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(12) Patent Application Publication (10) Pub. No.: US 2010/0286160 A1 Gilbert Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0286160 A1 Gilbert Et Al US 2010O286160A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0286160 A1 Gilbert et al. (43) Pub. Date: Nov. 11, 2010 (54) SUBSTITUTED PIPERAZINES AS CB1 Related U.S. Application Data ANTAGONSTS (60) Provisional application No. 60/946,896, filed on Jun. (75) Inventors: Eric J. Gilbert, Scotch Plains, NJ 28, 2007. (US); William J. Greenlee, Teaneck, NJ (US); Sarah Wei Li, Publication Classification Belle Mead, NJ (US); Michael W. (51) Int. Cl. Miller, Scotch Plains, NJ (US); A 6LX 3L/2197 (2006.01) Jack D. Scott, Scotch Plains, NJ C07D 24I/04 (2006.01) (US); Adrew Stamford, Chatham C07D 403/2 (2006.01) Township, NJ (US); Chander C07D 24I/02 (2006.01) Shekher Celly, Colonia, NJ (US) C07D 40/12 (2006.01) C07D 40/4 (2006.01) Correspondence Address: A6IP 9/00 (2006.01) MERCK PATENT DEPARTMENT (K-6-1, 1990) (52) U.S. Cl. .................... 514/252.11:544/400: 544/372: 2000 GALLOPNGHILL ROAD 544/370; 544/357: 514/254.01: 514/254.05; KENILWORTH, NJ 07033-0530 (US) 514/252.12:544/360; 514/253.13:544/364; 514/253.09 (73) Assignee: Intervet Inc. (57) ABSTRACT (21) Appl. No.: 12/665,253 Compounds of Formula (I): or pharmaceutically acceptable (22) PCT Fled: Jun. 25, 2008 salts, Solvates, oresters thereof, are useful in treating diseases or conditions mediated by CB1 receptors, such as metabolic (86) PCT NO.: PCT/US08/07917 syndrome and obesity, neuroinflammatory disorders, cogni tive disorders and psychosis, addiction (e.g., Smoking cessa S371 (c)(1), tion), gastrointestinal disorders, and cardiovascular condi (2), (4) Date: Jun. 14, 2010 tions. US 2010/0286160 A1 Nov. 11, 2010 SUBSTITUTED PPERAZINES AS CB1 0006 CB (CB-/-) and CB (CB-/-) receptor knockout ANTAGONSTS mice have been used to elucidate the specific role of the two cannabinoid receptor Subtypes. Furthermore, for ligands Such PRIORAPPLICATIONS as delta-9-THC which act as agonists at both receptors, these mice have allowed identification of which receptor subtype is 0001. This application claims the benefit of priority to mediating specific physiological effects. CB-/-, but not Application No. 60/946,896, filed Jun. 28, 2007, which is CB-/-, mice are resistant to the behavioural effects of ago incorporated in its entirety by reference. nists such as delta-9-THC. CB-/- animals have also been shown to be resistant to both the body weight gain associated BACKGROUND OF THE INVENTION with chronic high fat diet exposure, and the appetite-stimu lating effects of acute food deprivation. 0002 The CB receptor is one of the most abundant neu 0007. These findings suggest a clear role for both endog romodulatory receptors in the brain, and is expressed at high enous and exogenous cannabinoid receptor agonists in levels in the hippocampus, cortex, cerebellum, and basal gan increasing food intake and body weight via selective activa glia (e.g., Wilson et al., Science, 2002, vol. 296, 678-682). tion of the CB receptor subtype. Selective CB receptor antagonists, for example pyrazole 0008. The therapeutic potential for cannabinoid receptor derivatives such as rimonabant (e.g., U.S. Pat. No. 6,432, ligands has been extensively reviewed (Exp. Opin. Ther. Pat. 984), can be used to treat various conditions, such as obesity and metabolic syndrome (e.g., Bensaid et al., Molecular 1998, 8,301-313; Exp. Opin. Ther. Pat. 2000, 10, 1529-1538; Pharmacology, 2003 vol. 63, no. 4, pp. 908-914: Trillou et al., Trends in Pharm. Sci. 2000, 21, 218-224: Exp. Opin. Ther. Am. J. Physiol. Regul. Integr: Comp. Physiol. 2002 vol. 284, Pat. 2002, 12(10), 1475-1489). R345-R353; Kirkham, Am. J. Physiol. Regul. Integr: Comp. 0009. At least one compound (SR-14171 6A: Rimona Physiol. 2002 vol. 284, R343-R344), neuroinflammatory dis bant) characterised as a CB receptor antagonist/inverse ago orders (e.g., Adam, et al., Expert Opin. Ther. Patents, 2002, nist is known to be in clinical trials for the treatment of vol. 12, no. 10, 1475-1489; U.S. Pat. No. 6,642,258), cogni obesity. tive disorders and psychosis (e.g., Adam et al., Expert Opin. 0010 Clinical trials with the CB receptor antagonist Ther. Pat., 2002, vol. 12, pp. 1475-1489), addiction (e.g., rimonabant have also observed an antidiabetic action that smoking cessation; U.S. Patent Publ. 2003/0087933), gas exceeds that accounted for by weight loss alone (Scheen A.J., trointestinal disorders (e.g., Lange et al., J. Med. Chem. 2004, et al., Lancet, 2006 in press). CB receptor mRNA is located vol. 47, 627-643) and cardiovascular conditions (e.g., Porter on C- and B-cells in the Islets of Langerhans and it has been et al., Pharmacology and Therapeutics, 2001 Vol. 90, 45-60; reported that CB receptor agonists reduce insulin release Sanofi-Aventis Publication, Bear Stearns Conference, New from pancreatic beta cells in vitro in response to a glucose York, Sep. 14, 2004, pages 19-24). There now exists extensive load (Juan-Pico et al. Cell Calcium, 39, (2006), 155-162). pre-clinical and clinical data Supporting the use of CB1 recep Consistent with this, Bermudez-Siva et al., (Eur J. Pharma tor antagonists/inverse agonists for the treatment of obesity. col., 531 (2006), 282-284) have reported that CB receptor 0003 Preparations of marijuana (Cannabis sativa) have agonists increase glucose intolerance following ip injection been used for over 5000 years for both medicinal and recre of a glucose load to rats. This effect was reversed by a CB ational purposes. The major psychoactive ingredient of mari receptorantagonist that increased glucose tolerance in the test juana has been identified as delta-9-tetrahydrocannabinol when given alone. Thus, the action of rimonabant may be due (delta-9-THC), one of a member of over 60 related cannab to a direct action on the pancreas. It is also possible that CB inoid compounds isolated from this plant. It has been dem receptor antagonists affect insulin sensitivity indirectly via an onstrated that delta-9-THC exerts its effects via agonist inter action on adiponectin (Chandran et al., Diabetes care, 26. action with cannabinoid (CB) receptors. So far, two (2003), 2442-2450) which is elevated by CB receptor cannabinoid receptor subtypes have been characterised (CB antagonists (Cota et al., J. Clin Invest., 112 (2003), 423-431; and CB). The CB receptor subtype is found predominantly Bensaid et al., Mol. Pharmacol., 63 (2003, 908-914). Indeed, in the central nervous system, and to a lesser extent in the it has been reported that endocannabinoid levels are enhanced peripheral nervous system and various peripheral organs. The in the pancreas and adipose tissue of obese and diabetic mice CB receptor Subtype is found predominantly in lymphoid and in the plasma and adipose tissue of obese or type 2 tissues and cells. To date, three endogenous agonists (en diabetic patients (Matias et al., JClin Endocrinol and Metab., docannabinoids) have been identified which interact with 91 (2006), 3171-3180) suggesting a possible causal role of both CB and CB receptors (anandamide, 2-arachidonyl elevated cannabinoid tone in the onset of type 2 diabetes. glycerol and noladin ether). 0011. However, there is still a need for improved cannab 0004 Genetically obese rats and mice exhibit markedly inoid agents, particularly selective CB receptor antagonists, elevated endocannabinoid levels in brain regions associated with fewer side-effects and improved efficacy. with ingestive behaviour (DiMarzo et al. 2001 Nature 410: 0012 WO95/25443, U.S. Pat. No. 5,464,788, and U.S. 822-825). Furthermore, increased levels of endocannab Pat. No. 5,756,504 describe N-arylpiperazine compounds inoids are observed upon the fasting of normal, lean animals useful for treating preterm labor, stopping labor, and dysmen (Kirkham et al., British Journal of Pharmacology 2002, 136 orrhea. However, none of the N-aryl piperazines exemplified (4) 550-557). therein have an aryland/or heteroaryl substituent at both the 0005 Exogenous application of endocannabinoids leads 1- and 2-positions of the piperazine ring. to the same physiological effects observed with delta-9-THC (0013 WO 01/02372 and U.S. Published Application No. treatment, including appetite stimulation (Jamshida et al., 2003/0186960 describe cyclized amino acid derivatives for British Journal of Pharmacology 2001, 134: 1151-1 154), treating or preventing neuronal damage associated with neu analgesia, hypolocomotion, hypothermia, and catalepsy. rological diseases. However, none of the 3-aryl piperazine US 2010/0286160 A1 Nov. 11, 2010 2-ones exemplified therein have an aryl and/or heteroaryl compounds disclosed have a Substituted aryl and/or het substituent at both the 1- and 2-positions of the piperazine eroaryl Substituent at both the 1- and 2-positions of a pipera ring. Zine ring. 0014 WO 96/01656 describes radiolabelled substituted (0024 WO 2007/020502 describes pyrrolidone com piperazines useful in pharmacological screening procedures, pounds as cannabinoid receptor ligands, in particular CB1 receptor ligands, and their use intreating diseases, conditions, including labeled N-aryl piperazines. However, none of the and/or disorders modulated by cannabinoid receptor antago N-aryl piperazines exemplified therein have an aryl and/or nists. However, none of the compounds disclosed have a heteroaryl substituent at both the 1- and 2-positions of the substituted aryl and/or heteroaryl substituent at both the 1 piperazine ring. and 2-positions of a piperazine ring. 0015 U.S. Pat. No. 5,780,480 describes N-aryl pipera 0025 WO 2007/057687 and WO2006/060461 describe Zines useful as fibrinogen receptor antagonists for inhibiting piperazine derivatives and their use as CB1 antagonists and in the binding offibrinogen to blood platelets, and for inhibiting treating various diseases, conditions, and/or disorders modu the aggregation of blood platelets. However, none of the lated by cannabinoid receptor antagonists.
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