CN101431994A - Use of CBx cannabinoid receptor modulators as potassium channel modulators - Google Patents

Use of CBx cannabinoid receptor modulators as potassium channel modulators Download PDF

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CN101431994A
CN101431994A CNA2007800151866A CN200780015186A CN101431994A CN 101431994 A CN101431994 A CN 101431994A CN A2007800151866 A CNA2007800151866 A CN A2007800151866A CN 200780015186 A CN200780015186 A CN 200780015186A CN 101431994 A CN101431994 A CN 101431994A
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phenyl
chloro
amide
carboxylic acid
dihydro
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J·安特尔
P-C·格雷戈里
J·H·M·兰格
M·菲恩格斯
D·赖歇
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Abbott Products GmbH
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Solvay Pharmaceuticals GmbH
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Abstract

The invention is directed to the use of at least one CBx modulator wherein the CBx modulator is selected from the group consisting of CB1 agonists; CB2 agonists; CB2 partial agonists; CB2 antagonists; CB2 inverse agonists; and dually acting compounds which are both a CB1 agonist and a CB2 agonist; and mixtures thereof, as KATP channel modulator for the prophylaxis, treatment, delayed progression, delayed onset and/or inhibition of a variety of disease conditions including obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans. The invention further relates to methods of treating, preventing, delaying progression of, delaying onset of and/or inhibiting a variety of disease conditions including obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans comprising administering to a subject in need thereof an effective amount of at least one CBx modulator having KATP channel modulating properties.

Description

CB xCannibinoid receptor modulators is as the purposes of potassium channel modulating agents
Technical field
The present invention relates to CB xRegulator is as K ATPThe new purposes of channel modulators.The invention still further relates to treatment; prevent disease; delay the progress of disease; delay the outbreak of disease and/or the method for inhibition disease; described disease is mammal and people's a obesity; diabetes; metabolism syndrome; X syndrome; insulinoma; familial hyperinsulinism hypoglycemia; male pattern alopecia; force the flesh hyperactivity; asthma; neuroprotective; epilepsy; analgesia; Cardioprotective; angina pectoris; cardioplegia; arrhythmia; coronary spasm; peripheral vascular disease; cerebral vasospasm; appetite stimulator; neural degeneration; pain-comprise neuropathic pain and chronic pain-and sexual impotence, this method comprises at least a as K of the curee of its needs effective dose ATPThe CB of channel modulators xRegulator.
Background technology
Obesity of the present invention means and comprises any increase that causes the body fat of weight increase, preferably includes but is not limited to the medical definition of obesity.Thereby according to the present invention, obesity also comprises antimedical, and for example, beauty treatment property is overweight.Thereby the invention still further relates to antimedical losing weight, for example, the beauty treatment gonosome heavily reduces, and generally speaking comprises improvement health external form.More on narrower meaning, usually obesity is interpreted as that body weight surpasses ideal body weight more than 20%.Even on this narrower meaning, obesity also is the main healthy worry of Western society.According to estimates, overweight or fat about 97,000,000 adult of the U.S..Obesity is the equilibrated result of positive energy to a great extent, and its reason is that the ratio of calorie absorption and energy expenditure increases.The molecule factor of food intake and body weight of regulating is not understood as yet fully, but has identified several inherited genetic factorss.
Epidemiological study shows that overweight and increase degree obesity is the important prediction index that reduces life expectancy.Obesity, not only independent but also combine with other disease, cause or increase the weight of multiple health problem.The medical problem relevant with obesity (it can be serious and life-threatening) generally comprises hypertension; Type ii diabetes; The plasma insulin concentration that raises; Insulin resistant; Dyslipidaemia (dyslipidemias); Hyperlipemia; Endometrium, breast, prostate and colon cancer; Osteoarthritis; Respiratory complication, for example obstructive sleep apnea; Cholelithiasis; Cholelithiasis; Arteriosclerosis; Heart disease; Rhythm abnormality; And arrhythmia.Obesity more with premature death and apoplexy after, the mortality rate and the sickness rate of myocardial infarction, congestive heart failure, coronary heart disease and sudden death significantly improve relevant.
Usually by encourage the patient by reducing them food intake or lose weight by temper competence that increases them and the energy output that therefore increases them, come treatment of obesity.Show, continue to lose weight and 5% to 10% improved the symbiosis disease relevant with obesity, for example diabetes and hypertension, and can cause improving the situation relevant, for example osteoarthritis, sleep apnea and lung and cardiac dysfunctions with obesity.
The efficacy of drugs that loses weight that uses in the monotherapy of treatment of obesity at present is limited and side effect is remarkable.Interim at the chronic treatment that surpasses 6 months, the effect of most medicament descends, and produces than contrast and is no more than 10% lose weight.Fat body weight for humans may be easy to surpass 150 kilograms, therefore need deduct their body weight more than 50% to return to normal type.
Term " metabolism syndrome " mean cover clinical picture complex-except the centre type obesity, it mainly comprises hypertension, particularly arterial hypertension; Insulin resistant, particularly type ii diabetes; Glucose intolerance; Dyslipoproteinemia, particularly hypertriglyceridemia, it is accompanied by dyslipoproteinemia, and highdensity lipoprotein-cholesterol takes place simultaneously to be reduced, and the hyperuricemia that can cause gout in addition.
According to the information from american heart community (American Heart Association), metabolism syndrome and insulin resistant are closely related.Some easily suffer from insulin resistant in heredity.Acquired factor as too much body fat and health inertia, can cause insulin resistant and metabolism syndrome in these people.The people that great majority have insulin resistant suffers from the center obesity.Mechanism biology on the molecular level between insulin resistant and the metabolism risk factor is not understood fully and is seemingly complicated.The people that one class has the danger of development metabolism syndrome is the people who suffers from diabetes, and they have defective and can not keep suitable glucose level in the blood at them aspect the insulin action.Another kind of mainly is to suffer from hypertensive those people, and they do not have diabetes and insulin resistant, but compensates by secreting a large amount of insulins.This situation is called as hyperinsulinemia.The 3rd class is the heart attack survivor, and they are different from hypertensive people, suffer from hyperinsulinemia, do not have unusual glucose level.In highly developed country U.S. for example, it is more and more common that metabolism syndrome has become, the U.S. according to estimates the U.S. adult of about 20-25% suffer from metabolism syndrome.For the diagnosis metabolism syndrome, still there is not the standard of fully being accepted.By being responsible for detecting, estimating and treat (NationalCholesterol Education Program (NCEP) the Expert Panel on Detection of national cholesterol education project (NCEP) expert group (adult's treatment group III) of adult's high blood cholesterol, Evaluation, and Treatment of High Blood Cholesterol in Adults (AdultTreatment Panel III)) standard that the 3rd part of report proposes is up-to-date at present and is widely used.According to ATP III standard, identify metabolism syndrome by three kinds in following these key elements or more kinds of existence:
A. centre type obesity is measured (male-above 40 inches according to waistline; The women-above 35 inches).
B. under the fasting state blood triglyceride more than or equal to 150mg/dL.
C. blood HDL-C (male-less than 40mg/dL; The women-less than 50mg/dL)
D. blood pressure is more than or equal to 130/85mmHg.
E. under the fasting state glucose more than or equal to 110mg/dL.
Term " X syndrome " is closely related with term " metabolism syndrome ", and is considered to censure same disease or situation usually.Yet according to the information from american heart community, term " X syndrome " refers to heart in addition, wherein has chest pain and ECG change (its prompting has ischemic heart desease), but does not have the angiography of coronary disease to find.The patient who suffers from the heart X syndrome also has dyslipidemias sometimes.
Therefore; the purpose of this invention is to provide a kind of more efficiently and/or treatment more selectively, it is used for obesity, diabetes, metabolism syndrome, X syndrome, insulinoma, familial hyperinsulinism hypoglycemia, male pattern alopecia, forces the flesh hyperactivity, asthma, neuroprotective, epilepsy, analgesia, Cardioprotective, angina pectoris, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite stimulator, neural degeneration, pain-comprise neuropathic pain and chronic pain-and sexual impotence.
ATP-sensitive potassium channel (K ATPPassage) adjusting interrelates with several potential clinical practices; it comprises diabetes; insulinoma; familial hyperinsulinism hypoglycemia; male pattern alopecia; force the flesh hyperactivity; asthma; neuroprotective; epilepsy; analgesia; Cardioprotective; angina pectoris; cardioplegia; arrhythmia; coronary spasm; hypertension; peripheral vascular disease; cerebral vasospasm; appetite stimulator; neural degeneration; pain-comprise neuropathic pain and chronic pain-and sexual impotence (with reference to people J.Mol.Cell.Cardiology such as Jahangir; 2005; 39,99-112 and the list of references of wherein quoting).
K ATPChannel opener and potential purposes in suppressing insulin secretion and/or treatment metabolism disorder thereof are for example from file US 6,492,130; WO 02/00223; WO 02/00665 or from people such as R.D.Carr, Diabetes 52(2003) people such as 2513-2518 or J.B.Hansen, Current Medicinal Chemistry 11(2004) be known among the 1595-1615.
Specific K ATPThe beneficial effect of channel opener diazoxide in treatment i.a. metabolism syndrome be for example from file US 5,284,845 or US 6,197,765 or from people such as R.Alemzadeh, Endocrinology 133(2) people such as (1993) 705-712 or R.Alemzadeh are known among Journal ofClinical Endocrinology and Metabolism 83 (6) (1998) 1911-1915.
K ATPPassage interrelates glucose metabolism and insulin secretion.Reported K ATPThe defective regulating action of channel activity has been facilitated the etiology (with reference to Ashcroft, J.Clin.Investig.2005,115 (8), 2047-2057 and the list of references of wherein quoting) of type 2 diabetes mellitus.K ATPPassage is eight aggressiveness complex of the SURy subunit (Y=1,2A or 2B) of 4Kir6.x (x=1 or 2) and 4 regulation and control.Especially (with reference to people such as Aguilar-Bryan, Science 1995,268,423-426) to have found SUR1 regulation and control subunit in pancreas and brain.K ATPThe Kir6.2/SUR1 combination is present in the pancreas.Measured recently its structure (with reference to Mikhailov, EMBOJournal, 2005,24, (23), 4166-4175).The existing summary of latest developments in finding ATP-sensitive potassium channel opener (people such as Pirotte, Exp Opin.Ther.Patents2005,15 (5), 497-504).
Insulin is the major hormone that participates in the blood-glucose homeostasis.Insulin participates in regulating glucemia, and therefore relevant with I type and type ii diabetes.In addition, insulin participates in lipogenesis and weight increase, excites satiety because of it when working in brain, so excite appetite decline (with reference to people such as Juan-Pico, Cell Calcium 2006,39,155-163 and the list of references of wherein quoting).
Therefore, regulating insulin secretion will be useful in type i diabetes, type ii diabetes, obesity, metabolism syndrome and the X syndrome for example in the treatment disease.
(Br.J.Pharmacol.2004 141,765-774 for reference (a) De Petrocellis, people such as L. to have reported the Endocannabinoids system; (b) Di Marzo, people such as V., Nature Rev.DrugDiscov.2004,3,771-784; (c) Lambert, D.M. and Fowler, C.J.J.Med.Chem.2005,48,5059-5087) in physiological regulation food intake, the energy balance and glucose and lipid metabolism, play a role.Confirmed in the endocrine pancreas, to exist cannabinoid CB 1And CB 2Receptor.Reported endogenous CB 1/2Receptor stimulating agent 2-arachidonic acyl group glycerol (2-AG) (Fig. 2) passes through CB 2[Ca in the receptor endocrine regulation pancreas in the beta cell 2+] iSignal and therefore (conclusion that obtains as people such as Juan-Pico) its reduced insulin secretion (with reference to people such as Juan-Pico, Cell Calcium 2006,39,155-163).At CB 2Nearest progress in the receptors ligand field by people such as Raitio carried out summarizing (Curr.Med.Chem.2005,12,1217-1237).
Find unexpectedly now, at CB xViewed quantitative effect also can be passed through single CB greater than what expect during regulator used in indication described herein xThe effect that regulatory mechanism is explained.Through research more completely, proved and confirmed CB xRegulator is as K ATPChannel modulators works.Therefore, CB xRegulator can be used for and resists all and need open K ATPThe disease of passage and disease.More particularly, CB xRegulator can be used for treatment; prevent disease; delay the process of disease; delay the outbreak of disease and/or suppress disease, this disease is mammal and people's a obesity; diabetes; metabolism syndrome; X syndrome; insulinoma; familial hyperinsulinism hypoglycemia; male pattern alopecia; force the flesh hyperactivity; asthma; neuroprotective; epilepsy; analgesia; Cardioprotective; angina pectoris; cardioplegia; arrhythmia; coronary spasm; peripheral vascular disease; cerebral vasospasm; appetite stimulator; neural degeneration; pain-comprise neuropathic pain and chronic pain-and sexual impotence.
Summary of the invention
Summary of the invention
In first aspect, the present invention relates at least a CB xRegulator is as K ATPChannel modulators is used to prevent, treat disease, delays the process of disease, delays the outbreak of disease and/or the purposes of inhibition disease, wherein said CB xRegulator is selected from CB 1Agonist; CB 2Agonist; CB 2Partial agonist; CB 2Antagonist; CB 2Inverse agonists; And be CB 1Agonist is again CB 2The chemical compound with dual function of agonist; And composition thereof, described disease be mammal and people obesity, diabetes, metabolism syndrome, X syndrome, insulinoma, familial hyperinsulinism hypoglycemia, male pattern alopecia, force flesh hyperactivity, asthma, neuroprotective, epilepsy, analgesia, Cardioprotective, angina pectoris, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite stimulator, neural degeneration, pain-comprise neuropathic pain and chronic pain-and sexual impotence.
In second aspect; the invention still further relates to treatment; prevent disease; delay the process of disease; delay the outbreak of disease and/or the method for inhibition disease; described disease is mammal and people's a obesity; diabetes; metabolism syndrome; X syndrome; insulinoma; familial hyperinsulinism hypoglycemia; male pattern alopecia; force the flesh hyperactivity; asthma; neuroprotective; epilepsy; analgesia; Cardioprotective; angina pectoris; cardioplegia; arrhythmia; coronary spasm; peripheral vascular disease; cerebral vasospasm; appetite stimulator; neural degeneration; pain-comprise neuropathic pain and chronic pain-and sexual impotence, this method comprises at least a CB that the experimenter of its needs effective dose is arranged xRegulator, wherein this CB xRegulator is selected from CB 1Agonist; CB 2Agonist; CB 2Partial agonist; CB 2Antagonist; CB 2Inverse agonists; And be CB 1Agonist is again CB 2The chemical compound with dual function of agonist; And composition thereof, and this CB wherein xRegulator has adjusting K ATPThe character of passage.
Detailed Description Of The Invention
In a specific embodiment of the present invention, CB xRegulator is as K ATPChannel modulators; be used for prevention; the treatment disease; delay the process of disease; delay the outbreak of disease and/or suppress disease, this disease is mammal and people's a obesity; diabetes; metabolism syndrome; X syndrome; insulinoma; familial hyperinsulinism hypoglycemia; male pattern alopecia; force the flesh hyperactivity; asthma; neuroprotective; epilepsy; analgesia; Cardioprotective; angina pectoris; cardioplegia; arrhythmia; coronary spasm; peripheral vascular disease; cerebral vasospasm; appetite stimulator; neural degeneration; pain-comprise neuropathic pain and chronic pain-and sexual impotence.More particularly, if CB xRegulator is used for prevention of metabolic syndrome and/or X syndrome, treatment metabolism syndrome and/or X syndrome, delays the process of metabolism syndrome and/or X syndrome, delays the outbreak of metabolism syndrome and/or X syndrome and/or suppresses metabolism syndrome and/or X syndrome, should understand metabolism syndrome and/or X syndrome and comprise obstacle or the disease that is selected from down group: hypertension particularly is arterial hypertension; Insulin resistant, particularly type ii diabetes; Glucose intolerance; Dyslipoproteinemia, particularly hypertriglyceridemia, it has highdensity lipoprotein-cholesterol simultaneously and reduces and hyperuricemia with dyslipoproteinemia.
Suitable K ATPChannel modulators is preferably as Kir6.2/SUR1 K ATPPassage and/or Kir6.2/SUR2 K ATPThe compounds effective of opener wholly or in part of passage.Effectively those with the sulfonylureas of rat and/or people SUR1 and/or SUR2 isoform (=SUR) and the potassium channel openers site (show IC in=the test model that KCO) bonded affinity test-for example provides hereinafter less than 50 50The chemical compound of value [μ mol].Preferably has K as Kir6.2/SUR1 ATPThe opener wholly or in part of passage is particularly as Kir6.2/SUR1K ATPThe chemical compound of the effect of the selective opening agent of passage.If according to the mensuration in aforementioned combination test, chemical compound is to Kir6.2/SUR1K ATPThe IC of passage 50Value less than this same compound to Kir6.2/SUR2 K ATPThe IC of passage 50Half of value more preferably only is 1/4th, then will be as Kir6.2/SUR1 K ATPThe compounds effective of opener wholly or in part of passage is thought optionally.
Find the CB of different types of structure unexpectedly xRegulator all can be used as effectively and SUR1/SUR2 K optionally ATPThe Kir6.2 channel modulators works.CB among the present invention yRegulator is CB 1Agonist; CB 2Agonist; CB 2Partial agonist; CB 2Antagonist; CB 2Inverse agonists; And be CB 1Agonist is again CB 2The chemical compound with dual function of agonist; And composition thereof.K ATPChannel modulators is SUR1/K preferably ATPKir6.2 channel modulators, particularly SUR1/K ATPKir6.2 channel modulators or part SUR1/K ATPThe Kir6.2 channel modulators.Preferred CB XRegulator is to have the K as Kir6.2/SUR1 ATPPassage, Kir6.2/SUR2B K ATPPassage, Kir6.1/SUR2B K ATPPassage and/or Kir6.2/SUR2A K ATPThe chemical compound of the effect of the regulator of passage.
In preferred embodiment of the present invention, K ATPChannel modulators is K ATPChannel opener.
The applicable K that does on meaning of the present inventionATPThe CB of passage conditioning agentXAdjusting agent is selected from, but Limited to the group consisting of the following: 3 - (1,1 - dimethyl - butyl) -6,6,9 - trimethyl- -6a, 7,10,10 a-tetrahydro-6H-benzo [c] chromene; N-adamantyl alkyl-4 - pentyl-5 - phenyl - thiazol-2 - Carboxamide; N-{1,3,3 - trimethyl - Bridge - (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 - G Yl) -2,6 - dimethoxy - phenyl] -6,6 - dimethyl - bicyclo [3.1.1] hept-2 - ene-2 ​​- yl} - methanol; 3 - (1,1 - dimethyl - heptyl)-9 - hydroxy-methyl-6 ,6 - dimethyl-6a, 7,10,10 a-tetrahydro-6H-benzo (Enzo) [c] Color-1 - ol; eicosatetraenoic -5,8,11,14 - Four enoic acid 2 - hydroxy-1 - hydroxy methyl - ethyl ester; 1 - N C-1 - yl - twenty-one carbon -6,9,12,15 - four en-2 - one; Noladine ether; 4,4,4 - trifluoro - Butane-1 - sulfinic acid 3 - (2 - hydroxy-methyl - indan -4 - yloxy) - phenyl ester, to form an aldehyde compound Thereof; 7 - methoxy-2 - oxo-8 - pentyl-1 ,2 - dihydro - quinoline-3 - carboxylic acid (benzo [1,3] dioxa Cyclopentyl-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 - yl amide; (2 - methyl-1 - propyl-2 ,3 - dihydro-1H-indole -3 - Yl) - naphthalene-1 - yl - methanone; 5 - (1,1 - dimethyl - heptyl) -2 - [5 - hydroxy-2 - (3 - hydroxy - propyl) - Cyclohexyl] - phenol; (2 - methyl -3 - morpholin-4 - yl-3 ,4 - dihydro-5 - oxa-2a-aza-acenaphthylene -1 - Yl) - naphthalene-1 - yl - methanone; 5 - (4 - chloro - phenyl) -1 - (2,4 - dichloro - phenyl)-4 - methyl-1H-pyrazole -3 - Carboxylic acid piperidin-1 - yl amide; 5 - (4 - bromo - phenyl) -1 - (2,4 - dichloro - phenyl)-4 - ethyl-1H-pyrazol Zol-3 - carboxylic acid piperidin-1 - yl amide; 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 - two H - 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 - benzene Yl) -4 - pyridin-3 - yl-4 ,5 - dihydro - pyrazol-1 - yl] - methylamino - methylene} -4 - (trifluoromethyl) - phenyl Sulfonamide; 4 - chloro-N-{[3 - (4 - chloro - phenyl) -4 - pyridin-3 - yl-4 ,5 - dihydro - pyrazol-1 - yl] - methylamino Yl - methylene} - benzenesulfonamide; 4 - chloro-N-{[3 - (4 - chloro - phenyl) -4 - (3 - fluoro - phenyl) -4,5 - dihydro - Pyrazol-1 - yl] - methoxy-amino - methylene} - benzenesulfonamide; morpholin-4 - sulfonic acid [3 - (4 - chloro - benzene Yl) -4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - methylamino - methylene amide; N-{[3 - (4 - chloro - benzene Yl) -4 - (3 - fluoro - phenyl) -4,5 - dihydro - pyrazol-1 - yl] - methylamino - methylene}-N, N-dimethyl - sulfo Amide; heterocyclic heptane-1 - sulfonic acid [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - Methylamino - methylene amide; 4 - chloro-N-{[3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol - Yl] - [(1 - methyl - pyrrolidin-3 - yl methyl) - amino] - methylene} - benzenesulfonamide; 1 - (4 - chloro - benzene Yl) -5 - phenyl-4 ,5 - dihydro-1H-pyrazole-3 - carboxamidine; N-{[3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - two H - pyrazol-1 - yl] - methylamino - methylene} -4 - (trifluoromethyl) - benzene - sulfonamide; piperidin-1 - sulfonic acid [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - methylamino - methylene amide; piperidine -1 - Sulfonic acid [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - (2 - dimethylamino - ethylamino Yl) - methylene amide; N, N-diethylamino-1 - sulfonic acid [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - Pyrazol-1 - yl] - methylsulfanyl - methylene amide China; - amino-1 - [3 - (4 - chloro - phenyl) -4 - phenyl- -4,5 - Dihydro - pyrazol-1 - yl] -3 - (3,4 - dichloro - phenyl) - propan-1 - one; morpholin-4 - sulfonic acid [3 - (4 - Chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - methylamino - methylene amide; N, N-dimethylamino -1 - sulfonic acid [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - (2 - fluoro - ethylamino) - 2nd Methylamide;-piperidin-1 - sulfonic acid [3 - (4 - chloro - phenyl) -4 - (3 - fluoro - phenyl) -4,5 - dihydro - pyrazol - Yl] - methylamino - methylene amide; 5 - (4 - chloro - phenyl) -1 - (2,4 - dichloro - phenyl) -4,5 - dihydro-1H- Pyrazole-3 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - phenyl) -5 - phenyl-4 ,5 - dihydro-1H-pyrazol-3 - Carboxylic acid piperidin-1 - yl amide;-piperidin-1 - sulfonic acid [1 - (4 - chloro - phenyl) -5 - phenyl-4 ,5 - dihydro-1H- Pyrazol-3 - yl] - methylamino - methylene amide; morpholin-4 - sulfonic acid [1 - (2,4 - dichloro - phenyl) - phenyl -4,5 - Dihydro-1H-pyrazol-3 - yl] - methylamino - methylene amide; 4 - chloro-N-[[3 - (4 - chloro - benzene Yl) -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 Yl] - benzenesulfonamide; N-{Amino - [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - 2nd Methyl}-4 - chloro - benzenesulfonamide; 4 - chloro-N-[3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol - Carbonyl] - benzenesulfonamide; 4 - chloro-N-[[3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol - 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 - pyrrolo Adamantan-1 - yl - butylamino) - methylene] - benzenesulfonamide; 4 - chloro-N-{[3 - (4 - chloro - phenyl) -4 - phenyl- -4,5 - Dihydro - pyrazol-1 - yl] - [(pyridin-3 - yl methyl) - amino] - methylene} - benzenesulfonamide; 1 - [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] -3 - (1H-indol-2 - yl) -2 - methyl ammonia Yl - propan-1 - one; 2 - [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] -5 - ethyl-4 ,5 - Dihydro - oxazole; 4 - chloro-N-[[3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - (3 - hydroxy -2,2 - Dimethyl - propylamino) - methylene] - benzenesulfonamide; N, N-diethylamino-1 - sulfonic acid [3 - (4 - chloro- - Phenyl)-4 - hydroxy - 4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - methylamino - methylene amide; 5 - (4 - Bromine - phenyl) -1 - (2,4 - dichloro - phenyl)-1H-pyrazole-3 - carbonitrile; 8 - chloro-1 - (2,4 - dichloro - phenyl Yl) -1,3 a, 4,5,6,10 b-hexahydro-1,2 - diaza - benzo [e] azulene -3 - carboxylic acid piperidin-1 - yl acid Amine; 5 - (4 - bromo - phenyl) -1 - (2,4 - dichloro - phenyl) -3 - [2 - (3,5 - difluoro - phenyl) -2 - methanesulfonyl - Ethenyl]-4 - methyl-1H-pyrazole; piperidine-1 - carboxylic acid [5 - (4 - chloro - phenyl) -1 - (2,4 - dichloro - phenyl Yl) -4 - methyl-1H-pyrazol-3 - yl] - amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl) - acetic Ylthio group-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 2 - (2,4 - dichloro - phenyl) -1 - (4 - trifluoromethyl Methyl - phenyl)-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - Phenyl) -5 - methylsulfanyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - benzene Yl) -2 - (2,4 - dichloro - phenyl)-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - benzene Yl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - bromo - Phenyl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - Bromine - phenyl) -5 - chloro-2 - (2,4 - dichloro - phenyl)-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - Bromine - phenyl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-imidazole-4 - carboxylic acid cyclohexyl amide; 1 - (4 - Bromine - phenyl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-imidazole-4 - carboxylic acid pentyl amide; 4 - (4 - chloro - Phenyl) -5 - (2,4 - dichloro - phenyl) -1 - methyl-1H-imidazole-2 - carboxylic acid cyclohexyl amide; 4 - (4 - chloro - Phenyl) -5 - (2,4 - dichloro - phenyl) -3 - methyl-1H-imidazole-2 - carboxylic acid cyclohexyl amide; 1 - (5 - chloro - Pyridin-2 - yl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl)-5 - methyl-1H-imidazole-4 - carboxylic acid (4 - hydroxy - cyclohexyl Yl) - amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl)-5 - methyl-1H-imidazole-4 - carboxylic acid aza Ring heptane-1 - yl amide; 2 - (2,4 - dichloro - phenyl) - ethyl-1 - phenyl-1H-imidazole-4 - carboxylic acid piperazine -1 - yl amide; 2 - (1,5 - dimethyl-1H-pyrrol-2 - yl) -5 - ethyl-1 - phenyl-1H-imidazol-4 - Cyclohexyl carboxylic acid amide; 1 - (4 - chloro - phenyl)-5 - ethyl-2 - (3 - methyl - pyridin-2 - yl)-1H-imidazole -4 - Carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-Mic -4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - bromo - phenyl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H- Imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - bromo - phenyl) -5 - chloro-2 - (2,4 - dichloro - phenyl)-1H- Imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - bromo - phenyl) -2 - (2,4 - dichloro - phenyl) - ethyl -1H-imidazole-4 - carboxylic acid cyclohexyl amide; 1 - (4 - bromo - phenyl) -2 - (2,4 - dichloro - phenyl) - ethyl -1H-imidazole-4 - carboxylic acid pentyl-amide; 4 - (4 - chloro - phenyl) -5 - (2,4 - dichloro - phenyl) -1 - methyl- -1H-imidazole-2 - carboxylic acid cyclohexyl amide; 4 - (4 - chloro - phenyl) -5 - (2,4 - dichloro - phenyl) -3 - methyl- -1H-imidazole-2 - carboxylic acid cyclohexyl amide; 1 - (5 - chloro - pyridin-2 - yl) -2 - (2,4 - dichloro - phenyl) - Ethyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl Yl) -5 - methyl-1H-imidazole-4 - carboxylic acid (4 - hydroxy - cyclohexyl) - amide; 1 - (4 - chloro - benzene Yl) -2 - (2,4 - dichloro - phenyl)-5 - methyl-1H-imidazole-4 - carboxylic acid heterocyclic heptane-1 - yl amide; 2 - (2,4 - dichloro - phenyl) - ethyl-1 - phenyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 2 - (1,5 - dimethyl-1H-pyrrol-2 - yl) -5 - ethyl-1 - phenyl-1H-imidazole-4 - carboxylic acid cyclohexyl Amine; 1 - (4 - chloro - phenyl)-5 - ethyl-2 - (3 - methyl - pyridin-2 - yl)-1H-imidazole-4 - carboxylic acid piperidin-1 - Amide; 1 - (4 - chloro - phenyl)-5 - ethyl-2 - (3 - methyl - pyridin-2 - yl)-1H-imidazole-4 - carboxylic acid ring Hexyl amide; 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 - yl amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl)-5 - fluoro-methyl-1H- Imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl)-5 - hydroxy-methyl Yl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl) - Methylsulfanyl-1H-imidazole-4 - carboxylic acid cyclohexyl amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - Phenyl) -5 - methylsulfonyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - benzene Yl) -2 - (2,4 - dichloro - phenyl) - methane sulfinyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl acid Amine; 5 - (4 - chloro - phenyl) -4 - (2,5 - dichloro - phenyl) -1 - methyl-1H-imidazole-2 - carboxylic acid piperidin-1 - yl Amide; 2 - (2 - chloro - phenyl) -1 - (5 - chloro - pyridin-2 - yl) -5 - ethyl-1H-imidazole-4 - carboxylic acid piperidin-1 - Amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl) -5 - (2,2,2 - trifluoro - ethyl)-1H-imidazole -4 - Carboxylic acid piperidin-1 - yl amide; 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) - pyrrolidin-1 - yl Methyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 2 - [1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl Yl) -5 - methyl-1H-imidazol-4 - yl] - hexan-2 - ol; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl Yl) -5 - methyl - 4 - pentyl-1H-imidazole; 2,5 - dimethyl-1 - phenyl-1H-imidazole-4 - carboxylic acid adamantane -2 - Amide; 1 - (4 - chloro - phenyl) -2 - (2 - chloro - phenyl) -5 - methylsulfanyl-1H-imidazole-4 - carboxylic acid Piperidin-1 - yl amide; 2 - (2 - chloro - phenyl) -1 - (4 - (trifluoromethyl) - phenyl)-1H-imidazole-4 - carboxylic acid piperazine -1 - yl amide; 5 - (4 - chloro - phenyl) -4 - (2,4 - dichloro - phenyl) - thiazol-2 - carboxylic acid piperidin-1 - yl acid Amine; 5 - (4 - chloro - phenyl) -1 - (2,4 - dichloro - phenyl)-1H-[1,2,4] triazole-3 - carboxylic acid pyrrolidin-1 - Amide; 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 - thiazol-2 - carboxylic acid (hexahydro-2 ,5 - methylene bridge - and cyclopentadiene -3a-yl) - amide; 4 - pentyl-5 - phenyl - thiazol-2 - carboxylic acid (hexahydro-2 ,5 - methylene bridge - and cyclopentadiene Ene-3a-yl) - amide; 1 - {(4 - chloro - phenyl - sulphonyl-imino) - [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} - phenyl Sulfonamide; 4 - chloro-N-[[3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - (2 - cyano - ethylamino Yl) - 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 - benzene Yl) -4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - [(piperidin-4 - ylmethyl) - amino] - methylene} - benzenesulfonamide Amide; 4 - chloro-N-[[3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - (piperidin-4 - yl amino Yl) - methylene] - benzenesulfonamide;, and morpholin-4 - sulfonic acid [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - two H - pyrazol-1 - yl] - (cyclopropylmethyl - amino) - methylene amide. ...
In another specific embodiment of the present invention, be suitable on the meaning of the present invention and make K ATPThe CB of passage XRegulator is selected from the group of being made up of following material: 3-(1,1-dimethyl-butyl)-6,6,9-trimethyl-6a, 7,10,10a-tetrahydrochysene-6H-benzo [c] color alkene; N-adamantyl-4-amyl group-5-phenyl-thiazole-2-Methanamide; N-{1,3,3-trimethyl-bridge-(1S)-dicyclo [2.2.1] heptan-2-yl }-1-[1-(4-methyl)-benzyl-5-(4-chloro-3-methyl-phenyl)-1H-pyrazole-3-formamide; (2-iodo-5-nitro-phenyl)-[1-(1-methyl-piperidines-2-ylmethyl)-1H-indol-3-yl]-ketone; 4-[4-(1,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl]-6,6-dimethyl-dicyclo [3.1.1] reaches-2-alkene-2-yl }-methanol; 3-(1,1-dimethyl-heptyl)-9-hydroxymethyl-6,6-dimethyl-6a, 7,10,10a-tetrahydrochysene-6H-benzo [c] chromene-1-alcohol; 20 carbon-5,8,11,14-tetraenoic acid 2-hydroxyl-1-hydroxymethyl-ethyl ester; 1-aziridine-1-base-21 carbon-6,9,12,15-four-2-ketone; Noladine ether; 4,4,4-three fluoro-butane-1-sulfinic acid 3-(2-hydroxymethyl-indane-4-base oxygen base)-phenylester, the chemical compound of formation aldehyde; 7-methoxyl group-2-oxo-8-amoxy-1,2-dihydro-quinoline-3-carboxylic acid (benzo [1,3] dioxole-5-ylmethyl)-amide; N-(1-{4-[4-chloro-2-(2-fluoro-benzenesulfonyl)-benzenesulfonyl]-phenyl }-ethyl)-Methanesulfomide; [6-iodo-2-methyl isophthalic acid-(2-morpholine-4-base-ethyl)-2,3-dihydro-1H-indol-3-yl]-(4-methoxyl group-phenyl)-ketone; 1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-ethyl-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; (2-methyl isophthalic acid-propyl group-2,3-dihydro-1H-indol-3-yl)-naphthalene-1-base-ketone; 5-(1,1-dimethyl-heptyl)-2-[5-hydroxyl-2-(3-hydroxyl-propyl group)-cyclohexyl]-phenol; (2-methyl-3-morpholine-4-ylmethyl-3,4-dihydro-5-oxa--2a-azepine acenaphthylene-1-yl)-naphthalene-1-base-ketone; 5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base amide; 5-(4-bromo-phenyl)-1-(2,4-two chloro-phenyl)-4-ethyl-1H-pyrazoles-3-carboxylic acid piperidines-1-base amide; 1-[two-(4-chloro-phenyl)-methyl]-3-[(3,5-two fluoro-phenyl)-mesyl-methylene]-azetidine.
In another specific embodiment of the present invention, be suitable for the K that does on the meaning of the present invention ATPThe CB of channel modulators XRegulator is selected from the group of being made up of following material: 4-chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylamino-methylene }-benzsulfamide; N-{ amino-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylene }-4-chloro-benzsulfamide; 4-chloro-N-{[3-(4-chloro-phenyl)-4-pyridin-3-yl-4,5-dihydro-pyrazol-1-yl]-methylamino-methylene }-benzsulfamide; 4-chloro-N-{[3-(4-chloro-phenyl)-4-(3-fluoro-phenyl)-4,5-dihydro-pyrazol-1-yl]-methoxyl group amino-methylene }-benzsulfamide; 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-two chloro-phenyl)-4,5-dihydro-1 h-pyrazole-3-carboxylic acid piperidines-1-base amide; Morpholine-4-sulfonic acid [1-(2,4-two chloro-phenyl)-5-phenyl-4,5-dihydro-1 h-pyrazole-3-yl]-methylamino-methylene amide; N-{ amino-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylene }-4-chloro-benzsulfamide; 4-chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-ethylamino-ethylamino)-methylene]-benzsulfamide; 4-chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(1-methyl-pyrrolidine-2-ylmethyl)-amino]-methylene }-benzsulfamide; 4-chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(pyridin-3-yl methyl)-amino]-methylene }-benzsulfamide; 1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-ethyl sulfane base-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 2-(2,4-two chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-methyl sulfane base-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-ethyl-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 1-(4-bromo-phenyl)-2-(2,4-two chloro-phenyl)-5-ethyl-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 1-(4-bromo-phenyl)-5-chloro-2-(2,4-two chloro-phenyl)-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 1-(4-bromo-phenyl)-2-(2,4-two chloro-phenyl)-5-ethyl-1H-imidazoles-4-carboxylic acid amyl group amide; 1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-methyl isophthalic acid H-imidazoles-4-carboxylic acid azepan-1-base amide; 1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-methyl fluoride-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-methyl sulfane base-1H-imidazoles-4-carboxylic acid cyclohexyl amide; N-[1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-methyl isophthalic acid H-imidazol-4 yl]-Benzoylamide; 2-[1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-methyl isophthalic acid H-imidazol-4 yl]-hexane-2-alcohol; 1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-methyl-4-amyl group-1H-imidazoles; 1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-methyl sulfane base-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 2-(2-chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 5-(4-chloro-phenyl)-4-(2,4-two chloro-phenyl)-thiazole-2-carboxylic acid piperidines-1-base amide; 1-(4-chloro-phenyl)-5-(2,4-two chloro-phenyl)-1H-[1,2,4] triazole-3-carboxylic acid piperidines-1-base-amide; 1-{ (4-chloro-benzene-sulphonyl imino group)-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methyl }-piperidines-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 }-benzsulfamide; 4-chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-cyano group-ethylamino)-methylene]-benzene-sulfonamide; 4-chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(methoxyl group-methyl-amino)-methylene]-benzsulfamide; Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(cyclopropyl methyl-amino)-methylene amide.
Be suitable for the K that does on the meaning of the present invention ATPThe CB of channel modulators 1Agonist or CB 2Agonist is selected from, but is not limited to the group be made up of following material: L759633; L759656; 4-[4-(1,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl] and-6,6-dimethyl-dicyclo-[3.1.1] hept-2-ene"-2-yl }-methanol (=HU308); JWH015; (2-iodo-5-nitro-phenyl)-[1-(1-methyl-piperidines-2-ylmethyl)-IH-indol-3-yl]-ketone (=AM-1241); 3-(1,1-dimethyl-butyl)-6,6,9-trimethyl-6a, 7,10,10a-tetrahydrochysene-6H-benzo [c]-chromene (JWH133); N-adamantyl-4-amyl group-5-phenyl-thiazole-2-Methanamide; 6,6,9-trimethyl-3-amyl group-6a, 7,8,10a-tetrahydrochysene-6H-benzo [c] chromene-1-alcohol; (dicyclo [2.2.1] heptan-2-base is amino)-(5-amyl group-4-phenyl-thiazol-2-yl)-methane; 5-(1,1-dimethyl-heptyl)-2-[5-hydroxyl-2-(3-hydroxyl-propyl group)-cyclohexyl]-phenol (=CP-55,940); (2-methyl-3-morpholine-4-ylmethyl-3,4-dihydro-5-oxa--2a-azepine-acenaphthylene-1-yl)-naphthalene-1-base-ketone (=WIN-55,212-2); ACEA; ACPA; N-adamantyl-4-amyl group-5-phenyl-thiazole-2-Methanamide; Methyl arachidonic acid diethanolamide (methanandamide); The arachidonic acid diethanolamide; 2-arachidonic acyl glycerol; 2-20 carbon-5,8,11,14-tetraene oxygen base-propane-1,3-glycol (=noladin ether); BAY38-7271; SAB-378; BAY59-3074; O-1057; GW-1000; PRS-211375; PRS-211359; PRS-211355; PRS-211096; PXS-2076; AM-577; GW-842166X; And composition thereof.
In the preferred embodiment of the present invention, CB 2Agonist is selectivity CB 2Agonist, and be selected from: 3-(1,1-dimethyl-butyl)-6,6,9-trimethyl-6a, 7,10,10a-tetrahydrochysene-6H-benzo [c] chromene (=JWH133); L759633; L759656; 4-[4-(1,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl] and-6,6-dimethyl-dicyclo [3.1.1] hept-2-ene"-2-yl }-methanol (=HU308); JWH015; (2-iodo-5-nitro-phenyl)-[1-(1-methyl-piperidines-2-ylmethyl)-1H-indol-3-yl]-ketone (=AM-1241); And composition thereof.
Be suitable for use as the K on the meaning of the present invention ATPThe CB of channel modulators 2Antagonist or CB 2Inverse agonists is selected from: (1) document WO 01/0588869, PCT/EP2006/060009, WO2004/014825; EP1142877; US2002/0072529; WO02/062750; US6, the chemical compound of describing in 509,352; And (2) are selected from 1-[1-benzyl-5-(4-chloro-3-methyl-phenyl)-1H-pyrazole-3-yl]-ethyl ketone base (ethanonyl)-1,3,3-trimethyl-two-ring [2.2.1] heptan-2-base amine (=SR-144528), the chemical compound of JTE-907, AM630 and composition thereof; And (3) are selected from the mixture of the chemical compound of (1) and (2).
Be suitable for the K that does on the meaning of the present invention ATPChannel modulators be CB 1Agonist is again CB 2The chemical compound with dual function of agonist is selected from: 2-20 carbon-5,8,11,14-apos oxygen base-propane-1,3-glycol (=noladin ether); And composition thereof.
In preferred embodiment of the present invention, CB xRegulator is selected from: 6,6, and 9-trimethyl-3-amyl group-6a, 7,8,10a-tetrahydrochysene-6H-benzo [c] chromene-1-alcohol; (dicyclo [2.2.1] heptan-2-base is amino)-(5-amyl group-4-phenyl-thiazol-2-yl)-methane; 3-(1,1-dimethyl-butyl)-6,6,9-trimethyl-6a, 7,10,10a-tetrahydrochysene-6H-benzo [c] color alkene; N-adamantyl-4-amyl group-5-phenyl-thiazole-2-Methanamide; SR144528; (2-iodo-5-nitro-phenyl)-[1-(1-methyl-piperidines-2-ylmethyl)-1H-indol-3-yl]-ketone; 4-[4-(1,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl] and-6,6-dimethyl-dicyclo [3.1.1] hept-2-ene"-2-yl }-methanol; And composition thereof.
One group of representational CB has been described respectively in the table 1 xRegulator and to K ATPSUR1 and SUR2 regulate the affinity of subunit (hamster).(2-chloro-4-methyl-7,7-dioxo-4,7-dihydro-1,7 λ *6 *-dithia-4,6-diaza-indenes-5-yl)-(1-methyl-cyclopropyl)-amine and 7-chloro-3-methyl-2H-benzo [1,2,4] thiadiazine 1, the 1-dioxide is as K ATPThe active reference compound of/SUR1, they are known to those skilled in the art.For reason relatively, table 1 is also listed the CB1 of different chemical compounds and/or CB2 activity to prove that they are as CB 1Agonist, CB 2Agonist, CB 2Partial agonist, CB 2Antagonist, CB 2Inverse agonists and be CB 1Agonist is again CB 2The activity of the chemical compound with dual function of agonist.
The explanation of pharmacology's method of testing
1. test compound and rodent K ATP The external affinity of passage
Being at war with property goes up sulfonylureas and K to characterize test compound to hamster SUR1 in conjunction with test ATPChannel opener (=KCOs) the affinity of binding site.In order to assess affinity to the sulfonylureas site, [ 3H] glibenclamide exists down, hatches film from the COS cell of transient expression hamster SUR1 with the test compound that improves concentration.By existing the binding affinity of assessing the KCO site of hatching under the 100 μ MMgATP (, to wait people Naunyn-Schmiedeberg ｀ s Arch.Pharmacol. in addition referring to SchwanstecherM. 343(1991) people such as 83-89 and Schwanstecher M., EMBO J. 17(1998) 5529-5535 (people such as=Schwanstecher, 1998)).For each test compound, measured 4 displacement curves (from human and hamster isoform+/-MgATP).Every 9-15 different concentration that curve has been tested to contain relevant range.All measurements all repeat 5 times at least in testing separately.
Similar with SUR1 (as mentioned above), being at war with property goes up the affinity of sulfonylureas and KCOs binding site in conjunction with experiment to characterize test compound to rat SUR2A.By the displacement [ 3H] P1075 assessed the affinity that SUR2A goes up the KCO site (referring to people such as Schwanstecher, 1998; H. wait people Mol.Pharmacol. 55(1999) 1060-1066 (=
Figure A200780015186D00282
Deng the people, 1999)).Yet, [ 3H] glibenclamide to the affinity of human SUR2 isoform too a little less than, to such an extent as to can not use filtration test directly to detect combination.Therefore, can use two kinds of strategies to detect the combination of SUR2A being gone up the sulfonylureas site.At first, can pass through [ 3H] P1075 do not set up change indirect detection in conjunction with (
Figure A200780015186D00291
Deng the people, 1999).Secondly, can use have allow this tracer of direct replacement [ 3H] the sudden change SUR2A (SUR2A of increase affinity of glibenclamide Y1205S, as above).Select this second method to make it possible to distinguish the allosteric and competitive interaction the in KCO site, and guarantee not miss and do not induce the metathetical part combination of allosteric.
As mentioned above, in the presence of radioligand, will hatch with the test compound that improves concentration from the film of the COS cell of transient expression rat SUR2A.By there being in addition hatching under the 100 μ M MgATP, assessment is to the bonded affinity in KCO site people such as (, 1991 and 1998) Schwanstecher.For each test compound, measured 4 displacement curves (from the rat isoform displacement of wild-type receptor [ 3H] P1075 and from SUR2A Y1205SRat isoform displacement [3H] glibenclamide).Every 9-15 different concentration that curve has been tested to contain relevant range.In each was independently tested, all tests all repeated 5 times at least.
From Amersham Buchler (Braunschweig, Germany (Braunschweig)) bought [ 3H] P1075 (specific activity 116Ci mmol -1).From NEN (German Dreieich) obtained [ 3H] glibenclamide (specific activity 51Ci mmol -1).If suitable, in dimethyl sulfoxine, prepare stock solution, the final solvent strength in the media is less than 1%.
SUR-or Kir6.x isoform be used for sub-clone to pcDNA (hamster SUR1, mice Kir6.2) or pCMV carrier (rat SUR2A, SUR2B) in.
As described, rodent SUR-isoform and K ATPPassage is transient expression (referring to people such as Schwanstecher, 1998) in the COS-1 cell;
Figure A200780015186D00292
Deng the people, 1999); People such as Uhde I., J Biol Chem 274(1999) 28079-28082; People Mol.Pharmacol. such as Gross I. 56(1999) 1370-1373; Markworth E., Diabetes 49(2000) 1413-1418).The phenylalanine residue of use on 1205 is by the variant form (SUR2 of the metathetical SUR2 isoform of serine Y1205S), with allow by displacement [ 3H] glibenclamide detects the combination (Uhde I., paper 2001) to the sulfonylureas site of these isoforms.In brief, the COS-1 cell that will hatch in having replenished the DMEM HG (10mM glucose) of 10% hyclone (FCS) is whenever to hatch ware (94mm) 5 x 10 5The inoculation of the density of cell, and allow it adhere to spend the night.For transfection, cell was hatched 4 hours in having added the Tris-buffer salt solution that contains DNA (5-10 μ g/ml) of DEAE-glucosan (1mg/ml), in the HEPES-buffer salt solution that has added dimethyl sulfoxine (10%), hatched 2 minutes, and in the DMEM-HG that has added chloroquine (100 μ M), hatched 4 hours.Then cell is turned back among the DMEM-HG that has added 10%FCS.As described, after transfection 60-72 hour, prepare film (people such as Schwanstecher M., Br.J.Pharmacol. 106(1992) 295-301 (people such as=Schwanstecher, 1992)).For in conjunction with the experiment, contain [ 3H] glibenclamide (ultimate density is 0.3nM or 3nM, and respectively by to SUR1 or SUR2 Y1205SThe glibenclamide of the 100nM of isoform or 1 μ M defines non-specific bond) or [ 3H] P1075 (ultimate density is 3nM, defines non-specific bond by 100 μ M pinacidils) and increase the film (final protein concentration is 5-50 μ g/ml) of hatching resuspending among " Tris-buffer " (50mM, pH 7.4) of test compound of concentration.With free Mg 2+Concentration keeps near 0.7mM.In hatching base, add ATP (0.1mM) so that KCO (diazoxide for example, [ 3H] P1075) can be in conjunction with (referring to people such as Schwanstecher, 1998).At room temperature hatched 1 hour, and stop hatching by quick filtration of Whatman GF/B filter.
The inhibition constant of substances (Ki value) is from separately IC 50Value is calculated, and is expressed as its negative logarithm (pK i).
2. test compound is to CB 1 The external affinity of receptor
Use the film preparation thing of Chinese hamster ovary (CHO) cell, can measure The compounds of this invention cannabinoid CB 1The affinity of receptor, wherein human cannabinoid CB 1Receptor with as radioligand [ 3H] CP-55,940 are stabilized the ground transfection together.Adding or do not adding under the condition of The compounds of this invention, with [ 3H]-after part is hatched the cell membrane preparations of prepared fresh together, undertaken separating of combination and free ligand by filtering with glass fiber filter.Utilize the radioactivity on the liquid scintillation counting measurement filter.
3. test compound is to CB 2 The external binding affinity of receptor
Use the film preparation thing of Chinese hamster ovary (CHO) cell, can measure The compounds of this invention cannabinoid CB 2The affinity of receptor, wherein human cannabinoid CB 2Receptor with as radioligand [ 3H] CP-55,940 are stabilized the ground transfection together.Adding or do not adding under the condition of The compounds of this invention, with [ 3H]-after part is hatched the cell membrane preparations of prepared fresh together, undertaken separating of combination and free ligand by filtering with glass fiber filter.Utilize the radioactivity on the liquid scintillation counting measurement filter.
Table 1-CB xRegulator and to the affinity of CB1 and/or CB2 receptor affinity, (clone's who expresses in Chinese hamster ovary celI according to said method human cannabinoid (being respectively CB1 and CB2) receptor) uses pK iThis affinity of value representation.
Figure A200780015186D00311
Figure A200780015186D00321
Figure A200780015186D00322
Figure A200780015186D00331
Figure A200780015186D00341
Figure A200780015186D00351
Figure A200780015186D00361
Figure A200780015186D00381
Figure A200780015186D00391
Figure A200780015186D00401
Figure A200780015186D00411
Figure A200780015186D00421
Figure A200780015186D00431
Figure A200780015186D00441
Figure A200780015186D00451
Figure A200780015186D00461
The digital proof of table 1 CB that is tested xThe regulator selectively acting is in SUR1 subunit and/or SUR 2 subunits.
4. measure K by insulin secretion in the islets of langerhans of rat perfusion ATP Open effect
Animal: the male Wistar rat that with weight range is 175-200g divides into groups to be housed in the standard cage for animal under the humidity of 21 ± 2 ℃ temperature and 55 ± 10%.With 12 hours bright-dark cycle (bright 06.00-18.00 point) letting animals feeds, it obtained rodent standard food (B﹠amp arbitrarily; KUniversal Ltd standard rat and mice food (BK 001P), Beekay Feeds, B﹠amp; KUniversal Ltd, Hull, East Riding of Yorkshire) and tap water.Make rat get used at least one time-of-week of these conditions before the experiment.
Experimental procedure: after putting to death rat, clamp and lead to the bile duct branch of liver and the duodenum end of pancreatic duct, and expand pancreas by the ice-cold 0.9mg/ml collagenase solution of injection in bile duct.Take out pancreas then, it was hatched 10-12 minute 37 ℃ of following static state.After hatching, add the cold buffer of 10ml, and acutely shook up suspension 1 minute with hands.Allow islets of langerhans place on ice 5 minutes, and wash three times with ice-cold buffer.Selected (under low power microscope) also merges the suitable islets of langerhans of abundant formation, size of three rats, and the islets of langerhans of finally selecting is put into perfusion equipment.Except as otherwise noted, whole experimental session uses and contains the bovine serum albumin of 1mg/ml and the oxygenate (95%O of 4mM glucose 2/ 5%CO 2) Gey ﹠amp; The Gey buffer is (about further details, referring to people Eur.J.Pharmacol.1997 such as Dickinson; 339:69-76).
Determine dissolubility with the concentration detection compound of suggestion and at described experiment condition and the maximum solvable drug level that is used for testing (DMSO or ethanol are to measure buffer maximum 0.1% as solvent).
With parallel two experiments, the chamber composition of described each free sufficient amount of perfusion equipment of carrying out of identical, the independent perfusion equipment that is provided with.20 selected islets of langerhans are housed in each chamber.Islets of langerhans was carried out perfusion initial 30 minutes containing hatching in the base of 4mM glucose.Collecting perfusate was used for remaining experiment at interval with two minutes then.Behind initial 10 minutes of experiment (for collecting baseline insulin value), the base of hatching in each chamber is converted to the base of hatching that contains 11mM glucose and related drugs concentration/media/diazoxide concentration, and collected perfusate in addition 62 minutes, thereby make each chamber produce 36 fraction altogether.Then the perfusate sample is converged together, so that each chamber produces following three samples: baseline (4mM): sample 1-5 (at first 10 minutes); 0-30 minute (11mM glucose): sample 6-21; 30-60 minute (11mM glucose): sample 22-36.Storing the perfusate fraction down at-75 ℃ needs up to insulin assay.Use 96 holes ELISA algoscopy (Mercodia) to measure the insulin content of fraction.Three blended fraction from each chamber are carried out initial insulin assay in triplicate.
Medicine: all chemicals obtain from Sigma (or other suitable suppliers).
The result: three kinds of insulin prepared products show the glucose dependency islet secretion of consistent degree.At 0-30 with in 30-60 minute, the average insulin of 11mM glucose be respectively 98.3 ± 12.6pg/ islets of langerhans/minute and 130.4 ± 22.0pg/ islets of langerhans/minute.In the presence of the 4mM glucose, this numerical value significantly reduces, and 0-30 and be respectively in 30-60 minute 3.8 ± 0.6pg/ islets of langerhans/minute and 3.4 ± 0.1pg/ islets of langerhans/minute.Therefore, 0-30 and 30-60 minute, the 11mM glucose improved 26 times of insulin secretions and 38 times respectively.At first data are expressed as the simple average value of three experiments of insulin secretion (pg/ islets of langerhans/minute), and use multiple t-check (to the corresponding medium time cycle) to measure the potential remarkable result of treatment.Alternately, also with the percentage ratio of data computation for the media effect of each experiment day.This a kind of method in back is considered to stronger analysis, because it has proofreaied and correct the day of excreting insulin from islets of langerhans and the variation between day.Diazoxide has suppressed insulin secretion significantly with the average of average 55.3% (0-30 minute) and 58.9% (30-60 minute).
Table 2-is according to the described K of method mentioned above ATPChannel opener suppresses expression with %.
Figure A200780015186D00501
Figure A200780015186D00511
Figure A200780015186D00512
Figure A200780015186D00521
Figure A200780015186D00522
Figure A200780015186D00531
Figure A200780015186D00532
This test provides to be proved with them K ATPThe candidate compound that the affinity of passage is selected for the basis has suppressed the evidence of the insulin secretion of glucose stimulation really.Can think that this candidate compound is as K under these conditions ATPChannel opener plays a role.
By with reference to all lists of references that will quote herein, comprise that publication, patent application and patent incorporate this paper into, its degree is as individually and especially showing by with reference to incorporating them into this paper and setting forth with its integral body in this article.
Unless indication or obviously inconsistent with context is arranged herein in addition, and the use (in the context of especially following claim) of the term in the present disclosure context " a " and " an " and " the " and similar demonstrative pronoun should be interpreted as both having comprised that odd number also comprises plural number.Unless have in addition in the literary composition indication or obviously and context inconsistent, described herein all methods can be carried out according to any suitable order.Provide herein arbitrarily and all embodiment, or the illustrative language (for example, such as, preferably, use preferably) only is intended for use further to illustrate disclosed content, and the scope of claim is not applied restriction.Any language in the description should not be interpreted as representing that any not have claimed key element be essential to enforcement of the present invention.
Describe the alternative specific embodiment of invention required for protection herein, comprised the best mode of the known enforcement of inventor invention required for protection.Wherein, after reading aforementioned disclosure, the various versions of the disclosed specific embodiment are conspicuous for those of ordinary skills.The inventor expects and utilizes this class version when the technical staff needs, and the inventor plans the present invention and can implement according to the alternate manner beyond specifically described herein.
Therefore, the present invention includes all modifications and the equivalent of the theme that lists in this paper claims of applicable law permission.In addition, unless this paper points out in addition or obviously and context inconsistent, above-mentioned key element is with the combination in any of its all possible variation also all within the scope of the invention.
With approximation the use of individual numerical value is described, just as hat before these numerical value has " approximately " or " being similar to " printed words.Similarly, the numerical value among the application in the specified different range unless indication is clearly arranged in addition, is also described with approximation, just as before the maximum of described scope and the minima all hat " approximately " or " being similar to " printed words are arranged.By this way, can use on the described scope and under version, with obtain with this scope in the essentially identical result of numerical value.As used herein, when term " approximately " and " approx " when referring to numerical value, they should have common and common implication the those of ordinary skill in the relevant field of or the scope discussed the most closely-related for disclosed theme or key element.The amount of widening from strict Numerical Boundary depends on several factors.For example, some factors that can be considered comprise the variation of key and/or specified rate of element to the influence of the enforcement of theme required for protection, and other Considerations known to those of skill in the art.As employed in this article, use not commensurability significant numeral and do not mean that how restriction uses word " approximately " or " being similar to " can widen special numerical value for different numerical value.Therefore, generally, " approximately " or " being similar to " widened numerical value.In addition, disclosing of scope is intended to as successive range that comprises each numerical value between minima and the maximum and the expansion by this scope of providing of use term " approximately " or " being similar to ".Therefore, except as otherwise noted, the numerical range that this paper quotes only is intended to as a kind of stenography method that falls into each independent value in this scope that relates to individually, and each independent value is incorporated in this description as quoting it separately herein.
Should be appreciated that, any that can form by any data disclosed by the invention or all represent the further embodiment of the disclosure of invention from the scope of the scope, ratio and the ratio that wherein derive from, and clearly set forth as them, in being included in as the part of the disclosure content.This comprises the scope that can form, and it comprises or do not comprise the coboundary and/or the lower boundary of qualification.Therefore, the those of ordinary skill in the field of the closest scope that relates to specific scope, ratio or ratio will be understood, and this class numerical value can have no the qi free burial ground for the destitute and derive out from data provided by the present invention.

Claims (14)

1. at least a CB xRegulator is as K ATPChannel modulators is used for prevention; the treatment disease; delay the progress of disease; delay the outbreak of disease and/or the purposes of inhibition disease; this disease is mammal and people's a obesity; diabetes; metabolism syndrome; X syndrome; insulinoma; familial hyperinsulinism hypoglycemia; male pattern alopecia; force the flesh hyperactivity; asthma; neuroprotective; epilepsy; analgesia; Cardioprotective; angina pectoris; cardioplegia; arrhythmia; coronary spasm; peripheral vascular disease; cerebral vasospasm; appetite stimulator; neural degeneration; pain-comprise neuropathic pain and chronic pain-and sexual impotence, wherein said CB xRegulator is selected from CB 1Agonist; CB 2Agonist; CB 2Partial agonist; CB 2Antagonist; CB 2Inverse agonists; And be CB 1Agonist is again CB 2The chemical compound with dual function of agonist; And composition thereof.
2. at least a CB xRegulator is as K ATPChannel modulators is used to prepare the purposes of medicine, wherein said CB xRegulator is selected from CB 1Agonist; CB 2Agonist; CB 2Partial agonist; CB 2Antagonist; CB 2Inverse agonists; And be CB 1Agonist is again CB 2The chemical compound with dual function of agonist; And composition thereof; described medicine is used for prevention; the treatment disease; delay the progress of disease; delay the outbreak of disease and/or suppress disease, this disease is mammal and people's a obesity; diabetes; metabolism syndrome; X syndrome; insulinoma; familial hyperinsulinism hypoglycemia; male pattern alopecia; force the flesh hyperactivity; asthma; neuroprotective; epilepsy; analgesia; Cardioprotective; angina pectoris; cardioplegia; arrhythmia; coronary spasm; peripheral vascular disease; cerebral vasospasm; appetite stimulator; neural degeneration; pain-comprise neuropathic pain and chronic pain-and sexual impotence.
3. according to claim 1 or 2 each purposes, wherein metabolism syndrome and/or X syndrome comprise and are selected from following obstacle or disease: hypertension, particularly arterial hypertension; Insulin resistant, particularly type ii diabetes; Glucose intolerance; Dyslipoproteinemia, particularly hypertriglyceridemia, it is with dyslipoproteinemia and exist highdensity lipoprotein-cholesterol to reduce and hyperuricemia simultaneously.
4. treatment; prevent disease; delay the progress of disease; delay the outbreak of disease and/or the method for inhibition disease; wherein this disease is mammal and people's a obesity; diabetes; metabolism syndrome; X syndrome; insulinoma; familial hyperinsulinism hypoglycemia; male pattern alopecia; force the flesh hyperactivity; asthma; neuroprotective; epilepsy; analgesia; Cardioprotective; angina pectoris; cardioplegia; arrhythmia; coronary spasm; peripheral vascular disease; cerebral vasospasm; appetite stimulator; neural degeneration; pain-comprise neuropathic pain and chronic pain-and sexual impotence, this method comprises at least a CB that the experimenter of its needs effective dose is arranged xRegulator, wherein this CB xRegulator is selected from CB 1Agonist; CB 2Agonist; CB 2Partial agonist; CB 2Antagonist; CB 2Inverse agonists; And be CB 1Agonist is again CB 2The chemical compound with dual function of agonist, wherein said CB xRegulator has adjusting K ATPThe character of passage.
5. according to each purposes of claim 1 to 3, or according to the method for claim 4, wherein K ATPChannel modulators is to be selected from: Kir6.2/SUR1 K ATPPassage, Kir6.2/SUR2BK ATPPassage, Kir6.1/SUR2B K ATPPassage and Kir6.2/SUR2A K ATPThe regulator of at least a passage of passage.
6. according to claim 1 to 3 and 5 each purposes, or according to the method for claim 4 and 5, wherein K ATPChannel modulators is K ATPChannel opener.
7. the purposes of according to claim 1 to 3,5 and 6 any one, or the method for according to claim 4 to 6, wherein at least a CBxAdjusting agent is selected from: 3 - (1,1 - dimethyl - D Yl) -6,6,9 - trimethyl-6a, 7,10,10 a-tetrahydro-6H-benzo [c] chromene; N-adamantyl alkyl-4 - E -5 - phenyl - thiazol-2 - carboxamide; N-{1,3,3 - trimethyl - Bridge - (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 - bicyclo [3.1.1] hept- -2 - Ene-2 - yl} - methanol; 3 - (1,1 - dimethyl - heptyl) -9 - (hydroxymethyl) -6,6 - dimethyl- -6a, 7,10,10 a-tetrahydro-6H-benzo [c] Color-1 - ol; eicosatetraenoic -5,8,11,14 - Four enoic acid 2 - hydroxyethyl Yl-1 - (hydroxymethyl) -, ethyl; 1 - N C-1 - yl - twenty-one carbon -6,9,12,15 - four en-2 - one; Noladine ether; 4,4,4 - trifluoro - butane-1 - sulfinic acid 3 - (2 - (hydroxymethyl) - indan -4 - yloxy) - Phenyl ester compound to form an aldehyde; 7 - methoxy-2 - oxo-8 - pentyl-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 - benzene Yl) -2 - (2 - chloro - phenyl) -5 - ethyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; (2 - methyl-1 - C -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 - morpholin-4 - yl-3 ,4 - dihydro- -5 - Oxa-2a-aza-acenaphthylene-1 - yl) - naphthalene-1 - yl - methanone; 5 - (4 - chloro - phenyl) -1 - (2,4 - dichloro - Phenyl) -4 - methyl-1H-pyrazole-3 - carboxylic acid piperidin-1 - yl amide; 5 - (4 - bromo - phenyl) -1 - (2,4 - Chloro - phenyl)-4 - ethyl-1H-pyrazole-3 - carboxylic acid piperidin-1 - yl amide; 1 - [bis - (4 - chloro - phenyl) - A Yl] -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-{ammonia Yl - [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - methylene}-4 - chloro - benzenesulfonyl Amine; N-{[3 - (4 - chloro - phenyl) -4 - pyridin-3 - yl-4 ,5 - dihydro - pyrazol-1 - yl] - methylamino - methylene Yl} -4 - (trifluoromethyl) - benzenesulfonamide; 4 - chloro-N-{[3 - (4 - chloro - phenyl) -4 - pyridin-3 - yl-4 ,5 - two H - pyrazol-1 - yl] - methylamino - methylene} - benzenesulfonamide; 4 - chloro-N-{[3 - (4 - chloro - phenyl) -4 - (3 - Fluoro - phenyl) -4,5 - dihydro - pyrazol-1 - yl] - methoxy-amino - methylene} - benzenesulfonamide; morpholin-4 - Sulfonic acid [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - methylamino - methylene amide; N-{[3 - (4 - chloro - phenyl) -4 - (3 - fluoro - phenyl) -4,5 - dihydro - pyrazol-1 - yl] - methylamino - methylene Yl}-N, N-dimethyl - sulfonamide; azetidinyl heptane-1 - sulfonic acid [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - Dihydro - pyrazol-1 - yl] - methylamino - methylene amide; 4 - chloro-N-{[3 - (4 - chloro - phenyl) -4 - phenyl- -4,5 - Dihydro - pyrazol-1 - yl] - [(1 - methyl - pyrrolidin-3 - yl methyl) - amino] - methylene} - benzenesulfonamide Amide; 1 - (4 - chloro - phenyl) -5 - phenyl-4 ,5 - dihydro-1H-pyrazole-3 - carboxamidine; N-{[3 - (4 - chloro - benzene Yl) -4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - methylamino - methylene} -4 - (trifluoromethyl) - benzenesulfonyl Amine; piperidine-1 - sulfonic acid [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - methylamino - Asia Methylamide;-piperidin-1 - sulfonic acid [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - (2 - Dimethylamino - ethylamino) - methylene amide; N, N-diethylamino-1 - sulfonic acid [3 - (4 - chloro - phenyl) -4 - Phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - methylsulfanyl - methylene amide China; - 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 - methylene acid Amine; N, N-dimethylamino-1 - sulfonic acid [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol - Yl] - (2 - fluoro - ethylamino) - methylene amide;-piperidin-1 - sulfonic acid [3 - (4 - chloro - phenyl) -4 - (3 - fluoro - phenyl Yl) -4,5 - dihydro - pyrazol-1 - yl] - methylamino - methylene amide; 5 - (4 - chloro - phenyl) -1 - (2,4 - Chloro - phenyl) -4,5 - dihydro-1H-pyrazole-3 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - phenyl) - phenyl Yl -4,5 - dihydro-1H-pyrazole-3 - carboxylic acid piperidin-1 - yl amide;-piperidin-1 - sulfonic acid [1 - (4 - chloro - benzene Yl) -5 - phenyl-4 ,5 - dihydro-1H-pyrazol-3 - yl] - methylamino - methylene amide; morpholin-4 - sulfonic acid [1 - (2,4 - dichloro - phenyl) - phenyl-4 ,5 - dihydro-1H-pyrazol-3 - yl] - methylamino - methylene acid Amine; 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 - 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 - pyrazol-1 - yl-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 - yl Methyl) - amino] - methylene} - benzenesulfonamide; 4 - chloro-N-[[3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - two H - 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 - yl methyl) - amino Yl] - methylene} - benzenesulfonamide; 1 - [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol - 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] - benzenesulfonyl Amine; N, N-diethylamino-1 - sulfonic acid [3 - (4 - chloro - phenyl)-4 - hydroxy - 4 - phenyl-4 ,5 - dihydro - pyrazol -1 - Yl] - methylamino - methylene amide; 5 - (4 - bromo - phenyl) -1 - (2,4 - dichloro - phenyl)-1H-pyrazole -3 - Carbonitrile; 8 - chloro-1 - (2,4 - dichloro - phenyl) -1,3 a, 4,5,6,10 b-hexahydro-1,2 - diaza - benzo [e ] Azulene -3 - carboxylic acid piperidin-1 - yl amide; 5 - (4 - bromo - phenyl) -1 - (2,4 - dichloro - phenyl Yl) -3 - [2 - (3,5 - difluoro - phenyl) -2 - methanesulfonyl - ethenyl]-4 - methyl-1H-pyrazole; piperidin - 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 - Amide; 2 - (2,4 - dichloro - phenyl) -1 - (4 - (trifluoromethyl) - phenyl)-1H-imidazole-4 - carboxylic acid piperidin- -1 - Amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl) -5 - methylsulfanyl-1H-imidazol-4 - Carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl)-1H-imidazole-4 - carboxylic acid Piperidin-1 - yl amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-imidazol-4 - carboxylic Acid piperidin-1 - yl amide; 1 - (4 - bromo - phenyl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-imidazol-4 - Carboxylic acid piperidin-1 - yl amide; 1 - (4 - bromo - phenyl) -5 - chloro-2 - (2,4 - dichloro - phenyl)-1H-imidazol-4 - Carboxylic acid piperidin-1 - yl amide; 1 - (4 - bromo - phenyl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-imidazole -4 - Carboxylic acid cyclohexyl amide; 1 - (4 - bromo - phenyl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-imidazole -4 - Carboxylic acid pentyl-amide; 4 - (4 - chloro - phenyl) -5 - (2,4 - dichloro - phenyl) -1 - methyl-1H-imidazol-2 - Cyclohexyl carboxylic acid amide; 4 - (4 - chloro - phenyl) -5 - (2,4 - dichloro - phenyl) -3 - methyl-1H-imidazol-2 - Cyclohexyl carboxylic acid amide; 1 - (5 - chloro - pyridin-2 - yl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-Mic -4 - carboxylic acid piperidin-1 - yl amide; 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) - Methyl-1H-imidazole-4 - carboxylic acid heterocyclic heptane-1 - yl amide; 2 - (2,4 - dichloro - phenyl) - ethyl -1 - Phenyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 2 - (1,5 - dimethyl-1H-pyrrole-2 - Yl) -5 - ethyl-1 - phenyl-1H-imidazole-4 - carboxylic acid cyclohexyl amide; 1 - (4 - chloro - phenyl) -5 - ethyl- -2 - (3 - methyl - pyridin-2 - yl)-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - benzene Yl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - bromo - Phenyl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - Bromine - phenyl) -5 - chloro-2 - (2,4 - dichloro - phenyl)-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - Bromine - phenyl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-imidazole-4 - carboxylic acid cyclohexyl amide; 1 - (4 - Bromine - phenyl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-imidazole-4 - carboxylic acid pentyl amide; 4 - (4 - chloro - Phenyl) -5 - (2,4 - dichloro - phenyl) -1 - methyl-1H-imidazole-2 - carboxylic acid cyclohexyl amide; 4 - (4 - chloro - Phenyl) -5 - (2,4 - dichloro - phenyl) -3 - methyl-1H-imidazole-2 - carboxylic acid cyclohexyl amide; 1 - (5 - chloro - Pyridin-2 - yl) -2 - (2,4 - dichloro - phenyl) - ethyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl)-5 - methyl-1H-imidazole-4 - carboxylic acid (4 - hydroxy - cyclohexyl Yl) - amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl)-5 - methyl-1H-imidazole-4 - carboxylic acid aza Ring heptane-1 - yl amide; 2 - (2,4 - dichloro - phenyl) - ethyl-1 - phenyl-1H-imidazole-4 - carboxylic acid piperazine -1 - yl amide; 2 - (1,5 - dimethyl-1H-pyrrol-2 - yl) -5 - ethyl-1 - phenyl-1H-imidazol-4 - Cyclohexyl carboxylic acid amide; 1 - (4 - chloro - phenyl)-5 - ethyl-2 - (3 - methyl - pyridin-2 - yl)-1H-imidazole -4 - Carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - phenyl)-5 - ethyl-2 - (3 - methyl - pyridin-2 - yl)-1H- Imidazole-4 - carboxylic acid cyclohexyl amide; 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 - pyridine -2 - Yl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl Yl) -5 - fluoro-methyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - Chloro - phenyl)-5 - hydroxymethyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - benzene Yl) -2 - (2,4 - dichloro - phenyl) -5 - methylsulfanyl-1H-imidazole-4 - carboxylic acid cyclohexyl amide; 1 - (4 - Chloro - phenyl) -2 - (2,4 - dichloro - phenyl) -5 - methylsulfonyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl acid Amine; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl) - methane sulfinyl-1H-imidazole-4 - carboxylic acid Piperidin-1 - yl amide; 5 - (4 - chloro - phenyl) -4 - (2,5 - dichloro - phenyl) -1 - methyl-1H-imidazol-2 - carboxylic Acid piperidin-1 - yl amide; 2 - (2 - chloro - phenyl) -1 - (5 - chloro - pyridin-2 - yl) -5 - ethyl-1H-imidazol-4 - Carboxylic acid piperidin-1 - yl amide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl) -5 - (2,2,2 - trifluoro - B Yl)-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; N-[1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl Yl) -5 - methyl-1H-imidazol-4 - yl] - benzamide; 1 - (4 - chloro - phenyl) -2 - (2,4 - dichloro - phenyl Yl) -5 - pyrrolidin-1 - yl methyl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 2 - [1 - (4 - chloro - benzene Yl) -2 - (2,4 - dichloro - phenyl)-5 - methyl-1H-imidazol-4 - yl] - hexan-2 - ol; 1 - (4 - chloro - benzene Yl) -2 - (2,4 - dichloro - phenyl)-5 - methyl - 4 - pentyl-1H-imidazole; 2,5 - dimethyl-1 - phenyl-1H- Imidazole-4 - carboxylic acid adamantan-2 - yl amide; 1 - (4 - chloro - phenyl) -2 - (2 - chloro - phenyl) -5 - methyl-thioalkoxy Yl-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 2 - (2 - chloro - phenyl) -1 - (4 - (trifluoromethyl) - phenyl Yl)-1H-imidazole-4 - carboxylic acid piperidin-1 - yl amide; 5 - (4 - chloro - phenyl) -4 - (2,4 - dichloro - phenyl) - Thiazole-2 - carboxylic acid piperidin-1 - yl amide; 5 - (4 - chloro - phenyl) -1 - (2,4 - dichloro - phenyl)-1H-[1,2,4] Triazole-3 - carboxylic acid pyrrolidin-1 - yl amide; 1 - (4 - chloro - phenyl) -5 - (2,4 - dichloro - phenyl Yl)-1H-[1,2,4] triazole-3 - carboxylic acid piperidin-1 - yl - amide; 5 - pentyl-4 - phenyl - thiazol-2 - carboxylic acid (Hexahydro-2 ,5 - methylene bridge - and cyclopentadiene-3a-yl) - amide; 4 - pentyl-5 - phenyl - thiazol-2 - Carboxylic acid (hexahydro-2 ,5 - methylene bridge - and cyclopentadiene-3a-yl) - amide; 1 - {(4 - chloro - benzene - sulphonyl Asia Amino) - [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - methyl} - piperidine-4 - carboxylic acid Amine; 4 - chloro-N-{[3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - [2 - (2 - oxo - topiramate Slightly adamantan-1 - yl) - ethylamino] - methylene} - benzenesulfonamide; 4 - chloro-N-[[3 - (4 - chloro - phenyl) -4 - phenyl- -4,5 - Dihydro - pyrazol-1 - yl] - (2 - cyano - ethylamino) - methylene] - benzenesulfonamide; 4 - chloro- -N-[[3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - (methoxy - methyl - amino) - 2nd Methyl] - benzenesulfonamide; 4 - chloro-N-{[3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol - Yl] - [(piperidin-4 - ylmethyl) - amino] - methylene} - benzenesulfonamide; 4 - chloro-N-[[3 - (4 - chloro - benzene Yl) -4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - (piperidin-4 - ylamino) - methylene] - benzenesulfonamide; to And morpholine-4 - sulfonic acid [3 - (4 - chloro - phenyl)-4 - phenyl-4 ,5 - dihydro - pyrazol-1 - yl] - (cyclopropylmethyl - Amino) - methylene amide. ...
8. according to claim 1 to 3,5 to 7 each purposes, or according to the method for claim 4 to 7, wherein at least a CB xRegulator is selected from: 3-(1,1-dimethyl-butyl)-6,6,9-trimethyl-6a, 7,10,10a-tetrahydrochysene-6H-benzo [c] color alkene; N-adamantyl-4-amyl group-5-phenyl-thiazole-2-Methanamide; N-{1,3,3-trimethyl-bridge-(1S)-dicyclo [2.2.1] heptan-2-yl }-1-[1-(4-methyl)-benzyl-5-(4-chloro-3-methyl-phenyl)-1H-pyrazole-3-formamide; (2-iodo-5-nitro-phenyl)-[1-(1-methyl-piperidines-2-ylmethyl)-1H-indol-3-yl]-ketone; 4-[4-(1,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl] and-6,6-dimethyl-dicyclo [3.1.1] hept-2-ene"-2-yl }-methanol; 3-(1,1-dimethyl-heptyl)-9-hydroxymethyl-6,6-dimethyl-6a, 7,10,10a-tetrahydrochysene-6H-benzo [c] chromene-1-alcohol; 20 carbon-5,8,11,14-tetraenoic acid 2-hydroxyl-1-hydroxymethyl-ethyl ester; 1-aziridine-1-base-21 carbon-6,9,12,15-tetraene-2-ketone; Noladine ether; 4,4,4-three fluoro-butane-1-sulfinic acid 3-(2-hydroxymethyl-indane-4-base oxygen base)-phenylester, the chemical compound of formation aldehyde; 7-methoxyl group-2-oxo-8-amyl group Oxy-1,2-dihydro-quinoline-3-carboxylic acid (benzo [1,3] dioxole-5-ylmethyl)-amide; N-(1-{4-[4-chloro-2-(2-fluoro-benzenesulfonyl)-benzenesulfonyl]-phenyl }-ethyl)-Methanesulfomide; [6-iodo-2-methyl isophthalic acid-(2-morpholine-4-base-ethyl)-2,3-dihydro-1H-indol-3-yl]-(4-methoxyl group-phenyl)-ketone; 1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-ethyl-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; (2-methyl isophthalic acid-propyl group-2,3-dihydro-1H-indol-3-yl)-naphthalene-1-base-ketone; 5-(1,1-dimethyl-heptyl)-2-[5-hydroxyl-2-(3-hydroxyl-propyl group)-cyclohexyl]-phenol; (2-methyl-3-morpholine-4-ylmethyl-3,4-dihydro-5-oxa--2a-azepine acenaphthylene-1-yl)-naphthalene-1-base-ketone; 5-(4-chloro-phenyl)-1-(2,4-two chloro-phenyl)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid piperidines-1-base amide; 5-(4-bromo-phenyl)-1-(2,4-two chloro-phenyl)-4-ethyl-1H-pyrazoles-3-carboxylic acid piperidines-1-base amide; 1-[two-(4-chloro-phenyl)-methyl]-3-[(3,5-two fluoro-phenyl)-mesyl-methylene]-azetidine.
9. claim 1 to 3 and 5 to 8 each purposes, or according to the method for claim to 8, wherein at least a CBx regulator is selected from: 4-chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylamino-methylene }-benzsulfamide; N-{ amino-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylene }-4-chloro-benzsulfamide; 4-chloro-N-{[3-(4-chloro-phenyl)-4-pyridin-3-yl-4,5-dihydro-pyrazol-1-yl]-methylamino-methylene }-benzsulfamide; 4-chloro-N-{[3-(4-chloro-phenyl)-4-(3-fluoro-phenyl)-4,5-dihydro-pyrazol-1-yl]-methoxyl group amino-methylene }-benzsulfamide; 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-two chloro-phenyl)-4,5-dihydro-1 h-pyrazole-3-carboxylic acid piperidines-1-base amide; Morpholine-4-sulfonic acid [1-(2,4-two chloro-phenyl)-5-phenyl-4,5-dihydro-1 h-pyrazole-3-yl]-methylamino-methylene amide; N-{ amino-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylene }-4-chloro-benzsulfamide; 4-chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-ethylamino-ethylamino)-methylene]-benzsulfamide; 4-chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(1-methyl-pyrrolidine-2-ylmethyl)-amino]-methylene }-benzsulfamide; 4-chloro-N-{[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-[(pyridin-3-yl methyl)-amino]-methylene }-benzsulfamide; 1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-ethyl sulfane base-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 2-(2,4-two chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-methyl sulfane base-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-ethyl-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 1-(4-bromo-phenyl)-2-(2,4-two chloro-phenyl)-5-ethyl-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 1-(4-bromo-phenyl)-5-chloro-2-(2,4-two chloro-phenyl)-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 1-(4-bromo-phenyl)-2-(2,4-two chloro-phenyl)-5-ethyl-1H-imidazoles-4-carboxylic acid amyl group amide; 1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-methyl isophthalic acid H-imidazoles-4-carboxylic acid azepan-1-base amide; 1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-methyl fluoride-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-methyl sulfane base-1H-imidazoles-4-carboxylic acid cyclohexyl amide; N-[1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-methyl isophthalic acid H-imidazol-4 yl]-Benzoylamide; 2-[1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-methyl isophthalic acid H-imidazol-4 yl]-hexane-2-alcohol; 1-(4-chloro-phenyl)-2-(2,4-two chloro-phenyl)-5-methyl-4-amyl group-1H-imidazoles; 1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-methyl sulfane base-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 2-(2-chloro-phenyl)-1-(4-trifluoromethyl-phenyl)-1H-imidazoles-4-carboxylic acid piperidines-1-base amide; 5-(4-chloro-phenyl)-4-(2,4-two chloro-phenyl)-thiazole-2-carboxylic acid piperidines-1-base amide; 1-(4-chloro-phenyl)-5-(2,4-two chloro-phenyl)-1H-[1,2,4] triazole-3-carboxylic acid piperidines-1-base-amide; 1-{ (4-chloro-benzene-sulphonyl imino group)-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methyl }-piperidines-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 }-benzsulfamide; 4-chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(2-cyano group-ethylamino)-methylene]-benzene-sulfonamide; 4-chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(methoxyl group-methyl-amino)-methylene]-benzsulfamide; Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-(cyclopropyl methyl-amino)-methylene amide.
10. according to claim 1 to 3,5 and 6 each purposes, or according to the method for claim 4 to 6, wherein CB 1Agonist or CB 2Agonist is selected from: L759633; L759656; 4-[4-(1,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl] and-6,6-dimethyl-dicyclo-[3.1.1] hept-2-ene"-2-yl }-methanol (=HU308); JWH015; (2-iodo-5-nitro-phenyl)-[1-(1-methyl-piperidines-2-ylmethyl)-1H-indol-3-yl]-ketone (=AM-1241); 3-(1,1-dimethyl-butyl)-6,6,9-trimethyl-6a, 7,10,10a-tetrahydrochysene-6H-benzo [c]-chromene (JWH133); N-adamantyl-4-amyl group-5-phenyl-thiazole-2-Methanamide; 6,6,9-trimethyl-3-amyl group-6a, 7,8,10a-tetrahydrochysene-6H-benzo [c] chromene-1-alcohol; (dicyclo [2.2.1] heptan-2-base is amino)-(5-amyl group-4-phenyl-thiazol-2-yl)-methane; 5-(1,1-dimethyl-heptyl)-2-[5-hydroxyl-2-(3-hydroxyl-propyl group)-cyclohexyl]-phenol (=CP-55,940); (2-methyl-3-morpholine-4-ylmethyl-3,4-dihydro-5-oxa--2a-azepine-acenaphthylene-1-yl)-naphthalene-1-base-ketone (=WIN-55,212-2); ACEA; ACPA; N-adamantyl-4-amyl group-5-phenyl-thiazole-2-Methanamide; Methyl arachidonic acid diethanolamide; The arachidonic acid diethanolamide; 2-arachidonic acyl glycerol; 2-20 carbon-5,8,11,14-apos oxygen base-propane-1,3-glycol (=noladin ether); BAY38-7271; SAB-378; BAY59-3074; O-1057; GW-1000; PRS-211375; PRS-211359; PRS-211355; PRS-211096; PXS-2076; AM-577; GW-842166X; And composition thereof.
11. according to the purposes or the method for claim 10, wherein CB 2Agonist is selectivity CB 2Agonist and being selected from: 3-(1,1-dimethyl-butyl)-6,6,9-trimethyl-6a, 7,10,10a-tetrahydrochysene-6H-benzo [c] chromene (=JWH133); L759633; L759656; 4-[4-(1,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl] and-6,6-dimethyl-dicyclo [3.1.1] hept-2-ene"-2-yl }-methanol (=HU308); JWH015; (2-iodo-5-nitro-phenyl)-[1-(1-methyl-piperidines-2-ylmethyl)-1H-indol-3-yl]-ketone (=AM-1241); And composition thereof.
12. according to claim 1 to 3,5,6,10 to 11 each purposes, or according to claim 4,5,6,10 to 11 method, wherein CB 2Antagonist or CB 2Inverse agonists is selected from: (1) file WO 01/0588869, PCT/EP2006/060009, WO2004/014825; EP1142877; US2002/0072529; WO02/062750; US6, the chemical compound of describing in 509,352; And (2) are selected from: N-{1,3,3-trimethyl-bridge-(1S)-dicyclo [2.2.1] heptan-2-yl }-1-[1-(4-methyl)-benzyl-5-(4-chloro-3-methyl-phenyl)-1H-pyrazole-3-formamide (=SR-144528), the chemical compound of JTE-907, AM630 and composition thereof; And (3) are selected from the mixture of the chemical compound of (1) and (2).
13., or, wherein be CB according to claim 4,5,6,10 to 12 method according to claim 1 to 3,5,6,10 to 12 each purposes 1Agonist is again CB 2The chemical compound with dual function of agonist is selected from: 2-20 carbon-5,8,11,14-apos oxygen base-propane-1,3-glycol (=noladin ether); And composition thereof.
14. according to claim 1 to 3,5,6,10 to 13 each purposes, or according to claim 4,5,6,10 to 13 method, wherein CB xRegulator is selected from: 6,6, and 9-trimethyl-3-amyl group-6a, 7,8,10a-tetrahydrochysene-6H-benzo [c] chromene-1-alcohol; N-(interior-dicyclo [2.2.1] heptan-2-yl)-5-amyl group-4-phenyl-thiazole-2-Methanamide; 3-(1,1-dimethyl-butyl)-6,6,9-trimethyl-6a, 7,10,10a-tetrahydrochysene-6H-benzo [c] color alkene; N-adamantyl-4-amyl group-5-phenyl-thiazole-2-Methanamide; 1-[1-benzyl-5-(4-chloro-3-methyl-phenyl)-1H-pyrazole-3-yl]-ethane ketone group-1,3,3-trimethyl-two-ring [2.2.1] heptan-2-base amine; (2-iodo-5-nitro-phenyl)-[1-(1-methyl-piperidines-2-ylmethyl)-1H-indol-3-yl]-ketone; 4-[4-(1,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl] and-6,6-dimethyl-dicyclo [3.1.1] hept-2-ene"-2-yl }-methanol; And composition thereof.
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