AU2007245734A1

AU2007245734A1 - Use of CBX cannabinoid receptor modulators as potassium channel modulators

Info

Publication number: AU2007245734A1
Application number: AU2007245734A
Authority: AU
Inventors: Jochen Antel; Michael Firnges; Peter-Colin Gregory; Josephus Hubertus Maria Lange; Dania Reiche
Original assignee: Solvay Pharmaceuticals GmbH
Current assignee: Abbott Products GmbH
Priority date: 2006-04-27
Filing date: 2007-04-20
Publication date: 2007-11-08
Also published as: EP2012775A1; MX2008013285A; WO2007125049A1; CA2650567A1; TW200812576A; RU2008146591A; AR060626A1; CN101431994A; JP2009534440A

Description

WO 2007/125049 PCT/EP2007/053915 1 USE OF CBX CANNABINOID RECEPTOR MODULATORS AS POTASSIUM CHANNEL MODULATORS 5 FIELD OF THE INVENTION The present invention relates to the novel use of CBx modulators as KATP channel modulators. The present invention also relates to a method of treating, preventing, 10 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, 15 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 CBx modulator as KATP channel modulator. BACKGROUND OF THE INVENTION 20 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 25 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 30 increased ratio of caloric intake to energy expenditure. The molecular factors WO 2007/125049 PCT/EP2007/053915 2 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 5 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 II diabetes mellitus; elevated plasma insulin concentrations; insulin resistance; dyslipidemias; hyperlipidemia; endometrial, breast, prostate and colon cancer; osteoarthritis; respiratory 10 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. 15 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 20 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 25 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 II diabetes; glucose intolerance; 30 dyslipoproteinaemia, in particular as hypertriglyceridaemia, accompanied by dyslipoproteinaemia occurring with lowered HDL-cholesterol, and also hyperuricaemia, which can lead to gout.

WO 2007/125049 PCT/EP2007/053915 3 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 5 people. Most people with insulin resistance have central obesity. The biologic 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, 10 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 15 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 Ill) are the most current and widely used. 20 According to the ATP Ill 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. 25 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 110 mg/dL. The term "syndrome X" is closely related to the term "metabolic syndrome" and 30 usually is supposed to denominate the identical disease or condition. According to information from the American Heart Association, the term "Syndrome X" refers, WO 2007/125049 PCT/EP2007/053915 4 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. 5 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, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, 10 cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence. ATP-sensitive potassium channel (KATP channel) modulation has been linked to several potential clinical uses including diabetes, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, 15 neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, hypertension, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence (ref. Jahangir et al. J. Mol. Cell. Cardiology, 2005, 39, 99-112 and references cited therein). 20 KATP 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 11 (2004) 1595-1615. The beneficial role of the specific KATP channel opener diazoxide in the treatment 25 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) 1911-1915. The KATP channel couples glucose metabolism to insulin secretion. Defective 30 regulation of KATP channel activity has been reported to contribute to the etiology of type 2 diabetes (ref. Ashcroft, J. Clin. Investig. 2005, 115 (8), 2047-2057 and references cited therein). The KATP channel is an octameric complex of 4 Kir6.x (x = 1 WO 2007/125049 PCT/EP2007/053915 5 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 KATP Kir6.2/SUR1 combination exists in the pancreas. Its structure has been determined recently (ref. Mikhailov, EMBO Journal, 2005, 24, (23), 4166-4175). 5 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). 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 II diabetes. Additionally, insulin is involved in lipogenesis and weight gain, provoking 10 an anorexigenic action as it provokesa 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 diabetus mellitus type I, diabetus mellitus type II, obesity, metabolic syndrome and syndrome X. 15 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, C.J. 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 CB 1 and CB 2 20 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) through CB 2 receptors regulates [Ca 2 +]i signals in 3-cells in the endocrine pancreas 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 25 CB 2 receptor ligands have been reviewed by Raitio et al. (Curr. Med. Chem. 2005, 12, 1217-1237). It has now surprisingly been found that the quantitative effects observed within the use of CBx modulators in the indications mentioned herein are greater than expected and explainable by a single mechanism of CBx modulation. By a more 30 thorough investigation, it has been proved and demonstrated that CBx modulators act as KATP channel modulators. Hence, CBx modulators can be used for and against all illnesses and diseases which require opening of KATP channels. More specifically, CBx modulators act can be used for treating, preventing, delaying progression of, delaying WO 2007/125049 PCT/EP2007/053915 6 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 5 vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans. SUMMARY OF THE INVENTION In a first aspect, the present invention relates to the use of at least one CBx 10 modulator wherein the CBx modulator is selected from the group consisting of CB 1 agonists; CB 2 agonists; CB 2 partial agonists; CB 2 antagonists; CB 2 inverse agonists; and dually acting compounds which are both a CB 1 agonist and a CB 2 agonist; and mixtures thereof, as KATP channel modulator for the prophylaxis, treatment, delayed progression, delayed onset and/or inhibition of obesity, diabetes mellitus, metabolic 15 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 20 in mammals and humans. In a second aspect, the invention also relates to 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, 25 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 CBx modulator wherein the CBx modulator is selected 30 from the group consisting of CB, agonists; CB 2 agonists; CB 2 partial agonists; CB 2 antagonists; CB 2 inverse agonists; and dually acting compounds which are both a CB, agonist and a CB 2 agonist; and mixtures thereof, and wherein the CBx modulator has KATP channel modulating properties.

WO 2007/125049 PCT/EP2007/053915 7 DETAILED DESCRIPTION OF THE INVENTION In one embodiment of the present invention, the CBx modulators are used as KATP channel modulators for the prophylaxis, treatment, delayed progression, delayed onset 5 and/or inhibition of 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 10 and chronic pain - and impotence in mammals and humans. More specifically, if the CBx modulators are used for the prophylaxis, treatment, delayed progression, delayed onset and/or inhibition of the metabolic syndrome and/or syndrome X, it is understood that the metabolic syndrome and/or syndrome X comprise disorders or diseases selected from the group consisting of hypertension, in particular arterial hypertension; 15 insulin resistance, in particular diabetes mellitus type II; glucose intolerance; dyslipoproteinaemia, in particular as hypertriglyceridaemia accompanied by dyslipoproteinaemia occurring with lowered HDL-cholesterol and hyperuricaemia. Suitable KATP channel modulators are preferably compounds which have effects as full or partial openers at the Kir6.2/SUR1 KATP channel, and/or the Kir6.2/ SUR2 KATP 20 channel. Effective are those compounds which exhibit an IC50 value [pmol] 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 SUR2 - e.g. the test model provided below. Compounds with an effect as full or partial openers at the Kir6.2/SUR1 KATP channel, in particular as selective openers at the 25 Kir6.2/SUR1 KATP channel are preferred. A compound with an effect as full or partial opener at the Kir6.2/SUR1 KATP channel is understood to be selective if its IC 50 value at the Kir6.2/SUR1 KATP channel, as measured in the aforementioned binding test, is less than half, more preferred only a quarter, of the IC 50 value of that same compound at the Kir6.2/SUR2 KATP channel. 30 It has surprisingly been found that CBx modulators from distinct structural classes act as potent and SUR1/SUR2 selective KATP Kir6.2 channel modulators. CBy modulators in this invention are CB 1 agonists; CB 2 agonists; CB 2 partial agonists; CB 2 antagonists; CB 2 inverse agonists; and dually acting compounds which are both a CB 1 WO 2007/125049 PCT/EP2007/053915 8 agonist and a CB 2 agonist; and mixtures thereof. KATP channel modulators are preferably SUR1/KATP Kir6.2 channel modulators, in particular SUR1/ KATP Kir6.2 channel modulators or partial SUR1/KATP Kir6.2 channel modulators. Preferred CBx modulators are compounds which have effects as modulators at the Kir6.2/SUR1 KATP 5 channel, at the Kir6.2/SUR2B KATP channel, the Kir6.1/ SUR2B KATP channel, and/or at the Kir6.2/SUR2A KATP channel. In a preferred embodiment of the present invention, the KATP channel modulator is a KATP channel opener. CBx modulator which are suitable for use as KATP channel modulator in the sense 10 of the present invention 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-(1S) 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)- 1H-indol-3 15 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,7,10,10 Oa-tetrahydro-6H-enzo[c]chromen-1 -ol; Icosa-5,8,11,14-tetraenoic acid 2-hydroxy-1l-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 20 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-1l-(2-morpholin-4-yl-ethyl)-2,3-dihydro-1lH-indol 3-yl]-(4-methoxy-phenyl)-methanone; 1-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-ethyl 25 1H-imidazole-4-carboxylic acid piperidin-1-ylamide; (2-Methyl-l-propyl-2,3-dihydro-1H 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-1lH-pyrazole-3-carboxylic acid piperidin-1-ylamide; 5-(4 30 Bromo-phenyl)-l1-(2,4-dichloro-phenyl)-4-ethyl-1lH-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- WO 2007/125049 PCT/EP2007/053915 9 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 5 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-1l-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5 dihydro-pyrazol-1-yl]-methylamino-methyleneamide; 4-Chloro-N-{[3-(4-chloro-phenyl) 10 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 15 methyleneamide; Piperidine-1l-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-l-[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 20 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-l1-sulfonic acid [3-(4-chloro-phenyl)-4-(3 fluoro-phenyl)-4,5-dihydro-pyrazol-1 -yl]-methylamino-methyleneamide; 5-(4-Chloro phenyl)-1l-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3-carboxylic acid piperidine-1 25 ylamide; 1-(4-Chloro-phenyl)-5-phenyl-4,5-dihydro- 1H-pyrazole-3-carboxylic acid piperidin-1-ylamide; Piperidine-1 -sulfonic acid [1-(4-chloro-phenyl)-5-phenyl-4,5 dihydro-1lH-pyrazol-3-yl]-methylamino-methyleneamide; 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] 30 (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 35 chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol- 1-yl]-(2-ethylamino-ethylamino)- WO 2007/125049 PCT/EP2007/053915 10 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]-(4-pyrrolidin-1-yl-butylamino)-methylene]-benzenesulfonamide; 4-Chloro-N-{[3-(4 5 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] 10 benzenesulfonamide; N,N-Diethylamino-1l-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)-1H-pyrazole-3-carbonitrile; 8-Chloro-1 -(2,4-dichloro-phenyl) 1,3a,4,5,6,10 Ob-hexahydro-1,2-diaza-benzo[e]azulene-3-carboxylic acid piperidin-1 ylamide; 5-(4-Bromo-phenyl)-1l-(2,4-dichloro-phenyl)-3-[2-(3,5-difluoro-phenyl)-2 15 methanesulfonyl-vinyl]-4-methyl- 1 H-pyrazole; Piperidine-1l-carboxylic acid [5-(4-chloro phenyl)-l1-(2,4-dichloro-phenyl)-4-methyl-1lH-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)-1l-(4-trifluoromethyl-phenyl)-1lH-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methylsulfanyl 20 1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Chloro-phenyl)-2-(2,4 dichloro-phenyl)-1lH-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Chloro phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1H-imidazole-4-carboxylic acid piperidin-1 ylamide; 1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-l1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Bromo-phenyl)-5-chloro-2-(2,4-dichloro-phenyl)-1 H 25 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-lH-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 30 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-1H-imidazole-4-carboxylic acid (4-hydroxy-cyclo-hexyl) amide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-l1H-imidazole-4-carboxylic acid azepan-1-ylamide; 2-(2,4-Dichloro-phenyl)-5-ethyl-1 -phenyl-1H-imidazole-4 35 carboxylic acid piperidin-1-ylamide; 2-(1,5-Dimethyl-lH-pyrrol-2-yl)-5-ethyl-l1-phenyl- WO 2007/125049 PCT/EP2007/053915 11 1H-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-l1H-imidazole-4-carboxylic 5 acid piperidin-1-ylamide; 1-(4-Bromo-phenyl)-5-chloro-2-(2,4-dichloro-phenyl)-1H 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-lH-imidazole-4-carboxylic acid pentylamide; 4-(4-Chloro phenyl)-5-(2,4-dichloro-phenyl)-1-methyl-1 H-imidazole-2-carboxylic acid 10 cyclohexylamide; 4-(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-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-1H-imidazole-4-carboxylic acid (4-hydroxy-cyclo-hexyl) amide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-l1H-imidazole-4-carboxylic 15 acid azepan-1-ylamide; 2-(2,4-Dichloro-phenyl)-5-ethyl-1 -phenyl-1H-imidazole-4 carboxylic acid piperidin-1-ylamide; 2-(1,5-Dimethyl-lH-pyrrol-2-yl)-5-ethyl-l1-phenyl 1H-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)-I H-imidazole-4-carboxylic acid 20 cyclohexylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-lH-imidazole-4 carboxylic acid (4-trifluoromethyl-phenyl)-amide; 2-(2,4-Dichloro-phenyl)-5-methyl-1 pyridin-2-yl-lH-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 25 acid piperidin-1-ylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methylsulfanyl 1H-imidazole-4-carboxylic acid cyclohexylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro phenyl)-5-methanesulfonyl-lH-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 30 imidazole-2-carboxylic acid piperidin-1-ylamide; 2-(2-Chloro-phenyl)-l1-(5-chloro pyridin-2-yl)-5-ethyl-l1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Chloro phenyl)-2-(2,4-dichloro-phenyl)-5-(2,2,2-trifluoro-ethyl)- 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 35 ylmethyl-lH-imidazole-4-carboxylic acid piperidin-1-ylamide; 2-[1-(4-Chloro-phenyl)-2- WO 2007/125049 PCT/EP2007/053915 12 (2,4-dich Ioro-phenyl)-5-methyl-1 H-imidazol-4-yl]-hexan-2-ol; 1-(4-Chloro-phenyl)-2 (2,4-dich Ioro-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-lH-imidazole-4-carboxylic acid piperidin-l1-ylamide; 2-(2 5 Chloro-phenyl)-l-(4-trifluoromethyl-phenyl)-lH-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)-1H-[1,2,4]triazole-3 carboxylic acid pyrrolidin-1-ylamide; 1-(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl)-1lH [1,2,4]triazole-3-carboxylic acid piperidin-1-yl-amide; 5-Pentyl-4-phenyl-thiazole-2 10 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} 15 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 20 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, CBx modulator which are suitable for use as KATP channel modulator in the sense of the present invention are 25 selected from the group consisting of: 3-(1,1-dimethyl-butyl)-6,6,9-trimethyl 6a,7,10,10 Oa-tetrahydro-6H-benzo[c]chromene; N-Adamantyl-4-pentyl-5-phenyl thiazole-2-carboxamide; N-{1,3,3-Trimethyl-endo-(1S)-bicyclo[2.2.1]hept-2-yl}-1l-[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)-1lH-indol-3-yl]-methanone; {4-[4-(1,1 30 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,7,10,10 a tetrahydro-6H-enzo[c]chromen-1 -ol; Icosa-5,8,11,14-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-1l-sulfinic acid 3-(2-hydroxymethyl-indan-4-yloxy) 35 phenyl ester, compound with form aldehyde; 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydro- WO 2007/125049 PCT/EP2007/053915 13 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-l1H-imidazole-4-carboxylic 5 acid piperidin-1-ylamide; (2-Methyl-l-propyl-2,3-dihydro-l1H-indol-3-yl)-naphthalen-1l-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)-1l-(2,4-dichloro-phenyl)-4-methyl-1lH pyrazole-3-carboxylic acid piperidin-1-ylamide; 5-(4-Bromo-phenyl)-l1-(2,4-dichloro 10 phenyl)-4-ethyl-l1H-pyrazole-3-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, CBx modulator which are suitable for use as KATP channel modulator in the sense of the present invention are selected from the group consisting of: 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5 15 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} 20 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-1lH-pyrazol-3 yl]-methylamino-methyleneamide; N-{Amino-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro 25 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] 30 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)-l-(4-trifluoromethyl-phenyl)-I H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methylsu Ifanyl-1 H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-1 H 35 imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Bromo-phenyl)-2-(2,4-dichloro- WO 2007/125049 PCT/EP2007/053915 14 phenyl)-5-ethyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Bromo phenyl)-5-chloro-2-(2,4-dichloro-phenyl)-lH-imidazole-4-carboxylic acid piperidin-1 ylamide; 1-(4-Bromo-phenyl)-2-(2,4-dichloro-phenyl)-5-ethyl-l1H-imidazole-4-carboxylic acid pentylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-l1H-imidazole 5 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-l1H-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; 10 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-4-pentyl-1H-imidazole; 1-(4 Chloro-phenyl)-2-(2-chloro-phenyl)-5-methylsulfanyl- 1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 2-(2-Chloro-phenyl)-I -(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 15 phenyl)-I 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]-methylene} benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 20 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.

CB

1 agonist or CB 2 agonists which are suitable for use as KATP channel modulator 25 in the sense of the present invention are selected from, but 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)-I H-indol-3-yl]-methanone (= AM-1241); 3-(1,1 -dimethyl-butyl)-6,6,9-trimethyl-6a,7,10,10 Oa-tetrahydro-6H-benzo[c]-chromene 30 (JWH133); N-adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; 6,6,9-trimethyl-3 pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-l-ol; (bicyclo[2.2.1]hept-2-ylamino) (5-pentyl-4-phenyl-thiazol-2-yl)-methane; 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 35 55,212-2); ACEA; ACPA; N-adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; WO 2007/125049 PCT/EP2007/053915 15 methanandamide; anandamide; 2-arachidonoyl glycerol; 2-icosa-5,8,11,14 tetraenyloxy-propane-1,3-diol (= noladin ether); BAY 38-7271; SAB-378; BAY 59-3074; O-1057; GW-1000; PRS-211375; PRS-211359; PRS-211355; PRS-211096; PXS-2076; AM-577; GW-842166X; and mixtures thereof. 5 In a preferred embodiment of the present invention, the CB 2 agonist is a selective

CB

2 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 (= JWH 133); L759633; L759656; {4-[4-(1,1 -dimethyl-heptyl)-2,6-d imethoxy-phenyl]-6,6-dimethyl bicyclo[3.1.1]hept-2-en-2-yl}-methanol (= HU308); JWH015; (2-iodo-5-nitro-phenyl)-[1 10 (1-methyl-piperidin-2-ylmethyl)-1lH-indol-3-yl]-methanone (= AM-1241); and mixtures thereof.

CB

2 antagonist or CB 2 inverse agonists which are suitable for use as KATP channel modulator in the sense of the present invention, are selected from the group consisting of: (1) compounds described in documents WO01/0588869, 15 PCT/EP2006/060009, WO2004/014825; EP1142877; US2002/0072529; W002/062750; US 6,509,352; and (2) compounds selected from the group consisting of: 1-[1-benzyl-5-(4-chloro-3-methyl-phenyl)-1 H-pyrazol-3-yl]-ethanonyl-1,3,3-trimethyl bi-cyclo[2.2.1]hept-2-ylamine (= SR-144528), JTE-907, AM630, and mixtures thereof; and (3) mixtures of compounds selected from (1) and (2). 20 Dually acting compounds which are both a CB 1 agonist and a CB 2 agonist, and which are suitable for use as KATP channel modulator in the sense of the present invention, are selected from the group consisting of: 2-icosa-5,8,11,14-tetraenyloxy propane-1,3-diol (= noladin ether); and mixtures thereof. In a preferred embodiment of the present invention, the CBx modulator is 25 selected from the group consisting of: 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; 3-(1,1 -dimethyl-butyl)-6,6,9-trimethyl-6a,7,10,10 Oa-tetrahydro-6H benzo[c]chromene; N-adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; SR144528; (2-iodo-5-nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1 H-indol-3-yl]-methanone; {4 30 [4-(1,1-Dimethyl-heptyl)-2,6-dimethoxy-phenyl]-6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2 yl}-methanol; and mixtures thereof.

WO 2007/125049 PCT/EP2007/053915 16 A set of representative CBx modulators with their affinities on the KATP SUR1 and SUR2 regulatory subunits (hamster), respectively are depicted in Table 1. (2-Chloro-4 methyl-7,7-dioxo-4,7-dihydro-1,71ambda*6*-dithia-4,6-diaza-inden-5-yl)-(1-methyl cyclopropyl)-amine and 7-Chloro-3-methyl-2H-benzo[1,2,4]thiadiazine 1,1-dioxide 5 serve as KAT/SUR1 active reference compounds which are known to those skilled in the art. For comparative reasons, Table 1 also lists the CB1 and/or CB2 activities of various compounds to prove that their activity as CB 1 agonists, CB 2 agonists, CB 2 partial agonists, CB 2 antagonists, CB 2 inverse agonists and dually acting compounds which are both a CB 1 agonist and a CB 2 agonist. 10 Description of the pharmacological test methods 1. In vitro binding affinity of the test compounds to rodent KATP channels Competitive binding experiments were performed to characterize the affinity of the test compounds for the binding sites for sulfonylureas and KATP channel openers (= 15 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 [ 3 H]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 pM MgATP (see Schwanstecher M., et al. Naunyn-Schmiedeberg's Arch. Pharmacol. 20 343 (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. 25 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 [ 3 H]P1075 (see Schwanstecher et al., 1998; D6rschner H. et al. Mol. Pharmacol. 55 (1999) 1060-1066 (= D6rschner et al., 1999)). The affinity of 30 [ 3 H]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 WO 2007/125049 PCT/EP2007/053915 17 indirectly through allosteric displacement of [ 3 H]P1075 (D6rschner et al., 1999). Second, a mutated SUR2A (SUR2Ay 1 2 05s, see above) with increased affinity for

[

3 H]glibenclamide allowing direct displacement of this tracer can be used. This second approach was chosen to enable discrimination between allosteric and competitive 5 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 10 in the additional presence of 100 pM MgATP (Schwanstecher et al., 1991 and 1998). For each test compound 4 displacement curves were measured (displacement of

[

3 H]P1075 from the rat isoform of the wild type receptor and displacement of

[

3 H]glibenclamide from the rat isoform of SUR2Ay 12 05s). Per curve 9-15 distinct concentrations were tested covering the relevant range. All measurements were 15 repeated at least 5 times in independent experiments.

[

3 H]P1075 (specific activity 116 Ci mmol

-

) was purchased from Amersham Buchler (Braunschweig, Germany). [ 3 H]glibenclamide (specific activity 51 Ci mmol

-

) was obtained from NEN (Dreieich, Germany). If suitable, stock solutions were prepared in dimethylsulfoxide with a final solvent concentration in the media below 1 %. 20 SUR- or Kir6.x isoforms were used either subcloned in the pcDNA (hamster SUR1, mouse Kir6.2) or pCMV vector (rat SUR2A, SUR2B). Rodent SUR-isoforms and KATP channels were transiently expressed in COS-1 cells as described (see Schwanstecher et al., 1998); D6rschner et al., 1999); Uhde I. et al. J Biol Chem 274 (1999) 28079-28082; Gross I. et al. Mol. Pharmacol. 56 (1999) 25 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 (SUR2y 12 05s) was used to allow detection of binding to the sulfonylurea site of these isoforms by displacement of [ 3 H]glibenclamide (Uhde I., Dissertation 2001). Briefly, COS-1 cells cultured in DMEM HG (10 mM glucose), supplemented with 10 % 30 fetal calf serum (FCS), were plated at a density of 5 x 10 5 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 pg/ml) plus DEAE-dextran (1 mg/ml), 2 min in HEPES-buffered salt solution plus dimethylsulfoxide (10 %) and 4 hours in WO 2007/125049 PCT/EP2007/053915 18 DMEM-HG plus chloroquine (100 pM). 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 5 concentration 5 - 50 pg/ml) were incubated in "Tris-buffer" (50 mM, pH 7.4) containing either [ 3 H]glibenclamide (final concentration 0.3 nM or 3 nM and nonspecific binding defined by 100 nM or 1 pM glibenclamide for SUR1 or SUR2y 12 05s-isoforms, respectively) or [ 3 H]P1075 (final concentration 3 nM, nonspecific binding defined by 100 pM pinacidil) and increasing concentrations of the test compounds. The free Mg 2 + 10 concentration were kept close to 0.7 mM. ATP (0.1 mM) was added to incubation media to enable KCO (e.g. diazoxide, [ 3 H]P1075) 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. The inhibition constant (Ki value) of the test substances was calculated from the 15 respective IC50 value, and was stated as the negative logarithmic value thereof (pKi). 2. In vitro binding affinity of the test compounds to CB, receptors The affinity of the compounds of the invention for cannabinoid CB 1 receptors can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in 20 which the human cannabinoid CB, receptor is stably transfected in conjunction with

[

3 H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [ 3 H]-ligand, with or without 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. 25 3. In vitro binding affinity of the test compounds to CB2 receptors The affinity of the compounds of the invention for cannabinoid CB 2 receptors can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB 2 receptor is stably transfected in conjunction with 30 [ 3 H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [ 3 H]-ligand, with or without addition of compounds of the invention, WO 2007/125049 PCT/EP2007/053915 19 separation of bound and free ligand is performed by filtration over glassfiber filters. Radioactivity on the filter is measured by liquid scintillation counting. Table 1 - CBx modulators with their affinities on the CB1 and/or CB2 receptor 5 affinities, (cloned human cannabinoid (CB1 and CB2 respectively) receptors expressed in CHO cells according to the procedures described hereinabove), expressed as pKi values.

WO 2007/125049 PCT/EP2007/053915 20 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 Chiral 3-(1,1 -dimethyl-butyl) H 6,6,9-trimethyl H 6a,7,10,10Oa-tetrahydro-6H- 6.7 7.8 5.9 3.6 0 benzo[c]chromene (= JW133) S N-Adamantyl-4-pentyl-5 phenyl-thiazole-2- 7.8 8.1 4.0 4.0 carboxamide Cl Chiral N-{1,3,3-Trimethyl-endo \ /(1S)-bicyclo[2.2.1]hept-2 SN, yl}-1-[1-(4-methyl)-benzyl 5-(4-chloro-3-methyl- 6.2 7.7 6.9 4.8 phenyl)-1 H-pyrazol-3 carboxamide (= SR 144528) 0 -N11 (2-lodo-5-nitro-phenyl)-[1 o- (1-methyl-piperidin-2 Sylmethyl)-1 H-indol-3-yl] I methanone 6.6 7.8 5.4 4.7 N (=AM-1241) o {4-[4-(1,1-Dimethyl heptyl)-2,6-dimethoxy phenyl]-6,6-dimethyl a bicyclo[3.1.1]hept-2-en-2- 6.0 7.8 6.4 3.6 yl}-methanol (= HU308) 3-(1,1-Dimethyl-heptyl)-9 hydroxymethyl-6,6 dimethyl-6a,7,10,lOa-tetra 7.3 n/a 6.1 5.1 hydro-6H-enzo[c]chromen o1 -ol (HU-210) WO 2007/125049 PCT/EP2007/053915 21 Affinity to compound/name Chemical name CB1 CB2 SUR SUR 1 2 0 Icosa-5,8,11,14-tetraenoic -o acid 2-hydroxy-1 o hydroxymethyl-ethyl ester 6.0 5.4 5.6 5.5 (2-AG) 1 -Aziridin-1 -yl-henicosa o 6,9,12,15-tetraen-2-one 7.7 7.1 3.9 4.7 N (ACPA) kO

O

z O Noladineether 6,9 6,6 5,4 4,4 O F O ir d 4,4,4-Trifluoro-butane-1 ... O F sulfinic acid 3-(2 F hydroxymethyl-indan-4- 8,0 7,3 6,0 5,2 o yloxy)-phenyl ester; compound with form aldehyde (BAY-38-7271) 0 7-Methoxy-2-oxo-8 V N O pentyloxy-1,2-dih ydro-quinoline-3-carboxylic 6,0 6,9 6,1 5,9 S N o acid (benzo[1,3]dioxol-5 o ylmethyl)-amide (JTE-907) - C cl N-(1-{4-[4-Chloro-2-(2 C I fluoro-benze 02s\ nesulfonyl)- 6,0 9,3 5,9 4,7 000 [ .0 0 benzenesulfonyl]-phenyl Oo }-ethyl) 0 methanesulfonamide (Schering) 1 0 [6-1odo-2-methyl-1 -(2 morpholin-4-y N I-ethyl)-2,3-dihydro-1H- 6,7 7,6 5,9 5,0 indol-3-yl] CN -(4-methoxy-phenyl) 0 methanone (AM-630) WO 2007/125049 PCT/EP2007/053915 22 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 CI a 1-(4-Chloro-phenyl)-2-(2 ,chloro-phenyl)-5-ethyl-1

H

imidazole-4-carboxylic acid 7,9 6,0 n/a 4,8 piperidin-1-ylamide (Bayer) CI (2-Methyl-1 -propyl-2,3 dihydro-1H-i 6,3 6,9 6,1 5,8 ndol-3-yl)-naphthalen-1 -yl methanone (JWH-015) 0 5-(1,1-Dimethyl-heptyl)-2 o [5-hydroxy-2-(3-hydroxy propyl)-cyclohexyl]- 9,0 9,3 5,3 5,2 phenol (CP55940) O O , O Chiral , .0 .., C l 5-(1,1 -Dimethyl-heptyl)-2 o [5-hydroxy-2-(3-hydroxy propyl)-cyclohexyl]- 7,2 7,0 5,3 5,3 phenol (CP55940-entantiomer) / (2-Methyl-3-morpholin-4 ylmethyl-3,4-dihydro-5 oxa-2a-azacenaphthylen I \ 1-yl)-naphthalen-1-yl- 7,1 8,1 4,4 5,4 methanone ..N (R(+)-WIN55212-2) a 5-(4-Chloro-phenyl)-1-(2,4 dichloro-phenyl)-4-methyl a 1H-pyrazole-3-carboxylic 8,2 6,0 5,3 5,4 acid piperidin-1-ylamide (Rimonabant)

O

WO 2007/125049 PCT/EP2007/053915 23 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 O N-NO 5-(4-Bromo-phenyl)-1-(2,4 N dichloro-phenyl)-4-ethyl B0 1 1H-pyrazole-3-carboxylic 7,9 5,9 5,5 5,6 Bri acid piperidin-1-ylamide (SR-147778) CI F o0 1 -[Bis-(4-chloro-phenyl) 0 F methyl]-3-[(3,5-difluoro N phenyl)-methanesulfonyl- 8,2 n/a 5,3 5,1 N methylene]-azetidine (Aventis) Cl Cl

I

I 4-Chloro-N-{[3-(4-chloro phenyl)-4-phenyl-4,5 N-N o dihydro-pyrazol-1-yl]- 8,4 n/a 6,3 5,4 N o methylamino-methylene} / benzenesulfonamide Cl Cl | 4-Chloro-N-{[3-(4-chloro phenyl)-4-phenyl-4,5- 6,3 5,7 6,0 6,1 N-N N o dihydro-pyrazol-1-yl] N o methylamino-methylene} / benzenesulfonamide Cl Cl | N-{Amino-[3-(4-chloro phenyl)-4-phenyl-4,5- 8,4 6,8 6,1 5,4 N-N dihydro-pyrazol-1-yl] 'so methylene}-4-chloro N 0 I benzenesulfonamide I Cl c N-{[3-(4-Chloro-phenyl)-4 pyridin-3-yl-4,5-dihydro N-N pyrazol-1-yl]-methylamino N-N N ,O methylene}-4- 8,2 - 6,3 4,9 N o ,S trifluoromethyl -F benzenesulfonamide F F WO 2007/125049 PCT/EP2007/053915 24 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 ci o 04-Chloro-N-{[3-(4-chloro Sphenyl)-4-pyridin-3-yl-4,5- 7,1 n/a 5,6 5,4 dihydro-pyrazol-1-yl] c methylamino-methylene} benzenesulfonamide F cl 4-Chloro-N-{[3-(4-chloro phenyl)-4-(3-fluoro phenyl)-4,5-dihydro- 7,7 n/a 5,6 6,1 N-N pyrazol-1-yl] aN s methoxyamino /N oS methylene} -obenzenesulfonamide Cl c1 Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4 phenyl-4,5-dihydro- 8,3 n/a 6,3 4,0 N-N pyrazol-1-yl]-methylamino SN S110Omethyleneamide /N 0 'NO 0 F F N-{[3-(4-Chloro-phenyl)-4 cl (3-fluoro-phenyl)-4,5 dihydro-pyrazol-1-yl]- 8,5 n/a 7,0 5,3 methylamino-methylene} N-N N,N-dimethyl-sulfonamide NO N 0' N Cl c Azepane-1-sulfonic acid [3-(4-chloro-phenyl)-4- 7,3 n/a 4,6 4,9 N-N phenyl-4,5-dihydro-pyra "\ N ,s1,Ozol-1 -yl]-methylamino N s N methyleneamide WO 2007/125049 PCT/EP2007/053915 25 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 c 4-Chloro-N-{[3-(4-chloro phenyl)-4-phenyl-4,5 dihydro-pyrazol-1 -yl] - [(1-methyl-pyrrolidin-3- 9,0 6,0 6,0 4,8 o ylmethyl)-amino] methylene} benzenesulfonamide N 1-(4-Chloro-phenyl)-5 phenyl-4,5-dihydro-1H- 6,2 6,3 4,0 4,0 a pyrazole-3-carboxamidine CI N-{[3-(4-Chloro-phenyl)-4 phenyl-4,5-dihydro F F pyrazol-1-yl]-methylamino , -methylene}-4- 8,4 n/a 6,3 4,2 N trifluoromethyl-benzene O sulfonamide N N 0 CI Chiral \1 Piperidine-1-sulfonic acid N [3-(4-chloro-phenyl)-4- 8,1 n/a 5,8 4,3 N phenyl-4,5-dihydro N pyrazol-1-yl]-methylamino o=- o methyleneamide CI Piperidine-1-sulfonic acid [3-(4-chloro-phenyl)-4 N phenyl-4,5-dihydro- 8,6 n/a 4,0 4,0 NL. NF pyrazol-1-yl]-(2 N dimethylamino-ethyl 0-S-o N amino)-methyleneamide Cl CI\N,N-Diethylamino-1 sulfonic acid [3-(4-chloro N phenyl)-4-phenyl-4,5- 7,1 n/a 4,0 4,7 N dihydro-pyrazol-1-yl] N methylsulfanyl o=s=0 methyleneamide

N

WO 2007/125049 PCT/EP2007/053915 26 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 CI Chiral CI 2-Amino-1 -[3-(4-chloro . phenyl)-4-phenyl-4,5 N dihydro-pyrazol-1-yl]-3- 6,0 6,2 5,4 4,8 c, (3,4-dichloro-phenyl) N- propan-1-one CI CI Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4 N phenyl-4,5-dihydro- 7,7 n/a 4,0 5,5 N pyrazol-1-yl]-methylamino SI O 0 S 0 methyleneamide F N,N-Dimethylamino-1 N - sulfonic acid [3-(4-chloro NN phenyl)-4-phenyl-4,5 cl dihydro-pyrazol-1-yl]-(2- 7,5 n/a 4,3 4,0 fluoro-ethylamino) methyleneamide -N O. Piperidine-1-sulfonic acid N -N 'b Ns[3-(4-chloro-phenyl)-4-(3 Sfluoro-phenyl)-4,5-dihydro- 7,5 6,1 4,5 6,3 cl pyrazol-1 -yl]-methylamino -methyleneamide F O c N N 5-(4-Chloro-phenyl)-1-(2,4 rN O dichloro-phenyl)-4,5 c - dihydro-1H-pyrazole-3- 7,4 6,1 5,4 5,6 I carboxylic acid piperidine 1-ylamide CI 0 -N 1-(4-Chloro-phenyl)-5 N - N \ phenyl-4,5-dihydro-1 H cl pyrazole-3-carboxylic acid 7,2 n/a 4,0 5,1 0 1piperidin-1-ylamide It* WO 2007/125049 PCT/EP2007/053915 27 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 Piperidine-1-sulfonic acid S .N [1-(4-chloro-phenyl)-5 N .s=o phenyl-4,5-dihydro-1 N- H-pyrazol-3-yl]- 7,3 n/a 6,1 4,5 methylamino c I methyleneamide / q.N Morpholine-4-sulfonic acid SN.s-o [1-(2,4-dichloro-phenyl)-5- 6,9 n/a 5,3 5,0 phenyl-4,5-dihydro-1 H c I pyrazol-3-yl]-methylamino I methyleneamide 4-Chloro-N-[[3-(4-chloro phenyl)-4-phenyl-4,5 .. dihydro-pyrazol-1 -yl]-(2 -fluoro-ethylamino)- 7,7 n/a 4,6 4,6 -o amethylene] benzenesulfonamide 4-Chloro-N-[[3-(4-chloro phenyl)-4-phenyl-4,5 - dihydro-pyrazol-1 -yl]-(2 F N -fluoro-ethylamino)- 6,9 n/a 4,6 5,0 a 0 methylene] benzenesulfonamide Cl N-{Amino-[3-(4-chloro N . Nphenyl)-4-phenyl-4,5 N dihydro-pyrazol-1-yl]- 7,4 6,4 6,0 5,1 N -N methylene}-4-chloro °s benzenesulfonamide Cl WO 2007/125049 PCT/EP2007/053915 28 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 O 10 S/ 4-Chloro-N-[3-(4-chloro a phenyl)-4-phenyl-4,5 N dihydro-pyrazole-1- 6,5 n/a 5,5 4,8 carbonyl] benzenesulfonamide Cl \4-Chloro-N-[[3-(4-chloro phenyl)-4-phenyl-4,5 dihydro-pyrazol-1-yl]-(2 8,1 n/a 5,1 5,3 -ethylamino-ethylamino) a-=0 methylene] Benzenesulfonamide 4-Chloro-N-{[3-(4-chloro phenyl)-4-phenyl-4,5 N dihydro-pyrazol-1-yl]-[( 8,3 n/a n/a 5,1 N/ - N 1-methyl-pyrrolidin-2 o=o ylmethyl)-amino] methylene} benzenesulfonamide a 4-Chloro-N-[[3-(4-chloro phenyl)-4-phenyl-4,5 dihydro-pyrazol-1 -yl]-(4 N -pyrrolidin-1-yl- 7,4 n/a 4,3 5,4 N Ns butylamino)-methylene] N S benzenesulfonamide O C1 4-Chloro-N-{[3-(4-chloro phenyl)-4-phenyl-4,5 dihydro-pyrazol-1 -yl]-[( N o pyridin-3-ylmethyl)-amino]- 6,4 6,3 5,9 5,7 -N'.s methylene} 01iI benzenesulfonamide N I WO 2007/125049 PCT/EP2007/053915 29 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 C Chirl \ 1-[3-(4-Chloro-phenyl)-4 phenyl-4,5-dihydro pyrazol-1-yl]-3-(1H-indol- 8,0 6,9 6,6 4,6 V2-yl)-2-methylamino o propan-1-one 2-[3-(4-Chloro-phenyl)-4 phenyl-4,5-dihydro pyrazol-1-yl]-5-ethyl-4,5- 6,2 n/a 5,5 4,4 dihydro-oxazole 4-Chloro-N-[[3-(4-chloro c phenyl)-4-phenyl-4,5 dihydro-pyrazol-1-yl]-(3 6,7 6,1 4,5 5,4 -hydroxy-2,2-dimethyl N-N ,o propylamino) N ,, methylene] S benzenesulfonamide CI 0 N,N-Diethylamino-1 sulfonic acid [3-(4-ch o Ioro-phenyl)-4-hydroxy-4- 7,4 n/a 4,0 5,9 N phenyl-4,5-dihydro N N pyrazol-1-yl]-methylamino I a- a methyleneamide N ,N 5-(4-Bromo-phenyl)-1-(2,4 N dichloro-phenyl)-1H- 6,3 n/a 4,0 5,4 Br C1C Br pyrazole-3-carbonitrile cI Cl 8-Chloro-1-(2,4-dichloro c, phenyl)-1,3a,4,5,6, lOb N hexahydro-1,2-diaza-be 6,9 6,9 5,5 4,0 N Cl nzo[e]azulene-3-carboxylic N Acid piperidin-1-ylamide WO 2007/125049 PCT/EP2007/053915 30 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 F F 5-(4-Bromo-phenyl)-1-(2,4 sO dichloro-phenyl)-3-[2-(3,5 N difluoro-phenyl)-2- 7,3 5,9 4,0 4,0 cB methanesulfonyl-vinyl]-4 methyl-1 H-pyrazole a N N Piperidine-1-carboxylic N acid [5-(4-chloro-phenyl)-l N (2,4-dichloro-phenyl)-4- 6,9 n/a 4,7 4,7 cI cI methyl-1 H-pyrazol-3-yl] amide CI N NsNro 1-(4-Chloro-phenyl)-2-(2,4 N S dichloro-phenyl)-5 SI ethylsulfanyl-1H-imidazole- 7,4 n/a 5,1 5,3 4-carboxylic acid piperidin 1-ylamide ClI Co C 2-(2,4-Dichloro-phenyl)-1 N N-N (4-trifluoromethyl-phenyl) 1H-imidazole-4-carboxylic 7,6 n/a 5,6 5,3 FF acid piperidin-1-ylamide F o c N 1 -(4-Chloro-phenyl)-2-(2,4 s- dichloro-phenyl)-5 c, methylsulfanyl-1H-imidaz 8,0 6,0 5,1 5,6 ole-4-carboxylic acid c1 piperidin-1-ylamide 0 N -N 1-(4-Chloro-phenyl)-2-(2,4 dichloro-phenyl)-lH- 8,1 6,2 4,5 5,3 imidazole-4-carboxylic acid piperidin-1-ylamide

CI

WO 2007/125049 PCT/EP2007/053915 31 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 O0 N N 1-(4-Chloro-phenyl)-2-(2,4 \ dichloro-phenyl)-5-ethyl- 8,7 6,3 5,3 5,5 1 H-imidazole-4-carboxylic acid piperidin-1-ylamide CI a 1-(4-Bromo-phenyl)-2-(2,4 dichloro-phenyl)-5-ethyl- 7,5 n/a 5,4 5,3 Cl 1 H-imidazole-4-carboxylic Said piperidin-1-ylamide Br O NN 1-(4-Bromo-phenyl)-5 N chloro-2-(2,4-dichloro Cl C phenyl)-1H-imidazole-4-car 8,6 n/a 5,4 5,5 I boxylic acid piperidin-1 ylamide Br ON 1-(4-Bromo-phenyl)-2-(2,4 CI dichloro-phenyl)-5-ethyl CI N 1H-imidazole-4-carboxylic 7,0 6,7 4,0 5,1 acid cyclohexylamide Br N 1-(4-Bromo-phenyl)-2-(2,4 1 dichloro-phenyl)-5-ethyl 1 H-imidazole-4-carboxylic 7,5 n/a 6,1 5,6 I acid pentylamide Br CI CI 4-(4-Chloro-phenyl)-5-(2,4 C, dichloro-phenyl)-1l-methyl -N N 1H-imidazole-2-carboxylic 7,2 n/a 4,0 4,7 - acid cyclohexylamide O - WO 2007/125049 PCT/EP2007/053915 32 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 CI CI 4-(4-Chloro-phenyl)-5-(2,4 , dichloro-phenyl)-3-methyl N N 1H-imidazole-2-carboxylic 7,1 n/a 4,0 4,9 o acid cyclohexylamide 0 N-0 / N 1-(5-Chloro-pyridin-2-yl)-2 c (2,4-dichloro-phenyl)-5- 7,6 n/a 4,0 4,4 N ethyl-1 H-imidazole N -4-carboxylic acid piperidin-1-ylamide Cl ' ,1 -(4-Chloro-phenyl)-2-(2,4 dichloro-phenyl)-5-methyl 1H-imidazole-4-carboxylic 6,6 n/a 4,0 5,0 N acid (4-hydroxy-cyclo ,o hexyl)-amide CI c 1-(4-Chloro-phenyl)-2-(2,4 dichloro-phenyl)-5-methyl N 1H-imidazole-4-carboxylic 7,2 7,6 5,2 5,7 N N acid azepan-1-ylamide 0 0 CIC C N I N 2-(2,4-Dichloro-phenyl)-5 c . Iethyl- 1 -phenyl-1H imidazole-4-carboxylic acid 7,0 7,6 4,0 5,3 a piperidin-1-ylamide N N 2-(1,5-Dimethyl-1 H-pyrrol 2-yl)-5-ethyl-1 -phenyl-1 H N imidazole-4-carboxylic acid n/a 6,8 4,0 4,0 cyclohexylamide 1-(4-Chloro-phenyl)-5 N ethyl-2-(3-methyl-pyridin-2 N yl)-1H-imidazole-4- n/a 6,6 4,0 4,8 O N N carboxylic acid piperidin-1 o ylamide WO 2007/125049 PCT/EP2007/053915 33 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 1-(4-Chloro-phenyl)-5 ethyl-2-(3-methyl-pyridin-2 N yl)-1 H-imidazole-4 N N carboxylic acid n/a 6,1 4,0 5,5 ci o cyclohexylamide 0 1-(4-Chloro-phenyl)-2-(2,4 Cl N N dichloro-phenyl)-5-methyl N 1 H-imidazole-4-carboxylic c F acid (4-trifluoromethyl- 6,7 n/a 4,5 5,3 FF phenyl)-amide CI a l3 0 o2-(2,4-Dichloro-phenyl)-5 "'0 - methyl-1-pyridin-2-yl-1

H

imidazole-4-carboxylic acid 7,3 6,2 4,0 4,1 piperidin-1-ylamide 1-(4-Chloro-phenyl)-2-(2,4 c odichloro-phenyl)-5 S.?F fluoromethyl-1 H-imidazol c, e-4-carboxylic acid 7,2 6,1 5,2 5,5 I piperidin-1-ylamide CI o N 1-(4-Chloro-phenyl)-2-(2,4 a o dichloro-phenyl)-5 N hydroxymethyl-1H-imidazo 7,6 6,2 4,0 4,7 CI le-4-carboxylic acid piperidin-1-ylamide CI c.O 1-(4-Chloro-phenyl)-2-(2,4 dichloro-phenyl)-5 methylsulfanyl-1H-imidaz 7,2 6,6 6,3 5,8 C ole-4-carboxylic acid cyclohexylamide

CI

WO 2007/125049 PCT/EP2007/053915 34 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 o 1-(4-Chloro-phenyl)-2-(2,4 c. I dichloro-phenyl)-5 ND . so methanesulfonyl-1 H-imida c o zole-4-carboxylic acid 7,8 n/a 4,0 5,0 piperidin-1-ylamide cI 0 cl N N 1-(4-Chloro-phenyl)-2-(2,4 s dichloro-phenyl)-5- 7,4 n/a 4,0 4,9 |o methanesulfinyl-1H-imida cl zole-4-carboxylic acid piperidin-1-ylamide CI \ No 5-(4-Chloro-phenyl)-4-(2,5 a \ N- dichloro-phenyl)-1-methyl 1H-imidazole-2-carboxylic 6,7 6,4 4,6 5,0 acid piperidin-1-ylamide a .N N, N2-(2-Chloro-phenyl)- 1 -(5 chloro-pyridin-2-yl)-5-ethyl 1H-imidazole-4-carboxylic 7,9 n/a 4,0 4,8 acid piperidin-1-ylamide Cl C 0 N 1-(4-Chloro-phenyl)-2-(2,4 N dichloro-phenyl)-5-(2,2,2 Strifluoro-ethyl)-1H- 7,5 n/a 4,8 5,7 cid F imidazole-4-carboxylic acid F piperidin-1-ylamide CI c N N-[1-(4-Chloro-phenyl)-2 N 8(2,4-dichloro-phenyl)-5 c N methyl-1 H-imidazol-4-yl]- 7,0 6,3 5,7 5,2 benzamide

CI

WO 2007/125049 PCT/EP2007/053915 35 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 ON CI N N 1-(4-Chloro-phenyl)-2-(2,4 dichloro-phenyl)-5 c1 N pyrrolidin-1-ylmethyl-1H 6,3 n/a 4,0 4,6 -imidazole-4-carboxylic acid piperidin-1-ylamide CI 0 .. N2-[1-(4-Chloro-phenyl)-2 C I(2,4-dichloro-phenyl)-5- 6,6 n/a 5,8 5,3 methyl-1 H-imidazol-4-yl] c hexan-2-ol c N 1-(4-Chloro-phenyl)-2-(2,4 N - dichloro-phenyl)-5-methyl- 7,0 n/a 5,8 5,3 c 4-pentyl-1 H-imidazole CI . N 2,5-Dimethyl-1-phenyl-1 H imidazole 4-carboxylic acid n/a 9,0 6,0 4,6 6 adamantan-2-ylamide ~~ 1-(4-Chloro-phenyl)-2-(2 I chloro-phenyl)-5 Smethylsulfanyl-1H- n/a 5,2 8,2 n/a imidazole-4-carboxylic acid piperidin-1-ylamide a C oN 2-(2-Chloro-phenyl)-1-(4 N-- trifluoromethyl-phenyl)-1

H

imidazole-4-carboxylic acid 7,0 n/a 6,0 5,7 piperidin-1-ylamide F F WO 2007/125049 PCT/EP2007/053915 36 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 CI CI

-

\5-(4-Chloro-phenyl)-4-(2,4 dichloro-phenyl)-thiazole C 2-carboxylic acid piperidin- 6,7 n/a 5,7 5,5 S NO 1-ylamide 0 O N N NN\ 5-(4-Chloro-phenyl)-1-(2,4 NN dichloro-phenyl)-1lH C1 c [1,2,4]triazole-3-carboxylic 6,6 n/a 4,0 4,4 acid pyrrolidin-1-ylamide CI S -N 1-(4-Chloro-phenyl)-5-(2,4 N dichloro-phenyl)-1 H N [1,2,4]triazole-3-carboxylic 6,5 n/a 5,0 5,0 I acid piperidin-1-yl-amide cI oN N 5-Pentyl-4-phenyl-thiazole 2-carboxylic acid (hexahydro-2,5-methano- 6,4 7,0 4,0 4,0 pentalen-3a-yl)-amide ON- 4-Pentyl-5-phenyl-thiazole 2-carboxylic acid 7,8 8,1 4,0 4,0 (hexahydro-2,5-methano pentalen-3a-yl)-amide o - I 1-{(4-Chloro-benzene \/ csulfonylimino)-[3-(4-chloro /S1 .phenyl)-4-phenyl-4,5 N dihydro-pyrazol-1-yl]- 8,2 n/a 5,5 5,2 -N methyl}-piperidine-4 carboxylic acid amide 0 Cl H 2 N / a 4-Chloro-N-{[3-(4-chloro ork phenyl)-4-phenyl-4,5 dihydro-pyrazol-1-yl]-[2-(2- 8,2 n/a 6,3 5,9 N oxo-pyrrolidin-1 -yl) ethylamino]-methylene} / benzenesulfonamide

C

WO 2007/125049 PCT/EP2007/053915 37 Affinity to compound/name chemical name CB1 CB2 SUR SUR 1 2 / 4-Chloro-N-[[3-(4-chloro \- phenyl)-4-phenyl-4,5 IN dihydro-pyrazol-1-yl]-(2- 7,9 n/a 6,7 5,9

S

N _ cyano-ethylamino) methylene]-benzene sulfonamide C /i a 4-Chloro-N-[[3-(4-chloro phenyl)-4-phenyl-4,5 NO dihydro-pyrazol-1-yl]- 6,7 n/a 5,9 5,9 N (methoxy-methyl-amino) methylene] benzenesulfonamide C a 4-Chloro-N-{[3-(4-chloro phenyl)-4-phenyl-4,5 N dihydro-pyrazol-1-yl]-[( 8,6 n/a 6,2 4,9 N piperidin-4-ylmethyl) N amino]-methylene} benzenesulfonamide a O C 4-Chloro-N-[[3-(4-chloro N-\ / phenyl)-4-phenyl-4,5 N-k O dihydro-pyrazol-1-yl] N N (piperidin-4-ylamino)- 8,2 n/a 4,5 4,6 methylene] N benzenesulfonamide Cl o 0'o Morpholine-4-sulfonic acid \N [3-(4-chloro-phenyl)-4 N phenyl-4,5-dihydro pyrazol-1-yl]- 8,5 n/a 6,0 5,7 (cyclopropylmethyl-amino) c1 methyleneamide The data in Table 1 demonstrate that the tested CBx modulators act selectively on the SUR1 subunit and/or on the SUR 2 subunit.

WO 2007/125049 PCT/EP2007/053915 38 4. Determination of the KATP openincq 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±20C and humidity of 55±10%. Animals 5 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 001P), 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 10 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 370C. 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 15 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% 02/5% CO2) Gey & Gey buffer containing 1mg/ml bovine serum albumin and 4mM glucose were used throughout the experiment unless otherwise stated (see Dickinson 20 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). 25 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 30 baseline insulin values), the media in each chamber was switched to one containing 11 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 WO 2007/125049 PCT/EP2007/053915 39 as follows: Baseline (4mM): Samples 1-5 (first 10 minutes); 0-30 minutes (11mM glucose): Samples 6-21; 30-60 minutes (11mM glucose): Samples 22-36. Perifusate fractions were stored at -750C until required for insulin assay. Insulin content of fractions were assayed using a 96-well ELISA assay (Mercodia). Initial insulin assays 5 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 11 mM glucose was 98.3 ± 10 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 11mM glucose at 0-30 and 30-60 minutes, respectively. Data were initially expressed as a simple mean of the 15 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 20 significantly inhibited insulin secretion by an average of 55.3% (0-30 min) and 58.9% (30-60 min). Table 2 - KATP channel openers according to the procedure described hereinabove, expressed as % inhibition 25 WO 2007/125049 PCT/EP2007/053915 40 Compound/name Chemical name % Inhibition 0-30 / 30-60 O-NI o (2-lodo-5-nitro-phenyl)-[1-(1- 97 / 74 methyl-piperidin-2-ylmethyl)- 1 H N \ indol-3-yl]-methanone N'0 (= AM-1241) CI O N0N -1-(4-Chloro-phenyl)-2-(2-chloro- 59 / 45 phenyl)-5-ethyl-1 H-imidazole-4 carboxylic acid piperidin-1-ylamide c, (Bayer) 0 0- 5-(1,1-Dimethyl-heptyl)-2-[5- 91 / 56 hydroxy-2-(3-hydroxy-propyl) . cyclohexyl]-phenol (CP55940) 0 -- (2-Methyl-3-morpholin-4-ylmethyl 3,4-dihydro-5-oxa-2a I \ azacenaphthylen-1-yl)- 80 / 35 o. naphthalen-1 -yl-methanone o (R(+)-WIN55212-2) o - (2-Methyl-3-morpholin-4-ylmethyl - \-/3,4-dihydro-5-oxa-2a S\ azacenaphthylen-1-yl)- 69 / 40 o . ,naphthalen-1 -yl-methanone .(R(+)-WIN55212-2) WO 2007/125049 PCT/EP2007/053915 41 Compound/name Chemical name % Inhibition 0-30 / 30-60 a / 5-(4-Chloro-phenyl)-1l-(2,4 a ;dichloro-phenyl)-4-methyl-1 H Spyrazole-3-carboxylic acid 22 / 18 piperidin-1-ylamide 0 (Rimonabant) CO I 4-Chloro-N-{[3-(4-chloro-phenyl) 4-phenyl-4,5-dihydro-pyrazol-1l-yl]- 42 / 22 N-NI= ,O methylamino-methylene} N benzenesulfonamide CI | 4-Chloro-N-{[3-(4-chloro-phenyl) 4-phenyl-4,5-dihydro-pyrazol-1l-yl]- 59 / 25 N-N methylamino-methylene} N benzenesulfonamide C1 Cl N-{[3-(4-Chloro-phenyl)-4-pyridin 3-yl-4,5-dihydro-pyrazol-1-yl] N-N -- N ,o methylamino-methylene}-4- 58 / 31 N S trifluoromethyl F benzenesulfonamide F F F II 4-Chloro-N-{[3-(4-chloro-phenyl) 4-(3-fluoro-phenyl)-4,5-dihydro N-N pyrazol-1-yl]-methoxyamino- 90 / 95 so methylene}-benzenesulfonamide -/ Cl WO 2007/125049 PCT/EP2007/053915 42 Compound/name Chemical name % Inhibition 0-30 / 30-60 Cl Morpholine-4-sulfonic acid [3-(4 chloro-phenyl)-4-phenyl-4,5- 83 / 91 N-N dihydro-pyrazol-1-yl] SN o 110 methylamino-methyleneamide , N O 'N 0 F Cl N-{[3-(4-Chloro-phenyl)-4-(3 fluoro-phenyl)-4,5-dihydro-pyrazol- 72 / 77 N-N 1-yl]-methylamino-methylene} NO N,N-dimethyl-sulfonamide NS N O N CI Chiral CPiperidine-1-sulfonic acid [3-(4 N chloro-phenyl)-4-phenyl-4,5- 49 / 40 N dihydro-pyrazol-1 -yl] N methylamino-methyleneamide o= so Cl Piperidine-1-sulfonic acid [3-(4 N. chloro-phenyl)-4-phenyl-4,5 LN dihydro-pyrazol-1-yl]-(2- 71 / 64 OS0 dimethylamino-ethylamino) N methyleneamide N NS=o Piperidine-1-sulfonic acid [1-(4 N- chloro-phenyl)-5-phenyl-4,5- 84 / 47 dihydro-1 H-pyrazol-3-yl] cl methylamino-methyleneamide G Chird 1-[3-(4-Chloro-phenyl)-4-phenyl / 4,5-dihydro-pyrazol-1-yl]-3-(1H- 64 / 53 indol-2-yl)-2-methylamino-propan IIo 1-one WO 2007/125049 PCT/EP2007/053915 43 Compound/name Chemical name % Inhibition 0-30 / 30-60 N 1-(4-Chloro-phenyl)-2-(2-chloro I phenyl)-5-methylsulfanyl-1H- 56 / 36 imidazole-4-carboxylic acid piperidin-1-ylamide a This test provides proof that candidate compounds selected on the basis of their affinity for the KATP channel do inhibit glucose-stimulated insulin secretion. It can be 5 followed that the candidate compounds function as KATP channel openers under the conditions described hereinabove. All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference 10 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 15 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 20 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 25 ordinary skill in the art upon reading the foregoing disclosure. The inventors expect WO 2007/125049 PCT/EP2007/053915 44 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. 5 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 10 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 15 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 disclosed 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 20 considered include the criticality of the element and/or the effect a given amount of variation will have on the performance of the claimed 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 25 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 30 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.

WO 2007/125049 PCT/EP2007/053915 45 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 5 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 use of at least one CBx modulator wherein the CBx modulator is selected from the group consisting of CB 1 agonists; CB 2 agonists; CB 2 partial agonists; CB 2 an 5 tagonists; CB 2 inverse agonists; and dually acting compounds which are both a CB 1 agonist and a CB 2 agonist; and mixtures thereof, as KATP channel modulator for the prophylaxis, treatment, delayed progression, delayed onset and/or inhibi tion of obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperre 10 activity, 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.

2. A use of at least one CBx modulator wherein the CBx modulator is selected from 15 the group consisting of CB, agonists; CB 2 agonists; CB 2 partial agonists; CB 2 an tagonists; CB 2 inverse agonists; and dually acting compounds which are both a CB, agonist and a CB 2 agonist; and mixtures thereof, as KATP channel modulator for the manufacture of a medicament for the prophylaxis, treatment, delayed pro gression, delayed onset and/or inhibition of obesity, diabetes mellitus, metabolic 20 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, neurode generation, pain - including neuropathic pain and chronic pain - and impotence in 25 mammals and humans.

3. Use according to any of Claims 1 or 2 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 30 as hypertriglyceridaemia accompanied by dyslipoproteinaemia occurring with lowered HDL-cholesterol and hyperuricaemia. WO 2007/125049 PCT/EP2007/053915 47

4. A method of treating, preventing, delaying progression of, delaying onset of and/or inhibiting obesity, diabetes mellitus, metabolic syndrome, syndrome X, in sulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, 5 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 CBx modulator wherein the CBx modulator is selected from the group 10 consisting of CB 1 agonists, CB 2 agonists, CB 2 partial agonists, CB 2 antagonists, CB 2 inverse agonists and dually acting compounds which are both a CB 1 agonist and a CB 2 agonist wherein the CBx modulator having KATP channel modulating properties.

5. Use according to any of Claims 1 to 3, or method according to Claim 4 wherein 15 the KATP channel modulator is a modulator of at least one channel selected from the group consisting of: the Kir6.2/SUR1 KATP channel, the Kir6.2/SUR2B KATP channel, the Kir6.1/SUR2B KATP channel, and the Kir6.2/SUR2A KATP channel.

6. Use according to any of Claims 1 to 3 and 5, or method according to Claims 4 and 5 wherein the KATP channel modulator is a KATP channel opener. 20

7. Use according to any of Claims 1 to 3, 5 and 6, or method according to Claims 4 to 6 wherein the at least one CBx modulator is selected from the group consisting of: 3-(1,1 -dimethyl-butyl)-6,6,9-trimethyl-6a,7,10,10 Oa-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 25 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,7,10,10 Oa tetrahydro-6H-enzo[c]chromen-1-ol; Icosa-5,8,11,14-tetraenoic acid 2-hydroxy-1 30 hydroxymethyl-ethyl ester; 1-Aziridin-1 -yl-henicosa-6,9,12,15-tetraen-2-one; Noladineether; 4,4,4-Trifluoro-butane-1l-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)- WO 2007/125049 PCT/EP2007/053915 48 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 5 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 10 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 15 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} 20 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-1l-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5 dihydro-pyrazol-1 -yl]-methylamino-methyleneamide; 4-Chloro-N-{[3-(4-chloro 25 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-1H-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 30 pyrazol-1 -yl]-methylamino-methyleneamide; Piperidine-l-sulfonic acid [3-(4 chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(2-dimethylamino-ethylamino) methyleneamide; N,N-Diethylamino-l-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; 35 Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1- WO 2007/125049 PCT/EP2007/053915 49 yI]-methylami no-methyleneamnide; N,N-Dimethylamino-1 -sulfonic acid [3-(4 chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yI]-(2-fluoro-ethylamino) methyleneamide; Piperidine- 1 -sulfonic acid [3-(4-chloro-phenyl)-4-(3-fluoro phenyl)-4,5-dihydro-pyrazol-1 -yI]-methylamino-methyleneamide; 5-(4-Chloro 5 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-yI]-methylamino-methyleneamide; Morpholine-4-sulfonic acid [1 -(2,4-dichloro-phenyl)-5-phenyl-4,5-dihydro-1 H 10 pyrazol-3-yI]-methylamino-methyleneamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4 phenyl-4,5-dihydro-pyrazol- 1 -yI]-(2-fluoro-ethylamino)-methylene] benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro pyrazol-1 -yI]-(2-fluoro-ethylamino)-methylene]-benzenesulfonamide; N-{Amino-[3 (4-chloro-phenyl)-4-phenyl-4, 5-dihydro-pyrazol-1 -yI]-methylene}-4-chloro 15 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 -yI]-(2-ethylamino-ethylamino)-methylene] benzenesulfonamide; 4-Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro pyrazol-1 -yI]-[(l -methyl-pyrrolidin-2-ylmethyl)-amino]-methylene 20 benzenesulfonamide; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro pyrazol-1 -yI]-(4-pyrrolidin-1 -yI-butylamino)-methylene]-benzenesulfonamide; 4 Chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yI]-[(pyridin-3 ylmethyl)-amino]-methylene}-benzenesulfonamide; 1 -[3-(4-Chloro-phenyl)-4 phenyl-4,5-dihydro-pyrazol-1 -yI]-3-(l H-indol-2-yI)-2-methylamino-propan-1 -one; 25 2-[3-(4-Chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol- 1 -yI]-5-ethyl-4,5-dihydro oxazole; 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yI]-(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 -yI]-methylamino-methyleneamide; 5-(4-Bromo-phenyl)-1 -(2,4-dichioro 30 phenyl)-1 H-pyrazole-3-carbonitrile; 8-Chloro-1 -(2,4-dichioro-phenyl) 1 ,3a,4,5,6, 1 b-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-l1-carboxylic acid [5 (4-chloro-phenyl)-l1-(2,4-dichloro-phenyl)-4-methyl-l1H-pyrazol-3-yI]-amide; 1 -(4 35 Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-ethylsulfanyl-1 H-imidazole-4-carboxylic WO 2007/125049 PCT/EP2007/053915 50 acid piperidin-1-ylamide; 2-(2,4-Dichloro-phenyl)-1l-(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 5 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 10 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 15 1H-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 20 ethyl-1 -phenyl- 1 H-imidazole-4-carboxylic acid cyclohexylamide; 1-(4-Chloro phenyl)-5-ethyl-2-(3-methyl-pyridin-2-yl)-I 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-l H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1-(4-Bromo-phenyl) 25 5-chloro-2-(2,4-dichloro-phenyl)- 1H-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)-l1-methyl-1 H-imidazole-2-carboxylic acid cyclohexylamide; 4-(4 30 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 35 4-carboxylic acid azepan-1 -ylamide; 2-(2,4-Dichloro-phenyl)-5-ethyl-1 -phenyl-1 H- WO 2007/125049 PCT/EP2007/053915 51 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)-I H-imidazole-4-carboxylic acid piperidin 1-ylamide; 1-(4-Chloro-phenyl)-5-ethyl-2-(3-methyl-pyridin-2-yl)-lH-imidazole-4 5 carboxylic acid cyclohexylamide; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5 methyl-l 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 10 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 15 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)-l H imidazole-4-carboxylic acid piperidin-1-ylamide; N-[1-(4-Chloro-phenyl)-2-(2,4 20 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-l H imidazol-4-yl]-hexan-2-ol; 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methyl-4 pentyl-l H-imidazole; 2,5-Dimethyl-l-phenyl-l H-imidazole-4-carboxylic acid ada 25 mantan-2-ylamide; 1-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-methylsulfanyl-l H imidazole-4-carboxylic acid piperidin-1 -ylamide; 2-(2-Chloro-phenyl)- 1-(4 trifluoromethyl-phenyl)-l 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)-I -(2,4-dichloro-phenyl)-I H-[1,2,4]triazole-3 30 carboxylic acid pyrrolidin-1-ylamide; 1-(4-Chloro-phenyl)-5-(2,4-dichloro-phenyl) 1H-[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 35 dihydro-pyrazol-1-yl]-methyl}-piperidine-4-carboxylic acid amide; 4-Chloro-N-{[3- WO 2007/125049 PCT/EP2007/053915 52 (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] 5 (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 10 yl]-(cyclopropylmethyl-amino)-methyleneamide.

8. Use according to any of Claims 1 to 3, 5 to 7, or method according to Claims 4 to 7 wherein the at least one CBx modulator is selected from the group consisting of: 3-(1,1 -dimethyl-butyl)-6,6,9-trimethyl-6a,7,10,10 Oa-tetrahydro-6H benzo[c]chromene; N-Adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; N 15 {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,7,10,10 Oa 20 tetrahydro-6H-enzo[c]chromen-1-ol; Icosa-5,8,11,14-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-1l-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) 25 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 30 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)-1l-(2,4 dichloro-phenyl)-4-ethyl-1 H-pyrazole-3-carboxylic acid piperidin-1-ylamide; 1- WO 2007/125049 PCT/EP2007/053915 53 [Bis-(4-chloro-phenyl)-methyl]-3-[(3,5-difluoro-phenyl)-methanesulfonyl methylene]-azetidine;

9. Use according to any of Claims 1 to 3 and 5 to 8, or method according to Claims to 8 wherein the at least one CBx modulator is selected from the group consisting 5 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) 10 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 15 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]-[(l -methyl 20 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)-1l-(4-trifluoromethyl-phenyl)-1 H-imidazole-4-carboxylic acid piperidin-1 25 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 30 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- WO 2007/125049 PCT/EP2007/053915 54 dichloro-phenyl)-5-methylsulfanyl-1 H-imidazole-4-carboxylic acid cyclohexyla mide; 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 5 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 10 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]-methylene}-benzenesulfonamide; 4-Chloro N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(2-cyano-ethylamino) 15 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.

10. Use according to any of Claims 1 to 3, 5 and 6, or method according to Claims 4 20 to 6 wherein the CB 1 agonist or CB 2 agonist is selected from 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] 25 chromene (JWH133); N-adamantantyl-4-pentyl-5-phenyl-thiazole-2-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; 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 30 acenaphthylen-1 -yl)-naphthalen-1 -yl-methanone (= WIN-55,212-2); ACEA; ACPA; N-adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; methanan damide; anandamide; 2-arachidonoyl glycerol; 2-icosa-5,8,11,14-tetraenyloxy propane- 1,3-diol (= noladin ether); BAY 38-7271; SAB-378; BAY 59-3074; O- WO 2007/125049 PCT/EP2007/053915 55 1057; GW-1000; PRS-211375; PRS-211359; PRS-211355; PRS-211096; PXS 2076; AM-577; GW-842166X; and mixtures thereof.

11. Use or method according to Claim 10 wherein the CB 2 agonist is a selective CB 2 agonist and is selected from the group consisting of: 3-(1,1-dimethyl-butyl)-6,6,9 5 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. 10

12. Use according to any of Claims 1 to 3, 5, 6, 10 to 11, or method according to Claims 4, 5, 6, 10 to 11 wherein the CB 2 antagonist or the CB 2 inverse agonist is selected from the group consisting of: (1) compounds described in documents WO01/0588869, PCT/EP2006/060009, WO2004/014825; EP1142877; US2002/0072529; W002/062750; US 6,509,352; and (2) compounds selected 15 from the group consisting of: N-{1,3,3-Trimethyl-endo-(1S)-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).

13. Use according to any of Claims 1 to 3, 5, 6, 10 to 12, or method according to 20 Claims 4, 5, 6, 10 to 12 wherein the dually acting compound which is both a CB 1 agonist and a CB 2 agonist, is selected from the group consisting of: 2-icosa 5,8,11,14-tetraenyloxy-propane-1,3-diol (= noladin ether); and mixtures thereof.

14. Use according to any of Claims 1 to 3, 5, 6, 10 to 13, or method according to Claim 4, 5, 6, 10 to 13 wherein the CBx modulator is selected from the group 25 consisting of: 6,6,9-trimethyl-3-pentyl-6a,7,8,10 Oa-tetrahydro-6H benzo[c]chromen-1 -ol; N-(Endo-bicyclo[2.2.1 ]hept-2-yl)-5-pentyl-4-phenyl thiazole-2-carboxamide; 3-(1,1 -dimethyl-butyl)-6,6,9-trimethyl-6a,7,10,10 Oa tetrahydro-6H-benzo[c]chromene; N-adamantyl-4-pentyl-5-phenyl-thiazole-2 carboxamide; 1-[1-Benzyl-5-(4-chloro-3-methyl-phenyl)-1 H-pyrazol-3-yl] 30 ethanonyl-1,3,3-trimethyl-bi-cyclo[2.2.1]hept-2-ylamine; (2-iodo-5-nitro-phenyl)-[1 (1 -methyl-piperidin-2-ylmethyl)-1 H-indol-3-yl]-methanone; {4-[4-(1,1 -Dimethyl- WO 2007/125049 PCT/EP2007/053915 56 heptyl)-2,6-dimethoxy-phenyl]-6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl} methanol; and mixtures thereof.