JP2009534440A - Use of CBX cannabinoid receptor modulators as potassium channel modulators - Google Patents

Abstract

The present invention relates to CB _x modulators, wherein CB _x modulators are CB ₁ agonists; CB ₂ agonists; CB ₂ partial agonists; CB ₂ antagonists; CB ₂ inverse agonists; and both CB ₁ agonists and CB ₂ agonists. At least one selected from the group consisting of certain dual-acting compounds and mixtures thereof with obesity, diabetes, metabolic syndrome, syndrome X, islet cell tumor, familial hyperinsulin hypoglycemia, male baldness, compression Muscle hyperreactivity, asthma, neuroprotection, mania, pain palsy, cardioprotection, angina, heart palsy, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite adjustment, nerve degeneration, pain-neuralgia and chronic Including pain-and prevention, treatment, delayed progression and delayed onset and / or suppression of incompatibility in mammals and humans It is intended to be used as a K _ATP channel modulators for. Furthermore, the present invention relates to obesity, diabetes, metabolic syndrome, syndrome X, islet cell tumor, familiality, when at least one CB _x modulator having _KATP channel regulatory properties is applied to a patient in need thereof. Hyperinsulin hypoglycemia, male type baldness, compression muscle hyperreactivity, asthma, neuroprotection, mania, pain palsy, cardioprotection, angina, heart palsy, arrhythmia, coronary artery spasm, peripheral vascular disease, cerebral vasospasm, Appetite regulation, nerve degeneration, pain-including neuralgia and chronic pain-and methods for treating, preventing, delaying progression and delaying and / or suppressing various disease states including incompatibility in mammals and humans .

Description

The present invention relates to a novel use of CB _X modulators as _KATP channel modulators. Furthermore, the present invention relates to obesity, diabetes, metabolic syndrome, syndrome X, islet cell tumor, comprising applying to a patient in need thereof at least one CB _x modulator as an effective amount of K _ATP channel modulator, Familial hyperinsulinemia, male baldness, compression muscle hyperreactivity, asthma, neuroprotection, mania, pain palsy, cardioprotection, angina, heart palsy, arrhythmia, coronary spasm, peripheral vascular disease, cerebrovascular It also relates to methods of treating, preventing, delaying progression and delaying onset and / or suppressing convulsions, appetite regulation, nerve degeneration, pain—including neuralgia and chronic pain—and incompetence in mammals and humans.

BACKGROUND ART Obesity in the present invention means an increase in body fat that results in weight gain, but is not limited to the medical definition of obesity. That is, obesity according to the present invention includes non-medical, for example, cosmetic overweight. Thus, the present invention also relates to non-medical weight loss, for example, cosmetic weight loss and general physical appearance improvements. In a narrower sense, obesity is usually understood to mean a weight that is 20% above the ideal weight. In Western society, obesity in this narrower sense is an important health concern. It is estimated that approximately 97 million American adults are overweight or obese. Obesity is the result of a positive energy balance, mostly as a result of an increase in the ratio of caloric absorption to energy expenditure. Although the molecular factors that regulate food intake and body weight are not fully understood, several genetic factors have been identified.

  Epidemiological studies have shown that the degree of overweight and obesity is an important reminder of a decrease in life expectancy. Obesity causes or exacerbates many health problems that are independent and combined with other diseases. Medical problems associated with severe and life-threatening obesity generally include the following: hypertension; type II diabetes; high plasma insulin levels; insulin resistance; dyslipidemia; Endometriosis; breast cancer; prostate and colon cancer; osteoarthritis; respiratory complications such as sleep breathing disorder; cholelithiasis; gallstones; arteriole sclerosis; heart disease; heart failure; In addition, obesity is associated with premature death from stroke, myocardial infarction, congestive heart failure, premature ring arterial disease and a significant increase in mortality and pathology and sudden death.

  Obesity is often treated by promoting weight loss in patients by reducing food intake or increasing their exercise level and concomitantly increasing energy excretion. Sustained weight loss of 5% to 10% of body weight has been shown to improve comorbidities associated with obesity, such as diabetes and hypertension, and obesity-related symptoms such as osteoarthritis, sleep disordered breathing and lung and heart Improve functional impairment.

  Weight loss agents commonly used in monotherapy for the treatment of obesity have limited efficacy and side effects. During a chronic treatment period of more than 6 months, the efficacy of most drugs declines and weighs less than 10% compared to controls. Obese people can easily have a weight of more than 150 kg, so it is necessary to lose more than 50% of their body weight to return to normal body weight.

  The term “metabolic syndrome” —in addition to central obesity—mainly associated with hypertension, especially arterial hypertension; insulin resistance; especially type II diabetes; glucose intolerance; abnormal lipoproteinemia, especially reduced HDL-cholesterol It is meant to encompass complex clinical features, including hypertriglyceridemia associated with abnormal lipoproteinemia and hyperuricemia that can lead to gout.

  According to information from the American Heart Association, metabolic syndrome is closely associated with insulin resistance. Some people are genetically susceptible to insulin resistance. Acquired factors, such as overweight fat and lack of exercise, can induce insulin resistance and metabolic syndrome in these people. Most people with insulin resistance have central obesity. The biological mechanisms at the molecular level between insulin resistance and metabolic risk factors are not fully understood and are clearly complex. The group of people at risk for developing metabolic syndrome are those with diabetes who have deficiencies in insulin action and are unable to maintain the proper concentration of sugars in their blood. Others have people who are primarily hypertensive, non-diabetic and insulin resistant, but make up for it by secreting a large amount of insulin. This condition is known as hyperinsulinemia. The third group is heart attack survivors, who, unlike hypertension, are people with hyperinsulinemia who do not have abnormal sugar levels. Metabolic syndrome is generally increasing in high-developed countries such as the United States, and it is estimated that about 20-25% of US adults have it. There are no well-accepted criteria for diagnosing metabolic syndrome.

The standard proposed by the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 3rd report (Adult Treatment Panel III) is the most common and widely used. . According to this ATPIII standard, metabolic syndrome has been identified by the presence of three or more of the following elements:
a. Central obesity measured around the waist (male-40 inches or more; women-35 inches or more),
b. Fasting blood triglycerides 150 mg / dL or more,
c. Blood HDL cholesterol (male-40 mg / dL or less; female-50 mg / dL or less),
d. Blood pressure 130 / 85mmHg or more,
e. Fasting glucose 110 mg / dL or more.

  The term “syndrome X” is closely related to the term “metabolic syndrome” and is usually considered to refer to the same disease or condition. However, according to information from the American Heart Association, the term “syndrome X” additionally indicates electrocardiographic changes indicating chest pain and ischemic heart disease, but angiographic findings of coronary artery disease. Not related to heart symptoms. Patients with cardiac syndrome X sometimes also have lipid abnormalities.

  Therefore, one subject of the present invention is obesity, diabetes, metabolic syndrome, syndrome X, islet cell tumor, familial hyperinsulin hypoglycemia, male baldness, compression muscle hyperreaction, asthma, neuroprotection, mania, pain palsy , Cardioprotection, angina pectoris, heart failure, arrhythmia, coronary artery spasm, peripheral vascular disease, cerebrovascular spasm, appetite adjustment, nerve degeneration, pain-including neuralgia and chronic pain-and more effective for incompatibility and / or It was to provide a more selective treatment.

ATP-sensitive potassium channel (K _ATP channel) regulation is diabetic, pancreatic islet cell tumor, familial hyperinsulin hypoglycemia, male baldness, compression muscle hyperreactivity, asthma, neuroprotection, mania, painful numbness, heart Protection, angina, heart failure, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite adjustment, nerve degeneration, pain-including neuralgia and chronic pain-and several in clinical practice including incompatibility Linked to possible uses (see Jahangir et al. J. Mol. Cell. Cardiology, 2005, 39, 99-112 and references cited therein).

K _ATP channel openers and their possible use in the inhibition of insulin secretion and / or treatment of metabolic deficiencies are described, for example, in publications US6492130; WO 02/00223; WO 02/00665 or RDCarr et al. Diabetes 52 (2003) 2513. -2518 or JBHansen et al. Current Medicinal Chemistry 11 (2004) 1595-1615.

The beneficial role of specific _KATP channel opener diazoxide in particular in the treatment of metabolic syndrome is known, e.g. publication US52848445 or US6197765 or R.Alemzadeh et al. Alemzadeh et al., Journal of Clinical Endocrinology and Metabolism 83 (6) (1998) 1911-1915.

K _ATP channels link glucose metabolism to insulin secretion. Incomplete regulation of _KATP channel activity has been reported to contribute to the etiology of type 2 diabetes (Ashcroft, J. Clin. Investig. 2005, 115 (8), 2047-2057 and therein). See cited references). The _KATP channel is Kir6. It is an octamer complex of 4 x (x = 1 or 2) and 4 regulated SURy subunits (y = 1, 2A or 2B). SUR1 regulatory subunits are particularly present in the pancreas and brain (see Aguilar-Bryan et al. Science 1995, 268, 423-426). The _KATP Kir6.2 / SUR1 combination is present in the pancreas. Its structure was recently determined (see Mikhailov, EMBO Journal, 2005, 24, (23), 4166-4175). Recent advances in the discovery of ATP-sensitive potassium channel openers have been reported (see Pirotte et al., EXP. Opin. Ther. Patents 2005. 15 (5), 497-504).

  Insulin is involved in blood glucose homeostasis. Insulin is involved in the regulation of glycemia and as a result is associated with type I and type II diabetes. In addition, insulin induces anorexia because it is involved in adipogenesis and weight gain and it causes satiety when acting in the brain (Juan-Pico et al., Cell Calcium 2006, 39, 155-163 and references cited therein).

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

Endocannabinoids ((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, DM and Fowler, CJJMed. Chem. 2005, 48, 5059-5087) reported to play a role in the physiological regulation of food intake, energy balance and sugar and lipid metabolism Has been. The presence of two cannabinoid CB ₁ and CB ₂ receptors has been described in pancreatic endocrine secretions. The endogenous CB _1/2 receptor agonist 2-arachidonoyl glycerol (2-AG) (FIG. 2) transmits [Ca ²⁺ ] i signal in β-cells in pancreatic endocrine secretion via the CB ₂ receptor. Adjusted and as a result (as inferred by Juan-Pico et al.) This has been reported to reduce insulin secretion (Juan-Pico et al., Cell Calcium 2006,39,155-163 reference). Recent advances in the field of CB ₂ receptor ligands have been reported by Raitio etc. (see Curr.Med. Chem. 2005,12,1217-1237).

Meanwhile Surprisingly, the quantitative effect effect observed when using CB _x modulator in the symptoms was found greater than a CB _x can anticipated and described solely mechanisms regulating. More thorough studies have demonstrated that CB _x modulators act as _KATP channel modulators. Therefore CB _x modulator can be used for for and it all diseases and diseases which require opening of a K _ATP channel. More specifically, CB _x modulators are obesity, diabetes, metabolic syndrome, syndrome X, islet cell tumor, familial hyperinsulin hypoglycemia, male baldness, compression muscle hyperreactivity, asthma, neuroprotection, epilepsy, nociception Paralysis, cardioprotection, angina, heart palsy, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite adjustment, nerve degeneration, pain-including neuralgia and chronic pain-and incompatibility of mammals and humans Can be used for the treatment, prevention, delay of progression and delay and / or suppression of onset.

SUMMARY OF THE INVENTION In a first aspect, the invention relates to a dual acting compound that is both a CB ₁ agonist, a CB ₂ agonist; a CB ₂ partial agonist; a CB ₂ antagonist; a CB ₂ inverse agonist; and a CB ₁ agonist and a CB ₂ agonist. At least one CB _x modulator selected from the group consisting of: obesity, diabetes, metabolic syndrome, syndrome X, islet cell tumor, familial hyperinsulin hypoglycemia, male baldness, compression muscle hyperreactivity, Asthma, neuroprotection, mania, pain palsy, cardioprotection, angina, heart palsy, arrhythmia, coronary artery spasm, peripheral vascular disease, cerebrovascular spasm, appetite adjustment, nerve degeneration, pain-including neuralgia and chronic pain- And K _ATP channel for prevention, treatment, delaying progression and delaying and / or suppression of incompatibility in mammals and humans To use as a modulator.

In a second aspect, the invention relates to obesity, diabetes, metabolic syndrome, syndrome X, islet cell tumor, familial hyperinsulin hypoglycemia comprising applying an effective amount of a CB _x modulator to a patient in need thereof Masculine baldness, compression muscle hyperreactivity, asthma, neuroprotection, mania, pain palsy, cardioprotection, angina, heart palsy, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite adjustment, nerve degenerate, pain - include neuralgia and chronic pain - and mammals and treating intercourse impotence in humans, prevention, delay of progression of, and delaying the onset of and / or a method of suppressing, where CB _x modulator, CB ₁ agonists , CB ₂ agonist; both with and CB ₁ agonists and CB ₂ agonist; CB ₂ partial agonist; CB ₂ antagonist; CB ₂ inverse agonists That two yuan active compound at least one and selected from the group of mixtures thereof, the CB _x modulator has a K _ATP channel modulating properties.

DETAILED DESCRIPTION OF THE INVENTION In one aspect of the invention, a CB _x modulator, as a _KATP channel modulator, is obesity, diabetes, metabolic syndrome, syndrome X, islet cell tumor, familial hyperinsulin hypoglycemia, male baldness, Compression muscle hyperreactivity, asthma, neuroprotection, mania, pain palsy, cardioprotection, angina, heart palsy, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, nerve degeneration, pain-neuralgia And chronic pain-and used for the prevention, treatment, delay of progression, delay of onset and / or suppression of incompatibility in mammals and humans. More specifically, when the CB _x modulator is used for prevention, treatment, delay of progression, delay of onset and / or suppression of metabolic syndrome and / or syndrome X, the metabolic syndrome and / or syndrome X is Hypertension, especially arterial hypertension; insulin resistance, especially type II diabetes; sugar intolerance; abnormal lipoproteinemia, especially abnormal lipoproteinemia that occurs with low HDL-cholesterol and hyperuricemia It is understood to consist of a disease or condition selected from the group consisting of hypertriglyceridemia.

Suitable K _ATP channel modulators are preferably compounds having the effect of acting as complete or partial openers of Kir6.2 / SUR1K _ATP channel and / or Kir6.2 / SUR2K _ATP channel. A test for the affinity of a compound that binds to rat and / or human isoforms of SUR1 and / or SUR2, such as the sulfonylurea (= SUR) and potassium channel opener sites (= KCO) of the test model prepared below: Compounds showing an IC ₅₀ value [μmol] below ₅₀ are effective. Kir6.2 / as a complete or partial openers SUR1K _ATP channel, in particular Kir6.2 / SUR1K compound which is effective as selective openers of _ATP channel advantageously. Kir6.2 / compounds having effects as full or partial openers SUR1K _ATP channel, its _{an IC 50} value in the Kir6.2 / SUR1K _ATP channel as measured by the binding assay of the can, the same compound It is understood that it should be selected if it is below 1/2, more preferably 1/4, of its IC ₅₀ value on the Kir6.2 / SUR2K _ATP channel.

Surprisingly, it has been discovered that CB _x modulators from distinct structural groups act as effective and SUR1 / SUR2 selective K _ATP Kir6.2 channel modulators. CB _y modulators in the present invention are CB ₁ agonists; CB ₂ agonists; CB ₂ partial agonists; CB ₂ antagonists; CB ₂ inverse agonists; and dual acting compounds that are both CB ₁ agonists and CB ₂ agonists; It is a mixture of The K _ATP channel modulator is preferably a SUR1 / K _ATP Kir6.2 channel modulator, in particular a SUR1 / K _ATP Kir6.2 channel modulator or a partial SUR1 / K _ATP Kir6.2 channel modulator. Preferred CB _x modulator is the Kir6.2 / SUR1K _ATP channel, Kir6.2 / SUR2BK _ATP channel, compounds that act as modulators at the Kir6.1 / SUR2BK _ATP channels and / or Kir6.2 / SUR2AK _ATP channel .

In a preferred embodiment of the invention, the _KATP channel modulator is a _KATP channel opener.

CB _x modulators suitable for use as _KATP channel modulators in the present invention are selected from, but not limited to, the following group of compounds: 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) -1H-pyrazole-3-carboxamide; (2-iodo-5-nitro-phenyl)-[1- (1-methyl-piperidin-2-ylmethyl) -1H-indole-3-i ] -Methanone; {4- [4- (1,1-dimethyl-heptyl) -2,6-dimethoxy-phenyl] -6,6-dimethyl-bicyclo [3.1.1] hept-2-ene-2 -Yl} -methanol; 3- (1,1-dimethyl-heptyl) -9-hydroxymethyl-6,6-dimethyl-6a, 7,10,10a-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; Gin ether; 4,4,4-trifluoro-butane-1-sulfinic acid 3- (2-hydroxymethyl-indan-4-yloxy) -phenyl ester, compound having aldehyde form 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-iodo-2-methyl-1- (2-morpholin-4-yl- Ethyl) -2,3-dihydro-1H-indol-3-yl]-(4-methoxy-phenyl) -methanone; 1- (4-chloro-phenyl) -2- (2-chloro-phenyl) -5 Ethyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; (2-methyl-1-propyl-2,3-dihydro-1H-indol-3-yl) -naphthalene-1- Ru-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-azacenaphthylene-1-yl) -naphthalene-1-methanone; 5- (4-chloro-phenyl) -1- (2,4-dichloro-phenyl) -4- Methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide; 5- (4-bromo-phenyl) -1- (2,4-dichloro-phenyl) -4-ethyl-1H-pyrazole-3-carboxylic acid Piperidin-1-ylamide; 1- [bis- (4-chloro-phenyl) -methyl] -3-[(3,5-difluoro-phenyl) -methanesulfonyl-methylene -Azetidine; 4-chloro-N-{[3- (4-chloro-phenyl) -4-phenyl) -4,5-dihydro-pyrazol-1-yl] -methylamino-methylene} -benzenesulfonamide; N -{Amino- [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -methylene} -4-chloro-benzenesulfonamide; N-{[3 (- 4-Chloro-phenyl) -4-pyridin-3-yl-4,5-dihydro-pyrazol-1-yl] -methylamino-methylene} -4-trihiloromethyl-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} -benzenesulfone Amido; morpholine-4-sulfonic acid [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -methylamino-methyleneamide; N-{[3- (4 -Chloro-phenyl) -4- (3-fluoro-phenyl) -4,5-dihydro-pyrazol-1-yl] -methylamino-methylene} -N, N-dimethyl-sulfonamide; azepane-1-sulfonic acid [3- (4-Chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -methylamino-methyleneamide; 4-chloro-N-{[3- (4- 1- (4-roro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(1-methyl-pyrrolidin-3-ylmethyl) -amino] -methylene) -benzenesulfonamide; Chloro-phenyl) -5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxamidine; N-{[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1 -Yl] -methylamino-methylene} -4-trifluoromethyl-benzene-sulfonamide; piperidine-1-sulfonic acid [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazole- 1-yl] -methylamino-methyleneamide; piperidine-1-sulfonic acid [3- (4-chloro-phenyl) -4-phenyl-4,5-di Dro-pyrazol-1-yl]-(2-dimethylamino-ethylamino) -methyleneamide; N, N-diethylamino-1-sulfonic acid [3- (4-chloro-phenyl) -4-phenyl-4,5 -Dihydro-pyrazol-1-yl] -methylsulfanyl-methyleneamide; 2-amino-1- [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]- 3- (3,4-dichloro-phenyl) -propan-1-one; morpholine-4-sulfonic acid [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl ] -Methylamino-methyleneamide; N, N-dimethylamino-1-sulfonic acid [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1 -Yl]-(2-fluoro-ethylamino) -methyleneamide; piperidine-1-sulfonic acid [3- (4-chloro-phenyl) -4- (3-fluoro-phenyl) -4,5-dihydro-pyrazole -1-yl] -methylamino-methyleneamide; 5- (4-chloro-phenyl) -1- (2,4-dichloro-phenyl) -4,5-dihydro-1H-pyrazole-3-carboxylic acid piperidine- 1-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-1H-pyrazol-3-yl] -methylamino-methyleneamide; morpholine-4-sulfonic acid [1 (2,4-dichloro-phenyl) -5-phenyl-4,5-dihydro-1H-pyrazol-3-yl] -methylamino-methyleneamide; 4-chloro-N-[[3- (4-chloro- Phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-fluoro-ethylamino) -methylene] -benzenesulfonamide; 4-chloro-N-[[3- (4-chloro -Phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-fluoro-ethylamino) -methylene] -benzenesulfonamide; N- {amino- [3- (4-chloro- Phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -methylene} -4-chloro-benzenesulfonamide; 4-chloro-N- [3- (4-chloro-phenyl) ) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -benzenesulfonamide; 4-chloro-N-[[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro -Pyrazol-1-yl]-(2-ethylamino-ethylamino) -methylene] -benzenesulfonamide; 4-chloro-N-{[3- (4-chloro-phenyl) -4-phenyl-4,5 -Dihydro-pyrazol-1-yl]-[(1-methyl-pyrrolidin-2-ylmethyl) -amino] -methylene} -benzenesulfonamide; 4-chloro-N-[[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-(4-pyrrolidin-1-yl-butylamino) -methylene] -benzenesulfonamide; 4-chloro-N -{[3- (4-Chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(pyridin-3-ylmethyl) -amino] -methylene} -benzenesulfonamide; 1 -[3- (4-Chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -3- (1H-indol-2-yl) -2-methylamino-propane-1- ON; 2- [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -5-ethyl-4,5-dihydro-oxazole; 4-chloro-N- [[3- (4-Chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-(3-hydroxy-2,2-dimethyl-propylamino) -methylene] -benzenesulfonamide N, N-dimethylamino-1-sulfonic acid [3- (4-chloro-phenyl) -4-hydroxy-4-phenyl-4,5-dihydro-pyrazol-1-yl] -methylamino-methyleneamide; 5 -(4-Bromo-phenyl) -1- (2,4-dichloro-phenyl) -1H-pyrazole-3-carbonitrile; 8-chloro-1- (2,4-dichloro-phenyl) -1,3a, 4,5,6,10b-Hexahydro-1,2-diaza-benzo [e] azulene-3-carboxylic acid piperidin-1-ylamide; 5- (4-bromo-phenyl) -1- (2,4-dichloro -Phenyl) -3- [2- (3,5-difluoro-phenyl) -2-methanesulfonyl-vinyl] -4-methyl-1H-pyrazole; piperidine-1-carboxylic acid [5- (4-chloro Phenyl) -1- (2,4-dichloro-phenyl) -4-methyl-1H-pyrazol-3-yl] -amide; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) ) -5-ethylsulfanyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 2- (2,4-dichloro-phenyl) -1- (4-trifluoromethyl-phenyl) -1H-imidazole-4 -Carboxylic acid piperidin-1-ylamide; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methylsulfanyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -1H-imidazole-4-carboxylic acid piperidin-1-ylamino 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-1H-imidazole-4-carboxylic 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-1H-imidazole-4-carboxylic acid cyclohexylamide; 1- (4-bromo-phenyl) -2- ( 2,4-dichloro-phenyl) -5-ethyl-1H-imidazole-4-carboxylic acid pentylamide; 4- (4-chloro-phenyl) -5- (2,4-dichloro-phenyl) -1-methyl- 1H-imidazole-2-carboxylic acid cyclohexylamide; 4- (4-chloro-phenyl) -5- (2,4-dichloro-phenyl) -3-methyl-1H-imidazole-2-carboxylic acid cyclohexylamide; (5-Chloro-pyridin-2-yl) -2- (2,4-dichloro-phenyl) -5-ethyl-1H-imidazole-4-carboxylic acid piperidine-1 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylic acid (4-hydroxy-cyclohexyl) -amide; 1- (4 -Chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylic 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-1H-pyrrol-2-yl) -5-ethyl-1-phenyl-1H-imidazole 4-carboxylic acid cyclohexylamide; 1- (4-chloro-phenyl) -5-ethyl-2- (3-methyl-pyridin-2-yl) -1H-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-1H-imidazole-4-carboxylic 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-1H-imidazole-4-carboxylic acid cyclohexylamide; 1- (4-bromo-phenyl) -2- (2,4-dichloro-phenyl) -5 Ethyl-1H-imidazole-4-carboxylic acid pentylamide; 4- (4-chloro-phenyl) -5- (2,4-dichloro-phenyl) -1-methyl-1H-imidazole-2-carboxylic acid 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-1H-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-cyclohexyl) -amide; 1- (4-chloro-phenyl) -2- 2,4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylic 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-1H-pyrrol-2-yl) -5-ethyl-1-phenyl-1H-imidazole-4-carboxylic acid cyclohexylamide; (4-Chloro-phenyl) -5-ethyl-2- (3-methyl-pyridin-2-yl) -1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1- (4-chloro-phenyl)- 5-ethyl-2- (3-methyl-pyridin-2-yl) -1H-imidazole-4-carboxylic acid cyclohexylamide; 1- (4-chloro-phenol ) -2- (2,4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylic acid (4-trifluoromethyl-phenyl) -amide; 2- (2,4-dichloro-phenyl) -5-methyl-1-pyridin-2-yl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5 -Fluoromethyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-hydroxymethyl-1H-imidazole-4 -Carboxylic acid piperidin-1-ylamide; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methylsulfanyl-1H-imi Dazole-4-carboxylic acid cyclohexylamide; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methanesulfonyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methanesulfinyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 5- (4-chloro-phenyl) -4- (2,5-dichloro-phenyl) -1-methyl-1H-imidazole-2-carboxylic acid piperidin-1-ylamide; 2- (2-chloro-phenyl) -1- (5-chloro-pyridine- 2-yl) -5-ethyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1- (4-chloro-phenyl) -2- 2,4-dichloro-phenyl) -5- (2,2,2-trifluoro-ethyl) -1H-imidazole-4-carboxylic acid piperidin-1-ylamide; N- [1- (4-chloro-phenyl) 2- (2,4-dichloro-phenyl) -5-methyl-1H-imidazol-4-yl] -benzamide; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl)- 5-pyrrolidin-1-ylmethyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 2- [1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl -1H-imidazol-4-yl] -hexan-2-ol; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-4-pentyl-1H-imi 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid adamantane-2-ylamide; 1- (4-chloro-phenyl) -2- (2-chloro-phenyl) -5-methylsulfanyl -1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 2- (2-chloro-phenyl) -1- (4-trifluoromethyl-phenyl) -1H-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) Enyl) -5- (2,4-dichloro-phenyl) -1H- [1,2,4] triazole-3-carboxylic acid piperidin-1-ylamide; 5-pentyl-4-phenyl-thiazole-2-carboxylic acid (Hexahydro-2,5-methano-pentalen-3a-yl) -amide; 4-pentyl-5-phenyl-thiazol-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-carvone Acid amide; 4-chloro-N-{[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-[2- (2-oxy) -Pyrrolidin-1-yl) -ethylamino] -methylene} -benzenesulfonamide; 4-chloro-N-[[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1 -Yl]-(2-cyano-ethylamino) -methylene] -benzene-sulfonamide; 4-chloro-N-[[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazole -1-yl]-(methoxy-methyl-amino) -methylene] -benzenesulfonamide; 4-chloro-N-{[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazole -1-yl]-[(piperidin-4-ylmethyl) -amino] -methylene} -benzenesulfonamide; 4-chloro-N-[[3- (4-chloro-phenyl) -4- Enyl-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, the CB _x modulator suitable for use as a _KATP channel modulator in the present invention is selected from the group of the following compounds: 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) -1H-pyrazole-3-carboxamide; (2-iodo-5-nitro-phenyl)-[1- (1-methyl-piperidin-2-ylmethyl) -1H-indole 3-yl] -methanone; {4- [4- (1,1-dimethyl-heptyl) -2,6-dimethoxy-phenyl] -6,6-dimethyl-bicyclo [3.1.1] hept-2- En-2-yl} -methanol; 3- (1,1-dimethyl-heptyl) -9-hydroxymethyl-6,6-dimethyl-6a, 7,10,10a-tetrahydro-6H-enzo [c] chromene- 1-ol; icosa-5,8,11,14-tetraenoic acid 2-hydroxy-1-hydroxymethyl-ethyl ester; 1-aziridin-1-yl-henicosa-6,9,12,15-tetraene-2- On; norazine ether; 4,4,4-trifluoro-butane-1-sulfinic acid 3- (2-hydroxymethyl-indan-4-yloxy) -phenyl ester, having aldehyde form 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-iodo-2-methyl-1- (2-morpholine-4- Yl-ethyl) -2,3-dihydro-1H-indol-3-yl]-(4-methoxy-phenyl) -methanone; 1- (4-chloro-phenyl) -2- (2-chloro-phenyl)- 5-ethyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; (2-methyl-1-propyl-2,3-dihydro-1H-indol-3-yl) -naphthalene -1-yl-methanone; 5- (1,1-dimethyl-heptyl) -2- [5-hydroxy-2- (3-hydroxy-propyl) -cyclohexyl] -phenol; (2-methyl-3-morpholine- 4-ylmethyl-3,4-dihydro-5-oxa-2a-azacenaphthylene-1-yl) -naphthalen-1-yl-methanone; 5- (4-chloro-phenyl) -1- (2,4-dichloro- Phenyl) -4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide; 5- (4-bromo-phenyl) -1- (2,4-dichloro-phenyl) -4-ethyl-1H-pyrazole -3-carboxylic acid piperidin-1-ylamide; 1- [bis-4-chloro-phenyl) -methyl] -3-[(3,5-difluoro-phenyl) -methanesulfonate - methylene] - azetidine.

In another embodiment of the present invention, the CB _x modulator suitable for use as a _KATP channel modulator in the present invention is selected from the group of the following compounds:
4-chloro-N-{[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -methylamino-methylene} -benzenesulfonamide; N- {amino- [3- (4-Chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -methylene} -4-chloro-benzenesulfonamide; 4-chloro-N-{[3- ( 4-chloro-phenyl) -4-pyridin-3-yl-4,5-dihydro-pyrazol-1-yl] -methylamino-methylene} -benzenesulfonamide; 4-chloro-N-{[3- (4 -Chloro-phenyl) -4- (3-fluoro-phenyl) -4,5-dihydro-pyrazol-1-yl] -methoxyamino-methylene} -benzenesulfonamide; N-{[3- (4- Rolo-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-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide; morpholine-4-sulfonic acid [1- (2,4-dichloro -Phenyl) -5-phenyl-4,5-dihydro-1H-pyrazol-3-yl] -methylamino-methyleneamide; N- {amino- [3- (4-chloro-phenyl) -4-phenyl-4 , 5-Dihydro-pyrazol-1-yl] -methylene} -4-chloro-benzenesulfonamide; 4-chloro-N-[[3- (4-chloro-phenyl) -4-phenyl 4,5-dihydro-pyrazol-1-yl]-(2-ethylamino-ethylamino) -methylene] -benzenesulfonamide; 4-chloro-N-{[3- (4-chloro-phenyl) -4- Phenyl-4,5-dihydro-pyrazol-1-yl]-[(1-methyl-pyrrolidin-2-ylmethyl) -amino] -methylene} -benzenesulfonamide; 4-chloro-N-{[3- (4 -Chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(pyridin-3-ylmethyl) -amino] -methylene} -benzenesulfonamide; 1- (4-chloro-phenyl) ) -2- (2,4-Dichloro-phenyl) -5-ethylsulfanyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 2- (2,4-dic Lolo-phenyl) -1- (4-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1- (4-chloro-phenyl) -2- (2,4-dichloro- Phenyl) -5-methylsulfanyl-1H-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-1H-imidazole-4-carboxylic acid piperidin-1-ylamide 1- (4-bromo-phenyl) -5-chloro-2- (2,4-dichloro-phenyl) -1H-imidazole-4-carboxylic acid Lysine-1-ylamide; 1- (4-bromo-phenyl) -2- (2,4-dichloro-phenyl) -5-ethyl-1H-imidazole-4-carboxylic acid pentylamide; 1- (4-chloro- Phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylic acid azepan-1-ylamide; 1- (4-chloro-phenyl) -2- (2,4- Dichloro-phenyl) -5-fluoromethyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methylsulfanyl -1H-imidazole-4-carboxylic acid cyclohexylamide; N- [1- (4-chloro-phenyl) -2- (2,4-dihydro-phenyl) -5-methyl -1H-imidazol-4-yl] -benzamide; 2- [1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-1H-imidazol-4-yl]- 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) -1- (4-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 5- (4-chloro-phenyl) -4- (2,4-dichloro-phenyl) -thiazole-2-carbo 1- (4-Chloro-phenyl) -5- (2,4-dichloro-phenyl) -1H- [1,2,4] triazole-3-carboxylic acid piperidin-1-yl 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-pyrrolidine) -1-yl) -ethylamino] -methylene} -benzenesulfonamide; 4-chloro-N-[[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl ]- 2-cyano-ethylamino) -methylene] -benzene-sulfonamide; 4-chloro-N-[[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -(Methoxy-methyl-amino) -methylene] -benzenesulfonamide; morpholine-4-sulfonic acid [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]- (Cyclopropylmethyl-amino) -methyleneamide.

A CB ₁ agonist or CB ₂ agonist that is suitable for use as a _KATP channel modulator in the present invention is selected from, but not limited to, the following group of compounds: 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) -1H-indol-3-yl] -methanone (= AM-1241); 3- (1 , 1-dimethyl-butyl) -6,6,9-trimethyl-6a, 7,10,10a-tetrahydro-6H-benzo [c] -chromene (JWH13) N-adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; 6,6,9-trimethyl-3-pentyl-6a, 7,8,10a-tetrahydro-6H-benzo [c] chromene- 1-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-acenaphthylene-1-yl) -naphthalen-1-yl-methanone (= WIN-55, 212-2); ACEA; ACPA; N-adaman Rutan-4-pentyl-5-phenyl-thiazole-2-carboxamide; methanandamide; anandamide; 2-arachidonoylglycerol; 2-icosa-5,8,11,14-tetraenyloxy-propane-1,3-diol ( BAY38-7271; SAB-378; BAY59-3074; O-1057; GW-1000; PRS-21375; PRS-21359; PRS-21355; PRS-2111096; PXS-2076; AM-577; GW-842166X; and mixtures thereof.

In a preferred embodiment of the invention, the CB ₂ agonist is a selective CB ₂ agonist and is selected from the group of the following compounds: 3- (1,1-dimethyl-butyl) -6,6,9- Trimethyl-6a, 7,10,10a-tetrahydro-6H-benzo [c] chromene (= JWH133); L759633; L759656; {4- [4- (1,1-dimethyl-heptyl) -2,6-dimethoxy- Phenyl] -6,6-dimethyl-bicyclo [3.1.1] hept-2-en-2-yl} -methanol (= HU308); JWH015; (2-iodo-5-nitro-phenyl- [1- (1-methyl-piperidin-2-ylmethyl) -1H-indol-3-yl] -methanone (= AM-1241); and mixtures thereof.

CB ₂ antagonists or CB ₂ inverse agonists suitable for use as _KATP channel modulators in the present invention are selected from the group of the following compounds: (1) Publications WO 01/0588869, PCT / EP2006 / 060009, WO 2004/014825; EP 1142877; US 2002/0072529; WO 02/062750; US 6509352; and (2) a compound selected from the following group: 1- [1-benzyl-5- (4-chloro-3-methyl) -Phenyl) -1H-pyrazol-3-yl] -ethanoyl-1.3.3-trimethyl-bicyclo [2.2.1] hept-2-ylamine (= SR-144528), JTE-907, AM630 and these And (3) (1) and (2 A mixture of compounds selected from

The dual acting compounds that are both CB ₁ agonists and CB ₂ agonists and are suitable for use as _KATP channel modulators according to the present invention are selected from the following group: 2-icosa-5,8, 11,14-tetraenyloxy-propane-1,3-diol (= norazine ether); and mixtures thereof.

In one advantageous embodiment of the invention, the CB _x modulator is selected from the group of the following compounds: 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, 7,10,10a-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) -1H-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; and mixtures thereof.

Each of a series of representative CB _x modulators with affinity on the K _ATP SUR1 and SUR2 regulatory subunits (hamsters) is listed in Table 1. (2-Chloro-4-methyl-7,7-dioxo-4,7-dihydro-1,7 lambda ^* 6 ^* -dithia-4,6-diaza-inden-5-yl)-(1-methyl-cyclo Propyl) -amine and 7-chloro-3-methyl-2H-benzo [1,2,4] thiadiazine 1,1-dioxide serve as _KATP / SUR1 active reference compounds known to those skilled in the art. ing. For comparison reasons, Table 1 shows CB ₁ agonists, CB ₂ agonists, CB ₂ partial agonists, CB ₂ antagonists, CB ₂ inverse agonists, and dual acting compounds that are both CB ₁ agonists and CB ₂ agonists. In order to verify their activity, the CB ₁ and / or CB ₂ activities of various compounds are also recorded.

Description of pharmacological test method
1. To characterize the affinity of test compounds for the binding sites of rodent K sulfonylurea and K _ATP channel opener over vitro binding affinity hamster SUR1 of the test compound to the _ATP channels (= KCOs), a competition binding experiments did. To assess affinity for sulfonylurea sites, membranes from COS-cells that transiently express hamster SUR1 were incubated with increasing concentrations of test compound in the presence of [ ³ H] glibenclamide. Incubation in the presence of additional 100 μM ATP assessed the affinity of binding to the KCO site (Schwanstecher M. et al. Naunyn Schmiedeberg's Arch. Pharmacol. 343 (1991) 83-89 and Schwanstecher M. et al. EMBO J. 17 (1998) 5529-5535 (= Schwanstecher et al. 1998)). Four displacement curves were measured for each test compound (+/− MgATP from human and hamster isoforms). Curves 9-15 tested a clear concentration covering the appropriate range. All measurements were repeated at least 5 times in independent experiments.

Similar to SUR1 (see above), competitive binding was performed to characterize the affinity of test compounds for the binding sites of sulfonylureas and KCOs on rat SUR2A. The affinity for the KCO site on SUR2A was assessed by displacement of [ ³ H] P1075 (Schwanstecher et al. 1998; Doerschner H. et al. Mol. Pharmacol. 55 (1999) 1060-1066 (= Doerschner et al. 1999)). However, the affinity of [ ³ H] glibenclamide for the human SUR2 isoform is too weak to allow direct testing of binding using a filtration assay. Thus, two strategies can be used to test binding to the sulfonylurea site on SUR2A. First, binding can be examined indirectly by [ ³ H] P1075 allosteric displacement (Doerschner et al., 1999). Second, the mutant SUR2A (SUR2A _Y1205S , see above) with increased affinity for [ ³ H] glibenclamide that allows direct displacement of the tracer can be used. This second method was chosen to allow discrimination between allosteric and competitive interactions with the KCO site and to ensure that ligand binding that does not induce allosteric displacement was not missed.

Membranes from COS-cells that transiently express rat SUR2A were incubated with increasing concentrations of the test compounds in the presence of radioligand. The affinity of binding to the KCO site was assessed by incubation in the presence of additional 100 μM MgATP (Schwanstecher et al. 1991 and 1998). Four displacement curves were measured for each test compound ([ ³ H] P1075 displacement from the rat isoform of the wild type receptor and [ ³ H] glibenclamide displacement from the rat isoform of SUR2A _Y1205S ). . Curves 9-15 tested a clear concentration covering the appropriate range. All measurements were repeated at least 5 times in independent experiments.

[ ³ H] P1075 (specific activity 116 Cimmol- ¹ ) was purchased from Amersham Buchler (Braunschweig, Germany). [ ³ H] glibenclamide (specific activity 51 Cimmol- ¹ ) was obtained from NEN (Dreieich, Germany). Where appropriate, stock solutions were made in dimethyl sulfoxide with final solvent concentrations in media below 1%.

  SUR- or Kir6. The x isoform was subcloned and used in pcDNA (hamster SUR1, mouse Kir6.2) or in pCMV vector (rat SUR2A, SUR2B).

Rodent SUR-isoforms and K _ATP channels were transiently expressed in COS-1 cells as described (Schwanstecher et al. 1998); Doerschner et al., 1999); Uhdel. Et al. J. Biol Chem 274 (1999) 28079-28082; Gross l. Et al. Mol. Pharmcol. 56 (1999) 1370-1373; Markworth E., Diabetes 49 (2000) 1413-1418). Mutation of the SUR2 isoform (SUR2 _Y1205S ) with a phenylalanine residue serine substituted at position 1205 to allow inspection of binding of this isoform to the sulfonylurea site by displacement of [ ³ H] glibenclamide The shape was used (Uhde L., Dissertation 2001). Briefly, COS-1 cells cultured in DMEM HG (10 mM glucose) supplemented with 10% fetal calf serum (FCS) are placed at a density of 5 × 10 ⁵ cells per dish (94 mm), Contacted overnight. For transfection, cells were incubated for 4 hours in Tris-buffered salt solution containing DNA (5-10 μg / ml) + DEAE-dextran (1 mg / ml), HEPES-buffered salt solution + dimethylsulfoxide (10 %) For 2 minutes and in DMEM-HG + chloroquine (100 μM) for 4 hours. Cells were then returned to DMEM-HG + 10% FCS. Membranes were made 60-72 hours after transfection as described (Schwanstecher M et al., Br. J. Pharmacol. 106 (1992) 295-301 (= Schwanstecher et al., 1992)) . Membranes resuspended for binding experiments (final protein concentration 5-50 μg / ml) were transformed into [ ³ H] glibenclamide (final concentration 0.3 nM or 3 nM and 100 nM or 1 μM glibenclamide for SUR1 or SUR2Y _{1205S -isoform} respectively. Non-specific binding defined by) or [ ³ H] P1075 (final concentration 3 nM, non-specific binding defined by 100 μM pinacidil) and an increasing concentration of test compound (Tris-buffer) ( Incubation in 50 mM, pH 7.4). The free Mg ²⁺ concentration was kept around 0.7 mM. ATP (0.1 mM) was added to the incubation medium to allow KCO (eg diazoxide, [ ³ H] P1075) binding (see Schwanstecher et al., 1998). Incubation was performed at room temperature for 1 hour and terminated by rapid filtration through Whatman GF / B filters.

The inhibition constant (K _i value) of the test substance was calculated from each IC ₅₀ value and described as its negative logarithmic value (pK _i ).

2. In vitro binding affinity of test compounds to the CB ₁ receptor The affinity of the compounds of the present invention for cannabinoid CB ₁ is measured in a membrane specimen of Chinese hamster ovary (CHO) cells, where the human cannabinoid CB ₁ receptor is a radioligand. As well as [ ³ H] CP-55940). After incubation of freshly prepared cell membrane specimens with [ ³ H] -ligand and with or without addition of the compounds of the invention, the separation of bound or free ligand is filtered through a glass fiber filter To implement. The radioactivity on the filter is measured by liquid scintillation counting.

3. In vitro binding affinity of test compounds to the CB ₂ receptor The affinity of the compounds of the present invention for the cannabinoid CB ₂ receptor can be determined using a membrane specimen of Chinese hamster ovary (CHO) cells, where the human cannabinoid CB ₂ receptor is Can be measured using [ ³ H] CP-55940 as a radioligand). After incubation of freshly prepared cell membrane specimens with [ ³ H] -ligand and with or without addition of the compounds of the invention, the separation of bound or free ligand is filtered through a glass fiber filter To implement. The radioactivity on the filter is measured by liquid scintillation counting.

TABLE ₁ CB _x modulator affinity with affinity on CB ₁ and / or CB ₂ receptors (cloned human cannabinoids expressed in CHO cells by the method described above (CB ₁ and CB ₂ respectively) Receptors) are displayed as pK _i values.

The data in Table 1 indicates that the tested CB _x modulators act selectively on the SUR1 subunit and / or on the SUR2 subunit.

4). Measurement of K _ATP open effect of compounds by insulin secretion in rat perfused islets Animals: Male Wistar rats weighing 175-200 g in groups in standard animal cages at a temperature of 21 ± 2 ° C. and a humidity of 55 ± 10% Accommodated. Animals are light-dark for 12 hours under 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 drinking water ad libitum. The cycle was maintained (lighting 6.00 to 18.00 h). Rats were habituated to this condition for at least 1 week prior to the experiment.

Experimental method: After killing the rat, the branch of the bile duct leading to the duodenal end of the duct in the liver and pancreas was tightened, and the pancreas was infused by injection of 0.9 mg / ml of ice-cold collagenase solution into the bile duct Inflated. The pancreas was then removed and gently incubated at 37 ° C. for 10-20 minutes. Following this incubation, 10 ml of cold buffer was added and the suspension was vigorously shaken by hand for 1 minute. The islets were left on ice for 5 minutes and washed 3 times with ice-cold buffer. Well-shaped and well-sized islets from 3 rats were manually removed (under a low power microscope), pooled, and the final selection of islets transferred to a perfusion device. Unless otherwise stated, oxygenated (O ₂ 95% / CO ₂ 5%) Gey & Gey buffer containing 1 mg / ml calf serum albumin and 4 mM glucose was used throughout this experiment. (For further details see Dickinson et al., Eur. J. Pharmacol. 1997; 339: 69-76).

  Compounds were tested at the recommended concentrations or solubility was measured under experimental conditions and the maximum soluble drug concentration was used for this experiment (DMSO or ethanol as solvent, 0.1% maximum in assay buffer) Used in).

  Two experiments were performed in parallel in the same two independent sets of perfusion devices, each with a sufficient number of chambers. Twenty islets that were manually removed were placed in each chamber. The islets were first perfused for 30 minutes in a medium containing 4 mM glucose. The perfusate was then collected at 2 minute intervals for the remainder of the experiment. After the first 10 minutes of the experiment (to collect baseline insulin values), the medium in each chamber was switched to that containing 11 mM glucose and related drug concentration / vehicle / diazoxide concentrations, and the perfusate was further 62%. Collected for a minute, a total of 36 fractions per chamber were obtained. The perfusate samples were then pooled to make 3 samples per chamber as follows: Baseline (4 mM): Sample 1-5 (first 10 minutes); 0-30 minutes (glucose 11 mM): Sample 6-21; 30-60 minutes (glucose 11 mM): Samples 22-36. Perfusate fractions were stored at -75 ° C until required for insulin assay. The insulin content of the fraction was assayed using a 96-well ELISA assay (Mercodia). Initial insulin assays were performed in triplicate with 3 pool fractions from each chamber.

  Drugs: All chemicals were obtained from Sigma (or other suitable market provider).

  Results: Three islet specimens showed a consistent degree of glucose-dependent insulin secretion. Mean insulin secretion at 11 mM glucose was 98.3 ± 12.6 pg / islet / min and 130.4 ± 22.0 pg / islet / min at 0-30 minutes and 30-60 minutes, respectively. This was very low in the presence of 4 mM glucose, 3.8 ± 0.6 pg / islet / minute and 3.4 ± 0.1 pg / islet / minute at 0-30 and 30-60 minutes, respectively. Therefore, in the case of 11 mM glucose, insulin secretion increased 26-fold and 38-fold at 0-30 minutes and 3-60 minutes, respectively. The data is first expressed as a simple average of 3 experiments of insulin secretion (pg / islet / min) and multiple t-tests (relative to the vehicle duration) to determine the possible significant effects of treatment. Was used. Optionally, the data was also calculated as the vehicle effect (%) for each experimental day. This latter was considered to be a more effective analysis when correcting for daily fluctuations in insulin release from the islets. Diazoxide significantly inhibited insulin secretion by an average of 55.3% (0-30 minutes) and 58.9% (30-60 minutes).

Table 2- _KATP channel openers according to the method described above showed inhibition as a percentage.

This test demonstrates that selected candidate compounds inhibit glucose-stimulated insulin secretion based on the affinity of their K _ATP channels. As a result, it can be said that the candidate compound functions as a _KATP channel opener under the aforementioned conditions.

  All references, including publications, patent applications, and patents cited herein, are individually and in detail indicated that each reference is considered here as a reference, and in which Reference should be made to the same scope as disclosed in its entirety with references.

  The use of the terms "a" and "an" and "the" and similar related terms in this specification (especially in the claims below) is not otherwise inconsistent unless otherwise stated or in context. To the extent it should be construed as including both singular and plural. 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 terms (e.g., advantageous, preferably etc.) proposed herein is for the purpose of further explaining the description and is intended to be within the scope of the claims. It does not claim a limitation. Terms not described in the specification should be construed as indicating elements that are not claimed as being important to the practice of the invention.

  Alternative embodiments of the claimed invention include the best mode known to the inventors for carrying out the claimed invention. Variations in the embodiments described therein will be apparent to those skilled in the art upon reading the foregoing description. The inventor anticipates that those skilled in the art will properly use such changes, and the inventor intends to be able to perform other than those described in detail there.

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

  The use of individual numerical values is stated as an approximation, such that the word “about” or “approximately” precedes the numerical value. Similarly, numerical values in the various ranges set forth in this specification, unless stated otherwise, are preceded by the words “about” or “approximately” which are both minimum and maximum values within the stated range. As shown, it is described as an approximate value. Thus, variations above or below the stated range can be used to reach essentially the same results as values within the range. As used herein, the terms “about” and “approximately” when related to a numerical value refer to the document to which the object being described is the closest relevant, or to the technical field related to the scope or element. It has a clear and usual meaning for those who are familiar with. The amount that extends from the exact numerical limit depends on many factors. For example, some of the possible factors include the risk of factors and / or effects, and given a predetermined amount of change, taking into account the performance of the claimed subject matter and other requirements known to those skilled in the art. Is included. As used herein, the use of different amounts of prominent Arabic numerals with different numbers means that the use of the term “about” or “approximately” limits the effect of expanding a particular number. do not do. Thus, in general, “about” or “approximately” expands a numerical value. The description of a range is also intended to extend the allowable range by the use of the terms “about” and “approximately” plus a continuous range that includes each value between the minimum and maximum values. . Accordingly, the description of a range of values in this specification is intended only to be used as a shorthand notation that the relevant individual values separately fall within this range unless otherwise stated. Each separate value is to be disclosed in the specification as individually described herein.

  Ranges, proportions and ranges of proportions that can be formed from or derived from the data described herein represent further aspects of the description of the present invention and are expressly included as part of the description as previously described. I can understand that. Ranges that can be formed include ranges that include or do not include a finite upper and / or lower limit. Accordingly, those skilled in the art who are most familiar with a particular range, percentage or range of percentages will appreciate that such values can be clearly derived from the data present here. Let's go.

Claims (14)

CB ₁ agonist; CB ₂ agonist; CB ₂ partial agonist; CB ₂ antagonist; CB ₂ inverse agonist; and a CB _x modulator selected from the group consisting of dual acting compounds that are both CB ₁ agonist and CB ₂ agonist 1 type and a mixture of these, obesity, diabetes, metabolic syndrome, syndrome X, islet cell tumor, familial hyperinsulin hypoglycemia, male baldness, compression muscle hyperreaction, asthma, neuroprotection, mania, pain palsy , Cardioprotection, angina pectoris, heart failure, arrhythmia, coronary artery spasm, peripheral vascular disease, cerebrovascular spasm, appetite adjustment, nerve degeneration, pain-including neuralgia and chronic pain-and incompetence of mammals and humans prevention, treatment, used as a K _ATP channel modulators for delay of progression of, and delaying the onset and / or inhibition To, use of CB _x modulator. CB ₁ agonist; CB ₂ agonist; CB ₂ partial agonist; CB ₂ antagonist; CB ₂ inverse agonist; and a CB _x modulator selected from the group consisting of dual acting compounds that are both CB ₁ agonist and CB ₂ agonist 1 type and a mixture of these, obesity, diabetes, metabolic syndrome, syndrome X, islet cell tumor, familial hyperinsulin hypoglycemia, male baldness, compression muscle hyperreaction, asthma, neuroprotection, mania, pain palsy , Cardioprotection, angina pectoris, heart failure, arrhythmia, coronary artery spasm, peripheral vascular disease, cerebrovascular spasm, appetite adjustment, nerve degeneration, pain-including neuralgia and chronic pain-and incompetence of mammals and humans prevention, treatment, K _ATP channel letter for the manufacture of a medicament for the delay of progression of, and delaying the onset and / or inhibition Used as aerator, the use of CB _x modulator.   Metabolic syndrome and / or syndrome X may be hypertension, especially arterial hypertension; insulin resistance, especially type II diabetes; glucose intolerance; abnormal lipoproteinemia, particularly abnormal lipoproteinemia that occurs with low HDL-cholesterol and hyperuricemia. The use according to claim 1 or 2, comprising a disorder or disease selected from the group consisting of hypertriglyceridemia with complications. In patients in need thereof, an effective amount of a CB _x modulator (where CB _x modulator is a CB ₁ agonist; a CB ₂ agonist; a CB ₂ partial agonist; a CB ₂ antagonist; a CB ₂ inverse agonist; and a CB ₁ agonist) Selected from the group consisting of dual acting compounds that are both CB ₂ agonists, wherein the CB _x modulator has _KATP channel modulating properties) obesity comprising applying at least one Disease, diabetes, metabolic syndrome, syndrome X, islet cell tumor, familial hyperinsulin hypoglycemia, male baldness, compression muscle hyperreaction, asthma, neuroprotection, mania, painful numbness, heart protection, angina, heart Paralysis, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite adjustment, nerve degeneration, pain-neuralgia and Encompasses sexual pain - and mammals and treating intercourse impotence in humans, prevention, delay of progression of, delaying the onset and / or inhibiting manner. The K _ATP channel modulator is a modulator of at least one channel selected from the group consisting of Kir6.2 / SUR1K _ATP channel, Kir6.2 / SUR2BK _ATP channel, Kir6.1 / SUR2BK _ATP channel, and Kir6.2 / SUR2AK _ATP channel. Use according to any one of claims 1 to 3, or a method according to claim 4. 6. The use according to any one of claims 1 to 3 or the method according to claims 4 and 5, wherein the _KATP channel modulator is a _KATP channel opener. At least one CB _x modulator is 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) -1H-pyrazole-3-carboxamide; (2-iodo-5-nitro-phenyl)-[1- (1- Methyl-piperidin-2-ylmethyl) -1H-indol-3-yl] -methanone; {4- [4- (1,1-dimethyl-heptyl) -2,6-dimethoxy-phenyl] -6,6-dimethyl Ru-bicyclo [3.1.1] hept-2-en-2-yl} -methanol; 3- (1,1-dimethyl-heptyl) -9-hydroxymethyl-6,6-dimethyl-6a, 7, 10,10a-tetrahydro-6H-enzo [c] chromen-1-ol; 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; norazine ether; 4,4,4-trifluoro-butane-1-sulfinic acid 3- (2-hydroxymethyl-indan-4-yloxy)- Phenyl ester, compound having aldehyde form; 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydro-quinoline-3-carboxylic acid (benzo [1, Dioxol-5-ylmethyl) -amide; N- (1- {4- [4-chloro-2- (2-fluoro-benzenesulfonyl) -benzenesulfonyl] -phenyl} -ethyl) -methanesulfonamide; [6 -Iodo-2-methyl-1- (2-morpholin-4-yl-ethyl) -2,3-dihydro-1H-indol-3-yl]-(4-methoxy-phenyl) -methanone; 1- (4 -Chloro-phenyl) -2- (2-chloro-phenyl) -5-ethyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; (2-methyl-1-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-azacenaphthylene-1-yl) -naphthalen-1-yl-methanone; 5- (4 -Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide; 5- (4-bromo-phenyl) -1- (2 , 4-Dichloro-phenyl) -4-ethyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide; 1- [bis- (4-chloro-phenyl) -methyl] -3-[(3,5- Difluoro-phenyl) -methanesulfonyl-methylene] -azetidine; 4-chloro-N-{[3- (4-chloro-phenyl) -4-phenyl) -4,5-dihydro- Pyrazol-1-yl] -methylamino-methylene} -benzenesulfonamide; N- {amino- [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]- Methylene} -4-chloro-benzenesulfonamide; N-{[3- (4-chloro-phenyl) -4-pyridin-3-yl-4,5-dihydro-pyrazol-1-yl] -methylamino-methylene } -4-trifluoromethyl-benzenesulfonamide; 4-chloro-N-{[3- (4-chloro-phenyl) -4-pyridin-3-yl-4,5-dihydro-pyrazol-1-yl] -Methylamino-methylene} -benzenesulfonamide; 4-chloro-N-{[3- (4-chloro-phenyl) -4- (3-fluoro-phenyl) -4,5-dihydride -Pyrazol-1-yl] -methoxyamino-methylene} -benzenesulfonamide; morpholine-4-sulfonic acid [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl ] -Methylamino-methyleneamide; N-{[3- (4-chloro-phenyl) -4- (3-fluoro-phenyl) -4,5-dihydro-pyrazol-1-yl] -methylamino-methylene} -N, N-dimethyl-sulfonamide; azepan-1-sulfonic acid [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -methylamino-methyleneamide; 4-chloro-N-{[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(1-methyl-pyrrole N-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-pyrazol-1-yl] -methylamino-methyleneamide; piperidine-1-sulfonic acid [3- (4-chloro-phenyl)- 4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-dimethylamino-ethylamino) -methyleneamide; N, N-diethyl Ruamino-1-sulfonic acid [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -methylsulfanyl-methyleneamide; 2-amino-1- [3- ( 4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -3- (3,4-dichloro-phenyl) -propan-1-one; morpholine-4-sulfonic acid [3 -(4-Chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -methylamino-methyleneamide; N, N-dimethylamino-1-sulfonic acid [3- (4-chloro -Phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-fluoro-ethylamino) -methyleneamide; piperidine-1-sulfonic acid [3- (4-c Ro-phenyl) -4- (3-fluoro-phenyl) -4,5-dihydro-pyrazol-1-yl] -methylamino-methyleneamide; 5- (4-chloro-phenyl) -1- (2,4 -Dichloro-phenyl) -4,5-dihydro-1H-pyrazole-3-carboxylic acid piperidin-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-1H-pyrazol-3-yl] -methylamino-methyleneamide; Morpholine-4-sulfonic acid [1- (2,4-dichloro-phenyl) -5-phenyl-4,5-dihydro-1H-pyrazol-3-yl] -methyl Mino-methyleneamide; 4-chloro-N-[[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-fluoro-ethylamino) -methylene ] -Benzenesulfonamide; 4-chloro-N-[[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-fluoro-ethylamino)- Methylene] -benzenesulfonamide; N- {amino- [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -methylene} -4-chloro-benzenesulfonamide 4-chloro-N- [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazole-1-carbonyl] -benzenesulfonamide; 4-chloro- N-[[3- (4-Chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-ethylamino-ethylamino) -methylene] -benzenesulfonamide; 4- Chloro-N-{[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(1-methyl-pyrrolidin-2-ylmethyl) -amino] -methylene } -Benzenesulfonamide; 4-chloro-N-[[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-(4-pyrrolidin-1-yl- Butylamino) -methylene] -benzenesulfonamide; 4-chloro-N-{[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(pyridy -3-ylmethyl) -amino] -methylene} -benzenesulfonamide; 1- [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -3- (1H -Indol-2-yl) -2-methylamino-propan-1-one; 2- [3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -5 -Ethyl-4,5-dihydro-oxazole; 4-chloro-N-[[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-(3-hydroxy -2,2-dimethyl-propylamino) -methylene] -benzenesulfonamide; N, N-diethylamino-1-sulfonic acid [3- (4-chloro-phenyl) -4-hydroxy-4-phenyl- , 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, 4,5,6,10b-hexahydro-1,2-diaza-benzo [e] azulene-3-carboxylic acid piperidin-1-ylamide 5- (4-bromo-phenyl) -1- (2,4-dichloro-phenyl) -3- [2- (3,5-difluoro-phenyl) -2-methanesulfonyl-vinyl] -4-methyl-; 1H-pyrazole; piperidine-1-carboxylic acid [5- (4-chloro-phenyl) -1- (2,4-dichloro-phenyl) -4-methyl-1H-pyrazol-3-yl] -amide; (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-ethylsulfanyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 2- (2,4-dichloro-phenyl) -1- (4-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid piperidin-1-ylamide;
1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methylsulfanyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1- (4-chloro-phenyl) 2- (2,4-Dichloro-phenyl) -1H-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-1H-imidazole-4-carboxylic acid Acid piperidin-1-ylamide; 1- (4-bromo-phenyl) -5-chloro-2- (2,4-dichloro-phenyl) -1H-imidazole-4-cal 1- (4-Bromo-phenyl) -2- (2,4-dichloro-phenyl) -5-ethyl-1H-imidazole-4-carboxylic acid cyclohexylamide; 1- (4- Bromo-phenyl) -2- (2,4-dichloro-phenyl) -5-ethyl-1H-imidazole-4-carboxylic acid pentylamide; 4- (4-chloro-phenyl) -5- (2,4-dichloro -Phenyl) -1-methyl-1H-imidazole-2-carboxylic acid cyclohexylamide; 4- (4-chloro-phenyl) -5- (2,4-dichloro-phenyl) -3-methyl-1H-imidazole-2 1- (5-chloro-pyridin-2-yl) -2- (2,4-dichloro-phenyl) -5-ethyl-1H-imidazo 4-carboxylic acid piperidin-1-ylamide; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylic acid (4-hydroxy 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylic 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-1H-pyrrol-2-yl) -5 Ethyl-1-phenyl-1H-imidazole-4-carboxylic acid cyclohexylamide; 1- (4-chloro-phenyl) -5-ethyl-2- (3-methyl-pyridine 2-yl) -1H-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-1H-imidazole-4-carboxylic 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-1H-imidazole-4-carboxylic acid cyclohexylamide; 1- (4-bromo-phenyl) -2- ( , 4-dichloro-phenyl) -5-ethyl-1H-imidazole-4-carboxylic acid pentylamide; 4- (4-chloro-phenyl) -5- (2,4-dichloro-phenyl) -1-methyl-1H -Imidazole-2-carboxylic acid 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-1H-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-cyclohexyl) -amide; -(4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylic 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-1H-pyrrol-2-yl) -5-ethyl-1-phenyl-1H -Imidazole-4-carboxylic acid cyclohexylamide; 1- (4-chloro-phenyl) -5-ethyl-2- (3-methyl-pyridin-2-yl) -1H-imidazole-4-carboxylic acid piperidine-1- 1- (4-chloro-phenyl) -5-ethyl-2- (3-methyl-pyridin-2-yl) -1H-imidazole-4-carboxylic acid cyclohexyl 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylic acid (4-trifluoromethyl-phenyl) -amide; 2- (2,4-Dichloro-phenyl) -5-methyl-1-pyridin-2-yl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1- (4-chloro-phenyl) -2- (2 , 4-dichloro-phenyl) -5-fluoromethyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5 -Hydroxymethyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl)- -Methylsulfanyl-1H-imidazole-4-carboxylic acid cyclohexylamide; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methanesulfonyl-1H-imidazole-4-carboxylic acid Piperidin-1-ylamide; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methanesulfinyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 5- ( 4-chloro-phenyl) -4- (2,5-dichloro-phenyl) -1-methyl-1H-imidazole-2-carboxylic acid piperidin-1-ylamide; 2- (2-chloro-phenyl) -1- ( 5-chloro-pyridin-2-yl) -5-ethyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; -(4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -5- (2,2,2-trifluoro-ethyl) -1H-imidazole-4-carboxylic acid piperidin-1-ylamide; N- [1- (4-Chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-1H-imidazol-4-yl] -benzamide; 1- (4-chloro-phenyl)- 2- [2,4-dichloro-phenyl) -5-pyrrolidin-1-ylmethyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 2- [1- (4-chloro-phenyl) -2- ( 2,4-dichloro-phenyl) -5-methyl-1H-imidazol-4-yl] -hexan-2-ol; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl)- 5- Methyl-4-pentyl-1H-imidazole; 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid adamantane-2-ylamide; 1- (4-chloro-phenyl) -2- (2-chloro -Phenyl) -5-methylsulfanyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 2- (2-chloro-phenyl) -1- (4-trifluoromethyl-phenyl) -1H-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 pyrrolidine-1 1- (4-chloro-phenyl) -5- (2,4-dichloro-phenyl) -1H- [1,2,4] triazole-3-carboxylic acid piperidin-1-ylamide; 5-pentyl-4 -Phenyl-thiazole-2-carboxylic acid (hexahydro-2,5-methano-pentalen-3a-yl) -amide; 4-pentyl-5-phenyl-thiazole-2-carboxylic acid (hexahydro-2,5-methano- Pentalen-3a-yl) -amide; 1-{(4-chloro-benzene-sulfonylimino)-[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -Methyl} -piperidine-4-carboxylic acid amide; 4-chloro-N-{[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazo Ru-1-yl]-[2- (2-oxo-pyrrolidin-1-yl) -ethylamino] -methylene} -benzenesulfonamide; 4-chloro-N-[[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-cyano-ethylamino) -methylene] -benzene-sulfonamide; 4-chloro-N-[[3- (4-chloro- Phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-(methoxy-methyl-amino) -methylene] -benzenesulfonamide; 4-chloro-N-{[3- (4-chloro- Phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(piperidin-4-ylmethyl) -amino] -methylene} -benzenesulfonamide; 4-chloro-N-[[3 -(4-Chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-(piperidin-4-ylamino) -methylene] -benzenesulfonamide; and morpholine-4-sulfonic acid [3 4. A process according to claim 1 selected from the group consisting of-(4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-(cyclopropylmethyl-amino) -methyleneamide. The use according to any one of claims 5 and 6, or the method according to claims 4-6. At least one CB _x modulator is 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) -1H-pyrazole-3-carboxamide; (2-iodo-5nitro-phenyl)-[1- (1-methyl -Piperidin-2-ylmethyl) -1H-indol-3-yl] -methanone; {4- [4- (1,1-dimethyl-heptyl) -2,6-dimethoxy-phenyl] -6,6-dimethyl -Bicyclo [3.1.1] hept-2-en-2-yl} -methanol; 3- (1,1-dimethyl-heptyl) -9-hydroxymethyl-6,6-dimethyl-6a, 7,10 , 10a-tetrahydro-6H-enzo [c] chromen-1-ol; 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; norazine ether; 4,4,4-trifluoro-butane-1-sulfinic acid 3- (2-hydroxymethyl-indan-4-yloxy) -phenyl Compound having ester or aldehyde form; 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- Iodo-2-methyl-1- (2-morpholin-4-yl-ethyl) -2,3-dihydro-1H-indol-3-yl]-(4-methoxy-phenyl) -methanone; 1- (4- (Chloro-phenyl) -2- (2-chloro-phenyl) -5-ethyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; (2-methyl-1-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-azacenaphthylene-1-yl) -naphthalen-1-yl-methanone; 5- (4- Chloro-phenyl) -1- (2,4-dichloro-phenyl) -4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide; 5- (4-bromo-phenyl) -1- (2, 4-dichloro-phenyl) -4-ethyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide; 1- [bis- (4-chloro-phenyl) -methyl] -3-[(3,5-difluoro Use according to any one of claims 1 to 3, 5 to 7 or selected from the group consisting of -phenyl) -methanesulfonyl-methylene] -azetidine The method according to claims 4-7. At least one CB _x modulator is 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; 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} -benzene 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-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide; morpholine- 4-sulfonic acid [1- (2,4-dichloro-phenyl) -5-phenyl-4,5-dihydro-1H-pyrazol-3-yl] -methylamino-methyleneamide; N- {amino- [3- (4-Chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl] -methylene} -4-chloro-benzenesulfonamide; 4-chloro-N-[[3 (4-Chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-ethylamino-ethylamino) -methylene] -benzenesulfonamide; 4-chloro-N-{[ 3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(1-methyl-pyrrolidin-2-ylmethyl) -amino] -methylene} -benzenesulfonamide; 4-chloro-N-{[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(pyridin-3-ylmethyl) -amino] -methylene}- Benzenesulfonamide; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-ethylsulfanyl-1H-imidazole-4-carboxylic acid pipette Din-1-ylamide; 2- (2,4-dichloro-phenyl) -1- (4-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1- (4-chloro -Phenyl) -2- (2,4-dichloro-phenyl) -5-methylsulfanyl-1H-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- 1H-imidazole-4-carboxylic 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-1H-imidazole-4-carboxylic acid 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-1H-imidazole-4-carboxylic acid azepan-1-ylamide; 1- (4-chloro- Phenyl) -2- (2,4-dichloro-phenyl) -5-fluoromethyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 1- (4-chloro-phenyl) -2- (2,4 -Dichloro-phenyl) -5-methylsulfanyl-1H-imidazole-4-carboxylic acid cyclohexylamide; N- [1- (4-chloro-phenyl) -2- 2,4-dihydro-phenyl) -5-methyl-1H-imidazol-4-yl] -benzamide; 2- [1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5 -Methyl-1H-imidazol-4-yl] -hexan-2-ol; 1- (4-chloro-phenyl) -2- (2,4-dichloro-phenyl) -5-methyl-4-pentyl-1H- 1- (4-Chloro-phenyl) -2- (2-chloro-phenyl) -5-methylsulfanyl-1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 2- (2-chloro-phenyl) -1- (4-trifluoromethyl-phenyl) -1H-imidazole-4-carboxylic acid piperidin-1-ylamide; 5- (4-chloro-phenyl) -4- (2,4-di Lolo-phenyl) -thiazole-2-carboxylic acid piperidin-1-ylamide; 1- (4-chloro-phenyl) -5- (2,4-dichloro-phenyl) -1H- [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-pyrazole-1 -Yl] -methyl} -piperidine-4-carboxylic acid amide; 4-chloro-N-{[3- (4-chloro-phenyl) -4-phenyl-4,5-dihydro-pyrazol-1-yl]- [2- (2-Oxo-pyrrolidin-1-yl) -ethylamino] -methylene} -benzenesulfonamide; 4-chloro-N-[[3- (4-chloro-phenyl) -4-phenyl-4 , 5-Dihydro-pyrazol-1-yl]-(2-cyano-ethylamino) -methylene] -benzene-sulfonamide; 4-chloro-N-[[3- (4-chloro-phenyl) -4-phenyl -4,5-dihydro-pyrazol-1-yl]-(methoxy-methyl-amino) -methylene] -benzenesulfonamide; morpholine-4-sulfonic acid [3- (4-chloro-phenyl) -4-phenyl- 9. The process according to any one of claims 1 to 3 and 5 to 8, selected from the group consisting of 4,5-dihydro-pyrazol-1-yl]-(cyclopropylmethyl-amino) -methyleneamide. Use or method according to claim 8. CB ₁ agonists or CB ₂ agonists are 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) -1H -Indol-3-yl] -methanone (= AM-1241); 3- (1,1-dimethyl-butyl) -6,6,9-trimethyl-6a, 7,10,10a-tetrahydro-6H-benzo [ c] -chromene (JWH133); N-adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; 6,6,9-trimethyl-3-penty -6a, 7,8,10a-tetrahydro-6H-benzo [c] chromen-1-ol; (bicyclo [2.2.1] hept-2-ylamino)-(5-pentyl-4-phenyl-thiazole- 2-yl) -methane; 5- (1,1-dimethyl-heptyl) -2- [5-hydroxy-2- (3-hydroxy-propyl) -cyclohexyl] -phenol (= CP-55940); Methyl-3-morpholin-4-ylmethyl-3,4-dihydro-5-oxa-2a-aza-acenaphthylene-1-yl) -naphthalen-1-yl-methanone (= WIN-5521-2); ACEA; ACPA N-adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; meta-anandamide; anandamide; 2-arachidonoyl glycero 2-icosa-5,8,11,14-tetraenyloxy-propane-1,3-diol (= norazine ether); BAY 38-7271; SAB-378; BAY 59-3074; O-1057; From 1 to 3, selected from the group consisting of: -1000; PRS-21375; PRS-21359; PRS-21355; PRS-2111096; PXS-2076; AM-577; GW-842166X; The use according to any one of claims 5 and 6, or the method according to claims 4-6. The CB ₂ agonist is a selective CB ₂ agonist and is 3- (1,1-dimethyl-butyl) -6,6,9-trimethyl-6a, 7,10,10a-tetrahydro-6H-benzo [c] chromene ( = JWH133); L759633; L759656; {4- [4- (1,1-dimethyl-heptyl) -2,6-dimethoxy-phenyl] -6,6-dimethyl-bicyclo [3.1.1] hepte-2 -En-2-yl} -methanol (= HU308); JWH015; (2-iodo-5-nitro-phenyl)-[1- (1-methyl-piperidin-2-ylmethyl) -1H-indol-3-yl 11. Use or method according to claim 10, selected from the group consisting of: -methanone (= AM-1241); and mixtures thereof. CB ₂ antagonists or CB ₂ inverse agonists are: (1) compounds described in publications WO01 / 0588869, PCT / EP2006 / 060009, WO2004 / 014825; EP1142877; US2002 / 0072529; WO02 / 062750; US6509352; and (2) 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) -1H-pyrazole-3-carboxamide (= SR-144528), JTE-907, AM630 and mixtures thereof; and (3) (1) and (2 From the group consisting of a mixture of compounds selected from Up method according to the use or claim 4,5,6,10 according to 11 in any one of 5, 6 and 10 to 11. Dual acting compounds that are both CB ₁ agonists and CB ₂ agonists are 2-icosa-5,8,11,14-tetraenyloxy-propane-1,3-diol (= norazine ether); The use according to any one of claims 1 to 3, 5, 6, 10 to 12, or the claims 4, 5, 6, 10 to 12, selected from the group consisting of: Method. CB _x modulators are 6,6,9-trimethyl-3-pentyl-6a, 7,8,10a-tetrahydro-6H-benzo [c] chromen-1-ol; N- (endo-bicyclo [2.2. 1] Hept-2-ylamino) -5-pentyl-4-phenyl-thiazole-2-carboxamide; 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; 1- [1-benzyl-5- (4-chloro-3-methyl-phenyl)- 1H-pyrazol-3-yl] -ethanonyl-1,3,3-trimethyl-bicyclo [2.2.1] -hept-2-ylamine; (2-iodo-5-nitro-phenyl) Enyl)-[1- (1-methyl-piperidin-2-ylmethyl) -1H-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; and mixtures thereof, Use according to any one of claims 5, 6, 10 to 13, or a method according to claims 4, 5, 6, 10 to 13.