USOO9428506B2 (12) United States Patent (10) Patent No.: US 9.428,506 B2 Mates et al. (45) Date of Patent: Aug. 30, 2016 (54) SUBSTITUTED (56) References Cited PYRIDO3',4':45PYRROLO1,2,3-DE) QUINOXALINES FOR THE TREATMENT OF U.S. PATENT DOCUMENTS NERVOUS SYSTEM DSORDERS 4,001,263. A 1, 1977 Plattner 4.389,330 A 6, 1983 Tice et al. (71) Applicant: INTRA-CELLULAR THERAPIES, 4,530,840 A 7, 1985 Tice INC., New York, NY (US) 5,538,739 A 7/1996 Bodmer 6,548.493 B1 4/2003 Robichaud 6,552,017 B1 4/2003 Robichaud (72) Inventors: Sharon Mates, New York, NY (US); 6,713,471 B1 3/2004 Robichaud Robert Davis, New York, NY (US); 7,081.455 B2 7/2006 Robichaud Peng Li, New York, NY (US); 7,183,282 B2 2/2007 Robichaud Lawrence Wennogle, New York, NY RE39,679 E 6/2007 Robichaud (US); Kimberly Vanover, New York, RE39,680 E 6/2007 Robichaud 7,238,690 B2 7/2007 Robichaud NY (US) 8,309,722 B2 11/2012 Tomesch (73) Assignee: INTRA-CELLULAR THERAPIES, (Continued) INC., New York, NY (US) FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 EP 00584.81 8, 1982 U.S.C. 154(b) by 0 days. EP 0976732 A1 2, 2000 (Continued) (21) Appl. No.: 14/394,467 OTHER PUBLICATIONS U.S. Appl. No. 14/627,968, filed Feb. 20, 2015, Mates. (22) PCT Fed: Apr. 14, 2013 International Preliminary Report on Patentability for International Application No. PCT/US2013/036514 issued Oct. 14, 2014. (86) PCT No.: PCT/US2O13/036514 Written Opinion of the International Searching Authority for Inter national Application No. PCT/US2013/036514 mailed Aug. 16, S 371 (c)(1), 2013. (2) Date: Oct. 14, 2014 U.S. Appl. No. 61/975,502, filed Apr. 4, 2014, Mates et al. U.S. Appl. No. 61/975,610, filed Apr. 4, 2014, Mates et al. (87) PCT Pub. No.: WO2O13A1SSSOS U.S. Appl. No. 62/009,849, filed Jun. 9, 2014, Davis et al. U.S. Appl. No. 62/015, 120, filed Jun. 20, 2014, Mates et al. PCT Pub. Date: Oct. 17, 2013 Bryan-Lluka, L. J. et al., “Potencies of haloperidol metabolites as inhibitors of the human noradrenaline, dopamine and serotonin (65) Prior Publication Data transporters in transfected COS-7 cells', Naunyn-Shemiedeberg's US 2015/OO79172 A1 Mar. 19, 2015 Arch Pharmacol, 1999, vol. 360, pp. 109-115. (Continued) Related U.S. Application Data Primary Examiner — Douglas M. Willis (60) Provisional application No. 61/671,713, filed on Jul. (74) Attorney, Agent, or Firm — Hoxie & Associates LLC 14, 2012, provisional application No. 61/624.293, (57) ABSTRACT filed on Apr. 14, 2012, provisional application No. The invention relates to particular substituted heterocycle 61/624.291, filed on Apr. 14, 2012, provisional fused gamma-carbolines, of Formula I, in free, Solid, phar application No. 61/624.292, filed on Apr. 14, 2012, maceutically acceptable salt and/or Substantially pure form provisional application No. 61/671,723, filed on Jul. as described herein, pharmaceutical compositions thereof, 14, 2012. and methods of use in the treatment of diseases involving 5-HT, receptor, serotonin transporter (SERT) and/or path (51) Int. C. ways involving dopamine D receptor signaling systems. A6 IK 3/4985 (2006.01) Such as disease of the central nervous system. CO7D 24I/38 (2006.01) CO7D 47L/4 (2006.01) A6 IK 45/06 (2006.01) Formula I A6 IK3I/5383 (2006.01) CO7D 47L/6 (2006.01) F A6 IK 3/445 (2006.01) (52) U.S. C. CPC ........... C07D 471/14 (2013.01); A61K 31/445 (2013.01); A61 K3I/4985 (2013.01); A61 K R2 RI 3 1/5383 (2013.01); A61K 45/06 (2013.01); C07D 471/16 (2013.01) H (58) Field of Classification Search X CPC ......................... A61K 31/4985; C07D 241/38 USPC ........................................... 514/250; 544/343 See application file for complete search history. 30 Claims, No Drawings US 9,428,506 B2 Page 2 (56) References Cited WO WO 2009, 145900 12/2009 WO WO 2011, 133224 10, 2011 U.S. PATENT DOCUMENTS WO WO 2013,155504 10, 2013 WO WO 2013,155.505 10, 2013 8,598,119 B2 12/2013 Mates WO WO 2013,155506 10, 2013 8,648,077 B2 2, 2014 Tomesch WO WO 2014f145.192 9, 2014 8,779,139 B2 T/2014 Tomesch WO WO 2015,085.004 6, 2015 8,993,572 B2 3/2015 Mates 2004/0092534 A1 5, 2004 Yam et al. OTHER PUBLICATIONS 2004/O142970 A1 T/2004 Chung Foster, "Acetylcholinesterase inhibitors reduce spreading activation 2004/0180875 A1 9, 2004 Lee et al. in dementia,” Neuropsychologia, 2012, 50, 2093-2099. 2004/022O178 A1 11, 2004 Robichaud et al. Hackman, JAMA 2006, 296(14), 1731-1732. 2008, OO69885 A1 3, 2008 Mesens et al. Harbert, C.A. et al., “Neuroleptic Activity in 5-Aryltetrahydro-y- 2008/O132552 A1 6, 2008 Kleinman carbolines”. J. Med. Chem., 1980, vol. 23, pp. 635-643. 2008/0280941 A1 11, 2008 Lourtie Harvey, "Serotonin and Stress: Protective or Malevolent Actions in 2009/0202631 A1 8, 2009 Yam the Biobehavioral Response to Repeated Trauma?' Annals of the 2010, O298382 A1 11, 2010 Seeman New York Academy of Sciences, 1032: 267-272 (2004) doi: 2011 0071080 A1 3, 2011 Mates 10.1196, annals. 1314.035. 2011/0112105 A1 5, 2011 Tomesch Jordan, V.C. Nature Reviews. Drug Discovery, 2003, 2:205. 2014/0050783 A1 2, 2014 Mates Khorana, et al., “Gamma-Carbolines: Binding at 5-HT5A Serotonin 2014/0323491 A1 10, 2014 Tomesch Receptors'. Bioorganic & Medicinal Chemistry, (2003), vol. 11, 2014/0364609 A1 12, 2014 Tomesch Issue 5, 6, pp. 717-722, p. 718 Table 1. 2015.OO72964 A1 3/2015 Mates et al. Lebert, “Trazodone in Fronto-Temporal Dementia'. Research and 2015.OO79172 A1 3/2015 Mates et al. Practice in Alzheimer's Disease, 2006, vol. 11, 356-360. 2015, 0080404 A1 3/2015 Mates et al. Lee, “Novel, highly potent, selective 5-HT2A/D2 receptor antago nists as potential atypical antipsychotics.” Bioorganic & Medicinal FOREIGN PATENT DOCUMENTS Chemistry Letters, 2003, vol. 13, Issue 4, pp. 767-770. Lounkine, “Formal Concept Analysis for the Identification of EP 1539115 6, 2005 Molecular Fragment Combinations Specific for Active and Highly GB 1476087 6, 1977 Potent Compounds,” J. Med. Chem., 2008, 51 (17), 5342-5348. GB 2145422 3, 1985 WO WO 94,241.25 10, 1994 March, Advanced Organic Chemistry, Reactions, Mechanisms and WO WO95/13814 5, 1995 Structures, Fourth Edition, pp. 910-911 (1992). WO WO 98.43956 10, 1998 Pond, S.M. et al. “Stereospecific reduction of haloperidol in human WO WOOO,35419 6, 2000 tissues'. Biochemical Pharmacology, vol. 44 (5), p. 867-871 WO WOOO,770O2 A1 12, 2000 (1992). WO WOOOf 77010 12/2000 Weschules, "Acetylcholinesterase Inhibitor and N-Methyl-D- WO WO 2004/O10981 2, 2004 Aspartic Acid Receptor Antagonist Use among Hospice Enrollees WO WO 2008, 112280 9, 2008 with a Primary Diagnosis of Dementia'. Journal of Palliative WO WO 2009/114181 9, 2009 Medicine, 2008, vol. 11, No. 5, 738-745. US 9,428,506 B2 1. 2 SUBSTITUTED out affecting or minimally affecting dopamine D receptors, PYRIDO3',4':45PYRROLO1,2,3-DE) thereby useful for the treatment of sleep disorders without QUINOXALINES FOR THE TREATMENT OF the side effects of the dopamine D pathways or side effects of other pathways (e.g., GABA receptors) associated with NERVOUS SYSTEM DSORDERS convention sedative-hypnotic agents (e.g., benzodiazepines) including but not limited to the development of drug depen CROSS REFERENCE TO RELATED dency, muscle hypotonia, weakness, headache, blurred APPLICATIONS vision, Vertigo, nausea, vomiting, epigastric distress, diar rhea, joint pains, and chest pains. This application is a national phase application filed under WO 2009/114181 discloses methods of preparing tolu 35 U.S.C. S371 of International Application No. PCT/ 10 enesulfonic acid addition salt crystals of particular Substi US2013/036514, filed on Apr. 14, 2013, which International tuted heterocycle fused gamma-carbolines, e.g., toluenesul Application claims priority from U.S. Provisional Applica fonic acid addition salt of 4-((6bR.10aS)-3-methyl-2,3,6b, tion Nos. 61/624,293, 61/624,292 and 61/624,291, all filed 9,10,10a-hexahydro-1H-pyrido3',4':45pyrrolo 1,2,3-de on Apr. 14, 2012; and U.S. Provisional Application Nos. quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone. 61/671,723 and 61/671,713, both filed on Jul 14, 2012, the 15 WO 2011/133224 discloses prodrugs/metabolites of sub contents of each of which are incorporated by reference in stituted heterocycle fused gamma-carboline for improved their entirety. formulation, e.g., extended/controlled release formulation. This application discloses that heterocycle fused gamma FIELD OF THE INVENTION carboline N-substituted with a 4-fluorophenyl(4-hydroxy) butanyl moiety are shown to have high selectivity for the The invention relates to particular substituted heterocycle serotonin transporter (SERT) relative to the heterocycle fused gamma-carbolines, in free, pharmaceutically accept fused gamma-carboline containing 4-fluorophenylbutanone. able salt and/or substantially pure form as described herein, The hydroxy group on these compounds, however, is inter pharmaceutical compositions thereof, and methods of use in converted to and from the ketone within the plasma and the the treatment of diseases involving 5-HT, receptor, sero 25 brain, allowing it to serve as a reservoir for the 4-fluoro tonin transporter (SERT) and/or pathways involving dop phenylbutanone drug. For the first time, the current invention provides com amine D receptor signaling systems, e.g., diseases or dis pounds which block the in vivo inter-conversion between orders such as anxiety, psychosis, Schizophrenia, sleep the hydroxy and the ketone, yielding compounds which disorders, sexual disorders, migraine, conditions associated antagonize 5-HT2A receptors and also inhibit serotonin with cephalic pain, social phobias, gastrointestinal disorders 30 re-uptake transporter.