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Definitions

• compositions comprising CB x Cannabinoid Receptor Modulators and Potassium Channel Modulators
• the present invention relates to a novel combination therapy for a variety of disease conditions including obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans.
• the invention also relates to novel pharmaceutical compositions comprising K A TP channel modulators and CB x modulators and the use of said pharmaceutical compositions for the prophylaxis, treatment, delayed progression, delayed onset and/or inhibition of a variety of disease conditions including obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans.
• the invention also relates to processes for the preparation of such compositions.
• 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.
• 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 biological mechanisms at the molecular level between insulin resistance and metabolic risk factors are not fully understood and appear to be complex.
• One group of people at risk for developing metabolic syndrome is those with diabetes who have a defect in insulin action and cannot maintain a proper level of glucose in their blood.
• Another is people, mainly those with high blood pressure, who are non-diabetic and insulin-resistant but who compensate by secreting large amounts of insulin. This condition is known as hyperinsulinemia.
• a third group is heart attack survivors who, unlike hypertensives, have hyperinsulinemia without having abnormal glucose levels.
• the metabolic syndrome has become increasingly common in higher developed countries like the United States, where it is estimated that about 20-25 percent of US adults have it.
• the criteria proposed by the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) are the most current and widely used.
• the metabolic syndrome is identified by the presence of three or more of these following components:
• 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 and impotence (ref. Jahangir et al. J. MoI. Cell. Cardiology, 2005, 39, 99-1 12 and references cited therein).
• Blockers of Kir6.2/SUR1 K A TP channels (e.g. repaglinde, tolbutamide and glibenclamide) stimulate insulin release and are used in the treatment of type Il diabetes.
• 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 V ⁇ _ (2004) 1595-1615.
• K A TP channel opener diazoxide in the treatment of i.a. the metabolic syndrome is known e.g. from documents US 5,284,845 or US 6,197,765 or from R. Alemzadeh et al., Endocrinology 133 (2) (1993) 705-712 or R. Alemzadeh et al., Journal of Clinical Endocrinology and Metabolism 83 (6) (1998) 191 1-1915.
• the K 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.
• 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. Its structure has been determined recently (ref. Mikhailov, EMBO Journal, 2005, 24, (23), 4166-4175).
• Insulin is the main hormone involved in blood glucose homeostasis. Insulin is involved in the regulation of glycaemia and as a consequence related to type I and type Il diabetes. Additionally, insulin is involved in lipogenesis and weight gain, provoking an anorexigenic action as it provokes a satiety when acting in the brain (ref. Juan-Pico et al., Cell Calcium 2006, 39, 155-163 and references cited therein).
• the regulation of insulin secretion will be useful in the treatment of diseases such as diabetes type I, diabetes type II, obesity, metabolic syndrome and syndrome X.
• a novel combination therapy which comprises administering a combination of at least one K A TP channel modulator as a first active agent and at least one CB x modulator as a second active agent to a patient in need thereof can provide an effective and/or selective therapy for a variety of disease conditions including obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans.
• this new combination therapy is particularly suited for the prophylaxis of diabetes mellitus, metabolic syndrome and/or syndrome X in patients exposed to an elevated risk of acquiring such diseases, like patients with established obesity.
• the novel combination therapy according to the invention is also well suited to treat type Il diabetes and insulin resistance in patients without concomitant obesity.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising pharmacologically effective quantities of each of:
• 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.
• the invention also relates to the use of at least one K A TP channel modulator in combination with at least one CB x modulator as a second active agent wherein the CB x modulator is selected from the group consisting of 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, for the manufacture of a medicament for the prophylaxis, treatment, delayed progression, delayed onset and/or inhibition of a variety of disease conditions including obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral va
• the invention relates to a method of treating, preventing, delaying progression of, delaying onset of and/or inhibiting a variety of disease conditions including obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotection, angina, cardioplegia, arrhythmia, coronary spasm, peripheral vascular disease, cerebral vasospasm, appetite regulation, neurodegeneration, pain - including neuropathic pain and chronic pain - and impotence in mammals and humans comprising administering to a subject in need thereof an effective amount of at least one K A TP channel modulator in combination with at least one CB x modulator as a second active agent wherein the CB x modulator is selected from the group consisting of CB 1 agonists; CB 2 agonists; CB 2 partial agonists; CB
• the invention further is directed to processes for the preparation of a medicament comprising the step of combining at least one K A TP channel modulator with 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, and wherein at least one K A TP channel modulator and the at least one CB x modulator are present in a combined amount effective for the prophylaxis, treatment, delayed progression, delayed onset and/or inhibition of a variety of disease conditions including obesity, diabetes mellitus, metabolic syndrome, syndrome X, insulinoma, familial hyperinsulemic hypoglycemia, male pattern baldness, detrusor hyperreactivity, asthma, neuroprotection, epilepsy, analgesia, cardioprotect
• Suitable K A TP channel modulators are preferably compounds selected from the group consisting of: K A TP channel openers, partial K A TP channel openers, K A TP channel closing agents, K AT p channel blocking agents, and mixtures thereof.
• Preferred K AT p channel modulators are compounds which have effects as modulators at the Kir6.2/SUR1 K ATP channel, at the Kir6.2/SUR2B K ATP channel, the Kir6.1/ SUR2B K ATP channel, and/or at the Kir6.2/SUR2A K AT p channel.
• Compounds with an effect as openers at the Kir6.2/SUR1 K AT p channel, in particular as selective openers at the Kir6.2/SUR1 K AT p channel are preferred.
• a compound with an effect as opener at the Kir6.2/SUR1 K ATP channel is understood to be selective if its 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/SUR2B K AT p channel, the Kir6.1/SUR2B K ATP channel, and/or at the Kir6.2/SUR2A K ATP channel.
• MCC-134 see e.g. M. J. Coghlan et al., J. Med. Chem. 44 (2001 ) 1627-1653); losimendan; SR 47063, WAY 135201 , and mixtures thereof.
• Suitable CB 1 agonists are preferably compounds which bind to and activate the CB 1 receptor. Effective are those compounds which exhibit an IC 5O value [ ⁇ mol] of more than 50 in a test for the affinity of the compounds in binding to the CB 1 receptor.
• Suitable CB 2 agonists are preferably compounds which bind to and activate the CB 2 receptor. Effective compounds are those which exhibit an IC 50 value [ ⁇ mol] of more than 50 in a test for the affinity of the compounds in binding to the CB 2 receptor.
• CB 1 agonists or CB 2 agonists have been described in the literature, for example: Thakur et al., Mini-Rev. Med. Chem. 2005, 5, 631-640; Palmer et al., Chem. Phys. Lipids 2002, 121 , 3-19; Hertzog, Expert Opin. Ther. Patents, 2004, 14, 1435-1452; Huffman, Curr. Med. Chem. 1999, 6, 705-720; Reggio, Curr. Pharm. Des. 2003, 9, 1607-1633; Padgett, Life Sci. 2005, 77, 1767-1798; Goya and Jagerovic, Expert. Opin. Ther. Patents, 2000, 10, 1529-1538.
• Suitable CB 1 agonists or CB2 agonists have been claimed and exemplified in other patent applications.
• Suitable CB 2 antagonists or suitable CB 2 inverse agonists are preferably compounds which bind to the CB2 receptor but do not produce agonistic or partial agonistic effects. Effective are those compounds which exhibit an IC 50 value [ ⁇ mol] of more than 50 in a test for the affinity of the compounds in binding to the CB2 receptor.
• CB 2 antagonists or suitable CB 2 inverse agonists have been described in the literature, for example: Lavey et al. Bioorg. Med. Chem. Lett. 2005, 15, 783-786; Shankar et al. Bioorg. Med. Chem. Lett. 2005, 15, 4417-4420; Iwamura et al. J. Pharmacol. Exp. Ther. 2001 , 296, 420-425.
• CB antagonism as related to inverse agonism and the active/inactive state of CB receptors see Reggio, Curr. Pharm. Des. 2003, 9, 1607-1633; Tuccinardi et al. J. Med. Chem. 2006, 49, 984- 994; Pertwee, Life Sci. 2005, 76, 1307-1324.
• Other suitable CB 2 antagonists or suitable CB 2 inverse agonists have been claimed and exemplified in other patent applications.
• Suitable dually acting compounds which are both a CB 1 agonist and a CB 2 agonist are preferably compounds which bind to the CB 1 as well as to the CB2 receptor. Effective are those compounds which exhibit an IC 50 value [ ⁇ mol] of more than 50 in a test for the affinity of the compounds in binding to the CB 1 as well as to the CB2 receptor.
• the K A TP channel modulator is a K ATP channel opener.
• CB x modulator suitable for use as K A TP channel modulator are selected from, but not limited to the group consisting of: 3-(1 ,1-dimethyl-butyl)-6,6,9-trimethyl-6a,7,10,10a- tetrahydro-6H-benzo[c]chromene; N-Adamantyl-4-pentyl-5-phenyl-thiazole-2- carboxamide; N- ⁇ 1 ,3,3-Trimethyl-endo-(1 S)-bicyclo[2.2.1]hept-2-yl ⁇ -1-[1-(4-methyl)- benzyl-5-(4-chloro-3-methyl-phenyl)-1 H-pyrazol-3-carboxamide; (2-lodo-5-nitro- phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1 H-indol-3-
• 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 suitable as K A TP channel modulator are selected from the group consisting of: 3-(1 , 1 -dimethyl-butyl)- 6,6,9-trimethyl-6a,7, 10, 10a-tetrahydro-6H-benzo[c]chromene; N-Adamantyl-4-pentyl-5- phenyl-thiazole-2-carboxamide; N- ⁇ 1 ,3,3-Trimethyl-endo-(1 S)-bicyclo[2.2.1]hept-2-yl ⁇ - 1-[1-(4-methyl)-benzyl-5-(4-chloro-3-methyl-phenyl)-1 H-pyrazol-3-carboxamide; (2- lodo-5-nitro-phenyl)-[1-(1-methyl-piperidin-2-ylmethyl)-1 H-indol-3-yl]-methanone; ⁇ 4-[4- (i .i-Dimethyl-heptyl
• 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 suitable as K A TP channel modulator are selected from the group consisting of: 4-Chloro-N- ⁇ [3-(4-chloro- phenyl)-4-phenyl-4,5-dihydro-pyrazol-1-yl]-methylamino-methylene ⁇ - benzenesulfonamide; N- ⁇ Amino-[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1- yl]-methylene ⁇ -4-chloro-benzenesulfonamide; 4-Chloro-N- ⁇ [3-(4-chloro-phenyl)-4- pyridin-3-yl-4,5-dihydro-pyrazol-1-yl]-methylamino-methylene ⁇ -benzenesulfonamide; 4- Chloro-N- ⁇ [3-(4-chloro-phenyl)-4-(3-fluoro
• the at least one K A TP channel modulator as a first active agent can act simultaneously as K A TP channel modulator and at the same time as CB x modulator and/or the CB x modulator as a second active agent can act simultaneously as CB x modulator and at the same time as K A TP channel modulator, provided that the at least one K ATP channel modulator as a first active agent and the at least one CB x modulator as a second active agent are separate, but not identical components of said composition.
• the K ATP channel modulator and the CB x modulator as a second active agent are administered simultaneously, sequentially or in a combined dosage form.
• the K AT p channel modulator and the CB x modulator are administered simultaneously in a fixed combination.
• binding can be detected indirectly through allosteric displacement of [ 3 H]PI 075 (D ⁇ rschner et al., 1999).
• a mutated SUR2A (SUR2A Y1205 s, see above) with increased affinity for [ 3 H]glibenclamide allowing direct displacement of this tracer can be used.
• This second approach was chosen to enable discrimination between allosteric and competitive interaction with the KCO site and make sure that binding of ligands which do not induce allosteric displacement are not missed.
• Membranes from COS-cells transiently expressing rat SUR2A were incubated in the presence of the radioligands with increasing concentrations of test compounds as described above. The affinity for binding to the KCO site was assessed by incubations in the additional presence of 100 ⁇ 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 %.
• SUR- or Kir ⁇ .x isoforms were used either subcloned in the pcDNA (hamster SUR1 , mouse Kir6.2) or pCMV vector (rat SUR2A, SUR2B).
• Rodent SUR-isoforms and K 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 logarithmised value thereof (pK).
• the binding affinity and selectivity of a given compound towards SUR1 and SUR2 can be used as criteria to reflect the modulation of the K-ATP channel (e.g. NN- 414, with a pKi 6.2, is 100 times more potent than diazoxide, with a pKi 3.8, to inhibit glucose-stimulated insulin release).
• the binding data can be used as first estimate of the potential of a given compound to preserve beta cell function and to prevent or delay the progression of diabetes.
• Compound having a pK, (SUR1 ) larger than pK, (SUR2) are particularly preferred for the purposes of the present invention.
• These compounds include but are not limited to: (4S)-3-(4-chlorophenyl)-N'-[(4-chlorophenyl)sulfonyl]-N-methyl-4-phenyl-4,5- dihydro-1 H-pyrazole-1-carboximid-amide; 5-(1 ,1-dimethylheptyl)-2-[(1 R,2R,5R)-5- hydroxy-2-(3-hydroxypropyl)cyclohexyl]-phenol; (2S)-1-[3-(4-chlorophenyl)-4-phenyl- 4,5-dihydro-1 H-pyrazol-1-yl]-3-(3,4-dichloro-phenyl)-1-oxopropan-2-amine; 3-(4- chlorophenyl)-N'-[(4-chlor
• 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 the addition of compounds of the invention, separation of bound and free ligand is performed by filtration over glassfiber filters. Radioactivity on the filter is measured by liquid scintillation counting.
• 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 the addition of compounds of the invention, separation of bound and free ligand is performed by filtration over glassfiber filters. Radioactivity on the filter is measured by liquid scintillation counting.
• 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 1 1 mM glucose at 0-30 and 30-60 minutes, respectively.
• compositions according to the invention can be prepared in a manner known to those of skill in the art and thus can be obtained as formulations suitable for enteral, such as oral or rectal, administration or parenteral, such as injectable or transdermal, administration to mammals or humans, comprising a therapeutical effective amount of the pharmacologically active agents, alone or in combination with one or more pharmaceutically acceptable excipients, especially suitable for enteral or parenteral application.
• Pharmaceutical compositions for enteral or parenteral administration in particular those suitable for oral administration, are preferred and comprise for example unit dosage forms, such as coated tablets, tablets, capsules or suppositories and also ampoules.
• Typical oral formulations include coated tablets, tablets, capsules, syrups, elixirs and suspensions.
• Capsules may contain the active agents e.g. in form of powders, granules, pellets, beadlets or microtablets.
• a pharmaceutical composition according to the invention may consist of from about 0.1 % to 90 %, preferably of from about 1 % to about 80 %, of the active agents, the balance being pharmaceutically acceptable excipients.
• compositions for oral use can be obtained by combining the active compounds with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances.
• Typical injectable formulations include solutions and suspensions.
• Typical transdermal administration forms comprise e.g. patches, gels, ointments and the like.
• the typical pharmaceutically acceptable excipients for use in the formulations described above are exemplified by: sugars such as lactose, sucrose, mannitol and sorbitol; starches such as cornstarch, tapioca starch and potato starch; cellulose and derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationic and anionic surfactants; ethylene glycol polymers; betacyclodextrin; fatty alcohols; and hydrolyzed cereal solids, as well as other non
• Example 1 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 2 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 3 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 4 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 5 Capsules comprising a K ATP channel modulator and a CB x modulator
• Example 6 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 7 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 8 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 9 Capsules comprising a K A TP channel modulator and a CB x modulator
• Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro- 50 mg pyrazol-1-yl]-methylamino-methyleneamide
• Example 10 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 1 1 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 12 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 13 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 14 Capsules comprising a K ATP channel modulator and a CB x modulator
• Example 15 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 16 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 17 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 18 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 19 Capsules comprising a K A TP channel modulator and a CB x modulator
• Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro- 50 mg pyrazol-1-yl]-methylamino-methyleneamide
• Example 20 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 21 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 22 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 23 Capsules comprising a K A TP channel modulator and a CB x modulator i- ⁇ -Chloro-phenyO-S-phenyW. ⁇ -dihydro-I H-pyrazole-S-carboxylic acid 50 mg piperidin-1-ylamide
• Example 24 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 25 Capsules comprising a K A TP channel modulator and a CB x modulator
• Morpholine-4-sulfonic acid [1-(2,4-dichloro-phenyl)-5-phenyl-4,5-dihydro- 50 mg
• Example 26 Capsules comprising a K A TP channel modulator and a CB x modulator 4-Chloro-N-[[3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro-pyrazol-1 -yl]-(2- 50 mg fluoro-ethylamino)-methylene]-benzenesulfonamide
• Example 27 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 28 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 29 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 30 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 31 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 32 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 33 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 34 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 35 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 36 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 37 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 38 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 39 Capsules comprising a K A TP channel modulator and a CB x modulator 5-(4-Bromo-phenyl)-1-(2,4-dichloro-phenyl)-1 H-pyrazole-3-carbonitrile 50 mg
• Example 40 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 41 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 42 Capsules comprising a K AT p channel modulator and a CB x modulator Piperidine-1-carboxylic acid [5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4- 50 mg methyl-1 H-pyrazol-3-yl]-amide 4,4,4-Trifluoro-butane-1-sulfinic acid 3-(2-hydroxymethyl-indan-4-yloxy)- 50 mg phenyl ester, compound with form aldehyde (BAY-38-7271 )
• Example 43 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 44 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 45 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 46 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 47 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 48 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 49 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 50 Capsules comprising a K A TP channel modulator and a CB x modulator 1-(4-Bromo-phenyl)-5-chloro-2-(2,4-dichloro-phenyl)-1 H-imidazole-4- 50 mg carboxylic acid piperidin-1-ylamide
• Example 51 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 52 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 53 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 54 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 55 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 56 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 57 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 58 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 59 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 60 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 61 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 62 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 63 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 64 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 65 Capsules comprising a K ATP channel modulator and a CB x modulator
• Example 66 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 67 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 68 Capsules comprising a K ATP channel modulator and a CB x modulator
• Example 69 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 70 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 71 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 72 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 73 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 74 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 75 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 76 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 77 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 78 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 79 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 80 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 81 Capsules comprising a K A TP channel modulator and a CB x modulator 1-(4-Chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-methylsulfanyl-1 H-imidazole- 50 mg 4-carboxylic acid cyclohexylamide
• Example 82 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 83 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 84 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 85 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 86 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 87 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 88 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 89 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 90 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 91 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 92 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 93 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 94 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 95 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 96 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 97 Capsules comprising a K A TP channel modulator and a CB x modulator ⁇ -PentyW-phenyl-thiazole ⁇ -carboxylic acid (hexahydro-2,5-methano- 50 mg pentalen-3a-yl)-amide
• Example 98 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 99 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 100 Capsules comprising a K ATP channel modulator and a CB x modulator
• Example 101 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 102 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 103 Capsules comprising a K ATP channel modulator and a CB x modulator
• Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro- 50 mg pyrazol-1-yl]-methylamino-methyleneamide
• Example 104 Capsules comprising a K A TP channel modulator and a CB x modulator
• Example 105 Capsules comprising a K A TP channel modulator and a CB x modulator
• Morpholine-4-sulfonic acid [3-(4-chloro-phenyl)-4-phenyl-4,5-dihydro- 50 mg pyrazol-1-yl]-(cyclopropylmethyl-amino)-methyleneamide
• Example 106 Capsules containing a K A TP opener and a CB1 agonist
• Example 107 Capsules containing a K ATP opener and a CB2 agonist
• Example 108 Capsules containing a K ATP opener and a selective CB2 agonist
• Example 109 Capsules containing a K A TP opener and a CB2 antagonist
• Example 1 10 Capsules containing a K A TP opener and a dually acting compound which is both a CB 1 agonist and a CB 2 agonist
• the active agents, the corn starch and the lactose were processed into a homogeneous pasty mixture using ethyl acetate.
• the paste was grounded and the resulting granules were placed on a suitable tray and dried at 45°C in order to remove the solvent.
• the dried granules were passed through a crusher and mixed in a mixer with the further following excipients:
• the first component represents the K A TP channel modulator as a first active agent; and the second component represents the CB x modulator as a second active agent, or vice versa, or the K A TP channel modulator as a first active acts simultaneously as CB x modulator and wherein the CB x modulator as a second active acts simultaneously as K A TP channel modulator provided that the at least one K A TP channel modulator as a first active agent and the at least one CB x modulator as a second active agent are not identical.
• the amount of broadening from the strict numerical boundary depends upon many factors. For example, some of the factors which may be considered include the criticality of the element and/or the effect a given amount of variation will have on the performance of the disclosed subject matter, as well as other considerations known to those of skill in the art. As used herein, the use of differing amounts of significant digits for different numerical values is not meant to limit how the use of the words “about” or “approximately” will serve to broaden a particular numerical value. Thus, as a general matter, "about” or “approximately” broaden the numerical value.
• 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.
• any ranges, ratios and ranges of ratios that can be formed by, or derived from, any of the data disclosed herein represent further embodiments of the present disclosure and are included as part of the disclosure as though they were explicitly set forth. This includes ranges that can be formed that do or do not include a finite upper and/or lower boundary. Accordingly, a person of ordinary skill in the art most closely related to a particular range, ratio or range of ratios will appreciate that such values are unambiguously derivable from the data presented herein.

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