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(12) United States Patent (10) Patent No.: US 8,853,205 B2 Makriyannis Et Al

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(12) United States Patent (10) Patent No.: US 8,853,205 B2 Makriyannis Et Al US008853205 B2 (12) United States Patent (10) Patent No.: US 8,853,205 B2 Makriyannis et al. (45) Date of Patent: *Oct. 7, 2014 (54) HETEROPYRROLE ANALOGSACTING ON 5,462,960 A * 10/1995 Barth et al. ................... 514,406 CANNABINOID RECEPTORS 6.432,984 B1 8, 2002 Barth et al. 6,509,367 B1 1/2003 Martin et al. 7,119, 108 B1 10/2006 Makriyannis et al. (75) Inventors: Alexandros Makriyannis, Watertown, 7,393,842 B2 7/2008 Makriyannis et al. MA (US); Venkata Kiran Vemuri, 7,745.440 B2 6/2010 Makriyannis et al. Boston, MA (US) 7,872,006 B2 1/2011 Moritani et al. 8,084,451 B2 * 12/2011 Makriyannis et al. ........ 514,241 (73) Assignee: University of Connecticut, Farmington, 2004/0192667 A1 9/2004 Makriyannis et al. CT (US) 2004/0248956 Al 12/2004 Hagmann et al. (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS past is tituted under 35 EP O576,357 A1 12/1993 .S.C. 154(b) by ayS. EP O656354 A1 6, 1995 This patent is Subject to a terminal disis- FREP 2758.723O658546 A1 6,T 19951998 Ca10. FR 2856683 A1 12/2004 WO 9719063 A1 5, 1997 (21) Appl. No.: 13/202,499 WO 972.1682 A1 6, 1997 WO 2005OOO820 1, 2005 (22) PCT Filed: Feb. 19, 2009 WO 2006067443 6, 2006 WO 2006O74445 A2 T 2006 (86). PCT No.: PCT/US2O09/OO 1054 WO 2007061948 A2 5, 2007 S371 (c)(1), OTHER PUBLICATIONS (2), (4) Date: Nov. 11, 2011 Fan, H. et al., “Analogs of JHU75528, a PET ligand for imaging of (87) PCT Pub. No.: WO2010/104488 cerebral cannabinoid receptors (CB1): Development of ligands with PCT Pub. Date: Sep. 16, 2010 optimized lipophilicity and binding affinity.” European Journal of Medicinal Chemistry, 44, pp. 593-609, 2009. (65) Prior Publication Data European Search Report dated Jun. 28, 2012. Notification of Transmittal, the International Search Report and Writ US 2012/OO46280 A1 Feb. 23, 2012 ten Opinion of the International Searching Authority for PCT/ US2009/001054 dated Sep. 14, 2009. Related U.S. Application Data International Preliminary Report on Patentability for PCT/US2009/ (63) Continuation-in-part of application No. 1 1/813.546, 001054 dated Aug. 23, 2011. filed as application No. PCT/US2006/000720 on Jan Howlett A.C. et al. "Azido- and isothiocyanato-substituted aryl 10, 2006, now Pat No. 8 O84,451 pyrazoles bind covalently to the CB1 cannabinoid receptor and impair signal transduction'. Journal of Neurochemistry, Wiley (60) Provisional application No. 60/642.544, filed on Jan. Interscience, New York, NY, US, vol. 74, No. 5, Jan. 1, 2000, 2174 10, 2005. 2181. (51) Int. Cl. (Continued) CO7D 231/4 (2006.01) C T E. 3:08: Primary Examiner — Kamal Saeed CO7D 405/2 (2006.01) (74) Attorney, Agent, or Firm — Alix, Yale & Ristas, LLP CO7D 40/0 (2006.01) (52) U.S. Cl. CPC ............ C07D 231/14 (2013.01); Co7D401/10 (7) ABSTRACT 405/12(2013.01); (2013.01); C07D 409/04 C07D 233/90(2013.01); (2013.01) C07D Disclosed are biologically- active hetero pyrrole analogs such USPC .................. 27.28.23 as imidazoles, thiazoles, oxazoles and pyrazoles capable of 514/318: 514/326 514,406. 544/139. 544/140. interacting with the CB1 and/or CB2 cannabinoid receptors. 544/406. 546/1 87; 546/21 1; 548/365.7 Aspects disclose hetero pyrrole analogs acting as CB1 and/or (58) Field of Classification Search CB1 receptor antagonists, having selectivity for the CB1 or None CB2 receptor, acting as neutral antagonists, acting preferen See application file for complete search history. tially on CB1 receptors located in the peripheral nervous system, and/or acting as nitric oxide donors. Pharmaceutical (56) References Cited preparations employing the disclosed analogs and methods of administering therapeutically effective amounts of the dis U.S. PATENT DOCUMENTS closed analogs to provide a physiological effect are also dis 4,256,727 A 3/1981 Triplett et al. closed. 4,732,900 A 3, 1988 Weber et al. 5,155,124 A 10, 1992 Kimata et al. 5,208,231 A 5, 1993 Kimata et al. 20 Claims, 2 Drawing Sheets US 8,853.205 B2 Page 2 (56) References Cited Cluny N. L.; Vemuri V. K.; Chambers A. P.; Limebeer C. L.; Bedard H.; Wood J. T.; Lutz B.; Zimmer A.; Parker L. A.; Makriyannis A.; OTHER PUBLICATIONS Sharkey K. A. A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does Lange J.H.M. et al. “Bioisosteric replacements of the pyrazole moi not cause malaise, in rodents. BrJ Pharmacol. 2010, 161, (3), 629-42. ety of rimonabant: synthesis, biological properties, and molecular Limebeer C. L.; Vemuri V. K.; Bedard H.; Lang S. T.; Ossenkopp K. modeling investigations of thiazoles, triazoles, and imidazoles as P; Makriyannis A.; Parker L. A. Inverse agonism of cannabinoid CB1 potent and selective CB1 cannabinoid receptor antagonists'. Journal receptors potentiates LiCI-induced nausea in the conditioned gaping of Medicinal Chemistry, American Chemical Society, US, vol. 48, model in rats. Br J Pharmacol. 2010, 161, (2), 336-49. Jan. 1, 2005, 1823-1838. Tam J.; Vemuri V. K. Liu J.; Batkai S.; Mukhopadhyay B.: Jarbe T. U.: Lemay B. J.; Vemuri V. K. Vadivel S. K.; Zvonok A.; Godlewski G.; Osei-Hyiaman D.; Ohnuma S.; Ambudkar S. V.; Makriyannis A. Central mediation and differential blockade by can Pickel J.; Makriyannis A.; Kunos G. Peripheral CB1 cannabinoid nabinergics of the discriminative stimulus effects of the cannabinoid receptor blockade improves cardiometabolic risk in mouse models of CB(1) receptor antagonist rimonabant in rats. Psychopharmacology obesity. J Clin Invest. 2010, 120, (8), 2953-66. (Berl). 2011 DOI 10.1007/s002 13-011-2226-3). Sink K. S.; Segovia K. N.; Collins L. E.; Markus E. J.; Vemuri V. K.; Cluny N. L.; Chambers A. P. Vemuri V. K. Wood J. T.; Eller L. K.; Makriyannis A.; Salamone J. D. The CB1 inverse agonist AM251, but Freni C.; Reimer R. A.; Makriyannis A.; Sharkey K. A. The neutral not the CB1 antagonist AM4113, enhances retention of contextual cannabinoid CB receptor antagonist AM41 13 regulates body weight fear conditioning in rats. Pharmacol Biochem Behav. 2010, 95, (4), through changes in energy intake in the rat. Pharmacol Biochem 479-84. Behav. 2011, 97, (3), 537-43. Sink K. S.; Segovia K. N.; Sink J.; Randall P. A.; Collins L. E.; Correa Randall P. A.; Vemuri V. K.; Segovia K. N.; Torres E. F.; Hosmer S.; M.; Markus E. J.; Vemuri V. K.; Makriyannis A.; Salamone J. D. Nunes E. J.; Santerre J. L.; Makriyannis A. Salamone J. D. The novel Potential anxiogenic effects of cannabinoid CB1 receptor antago cannabinoid CB1 antagonist AM6545 suppresses food intake and nists/inverse agonists in rats: comparisons between AM41 13, food-reinforced behavior. Pharmacol Biochem Behav. 2010, 97. (1), AM251, and the benzodiazepine inverse agonist FG-7142. Eur 179-84. Neuropsychopharmacol. 2010, 20, (2), 112-22. Jarbe T. U.: LeMay B. J.; Olszewska T., Vemuri V. K.; Wood J. T.; Storr M. A.; Bashashati M., Hirota C.; Vemuri V. K.; Keenan C. M.; Makriyannis A. Intrinsic effects of AM41 13, a putative neutral CB1 Duncan M.; Lutz B.; Mackie K.; Makriyannis A.; Macnaughton W. receptor selective antagonist, on open-field behaviors in rats. K.; Sharkey K. A. Differential effects of CB(1) neutral antagonists Pharmacol Biochem Behav. 2008,91, (1), 84-90. and inverse agonists on gastrointestinal motility in mice. Hodge J.; Bow J. P.; Plyler K. S.; Vemuri V. K.; Wisniecki A.; Neurogastroenterol Motil. 2010, 22, (7), 787-96, e223. Salamone J. D.; Makriyannis A.; McLaughlin P. J. The cannabinoid Chambers A. P.; Vemuri V. K.; Peng Y.; Wood J. T.; Olszewska T.; CB1 receptor inverse agonist AM 251 and antagonist AM 4113 Pittman Q. J.; Makriyannis A.; Sharkey K. A.; A neutral CB1 receptor produce similar effects on the behavioral Satiety sequence in rats. antagonist reduces weight gain in rat. Am J Physiol Regul Integr Behav Brain Res. 2008, 193, (2), 298–305. Comp Physiol. 2007, 293, (6), R2185-93. Bergman J.; Delatte M. S.; Paronis C. A.; Vemuri K.; Thakur G. A.; Sink K. S.; McLaughlin P. J.; Wood J. A.; Brown C.; Fan P.; Vemuri Makriyannis A. Some effects of CB1 antagonists with inverse agonist V. K. Peng Y.; Olszewska T.: Thakur G. A.; Makriyannis A.; Parker and neutral biochemical properties. Physiol Behav. 2008, 93, (4-5), L. A.; Salamone J. D. The novel cannabinoid CB1 receptor neutral 666-70. antagonist AM41 13 Suppresses food intake and food-reinforced Sink K. S.; Vemuri V. K. Wood J.; Makriyannis A.; Salamone J. D. behavior but does not induce signs of nausea in rats. Oral bioavailability of the novel cannabinoid CB1 antagonist Neuropsychopharmacology. 2008, 33, (4), 946-55. AM6527: effects on foodreinforced behavior and comparisons with AM4113. Pharmacol Biochem Behav. 2009, 91, (3), 303-6. * cited by examiner U.S. Patent Oct. 7, 2014 Sheet 1 of 2 US 8,853.205 B2 08), 09), UOenus UIOSISIOO % ’61-IVI, O O O O O CN O CO Co CN V v S. uOpen US uO)SIO JO % U.S. Patent Oct. 7, 2014 Sheet 2 of 2 US 8,853,205 B2 22 14. 18 15 -O- vehicle 12 -O-20 mg kg ------ Fig. 2A O 1 2 3 4. 5 24 922 CD S4 18 S S 15 -O- vehicle 12 -O-20 mg kg O 1 2 3 4 5 24 92.21 GD Sa 18 g t 9. 15 -O- vehicle 12 -O-20 mg kg -T-T-I-T- Fig.
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