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(12) United States Patent (10) Patent No.: US 8,680,131 B2 Mcelroy Et Al

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(12) United States Patent (10) Patent No.: US 8,680,131 B2 Mcelroy Et Al USOO868O131B2 (12) United States Patent (10) Patent No.: US 8,680,131 B2 McElroy et al. (45) Date of Patent: Mar. 25, 2014 (54) CANNABINOID RECEPTOR 8,580,768 B2 11/2013 McElroy et al. ANTAGONSTS/INVERSEAGONSTS 2008, 0255093 A1 10, 2008 Tam et al. 2012/0264797 A1 10/2012 McElroy et al. SSSSSS9 holic 2013/0005784 A1 1/2013 McElroy et al. DSORDERS AND CANCERS FOREIGN PATENT DOCUMENTS (71) Applicant: Jenrin Discovery, Wilmington, DE (US) EP 1429761 B2 11/2006 (72) Inventors: John Francis McElroy, Wilmington, OTHER PUBLICATIONS PES test t Chorvat, New data shows Acomplia(r) (rimonabant) benefited patients with s type 2 diabetes by improving blood Sugar control reducing weight (73) Assignee: Jenrin Discovery, Inc., Wilmington, DE and acting on other cardiometabolic risk factors. Cape Town, South (US) Africa, Dec. 5, 2006: http//en. Sanofi-aventis.com/press releases/ 2006, ppc 15161.asp. (*) Notice: Subject to any disclaimer, the term of this Lange, J.H.M. et al., Synthesis, Biological Properties and Molecular patent is extended or adjusted under 35 Investigations of Novel 3,4-Diarylpyrazolines as Potent and Selec U.S.C. 154(b) by 0 days. tive CB1 Cannabinoid Receptor Antagonists; J. Med. Chem. 2004, 47,627-643. Remington, et al. The Science and Practice of Pharmacy, 2000, Lip (21) Appl. No.: 13/950,195 pincott Williams and Wilkins, 20th Edition, pp. 218-220. 1-1. Wierzbicki, A.S., Rimonabant: endocannabinoid inhibition for the (22) Filed: Jul. 24, 2013 metabolic syndrome, Drug Focus 2006, 60(12), 1697-1706. O O Pi-Sunyer, F.X., Effect of Rimonabant, a Cannabinoid-1 Receptor (65) Prior Publication Data Blocker, on Weight and Cardiometabolic Risk Factors in Overweight US 2014/0031404 A1 Jan. 30, 2014 or Obese Patients, JAMA 2006, 297(7), 761-775. s Solvay'SSLV319 Obesity Candidate Treatment Advances in Phase II Related U.S. Application Data Clinical Trials, Solvay Press Release, Dec. 8, 2006. AV Stradivarius (Strategy to Reduce Althersclerosis Development (60) Provisional application No. 61/787,214, filed on Mar. Involving Administration of Rimonabant-the Intravascular 15, 2013, provisional application No. 61/675,806, Ultrasound Study), Clinical Trials.gov, http://clinicaltrials.gov/ct2/ filed on Jul 25, 2012. show? study/NCT00 124332, Jul. 26, 2005. s Tam, Joseph et al., Peripheral CB1 Cannabinoid Receptor Blockade (51) Int. Cl Imiproves Cardiometabolic Risk in Mouse models of Obesity. Jour we nal of Clinical Investigation 2010, 120(8), 2953-2966. gll, f R Kapur, et al., Mutation Studies of Ser7.39 and Ser2.60 in the Human ( .01) CB1 Cannabinoid Receptor: Evidence for a Serine-Induced Bend in (52) U.S. Cl. CB1 Transmembrane Helix 7, Mol. Pharmacol. 2007, 71, 1512-24. USPC ........................................ 514/403; 548/379.4 U.S. Appl. No. 14/065,376, filed Oct. 28, 2013. (58) Field of Classification Search USPC ........................................ 514/403: 548/379.4 Primary Examiner — Samantha Shterengarts See application file for complete search history. (74) Attorney, Agent, or Firm — Vance Intellectual Property PC (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS The present invention provides novel, diastereomeric pyra 6,476,060 B2 11/2002 Lange et al. Zolines that are useful as cannabinoid receptor blockers and 6,974,810 B2 12/2005 Lange et al. pharmaceutical compositions thereof and methods of using 7,482.470 B2 1/2009 McElroy et al. the same for treating obesity, diabetes, inflammatory disor 7,528, 162 B2 5, 2009 Kruse et al. 7,655,685 B2 2/2010 McElroy et al. ders, cardiometabolic disorders, hepatic disorders, and/or 7,666,889 B2 2/2010 McElroy et al. CaCCS. 8,088.809 B2 1/2012 McElroy et al. 8,138,216 B2 3/2012 McElroy et al. 19 Claims, No Drawings US 8,680,131 B2 1. 2 CANNABINOID RECEPTOR In humans, rimonabant and taranabant produce a clinically ANTAGONSTS/INVERSEAGONSTS meaningful weight loss in obese patients. Obese patients also USEFUL FOR TREATING DSEASE experience improvements in diabetic and cardiometabolic CONDITIONS, INCLUDING METABOLIC risk factors associated with obesity, including an increase in DSORDERS AND CANCERS the level of high density lipoprotein cholesterol (HDL), and decreases in triglycerides, glucose, and hemoglobin Alc (Hb Alc, a marker of cumulative exposure to glucose) levels. FIELD OF THE INVENTION Rimonabant also produces reductions in abdominal fat deposits, which area known risk factor for diabetes and heart The present invention provides pyrazoline cannabinoid 10 disease Science 2006, 311, 323. Taken together, these receptor antagonists/inverse agonists and pharmaceutical improvements in adiposity and cardiometabolic risk factors compositions thereof and methods of using the same for produce an overall decrease in the prevalence of the metabolic treating disease conditions including inflammatory diseases, syndrome Lancet 2005, 365, 1389 and NEJM 2005, 353, metabolic diseases such as obesity, diabetes, and hepatic dis 15 2121. orders, cardiometabolic disorders, and cancers. In patients with type 2 diabetes not currently treated with other anti-diabetic medications, rimonabant was shown to BACKGROUND OF THE INVENTION significantly improve blood Sugar control and weight, as well as other risk factors such as HDL and triglycerides, when The endocannabinoid system (ECS) is comprised of two compared to placebo. After six months of treatment, HbA1c cannabinoid receptor subtypes (CB1 and CB2), their endog levels were significantly lowered by 0.8% from a baseline enous ligands (i.e., the endocannabinoids anandamide and value of 7.9 as compared to a reduction of 0.3% in the placebo 2-arachidonoyl glycerol), and enzymes for ligand biosynthe group (Daibetes Care 2008, 31, 2169; Lancet 2006, 368 (95.48), 1660-7. Rimonabant also improved glycemic con sis and degradation (e.g., monoacylglycerol lipase, fatty acid 25 amide hydrolase). The ECS plays a prominent role in the trol and cardiometabolic risk factors in type 2 diabetic regulation of a variety of physiological functions, including patients receiving insulin Daibetes Care 2010, 33, 605. control of food intake and energy metabolism, emotional These results are consistent with preclinical studies that dem behavior, pain, cell division, and inflammation. CB1 recep onstrate improved glycemic and lipid control in diabetic and tors are widely expressed in numerous peripheral organs and 30 dyslipedemic mice, rats, and dogs (Pharmacology Biochem tissues, including thyroid gland, adrenal gland, reproductive istry & Behavior; 2006, 84,353 American Journal of Physi organs, bone, adipose tissue, liver, muscle, pancreas, kidney, ology, 2003, 284, R345, American Diabetes Association and gastrointestinal tract. CB1 receptors have also been iden Annual Meeting, 2007: Abstract Number 0372-OR). tified in brain, including cortex, hippocampus, amygdala, The beneficial effects of rimonabant on diabetic and car pituitary and hypothalamus. CB2 receptors are largel local 35 diometabolic risk factors such as high blood pressure, insulin ized in immune and blood cells, but have more recently been resistance, and eleveated triglycerides cannot be explained by identified in brain for reviews see Endocrine Reviews 2006, diet-related weight loss alone. For example, in patients 27, 73, Int J Obesity 2006, 30, S30; J Clin Endocrin Metab receiving 20 mg of rimonabant, only approximately 50% of 2006, 91, 3171 Int J Obesity 2009, 33,947). the beneficial effects on triglycerides, fasting insulin, and 40 Many disease states, including inflammatory and meta insulin resistance can be accounted for by weight loss sec bolic diseases and certain cancers are associated with over ondary to reduced food intake. These results suggest a direct activity of the ECS system. This is characterized by increased pharmacological effect of CB1 antagonists on glucose and ECS tone in peripheral tissues including adipose, liver, lipid metabolism, in addition to indirect effects on metabo muscle, and pancreas. Elevated ECS tone is reflected by 45 lism secondary to hypophagia-mediated weight loss Science increased tissue expression of CB1 receptors as well as 2006, 311, 323 and JAMA 2006, 311, 323). Taken together, elevated tissue levels of the main endogenous cannabinoids these results suggest that CB1 antagonists might be effective anandamide and/or 2-arachidonoyl glycerol. Preventing and/ in the treatment of diabetes, dyslipidemias (e.g., high triglyc or reversing overactivity of the ECS system has proven to be erides and LDL, low HDL), cardiovascular disorders (e.g., a useful approach toward the treatment of inflammatory and 50 atherosclerosis, hypertension), and hepatic disorders (e.g., metabolic diseases and certain cancers Mol Pharmacol fatty liver diseases, non-alcoholic steatohepatitis, cirrhosis, 2003, 63,908. J Clin Invest 2008: 118:3160, Diabetes 2010, liver cancers), even in patients that are not clinically over 59, 926. Cancer Res 2011, 71, 7471, Cell Metab 2010; weight or obese. 11:273, J Biol Chem 2008: 283:33021. Int J Obesity 2007, The CB1 receptor is overexpressed in alveolar rhabdomyo 31,692. 55 sarcoma (ARMS), a pediatric soft tissue tumor derived from The plant-derived cannabinoid agonist A-tetrahydrocan skeletal muscle, and upregulation of CB1 is a diagnostic nabinol (A-THC), the main psychoactive component of marker for ARMS Cancer Res 2004, 64, 5539. CB1 over marijuana, binds to both CB1 and CB2 receptors. A-THC is expression is essential for tumor cell proliferation and widely reported to increase appetite and food intake (hyper 60 metastasis, and the CB1 inverse
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