EP2026798A1

EP2026798A1 - Pharmaceutical compositions comprising cbx cannabinoid receptor modulators and potassium channel modulators

Info

Publication number: EP2026798A1
Application number: EP07728371A
Authority: EP
Inventors: Jochen Solvay Pharma GmbH Patent Dpt-IPSI ANTEL; Peter-Colin Solvay Pharma GmbH Patent Dpt-IPSI GREGORY; Josephus Hubertus Maria Solvay Pharma GmbH Patent Dpt-IPSI LANGE; Michael Solvay Pharma GmbH Patent Dpt-IPSI FIRNGES; Dania Solvay Pharma GmbH Patent Dpt-IPSI REICHE
Original assignee: Solvay Pharmaceuticals GmbH
Current assignee: Abbott Products GmbH
Priority date: 2006-04-27
Filing date: 2007-04-20
Publication date: 2009-02-25
Also published as: AU2007245733A1; MX2008013678A; KR20090007606A; TW200808785A; WO2007125048A1; CA2650566A1; IL194942A0; CN101431998A; EA200802132A1; JP2009534439A; AR060625A1; BRPI0711064A2

Abstract

The invention is directed to pharmaceutical compositions comprising pharmacologically effective quantities of each of a) at least one KATP channel modulator as a first active agent and b) at least one CBx modulator as a second active agent. The invention further relates to the use of such compositions and to methods of treating, preventing, delaying progression of, delaying onset of and/or inhibiting a variety of disease conditions including obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans by administering such compositions to subjects in need thereof. The invention also is directed to processes of manufacturing such compositions.

Description

Pharmaceutical Compositions Comprising CB_x Cannabinoid Receptor Modulators and Potassium Channel Modulators

FIELD OF THE INVENTION

The present invention relates to a novel combination therapy for a variety of disease conditions including obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans. The invention also relates to novel pharmaceutical compositions comprising K_ATP channel modulators and CB_x modulators and the use of said pharmaceutical compositions for the prophylaxis, treatment, delayed progression, delayed onset and/or inhibition of a variety of disease conditions including obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans. The invention also relates to processes for the preparation of such compositions.

BACKGROUND OF THE INVENTION

Obesity according to the present invention is meant to comprise any increase in body fat that results in increased bodyweight, preferably comprising but not limited to the medical definition of obesity. Thus, in accordance with the invention, obesity also comprises non-medical, e.g. cosmetic overweight. The invention thus also relates to non-medical weight loss, such as cosmetic weight loss and includes improving bodily appearance in general. In a more narrowed sense, obesity is usually understood to denominate a body weight more than 20 % above the ideal body weight. Even in this more narrowed sense, obesity is a major health concern in Western societies. It is estimated that about 97 million adults in the United States are overweight or obese. Obesity is largely the result of a positive energy balance as a consequence of increased ratio of caloric intake to energy expenditure. The molecular factors regulating food intake and body weight are incompletely understood, but several genetic factors have been identified.

Epidemiological studies have shown that increasing degrees of overweight and obesity are important predictors of decreased life expectancy. Obesity causes or exacerbates many health problems, both independently and in association with other diseases. The medical problems associated with obesity, which can be serious and life-threatening, generally include hypertension; type Il diabetes mellitus; elevated plasma insulin concentrations; insulin resistance; dyslipidemias; hyperlipidemia; endometrial, breast, prostate and colon cancer; osteoarthritis; respiratory complications, such as obstructive sleep apnea; cholelithiasis; gallstones; arteriosclerosis; heart disease; abnormal heart rhythms; and heart arrythmias. Obesity is further associated with premature death and with a significant increase in mortality and morbidity from stroke, myocardial infarction, congestive heart failure, coronary heart disease, and sudden death.

Obesity is often treated by encouraging patients to lose weight by reducing their food intake or by increasing their exercise level and therefore increasing their energy output. A sustained weight loss of 5% to 10% of body weight has been shown to improve the co-morbidities associated with obesity, such as diabetes and hypertension, and can lead to improvement of obesity-related conditions such as osteoarthritis, sleep apnea and pulmonary and cardiac dysfunction.

Weight loss drugs that are currently used in monotherapy for the treatment of obesity have limited efficacy and significant side effects. During chronic treatment periods of greater than six months the efficacy of most agents decreases yielding no more than 10% body weight loss compared to control. Obese humans can easily mass over 150 kg and would, therefore, need to lose more than 50% of their body mass to return to a normal body mass. The term "metabolic syndrome" is meant to cover a complex of clinical pictures which - besides central obesity - mainly comprises hypertension, in particular arterial hypertension; insulin resistance, in particular type Il diabetes; glucose intolerance; dyslipoproteinaemia, in particular as hypertriglyceridaemia, accompanied by dyslipoproteinaemia occurring with lowered HDL-cholesterol, and also hyperuricaemia, which can lead to gout.

According to information from the American Heart Association, the metabolic syndrome is closely linked to insulin resistance. Some people are genetically predisposed to insulin resistance. Acquired factors, such as excess body fat and physical inactivity, can elicit insulin resistance and the metabolic syndrome in these people. Most people with insulin resistance have central obesity. The biological mechanisms at the molecular level between insulin resistance and metabolic risk factors are not fully understood and appear to be complex. One group of people at risk for developing metabolic syndrome is those with diabetes who have a defect in insulin action and cannot maintain a proper level of glucose in their blood. Another is people, mainly those with high blood pressure, who are non-diabetic and insulin-resistant but who compensate by secreting large amounts of insulin. This condition is known as hyperinsulinemia. A third group is heart attack survivors who, unlike hypertensives, have hyperinsulinemia without having abnormal glucose levels. The metabolic syndrome has become increasingly common in higher developed countries like the United States, where it is estimated that about 20-25 percent of US adults have it. There are no well-accepted criteria for diagnosing the metabolic syndrome. The criteria proposed by the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) are the most current and widely used. According to the ATP III criteria, the metabolic syndrome is identified by the presence of three or more of these following components:

a. Central obesity as measured by waist circumference (Men - Greater than 40 inches; Women - Greater than 35 inches).

b. Fasting blood triglycerides greater than or equal to 150 mg/dL.

c. Blood HDL cholesterol (Men - Less than 40 mg/dL; Women - Less than 50 mg/dL) d. Blood pressure greater than or equal to 130/85 mmHg.

e. Fasting glucose greater than or equal to 1 10 mg/dL.

The term "syndrome X" is closely related to the term "metabolic syndrome" and usually is supposed to denominate the identical disease or condition. According to information from the American Heart Association, the term "Syndrome X" refers, however, additionally to a heart condition where chest pain and electrocardiographic changes that suggest ischemic heart disease are present, but where there are no angiographic findings of coronary disease. Patients with cardiac syndrome X also sometimes have lipid abnormalities.

Therefore, it was an objective of the present invention to provide a more effective and/or more selective therapy for obesity, diabetes mellitus, metabolic syndrome and/or syndrome X.

ATP-sensitive potassium channel (K_ATP channel) modulation has been linked to several potential clinical uses including diabetes, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, hypertension, peripheral vascular disease, cerebral vasospasm, appetite regulation and impotence (ref. Jahangir et al. J. MoI. Cell. Cardiology, 2005, 39, 99-1 12 and references cited therein).

Blockers of Kir6.2/SUR1 K_ATP channels (e.g. repaglinde, tolbutamide and glibenclamide) stimulate insulin release and are used in the treatment of type Il diabetes.

K_ATP channel openers and their potential use in the inhibition of insulin secretion and/or the treatment of metabolic disorders are known e.g. from documents US 6,492,130; WO 02/00223; WO 02/00665 or from R. D. Carr et al., Diabetes 52 (2003) 2513-2518 or J. B. Hansen et al., Current Medicinal Chemistry V\_ (2004) 1595-1615.

The beneficial role of the specific K_ATP channel opener diazoxide in the treatment of i.a. the metabolic syndrome is known e.g. from documents US 5,284,845 or US 6,197,765 or from R. Alemzadeh et al., Endocrinology 133 (2) (1993) 705-712 or R. Alemzadeh et al., Journal of Clinical Endocrinology and Metabolism 83 (6) (1998) 191 1-1915. The K_ATP channel couples glucose metabolism to insulin secretion. Defective regulation of K_ATP channel activity has been reported to contribute to the etiology of type 2 diabetes (ref. Ashcroft, J. Clin. Investig. 2005, 1 15 (8), 2047-2057 and references cited therein). The K_ATP channel is an octameric complex of 4 Kirδ.x (x = 1 or 2) and 4 regulatory SURy subunits (Y = 1 , 2A or 2B). The SUR1 regulatory subunit is in particular found in pancreas and brain (ref. Aguilar-Bryan et al., Science 1995, 268, 423-426). The K_ATP Kir6.2/SUR1 combination exists in the pancreas. Its structure has been determined recently (ref. Mikhailov, EMBO Journal, 2005, 24, (23), 4166-4175). Recent advances in the discovery of ATP-sensitive potassium channel openers have been reviewed (Pirotte et al., Exp Opin. Ther. Patents 2005, 15 (5), 497-504); Hansen, Curr. Med. Chem. 2006, 13, 361-376).

Insulin is the main hormone involved in blood glucose homeostasis. Insulin is involved in the regulation of glycaemia and as a consequence related to type I and type Il diabetes. Additionally, insulin is involved in lipogenesis and weight gain, provoking an anorexigenic action as it provokes a satiety when acting in the brain (ref. Juan-Pico et al., Cell Calcium 2006, 39, 155-163 and references cited therein).

Therefore, the regulation of insulin secretion will be useful in the treatment of diseases such as diabetes type I, diabetes type II, obesity, metabolic syndrome and syndrome X.

The endocannabinoid system (refs. (a) De Petrocellis, L. et al., Br. J. Pharmacol. 2004 141 , 765-774; (b) Di Marzo, V. et al., Nature Rev. Drug Discov. 2004, 3, 771-784; (c) Lambert, D. M. and Fowler, CJ. J. Med. Chem. 2005, 48, 5059-5087) has been reported to play a role in the physiological regulation of food intake, energy balance and glucose and lipid metabolism. The existence of both cannabinoid CB₁ and CB₂ receptors has been demonstrated in the endocrine pancreas. It has been reported that the endogenous CB_1/2 receptor agonist 2-arachidonoyl glycerol (2-AG) (Figure 2) regulates [Ca²⁺], signals in β-cells in the endocrine pancreas through CB₂ receptors and as a consequence (as was concluded by Juan-Pico et al.) it decreases insulin secretion (ref. Juan-Pico et al., Cell Calcium 2006, 39, 155-163). Recent advances in the field of CB₂ receptor ligands have been reviewed by Raitio et al. (Curr. Med. Chem. 2005, 12, 1217-1237).

It has now surprisingly been found that a novel combination therapy which comprises administering a combination of at least one K_ATP channel modulator as a first active agent and at least one CB_x modulator as a second active agent to a patient in need thereof can provide an effective and/or selective therapy for a variety of disease conditions including obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans. More specifically, due to the long term effect of therapy with a K_ATP channel modulator, this new combination therapy is particularly suited for the prophylaxis of diabetes mellitus, metabolic syndrome and/or syndrome X in patients exposed to an elevated risk of acquiring such diseases, like patients with established obesity. However, due to its direct effect on glucose metabolism, the novel combination therapy according to the invention is also well suited to treat type Il diabetes and insulin resistance in patients without concomitant obesity.

SUMMARY OF THE INVENTION

In a first aspect, the present invention relates to a pharmaceutical composition comprising pharmacologically effective quantities of each of:

a) at least one K_ATP channel modulator as a first active agent; and

b) at least one CB_x modulator as a second active agent

wherein the CB_x modulator is selected from the group consisting of CB₁ agonists; CB₂ agonists; CB₂ partial agonists; CB₂ antagonists; CB₂ inverse agonists; and dually acting compounds which are both a CB₁ agonist and a CB₂ agonist; and mixtures thereof.

In a second aspect, the invention also relates to the use of at least one K_ATP channel modulator in combination with at least one CB_x modulator as a second active agent wherein the CB_x modulator is selected from the group consisting of CB₁ agonists; CB₂ agonists; CB₂ partial agonists; CB₂ antagonists; CB₂ inverse agonists; and dually acting compounds which are both a CB₁ agonist and a CB₂ agonist; and mixtures thereof, for the manufacture of a medicament for the prophylaxis, treatment, delayed progression, delayed onset and/or inhibition of a variety of disease conditions including obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans.

In a third aspect, the invention relates to a method of treating, preventing, delaying progression of, delaying onset of and/or inhibiting a variety of disease conditions including obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans comprising administering to a subject in need thereof an effective amount of at least one K_ATP channel modulator in combination with at least one CB_x modulator as a second active agent wherein the CB_x modulator is selected from the group consisting of CB₁ agonists; CB₂ agonists; CB₂ partial agonists; CB₂ antagonists; CB₂ inverse agonists; and dually acting compounds which are both a CB₁ agonist and a CB₂ agonist; and mixtures thereof.

In a fourth aspect, the invention further is directed to processes for the preparation of a medicament comprising the step of combining at least one K_ATP channel modulator with at least one CB_x modulator wherein the CB_x modulator is selected from the group consisting of CB₁ agonists; CB₂ agonists; CB₂ partial agonists; CB₂ antagonists; CB₂ inverse agonists; and dually acting compounds which are both a CB₁ agonist and a CB₂ agonist; and mixtures thereof, and wherein at least one K_ATP channel modulator and the at least one CB_x modulator are present in a combined amount effective for the prophylaxis, treatment, delayed progression, delayed onset and/or inhibition of a variety of disease conditions including obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans. DETAILED DESCRIPTION OF THE INVENTION

Suitable K_ATP channel modulators are preferably compounds selected from the group consisting of: K_ATP channel openers, partial K_ATP channel openers, K_ATP channel closing agents, K_ATp channel blocking agents, and mixtures thereof. Preferred K_ATp channel modulators are compounds which have effects as modulators at the Kir6.2/SUR1 K_ATP channel, at the Kir6.2/SUR2B K_ATP channel, the Kir6.1/ SUR2B K_ATP channel, and/or at the Kir6.2/SUR2A K_ATp channel. Effective are those compounds which exhibit an IC₅₀ value [μmol] of less than 50 in a test for the affinity of the compounds in binding to the sulfonylurea (= SUR) and potassium channel opener site (= KCO) of rat and/or human isoforms of SUR1 and/or SUR2B - e.g. the test model provided below. Compounds with an effect as openers at the Kir6.2/SUR1 K_ATp channel, in particular as selective openers at the Kir6.2/SUR1 K_ATp channel are preferred. A compound with an effect as opener at the Kir6.2/SUR1 K_ATP channel is understood to be selective if its IC₅₀ value at the Kir6.2/SUR1 K_ATp channel, as measured in the aforementioned binding test, is less than half, more preferred only a quarter, of the IC₅₀ value of that same compound at the Kir6.2/SUR2B K_ATp channel, the Kir6.1/SUR2B K_ATP channel, and/or at the Kir6.2/SUR2A K_ATP channel. Specific compounds which are suitable as K_ATP channel openers according to the invention may be selected from the group, but are not limited to the group consisting of pinacidil; cromakalim; diazoxide; BPDZ 44; BPDZ 49; BPDZ 62; BPDZ 73; BPDZ 79; BPDZ 83; BPDZ 109; BPDZ 154; BPDZ 216 (= NNC 55-9216); NN414 (all: see e.g. Hansen et al.); NNC 55-01 18 (see e.g. T.M. Tagmose et al., J. Med. Chem. 47 (2004) 3202- 321 1 ); NNC 55-0462 (see e.g. Hansen et al.), MCC-134 (see e.g. M. J. Coghlan et al., J. Med. Chem. 44 (2001 ) 1627-1653); losimendan; SR 47063, WAY 135201 , and mixtures thereof. Diazoxide; BPDZ 44; BPDZ 62; BPDZ 73; BPDZ 154; BPDZ 216 (= NNC 55-9216); NN414; NNC 55-01 18; NNC 55-0462 and MCC-134 are preferred.

Suitable CB₁ agonists are preferably compounds which bind to and activate the CB₁ receptor. Effective are those compounds which exhibit an IC_5O value [μmol] of more than 50 in a test for the affinity of the compounds in binding to the CB 1 receptor. Suitable CB₂ agonists are preferably compounds which bind to and activate the CB₂ receptor. Effective compounds are those which exhibit an IC₅₀ value [μmol] of more than 50 in a test for the affinity of the compounds in binding to the CB₂ receptor. Specific compounds which are suitable as CB₁ agonists or CB₂ agonists according to the invention may be selected from the group, but are not limited to the group consisting of: L759633; L759656; {4-[4-(1 ,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl]- 6,6-dimethyl-bicyclo-[3.1 .1]hept-2-en-2-yl}-methanol (= HU308); JWH015; (2-iodo-5- nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1 H-indol-3-yl]-methanone (= AM-1241 ); 3-(1 , 1 -dimethyl-butyl)-6,6,9-trimethyl-6a,7, 10,10a-tetrahydro-6H-benzo[c]-chromene (JWH 133); N-adamantantyW-pentyl-δ-phenyl-thiazole^-carboxamide; 6,6,9-trimethyl- 3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol; (bicyclo[2.2.1]hept-2- ylamino)-(5-pentyl-4-phenyl-thiazol-2-yl)-methane; dronabinol; 5-(1 ,1-dimethyl-heptyl)- 2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol (= CP-55,940); (2-methyl-3- morpholin-4-ylmethyl-3,4-dihydro-5-oxa-2a-aza-acenaphthylen-1-yl)-naphthalen-1-yl- methanone (= WIN-55,212-2); HU210; ACEA; ACPA; N-adamantyl-4-pentyl-5-phenyl- thiazole-2-carboxamide; methanandamide; anandamide; 2-arachidonoyl glycerol; 2- icosa-5,8,1 1 ,14-tetraenyloxy-propane-1 ,3-diol (= noladin ether); BAY 38-7271 ; SAB- 378; BAY 59-3074; O-1057; GW-1000; PRS-211375; PRS-21 1359; PRS-21 1355; PRS-21 1096; PXS-2076; AM-577; GW-842166X; and mixtures thereof. Other suitable CB₁ agonists or CB₂ agonists have been described in the literature, for example: Thakur et al., Mini-Rev. Med. Chem. 2005, 5, 631-640; Palmer et al., Chem. Phys. Lipids 2002, 121 , 3-19; Hertzog, Expert Opin. Ther. Patents, 2004, 14, 1435-1452; Huffman, Curr. Med. Chem. 1999, 6, 705-720; Reggio, Curr. Pharm. Des. 2003, 9, 1607-1633; Padgett, Life Sci. 2005, 77, 1767-1798; Goya and Jagerovic, Expert. Opin. Ther. Patents, 2000, 10, 1529-1538.

In a preferred embodiment of the present invention, the CB₂ agonist is a selective CB₂ agonist and is selected from the group, but is not limited to the group consisting of: 3-(1 , 1 -dimethyl-butyl)-6,6,9-trimethyl-6a,7, 10,10a-tetrahydro-6H-benzo[c]chromene (= JWH 133); L759633; L759656; {4-[4-(1 ,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl]-6,6- dimethyl-bicyclo[3.1.1]hept-2-en-2-yl}-methanol (= HU308); JWH015; (2-iodo-5-nitro- phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1 H-indol-3-yl]-methanone (= AM-1241 ); and mixtures thereof. See for additional information on these compounds: L759633, L759656: Br. J. Pharmacol. 1999, 126, 665-672; Proc. Natl. Acad. Sci. USA 2003, 100, 10529-10533; Proc. Natl. Acad. Sci. USA 1999, 96, 14228-14233; Bioorg. Med. Chem. 1999, 7, 2905-2914.

Other suitable CB 1 agonists or CB2 agonists have been claimed and exemplified in other patent applications. Suitable CB₂ antagonists or suitable CB₂ inverse agonists are preferably compounds which bind to the CB2 receptor but do not produce agonistic or partial agonistic effects. Effective are those compounds which exhibit an IC₅₀ value [μmol] of more than 50 in a test for the affinity of the compounds in binding to the CB2 receptor. Specific compounds which are suitable as CB₂ antagonists or suitable CB₂ inverse agonists according to the invention may be selected from the group, but are not limited to the group consisting of: (1 ) compounds described in documents WO01/0588869, PCT/EP2006/060009, WO2004/014825; EP1 142877; US2002/0072529; WO02/062750; US 6,509,352; and (2) compounds selected from the group consisting of: N-{1 ,3,3-Trimethyl-endo-(1 S)-bicyclo[2.2.1]hept-2-yl}-1-[1-(4-methyl)-benzyl-5-(4- chloro-3-methyl-phenyl)-1 H-pyrazol-3-carboxamide (= SR-144528), JTE-907, AM630, and mixtures thereof; and (3) mixtures of compounds selected from (1 ) and (2). Other suitable CB₂ antagonists or suitable CB₂ inverse agonists have been described in the literature, for example: Lavey et al. Bioorg. Med. Chem. Lett. 2005, 15, 783-786; Shankar et al. Bioorg. Med. Chem. Lett. 2005, 15, 4417-4420; Iwamura et al. J. Pharmacol. Exp. Ther. 2001 , 296, 420-425. For more information on CB antagonism as related to inverse agonism and the active/inactive state of CB receptors see Reggio, Curr. Pharm. Des. 2003, 9, 1607-1633; Tuccinardi et al. J. Med. Chem. 2006, 49, 984- 994; Pertwee, Life Sci. 2005, 76, 1307-1324. Other suitable CB₂ antagonists or suitable CB₂ inverse agonists have been claimed and exemplified in other patent applications.

Suitable dually acting compounds which are both a CB₁ agonist and a CB₂ agonist are preferably compounds which bind to the CB 1 as well as to the CB2 receptor. Effective are those compounds which exhibit an IC₅₀ value [μmol] of more than 50 in a test for the affinity of the compounds in binding to the CB 1 as well as to the CB2 receptor. Specific compounds which are suitable as dually acting compounds which are both a CB 1 agonist and a CB2 agonists according to the invention may be selected from the group, but are not limited to the group consisting of: dronabinol; HU210; 2-icosa-5,8,1 1 ,14-tetraenyloxy-propane-1 ,3-diol (= noladin ether); N- adamantantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; and mixtures thereof.

In a preferred embodiment of the present invention, the K_ATP channel modulator is a K_ATP channel opener. CB_x modulator suitable for use as K_ATP channel modulator are selected from, but not limited to the group consisting of: 3-(1 ,1-dimethyl-butyl)-6,6,9-trimethyl-6a,7,10,10a- tetrahydro-6H-benzo[c]chromene; N-Adamantyl-4-pentyl-5-phenyl-thiazole-2- carboxamide; N-{1 ,3,3-Trimethyl-endo-(1 S)-bicyclo[2.2.1]hept-2-yl}-1-[1-(4-methyl)- benzyl-5-(4-chloro-3-methyl-phenyl)-1 H-pyrazol-3-carboxamide; (2-lodo-5-nitro- phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1 H-indol-3-yl]-methanone; {4-[4-(1 ,1-

Dimethyl-heptyl)-2,6-dimethoxy-phenyl]-6,6-dimethyl-bicyclo[3.1.1 ]hept-2-en-2-yl}- methanol; 3-( 1 , 1 -Dimethyl-heptyl)-9-hydroxymethyl-6,6-dimethyl-6a,7, 10, 10a- tetrahydro-6H-enzo[c]chromen-1-ol; lcosa-5,8,1 1 ,14-tetraenoic acid 2-hydroxy-1- hydroxymethyl-ethyl ester; 1 -Aziridin-1 -yl-henicosa-6,9, 12, 15-tetraen-2-one;

Noladineether; 4,4,4-Trifluoro-butane-1-sulfinic acid 3-(2-hydroxymethyl-indan-4-yloxy)- phenyl ester, compound with form aldehyde; 7-Methoxy-2-oxo-8-pentyloxy-1 ,2-dihydro- quinoline-3-carboxylic acid (benzo[1 ,3]dioxol-5-ylmethyl)-amide; N-(1-{4-[4-Chloro-2-(2- fluoro-benzenesulfonyl)-benzenesulfonyl]-phenyl}-ethyl)-methanesulfonamide; [6-lodo- 2-methyl-1-(2-morpholin-4-yl-ethyl)-2,3-dihydro-1 H-indol-3-yl]-(4-methoxy-phenyl)- methanone; 1-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; (2-Methyl-1 -propyl-2,3-dihydro-1 H-indol-3-yl)-naphthalen-1-yl- methanone; 5-(1 ,1-Dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]- phenol; (2-Methyl-3-morpholin-4-ylmethyl-3,4-dihydro-5-oxa-2a-azacenaphthylen-1-yl)- naphthalen-1-yl-methanone; 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide; 5-(4-Bromo-phenyl)-1-(2,4-dichloro- phenyl)-4-ethyl-1 H-pyrazole-3-carboxylic acid piperidin-1-ylamide; 1-[Bis-(4-chloro- phenyl)-methyl]-3-[(3,5-difluoro-phenyl)-methanesulfonyl-methylene]-azetidine; 4-

Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylamino- methylene}-benzenesulfonamide; N-{Amino-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro- pyrazol-1-yl]-methylene}-4-chloro-benzenesulfonamide; N-{[3-(4-Chloro-phenyl)-4- pyridin-3-yl-4,5-dihydro-pyrazol-1-yl]-methylamino-methylene}-4-trifluoromethyl- benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-pyridin-3-yl-4,5-dihydro- pyrazol-1-yl]-methylamino-methylene}-benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro- phenyl)-4-(3-fluoro-phenyl)-4,5-dihydro-pyrazol-1-yl]-methoxyamino-methylene}- benzenesulfonamide; Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5- dihydro-pyrazol-1-yl]-methylamino-methyleneamide; N-{[3-(4-Chloro-phenyl)-4-(3- fluoro-phenyl)-4,5-dihydro-pyrazol-1-yl]-methylamino-methylene}-N,N-dimethyl- sulfonamide; Azepane-1 -sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro- pyrazol-1-yl]-methylamino-methyleneamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl- 4,5-dihydro-pyrazol-1-yl]-[(1-methyl-pyrrolidin-3-ylmethyl)-amino]-methylene}- benzenesulfonamide; 1 -(4-Chloro-phenyl)-5-phenyl-4,5-dihydro-1 H-pyrazole-3- carboxamidine; N-{[3-(4-Chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]- methylamino-methylene}-4-trifluoromethyl-benzene-sulfonamide; Piperidine-1 -sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylamino- methyleneamide; Piperidine-1 -sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro- pyrazol-1-yl]-(2-dimethylamino-ethylamino)-methyleneamide; N,N-Diethylamino-1- sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-methylsulfanyl- methyleneamide; 2-Amino-1-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-3- (3,4-dichloro-phenyl)-propan-1-one; Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4- phenyl-4,5-dihydro-pyrazol-1-yl]-methylamino-methyleneamide; N,N-Dimethylamino-1- sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(2-fluoro- ethylamino)-methyleneamide; Piperidine-1 -sulfonic acid [3-(4-chloro-phenyl)-4-(3- fluoro-phenyl)-4,5-dihydro-pyrazol-1-yl]-methylamino-methyleneamide; 5-(4-Chloro- phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3-carboxylic acid piperidine-1 - ylamide; 1-(4-Chloro-phenyl)-5-phenyl-4,5-dihydro-1 H-pyrazole-3-carboxylic acid piperidin-1-ylamide; Piperidine-1 -sulfonic acid [1-(4-chloro-phenyl)-5-phenyl-4,5- dihydro-1 H-pyrazol-3-yl]-methylamino-metriyleneamide; Morpholine-4-sulfonic acid [1- (2,4-dichloro-phenyl)-5-phenyl-4,5-dihydro-1 H-pyrazol-3-yl]-methylamino- methyleneamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]- (2-fluoro-ethylamino)-methylene]-benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro- phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-fluoro-ethylamino)-methylene]- benzenesulfonamide; N-{Amino-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1- yl]-methylene}-4-chloro-benzenesulfonamide; 4-Chloro-N-[3-(4-chloro-phenyl)-4- phenyl-4,5-dihydro-pyrazole-1-carbonyl]-benzenesulfonamide; 4-Chloro-N-[[3-(4- chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-ethylamino-ethylamino)- methylene]-benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5- dihydro-pyrazol-1-yl]-[(1-metriyl-pyrrolidin-2-ylmetriyl)-amino]-metriylene}- benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1- yl]-(4-pyrrolidin-1-yl-butylamino)-methylene]-benzenesulfonamide; 4-Chloro-N-{[3-(4- chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(pyridin-3-ylmethyl)-amino]- methylene}-benzenesulfonamide; 1-[3-(4-Chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol- 1-yl]-3-(1 H-indol-2-yl)-2-methylamino-propan-1-one; 2-[3-(4-Chloro-phenyl)-4-phenyl- 4,5-dihydro-pyrazol-1-yl]-5-ethyl-4,5-dihydro-oxazole; 4-Chloro-N-[[3-(4-chloro-phenyl)- 4-phenyl-4,5-dihydro-pyrazol-1-yl]-(3-hydroxy-2,2-dimethyl-propylamino)-methylene]- benzenesulfonamide; N,N-Diethylamino-1-sulfonic acid [3-(4-chloro-phenyl)-4-hydroxy- 4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylamino-methyleneamide; 5-(4-Bromo-phenyl)- 1 -(2,4-dichloro-phenyl)-1 H-pyrazole-3-carbonitrile; 8-Chloro-1 -(2,4-dichloro-phenyl)- 1 ,3a, 4, 5, 6, 10b-hexahydro-1 ,2-diaza-benzo[e]azulene-3-carboxylic acid piperidin-1 - ylamide; 5-(4-Bromo-phenyl)-1-(2,4-dichloro-phenyl)-3-[2-(3,5-difluoro-phenyl)-2- methanesulfonyl-vinyl]-4-methyl-1 H-pyrazole; Piperidine-1-carboxylic acid [5-(4-chloro- phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazol-3-yl]-amide; 1-(4-Chloro-phenyl)- 2-(2,4-dichloro-phenyl)-5-ethylsulfanyl-1 H-imidazole-4-carboxylic acid piperidin-1 - ylamide; 2-(2,4-Dichloro-phenyl)-1 -(4-trifluoromethyl-phenyl)-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methylsulfanyl- 1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 1-(4-Chloro-phenyl)-2-(2,4- dichloro-phenyl)-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 1-(4-Chloro- phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid piperidin-1 - ylamide; 1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 1 -(4-Bromo-phenyl)-5-chloro-2-(2,4-dichloro-phenyl)-1 H- imidazole-4-carboxylic acid piperidin-1 -ylamide; 1-(4-Bromo-phenyl)-2-(2,4-dichloro- phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid cyclohexylamide; 1-(4-Bromo-phenyl)-2- (2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid pentylamide; 4-(4-Chloro- phenyl)-5-(2,4-dichloro-phenyl)-1-methyl-1 H-imidazole-2-carboxylic acid cyclohexylamide; 4-(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)-3-methyl-1 H-imidazole-2- carboxylic acid cyclohexylamide; 1-(5-Chloro-pyridin-2-yl)-2-(2,4-dichloro-phenyl)-5- ethyl-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 1-(4-Chloro-phenyl)-2-(2,4- dichloro-phenyl)-5-methyl-1 H-imidazole-4-carboxylic acid (4-hydroxy-cyclo-hexyl)- amide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4-carboxylic acid azepan-1 -ylamide; 2-(2,4-Dichloro-phenyl)-5-ethyl-1-phenyl-1 H-imidazole-4- carboxylic acid piperidin-1 -ylamide; 2-(1 ,5-Dimethyl-1 H-pyrrol-2-yl)-5-ethyl-1-phenyl- 1 H-imidazole-4-carboxylic acid cyclohexylamide; 1-(4-Chloro-phenyl)-5-ethyl-2-(3- methyl-pyridin-2-yl)-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 1-(4-Chloro- phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid piperidin-1 - ylamide; 1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 1 -(4-Bromo-phenyl)-5-chloro-2-(2,4-dichloro-phenyl)-1 H- imidazole-4-carboxylic acid piperidin-1 -ylamide; 1-(4-Bromo-phenyl)-2-(2,4-dichloro- phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid cyclohexylamide; 1-(4-Bromo-phenyl)-2- (2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid pentylamide; 4-(4-Chloro- phenyl)-5-(2,4-dichloro-phenyl)-1-methyl-1 H-imidazole-2-carboxylic acid cyclohexylamide; 4-(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)-3-methyl-1 H-imidazole-2- carboxylic acid cyclohexylamide; 1-(5-Chloro-pyridin-2-yl)-2-(2,4-dichloro-phenyl)-5- ethyl-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Chloro-phenyl)-2-(2,4- dichloro-phenyl)-5-methyl-1 H-imidazole-4-carboxylic acid (4-hydroxy-cyclo-hexyl)- amide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4-carboxylic acid azepan-1-ylamide; 2-(2,4-Dichloro-phenyl)-5-ethyl-1-phenyl-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide; 2-(1 ,5-Dimethyl-1 H-pyrrol-2-yl)-5-ethyl-1-phenyl- 1 H-imidazole-4-carboxylic acid cyclohexylamide; 1-(4-Chloro-phenyl)-5-ethyl-2-(3- methyl-pyridin-2-yl)-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Chloro- phenyl)-5-ethyl-2-(3-methyl-pyridin-2-yl)-1 H-imidazole-4-carboxylic acid cyclohexylamide; 1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- carboxylic acid (4-trifluoromethyl-phenyl)-amide; 2-(2,4-Dichloro-phenyl)-5-methyl-1- pyridin-2-yl-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Chloro-phenyl)-2- (2,4-dichloro-phenyl)-5-fluoromethyl-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-hydroxymethyl-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methylsulfanyl- 1 H-imidazole-4-carboxylic acid cyclohexylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro- phenyl)-5-methanesulfonyl-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 1-(4- Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methanesulfinyl-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 5-(4-Chloro-phenyl)-4-(2,5-dichloro-phenyl)-1 -methyl- 1 H- imidazole-2-carboxylic acid piperidin-1-ylamide; 2-(2-Chloro-phenyl)-1-(5-chloro- py rid in-2-yl )-5-ethy I- 1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Chloro- phenyl)-2-(2, 4-dichloro-phenyl)-5-(2, 2, 2-trifluoro-ethyl)-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; N-[1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H- imidazol-4-yl]-benzamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-pyrrolidin-1- ylmethyl-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 2-[1-(4-Chloro-phenyl)-2- (2,4-dichloro-phenyl)-5-methyl-1 H-imidazol-4-yl]-hexan-2-ol; 1-(4-Chloro-phenyl)-2- (2,4-dichloro-phenyl)-5-methyl-4-pentyl-1 H-imidazole; 2,5-Dimethyl-1-phenyl-1 H- imidazole-4-carboxylic acid adamantan-2-ylamide; 1-(4-Chloro-phenyl)-2-(2-chloro- phenyl)-5-methylsulfanyl-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 2-(2- Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-1 H-imidazole-4-carboxylic acid piperidin-1- ylamide; 5-(4-Chloro-phenyl)-4-(2,4-dichloro-phenyl)-thiazole-2-carboxylic acid piperidin-1-ylamide; 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-1 H-[1 ,2,4]triazole-3- carboxylic acid pyrrolidin-1-ylamide; 1-(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)-1 H- [1 ,2,4]triazole-3-carboxylic acid piperidin-1-yl-amide; 5-Pentyl-4-phenyl-thiazole-2- carboxylic acid (hexahydro-2,5-methano-pentalen-3a-yl)-amide; 4-Pentyl-5-phenyl- thiazole-2-carboxylic acid (hexahydro-2,5-methano-pentalen-3a-yl)-amide; 1-{(4- Chloro-benzene-sulfonylimino)-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]- methyl}-piperidine-4-carboxylic acid amide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl- 4,5-dihydro-pyrazol-1-yl]-[2-(2-oxo-pyrrolidin-1-yl)-ethylamino]-methylene}- benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1- yl]-(2-cyano-ethylamino)-methylene]-benzene-sulfonamide; 4-Chloro-N-[[3-(4-chloro- phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(methoxy-methyl-amino)-methylene]- benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1- yl]-[(piperidin-4-ylmethyl)-amino]-methylene}-benzenesulfonamide; 4-Chloro-N-[[3-(4- chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(piperidin-4-ylamino)-methylene]- benzenesulfonamide; and Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5- dihydro-pyrazol-1-yl]-(cyclopropylmethyl-amino)-methyleneamide.

In another embodiment of the present invention, CB_x modulator suitable as K_ATP channel modulator are selected from the group consisting of: 3-(1 , 1 -dimethyl-butyl)- 6,6,9-trimethyl-6a,7, 10, 10a-tetrahydro-6H-benzo[c]chromene; N-Adamantyl-4-pentyl-5- phenyl-thiazole-2-carboxamide; N-{1 ,3,3-Trimethyl-endo-(1 S)-bicyclo[2.2.1]hept-2-yl}- 1-[1-(4-methyl)-benzyl-5-(4-chloro-3-methyl-phenyl)-1 H-pyrazol-3-carboxamide; (2- lodo-5-nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1 H-indol-3-yl]-methanone; {4-[4- (i .i-Dimethyl-heptyl^.e-dimethoxy-phenyll-e.e-dimethyl-bicycloIS.I .Ilhept^-en^-yl}- methanol; 3-( 1 , 1 -Dimethyl-heptyl)-9-hydroxymethyl-6,6-dimethyl-6a,7, 10, 10a- tetrahydro-6H-enzo[c]chromen-1-ol; lcosa-5,8,1 1 ,14-tetraenoic acid 2-hydroxy-1- hydroxymethyl-ethyl ester; 1 -Aziridin-1 -yl-henicosa-6,9, 12, 15-tetraen-2-one;

Noladineether; 4,4,4-Trifluoro-butane-1-sulfinic acid 3-(2-hydroxymethyl-indan-4-yloxy)- phenyl ester, compound with form aldehyde; 7-Methoxy-2-oxo-8-pentyloxy-1 ,2-dihydro- quinoline-3-carboxylic acid (benzo[1 ,3]dioxol-5-ylmethyl)-amide; N-(1-{4-[4-Chloro-2-(2- fluoro-benzenesulfonyl)-benzenesulfonyl]-phenyl}-ethyl)-methanesulfonamide; [6-lodo- 2-methyl-1-(2-morpholin-4-yl-ethyl)-2,3-dihydro-1 H-indol-3-yl]-(4-methoxy-phenyl)- methanone; 1-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; (2-Methyl-1 -propyl-2,3-dihydro-1 H-indol-3-yl)-naphthalen-1-yl- methanone; 5-(1 ,1-Dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]- phenol; (2-Methyl-3-morpholin-4-ylmethyl-3,4-dihydro-5-oxa-2a-azacenaphthylen-1-yl)- naphthalen-1-yl-methanone; 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide; 5-(4-Bromo-phenyl)-1-(2,4-dichloro- phenyl^-ethyl-I H-pyrazole-S-carboxylic acid piperidin-1-ylamide; 1-[Bis-(4-chloro- phenyl)-methyl]-3-[(3,5-difluoro-phenyl)-methanesulfonyl-methylene]-azetidine.

In another embodiment of the present invention, CB_x modulator suitable as K_ATP channel modulator are selected from the group consisting of: 4-Chloro-N-{[3-(4-chloro- phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylamino-methylene}- benzenesulfonamide; N-{Amino-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1- yl]-methylene}-4-chloro-benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4- pyridin-3-yl-4,5-dihydro-pyrazol-1-yl]-methylamino-methylene}-benzenesulfonamide; 4- Chloro-N-{[3-(4-chloro-phenyl)-4-(3-fluoro-phenyl)-4,5-dihydro-pyrazol-1-yl]- methoxyamino-methylene}-benzenesulfonamide; N-{[3-(4-Chloro-phenyl)-4-(3-fluoro- phenyl)-4,5-dihydro-pyrazol-1-yl]-methylamino-methylene}-N,N-dimethyl-sulfonamide; 5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3-carboxylic acid piperidine-1-ylamide; Morpholine-4-sulfonic acid [1-(2,4-dichloro-phenyl)-5-phenyl-4,5- dihydro-1 H-pyrazol-3-yl]-methylamino-methyleneamide; N-{Amino-[3-(4-chloro-phenyl)- 4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylene}-4-chloro-benzenesulfonamide; 4-Chloro- N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-ethylamino-ethylamino)- methylene]-benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5- dihydro-pyrazol-1-yl]-[(1-methyl-pyrrolidin-2-ylmethyl)-amino]-methylene}- benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1- yl]-[(pyridin-3-ylmethyl)-amino]-methylene}-benzenesulfonamide; 1-(4-Chloro-phenyl)- 2-(2,4-dichloro-phenyl)-5-ethylsulfanyl-1 H-imidazole-4-carboxylic acid piperidin-1 - ylamide; 2-(2,4-Dichloro-phenyl)-1 -(4-trifluoromethyl-phenyl)-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methylsulfanyl- 1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Chloro-phenyl)-2-(2,4- dichloro-phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4- Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid piperidin- 1 -ylamide; 1 -(4-Bromo-phenyl)-5-chloro-2-(2,4-dichloro-phenyl)-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide; 1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl- 1 H-imidazole-4-carboxylic acid pentylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro- phenyl)-5-methyl-1 H-imidazole-4-carboxylic acid azepan-1 -ylamide; 1-(4-Chloro- phenyl)-2-(2,4-dichloro-phenyl)-5-fluoromethyl-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methylsulfanyl-1 H- imidazole-4-carboxylic acid cyclohexylamide; N-[1-(4-Chloro-phenyl)-2-(2,4-dichloro- phenyl)-5-methyl-1 H-imidazol-4-yl]-benzamide; 2-[1 -(4-Chloro-phenyl)-2-(2,4-dichloro- phenyl)-5-methyl-1 H-imidazol-4-yl]-hexan-2-ol; 1-(4-Chloro-phenyl)-2-(2,4-dichloro- phenyl)-5-methyl-4-pentyl-1 H-imidazole; 1 -(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5- methylsulfanyl-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 2-(2-Chloro-phenyl)- 1-(4-trifluoromethyl-phenyl)-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 5-(4- Chloro-phenyl)-4-(2,4-dichloro-phenyl)-thiazole-2-carboxylic acid piperidin-1-ylamide; 1 -(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)-1 H-[1 ,2,4]triazole-3-carboxylic acid piperidin-1 -yl-amide; 1 -{(4-Chloro-benzene-sulfonylimino)-[3-(4-chloro-phenyl)-4- phenyW.δ-dihydro-pyrazol-i-yll-methylJ-piperidine^-carboxylic acid amide; 4-Chloro- N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-[2-(2-oxo-pyrrolidin-1-yl)- ethylamino]-methylene}-benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4- phenyl-4,5-dihydro-pyrazol-1-yl]-(2-cyano-ethylamino)-methylene]-benzene- sulfonamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-

(methoxy-methyl-amino)-methylene]-benzenesulfonamide; Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(cyclopropylmethyl-amino)- methyleneamide.

In another embodiment of the present invention, the at least one K_ATP channel modulator as a first active agent, can act simultaneously as K_ATP channel modulator and at the same time as CB_x modulator and/or the CB_x modulator as a second active agent can act simultaneously as CB_x modulator and at the same time as K_ATP channel modulator, provided that the at least one K_ATP channel modulator as a first active agent and the at least one CB_x modulator as a second active agent are separate, but not identical components of said composition.

In one embodiment, the K_ATP channel modulator and the CB_x modulator as a second active agent are administered simultaneously, sequentially or in a combined dosage form. In another embodiment, the K_ATp channel modulator and the CB_x modulator are administered simultaneously in a fixed combination.

Description of the pharmacological test methods

1. In vitro binding affinity of the test compounds to rodent K_ATP channels

Competitive binding experiments were performed to characterize the affinity of the test compounds for the binding sites for sulfonylureas and K_ATp channel openers (= KCOs) on hamster SUR1. To assess the affinity for the sulfonylurea site membranes from COS-cells transiently expressing hamster SUR1 were incubated in the presence of [³H]glibenclamide with increasing concentrations of test compounds. The affinity for binding to the KCO site was assessed by incubations in the additional presence of 100 μM MgATP (see Schwanstecher M., et al. Naunyn-Schmiedeberg's Arch. Pharmacol. 343 (1991 ) 83-89 and Schwanstecher M. et al., EMBO J. 17 (1998) 5529-5535 (= Schwanstecher et al., 1998)). For each test compound 4 displacement curves were measured (+/- MgATP from the human and hamster isoform). Per curve 9-15 distinct concentrations were tested covering the relevant range. All measurements were repeated at least 5 times in independent experiments.

Similar to SUR1 (see above) competitive binding experiments were performed to characterize the affinity of the test compounds for the binding sites for sulfonylureas and KCOs on rat SUR2A. The affinity for the KCO site on SUR2A was assessed by displacement of [³H]PI 075 (see Schwanstecher et al., 1998; Dόrschner H. et al. MoI. Pharmacol. 55 (1999) 1060-1066 (= Dόrschner et al., 1999)). The affinity of [³H]glibenclamide for the human SUR2 isoforms, however, is too weak to allow direct detection of binding using filtration assays. Therefore, two strategies can be used to detect binding to the sulfonylurea site on SUR2A. First, binding can be detected indirectly through allosteric displacement of [³H]PI 075 (Dόrschner et al., 1999). Second, a mutated SUR2A (SUR2A_Y1205s, see above) with increased affinity for [³H]glibenclamide allowing direct displacement of this tracer can be used. This second approach was chosen to enable discrimination between allosteric and competitive interaction with the KCO site and make sure that binding of ligands which do not induce allosteric displacement are not missed.

Membranes from COS-cells transiently expressing rat SUR2A were incubated in the presence of the radioligands with increasing concentrations of test compounds as described above. The affinity for binding to the KCO site was assessed by incubations in the additional presence of 100 μM MgATP (Schwanstecher et al., 1991 and 1998). For each test compound 4 displacement curves were measured (displacement of [³H]PI 075 from the rat isoform of the wild type receptor and displacement of [³H]glibenclamide from the rat isoform of SUR2A_Y1205s)- Per curve 9-15 distinct concentrations were tested covering the relevant range. All measurements were repeated at least 5 times in independent experiments. [³H]P1075 (specific activity 1 16 Ci mmol^'1) was purchased from Amersham Buchler (Braunschweig, Germany). [³H]glibenclamide (specific activity 51 Ci mmol^'1) was obtained from NEN (Dreieich, Germany). If suitable, stock solutions were prepared in dimethylsulfoxide with a final solvent concentration in the media below 1 %.

SUR- or Kirδ.x isoforms were used either subcloned in the pcDNA (hamster SUR1 , mouse Kir6.2) or pCMV vector (rat SUR2A, SUR2B).

Rodent SUR-isoforms and K_ATP channels were transiently expressed in COS-1 cells as described (see Schwanstecher et al., 1998); Dόrschner et al., 1999); Uhde I. et al. J Biol Chem 274 (1999) 28079-28082; Gross I. et al. MoI. Pharmacol. 56 (1999) 1370-1373; Markworth E., Diabetes 49 (2000) 1413-1418). A mutated form of the SUR2 isoforms with the phenylalanine residue in position 1205 substituted with a serine (SUR2_Y1205s) was used to allow detection of binding to the sulfonylurea site of these isoforms by displacement of [³H]glibenclamide (Uhde I., Dissertation 2001 ). Briefly, COS-1 cells cultured in DMEM HG (10 mM glucose), supplemented with 10 % fetal calf serum (FCS), were plated at a density of 5 x 10⁵ cells per dish (94 mm) and allowed to attach overnight. For transfection the cells were incubated 4 hours in a Tris- buffered salt solution containing DNA (5 - 10 μg/ml) plus DEAE-dextran (1 mg/ml), 2 min in HEPES-buffered salt solution plus dimethylsulfoxide (10 %) and 4 hours in DMEM-HG plus chloroquine (100 μM). Cells were then returned to DMEM-HG plus 10 % FCS. Membranes were prepared 60-72 h post transfection as described (Schwanstecher M. et al., Br. J. Pharmacol. 106 (1992) 295-301 (= Schwanstecher et al., 1992)). For binding experiments resuspended membranes (final protein concentration 5 - 50 μg/ml) were incubated in "Tris-buffer" (50 mM, pH 7.4) containing either [³H]glibenclamide (final concentration 0.3 nM or 3 nM and nonspecific binding defined by 100 nM or 1 μM glibenclamide for SUR1 or SUR2_Y12o₅s-isoforms, respectively) or [³H]PI 075 (final concentration 3 nM, nonspecific binding defined by 100 μM pinacidil) and increasing concentrations of the test compounds. The free Mg²⁺ concentration were kept close to 0.7 mM. ATP (0.1 mM) was added to incubation media to enable KCO (e.g. diazoxide, [³H]PI 075) binding (see Schwanstecher et al., 1998). Incubations were carried out for 1 h at room temperature and were terminated by rapid filtration through Whatman GF/B filters.

Similar to SUR2A (see above) competitive binding experiments were performed to characterize the affinity of the test compounds for the binding sites for sulfonylureas and KCOs on rat SUR2b. The binding protocol for SUR2B is identical with the binding protocol for SUR2A with the exception that cDNA encoding the isoform SUR2B is used for transient expression in COS cells instead of cDNA encoing SUR2A. Ligands and conditions are the same as for SUR2A.

The inhibition constant (Ki value) of the test substances was calculated from the respective IC50 value, and was stated as the negative logarithmised value thereof (pK).

The binding affinity and selectivity of a given compound towards SUR1 and SUR2 can be used as criteria to reflect the modulation of the K-ATP channel (e.g. NN- 414, with a pKi 6.2, is 100 times more potent than diazoxide, with a pKi 3.8, to inhibit glucose-stimulated insulin release). The binding data can be used as first estimate of the potential of a given compound to preserve beta cell function and to prevent or delay the progression of diabetes.

Compound having a pK, (SUR1 ) larger than pK, (SUR2) are particularly preferred for the purposes of the present invention. These compounds include but are not limited to: (4S)-3-(4-chlorophenyl)-N'-[(4-chlorophenyl)sulfonyl]-N-methyl-4-phenyl-4,5- dihydro-1 H-pyrazole-1-carboximid-amide; 5-(1 ,1-dimethylheptyl)-2-[(1 R,2R,5R)-5- hydroxy-2-(3-hydroxypropyl)cyclohexyl]-phenol; (2S)-1-[3-(4-chlorophenyl)-4-phenyl- 4,5-dihydro-1 H-pyrazol-1-yl]-3-(3,4-dichloro-phenyl)-1-oxopropan-2-amine; 3-(4- chlorophenyl)-N'-[(4-chlorophenyl)sulfonyl]-4-phenyl-N-(pyridin-3-ylmethyl)-4,5-dihydro- 1 H-pyrazole-1-carboximidamide; (2S)-1-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-1 H- pyrazol-1-yl]-3-(1 H-indol-3-yl)-N-methyl-1 -oxopropan-2-amine; 2-[3-(4-chlorophenyl)-4- phenyl-4,5-dihydro-1 H-pyrazol-1-yl]-5-ethyl-4,5-dihydro-1 ,3-oxazole; 3-(4- chlorophenyl)-N'-[(4-chlorophenyl)sulfonyl]-N-[(1-methylpyrrolidin-3-yl)-methyl]-4- phenyl-4,5-dihydro-1 H-pyrazole-1 -carboximidamide; 5-(4-bromophenyl)-N-[(4- chlorophenyl)sulfonyl]-1-(2,4-dichlorophenyl)-1 H-pyrazole-3-carboxamide; 8-chloro-1- (2,4-dichlorophenyl)-N-piperidin-1-yl-1 ,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1 ,2- c]pyrazole-3-carboxamide; 1-[bis(4-chlorophenyl)methyl]-3-[(3,5- difluorophenyl)(methylsulfonyl)-methylene]azetidine; 2-{1-[bis(4- chlorophenyl)methyl]azetidin-3-yl}-1 ,2-benzisothiazol-3(2H)-one 1 , 1 -dioxide; 1 -(4- bromophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-N-pentyl-1 H-imidazole-4-carboxamide; 3- (4-chlorophenyl)-N'-[(dimethylamino)sulfonyl]-N-(2-fluoro-ethyl)-4-phenyl-4,5-dihydro- 1 H-pyrazole-1 -carboximidamide; 3-(4-chlorophenyl)-N-methyl-N'-(morpholin-4- ylsulfonyl)-4-phenyl-4,5-dihydro-1 H-pyrazole-1 -carboximidamide; 1-(4-chlorophenyl)-2- (2,4-dichlorophenyl)-N,N-diethyl-1 H-imidazole-4-carboxamide; 3-(4-chlorophenyl)-N'- [(4-chlorophenyl)sulfonyl]-N-methyl-4-pyridin-3-yl-4,5-dihydro-1 H-pyrazole-1- carboximidamide; 1-(4-chlorophenyl)-N-methyl-5-phenyl-N'-(piperidin-1-yl-sulfonyl)-4,5- dihydro-1 H-pyrazole-3-carboximidamide; 1-(4-bromophenyl)-2-(2,4-dichloro-phenyl)-5- ethyl-N-piperidin-1-yl-1 H-imidazole-4-carboxamide; 1-(2,4-dichlorophenyl)-N-methyl-N'- (morpholin-4-ylsulfonyl)-5-phenyl-4,5-dihydro-1 H-pyrazole-3-carboximidamide; 1 -(4- chlorophenyl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-5-(methylthio)-1 H-imidazole-4- carboxamide; 3-(4-chlorophenyl)-N-methyl-4-pyridin-3-yl-N'-{[4-(trifluoromethyl)phenyl]- sulfonyl}-4,5-dihydro-1 H-pyrazole-1 -carboximidamide; N-[1 -(4-chlorophenyl)-2-(2,4-di- chlorophenyl)-5-methyl-1 H-imidazol-4-yl]benzamide; 3-(4-chlorophenyl)-N'-[(dimethyl- amino)sulfonyl]-4-(3-fluorophenyl)-N-methyl-4,5-dihydro-1 H-pyrazole-1 - carboximidamide; 2-[1 -(4-chlorophenyl)-2-(2,4-dichloroprienyl)-5-metriyl-1 H-imidazol-4- yl]hexan-2-ol; 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-4-pentyl-1 H- imidazole; 3-(4-chlorophenyl)-N'-[(4-chloroprienyl)sulfonyl]-4-prienyl-4,5-diriydro-1 H- pyrazole-1 -carboximidamide; (4S)-3-(4-chlorophenyl)-N'-[(4-chlorophenyl)sulfonyl]-4- phenyl-4,5-dihydro-1 H-pyrazole-1 -carboximidamide; and mixtures of any of the above compounds.

2. In vitro binding affinity of the test compounds to CB₁ receptors

The affinity of the compounds of the invention for cannabinoid CB₁ receptors can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB₁ receptor is stably transfected in conjunction with [³H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [³H]-ligand, with or without the addition of compounds of the invention, separation of bound and free ligand is performed by filtration over glassfiber filters. Radioactivity on the filter is measured by liquid scintillation counting.

3. In vitro binding affinity of the test compounds to CB? receptors

The affinity of the compounds of the invention for cannabinoid CB₂ receptors can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB₂ receptor is stably transfected in conjunction with [³H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [³H]-ligand, with or without the addition of compounds of the invention, separation of bound and free ligand is performed by filtration over glassfiber filters. Radioactivity on the filter is measured by liquid scintillation counting.

In vivo and in vitro pharmacological assays related to cannabinoid CB_1/2 receptor neurotransmission have been described in the literature. Some examples are:

• Cannabinoid receptors, Ed. R. G. Pertwee, Academic Press, San Diego, 1995, ISBN 0-12-551460-3

• Grotenhermen, F. (2004) J. Cannabis Therapeutics 4(1 ), 29-77.

In vivo and in vitro pharmacological assays related to cannabinoid CB₂ receptor neurotransmission have been described in the literature. Some examples are:

• Ibrahim, M. M. et al. (2003) Proc. Natl. Acad. Sci. USA 100, 10529-10533

• Hanus, L. et al. (1999) Proc. Natl. Acad. Sci. USA 96, 14228-14233

• Zhang, J. et al. (2003) Eur. J. Neuroscience 17, 2750-2754.

• Klein, T.W. et al. (2003) J. Leukoc. Biol. 74, 486-496

• Shoemaker, J. L. et al. (2005), J. Pharmacol. Exp. Ther. 315, 828-838

• Iwamura, H. et al. (2001 ), J. Pharmacol. Exp. Ther. 296, 420-425.

Table 1 - CB_x modulators with their affinities on the CB 1 and/or CB2 receptor affinities, (cloned human cannabinoid (CB1 and CB2 respectively) receptors expressed in CHO cells according to the procedures described hereinabove), expressed as pK, values. Affinity to compound/name chemical name CB1 ;B2 SUR SUR 1 2

4-Chloro-N-[[3-(4-chloro- phenyl)-4-phenyl-4,5- dihydro-pyrazol-1 -yl]-(2- 7,9 n/a 6,7 5,9 cyano-ethylamino)- methylene]-benzene- sulfonamide

4-Chloro-N-[[3-(4-chloro- phenyl)-4-phenyl-4,5- dihydro-pyrazol-1-yl]- 6,7 n/a 5,9 5,9

(methoxy-methyl-amino)- methylene]- benzenesulfonamide

4-Chloro-N-{[3-(4-chloro- phenyl)-4-phenyl-4,5- dihydro-pyrazol-1 -yl]-[( 8,6 n/a 6,2 4,9 piperidin-4-ylmethyl)- amino]-methylene}- benzenesulfonamide

4-Chloro-N-[[3-(4-chloro- phenyl)-4-phenyl-4,5- dihydro-pyrazol-1-yl]- (piperidin-4-ylamino)- 8,2 n/a 4,5 4,6 methylene]- benzenesulfonamide

Morpholine-4-sulfonic acid

[3-(4-chloro-phenyl)-4- phenyl-4,5-dihydro- pyrazol-1-yl]- 8,5 n/a 6,0 5,7

(cyclopropylmethyl-amino)- methyleneamide

The data in Table 1 demonstrate that the tested CB_x modulators act selectively on the SUR1 subunit and/or on the SUR 2 subunit. 4. Determination of the KATP opening effects of compounds through insulin secretion in rat perifused pancreatic islets

Animals: Male Wistar rats in the weight range 175-200 g were group housed in standard animal cages at a temperature of 21 ±2°C and humidity of 55±10%. Animals were maintained on a 12 h light-dark cycle (lights on 06.00-18.00 h) with free access to standard rodent diet (B&K Universal Ltd standard rat and mouse diet (BK 001 P), Beekay Feeds, B&K Universal Ltd, Hull, East Riding of Yorkshire) and tap water. The rats were accustomed to these conditions for at least one week before experimentation.

Experimental procedures: After the rats were sacrificed, the branch of the bile duct leading to the liver and the duodenal end of the duct in the pancreas were clamped and the pancreas distended by injection of ice-cold 0.9 mg/ml collagenase solution into the bile duct. The pancreas were then removed and incubated statically for 10-12 min at 37°C. Following the incubation, 10 ml of cold buffer was added and the suspension shaken vigorously by hand for 1 min. The islets were allowed to settle for 5 min on ice and washed three times using ice-cold buffer. Well formed and good sized islets from 3 rats were hand-picked (under a low power microscope) and pooled and a final selection of islet transferred to the perifusion apparatus. Oxygenated (95% O₂/5% CO₂) Gey & Gey buffer containing 1 mg/ml bovine serum albumin and 4mM glucose were used throughout the experiment unless otherwise stated (see Dickinson et al. Eur. J. Pharmacol. 1997; 339: 69-76 for further details).

Compounds were either tested at an advised concentration or the solubility was determined in the experimental conditions and a maximum soluble drug concentration used for experiments (DMSO or ethanol will be used as the solvents at a maximum 0.1 % in the assay buffer).

Two experiments were performed in parallel in two identical, independent sets of perifusion apparatus each consisting of sufficient number of chambers. Each chamber was loaded with 20 hand-picked islets. Islets were perifused for an initial 30 min period in media containing 4 mM glucose. Perifusate was then collected at 2 min intervals for the remainder of the experiment. After the first 10 min of the experiment (to collect baseline insulin values), the media in each chamber was switched to one containing 1 1 mM glucose and the relevant drug concentration/vehicle/diazoxide concentration and perifusate collected for a further 62 min to produce a total of 36 fractions for each chamber. Perifusate samples were then pooled to create three samples per chamber as follows: Baseline (4mM): Samples 1-5 (first 10 minutes); 0-30 minutes (1 1 mM glucose): Samples 6-21 ; 30-60 minutes (1 1 mM glucose): Samples 22-36. Perifusate fractions were stored at -75°C until required for insulin assay. Insulin content of fractions were assayed using a 96-well ELISA assay (Mercodia). Initial insulin assays were performed in triplicate on three pooled fractions from each chamber.

Drugs: All chemicals were obtained from Sigma (or other appropriate commercial supplier).

Result: The three islet preparations showed a consistent degree of glucose dependent insulin secretion. The mean insulin secretion at 1 1 mM glucose was 98.3 ± 12.6 pg/islet/min and 130.4 ± 22.0 pg/islet/min at 0-30 and 30-60 minutes, respectively. In the presence of 4 mM glucose this was significantly lower and was 3.8 ± 0.6 pg/islet/min and 3.4 ± 0.1 pg/islet/min at 0-30 and 30-60 minutes, respectively. Thus, insulin secretion was increased by 26 times and 38 times by 1 1 mM glucose at 0-30 and 30-60 minutes, respectively. Data were initially expressed as a simple mean of the three experiments for insulin secretion (pg/islet/min) and multiple t-tests (against the corresponding vehicle time period) used to determine potential significant effects of treatments. Alternatively, data were also calculated as a % vehicle effect for each experimental day. This latter approach was deemed to be the more powerful analysis as it corrected for the day to day variation in insulin release from the islets. Diazoxide significantly inhibited insulin secretion by an average of 55.3% (0-30 min) and 58.9% (30-60 min).

Table 2 - K_ATP channel openers according to the procedure described hereinabove, expressed as % inhibition

This test provides proof that candidate compounds selected on the basis of their affinity for the K_ATP channel do inhibit glucose-stimulated insulin secretion. It can be followed that the candidate compounds function as K_ATP channel openers under the conditions described hereinabove.

The pharmaceutical compositions according to the invention can be prepared in a manner known to those of skill in the art and thus can be obtained as formulations suitable for enteral, such as oral or rectal, administration or parenteral, such as injectable or transdermal, administration to mammals or humans, comprising a therapeutical effective amount of the pharmacologically active agents, alone or in combination with one or more pharmaceutically acceptable excipients, especially suitable for enteral or parenteral application. Pharmaceutical compositions for enteral or parenteral administration, in particular those suitable for oral administration, are preferred and comprise for example unit dosage forms, such as coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared by methods known to those of skill in the art, for example using conventional mixing, granulation, coating, solubilizing or lyophilizing processes. Typical oral formulations include coated tablets, tablets, capsules, syrups, elixirs and suspensions. Capsules may contain the active agents e.g. in form of powders, granules, pellets, beadlets or microtablets. For example, a pharmaceutical composition according to the invention may consist of from about 0.1 % to 90 %, preferably of from about 1 % to about 80 %, of the active agents, the balance being pharmaceutically acceptable excipients. Thus, pharmaceutical compositions for oral use can be obtained by combining the active compounds with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances. Typical injectable formulations include solutions and suspensions. Typical transdermal administration forms comprise e.g. patches, gels, ointments and the like.

The typical pharmaceutically acceptable excipients for use in the formulations described above are exemplified by: sugars such as lactose, sucrose, mannitol and sorbitol; starches such as cornstarch, tapioca starch and potato starch; cellulose and derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationic and anionic surfactants; ethylene glycol polymers; betacyclodextrin; fatty alcohols; and hydrolyzed cereal solids, as well as other non-toxic compatible fillers, binders, disintegrants, agents, e.g. talcum; buffers, preservatives, antioxidants, lubricants, flavoring and the like useful in preparing pharmaceutical formulations.

Example 1 : Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]- 50 mg methylamino-methylene}-benzenesulfonamide

3-(1 , 1 -dimethyl-butyl)-6,6,9-trimethyl-6a,7, 10,10a-tetrahydro-6H- 50 mg benzo[c]chromene (JW133)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 2: Capsules comprising a K_ATP channel modulator and a CB_x modulator

N-{Amino-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]- 50 mg methylene}-4-chloro-benzenesulfonamide

Corn starch 150 mg Lactose 150 mg

Ethyl acetate q.s.

Example 3: Capsules comprising a K_ATP channel modulator and a CB_x modulator

N-{[3-(4-Chloro-phenyl)-4-pyridin-3-yl-4,5-dihydro-pyrazol-1-yl]- 50 mg methylamino-methylene}-4-trifluoromethyl-benzenesulfonamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 4: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-{[3-(4-chloro-phenyl)-4-pyridin-3-yl-4,5-dihydro-pyrazol-1-yl]- 50 mg methylamino-methylene}-benzenesulfonamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 5: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 6: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-{[3-(4-chloro-phenyl)-4-(3-fluoro-phenyl)-4,5-dihydro-pyrazol-1- 50 mg yl]-methoxyamino-methylene}-benzenesulfonamide

N-Adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide 50 mg

Corn starch 150 mg Lactose 150 mg

Ethyl acetate q.s.

Example 7: Capsules comprising a K_ATP channel modulator and a CB_x modulator

N-Adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide 50 mg

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 8: Capsules comprising a K_ATP channel modulator and a CB_x modulator

N-Adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide 50 mg

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 9: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro- 50 mg pyrazol-1-yl]-methylamino-methyleneamide

N-Adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide 50 mg

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 10: Capsules comprising a K_ATP channel modulator and a CB_x modulator

N-{[3-(4-Chloro-phenyl)-4-(3-fluoro-phenyl)-4,5-dihydro-pyrazol-1-yl]- 50 mg methylamino-methylene}-N,N-dimethyl-sulfonamide

N-Adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide 50 mg

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s. Example 1 1 : Capsules comprising a K_ATP channel modulator and a CB_x modulator

Azepane-1 -sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol- 50 mg

1-yl]-methylamino-methyleneamide

N-{1 ,3,3-Trimethyl-endo-(1 S)-bicyclo[2.2.1 ]hept-2-yl}-1 -[1 -(4-methyl)- 50 mg benzyl-5-(4-chloro-3-methyl-phenyl)-1 H-pyrazol-3-carboxamide (SR-

144528)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 12: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(1- 50 mg methyl-pyrrolidin-3-ylmethyl)-amino]-methylene}-benzenesulfonamide

144528)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 13: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-(4-Chloro-phenyl)-5-phenyl-4,5-dihydro-1 H-pyrazole-3-carboxamidine 50 mg

N-{1 ,3,3-Trimethyl-endo-(1 S)-bicyclo[2.2.1 ]hept-2-yl}-1 -[1 -(4-methyl)- 50 mg benzyl-5-(4-chloro-3-methyl-phenyl)-1 H-pyrazol-3-carboxamide (SR- 144528)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 14: Capsules comprising a K_ATP channel modulator and a CB_x modulator

N-{[3-(4-Chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylamino- 50 mg methylene}-4-trifluoromethyl-benzene-sulfonamide

144528) Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 15: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Piperidine-1 -sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro- 50 mg pyrazol-1-yl]-methylamino-methyleneamide

144528)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 16: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Piperidine-1 -sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro- 50 mg pyrazol-1-yl]-(2-dimethylamino-ethylamino)-methyleneamide

(2-lodo-5-nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1 H-indol-3-yl]- 50 mg methanone (AM-1241 )

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 17: Capsules comprising a K_ATP channel modulator and a CB_x modulator

N, N-Diethylamino-1 -sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5- 50 mg dihydro-pyrazol-1-yl]-methylsulfanyl-methyleneamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 18: Capsules comprising a K_ATP channel modulator and a CB_x modulator

2-Amino-1 -[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-3-(3,4- 50 mg dichloro-phenyl)-propan-1-one (2-lodo-5-nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1 H-indol-3-yl]- 50 mg methanone (AM-1241 )

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 19: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 20: Capsules comprising a K_ATP channel modulator and a CB_x modulator

N, N-Dimethylamino-1 -sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5- 50 mg dihydro-pyrazol-1-yl]-(2-fluoro-ethylamino)-methyleneamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 21 : Capsules comprising a K_ATP channel modulator and a CB_x modulator

Piperidine-1 -sulfonic acid [3-(4-chloro-phenyl)-4-(3-fluoro-phenyl)-4,5- 50 mg dihydro-pyrazol-1-yl]-methylamino-methyleneamide

{4-[4-(1 ,1-Dimethyl-heptyl)-2,6-dimethoxy-phenyl]-6,6-dimethyl- 50 mg bicyclo[3.1.1]hept-2-en-2-yl}-methanol (HU-308)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 22: Capsules comprising a K_ATP channel modulator and a CB_x modulator

5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3- 50 mg carboxylic acid piperidine-1-ylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 23: Capsules comprising a K_ATP channel modulator and a CB_x modulator i-^-Chloro-phenyO-S-phenyW.δ-dihydro-I H-pyrazole-S-carboxylic acid 50 mg piperidin-1-ylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 24: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Piperidine-1 -sulfonic acid [1-(4-chloro-phenyl)-5-phenyl-4,5-dihydro-1 H- 50 mg pyrazol-3-yl]-methylamino-methyleneamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 25: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Morpholine-4-sulfonic acid [1-(2,4-dichloro-phenyl)-5-phenyl-4,5-dihydro- 50 mg

1 H-pyrazol-3-yl]-methylamino-methyleneamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 26: Capsules comprising a K_ATP channel modulator and a CB_x modulator 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(2- 50 mg fluoro-ethylamino)-methylene]-benzenesulfonamide

3-(1 , 1 -Dimethyl-heptyl)-9-hydroxymethyl-6,6-dimethyl-6a,7, 10, 10a- 50 mg tetrahydro-eH-enzotφhromen-i-ol (HU-210)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 27: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(2- 50 mg fluoro-ethylamino)-methylene]-benzenesulfonamide

3-(1 , 1 -Dimethyl-heptyl)-9-hydroxymethyl-6,6-dimethyl-6a,7, 10, 10a- 50 mg tetrahydro-6H-enzo[c]chromen-1-ol (HU-210)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 28: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 29: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazole-1-carbonyl]- 50 mg benzenesulfonamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s. Example 30: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(2- 50 mg ethylamino-ethylamino)-methylene]-benzenesulfonamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 31 : Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(1- 50 mg methyl-pyrrolidin-2-ylmethyl)-amino]-methylene}-benzenesulfonamide lcosa-5,8,1 1 ,14-tetraenoic acid 2-hydroxy-1-hydroxymethyl-ethyl ester; 1- 50 mg Aziridin-1 -yl-henicosa-6,9, 12, 15-tetraen-2-one (2-AG)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 32: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(4- 50 mg pyrrolidin-1-yl-butylamino)-methylene]-benzenesulfonamide lcosa-5,8,1 1 ,14-tetraenoic acid 2-hydroxy-1-hydroxymethyl-ethyl ester; 1- 50 mg Aziridin-1 -yl-henicosa-6,9, 12, 15-tetraen-2-one (2-AG)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 33: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]- 50 mg [(pyridin-3-ylmethyl)-amino]-methylene}-benzenesulfonamide lcosa-5,8,1 1 ,14-tetraenoic acid 2-hydroxy-1-hydroxymethyl-ethyl ester; 1- 50 mg Aziridin-1 -yl-henicosa-6,9, 12, 15-tetraen-2-one (2-AG)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s. Example 34: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 35: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-[3-(4-Chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-3-(1 H-indol-2-yl)- 50 mg

2-methylamino-propan-1-one lcosa-5,8,1 1 ,14-tetraenoic acid 2-hydroxy-1-hydroxymethyl-ethyl ester; 1- 50 mg

Aziridin-1 -yl-henicosa-6,9, 12, 15-tetraen-2-one (2-AG)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 36: Capsules comprising a K_ATP channel modulator and a CB_x modulator

2-[3-(4-Chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-5-ethyl-4,5- 50 mg dihydro-oxazole

Noladineether 50 mg

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 37: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(3- 50 mg hydroxy-2,2-dimethyl-propylamino)-methylene]-benzenesulfonamide

Noladineether 50 mg

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s. Example 38: Capsules comprising a K_ATP channel modulator and a CB_x modulator

N, N-Diethylamino-1 -sulfonic acid [3-(4-chloro-phenyl)-4-hydroxy-4-phenyl- 50 mg

4,5-dihydro-pyrazol-1-yl]-methylamino-methyleneamide

Noladineether 50 mg

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 39: Capsules comprising a K_ATP channel modulator and a CB_x modulator 5-(4-Bromo-phenyl)-1-(2,4-dichloro-phenyl)-1 H-pyrazole-3-carbonitrile 50 mg

Noladineether 50 mg

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 40: Capsules comprising a K_ATP channel modulator and a CB_x modulator

8-Chloro-1-(2,4-dichloro-phenyl)-1 ,3a,4,5,6,10b-hexahydro-1 ,2-diaza- 50 mg benzo[e]azulene-3-carboxylic acid piperidin-1-ylamide

Noladineether 50 mg

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 41 : Capsules comprising a K_ATP channel modulator and a CB_x modulator

5-(4-Bromo-phenyl)-1 -(2,4-dichloro-phenyl)-3-[2-(3,5-difluoro-phenyl)-2- 50 mg methanesulfonyl-vinyl]-4-methyl-1 H-pyrazole

4,4,4-Trifluoro-butane-1-sulfinic acid 3-(2-hydroxymethyl-indan-4-yloxy)- 50 mg phenyl ester, compound with form aldehyde (BAY-38-7271 )

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 42: Capsules comprising a K_ATp channel modulator and a CB_x modulator Piperidine-1-carboxylic acid [5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4- 50 mg methyl-1 H-pyrazol-3-yl]-amide 4,4,4-Trifluoro-butane-1-sulfinic acid 3-(2-hydroxymethyl-indan-4-yloxy)- 50 mg phenyl ester, compound with form aldehyde (BAY-38-7271 )

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 43: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-ethylsulfanyl-1 H-imidazole-4- 50 mg carboxylic acid piperidin-1-ylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 44: Capsules comprising a K_ATP channel modulator and a CB_x modulator

2-(2,4-Dichloro-phenyl)-1-(4-trifluoromethyl-phenyl)-1 H-imidazole-4- 50 mg carboxylic acid piperidin-1-ylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 45: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 46: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methylsulfanyl-1 H-imidazole- 50 mg 4-carboxylic acid piperidin-1-ylamide

7-Methoxy-2-oxo-8-pentyloxy-1 ,2-dihydro-quinoline-3-carboxylic acid 50 mg

(benzo[1 ,3]dioxol-5-ylmethyl)-amide (JTE-907)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 47: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-1 H-imidazole-4-carboxylic acid 50 mg piperidin-1-ylamide

7-Methoxy-2-oxo-8-pentyloxy-1 ,2-dihydro-quinoline-3-carboxylic acid 50 mg

(benzo[1 ,3]dioxol-5-ylmethyl)-amide (JTE-907)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 48: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- 50 mg carboxylic acid piperidin-1-ylamide

7-Methoxy-2-oxo-8-pentyloxy-1 ,2-dihydro-quinoline-3-carboxylic acid 50 mg

(benzo[1 ,3]dioxol-5-ylmethyl)-amide (JTE-907)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 49: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1 -(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- 50 mg carboxylic acid piperidin-1-ylamide

7-Methoxy-2-oxo-8-pentyloxy-1 ,2-dihydro-quinoline-3-carboxylic acid 50 mg

(benzo[1 ,3]dioxol-5-ylmethyl)-amide (JTE-907)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 50: Capsules comprising a K_ATP channel modulator and a CB_x modulator 1-(4-Bromo-phenyl)-5-chloro-2-(2,4-dichloro-phenyl)-1 H-imidazole-4- 50 mg carboxylic acid piperidin-1-ylamide

7-Methoxy-2-oxo-8-pentyloxy-1 ^-dihydro-quinoline-S-carboxylic acid 50 mg

(benzo[1 ,3]dioxol-5-ylmethyl)-amide (JTE-907)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 51 : Capsules comprising a K_ATP channel modulator and a CB_x modulator

1 -(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- 50 mg carboxylic acid cyclohexylamide

N-(1-{4-[4-Chloro-2-(2-fluoro-benzenesulfonyl)-benzenesulfonyl]-phenyl}- 50 mg ethyl)-methanesulfonamide (Schering)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 52: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1 -(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- 50 mg carboxylic acid pentylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 53: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)-1-methyl-1 H-imidazole-2- 50 mg carboxylic acid cyclohexylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s. Example 54: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)-3-methyl-1 H-imidazole-2- 50 mg carboxylic acid cyclohexylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 55: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 56: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1 -(5-Chloro-pyridin-2-yl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- 50 mg carboxylic acid piperidin-1-ylamide

[6-lodo-2-methyl-1-(2-morpholin-4-yl-ethyl)-2,3-dihydro-1 H-indol-3-yl]-(4- 50 mg methoxy-phenyl)-methanone (AM-630)

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 57: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- 50 mg carboxylic acid (4-hydroxy-cyclo-hexyl)-amide

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s. Example 58: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- 50 mg carboxylic acid azepan-1-ylamide

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 59: Capsules comprising a K_ATP channel modulator and a CB_x modulator

2-(2,4-Dichloro-phenyl)-5-ethyl-1-phenyl-1 H-imidazole-4-carboxylic acid 50 mg piperidin-1-ylamide

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 60: Capsules comprising a K_ATP channel modulator and a CB_x modulator

2-(1 ,5-Dimethyl-1 H-pyrrol-2-yl)-5-ethyl-1-phenyl-1 H-imidazole-4-carboxylic 50 mg acid cyclohexylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 61 : Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-(4-Chloro-phenyl)-5-ethyl-2-(3-methyl-pyridin-2-yl)-1 H-imidazole-4- 50 mg carboxylic acid piperidin-1-ylamide

1-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-ethyl-1 H-imidazole-4-carboxylic 50 mg acid piperidin-1-ylamide (Bayer)

Corn Starch 150 mg

Lactose 150 mg Ethyl acetate q.s.

Example 62: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 63: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 64: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-(4-Bromo-phenyl)-5-chloro-2-(2,4-dichloro-phenyl)-1 H-imidazole-4- 50 mg carboxylic acid piperidin-1-ylamide

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 65: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Corn starch 150 mg Lactose 150 mg

Ethyl acetate q.s.

Example 66: Capsules comprising a K_ATP channel modulator and a CB_x modulator

(2-Methyl-1 -propyl-2,3-dihydro-1 H-indol-3-yl)-naphthalen-1 -yl-methanone 50 mg

(JWH-015)

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 67: Capsules comprising a K_ATP channel modulator and a CB_x modulator

(JWH-015)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 68: Capsules comprising a K_ATP channel modulator and a CB_x modulator

(JWH-015)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 69: Capsules comprising a K_ATP channel modulator and a CB_x modulator

(JWH-015) Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 70: Capsules comprising a K_ATP channel modulator and a CB_x modulator

(JWH-015)

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 71 : Capsules comprising a K_ATP channel modulator and a CB_x modulator

5-(1 ,1-Dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]- 50 mg phenol (CP55940)

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 72: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 73: Capsules comprising a K_ATP channel modulator and a CB_x modulator

2-(2,4-Dichloro-phenyl)-5-ethyl-1-phenyl-1 H-imidazole-4-carboxylic acid 50 mg piperidin-1-ylamide 5-(1 ,1-Dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]- 50 mg phenol (CP55940)

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 74: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 75: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 76: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-(4-Chloro-phenyl)-5-ethyl-2-(3-methyl-pyridin-2-yl)-1 H-imidazole-4- 50 mg carboxylic acid cyclohexylamide

(2-Methyl-3-morpholin-4-ylmethyl-3,4-dihydro-5-oxa-2a-azacenaphthylen- 50 mg 1-yl)-naphthalen-1-yl-methanone (WIN55212-2)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 77: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- 50 mg carboxylic acid (4-trifluoromethyl-phenyl)-amide

(2-Methyl-3-morpholin-4-ylmethyl-3,4-dihydro-5-oxa-2a-azacenaphthylen- 50 mg

1-yl)-naphthalen-1-yl-methanone (WIN55212-2)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 78: Capsules comprising a K_ATP channel modulator and a CB_x modulator

2-(2,4-Dichloro-phenyl)-5-methyl-1-pyridin-2-yl-1 H-imidazole-4-carboxylic 50 mg acid piperidin-1-ylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 79: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-fluoromethyl-1 H-imidazole-4- 50 mg carboxylic acid piperidin-1-ylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 80: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-hydroxymethyl-1 H-imidazole- 50 mg 4-carboxylic acid piperidin-1-ylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 81 : Capsules comprising a K_ATP channel modulator and a CB_x modulator 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methylsulfanyl-1 H-imidazole- 50 mg 4-carboxylic acid cyclohexylamide

5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3- 50 mg carboxylic acid piperidin-1-ylamide (Rimonabant)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 82: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methanesulfonyl-1 H- 50 mg imidazole-4-carboxylic acid piperidin-1-ylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 83: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methanesulf inyl-1 H- 50 mg imidazole-4-carboxylic acid piperidin-1-ylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 84: Capsules comprising a K_ATP channel modulator and a CB_x modulator

5-(4-Chloro-phenyl)-4-(2,5-dichloro-phenyl)-1-methyl-1 H-imidazole-2- 50 mg carboxylic acid piperidin-1-ylamide

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s. Example 85: Capsules comprising a K_ATP channel modulator and a CB_x modulator

2-(2-Chloro-phenyl)-1-(5-chloro-pyridin-2-yl)-5-ethyl-1 H-imidazole-4- 50 mg carboxylic acid piperidin-1-ylamide

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 86: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-(2,2,2-trifluoro-ethyl)-1 H- 50 mg imidazole-4-carboxylic acid piperidin-1-ylamide

5-(4-Bromo-phenyl)-1 -(2, 4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3- 50 mg carboxylic acid piperidin-1-ylamide (SR-147778)

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 87: Capsules comprising a K_ATP channel modulator and a CB_x modulator

N-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazol-4-yl]- 50 mg benzamide

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 88: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-pyrrolidin-1-ylmethyl-1 H- 50 mg imidazole-4-carboxylic acid piperidin-1-ylamide

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s. Example 89: Capsules comprising a K_ATP channel modulator and a CB_x modulator

2-[1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazol-4-yl]- 50 mg hexan-2-ol

5-(4-Bromo-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3- 50 mg carboxylic acid piperidin-1-ylamide (SR-147778)

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 90: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-4-pentyl-1 H-imidazole 50 mg

Corn Starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 91 : Capsules comprising a K_ATP channel modulator and a CB_x modulator

2,5-Dimethyl-1-phenyl-1 H-imidazole-4-carboxylic acid adamantan-2- 50 mg ylamide

1-[Bis-(4-chloro-phenyl)-methyl]-3-[(3,5-difluoro-phenyl)-methanesulfonyl- 50 mg methylene]-azetidine (Aventis)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 92: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-methylsulfanyl-1 H-imidazole-4- 50 mg carboxylic acid piperidin-1-ylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s. Example 93: Capsules comprising a K_ATP channel modulator and a CB_x modulator

2-(2-Chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-1 H-imidazole-4-carboxylic 50 mg acid piperidin-1-ylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 94: Capsules comprising a K_ATP channel modulator and a CB_x modulator

5-(4-Chloro-phenyl)-4-(2,4-dichloro-phenyl)-thiazole-2-carboxylic acid 50 mg piperidin-1-ylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 95: Capsules comprising a K_ATP channel modulator and a CB_x modulator

5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-1 H-[1 ,2,4]triazole-3-carboxylic 50 mg acid pyrrolidin-1-ylamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 96: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1 -(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)-1 H-[1 ,2,4]triazole-3-carboxylic 50 mg acid piperidin-1-yl-amide

Corn starch 150 mg

Lactose 150 mg Ethyl acetate q.s.

Example 97: Capsules comprising a K_ATP channel modulator and a CB_x modulator δ-PentyW-phenyl-thiazole^-carboxylic acid (hexahydro-2,5-methano- 50 mg pentalen-3a-yl)-amide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 98: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Pentyl-5-phenyl-thiazole-2-carboxylic acid (hexahydro-2,5-methano- 50 mg pentalen-3a-yl)-amide

N-{[3-(4-Chloro-phenyl)-4-pyridin-3-yl-4,5-dihydro-pyrazol-1 -yl]- 50 mg methylamino-methylene}-4-trifluoromethyl-benzenesulfonamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 99: Capsules comprising a K_ATP channel modulator and a CB_x modulator

1 -{(4-Chloro-benzene-sulfonylimino)-[3-(4-chloro-phenyl)-4-phenyl-4,5- 50 mg dihydro-pyrazol-1-yl]-methyl}-piperidine-4-carboxylic acid amide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 100: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-[2-(2- 50 mg oxo-pyrrolidin-1-yl)-ethylamino]-methylene}-benzenesulfonamide

Corn starch 150 mg Lactose 150 mg

Ethyl acetate q.s.

Example 101 : Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(2- 50 mg cyano-ethylamino)-methylene]-benzene-sulfonamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 102: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]- 50 mg

(methoxy-methyl-amino)-methylene]-benzenesulfonamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 103: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]- 50 mg [(piperidin-4-ylmethyl)-amino]-methylene}-benzenesulfonamide

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 104: Capsules comprising a K_ATP channel modulator and a CB_x modulator

4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]- 50 mg (piperidin-4-ylamino)-methylene]-benzenesulfonamide

2-(1 ,5-Dimethyl-1 H-pyrrol-2-yl)-5-ethyl-1-phenyl-1 H-imidazole-4-carboxylic 50 mg acid cyclohexylamide Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 105: Capsules comprising a K_ATP channel modulator and a CB_x modulator

Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro- 50 mg pyrazol-1-yl]-(cyclopropylmethyl-amino)-methyleneamide

1-[3-(4-Chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-3-(1 H-indol-2-yl)- 50 mg 2-methylamino-propan-1-one

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 106: Capsules containing a K_ATP opener and a CB1 agonist

(4S)-3-(4-Chlorophenyl)-N'-[(4-chlorophenyl)sulfonyl]-N-methyl-4-phenyl- 50 mg 4,5-dihydro-1 H-pyrazole-1 -carboximid-amide

N-Adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide 50 mg

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 107: Capsules containing a K_ATP opener and a CB2 agonist

N-(Endo-bicyclo[2.2.1]hept-2-yl)-5-pentyl-4-phenyl-thiazole-2-carboxamide 50 mg

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 108: Capsules containing a K_ATP opener and a selective CB2 agonist

(4S)-3-(4-Chlorophenyl)-N'-[(4-chlorophenyl)sulfonyl]-N-methyl-4-phenyl- 50 mg

4,5-dihydro-1 H-pyrazole-1 -carboximid-amide

{4-[4-(1 ,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl]-6,6-dimethyl- 50 mg bicyclo[3.1.1 ]hept-2-en-2-yl}-methanol (= HU308)

Corn starch 150 mg Lactose 150 mg

Ethyl acetate q.s.

Example 109: Capsules containing a K_ATP opener and a CB2 antagonist

(4S)-3-(4-Chlorophenyl)-N'-[(4-chlorophenyl)sulfonyl]-N-methyl-4-phenyl- 50 mg

4,5-dihydro-1 H-pyrazole-1 -carboximid-amide

N-{1 ,3,3-Trimethyl-endo-(1 S)-bicyclo[2.2.1 ]hept-2-yl}-1 -[1 -(4-methyl)- 50 mg benzyl-5-(4-chloro-3-methyl-phenyl)-1 H-pyrazol-3-carboxamide (=

SR144528)

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

Example 1 10: Capsules containing a K_ATP opener and a dually acting compound which is both a CB₁ agonist and a CB₂ agonist

WIN 55-212-2 50 mg

Corn starch 150 mg

Lactose 150 mg

Ethyl acetate q.s.

For each of the above 1 10 examples, the active agents, the corn starch and the lactose were processed into a homogeneous pasty mixture using ethyl acetate. The paste was grounded and the resulting granules were placed on a suitable tray and dried at 45°C in order to remove the solvent. The dried granules were passed through a crusher and mixed in a mixer with the further following excipients:

Talcum 15 mg

Magnesium stearate 15 mg

Corn starch 20 mg

and then poured into 400 mg capsules (= capsule size 0) to form 1 10 capsules, each having a different composition as disclosed above. In examples number 1 to 105, the first component represents the K_ATP channel modulator as a first active agent; and the second component represents the CB_x modulator as a second active agent, or vice versa, or the K_ATP channel modulator as a first active acts simultaneously as CB_x modulator and wherein the CB_x modulator as a second active acts simultaneously as K_ATP channel modulator provided that the at least one K_ATP channel modulator as a first active agent and the at least one CB_x modulator as a second active agent are not identical.

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference there individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

The use of the terms "a" and "an" and "the" and similar referents in the context of this disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., such as, preferred, preferably) provided herein, is intended merely to further illustrate the content of the disclosure and does not pose a limitation on the scope of the claims. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Alternative embodiments of the claimed invention are described herein, including the best mode known to the inventors for carrying out the claimed invention. Of these, variations of the disclosed embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing disclosure. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein.

Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

The use of individual numerical values are stated as approximations as though the values were preceded by the word "about" or "approximately." Similarly, the numerical values in the various ranges specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges were both preceded by the word "about" or "approximately." In this manner, variations above and below the stated ranges can be used to achieve substantially the same results as values within the ranges. As used herein, the terms "about" and "approximately" when referring to a numerical value shall have their plain and ordinary meanings to a person of ordinary skill in the art to which the claimed subject matter is most closely related or the art relevant to the range or element at issue. The amount of broadening from the strict numerical boundary depends upon many factors. For example, some of the factors which may be considered include the criticality of the element and/or the effect a given amount of variation will have on the performance of the disclosed subject matter, as well as other considerations known to those of skill in the art. As used herein, the use of differing amounts of significant digits for different numerical values is not meant to limit how the use of the words "about" or "approximately" will serve to broaden a particular numerical value. Thus, as a general matter, "about" or "approximately" broaden the numerical value. Also, the disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values plus the broadening of the range afforded by the use of the term "about" or "approximately." Thus, recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it there individually recited herein.

It is to be understood that any ranges, ratios and ranges of ratios that can be formed by, or derived from, any of the data disclosed herein represent further embodiments of the present disclosure and are included as part of the disclosure as though they were explicitly set forth. This includes ranges that can be formed that do or do not include a finite upper and/or lower boundary. Accordingly, a person of ordinary skill in the art most closely related to a particular range, ratio or range of ratios will appreciate that such values are unambiguously derivable from the data presented herein.

Claims

1 . A pharmaceutical composition comprising pharmacologically effective quantities of each of:

a) at least one K_ATP channel modulator as a first active agent; and

b) at least one CB_x modulator as a second active agent

2. Pharmaceutical composition according to Claim 1 , further comprising conventional pharmaceutically acceptable excipient.

3. Pharmaceutical composition according to Claim 1 or Claim 2 which is suitable for oral administration.

4. Pharmaceutical composition according to Claim 3 wherein the active agents are present in one or more dosage form(s) suitable for oral administration selected from the group consisting of tablets, coated tablets, capsules, syrups, elixirs or suspensions.

5. Pharmaceutical composition according to any of the preceding claims wherein the K_ATP channel modulator is selected from the group consisting of: K_ATP channel openers, partial K_ATP channel openers, K_ATP channel closing agents, K_ATP channel blocking agents, and mixtures thereof.

6. Pharmaceutical composition according to any of the preceding claims wherein the K_ATP channel modulator is a modulator of at least one channel selected from the group consisting of: the Kir6.2/SUR1 K_ATP channel, the Kir6.2/SUR2B K_ATP channel, the Kir6.1/SUR2B K_ATP channel, and the Kir6.2/SUR2A K_ATP channel.

7. Pharmaceutical composition according to any of the preceding claims wherein the K_ATP channel modulator is selected from the group consisting of: 3-(1 ,1 - dimethyl-butyl)-6,6,9-trimethyl-6a,7,10,1 Oa-tetrahydro-eH-benzoIcJchromene; N- Adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; N-{1 ,3,3-Trimethyl-endo- (1 S)-bicyclo[2.2.1 ]hept-2-yl}-1 -[1 -(4-methyl)-benzyl-5-(4-chloro-3-methyl-phenyl)- 1 H-pyrazol-3-carboxamide; (2-lodo-5-nitro-phenyl)-[1 -(1 -methyl-piperidin-2- ylmethyl)-1 H-indol-3-yl]-methanone; {4-[4-(1 ,1 -Dimethyl-heptyl)-2,6-dimethoxy- phenyl]-6,6-dimethyl-bicyclo[3.1 .1 ]hept-2-en-2-yl}-methanol; 3-(1 ,1 -Dimethyl- heptyl)-9-hydroxymethyl-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H- enzo[c]chromen-1 -ol; lcosa-5,8,1 1 ,14-tetraenoic acid 2-hydroxy-1 -hydroxymethyl- ethyl ester; 1 -Aziridin-1 -yl-henicosa-6,9,12,15-tetraen-2-one; Noladineether; 4,4,4-Trifluoro-butane-1 -sulfinic acid 3-(2-hydroxymethyl-indan-4-yloxy)-phenyl ester, compound with form aldehyde; 7-Methoxy-2-oxo-8-pentyloxy-1 ,2-dihydro- quinoline-3-carboxylic acid (benzo[1 ,3]dioxol-5-ylmethyl)-amide; N-(1 -{4-[4- Chloro-2-(2-fluoro-benzenesulfonyl)-benzenesulfonyl]-phenyl}-ethyl)- methanesulfonamide; [6-lodo-2-methyl-1 -(2-morpholin-4-yl-ethyl)-2,3-dihydro-1 H- indol-3-yl]-(4-methoxy-phenyl)-methanone; 1 -(4-Chloro-phenyl)-2-(2-chloro- phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; (2-Methyl-1 - propyl-2,3-dihydro-1 H-indol-3-yl)-naphthalen-1 -yl-methanone; 5-(1 ,1 -Dimethyl- heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol; (2-Methyl-3- morpholin-4-ylmethyl-3,4-dihydro-5-oxa-2a-azacenaphthylen-1 -yl)-naphthalen-1 - yl-methanone; 5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-

3-carboxylic acid piperidin-1 -ylamide; 5-(4-Bromo-phenyl)-1 -(2,4-dichloro- phenyl)-4-ethyl-1 H-pyrazole-3-carboxylic acid piperidin-1 -ylamide; 1 -[Bis-(4- chloro-phenyl)-methyl]-3-[(3,5-difluoro-phenyl)-methanesulfonyl-methylene]- azetidine; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]- methylamino-methylenej-benzenesulfonamide; N-{Amino-[3-(4-chloro-phenyl)-4- phenyl-4,5-dihydro-pyrazol-1 -yl]-methylene}-4-chloro-benzenesulfonamide; N-{[3- (4-Chloro-phenyl)-4-pyridin-3-yl-4,5-dihydro-pyrazol-1 -yl]-methylamino- methylene}-4-trifluoromethyl-benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro- phenyl)-4-pyridin-3-yl-4,5-dihydro-pyrazol-1 -yl]-methylamino-methylene}- benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-(3-fluoro-phenyl)-4,5- dihydro-pyrazol-1 -yl]-methoxyamino-methylene}-benzenesulfonamide; Mor- pholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]- methylamino-methyleneamide; N-{[3-(4-Chloro-phenyl)-4-(3-fluoro-phenyl)-4,5- dihydro-pyrazol-1 -yl]-methylamino-methylene}-N,N-dimethyl-sulfonamide; Aze- pane-1 -sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]- methylamino-methyleneamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5- dihydro-pyrazol-1 -yl]-[(1 -methyl-pyrroliclin-3-ylιτiethyl)-amino]-ιτiethylene}- benzenesulfonamide; 1 -(4-Chloro-phenyl)-5-phenyl-4,5-dihydro-1 H-pyrazole-3- carboxamidine; N-{[3-(4-Chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]- methylamino-methylene}-4-trifluoromethyl-benzene-sulfonamide; Piperidine-1 - sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]- methylamino-methyleneamide; Piperidine-1 -sulfonic acid [3-(4-chloro-phenyl)-4- phenyl-4,5-dihydro-pyrazol-1 -yl]-(2-dimethylamino-ethylamino)-methyleneamide; N,N-Diethylamino-1 -sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro- pyrazol-1 -yl]-methylsulfanyl-methyleneamide; 2-Amino-1 -[3-(4-chloro-phenyl)-4- phenyl-4,5-dihydro-pyrazol-1 -yl]-3-(3,4-dichloro-phenyl)-propan-1 -one; Mor- pholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]- methylamino-methyleneamide; N, N-Dimethylamino-1 -sulfonic acid [3-(4-chloro- phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(2-fluoro-ethylamino)-methyleneamide; Piperidine-1 -sulfonic acid [3-(4-chloro-phenyl)-4-(3-fluoro-phenyl)-4,5-dihydro- pyrazol-1 -yl]-methylamino-methyleneamide; 5-(4-Chloro-phenyl)-1 -(2,4-dichloro- phenyl)-4,5-dihydro-1 H-pyrazole-3-carboxylic acid piperidine-1 -ylamide; 1 -(4- Chloro-phenyl)-5-phenyl-4,5-dihydro-1 H-pyrazole-3-carboxylic acid piperidin-1 - ylamide; Piperidine-1 -sulfonic acid [1 -(4-chloro-phenyl)-5-phenyl-4,5-dihydro-1 H- pyrazol-3-yl]-methylamino-metriyleneamide; Morpholine-4-sulfonic acid [1 -(2,4- dichloro-phenyl)-5-phenyl-4,5-dihydro-1 H-pyrazol-3-yl]-metriylamino- methyleneamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol- 1 -yl]-(2-fluoro-ethylamino)-methylene]-benzenesulfonamide; 4-Chloro-N-[[3-(4- chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(2-fluoro-ethylamino)- methylene]-benzenesulfonamide; N-{Amino-[3-(4-chloro-phenyl)-4-phenyl-4,5- dihydro-pyrazol-1 -yl]-methylene}-4-chloro-benzenesulfonamide; 4-Chloro-N-[3-(4- chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazole-1 -carbonyl]-benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(2- ethylamino-ethylamino)-metriylene]-benzenesulfonamide; 4-Chloro-N-{[3-(4- chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-[(1 -methyl-pyrrolidin-2- ylmethyl)-amino]-methylene}-benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro- phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(4-pyrrolidin-1 -yl-butylamino)- methylene]-benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5- dihydro-pyrazol-1 -yl]-[(pyridin-3-ylmethyl)-amino]-methylene}- benzenesulfonamide; 1 -[3-(4-Chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]- 3-(1 H-indol-2-yl)-2-methylamino-propan-1 -one; 2-[3-(4-Chloro-phenyl)-4-phenyl- 4,5-dihydro-pyrazol-1 -yl]-5-ethyl-4,5-dihydro-oxazole; 4-Chloro-N-[[3-(4-chloro- phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(3-hydroxy-2,2-dimethyl-propylamino)- methylene]-benzenesulfonamide; N, N-Diethylamino-1 -sulfonic acid [3-(4-chloro- phenyl)-4-hydroxy-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-methylamino- methyleneamide; 5-(4-Bromo-phenyl)-1 -(2,4-dichloro-phenyl)-1 H-pyrazole-3- carbonitrile; 8-Chloro-1 -(2,4-dichloro-phenyl)-1 ,3a,4,5,6,1 Ob-hexahydro-1 ,2- diaza-benzo[e]azulene-3-carboxylic acid piperidin-1 -ylamide; 5-(4-Bromo- phenyl)-1 -(2,4-dichloro-phenyl)-3-[2-(3,5-difluoro-phenyl)-2-methanesulfonyl- vinyl]-4-methyl-1 H-pyrazole; Piperidine-1 -carboxylic acid [5-(4-chloro-phenyl)-1 -

(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazol-3-yl]-amide; 1 -(4-Chloro-phenyl)-2- (2,4-dichloro-phenyl)-5-ethylsulfanyl-1 H-imidazole-4-carboxylic acid piperidin-1 - ylamide; 2-(2,4-Dichloro-phenyl)-1 -(4-trifluoromethyl-phenyl)-1 H-imidazole-4- carboxylic acid piperidin-1 -ylamide; 1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)- 5-methylsulfanyl-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 1 -(4-Chloro- phenyl)-2-(2,4-dichloro-phenyl)-1 H-imidazole-4-carboxylic acid piperidin-1 - ylamide; 1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid piperidin-1 -ylamide; 1 -(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)- 5-ethyl-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 1 -(4-Bromo-phenyl)- 5-chloro-2-(2,4-dichloro-phenyl)-1 H-imidazole-4-carboxylic acid piperidin-1 - ylamide; 1 -(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid cyclohexylamide; 1 -(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5- ethyl-1 H-imidazole-4-carboxylic acid pentylamide; 4-(4-Chloro-phenyl)-5-(2,4- dichloro-phenyl)-1 -methyl-1 H-imidazole-2-carboxylic acid cyclohexylamide; 4-(4- Chloro-phenyl)-5-(2,4-dichloro-phenyl)-3-methyl-1 H-imidazole-2-carboxylic acid cyclohexylamide; 1 -(5-Chloro-pyridin-2-yl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H- imidazole-4-carboxylic acid piperidin-1 -ylamide; 1 -(4-Chloro-phenyl)-2-(2,4- dichloro-phenyl)-5-methyl-1 H-imidazole-4-carboxylic acid (4-hydroxy-cyclo- hexyl)-amide; 1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole- 4-carboxylic acid azepan-1 -ylamide; 2-(2,4-Dichloro-phenyl)-5-ethyl-1 -phenyl-1 H- imidazole-4-carboxylic acid piperidin-1 -ylamide; 2-(1 ,5-Dimethyl-1 H-pyrrol-2-yl)-5- ethyl-1 -phenyl-1 H-imidazole-4-carboxylic acid cyclohexylamide; 1 -(4-Chloro- phenyl)-5-ethyl-2-(3-methyl-pyridin-2-yl)-1 H-imidazole-4-carboxylic acid piperidin- 1 -ylamide; 1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid piperidin-1 -ylamide; 1 -(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)- 5-ethyl-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 1 -(4-Bromo-phenyl)- 5-chloro-2-(2,4-dichloro-phenyl)-1 H-imidazole-4-carboxylic acid piperidin-1 - ylamide; 1 -(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid cyclohexylamide; 1 -(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5- ethyl-1 H-imidazole-4-carboxylic acid pentylamide; 4-(4-Chloro-phenyl)-5-(2,4- dichloro-phenyl)-1 -methyl-1 H-imidazole-2-carboxylic acid cyclohexylamide; 4-(4- Chloro-phenyl)-5-(2,4-dichloro-phenyl)-3-methyl-1 H-imidazole-2-carboxylic acid cyclohexylamide; 1 -(5-Chloro-pyridin-2-yl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H- imidazole-4-carboxylic acid piperidin-1 -ylamide; 1 -(4-Chloro-phenyl)-2-(2,4- dichloro-phenyl)-5-methyl-1 H-imidazole-4-carboxylic acid (4-hydroxy-cyclo- hexyl)-amide; 1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole- 4-carboxylic acid azepan-1 -ylamide; 2-(2,4-Dichloro-phenyl)-5-ethyl-1 -phenyl-1 H- imidazole-4-carboxylic acid piperidin-1 -ylamide; 2-(1 ,5-Dimethyl-1 H-pyrrol-2-yl)-5- ethyl-1 -phenyl-1 H-imidazole-4-carboxylic acid cyclohexylamide; 1 -(4-Chloro- phenyl)-5-ethyl-2-(3-methyl-pyridin-2-yl)-1 H-imidazole-4-carboxylic acid piperidin-

1 -ylamide; 1 -(4-Chloro-phenyl)-5-ethyl-2-(3-methyl-pyridin-2-yl)-1 H-imidazole-4- carboxylic acid cyclohexylamide; 1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5- methyl-1 H-imidazole-4-carboxylic acid (4-trifluoromethyl-phenyl)-amide; 2-(2,4- Dichloro-phenyl)-5-methyl-1 -pyridin-2-yl-1 H-imidazole-4-carboxylic acid piperidin- 1 -ylamide; 1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-fluoromethyl-1 H- imidazole-4-carboxylic acid piperidin-1 -ylamide; 1 -(4-Chloro-phenyl)-2-(2,4- dichloro-phenyl)-5-hydroxymethyl-1 H-imidazole-4-carboxylic acid piperidin-1 - ylamide; 1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methylsulfanyl-1 H- imidazole-4-carboxylic acid cyclohexylamide; 1 -(4-Chloro-phenyl)-2-(2,4-dichloro- phenyl)-5-methanesulfonyl-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 1 -

(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methanesulfinyl-1 H-imidazole-4- carboxylic acid piperidin-1 -ylamide; 5-(4-Chloro-phenyl)-4-(2,5-dichloro-phenyl)- 1 -methyl-1 H-imidazole-2-carboxylic acid piperidin-1 -ylamide; 2-(2-Chloro-phenyl)- 1 -(5-chloro-pyridin-2-yl)-5-ethyl-1 H-imidazole-4-carboxylic acid piperidin-1 - ylamide; 1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-(2,2,2-trifluoro-ethyl)-1 H- imidazole-4-carboxylic acid piperidin-1 -ylamide; N-[1 -(4-Chloro-phenyl)-2-(2,4- dichloro-phenyl)-5-methyl-1 H-imidazol-4-yl]-benzamide; 1 -(4-Chloro-phenyl)-2- (2,4-dichloro-phenyl)-5-pyrrolidin-1 -ylmethyl-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 2-[1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-1 H- imidazol-4-yl]-hexan-2-ol; 1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-4- pentyl-1 H-imidazole; 2,5-Dimethyl-1 -phenyl-1 H-imidazole-4-carboxylic acid ada- mantan-2-ylamide; 1 -(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-methylsulfanyl-1 H- imidazole-4-carboxylic acid piperidin-1 -ylamide; 2-(2-Chloro-phenyl)-1 -(4- trifluoromethyl-phenyl)-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 5-(4- Chloro-phenyl)-4-(2,4-dichloro-prienyl)-triiazole-2-carboxylic acid piperidin-1 - ylamide; 5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-1 H-[1 ,2,4]triazole-3- carboxylic acid pyrrolidin-1 -ylamide; 1 -(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)- 1 H-[1 ,2,4]triazole-3-carboxylic acid piperidin-1 -yl-amide; 5-Pentyl-4-phenyl- thiazole-2-carboxylic acid (hexahydro-2,5-methano-pentalen-3a-yl)-amide; A- Pentyl-δ-phenyl-thiazole^-carboxylic acid (hexahydro-2,5-methano-pentalen-3a- yl)-amide; 1 -{(4-Chloro-benzene-sulfonylimino)-[3-(4-chloro-prienyl)-4-prienyl-4,5- dihydro-pyrazol-1 -yl]-methyl}-piperidine-4-carboxylic acid amide; 4-Chloro-N-{[3- (4-chloro-phenyl)-4-phenyl-4,5-diriydro-pyrazol-1 -yl]-[2-(2-oxo-pyrrolidin-1 -yl)- ethylamino]-methylene}-benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4- phenyl-4,5-dihydro-pyrazol-1 -yl]-(2-cyano-ethylamino)-methylene]-benzene- sulfonamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-prienyl-4,5-diriydro-pyrazol-1 -yl]- (methoxy-methyl-amino)-metriylene]-benzenesulfonamide; 4-Chloro-N-{[3-(4- chloro-phenyl)-4-phenyl-4,5-diriydro-pyrazol-1 -yl]-[(piperidin-4-ylmetriyl)-amino]- methylenej-benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-prienyl-4,5- dihydro-pyrazol-1 -yl]-(piperidin-4-ylamino)-methylene]-benzenesulfonamide; and

Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 - yl]-(cyclopropylmethyl-amino)-methyleneamide.

8. Pharmaceutical composition according to any of the preceding claims wherein the K_ATP channel modulator is selected from the group consisting of: 3-(1 ,1 - dimethyl-butyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene; N-

Adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; N-{1 ,3,3-Trimethyl-endo- (1 S)-bicyclo[2.2.1 ]hept-2-yl}-1 -[1 -(4-methyl)-benzyl-5-(4-chloro-3-methyl-phenyl)- 1 H-pyrazol-3-carboxamide; (2-lodo-5-nitro-phenyl)-[1 -(1 -methyl-piperidin-2- ylmethyl)-1 H-indol-3-yl]-methanone; {4-[4-(1 ,1 -Dimethyl-heptyl)-2,6-dimethoxy- phenyl]-6,6-dimethyl-bicyclo[3.1 .1 ]hept-2-en-2-yl}-methanol; 3-(1 ,1 -Dimethyl- heptyl)-9-hydroxymethyl-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H- enzo[c]chromen-1 -ol; lcosa-5,8,1 1 ,14-tetraenoic acid 2-hydroxy-1 -hydroxymethyl- ethyl ester; 1 -Aziridin-1 -yl-henicosa-6,9,12,15-tetraen-2-one; Noladineether; 4,4,4-Trifluoro-butane-1 -sulfinic acid 3-(2-hydroxymethyl-indan-4-yloxy)-phenyl ester, compound with form aldehyde; 7-Methoxy-2-oxo-8-pentyloxy-1 ,2-dihydro- quinoline-3-carboxylic acid (benzo[1 ,3]dioxol-5-ylmethyl)-amide; N-(1 -{4-[4- Chloro-2-(2-fluoro-benzenesulfonyl)-benzenesulfonyl]-phenyl}-ethyl)- methanesulfonamide; [6-lodo-2-methyl-1 -(2-morpholin-4-yl-ethyl)-2,3-dihydro-1 H- indol-3-yl]-(4-methoxy-phenyl)-methanone; 1 -(4-Chloro-phenyl)-2-(2-chloro- phenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; (2-Methyl-1 - propyl-2,3-dihydro-1 H-indol-3-yl)-naphthalen-1 -yl-methanone; 5-(1 ,1 -Dimethyl- heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol; (2-Methyl-3- morpholin-4-ylmethyl-3,4-dihydro-5-oxa-2a-azacenaphthylen-1 -yl)-naphthalen-1 - yl-methanone; 5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole- 3-carboxylic acid piperidin-1 -ylamide; 5-(4-Bromo-phenyl)-1 -(2,4-dichloro- phenyl)-4-ethyl-1 H-pyrazole-3-carboxylic acid piperidin-1 -ylamide; 1 -[Bis-(4- chloro-phenyl)-methyl]-3-[(3,5-difluoro-phenyl)-methanesulfonyl-methylene]- azetidine;

9. Pharmaceutical composition according to any of the preceding claims wherein the K_ATP channel modulator is selected from the group consisting of: 4-Chloro-N-

{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-methylamino-methylene}- benzenesulfonamide; N-{Amino-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro- pyrazol-1 -yl]-methylene}-4-chloro-benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro- phenyl)-4-pyridin-3-yl-4,5-dihydro-pyrazol-1 -yl]-methylamino-methylene}- benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-(3-fluoro-phenyl)-4,5- dihydro-pyrazol-1 -yl]-methoxyamino-methylene}-benzenesulfonamide; N-{[3-(4- Chloro-phenyl)-4-(3-fluoro-phenyl)-4,5-dihydro-pyrazol-1 -yl]-methylamino- methylene}-N,N-dimethyl-sulfonamide; 5-(4-Chloro-phenyl)-1 -(2,4-dichloro- phenyl)-4,5-dihydro-1 H-pyrazole-3-carboxylic acid piperidine-1 -ylamide; Mor- pholine-4-sulfonic acid [1 -(2,4-dichloro-phenyl)-5-phenyl-4,5-dihydro-1 H-pyrazol-

3-yl]-methylamino-methyleneamide; N-{Amino-[3-(4-chloro-phenyl)-4-phenyl-4,5- dihydro-pyrazol-1 -yl]-methylene}-4-chloro-benzenesulfonamide; 4-Chloro-N-[[3- (4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(2-ethylamino-ethylamino)- methylene]-benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5- dihydro-pyrazol-1 -yl]-[(1 -methyl-pyrrolidin-2-ylmethyl)-amino]-methylene}- benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro- pyrazol-1 -yl]-[(pyridin-3-ylmethyl)-amino]-methylene}-benzenesulfonamide; 1 -(4- Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-ethylsulfanyl-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 2-(2,4-Dichloro-phenyl)-1 -(4-trifluoromethyl-phenyl)-1 H- imidazole-4-carboxylic acid piperidin-1 -ylamide; 1 -(4-Chloro-phenyl)-2-(2,4- dichloro-phenyl)-5-methylsulfanyl-1 H-imidazole-4-carboxylic acid piperidin-1 - ylamide; 1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid piperidin-1 -ylamide; 1 -(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)- 5-ethyl-1 H-imidazole-4-carboxylic acid piperidin-1 -ylamide; 1 -(4-Bromo-phenyl)- 5-chloro-2-(2,4-dichloro-phenyl)-1 H-imidazole-4-carboxylic acid piperidin-1 - ylamide; 1 -(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid pentylamide; 1 -(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5- methyl-1 H-imidazole-4-carboxylic acid azepan-1 -ylamide; 1 -(4-Chloro-phenyl)-2- (2,4-dichloro-phenyl)-5-fluoromethyl-1 H-imidazole-4-carboxylic acid piperidin-1 - ylamide; 1 -(4-Chloro-phenyl)-2-(2,4-dichloro-prienyl)-5-metriylsulfanyl-1 H- imidazole-4-carboxylic acid cyclohexylamide; N-[1 -(4-Chloro-phenyl)-2-(2,4- dichloro-phenyl)-5-methyl-1 H-imidazol-4-yl]-benzamide; 2-[1 -(4-Chloro-phenyl)-2- (2,4-dichloro-phenyl)-5-methyl-1 H-imidazol-4-yl]-hexan-2-ol; 1 -(4-Chloro-phenyl)- 2-(2,4-dichloro-phenyl)-5-methyl-4-pentyl-1 H-imidazole; 1 -(4-Chloro-phenyl)-2-(2- chloro-phenyl)-5-methylsulfanyl-1 H-imidazole-4-carboxylic acid piperidin-1 - ylamide; 2-(2-Chloro-phenyl)-1 -(4-trifluoromethyl-phenyl)-1 H-imidazole-4- carboxylic acid piperidin-1 -ylamide; 5-(4-Chloro-phenyl)-4-(2,4-dichloro-phenyl)- thiazole-2-carboxylic acid piperidin-1 -ylamide; 1 -(4-Chloro-phenyl)-5-(2,4- dichloro-phenyl)-1 H-[1 ,2,4]triazole-3-carboxylic acid piperidin-1 -yl-amide; 1 -{(4- Chloro-benzene-sulfonylimino)-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-

1 -yl]-methyl}-piperidine-4-carboxylic acid amide; 4-Chloro-N-{[3-(4-chloro- phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-[2-(2-oxo-pyrrolidin-1 -yl)-ethylamino]- methylenej-benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5- dihydro-pyrazol-1 -yl]-(2-cyano-ethylamino)-methylene]-benzene-sulfonamide; 4- Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(metrioxy- methyl-amino)-methylene]-benzenesulfonamide; Morpholine-4-sulfonic acid [3-(4- chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(cyclopropylmethyl-amino)- methyleneamide.

10. Pharmaceutical composition according to any of the preceding claims wherein the K_ATP channel modulator is a K_ATP channel opener and is selected from the group consisting of pinacidil; cromakalim; diazoxide; BPDZ 44; BPDZ 49; BPDZ 62; BPDZ 73; BPDZ 79; BPDZ 83; BPDZ 109; BPDZ 154; BPDZ 216 (= NNC 55- 9216); NN414; NNC 55-01 18; NNC 55-0462; MCC-134; losimendan; SR 47063; WAY 135201 ; and mixtures thereof.

1 1 . Pharmaceutical composition according to any of the preceding claims wherein the CB₁ agonist or CB₂ agonist is selected from the group consisting of: L759633; L759656; {4-[4-(1 ,1 -dimethyl-heptyl)-2,6-dimetrioxy-prienyl]-6,6-climetriyl-bicyclo- [3.1 .1 ]hept-2-en-2-yl}-methanol (= HU308); JWH015; (2-iodo-5-nitro-phenyl)-[1 - (1 -methyl-piperidin-2-ylmethyl)-1 H-indol-3-yl]-methanone (= AM-1241 ); 3-(1 ,1 - dimethyl-butyO-e.e^-trimethyl-ea.yj CI Oa-tetrahydro-eH-benzoIcJ-chromene (JWH133); N-adamantantyM-pentyl-δ-phenyl-thiazole^-carboxamide; 6,6,9- trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1 -ol; (bicy- clo[2.2.1 ]hept-2-ylamino)-(5-pentyl-4-phenyl-thiazol-2-yl)-methane; dronabinol; 5- (I J -dimethyl-heptyO^-β-hydroxy^-β-hydroxy-propyO-cyclohexylJ-phenol (= CP-

55,940); (2-methyl-3-morpholin-4-ylmethyl-3,4-dihydro-5-oxa-2a-aza- acenaphthylen-1 -yl)-naphthalen-1 -yl-methanone (= WIN-55,212-2); HU210; ACEA; ACPA; N-adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; methan- andamide; anandamide; 2-arachidonoyl glycerol; 2-icosa-5,8,1 1 ,14-tetraenyloxy- propane-1 ,3-diol (= noladin ether); BAY 38-7271 ; SAB-378; BAY 59-3074; O-

1057; GW-1000; PRS-21 1375; PRS-21 1359; PRS-21 1355; PRS-21 1096; PXS- 2076; AM-577; GW-842166X; and mixtures thereof.

12. Pharmaceutical composition according to Claim 8 wherein the CB₂ agonist is a selective CB₂ agonist and is selected from the group consisting of: 3-(1 ,1 - dimethyl-butyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromene (=

JWH133); L759633; L759656; {4-[4-(1 ,1 -dimethyl-heptyl)-2,6-dimethoxy-phenyl]- 6,6-dimethyl-bicyclo[3.1 .1 ]hept-2-en-2-yl}-methanol (= HU308); JWH015; (2-iodo- 5-nitro-phenyl)-[1 -(1 -methyl-piperidin-2-ylmethyl)-1 H-indol-3-yl]-methanone (= AM-1241 ); and mixtures thereof.

13. Pharmaceutical composition according to any of the preceding claims wherein the CB₂ antagonist and/or the CB₂ inverse agonist is selected from the group consisting of: N-{1 ,3,3-Trimethyl-endo-(1 S)-bicyclo[2.2.1 ]hept-2-yl}-1 -[1 -(4-methyl)- benzyl-5-(4-chloro-3-methyl-phenyl)-1 H-pyrazol-3-carboxamide (= SR-144528), JTE-907, AM630, and mixtures thereof.

14. Pharmaceutical composition according to any of the preceding claims wherein the dually acting compound which is both a CB₁ agonist and a CB₂ agonist, is selected from the group consisting of: dronabinol; HU210; 2-icosa-5,8,1 1 ,14- tetraenyloxy-propane-1 ,3-diol (noladin ether); N-adamantantyl-4-pentyl-5-phenyl- thiazole-2-carboxamide; and mixtures thereof.

15. Pharmaceutical composition according to any of the preceding claims wherein the K_ATP channel modulator as a first active acts simultaneously as CB_x modulator and/or wherein the CB_x modulator as a second active acts simultaneously as K_ATP channel modulator provided that the at least one K_ATP channel modulator as a first active agent and the at least one CB_x modulator as a second active agent are separate, but not identical components of said composition.

16. A use of at least one K_ATP channel modulator in combination with at least one CB_x modulator as a second active agent wherein the CB_x modulator is selected from the group consisting of CB₁ agonists; CB₂ agonists; CB₂ partial agonists; CB₂ antagonists; CB₂ inverse agonists; and dually acting compounds which are both a CB₁ agonist and a CB₂ agonist; and mixtures thereof, for the manufacture of a medicament for the prophylaxis, treatment, delayed progression, delayed onset and/or inhibition of obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotec- tion, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - includ- ing neuropathic pain and chronic pain - and impotence in mammals and humans.

17. Use according to Claim 16 wherein the metabolic syndrome and/or syndrome X comprise disorders or diseases selected from the group consisting of: hypertension, in particular arterial hypertension; insulin resistance, in particular diabetes mellitus type II; glucose intolerance; dyslipoproteinaemia, in particular as hyper- triglyceridaemia accompanied by dyslipoproteinaemia occurring with lowered

HDL-cholesterol and hyperuricaemia.

18. Use according to Claims 16 and 17 wherein the K_ATP channel modulator as a first active acts simultaneously as CB_x modulator and/or wherein the CB_x modulator as a second active acts simultaneously as K_ATp channel modulator provided that the at least one K_ATP channel modulator as a first active agent and the at least one

CB_x modulator as a second active agent are separate, but not identical components of said composition.

19. A method of treating, preventing, delaying progression of, delaying onset of and/or inhibiting obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans comprising administering to a subject in need thereof an effective amount of at least one K_ATP channel modulator in combination with at least one CB_x modulator as a second active agent wherein the CB_x modulator is selected from the group consisting of CB₁ agonists; CB₂ agonists; CB₂ partial agonists; CB₂ antagonists; CB₂ inverse agonists; and dually acting compounds which are both a CB₁ agonist and a CB₂ agonist; and mixtures thereof.

20. Method according to Claim 19 wherein the K_ATP channel modulator and the CB_x modulator as a second active agent are administered simultaneously, sequentially or in a combined dosage form.

21 . Method according to any of Claims 19 and 20 wherein the K_ATP channel modulator and the CB_x modulator are administered simultaneously in a fixed combination.

22. Method according to Claims 19 to 21 wherein the K_ATP channel modulator as a first active acts simultaneously as CB_x modulator and/or wherein the CB_x modulator as a second active acts simultaneously as K_ATP channel modulator provided that the at least one K_ATp channel modulator as a first active agent and the at least one CB_x modulator as a second active agent are separate, but not identical components of said composition.

23. A process for the preparation of a medicament comprising the step of combining at least one K_ATP channel modulator with at least one CB_x modulator wherein the CB_x modulator is selected from the group consisting of CB₁ agonists; CB₂ agonists; CB₂ partial agonists; CB₂ antagonists; CB₂ inverse agonists; and dually acting compounds which are both a CB₁ agonist and a CB₂ agonist; and mixtures thereof, and wherein at least one K_ATP channel modulator and the at least one

CB_x modulator are present in a combined amount effective for the prophylaxis, treatment, delayed progression, delayed onset and/or inhibition of obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperin- sulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans.