the phar maceutically acceptable salts of MITIGLINIDE are the UTAMIDE (CAS-No. 000064-77-7), monopotassium or the calcium salt of MITIGLINIDE. (CAS-No. 001156-19-0), (CAS-No. 029094 In another embodiment of the present invention the other 61-9), (CAS-No. 000339-43-5), 10 active compound which is used in the treatment of diabetes GLISOXEPIDE (CAS-No. 025046-79-1), GLISENTIDE mellitus type 2 and/or type 1 is a DPP-IV inhibitor or a (CAS-No. 032797-92-5), (CAS-No. pharmaceutically acceptable salt thereof. Specific examples 026944-48-9), (CAS-NO. 010238-21 of DPP IV inhibitors include, but are not limited to SITA 8), (CAS-No. 033342-05-1), GLIME 15 GLIPTIN(CAS-No. 486-460-32-6), (CAS PIRIDE (CAS-No. 093479-97-1) and (CAS No. 361442-04-8), (CAS-No. 274901-16 No. 021187-98-4). 5), DENAGLIPTIN(CAS-No. 483369-58-0), P32/98 (CAS In another embodiment of the present invention the phar No. 251572-70-0)and NVP-DPP-728 (CAS-No. 247016-69 maceutically acceptable salt of is the 9). sodium salt of TOLBUTAMIDE. In another embodiment of 20 In another embodiment of the present invention the phar the present invention the pharmaceutically acceptable salt of maceutically acceptable salt of is the phos GLIQUIDONE is the sodium salt of GLIQUIDONE. phate salt of SITAGLIPTIN. In another embodiment of the In another embodiment of the present invention the other present invention the pharmaceutically acceptable salts of active compound which is used in the treatment of diabetes P32/98 are the fumarate or hydrochloride salt of P32/98. mellitus type 2 and/or type 1 is a biguanide agent or a phar- 25 In another embodiment of the present invention the other maceutically acceptable salt thereof. A specific example of a active compound which is used in the treatment of diabetes biguanide agent includes, but is not limited to METFORMIN mellitus type 2 and/or type 1 is a PDE5 inhibitor or a phar (CAS-No. 000657-24-9). maceutically acceptable salt thereof. Specific examples of In another embodiment of the present invention the phar PDE5 inhibitors include, but are not limited to SILDENAFIL maceutically acceptable salt of METFORMIN is the mono- 30 (CAS-No. 139755-83-2), VARDENAFIL (CAS-No. hydrochloride salt of METFORMIN. 224785-90-4) and TADALAFIL (CAS-No. 171596-29-5). In another embodiment of the present invention the other In another embodiment of the present invention the phar active compound which is used in the treatment of diabetes maceutically acceptable salts of SILDENAFIL are the hemi mellitus type 2 and/or type 1 is an alpha-glucosidase-inhibitor citrate, the citrate or the mesilate salt of SILDENAFIL; par or a pharmaceutically acceptable salt thereof. Specific 35 ticularly preferred is the citrate salt of SILDENAFIL. In examples of alpha-glucosidase-inhibitors include, but are not another embodiment of the present invention the pharmaceu limited to ACARBOSE (Cas-No. 056180-94-0), MIGLITOL tically acceptable salts of VARDENAFIL are the mono-hy (CAS-No. 072432-03-2) and (CAS-No. drochloride salt of VARDENAFIL or the dihydrochloride salt 083480-29-9). of VARDENAFIL. In another embodiment of the present invention the other 40 In another embodiment of the present invention the other active compound which is used in the treatment of diabetes active compound which is used in the treatment of diabetes mellitus type 2 and/or type 1 is a PPAR-agonist or a pharma mellitus type 2 and/or type 1 is a PDE1, PDE9, PDE10 or ceutically acceptable salt thereof. Specific examples of PDE11 inhibitor or a pharmaceutically acceptable salt PPAR-agonists include, but are not limited to MURAGLI thereof. PDE1, PDE9, PDE10 or PDE11 inhibitors which TAZAR(CAS-No.331741-94-7), ROSIGLITAZONE (CAS 45 may be useful employed according to the present invention, NO. 122320-73-4), PIOGLITAZONE (CAS-No. 111025-46 can be found, for example, in US2002.0160939, 8), RAGAGLITAZAR(CAS-No. 222834-30-2), WO2003037432, US2004220186, WO2005/003129, FARGLITAZAR(CAS-No. 196808-45-4), TESAGLI WO2005012485, WO2005120514 and WO03077949. TAZAR(CAS-No. 251565-85-2), NAVEGLITAZAR(CAS In another embodiment of the present invention the other No. 476-436-68-7), (CAS-NO. 50 active compound which is used in the treatment of diabetes 161600-01-7), (CAS-No. 185428-18 mellitus type 2 and/or type 1 is a amylin agonist or a pharma 6), K-111 (CAS-No. 221564-97-2), GW-677954 (CAS-No. ceutically acceptable Salt thereof. A specific example of a 622402-24-8), FK-614 (CAS-No 193012-35-0) and (-)-Ha amylin agonist includes, but is not limited to PRAMLIN lofenate (CAS-No. 024136-23-0). Preferred PPAR-agonists ITIDE (CAS-No. 151126-32-8) are ROSGLITAZONE and PIOGLITAZONE. 55 In another embodiment of the present invention the phar In another embodiment of the present invention the phar maceutically acceptable salt of PRAMLINITIDE is the maceutically acceptable salt of ROSIGLITAZONE is the acetate Salt of PRAMLINITIDE. maleate Salt of ROSIGLITAZONE. In another embodiment In another embodiment of the present invention the other of the present invention the pharmaceutically acceptable salt active compound which is used in the treatment of diabetes of RIVOGLITAZONE is the mono-hydrochloride salt of 60 mellitus type 2 and/or type 1 is a Coenzyme A inhibitor or a RIVOGLITAZONE. In another embodiment of the present pharmaceutically acceptable salt thereof. A specific example invention the pharmaceutically acceptable salt of K-1 11 is the of a Coenzyme A inhibitor includes, but is not limited to sodium salt of K-1 11. In another embodiment of the present ETOMOXIR(CAS-No. 082258-36-4). invention the pharmaceutically acceptable salt of PIOGLI In another embodiment of the present invention the other TAZONE is the dihydrochloride salt of PIOGLITAZONE. 65 active compound which is used in the treatment of diabetes In another embodiment of the present invention the other mellitus type 2 and/or type 1 is an anti-obesity drug or a active compound which is used in the treatment of diabetes pharmaceutically acceptable salt thereof. Specific examples

US 8,017,633 B2 32 TABLE 1-continued

INN or Research Code Structure? Chemical Name

HMR-1426 C

S Ho Y2

6-chloro-2-phenyl-8,8a-dihydro-3ah-indeno1,2-d1.3thiazol-3a-ol CETILISTAT Ns O O H3C O

HC 2-(hexadecyloxy)-6-methyl-4H-3,1-benzoxazin-4-one

SIBUTRAMINE

CH NH C 1-1-(4-chlorophenyl)cyclobutyl-3-methylbutan-1-amine

Additional information with regard to the preparation, Suit 35 listed in Table 1 can be found in the following patents/patent able dosage forms and dose ranges of the glucagon-like applications: WO03004498, WO0168603, WO0034241, peptide-1 receptor agonists listed in Table 1 can be found in WO0302531, WO9961431 and WO9919998. the following patents/patent applications: WO0334331, Additional information with regard to the preparation, Suit EP0981611, EP1180121, WO9808871 and WO0104.156. able dosage forms and dose ranges of the PDE5 inhibitors The sulfonylurea agents TOLBUTAMIDE, TOLAZA 40 listed in Table 1 can be found in the following patents/patent MIDE, GLIPIZIDE, CARBUTAMIDE, GLISOXEPIDE; applications: WO0213798, WOO26O422 and GLISENTIDE, GLIBORNURIDE, GLIBENCLAMIDE, WO2004082667. GLIQUIDONE, and GLICLAZIDE listed in Additional information with regard to the preparation, Suit Table 1 are commercially available. The person skilled in the able dosage forms and dose ranges of the amylin analogue art is familiar with Suitable formulations and dose ranges of 45 listed in Table 1 can be found in these compounds. EPO567626. The biguanide agent METFORMIN listed in Table 1 is Additional information with regard to the preparation, Suit commercially available. The person skilled in the artis famil able dosage forms and dose ranges of ETOXOMIR, HMR iar with Suitable formulations and dose ranges of this com 1426, CETILISTAT and SIBUTRAMINE listed in Table 1 pound. 50 can be found in the following patents/patent applications: The alpha-glucosidase inhibitors ACARBOSE, MIGLI EP0046590, WO0018749, EP1144395 and EP0397831. TOL and VOGLIBOSE listed in Table 1 are commercially "Pharmaceutically acceptable salts' of the other active available. The person skilled in the artis familiar with suitable compound(s) which is (are) used in the treatment of diabetes formulations and dose ranges of this compound. mellitus type 2 and/or type 1 are not limited to the specific Additional information with regard to the preparation, Suit 55 examples given above. The term refers to non-toxic salts of able dosage forms and dose ranges of the PPAR-agonists these compounds. These pharmaceutically acceptable salts listed in Table 1 can be found in the following patents/patent are generally prepared by reacting a free base with a suitable applications: WO0121602, EP03306228, EP0658161, organic or inorganic acid or by reacting an acid with a suitable EP0193256, WO991.9313, WO973 1907, WO9962870, organic or inorganic base. Particular mention may be made of WOO140169, WO02100813, EP0604983, EP0745600, 60 the pharmaceutically acceptable inorganic and organic acids WO9615784, WO0259098, EP0882718 and EP1183020. customarily used in pharmacy. Those Suitable are in particu The metiglinide agents , NATEGLINIDE lar water-soluble and water-insoluble acid addition salts with and MITIGLINIDE listed in Table 1 are commercially avail acids Such as, for example, hydrochloric acid, hydrobromic able. The person skilled in the art is familiar with suitable acid, phosphoric acid, nitric acid, Sulfuric acid, acetic acid, formulations and dose ranges of this compound. 65 citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxyben Additional information with regard to the preparation, Suit Zoyl)-benzoic acid, butyric acid, Sulfosalicylic acid, maleic able dosage forms and dose ranges of the DPP IV inhibitors acid, lauric acid, malic acid, fumaric acid, Succinic acid, US 8,017,633 B2 33 34 oxalic acid, tartaric acid, embonic acid, Stearic acid, toluene compound(s) which are used in the treatment of diabetes Sulfonic acid, methanesulfonic acid or 1-hydroxy-2-naph mellitus type 2 and/or type 1 and at least one pharmaceuti thoic acid. As examples of pharmaceutically acceptable salts cally acceptable auxiliary can be manufactured in a manner with bases may be mentioned the lithium, Sodium, potassium, known to a person skilled in the art, e.g. by dissolving, mix calcium, aluminium, magnesium, titanium, ammonium, ing, granulating, dragee-making, levigating, emulsifying, meglumine or guanidinium salts. encapsulating, entrapping or lyophilizing processes. It is understood that the other active compound(s) which is As pharmaceutically acceptable auxiliaries, any auxiliaries (are) used in the treatment of diabetes mellitus type 2 and/or known to be Suitable for preparing pharmaceutical composi type 1 and their pharmaceutically acceptable salts can also be tions (formulations) can be used. Examples thereof include, present in the form of their pharmaceutically acceptable sol 10 but are not limited to, solvents, excipients, dispersants, emul vates, and in particular in the form of their hydrates. sifiers, solubilizers, gel formers, ointment bases, antioxi Mode of administration, dosage forms and dosage of the dants, preservatives, stabilizers, carriers, fillers, binders, combinations: thickeners, complexing agents, disintegrating agents, buffers, The combinations according to the invention may be permeation promoters, polymers, lubricants, coating agents, administered by any suitable route, for example, by the oral, 15 propellants, tonicity adjusting agents, Surfactants, colorants, Sublingual, buccal, intravenous, intraarterial, intramuscular, flavorings, Sweeteners and dyes. In particular, auxiliaries of a Subcutaneous, intracutaneous, topical, transdermal, intrana type appropriate to the desired formulation and the desired sal, intraperitoneal, rectal or vaginal route, by inhalation or by mode of administration are used. insufflation. The preferred mode of administration of the combinations Tablets, coated tablets (dragees), pills, cachets, capsules according to the invention depend on the specific combina (caplets), granules, Solutions, emulsions and Suspensions are tion partners. e.g. Suitable for oral administration. In particular, said formu As mentioned above Roflumilast, Roflumilast-N-oxide or lations can be adapted so as to represent, for example, an a pharmaceutically acceptable salt of either may be adminis enteric form, an immediate release form, a delayed release tered in a variety of forms. These include, for example, liquid, form, a repeated dose release form, a prolonged release form 25 semi-solid and solid dosage forms, such as liquid solutions or a sustained release form. Said forms can be obtained, for (e.g., injectable and infusible solutions), dispersions or Sus example, by coating tablets, by dividing tablets into several pensions, tablets, pills, powders, liposomes or Suppositories. compartments separated by layers disintegrating under dif The preferred form depends on the intended mode of admin ferent conditions (e.g. pH conditions) or by coupling the istration and the combination partner. active compound to a biodegradable polymer. 30 The most preferred mode of administration of Roflumilast, Administration by inhalation is preferably made by using Roflumilast-N-oxide or a pharmaceutically acceptable salt of an aerosol. The aerosol is a liquid-gaseous dispersion, a solid either is oral. In another preferred embodiment Roflumilast, gaseous dispersion or a mixed liquid/solid-gaseous disper Roflumilast-N-oxide or a pharmaceutically acceptable salt of Sion. either is administered by intravenous infusion or injection. In The aerosol may be generated by means of aerosol-produc 35 a further embodiment the Roflumilast, Roflumilast-N-oxide ing devices such as dry powder inhalers (DPIs), pressurized ora pharmaceutically acceptable salt of dither is administered metered dose inhalers (PMDIs) and nebulizers. Depending on by intramuscular or subcutaneous injection. Other routes of the kind of the active compound to be administered, the administration are also contemplated, including for example aerosol-producing device can contain the active compound in intranasal and transdermal routes, and by inhalation. form of a powder, a solution or a dispersion. The powder may 40 The preferred mode of administration of the other active contain, for example, one or more of the following auxilia compound(s) which is (are) used in combination with Roflu ries: carriers, stabilizers and fillers. The solution may contain milast, Roflumilast-N-oxide or a pharmaceutically accept in addition to the solvent, for example, one or more of the able salt of either depends on the specific agent. following auxiliaries: propellants, solubilizers (co-solvents), EXENATIDE, BIM-51077, CJC-1131, ZP-10 or PRAMLIN Surfactants, stabilizers, buffers, tonicity adjusting agents, pre 45 TIDE, for example, are preferably administered via subcuta servatives and flavorings. The dispersion may contain in addi neous injection. The preferred mode of administration of tion to the dispersant, for example, one or more of the follow compounds like TOLBUTAMIDE, TOLAZAMIDE, GLIP ing auxiliaries: propellants, Surfactants, stabilizers, buffers, IZIDE, CARBUTAMIDE, GLISOXEPIDE, GLISENTIDE, preservatives and flavorings. Examples of carriers include, GLIBORNURIDE, GLIBENCLAMIDE, GLIQUIDONE, but are not limited to, saccharides, e.g. lactose and glucose. 50 GLIMEPIRIDE, GLICLAZIDE, METFORMIN, ACAR Examples of propellants include, but are not limited to, fluo BOSE, MIGLITOL, VOGLIBOSE, ROSIGLITAZONE, rohydrocarbons, e.g. 1,1,1,2-tetrafluoroethane and 1.1.1.2.3, PIOGLITAZONE, RAGAGLITAZAR, FARGLITAZAR, 3.3-heptafluoropropane. NAVEGLITAZAR, NETOGLITAZONE, RIVOGLITA The particle size of the aerosol particles (solid, liquid or ZONE, K-1 11, GW-677954, FK-614, (-)-HALOFENATE, solid/liquid particles) is preferably less than 100 um, more 55 REPAGLINIDE, NATEGLINIDE, MITIGLINIDE, SITA preferably it is in the range of from 0.5 to 10um, in particular GLIPTIN, SAXAGLIPTIN, VILDAGLIPTIN, DENAGLIP in the range of from 2 to 6 um (D50 value, measured by laser TIN, P32/98, NVP-DPP-728, SILDENAFIL; VARDENA diffraction). FIL, TADALAFIL., ETOMOXIR, HMR-1426, CETILISTAT For parenteral modes of administration Such as, for and SIBUTRAMINE is oral. Further information with regard example, intravenous, intraarterial, intramuscular, Subcuta 60 to the preferred mode of administration of the other active neous, intracutaneous and intraperitoneal administration, agent(s) which is (are) used in combination with Roflumilast, preferably solutions (e.g. sterile solutions, isotonic Solutions) Roflumilast-N-oxide or a pharmaceutically acceptable salt of are used. They are preferably administered by injection or either is summarized in Table 2 below. infusion techniques. As part of the combination therapy according to the inven The pharmaceutical compositions (formulations) compris 65 tion Roflumilast, Roflumilast-N-oxide or a pharmaceutically ing Roflumilast, Roflumilast-N-oxide or a pharmaceutically acceptable salt of either and the one or more other active acceptable salt of either and/or one or more other active compounds which are used in the treatment of diabetes mel US 8,017,633 B2 35 36 litus type 2 and/or type 1 are dosed in an order of magnitude adult patient) for the mono-therapy is in the range from 50 to customary for the mono-therapy, it more likely being pos 500g per day, preferably by once daily administration. In the sible, on account of the individual actions, which are mutually case of intravenous administration of 3-cyclopropylmethoxy positively influencing and reinforcing, to reduce the respec 4-difluoromethoxy-N-(3,5-dichloropyrid-4-yl)benzamide tive doses on the combined administration of Roflumilast, (Roflumilast) the daily dose (for an adult patient) is in the Roflumilast-N-oxide or a pharmaceutically acceptable salt of range from 50 to 500 ug per day, preferably 150 to 300g per dither and the one or more other active compounds which are day. used in the treatment of diabetes mellitus type 2 and/or type 1 Further information with regard to the preferred routes of with the norm. administration and typical dosages (for mono-therapy) of the As mentioned above in the case of oral administration of 10 other active compound(s) which is (are) used in combination 3-cyclopropylmethoxy-4-difluoromethoxy-N-(3,5-dichloro with Roflumilast, Roflumilast-N-oxide or a pharmaceutically pyrid-4-yl)benzamide (Roflumilast) the daily dose (for an acceptable salt of either is summarized in Table 2. TABLE 2 Preferred routes of administration and dosages: Typical Daily dose INN or Research Preferred route of (dose ranges) used Code Preferred Treatment of Administration for mono-therapy Insulin Insulin analogs Diabetes mellitus type 1 subcutaneous injection On demand Diabetes mellitus type 2 EXUBERA Diabetes mellitus type 1 Inhalation On demand Diabetes mellitus type 2 M-51077 Diabetes mellitus type 2 subcutaneous injection ENATIDE Diabetes mellitus type 2 subcutaneous injection 10-201g C-1131 Diabetes mellitus type 2 subcutaneous injection s200 g 10 Diabetes mellitus type 2 subcutaneous injection LBUTAMIDE Diabetes mellitus type 2 ora 0.5 to 2.0 g LAZAMIDE Diabetes mellitus type 2 ora 100 to 150 mg i. PIZIDE Diabetes mellitus type 2 ora 5 to 40 mg, preferably 5 to 20 mg CA. RBUTAMIDE Diabetes mellitus type 2 ora up to 17 mg/kg LISOXEPIDE Diabetes mellitus type 2 ora 2 to 16 mg LISENTIDE Diabetes mellitus type 2 ora LIBORNURIDE Diabetes mellitus type 2 ora 12.5 to 75 mg BE NC LA. MI D E Diabetes mellitus type 2 ora 1.75 to 10.5 mg Diabetes mellitus type 2 ora 15 to 120 mg Diabetes mellitus type 2 ora 1 to 6 mg LICLAZIDE Diabetes mellitus type 2 ora 30 to 120 mg METFORMIN Diabetes mellitus type 2 ora 1000 to 3800 mg ACARBOSE Diabetes mellitus type 2 ora 150 to 600 mg, preferably 150 to 300 mg MIGLITOL Diabetes mellitus type 2 ora 150 to 300 mg WOGLIBOSE Diabetes mellitus type 2 ora 0.6 to 0.9 mg Diabetes mellitus type 2 oral or by injection 2.5 to 5 mg ROSIGLITAZONE Diabetes mellitus type 2 ora 4 to 8 mg PIOGLITAZONE Diabetes mellitus type 2 ora 15 to 45 mg RAGAGLITAZAR Diabetes mellitus type 2 ora 0.1 to 10 mg FARGLITAZAR Diabetes mellitus type 2 ora 0.5 to 10 mg TES AGLITAZAR Diabetes mellitus type 2 ora 0.5 to 1 mg NAVEGLITAZAR Diabetes mellitus type 2 ora 0.004 to 1.2 mg NETOGLITAZONE Diabetes mellitus type 2 ora RIVOGLITAZONE Diabetes mellitus type 2 ora K-111 Diabetes mellitus type 2 ora 10 to 20 mg GW-677954 Diabetes mellitus type 2 ora 2.5 to 20 mg FK-614 Diabetes mellitus type 2 ora s150 to 200 mg (-)-Halofenate Diabetes mellitus type 2 ora 21000 mg REPAGLINIDE Diabetes mellitus type 2 ora 0.5 to 16 mg NATEGLINIDE Diabetes mellitus type 2 ora 180 to 540 mg MITIGLINIDE Diabetes mellitus type 2 ora 40 mg/meal SITAGLIPTIN Diabetes mellitus type 2 ora 2100 mg SAXAGLIPTIN Diabetes mellitus type 2 ora 210 mg WILDAGLIPTIN Diabetes mellitus type 2 ora 25-100 mg DENAGLIPTIN Diabetes mellitus type 2 ora P32/98 Diabetes mellitus type 2 ora NVP-DPP-728 Diabetes mellitus type 2 ora 300 mg SILDENAFIL Diabetes mellitus type 2 ora 50 to 100 mg Diabetes mellitus type 1 WARDENAFIL Diabetes mellitus type 2 ora 2.5 to 20 mg Diabetes mellitus type 1 TADALAFIL Diabetes mellitus type 2 ora 10 to 20 mg Diabetes mellitus type 1 PRAMLINTIDE Diabetes mellitus type 2 subcutaneous injection 20 to 120 Ig Diabetes mellitus type 1 ETOMOXIR Diabetes mellitus type 2 ora 10 to 50 mg HMR-1426 Diabetes mellitus type 2 ora US 8,017,633 B2 37 38 TABLE 2-continued Preferred routes of administration and dosages: Typical Daily dose INN or Research Preferred route of (dose ranges) used Code Preferred Treatment of Administration for mono-therapy CETILISTAT Diabetes mellitus type 2 oral 120 to 920 mg SIBUTRAMINE Diabetes mellitus type 2 oral 10 to 15 mg

EXAMPLES TABLE 3-continued

Preferred combinations TABLE 3 15 Example Number Combination Preferred combinations 59 Roflumilas RAGAGLITAZAR Example 60 Roflumilast-N-Oxide RAGAGLITAZAR Number Combination 61 Roflumilas FARGLITAZAR 2O 62 Roflumilast-N-Oxide FARGLITAZAR 1 Ro umi 8S human insulin 63 Roflumilas 2 Ro umi ast-N-Oxide human insulin 64 Roflumilast-N-Oxide TESAGLITAZAR 3 Ro umi 8S Insulin analogue 65 Roflumilas NAVEGLITAZAR 4 Ro umi ast-N-Oxi Insulin analogue 66 Roflumilast-N-Oxide NAVEGLITAZAR 5 Ro umi 8S BIM-S1077 67 Roflumilas NETOGLITAZONE 6 Ro umi ast-N-Oxi BIM-S1077 68 Roflumilast-N-Oxide NETOGLITAZONE 7 Ro umi 8S EXENATIDE 25 69 Roflumilas RIVOGLITAZONE 8 Ro umi ast-N-Oxi EXENATIDE 70 Roflumilast-N-Oxide RIVOGLITAZONE 9 Ro umi 8S CJC-1131 71 Roflumilas RIVOGLTAZONE hydrochloride 10 Ro umi ast-N-Oxi CJC-1131 72 Roflumilast-N-Oxide RIVOGLITAZONE hydrochloride 11 Ro umi 8S ZP-10 73 Roflumilas K-111 12 Ro umi ast-N-Oxi ZP-10 74 Roflumilast-N-Oxide K-111 13 Ro umi 8S TOLBUTAMIDE 30 75 Roflumilas K-111 sodium 14 Ro umi ast-N-Oxi TOLBUTAMIDE 76 Roflumilast-N-Oxide K-111 sodium 15 Ro umi 8S TOLBUTAMIDE Sodium 77 Roflumilas GW-677954 16 Ro umi ast-N-Oxi TOLBUTAMIDE Sodium 78 Roflumilast-N-Oxide GW-677954 17 Ro umi 8S TOLAZAMIDE 79 Roflumilas FK-614 18 Ro umi ast-N-Oxi TOLAZAMIDE 8O Roflumilast-N-Oxide FK-614 19 Ro umi 8S GLIPIZIDE 35 81 Roflumilas (-)-Halofenate 2O Ro umi ast-N-Oxi GLIPIZIDE 82 Roflumilast-N-Oxide (-)-Halofenate 21 Ro umi 8S CARBUTAMIDE 83 Roflumilas REPAGLINIDE 22 Ro umi ast-N-Oxi CARBUTAMIDE 84 Roflumilast-N-Oxide REPAGLINIDE 23 Ro umi 8S GLISOXEPIDE 85 Roflumilas NATEGLINIDE 24 Ro umi ast-N-Oxi GLISOXEPIDE 86 Roflumilast-N-Oxide NATEGLINIDE 25 Ro umi 8S GLISENTIDE 40 87 Roflumilas MITIGLINIDE 26 Ro umi ast-N-Oxi GLISENTIDE 88 Roflumilast-N-Oxide MITIGLINIDE 27 Ro umi 8S GLIBORNURIDE 89 Roflumilas MITIGLINIDE potassium 28 Ro umi ast-N-Oxi GLIBORNURIDE 90 Roflumilast-N-Oxide MITIGLINIDE potassium 29 Ro umi 8S GLIBENCLAMIDE 91 Roflumilas MITIGLINIDE calcium 30 Ro umi ast-N-Oxi GLIBENCLAMIDE 92 Roflumilast-N-Oxide MITIGLINIDE calcium 31 Ro umi 8S GLIQUIDONE 93 Roflumilas SITAGLIPTIN 32 Ro umi ast-N-Oxi GLIQUIDONE 45 94 Roflumilast-N-Oxide SITAGLIPTIN 33 Ro umi 8S GLIQUIDONE sodium 95 Roflumilas SITAGLIPTIN phosphate 34 Ro umi ast-N-Oxi GLIQUIDONE sodium 96 Roflumilast-N-Oxide SITAGLIPTIN phosphate 35 Ro umi 8S GLIMEPIRIDE 97 Roflumilas SAXAGLIPTIN 36 Ro umi ast-N-Oxi GLIMEPIRIDE 98 Roflumilast-N-Oxide SAXAGLIPTIN 37 Ro umi 8S GLICLAZIDE 99 Roflumilas WILDAGLIPTIN 38 Ro umi ast-N-Oxi GLICLAZIDE 50 OO Roflumilast-N-Oxide WILDAGLIPTIN 39 Ro umi 8S METFORMIN O1 Roflumilas DENAGLIPTIN 40 Ro umi ast-N-Oxi METFORMIN O2 Roflumilast-N-Oxide DENAGLIPTIN 41 Ro umi 8S METFORMIN hydrochloride O3 Roflumilas P32/98 42 Ro umi ast-N-Oxi METFORMIN hydrochloride O4 Roflumilast-N-Oxide P32.98 43 Ro umi 8S ACARBOSE 05 Roflumilas P3298 fumarate 44 Ro umi ast-N-Oxi ACARBOSE 55 O6 Roflumilast-N-Oxide P32.98 fumarate 45 Ro umi 8S MIGLITOL O7 Roflumilas P32/98 hydrochloride 46 Ro umi ast-N-Oxi MIGLITOL - - - 47 Ro umi 8S WOGLIBOSE O8 Ro uml ast-N-Oxide P32/98 hydrochloride 48 Ro umi ast-N-Oxi WOGLIBOSE 09 Ro uum 8S NVP-DPP-728 49 Ro umi 8S MURAGLITAZAR 10 Ro uum ast-N-Oxide NVP-DPP-728 50 Ro umi ast-N-Oxi MURAGLITAZAR 11 Roflumias SILDENAFIL 51 Ro umi 8S ROSIGLTAZONE 60 12 Roflumilast-N-Oxide SILDENAFIL 52 Ro umi ast-N-Oxi ROSIGLITAZONE 13 Roflumilas SILDENAFIL citrate 53 Ro umi 8S ROSIGLITAZONE maleate 14 Roflumilast-N-Oxide SILDENAFIL citrate S4 Ro umi ast-N-Oxi ROSIGLITAZONE maleate 15 Roflumilas SILDENAFIL hemi-citrate 55 Ro umi 8S PIOGLITAZONE 16 Roflumilast-N-Oxide SILDENAFIL hemi-citrate 56 Ro umi ast-N-Oxi PIOGLITAZONE 17 Roflumilas SILDENAFIL mesilate 57 Ro umi 8S PIOGLITAZONE dihydrochloride 65 18 Roflumilast-N-Oxide SILDENAFIL mesilate 58 Ro umi ast-N-Oxi PIOGLITAZONE dihydrochloride 19 Roflumilas WARDENAFIL US 8,017,633 B2 39 40 TABLE 3-continued TABLE 3-continued

Preferred combinations Preferred combinations Example Example Number Combination 5 Number Combination

120 Roflumilast-N-Oxide WARDENAFIL 131 Roflumilast ETOMOXIR 121 Roflumilast VARDENAFIL hydrochloride 132 Roflumilast-N-Oxide ETOMOXIR 122 Roflumilast-N-Oxide VARDENAFIL hydrochloride 133 Roflumilast HMR-1426 123 Roflumilast VARDENAFIL dihydrochloride 134 Roflumilast-N-Oxide HMR-1426 124 Roflumilast-N-Oxide VARDENAFIL dihydrochloride 10 135 Roflumilast CETILISTAT 125 Roflumilast TADALAFIL 136 Roflumilast-N-Oxide CETILISTAT 126 Roflumilast-N-Oxide TADALAFIL 137 Roflumilast SIBUTRAMINE 127 Roflumilast PRAMLINTIDE 138 Roflumilast-N-Oxide SIBUTRAMINE 128 Roflumilast-N-Oxide PRAMLINTIDE 139 Roflumilast SIBUTRAMINE hydrochloride 129 Roflumilast PRAMLINTIDE acetate 140 Roflumilast-N-Oxide SIBUTRAMINE hydrochloride 130 Roflumilast-N-Oxide PRAMLINTIDE acetate

TABLE 4 Preferred triple combinations: Example Number Triple Combination 41 Roflumilas METFORMIN Human Insulin 42 Roflumilast-N-Oxide METFORMIN Human Insulin 43 Roflumilas METFORMIN hydro- Human Insulin chloride 44 Roflumilast-N-Oxide METFORMIN hydro- Human Insulin chloride 45 Roflumilas ROSIGLITAZONE Human Insulin 46 Roflumilast-N-Oxide ROSIGLITAZONE Human Insulin 47 Roflumilas ROSIGLITAZONE Human Insulin maleate 48 Roflumilast-N-Oxide ROSIGLITAZONE Human Insulin maleate 49 Roflumilas ROSIGLITAZONE METFORMIN 50 Roflumilast-N-Oxide ROSIGLITAZONE METFORMIN 51 Roflumilas ROSIGLITAZONE METFORMIN maleate 52 Roflumilast-N-Oxide ROSIGLITAZONE METFORMIN maleate 53 Roflumilas ROSIGLITAZONE METFORMIN hydrochloride maleate S4 Roflumilast-N-Oxide ROSIGLITAZONE METFORMIN hydrochloride maleate 55 Roflumilas PIOGLITAZONE Insulin 56 Roflumilast-N-Oxide PIOGLITAZONE Insulin 57 Roflumilas PIOGLITAZONE Insulin dihyrochloride 58 Roflumilast-N-Oxide PIOGLITAZONE Insulin dihyrochloride 59 Roflumilas PIOGLITAZONE ME 60 Roflumilast-N-Oxide PIOGLITAZONE ME 61 Roflumilas PIOGLITAZONE METFORMIN hydro chloride 62 Roflumilast-N-Oxide PIOGLITAZONE METFORMIN hydro chloride 63 Roflumilas PIOGLITAZONE METFORMIN dihyrochloride 64 Roflumilast-N-Oxide PIOGLITAZONE METFORMIN dihyrochloride 65 Roflumilas PIOGLITAZONE ETFORMIN hydro dihyrochloride chloride 66 Roflumilast-N-Oxide PIOGLITAZONE METFORMIN hydro dihyrochloride chloride 67 Roflumilas GLIMEPIRIDE Insulin 68 Roflumilast-N-Oxide GLIMEPIRIDE Insulin 69 Roflumilas GLIMEPIRIDE METFORMIN 70 Roflumilast-N-Oxide GLIMEPIRIDE METFORMIN 71 Roflumilas GLIMEPIRIDE ME RMIN hydro chlo 72 Roflumilast-N-Oxide GLIMEPIRIDE METFORMIN hydro chloride 73 Roflumilas GLIMEPIRIDE ROSIGLITAZONE 74 Roflumilast-N-Oxide GLIMEPIRIDE ROSIGLITAZONE 75 Roflumilas GLIMEPIRIDE ROSIGLTAZONE maleate US 8,017,633 B2 41 42 TABLE 4-continued Preferred triple combinations: Example Number Triple Combination 176 Roflumilast-N-Oxide GLIMEPIRIDE ROSIGLITAZONE maleate 177 Roflumilast GLIMEPIRIDE PIOGLITAZONE 178 Roflumilast-N-Oxide GLIMEPIRIDE PIOGLITAZONE 179 Roflumilast GLIMEPIRIDE PIOGLITAZONE dihydrochloride 18O Roflumilast-N-Oxide GLIMEPIRIDE PIOGLITAZONE dihydrochloride

Pharmacology (Mono-Therapy) 15 The daily intake of food (chow 3433) and water was mea Model sured per animal (total daily intake of food divided by the Female C57BLKS db/db mice obtained from M&B A/S number of animals) before and during the treatment with (86.80 Ry, Denmark) were used in the studies at 10 to 11 Roflumilast or Roflumilast-N-Oxide. weeks of age. Mice were housed 10 per cage and allowed free 10 days studies: Mice were treated with vehicle, Roflumi access to water and standard laboratory diet for rodents (chow last or Roflumilast-N-Oxide once daily in the morning. On 3433, Provimi Kliba SA, 4303 Kaiseraugst, Switzerland). day 9, mice were fasted for 24 hours by removing standard Experimental Protocol diet for laboratory animals 1 hour after drug application. On Mice were allowed to acclimate to the local animal facili day 10, one hour after administration of vehicle, Roflumilast ties for 1 week and retro-orbital blood samples were obtained or Roflumilast-N-Oxide glucose tolerance was assessed by 3 to 7 days prior to the start of the study. oral application of 1 g/kg/10 ml glucose. Blood was sampled Mice were treated with vehicle, Roflumilast or Roflumi 25 before and 15 minutes after glucose application and levels of last-N-Oxide, respectively once daily in the morning. Roflu glucose (accu-chek, Roche Diagnostics GmbH, 68298 Man milast or Roflumilast-N-Oxide was suspended in 4% metho nheim, Germany) were measured. cel and applied via oral gavage using oral feeding & dosing Results needles (outer diameter: 1.5 mm, TSE GmbH, 61350 Bad Table 5 illustrates food intake of the mice on the days (24h Homburg, Germany). A volume of 10 ml/kg body weight was 30 time periods) before and during application of Roflumilast administered for each dose. N-Oxide: TABLE 5 Daily food intake g per mouse on the days (24 h time periods) before the first Daily food intakeg per mouse application of vehicle, on the days (24 h time periods) respectively of application of vehicle, ROf-N-Oxide respectively Rof-N-Oxide Day

-5 -4 -3 -2 - 1 1 2 3 4 5 6 7 8 Vehicle (4% methocel) 5.2 5.7 5.8 5.6 5.7 5.7 5.4 5.5 5.5 5.8 5.9 5.1 5.1 Rof-N-Oxide - 1 mg/kg 6.0 S.9 6.4 6.4 6.4 S4 S4 S.8 S.S. S.6 S.8 S4 S.S Rof-N-Oxide - 3 mg/kg 5.5 6.4 6-4 6.1 6.1 49 49 4.5 4.5 4.6 4.9 4.3 4.2 Rof-N-Oxide - 10 mg/kg 6.O 6.2 6-4 6-4 6.5 2.9 33 3.5 2.9 30 3.1 2.6 3.8 Rof-N-Oxide - 30 mg/kg 5.8 6.4 6.5 6.2 6.3 14 O.9 12 O.8 O.9 11 O.7 0.6 Day “-1” means the 24 h time period before the first applicati on of vehicle/Roflumilast-N-Oxide; Day “1” means means the 24 h time period after first application of vehicle Roflumilast-N-Oxide; Day “2” means the 24 h time period after the second application of vehicle Roflumilast-N-Oxide; and so on

Table 6 illustrates water intake of the mice on the days (24 h time periods) before and during application of Roflumilast N-Oxide. TABLE 6 Daily water intakeg per mouse on the days (24h Daily water intakeg per mouse time periods) before the on the days (24 h time periods) first application of vehicle, of application of vehicle, respectively Rof-N-Oxide respectively Rof-N-Oxide

-5 -4 -3 -2 -1 1 2 3 4 S 6 7 8

Vehicle (4% methocel) 7.9 8.8 6.5 6.9 6.7 7.2 7.7 * 9.0 8.S 8.1 7.9 8.1 Rof-N-Oxide - 1 mg/kg 9.2 9.4 8.4 7.9 8.6 7.6 6.9 * 7.1 8.O 7.7 8.5 7.2 US 8,017,633 B2 43 44 TABLE 6-continued Daily water intakeg per mouse on the days (24h Daily water intakeg per mouse time periods) before the on the days (24 h time periods) first application of vehicle, of application of vehicle, respectively Rof-N-Oxide respectively Rof-N-Oxide

Rof-N-Oxide - 3 mg/kg 9.8 4.3 7.6 7.6 9.1 5.1 5.9 * 5.9 5.7 5.4 5.4 5.2 Rof-N-Oxide - 10 mg/kg 12.1 9.6 7.9 8.2 9.6 2.9 3.5 * 3.2 3.7 33 3.0 4.1 Rof-N-Oxide - 30 mg/kg 10.1 12.4 10.0 9.4 10.1 2.3 2.4 * 2.6 3.0 2.9 3.3 2.5

no value due to technical artefact Day “-1” means the 24 h time period before the first application of vehicle? Roflumilast-N-Oxide; Day “1” means means the 24 h time period after first application of vehicle? Roflumilast-N-Oxide; Day “2” means the 24 h time period after the second application of vehicle Roflumilast-N-Oxide; and so on

Table 7 illustrates blood glucose levels before and 15 min- The invention claimed is: utes after glucose application. Mice were treated 10 days with 1. A pharmaceutical composition comprising a pharma Roflumilast. ceutical formulation including an amount of a compound of 20 formula 1.1 TABLE 7 (1.1) Blood glucose Blood glucose F F mg/dl) (before mg/dl) (15 min 25 N glucose application) after glucose application) O C

Vehicle(CIC (4%O methocel)(OCC 360 574 O N Roflumilast - 1 mg/kg 347 507 30 Roflumilast - 10 mg/kg 191 412 O 2 N C

Table 8 illustrates blood glucose levels before and 15 min utes afterglucose application. Mice were treated 10 days with or a pharmaceutically acceptable salt thereofand/or a com Roflumilast-N-oxide (-Rof-N-Oxide) pound of formula 1.2

TABLE 8 (1.2) Blood glucose Blood glucose 40 F F mg/dl) (before mg/dl) (15 min glucose application) after glucose application) O C Vehicle (4% methocel) 301 533 H Rof-N-Oxide - 1 mg/kg 220 595 45 O N N Rof-N-Oxide - 3 mg/kg 174 467 Rof-N-Oxide - 10 mg/kg 139 423 O 2NN Rof-N-Oxide - 30 mg/kg 146 326 C O

50 or a pharmaceutically acceptable salt thereof, an amount of SUMMARY a dipeptidyl-peptidase IV inhibitor selected from the group consisting of SITAGLIPTIN, SAXAGLIPTIN, VILDAGLIPTIN, DENAGLIPTIN, P32/98, NVP Treatment with Roflumilast-N-oxide has been demon- ss DPP-728 and the pharmaceutically acceptable salts of strated to reduce in a dose-dependent manner the daily food these compounds, wherein the first amount and the sec intake indb/db mice. Additionally, the increased daily water ond amount together comprise an effective amount for intake in db/db mice due to glucosuria, which is a result of the treatment of diabetes mellitus type 2, and at least one high blood glucose levels, was reduced during treatment with pharmaceutically acceptable auxiliary. Roflumilast-N-oxide. Furthermore, treatment with Roflumi- 60 2. The pharmaceutical composition according to claim 1, last or Roflumilast-N-oxide has been demonstrated to reduce wherein the dipeptidyl-peptidase IV inhibitoris selected from fasting and postprandial blood glucose levels indb/db mice in the group consisting of SITAGLIPTIN and the pharmaceuti accordance with the biochemical test methods detailed here- cally acceptable salts thereof. inbefore. k . . . .