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(12) United States Patent (10) Patent No.: US 9,156,822 B2 Jin Et Al

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(12) United States Patent (10) Patent No.: US 9,156,822 B2 Jin Et Al US009 156822B2 (12) United States Patent (10) Patent No.: US 9,156,822 B2 Jin et al. (45) Date of Patent: Oct. 13, 2015 (54) FUNCTIONALLY SELECTIVE LIGANDS OF (2013.01); A61K 45/00 (2013.01); C07D DOPAMINED, RECEPTORS 215/20 (2013.01); C07D 217/24 (2013.01); (75) Inventors: Jian Jin, Chapel Hill, NC (US); Bryan C07D 231/56 (2013.01); C07D 235/26 Roth. Durham, NC (US); Stephen Frye, (2013.01); C07D 24I/04 (2013.01); C07D Chapel Hill, NC (US) 277/62 (2013.01); C07D 295/088 (2013.01); (73) Assignee: The University of North Carolina at of 6. 4. ES E. Chapel Hill, Chapel Hill, NC (US) ( .01); ( .01): s s 413/12 (2013.01); C07D 413/14 (2013.01); (*) Notice: Subject to any disclaimer, the term of this C07D 417/12 (2013.01); C07D 471/04 patent is extended or adjusted under 35 (2013.01) U.S.C. 154(b) by 150 days. (58) Field of Classification Search (21) Appl. No.: 13/807,347 CPC. A61 K31/551; C07D 401/02: C07D401/14: C07D 417/14: CO7D 471/04 (86). PCT No.: PCT/US2O11?042734 USPC ........................................... 514/218; 540/575 S371 (c)(1), See application file for complete search history. (2), (4) Date: Feb. 15, 2013 (87) PCT Pub. No.: WO2012/003418 (56) References Cited PCT Pub. Date: Jan. 5, 2012 U.S. PATENT DOCUMENTS (65) Prior Publication Data 5,006,528 A 4, 1991 Oshiro et al. 6,352,981 B1* 3/2002 Treiber et al. ................. 514, 183 US 2013/0137679 A1 May 30, 2013 7,160,888 B2 1/2007 Johnson et al. O O 7,491,726 B2 2/2009 Parthasaradhi et al. Related U.S. Application Data 2006/0223820 A1 10, 2006 Brand et al. (60) Provisional application No. 61/360,951, filed on Jul. 2, 2006/0270683 Al 1 1/2006 Lohray et al. 2010. FOREIGN PATENT DOCUMENTS (51) Int. Cl. WO WO 2005/O19215 A1 3f2005 gll, 25 3. WO WO 2006/090272 A1 8, 2006 ( .01) WO WO 2006/090273 A2 8, 2006 CO7D 40/4 (2006.01) WO WO 2006,103559 A1 10, 2006 CO7D 403/02 (2006.01) WO WO 2008/020306 A2 2, 2008 CO7D 403/4 (2006.01) WO WO 2008/084324 A1 T 2008 C07D 417/02 (2006.01) OTHER PUBLICATIONS CO7D 417/4 (2006.01) CO7D 47L/04 (2006.01) CAPLUS printout of JP 56046812, JP 55162774, JP 55124766, and CO7D 403/2 (2006.01) JP 55127371, 1980.* C07D 215/20 (2006.01) Allen et al., “Discovery of B-Arrestin-Biased Dopamine D. Ligands C07D 21 7/24 (2006.01) for Probing Signal Transduction Pathways Essential for CO7D 23L/56 (2006.01) Antipsychotic Efficacy”, PNAS, vol. 108, No. 45, Nov. 8, 2011, CO7D 235/26 (2006.01) 18488-18493. C07D 277/62 (2006.01) International Preliminary Report on Patentability Corresponding to C07D 295/088 (2006.01) International Application No. PCT/US2011/042734; Date of Mail CO7D 40/12 (2006.01) ing: Jan. 17, 2013; 7 Pages. CO7D 405/2 (2006.01) International Search Report and Written Opinion Corresponding to CO7D 413/2 (2006.01) International Application No. PCT/US2011/042734; Date of Mail C07D 417/12 (2006.01) ing: Mar. 27, 2012; 9 Pages. A6 IK3 L/454 (2006.01) k . A6 IK3I/4725 (2006.01) cited by examiner 3. ife5 3:08: Primary Examiner — Brenda Coleman A6 IK3I/538 (2006.01) (74) Attorney, Agent, or Firm — Myers Bigel Sibley & A6 IK3I/55 (2006.01) Sajovec, P.A. A6 IK 45/00 (2006.01) CO7D 24I/04 (2006.01) (57) ABSTRACT CO7D 405/4 (2006.01) The present invention relates to novel functionally selective CO7D 413/4 (2006.01) ligands of dopamine D receptors, including agonists, (52) U.S. Cl. antagonists, and inverse agonists. The invention further CPC ............ C07D 403/12 (2013.01); A61 K3I/454 relates to the use of these compounds for treating central (2013.01); A61K3I/4725 (2013.01); A61 K nervous system disorders related to D receptors. 3 1/496 (2013.01); A61 K3I/4965 (2013.01): A6 IK3I/538 (2013.01); A61 K3I/55 11 Claims, 2 Drawing Sheets U.S. Patent Oct. 13, 2015 Sheet 2 of 2 US 9,156,822 B2 FIG. 2 A 30 min after drug Vehicle E Aripiprazole C UNC9975 s5- HaloperidolUNCOOO6 9 O: a 5. 9 WT B-ARR2 KO B 60 min after drug O Vehicle Aripiprazole UNC9975 UNCOOO6 | Haloperidol US 9,156,822 B2 1. 2 FUNCTIONALLY SELECTIVE LIGANDS OF Chidiac et al., Mol. Pharmacol. 45:490 (1994); Gilliland and DOPAMINED, RECEPTORS Alper, Naunyn Schmiedebergs Arch. Pharmacol. 361:498 (2000); Rauser et al., J. Pharmacol. Exp. Ther: 299:83 STATEMENT OF PRIORITY (2001)); (3) antagonists can also induce receptor down regu lation (Peroutka and Snyder, Science 210:88 (1980)) and This application is a 35 U.S.C. S371 national phase appli receptor internalization in vitro (Berry et al., Mol. Pharma cation of PCT Application No. PCT/US2011/042734, filed col. 50:306 (1996)) and in vivo (Gray and Roth, Brain Res. Jul. 1, 2011 which claims the benefit of U.S. Provisional Bull. 56:441 (2001); Willins et al., Ann. NY Acad. Sci. 861: Application Ser. No. 61/360,951, filed Jul. 2, 2010, the entire 121 (1998); Willins et al., Neuroscience 91:599 (1999))— contents of each of which is incorporated by reference herein. 10 properties typically associated with agonists. The processes by which agonists and antagonists differen STATEMENT OF GOVERNMENT SUPPORT tially modulate signaling pathways and receptor trafficking have been variously dubbed functional selectivity, biased This invention was made with government Support under agonism or agonist-directed trafficking. Currently, the pre Grant Nos. MHO82441 awarded by the National Institutes of 15 ferred term for the process by which ligands can differentially Health. The government has certain rights in the invention. activate signaling pathways mediated via a single GPCR is functional selectivity (Urban et al., J. Pharmacol. Exp. Ther. FIELD OF THE INVENTION 320:1 (2007)). Functional selectivity has been demonstrated for more than a dozen GPCRs (reviewed in (Urban et al., The present invention relates to novel functionally selec Neuropsychopharmacology 32:67 (2007)) and is, likely, a tive ligands of dopamine D receptors, including agonists, ubiquitous phenomenon. In particular, functional selectivity antagonists, and inverse agonists. The invention further has been widely observed among DA receptor subtypes. relates to the use of these compounds in research and for It is desirable to identify novel, functionally selective treating central nervous system disorders related to D recep ligands of dopamine D receptors to elucidate the key signal tOrS. transduction pathways essential for antipsychotic efficacy 25 and the undesired ones associated with side-effects. Such BACKGROUND OF THE INVENTION compounds would also be useful agents for treating central nervous system (CNS) disorders including Schizophrenia and Classical notions of receptor pharmacology imply that depression. when a ligand interacts with a receptor, only a unitary out come is possible. According to these models of receptor phar 30 macology, a full or partial agonist can activate only a single SUMMARY OF THE INVENTION signal transduction pathway while an antagonist can only The present invention relates to novel, functionally selec block the actions of an agonist. The key theoretical construct tive ligands of dopamine D, receptors. When evaluated in underlying this model was the concept of intrinsic efficacy multiple D binding and functional assays, the compounds of (Furchgott, Advances in Drug Research (Harper N and Sim 35 the invention showed different activity profiles ranging from monds A eds) Academic Press, New York., pp 21-55 (1966)). full agonists to antagonists to inverse agonists. In particular, According to this conceptualization, a full agonist has maxi the compounds of the invention are 3-arrestin biased and, in mum intrinsic efficacy and maximally stimulates all cellular certain embodiments, also are inverse agonists of G-regu responses induced by ligand binding. A partial agonist pos lated pathways. These pharmacologically active compounds sesses a lower degree of intrinsic efficacy and partially acti 40 exhibit fewer side effects and are useful in research to study Vates all cellular responses induced by an agonist. Antago D. receptor function and its role in psychosis and for the nists, according to this schema, are neutral entities which treatment of CNS disorders. possess no intrinsic activity but are able to block the receptor Accordingly, as one aspect, the invention provides a com and preclude activation by full or partial agonists (Furchgott, pound of formula I: Advances in Drug Research (Harper N and Simmonds A eds) Academic Press, New York., pp 21-55 (1966)). An extension 45 of this model has been that a single G-protein coupled recep tor (GPCR) interacts with a single G protein subtype (e.g., Gi. Gs, Gq, Go and so on) and that full and partial agonists activate only a single transduction pathway. For many decades, however, it has been clear that these 50 simplistic notions of GPCR (also known as 7-transmembrane receptor or 7-TM) function cannot account for the myriad of actions induced by agonist or antagonist binding. This was first convincingly demonstrated for the serotonin (5-hydrox ytryptamine; 5-HT) and dopamine (DA) families of receptors wherein m is 0 or 1; where it has been demonstrated that: (1) agonists differen 55 n is 0, 1, or 2: tially activate distinct signal transduction pathways (Beaulieu q is 1 or 2; et al., J. Neurosci. 27:881 (2007); Berget al., Mol. Pharma X is O, NH, or CH: col. 54:94 (1998); Ghoshet al., J. Med. Chem. 39:549 (1996): Y is N or CH: Kilts et al., J.
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