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Definitions

• the present invention relates to the novel use of CB x modulators as K A TP channel modulators.
• the present invention also relates to a method of treating, preventing, delaying progression of, delaying onset of and/or inhibiting obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, 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 CB x modulator as K A TP channel modulator.
• Obesity according to the present invention is meant to comprise any increase in body fat that results in increased bodyweight, preferably comprising but not limited to the medical definition of obesity.
• obesity also comprises non-medical, e.g. cosmetic overweight.
• the invention thus also relates to non-medical weight loss, such as cosmetic weight loss and includes improving bodily appearance in general.
• non-medical weight loss such as cosmetic weight loss and includes improving bodily appearance in general.
• obesity is usually understood to denominate a body weight more than 20 % above the ideal body weight.
• Even in this more narrowed sense obesity is a major health concern in Western societies. It is estimated that about 97 million adults in the United States are overweight or obese.
• Obesity is largely the result of a positive energy balance as a consequence of increased ratio of caloric intake to energy expenditure.
• the molecular factors regulating food intake and body weight are incompletely understood, but several genetic factors have been identified.
• Obesity causes or exacerbates many health problems, both independently and in association with other diseases.
• the medical problems associated with obesity which can be serious and life-threatening, generally include hypertension; type Il diabetes mellitus; elevated plasma insulin concentrations; insulin resistance; dyslipidemias; hyperlipidemia; endometrial, breast, prostate and colon cancer; osteoarthritis; respiratory complications, such as obstructive sleep apnea; cholelithiasis; gallstones; arteriosclerosis; heart disease; abnormal heart rhythms; and heart arrythmias.
• Obesity is further associated with premature death and with a significant increase in mortality and morbidity from stroke, myocardial infarction, congestive heart failure, coronary heart disease, and sudden death.
• Obesity is often treated by encouraging patients to lose weight by reducing their food intake or by increasing their exercise level and therefore increasing their energy output.
• a sustained weight loss of 5% to 10% of body weight has been shown to improve the co-morbidities associated with obesity, such as diabetes and hypertension, and can lead to improvement of obesity-related conditions such as osteoarthritis, sleep apnea and pulmonary and cardiac dysfunction.
• Weight loss drugs that are currently used in monotherapy for the treatment of obesity have limited efficacy and significant side effects. During chronic treatment periods of greater than six months the efficacy of most agents decreases yielding no more than 10% body weight loss compared to control. Obese humans can easily mass over 150 kg and would, therefore, need to lose more than 50% of their body mass to return to a normal body mass.
• the term "metabolic syndrome” is meant to cover a complex of clinical pictures which - besides central obesity - mainly comprises hypertension, in particular arterial hypertension; insulin resistance, in particular type Il diabetes; glucose intolerance; dyslipoproteinaemia, in particular as hypertriglyceridaemia, accompanied by dyslipoproteinaemia occurring with lowered HDL-cholesterol, and also hyperuricaemia, which can lead to gout.
• the metabolic syndrome is closely linked to insulin resistance. Some people are genetically predisposed to insulin resistance. Acquired factors, such as excess body fat and physical inactivity, can elicit insulin resistance and the metabolic syndrome in these people. Most people with insulin resistance have central obesity.
• the biologic mechanisms at the molecular level between insulin resistance and metabolic risk factors are not fully understood and appear to be complex.
• One group of people at risk for developing metabolic syndrome is those with diabetes who have a defect in insulin action and cannot maintain a proper level of glucose in their blood.
• a third group is heart attack survivors who, unlike hypertensives, have hyperinsulinemia without having abnormal glucose levels.
• the metabolic syndrome has become increasingly common in higher developed countries like the United States, where it is estimated that about 20-25 percent of US adults have it. There are no well-accepted criteria for diagnosing the metabolic syndrome.
• the term “syndrome X” is closely related to the term “metabolic syndrome” and usually is supposed to denominate the identical disease or condition. According to information from the American Heart Association, the term “Syndrome X” refers, however, additionally to a heart condition where chest pain and electrocardiographic changes that suggest ischemic heart disease are present, but where there are no angiographic findings of coronary disease. Patients with cardiac syndrome X also sometimes have lipid abnormalities.
• ATP-sensitive potassium channel (K A TP channel) modulation has been linked to several potential clinical uses including diabetes, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, hypertension, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence (ref. Jahangir et al. J. MoI. Cell. Cardiology, 2005, 39, 99-1 12 and references cited therein).
• K A TP channel openers and their potential use in the inhibition of insulin secretion and/or the treatment of metabolic disorders are known e.g. from documents US 6,492,130; WO 02/00223; WO 02/00665 or from R. D. Carr et al., Diabetes 52 (2003) 2513-2518 or J. B. Hansen et al., Current Medicinal Chemistry H (2004) 1595-1615.
• the K A TP channel couples glucose metabolism to insulin secretion. Defective regulation of K A TP channel activity has been reported to contribute to the etiology of type 2 diabetes (ref. Ashcroft, J. Clin. Investig. 2005, 1 15 (8), 2047-2057 and references cited therein).
• the SUR1 regulatory subunit is in particular found in pancreas and brain (ref. Aguilar-Bryan et al., Science 1995, 268, 423-426).
• the K A TP Kir6.2/SUR1 combination exists in the pancreas.
• Insulin is the main hormone involved in blood glucose homeostasis. Insulin is involved in the regulation of glycaemia and as a consequence related to type I and type
• the regulation of insulin secretion will be useful in the treatment of diseases such as diabetus mellitus type I, diabetus mellitus type II, obesity, metabolic syndrome and syndrome X.
• the present invention relates to the use of at least one CB x modulator wherein the CB x modulator is selected from the group consisting of CB 1 agonists; CB 2 agonists; CB 2 partial agonists; CB 2 antagonists; CB 2 inverse agonists; and dually acting compounds which are both a CB 1 agonist and a CB 2 agonist; and mixtures thereof, as K A TP channel modulator for the prophylaxis, treatment, delayed progression, delayed onset and/or inhibition of obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain
• the invention also relates to a method of treating, preventing, delaying progression of, delaying onset of and/or inhibiting obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, 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 CB x modulator wherein the CB x modulator is selected from the group consisting of CB 1 agonists; CB 2 agonists; CB 2 partial agonists; CB 2 antagonists; CB 2 inverse agonists; and dually acting compounds which are both a CB
• the CB x modulators are used as K A TP channel modulators for the prophylaxis, treatment, delayed progression, delayed onset and/or inhibition of obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, 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.
• a compound with an effect as full or partial opener at the Kir6.2/SUR1 K AT p channel is understood to be selective if its IC 50 value at the Kir6.2/SUR1 K AT p channel, as measured in the aforementioned binding test, is less than half, more preferred only a quarter, of the IC 50 value of that same compound at the Kir6.2/SUR2 K ATP channel.
• Preferred CB x modulators are compounds which have effects as modulators at the Kir6.2/SUR1 K AT p channel, at the Kir6.2/SUR2B K ATP channel, the Kir6.1/ SUR2B K ATP channel, and/or at the Kir6.2/SUR2A K ATP channel.
• the K AT p channel modulator is a K AT p channel opener.
• CB x modulator which are suitable for use as K AT p channel modulator in the sense of the present invention are selected from, but not limited to the group consisting of: 3- (i .i-dimethyl-butyO- ⁇ . ⁇ . ⁇ -trimethyl- ⁇ aJ.I O.I Oa-tetrahydro- ⁇ H-benzoIclchromene; N- Adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; N- ⁇ 1 ,3,3-Trimethyl-endo-(1 S)- bicyclo[2.2.1 ]hept-2-yl ⁇ -1 -[1 -(4-methyl)-benzyl-5-(4-chloro-3-methyl-phenyl)-1 H-pyrazol- 3-carboxamide; (2-lodo-5-nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1 H-indol-3- yl]-methanone; ⁇ 4-[
• CB x modulator which are suitable for use as K A TP channel modulator in the sense of the present invention are selected from the group consisting of: 3-(1 ,1-dimethyl-butyl)-6,6,9-trimethyl- 6a, 7, 10, 10a-tetrahydro-6H-benzo[c]chromene; N-Adamantyl-4-pentyl-5-phenyl- thiazole-2-carboxamide; N- ⁇ 1 ,3,3-Trimethyl-endo-(1 S)-bicyclo[2.2.1]hept-2-yl ⁇ -1-[1-(4- methyl)-benzyl-5-(4-chloro-3-methyl-phenyl)-1 H-pyrazol-3-carboxamide; (2-lodo-5- nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1 H-indol-3-yl]-methanone; ⁇ 4-[4-(
• Noladineether 4,4,4-Trifluoro-butane-1-sulfinic acid 3-(2-hydroxymethyl-indan-4-yloxy)- phenyl ester, compound with form aldehyde; 7-Methoxy-2-oxo-8-pentyloxy-1 ,2-dihydro- quinoline-3-carboxylic acid (benzo[1 ,3]dioxol-5-ylmethyl)-amide; N-(1- ⁇ 4-[4-Chloro-2-(2- fluoro-benzenesulfonyl)-benzenesulfonyl]-phenyl ⁇ -ethyl)-methanesulfonamide; [6-lodo- 2-methyl-1-(2-morpholin-4-yl-ethyl)-2,3-dihydro-1 H-indol-3-yl]-(4-methoxy-phenyl)- methanone; 1-(4-Chloro-phenyl)
• CB x modulator which are suitable for use as K A TP channel modulator in the sense of the present invention are selected from the group consisting of: 4-Chloro-N- ⁇ [3-(4-chloro-phenyl)-4-phenyl-4,5- dihydro-pyrazol-1 -yl]-methylamino-methylene ⁇ -benzenesulfonamide; N- ⁇ Amino-[3-(4- chloro-phenyl ⁇ -phenyM. ⁇ -dihydro-pyrazol-i-ylJ-methylene ⁇ -chloro- benzenesulfonamide; 4-Chloro-N- ⁇ [3-(4-chloro-phenyl)-4-pyridin-3-yl-4,5-dihydro- pyrazol-1-yl]-methylamino-methylene ⁇ -benzenesulfonamide; 4-Chloro-N- ⁇ [3-(4-chloro- phenyl)
• CB 1 agonist or CB 2 agonists which are suitable for use as K A TP channel modulator in the sense of the present invention are selected from, but not limited to the group consisting of: L759633; L759656; ⁇ 4-[4-(1 ,1-dimethyl-heptyl)-2,6-dimethoxy-phenyl]-
• the CB 2 agonist is a selective
• the CB x modulator is selected from the group consisting of: 6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro- 6H-benzo[c]chromen-1-ol; (bicyclo[2.2.1]hept-2-ylamino)-(5-pentyl-4-phenyl-thiazol-2- yl)-methane; 3-(1 , 1 -dimethyl-butyl)-6,6,9-trimethyl-6a,7, 10,10a-tetrahydro-6H- benzo[c]chromene; N-adamantyl-4-pentyl-5-phenyl-thiazole-2-carboxamide; SR144528; (2-iodo-5-nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1 H-indol-3-yl]-methanone; ⁇ 4- [4-(1.i
• Table 1 also lists the CB 1 and/or CB2 activities of various compounds to prove that their activity as CB 1 agonists, CB 2 agonists, CB 2 partial agonists, CB 2 antagonists, CB 2 inverse agonists and dually acting compounds which are both a CB 1 agonist and a CB 2 agonist.
• Membranes from COS-cells transiently expressing rat SUR2A were incubated in the presence of the radioligands with increasing concentrations of test compounds as described above. The affinity for binding to the KCO site was assessed by incubations in the additional presence of 100 ⁇ M MgATP (Schwanstecher et al., 1991 and 1998). For each test compound 4 displacement curves were measured (displacement of [ 3 H]PI 075 from the rat isoform of the wild type receptor and displacement of [ 3 H]glibenclamide from the rat isoform of SUR2A Y1205 s)- Per curve 9-15 distinct concentrations were tested covering the relevant range. All measurements were repeated at least 5 times in independent experiments.
• [ 3 H]P1075 (specific activity 1 16 Ci mmol '1 ) was purchased from Amersham Buchler (Braunschweig, Germany).
• [ 3 H]glibenclamide (specific activity 51 Ci mmol '1 ) was obtained from NEN (Dreieich, Germany). If suitable, stock solutions were prepared in dimethylsulfoxide with a final solvent concentration in the media below 1 %.
• Rodent SUR-isoforms and K A TP channels were transiently expressed in COS-1 cells as described (see Schwanstecher et al., 1998); D ⁇ rschner et al., 1999); Uhde I. et al. J Biol Chem 274 (1999) 28079-28082; Gross I. et al. MoI. Pharmacol. 56 (1999) 1370-1373; Markworth E., Diabetes 49 (2000) 1413-1418).
• SUR2 Y1205 s A mutated form of the SUR2 isoforms with the phenylalanine residue in position 1205 substituted with a serine (SUR2 Y1205 s) was used to allow detection of binding to the sulfonylurea site of these isoforms by displacement of [ 3 H]glibenclamide (Uhde I., Dissertation 2001 ). Briefly, COS-1 cells cultured in DMEM HG (10 mM glucose), supplemented with 10 % fetal calf serum (FCS), were plated at a density of 5 x 10 5 cells per dish (94 mm) and allowed to attach overnight.
• FCS % fetal calf serum
• ATP 0.1 mM
• KCO e.g. diazoxide, [ 3 H]PI 075
• Incubations were carried out for 1 h at room temperature and were terminated by rapid filtration through Whatman GF/B filters.
• the inhibition constant (Ki value) of the test substances was calculated from the respective IC50 value, and was stated as the negative logarithmic value thereof (pK).
• the affinity of the compounds of the invention for cannabinoid CB 1 receptors can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB 1 receptor is stably transfected in conjunction with [ 3 H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [ 3 H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand is performed by filtration over glassfiber filters. Radioactivity on the filter is measured by liquid scintillation counting.
• CHO Chinese hamster ovary
• the affinity of the compounds of the invention for cannabinoid CB 2 receptors can be determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB 2 receptor is stably transfected in conjunction with [ 3 H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [ 3 H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand is performed by filtration over glassfiber filters. Radioactivity on the filter is measured by liquid scintillation counting.
• CHO Chinese hamster ovary
• mice Male Wistar rats in the weight range 175-200 g were group housed in standard animal cages at a temperature of 21 ⁇ 2°C and humidity of 55 ⁇ 10%. Animals were maintained on a 12 h light-dark cycle (lights on 06.00-18.00 h) with free access to standard rodent diet (B&K Universal Ltd standard rat and mouse diet (BK 001 P), Beekay Feeds, B&K Universal Ltd, Hull, East Riding of Yorkshire) and tap water. The rats were accustomed to these conditions for at least one week before experimentation.
• Perifusate samples were then pooled to create three samples per chamber as follows: Baseline (4mM): Samples 1-5 (first 10 minutes); 0-30 minutes (1 1 mM glucose): Samples 6-21 ; 30-60 minutes (1 1 mM glucose): Samples 22-36. Perifusate fractions were stored at -75°C until required for insulin assay. Insulin content of fractions were assayed using a 96-well ELISA assay (Mercodia). Initial insulin assays were performed in triplicate on three pooled fractions from each chamber.
• the three islet preparations showed a consistent degree of glucose dependent insulin secretion.
• the mean insulin secretion at 1 1 mM glucose was 98.3 ⁇ 12.6 pg/islet/min and 130.4 ⁇ 22.0 pg/islet/min at 0-30 and 30-60 minutes, respectively.
• insulin secretion was increased by 26 times and 38 times by 11 mM glucose at 0-30 and 30-60 minutes, respectively.
• the amount of broadening from the strict numerical boundary depends upon many factors. For example, some of the factors which may be considered include the criticality of the element and/or the effect a given amount of variation will have on the performance of the claimed subject matter, as well as other considerations known to those of skill in the art. As used herein, the use of differing amounts of significant digits for different numerical values is not meant to limit how the use of the words “about” or “approximately” will serve to broaden a particular numerical value. Thus, as a general matter, "about” or “approximately” broaden the numerical value.
• ranges is intended as a continuous range including every value between the minimum and maximum values plus the broadening of the range afforded by the use of the term "about” or “approximately.”
• ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it there individually recited herein. It is to be understood that any ranges, ratios and ranges of ratios that can be formed by, or derived from, any of the data disclosed herein represent further embodiments of the present disclosure and are included as part of the disclosure as though they were explicitly set forth.

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