(19) TZZ T (11) EP 2 548 874 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 23.01.2013 Bulletin 2013/04 C07D 241/04 (2006.01) C07D 401/06 (2006.01) C07D 401/14 (2006.01) C07D 403/12 (2006.01) (2006.01) (2006.01) (21) Application number: 12166523.6 C07D 403/14 A61K 31/496 A61K 31/506 (2006.01) A61P 3/00 (2006.01) (2006.01) (22) Date of filing: 25.06.2008 A61P 9/10 (84) Designated Contracting States: • Miller, Michael W. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Scotch Plains, NJ 07076 (US) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT • Scott, Jack D. RO SE SI SK TR Scotch Plains, NJ 07076 (US) Designated Extension States: • Demong, Duane Eugene AL BA MK RS Sommerset, NJ 08873 (US) • Stamford, Andrew (30) Priority: 28.06.2007 US 946873 P Chatham Township, NJ 07928 (US) • Greenlee, William J. (62) Document number(s) of the earlier application(s) in Teaneck, NJ 07666 (US) accordance with Art. 76 EPC: • Celly, Chander Sheker 08768747.1 / 2 170 846 Colonia, NJ 07067 (US) (27) Previously filed application: (74) Representative: Stumm, Karin 25.06.2008 PCT/US2008/007868 Merck Sharp & Dohme Ltd. Hertford Road (71) Applicant: Intervet International B.V. Hoddesdon, Hertfordshire 5831 AN Boxmeer (NL) EN11 9BU (GB) (72) Inventors: Remarks: • Gilbert, Eric J. This application was filed on 03-05-2012 as a Scotch Plains, NJ 07076 (US) divisional application to the application mentioned under INID code 62. (54) Substituted piperazines as CB1 antagonists (57) Compounds of Formula (I): or pharmaceutically acceptable salts, solvates, or esters thereof, are useful in treating diseases or conditions me- diated by CB, receptors, such as metabolic syndrome and obesity, neuroinflammatory disorders, cognitive dis- orders and psychosis, addiction (e.g., smoking cessa- tion), gastrointestinal disorders, and cardiovascular con- ditions. EP 2 548 874 A2 Printed by Jouve, 75001 PARIS (FR) EP 2 548 874 A2 Description PRIOR APPLICATIONS 5 [0001] 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 10 [0002] The CB1 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. 15 2002 vol. 284, R345- R353; Kirkham, Am. J. Physiol. Regul. Integr. Comp. Physiol. 2002 vol. 284, R343- R344), neuroin- flammatory 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. 20 90, 45-60; Sanofi-Aventis Publication, Bear Stearns Conference, New York, September 14, 2004, pages 19-24). [0003] There now exists extensive pre-clinical and clinical data supporting the use of CB1 receptor antagonists / inverse agonists for the treatment of obesity. [0004] Preparations of marijuana (Cannabis sativa) have been used for over 5000 years for both medicinal and rec- reational purposes. The major psychoactive ingredient of marijuana has been identified as delta- 9-tetrahydrocannabinol 25 (delta-9-THC), one of a member of over 60 related cannabinoid compounds isolated from this plant. It has been dem- onstrated that delta-9-THC exerts its effects via agonist interaction with cannabinoid (CB) receptors. So far, two can- nabinoid receptor subtypes have been characterised (CB 1 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 30 (endocannabinoids) have been identified which interact with both CB 1 and CB2 receptors (anandamide, 2-arachidonyl glycerol and noladin ether). [0005] 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) 35 550-557). [0006] 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. [0007] CB1 (CB1-/-) and CB2 (CB2-/-) receptor knockout mice have been used to elucidate the specific role of the two 40 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. CB 1-/-, 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. 45 [0008] 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 CB 1 receptor subtype. [0009] 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, 218-224; Exp. Opin. Ther. Pat. 2002, 12(10), 1475-1489). 50 [0010] At least one compound (SR-14171 6A; Rimonabant) characterised as a CB1 receptor antagonist / inverse agonist is known to be in clinical trials for the treatment of obesity. [0011] Clinical trials with the CB1 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). CB1 receptor mRNA is located on α- and β-cells in the Islets of Langerhans and it has been reported that CB 1 receptor agonists reduce insulin 55 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 CB1 receptor agonists increase glucose intolerance following ip injection of a glucose load to rats. This effect was reversed by a CB 1 receptor antagonist that increased glucose tolerance in the test when given alone. Thus, the action of rimonabant 2 EP 2 548 874 A2 may be due to a direct action on the pancreas. It is also possible that CB 1 receptor antagonists affect insulin sensitivity indirectly via an action on adiponectin (Chandran et al., Diabetes care, 26, (2003), 2442-2450) which is elevated by CB 1 receptor antagonists (Cota et al., J Clin Invest., 112 (2003), 423-431 ; Bensaid et al., Mol Pharmacol., 63 (2003, 908-914). Indeed, it has been reported that endocannabinoid levels are enhanced in the pancreas and adipose tissue of obese 5 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. [0012] However, there is still a need for improved cannabinoid agents, particularly selective CB 1 receptor antagonists, with fewer side-effects and improved efficacy. 10 [0013] 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. [0014] WO 01/02372 and U.S. Published Application No. 2003/0186960 describe cyclized amino acid derivatives for treating or preventing neuronal damage associated with neurological diseases. However, none of the 3- aryl piperazine 15 2-ones exemplified therein have an aryl and/or heteroaryl substituent at both the 1- and 2-positions of the piperazine ring. [0015] WO 96/01656 describes radiolabelled substituted piperazines useful in pharmacological screening procedures, including labeled N-aryl piperazines. 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. [0016] U.S. 5,780,480 describes N- aryl piperazines useful as fibrinogen receptor antagonists for inhibiting the binding 20 of fibrinogen to blood platelets, and for inhibiting the aggregation of blood platelets. However, none of the N- aryl piper- azines exemplified therein have an aryl and/or heteroaryl substituent at both the 1- and 2- positions of the piperazine ring. [0017] WO 03/008559 describes choline analogs useful for treating conditions or disorders. However, the only sub- stituted piperazine derivative exemplified is N-(2-hydroxyethyl)-N’-(2-pyridylmethyl)-piperazine.