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 metabolites as inhibitors of the human noradrenaline, and (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, “ 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 .” 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 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 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 - agents (e.g., ) 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. Such as dysfunction of the gastrointestinal tract motility and obesity; depression and mood disorders associated with SUMMARY OF THE INVENTION psychosis or Parkinson's disease; psychosis such as Schizo phrenia associated with depression; bipolar disorder; and In the first aspect, the invention provides a compound of other psychiatric and neurological conditions, as well as to 35 formula I: combinations with other agents.

BACKGROUND OF THE INVENTION Formula I F Substituted heterocycle fused gamma-carbolines are 40 known to be agonists or antagonists of 5-HT2 receptors, particularly 5-HT, and 5-HT, receptors, in treating central nervous system disorders. These compounds have been disclosed in U.S. Pat. Nos. 6,548,493; 7.238,690; 6,552,017; 6,713,471; 7,183,282: U.S. RE39680, and U.S. RE39679, as 45 novel compounds useful for the treatment of disorders associated with 5-HT, receptor modulation such as obesity, anxiety, depression, psychosis, Schizophrenia, sleep disor ders, sexual disorders migraine, conditions associated with cephalic pain, social phobias, gastrointestinal disorders such 50 wherein: X is N(H), N(Calkyl) or O: as dysfunction of the gastrointestinal tract motility, and R" is H or Calkyl (e.g., methyl); obesity. R’ is Hor OR wherein R is Hor C-alkyl (e.g., methyl); PCT/US08/03340 (WO 2008/112280) and U.S. applica provided that R' and Rare not both H, and R' and Rare tion Ser. No. 10/786,935 disclose methods of making sub not both H; in free or salt form. stituted heterocycle fused gamma-carbolines and uses of 55 In a further embodiment, the invention provides the these gamma-carbolines as serotonin agonists and antago Compound of Formula I, in free or salt form as described in nists useful for the control and prevention of central nervous the following formulae: system disorders such as addictive behavior and sleep dis 1.1 the compound of Formula I, wherein R is OR; orders. 1.2 the compound of Formula I or 1.1, wherein R' is WO/2009/145900 discloses use of particular substituted 60 Coalkyl (e.g., methyl); heterocycle fused gamma-carbolines for the treatment of a 1.3 the compound of Formula I, 1.1 or 1.2, wherein R is combination of psychosis and depressive disorders as well methyl; as sleep, depressive and/or mood disorders in patients with 1.4 the compound of Formula I or any of formulae psychosis or Parkinson's disease. In addition to disorders 1.1-1.3, wherein R is OR and R is Calkyl (e.g., associated with psychosis and/or depression, this patent 65 methyl); application discloses and claims use of these compounds at 1.5 the compound of Formula I or any of formulae a low dose to selectively antagonize 5-HT2 receptors with 1.1-1.4, wherein R is OR and R is methyl: US 9,428,506 B2 3 4 1.6 the compound of Formula I or any of formulae 1.1-1.5, any of 1.1-1.14 or 4.1-4.4 (the Compounds of the Invention), wherein X is N(H), N(Calkyl) or O; in free orpharmaceutically acceptable salt form, in admixture 1.7 the compound of Formula I or any of formulae 1.1-1.6, with a pharmaceutically acceptable diluent or carrier. wherein X is O: In a further embodiment of the second aspect, the Pharma 1.8 the compound of Formula I or any of formulae 1.1-1.6, 5 ceutical Composition of the Invention is for a Sustained or wherein X is N(H): delayed release, e.g., depot, formulation. In one embodiment, 1.9 the compound of Formula I or any of formulae 1.1-1.6, the depot formulation comprises the Compounds of the wherein X is N(Calkyl: Invention in a polymeric matrix. In another embodiment, the 1.10 the compound of Formula I or any of formulae 1.1- Compounds of the Invention are dispersed or dissolved 1.6, wherein X is N(CH): 10 within the polymeric matrix. In a further embodiment, the 1.11 the Compound of Formula I or any of formulae 1.1- polymeric matrix comprises standard polymers used in depot 1.10, wherein the Compound is: formulations such as polymers selected from a polyester of a hydroxyfatty acid and derivatives thereof, or a polymer of an alkyl alpha-cyanoacrylate, a polyalkylene oxalate, a poly F 15 ortho ester, a polycarbonate, a polyortho-carbonate, a polyamino acid, a hyaluronic acid ester, and mixtures thereof. H In a further embodiment, the polymeris selected from a group N consisting of polylactide, poly d.l-lactide, poly glycolide, PLGA 50:50, PLGA 85:15 and PLGA 90:10 polymer. In N -O 2O another embodiment, the polymer is selected from poly(gly H colic acid), poly-D.L-lactic acid, poly-L-lactic acid, copoly mers of the foregoing, poly(aliphatic carboxylic acids), --- copolyoxalates, polycaprolactone, polydioxonone, poly (ortho carbonates), poly(acetals), poly(lactic acid-caprolac 1.12 the Compound of Formula I or any of 1.1-1.11, 25 tone), polyorthoesters, poly(glycolic acid-caprolactone), wherein the Compound is: polyanhydrides, and natural polymers including albumin, casein, and waxes, such as, glycerol mono- and distearate, and the like. In a particular embodiment, the polymeric matrix F comprises poly(d.1-lactide-co-glycolide). Any of the Compo sitions hereinbefore described may be a pharmaceutical com H position wherein said composition is in admixture with a N pharmaceutically acceptable diluent or carrier. The (Pharmaceutical) depot formulations as hereinbefore OH described are particularly useful for sustained or delayed N release, wherein the Compounds of the Invention are released upon degradation of the polymeric matrix. These Composi 1N su!" tions may be formulated for controlled- and/or sustained release of the Compounds of the Invention (e.g., as a depot 1.13 the Compound of Formula I or any of 1.11-1.12, composition) over a period of up to 180 days, e.g., from about wherein the Compound is in Substantially pure diaste- 40 14 to about 30 to about 180 days. For example, the polymeric reomeric form (i.e., substantially free from other diaste matrix may degrade and release the Compounds of the Inven reomers); tion over a period of about 30, about 60 or about 90 days. In 1.14 the Compound of Formula I or any of 1.1-1.13. another example, the polymeric matrix may degrade and wherein the Compound has a diasteromeric excess of release the Compounds of the Invention over a period of about greater than 70%, preferably greater than 80%, more 45 120, or about 180 days. preferably greater than 90% and most preferably greater In still another further embodiment, the Pharmaceutical than 95%; in free or salt form. Compositions of the Invention, particularly the depot com In a further embodiment of the first aspect, the invention positions of the Invention are formulated for administration provides a compound of Formula I, in free or salt form as by injection. described in the following formulae: 50 In the third aspect, the invention provides the Compounds 4.1 the Compound of Formula I or any of 1.1-1. 14, wherein of the Invention as hereinbefore described in an osmotic the salt is selected from a group consisting of hydrochlo controlled release oral delivery system (OROS), which is ric, hydrobromic, Sulfuric, Sulfamic, phosphoric, nitric, described in WO 2000/35419 and EP 1539 115 (U.S. Pub. acetic, propionic, succinic, glycolic, Stearic, lactic, No. 2009/0202631), the contents of each of which applica malic, tartaric, citric, ascorbic, pamoic, maleic, 55 tions are incorporated by reference in their entirety. Therefore hydroxymaleic, phenylacetic, glutamic, benzoic, Sali in one embodiment of the third aspect, the invention provides cylic, Sulfanilic, 2-acetoxybenzoic, fumaric, a pharmaceutical composition or device comprising (a) a Sulfonic, methanesulfonic, ethane disulfonic, oxalic, gelatin capsule containing a Compound of the Invention in isethionic, and the like; free or pharmaceutically acceptable salt form or a Pharma 4.2 the Compound of Formula I or formula 4.1, wherein the 60 ceutical Composition of the Invention, as hereinbefore salt is fumaric acid addition salt; described; (b) a multilayer wall Superposed on the gelatin 4.3 the Compound of Formula I or formula 4.1, wherein the capsule comprising, in outward order from the capsule: (i) a salt is phosphoric acid addition salt; barrier layer, (ii) an expandable layer, and (iii) a semiperme 4.4 the Compound of Formula I or formula 4.1, wherein the able layer; and (c) and orifice formed or formable through the salt is a toluenesulfonic acid addition salt; 65 wall. (Composition P.1) In the second aspect, the invention provides a pharmaceu In another embodiment of the third aspect, the invention tical composition comprising the compound of formula I, or provides a composition comprising a gelatin capsule contain US 9,428,506 B2 5 6 ing a liquid, the Compounds of the Invention in free or phar referred to as the second drug layer contains higher amounts maceutically acceptable salt form or a Pharmaceutical Com of drug, excipients and no salt; and the third layer referred to position of the Invention as hereinbefore described, the as the push layer contains osmotic agents and no drug. At least gelatin capsule being Surrounded by a composite wall com one orifice is drilled through the membrane on the first drug prising a barrier layer contacting the external Surface of the layer end of the capsule-shaped tablet. (Composition P.6) gelatin capsule, an expandable layer contacting the barrier Composition P5 or P.6 may comprise a membrane defining layer, a semi-permeable layer encompassing the expandable a compartment, the membrane Surrounding an inner protec layer, and an exit orifice formed or formable in the wall. tive subcoat, at least one exit orifice formed or formable (Composition P2) therein and at least a portion of the membrane being semi In still another embodiment of the third aspect, the inven 10 permeable; an expandable layer located within the compart tion provides a composition comprising a gelatin capsule ment remote from the exit orifice and in fluid communication containing a liquid, the Compound of the Invention in free or with the semi-permeable portion of the membrane; a first pharmaceutically acceptable salt form or a Pharmaceutical drug layer located adjacent the exit orifice; and a second drug Composition of the Invention as hereinbefore described, the layer located within the compartment between the first drug gelatin capsule being Surrounded by a composite wall com 15 layer and the expandable layer, the drug layers comprising the prising a barrier layer contacting the external Surface of the Compound of the Invention in free or pharmaceutically gelatin capsule, an expandable layer contacting the barrier acceptable salt thereof. Depending upon the relative viscosity layer, a semipermeable layer encompassing the expandable of the first drug layer and second drug layer, different release layer, and an exit orifice formed or formable in the wall, profiles are obtained. It is imperative to identify the optimum wherein the barrier layerforms a seal between the expandable Viscosity for each layer. In the present invention, Viscosity is layer and the environment at the exit orifice. (Composition modulated by addition of salt, sodium chloride. The delivery P3) profile from the core is dependent on the weight, formulation In still another embodiment of the third aspect, the inven and thickness of each of the drug layers. (Composition P.7) tion provides a composition comprising a gelatin capsule In a particular embodiment, the invention provides Com containing a liquid, the Compound of the Invention in free or 25 position P7 wherein the first drug layer comprising salt and pharmaceutically acceptable salt form or a Pharmaceutical the second drug layer containing no salt. Composition P.5-P7 Composition of the Invention as hereinbefore described, the may optionally comprise a flow-promoting layer between the gelatin capsule being Surrounded by a barrier layer contacting membrane and the drug layers. Compositions P1-P7 will the external Surface of the gelatin capsule, an expandable generally be referred to as Osmotic-controlled Release Oral layer contacting a portion of the barrier layer, a semi-perme 30 delivery System Composition. able layer encompassing at least the expandable layer, and an In the fourth aspect, the invention provides a method exit orifice formed or formable in the dosage form extending (Method I) for the treatment or prophylaxis of a central ner from the external surface of the gelatin capsule to the envi Vous system disorder, comprising administering to a patient ronment of use. (Composition P.4). The expandable layer in need thereof, a Compound of Formula I or any of formulae may be formed in one or more discrete sections, such as for 35 1.1-1.14, in free or pharmaceutically acceptable salt form as example, two sections located on opposing sides or ends of described in any of 4.1-4.4, or a pharmaceutical composition the gelatin capsule. as hereinbefore described. In a particular embodiment of the third aspect, the Com In a further embodiment of the fourth aspect, the invention pound of the Inventions in the Osmotic-controlled Release provides Method I wherein the method is further as described Oral delivery System (i.e., in Composition P1-P4) are in a 40 in the following formulae: liquid formulation, which formulation may be neat, liquid 7.1 Method I, wherein the central nervous system disorder active agent, liquid active agent in a solution, Suspension, is one or more disorders associated with dementia, e.g., emulsion or self-emulsifying composition or the like. disorders associated with mild cognition impairment Further information on Osmotic-controlled Release Oral and dementing illnesses including senile dementia, delivery System composition including characteristics of the 45 Alzheimer's disease, Pick's disease, frontotemporal gelatin capsule, barrier layer, an expandable layer, a semi dementia, parasupranculear palsy, dementia with Lewy permeable layer; and orifice may be found in WO 2000/ bodies, vascular dementia, Huntington's disease, Par 35419, the contents of which are incorporated by reference in kinson's disease, multiple Sclerosis, amyotrophic lateral their entirety. Other Osmotic-controlled Release Oral deliv sclerosis, Down syndrome, elderly depression, Wer ery System for the Compound or the Pharmaceutical Com 50 nicke-Korsakoffs syndrome, corticobasal degenerations position of the Invention may be found in EP 1539 115 (U.S. and prion disease; Pub. No. 2009/0202631), the contents of which are incorpo 7.2 Method I or 7.1, wherein the disorders associated with rated by reference in their entirety. dementia is selected from the group consisting of (1) Therefore, in another embodiment of the third aspect, the behavioral or mood disorders such as agitation/irrita invention provides a composition or device comprising (a) 55 tion, aggressive/assaultive behavior, anger, physical or two or more layers, said two or more layers comprising a first emotional outbursts; (2) psychosis; (3) depression; and layer and a second layer, said first layer comprises the Com (4) sleep disorders; pound of the Invention, in free or pharmaceutically accept 7.3 Method I or 7.1, wherein the central nervous system able salt form, or a Pharmaceutical Composition as herein disorder is agitation/irritation, aggressive/assaultive before described said second layer comprises a polymer; (b) 60 behavior, anger, physical or emotional outbursts; an outer wall Surrounding said two or more layers; and (c) an 7.4 Method I, wherein the central nervous system disorder orifice in said outer wall. (Composition P.5) is a disorder selected from a group consisting of obesity, Composition P.5 preferably utilizes a semi-permeable anxiety, depression (for example refractory depression membrane Surrounding a three-layer-core: in these embodi and MDD), psychosis, Schizophrenia, sleep disorders ments the first layer is referred to as a first drug layer and 65 (particularly sleep disorders associated with Schizophre contains low amounts of drug (e.g., the Compounds of the nia and other psychiatric and neurological diseases), Invention) and an osmotic agent Such as salt, the middle layer sexual disorders, migraine, conditions associated with US 9,428,506 B2 7 8 cephalic pain, Social phobias, agitation in dementia mg/day, e.g., 10 mg/day, 20 mg/day, greater 20 mg/day, (e.g., agitation in Alzheimer's disease), agitation in e.g., 30 mg/day, 40 mg/day; autism and related autistic disorders, and gastrointesti 7.18 Any of the foregoing methods wherein a condition to nal disorders such as dysfunction of the gastrointestinal be treated is dyskinesia, e.g. in a patient receiving tract motility; dopaminergic medications, e.g., medications selected 7.5 Method I or any of 7.1-7.4, wherein the central nervous from levodopa and levodopa adjuncts (carbidopa, system disorder is a disorder involving serotonin COMT inhibitors, MAO-B inhibitors), dopamine ago 5-HT, dopamine D2 receptor system and/or serotonin nists, and anticholinergics, e.g., levodopa; reuptake transporter (SERT) pathways as similarly 7.19 Any of the foregoing methods wherein the patient 10 suffers from Parkinson's disease. described in WO/2009/145900, the contents of which 7.20 Any of the foregoing methods wherein the patient are herein incorporated by reference in their entirety: does not respond to a selective serotonin re-uptake 7.6 Method I or any of Formulae 7.1-7.5, wherein the inhibitor, e.g. selected from one or more of citalopram central nervous system disorder is a disorder involving (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, serotonin reuptake transporter (SERT) pathways; 15 Sepram, Seropram, Citox, Cital); dapoxetine (Priligy); 7.7 Method I or any of Formulae 7.1-7.6, wherein the escitalopram (Lexapro, Cipralex, Seroplex, Esertia); central nervous system disorder is a disorder selected (Depex, Prozac, Fontex, Seromex, Seronil, from the following: (i) psychosis, e.g., Schizophrenia, in Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), a patient Suffering from depression; (2) depression in a Fluox (NZ), Depress (UZB), Lovan (AUS), Prodep patient Suffering from psychosis, e.g., Schizophrenia; (3) (IND)); fluvoxamine (Luvox, Fevarin, Faverin, Dumy mood disorders associated with psychosis, e.g., Schizo rox, Favoxil, Movox); indalpine (Upstene); paroxetine phrenia or Parkinson's disease; and (4) sleep disorders (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Divarius, associated with psychosis, e.g., Schizophrenia or Parkin Rexetin, Xetanor, Paroxat, Loxamine, Deparoc); Sertra Son's disease; (5) depression; (6) anxiety; (7) post-trau line (Zoloft, Lustral, Serlain, Asentra); (Vii matic stress disorder; or (8) impulse control disorder, 25 bryd); or Zimelidine (Zelmid, Normud). e.g., intermittent explosive disorder, 7.21 Any of the foregoing methods wherein the patients is 7.8 Method I or any of Formulae 7.1-7.7, wherein the also receiving a selective serotonin re-uptake inhibitor, central nervous system disorder is psychosis, e.g., e.g. selected from one or more of citalopram (Celexa, Schizophrenia and said patient is a patient Suffering from Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, depression; 30 Seropram, Citox, Cital); dapoxetine (Priligy); escitalo 7.9 Method I or any of Formulae 7.1-7.8, wherein said pram (Lexapro, Cipralex, Seroplex, Esertia); fluoxetine patient is unable to tolerate the side effects of convention (Depex, Prozac, Fontex, Seromex, Seronil, Sarafem, drugs, e.g., , haloperidol Ladose, Motivest, Flutop, Fluctin (EUR), Fluox (NZ), , , , moli Depress (UZB), Lovan (AUS), Prodep (IND)); fluvox done, , , pro 35 amine (Luvox, Fevarin, Faverin, Dumyrox. Favoxil, mazine, , thiothixene, , Movox); indalpine (Upstene); paroxetine (Paxil, , aripiparazole, , , ris Seroxat, Sereupin, Aropax, Deroxat, Divarius, Rexetin, peridone and ; Xetanor, Paroxat, Loxamine, Deparoc); Sertraline 7.10 Method I or any of Formulae 7.1-7.9, wherein said (Zoloft, Lustral, Serlain, Asentra); Vilazodone (Vii patient is unable to tolerate the side effects of convention 40 bryd); or Zimelidine (Zelmid, Normud). antipsychotic drugs, e.g., haloperidol, aripiparazole, 7.22 Any of the foregoing methods wherein the patients is clozapine, olanzapine, quetiapine, , and Suffering from autistic spectrum disorder, e.g., autism or Zipasidone; Asperger Syndrome. 7.11 Method I or any of Formulae 7.1-7.10, wherein said 7.23 Any of the foregoing methods wherein the patients is disorder is depression and said patient is a patient Suf 45 Suffering from dementia, e.g., disorders associated with fering from psychosis, e.g., Schizophrenia, or Parkin mild cognition impairment and dementing illnesses Son's disease; including senile dementia, Alzheimer's disease, Pick's 7.12 Method I or any of Formulae 7.1-7.6, wherein said disease, frontotemporal dementia, parasupranculear disorder is sleep disorder and said patient is suffering palsy, dementia with Lewy bodies, vascular dementia, from depression; 50 Huntington's disease, Parkinson's disease, multiple 7.13 Method I or any of 7.1-7.6, wherein said one or more Sclerosis, amyotrophic lateral sclerosis, Down syn disorders is sleep disorder and said patient is suffering drome, elderly depression, Wernicke-Korsakoffs syn from psychosis, e.g., Schizophrenia; drome, corticobasal degenerations and prion disease. 7.14 Method I or any of 7.1-7.6, wherein said one or more 7.24 Any of the foregoing methods wherein the patient is disorders is sleep disorder and said patient is suffering 55 also receiving a cholinesterase inhibitor (e.g., acetylcho from Parkinson's disease; linesterase inhibitor) or an N-Methyl D-Asparate 7.15 Method I or any of 7.1-7.6, wherein said one or more (NMDA) receptor antagonist, in free or pharmaceuti disorders is sleep disorder and said patient is suffering cally acceptable salt form. from depression and psychosis, e.g., Schizophrenia, or 7.25 Method 7.24, wherein the cholinesterase inhibitor Parkinson's disease. 60 (e.g., acetylcholinesterase inhibitor) is selected from the 7.16. Any of the foregoing methods, wherein the effective group consisting of Tacrine, rivastigmine (Exelon), amount is 1 mg-1000 mg, preferably 2.5 mg-50 mg, still donepezil (Aricept), and galantamine (Razadyne, for preferably 1-40 mg, e.g., 1-10 mg, e.g., 10 mg, 20 mg. merly called Reminyl)) in free or pharmaceutically greater 20 mg, e.g., 30 mg. 40 mg: acceptable salt form. 7.17 Any of the foregoing methods, wherein the effective 65 7.26 Method 7.24, wherein the cholinesterase inhibitor amount is 1 mg-100 mg per day, preferably 2.5 mg-50 (e.g., acetylcholinesterase inhibitor) is donepezil in free mg per day, still preferably 1-40 mg/day, e.g., 1-10 or pharmaceutically acceptable salt form. US 9,428,506 B2 10 7.27 Method 7.24, wherein the NMDA receptor antagonist invention provides Method II, wherein the disorder is agita is in free orpharmaceutically acceptable salt tion, aggressive behaviors, post-traumatic stress disorder and/ form. or impulse control disorder, e.g., intermittent explosive dis In a particular embodiment of the fourth aspect, the inven order. tion provides a method (Method I) for the treatment or In a further embodiment of the fifth aspect, the invention prophylaxis of a central nervous system disorder as herein provides Method II, 8.1-8.3, wherein the sleep disorder before described, comprising administering to a patient in includes sleep maintenance , frequent awakenings, need thereof: and waking up feeling unrefreshed; 7.4P a compound of Formula I or any of formulae 1.1-1. 14, 8.11 Any of the foregoing methods, wherein the sleep in free or (pharmaceutically acceptable) salt form as 10 disorder is sleep maintenance insomnia; described in any of 4.1-4.4: 8.12 Any of the foregoing methods, wherein the effective 7.8P a Pharmaceutical or Depot Composition as hereinbe amount is 1 mg-10 mg per day, e.g., 1 mg-5 mg, prefer fore described; or ably 2.5-5 mg, per day, still preferably 10 mg per day; 7.11P Osmotic-controlled Release Oral delivery System 8.13 Any of the foregoing methods, wherein the effective Composition as hereinbefore described. 15 amount is 2.5 mg or 5 mg, per day or 10 mg per day; In a further embodiment of the fourth aspect, the invention 8.14 Any of the foregoing methods wherein the sleep dis provides Method I, wherein the method is further described order is in a patient Suffering from or at risk of dyskine in any one of formulae 7.1-7.27. sia, e.g., a patient receiving dopaminergic medications, In a particular embodiment of the fourth aspect, the inven e.g., selected from levodopa and levodopa adjuncts (car tion provides Method I or any of 7.1-7.27, wherein the disor bidopa, COMT inhibitors, MAO-B inhibitors), dopam der is schizophrenia or sleep disorder. ine agonists, and anticholinergics, e.g., receiving In a particular embodiment of the fourth aspect, the inven levodopa; tion provides Method I or any of 7.1-7.27, wherein the disor 8.15 Any of the foregoing methods wherein the patient der is depression or anxiety. suffers from Parkinson's disease. In a particular embodiment of the fourth aspect, the inven 25 The Compounds of Invention provide effective treatment tion provides Method I or any of 7.1-7.27, wherein the disor of 5-HT, SERT and/or D receptor related disorders with der is post-traumatic stress disorder or an impulse control out or with minimal extrapyramidal side effects as similarly disorder, e.g., intermittent explosive disorder. disclosed and claimed in WO 2009/145900, the contents of In a particular embodiment of the fourth aspect, the inven which are incorporated by reference in their entirety. There tion provides Method I or any of 7.1-7.27, wherein the disor 30 fore, the Compounds of the Invention, the Pharmaceutical der is post-traumatic stress disorder or an impulse control Compositions of the Invention or the Depot Compositions of disorder, e.g., intermittent explosive disorder in a patient suf the Invention may be used in combination with a second fering from dementia, e.g., senile dementia, Alzheimer's dis therapeutic agent, particularly at lower dosages than when the ease, Pick's disease, frontotemporal dementia, parasupran individual agents are used as a monotherapy so as to enhance culear palsy, dementia with Lewy bodies, vascular dementia, 35 the therapeutic activities of the combined agents without Huntington's disease, Parkinson's disease, multiple Sclero causing the undesirable side effects commonly occur in con sis, amyotrophic lateral Sclerosis, Down syndrome, elderly ventional monotherapy. Therefore, the Compounds of the depression, Wernicke-Korsakoffs syndrome, corticobasal Invention may be simultaneously, sequentially, or contempo degenerations and/or prion disease. raneously administered with other anti-depressant, anti-psy In still another embodiment of the fourth aspect, the inven 40 chotic, other hypnotic agents, and/or agents use to treat Par tion provides Method I or any of 7.1-7.27, wherein the Depot kinson's disease or mood disorders or dementia. In another Composition of the Invention is administered for controlled example, side effects may be reduced or minimized by admin and/or sustained-release of the Compounds of the Invention istering a Compound of the Invention in combination with over a period of from about 14 days, about 30 to about 180 one or more second therapeutic agents in free or salt form, days, preferably over the period of about 30, about 60 or about 45 wherein the dosages of (i) the second therapeutic agent(s) or 90 days. Controlled- and/or sustained-release is particularly (ii) both Compound of the Invention and the second thera useful for circumventing premature discontinuation of peutic agent, are lower than if the agent/compound are admin therapy, particularly for antipsychotic drug therapy where istered as a monotherapy. In a particular embodiment, the non-compliance or non-adherence to medication regimes is a Compounds of the Invention are useful to treat dyskinesia in COO OCCUCC. 50 a patient receiving dopaminergic medications, e.g., selected In the fifth aspect, the invention provides a method from levodopa and levodopa adjuncts (carbidopa, COMT (Method II) for the prophylaxis or treatment one or more inhibitors, MAO-B inhibitors), dopamine agonists, and anti sleep disorders, agitation, aggressive behaviors, post-trau cholinergics, e.g., such as are used in the treatment of Parkin matic stress disorder and/or impulse control disorder, e.g., son's disease. intermittent explosive disorder, comprising administering to 55 Therefore, in the sixth aspect, the current invention pro a patient in need thereof a compound as described in the vides Method I, e.g., or any of formulae 7.1-7.27, or Method following formulae: II or any of 8.1-8.15, further comprises one or more thera 8.1 a compound of Formula I or any of formulae 1.1-1. 14, peutic agents selected from compounds that modulate GABA in free or (pharmaceutically acceptable) salt form as activity (e.g., enhances the activity and facilitates GABA described in any of 4.1-4.4: 60 transmission), a GABA-B agonist, a 5-HT modulator (e.g., a 8.2 a Pharmaceutical or Depot Composition as hereinbe 5-HT agonist, a 5-HT, antagonist, a 5-HT, inverse ago fore described: nist, etc.), a agonist, an ion channel modulator 8.3 Osmotic-controlled Release Oral delivery System (e.g., blocker), a serotonin-2 antagonist/reuptake inhibitor Composition as hereinbefore described. (SARIs), an antagonist, an H3 agonist or In one embodiment of the fifth aspect, the invention pro 65 antagonist, a noradrenergic agonist or antagonist, a galanin vides Method II or any of 8.1-8.3, wherein the disorder is agonist, a CRHantagonist, human growth hormone, a growth sleep disorders. In another embodiment of the fifth aspect, the hormone agonist, estrogen, an estrogen agonist, a neuroki US 9,428,506 B2 11 12 nin-1 drug, an anti-depressant, and an antipsychotic agent, 9.11 Method I-A or II-A, wherein the therapeutic agent is e.g., an agent, in free or pharmaceuti the serotonin-2 antagonist/reuptake inhibitor (SARI): cally acceptable salt form (Method I-A and II-A respec 9.12 Method I-A or II-A or 9.11, wherein the serotonin-2 tively). antagonist/reuptake inhibitor (SARI) is selected from a In another embodiment of the sixth aspect, Method I-A and group consisting of one or more Org 50081 (Organon II-A, Method I, e.g., or any of formulae 7.1-7.27, or Method Netherlands), , , serZone and traZ II or any of 8.1-8.15, further comprises one or more thera odone; peutic agents selected from a cholinesterase inhibitor (e.g., 9.13 Method I-A or II-A, wherein the therapeutic agent is acetylcholinesterase inhibitor) or an N-Methyl D-Asparate the 5HT1a agonist; (NMDA) receptor antagonist, in free or pharmaceutically 10 9.14 Method I-A or II-A or 9.13, wherein the 5HTIa ago acceptable salt form. In a specific embodiment, the cholinest nist is selected from a group consisting of one or more of erase inhibitor (e.g., acetylcholinesterase inhibitor) is , , , and MN-305 selected from the group consisting of Tacrine, rivastigmine (MediciNova, San Diego, Calif); (Exelon), donepezil (Aricept), and galantamine (Razadyne, 9.15 Method I-A or II-A, wherein the therapeutic agent is formerly called Reminyl)) in free orpharmaceutically accept 15 the neurokinin-1 drug; able salt form. In a further embodiment, the cholinesterase 9.16 Method I-A or II-A or 9.15, wherein the neurokinin-1 inhibitor (e.g., acetylcholinesterase inhibitor) is donepezil in drug is Casopitant (GlaxoSmithKline); free or pharmaceutically acceptable salt form. In another 9.17 Method I-A or II-A, wherein the therapeutic agent is embodiment, the NMDA receptor antagonist is memantine in an antipsychotic agent; free or pharmaceutically acceptable salt form. 9.18 Method I-A or II-A or 9.17, wherein the antipsychotic In a further embodiment of the sixth aspect, the invention agent is selected from a group consisting of chlorprom provides Method I-A or II-A as follows, further comprising azine, haloperidol, droperidol, fluiphenazine, loxapine, one or more therapeutic agents. mesoridazine mollidone, perphenazine, pimozide, 9.1 Method I-A or II-A, wherein the therapeutic agent(s) is prochlorperazine , thioridazine, thiothixene, compounds that modulate GABA activity (e.g., 25 trifluoperazine, clozapine, aripiparazole, olanzapine, enhances the activity and facilitates GABA transmis quetiapine, risperidone, Ziprasidone and ; sion); 9.19 Method I-A or II-A, wherein the therapeutic agent is 9.2 Method I-A or II-A or 9.1, wherein the GABA com an anti-depressant; pound is selected from a group consisting of one or more 9.20 Method I-A or II-A or 9.19, wherein the anti-depres of , alprazolam, bromazepam, clobazam, clon 30 Sant is selected from , , bupro azepam, cloraZepate, diazepam, , pion, citalopram, , , doxepin, fiurazepam, , , , duloxetine, escitaloprame, fluoxetine, fluvoxamine, imi oxazepam, temaZapam, , , , pramine, isocarboxazid, , , nefa , , , gabaxadol, vigabatrin, Zodone, , paroxetine, phenlzine Sulfate, tiagabine, EVT 201 (Evotec Pharmaceuticals) and esta 35 protiptyline, Sertraline, tranylcypromine, trazodone, Zolam; , and Velafaxine; 9.3 Method I-A or II-A, wherein the therapeutic agent is an 9.21 Method I-A or II-A, 9.17 or 9.18, wherein the antip additional 5HT antagonist; sychotic agent is an atypical antipsychotic agent; 9.4 Method I-A or II-A or 9.3, wherein said additional 9.22 Method I-A or II-A, or any of 9.17-9.21, wherein the 5HT antagonist is selected from one or more of ket 40 atypical antipsychotic agent is selected from a group anserin, risperidone, , (Sanofi consisting of clozapine, aripiparazole, olanzapine, que Aventis, France), pruvanserin, MDL 100907 (Sanofi tiapine, risperidone, Ziprasidone, and paliperidone; Aventis, France), HY 10275 (Eli Lilly), APD 125 (Arena 9.23 Method I-A or II-A, wherein the therapeutic agent is Pharmaceuticals, San Diego, Calif.), and AVE8488 selected from any of methods 9.1-9.22, e.g., selected (Sanofi-Aventis, France); Method I-A or II-A, 9.3 or 9.4 45 from a group consisting of modafinil, armodafinil, additionally selected from (ACP-103) and epin, alprazolam, bromazepam, clobazam, , ; cloraZepate, diazepam, flunitrazepam, , 9.5 Method I-A or II-A, wherein the therapeutic agent is a lorazepam, midazolam, nitrazepam, oxazepam, temaza melatonin agonist; pam, triazolam, indiplon, Zopiclone, esZopiclone, Zale 9.6 Method I-A or II-A or 9.5, wherein the melatonin 50 plon, Zolpidem, gabaxadol, vigabatrin, tiagabine, EVT agonist is selected from a group consisting of one or 201 (Evotec Pharmaceuticals), , , more of melatonin, (ROZEREMR), Takeda risperidone, eplivanserin, Volinanserin (Sanofi-Aventis, Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceu France), pruvanserin, MDL 100907 (Sanofi-Aventis, ticals, Rockville, Md.), PD-6735 (Phase II Discovery) France), HY 10275 (Eli Lilly), APD 125 (Arena Phar and ; 55 maceuticals, San Diego, Calif.), AVE8488 (Sanofi 9.7 Method I-A or II-A, wherein the therapeutic agent is an Aventis, France), repinotan, Sarizotan, eptapirone, bus ion channel blocker; pirone, MN-305 (MediciNova, San Diego, Calif.), 9.8 Method I-A or II-A or 9.7, wherein said ion channel melatonin, ramelteon (ROZEREMR), Takeda Pharma blocker is one or more of lamotrigine, and ceuticals, Japan), VEC-162 (Vanda Pharmaceuticals, . 60 Rockville, Md.), PD-6735 (Phase II Discovery), ago 9.9 Method I-A or II-A, wherein the therapeutic agent is an melatine, lamotrigine, gabapentin, pregabalin, orexin, a orexin receptor antagonist; 1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), 9.10 Method I-A or II-A or 9.9, wherein the orexin receptor GW649868 (GlaxoSmithKline), a benzamide deriva antagonist is selected from a group consisting of orexin, tive, Org 50081 (Organon-Netherlands), ritanserin, a 1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), 65 nefazodone, serZone, traZodone, Casopitant (Glaxo GW649868 (GlaxoSmithKline) and a benzamide SmithKline), amitriptyline, amoxapine, , cit derivative; allopram, clomipramine, desipramine, doxepin, dulloxet US 9,428,506 B2 13 14 ine, escitaloprame, fluoxetine, fluvoxamine, nist, human growth hormone, a growth hormone agonist, , isocarboxazid, maprotiline, mirtazapine, estrogen, an estrogen agonist, a neurokinin-1 drug, an anti nefazodone, nortriptyline, paroxetine, phenlzine Sulfate, depressant, and an antipsychotic agent, e.g., an atypical antip protiptyline, Sertraline, tranylcypromine, traZodone, sychotic agent, in free or pharmaceutically acceptable salt trimipramine, Velafaxine, chlorpromazine, haloperidol, form (Method I-A and II-A respectively). In a further droperidol, fluphenazine, loxapine, mesoridazine moli embodiment of this aspect, the invention provides Method done, perphenazine, pimozide, prochlorperazine pro I-A or II-A as similarly described in any one of formulae mazine, thioridazine, thiothixene, trifluoperazine, 91-938. clozapine, aripiparazole, olanzapine, quetiapine, ris In still another embodiment of the sixth aspect, Method I peridone, Ziprasidone and paliperidone; In addition to 10 or Method II, as hereinbefore described further comprises the therapeutic agents listed herewith, Method I-A or one or more therapeutic agents selected from a cholinesterase II-A, is further selected from pimavanserin (ACP-103) inhibitor (e.g., acetylcholinesterase inhibitor) or an N-Methyl and pizotifen; D-Asparate (NMDA) receptor antagonist, in free or pharma 9.24 Method I-A or II-A wherein the therapeutic agent is an ceutically acceptable salt form. In a specific embodiment, the H3 agonist; 15 cholinesterase inhibitor (e.g., acetylcholinesterase inhibitor) 9.25 Method I-A or II-A, wherein the therapeutic agent is is selected from the group consisting of Tacrine, rivastigmine an H3 antagonist; (Exelon), donepezil (Aricept), and galantamine (Razadyne, 9.26 Method I-A or II-A, wherein the therapeutic agent is formerly called Reminyl)) in free orpharmaceutically accept a noradrenergic agonist or antagonist; able salt form. In a further embodiment, the cholinesterase 9.27 Method I-A or II-A, wherein the therapeutic agent is inhibitor (e.g., acetylcholinesterase inhibitor) is donepezil in a galanin agonist, free or pharmaceutically acceptable salt form. In another 9.28 Method I-A or II-A, wherein the therapeutic agent is embodiment, the NMDA receptor antagonist is memantine in a CRH antagonist; free or pharmaceutically acceptable salt form. 9.29 Method I-A or II-A, wherein the therapeutic agent is In the seventh aspect of the invention, the combination of a a human growth hormone; 25 Compound of the Invention and one or more second thera 9.30 Method I-A or II-A, wherein the therapeutic agent is peutic agents as described in Methods I-A, II-A or any of a growth hormone agonist; 9.1-9.38, may be administered as a Pharmaceutical Compo 9.31 Method I-A or II-A, wherein the therapeutic agent is sition or a depot Composition as hereinbefore described. estrogen; Similarly, the combination of a Compound of the Invention 9.32 Method I-A or II-A, wherein the therapeutic agent is 30 and one or more second therapeutic agents as described in an estrogen agonist; Methods I-A, II-A or any of 9.1-9.38, may be administered 9.33 Method I-A or II-A, wherein the therapeutic agent is as a Pharmaceutical Composition or a depot Composition as a neurokinin-1 drug; hereinbefore described. The combination compositions can 9.34 Method I-A or II-A, wherein a therapeutic agent is include mixtures of the combined drugs, as well as two or combined with compounds of Formula (I) and the thera 35 more separate compositions of the drugs, which individual peutic agent is an anti-Parkinson agent such as L-dopa, compositions can be, for example, co-administered together co-careldopa, duodopa, stalova, Symmetrel, benzotro to a patient. pine, biperiden, bromocryiptine, entacapone, , In a particular embodiment, Methods I-A, II-A. I.-A, II-A pramipexole, procyclidine, ropinirole, selegiline and or any of 9.1-9.38 comprises administering to a patient in tolcapone; 40 need thereof, a Compound of the Invention in combination 9.35 Method I-A or II-A, wherein compounds of Formula with an atypical antipsychotic agent, e.g., a compound (I) may be used to treat sleep disorders, depression, selected from clozapine, aripiparazole, olanzapine, quetiap pyschosis, or any combinations thereof, in patients Suf ine, risperidone, Ziprasidone, or paliperidone, in free or phar fering from the listed diseases and/or Parkinson's dis maceutically acceptable Salt form, for example wherein the ease, 45 dosage of the atypical antipsychotic agent is reduced and/or 9.36 Method I-A or II-A, wherein the disorder is selected side effects are reduced. from at least one or more of psychosis, e.g., Schizophre In another embodiment, Methods I-A, II-A. Methods I-A nia, depression, mood disorders, sleep disorders (e.g., II-A or any of 9.1-9.38 comprises administering to a patient sleep maintenance and/or sleep onset) or any combina in need thereof, a Compound of the Invention in combination tion of disorders thereof; 50 with an anti-depressant, e.g., amitriptyline, amoxapine, 9.37 Any of the foregoing methods wherein the disorder is bupropion, citalopram, clomipramine, desipramine, doxepin, sleep disorder; dulloxetine, escitaloprame, fluoxetine, fluvoxamine, imi 9.38 Any of the foregoing methods, wherein the disorder is pramine, isocarboxazid, maprotiline, mirtazapine, nefaZ sleep disorder associated with psychosis, e.g., Schizo odone, nortriptyline, paroxetine, phenlzine Sulfate, protip phrenia or Parkinson's disease; in free or pharmaceuti 55 tyline, Sertraline, tranylcypromine, traZodone, trimipramine, cally acceptable salt form. or Velafaxine, in free or pharmaceutically acceptable salt In another embodiment of the sixth aspect, the current form. Alternatively, the anti-depressant may be used as an invention provides Method I or Method II, as hereinbefore adjunct medication in addition to the compounds of the described, further comprises one or more therapeutic agents Invention. selected from compounds that modulate GABA activity (e.g., 60 In still another embodiment, Methods I-A, II-A, I-A enhances the activity and facilitates GABA transmission), a II-A or any of 9.1-9.38 comprises administering to a patient GABA-B agonist, a 5-HT modulator (e.g., a 5-HTagonist, in need thereof, a Compound of the Invention in combination a 5-HT, antagonist, a 5-HT, inverse agonist, etc.), a mela with a compound that modulates GABA activity, e.g., a com tonin agonist, an ion channel modulator (e.g., blocker), a pound selected from doxepin, alprazolam, bromazepam, clo serotonin-2 antagonist/reuptake inhibitor (SARIs), an orexin 65 bazam, clonazepam, cloraZepate, diazepam, flunitrazepam, receptor antagonist, an H3 agonist orantagonist, a noradren flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, ergic agonist or antagonist, a galanin agonist, a CRH antago temazapam, triazolam, indiplon, Zopiclone, esZopiclone, US 9,428,506 B2 15 16 Zaleplon, Zolpidem, gabaxadol, vigabatrin, tiagabine, EVT acid-addition salt with, for example, an inorganic or organic 201 (Evotec Pharmaceuticals), estazolam or any combina acid, for example hydrochloric, hydrobromic, Sulphuric, tions thereof, in free or pharmaceutically acceptable salt phosphoric, acid acetic, trifluoroacetic, citric, maleic acid, form. toluene Sulfonic, propionic, Succinic, glycolic, Stearic, lactic, In another particular embodiment, Methods I-A, II-A. malic, tartaric, citric, ascorbic, pamoic, hydroxymaleic, phe I-A, II-A or any of 9.1-9.38 comprises administering to a nylacetic, glutamic, benzoic, Salicylic, Sulfanilic, 2-acetoxy patient in need thereof, a Compound of the Invention in benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane combination with doxepin in free orpharmaceutically accept disulfonic, oxalic, isethionic acid, and the like. In addition a able salt form. Dosages of doxepin can vary in any range salt of a compound of the invention which is sufficiently known to a person of ordinary skill in the art. In one example, 10 acidic is an alkali metal salt, for example a sodium or potas a 10 mg dose of doxepin may be combined with any dosage of sium salt, an alkaline earth metal salt, for example a calcium a compound of the Invention. or magnesium salt, an ammonium salt or a salt with an organic In another embodiment, Methods I-A, II-A, I-A, II-A or base which affords a physiologically-acceptable cation, for any of 9.1-9.38 comprises administering to a patient in need example a salt with methylamine, dimethylamine, trimethy thereof, a Compound of the Invention in combination (includ 15 lamine, piperidine, morpholine or tris-(2-hydroxyethyl)- ing as part of a daily dosage regimen) with an atypical stimu amine. In a particular embodiment, the salt of the Compounds lant, e.g., a modafinil, adrafinil, or armodafinil. A regimin of the Invention is a toluenesulfonic acid addition salt. In incorporating a Compound of the Invention with Such drugs another particular embodiment, the salt of the Compounds of promotes more regular sleep, and avoids side effects Such as the Invention is a fumeric acid addition salt. In a particular psychosis or mania associated with higher levels of Such embodiment, the salt of the Compounds of the Invention is a drugs, e.g., in the treatment of bipolar depression, cognition phosphoric acid addition salt. associated with Schizophrenia, and excessive sleepiness and The Compounds of the Invention are intended for use as fatigue in conditions such as Parkinson's disease and cancer. pharmaceuticals, therefore pharmaceutically acceptable salts In the eighth aspect, the invention provides use of a com are preferred. Salts which are unsuitable for pharmaceutical pound as described in the following formulae: 25 uses may be useful, for example, for the isolation or purifi 11.1 Compound of Formula I or any of formulae 1.1-1.14, cation of free Compounds of the Invention, and are therefore in free or pharmaceutically acceptable salt form; also included. 11.2 a Pharmaceutical Composition as hereinbefore The Compounds of the Invention may comprise one or described; more chiral carbon atoms. The compounds thus exist in indi 11.3 Depot Composition as hereinbefore described; or 30 vidual isomeric, e.g., enantiomeric or diasteriomeric form or 11.4 Osmotic-controlled Release Oral delivery System as mixtures of individual forms, e.g., racemic? diastereomeric Composition as hereinbefore described, mixtures. Any isomer may be present in which the asymmet (in the manufacture of a medicament) for the treatment or ric center is in the (R)-, (S)-, or (R.S)-configuration. The prophylaxis of one or more disorders as disclosed hereinbe invention is to be understood as embracing both individual fore, e.g., in any of Method I, any of 7.1-7.27, Method II, any 35 optically active isomers as well as mixtures (e.g., racemic/ of 8.1-8.15, Methods I-A, II-A, any of 9.1-9.38, Method I, diasteromeric mixtures) thereof. Accordingly, the Com Method II, Methods I-A, II-A, or any methods described pounds of the Invention may be a racemic mixture or it may be in the sixth or seventh aspect of the invention. predominantly, e.g., in pure, or Substantially pure, isomeric In the ninth aspect, the invention provides a pharmaceutical form, e.g., greater than 70% enantiomeric? diastereomeric composition as hereinbefore described, e.g., in the following 40 excess (“ee'), preferably greater than 80% ee, more prefer formulae: ably greater than 90% ee, most preferably greater than 95% 12.1 a Pharmaceutical Composition as hereinbefore ee. The purification of said isomers and the separation of said described; isomeric mixtures may be accomplished by Standard tech 12.2 Depot Composition as hereinbefore described; or niques known in the art (e.g., column chromatography, pre 12.3 Osmotic-controlled Release Oral delivery System 45 parative TLC, preparative HPLC, simulated moving bed and Composition as hereinbefore described, the like). for use in the treatment or prophylaxis of one or more disor Geometric isomers by nature of substituents about a double ders as disclosed hereinbefore, e.g., in any of Method I, any of bond or a ring may be present in cis (Z) or trans (E) form, and 7.1-7.27, Method II, any of 8.1-8.15, Methods I-A, II-A, any both isomeric forms are encompassed within the scope of this of 9.1-9.38, Method I, Method II, Methods I-A, II-A, or 50 invention. any methods described in the sixth or seventh aspect of the Compounds of the Invention may in some cases also exist invention. in prodrug form. The term “prodrug is an art recognized term and refers to a drug precursor prior to administration, but DETAILED DESCRIPTION OF THE INVENTION generates or releases the active metabolite in Vivo following 55 administration, via Some chemical or physiological process. If not otherwise specified or clear from context, the follow In some instances, the Compounds of the Invention may be a ing terms as used herein have the following meetings: prodrug as well as a metabolite. Our inventors have found that a. Alkyl as used herein is a saturated or unsaturated by blocking the in vivo back formation of the active 1-(4- hydrocarbon moiety, e.g., one to six carbon atom, e.g., Fluoro-phenyl)-4-((6bR.10aS)-3-methyl-2,3,6b.9.10.10a one to four carbon atom in length, which may be linear 60 hexahydro-1H,7H-pyrido 3',4':4.5 pyrrolo 1,2,3-dequi or branched (e.g., n-butyl or tert-butyl), unless otherwise noxalin-8-yl)-butan-1-one, the Compounds of the Invention specified. would prevent dopamine antagonism while maintaining Unless otherwise indicated, the Compounds of the Inven binding to 5-HT, and SERT. tion, e.g., Compounds of Formula I or any of 1.1-1.14, or any Wherein X is —N(CH)—, the Compounds of the Inven of formulae 4.1-4.4 may exist in free or salt, e.g., as acid 65 tion may further be metabolized in vivo to form the des addition salts, form. An acid-addition salt of a compound of methyl derivative (i.e., wherein X is N(H)—. In particular, the invention which is sufficiently basic, for example, an the Compound of Formula I, wherein X is N(CH) and Y is US 9,428,506 B2 17 18 —C(H)(OH)—or —C(=O), may be metabolized to form the material should be biodegradable wherein the polymeric des-methyl derivative (e.g., wherein X is —N(H)—and Y is material should degrade by bodily processes to products —C(H)(OH) or —C(=O)— respectively), wherein the readily disposable by the body and should not accumulate in hydroxy compound may then be oxidized in vivo to form the the body. The products of the biodegradation should also be respective active desmethyl Compound of Formula Q. biocompatible with the body in that the polymeric matrix is wherein X N(H)—and Y is —C(=O). biocompatible with the body. Particular useful examples of Similarly, wherein the Compounds of the Invention con polymeric matrix materials include poly(glycolic acid), poly tain an amine group, prodrug of Such amine, e.g., methyl D.L-lactic acid, poly-L-lactic acid, copolymers of the fore amine prodrugs may also exist wherein the prodrug is cleaved going, poly(aliphatic carboxylic acids), copolyoxalates, to release the amine metabolite in vivo following administra 10 polycaprolactone, polydioxonone, poly(ortho carbonates), tion. poly(acetals), poly(lactic acid-caprolactone), polyorthoe Alternatively and/or additionally, the Compounds of the sters, poly(glycolic acid-caprolactone), polyanhydrides, and Invention may be included as a depot formulation, e.g., by natural polymers including albumin, casein, and waxes. Such dispersing, dissolving or encapsulating the Compounds of the as, glycerol mono- and distearate, and the like. The preferred Invention in a polymeric matrix as described in the second 15 polymer for use in the practice of this invention is dl(polylac and third aspect, such that the Compound is continually tide-co-glycolide). It is preferred that the molar ratio of lac released as the polymer degrades overtime. The release of the tide to glycolide in Such a copolymer be in the range of from Compounds of the Invention from the polymeric matrix pro about 75:25 to 50:50. vides for the controlled- and/or delayed- and/or sustained Useful PLGA polymers may have a weight-average release of the Compounds, e.g., from the pharmaceutical molecular weight of from about 5,000 to 500,000 daltons, depot composition, into a Subject, for example a warm preferably about 150,000 daltons. Dependent on the rate of blooded animal Such as man, to which the pharmaceutical degradation to be achieved, different molecular weight of depot is administered. Thus, the pharmaceutical depot deliv polymers may be used. For a diffusional mechanism of drug ers the Compounds of the Invention to the Subject at concen release, the polymer should remain intact until all of the drug trations effective for treatment of the particular disease or 25 is released from the polymeric matrix and then degrade. The medical condition over a Sustained period of time, e.g., drug can also be released from the polymeric matrix as the 14-180 days, preferably about 30, about 60 or about 90 days. polymeric excipient bioerodes. Polymers useful for the polymeric matrix in the Composi The PLGA may be prepared by any conventional method, tion of the Invention (e.g., Depot composition of the Inven or may be commercially available. For example, PLGA can tion) may include a polyester of a hydroxyfatty acid and 30 be produced by ring-opening polymerisation with a suitable derivatives thereof or other agents such as polylactic acid, catalyst from cyclic lactide, glycolide, etc. (see polyglycolic acid, polycitric acid, polymalic acid, poly-beta.- EP-00584.81B2: Effects of polymerization variables on hydroxybutyric acid, epsilon.-capro-lactone ring opening PLGA properties: molecular weight, composition and chain polymer, lactic acid-glycolic acid copolymer, 2-hydroxybu structure). tyric acid-glycolic acid copolymer, polylactic acid-polyeth 35 It is believed that PLGA is biodegradable by means of the yleneglycol copolymer or polyglycolic acid-polyethyleneg degradation of the entire Solid polymer composition, due to lycol copolymer), a polymer of an alkyl alpha-cyanoacrylate the break-down of hydrolysable and enzymatically cleavable (for example poly(butyl 2-cyanoacrylate)), a polyalkylene ester linkages under biological conditions (for example in the oxalate (for example polytrimethylene oxalate or polytetram presence of water and biological enzymes found in tissues of ethylene oxalate), a polyortho ester, a polycarbonate (for 40 warm-blooded animals such as humans) to form lactic acid example polyethylene carbonate or polyethylenepropylene and glycolic acid. Both lactic acid and glycolic acid are water carbonate), a polyortho-carbonate, a polyamino acid (for soluble, non-toxic products of normal metabolism, which example poly-gamma.-L-alanine, poly-gamma.-benzyl-L- may further biodegrade to form carbon dioxide and water. In glutamic acid or poly-y-methyl-L-glutamic acid), a hyalu other words, PLGA is believed to degrade by means of ronic acid ester, and the like, and one or more of these poly 45 hydrolysis of its ester groups in the presence of water, for mers can be used. example in the body of a warm-blooded animal Such as man, If the polymers are copolymers, they may be any of ran to produce lactic acid and glycolic acid and create the acidic dom, block and/or graft copolymers. When the above alpha microclimate. Lactic and glycolic acid are by-products of hydroxycarboxylic acids, hydroxydicarboxylic acids and various metabolic pathways in the body of a warm-blooded hydroxytricarboxylic acids have optical activity in their mol 50 animal Such as man under normal physiological conditions ecules, any one of D-isomers, L-isomers and/or DL-isomers and therefore are well tolerated and produce minimal sys may be used. Among others, alpha-hydroxycarboxylic acid temic toxicity. polymer (preferably lactic acid-glycolic acid polymer), its In another embodiment, the polymeric matrix useful for the ester, poly-alpha-cyanoacrylic acid esters, etc. may be used, invention may comprise a star polymer wherein the structure and lactic acid-glycolic acid copolymer (also referred to as 55 of the polyester is star-shaped. These polyesters have a single poly(lactide-alpha-glycolide) or poly(lactic-co-glycolic polyol residue as a central moiety Surrounded by acid residue acid), and hereinafter referred to as PLGA) are preferred. chains. The polyol moiety may be, e.g., glucose or, e.g., Thus, in one aspect the polymer useful for the polymeric mannitol. These esters are known and described in GB2,145, matrix is PLGA. As used herein, the term PLGA includes 422 and in U.S. Pat. No. 5,538,739, the contents of which are polymers of lactic acid (also referred to as polylactide, poly 60 incorporated by reference. (lactic acid), or PLA). Most preferably, the polymer is the The star polymers may be prepared using polyhydroxy biodegradable poly(d.1-lactide-co-glycolide) polymer. compounds, e.g., polyol, e.g., glucose or mannitol as the In a preferred embodiment, the polymeric matrix of the initiator. The polyol contains at least 3 hydroxy groups and invention is a biocompatible and biodegradable polymeric has a molecular weight of up to about 20,000 Daltons, with at material. The term “biocompatible' is defined as a polymeric 65 least 1, preferably at least 2, e.g., as a mean 3 of the hydroxy material that is not toxic, is not carcinogenic, and does not groups of the polyol being in the form of ester groups, which significantly induce inflammation in body tissues. The matrix contain polylactide or co-polylactide chains. The branched US 9,428,506 B2 19 20 polyesters, e.g., poly(d.1-lactide-co-glycolide) have a central 35 to 40 wt.%. By weight% is meant parts of the Compounds glucose moiety having rays of linear polylactide chains. of the Invention per total weight of microparticle. The depot composition of the invention as hereinbefore The pharmaceutical depot may comprise a pharmaceuti described may comprise the polymer in the form of micro cally-acceptable diluent or carrier, Such as a water miscible particles or nanoparticles, or in a liquid form, with the Com diluent or carrier. pounds of the Invention dispersed or encapsulated therein. Details of Osmotic-controlled Release Oral delivery Sys “Microparticles' is meant solid particles that contain the tem composition may be found in EP 1539 115 (U.S. Pub. Compounds of the Invention either in solution or in solid form No. 2009/0202631) and WO 2000/35419, the contents of wherein such compound is dispersed or dissolved within the each of which are incorporated by reference in their entirety. polymer that serves as the matrix of the particle. By an appro 10 A “therapeutically effective amount” is any amount of the priate selection of polymeric materials, a microparticle for Compounds of the invention (for example as contained in the mulation can be made in which the resulting microparticles pharmaceutical depot) which, when administered to a subject exhibit both diffusional release and biodegradation release Suffering from a disease or disorder, is effective to cause a properties. reduction, remission, or regression of the disease or disorder When the polymer is in the form of microparticles, the 15 over the period of time as intended for the treatment. microparticles may be prepared using any appropriate Dosages employed in practicing the present invention will method, Such as by a solvent evaporation or solvent extraction of course vary depending, e.g. on the particular disease or method. For example, in the solvent evaporation method, the condition to be treated, the particular Compounds of the Compounds of the Invention and the polymer may be dis Invention used, the mode of administration, and the therapy Solved in a volatile organic solvent (for example aketone Such desired. Unless otherwise indicated, an amount of the Com as acetone, a halogenated hydrocarbon Such as chloroform or pounds of the Invention for administration (whether admin methylene chloride, a halogenated aromatic hydrocarbon, a istered as a free base or as a salt form) refers to or is based on cyclic ether such as dioxane, an ester Such as ethyl acetate, a the amount of the Compound of the Invention in free base nitrile Such as acetonitrile, or an Such as ethanol) and form (i.e., the calculation of the amount is based on the free dispersed in an aqueous phase containing a Suitable emulsion 25 base amount). stabiliser (for example polyvinyl alcohol, PVA). The organic Compounds of the Invention may be administered by any solvent is then evaporated to provide microparticles with the satisfactory route, including orally, parenterally (intrave Compounds of the Invention encapsulated therein. In the nously, intramuscular or Subcutaneous) or transdermally, but solvent extraction method, the Compounds of the Invention are preferably administered orally. In certain embodiment, and polymer may be dissolved in a polar solvent (Such as 30 the Compounds of the Invention, e.g., in depot formulation, is acetonitrile, dichloromethane, methanol, ethyl acetate or preferably administered parenterally, e.g., by injection. methyl formate) and then dispersed in an aqueous phase (such In general, satisfactory results for Method I or any of for as a water/PVA solution). An emulsion is produced to provide mulae 7.1-7.27 or Method I or use of the Compounds of the microparticles with the Compounds of the Invention encap Invention as hereinbefore described, e.g. for the treatment of Sulated therein. Spray drying is an alternative manufacturing 35 a combination of diseases such as a combination of at least technique for preparing the microparticles. depression, psychosis, e.g., (1) psychosis, e.g., Schizophre Another method for preparing the microparticles of the nia, in a patient Suffering from depression; (2) depression in a invention is also described in both U.S. Pat. No. 4,389,330 patient Suffering from psychosis, e.g., Schizophrenia; (3) and U.S. Pat. No. 4,530,840. mood disorders associated with psychosis, e.g., Schizophre The microparticle of the present invention can be prepared 40 nia, or Parkinson's disease; and (4) sleep disorders associated by any method capable of producing microparticles in a size with psychosis, e.g., Schizophrenia, or Parkinson's disease, as range acceptable for use in an injectable composition. One set forth above are indicated to be obtained on oral adminis preferred method of preparation is that described in U.S. Pat. tration at dosages of the order from about 1 mg to 100mg once No. 4.389.330. In this method the active agent is dissolved or daily, preferably about 2.5 mg-50 mg, e.g., 2.5 mg, 5 mg, 10 dispersed in an appropriate solvent. To the agent-containing 45 mg, 20 mg, 30 mg, 40 mg or 50 mg. once daily, preferably via medium is added the polymeric matrix material in an amount oral administration. relative to the active ingredient that provides a product having Satisfactory results for Method II or any of 8.1-8.15, the desired loading of active agent. Optionally, all of the Method II, or use of the Compounds of the Invention as ingredients of the microparticle product can be blended in the hereinbefore described, e.g. for the treatment of sleep disor Solvent medium together. 50 der alone or agitation, aggressive behaviors, post-traumatic Solvents for the Compounds of the Invention and the poly stress disorder or impulse control disorder alone, e.g., inter meric matrix material that can be employed in the practice of mittent explosive disorder alone are indicated to be obtained the present invention include organic solvents, such as on oral administration at dosages of the order from about 1 acetone; halogenated hydrocarbons, such as chloroform, mg-10 mg once daily, e.g., about 2.5 mg-5 mg, e.g., 2.5 mg. 3 methylene chloride, and the like; aromatic hydrocarbon com 55 mg, 4 mg, 5 mg or 10 mg. of a Compound of the Invention, in pounds; halogenated aromatic hydrocarbon compounds; free or pharmaceutically acceptable salt form, once daily, cyclic ethers; , such as, benzyl alcohol; ethyl acetate; preferably via oral administration. and the like. In one embodiment, the solvent for use in the Satisfactory results for Method I-A or any of 9.1-9.38 or practice of the present invention may be a mixture of benzyl Method I-A are indicated to be obtained at less than 100 mg. alcohol and ethyl acetate. Further information for the prepa 60 preferably less than 50 mg, e.g., less than 40 mg, less than 30 ration of microparticles useful for the invention can be found mg, less than 20 mg, less than 10 mg, less than 5 mg, less than in U.S. Patent Publication Number 2008/0069885, the con 2.5 mg. once daily. Satisfactory results for Method II-A or any tents of which are incorporated herein by reference in their of 9.1-9.38 are indicated to be obtained at less than 10 mg. entirety. e.g., less than 5 mg or, preferably less than 2.5 mg. The amount of the Compounds of the Invention incorpo 65 For treatment of the disorders disclosed herein wherein the rated in the microparticles usually ranges from about 1 wt % depot composition is used to achieve longer duration of to about 90 wt.%, preferably 30 to 50 wt.%, more preferably action, the dosages will be higher relative to the shorter action US 9,428,506 B2 21 22 composition, e.g., higher than 1-100 mg, e.g., 25 mg, 50 mg. -continued 100 mg, 500 mg, 1,000 mg, or greater than 1000 mg. Duration F of action of the Compounds of the Invention may be con trolled by manipulation of the polymer composition, i.e., the H polymer:drug ratio and microparticle size. Wherein the com 5 N position of the invention is a depot composition, administra R1 OH tion by injection is preferred. N H The pharmaceutically acceptable salts of the Compounds X of the Invention can be synthesized from the parent com 10 pound which contains a basic or acidic moiety by conven tional chemical methods. Generally, such salts can be pre The Compound of Formula I, wherein R is —OR pared by reacting the free base forms of these compounds wherein R is Calkyl may be prepared by reacting Int-B with a stoichiometric amount of the appropriate acid in water with R OH and BF3.OEt wherein R is Calkyl. The or in an organic solvent, or in a mixture of the two; generally, 15 reaction may be summarized in the reaction scheme below: nonaqueous media like ether, ethyl acetate, ethanol, isopro panol, or acetonitrile are preferred. Further details for the preparation of these salts, e.g., toluenesulfonic salt in amor phous or crystal form, may be found in PCT/US08/03340 and/or U.S. Provisional Appl. No. 61/036,069. Pharmaceutical compositions comprising Compounds of the Invention may be prepared using conventional diluents or excipients (an example include, but is not limited to sesame oil) and techniques known in the galenic art. Thus oral dosage 25 forms may include tablets, capsules, solutions, Suspensions and the like. Methods of Making the Compounds of the Invention: The intermediates of the Compounds of the Invention may be prepared as described in WO PCT/US08/03340 (WO 30 2008/112280); U.S. application Ser. No. 10/786,935; U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183, 282: U.S. RE39680, and U.S. RE39679, the contents of which are incorporated by reference in their entirety. Salts of 35 the Compounds of the Invention may also be prepared as similarly described in U.S. Pat. Nos. 6,548.493; 7.238,690; 6,552,017; 6,713,471; 7,183,282: U.S. RE39680; U.S. Example 1 RE39679; and WO 2009/114181, the contents of each of which are incorporated by reference in their entirety. 40 2-(4-Fluoro-phenyl)-5-((6bR.10aS)-3-methyl-2,3,6b, 9,10,10a-hexahydro-1H,7H-pyrido3',4':4.5 pyrrolo Isolation or purification of the diastereomers of the Com 1,2,3-dequinoxalin-8-yl)-pentan-2-ol pounds of the Invention may be achieved by conventional methods known in the art, e.g., column purification, prepara tive thin layer chromatography, preparative HPLC, crystalli Zation, trituration, simulated moving beds and the like. 45 The Compound of Formula I, wherein R is —OR wherein R is H, may be prepared by reacting Int-A with a Grignard reagent, R' MgX wherein X is halide, e.g., bro mide orchloride, preferably , R' and Xare defined in 50 Formula I, e.g., R is methyl and X is for example N(CH), e.g., in a solvent such as tetrahydrofuran or diethyl ether, preferably tetrahydrofuran. The reaction may be summarized OH in the reaction scheme below: 55

(R) (S)

N H 60 --- To a solution of 1-(4-fluoro-phenyl)-4-((6bR.10aS)-3-me Int-A 65 thyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido3',4':4.5 pyrrolo 1,2,3-dequinoxalin-8-yl)-butan-1-one (99 mg, 0.25 mmol) in THF is added 3.0 M methyl magnesium bromide in US 9,428,506 B2 23 24 ether (0.25 mL, 0.75 mmol) dropwise at 0° C. Upon the Example 3 completion of the addition of CHMgBr, the cooling bath is removed and the reaction mixture is stirred at room tem Receptor Binding Activity perature for 2 hours. Another batch of 3.0 M methyl mag nesium bromide in ether (0.25 mL, 0.75 mmol) is added 5 Binding to 5HT2, D and SERT is assessed, using the dropwise, and the reaction mixture was stirred at room methods described in WO/2009/145900. The compounds of temperature overnight. The mixture is carefully quenched Examples 1 and 2 are found to have potent binding to with water, basified with saturated sodium bicarbonate, and 5-HT, SERT and D, with affinity constants in the sub then extracted with methylene chloride four times. The micromolar range: combined organic phase is evaporated to dryness, and the 10 residue is purified on a basic alumina column to give 28 mg of pure product as a white solid. "H NMR (500 MHz, Receptor Ki (nM) for Ex. 1 Ki (nM) for Ex. 2 Chloroform-d) & 8.22 (br. 1H), 7.58-7.37 (m, 2H), 7.07 (t, 5-HT2 350 96 J=8.5 Hz, 1H), 7.01 (t, J–8.7 Hz, 1H), 6.65 (dt, J=10.6, 7.7 15 D2 740 810 HZ, 1H), 6.57-6.29 (m, 2H), 3.59 (td, J=11.1, 3.0 Hz, 1H), SERT 520 3OO 3.37-3.12 (m, 4H), 3.00-2.65 (m, 5H), 2.55-2.13 (m, 5H), 2.12-1.78 (m, 4H), 1.69-1.30 (m, 5H). MS (ESI) m/z 410.2 M+H". The invention claimed is: Example 2 1. A compound of formula I: (6bR.10aS)-8-4-(4-Fluoro-phenyl)-4-methoxy-bu tyl-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H Formula I pyrido3',4':45pyrrolo 1,2,3-dequinoxaline 25 F H

N R2 RI 30 N H X

35 wherein: X is N(H) or N(Calkyl); R" is H or C-alkyl; R’ is H or OR, wherein R is H or C. alkyl: (R) 40 (S) provided that R' and Rare not both H, and R' and Rare not both H; in free base or pharmaceutically acceptable salt form. 2. The compound according to claim 1, wherein R is --- 45 OR. 3. The compound according to claim 2, wherein R' is To a solution of 1-(4-fluoro-phenyl)-4-((6bR.10aS)-3- Calkyl. methyl-2,3,6b.9.10.10a-hexahydro-1H,7H-pyrido 3',4':4.5 4. The compound according to claim 3, wherein R' is pyrrolo 1,2,3-dequinoxalin-8-yl)-butan-1-ol (225 mg, 0.57 CH. mmol) in anhydrous dichloromethane (3 mL) is added 50 anhydrous methanol (100 uL., 2.28 mmol), and then BF.OEt 5. The compound according to claim 1, wherein R is OR (300 uL., 2.28 mmol. 1.0 M in THF) is added dropwise at and R is Calkyl. room temperature. The reaction mixture is stirred at room 6. The compound according to claim 5, wherein R is temperature overnight, and then poured into ice water. After CH. the mixture is basified with triethylamine, the organic phase 55 7. The compound according to claim 1, wherein X is is separated and dried over MgSO, and then evaporated to N(Calkyl). dryness under reduced pressure. The obtained residue is 8. The compound according to claim 7, wherein X is purified with a semi-preparative HPLC system to give 80 mg N(CH). of pure product as a brown oil. "H NMR (500 MHz, 9. The compound according to claim 1, wherein X is DMSO-d) & 7.31 (ddd, J=8.6, 5.6, 1.2 Hz, 2H), 7.18 (t, 60 J=8.7 Hz, 2H), 6.50 (td, J=7.6, 1.3 Hz, 1H), 6.39 (d. J=7.3 N(H). HZ, 1H), 6.32 (d. J=7.9 Hz, 1H), 4.15 (td, J=6.5, 3.5 Hz, 1H), 10. The compound according to claim 1, wherein said 3.49-3.37 (m. 1H), 3.31-3.22 (m, 3H), 3.15-3.04 (m, 4H), compound is in pharmaceutically acceptable salt form. 3.02–2.91 (m. 1H), 2.77 (s, 3H), 2.70-2.61 (m, 2H), 2.29 11. The compound according to claim 10, wherein the 2.11 (m, 2H), 2.09-1.97 (m, 1H), 1.92-1.81 (m, 1H), 1.78 65 pharmaceutically acceptable salt is selected from a group 1.63 (m, 3H), 1.60-1.49 (m. 1H), 1.49-1.37 (m. 1H), 1.37 consisting of toluenesulfonic, fumaric and phosphoric acid 1.22 (m, 1H). MS (ESI) m/z 410.6 M+H". addition salts. US 9,428,506 B2 25 26 12. The compound according to claim 1, which is: 21. The method according to claim 20, wherein said patient Suffers from a disorder selected from a group con sisting of obesity, anxiety, depression, psychosis, Schizo F. phrenia, sleep disorders, sexual disorders, migraine, condi 5 tions associated with cephalic pain, Social phobias, agitation, H gastrointestinal disorders, dysfunction of the gastrointestinal N tract motility, post-traumatic stress disorder, impulse control disorders, and intermittent explosive disorder. 22. The method according to claim 20, wherein said N 19 patient suffers from one or more disorders associated with H 10 dementia selected from a group consisting of one or more --- disorders associated with mild cognition impairment and dementing illnesses, one or more disorders associated with senile dementia, one or more disorders associated with 13. The compound according to claim 1, which is: Alzheimer's disease, one or more disorders associated with 15 Pick's disease, one or more disorders associated with fron totemporal dementia, one or more disorders associated with F. parasupranculear palsy, one or more disorders associated H with dementia with Lewy bodies, one or more disorders associated with vascular dementia, one or more disorders N associated with Huntington's disease, one or more disorders OH associated with Parkinson's disease, one or more disorders N associated with multiple Sclerosis, one or more disorders H associated with amyotrophic lateral Sclerosis, one or more -N disorders associated with Down syndrome, one or more 25 disorders associated with elderly depression, Wernicke-Kor sakoff S syndrome, one or more disorders associated with 14. A pharmaceutical composition comprising the com corticobasal degenerations and one or more disorders asso pound according to claim 1, in free base or pharmaceutically ciated with prion disease. acceptable salt form, in combination or association with a 23. The method according to claim 20, wherein said pharmaceutically acceptable diluent or carrier. 30 patient suffers from one or more disorders associated with 15. The pharmaceutical composition according to claim dementia. 14, further comprising a second therapeutic agent selected 24. The method according to claim 20, wherein said from a group consisting of an anti-depressant, an anti patient suffers from a disorder involving the serotonin psychotic, a hypnotic agent, and an agent for the treatment 5-HT, receptor pathway, dopamine D2 receptor pathway of Parkinson's disease, mood disorders or dementia. 35 and/or serotonin reuptake transporter pathway. 16. A pharmaceutical composition comprising the com 25. The method according to claim 20, wherein said pound according to claim 1, in free base or pharmaceutically patient Suffers from a disorder selected from a group con acceptable salt form, in a polymeric matrix. sisting of agitation and aggressive behaviors. 26. The method according to claim 20, wherein said 17. The pharmaceutical composition according to claim 40 16, wherein the compound is in the form of microparticles patient suffers from one or more disorders selected from a or nanoparticles. group consisting of schizophrenia, depression, anxiety, sleep 18. The pharmaceutical composition according to claim disorder, agitation, aggressive behaviors, post-traumatic 16, wherein the polymeric matrix comprises poly(D.L- stress disorder and impulse control disorder. lactide-co-glycolide). 27. The method according to claim 26, wherein said 19. The pharmaceutical composition according to claim 45 disorder is schizophrenia. 18, wherein the molar ratio of lactide to glycolide is 75:25. 28. The method according to claim 26, wherein said 20. A method for modulating 5-hydroxytryptamine recep disorder is post-traumatic stress disorder. tor 2A activity in a patient and/or modulating serotonin 29. The method according to claim 26, wherein said disorder is impulse control disorder. transporter activity in a patient, comprising administering to 50 a patient in need thereof an active amount of the compound 30. The method according to claim 29, wherein said according to claim 1, in free base or pharmaceutically disorder is intermittent explosive disorder. acceptable salt form. k k k k k