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US008252799B2

(12) United States Patent (10) Patent No.: US 8,252,799 B2 Bilodeau et al. (45) Date of Patent: Aug. 28, 2012

(54) HEXAHYDRO-1H-4,7-METHANOISOINDOLE Dodd et al. Current Drug Safety vol. 1, pp. 25-33 (2006).* 1,3-DIONE COMPOUNDS Perrone et al. J. Med. Chem. vol. 37pp. 99-104.* Jones et al. Pharmacology, Biochemistry and Behavior, vol. 71, p. 555-568 (2002).* (75) Inventors: Mark T. Bilodeau, Lansdale, PA (US); Robichaud et al. in Annual Reports in Medicinal Chemistry, vol. 36. Kausik K. Nanda, Norristown, PA (US); p. 11-20 (2000).* B. Wesley Trotter, Glenside, PA (US) Kossakowski et al. Chemical Abstracts, vol. 128, No. 244028 (1998) Abstract for Acta Poloniae Pharmaceutica 54(6), pp. 479-481 (73) Assignee: Merck Sharp & Dohme Corp., (1997).* Rahway, NJ (US) K. Ishizumi et al., “Succinimide Derivatives. II. Synthesis and Activity of N-4-4-(1.2-Benzisothiazol-3-yl)-1- (*) Notice: Subject to any disclaimer, the term of this Piperazinylbutyl-1,2-Cis-Cyclohexandedicarboximide (SM-9018) patent is extended or adjusted under 35 and Related Compounds', Chem. Pharm. Bull., vol.43, vol. 12, pp. U.S.C. 154(b) by 144 days. 2139-2151, XP001026361, 1995. J. A. Cipollina et al., “Synthesis and Biological Activity of the Puta (21) Appl. No.: 12/530,944 tive Metabolites of the Agent '. J. Med. Chem, vol. 34, pp. 33.16-3328, XP002157852, 1991. P. Cole et al. “ Hydrochloride”. Drugs of the Future, vol. (22) PCT Filed: Apr. 3, 2008 33, pp. 316-322, 2008. T. Horisawa et al., “The Effects of Selective Antagonists of (86). PCT No.: PCT/US2O08/OO4336 5-HT7 and 5-HT1a Receptors on Mk-801-Induced impairment of S371 (c)(1), learning and memory in the passive avoidance and Morris Water (2), (4) Date: Sep. 11, 2009 Maze Tests in Rats: Mechanistic Implications for the Beneficial Effects of the Novel Atypical Antipsychotic Lurasidone”. Behavioral (87) PCT Pub. No.: WO2008/124030 Brain Research, vol. 220, pp. 83-90, 2011. T. Ishibashi et al., “Pharmacological Profile of Lurasidone, a Novel PCT Pub. Date: Oct. 16, 2008 Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT7) and 5-HT1A Receptor Activity” Pharmacology and Experimental (65) Prior Publication Data Therapeutics, vol. 334, pp. 171-181, 2010. T. Ishiyama et al., “Lurasidone (SM-13496), A Novel Atypical US 2010/O 105697 A1 Apr. 29, 2010 Antipsychotic Drug, Reverses MK-801-Induced Impariment of Learning and Memory in the Rat Passive-Avoidance Test'. E. Journal Related U.S. Application Data of Pharmacology, vol. 572, pp. 160-170, 2007. (60) Provisional application No. 60/921,759, filed on Apr. (Continued) 4, 2007. (51) Int. Cl. Primary Examiner — Emily Bernhardt A6 IK3I/496 (2006.01) (74) Attorney, Agent, or Firm — J. Eric Thies; Gerard M. C07D 417/12 (2006.01) Devlin (52) U.S. Cl...... 514/254.04:544/368 (58) Field of Classification Search ...... None See application file for complete search history. (57) ABSTRACT (56) References Cited The present invention is directed to therapeutic agents of the formula (I) which are atypical and which are U.S. PATENT DOCUMENTS useful in the treatment of neurological and psychiatric disor 4,366,172 A 12, 1982 Lednicer ...... 514,646 ders associated with D2 and serotonin 5-HT2A 4,745,117 A 5, 1988 Ishizumi et al. neurotransmission dysfunction. wherein; R' is C-6alkyl, 5,219,879 A * 6/1993 Ko et al...... 514,438 which is unsubstituted or substituted with 1-6 fluoro, wherein 5,532,372 A 7/1996 Saji et al. 5,780,632 A 7/1998 Saji et al. R" and the hydroxyl group on the ring are attached to the same 7,605.260 B2 10/2009 Kakiya et al. carbon atom; or a pharmaceutically acceptable salt thereof. 2006, O142276 A1 6, 2006 Ohno et al. 2008, 0255148 A1 10, 2008 Ohno et al. 2009/0076O27 A1 3/2009 Czarnik

FOREIGN PATENT DOCUMENTS O EP O 464 846 7, 1991 JP 8-333368 * 12/1996 R-C $ A v s S JP 8.333368 A 12/1996 -- N- N N WO WO2O110O2103 1, 2011 HO N M

OTHER PUBLICATIONS O Mayumietal. Chemical Abstracts, vol. 126 No. 30466h, Abstract for JP 8-333368 (Dec. 17, 1996) (1997).* Abstract for JP8333368 (Dec. 17, 1996), Obtained online from http:// v3.espacenet.com/publicationDetails/biblio?DB-EPOOC &adjacent=true&locale=en ep&FT=D&date= ... Mar. 26, 2011.* 8 Claims, No Drawings US 8,252,799 B2 Page 2

OTHER PUBLICATIONS L. Citrome et al., “Lurasidone for : A Review of the Efficacy and Safety Profile for this Newly Approved Second-Gen Meyer et al., "Lurasidone: a new drug in development for Schizo eration Antipsychotic'. Int. J. Clin. Pract, 2011, pp. 189-210, vol. 65. phrenia'. Expert Opin Investig Drugs, 18(11), pp. 1715-1726, 2009. M. Cruz et al., “Lurasidone HCI (Latuda), an Oral. Once-Daily M. Nakamura et al., "Lurasidone in the Treatment of Acute Schizo Atypical Antipsychotic Agent for the Treatment of Patients with phrenia: A Double-Blind, Placebo-Controlled Trial'. J. Clin. Psy Schizophrenia'. Drug Forecast, 2011, pp. 489-492, vol. 36. chiatry, pp. el-e8, 2009. T. Ishibashi et al., “Pharmacological profile of Lurasidone, a Novel Communication from European Patent Office for EPO Patent Appli Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT7) cation No. 08742 520.3 (Jul 22, 2010). and 5-HT1A Receptor Activity”. J. Pharmacology and Experimental Response submitted in EPO Patent Application No. 08 742 520.3 Therapeutics, 2010, vol. 171-181, vol. 334. (Sep. 23, 2010). J. Meyer et al., “Luasidone: A New Drug in Development for Schizo Written Opinion from Singapore Patent Office for Singapore Patent phrenia'. Drug Evaluation, 2009, pp. 1715-1726, vol. 18. Application No. 200906459-3 (Nov. 19, 2010). PCT International Preliminary Examination Report for PCT/ S. Caccia et al., “ and Metabolism Update for Some US2008/004336 (Oct. 15, 2009). Recent Antipsychotics”. Expert Opinion Drug Metab. Toxicol., 2011, pp. 829-846. * cited by examiner US 8,252,799 B2 1. 2 HEXAHYDRO-1H-4,7-METHANOISOINDOLE wherein: 1,3-DIONE COMPOUNDS R" is Calkyl, which is unsubstituted or substituted with 1-6 fluoro, wherein R' and the hydroxyl group on the ring are CROSS REFERENCE TO RELATED attached to the same carbon atom; APPLICATIONS or a pharmaceutically acceptable salt thereof. This application is a U.S. National Phase application under Within this embodiment, the present invention includes 35 U.S.C. S371 of PCT Application No. PCT/US2008/ compounds wherein R' is Calkyl which is unsubstituted or 004336, filed Apr. 3, 2008, which claims priority under 35 substituted with 1-6 fluoro. U.S.C. S 119(e) from U.S. Ser. No. 60/921,759, filed Apr. 4, 10 Further within this embodiment, the present invention 2007. includes compounds wherein R' is selected from the group consisting of: BACKGROUND OF THE INVENTION (1) methyl, Schizophrenia is a debilitating psychiatric disorder char 15 (2) ethyl, acterized by a combination of negative (blunted affect, with (3) n-propyl. drawal, anhedonia) and positive (paranoia, hallucinations, delusions) symptoms as well as marked cognitive deficits. (4) isopropyl. While the etiology of schizophrenia is currently unknown, the (5) trifluoromethyl, and disease appears to be produced by a complex interaction of (6) trifluoroethyl. biological, environmental, and genetic factors. Atypical antipsychotics form the front line in the treatment of schizo Further within this embodiment, the present invention phrenia and more recently in bipolar disorder. However, up to includes compounds wherein R' is methyl. Also further 30% of schizophrenic patients are not adequately treated by within this embodiment, the present invention includes com currently available . While there are a number of 25 pounds wherein R is ethyl. Also further within this embodi atypical antipsychotic agents currently available, these agents ment, the present invention includes compounds wherein R' suffer from a high rate of discontinuation due to either patient is trifluoromethyl. and/or physician dissatisfaction with efficacy or safety/toler An embodiment of the present invention includes com ability. Atypical antipsychotics possess a pharmacology pounds of the formula Ia: which is thought to underlie their ability to achieve efficacy at 30 positive symptoms via antagonism at dopamine D2 and sero tonin 5-HT, receptors. These activities produce some effi cacy on negative symptoms but also contribute to adverse side effects. These adverse side effects include weight gain/meta Ia bolic effects (thought to be associated with antagonism at 35 5-HT, and antagonism at histamine H1 receptors), extra pyramidal effects and prolactin secretion (thought to be asso ciated with antagonism at dopamine D2 receptors), sedation (thought to be associated with antagonism at C1 adrenergic HO and antagonism at histamine H1 receptors) and cognitive impairment (thought to be associated with antagonism at 40 muscarinic M1 receptors). Accordingly, there is a need in the art for atypical antipsychotic agents with better efficacy on positive symptoms, negative symptoms and/or decreased adverse side effects. 45 SUMMARY OF THE INVENTION wherein R' is defined herein; or a pharmaceutically acceptable salt thereof. The present invention is directed to therapeutic agents An embodiment of the present invention includes com which are atypical antipsychotics and which are useful in the pounds of the formula la': treatment of neurological and psychiatric disorders associ 50 ated with dopamine D2 and serotonin 5-HT2A neurotrans mission dysfunction. DETAILED DESCRIPTION OF THE INVENTION Ia 55 The present invention is directed to compounds of the formula I:

65 wherein R' is defined herein; or a pharmaceutically acceptable salt thereof. US 8,252,799 B2 3 4 An embodiment of the present invention includes com coupling reaction is often the formation of salts using an pounds of the formula Ib: enantiomerically pure acid or base. The diasteromeric deriva tives may then be converted to the pure enantiomers by cleav age of the added chiral residue. The racemic mixture of the Ib compounds can also be separated directly by chromato graphic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enanti O omer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of R. $ w /NN's known configuration by methods well known in the art. N- N N As appreciated by those of skill in the art, halo or halogen HO \ / as used herein are intended to include fluoro, chloro, bromo and iodo. Similarly, Ce, as in Calkyl is defined to identify O the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that Calkyl specifically 15 includes methyl, ethyl, n-propyl, iso-propyl. n-butyl, iso-bu wherein R' is defined herein; tyl, tert-butyl, penty1 and hexyl. A group which is designated or a pharmaceutically acceptable salt thereof. as being independently substituted with substituents may be An embodiment of the present invention includes com independently substituted with multiple numbers of such sub pounds of the formula Ib': stituents. The term “pharmaceutically acceptable salts' refers to salts prepared from pharmaceutically acceptable non-toxic Ib bases or acids including inorganic or organic bases and inor ganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, fer O 25 rous, lithium, magnesium, manganic salts, manganous, potassium, Sodium, Zinc, and the like. Particular embodi SS. / \ WNN S ments include the ammonium, calcium, magnesium, potas R N- N N sium, and Sodium salts. Salts in the Solid form may exist in HO \ / more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable O 30 organic non-toxic bases include salts of primary, secondary, and tertiary amines, Substituted amines including naturally occurring Substituted amines, cyclic amines, and basic ion wherein R' is defined herein; exchange resins, such as arginine, betaine, caffeine, choline, or a pharmaceutically acceptable salt thereof. N,N'-dibenzylethylene-diamine, diethylamine, 2-diethy Specific embodiments of the present invention include a 35 laminoethanol, 2-dimethylamino-ethanol, ethanolamine, compound which is selected from the group consisting of the ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, Subject compounds of the Examples herein and pharmaceu glucamine, glucosamine, histidine, hydrabamine, isopropy lamine, , methylglucamine, morpholine, , tically acceptable salts thereof and individual enantiomers piperidine, polyamine resins, procaine, purines, theobro and diastereomers thereof. 40 mine, triethylamine, trimethylamine, tripropylamine, The compounds of the present invention may contain one tromethamine, and the like. When the compound of the or more chiral centers and can thus occur as racemates and present invention is basic, salts may be prepared from phar racemic mixtures, single enantiomers, diastereomeric mix maceutically acceptable non-toxic acids, including inorganic tures and individual diastereomers. Additional asymmetric and organic acids. Such acids include acetic, Sulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, centers may be present depending upon the nature of the 45 fumaric, gluconic, glutamic, hydrobromic, hydrochloric, various Substituents on the molecule. Each Such asymmetric isethionic, lactic, maleic, malic, mandelic, methanesulfonic, center will independently produce two optical isomers and it mucic, nitric, pamoic, pantothenic, phosphoric, succinic, Sul is intended that all of the possible optical isomers and dias furic, tartaric, p-toluenesulfonic acid, and the like. Particular tereomers in mixtures and as pure or partially purified com embodiments citric, hydrobromic, hydrochloric, maleic, pounds are included within the ambit of this invention. The 50 phosphoric, Sulfuric, fumaric, and tartaric acids. It will be present invention is meant to comprehend all Such isomeric understood that, as used herein, references to the compounds forms of these compounds. of the present invention are meant to also include the phar The independent syntheses of these diastereomers or their maceutically acceptable salts. Exemplifying the invention is chromatographic separations may be achieved as known in the use of the compounds disclosed in the Examples and the art by appropriate modification of the methodology dis 55 herein. closed herein. Their absolute stereochemistry may be deter The Subject compounds are useful in a method of treating mined by the X-ray crystallography of crystalline products or a neurological or psychiatric disorder associated with dopam crystalline intermediates which are derivatized, if necessary, ine D2 and serotonin 5-HT2A neurotransmission dysfunction with a reagent containing an asymmetric center of known in a patient Such as a mammal in need of Such inhibition absolute configuration. If desired, racemic mixtures of the 60 comprising the administration of an effective amount of the compounds may be separated so that the individual enanti compound. In addition to primates, especially humans, a omers are isolated. The separation can be carried out by variety of other mammals can be treated according to the methods well known in the art, such as the coupling of a method of the present invention. racemic mixture of compounds to an enantiomerically pure The present invention is further directed to a method for the compound to form a diastereomeric mixture, followed by 65 manufacture of a medicament for treating neurological or separation of the individual diastereomers by standard meth psychiatric disorder associated with dopamine D2 and sero ods, such as fractional crystallization or chromatography. The tonin 5-HT2A neurotransmission dysfunction in humans and US 8,252,799 B2 5 6 animals comprising combining a compound of the present present compounds are also expected to have a lower propen invention with a pharmaceutical carrier or diluent. sity for weight gain and treatment related metabolic disorders The Subject treated in the present methods is generally a relative to currently-marketed atypical antipsychotics. mammal, in particular, a human being, male or female, in The compounds of the present invention have utility in whom therapy is desired. The term “therapeutically effective treating a variety of neurological and psychiatric disorders, amount’ means the amount of the Subject compound that will including one or more of the following conditions or diseases: elicit the biological or medical response of a tissue, system, Schizophrenia or psychosis including schizophrenia (para animal or human that is being sought by the researcher, Vet noid, disorganized, catatonic or undifferentiated), Schizo erinarian, medical doctor or other clinician. It is recognized phreniform disorder, schizoaffective disorder, delusional dis that one skilled in the art may affect the neurological and 10 order, brief psychotic disorder, shared psychotic disorder, psychiatric disorders by treating a patient presently afflicted psychotic disorder due to a general medical condition and with the disorders or by prophylactically treating a patient Substance-induced or drug-induced (, afflicted with such disorders with an effective amount of the and other dissociative anesthetics, and other compound of the present invention. As used herein, the terms psychostimulants and ) psychosispsychotic disorder, “treatment and “treating refer to all processes wherein there 15 psychosis associated with affective disorders, brief reactive may be a slowing, interrupting, arresting, controlling, or stop psychosis, Schizoaffective psychosis, "schizophrenia-spec ping of the progression of the neurological and psychiatric trum” disorders such as Schizoid or Schizotypal personality disorders described herein, but does not necessarily indicate a disorders, or illness associated with psychosis (such as major total elimination of all disorder symptoms, as well as the depression, manic depressive (bipolar) disorder, Alzheimer's prophylactic therapy to retard the progression or reduce the disease and post-traumatic stress syndrome), including both risk of the noted conditions, particularly in a patient who is the positive and the negative symptoms of schizophrenia and predisposed to Such disease or disorder. other psychoses; cognitive disorders including dementia (as The term “composition” as used herein is intended to Sociated with Alzheimer's disease, ischemia, multi-infarct encompass a product comprising the specified ingredients in dementia, trauma, Vascular problems or stroke, HIV disease, the specified amounts, as well as any product which results, 25 Parkinson's disease, Huntington's disease, Pick's disease, directly or indirectly, from combination of the specified Creutzfeldt-Jacob disease, perinatal hypoxia, other general ingredients in the specified amounts. Such term in relation to medical conditions or Substance abuse); delirium, amnestic pharmaceutical composition, is intended to encompass a disorders or age related cognitive decline; anxiety disorders product comprising the active ingredient(s), and the inert including acute stress disorder, agoraphobia, generalized ingredient(s) that make up the carrier, as well as any product 30 anxiety disorder, obsessive-compulsive disorder, panic which results, directly or indirectly, from combination, com attack, panic disorder, post-traumatic stress disorder, separa plexation or aggregation of any two or more of the ingredi tion anxiety disorder, social phobia, specific phobia, sub ents, or from dissociation of one or more of the ingredients, or stance-induced anxiety disorder and anxiety due to a general from other types of reactions or interactions of one or more of medical condition; Substance-related disorders and addictive the ingredients. Accordingly, the pharmaceutical composi 35 behaviors (including Substance-induced delirium, persisting tions of the present invention encompass any composition dementia, persisting amnestic disorder, psychotic disorder or made by admixing a compound of the present invention and a anxiety disorder, tolerance, dependence or withdrawal from pharmaceutically acceptable carrier. By “pharmaceutically Substances including , , cannabis, acceptable' it is meant the carrier, diluent or excipient must cocaine, hallucinogens, inhalants, nicotine, opioids, phen be compatible with the other ingredients of the formulation 40 cyclidine, sedatives, hypnotics or anxiolytics), obesity, and not deleterious to the recipient thereof. The terms bulimia nervosa and compulsive eating disorders; bipolar “administration of and or “administering a compound disorders, mood disorders including depressive disorders; should be understood to mean providing a compound of the depression including unipolar depression, seasonal depres invention or a prodrug of a compound of the invention to the sion and post-partum depression, premenstrual syndrome individual in need of treatment. 45 (PMS) and premenstrual dysphoric disorder (PDD), mood The utility of the compounds in accordance with the disorders due to a general medical condition, and Substance present invention as atypical antipsychotics may be demon induced mood disorders; learning disorders, pervasive devel strated by methodology well known in the art. In particular, opmental disorder including autistic disorder, attention dis the compounds of the following examples had activity in orders including attention-deficit hyperactivity disorder reference assays by exhibiting high affinity antagonism for 50 (ADHD) and conduct disorder; NMDA receptor-related dis dopamine D2, serotonin 5-HT2A. C2C adrenergic receptors, orders such as autism, depression, benign forgetfulness, partial agonism at 5-HT1A receptors and weak affinity at childhood learning disorders and closed head injury; move 5-HT2C, histamine H1 and M1 receptors. ment disorders, including akinesias and akinetic-rigid syn With respect to other imide compounds such as those dis dromes (including Parkinson's disease, drug-induced parkin closed in U.S. Pat. No. 5,532,372 (issued Jul. 2, 1996) and 55 Sonism, postencephalitic parkinsonism, progressive Japanese Patent Application.JP8-333368 (published Dec. 17, Supranuclear palsy, multiple system atrophy, corticobasal 1996), the present compounds exhibit unexpected properties, degeneration, parkinsonism-ALS dementia complex and Such as with respect to increased metabolic Stability, oral basal ganglia calcification), medication-induced parkin bioavailability, safety and/or selectivity with respect to rel Sonism (such as neuroleptic-induced parkinsonism, neuro evant receptors. In general, the present compounds possess 60 leptic malignant syndrome, neuroleptic-induced acute dysto relatively high affinity antagonism for dopamine D2, seroto nia, neuroleptic-induced acute akathisia, neuroleptic-induced nin 5-HT2A, C2C adrenergic receptors, partial agonism at tardive dyskinesia and medication-induced postural tremor), 5-HT1A receptors and weak affinity at 5-HT2C, histamine Gilles de la Tourette's syndrome, epilepsy, muscular spasms H1 and M1 receptors. Based on this receptor profile, the and disorders associated with muscular spasticity or weak present compounds are expected to have efficacy on positive 65 ness including tremors; dyskinesias including tremor (Such and negative symptoms of Schizophrenia. The present com as rest tremor, postural tremor and intention tremor), chorea pounds are also expected to be relatively well tolerated. The (such as Sydenham's chorea, Huntington's disease, benign US 8,252,799 B2 7 8 hereditary chorea, neuroacanthocytosis, symptomatic cho prising: administering to a patient in need thereofan effective rea, drug-induced chorea and hemibalism), myoclonus (in amount of a compound of the present invention. Particular cluding generalised myoclonus and focal myoclonus), tics Schizophrenia or psychosis pathologies are paranoid, disor (including simpletics, complex tics and symptomatic tics), ganized, catatonic or undifferentiated Schizophrenia and Sub and dystonia (including generalised dystonia Such as iodio stance-induced psychotic disorder. At present, the text revi pathic dystonia, drug-induced dystonia, symptomatic dysto sion of the fourth edition of the Diagnostic and Statistical nia and paroxymal dystonia, and focal dystonia Such as ble Manual of Mental Disorders (DSM-IV-TR) (2000, American pharospasm, oromandibular dystonia, spasmodic dysphonia, Psychiatric Association, Washington D.C.) provides a diag spasmodic torticollis, axial dystonia, dystonic writer's cramp nostic tool that includes paranoid, disorganized, catatonic or and hemiplegic dystonia); urinary incontinence; neuronal 10 undifferentiated Schizophrenia and Substance-induced psy damage including ocular damage, retinopathy or macular chotic disorder. As used herein, the term "schizophrenia or degeneration of the eye, tinnitus, hearing impairment and psychosis' includes treatment of those mental disorders as loss, and brain edema; emesis; and sleep disorders including described in DSM-IV-TR. The skilled artisan will recognize insomnia and narcolepsy. that there are alternative nomenclatures, noSologies and clas Of the disorders above, the treatment of schizophrenia, 15 sification systems for mental disorders, and that these systems bipolar disorder, depression including unipolar depression, evolve with medical and scientific progress. Thus the term seasonal depression and post-partum depression, premen “schizophrenia or psychosis” is intended to include like dis strual syndrome (PMS) and premenstrual dysphoric disorder orders that are described in other diagnostic sources. (PDD), learning disorders, pervasive developmental disorder In another specific embodiment, the present invention pro including autistic disorder, attention disorders including vides a method for treating Substance-related disorders and Attention-Deficit/Hyperactivity Disorder, autism, tic disor addictive behaviors, comprising: administering to a patient in ders including Tourette's disorder, anxiety disorders includ need thereof an effective amount of a compound of the ing phobia and post traumatic stress disorder, cognitive dis present invention. Particular substance-related disorders and orders associated with dementia, AIDS dementia, addictive behaviors are persisting dementia, persisting Alzheimer's, Parkinson's, Huntington's disease, spasticity, 25 amnestic disorder, psychotic disorder or anxiety disorder myoclonus, muscle spasm, tinnitus and hearing impairment induced by Substance abuse; and tolerance of dependence on and loss are of particular importance. or withdrawal from substances of abuse. At present, the text In a specific embodiment, the present invention provides a revision of the fourth edition of the Diagnostic and Statistical method for treating cognitive disorders, comprising: admin Manual of Mental Disorders (DSM-IV-TR) (2000, American istering to a patient in need thereof an effective amount of a 30 Psychiatric Association, Washington D.C.) provides a diag compound of the present invention. Particular cognitive dis nostic tool that includes persisting dementia, persisting orders are dementia, delirium, amnestic disorders and age amnestic disorder, psychotic disorder or anxiety disorder related cognitive decline. At present, the text revision of the induced by Substance abuse; and tolerance of dependence on fourth edition of the Diagnostic and Statistical Manual of or withdrawal from substances of abuse. As used herein, the Mental Disorders (DSM-IV-TR) (2000, American Psychiat 35 term "substance-related disorders and addictive behaviors’ ric Association, Washington D.C.) provides a diagnostic tool includes treatment of those mental disorders as described in that includes cognitive disorders including dementia, DSM-IV-TR. The skilled artisan will recognize that there are delirium, amnestic disorders and age-related cognitive alternative nomenclatures, noSologies and classification sys decline. As used herein, the term “cognitive disorders' tems for mental disorders, and that these systems evolve with includes treatment of those mental disorders as described in 40 medical and Scientific progress. Thus the term 'substance DSM-IV-TR. The skilled artisan will recognize that there are related disorders and addictive behaviors' is intended to alternative nomenclatures, noSologies and classification sys include like disorders that are described in other diagnostic tems for mental disorders, and that these systems evolve with SOUCS. medical and Scientific progress. Thus the term “cognitive In another specific embodiment, the present invention pro disorders' is intended to include like disorders that are 45 vides a method for treating pain, comprising: administering to described in other diagnostic Sources. a patient in need thereof an effective amount of a compound In another specific embodiment, the present invention pro of the present invention. Particular pain embodiments are vides a method for treating anxiety disorders, comprising: bone and joint pain (osteoarthritis), repetitive motion pain, administering to a patient in need thereofan effective amount dental pain, cancer pain, myofascial pain (muscular injury, of a compound of the present invention. Particular anxiety 50 fibromyalgia), perioperative pain (general Surgery, gyneco disorders are generalized anxiety disorder, obsessive-com logical), chronic pain and neuropathic pain. pulsive disorder and panic attack. At present, the text revision In another specific embodiment, the present invention pro of the fourth edition of the Diagnostic and Statistical Manual vides a method for treating obesity or eating disorders asso of Mental Disorders (DSM-IV-TR) (2000, American Psychi ciated with excessive food intake and complications associ atric Association, Washington D.C.) provides a diagnostic 55 ated therewith, comprising: administering to a patient in need tool that includes anxiety disorders are generalized anxiety thereof an effective amount of a compound of the present disorder, obsessive-compulsive disorder and panic attack. As invention. At present, obesity is included in the tenth edition used herein, the term “anxiety disorders' includes treatment of the International Classification of Diseases and Related of those mental disorders as described in DSM-IV-TR. The Health Problems (ICD-10) (1992 World Health Organiza skilled artisan will recognize that there are alternative nomen 60 tion) as a general medical condition. The text revision of the clatures, noSologies and classification systems for mental fourth edition of the Diagnostic and Statistical Manual of disorders, and that these systems evolve with medical and Mental Disorders (DSM-IV-TR) (2000, American Psychiat scientific progress. Thus the term "anxiety disorders” is ric Association, Washington D.C.) provides a diagnostic tool intended to include like disorders that are described in other that includes obesity in the presence of psychological factors diagnostic sources. 65 affecting medical condition. As used herein, the term “obesity In another specific embodiment, the present invention pro or eating disorders associated with excessive food intake vides a method for treating schizophrenia or psychosis com includes treatment of those medical conditions and disorders US 8,252,799 B2 9 10 described in ICD-10 and DSM-IV-TR. The skilled artisan ment may be prior to, concurrent to, or Subsequent to the will recognize that there are alternative nomenclatures, noso administration of other agent(s). logies and classification systems for general medical condi Accordingly, the Subject compounds may be used alone or tions, and that these systems evolve with medical and Scien in combination with other agents which are known to be tific progress. Thus the term “obesity or eating disorders beneficial in the subject indications or other drugs that affect associated with excessive food intake' is intended to include receptors or enzymes that either increase the efficacy, safety, like conditions and disorders that are described in other diag convenience, or reduce unwanted side effects or toxicity of nostic sources. the compounds of the present invention. The Subject com The subject compounds are further useful in a method for pound and the other agent may be co-administered, either in the prevention, treatment, control, amelioration, or reeduca 10 concomitant therapy or in a fixed combination. tion of risk of the diseases, disorders and conditions noted In one embodiment, the Subject compound may be herein. The subject compounds are further useful in a method employed in combination with anti-Alzheimer's agents, beta for the prevention, treatment, control, amelioration, or reduc secretase inhibitors, gamma-secretase inhibitors, HMG-CoA tion of risk of the aforementioned diseases, disorders and 15 reductase inhibitors, NSAID’s including ibuprofen, vitamin conditions in combination with other agents. The compounds E. and anti-amyloid antibodies. of the present invention may be used in combination with one In another embodiment, the Subject compound may be or more other drugs in the treatment, prevention, control, employed in combination with sedatives, hypnotics, anxi amelioration, or reduction of risk of diseases or conditions for olytics, antipsychotics, antianxiety agents, cyclopyrrolones, which compounds of the present invention or the other drugs imidazopyridines, pyrazolopyrimidines, minor tranquilizers, may have utility, where the combination of the drugs together melatonin and antagonists, melationergic agents, are safer or more effective than either drug alone. Such other , barbiturates, 5HT-2 antagonists, and the drug(s) may be administered, by a route and in an amount like. Such as: adinazolam, allobarbital, alonimid, alprazolam, commonly used therefor, contemporaneously or sequentially , , amobarbital, , arip with a compound of the present invention. When a compound 25 iprazole, bentazepam, , brotizolam, , of the present invention is used contemporaneously with one buspirione, butabarbital, butalbital, capuride, carbocloral, or more other drugs, a pharmaceutical composition in unit chloral betaine, chloral hydrate, , clonazepam, dosage form containing Such other drugs and the compound cloperidone, cloraZepate, chlordiazepoxide, clorethate, chlo of the present invention may be desirable. However, the com rpromazine, , cyprazepam, , dex bination therapy may also includes therapies in which the 30 clamol, diazepam, dichloralphenaZone, divalproex, diphen compound of the present invention and one or more other hydramine, , estazolam, ethchlorVynol, etomidate, drugs are administered on different overlapping schedules. It fenobam, flunitrazepam, , , flu is also contemplated that when used in combination with one razepam, , , fosazepam, glutethimide, or more other active ingredients, the compounds of the halazepam, , hydroxy Zine, , lithium, present invention and the otheractive ingredients may be used 35 lorazepam, lormetazepam, , mecloqualone, mela in lower doses than when each is used singly. Accordingly, the tonin, mephobarbital, meprobamate, methaqualone, pharmaceutical compositions of the present invention include midaflur, midazolam, , nisobamate, nitrazepam, those that contain one or more other active ingredients, in , , oxazepam, paraldehyde, paroxet addition to a compound of the present invention. The above ine, pentobarbital, , , phenelzine, phe combinations include combinations of a compound of the 40 nobarbital, prazepam, , propofol, , present invention not only with one other active compound, quazepam, , reclazepam, , roletamide, but also with two or more other active compounds. Likewise, secobarbital, , Suproclone, temazepam, thior compounds of the present invention may be used in combi idazine, thiothixene, tracazolate, tranylcypromaine, traZ nation with other drugs that are used in the prevention, treat odone, triazolam, , tricetamide, triclofos, trifluop ment, control, amelioration, or reduction of risk of the dis 45 erazine, trimetozine, , uldazepam, , eases or conditions for which compounds of the present Zaleplon, , Zolazepam, Zolpidem, and salts invention are useful. Such other drugs may be administered, thereof, and combinations thereof, and the like, or the subject by a route and in an amount commonly used therefor, con compound may be administered in conjunction with the use temporaneously or sequentially with a compound of the of physical methods such as with light therapy or electrical present invention. Accordingly, the pharmaceutical composi 50 stimulation. tions of the present invention include those that also contain In another embodiment, the Subject compound may be one or more other active ingredients, in addition to a com employed in combination with levodopa (with or without a pound of the present invention. The weight ratio of the com selective extracerebral decarboxylase inhibitor such as carbi pound of the present invention to the second active ingredient dopa or benserazide), anticholinergics Such as biperiden (op may be varied and will depend upon the effective dose of each 55 tionally as its hydrochloride or lactate salt) and trihex ingredient. Generally, an effective dose of each will be used. yphenidyl (benzhexyl)hydrochloride, COMT inhibitors such Thus, for example, when a compound of the present invention as entacapone, MOA-B inhibitors, antioxidants, A2a adenos is combined with another agent, the weight ratio of the com ine receptor antagonists, cholinergic agonists, NMDA recep pound of the present invention to the other agent will gener tor antagonists, serotonin receptor antagonists and dopamine ally range from about 1000:1 to about 1:1000, such as about 60 receptor agonists such as , , 200:1 to about 1:200. Combinations of a compound of the , , naxagolide, and pramipex present invention and other active ingredients will generally ole. It will be appreciated that the dopamine may be in also be within the aforementioned range, but in each case, an the form of a pharmaceutically acceptable salt, for example, effective dose of each active ingredient should be used. alentemol hydrobromide, bromocriptine mesylate, In Such combinations the compound of the present inven 65 fenoldopam mesylate, naxagolide hydrochloride and per tion and other active agents may be administered separately golide mesylate. Lisuride and pramipexol are commonly used or in conjunction. In addition, the administration of one ele in a non-salt form. US 8,252,799 B2 11 12 In another embodiment, the Subject compound may be vaginal, rectal, Sublingual, or topical routes of administration employed in combination with a compound from the phe and may be formulated, alone or together, in Suitable dosage nothiazine, , heterocyclic dibenzazepine, buty unit formulations containing conventional non-toxic pharma rophenone, and indolone classes of ceutically acceptable carriers, adjuvants and vehicles appro neuroleptic agent. Suitable examples of 5 priate for each route of administration. In addition to the include , , , treatment of warm-blooded animals such as mice, rats, , fluiphenazine, perphenazine and trifluopera horses, cattle, sheep, dogs, cats, monkeys, etc., the com zine. Suitable examples of include chlorpro pounds of the invention are effective for use in humans. thixene and thiothixene. An example of a dibenzazepine is 10 The term “composition” as used herein is intended to clozapine. An example of abutyrophenone is haloperidol. An encompass a product comprising specified ingredients in pre example of a diphenylbutylpiperidine is . An determined amounts or proportions, as well as any product example of an indolone is molindolone. Other neuroleptic which results, directly or indirectly, from combination of the agents include , and risperidone. It will be specified ingredients in the specified amounts. This term in appreciated that the neuroleptic agents when used in combi 15 relation to pharmaceutical compositions is intended to nation with the subject compound may be in the form of a encompass a product comprising one or more active ingredi pharmaceutically acceptable salt, for example, chlorprom ents, and an optional carrier comprising inert ingredients, as azine hydrochloride, mesoridazine besylate, thioridazine well as any product which results, directly or indirectly, from hydrochloride, acetophenazine maleate, fluiphenazine hydro combination, complexation or aggregation of any two or chloride, flurphenazine enathate, fluiphenazine decanoate, tri more of the ingredients, or from dissociation of one or more fluoperazine hydrochloride, thiothixene hydrochloride, halo of the ingredients, or from other types of reactions or inter peridol decanoate, loxapine Succinate and actions of one or more of the ingredients. In general, pharma hydrochloride. Perphenazine, , clozapine, ceutical compositions are prepared by uniformly and inti haloperidol, pimozide and risperidone are commonly used in 25 mately bringing the active ingredient into association with a a non-salt form. Thus, the Subject compound may be liquid carrier or a finely divided solid carrier or both, and then, employed in combination with acetophenazine, alentemol. if necessary, shaping the product into the desired formulation. , amisulpride, benzhexyl, bromocriptine, In the pharmaceutical composition the active object com biperiden, chlorpromazine, chlorprothixene, clozapine, diaz 30 pound is included in an amount Sufficient to produce the epam, fenoldopam, fluphenazine, haloperidol, levodopa, desired effect upon the process or condition of diseases. levodopa with benserazide, levodopa with carbidopa, Accordingly, the pharmaceutical compositions of the present lisuride, loxapine, mesoridazine, molindolone, naxagolide, invention encompass any composition made by admixing a olanzapine, pergolide, perphenazine, pimozide, , compound of the present invention and a pharmaceutically quetiapine, risperidone, Sulpiride, , trihex 35 acceptable carrier. yphenidyl, thioridazine, thiothixene, or Pharmaceutical compositions intended for oral use may be Ziprasidone. prepared according to any method known to the art for the In another embodiment, the Subject compound may be manufacture of pharmaceutical compositions and Such com employed in combination with an anti-depressant or anti positions may contain one or more agents selected from the anxiety agent, including reuptake inhibitors 40 group consisting of Sweetening agents, flavoring agents, col (including tertiary amine and secondary amine tri oring agents and preserving agents in order to provide phar cyclics), selective serotonin reuptake inhibitors (SSRIs), maceutically elegant and palatable preparations. Tablets con monoamine oxidase inhibitors (MAOIs), reversible inhibi tain the active ingredient in admixture with non-toxic tors of monoamine oxidase (RIMAS), serotonin and norad 45 pharmaceutically acceptable excipients that are Suitable for renaline reuptake inhibitors (SNRIs), corticotropin releasing the manufacture of tablets. The tablets may be uncoated or factor (CRF) antagonists, C.-adrenoreceptor antagonists, neu they may be coated by known techniques to delay disintegra rokinin-1 receptor antagonists, atypical anti-depressants, tion and absorption in the gastrointestinal tract and thereby benzodiazepines, 5-HT agonists or antagonists, especially provide a Sustained action over alonger period. Compositions 5-HT, partial agonists, and corticotropin releasing factor 50 for oral use may also be presented as hard gelatin capsules (CRF) antagonists. Specific agents include: amitriptyline, wherein the active ingredients are mixed with an inert solid clomipramine, doxepin, imipramine and trimipramine; diluent, for example, calcium carbonate, calcium phosphate amoxapine, desipramine, maprotiline, nortriptyline and pro or kaolin, or as Softgelatin capsules wherein the active ingre triptyline; fluoxetine, fluvoxamine, paroxetine and Sertraline; 55 dient is mixed with water or an oil medium, for example isocarboxazid, phenelzine, tranylcypromine and ; peanut oil, liquid paraffin, or olive oil. Aqueous suspensions, moclobemide: Venlafaxine; dulloxetine; aprepitant; bupro oily suspensions, dispersible powders or granules, oil-in-wa pion, lithium, nefazodone, and ; alpra ter emulsions, and sterile injectable aqueous or oleagenous Zolam, chlordiazepoxide, clonazepam, chloraZepate, diaz Suspension may be prepared by standard methods known in epam, halazepam, loraZepam, oxazepam and prazepam, 60 the art. , , and , and pharma The subject compounds are further useful in a method for ceutically acceptable salts thereof. the prevention, treatment, control, amelioration, or reeduca The compounds of the present invention may be adminis tion of risk of the diseases, disorders and conditions noted tered by oral, parenteral (e.g., intramuscular, intraperitoneal, 65 herein. The dosage of active ingredient in the compositions of intravenous, ICV, intracisternal injection or infusion, Subcu this invention may be varied, however, it is necessary that the taneous injection, or implant), by inhalation spray, nasal, amount of the active ingredient be such that a Suitable dosage US 8,252,799 B2 13 14 form is obtained. The active ingredient may be administered Several methods for preparing the compounds of this to patients (animals and human) in need of such treatment in invention are illustrated in the following Schemes and dosages that will provide optimal pharmaceutical efficacy. Examples. Starting materials and the requisite intermediates The selected dosage depends upon the desired therapeutic are in Some cases commercially available, or can be prepared effect, on the route of administration, and on the duration of 5 according to literature procedures or as illustrated herein. The the treatment. The dose will vary from patient to patient compounds of this invention may be prepared by employing depending upon the nature and severity of disease, the reactions as shown in the following schemes, in addition to patients weight, special diets then being followed by a other standard manipulations that are known in the literature patient, concurrent medication, and other factors which those 10 skilled in the art will recognize. Generally, dosage levels of or exemplified in the experimental procedures. Substituent between 0.0001 to 10 mg/kg. of body weight daily are admin numbering as shown in the schemes does not necessarily istered to the patient, e.g., humans and elderly humans. The correlate to that used in the claims and often, for clarity, a dosage range will generally be about 0.5 mg to 1.0 g. per single Substituent is shown attached to the compound where patient per day which may be administered in single or mul 15 multiple substituents are allowed under the definitions here tiple doses. In one embodiment, the dosage range will be inabove. Reactions used to generate the compounds of this about 0.5 mg to 500 mg per patient per day; in another invention are prepared by employing reactions as shown in embodiment about 0.5 mg to 200 mg per patient per day; and the schemes and examples herein, in addition to other stan in yet another embodiment about 5 mg to 50 mg per patient dard manipulations such as ester hydrolysis, cleavage of pro per day. Pharmaceutical compositions of the present inven tecting groups, etc., as may be known in the literature or tion may be provided in a Solid dosage formulation Such as exemplified in the experimental procedures. comprising about 0.5 mg to 500 mg active ingredient, or In some cases the final product may be further modified, for comprising about 1 mg to 250 mg active ingredient. The example, by manipulation of Substituents. These manipula pharmaceutical composition may be provided in a solid dos 25 tions may include, but are not limited to, reduction, oxidation, age formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg. alkylation, acylation, and hydrolysis reactions which are 50 mg, 100 mg, 200 mg or 250 mg active ingredient. For oral commonly known to those skilled in the art. In some cases the administration, the compositions may be provided in the form order of carrying out the foregoing reaction schemes may be of tablets containing 1.0 to 1000 milligrams of the active 30 varied to facilitate the reaction or to avoid unwanted reaction ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, products. The following examples are provided so that the 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams invention might be more fully understood. These examples of the active ingredient for the symptomatic adjustment of the are illustrative only and should not be construed as limiting dosage to the patient to be treated. The compounds may be the invention in any way. administered on a regimen of 1 to 4 times per day, Such as 35 once or twice per day. EXAMPLE 1.

O

NH CrO3 NH CHMgBr CH NH HO How O racemic racemic racemic

single enantiomer US 8,252,799 B2 15 16

-continued

CH3 N/ \N 7. Ho \ /

and

HO a. / \ s S CH N N \ /

O

(Separated by chiral HPLC)

Step 1: rac-(3aS4S,7S,7aR)-tetrahydro-1H-4,7- To a -78° C. solution of rac-(3aS.4S,7S,7aR)-tetrahydro methanoisoindole-1,3,5(4H)-trione 25 1H-4,7-methanoisoindole-1,3,5(4H)-trione (1.08 g. 6.03 mmol) (Kossakowski, Jerzy. Zawadowski, Teodor; Balicka, Eliza. Acta Poloniae Pharmaceutica (1997), 54 (6), 479-481) O in 50 ml of anhydrous THF was added methylmagnesium ' bromide (5.02 ml of a 3 M solution in THF, 15.07 mmol). NH After 2 hr, an additional 3 mL of methylmagnesium bromide solution was added. After another 2 hr., an additional 2 mL of methylmagnesium bromide solution was added. After 6 hr total at -78°C., the cooling bath was removed and the reac tion allowed to warm to room temperature. The reaction was Chromium trioxide (2.7 g) was dissolved in concentrated quenched with acetic acid (1.725 ml, 30.1 mmol) (Carefully). sulfuric acid (2.3 mL) and water (10 mL). 12.17 mL of this 200 uL of water was added, and the mixture was diluted with solution was added dropwise to a 0°C. solution of rac-(3aS, 40 CH2Cl and 2 mL MeOH. The mixture was dried over 4R.5S,7R,7ar)-5-hydroxyhexahydro-1H-4,7-methanoisoin NaSO filtered, and concentrated to give a white foam. The dole-1,3-dione (4.21 g) (prepared by modification of the pro- foam was dissolved in 5% MeOH/CH2Cl and filtered cedures in Japanese Patent Publication.JP8-333368, Dec. 17, through a plug of silica to give the titled compound as an 1996) in 20 mL of acetone. After 1 hr. 2-propanol (20 mL) 45 off-white solid. was added, and the reaction was stirred 30 min (orange color dissipates). The reaction was filtered through celite and con- Step 3: (3aS4S.5R,7S,7aR)-2-[(1R,2R)-2-[4-(1,2- centrated in vacuo. Silica gel chromatography eluting with benzisothiazol-3-yl)piperazin-1-yl) 98:2CHCl:MeoHafforded 4 g of the titled compound as a 50 methylcyclohexyl)methyl-5-hydroxy-5-methyl white solid. hexahydro-1H-4,7-methanoisoindole-1,3-dione

ylhexahydro-1H-4,7-methanoisoindole-1,3-dione 55

O 60 N-Ns CH3 NH CH3 7 How HO

US 8,252,799 B2 19 20 TABLE 1-continued

Compound Nomenclature MS M - 1 (3aR,4S,5S,7S,7aS)-2- 577.2432 ((1R,2R)-2-[4-(1,2- benzisothiazol-3- yl)piperazin-1- HO, yl)methylcyclohexyl)- CF N N 7s methyl-5-hydroxy-5- trifluoromethylhexahydro H-4,7-methanoisoindole 3-dione

(3.a.S.4S,5R,7S,7aR)-2- 577.2433 ((1R,2R)-2-[4-(1,2- benzisothiazol-3- yl)piperazin-1- Imethylcyclohexyl)- CF N N 7s methyl-5-hydroxy-5- y trifluoromethylhexahydro H-4,7-methanoisoindole 3-dione

While the invention has been described and illustrated with 25 3. A pharmaceutical composition which comprises a phar reference to certain particular embodiments thereof, those maceutically acceptable carrier and the compound of claim 1 skilled in the art will appreciate that various adaptations, changes, modifications, Substitutions, deletions, or additions or a pharmaceutically acceptable salt thereof. of procedures and protocols may be made without departing 4. A pharmaceutical composition which comprises a phar from the spirit and scope of the invention. What is claimed is: 30 maceutically acceptable carrier and the compound of claim 2 1. A compound which is: or a pharmaceutically acceptable salt thereof. 5. A method for treating schizophrenia in a human patient O in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 HO, S / V NN's 35 or a pharmaceutically acceptable salt thereof. CF N-f N N W 6. A method for treating schizophrenia in a human patient in need thereof which comprises administering to the patient O a therapeutically effective amount of a compound of claim 2 40 or a pharmaceutically acceptable salt thereof. or a pharmaceutically acceptable salt thereof. 7. A method for treating bipolar disorder in a human patient 2. A compound which is: in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 45 or a pharmaceutically acceptable salt thereof. O 8. A method for treating bipolar disorder in a human patient SS / \ 7NN in need thereof which comprises administering to the patient CF N- N N a therapeutically effective amount of a compound of claim 2 HO \ / or a pharmaceutically acceptable salt thereof. O

or a pharmaceutically acceptable salt thereof.