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Wo 2009/005646 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 8 January 2009 (08.01.2009) WO 2009/005646 A2 (51) International Patent Classification: (US). GREENLEE, William, J. [US/US]; 115 Herrick C07D 241/04 (2006.01) A61K 31/496 (2006.01) Avenue, Teaneck, New Jersey 07666 (US). CELLY,Chan- C07D 401/06 (2006.01) A61K 31/506 (2006.01) der, Shekher [CA/US]; 85 West Street, Colonia, New Jer C07D 401/14 (2006.01) A61P 3/00 (2006.01) sey 07067 (US). C07D 403/12 (2006.01) A61P 9/10 (2006.01) C07D 403/14 (2006.01) (74) Agent: MACMILLAN, Keith; Schering-Plough Corpo ration, Patent Department, K-6-1 1990, 2000 Galloping (21) International Application Number: Hill Road, Kenilworth, New Jersey 07033-0530 (US). PCT/US2008/007868 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: 25 June 2008 (25.06.2008) kind of national protection available): AE, AG, AL, AM, AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, (25) Filing Language: English CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, (26) Publication Language: English IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, (30) Priority Data: MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, 60/946,873 28 June 2007 (28.06.2007) US PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (71) Applicant (for all designated States except US): SCHER- ZA, ZM, ZW ING CORPORATION [US/US]; 2000 Galloping Hill Road, Kenilworth, New Jersey 07033-0530 (US). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors; and GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (75) Inventors/Applicants (for US only): GILBERT, Eric, J. ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), [US/US]; 2 119 Gamble Road, Scotch Plains, New Jersey European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, 07076 (US). MILLER, Michael, W. [US/US]; 1862 Lam FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, berts Mill Road, Scotch Plains, New Jersey 07076 (US). NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, SCOTT, Jack, D. [US/US]; 2089 Westfield Road Circle, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Scotch Plains, New Jersey 07076 (US). DEMONG, Du- ane, Eugene [US/US]; 14 Landry Road, Somerset, New Published: Jersey 08873 (US). STAMFORD, Andrew [AU/US]; 27 — without international search report and to be republished Overlook Road, Chatham Township, New Jersey 07928 upon receipt of that report (54) Title: SUBSTITUTED PIPERAZINES AS CBl ANTAGONISTS (57) Abstract: Compounds of Formula (I) or pharmaceutically accept able salts, solvates, or esters thereof, are useful in treating diseases or conditions mediated by CBireceptors, such as metabolic syndrome and obesity, neuroinflammatory disorders, cognitive disorders and psychosis, addiction (e.g., smoking cessation), gastrointestinal disorders, and cardio (I) vascular conditions. SUBSTITUTED PIPERAZINES AS CB1 ANTAGONISTS PRIOR APPLICATIONS This application claims the benefit of priority to Application No. 60/946,873, filed June 28, 2007, which is incorporated in its entirety by reference. BACKGROUND OF THE INVENTION The CBi receptor is one of the most abundant neuromodulatory receptors in the brain, and is expressed at high levels in the hippocampus, cortex, cerebellum, and basal ganglia (e.g., Wilson et al., Science, 2002, vol. 296, 678- 682). Selective CB1 receptor antagonists, for example pyrazole derivatives such as rimonabant (e.g., U.S. 6,432,984), can be used to treat various conditions, such as obesity and metabolic syndrome (e.g., Bensaid et al., Molecular Pharmacology, 2003 vol. 63, no. 4, pp. 908-914; Trillou et al., Am. J. Physiol. Regul. Integr. Comp. Physiol. 2002 vol. 284, R345-R353; Kirkham, Am. J. Physiol. Regul. Integr. Comp. Physiol. 2002 vol. 284, R343-R344), neuroinflammatory disorders (e.g., Adam, et al., Expert Opin. Ther. Patents, 2002, vol. 12, no. 10, 1475-1489; U.S. 6,642,258), cognitive disorders and psychosis (e.g., Adam et al., Expert Opin. Ther. Pat, 2002, vol. 12, pp. 1475- 1489), addiction (e.g., smoking cessation; U.S. Patent Publ. 2003/0087933), gastrointestinal disorders (e.g., Lange et al., J. Med. Chem. 2004, vol. 47, 627- 643) and cardiovascular conditions (e.g., Porter et al., Pharmacology and Therapeutics, 2001 vol. 90, 45-60; Sanofi-Aventis Publication, Bear Stearns Conference, New York, September 14, 2004, pages 19-24). There now exists extensive pre-clinical and clinical data supporting the use of CB1 receptor antagonists / inverse agonists for the treatment of obesity. Preparations of marijuana (Cannabis sativa) have been used for over 5000 years for both medicinal and recreational purposes. The major psychoactive ingredient of marijuana has been identified as delta-9-tetrahydrocannabinol (delta-9-THC), one of a member of over 60 related cannabinoid compounds isolated from this plant. It has been demonstrated that delta-9-THC exerts its effects via agonist interaction with cannabinoid (CB) receptors. So far, two cannabinoid receptor subtypes have been characterised (CBi and CB2). The CB1 receptor subtype is found predominantly in the central nervous system, and to a lesser extent in the peripheral nervous system and various peripheral organs. The CB2 receptor subtype is found predominantly in lymphoid tissues and cells. To date, three endogenous agonists (endocannabinoids) have been identified which interact with both CB1 and CB2 receptors (anandamide, 2-arachidonyl glycerol and noladin ether). Genetically obese rats and mice exhibit markedly elevated endocannabinoid levels in brain regions associated with ingestive behaviour (Di Marzo et al. 2001 Nature 410: 822 - 825). Furthermore, increased levels of endocannabinoids are observed upon the fasting of normal, lean animals (Kirkham et al., British Journal of Pharmacology 2002, 136(4) 550-557). Exogenous application of endocannabinoids leads to the same physiological effects observed with delta-9-THC treatment, including appetite stimulation (Jamshida et al., British Journal of Pharmacology 2001 , 134: 1151 - 1 154), analgesia, hypolocomotion, hypothermia, and catalepsy. CB1 (CB1-/-) and CB2 (CB2-/-) receptor knockout mice have been used to elucidate the specific role of the two cannabinoid receptor subtypes. Furthermore, for ligands such as delta-9-THC which act as agonists at both receptors, these mice have allowed identification of which receptor subtype is mediating specific physiological effects. CB1-/-, but not CB2-/-, mice are resistant to the behavioural effects of agonists such as delta-9-THC. CB1-/- animals have also been shown to be resistant to both the body weight gain associated with chronic high fat diet exposure, and the appetite-stimulating effects of acute food deprivation. These findings suggest a clear role for both endogenous and exogenous cannabinoid receptor agonists in increasing food intake and body weight via selective activation of the CB1 receptor subtype. The therapeutic potential for cannabinoid receptor ligands has been extensively reviewed (Exp. Opin. Ther. Pat. 1998, 8, 301-313; Exp. Opin. Ther. Pat. 2000, 10, 1529-1538; Trends in Pharm. Sci. 2000, 2 1, 2 18-224; Exp. Opin. Ther. Pat. 2002, 12(10), 1475-1489). At least one compound (SR-14171 6A; Rimonabant) characterised as a CBi receptor antagonist / inverse agonist is known to be in clinical trials for the treatment of obesity. Clinical trials with the CBi receptor antagonist rimonabant have also observed an antidiabetic action that exceeds that accounted for by weight loss alone (Scheen A.J., et al., Lancet, 2006 in press). CBi receptor mRNA is located on α- and β-cells in the Islets of Langerhans and it has been reported that CBi receptor agonists reduce insulin release from pancreatic beta cells in vitro in response to a glucose load (Juan-Pico et al, Cell Calcium, 39, (2006), 155-162). Consistent with this, Bermudez-Siva et al., (Eur J Pharmacol., 531 (2006), 282- 284) have reported that CBi receptor agonists increase glucose intolerance following ip injection of a glucose load to rats. This effect was reversed by a CBi receptor antagonist that increased glucose tolerance in the test when given alone. Thus, the action of rimonabant may be due to a direct action on the pancreas. It is also possible that CBi receptor antagonists affect insulin sensitivity indirectly via an action on adiponectin (Chandran et al., Diabetes care, 26, (2003), 2442-2450) which is elevated by CBi receptor antagonists (Cota et al., J Clin Invest., 112 (2003), 423-431 ; Bensaid et al., MoI Pharmacol., 63 (2003, 908-914). Indeed, it has been reported that endocannabinoid levels are enhanced in the pancreas and adipose tissue of obese and diabetic mice and in the plasma and adipose tissue of obese or type 2 diabetic patients (Matias et al., J Clin Endocrinol and Metab., 9 1 (2006), 3171-3180) suggesting a possible causal role of elevated cannabinoid tone in the onset of type 2 diabetes. However, there is still a need for improved cannabinoid agents, particularly selective CBi receptor antagonists, with fewer side-effects and improved efficacy. WO 95/25443, U.S. 5,464,788, and U.S. 5,756,504 describe N- arylpiperazine compounds useful for treating preterm labor, stopping labor, and dysmenorrhea. However, none of the N-aryl piperazines exemplified therein have an aryl and/or heteroaryl substituent at both the 1- and 2-positions of the piperazine ring.
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