US 201001791.31A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0179131 A1 Klein et al. (43) Pub. Date: Jul. 15, 2010

(54) COMBINATION TREATMENT FOR (86). PCT No.: PCT/EP2007/059253 DABETES MELLITUS S371 (c)(1), (75) Inventors: Thomas Klein, Radolfzell (DE); (2), (4) Date: Feb. 27, 2009 Anja Blaser, Konstanz (DE); (30) Foreign Application Priority Data Bettina Rudolph, Basel (CH): Ulrich Kautz, Allensbach (DE); Sep. 7, 2006 (EP) ...... O612O305.5 Jens Selige, Konstanz (DE); Wolfgang Kromer, Konstanz (DE) Publication Classification (51) Int. Cl. Correspondence Address: A6II 3/55 (2006.01) NATH & ASSOCATES PLLC A6IP3/10 (2006.01) 112 South West Street A6II 3/473 (2006.01) Alexandria, VA 22314 (US) (52) U.S. Cl...... 514/217.11: 514/298 (73) Assignee: NYCOMED GMBH, Konstanz (57) ABSTRACT (DE) The invention relates to combinations of (2R,4aR,10bR)-6- (2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4, (21) Appl. No.: 12/310,547 4a, 10b-hexahydrophenanthridine-2-ol with other active compounds for the treatment of diabetes mellitus type 2 and/ (22) PCT Filed: Sep. 4, 2007 or type 1. Patent Application Publication Jul. 15, 2010 Sheet 1 of 2 US 2010/01791.31 A1

Fig. 1: Effect of RIMONABANT Hydrochloride, Compound A and a combination of RIMONA BANT Hydrochloride and Compound A on HbA indbladb-mice.

Patent Application Publication Jul. 15, 2010 Sheet 2 of 2 US 2010/01791.31 A1

Fig. 2: Effect of RIMONABANT Hydrochloride, Compound A and a combination of RMONABANT Hydrochloride and Compound A on glucose tolerance in dblob-mice 3456 OOOO OOOO 20 O

1 O 9 2 O -60 0 60 120 time min - O- vehicle - A - Compound A3mg/kg/d) -V-REMONABANT Hydrochloride 10 mg/kg/d -- Compound A3mg/kg/dt RIMONABANT Hydrochloride 10mg/kg/d) US 2010/01791.31 A1 Jul. 15, 2010

COMBINATION TREATMENT FOR level of the B-cell, muscle and liver can lead to the develop DABETES MELLITUS ment of glucose intolerance and diabetes mellitus. All the abnormalities in diabetes basically result from an imbalance TECHNICAL FIELD between sensitivity and insulin secretion. The initial stage of diabetes is characterised by impaired glucose toler 0001. The invention relates to combinations of a known ance and postprandial hyperglycemia. As the disease PDE4 inhibitor with one or two other active compounds progresses, fasting hyperglycemia is observed. which are used in the treatment of diabetes mellitus type 2 0005. The earliest detectable abnormality in NIDDM is an and/or diabetes mellitus type 1; the invention also relates to impairment in the body's ability to respond to insulin. pharmaceutical compositions, combination products and kits Because the pancreas is able to appropriately augment its containing these combinations as well as uses of Such com secretion of insulin to offset the insulin resistance, glucose binations in the treatment of diabetes mellitus type 2 and/or tolerance remains normal. With time, however, the beta-cell diabetes mellitus type 1. fails to maintain its high rate of insulin secretion and the insulin resistance leads to the development of impaired glu BACKGROUND OF THE INVENTION cose tolerance and eventually overt diabetes mellitus. The 0002 Diabetes mellitus is on the rise worldwide and is cause of pancreatic “exhaustion” remains unknown, however considered to be at an epidemic level by the World Health lipo- and glucotoxicity with an increased level of oxygen Organization. The clinical manifestation and progression of radical stress are discussed more recently. Insulin resistance diabetes often vary considerably between countries and com in NIDDM involves both hepatic and peripheral tissues. In monly between ethnic groups in the same country. Currently response to both endogenously secreted or exogenously diabetes affects 151 million people worldwide and an esti administered insulin, hepatic glucose production fails to Sup mate 300 million people in 2025. There are two mainforms of press normally and muscle glucose uptake is diminished. The diabetes. Type 1 (insulin-dependent diabetes mellitus, accelerated rate of hepatic glurose output is due mainly to IDDM) is due primarily to autoimmune-mediated destruction augmented gluconeogenesis. In muscle many cellular defects of pancreatic B-cells, resulting in absolute insulin deficiency. in insulin action have been described including impaired It is the second most common chronic disease of children. By insulin-receptor tyrosine kinase activity, diminished glucose contrast, (non-insulin-dependent diabetes transport, and reduced glycogen synthase and pyruvate dehy mellitus, NIDDM) is characterized by insulin-resistance and drogenase activities. The abnormalities account for distur inadequate insulin secretion. A significant fraction of indi bances in the two major intracellular pathways of glucose viduals originally diagnosed with type 2 diabetes evolve with disposal, glycogen synthesis and glucose oxidation. In the time to a type 1 state, which is defined as exhibiting anti-B- earliest stages of NIDDM, the major defect involves the cell autoimmunity. inability of insulin to promote glucose uptake and storage as 0003 Because genetic factors contribute to the develop glycogen. Other potential mechanisms that have been put ment of diabetes, the disease displays a strong familial aggre forward to explain the glucose intolerance include increased gation. Although there are monogenic syndromes of insulin levels of free fatty acids, chronic low-grade activation of the resistance, in which a definite gene has been identified as the immune system (increased levels of TNFC. and IL6), altered cause of insulin resistance, these are relative rare. The more skeletal muscle blood flow, increased conversion of amylinto common presentation of diabetes appears to be polygenic. its insoluble amyloid form and glucose toxicity. Additionally, behavioural- and lifestyle-related risk factors 0006 Diabetes is associated with a variety of physiologic exist. Type 2 diabetes is increasingly common primarily disorders such as hypertension and dyslipidemia. Diabetes because of increases in the prevalence of a sedentary lifestyle also increases the risk of macrovascular (coronary artery dis and obesity. One of the major arguments for the role of behav ease, stroke, amputation) and microvascular (blindness, renal ioural factors in the etiology of diabetes has been the rapid failure, neuropathies) diseases. Myocardial infarction, stroke increase in the prevalence and incidence of the disease in or renal failure are the cause of death for more than 70% of populations undergoing rapid westernization. The western diabetes patients. The huge mortality and debilitating neuro ization transition is usually accompanied by increases in obe pathies associated with diabetes underline the importance of sity, decreases in physical activity and alterations in dietary active medical intervention. intake toward more calories, fat and non-complex carbohy 0007. There are several ways to counteract diabetes. The drates. first is lifestyle adjustments aimed at improving endogenous 0004 Plasma glucose concentrations are normally main insulin sensitivity. This can beachieved by increased physical tained within a fairly narrow range despite wide fluctuations activity and bodyweight reduction with diet and behavioural in the body's Supply (e.g. meals) and demand (e.g. exercise) modification. Unfortunately, most people with non-insulin for nutrients. After an overnight fast, insulin-independent dependent diabetes mellitus never receive sufficient nutri tissues, the brain (50%) and splanchnic organs (25%), tional education or are not capable of complying with a strict account for most of the total body glucose disposal. Insulin diet regimen. dependent tissues, adipose tissue and primarily skeletal 0008 Another therapeutic way involves increasing insulin muscles, are responsible for the remaining 25% of glucose availability by the administration of exogenous insulin, insu utilization. This basal glucose uptake is precisely matched by lin analogues and insulin Secretagogues such as Sulphony the release of glucose from the liver. In response to hyperg lureas. The primary mode of action of Sulphonylureas is lycemia after a meal, pancreatic insulin secretion is stimu through the depolarisation of the pancreatic a-cells by block lated and the combination of hyperinsulinemia plus hyperg ing the ATP-dependent potassium channels and causing an lycemia promotes glucose uptake (by splanchnic and influx of calcium ions, which stimulate insulin secretion. peripheral, primarily muscle, tissues) and Suppresses hepatic 0009 , of which is the most com glucose production. It follows, therefore, that defects at the monly used, also have proven to be effective anti-hypergly US 2010/01791.31 A1 Jul. 15, 2010 cemic agents. Metformin reduces hepatic gluconeogenesis 0013. It is an object of the present invention to provide and basal hepatic glucose output. Oral antidiabetics such as combinations and methods of treatment that take advantage Sulphonylureas and metformin as monotherapy or in combi of the different therapeutic pathways of a PDE4 inhibitor on nation have been shown to decrease fasting plasma glucose the one hand side and other known anti-diabetic compounds levels, but postprandial hyperglycemia persists in more than on the other hand side to more effectively treat diabetes mel 60% of patients and probably accounts for sustained litus type 2 and/or type 1. increases of hemoglobin A levels. 0010 C.-Glucosidase inhibitors, e.g. and migli DESCRIPTION OF THE INVENTION tol, primarily target postprandial hyperglycemia. The therapy 0014. The invention is based on the expectation that the of diabetes mellitus with C-glucosidase inhibitors is based on use of the selective PDE4 inhibitor (2R,4aR,10bR)-6-(2,6- a delayed intestinal degradation of starch and Sucrose. These Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a, carbohydrates must be hydrolysed by C-glucosidases to 10b-hexahydrophenanthridine-2-ol (hereinafter referred to monosaccharides before they can be transported through the as "Compound A') or a pharmaceutical acceptable salt mucosa of the small intestine. The reversible inhibition of the thereof in combination with one or two other active com brush border glucosidases results in redistribution of carbo pound(s) or pharmaceutically acceptable salt(s) thereof hydrate absorption from the upper portion of the gut to a more which is (are) used in the treatment of diabetes mellitus type extended surface area covering the whole length of the Small 2 and/or type 1 leads to beneficial effects in the treatment of intestine. This is accompanied by a delayed absorption of diabetes mellitus type 2 and/or type 1 in comparison to the monosaccharides and a decrease in the postprandial elevation treatment with either the selective PDE4 inhibitor (2R,4aR, of blood glucose. 10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-meth 0011. Another class of antidiabetic drugs are thiazo oxy-1,2,3,4,4a, 10b-hexahydrophenanthridine-2-ol or the lidinediones, such as and , which above-mentioned active compound(s) alone. are insulin sensitizers and act through activation of peroxi 0015 Therefore, according to a first aspect of the present some proliferator-activated receptor Y (PPARY). PPARY is invention there is provided a pharmaceutical composition mainly expressed in adipose tissues, plays an important role comprising a pharmaceutical formulation including Com in adipogenesis and modifies fatty acid synthesis and storage. pound A or a pharmaceutically acceptable salt thereof, one Binding of rosiglitazone to PPARY results in reduced endog other active compound or a pharmaceutically acceptable salt enous glucose production and increased blood glucose thereof which is used in the treatment of diabetes mellitus uptake. It increases the sensitivity of skeletal muscle, liver type 2 and/or type 1, and at least one pharmaceutically accept and adipose tissues to insulin. Improvements in glucose able auxiliary. metabolism with rosiglitaZone treatment are closely corre 0016. As an embodiment of the first aspect of the present lated with decreased plasma free fatty acid metabolism. The invention there is provided a pharmaceutical composition stimulation by rosiglitazone of PPARY in adipose tissue and comprising a pharmaceutical formulation including an Subsequent adipocyte differentiation results in the generation amount of Compound Aora pharmaceutically acceptable salt of more, but Smaller, adipocytes which are more insulin sen thereof, an amount of one other active compound or a phar sitive and produce less free fatty acid, TNFC. and leptin. maceutically acceptable salt thereof which is used in the 0012. In the International Patent Application WO9914239 treatment of diabetes mellitus type 2 and/or type 1, wherein compositions for treating diabetes mellitus and obesity are the first amount and the second amount together comprise an disclosed. The compositions contain at least two of the active effective amount for the treatment of diabetes mellitus type 2 agents A, B and C, wherein A is at least one hormone which and/or type 1, and at least one pharmaceutically acceptable stimulates the production of cAMP, B is at least one substance auxiliary. which inhibits the breakdown of a cyclic nucleotide, and C is 0017. According to a second aspect of the present inven at least one hormone which stimulates the production of tion there is provided a pharmaceutical composition compris cGMP. In the International Patent Application WO0135979 ing a pharmaceutical formulation including Compound A or the combined use of a PDE3 and a PDE4 inhibitor for the a pharmaceutical acceptable salt thereof, two other active treatment of obesity is disclosed. In the International Patent compounds or pharmaceutically acceptable salts thereof Application WO0213798 the use of a selective c(GMP PDE5 which are used in the treatment of diabetes mellitus type 2 inhibitor for the treatment of Insulin Resistance Syndrome is and/or type 1, and at least one pharmaceutically acceptable disclosed, wherein the Insulin Resistance Syndrome is auxiliary. defined as the concomitant existence of two or more disease 0018. As an embodiment of the second aspect of the states selected from dyslipidemia, hypertension, type 2 dia present invention there is provided a pharmaceutical compo betes mellitus, impaired glucose tolerance, a family history of sition comprising a pharmaceutical formulation including an diabetes, hyperuricaemia and/or gout, a pro-coalgulant state, amount of Compound Aora pharmaceutically acceptable salt atherosclerosis and truncal obesity. In the unexamined Ger thereof, amounts of two other active compounds or pharma man application DE 10150517 tetra-hydropyridazin-3-one ceutically acceptable salts thereof which are used in the treat derivatives are described which may be useful inter alia for ment of diabetes mellitus type 2 and/or type 1, wherein the the treatment of diabetes mellitus. In the International Patent first, second and third amount together comprise an effective Application WO2005023253 several PDE4 inhibitors are dis amount for the treatment of diabetes mellitus type 2 and/or closed to be useful in the treatment of diabetes mellitus. In type 1, and at least one pharmaceutically acceptable auxiliary. Diabetes 47, pp. 570-575, 1998 is disclosed that pentoxifyl 0019. The above-mentioned pharmaceutical composi line and rolipram may be effective in the treatment of autoim tions provide for the administration of Compound A or a mune diabetes or other conditions characterized by excessive pharmaceutically acceptable salt thereof with one or two production of inflammatory cytokines. other active compound(s) or pharmaceutically acceptable US 2010/01791.31 A1 Jul. 15, 2010

salts thereof which is (are) used in the treatment of diabetes 0027. As an embodiment of the above-mentioned kit there mellitus type 2 and/or type 1 and is thus presented as a single is provided a kit comprising the components: (A) a pharma formulation. ceutical formulation including an amount of Compound A or 0020. Alternatively, Compound A or a pharmaceutically a pharmaceutically acceptable salt thereof, in admixture with acceptable salt thereof and the one or two other active com at least one pharmaceutically acceptable auxiliary; and (B) a pound(s) or pharmaceutically acceptable salt(s) thereof pharmaceutical formulation including an amount of one other which is (are) used in the treatment of diabetes mellitus type active compound or pharmaceutically acceptable salt thereof 2 and/or type 1 may be presented as separate formulations, which is used in the treatment of diabetes mellitus type 2 wherein at least one of those formulations comprises Com and/or type 1, in admixture with at least one pharmaceutically pound A or a pharmaceutically acceptable salt thereof and at acceptable auxiliary, wherein the first and the second amount least one comprises one or two other active compound(s) or together comprise an effective amount for the treatment of pharmaceutically acceptable salt(s) thereof which is (are) diabetes mellitus type 2 and/or type 1. used in the treatment of diabetes mellitus type 2 and/or type 1. 0028 Akit comprising the components: (A) a pharmaceu 0021. Thus, there is further provided: tical formulation including Compound A or a pharmaceuti 0022. A combination product comprising the compo cally acceptable salt thereof, in admixture with at least one nents: (A) Compound Aora pharmaceutically acceptable salt pharmaceutically acceptable auxiliary; (B) a pharmaceutical thereof, and (B) one other active compound or pharmaceuti formulation including an amount of one other active com cally acceptable salt thereof which is used in the treatment of pound or pharmaceutically acceptable salt thereof which is diabetes mellitus type 2 and/or type 1, wherein each of the used in the treatment of diabetes mellitus type 2 and/or type 1, components (A) and (B) is formulated in admixture with at in admixture with at least one pharmaceutically acceptable least one pharmaceutically acceptable auxiliary. auxiliary; and (C) a pharmaceutical formulation including 0023. As an embodiment of the above-mentioned combi still another active compound or a pharmaceutically accept nation product there is provided a combination product com able salt thereof which is used in the treatment of diabetes prising the components: (A) an amount of Compound A or a mellitus type 2 and/or type 1, in admixture with at least one pharmaceutically acceptable salt thereof, and (B) an amount pharmaceutically acceptable auxiliary. of one other active compound orpharmaceutically acceptable 0029. As an embodiment to the above-mentioned kit there salt thereof which is used in the treatment of diabetes mellitus is provided a kit comprising the components: (A) a pharma type 2 and/or type 1, wherein the first and the second amount ceutical formulation including an amount of Compound A or together comprise an effective amount for the treatment of a pharmaceutically acceptable salt thereof, in admixture with diabetes mellitus type 2 and/or type 1 and wherein each of the at least one pharmaceutically acceptable auxiliary; (B) a phar components (A) and (B) is formulated in admixture with at maceutical formulation including an amount of one other least one pharmaceutically acceptable auxiliary. active compound or pharmaceutically acceptable salt thereof 0024. A combination product comprising the compo which is used in the treatment of diabetes mellitus type 2 nents: (A) Compound Aora pharmaceutically acceptable salt and/or type 1, in admixture with at least one pharmaceutically thereof (B) one other active compound or pharmaceutically acceptable auxiliary; and (C) a pharmaceutical formulation acceptable salt thereof which is used in the treatment of including an amount of still another active compound or a diabetes mellitus type 2 and/or type 1; and (C) still another pharmaceutically acceptable salt thereof which is used in the active compound or pharmaceutically acceptable salt thereof treatment of diabetes mellitus type 2 and/or type 1, in admix which is used in the treatment of diabetes mellitus type 2 ture with at least one pharmaceutically acceptable auxiliary, and/or type 1, wherein each of the components (A), (B) and wherein the first, second and third amount together comprise (C) is formulated in admixture with at least one pharmaceu an effective amount for the treatment of diabetes mellitus type tically acceptable auxiliary. 2 and/or type 1. 0025. As an embodiment of the above-mentioned combi 0030. In addition, to the components A and B (or A, B and nation product there is provided a combination product com C) the kits according to the invention may include informa prising the components: (A) an amount of Compound A or a tion for the sequential or separate administration of the com pharmaceutically acceptable salt thereof; (B) an amount of ponents to the patient in need of diabetes mellitus type 2 one other active compound or pharmaceutically acceptable and/or type 1 therapy. salt thereof which is used in the treatment of diabetes mellitus 0031. The combinations according to the present inven type 2 and/or type 1; and (C) an amount of still another active tion are used for the treatment of diabetes mellitus type 2 compound or pharmaceutically acceptable salt thereof which and/or type 1, preferably for the treatment of diabetes mellitus is used in the treatment of diabetes mellitus type 2 and/or type type 2. 1, wherein the first, second and third amount together com 0032. Therefore, further aspects of the invention are: prise an effective amount for the treatment of diabetes melli 0033. The use of Compound A or a pharmaceutically tus type 2 and/or type 1 and wherein each of the components acceptable salt thereof and one other active compound or (A), (B) and (C) is formulated in admixture with at least one pharmaceutically acceptable salt thereof which is used in the pharmaceutically acceptable auxiliary. treatment of diabetes mellitus type 2 and/or type 1 for the 0026. A kit comprising the components: (A) a pharmaceu manufacture of a medicament, in particular a pharmaceutical tical formulation including Compound A or a pharmaceuti composition according to the invention, for the treatment of cally acceptable salt thereof, in admixture with at least one diabetes mellitus type 2 and/or type 1. pharmaceutically acceptable auxiliary; and (B) a pharmaceu 0034. The use of Compound A or a pharmaceutically tical formulation including one other active compound or acceptable salt thereof and two other active compounds or pharmaceutically acceptable salt thereof which is used in the pharmaceutically acceptable salts thereof which are used in treatment of diabetes mellitus type 2 and/or type 1, in admix the treatment of diabetes mellitus type 2 and/or type 1 for the ture with at least one pharmaceutically acceptable auxiliary. manufacture of a medicament, in particular a pharmaceutical US 2010/01791.31 A1 Jul. 15, 2010 composition according to the invention, for the treatment of wherein the first and second amount together comprise an diabetes mellitus type 2 and/or type 1. effective amount for the treatment of diabetes mellitus type 2 0035. The use of Compound A or a pharmaceutically and/or type 1; acceptable salt thereof and one other active compound or wherein each of the components (A) and (B) is formulated in pharmaceutically acceptable salt thereof which is used in the admixture with at least one pharmaceutically acceptableaux treatment of diabetes mellitus type 2 and/or type 1 for the iliary: manufacture of a sequentially or separately co-administrable and wherein the components (A) and (B) are administered medicament, in particular the combination product or kit sequentially or separately. according to the invention, for the treatment of diabetes mel 0043 Still a further aspect of the present invention is a litus type 2 and/or type 1. method for treating diabetes mellitus type 2 and/or type 1 0036. The use of Compound A or a pharmaceutically comprising administering to a patient in need thereof a com acceptable salt thereof and two other active compounds or bination product comprising the components: pharmaceutically acceptable salts thereof which are used in (A) an amount of Compound A or a pharmaceutically accept the treatment of diabetes mellitus type 2 and/or type 1 for the able salt thereof; manufacture of a sequentially or separately co-administrable (B) an amount of one other active compound or a pharmaceu medicament, in particular a combination product or kit tically acceptable salt thereof which is used in the treatment of according to the invention, for the treatment of diabetes mel litus type 2 and/or type 1. diabetes mellitus type 2 and/or type 1; and 0037 Compound A or a pharmaceutically acceptable salt (C) an amount of still another active compound or a pharma thereof and one other active compound or pharmaceutically ceutically acceptable salt thereof which is used in the treat acceptable salt thereof which is used in the treatment of ment of diabetes mellitus type 2 and/or type 1, diabetes mellitus type 2 and/or type 1 for the treatment of wherein the first, second and third amount together comprise diabetes mellitus type 2 and/or type 1. an effective amount for the treatment of diabetes mellitus type 0038 Compound A or a pharmaceutically acceptable salt 2 and/or type 1; thereof and two other active compounds or pharmaceutically wherein each of the components (A), (B) and (C) is formu acceptable salts thereof which are used in the treatment of lated in admixture with at least one pharmaceutically accept diabetes mellitus type 2 and/or type 1 for the treatment of able auxiliary; and wherein the components (A), (B) and (C) diabetes mellitus type 2 and/or type 1. are administered sequentially or separately. 0039. A pharmaceutical composition, combination prod 0044. The pharmaceutical compositions according to the uct or kit according to the invention for the treatment of invention may be prepared by mixing the first active agent diabetes mellitus type 2 and/or type 1. with the second (and optionally third) active agent. 0040 Another aspect of the present invention is a method 0045. In the above-mentioned mixing process the first for treating diabetes mellitus type 2 and/or type 1 comprising active agent and the second (and optionally third) active agent administering to a patient in need thereof a pharmaceutical Ca composition comprising a pharmaceutical formulation a) in a first step be mixed as such, afterwards be processed including an amount of Compound A or a pharmaceutically with at least one pharmaceutically acceptable auxiliary and acceptable salt thereof, an amount of one other active com finally, for example, be pressed to tablets or caplets or pound or a pharmaceutically acceptable salt thereof which is b) in a first step separately be processed with at least one used in the treatment of diabetes mellitus type 2 and/or type 1, pharmaceutically acceptable auxiliary to give granules or wherein the first amount and the second amount together pellets containing each only one of the two (or three) active comprise an effective amount for the treatment of diabetes agents; the pellets or granules for their part then can be mixed mellitus type 2 and/or type 1, and at least one pharmaceuti in an appropriate ratio and either pressed—optionally with cally acceptable auxiliary. further pharmaceutically acceptable auxiliaries—to give, for 0041. Still another aspect of the present invention is a example tablets or caplets, or can be filled in loose form in method for treating diabetes mellitus type 2 and/or type 1 capsules. comprising administering to a patient in need thereof a phar 0046. Therefore, in a still further aspect of the present maceutical composition comprising a pharmaceutical formu invention there is provided a process for the preparation of a lation including an amount of Compound A or a pharmaceu pharmaceutical composition which comprises mixing a first tically acceptable salt thereof, amounts of two other active active agent, which is Compound A or a pharmaceutically compounds or pharmaceutically acceptable salts thereof acceptable salt thereof with a second (and optionally a third) which are used in the treatment of diabetes mellitus type 2 active agent, which is (are) one or two other active com and/or type 1, wherein the first, second and third amount pounds which is (are) used in the treatment of diabetes mel together comprise an effective amount for the treatment of litus type 2 and/or type 1. diabetes mellitus type 2 and/or type 1, and at least one phar 0047 Simultaneous administration of Compound A or a maceutically acceptable auxiliary. pharmaceutically acceptable salt thereofandone or two other 0042. A further aspect of the present invention is a method active compound(s) or pharmaceutically acceptable salt(s) for treating diabetes mellitus type 2 and/or type 1 comprising thereof which is (are) used in the treatment of diabetes mel administering to a patient in need thereofa combination prod litus type 2 and/or type 1 can be preferably accomplished, by uct comprising the components: administering to the patient in need of diabetes mellitus type (A) an amount of Compound A or a pharmaceutically accept 2 and/or type 1 therapy the pharmaceutical composition able salt thereof, and according to the invention in one dosage form, Such as for (B) an amount of one other active compound or a pharmaceu example, in a single capsule, tablet or injection. tically acceptable salt thereof which is used in the treatment of 0048 Components (A), (B) and optionally (C) of the com diabetes mellitus type 2 and/or type 1, bination product as well as of the kit may be administered US 2010/01791.31 A1 Jul. 15, 2010 sequentially or separately over the course of the treatment of therapy. The combined administration of Compound A or a diabetes mellitus type 2 and/or type 1. pharmaceutically acceptable salt thereofandone or two other 0049 Sequential or separate administration of Compound active compound(s) or pharmaceutically acceptable salts A or a pharmaceutically acceptable salt thereof and one or thereof which is (are) used in the treatment of diabetes mel two other active compound(s) or pharmaceutically accept litus type 2 and/or type 1 may also be useful for decreasing the able salt(s) thereof which is (are) used in the treatment of required number of separate dosages, thus, potentially diabetes mellitus type 2 and/or type 1 can be preferably improving compliance of the patient in need of diabetes mel accomplished, by administering to the patient in need of litus type 2 and/or type 1 therapy. diabetes mellitus type 2 and/or type 1 therapy components 0055. The term “active agent” as used herein refers either (A), (B) and optionally (C) of the combination product or the to Compound A or a pharmaceutically acceptable salt thereof kit according to the invention in (multiple) separate dosage or to the active compound(s) or pharmaceutically acceptable forms, such as for example, in separate capsules, tablets or salt(s) thereof, which is (are) used in the treatment of diabetes injections. mellitus type 2 and/or type 1. 0050. In an alternative, one (or two) of the components 0056. The term “active compound as used herein refers to (A), (B) and optionally (C) may be formulated as tablet or a compound useful in the treatment of a disease, here in capsule and the remaining component(s) may be formulated particular in the treatment of diabetes mellitus type 2 and/or for administration, for example, by injection or inhalation. type 1. 0051 Sequential administration encompasses a short time period between the administration of components (A), (B) 0057 The term “effective amount as used herein refers to and optionally (C) of the combination product or the kit a therapeutically effective amount for treating diabetes mel according to the invention (for example, the time that is litus type 2 and/or type 1. In case of a combination therapy the needed to swallow one tablet after the other). term “effective amount” refers to the sum of the amounts of 0052 Separate administration encompasses both short the combination partners, which is therapeutically effective and long time periods between the administration of compo for the treatment of diabetes mellitus type 2 and/or type 1. nents (A), (B) and optionally (C) of the combination product 0058. In case of the pharmaceutical compositions, combi or the kit according to the invention. However, for the pur nation products and kits according to the invention the term poses of the present invention at least one of the components 'amount’ is mentioned in connection with the pharmaceuti is administered while the other component(s) is (are) still cal formulations which form part of the pharmaceutical com having an effect on the patient being treated. In a preferred positions, or in connection with the components which form embodiment of the invention the effect on the patient being part of the combination products or kits. The term “effective treated is a synergistic effect. amount' is mentioned in phrases, such as “wherein the first and second amount (or the first, second and third amount) 0053. The combined administration of Compound A or a together comprise an effective amount for the treatment of pharmaceutically acceptable salt thereofandone or two other diabetes mellitus type 2 and/or type 1. In case, a once daily active compound(s) or pharmaceutically acceptable salt(s) administration of the pharmaceutical formulation of the phar thereof which is (are) used in the treatment of diabetes mel maceutical composition, or a once daily administration of the litus type 2 and/or type 1, either inform of the pharmaceutical components of the combination product is intended, the composition, combination product or kit according to the respective amount(s) correspond to the daily dosage neces invention, lead to an effective treatment of diabetes type 2 sary for the treatment of diabetes mellitus type 2 and/or type and/or type 1, and in a preferred embodiment is Superior to the 1. In case, a twice a day administration of the pharmaceutical use of either active agent alone. Moreover, in a particularly formulation of the pharmaceutical composition, or a twice a preferred embodiment, the combined administration of Com day administration of the components (or one of the compo pound A or a pharmaceutically acceptable thereof and one or nents) of the combination product or kit is intended, the two other active compound(s) or pharmaceutically accept respective amount(s) correspond to the daily dosage neces able salt(s) thereof which is (are) used in the treatment of sary for the treatment of diabetes mellitus type 2 and/or type diabetes type 2 and/or type 1 shows a synergistic efficacy for 1 multiplied by the factor 0.5. In case, a three times a day treating diabetes mellitus type 2 and/or type 1. administration of the pharmaceutical formulation of the phar 0054 As used herein, the term “synergistic’ refers to the maceutical composition, or a three times a day administration combination of Compound A or a pharmaceutically accept of the components (or one of the components) of the combi able salt thereof with one or two other active compound(s) or nation product or kit is intended, the respective amount(s) pharmaceutically acceptable salt(s) thereof which is (are) correspond to the daily dosage necessary for the treatment of used in the treatment of diabetes mellitus type 2 and/or type 1 either in form of the pharmaceutical composition, combina diabetes mellitus type 2 and/or type 1 multiplied by the factor tion product or kit according to the invention having an effi 0.33 and so on. cacy for the treatment of diabetes mellitus type 2 and/or type 0059. The term “patient” includes both humans and other 1 that is greater than would be expected from the sum of their mammals. In a preferred embodiment of the invention the individuals effects. The synergistic effects of the embodi term “patient' stands for humans. ments of the present invention encompass additional unex 0060. The term “one other active compound in connec pected advantages for the treatment of diabetes mellitus type tion with the term “still another active compound' means that 2 and/or type 1. Such additional advantages may include, but the two mentioned active compounds are not identical. As are not limited to, lowering the required dose of one or more well, the term “two other active compounds' stands for two of the active agents of the combination, reducing the side active compounds that are not identical. effects of one or more of the active agents of the combination 0061 The term “Compound A' as used herein stands for or rendering one or more of the active agents more tolerable (2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy to the patient in need of a diabetes type 2 and/or type 1 8-methoxy-1,2,3,4,4a, 10b-hexahydrophenanthridine-2-ol. US 2010/01791.31 A1 Jul. 15, 2010

0062. In one embodiment of the present invention a pre (rDNA origin), Velosulin(R) BR human buffered regular ferred pharmaceutically acceptable salt of Compound A is insulin, (rDNA origin) and Exubera.R. human insulin, selected from the tosylate, esylate, hydrobromide and hydro inhaled. chloride salt of Compound A. 0100. In another embodiment of the present invention the 0063. In another embodiment of the present invention a other active compound which is used in the treatment of preferred pharmaceutically acceptable Salt of Compound A is diabetes mellitus type 2 and/or type 1 is an insulin analogue or the hydrochloride salt of Compound A. a pharmaceutically acceptable salt thereof. Specific examples 0064. Additional information with regard to the prepara of insulin analogues include, but are not limited to, novarapid, tion and Suitable dosage forms of Compound A and the phar , , , insulin Zinc maceutically acceptable salts thereof can be found in the Suspension and Lys-Pro insulin. following patents/patent applications: WO2005/085225 and 0101. In another embodiment of the present invention the PCT/EP2006/060377 (WO2006092422). other active compound which is used in the treatment of 0065. Non-limiting examples of other active compounds diabetes mellitus type 2 and/or type 1 is a Glucagon-Like which are used in the treatment of diabetes mellitus type 2 Peptide-1 receptor agonist or a pharmaceutically acceptable and/or type 1 are provided in the following list: salt thereof. Specific examples of Glucagon-Like-Peptide-1 0.066 Insulin and insulin analogues receptor agonists include, but are not limited to BIM-51077 0067. Glucagon-Like-Peptide-1 (GLP-1) receptor ago (CAS-No. 275371-94-3), (CAS-No. 141758 nists 74-9), (CAS-No. 20656-20-2), ALBIG 0068 agents LUTIDE (CAS-No. 782500-75-8) and ZP-10 (CAS-No. 0069 agents 320367-13-3). A preferred Glucagon-Like-Peptide-1 recep 0070 Alpha-glucosidase inhibitors toragonist is EXENATIDE. (0071 PPAR-Agonists 0102. In another embodiment of the present invention the 0072 agents other active compound which is used in the treatment of (0073 Dipeptidyl-peptidase (DPP) IV inhibitors diabetes mellitus type 2 and/or type 1 is a Sulfonylurea agent 0074 PDE1, PDE5, PDE9, PDE10 or PDE11 inhibitors or a pharmaceutically acceptable salt thereof. Specific 0075 agonists examples of Sulfonylurea agents include, but are not limited 0076 Cinnamon to, (CAS-No. 000064-77-7), TOLAZA 0077. Glucagon receptor antagonists MIDE (CAS-No. 001156-19-0), (CAS-No. 0078 Glycogen-Phosphorylase inhibitors 029094-61-9), (CAS-No. 000339-43-5), (0079 Fructose-1,6-Bisphosphate inhibitors (CAS-No. 025046-79-1), GLISENTIDE 0080 Cannabinoid (CB1) receptor antagonists (CAS-No. 032797-92-5), (CAS-No. 0081 Anti-obesity drugs such as appetite Suppressors, 026944-48-9), (CAS-NO. 010238-21 Satiety increasing Substances, and energy expenditure 8), (CAS-No. 033342-05-1), GLIME increasing drugs PIRIDE (CAS-No. 093479-97-1) and (CAS and pharmaceutically acceptable salts thereof. No. 021187-98-4). 0082 In one embodiment of the invention, the one of two 0103) In another embodiment of the present invention the other active compound(s) which is (are) used in the treatment pharmaceutically acceptable salt of TOLBUTAMIDE is the of diabetes mellitus type 2 and/or type 1 is (are) selected from Sodium salt of TOLBUTAMIDE. In another embodiment of the group consisting of the present invention the pharmaceutically acceptable salt of I0083. Insulin and insulin analogues GLIQUIDONE is the sodium salt of GLIQUIDONE. I0084) Glucagon-Like-Peptide-1 (GLP-1) receptor ago 0104. In another embodiment of the present invention the nists other active compound which is used in the treatment of I0085 Sulfonylurea agents diabetes mellitus type 2 and/or type 1 is a biguanide agent or I0086) Biguanide agents a pharmaceutically acceptable salt thereof. A specific I0087 Alpha-glucosidase inhibitors example of a biguanide agent includes, but is not limited to I0088 PPAR-Agonists METFORMIN (CAS-No. 000657-24-9). I0089 Meglitinide agents 0105. In another embodiment of the present invention the (0090 Dipeptidyl-peptidase (DPP) IV inhibitors pharmaceutically acceptable salt of METFORMIN is the 0.091 PDE1, PDE5, PDE9, PDE10 or PDE11 inhibitors hydrochloride salt of METFORMIN. 0092 Amylin agonists 0106. In another embodiment of the present invention the 0093 Cinnamon other active compound which is used in the treatment of 0094) Glucagon receptor antagonists diabetes mellitus type 2 and/or type 1 is an alpha-glucosidase 0.095 Glycogen-Phosphorylase inhibitors inhibitor or a pharmaceutically acceptable salt thereof. Spe 0096. Fructose-1,6-Bisphosphate inhibitors cific examples of alpha-glucosidase-inhibitors include, but 0097 Cannabinoid (CB1) receptor antagonists are not limited to ACARBOSE (Cas-No. 056180-94-0), 0.098 Anti-obesity drugs such as appetite suppressors, (CAS-No. 072432-03-2) and Satiety increasing Substances, and energy expenditure (CAS-No. 083480-29-9). increasing drugs 0107. In another embodiment of the present invention the and pharmaceutically acceptable salts thereof. other active compound which is used in the treatment of 0099. In another embodiment of the present invention the diabetes mellitus type 2 and/or type 1 is a PPAR-agonist or a other active compound which is used in the treatment of pharmaceutically acceptable salt thereof. Specific examples diabetes mellitus type 2 and/or type 1 is insulin. Specific of PPAR-agonists include, but are not limited to MURAGLI examples of insulin include, but are not limited to Humulin(R) TAZAR (CAS-No. 331741-94-7), ROSIGLITAZONE human insulin, (rDNA origin), Novolin R. human insulin, (CAS-NO. 122320-73-4), PIOGLITAZONE (CAS-No. US 2010/01791.31 A1 Jul. 15, 2010

111025-46-8), (CAS-No. 196808-45-4), of VARDENAFIL. In another embodiment of the present NAVEGLITAZAR (CAS-No. 476-436-68-7), NETOGLI invention the pharmaceutically acceptable salt of AVANAFIL TAZONE (CAS-NO. 161600-01-7), is the besilate Salt of AVANAFIL. (CAS-No. 185428-18-6), K-111 (CAS-No. 221564-97-2), 0116. In another embodiment of the present invention the (=GW-677954; CAS-No. 622402-24-8) other active compound which is used in the treatment of and (-)-Halofenate (CAS-No. 024136-23-0). Preferred diabetes mellitus type 2 and/or type 1 is a PDE1, PDE9, PPAR-agonists are ROSGLITAZONE and PIOGLITA PDE10 or PDE11 inhibitor or a pharmaceutically acceptable ZONE. salt thereof. PDE1, PDE9, PDE10 or PDE11 inhibitors which 0108. In another embodiment of the present invention the may be useful employed according to the present invention, pharmaceutically acceptable salt of ROSIGLITAZONE is the can be found, for example, in US2002.0160939, maleate Salt of ROSIGLITAZONE. In another embodiment WO03037432, US20042201.86, WO2005003129, of the present invention the pharmaceutically acceptable salt WO2005012485, WO2005120514 and WO03077949. of RIVOGLITAZONE is the hydrochloride salt of RIVOGLI 0117. In another embodiment of the present invention the TAZONE. other active compound which is used in the treatment of 0109. In another embodiment of the present invention the diabetes mellitus type 2 and/or type 1 is an amylin agonist or pharmaceutically acceptable salt of K-1 11 is the sodium salt a pharmaceutically acceptable salt thereof. A specific of K-111. In another embodiment of the present invention the example of an amylin agonist includes, but is not limited to pharmaceutically acceptable salt of PIOGLITAZONE is the PRAMLINITIDE (CAS-No. 151126-32-8). dihydrochloride salt of PIOGLITAZONE. 0118. In another embodiment of the present invention the 0110. In another embodiment of the present invention the pharmaceutically acceptable salt of PRAMLINITIDE is the other active compound which is used in the treatment of acetate Salt of PRAMLINITIDE. diabetes mellitus type 2 and/or type 1 is a meglitinide agent or 0119. In another embodiment of the present invention the a pharmaceutically acceptable salt thereof. Specific examples other active compound which is used in the treatment of of meglitinide agents include, but are not limited to REPA diabetes mellitus type 2 and/or type 1 is cinnamon. GLINIDE (CAS-No. 135062-02-1), (CAS I0120 In another embodiment of the present invention the No. 105816-04-4) and (CAS-No. 145375 other active compound which is used in the treatment of 43-5). diabetes mellitus type 2 and/or type 1 is a glucagon receptor 0111. In another embodiment of the present invention the antagonist or a pharmaceutically acceptable salt thereof. A pharmaceutically acceptable salts of MITIGLINIDE are the specific example of a glucagons receptor antagonist includes, monopotassium or the calcium salt of MITIGLINIDE. but is not limited to BAY-27-9955 (CAS-No. 202855-56-9). 0112. In another embodiment of the present invention the I0121. In another embodiment of the present invention the other active compound which is used in the treatment of other active compound which is used in the treatment of diabetes mellitus type 2 and/or type 1 is a DPP-IV inhibitor or diabetes mellitus type 2 and/or type 1 is a glycogen-phospho a pharmaceutically acceptable salt thereof. Specific examples rylase inhibitor or a pharmaceutically acceptable salt thereof. of DPP IV inhibitors include, but are not limited to SITA An example of a glycogen-phosphorylase inhibitor includes, GLIPTIN (CAS-No. 486-460-32-6), (CAS but is not limited to INGLIFORIB (CAS-No. 186392-65-4). No. 361442-04-8), (CAS-No. 274901-16 I0122. In another embodiment of the present invention the 5), DENAGLIPTIN (CAS-No. 483369-58-0), other active compound which is used in the treatment of (CAS-No. 850649-61-5) and P32/98 (CAS-No. 251572-70 diabetes mellitus type 2 and/or type 1 is a fructose-1,6-bis 0). phosphate inhibitor or a pharmaceutically acceptable salt 0113. In another embodiment of the present invention the thereof. An example of a fructose-1,6-bisphosphate inhibitor pharmaceutically acceptable salt of is the includes, but is not limited to MANAGLINAT DIALANETIL phosphate salt of SITAGLIPTIN. In another embodiment of (=MB-06322; CAS-No. 280782-97-0) and MB-05032 (Cas the present invention the pharmaceutically acceptable salt of No. 261365-11-1). ALOGLIPTIN is the benzoate Salt of ALOGLIPTIN. In I0123. In another embodiment of the present invention the another embodiment of the present invention the pharmaceu pharmaceutically acceptable salt of MB-05032 is the hydro tically acceptable salts of P32/98 are the fumarate or hydro bromide Salt of MB-05032. chloride Salt of P32/98. 0.124. In another embodiment of the present invention the 0114. In another embodiment of the present invention the other active compound which is used in the treatment of other active compound which is used in the treatment of diabetes mellitus type 2 and/or type 1 is a cannabinoid (CB1) diabetes mellitus type 2 and/or type 1 is a PDE5 inhibitor or receptor antagonist or a pharmaceutically acceptable salt a pharmaceutically acceptable salt thereof. Specific examples thereof. Specific examples of cannabinoid (CB1) receptor of PDE5 inhibitors include, but are not limited to SILDENA antagonists include, but are not limited to AVE-1625 (CAS FIL (CAS-No. 139755-83-2), VARDENAFIL (CAS-No. No. 261922-46-7), RIMONABANT (CAS-No. 168273-06 224785-90-4), TADALAFIL (CAS-No. 171596-29-5), 1) and SURINABANT (CAS-No. 288104-79-0). UDENAFIL (CAS-No. 268203-93-6) and AVANAFIL 0.125. In another embodiment of the present invention the (CAS-No. 330784-47-9). pharmaceutically acceptable salt of RIMONABANT is the 0115. In another embodiment of the present invention the hydrochloride salt of RIMONABANT. pharmaceutically acceptable salts of SILDENAFIL are the I0126. In another embodiment of the present invention the hemi-citrate, the citrate or the mesilate salt of SILDENAFIL; other active compound which is used in the treatment of particularly preferred is the citrate salt of SILDENAFIL. In diabetes mellitus type 2 and/or type 1 is an anti-obesity drug another embodiment of the present invention the pharmaceu or a pharmaceutically acceptable salt thereof. Specific tically acceptable salts of VARDENAFIL are the mono-hy examples of anti-obesity drugs include, but are not limited to drochloride salt of VARDENAFIL or the dihydrochloride salt HMR-1426 (CAS-No. 262376-75-0), CETILISTAT (CAS

US 2010/01791.31 A1 Jul. 15, 2010 18

TABLE 1-continued

INN or Research Code Structure? Chemical Name SURINABANT C O

N N N1/ N N1

C H CH3

B 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-piperidin-1-yl-1H pyrazole-3-carboxamide HMR-1426 C

S

e HO N

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

HC

CH NH2 C 1-1-(4-chlorophenyl)cyclobutyl-3-methylbutan-1-amine

0129. Additional information with regard to the prepara cially available. The person skilled in the art is familiar with tion, Suitable dosage forms and dose ranges of the glucagon Suitable formulations and dose ranges of this compound. like-peptide-1 receptoragonists listed in Table 1 can be found in the following patents/patent applications: WO0334331, 0.133 Additional information with regard to the prepara EP0981611, WO9808871, WO0104156 and WO03059934. tion, suitable dosage forms and dose ranges of the PPAR 0130. The sulfonylurea agents TOLBUTAMIDE, agonists listed in Table 1 can be found in the following pat , GLIPIZIDE, CARBUTAMIDE, GLISOX ents/patent applications: WO0121602, EP03306228, EPIDE; GLISENTIDE, GLIBORNURIDE, GLIBENCLA EP06581.61, EP0193256, WO973 1907, WOO140169, MIDE, GLIQUIDONE, and GLICLAZIDE WO02100813, EP0604983, EP0745600, WO9615784, listed in Table 1 are commercially available. The person WOO259.098 and EP1183O2O. skilled in the art is familiar with suitable formulations and dose ranges of these compounds. I0134) The metiglinide agents , NATEG 0131 Thebiguanide agent METFORMIN listed in Table 1 LINIDE and MITIGLINIDE listed in Table 1 are commer is commercially available. The person skilled in the art is cially available. The person skilled in the art is familiar with familiar with suitable formulations and dose ranges of this Suitable formulations and dose ranges of this compound. compound. 0.135 Additional information with regard to the prepara 0132) The alpha-glucosidase inhibitors ACARBOSE, tion, suitable dosage forms and dose ranges of the DPP IV MIGLITOL and VOGLIBOSE listed in Table 1 are commer inhibitors listed in Table 1 can be found in the following US 2010/01791.31 A1 Jul. 15, 2010

patents/patent applications: WO03004498, WO0168603, Subcutaneous, intracutaneous, topical, transdermal, intrana WO0034241, WO0302531, WO9961431 and sal, intraperitoneal, rectal or vaginal route, by inhalation or by WO2005095381. insufflation. 0.136 Additional information with regard to the prepara 0146 Tablets, coated tablets (dragees), pills, cachets, cap tion, suitable dosage forms and dose ranges of the PDE5 Sules (caplets), granules, solutions, emulsions and Suspen inhibitors listed in Table 1 can be found in the following sions are e.g. suitable for oral administration. In particular, patents/patent applications: WO0213798, WO0260422, said formulations can be adapted so as to represent, for WO2004082667, WO0027848 and EP1219609. example, an enteric form, an immediate release form, a 0.137 Additional information with regard to the prepara delayed release form, a repeated dose release form, a pro tion, Suitable dosage forms and dose ranges of the amylin longed release form or a Sustained release form. Said forms analogue listed in Table 1 can be found in can be obtained, for example, by coating tablets, by dividing EPO567626. tablets into several compartments separated by layers disin 0.138. Additional information with regard to the prepara tegrating under different conditions (e.g. pH conditions) or by tion, Suitable dosage forms and dose ranges of the glucagon coupling the active compound to a biodegradable polymer. receptor antagonist listed in Table 1 can be found in 0147 Administration by inhalation is preferably made by WO9804528. using an aerosol. The aerosol is a liquid-gaseous dispersion, a 0.139. Additional information with regard to the prepara Solid-gaseous dispersion or a mixed liquid/solid-gaseous dis tion, Suitable dosage forms and dose ranges of the glycogen persion. phosphorylase inhibitor listed in Table 1 can be found in 0.148. The aerosol may be generated by means of aerosol WO9639385. producing devices such as dry powder inhalers (DPIs), pres 0140. Additional information with regard to the prepara surized metered dose inhalers (PMDIs) and nebulizers. tion, Suitable dosage forms and dose ranges of the fructose Depending on the kind of the active compound to be admin 1,6-bisphosphate inhibitors can be found in WO0001495 and istered, the aerosol-producing device can contain the active WOO 147935. compound inform of a powder, a solution or a dispersion. The 0141 Additional information with regard to the prepara powder may contain, for example, one or more of the follow tion, Suitable dosage forms and dose ranges of the cannab ing auxiliaries: carriers, stabilizers and fillers. The Solution inoid (CB1) receptor antagonist listed in Table 1 can be found may contain in addition to the solvent, for example, one or in EP1112251, EP0576357 and WO0046209. more of the following auxiliaries: propellants, solubilizers 0142. Additional information with regard to the prepara (co-solvents), surfactants, stabilizers, buffers, tonicity adjust tion, suitable dosage forms and dose ranges of HMR-1426, ing agents, preservatives and flavorings. The dispersion may CETILISTAT and SIBUTRAMINE listed in Table 1 can be contain in addition to the dispersant, for example, one or more found in the following patents/patent applications: of the following auxiliaries: propellants, Surfactants, stabiliz WO0018749, EP1144395 and EP0397831. ers, buffers, preservatives and flavorings. Examples of carri 0143 “Pharmaceutically acceptable salts' of Compound ers include, but are not limited to, Saccharides, e.g. lactose and A or the other active compound(s) which is (are) used in the glucose. Examples of propellants include, but are not limited treatment of diabetes mellitus type 2 and/or type 1 are not to, fluorohydrocarbons, e.g. 1,1,1,2-tetrafluoroethane and limited to the specific examples given above. The term refers 1.1.1.2.3.3.3-heptafluoropropane. to non-toxic salts of these compounds. These pharmaceuti 014.9 The particle size of the aerosol particles (solid, liq cally acceptable salts are generally prepared by reacting a free uid or solid/liquid particles) is preferably less than 100 um, base with a Suitable organic or inorganic acid or by reacting an more preferably it is in the range of from 0.5 to 10 um, in acid with a suitable organic or inorganic base. Particular particular in the range of from 2 to 6 um (D50 value, measured mention may be made of the pharmaceutically acceptable by laser diffraction). inorganic and organic acids customarily used in pharmacy. 0150. For parenteral modes of administration such as, for Those suitable are in particular water-soluble and water-in example, intravenous, intraarterial, intramuscular, Subcuta soluble acid addition salts with acids such as, for example, neous, intracutaneous and intraperitoneal administration, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric preferably solutions (e.g. sterile solutions, isotonic Solutions) acid, Sulfuric acid, acetic acid, citric acid, D-gluconic acid, are used. They are preferably administered by injection or benzoic acid, 2-(4-hydroxybenzoyl)-benzoic acid, butyric infusion techniques. acid, Sulfosalicylic acid, maleic acid, lauric acid, malic acid, 0151. The pharmaceutical compositions (formulations) fumaric acid, Succinic acid, oxalic acid, tartaric acid, embonic comprising Compound A or a pharmaceutically acceptable acid, Stearic acid, toluenesulfonic acid, methanesulfonic acid salt thereof and/or one or two other active compound(s) or or 1-hydroxy-2-naphthoic acid. As examples of pharmaceu pharmaceutically acceptable salt(s) thereof which is (are) tically acceptable salts with bases may be mentioned the used in the treatment of diabetes mellitus type 2 and/or type 1 lithium, Sodium, potassium, calcium, aluminum, , and at least one pharmaceutically acceptable auxiliary can be titanium, ammonium, meglumine or guanidinium salts. manufactured in a manner known to a person skilled in the art, 0144. It is understood that Compound A and the other e.g. by dissolving, mixing, granulating, dragee-making, levi active compound(s) which is (are) used in the treatment of gating, emulsifying, encapsulating, entrapping or lyophiliz diabetes mellitus type 2 and/or type 1 and their pharmaceu ing processes. tically acceptable salts can also be present in the form of their 0152. As pharmaceutically acceptable auxiliaries, any pharmaceutically acceptable Solvates, and in particular in the auxiliaries known to be suitable for preparing pharmaceutical form of their hydrates. compositions (formulations) can be used. Examples thereof 0145 The combinations according to the invention may be include, but are not limited to, Solvents, excipients, dispers administered by any suitable route, for example, by the oral, ants, emulsifiers, solubilizers, gel formers, ointment bases, Sublingual, buccal, intravenous, intraarterial, intramuscular, antioxidants, preservatives, stabilizers, carriers, fillers, bind US 2010/01791.31 A1 Jul. 15, 2010 20 ers, thickeners, complexing agents, disintegrating agents, pound(s) which is (are) used in the treatment of diabetes buffers, permeation promoters, polymers, lubricants, coating mellitus type 2 and/or type 1 with the norm. agents, propellants, tonicity adjusting agents, Surfactants, 0159. In the case of oral administration of Compound A colorants, flavorings, Sweeteners and dyes. In particular, aux the daily dose for an adult patient for the mono-therapy is in iliaries of a type appropriate to the desired formulation and the range from 0.2 to 30 mg per day, preferably in the range of the desired mode of administration are used. 0.2 to 10 mg per day, more preferably in the range of 0.5 to 5 0153. The preferred mode of administration of the combi mg per day. nations according to the invention depend on the specific 0.160) Further information with regard to the preferred combination partners. routes of administration and typical dosages (for mono 0154 As mentioned above Compound A or a pharmaceu therapy) of the other active compound(s) which is (are) used tically acceptable salt of either may be administered in a in combination with Compound A is summarized in Table 2. variety of forms. These include, for example, liquid, semi 0.161 The proportions in which Compound A or a phar Solid and solid dosage forms, such as liquid solutions (e.g., maceutically acceptable salt thereof and the other active com injectable and infusible solutions), dispersions or Suspen pound(s) or a pharmaceutically acceptable salt thereof may sions, tablets, pills, powders, liposomes or Suppositories. The be used in the pharmaceutical compositions, combinations preferred form depends on the intended mode of administra products or kits according to the invention are variable. tion and the combination partner. Depending on the choice of the Compound A or a pharma 0155 The most preferred mode of administration of Com ceutically acceptable salt thereof and the choice of the other pound A or a pharmaceutically acceptable salt of either is active compound(s) or a pharmaceutically acceptable salt oral. In another preferred embodiment Compound A or a thereof, the weight ratios which may be used within the scope pharmaceutically acceptable salt of either is administered by of the present invention vary on the basis of the different intravenous infusion or injection. In a further embodiment molecular weights of the various compounds and their differ Compound A or a pharmaceutically acceptable salt of either ent potencies. is administered by intramuscular or Subcutaneous injection. 0162. As a general rule, without intended to be limiting, Other routes of administration are also contemplated, includ the pharmaceutical compositions, combination products or ing for example intranasal and transdermal routes, and by kits according to the invention may contain inhalation. Compound A and BIM-51077 in ratios by weight ranging 0156 The preferred mode of administration of the other from 50:1 to 1:2, preferably from 20:1 to 1:1; active compound(s) which is (are) used in combination with Compound A and EXENATIDE in ratios by weight ranging Compound A or a pharmaceutically acceptable salt of either from 500:1 to 25:1, preferably from 200:1 to 50:1, depends on the specific agent. Compound A and LIRAGLUTIDE in ratios by weight rang O157 EXENATIDE, BIM-51077, , ing from 10:1 to 1:1, preferably from 5:1 to 2:1; ZP-10 or PRAMLINTIDE, for example, are preferably Compound A and TOLBUTAMIDE in ratios by weight rang administered via Subcutaneous injection. The preferred mode ing from 1:4000 to 1:100, preferably from 1:1000 to 1:250: of administration of compounds like TOLBUTAMIDE, Compound A and TOLAZAMIDE in ratios by weight rang TOLAZAMIDE, GLIPIZIDE, CARBUTAMIDE, GLISOX ing from 1:300 to 1:20, preferably from 1:150 to 1:50: EPIDE, GLISENTIDE, GLIBORNURIDE, GLIBENCLA Compound A and GLIPIZIDE in ratios by weight ranging MIDE, GLIQUIDONE, GLIMEPIRIDE, GLICLAZIDE, from 1:80 to 1:1, preferably from 1:40 to 1:2: METFORMIN, ACARBOSE, MIGLITOL, VOGLIBOSE, Compound A and GLISOXEPIDE in ratios by weight ranging ROSIGLITAZONE, PIOGLITAZONE, FARGLITAZAR, from 1:32 to 2:1, preferably from 1:10 to 1:1; NAVEGLITAZAR, , RIVOGLITA Compound A and GLIBORNURIDE in ratios by weight ZONE, K-1 11, GW-677954, (-)-HALOFENATE, REPA ranging from 1:150 to 1:3; preferably from 1:50 to 1:6; GLINIDE, NATEGLINIDE, MITIGLINIDE, SITAGLIP Compound A and GLIBENCLAMIDE in ratios by weight TIN, SAXAGLIPTIN, VILDAGLIPTIN, DE-NAGLIPTIN, ranging from 1:20 to 3:1, preferably from 1:5 to 1:1; ALOGLIPTIN, P32/98, SILDENAFIL; VARDENAFIL, Compound A and GLIQUIDONE in ratios by weight ranging TADALAFIL, UDENAFIL, AVANAFIL, BAY-27-9955, from 1:250 to 1:3, preferably from 1:60 to 1:6; INFLIGORIB, MB-06322, MB-05022, AVE-1625, Compound A and GLIMEPIRIDE in ratios by weight ranging RIMONABANT, SURINABANT, HMR-1426, from 1:12 to 5:1, preferably from 1:4 to 2:1; CETILISTAT, SIBUTRAMINE and cinnamon is oral. Fur Compound A and GLICLAZIDE in ratios by weight ranging ther information with regard to the preferred mode of admin from 1:250 to 1:6, preferably from 1:60 to 1:15: istration of the other active agent(s) which is (are) used in Compound A and METFORMIN in ratios by weight ranging combination with Compound Aora pharmaceutically accept from 1:8000 to 1:200, preferably from 1:2000 to 1:500; able salt of either is summarized in Table 2 below. Compound A and ACARBOSE in ratios by weight ranging 0158. As part of the combination therapy according to the from 1:1200 to 1:30, preferably from 1:300 to 1:75; invention Compound A or a pharmaceutically acceptable salt Compound A and MIGLITOL in ratios by weight ranging thereof and the one or two other active compound(s) or phar from 1:600 to 1:30, preferably from 1:150 to 1:75; maceutically acceptable salt(s) thereof which is (are) used in Compound A and VOGLIBOSE in ratios by weight ranging the treatment of diabetes mellitus type 2 and/or type 1 are from 5:1 to 1:2, preferably from 2:1 to 1:1; dosed in an order of magnitude customary for the mono Compound A and in ratios by weight therapy, it more likely being possible, on account of the ranging from 1:10 to 2:1, preferably from 1:5 to 1:1; individual actions, which are mutually positively influencing Compound A and ROSIGLITAZONE in ratios by weight and reinforcing, to reduce the respective doses on the com ranging from 1:16 to 1:1, preferably from 1:8 to 1:2: bined administration of Compound A or a pharmaceutically Compound A and PIOGLITAZONE in ratios by weight rang acceptable salt thereof and the one or two other active com ing from 1:90 to 1:3, preferably from 1:45 to 1:8: US 2010/01791.31 A1 Jul. 15, 2010 21

Compound A and FARGLITAZAR in ratios by weight rang Compound A and SILDENAFIL in ratios by weight ranging ing from 1:20 to 10:1, preferably from 1:10 to 4:1; from 1:200 to 1:10, preferably from 1:100 to 1:25: Compound A and NAVEGLITAZAR in ratios by weight Compound A and VARDENAFIL in ratios by weight ranging ranging from 50:1 to 1:2, preferably from 20:1 to 1:1; from 1:40 to 2:1, preferably from 1:20 to 1:1; Compound A and NETOGLITAZONE in ratios by weight Compound A and TADALAFIL in ratios by weight ranging ranging from 1:100 to 5:1, preferably from 1:50 to 2:1; from 1:40 to 1:2, preferably from 1:20 to 1:5; Compound A and RIVOGLTAZONE in ratios by weight Compound A and UDENAFIL in ratios by weight ranging ranging from 1:20 to 5:1, preferably from 1:10 to 2:1; from 1:400 to 1:20, preferably 1:200 to 1:50: Compound A and K-1 11 in ratios by weight ranging from Compound A and AVANAFIL in ratios by weight ranging 1:40 to 1:2, preferably from 1:20 to 1:5; from 1:600 to 1:10, preferably from 1:300 to 1:25: Compound A and GW-677954 in ratios by weight ranging Compound A and PRIMLINTIDE in ratios by weight ranging from 1:20 to 2:1, preferably from 1:10 to 1:1; from 250:1 to 5:1, preferably from 100:1 to 10:1; Compound A and (-)-HALOFENATE in ratios by weight Compound A and cinnamon in ratios by weight ranging from ranging from 1:2000 to 1:200, preferably from 1:1000 to 1:12000 to 1:200, preferably from 1:6000 to 1:500; 1:500; Compound A and BAY-27-9955 in ratios by weight ranging Compound A and REPAGLINIDE in ratios by weight rang from 1:400 to 1:10, preferably from 1:2000 to 1:25: ing from 1:32 to 10:1, preferably from 1:16 to 4:1; Compound A and NATEGLINIDE in ratios by weight rang Compound A and INGLIFORIB in ratios by weight ranging ing from 1:1000 to 1:40, preferably from 1:500 to 1:100: from 1:100 to 1:4, preferably from 1:50 to 1:10: Compound A and MITIGLINIDE in ratios by weight ranging Compound A and MB-06322 in ratios by weight ranging from 1:250 to 1:8, preferably from 1:120 to 1:20; from 1:1600 to 1:40, preferably from 1:800 to 1:100: Compound A and SITAGLIPTIN in ratios by weight ranging Compound A and AVE-1625 in ratios by weight ranging from from 1:200 to 1:20, preferably from 1:100 to 1:50: 1:20 to 1:2, preferably from 1:10 to 1:5; Compound A and SAXAGLIPTIN in ratios by weight rang Compound A and RIMONABANT in ratios by weight rang ing from 1:20 to 1:2; preferably from 1:10 to 1:2: ing from 1:40 to 1:4, preferably from 1:20 to 1:10: Compound A and VILDAGLIPTIN in ratios by weight rang Compound A and SURINABANT in ratios by weight ranging ing from 1:200 to 1:5, preferably from 1:100 to 1:10: from 1:20 to 2:1, preferably from 1:10 to 1:1; Compound A and DENAGLIPTIN in ratios by weight rang Compound A and CETILISTAT in ratios by weight ranging ing from 1:100 to 1:1, preferably from 1:50 to 1:2: from 1:1800 to 1:25, preferably from 1:900 to 1:60; Compound A and ALOGLIPTIN in ratios by weight ranging Compound A and SIBUTRAMINE in ratios by weight rang from 1:100 to 1:2, preferably from 1:50 to 1:5; ing from 1:30 to 1:2, preferably from 1:15 to 1:5; Compound A and P32/98 in ratios by weight ranging from Corresponding ratios likely may be used in the triple combi 1:200 to 1:6, preferably from 1:100 to 1:15: nations according to the invention.

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 BIM-S1077 Diabetes mellitus type 2 subcutaneous injection 100-800 g EXENATIDE Diabetes mellitus type 2 subcutaneous injection 10-20 Ig LIRAGLUTIDE Diabetes mellitus type 2 subcutaneous injection 0.5-2 mg ALBIGLUTIDE Diabetes mellitus type 2 subcutaneous injection 2-20 g ZP-10 Diabetes mellitus type 2 subcutaneous injection TOLBUTAMIDE Diabetes mellitus type 2 ora 0.5 to 2.0 g LAZAMIDE Diabetes mellitus type 2 ora 100 to 150 mg LIPIZIDE Diabetes mellitus type 2 ora 5 to 40 mg, preferably 5 to 20 mg TAMIDE Diabetes mellitus type 2 ora up to 17 mg/kg SOXEPIDE Diabetes mellitus type 2 ora 2 to 16 mg TIDE Diabetes mellitus type 2 ora BORNURIDE Diabetes mellitus type 2 ora 12.5 to 75 mg BE NC LA. MI DE 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 Diabetes mellitus type 2 ora 30 to 120 mg Diabetes mellitus type 2 ora 1000 to 3800 mg 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 MURAGLITAZAR Diabetes mellitus type 2 oral or by injection 2.5 to 5 mg US 2010/01791.31 A1 Jul. 15, 2010 22

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 ROSIGLITAZONE Diabetes mellitus type 2 ora 4 to 8 ng PIOGLITAZONE Diabetes mellitus type 2 ora 15 to 45 ng FARGLITAZAR Diabetes mellitus type 2 ora OS to 10 ng NAVEGLITAZAR Diabetes mellitus type 2 ora OOO4 to 1.2 ng NETOGLITAZONE Diabetes mellitus type 2 ora 1-SO ng RIVOGLITAZONE Diabetes mellitus type 2 ora 1-10 ng K-111 Diabetes mellitus type 2 ora 10 to 20 ng GW-677954 Diabetes mellitus type 2 ora 25 to 20 ng (-)-Halofenate Diabetes mellitus type 2 ora a1000 ng REPAGLINIDE Diabetes mellitus type 2 ora OS to 16 ng NATEGLINIDE Diabetes mellitus type 2 ora 180 to 540 ng MITIGLINIDE Diabetes mellitus type 2 ora 40 mg/meal SITAGLIPTIN Diabetes mellitus type 2 ora a100 ng SAXAGLIPTIN Diabetes mellitus type 2 ora s10 ng WILDAGLIPTIN Diabetes mellitus type 2 ora 25-100 ng DENAGLIPTIN Diabetes mellitus type 2 ora 5-50 ng ALOGLIPTIN Diabetes mellitus type 2 ora 10-50 ng P3298 Diabetes mellitus type 2 ora 30-100 ng SILDENAFIL Diabetes mellitus type 2 ora SO to 100 ng 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 UDENAFIL Diabetes mellitus type 2 ora 100-200 mg Diabetes mellitus type 1 AVANAFIL Diabetes mellitus type 2 ora 50-300 mg Diabetes mellitus type 1 PRAMLINTIDE Diabetes mellitus type 2 subcutaneous injection 20 to 120 g Diabetes mellitus type 1 cinnamon Diabetes mellitus type 2 ora 1 to 6 g BAY-27-995S Diabetes mellitus type 2 ora 50 to 200 mg INGLIFORIB Diabetes mellitus type 2 ora 20 to 50 mg MB-06322 Diabetes mellitus type 2 ora 200 to 800 mg MB-OSO32 Diabetes mellitus type 2 ora AVE-1625 Diabetes mellitus type 2 ora s10 ng RIMONABANT Diabetes mellitus type 2 ora 2O ng SURINABANT Diabetes mellitus type 2 ora 3 to 10 ng HMR-1426 Diabetes mellitus type 2 ora CETILISTAT Diabetes mellitus type 2 ora 120 to 920 ng SIBUTRAMINE Diabetes mellitus type 2 ora 10 to 15 ng

EXAMPLES TABLE 3-continued (0163 Pre erred combinations TABLE 3 Example Number Combination

Preferred combinations 16 Com Oll A: GLIBENCLAMIDE 17 Com Oll A: GLIQUIDONE Example Number Combination 18 Com Oll A: GLIQUIDONE sodium 19 Com Oll A: GLIMEPIRIDE 1 Compound A* human insulin 2O Com Oll A: GLICLAZIDE 2 Compound A* Insulin analogue 21 Com Oll A: METFORMIN 3 Compound A* BIM-S1077 22 Com Oll A: METFORMIN hydrochloride 4 Compound A* EXENATIDE 23 Com Oll A: ACARBOSE 5 Compound A* LIRAGLUTIDE 24 Com Oll A: MIGLITOL 6 Compound A* ALBIGLUTIDE 7 Compound A* ZP-10 25 Com Oll A: WOGLIBOSE 8 Compound A* TOLBUTAMIDE 26 Com Oll A: MURAGLITAZAR 9 Compound A* TOLBUTAMIDE Sodium 27 Com Oll A: ROSIGLTAZONE 10 Compound A* TOLAZAMIDE 28 Com Oll A: ROSIGLITAZONE maleate 11 Compound A* GLIPIZIDE 29 Com Oll A: PIOGLITAZONE 12 Compound A* CARBUTAMIDE 30 Com Oll A: PIOGLITAZONE dihydrochloride 13 Compound A* GLISOXEPIDE 31 Com Oll A: FARGLITAZAR 14 Compound A* GLISENTIDE 32 Com Oll A: NAVEGLITAZAR 15 Compound A* GLIBORNURIDE 33 Com Oll A: NETOGLITAZONE US 2010/01791.31 A1 Jul. 15, 2010

TABLE 3-continued TABLE 3-continued

Preferred combinations Preferred combinations Example Number Combination Example Number Combination 34 Compound A* RIVOGLITAZONE 60 Compound A* VARDENAFIL hydrochloride 35 Compound A* RIVOGLTAZONE hydrochloride 61 Compound A* VARDENAFIL dihydrochloride 36 Compound A* K-111 62 Compound A* TADALAFIL 37 Compound A* K-111 sodium 63 Compound A* UDENAFIL 38 Compound A* GW-677954 64 Compound A* AVANAFIL 2. I Oll A. REN5. 65 Compound A* AVANAFIL besilate 41 CNN NATELINE 66 Compound A* PRAMLINTIDE OOll 67 Compound A* PRAMLINTIDE acetate 42 Compound A* MITIGLINIDE 68 C A: 42 Compound A* MITIGLINIDE potassium ompound. Inition 44 Compound A* MITIGLINIDE calcium 69 Compound A. R.Y.25 45 Compound A* SITAGLIPTIN 70 Compoun A. INGLIFORIB 46 Compound A* SITAGLIPTIN phosphate 71 Compound A MB-06322 47 Compound A* SAXAGLIPTIN 72 Compound A* MB-OSO32 48 Compound A* WILDAGLIPTIN 73 Compound A* MB-05032 hydrobromide 49 Compound A* DENAGLIPTIN 74 Compound A* AVE-1625 50 Compound A* ALOGLIPTIN 75 Compound A* RIMONABANT 51 Compound A* ALOGLIPTIN benzoate 76 Compound A* RIMONABANT hydrochloride 52 Compound A* P32.98 77 Compound A* SURINABANT 53 Compound A* P3298 fumarate 78 Compound A* HMR-1426 S4 Compoun A. P32/98 hydrochloride 79 Compound A* CETILISTAT 55 Compound A SIPENAFIL 8O Compound A* SIBUTRAMINE 56 Compound A SILDENAFIL citrate 81 Compound A* SIBUTRAMINE hydrochloride 57 Compound A* SILDENAFIL hemi-citrate 58 Compoun A. SILDENAF IL mesilate CompoundA represents Compound A or a pharmaceutically acceptable salt of Compound 59 Compound A WARDENAFIL A, in particular the hydrochloride salt of Compound A.

TABLE 4

Preferred triple combinations: Example Number Triple Combination

82 Compound A* METFORMIN Human Insulin 83 Compound A* METFORMIN hydrochloride Human Insulin 84 Compound A* ROSIGLITAZONE Human Insulin 85 Compound A* ROSIGLITAZONE Human Insulin maleate 86 Compound A* ROSIGLITAZONE METFORMIN 87 Compound A* ROSIGLITAZONE METFORMIN maleate 88 Compound A* ROSIGLITAZONE METFORMIN hydrochloride maleate 89 Compound A* PIOGLITAZONE Insulin 90 Compound A* PIOGLITAZONE Insulin dihyrochloride 91 Compound A* PIOGLITAZONE METFORMIN 92 Compound A* PIOGLITAZONE METFORMIN hydrochloride 93 Compound A* PIOGLITAZONE METFORMIN dihyrochloride 94 Compound A* PIOGLITAZONE METFORMIN hydrochloride dihyrochloride 95 Compound A* GLIMEPIRIDE Insulin 96 Compound A* GLIMEPIRIDE METFORMIN 97 Compound A* GLIMEPIRIDE METFORMIN hydrochloride 98 Compound A* GLIMEPIRIDE ROSIGLITAZONE 99 Compound A* GLIMEPIRIDE ROSIGLTAZONE maleate 100 Compound A* GLIMEPIRIDE PIOGLITAZONE 101 Compound A* GLIMEPIRIDE PIOGLITAZONE dihydrochloride

Compound A represents Compound A or a pharmaceutically acceptable salt of Compound A, in particular the hydro chloride Salt of Compound A. US 2010/01791.31 A1 Jul. 15, 2010 24

Pharmacology 10b-hexahydrophenanthridine-2-ol or a pharmaceutically acceptable salt thereof, one other active compound or a phar Aim of the Study was to Investigate the Influence of a Com maceutically acceptable salt thereof which is used in the bination of RIMONABANT Hydrochloride and Compound treatment of diabetes mellitus type 2 and/or type 1, and at least A on HbA and Glucose Tolerance. one pharmaceutically acceptable auxiliary. Animals 2.-13. (canceled) 0164. Female obese db/db-mice (BKS.Cg/BomTac-m+/+ 14. Pharmaceutical composition according to claim 1 Lepr"), supplied by Taconic Europe (Denmark) were used at wherein the other active compound which is used in the the age of 10-11 weeks. Animals were kept under controlled treatment of diabetes mellitus type 2 and/or type 1 is a sulfo conditions (22°C., 12 h light/12 h dark cycle) and received nylurea agent or a pharmaceutically acceptable salt thereof. standard laboratory chow and water ad libitum. For each 15. Pharmaceutical composition according to claim 14 group a number of 15 animals were used. wherein the Sulfonylurea agent is selected from the group consisting of TOLBUTAMIDE, TOLAZAMIDE, GLIPIZ Experimental Protocol IDE, CARBUTAMIDE, GLISOXEPIDE, GLISENTIDE, GLIBORNURIDE, GLIBENCLAMIDE, GLIQUIDONE 0.165 Animals were treated with Compound A3 mg/kg GLIMEPIRIDE, GLICLAZIDE and the pharmaceutically orally, Suspended in methocel (hypromellose, 4% aqeuous acceptable salts of these compounds. solution). RIMONABANT Hydrochloride 10 mg/kg orally, Suspended in methocel (hypromellose, 4% aqeuous Solution), 16. Pharmaceutical composition, combination according Sequoia Research Products, Pangbourne, UK or a combina to claim 1 wherein the other active compound which is used tion of both once daily for 4 weeks. Vehicle treated animals in the treatment of diabetes mellitus type 2 and/or type 1 is a served as control. HbA levels were analyzed using the biguanide agent or a pharmaceutically acceptable salt Micromat II Hemoglobin A1c Test (Bio-Rad Laboratories thereof. GmbH, 80939 Munchen, Germany). An intraperitoneal glu 17. Pharmaceutical composition according to claim 16 cose tolerance test was performed in 24 h fasted animals. A wherein the biguanide agent is METFORMIN or a pharma glucose bolus (1 g/kg body weight) was administered intra ceutically acceptable salt of this compound. peritoneally. Blood glucose was monitored for the following 18.-19. (canceled) time points: t—-120 min, O min (before glucose administra 20. Pharmaceutical composition according to claim 1 tion), 30 min, 60 min, 90 min, 120 min (after glucose admin wherein the other active compound which is used in the istration). Blood was taken by tail-tip-bleeding (5ul) and was treatment of diabetes mellitus type 2 and/or type 1 is a PPAR determined from hemolysate using an analyzing machine agonist or a pharmaceutically acceptable salt thereof. (Biosen S line, EKF Diagnostic, Germany). Data are given as 21. Pharmaceutical composition according to claim 20 mean+/-SEM. The numbers of animals were 15 per group. wherein the PPAR-agonist is selected from the group consist ing of MURAGLITAZAR, ROSIGLITAZONE, PIOGLITA Results ZONE, FARGLITAZAR, NAVEGLITAZAR, NETOGLI (0166 Treatment with Compound A or RIMONABANT TAZONE, RIVOGLITAZONE, K-1 11, GW-677954, (-)- Hydrochloride alone had no effect on HbA (FIG. 1), the Halofenate and the pharmaceutically acceptable salts of these relevant diagnostic parameter for type 2 diabetes mellitus. In compounds. contrast, the combination of both compounds resulted in a 22.-60. (canceled) decrease of HbA (FIG. 1). Treatment with Compound A or 61. A method for treating diabetes mellitus type 2 and/or RIMONABANT Hydrochloride alone had no effect on glu type 1 comprising administering to a patient in need thereof a cose tolerance (FIG. 2). In contrast, the combination of both pharmaceutical composition comprising a pharmaceutical compounds resulted in an improvement of glucose tolerance formulation including an amount of (2R,4aR1ObR)-6-(2,6- (FIG. 2). Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a, 10b-hexahydrophenanthridine-2-ol or a pharmaceutically CONCLUSION acceptable Salt thereof, an amount of one other active com pound or a pharmaceutically acceptable salt thereof which is (0167. It is shown that a combination of RIMONABANT used in the treatment of diabetes mellitus type 2 and/or type 1, Hydrochloride and Compound A demonstrate over additive wherein the first amount and the second amount together (synergistic) effects in the db/db mice model and therefore comprise an effective amount for the treatment of diabetes Compound A may be a ideal drug for combinational therapy mellitus type 2 and/or type 1, and at least one pharmaceuti to treat type 2 diabetes mellitus. cally acceptable auxiliary. DESCRIPTION OF THE FIGURES 62.-71. (canceled) 72. The method according to claim 61 wherein the other (0168 FIG. 1: Effect of RIMONABANT Hydrochloride, active compound which is used in the treatment of diabetes Compound A and a combination of RIMONABANT Hydro mellitus type 2 and/or type 1 is a Sulfonylurea agent or a chloride and Compound A on HbA indb/db-mice pharmaceutically acceptable salt thereof. (0169 FIG. 2: Effect of RIMONABANT Hydrochloride, 73. The method according to claim 72 wherein the sulfo Compound A and a combination of RIMONABANT Hydro nylurea agent is selected from the group consisting of TOLEB chloride and Compound A on glucose tolerance in dbfdb UTAMIDE, TOLAZAMIDE, GLIPIZIDE, CARBUTA 1C MIDE, GLISOXEPIDE, GLISENTIDE, GLIBORNURIDE, 1. A pharmaceutical composition comprising a pharma GLIBENCLAMIDE, GLIQUIDONE, GLIMEPIRIDE, ceutical formulation including (2R,4aR1ObR)-6-(2,6- GLICLAZIDE and the pharmaceutically acceptable salts of Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a, these compounds. US 2010/01791.31 A1 Jul. 15, 2010

74. The method according to claim 61 wherein the other mellitus type 2 and/or type 1 is a PPAR-agonist or a pharma active compound which is used in the treatment of diabetes ceutically acceptable salt thereof. 79. The method according to claim 78 wherein the PPAR mellitus type 2 and/or type 1 is a biguanide agent or a phar agonist is selected from the group consisting of MURAGLI maceutically acceptable salt thereof. TAZAR, ROSIGLITAZONE, PIOGLITAZONE, FARGLI 75. The method according to claim 74 wherein the bigu TAZAR, NAVEGLITAZAR, REGLITAZAR, anide agent is METFORMIN or a pharmaceutically accept NETOGLITAZONE, RIVOGLITAZONE, K-1 11, able salt of this compound. GW-677954, (-)-Halofenate and the pharmaceutically acceptable salts of these compounds. 76.-77. (canceled) 80-115. (canceled) 78. The method according to claim 61 wherein the other active compound which is used in the treatment of diabetes c c c c c