US007820695B2

(12) United States Patent (10) Patent No.: US 7820,695 B2 Weiner et al. (45) Date of Patent: *Oct. 26, 2010

(54) SELECTIVE SEROTONIN RECEPTOR 7,041,667 B1 5/2006 Armour et al. NVERSEAGONSTS AS THERAPEUTICS 7,115,634 B2 10/2006 Thurieau et al. FOR DISEASE 7,253,186 B2 8/2007 Andersson et al. 2002, 0004513 A1 1/2002 Andersson et al. 2002fO156068 A1 10/2002 Behan et al. (75) Inventors: David M. Weiner, San Diego, CA (US); 2002fO165225 A1 11/2002 Hamied et al. Robert E. Davis, San Diego, CA (US); 2004.0006081 A1 1/2004 Burrows et al. Mark R. Brann, Del Mar, CA (US) 2004/0106600 A1 6/2004 Andersson et al. 2004/021381.6 A1 10/2004 Weiner et al. (73) Assignee: ACADIA Pharmaceuticals, Inc., San 2005, OO14757 A1 1/2005 Andersson et al. Diego, CA (US) 2005, 0148018 A1 7/2005 Weiner et al. 2005/0244862 A1 11/2005 Brann (*) Notice: Subject to any disclaimer, the term of this 2005/0256.108 A1 1 1/2005 Schlienger patent is extended or adjusted under 35 2006/0094758 A1 5/2006 Andersson et al. U.S.C. 154(b) by 1474 days. 2006/0106063 A1 5/2006 Thygesen et al. 2006/01 11399 A1 5/2006 Thygesen et al. This patent is Subject to a terminal dis 2006/O194778 A1 8/2006 Andersson et al. claimer. 2006, O194834 A1 8/2006 Andersson et al. 2006/O1997.94 A1 9/2006 Schlienger 2006, O1998.18 A1 9/2006 Andersson et al. (21) Appl. No.: 10/850,819 2006, O199842 A1 9, 2006 Weiner et al. 2006/0205710 A1 9/2006 Schlienger et al. (22) Filed: May 21, 2004 2006/0205722 A1 9/2006 Andersson et al. 2006/0205780 A1 9/2006 Thygesen et al. (65) Prior Publication Data 2006/0205781 A1 9/2006 Thygesen et al. US 2005/0261340 A1 Nov. 24, 2005 2006/0264465 A1 11/2006 Weiner et al. (51) Int. Cl. (Continued) A6 IK 3/445 (2006.01) FOREIGN PATENT DOCUMENTS A6 IK3I/37 (2006.01) A6IP 25/24 (2006.01) CA 984843 3, 1976 (52) U.S. Cl...... 514/317; 514/277 (58) Field of Classification Search ...... 514/224.5, (Continued) 514/279, 595, 277, 317, 649 See application file for complete search history. OTHER PUBLICATIONS Benfield P. Heel RC, Lewis SP, “Fluoxetine. A review of its (56) References Cited pharmacodynamic and pharmacokinetic properties, and therapeutic U.S. PATENT DOCUMENTS efficacy in depressive illness.” Drugs, 1986, 32(6), pp. 481-508.* R&D Focus Drug News (Nov. 12, 2001).* 3,983,234 A 9/1976 Sayers Goodman and Gilman, The Pharmacological Basis of Therapeutics, 4,138.492. A 2f1979 Noverola et al. McGraw Hill, 1996, 9th ed., p. 434-435.* 4.255.432 A 3/1981 Kluge et al. Adam, et al. 1989. Effects of repeated ritanserin on middle-aged poor 4,332,804 A 6, 1982 Clark sleepers. Psychopharmacology, 99:219-221. 4,353,900 A 10, 1982 Clark Adell, et al. 2005. Strategies for producing faster acting antidepres 4,353,901 A 10, 1982 Clark sants. Drug Discovery Today, 10(8):578-585. 4,367,232 A 1/1983 Boix-Igleasias et al. Akin, et al. 2004. Decreased serotonin 5-HT, receptor-stimulated 4,853,394 A 8/1989 King et al. phosphoinositide signaling in fibroblasts from melancholic 5,025,013 A 6, 1991 Barreau et al. depressed patients. Neuropsychopharmacology, 29:2081-2087. 5,214,055 A 5/1993 Peglion et al. Alvisi, N. 1892. Sulla formazione di derivati pirazolici dalle 5,216,165 A 6, 1993 Mobilio et al. dicloridrine e dalla tribromidrina della glicerina ordinaria, Gazz. 5,461,066 A 10, 1995 Gericke et al. Chen. Ital. 22:158-168. 5,595,872 A 1/1997 Wetterau, II et al. 5,621,010 A 4/1997 Sueda et al. (Continued) 5,707,798 A 1/1998 Brann 5,795,894. A 8, 1998 Shue et al. Primary Examiner Sreeni Padmanabhan 5,869,488 A 2f1999 Shue et al. Assistant Examiner Sahar Javanmard 5,877,173 A 3/1999 Olney et al. (74) Attorney, Agent, or Firm Jones Day 5,912,132 A 6, 1999 Brann 5,955,281 A 9, 1999 Brann (57) ABSTRACT 6,107,324 A 8, 2000 Behan et al. 6,140,509 A 10, 2000 Behan et al. Disclosed herein are pharmaceutical compositions compris 6,150,393 A 11/2000 Behan et al. 6,358,698 B1 3, 2002 Weiner et al. ing an inverse serotonin receptoragonist or a serotonin recep 6.479,480 B1 1 1/2002 Moyes et al. tor antagonist and an anti-psychotic agent. Disclosed herein 6,756,393 B2 6/2004 Andersson et al. are also methods of treating psychotic disorders using the 6,815,458 B2 11/2004 Andersson et al. disclosed pharmaceutical compositions. 6,911,452 B2 6/2005 Schlienger 7,022,698 B2 4/2006 Hamied et al. 13 Claims, No Drawings US 7820,695 B2 Page 2

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Office Action dated Jul. 14, 2006, from U.S. Appl. No. 10/601,070, Office Action dated Aug. 22, 2007 in U.S. Appl. No. 11/122.293, filed filed Jun. 20, 2003. May 4, 2005. Supplemental Notice of Allowability dated May 23, 2008, from U.S. Appl. No. 11/417,439, filed May 3, 2006. * cited by examiner US 7,820,695 B2 1. 2 SELECTIVE SEROTONN RECEPTOR compulsive disorders, psychosis, Schizophrenia, Suicidal ten INVERSEAGONSTS AS THERAPEUTICS dency), certain neurodegenerative disorders (Alzheimer-type FOR DISEASE dementia, Parkinsonism, Huntington's chorea), anorexia, bulimia, disorders associated with alcoholism, cerebral vas BACKGROUND OF THE INVENTION 5 cular accidents, and migraine (Meltzer, Neuropsychophar macology, 21:106S-115S (1999); Barnes & Sharp, Neurop 1. Field of the Invention harmacology, 38:1083-1152 (1999); Glennon, Neurosci. The present invention relates to novel combinations of Biobehavioral Rev., 14:35 (1990)). Recent evidence strongly compounds that are effective as therapeutic agents in the implicates the 5-HT2 receptor subtype in the etiology of such treatment of depression, mania, or social phobia, and other 10 medical conditions as hypertension, thrombosis, migraine, psychotic disorders. The combinations include inverse sero vasospasm, ischemia, depression, anxiety, psychosis, Schizo tonin agonists and another antidepressant, anti-maniac, anti phrenia, sleep disorders and appetite disorders. phobia, or antipsychotic agent. Schizophrenia is a particularly devastating neuropsychiat 2. Description of the Related Art ric disorder that affects approximately 1% of the human Serotonin or 5-hydroxytryptamine (5-HT) plays a signifi- 15 population. It has been estimated that the total financial cost cant role in the functioning of the mammalian body. In the for the diagnosis, treatment, and lost Societal productivity of central nervous system, 5-HT is an important neurotransmit individuals affected by this disease exceeds 2% of the gross ter and neuromodulator that is implicated in Such diverse national product (GNP) of the United States. Current treat behaviors and responses as sleeping, eating, locomotion, per ment primarily involves pharmacotherapy with a class of ceiving pain, learning and memory, sexual behavior, control- 20 drugs known as antipsychotics. Antipsychotics are effective ling body temperature and blood pressure. In the spinal col in ameliorating positive symptoms (e.g., hallucinations and umn, serotonin plays an important role in the control systems delusions), yet they frequently do not improve negative of the afferent peripheral nociceptors (Moulignier, Rev. Neu symptoms (e.g., social and emotional withdrawal, apathy, and rol. 150:3-15, (1994)). Peripheral functions in the cardiovas poverty of speech). cular, hematological and gastrointestinal systems have also 25 Currently, nine major classes of antipsychotics are pre been ascribed to 5-HT. 5-HT has been found to mediate a scribed to treat psychotic symptoms. Use of these compounds variety of contractile, secretory, and electrophysiologic is limited, however, by their side effect profiles. Nearly all of effects including vascular and nonvascular Smooth muscle the “typical or older generation compounds have significant contraction, and platelet aggregation. (Fuller, Biology of adverse effects on human motor function. These “extrapyra Serotonergic Transmission, 1982; Boullin, Serotonin In Men- 30 midal' side effects, so termed due to their effects on modu tal Abnormalities 1:316 (1978); Barchas, et al., Serotonin and latory human motor systems, can be both acute (e.g., dystonic Behavior, (1973)). The 5-HT2A receptor subtype (also ref reactions, a potentially life threatening but rare neuroleptic erered to as subclass) is widely yet discretely expressed in the malignant syndrome) and chronic (e.g., akathisias, tremors, human brain, including many cortical, limbic, and forebrain and tardive dyskinesia). Drug development efforts have, regions postulated to be involved in the modulation of higher 35 therefore, focused on newer "atypical agents free of these cognitive and affective functions. This receptor Subtype is adverse effects. also expressed on mature platelets where it mediates, in part, Antipsychotic drugs have been shown to interact with a platelet aggregation, one of the initial steps in the process of large number of central monoaminergic neurotransmitter vascular thrombosis. receptors, including dopaminergic, serotonergic, adrenergic, Given the broad distribution of serotonin within the body, 40 muscarinic, and histaminergic receptors. It is likely that the it is understandable that tremendous interest in drugs that therapeutic and adverse effects of these drugs are mediated by affect serotonergic systems exists (Gershon, et al., The distinct receptor Subtypes. The high degree of genetic and Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); Sax pharmacological homology between these receptor Subtypes ena, et al., J. Cardiovascular Pharmacol. 15: Supp. 7 (1990)). has hampered the development of Subtype-selective com Serotonin receptors are members of a large human gene fam- 45 pounds, as well as the determination of the normal physi ily of membrane-spanning proteins that function as transduc ologic or pathophysiologic role of any particular receptor ers of intercellular communication. They exist on the Surface Subtype. Thus there is a need to develop drugs that are selec of various cell types, including neurons and platelets, where, tive for individual receptor classes and Subclasses amongst upon their activation by either their endogenous ligand sero monoaminergic neurotransmitter receptors. tonin or exogenously administered drugs, they change their 50 The prevailing theory for the mechanism of action of antip conformational structure and Subsequently interact with sychotic drugs involves antagonism of dopamine D2 recep downstream mediators of cellular signaling. Many of these tors. Unfortunately, it is likely that antagonism of dopamine receptors, including the 5-HT2A subclass, are G-protein D2 receptors also mediates the extrapyramidal side effects. coupled receptors (GPCRs) that signal by activating guanine Antagonism of 5-HT2A is an alternate molecular mechanism nucleotide binding proteins (G-proteins), resulting in the gen- 55 for drugs with antipsychotic efficacy, possibly through eration, or inhibition of second messenger molecules Such as antagonism of heightened or exaggerated signal transduction cyclic AMP. inositol phosphates, and diacylglycerol. These through serotonergic systems. 5-HT2A antagonists are there second messengers then modulate the function of a variety of fore good candidates for treating psychosis without extrapy intracellular enzymes, including kinases and ion channels, ramidal side effects. which ultimately affect cellular excitability and function. 60 Traditionally, these receptors have been assumed to existin At least 15 genetically distinct 5-HT receptor subtypes a quiescent state unless activated by the binding of an agonist have been identified and assigned to one of seven families (a drug that activates a receptor). It is now appreciated that (5-HT1-7). Each subtype displays a unique distribution, pref many, if not most, of the GPCR monoamine receptors, includ erence for various ligands, and functional correlate(s). ing serotonin receptors, can exist in a partially activated State Serotonin may be an important component in various types 65 in the absence of their endogenous agonists. This increased of pathological conditions such as certain psychiatric disor basal activity (constitutive activity) can be inhibited by com ders (depression, aggressiveness, panic attacks, obsessive pounds called inverse agonists. Both agonists and inverse US 7,820,695 B2 3 4 agonists possess intrinsic activity at a receptor, in that they and functional cellular assays (U.S. Patent Application Ser. alone can activate or inactivate these molecules, respectively. No. 60/103,317) or any other method known in the art. In contrast, classic or neutral antagonists compete against "Agonist’ is defined as a compound that increases the basal agonists and inverse agonists for access to the receptor, but do activity of a receptor when it contacts the receptor. not possess the intrinsic ability to inhibit elevated basal or 5 An “antagonist' is defined as a compound that competes constitutive receptor responses. with an agonist or inverse agonist for binding to a receptor, We have recently elucidated an important aspect of thereby blocking the action of an agonist or inverse agonist on 5-HT2A receptor function by applying the Receptor Selec the receptor. However, an antagonist (also known as a “neu tion and Amplification Technology (U.S. Pat. No. 5,707,798, tral antagonist) has no effect on constitutive receptor activ 1998; Chem Abstr. 128:111548 (1998) and citations therein), 10 ity. to the study of the 5-HT2 subclass of serotonin receptors. An “inverse agonist’ is defined as a compound that R-SAT is a phenotypic assay of receptor function that decreases the basal activity of a receptor (i.e., signaling medi involves the heterologous expression of receptors in mamma ated by the receptor). Such compounds are also known as lian fibroblasts. Using this technology we were able to dem negative antagonists. An inverse agonist is a ligand for a onstrate that native 5-HT2A receptors possess significant receptor that causes the receptor to adopt an inactive state constitutive, or agonist-independent, receptor activity (U.S. 15 relative to a basal state occurring in the absence of any ligand. Patent Application Ser. No. 60/103,317, herein incorporated Thus, while an antagonist can inhibit the activity of an ago by reference). Furthermore, by directly testing a large number nist, an inverse agonist is a ligand that can alter the confor of centrally acting medicinal compounds with known clinical mation of the receptor in the absence of an agonist. The activity in neuropsychiatric disease, we determined that com concept of an inverse agonist has been explored by Bond etal. pounds with antipsychotic efficacy all shared a common in Nature 374:272 (1995). More specifically, Bondet al. have molecular property. Nearly all of these compounds, which are proposed that unliganded f-adrenoceptor exists in an equi used by psychiatrists to treat psychosis, were found to be librium between an inactive conformation and a spontane potent 5-HT2A inverse agonists. This unique clinico-phar ously active conformation. Agonists are proposed to stabilize macologic correlation at a single receptor Subtype is compel the receptor in an active conformation. Conversely, inverse ling evidence that 5-HT2A receptor inverse agonism is a 25 agonists are believed to stabilize an inactive receptor confor molecular mechanism of antipsychotic efficacy in humans. mation. Thus, while an antagonist manifests its activity by Detailed pharmacological characterization of a large num virtue of inhibiting an agonist, an inverse agonist can addi ber of antipsychotic compounds revealed that they possess tionally manifest its activity in the absence of an agonist by broad activity at multiple related receptor subtypes. Most of inhibiting the spontaneous conversion of an unliganded these compounds display agonist, competitive antagonist, or 30 receptor to an active conformation. inverse agonist activity at multiple monoaminergic receptor The “5-HT2A receptor is defined as a receptor, having an Subtypes, including Serotoninergic, dopaminergic, adrener activity corresponding to the activity of the human serotonin gic, muscarinic and histaminergic receptors. This broad activ receptor Subtype, which was characterized through molecular ity is likely responsible for the sedating, hypotensive, and cloning and pharmacology as detailed in Saltzman et al., motor side effects of these compounds. It would therefore be Biochem. Biophys. Res. Comm. 181: 1469-78; and Julius et of great advantage to develop compounds that are selective 35 al., Proc. Natl. Acad. Sci. USA 87:928-932, the disclosures of inverse agonists of the 5-HT2A receptor, but which have little which are incorporated herein by reference in their entireties. or no activity on other monamine receptors Subtypes, espe The term “subject” refers to an animal, preferably a mam cially dopamine D2 receptors. Such compounds may be use mal, most preferably a human, who is the object of treatment, ful in the treatment of human disease (e.g., as anti-psychot observation or experiment. ics), and may avoid the adverse side effects associated with 40 “Selective' is defined as a property of a compound non-selective receptor interactions. whereby an amount of the compound sufficient to effect a desired response from a particular receptor type, Subtype, SUMMARY OF THE INVENTION class or Subclass with significantly less or Substantially little or no effect upon the activity other receptor types. For Disclosed herein are pharmaceutical compositions com 45 example, a selective compound may have at least a 10-fold prising an inverse serotonin receptor agonist or a serotonin greater effect on activity of the desired receptor than on other receptor antagonist and an anti-psychotic agent. Disclosed receptor types. In some cases, a selective compound may have herein are also methods of treating psychotic disorders using at least a 20-fold greater effect on activity of the desired the disclosed pharmaceutical compositions. receptor than on other receptor types, or at least a 50-fold 50 greater effect, or at least a 100-fold greater effect, or at least a DETAILED DESCRIPTION OF THE PREFERRED 1000-fold greater effect, or at least a 10,000-fold greater EMBODIMENT effect, or at least a 100,000-fold greater effect, or more thana 100,000-fold greater effect. “Selectivity” or “selective,” as an Definitions inverse agonist is understood as a property of the compound of the invention whereby an amount of compound that effec For the purpose of the current disclosure, the following 55 tively inversely agonizes the 5-HT2A receptor, and thereby definitions shall in their entireties be used to define technical decreases its activity, causes little or no inverse agonistic or terms, and shall also, in their entireties, be used to define the antagonistic activity at other, related or unrelated, receptors. Scope of the composition of matter for which protection is In particular, in one embodiment, a compound has Surpris sought in the claims. ingly been found not to interact strongly with other serotonin “Constitutive activity” is defined as the elevated basal 60 receptors (5-HT1A, 1B, 1D, 1E, 1F, 2B, 2C, 4A, 6, and 7) at activity of a receptor that is independent of the presence of an concentrations where the signaling of the 5-HT2A receptor is agonist. Constitutive activity of a receptor may be measured strongly or completely inhibited. In one embodiment, the using a number of different methods, including cellular (e.g., compound is also selective with respect to other monoamine membrane) preparations (see, e.g., Barr &. Manning, J. Biol. binding receptors, such as the dopaminergic, histaminergic, Chem. 272:32979-87 (1997)), purified reconstituted recep 65 adrenergic and muscarinic receptors. Compounds that are tors with, or without the associated G-protein in phospholipid highly selective for 5-HT2A receptors may have a beneficial vesicles (Cerione et al., Biochemistry 23:4519-25 (1984)), effect in the treatment of psychosis, Schizophrenia or similar US 7,820,695 B2 5 6 neuropsychiatric disorders, while avoiding adverse effects therapeutically effective amount of a first compound in com associated with drugs hitherto Suggested for this purpose. bination with a therapeutically effective amount of a second Serotonin or 5-hydroxytryptamine (5-HT) plays a signifi compound. cant role in the functioning of the mammalian body. In the central nervous system, 5-HT is an important neurotransmit- 5 In another aspect, the present invention relates to a method ter and neuromodulator that is implicated in Such diverse of treating mania in a patient comprising identifying a patient behaviors and responses as sleeping, eating, locomotion, per in need thereof, and administering to the patient a therapeu ceiving pain, learning and memory, sexual behavior, control tically effective amount of a first compound in combination ling body temperature and blood pressure. In the spinal col with a therapeutically effective amount of a second com umn, serotonin plays an important role in the control systems 10 pound. of the afferent peripheral nociceptors (Moulignier, Rev. Neu In yet another aspect, the present invention relates to a rol. 150:3-15, (1994)). Peripheral functions in the cardiovas cular, hematological, and gastrointestinal systems have also method of treating Social phobia in a patient comprising iden been ascribed to 5-HT. 5-HT has been found to mediate a tifying a patient in need thereof, and administering to the variety of contractile, secretory, and electrophysiologic patientatherapeutically effective amount of a first compound effects including vascular and nonvascular Smooth muscle 15 in combination with a therapeutically effective amount of a contraction, and platelet aggregation. (Fuller, Biology of second compound. Serotonergic Transmission, 1982: Botillin, Serotonin In Men In a further aspect, the present invention relates to a method tal Abnormalities 1:316 (1978); Barchas, et al., Serotonin and of treating psychosis in a patient comprising identifying a Behavior, (1973)). The 5-HT2A receptor subtype (also patient in need thereof, and administering to the patient a referred to as subclass) is widely yet discretely expressed in 20 the human brain, including many cortical, limbic, and fore therapeutically effective amount of a first compound in com brain regions postulated to be involved in the modulation of bination with a therapeutically effective amount of a second higher cognitive and affective functions. This receptor Sub compound. type is also expressed on mature platelets where it mediates, In another aspect, the present invention relates to a method in part, platelet aggregation, one of the initial steps in the 25 of treating a neuropsychiatric disorderina patient comprising process of vascular thrombosis. identifyingapatient in need thereof, and administering to said Given the broad distribution of serotonin within the body, patientatherapeutically effective amount of a first compound it is understandable that tremendous interest in drugs that in combination with a therapeutically effective amount of a affect serotonergic systems exists (Gershon, etat, The Periph second compound. In some embodiments, the neuropsychi eral Actions of 5-Hydroxytryptamine, 246 (1989); Saxena, et 30 atric disorder is selected from the group consisting of schizo at, J. Cardiovascular Pharmacol. 15: Supp. 7 (1990)). Sero phrenia and related idiopathic psychoses, anxiety, sleep dis tonin receptors are members of a large human gene family of orders, appetite disorders, affective disorders such as major membrane-spanning proteins that function as transducers of depression, bipolar disorder, and depression with psychotic intercellular communication. They exist on the Surface of features, and Tourette’s Syndrome, drug-induced psychoses, various cell types, including neurons and platelets, where, psychoses secondary to neurodegenerative disorders such upon their activation by either their endogenous ligand sero 35 tonin or exogenously administered drugs, they change their Alzheimer's or Huntington's Disease. conformational structure and Subsequently interact with The term “therapeutically effective amount” as used herein downstream mediators of cellular signaling. Many of these means an amount of an active compound or pharmaceutical receptors, including the 5-HT2A subclass, are G-protein agent that elicits the biological or medicinal response in a coupled receptors (GPCRs) that signal by activating guanine 40 tissue, system, animal or human that is being sought by a nucleotide binding proteins (G-proteins), resulting in the gen researcher, Veterinarian, medical doctor or other clinician, eration, or inhibition of second messenger molecules Such as which includes alleviation, amelioration, or lessening of the cyclic AMP. inositol phosphates, and diacylglycerol. These symptoms of the disease being treated, or prevents or slows second messengers then modulate the function of a variety of the progress of the disease or increase of the symptoms. intracellular enzymes, including kinases and ion channels, 45 In certain embodiments, the patient may be a mammal. The which ultimately affect cellular excitability and function. mammal may be selected from the group consisting of mice, At least 15 genetically distinct 5-HT receptor subtypes rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, pri have been identified and assigned to one of seven families mates, such as monkeys, chimpanzees, and apes, and humans. (5-HT1-7). Each subtype displays a unique distribution, pref In some embodiments, the patient is a human. erence for various ligands, and functional correlate(s). Sero 50 tonin may be an important component in various types of In some embodiments, the first compound in the above pathological conditions such as certain psychiatric disorders methods is an inverse agonist selective for a serotonin recep (depression, aggressiveness, panic attacks, obsessive com tor. In certain embodiments, the serotonin receptor is a pulsive disorders, psychosis, Schizophrenia, Suicidal ten 5HT2A receptor, while in other embodiments the serotonin dency), certain neurodegenerative disorders (Alzheimer-type receptor is a 5HT2C receptor. In other embodiments, the dementia, Parkinsonism, Huntington's chorea), anorexia, inverse agonists binds to a 5HT2A receptor and a 5HT2C bulimia, disorders associated with alcoholism, cerebral vas receptor. cular accidents, and migraine (Meltzer, Neuropsychophar In some embodiments, the first compound is a compound macology, 21 : 106S-115S (1999); Barnes & Sharp, Neurop of formula (I) harmacology, 38:1083-1152 (1999); Glennon, Neurosci. Biobehavioral Rev., 14:35 (1990)). Recent evidence strongly 60 implicates the 5-HT2 receptor subtype in the etiology of such medical conditions as hypertension, thrombosis, migraine, Z vasospasm, ischemia, depression, anxiety, psychosis, Schizo phrenia, sleep disorders and appetite disorders. Y X Ar2 In one aspect, the present invention relates to a method of 65 A1 ny- r Nx1 treating depression in a patient comprising identifying a W patient in need thereof, and administering to the patient a US 7,820,695 B2 7 8 is a 5HT2C receptor. In other embodiments, the antagonists -continued binds to a 5HT2A receptor and a 5HT2C receptor. where R In some embodiments, the second compound in the above methods is a selective serotonin reuptake inhibitor (SSRI). Examples of SSRIs include, but are not limited to, bupropion (Wellbutrin, Zyban), citalopram (Celexa), dulloxetine, escit (CH2) allopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Lu VOX), nefazodone (SerZone), paroxetine (Paxil), Sertaline Z is O (Zoloft), sibutramine, trazodone (Dividose), and Venlafaxine. 10 Any other SSRI currently known or later developed are within the scope of the present disclosure. In other embodiments, the second compound in the above methods is a serotonin/norepinephrine reuptake inhibitor wherein R is a hydrogen, a cyclic or straight-chained or (SNRI). Examples of SNRIs include, but are not limited to, branched acyclic organyl group, a lower hydroxyalkyl group, 15 citalopram (Celexa), dulexetine, escitalopram (Lexapro), flu a lower aminoalkyl group, or an aralkyl or heteroaralkyl Voxamine (LuVOX), and Venfalaxine (effexor). Any other group; and n is 1: SNRI currently known or later developed are within the scope X is methylene, vinylene, or an NH or N(lower alkyl) of the present disclosure. group; and X is methylene; or, when X is methylene or Infurther embodiments, the second compound in the above vinylene, X is methylene or a bond; or when X is methods is a monoamine oxidase inhibitor (MAO-I). methylene, X is O, S, NH, or N(lower alkyl) or a bond; Examples of MAO-Is include, but are not limited to, tranyl Y is methylene and Y is methylene, vinylene, ethylene, cypromine (Pamate), phenelZine (Nardil), maprotiline, and propylene, or a bond; or isocarboxazid (Marplan). Any other MAO-I currently known Y is a bond and Y is vinylene; or or later developed are within the scope of the present disclo 25 SUC. Y is ethylene and Y, is O, S, NH, or N(lower alkyl); In yet other embodiments, the second compound in the Ar and Arindependently are unsubstituted or substituted above methods is a tricyclic antidepressant (TCA). Examples aryl or heteroaryl groups, provided that Ar and Arare of TCAS include, but are not limited to, amitryptiline (Nor not simultaneously unsubstituted phenyl; and pramine), amoxapineclomipramine (Anafranil), W is oxygen; or 30 desipramine, doxepin (Sinequan), imipramine (Tofranil), a pharmaceutically acceptable salt or prodrug thereof. maprotiline, (Elavil), protryptiline, and trimipramine. Any In other embodiments, the first compound is a compound other TCA currently known or later developed are within the disclosed in U.S. patent application Publication Ser. No. Scope of the present disclosure. 2002/0004513 A1, published on Jan. 10, 2002, by Andersson In some other embodiments, the second compound in the et al., and entitled “AZACYCLIC COMPOUNDS, which is 35 above methods is a compound selected from aripiprazole the publication of the U.S. application Ser. No. 09/800,096, or (Abilify), clozapine, fluoxetinefolanzapine (Symbyax), olan in U.S. patent application Publication Ser. No. 2003/0220316 Zapine (Zyprexa), quetiapine (Seroquel), risperidone (Risper A1, published on Nov. 27, 2003, by Andersson et al., and dal), Valproic acid (Depakote), and Ziprasidone (Geodon). entitled “AZACYCLIC COMPOUNDS,” which is the publi Any other atypical antidepressant currently known or later cation of the U.S. application Ser. No. 10/409,782, or in U.S. 40 developed are within the scope of the present disclosure. application Ser. No. 10/802,970, filed on Mar. 16, 2004, by In some embodiments, the second compound in the above Andersson et al., and entitled “AZACYCLIC COM methods is a compound selected from chlorpromazine POUNDS,” the entire disclosure of all of which is hereby (Thorazine(R), mesoridazine (Serentil(R), prochlorperazine incorporated by reference herein in their entirety, including (Compazine(R), thioridazine (Mellaril.R.), haloperidol (Hal any drawings. 45 dolR), pimozide (Orap(R), clozapine (Clozaril(R), loxapine In another embodiment, the first compound is N-(1-meth (Loxitane(R), olanzapine (ZyprexaR), quetiapine (Sero ylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2-meth quel(R), resperidone (Resperidal(R), Ziprasidone (Geodon(R), ylpropyloxy)phenylmethyl)carbamide, which is the lithium carbonate, Aripiprazole (Abilify), Clozapine, Cloz aril, Compazine, Etrafon, Geodon, Haldol, Inapsine, Loxi 50 tane, Mellaril, Moban, Navane, Olanzapine (Zyprexa), Orap, (I) Permitil, Prolixin, Phenergan, Quetiapine (Seroquel), Reglan, Risperdal, Serentil, Seroquel, Stelazine, Taractan, CH3 Thorazine, Triavil, Trilafon, and Zyprexa. In some embodiments, the second compound in the above 55 methods is an antipsychotic agent. The antipsychotic agent may be selected from the group consisting of a phenothiazine, F - phenylbutylpiperadine, debenzapine, benzisoxidil, and salt H of lithium. The phenothiazine group of compounds may be N N selected from the group consisting of chlorpromazine (Thora 60 zine(R), mesoridazine (Serentil(R), prochlorperazine (Com r pazine(R), and thioridazine (MellarilR). The phenylbutylpip O eradine group of compounds may be selected from the group consisting of haloperidol (HaldolR), and pimozide (Orap(R). In another embodiment, the first compound in the above The debenzapine group of compounds may be selected from methods is an antagonist selective for a serotonin receptor. In 65 the group consisting of clozapine (CloZaril.R.), loxapine certain embodiments, the serotonin receptor is a 5HT2A (LoxitaneR), olanzapine (ZyprexaR) and quetiapine (Sero receptor, while in other embodiments the serotonin receptor quelR). The benzisoxidil group of compounds may be US 7,820,695 B2 10 selected from the group consisting of resperidone (Res single tablet, pill, or capsule, or a single solution for intrave peridal(R) and ziprasidone (Geodon(R). The salt of lithium nous injection, or a single drinkable solution, or a single may be lithium carbonate. In some embodiments, the antip dragee formulation or patch, contains both compounds. The sychotic agent may be selected from the group consisting of embodiments also include those in which each compound is Aripiprazole (Abilify), Clozapine, Clozaril, Compazine, 5 in a separate administrable composition, but the patient is Etrafon, Geodon, Haldol, Inapsine, Loxitane, Mellaril, directed to take the separate compositions nearly simulta Moban, Navane, Olanzapine (Zyprexa), Orap, Permitil, Pro neously, i.e., one pill is taken right after the other or that one lixin, Phenergan, Quetiapine (Seroquel), Reglan, Risperdal, injection of one compound is made right after the injection of Serentil, Seroquel, Stelazine, Taractan, Thorazine, Triavil, another compound, etc. Trilafon, and Zyprexa, or pharmaceutically acceptable salts 10 In other embodiments the administering step comprises thereof. administering one of the first compound and the second com In other embodiments, the second compound in the above pound first and then administering the other one of the first methods is a norepinephrine reuptake inhibitor. The norepi compound and the second compound. In these embodiments, nephrine reuptake inhibitor is selected from the group con the patient may be administered a composition comprising sisting of thionisoxetine and reboxetine. 15 one of the compounds and then at Some time, a few minutes or Infurther embodiments, the second compound in the above a few hours, later be administered another composition com methods is a dopamine agonist. The dopamine agonist may be prising the other one of the compounds. Also included in selected from the group consisting of Sumatriptan, almotrip these embodiments are those in which the patient is admin tan, naratriptan, froVatriptan, rizatriptan, Zomitriptan, caber istered a composition comprising one of the compounds on a goline, amantadine, lisuride, pergolide, ropinirole, pramipex routine or continuous basis while receiving a composition ole, and bromocriptine. comprising the other compound occasionally. In yet another embodiment, the second compound in the In another aspect, the present invention relates to a phar above methods is an anti-insomnia drug. Examples of anti maceutical composition comprising a first compound and a insomnia drugs include, but are not limited to, alprazolam second compound. (Xanax), chlordiazepoxide (Librium, Limbitrol), cloraZepate 25 In some embodiments, the first compound in the above (Tranxene), estazolam (ProSom), flurazepam (Dalmane), pharmaceutical composition is an inverse agonist selective hydroxy Zine (Atarax), lorazepam (Ativan), pentobarbital for a serotonin receptor. In certain embodiments, the seroto (Nembutal), quazepam (Doral), secobarbital (Seconal), nin receptor is a 5HT2A receptor, while in other embodiments temazepam (Restoril), triazolam (Halcion), Valium, Zaleplon the serotonin receptor is a 5HT2C receptor. In other embodi (Sonata), Zolpidem (Ambien), and the benzodiazepine family 30 ments, the inverse agonists binds to a 5HT2A receptor and a of drugs. Any other anti-insomnia drug currently known or 5HT2C receptor. later developed are within the scope of the present disclosure. In some embodiments, the first compound is a compound In other embodiments, the second compound in the above of formula (I) methods is an anti-manic drug. Examples of anti-manic drugs include, but are not limited to, divalproex (Depakote), lithium 35 carbonate (Eskalith), and lithium citrate. Any other anti I manic drug currently known or later developed are within the f Scope of the present disclosure. 2 N X Ar2 In some embodiments, the second compound in the above 40 A1 in 1 r Nx1 methods is an anti-phobia drug. An example of anti-phobia W drugs includes, but is not limited to, D-cycloserine. Those of where skill in the art recognize that Some of the other drugs disclosed R herein also work as anti-phobia drugs. Any other anti-manic drug currently known or later developed are within the scope 45 N N1 of the present disclosure. (CH2) In another embodiment, the second compound in the above methods is a serotonin 2A antagonist. Tthe serotonin 2A antagonist may be M 100.907 or an analog thereof. By “M Z is O 100,907 it is meant the compound of Formula II. 50

(II) wherein R is a hydrogen, a cyclic or straight-chained or H branched acyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an aralkyl or heteroaralkyl 55 group; and n is 1: X is methylene, vinylene, or an NH or N(lower alkyl) group; and X is methylene; or, when X is methylene or vinylene, X is methylene or a bond; or when X is methylene, X is O, S, NH, or N(lower alkyl) or a bond; -O F 60 Y is methylene and Y is methylene, vinylene, ethylene, propylene, or a bond; or In some embodiments, the administering step in the above Y is a bond and Y is vinylene; or methods comprises administering the first compound and the Y is ethylene and Y is O, S, NH, or N(lower alkyl); second compound simultaneously. These embodiments 65 Ar and Arindependently are unsubstituted or Substituted include those in which the first compound and the second aryl or heteroaryl groups, provided that Ar and Arare compound are in the same administrable composition, i.e., a not simultaneously unsubstituted phenyl; and US 7,820,695 B2 11 12 W is oxygen; or In yet other embodiments, the second compound in the a pharmaceutically acceptable salt or prodrug thereof. above pharmaceutical composition is a tricyclic antidepres sant (TCA). Examples of TCAS include, but are not limited to, In other embodiments, the first compound is a compound amitryptiline (Norpramine), amoxapineclomipramine (Anaf disclosed in U.S. patent application Publication Ser. No. ranil), desipramine, doxepin (Sinequan), imipramine (Tofra 2002/0004513 A1, published on Jan. 10, 2002, by Andersson nil), maprotiline, (Elavil), protryptiline, and trimipramine. et al., and entitled “AZACYCLIC COMPOUNDS, which is Any other TCA currently known or later developed are within the publication of the U.S. application Ser. No. 09/800,096, or the scope of the present disclosure. in U.S. patent application Publication Ser. No. 2003/0220316 In some other embodiments, the second compound in the A1, published on Nov. 27, 2003, by Andersson et al., and 10 above pharmaceutical composition is a compound selected entitled “AZACYCLIC COMPOUNDS,” which is the publi from aripiprazole (Abilify), clozapine, fluoxetine/olanzapine cation of the U.S. application Ser. No. 10/409,782, or in U.S. (Symbyax), olanzapine (Zyprexa), quetiapine (Seroquel), ris application Ser. No. 10/802,970, filed on Mar. 16, 2004, by peridone (Risperdal), Valproic acid (Depakote), and Ziprasi Andersson et al., and entitled “AZACYCLIC COM POUNDS,” the entire disclosure of all of which is hereby done (Geodon). Any other atypical antidepressant currently incorporated by reference herein in their entirety, including 15 known or later developed are within the scope of the present any drawings. disclosure. In some embodiments, the second compound in the above In another embodiment, the first compound is N-(1-meth pharmaceutical composition is a compound selected from ylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N'-(4-(2-meth chlorpromazine (Thorazine(R), mesoridazine (Serentil(R), ylpropyloxy)phenylmethyl)carbamide, which is the com prochlorperazine (Compazine(R), thioridazine (MellarilR), pound of Formula (I): haloperidol (HaldolR), pimozide (Orap(R), clozapine (Cloz aril(R), loxapine (LOXitane(R), olanzapine (ZyprexaR), que tiapine (Seroquel(R), resperidone (Resperidal(R), Ziprasi (I) done (Geodon(R), lithium carbonate, Aripiprazole (Abilify), CH3 25 Clozapine, Clozaril, Compazine, Etrafon, Geodon, Haldol, Inapsine, Loxitane, Mellaril, Moban, Navane, Olanzapine (Zyprexa), Orap, Permitil, Prolixin, Phenergan, Quetiapine (Seroquel), Reglan, Risperdal, Serentil, Seroquel, Stelazine, F - Taractan, Thorazine, Triavil, Trilafon, and Zyprexa. 30 In some embodiments, the second compound in the above H pharmaceutical composition is an antipsychotic agent. The N N antipsychotic agent may be selected from the group consist r ing of a phenothiazine, phenylbutylpiperadine, debenzapine, O benzisoxidil, and salt of lithium. The phenothiazine group of 35 compounds may be selected from the group consisting of In another embodiment, the first compound in the above chlorpromazine (Thorazine(R), mesoridazine (Serentil(R), pharmaceutical composition is an antagonist selective for a prochlorperazine (Compazine(R), and thioridazine (Mel serotonin receptor. In certain embodiments, the serotonin larilR). The phenylbutylpiperadine group of compounds may receptor is a 5HT2A receptor, while in other embodiments the be selected from the group consisting of haloperidol (Hal 40 dolR), and pimozide (Orap(R). The debenzapine group of serotonin receptor is a 5HT2C receptor. In other embodi compounds may be selected from the group consisting of ments, the antagonists binds to a 5HT2A receptor and a clozapine (CloZaril(R), loxapine (Loxitane(R), olanzapine 5HT2C receptor. (ZyprexaR) and quetiapine (Seroquel(R). The benzisoxidil In some embodiments, the second compound in the above group of compounds may be selected from the group consist pharmaceutical composition is a selective serotonin reuptake 45 ing of resperidone (Resperidal(R) and Ziprasidone (Geodon inhibitor (SSRI). Examples of SSRIs include, but are not (R). The salt of lithium may be lithium carbonate. In some limited to, bupropion (Wellbutrin, Zyban), citalopram (Cel embodiments, the antipsychotic agent may be selected from exa), dulloxetine, escitalopram (Lexapro), fluoxetine the group consisting of Aripiprazole (Abilify), Clozapine, (Prozac), fluvoxamine (Luvox), nefazodone (SerZone), par CloZaril. Compazine, Etrafon, Geodon, Haldol, Inapsine, oxetine (Paxil), sertaline (Zoloft), sibutramine, trazodone 50 Loxitane, Mellaril, Moban, Navane, Olanzapine (Zyprexa), (Dividose), and Venlafaxine. Any other SSRI currently Orap, Permitil, Prolixin, Phenergan, Quetiapine (Seroquel), known or later developed are within the scope of the present Reglan, Risperdal, Serentil, Seroquel, Stelazine, Taractan, disclosure. Thorazine, Triavil, Trilafon, and Zyprexa, or pharmaceuti In other embodiments, the second compound in the above cally acceptable salts thereof. pharmaceutical composition is a serotonin/norepinephrine 55 In other embodiments, the second compound in the above reuptake inhibitor (SNRI). Examples of SNRIs include, but pharmaceutical composition is a norepinephrine reuptake are not limited to, citalopram (Celexa), dulexetine, escitalo inhibitor. The norepinephrine reuptake inhibitor is selected pram (Lexapro), fluvoxamine (LuVOX), and Venfalaxine (ef from the group consisting of thionisoxetine and reboxetine. fexor). Any other SNRI currently known or later developed Infurther embodiments, the second compound in the above are within the scope of the present disclosure. 60 pharmaceutical composition is a dopamine agonist. The Infurther embodiments, the second compound in the above dopamine agonist may be selected from the group consisting pharmaceutical composition is a monoamine oxidase inhibi of Sumatriptan, almotriptan, naratriptan, froVatriptan, riza tor (MAO-I). Examples of MAO-Is include, but are not lim triptan, Zomitriptan, cabergoline, amantadine, lisuride, per ited to, tranylcypromine (Parnate), phenelzine (Nardil), golide, ropinirole, pramipexole, and bromocriptine. maprotiline, and isocarboxazid (Marplan). Any other MAO-I 65 In yet another embodiment, the second compound in the currently known or later developed are within the scope of the above pharmaceutical composition is an anti-insomnia drug. present disclosure. Examples of anti-insomnia drugs include, but are not limited US 7,820,695 B2 13 14 to, alprazolam (Xanax), chlordiazepoxide (Librium, Lim lamine, N-methyl-D-glucamine, tris(hydroxymethyl)methy bitrol), clorazepate (Tranxene), estazolam (ProSom), flu lamine, and salts with amino acids such as arginine, lysine, razepam (Dalmane), hydroxy Zine (Atarax), lorazepam (Ati and the like. Van), pentobarbital (Nembutal), quazepam (Doral), The term “ester refers to a chemical moiety with formula secobarbital (Seconal), temazepam (Restoril), triazolam —(R), COOR', where R and R' are independently selected (Halcion), Valium, Zaleplon (Sonata), Zolpidem (Ambien), from the group consisting of alkyl, cycloalkyl, aryl, het and the benzodiazepine family of drugs. Any other anti-in eroaryl (bonded through a ring carbon) and heteroalicyclic Somnia drug currently known or later developed are within (bonded through a ring carbon), and where n is 0 or 1. the scope of the present disclosure. An "amide' is a chemical moiety with formula —(R)- In other embodiments, the second compound in the above 10 C(O)NHR' or - (R), NHC(O)R', where Rand Rare inde pharmaceutical composition is an anti-manic drug. Examples pendently selected from the group consisting of alkyl, of anti-manic drugs include, but are not limited to, divalproex cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) (Depakote), lithium carbonate (Eskalith), and lithium citrate. and heteroalicyclic (bonded through a ring carbon), and Any other anti-manic drug currently known or later devel where n is 0 or 1. An amide may be an amino acid or a peptide oped are within the scope of the present disclosure. 15 molecule attached to a molecule of the present invention, In some embodiments, the second compound in the above thereby forming a prodrug. pharmaceutical composition is an anti-phobia drug. An Any amine, hydroxy, or carboxyl side chain on any of the example of anti-phobia drugs includes, but is not limited to, compounds disclosed herein can be esterified or amidified. D-cycloserine. Those of skill in the art recognize that some of The procedures and specific groups to be used to achieve this the other drugs disclosed herein also work as anti-phobia end are known to those of skill in the art and can readily be drugs. Any other anti-manic drug currently known or later found in reference sources such as Greene and Wuts, Protec developed are within the scope of the present disclosure. tive Groups in Organic Synthesis, 3" Ed., John Wiley & Sons, In another embodiment, the second compound in the above New York, N.Y., 1999, which is incorporated herein in its pharmaceutical composition is a serotonin 2A antagonist. entirety. 25 A “prodrug” refers to an agent that is converted into the Tthe serotonin 2A antagonist may be M100.907 or an analog parent drug in vivo. Prodrugs are often useful because, in thereof. By “M 100.907, it is meant the compound of For Some situations, they may be easier to administer than the mula II. parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may (II) 30 also have improved solubility in pharmaceutical composi H tions over the parent drug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the “prodrug') to facilitate transmittal across a cell membrane where water solubility is 35 detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further -O F example of a prodrug might be a short peptide (polyami noacid) bonded to an acid group where the peptide is metabo 40 lized to reveal the active moiety. In some embodiments, the pharmaceutical compositions In some embodiments, the pharmaceutical composition described herein are used to treat disorders disclosed in U.S. described herein further comprises a physiologically accept patent application Ser. No. 10/759,561, filed on Jan. 15, 2004, able carrier, diluent, or excipient, or a combination thereof. by Weiner et al., and entitled “SELECTIVE SEROTONIN The term “pharmaceutical composition” refers to a mixture 2AF2C RECEPTOR INVERSE AGONISTS AS THERA 45 of a compound of the invention with other chemical compo PEUTICS FOR NEURODEGENERATIVE DISEASES.” nents, such as diluents or carriers. The pharmaceutical com which is hereby incorporated by reference herein in its position facilitates administration of the compound to an entirety, including any drawings. organism. Multiple techniques of administering a compound It is understood by those of skill in the art that the com exist in the art including, but not limited to, oral, injection, pounds disclosed herein may be present as the compounds 50 aerosol, parenteral, and topical administration. Pharmaceuti themselves, or as pharmaceutically acceptable salts, esters, cal compositions can also be obtained by reacting compounds amides, or prodrugs thereof, all of which are contemplated by with inorganic or organic acids such as hydrochloric acid, the present invention. hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, The term “pharmaceutically acceptable salt” refers to a methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic formulation of a compound that does not cause significant 55 acid, salicylic acid and the like. irritation to an organism to which it is administered and does The term “carrier defines a chemical compound that not abrogate the biological activity and properties of the facilitates the incorporation of a compound into cells or tis compound. Pharmaceutical salts can be obtained by reacting sues. For example dimethyl sulfoxide (DMSO) is a com a compound of the invention with inorganic acids Such as monly utilized carrier as it facilitates the uptake of many hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric 60 organic compounds into the cells or tissues of an organism. acid, phosphoric acid, methanesulfonic acid, ethanesulfonic The term "diluent defines chemical compounds diluted in acid, p-toluenesulfonic acid, Salicylic acid and the like. Phar water that will dissolve the compound of interest as well as maceutical salts can also be obtained by reacting a compound stabilize the biologically active form of the compound. Salts of the invention with a base to form a salt such as an ammo dissolved in buffered solutions are utilized as diluents in the nium salt, analkali metal salt, Such as a Sodium orapotassium 65 art. One commonly used buffered solution is phosphate buff salt, an alkaline earth metal salt, such as a calcium or a ered saline because it mimics the salt conditions of human magnesium salt, a salt of organic bases such as dicyclohexy blood. Since buffer salts can control the pH of a solution at US 7,820,695 B2 15 16 low concentrations, a buffered diluent rarely modifies the Such as the cross-linked polyvinyl pyrrolidone, agar, or alg biological activity of a compound. inic acid or a salt thereof Such as Sodium alginate. The term “physiologically acceptable' defines a carrier or Dragee cores are provided with suitable coatings. For this diluent that does not abrogate the biological activity and purpose, concentrated Sugar Solutions may be used, which properties of the compound. may optionally contain gum arabic, talc, polyvinyl pyrroli The pharmaceutical compositions described herein can be done, carbopol gel, polyethylene glycol, and/or titanium administered to a human patient perse, or in pharmaceutical dioxide, lacquer Solutions, and Suitable organic solvents or compositions where they are mixed with other active ingre solvent mixtures. Dyestuffs or pigments may be added to the dients, as in combination therapy, or suitable carriers or tablets or dragee coatings for identification or to characterize excipient(s). Techniques for formulation and administration 10 different combinations of active compound doses. of the compounds of the instant application may be found in Pharmaceutical preparations which can be used orally “Remington’s Pharmaceutical Sciences.” Mack Publishing include push-fit capsules made of gelatin, as well as Soft, Co., Easton, Pa., 18th edition, 1990. sealed capsules made of gelatin and a plasticizer, Such as Suitable routes of administration may, for example, glycerol or Sorbitol. The push-fit capsules can contain the include oral, rectal, transmucosal, or intestinal administra 15 active ingredients in admixture with filler Such as lactose, tion; parenteral delivery, including intramuscular, Subcutane binders such as starches, and/or lubricants such as talc or ous, intravenous, intramedullary injections, as well as intrath magnesium Stearate and, optionally, stabilizers. In soft cap ecal, direct intraventricular, intraperitoneal, intranasal, or Sules, the active compounds may be dissolved or Suspended in intraocular injections. Suitable liquids, such as fatty oils, liquid paraffin, or liquid Alternately, one may administer the compound in a local polyethylene glycols. In addition, stabilizers may be added: rather than systemic manner, for example, via injection of the All formulations for oral administration should be in dosages compound directly in the renal or cardiac area, often in a Suitable for Such administration. depot or Sustained release formulation. Furthermore, one may For buccal administration, the compositions may take the administer the drug in a targeted drug delivery system, for form of tablets or lozenges formulated in conventional man example, in a liposome coated with a tissue-specificantibody. 25 . The liposomes will be targeted to and taken up selectively by For administration by inhalation, the compounds for use the organ. according to the present invention are conveniently delivered The pharmaceutical compositions of the present invention in the form of an aerosol spray presentation from pressurized may be manufactured in a manner that is itself known, e.g., by packs or a nebulizer, with the use of a Suitable propellant, e.g., means of conventional mixing, dissolving, granulating, dra 30 dichlorodifluoromethane, trichlorofluoromethane, dichlo gee-making, levigating, emulsifying, encapsulating, entrap rotetrafluoroethane, carbon dioxide or other suitable gas. In ping or tabletting processes. the case of a pressurized aerosol the dosage unit may be Pharmaceutical compositions for use in accordance with determined by providing a valve to deliver a metered amount. the present invention thus may be formulated in conventional Capsules and cartridges of, e.g., gelatin for use in an inhaleror manner using one or more physiologically acceptable carriers 35 insufflator may be formulated containing a powder mix of the comprising excipients and auxiliaries which facilitate pro compound and a suitable powder base such as lactose or cessing of the active compounds into preparations which can starch. be used pharmaceutically. Proper formulation is dependent The compounds may be formulated for parenteral admin upon the route of administration chosen. Any of the well istration by injection, e.g., by bolus injection or continuous known techniques, carriers, and excipients may be used as 40 infusion. Formulations for injection may be presented in unit Suitable and as understood in the art; e.g., in Remington's dosage form, e.g., in ampoules or in multi-dose containers, Pharmaceutical Sciences, above. with an added preservative. The compositions may take Such For injection, the agents of the invention may be formu forms as Suspensions, solutions or emulsions in oily or aque lated in aqueous solutions, preferably in physiologically ous vehicles, and may contain formulatory agents such as compatible buffers such as Hanks’s solution, Ringer's solu 45 Suspending, stabilizing and/or dispersing agents. tion, or physiological saline buffer. For transmucosal admin Pharmaceutical formulations for parenteral administration istration, penetrants appropriate to the barrier to be permeated include aqueous solutions of the active compounds in water are used in the formulation. Such penetrants are generally soluble form. Additionally, Suspensions of the active com known in the art. pounds may be prepared as appropriate oily injection Suspen For oral administration, the compounds can be formulated 50 sions. Suitable lipophilic solvents or vehicles include fatty readily by combining the active compounds with pharmaceu oils such as sesame oil, or synthetic fatty acid esters. Such as tically acceptable carriers well known in the art. Such carriers ethyl oleate or triglycerides, or liposomes. Aqueous injection enable the compounds of the invention to be formulated as Suspensions may contain Substances which increase the vis tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, cosity of the Suspension, Such as Sodium carboxymethyl cel Suspensions and the like, for oral ingestion by a patient to be 55 lulose, Sorbitol, or dextran. Optionally, the Suspension may treated. Pharmaceutical preparations for oral use can be also contain Suitable stabilizers or agents which increase the obtained by mixing one or more Solid excipient with pharma solubility of the compounds to allow for the preparation of ceutical combination of the invention, optionally grinding the highly concentrated Solutions. resulting mixture, and processing the mixture of granules, Alternatively, the active ingredient may be in powderform after adding suitable auxiliaries, if desired, to obtaintablets or 60 for constitution with a suitable vehicle, e.g., Sterile pyrogen dragee cores. Suitable excipients are, in particular, fillers such free water, before use. as Sugars, including lactose, Sucrose, mannitol, or Sorbitol; The compounds may also be formulated in rectal compo cellulose preparations such as, for example, maize starch, sitions such as Suppositories or retention enemas, e.g., con wheat starch, rice starch, potato starch, gelatin, gum traga taining conventional Suppository bases such as cocoa butter canth, methyl cellulose, hydroxypropylmethyl-cellulose, 65 or other glycerides. Sodium carboxymethylcellulose, and/or polyvinylpyrroli In addition to the formulations described previously, the done (PVP). If desired, disintegrating agents may be added, compounds may also be formulated as a depot preparation. US 7,820,695 B2 17 18 Such long acting formulations may be administered by in most instances, the present invention will use those same implantation (for example Subcutaneously or intramuscu dosages, or dosages that are between about 0.1% and 500%. larly) or by intramuscular injection. Thus, for example, the more preferably between about 25% and 250% of the estab compounds may be formulated with Suitable polymeric or lished human dosage. Where no human dosage is established, hydrophobic materials (for example as an emulsion in an 5 as will be the case for newly-discovered pharmaceutical com acceptable oil) or ion exchange resins, or as sparingly soluble pounds, a Suitable human dosage can be inferred from EDso derivatives, for example, as a sparingly soluble salt. or IDs values, or other appropriate values derived from in A pharmaceutical carrier for the hydrophobic compounds vitro or in vivo studies, as qualified by toxicity studies and of the invention is a cosolvent system comprising benzyl efficacy studies in animals. alcohol, a nonpolar Surfactant, a water-miscible organic poly 10 Although the exact dosage will be determined on a drug mer, and an aqueous phase. A common cosolvent system used by-drug basis, in most cases, some generalizations regarding is the VPD co-solvent system, which is a solution of 3% w/v. benzyl alcohol, 8% w/v of the nonpolar surfactant Polysor the dosage can be made. The daily dosage regimen for an bate 80TM, and 65% w/v polyethylene glycol 300, made up to adult human patient may be, for example, an oral dose of volume in absolute ethanol. Naturally, the proportions of a between 0.1 mg and 500 mg of each ingredient, preferably co-solvent system may be varied considerably without 15 between 1 mg and 250 mg, e.g. 5 to 200 mg oran intravenous, destroying its solubility and toxicity characteristics. Further Subcutaneous, or intramuscular dose of each ingredient more, the identity of the co-solvent components may be var between 0.01 mg and 100 mg, preferably between 0.1 mg and ied: for example, other low-toxicity nonpolar Surfactants may 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceu be used instead of POLYSORBATE 80TM; the fraction size of tical compositions of the present invention or a pharmaceuti polyethylene glycol may be varied; other biocompatible cally acceptable salt thereof calculated as the free base, the polymers may replace polyethylene glycol, e.g., polyvinyl composition being administered 1 to 4 times per day. Alter pyrrolidone; and other Sugars or polysaccharides may substi natively the compositions of the invention may be adminis tute for dextrose. tered by continuous intravenous infusion, preferably at a dose Alternatively, other delivery systems for hydrophobic of each ingredient up to 400 mg per day. Thus, the total daily pharmaceutical compounds may be employed. Liposomes 25 dosage by oral administration of each ingredient will typi and emulsions are well known examples of delivery vehicles cally be in the range 1 to 2000 mg and the total daily dosage or carriers for hydrophobic drugs. Certain organic solvents by parenteral administration will typically be in the range 0.1 Such as dimethylsulfoxide also may be employed, although to 400 mg. Suitably the compounds will be administered for usually at the cost of greater toxicity. Additionally, the com a period of continuous therapy, for example for a week or pounds may be delivered using a Sustained-release system, 30 more, or for months or years. Such as semipermeable matrices of Solid hydrophobic poly Dosage amount and interval may be adjusted individually mers containing the therapeutic agent. Various sustained-re to provide plasma levels of the active moiety which are suf lease materials have been established and are well known by ficient to maintain the modulating effects, or minimal effec those skilled in the art. Sustained-release capsules may, tive concentration (MEC). The MEC will vary for each com depending on their chemical nature, release the compounds 35 pound but can be estimated from in vitro data. Dosages for a few weeks up to over 100 days. Depending on the necessary to achieve the MEC will depend on individual chemical nature and the biological stability of the therapeutic characteristics and route of administration. However, HPLC reagent, additional strategies for protein stabilization may be assays or bioassays can be used to determine plasma concen employed. trations. Many of the compounds used in the pharmaceutical com binations of the invention may be provided as salts with 40 Dosage intervals can also be determined using MEC value. pharmaceutically compatible counterions. Pharmaceutically Compositions should be administered using a regimen which compatible salts may be formed with many acids, including maintains plasma levels above the MEC for 10-90% of the but not limited to hydrochloric, Sulfuric, acetic, lactic, tar time, preferably between 30-90% and most preferably taric, malic, succinic, etc. Salts tend to be more soluble in between 50-90%. aqueous or other protonic solvents than are the corresponding 45 In cases of local administration or selective uptake, the free acid or base forms. effective local concentration of the drug may not be related to Pharmaceutical compositions suitable for use in the plasma concentration. present invention include compositions where the active The amount of composition administered will, of course, ingredients are contained in an amount effective to achieve its be dependent on the subject being treated, on the subjects intended purpose. More specifically, a therapeutically effec 50 weight, the severity of the affliction, the manner of adminis tive amount means an amount of compound effective to pre tration and the judgment of the prescribing physician. vent, alleviate or ameliorate symptoms of disease or prolong The compositions may, if desired, be presented in a pack or the survival of the subject being treated. Determination of a dispenser device which may contain one or more unit dosage therapeutically effective amount is well within the capability forms containing the active ingredient. The pack may for of those skilled in the art, especially in light of the detailed example comprise metal or plastic foil. Such as ablisterpack. disclosure provided herein. 55 The pack or dispenser device may be accompanied by instruc The exact formulation, route of administration and dosage tions for administration. The pack or dispenser may also be for the pharmaceutical compositions of the present invention accompanied with a notice associated with the container in can be chosen by the individual physician in view of the form prescribed by a governmental agency regulating the patient’s condition. (See e.g., Fingletal. 1975, in “The Phar manufacture, use, or sale of pharmaceuticals, which notice is macological Basis of Therapeutics' Ch. 1 p. 1). Typically, the 60 reflective of approval by the agency of the form of the drug for dose range of the composition administered to the patient can human or veterinary administration. Such notice, for be from about 0.5 to 1000 mg/kg of the patient’s body weight. example, may be the labeling approved by the U.S. Food and The dosage may be a single one or a series of two or more Drug Administration for prescription drugs, or the approved given in the course of one or more days, as is needed by the product insert. Compositions comprising a compound of the patient. Note that for almost all of the specific compounds 65 invention formulated in a compatible pharmaceutical carrier mentioned in the present disclosure, human dosages for treat may also be prepared, placed in an appropriate container, and ment of at least some condition have been established. Thus, labeled for treatment of an indicated condition. US 7,820,695 B2 19 20 What is claimed is: or a pharmaceutically acceptable salt thereof, and a selec 1. A pharmaceutical composition comprising a compound tive serotonin reuptake inhibitor. of Formula (I) 4. The composition of claim3, wherein the selective sero tonin reuptake inhibitor is selected from the group consisting CH3 of bupropion, citalopram, duloxetine, escitalopram, fluvox amine, nefazodone, paroxetine, Sertaline, sibutramine, traZ odone, and Venlafaxine. 5. The pharmaceutical composition of claim 3, further comprising a physiologically acceptable carrier, diluent, or excipient, or a combination thereof. 6. The composition of claim 1, wherein the compound of formula (I) is the free base. 7. The composition of claim 1, wherein the composition is 15 in a single unit dosage form. or a pharmaceutically acceptable salt thereof, and fluoxetine. 8. The composition of claim 7, wherein the composition is 2. The pharmaceutical composition of claim 1, further in a single unit dosage form Suitable for oral administration to comprising a physiologically acceptable carrier, diluent, or a human. excipient, or a combination thereof. 9. The composition of claim 8, wherein the dosage form is 3. A pharmaceutical composition comprising a compound 20 solid. of Formula (I) 10. The composition of claim 9, wherein the composition is (I) in the form of a tablet or a capsule. CH 11. The composition of claim 10, wherein the composition l 25 is in the form of a tablet. 12. The composition of claim 1, wherein the amount of the compound of formula (I), or a pharmaceutically acceptable F N salt thereof, is from about 0.1 mg to about 500 mg. H 13. The composition of claim 1, wherein the amount of the compound of formula (I), or a pharmaceutically acceptable N 30 salt thereof, is from about 1 mg to about 40 mg. O