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US 2006OOO9465A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/00094.65 A1 Edgar et al. (43) Pub. Date: Jan. 12, 2006

(54) TREATMENT OF SLEEP DSORDERS USING Related U.S. Application Data SLEEPTARGET MODULATORS (60) Provisional application No. 60/349,912, filed on Jan. 18, 2002. Provisional application No. 60/357,320, (76) Inventors: Dale Edgar, Wayland, MA (US); David filed on Feb. 15, 2002. G. Hangauer, East Amherst, NY (US); Harry Jefferson Leighton, Rockport, Publication Classification ME (US) (51) Int. Cl. A61K 31/496 (2006.01) Correspondence Address: C07D 471/04 (2006.01) MINTZ, LEVIN, COHN, FERRIS, GLOWSKY (52) U.S. Cl...... 514/253.04; 544/362 AND POPEO, PC. ONE FINANCIAL CENTER (57) ABSTRACT BOSTON, MA 02111 (US) The invention is directed to compositions used for treating Sleep disorders. In addition, the invention provides conve Appl. No.: 10/501,855 nient methods of treatment of a sleep disorder. Furthermore, (21) the invention provides methods of treating Sleep disorders using compositions that remain active for a discrete period (22) PCT Fed: Jan. 21, 2003 of time to reduce side effects. More specifically, the inven tion is directed to the compositions and use of ester deriva tized compounds for the treatment of Sleep dis (86) PCT No.: PCT/US03/01845 orders. Patent Application Publication Jan. 12, 2006 Sheet 1 of 8 US 2006/00094.65 A1

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FIGURES

NREMSLEEP

120 180 MINUTES AFTER TREAMENT - (A) Methylcellulose vehicle 1 ml/kg PO (n=10) P CO.025 -- (B) HY2725:30mg/kg PO CT-18 (n=8) NREM SLEEP

120 MNUTSAFER TREATMENT - (A) Methylcellulose vehicle 1 ml/kg PO (n=10) * P & O.O25 - (B) Trazodone: 30mg/kg PO CT-18 (n=9) Patent Application Publication Jan. 12, 2006 Sheet 6 of 8 US 2006/00094.65 A1

FIGURE 6

REMSLEEP

12:00 O:00 CRC NTIME - (A) Methylcellulose vehicle 1 ml/kg PO (n=10) * P & O.025 - (B) HY2725; 30mg/kg PO CT-18 (n=8)

2. REMSLEEP

0:00 12:DO CRC NTIME - (A) Methylcellulose vehicle 1 ml/kg PO (n=10) P a 0.025 - (B) Trazodone: 30mg/kg PO CT-18 (n=9) Patent Application Publication Jan. 12, 2006 Sheet 7 of 8 US 2006/00094.65 A1

LGIRI[15)IH Patent Application Publication Jan. 12, 2006 Sheet 8 of 8 US 2006/00094.65 A1

8CHRIQ?INH US 2006/0009465 A1 Jan. 12, 2006

TREATMENT OF SLEEP DSORDERS USING Such that the disorder is treated. Accordingly, the therapeutic SLEEPTARGET MODULATORS compound can have the formula:

REFERENCE TO RELATED APPLICATION wherein SR is a Serotonin receptor antagonist, MR is a 0001. This application claims priority to pending U.S. metabolite reducing moiety that reduces the formation of Provisional Patent Application Attorney Docket Number wake promoting metabolites, EG is an ester group that HPZ-010-1 (Application No.60/349,912) filed on Jan. 18, modifies the half-life of the therapeutic compound, SP and 2002, and pending U.S. Provisional Patent Application SP are spacer molecules, n, q, and rare independently 0 or Attorney Docket Number HPZ-010-2 (Application No.60/ 1, and r and q are 0 when MR is the ester group. 357,320) filed on Feb. 15, 2002. This application is also 0009. Another aspect of the invention is a method of related to pending U.S. Provisional Patent Application Serial treating a Serotonin receptor associated disorder, comprising No. 60/ (Attorney Docket Number HPZ-010-3), filed administering to a Subject an effective amount of a thera on even date herewith, entitled “Treatment of Sleep Disor ders Using Sleep Target Modulators'. The entire content of peutic compound, Such that the disorder is treated. Accord each of the above-identified applications is hereby incorpo ingly, the therapeutic compound can have the formula: rated herein by reference. wherein SR is a Serotonin receptor antagonist, EG is an ester BACKGROUND OF THE INVENTION group that modifies the half-life of the therapeutic com 0002 Difficulties in falling asleep, remaining asleep, pound, SP is a Spacer molecule, and n is 0 or 1. Sleeping for adequate lengths of time, or abnormal Sleep 0010. In another aspect of the invention, the invention is behavior are common Symptoms for those Suffering with a a method of treating a sleep disorder. The method comprises Sleep disorder. A number of Sleep disorders, e.g., insomnia administering an effective amount of a therapeutic com or sleep apnea, are described in the online Merck Manual of pound, Such that the sleep disorder is treated, wherein the Medicinal Information. compound has a favorable biological property (FBP). 0.003 Current treatment of many sleep disorders include 0011. An additional aspect of the invention is a method of the use of prescription , e.g., benzodiazapines, that treating a sleep disorder. The method comprises administer may be habit-forming, lose their effectiveness after extended ing an effective amount of a therapeutic compound to a use, and metabolize more slowly for certain designated Subject, Such that the Sleep disorder is treated. Accordingly, groups, e.g., elderly perSons, resulting in persisting medica the therapeutic compound is traZodone compound that con tive effects. tains a moiety Selected and positioned, Such that a wake promoting metabolite is not formed. The therapeutic com 0004) Other, more mild manners of treatment include pound can have the formula: over-the-counter , e.g., or dimenhydrinate, which are not designed to be strictly Seda tive in their activity. This method of treatment is also wherein TZ is a trazodone compound, MR is a metabolite asSociated with a number of adverse side effects, e.g., reducing moiety that reduces the formation of wake pro persistence of the Sedating medication after the prescribed moting metabolites, EG is an ester group that modifies the time of treatment, or the so-called “hangover effect”. Many half-life of the therapeutic compound, SP and SP are of these side effects result from nonspecific activity in both Spacer molecules, n, q, and r are independently 0 or 1, and the periphery as well as the Central Nervous System (CNS) r and q are 0 when MR is the ester group that modifies the during this period of extended medication. half-life of the therapeutic compound. 0012 Another aspect of the invention is directed to a SUMMARY OF THE INVENTION method of treating a sleep disorder. The method comprises 0005. A need exists for the development of new compo administering an effective amount of a therapeutic com Sitions used for the improved treatment of Sleep disorders pound to a Subject, Such that the Sleep disorder is treated. that remain active for a discrete period of time to reduce side Accordingly, the therapeutic compound can have the for effects, such as the “hangover effect.” mula: 0006 Therefore, the invention is directed to composi tions used for treating sleep disorders. In addition, the wherein TZ is a traZOdone compound, EG is an ester group invention provides convenient methods of treatment of a that modifies the half-life of the therapeutic compound, SP Sleep disorder. Furthermore, the invention provides methods is a Spacer molecule, and n is 0 or 1. of treating sleep disorders using compositions that remain 0013 Another aspect of the invention is a method of active for a discrete period of time to reduce Side effects. modulating a Serotonin receptor associated disorder target. 0007 More specifically, the invention is directed to the The method comprises administering an effective amount of compositions and use of ester derivatized traZodone com a therapeutic compound to a Subject, Such that the disorder pounds for the treatment of Sleep disorders. target is modulated, wherein the therapeutic compound comprises the formula: 0008 Thus, in one aspect of the invention, the invention is directed to a method of treating a Serotonin receptor EG-(SP)-ISR-(SP)-IMR) asSociated disorder. The method comprises administering an wherein SR is a Serotonin receptor antagonist, MR is a effective amount of a therapeutic compound to a Subject, metabolite reducing moiety that reduces the formation of US 2006/0009465 A1 Jan. 12, 2006

wake promoting metabolites, EG is an ester group that wherein TZ is a trazodone compound, MR is a metabolite modifies the half-life of the therapeutic compound, SP, and reducing moiety that reduces the formation of wake pro SP are spacer molecules, n, q, and rare independently 0 or moting metabolites, EG is an ester group that modifies the 1, and r and q are 0 when MR is the ester group. half-life of the therapeutic compound, SP, and SP are 0.014) Another aspect of the invention is a method of Spacer molecules, n, q, and r are independently 0 or 1, and modulating a Serotonin receptor associated disorder target. r and q are 0 when MR is the ester group that modifies the The method comprises administering an effective amount of half-life of the therapeutic compound. a therapeutic compound to a Subject, Such that the disorder 0021. A further aspect of the invention is a compound target is modulated, wherein the therapeutic compound comprising the formula: comprises the formula: wherein TZ is a traZOdone compound, EG is an ester group wherein SR is a Serotonin receptor antagonist, EG is an ester that modifies the half-life of the therapeutic compound, SP group that modifies the half-life of the therapeutic com is a Spacer molecule, and n is 0 or 1. pound, SP is a Spacer molecule, and n is 0 or 1. 0022. Another aspect of the invention is a pharmaceutical 0.015. Another aspect of the invention is a method of composition comprising a therapeutic compound as pre modulating a sleep disorder target. pared according to the methodology of this invention, and a pharmaceutically acceptable carrier. 0016. The method comprises administering an effective amount of a therapeutic compound to a Subject, Such that the DETAILED DESCRIPTION OF THE Sleep disorder target is modulated, wherein the therapeutic INVENTION compound comprises the formula: 0023 The invention is directed to compositions used for treating sleep disorders. In addition, the invention provides wherein TZ is a trazodone compound, MR is a metabolite convenient methods of treatment of a sleep disorder. Fur reducing moiety that reduces the formation of wake pro thermore, the invention provides methods of treating Sleep moting metabolites, EG is an ester group that modifies the disorders using compositions that remain active for a dis s half-life of the therapeutic compound, SP and SP are crete period of time to reduce Side effects. More specifically, Spacer molecules, n, q, and r are independently 0 or 1, and the invention is directed to the compositions and use of ester r and q are 0 when MR is the ester group that modifies the derivatized traZOdone compounds for the treatment of Sleep half-life of the therapeutic compound. disorders. 0.017. An additional aspect of the invention is a method of modulating a sleep disorder target. The method comprises METHODS OF THE INVENTION administering an effective amount of a therapeutic com 0024. One embodiment of the invention is a method of pound to a Subject, Such that the Sleep disorder target is treating a Serotonin receptor associated disorder. The modulated, wherein the therapeutic compound comprises method comprises administering an effective amount of a the formula: therapeutic compound to a Subject, Such that the disorder is treated. Accordingly, the therapeutic compound can have the formula: wherein TZ is a traZOdone compound, EG is an ester group that modifies the half-life of the therapeutic compound, SP EG-(SP)-ISR-(SP)-IMR) is a Spacer molecule, and n is 0 or 1. wherein SR is a Serotonin receptor antagonist, MR is a metabolite reducing moiety that reduces the formation of 0.018. Another aspect of the invention is a compound wake promoting metabolites, EG is an ester group that comprising the formula: modifies the half-life of the therapeutic compound, SP and SP are spacer molecules, n, q, and rare independently 0 or wherein SR is a Serotonin receptor antagonist, MR is a 1, and r and q are 0 when MR is the ester group. In certain metabolite reducing moiety that reduces the formation of embodiments, the disorder is a Sleep disorder. wake promoting metabolites, EG is an ester group that 0025 The language “serotonin receptor antagonist” or modifies the half-life of the therapeutic compound, SP, and “SR’ is intended to include antagonists for the receptors for SP are spacer molecules, n, q, and rare independently 0 or Serotonin or 5-HT (5-hydroxytryptamine), i.e., compounds 1, and r and q are 0 when MR is the ester group. that inhibit the activity of the Serotonin receptor and agents 0019. In an additional aspect, the invention is a com that down-regulate (i.e., inhibit) the Synthesis or production pound comprising the formula: of the Serotonin receptor. 0026. The language “serotonin receptor” is intended to include receptors for serotonin or 5-HT (5-hydrox wherein SR is a Serotonin receptor antagonist, EG is an ester ytryptamine). In certain embodiments of the invention, the group that modifies the half-life of the therapeutic com receptor is the 5-HT, receptor, which belongs to the family pound, SP is a Spacer molecule, and n is 0 or 1. of rhodopsin-like Signal transducers, distinguished by their Seven-transmembrane configuration and their functional 0020. One aspect of the invention is a compound com linkage to G-proteins. While all the receptors of the sero prising the formula: tonin type are recognized by Serotonin, they are pharmaco logically distinct and are encoded by Separate genes. These US 2006/0009465 A1 Jan. 12, 2006 receptors, known as Subtypes, are generally coupled to Accordingly, the therapeutic compound can have the for different Second messenger pathways that are linked through mula: guanine-nucleotide regulatory (G) proteins. In certain embodiments, 5-HT, receptors activate phospholipase C pathways, Stimulating breakdown of polyphosphoinositides. wherein SR is a Serotonin receptor antagonist, EG is an ester group that modifies the half-life of the therapeutic com 0027. The 5-HT subfamily is divided into three recep pound, SP is a Spacer molecule, and n is 0 or 1. tor Subtypes: 5-HTA, 5-HT, and 5-HT. The human 0032) Another aspect of the invention is a compound 5-HT, receptor was first isolated and cloned in 1987, and the comprising the formula: human 5-HT, receptor was first isolated and cloned in 1990. These two receptors are thought to be the site of action of hallucinogenic drugs. Additionally, antagonists to the wherein SR is a Serotonin receptor antagonist, MR is a 5-HT, and 5-HT2 receptors are believed to be useful in metabolite reducing moiety that reduces the formation of treating depression, , psychosis and eating disorders. wake promoting metabolites, EG is an ester group that modifies the half-life of the therapeutic compound, SP, and 0028. In specific embodiments of the invention, the sero SP are spacer molecules, n, q, and rare independently 0 or tonin receptor is a 5-HT2A receptor. In certain embodiments, the 5-HT2A receptor is a Specific receptor, which has low 1, and r and q are 0 when MR is the ester group. affinity for other 5-HT receptor Subtypes. Alternatively, the 0033. In an additional aspect, the invention is a com 5-HT2A receptor is a general 5-HT2A receptor, which has a pound comprising the formula: significant affinity to two or more 5-HT receptor subtypes. 0029. The language “a serotonin receptor associated dis wherein SR is a Serotonin receptor antagonist, EG is an ester order is intended to include any disorder that is associated group that modifies the half-life of the therapeutic com with the 5-HT receptor. In certain embodiments of the pound, SP is a Spacer molecule, and n is 0 or 1. invention, the disorder is associated with the 5-HT2 receptor, 0034. Another aspect of the invention is a method of e.g., the 5-HT, receptor. Serotonin is thought to play a role modulating a Serotonin receptor associated disorder target. in processes related to learning and memory, Sleep, ther The method comprises administering an effective amount of moregulation, mood, motor activity, pain, Sexual and aggres a therapeutic compound to a Subject, Such that the disorder Sive behaviors, appetite, neurodegenerative regulation, and target is modulated, wherein the therapeutic compound biological rhythms. Moreover, serotonin has been linked to pathophysiological conditions Such as anxiety, depression, comprises the formula: obsessive-compulsive disorders, Schizophrenia, Suicide, autism, migraine, emesis, alcoholism and neurodegenerative wherein SR is a Serotonin receptor antagonist, MR is a disorders. metabolite reducing moiety that reduces the formation of wake promoting metabolites, EG is an ester group that 0030 Exemplary 5-HT, antagonists which are consid modifies the half-life of the therapeutic compound, SP and ered to be within the Scope of the present invention include, SP are spacer molecules, n, q, and rare independently 0 or but are not limited to , , alonimid, , , , , ben 1, and r and q are 0 when MR is the ester group. tazepam, , , , buSprione, 0035) Another aspect of the invention is a method of , butalbital, capuride, carbocloral, chloral modulating a Serotonin receptor associated disorder target. betaine, , , , The method comprises administering an effective amount of cloperidone, , clore thate, , cyprazepam, a therapeutic compound to a Subject, Such that the disorder desipramine, dexclamol, , , target is modulated, wherein is the therapeutic compound divalproex, diphenhydramine, , , ethchlo comprises the formula: rVynol, , fenobam, , , flu Voxamine, fluoxetine, foSazepam, , , hydroxy Zine, imipramine, lithium, , wherein SR is a Serotonin receptor antagonist, EG is an ester , maprotiline, , , group that modifies the half-life of the therapeutic com mephobarbital, , , , pound, SP is a Spacer molecule, and n is 0 or 1. , , nisobamate, , nortrip 0036) Another embodiment of the invention is a method tyline, , , paroxetine, , of treating a sleep disorder. The method of treating com , , , , prises administering to a Subject an effective amount of a , , , protriptyline, , therapeutic compound, Such that the Sleep disorder is reclazepam, roletamide, , Sertraline, , treated. , , tracazolate, tranylcypromaine, , trepipam, tricetamide, , , 0037. The language “sleep disorder,” is art recognized trimetozine, , uldazepam, Valproate, Venlafax and includes disorders or States that affect a Subjects ability ine, , Zolazepam, , and Salts thereof, and to Sleep, and which are treatable by the compounds combinations thereof. described herein. Sleep disorders generally involve distur bances of sleep that affect a subjects ability to fall and/or 0.031) Another embodiment of the invention is a method Stay asleep, and involve Sleeping too little, too much or of treating a Serotonin receptor associated disorder, com resulting in abnormal behavior associated with sleep. prising administering to a Subject an effective amount of a Examples include, but are not limited to disturbed biological therapeutic compound, Such that the disorder is treated. and circadian rhythms, and Sleep disturbances associated US 2006/0009465 A1 Jan. 12, 2006

with Such diseaseS as neurological disorders, neuropathic prevention or treatment of conditions associated with circa pain and restleSS leg Syndrome, allergies, tolerance to nar dian rhythmicity as well as mental and physical disorders cotics or withdrawal from narcotics, Sleep apnea; narco asSociated with travel acroSS time Zones and with rotating lepsy, insomnia, Disorders of Initiating and Maintaining shift-work Schedules. Sleep (insomnias) (“DIMS") which can arise from psycho physiological causes, as a consequence of psychiatric dis 0039 The language “insomnia” is characterized by dif orders particularly related to anxiety), from drugs and alco ficulty in Sleeping or disturbed sleep patterns. Insomnia may hol use and abuse (particularly during withdrawal stages), be of a primary nature with little apparent relationship to childhood onset DIMS, nocturnal myoclonus and restless immediate Somatic or psychic events, or Secondary to Some legs and non Specific REM disturbances as Seen in aging, acquired pain, anxiety or depression, and is further described parasomnia, jet-lag Syndrome, hyperSomnia, Sleep apnea, by Mondadori et al. in U.S. Pat. No. 6,277.864. REM sleep interruptions, shift workers' sleep disturbances, 0040. The terms “treating” or “treatment” include admin dySomnias, night terror, insomnias associated with depres istering a therapeutically effective compound Sufficient to Sion or with emotional/mood disorders, as well as Sleep reduce or eliminate at least one Symptom of the State, disease walking and enuresis, as well as sleep disorders which or disorder, e.g., a Sleep disorder. It will be appreciated to accompany aging, mental and physical disorders associated those skilled in the art that reference herein to treatment with travel acroSS time Zones and with rotating shift-work extends to prophylaxis (prevention) as well as the treatment Schedules, or Syndromes Such as fibromyalgia that are mani of the noted diseases/disorders and Symptoms. fested by non-restorative Sleep and muscle pain or Sleep 0041. The language “administering” includes delivery to apnea which is associated with respiratory disturbances a subject by any means that does not affect the ability of the during Sleep; and drug abuse. Difficulties in falling asleep, therapeutic compound to perform is intended function. The remaining asleep, Sleeping for adequate lengths of time, or therapeutic compound may be administered by any means abnormal Sleep behavior are common Symptoms for those that Sufficiently treats the disorder target. Administration Suffering with a sleep disorder. A number of sleep disorders, includes, but is not limited to parenteral, enteral, and topical e.g., insomnia or Sleep apnea, are described in the online administration. While it is possible for a compound of the Merck Manual of Medicinal Information. present invention to be administered alone, it is preferable to 0.038. The administration to a subject of an appropriate administer the compound as a pharmaceutical composition, amount of a compound of the invention, is useful, for which includes compositions that comprise the compounds example, in the prevention or treatment of the following of the present invention and a pharmaceutically acceptable conditions to achieve chronobiological effects and/or to carrier. In a specific embodiment, the therapeutic compound alleviate circadian rhythm phase disturbances: disorders of is administered orally. the Sleep-wake Schedule; jet lag; shift work, people who 0042 Administration also includes the use of an addi have a maladaption to work and off-work Schedules, medical tional modulating factor (AMF) in “combination therapy.” residents, nurses, firemen, policemen or those whose duties The language “additional modulating factor (AMF)” require alertneSS and wakefulness at evening or nighttime includes additional factors, Such as additional therapeutics hours, or those deprived of Sleep for various periods because or abnormalities in the Subject, e.g., a chemical imbalance. of their duties or responsibilities, animal workers, athletes It should be understood that the additional modulating factor who wish to reset their internal clock to a more beneficial may be directed to or affect the same or a different disorder time; the infantry, or other members of the armed forces target as that being modulated by the compounds of the whose duties require extreme levels of alertneSS and wake present invention. The language “combination therapy' fulness, and those who may be sleep deprived in the per includes the co-administration of the modulating compound formance of these duties; Submariners, or people confined of the present invention in the presence of an additional for research, exploration or industrial purposes below the modulating factor, e.g., an additional therapeutic agent. Seas, miners, Spelunkers, researchers or those confined Administration of the modulating compound may be first, beneath the Earth; astronauts in orbit around the Earth, on followed by the other therapeutic agent, or administration of missions in Space to the Earth's moon or to the planets or out the other therapeutic agent may be first, followed by the of the Solar System, or in training for Such missions, the blind modulating, e.g., inhibiting, compound. The other therapeu or Sight-impaired or those perSons whose ability to distin tic agent may be any agent which is known in the art to treat, guish differences in light and dark may be permanently or prevent, or reduce the Symptoms of the targeted disorder, temporarily impaired; psychiatric patients, insomniacs, the e.g., a Sleep disorder. Furthermore, the other therapeutic comatose, or those who need to be maintained in a State of agent may be any agent of benefit to the patient when unconsciousness for medical, psychiatric or other reasons, administered in combination with the administration of a residents of the far North or Antarctica, or those persons who modulating, e.g., inhibiting, compound. live in a climate or climates which possess abnormal amounts of light or darkness, those Suffering from Seasonal 0043. For example, a therapeutic compound of the inven affective disorder (SAD), winter depression, or other forms tion may be administered in conjunction with a variety of of depression; the aged; Alzheimer's disease patients, or commercially-available drugs, including, but not limited to, those Suffering from other forms of dementia; patients who antimicrobial agents, Such as pentamidine, lomefloxacin, require dosages of medication at appropriate times in the metronidazole; fungistatic agents, germicidal agents, hor circadian cycles, patients Suffering from delayed sleep phase mones, antipyretic agents, antidiabetic agents, bronchodila Syndrome, advanced Sleep phase Syndrome, or non-24 hr tors, Such as aminophylline; antidiarrheal agents, Such as Sleep phase Syndrome; and patients Suffering from primary diphenoxylate hydrochloride with atropine Sulfate; antiar or Secondary insomnia or circadian rhythm-related insom rhythmic agents, Such as disopyramide phosphate and bidi nia. The present invention is useful, for example, in the Somide; coronary dilation agents, glycosides, Spasmolytics, US 2006/0009465 A1 Jan. 12, 2006 antihypertensive agents, Such as Verapamil and Verapamil fen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, hydrochloride and their enantiomers, and betaxolol, antide Oxaprozin, pranoprofen, miroprofen, tioxaprofen, Suprofen, preSSants, antianxiety agents; other psychotherapeutic albinoprofen, tiaprofenic acid, fluprofen, bucloxic acid, or agents, Such as Zolpidem, and millacemide; cor pharmaceutically acceptable Salts thereof. ticosteroids, analgesics, Such as misoprostol with diclofenac, contraceptives, Such as ethynodiol diacetate with 0046. Furthermore, a compound of the invention also ethinyl estradiol, and norethynodrel with meStranol; nonste may be administered in conjunction with any one or com roidal anti-inflammatory drugs, Such as Oxaprozen, blood bination of the commercially-available, over-the-counter or glucose lowering agents, cholesterol lowering agents, anti prescription medications, including, but not limited to convulsant agents; other antiepileptic agents, immunomodu Avobenzene/padimate-O, ACCUPRIL(R) tablets (quinapril lators, antioholinergics, , Sympathomimetics, hydrochloride), Accutane capsules (isotretinoin), Achromy vasodilatory agents, anticoagulants, antiarrhythmics, Such cin V capsules (the monohydrochloride of (4S-(4C,4a. al as disopyramide or disobutamide, prostaglandins having pha.,5ao.6.f3, 12ao.))-4-(dimethylamino)-1,4,4a,5.5a,6,11, various pharmacologic activities, Such as misoprostol and 12a-octBPydro-3,6,10,12,12a-pentBPydroxy-6-methyl-1, enisoprost, diuretics, Such as Spironolactone and Spirono 11-dioxo-2-naphthacenecarboxamide), Actifed cough syrup lactone with hydrochlorothiazide, Sleep aids, Such as Zolpi (codeine phosphate, triprolidine hydrochloride and pseu dem tartrate; antihistaminic agents, antineoplastic agents, doephedrine hydrochloride), Aldactazide tablets (spirono Oncolytic agents, antiandrogens, antimalarial agents, anti lactone and hydrochlorothiazide), ALDOCLOR(R) tablets (methyldopa and chlorothiazide), Aldoril tablets (methyl leprosy agents, and various other types of drugs. See Good dopa-hydrochlorothiazide), Alferon(R) N injection (inter man and Gilman's The Basis of Therapeutics (Eighth Edi feron alpha-n3 (human leukocyte derived)), ALTACETM tion, Pergamon Press, Inc., USA, 1990) and The Merck capsules (ramipril), AMBIENOR tablets (Zolpidem tartrate), Index (Eleventh Edition, Merck & Co., Inc., USA, 1989), Anafranil capsules (clomipramine hydrochloride), each of which is incorporated herein by reference.) ANAPROX(R) tablets (naproxen sodium), Ancobon capsules 0044) The other therapeutic agent may also be a modu (flucytosine), Ansaid tablets (flurbiprofen), Apresazide cap lating compound. In addition, the compounds of the present Sules (hydralazine hydrochloride and hydrochlorothiazide), invention can also be administered in combination with Asendin tablets (2-chloro-11-(1-piperazinyl)dibenz(b,f)(1, other known therapies for the target disorder. For example, 4)-oxazepine), Atretol" tablets (carbamazepine), Aureomy the traZodone compound may be administered in conjunc cin ophthalmic ointment (chlortetracycline hydrochloride), tion with other compounds that are known in the art to be AZo Gantanol(R) tablets (sulfamethoxazole and phenazopy useful for enhancing Sleep quality and preventing and treat ridine hydrochloride), AZo Gantrisin tablets (sulfisoxazole ing Sleep disorders and sleep disturbances, including com and phenazopyridine hydrochloride), AZulfidine(R) tablets pounds known in the art to be useful for Suppressing or and EN-tabs (5-(p-(2-pyridylsulfamoyl)phenyl)-azo)sali Stimulating melatonin production, Such as, melationergic cylic acid), Bactrim tablets (trimethoprim and Sulfamethox agents, noradrenergic and Serotonergic re-uptake blockers, azole), Bactrim I.V. infusion (trimethoprim and Sul alpha-1-noradrenergic agonists, monamine oxidase inhibi famethoxazole), Bactrim pediatric Suspension (trimethoprim tors, neuropeptide Yagonists or antagonists, neurokinin-1 and Sulfamethoxazole), Bactrim Suspension (trimethoprim agonists; Substance P, beta-adrenergic blockers and benzo and Sulfamethoxazole), Bactrim tablets (trimethoprim and diazepines, Such as atenolol, other compounds that are Sulfamethoxazole), BenadrylE capsules (diphenhydramine known in the art to be useful for Stimulating melatonin hydrochloride USP), Benadryl(R) kapseals (diphenhydramine production including tricyclic and alpha-2- hydrochloride USP), Benadryl(R) tablets (diphenhydramine adrenergic antagonists, melatonin precursorS Such as tryp hydrochloride USP), Benadryl(R) parenteral (diphenhy tophan, 5-hydroxytryptophan, Serotonin and N-acetylsero dramine hydrochloride USP), Benadryl(R) steri-vials, tonin; as well as melatonin analogs, melatonin agonists and ampoules, and steri-dose Syringe (diphenhydramine hydro melatonin antagonists, and melatonin, itself. In addition, the chloride USP), Capoten tablets (captopril), Capozide tablets traZodone compound may be administered in conjunction (captopril-hydrochlorothiazide), Cardizeme CD capsules with other compounds which are known in the art to be (diltiazem hydrochloride), Cardizeme SR capsules (dilt useful for enhancing Sleep quality and preventing and treat iazem hydrochloride), Cardizeme tablets (diltiazem hydro ing Sleep disorders and sleep disturbances, including e.g., chloride), Chibroxin sterile ophthalmic solution (with oral , hypnotics, , , antianxiety form) (norfloxacin), Children's Advil(R) suspension (ibupro agents, minor tranquilizers, , barbituates, fen), Cipro(R. I.V. (), Cipro(R) tablets (ciprof and the like, as well as admixtures and combinations thereof. loxacin), Claritin tablets (loratadine), Clinoril tablets (sulin The traZodone compound may also be administered in dac), Combipres(R tablets ( hydrochloride and conjunction with the use of physical methods Such as with chlorthalidone), Compazine(E) injection ( light therapy or electrical Stimulation. maleate), Compazine(R) multi-dose vials (prochlorperazine 0.045. In addition, the trazodone compound may be maleate), Compazine(R) Syringes (prochlorperazine maleate), administered in association with therapeutically effective Compazine(E SpanSule capsules (prochlorperazine maleate), amounts of one or more adjunct active ingredients Selected Compazine(E Suppositories (prochlorperazine maleate), from decongestants, aspirin, (acetylsalicylic acid), acetami Compazine(E) Syrup (prochlorperazine maleate), Com nophen, non-Steroidal anti-inflammatory drugs (NSAIDs), pazine(E) tablets (prochlorperazine maleate), Cordarone tab cough SuppreSSants, and expectorants. Said adjunct ingre lets (amiodarone hydrochloride), Corzide tablets (nadolol dients are dosed at levels known to those skilled in the art and bendroflumethiazide), Dantrium capsules (dantrolene and as described in the Physicians’ Desk Reference. Rep Sodium), Dapsone tablets (4-4'diaminodiphenylsulfone), resentative NSAIDs include, but are not limited to, DAYPRO(E) caplets (oxaproxin), Declomycin tablets (deme naproxen, ibuprofen, ketoprofen, benoxaprofen, fluribipro clacycline or (4S-(4C,4ac,5aC.6B,12ao))-7-Chloro-4-dim US 2006/0009465 A1 Jan. 12, 2006 ethyl amino)-1,4,4a,5.5a,6,11,12a-octBPydro-3,6,10,12, nolol hydrochloride and hydrochlorothiazide), Inderides 12a-pentBPydroxy-1,11-dioxo-2-naphthacenecarboxamide capsule(E) ( hydrochloride and hydrochlorothiaz monohydrochloride), DECONAMINE(R) capsules (chlor ide), Intal inhaler (cromolyn Sodium), Intron A injection maleate and d-pSuedoephedrine hydrochlo (recombinant interferon alpha-2b), Lamprene capsules ride), DECONAMINE(R) syrup (chlorpheniramine maleate (clofazimine), Lasix oral Solution (furosemide), Lasix tab and d-psudoephedrine hydrochloride), DECONAMINE(R) lets (furosemide), Lasix injection (furosemide), Limbitrol tablets (chlorpheniramine maleate and d-pSudoephedrine tablets (chlordiazepoxide and amitriptyline hydrochloride), hydrochloride), Depakene capsules (valproic acid), Depak Lodine capsules (etodolac), Lopressor HCT tablets (meto ene Syrup (Valproic acid), Depakote sprinkle capsules (dival prolol tartrate USP and hydrochlorothiazide USP), Lotensin proex Sodium), Depakote tablets (divalproex Sodium), Dia tablets (benazepril hydrochloride), LOZOL(R) tablets (inda Beta(R) tablets (glyburide), Diabinese tablets pamide), Ludiomil tablets (maprotiline hydrochloride USP), (chlorpropamide), Diamox parenteral (acetazolamide), Marplan tablets (isocarboxazid), MAXAQUIN(R) tablets Diamox sequels (acetazolamide), Diamox tablets (aceta (lomefloxacin HCl), Maxzide tablets (triamterene USP and Zolamide), Dimetane-DC cough syrup (brompheniramine hydrochlorothiazide USP), Mellaril(R) concentrate (thior maleate, phenylpropanolamine hydrochloride and codeine idazine), Mellarilg tablets (thioridazine), Mellaril-S suspen phosphate), Dimetane-DX cough syrup (brompheniramine Sion (thioridazine), Mepergan injection (meperidine hydro maleate, phenylpropanolamine hydrochloride and codeine chloride and promethazine hydrochloride), Methotrexate phosphate), Dipentum(E) capsules (olsalazine Sodium), Diu tablets (methotrexate), Mevacor tablets (lovastatin), Micro cardin tablets (hydroflumethiazide), Diuprestablets (reser nase tablets (glyburide), Minizide capsules ( hydro pine and chlorothiazide), Diuril oral Suspension (chlorothi chloride and polythiazide), Minocin intravenous ((4S-(4C, azide), Diuril sodium intravenous (chlorothiazide), Diuril 4aC.5ao, 12aC))-4,7-bis(dimethylamino)-1,4,4a,5.5a,6,11, tablets (chlorothiazide), Dolobid tablets (diflunisal), 12a-octBPydro-3,10,12,12a-tetrBPydroxy-1,11-dioxo-2- DORYX(R) capsules (doxycycline hyclate), Dyazide cap naphthace necarboxamide monohydrochloride), Minocin Sules (hydrochlorothiazide and triamterene), Dyrenium cap oral Suspension ((4S-(4C,4ao.5ao, 12ao))-4,7-bis(dimethy Sules (triamterene), Efudex cream (5-fluorouracil), EfuideX lamino)-1,4,4a,5.5a,6,11,12a-octBPydro-3,10,12,12a-tetrB Solutions (5-fluorouracil), Elavil injection (amitriptyline Pydroxy-1,11-dioxo-2-naphthacenecarboxamide monohy HCl), Elavil tablets (amitriptyline HCl), Eldepryl tablets drochloride), Minocin capsules ((4S-(4.alpha.,4a.alpha, (Selegiline hydrochloride), Endep tablets (amitriptyline 5a.alpha,12a.alpha.))-4,7-bis(dimethylamino)-1,4,4a,5.5a,6, HCl), Enduron tablets (methyclothiazide), Enduronyl Forte 11,12a-octBPydro-3,10,12,12a-tetrBPydroxy-1,11-dioxo-2- tablets (methyclothiazide and deserpidine), Enduronyl tab naphthace necarboxamide monohydrochloride), Moduretic lets (methyclothiazide and deserpidine), Ergamisol tablets tablets (amiloride HC1-hydrochlorothiazide), Monodox(R) (levamisole hydrochloride), Esidrix tablets (hydrochlorothi capsules (doxycycline monohydrate), Monopril tablets azide USP), Esimil tablets (guanethidine monosulfate USP (fosinopril sodium), Children's Motrin liquid suspension and hydrochlorothiazide USP), Etrafon Forte tablets (per (ibuprofen), Motrin tablets (ibuprofen), Mykrox tablets phenazine, USP and amitriptyline hydrochloride, USP), (metolazone), NAPROSYNCR) suspension (naproxen), Etrafon 2-10 tablets (perphenazine, USP and amitriptyline NAPROSYNCR) tablets (naproxen), Navane capsules (thio hydrochloride, USP), Etrafon tablets (perphenazine, USP thixene), Navane intramuscular (thiothixene), NegGram and amitriptyline hydrochloride, USP), Etrafon-A tablets caplets (nalidixic acid), NegGram Suspension (nalidixic (perphenazine, USP and amitriptyline hydrochloride, USP), acid), Neptazane tablets (methazolamide), Nipent injection Eulexin capsules (flutamide), Exna tablets (benzthiazide), (pentostatin), Normodyne tablets (labetalol HCl), FUDR injection (floxuridine), Fansidar tablets (N1-(5,6- NOROXIN tablets (norfloxacin), Norpramin tablets dinethoxy-4-pyrimidinyl) sulfanilamide (Sulfadoxine) and (desipramine hydrochloride USP), oretic tablets (hydrochlo 2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine rothiazide), Oreticyl Forte tablets (hydrochlorothiazide and (pyrimethamine), Feldene capsules (piroXicam), Flexeril deserpidine), Orinase tablets (tolbutamide), Ornade capsules tablets (cyclobenzaprine hydrochloride), FLOXINGR I.V. (phenylpropanolamine hydrochloride and chlorpheniramine (ofloxacin injection), FLOXINS(R) tablets (ofloxacin), Fluo maleate), Orudis capsules (ketoprofen), OXSoralen lotion rouracil injection (5-fluoro-2,4 (1H,3H)-pyrimidinedione), (methoxypsoralen), PBZ tablets (tripelennamine hydrochlo Fulvicin tablets (griseofulvin), Gantanol E Suspension (Sul ride USP), PBZ-SR tablets (tripelennamine hydrochloride famethoxazole), Gantanol E tablets (Sulfamethoxazole), USP), pHisoHex topical emulsion (hexachlorophene), P & S Gantrisin ophthalmic ointaent/Solution (Sulfisoxazole), Gan PLUS(R) topical targel (crude coal tar), Pamelor(R) capsules trisin pediatric Suspension (Sulfisoxazole), Gantrisin Syrup (nortriptyline HCl), Pamelor(R) solution (nortriptyline HCl), (Sulfisoxazole), Gantrisin tablets (sulfisoxazole), Glucotrol Paxil tablets (paroxetine hydrochloride), Pediazole oral sus tablets (glipizide), Glynase PresTab tablets (glyburide), Gri pension (erythromycin ethylsuccinate, USP and SulfiSOX fuilvin V tablets (griseofulvin), Grifulvin oral suspension azole acetyl, USP), PenetrexTM tablets (enoxacin), Pentasa (griseofulvin), Gristactin capsules (griseofulvin), Grisactin capsules (meSalamine), Periactin Syrup ( tablets (griseofulvin), Gris-PEG tablets (griseofulvin), Gri HCl), Periactin tablets (cyproheptadine HCl), Phenergan vate tablets (griseofulvin), Grivate Suspension (griseoful tablets (promethazine hydrochloride), Phenergan injection Vin), Haldol Decanoate 50 injection aloperidol decanoate), (promethazine hydrochloride), Phenergan Suppositories Haldol Decanoate 100 injection ( decanoate), (promethazine hydrochloride), Phenergan Syrup (promet Haldol tablets (), Hibistat germicidal hazine hydrochloride), Polytrim(R) ophthalmic solution (tri hand rinse (chlorhexidine gluconate), HISMANAL(R) tablets methoprim sulfate and polymyxin B sulfate), Pravachol (astemizole), HydroDIURIL tablets (hydrochlorothiazide), (pravastatin sodium), Prinivil(R) tablets (lisinopril, MSD), Hydromox tablets (quinethaZone), Hydroprestablets (reser Prinzide tablets (lisinopril-hydrochlorothiazide), Prolixin pine and hydrochlorothiazide), Inderide(E) tablets (propra elixir ( hydrochloride), Prolixin enanthate US 2006/0009465 A1 Jan. 12, 2006

(fluphenazine hydrochloride), Prolixin injection (fluphena (azithromycin), Zocortablets (simvastatin), ZOLOFT(R) tab Zine hydrochloride), Prolixin oral concentrate (fluiphenazine lets (sertraline hydrochloride) and others. hydrochloride), Prolixin tablets (fluphenazine hydrochlo 0047 The term “pharmaceutically acceptable carrier' ride), ProSom tablets (estazolam), Prozac(R) oral solution include a pharmaceutically acceptable material, composition (fluoxetine hydrochloride), Prozac(R) oral Pulvules(R (fluox or vehicle, Such as a liquid or Solid filler, diluent, excipient, etine hydrochloride), Pyrazinamide tablets (pyrazinamide), Solvent or encapsulating material, involved in carrying or QUINAGLUTE(R) tablets (quinidine gluconate), Quinidex transporting a compound(s) of the present invention within tablets (quinidine Sulfate), Relafen tablets (nabumetone), or to the Subject Such that it can perform its intended Ru-TuSS II capsules (chlorpheniramine maleate and phenyl function. Typically, Such compounds are carried or trans propanolamine hydrochloride), Seldane tablets (terfena ported from one organ, or portion of the body, to another dine), Septra tablets (trimethoprim and Sulfamethoxazole), organ, or portion of the body. Each carrier must be “accept Septra Suspension (trimethoprim and Sulfamethoxazole), able” in the sense of being compatible with the other Septra I.V. infusion (trimethoprim and sulfamethoxazole), ingredients of the formulation and not injurious to the Septra tablets (trimethoprim and Sulfamethoxazole), Ser patient. Some examples of materials which can Serve as Ap-Es tablets ( USP, hydralazine hydrochloride pharmaceutically acceptable carriers include: Sugars, Such as USP and hydrochlorothiazide USP), Sinequan capsules lactose, glucose and Sucrose, Starches, Such as corn Starch (doxepin HCl), Solganal injection (aurothioglucose, USP), and potato Starch, cellulose, and its derivatives, Such as Stelazine concentrate (trifluoperazine hydrochloride), Stela Sodium carboxymethyl cellulose, ethyl cellulose and cellu Zine injection (trifluoperazine hydrochloride), Stelazine tab lose acetate; powdered tragacanth; malt, gelatin; talc, excipi lets (trifluoperazine hydrochloride), Surmontil capsules ents, Such as cocoa butter and Suppository waxes, oils, Such (trimipramine maleate), SYMMETREL capsules and syrup as peanut oil, cottonSeed oil, Safflower oil, Sesame oil, olive (amantadine hydrochloride), Taractan concentrate (chlorpro oil, corn oil and Soybean oil; glycols, Such as propylene thixene), Taractan injectable (), Taractan glycol, polyols, Such as glycerin, Sorbitol, mannitol and tablets (chlorprothixene), TAVIST(R) syrup (clemastine polyethylene glycol, esters, Such as ethyl oleate and ethyl fumarate, USP), TAVIST(R) tablets (clemastine fumarate, laurate; agar; buffering agents, Such as magnesium hydrox USP), TAVIST(R)-1 12 hour relief medicine (clemastine ide and aluminum hydroxide; alginic acid; pyrogen-free fumarate, USP), TAVIST(R-D12 hour relief medicine (clem water, isotonic Saline, Ringer's Solution; ethyl , astine fumarate, USP), Tegretol Tablets (carbamazepine phosphate buffer Solutions, and other non-toxic compatible USP), Tegretol suspension (carbamazepine USP), Temaril Substances employed in pharmaceutical formulations. tablets (trimeprazine tartrate), Temaril Syrup (trimeprazine 0048 Wetting agents, emulsifiers and lubricants, such as tartrate), Temaril capsules (trimeprazine tartrate), TENO Sodium lauryl Sulfate and magnesium Stearate, as well as RETIC(R) tablets (atenolol and chlorthalidone), Terramycin coloring agents, release agents, coating agents, Sweetening, intramuscular Solution (oxytetracycline), Thiosulfil Forte flavoring and perfuming agents, preservatives and antioxi tablets (Sulfamethizole), Thorazine ampuls ( hydrochloride), Thorazine concentrate (chlorpromazine dants can also be present in the compositions. hydrochloride), Thorazine multi-dose vials (chlorpromazine 0049. Examples of pharmaceutically acceptable antioxi hydrochloride), Thorazine capsules (chlorpromazine hydro dants include: water Soluble antioxidants, Such as ascorbic chloride), Thorazine Suppositories (chlorpromazine hydro acid, cysteine hydrochloride, Sodium bisulfate, Sodium met chloride), Thorazine Syrup (chlorpromazine hydrochloride), abisulfite, Sodium Sulfite and the like; oil-soluble antioxi Thorazine tablets (chlorpromazine hydrochloride), Timolide dants, Such as ascorbyl palmitate, butylated hydroxyanisole tablets (timolol maleate-hydrochlorothiazide), Tofranil (BHA), butylated hydroxytoluene (BHT), lecithin, propyl ampuls (imipramine hydrochloride USP), Tofranil tablets gallate, alpha-tocopherol, and the like; and metal chelating (imipramine hydrochloride USP), Tofranil capsules (imi agents, Such as citric acid, ethylenediamine tetraacetic acid pramine hydrochloride USP), Tolinase tablets (tollazamide), (EDTA), Sorbitol, tartaric acid, phosphoric acid, and the like. Triaminic Expectorant DH (phenylpropanolamine hydro 0050 Formulations of the present invention include those chloride and ), Triaminic oral infant drops (phe Suitable for oral, nasal, topical, transdermal, buccal, Sublin nylpropanolamine hydrochloride, pheniramine maleate and gual, rectal, vaginal and/or parenteral administration. The pyrilamine maleate), Triavil tablets (perphenazine-amitrip formulations may conveniently be presented in unit dosage tyline HCl), Trilafon concentrate (perphenazine USP), form and may be prepared by any methods well known in Trilafon injection (perphenazine USP), Trilafon tablets (per the art of pharmacy. The amount of active ingredient that can phenazine, USP), Trinalin tablets (azatadine maleate, USP, be combined with a carrier material to produce a single and pseudoephedrine sulfate, USP), Vaseretic tablets (enala dosage form will generally be that amount of the compound pril maleate-hydrochlorothiazide), VasoSulf opthalmic Solu that produces a therapeutic effect. Generally, out of one tion (Sulfacetamide Sodium-phenylephrine hydrochloride), hundred percent, this amount will range from about 1 Vasotec I.V. (enalapril maleate), Vasotec tablets (enalapril percent to about ninety-nine percent of active ingredient, maleate), Velban(R) vials (vinblastine sulfate, USP), Vibra mycin capsules (doxycycline monohydrate), Vibramycin preferably from about 5 percent to about 70 percent, most intravenous (doxycycline monohydrate), Vibramycin oral preferably from about 10 percent to about 30 percent. Suspension (doxycycline monohydrate), Vibra-Tabs tablets 0051 Methods of preparing these formulations or com (oxytetracycline), Vivactil tablets (protriptyline HCl), positions include the Step of bringing into association a Voltaren tablets (diclofenac sodium), X-SEBTR) shampoo compound of the present invention with the carrier and, (crude coal tar), Zaroxolyn tablets (metolazone), optionally, one or more accessory ingredients. In general, the ZESTORETIC(R) oral (lisinopril and hydrochlorothiazide), formulations are prepared by uniformly and intimately ZESTRIL(R) tablets (lisinopril), ZITHROMAXTM capsules bringing into association a compound of the present inven US 2006/0009465 A1 Jan. 12, 2006

tion with liquid carriers, or finely divided Solid carriers, or medium immediately before use. These compositions may both, and then, if necessary, Shaping the product. also optionally contain opacilying agents and may be of a composition that releases the active ingredient(s) only, or 0.052 Formulations of the invention suitable for oral preferentially, in a certain portion of the gastrointestinal administration may be in the form of capsules, cachets, pills, tract, optionally, in a delayed manner. Examples of embed tablets, lozenges (using a flavored basis, usually Sucrose and ding compositions that can be used include polymeric Sub acacia or tragacanth), powders, granules, or as a Solution or stances and waxes. The active ingredient can also be in a Suspension in an aqueous or non-aqueous liquid, or as an microencapsulated form, if appropriate, with one or more of oil-in-water or water-in-oil liquid emulsion, or as an elixir or Syrup, or as pastilles (using an inert base, Such as gelatin and the above-described excipients. glycerin, or Sucrose and acacia) and/or as mouth washes and 0056 Liquid dosage forms for oral administration of the the like, each containing a predetermined amount of a compounds of the invention include pharmaceutically compound of the present invention as an active ingredient. acceptable emulsions, microemulsions, Solutions, Suspen A compound of the present invention may also be admin Sions, Syrups and elixirs. In addition to the active ingredient, istered as a bolus, electuary or paste. the liquid dosage forms may contain inert diluents com monly used in the art. For example, Such inert diluents, 0053. In solid dosage forms of the invention for oral include but are not limited to, water or other Solvents, administration (capsules, tablets, pills, dragees, powders, Solubilizing agents and emulsifiers, Such as ethyl alcohol, granules and the like), the active ingredient is mixed with isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl one or more pharmaceutically acceptable carriers, Such as alcohol, benzyl benzoate, propylene glycol, 1,3-butylene Sodium citrate or dicalcium phosphate, and/or any of the glycol, oils (in particular, cottonseed, groundnut, corn, germ, following: fillers or extenders, Such as Starches, lactose, olive, castor and Sesame oils), glycerol, tetrrhydrofuryl Sucrose, glucose, mannitol, and/or Silicic acid; binders, Such alcohol, polyethylene glycols and fatty acid esters of Sorbi as, for example, carboxymethylcellulose, alginates, gelatin, tan, and mixtures thereof. Besides inert diluents, the oral polyvinyl pyrrolidone, Sucrose and/or acacia, humectants, compositions can also include adjuvants Such as wetting Such as glycerol, disintegrating agents, Such as agar-agar, agents, emulsifying and Suspending agents, Sweetening, calcium carbonate, potato or tapioca Starch, alginic acid, flavoring, coloring, perfuming and preservative agents. certain Silicates, and Sodium carbonate; Solution retarding agents, Such as paraffin, absorption accelerators, Such as 0057 Suspensions, in addition to the active compounds, quaternary ammonium compounds, Wetting agents, Such as, may contain Suspending agents as, for example, ethoxylated for example, cetyl alcohol and glycerol monoStearate; absor isoStearyl , polyoxyethylene Sorbitol and Sorbitan bents, Such as kaolin and bentonite clay, lubricants, Such a esters, microcrystalline cellulose, aluminum metahydroxide, talc, calcium Stearate, magnesium Stearate, Solid polyethyl bentonite, agar-agar and tragacanth, and mixtures thereof. ene glycols, Sodium lauryl Sulfate, and mixtures thereof, and 0058 Formulations of the pharmaceutical compositions coloring agents. In the case of capsules, tablets and pills, the of the invention for rectal or vaginal administration may be pharmaceutical compositions may also comprise buffering presented as a Suppository, which may be prepared by agents. Solid compositions of a Similar type may also be mixing one or more compounds of the invention with one or employed as fillers in Soft and hard-filled gelatin capsules more Suitable nonirritating excipients or carriers comprising. using Such excipients as lactose or milk Sugars, as well as For example, a formulation of the invention may be prepared high molecular weight polyethylene glycols and the like. from cocoa butter, polyethylene glycol, a Suppository wax or 0054) A tablet may be made by compression or molding, a Salicylate, which is Solid at room temperature, but liquid at optionally with one or more accessory ingredients. Com body temperature, and will, therefore, melt in the rectum or pressed tablets may be prepared using binder (for example, vaginal cavity and release the active compound. gelatin or hydroxypropylmethyl cellulose), lubricant, inert 0059 Formulations of the present invention which are diluent, preservative, disintegrant (for example, Sodium Suitable for vaginal administration also include pessaries, Starch glycolate or cross-linked Sodium carboxymethyl cel tampons, creams, gels, pastes, foams or Spray formulations lulose), Surface-active or dispersing agent. Molded tablets containing Such carriers as are known in the art to be may be made in a Suitable machine by molding a mixture of appropriate. the powdered compound moistened with an inert liquid 0060 Dosage forms for the topical or transdermal admin diluent istration of a compound of this invention include powders, 0.055 The tablets, and other solid dosage forms of the Sprays, ointments, pastes, creams, lotions, gels, Solutions, pharmaceutical compositions of the present invention, Such patches and inhalants. The active compound may be mixed as dragees, capsules, pills and granules, may optionally be under Sterile conditions with a pharmaceutically acceptable Scored or prepared with coatings and shells, Such as enteric carrier, and with any preservatives, buffers, or propellants coatings and other coatings well known in the pharmaceu that may be required. tical-formulating art. They may also be formulated So as to provide Slow or controlled release of the active ingredient 0061 The ointments, pastes, creams and gels may con therein using, for example, hydroxypropylmethyl cellulose tain, in addition to an active compound of this invention, in varying proportions to provide the desired release profile, excipients, Such as animal and vegetable fats, oils, waxes, other polymer matrices, liposomes and/or microSpheres. paraffins, Starch, tragacanth, cellulose derivatives, polyeth They may be Sterilized by, for example, filtration through a ylene glycols, Silicones, bentonites, Silicic acid, talc and Zinc bacteria-retaining filter, or by incorporating Sterilizing oxide, or mixtures thereof. agents in the form of Sterile Solid compositions that can be 0062 Powders and sprays can contain, in addition to a dissolved in Sterile water, or Some other Sterile injectable compound of this invention, excipients Such as lactose, talc, US 2006/0009465 A1 Jan. 12, 2006

Silicic acid, aluminum hydroxide, calcium Silicates and Depending on the ratio of drug to polymer, and the nature of polyamide powder, or mixtures of these Substances. SprayS the particular polymer employed, the rate of drug release can can additionally contain customary propellants, Such as be controlled. Examples of other biodegradable polymers chlorofluorohydrocarbons and volatile unsubstituted hydro include poly(orthoesters) and poly(anhydrides). Depot carbons, Such as butane and propane. injectable formulations are also prepared by entrapping the 0.063 Transdermal patches have the added advantage of drug in liposomes or microemulsions that are compatible providing controlled delivery of a compound of the present with body tissue. invention to the body. Such dosage forms can be made by 0070 The preparations of the present invention may be dissolving or dispersing the compound in the proper given orally, parenterally, topically, or rectally, and are of medium. Absorption enhancers can also be used to increase course given by forms Suitable for each administration route. the flux of the compound across the skin. The rate of Such For example, the preparations are administered in tablets or flux can be controlled by either providing a rate controlling capsule form, by injection, inhalation, eye lotion, ointment, membrane or dispersing the active compound in a polymer Suppository, etc. administration by injection, infusion or matrix or gel. inhalation; topical by lotion or ointment; and rectal by 0.064 Ophthalmic formulations, eye ointments, powders, Suppositories. Oral administration is preferred. Solutions and the like, are also contemplated as being within 0071. The terms “parenteral administration” and “admin the Scope of this invention. istered parenterally as used herein means modes of admin 0065 Pharmaceutical compositions of this invention Suit istration other than enteral and topical administration, usu able for parenteral administration comprise one or more ally by injection, and includes, without limitation, compounds of the invention in combination with one or intravenous, intramuscular, intraarterial, intrathecal, intrac more pharmaceutically acceptable Sterile isotonic aqueous apSular, intraorbital, intracardiac, intradermal, intraperito or nonaqueous Solutions, dispersions, Suspensions or emul neal, transtracheal, Subcutaneous, Subcuticular, intraarticu Sions, or Sterile powders, which may be reconstituted into lar, Subcapsular, Subaracinoid, intraspinal and intrastemal Sterile injectable Solutions or dispersions just prior to use, injection and infusion. which may contain antioxidants, buffers, bacterioStats, Sol 0072 The terms “systemic administration,”“adminis utes which render the formulation isotonic with the blood of tered Systematically,”“peripheral administration' and the intended recipient or Suspending or thickening agents. “administered peripherally' as used herein mean the admin 0.066 Examples of suitable aqueous and nonaqueous istration of a compound, drug or other material other than carriers which may be employed in the pharmaceutical directly into the central nervous System, for example, Sub compositions of the invention include water, ethanol, poly cutaneous administration, Such that it enters the patient's ols (such as glycerol, propylene glycol, polyethylene glycol, System and thus, is possibly Subject to metabolism and other and the like), and Suitable mixtures thereof, vegetable oils, like processes. Such as olive oil, and injectable organic esters, Such as ethyl oleate. Proper fluidity can be maintained, for example, by 0073. These compounds may be administered to humans and other animals for therapy by any Suitable route of the use of coating materials, Such as lecithin, by the main administration, including orally, nasally, as by, for example, tenance of the required particle size in the case of disper a spray, rectally, intravaginally, parenterally, intracistemally Sions, and by the use of Surfactants. and topically, as by powders, ointments or drops, including 0067. These compositions may also contain adjuvants buccally and Sublingually. Such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microor 0074 Regardless of the route of administration selected, ganisms may be ensured by the inclusion of various anti the compounds of the present invention, which may be used bacterial and antifungal agents, for example, paraben, chlo in a Suitable hydrated form, and/or the pharmaceutical robutanol, Sorbic acid, and the like. It may also be compositions of the present invention, are formulated into desirable to include isotonic agents, Such as Sugars, Sodium pharmaceutically acceptable dosage forms by conventional chloride, and the like into the compositions. In addition, methods known to those of skill in the art. prolonged absorption of the injectable pharmaceutical form 0075 Actual dosage levels of the active ingredients in the may be brought about by the inclusion of agents that delay pharmaceutical compositions of this invention may be var absorption Such as aluminum monoStearate and gelatin. ied So as to obtain an amount of the active ingredient which 0068. In some cases, in order to prolong the effect of a is effective to achieve the desired therapeutic response for a drug, it is desirable to slow the absorption of the drug from particular patient, composition, and mode of administration, Subcutaneous or intramuscular injection. This may be without being toxic to the patient. accomplished by the use of a liquid Suspension of crystalline 0076. The selected dosage level will depend upon a or amorphous material having poor water Solubility. The rate variety of factors including the activity of the particular of absorption of the drug then depends upon its rate of compound of the present invention employed, the route of dissolution which, in turn, may depend upon crystal Size and administration, the time of administration, the rate of excre crystalline form. Alternatively, delayed absorption of a tion of the particular compound being employed, the dura parenterally administered drug form is accomplished by tion of the treatment, other drugs, compounds and/or mate dissolving or Suspending the drug in an oil vehicle. rials used in combination with the particular compound 0069. Injectable depot forms are made by forming employed, the age, Sex, weight, condition, general health microencapsule matrices of the Subject compounds in bio and prior medical history of the patient being treated, and degradable polymerS Such as polylactide-polyglycolide. like factors well known in the medical arts. US 2006/0009465 A1 Jan. 12, 2006

0077. A physician or veterinarian having ordinary skill in moiety can optionally be positioned elsewhere in the drug So the art can readily determine and prescribe the effective as to control its half-life through esterase catalyzed inacti amount of the pharmaceutical composition required. For Vation. However, if an ester group is used to inhibit the example, the physician or veterinarian could start doses of formation of a wake promoting metabolite then the same the compounds of the invention employed in the pharma ester group can be, but is not necessarily, used to control the ceutical composition at levels lower than that required in half life of the drug. order to achieve the desired therapeutic effect and gradually 0085. The language “trazodone compound”, or “TZ is increase the dosage until the desired effect is achieved. intended to include traZOdone or analogs thereof The traZ 0078. The regimen of administration can affect what odone analogs include, but are not limited to, traZOdones constitutes an effective amount. The disorder target modu containing Substituents that do not significantly effect the lators, e.g., sleep disorder target modulators, can be admin analogs ability to perform its intended function. istered to the Subject either prior to or after the onset of a 0086 The language “metabolism reducing moiety', or Sleep disorder associated State. Further, Several divided “MR’ is a moiety that provides the ability to reduce the dosages, as well as Staggered dosages, can be administered metabolism of the therapeutic compound Such that there is daily or Sequentially, or the dose can be continuously a reduction in the wake promoting metabolites formed. infused, or can be a bolus injection. Further, the dosages of Alternatively, MR can be a moiety that modifies the activity the disorder target modulators, e.g., sleep disorder target of the metabolite. Examples include functional moieties, modulators, compound(s) can be proportionally increased or e.g., esters or alkyl groups, Selected and positioned within decreased as indicated by the exigencies of the therapeutic the therapeutic drug to provide the ability for a reduction in or prophylactic Situation. the wake promoting metabolites formed. In certain embodi 0079 The language “subject” includes animals (e.g., ments, the MR provides the ability to modulate the activity mammals, e.g., cats, dogs, horses, pigs, cows, sheep, of the drug, e.g., half-life. In certain embodiments of the rodents, rabbits, Squirrels, bears, primates (e.g., chimpan invention, the metabolism reducing moiety is an ester group, Zees, gorillas, and humans) which are capable of Suffering EG. Alternatively, in particular embodiments of the inven from a Sleep associated disorder. tion the MR is alkyl, e.g., cyclopropyl or gem-dimethyl, as 0080. The language “therapeutically effective amount” of depicted below in Table 2. the compound is that amount necessary or Sufficient to treat 0087. The language “wake promoting metabolite” is or prevent a state associated with a disorder, e.g., sleep intended to include a metabolite of the therapeutic com disorder. The effective amount can vary depending on Such pound, produced in Vivo that reduces the therapeutic effect factors as the size and weight of the Subject, the type of on the Sleep disorder. In certain embodiments, the wake illness, or the particular compound. For example, the choice promoting metabolite is meta-chlorophenylpiperazine of the therapeutic compound can affect what constitutes an (m-CPP). “effective amount'. One of ordinary skill in the art would be 0088. The language “ester group” or “EG' are used able to Study the aforementioned factors and make the interchangeably and are intended to include an organic ester determination regarding the effective amount of the thera functionality that is Selected and positioned within the peutic compound without undue experimentation. compound providing the ability to modulate the activity or 0081. The language “penetrates into the CNS” includes modify the properties of the corresponding therapeutic com the favorable biological property of a compound of the pound, e.g., half-life or metabolite formation. In certain current invention to pass through, or penetrate, the blood embodiments, the EG modifies the half-life of the therapeu brain barrier (BBB) and enter into the CNS. tic compound and/or reduces the formation of wake pro moting metabolites. The organic ester group may be termi 0082 The language “therapeutic compound” includes nal, e.g., a Substituent, or internal. The carboxylate of the compounds of the invention capable of performing their ester may be oriented from left to right or from right to left, intended function, e.g., treating Sleep disorders and/or e.g., a reverse ester. Examples of esters of the current modulating Sleep targets. The therapeutic compounds of the invention include, but are not limited to hydrocarbons and invention are described in detail herein. perfluorocarbons. In a preferred embodiment, the hydrocar 0.083. Accordingly, the therapeutic compound can have bon possesses 1 to 20 carbons. In certain embodiments, the the formula: hydrocarbon can be linear, branched, cyclic, aromatic, or a combination of Saturated or unsaturated aliphatic and aro IEG) (SP)-ITZH(SP)-IMR) matic groups, which are optionally Substituted with O, N, S, wherein TZ is a trazodone compound, MR is a metabolite and/or halogens and may additionally include a center of reducing moiety that reduces the formation of wake pro chirality. In particular embodiments, the ester can be an moting metabolites, EG is an ester group that modifies the n-propyl, an isopropyl, a t-butyl, an isobutyl, a cyclopentyl, half-life of the therapeutic compound, SP, and SP are a cyclohexyl, a cycloheptyl, and a benzyl group. Spacer molecules, n, q, and r are independently 0 or 1, and 0089. In particular embodiments, the activity of the drug, r and q are 0 when MR is the ester group that modifies the e.g., half-life, of the therapeutic drug is modulated by half-life of the therapeutic compound. controlling the rate of hydrolysis of the ester group by 0084. Moreover, an ester moiety can function as the Selection and positioning of Steric bulk near the ester car moiety that inhibits the formation of a wake promoting bonyl of the ester group, or by the incorporation of electron metabolite, Lie., MR, or a separate group can be used for withdrawing or donating moieties into, or adjacent to, the that purpose. If a separate group is used to inhibit the ester. In certain embodiments, the steric bulk is provided by formation of the wake-promoting metabolite, then an ester the Selection of a bulky ester group. In alternative embodi US 2006/0009465 A1 Jan. 12, 2006 11 ments the steric bulk is provided by substitution selected and positioned on the TZ moiety near the carbonyl of the ester TABLE 1-continued grOup. Bulky Ester Groups For H1 Antagonists

0090 The language “bulky ester' is intended to include an ester that has Sufficient Steric properties Such that the rate R = Parent Drug Core Structure of hydrolysis of the therapeutic compound is modulated, RR = Ester from Alcohols below e.g., reduced, Such that the activity of the therapeutic com pound is modified, e.g., the length of activity is increased (i.e., the half-life of the therapeutic compound is increased). r rx Examples of bulky ester groups are depicted in Table 1. O Aldrich TABLE 1. HO ON-1 Bulky Ester Groups For H1 Antagonists Lancaster or TCI

R = Parent Drug Core Structure RR = Ester from Alcohols below 0091. The language “hydrocarbon” includes substituted or unsubstituted alkyl, alkenyl, alkynyl, or aryl moieties. The term “alkyl includes Saturated aliphatic groups, includ ing Straight-chain alkyl groups (e.g., methyl, ethyl, propyl, Type A: butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopen tyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl Substituted HO HO HO cycloalkyl groups, and cycloalkyl Substituted alkyl groups. The term alkyl further includes alkyl groups, which can further include OXygen, nitrogen, Sulfur or phosphorous Type B: atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a Straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., C-C for Straight chain, C-C for branched chain), and more preferably 4 or fewer. Likewise, preferred HO HO cycloalkyls have from 3-8 carbon atoms in their ring Struc H Aldrich ture, and more preferably have 5 or 6 carbons in the ring Aldrich as R,S mixture Structure. The term C-C includes alkyl groups containing and pure R or Senantiomers. Prepare esters with R.S mixture first. 1 to 6 carbon atoms. 0092. Moreover, the term alkyl includes both “unsubsti tuted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having Substituents replacing a hydrogen on one or more carbons of the hydrocarbon HO HO backbone. Such Substituents can include, for example, alk Aldrich enyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcar bonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, car boxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, O aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, O alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phos

1- HO phinato, cyano, amino (including alkylamino, dialkylamino, O arylamino, diarylamino, and alkylarylamino), acylamino HO N Aldrich (including alkylcarbonylamino, arylcarbonylamino, car 1,3-dimethoxy-2-propanol bamoyl and ureido), amidino, imino, Sulfhydryl, alkylthio, Tyger Scientific Inc. arylthio, thiocarboxylate, Sulfates, alkylsulfinyl, Sulfonato, Ewing, NJ Sulfamoyl, Sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls can be further Substituted, e.g., with the -ku O substituents described above. An “alkylaryl' or an “aralkyl HO N moiety is an alkyl Substituted with an aryl (e.g., phenylm HO Aldrich as R,S mixture ethyl (benzyl)). The term “alkyl” also includes the side Acros as pure R or Senantiomers. chains of natural and unnatural amino acids. Prepare esters with R.S mixture first. Aldrich 0093. The term “aryl” includes groups, including 5- and 6-membered single-ring aromatic groups that may include from Zero to four heteroatoms, for example, , phe US 2006/0009465 A1 Jan. 12, 2006 nyl, , , , , isothiaozole, imida alkylarylamino), acylamino (including alkylcarbonylamino, Zole, , , , , isooxazole, pyri arylcarbonylamino, carbamoyl and ureido), amidino, imino, dine, , , and , and the like. Sulfhydryl, alkylthio, arylthio, thiocarboxylate, Sulfates, Furthermore, the term “aryl” includes multicyclic aryl alkylsulfinyl, Sulfonato, Sulfamoyl, Sulfonamido, nitro, trif groups, e.g., tricyclic, bicyclic, e.g., , benzoX luoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an azole, benzodioxazole, , benzoimidazole, ben aromatic or heteroaromatic moiety. Zothiophene, methylenedioxyphenyl, , isoquino line, napthridine, , , , benzofuran, 0097. The term “alkynyl' includes unsaturated aliphatic deaZapurine, or indolizine. Those aryl groups having het groupS analogous in length and possible Substitution to the eroatoms in the ring structure may also be referred to as alkyls described above, but which contain at least one triple “aryl heterocycles”, “heterocycles,”“heteroaryls” or “het bond. eroaromatics”. The aromatic ring can be Substituted at one or 0098. For example, the term “alkynyl' includes straight more ring positions with Such Substituents as described chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pen above, as for example, halogen, hydroxyl, alkoxy, alkylcar tynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), bonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycar branched-chain alkynyl groups, and cycloalkyl or cycloalk bonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, enyl Substituted alkynyl groups. The term alkynyl further aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbo includes alkynyl groups which include oxygen, nitrogen, nyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxy Sulfur or phosphorous atoms replacing one or more carbons carbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, of the hydrocarbon backbone. In certain embodiments, a phosphonato, phosphinato, cyano, amino (including alkyl Straight chain or branched chain alkynyl group has 6 or amino, dialkylamino, arylamino, diarylamino, and alkylary fewer carbon atoms in its backbone (e.g., C-C for Straight lamino), acylamino (including alkylcarbonylamino, arylcar chain, C-C for branched chain). The term C-C includes bonylamino, carbamoyl and ureido), amidino, imino, Sulf alkynyl groups containing 2 to 6 carbon atoms. hydryl, alkylthio, arylthio, thiocarboxylate, Sulfates, 0099 Moreover, the term alkynyl includes both “unsub alkylsulfinyl, Sulfonato, Sulfamoyl, Sulfonamido, nitro, trif stituted alkynyls' and “substituted alkynyls', the latter of luoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an which refers to alkynyl moieties having Substituents replac aromatic or heteroaromatic moiety. Aryl groups can also be ing a hydrogen on one or more carbons of the hydrocarbon fused or bridged with alicyclic or heterocyclic rings which backbone. Such Substituents can include, for example, alkyl are not aromatic So as to form a polycycle (e.g., tetralin). groups, alkynyl groups, halogens, hydroxyl, alkylcarbony 0094. The term “alkenyl' includes unsaturated aliphatic loxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbony groupS analogous in length and possible Substitution to the loxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycar alkyls described above, but that contain at least one double bonyl, aminocarbonyl, alkylaminocarbonyl, bond. dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phos 0.095 For example, the term “alkenyl' includes straight phate, phosphonato, phosphinato, cyano, amino (including chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pen alkyl amino, dialkylamino, arylamino, diarylamino, and tenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), alkylarylamino), acylamino (including alkylcarbony branched-chain alkenyl groups, cycloalkenyl (alicyclic) lamino, arylcarbonylamino, carbamoyl and ureido), ami groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cyclo dino, imino, Sulfhydryl, alkylthio, arylthio, thiocarboxylate, heptenyl, cyclooctenyl), alkyl or alkenyl Substituted Sulfates, alkylsulfinyl, Sulfonato, Sulfamoyl, Sulfonamido, cycloalkenyl groups, and cycloalkyl or cycloalkenyl Substi nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, tuted alkenyl groups. The term alkenyl further includes or an aromatic or heteroaromatic moiety. alkenyl groups which include oxygen, nitrogen, Sulfur or 0100. Unless the number of carbons is otherwise speci phosphorous atoms replacing one or more carbons of the fied, “lower alkyl as used herein means an alkyl group, as hydrocarbon backbone. In certain embodiments, a Straight defined above, but having from one to five carbon atoms in chain or branched chain alkenyl group has 6 or fewer carbon its backbone structure. “Lower alkenyl' and “lower alkynyl atoms in its backbone (e.g., C-C for Straight chain, C-C, have chain lengths of, for example, 2-5 carbon atoms. for branched chain). Likewise, cycloalkenyl groups may 0101 The term “acyl” includes compounds and moieties have from 3-8 carbon atoms in their ring Structure, and more that contain the acyl radical (CHCO-) or a carbonyl preferably have 5 or 6 carbons in the ring structure. The term group. The term “Substituted acyl” includes acyl groups C-C includes alkenyl groups containing 2 to 6 carbon where one or more of the hydrogen atoms are replaced by for atOmS. example, alkyl groups, alkynyl groups, halogens, hydroxyl, 0.096 Moreover, the term alkenyl includes both “unsub alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, stituted alkenyls' and “substituted alkenyls', the latter of aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbo which refers to alkenyl moieties having Substituents replac nyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, ing a hydrogen on one or more carbons of the hydrocarbon dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phos backbone. Such Substituents can include, for example, alkyl phate, phosphonato, phosphinato, cyano, amino (including groups, alkynyl groups, halogens, hydroxyl, alkylcarbony alkyl amino, dialkylamino, arylamino, diarylamino, and loxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbony alkylarylamino), acylamino (including alkylcarbonylamino, loxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycar arylcarbonylamino, carbamoyl and ureido), amidino, imino, bonyl, aminocarbonyl, alkylaminocarbonyl, Sulfhydryl, alkylthio, arylthio, thiocarboxylate, Sulfates, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phos alkylsulfinyl, Sulfonato, Sulfamoyl, Sulfonamido, nitro, trif phate, phosphonato, phosphinato, cyano, amino (including luoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an alkyl amino, dialkylamino, arylamino, diarylamino, and aromatic or heteroaromatic moiety. US 2006/0009465 A1 Jan. 12, 2006

0102) The term “acylamino” includes moieties wherein 0108). The term “carbonyl” or “carboxy” includes com an acyl moiety is bonded to an amino group. For example, pounds and moieties that contain a carbon connected with a the term includes alkylcarbonylamino, arylcarbonylamino, double bond to an oxygen atom. Examples of moieties that carbamoyl and ureido groups. contain a carbonyl include aldehydes, ketones, carboxylic 0103) The term “aroyl” includes compounds and moieties acids, amides, esters, anhydrides, etc. with an aryl or heteroaromatic moiety bound to a carbonyl 0109) The term “thiocarbonyl” or “thiocarboxy” includes group. Examples of aroyl groups include phenylcarboxy, compounds and moieties that contain a carbon connected naphthyl carboxy, etc. with a double bond to a Sulfur atom. 0104. The terms “alkoxyalkyl”, “alkylaminoalkyl and 0110. The term “ether” includes compounds or moieties “thioalkoxyalkyl” include alkyl groups, as described above, that contain an oxygen bonded to two different carbon atoms which further include oxygen, nitrogen or Sulfur atoms or heteroatoms. For example, the term includes “alkoxy replacing one or more carbons of the hydrocarbon backbone, alkyl” which refers to an alkyl, alkenyl, or alkynyl group e.g., Oxygen, nitrogen or Sulfur atoms. covalently bonded to an oxygen atom that is covalently 0105 The term “alkoxy” includes substituted and unsub bonded to another alkyl group. Stituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include 0111. The term “thioether” includes compounds and moi methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pen eties that contain a Sulfur atom bonded to two different toxy groups. Examples of Substituted alkoxy groups include carbon or hetero atoms. Examples of thioethers include, but halogenated alkoxy groups. The alkoxy groups can be are not limited to alkthioalkyls, alkthioalkenyls, and alkthio Substituted with groupS Such as alkenyl, alkynyl, halogen, alkynyls. The term “alkthioalkyls' include compounds with hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbo an alkyl, alkenyl, or alkynyl group bonded to a Sulfur atom nyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, that is bonded to an alkyl group. Similarly, the term “alk arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylami thioalkenyls' and alkthioalkynyls' refer to compounds or nocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, moieties wherein an alkyl, alkenyl, or alkynyl group is alkoxyl, phosphate, phosphonato, phosphinato, cyano, bonded to a sulfur atom that is covalently bonded to an amino (including alkyl amino, dialkylamino, arylamino, alkynyl group. diarylamino, and alkylarylamino), acylamino (including 0112 The term “hydroxy” or “hydroxyl” includes groups alkylcarbonylamino, arylcarbonylamino, carbamoyl and with an -OH or -OT. ureido), amidino, imino, Sulfhydryl, alkylthio, arylthio, thio carboxylate, Sulfates, alkylsulfinyl, Sulfonato, Sulfamoyl, 0113. The term “halogen' includes fluorine, bromine, Sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocy chlorine, iodine, etc. The term "perhalogenated, e.g., per clyl, alkylaryl, or an aromatic or heteroaromatic moieties. fluorinated, generally refers to a moiety, e.g., perfluorocar Examples of halogen Substituted alkoxy groups include, but bons, wherein all hydrogens are replaced by halogen atoms, are not limited to, fluoromethoxy, difluoromethoxy, trifluo e.g., fluorine. romethoxy, chloromethoxy, dichloromethoxy, trichlo 0114. The terms “polycyclyl” or “polycyclic radical” romethoxy, etc. refer to two or more cyclic rings (e.g., cycloalkyls, cycloalk 0106 The term “amine” or “amino” includes compounds enyls, cycloalkynyls, aryls and/or heterocyclyls) in which where a nitrogen atom is covalently bonded to at least one two or more carbons are common to two adjoining rings, carbon or heteroatom. The term “alkyl amino” includes e.g., the rings are “fused rings'. Rings that are joined groupS and compounds wherein the nitrogen is bound to at through non-adjacent atoms are termed "bridged” rings. least one additional alkyl group. The term “dialkyl amino” Each of the rings of the polycycle can be substituted with includes groups wherein the nitrogen atom is bound to at Such Substituents as described above, as for example, halo least two additional alkyl groups. The term “arylamino” and gen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy "diarylamino' include groups wherein the nitrogen is bound carbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbo to at least one or two aryl groups, respectively. The term nyl, alkoxycarbonyl, alkylaminoacarbonyl, “alkylarylamino,”“alkylaminoaryl' or “arylaminoalkyl aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbo refers to an amino group that is bound to at least one alkyl nyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, ami group and at least one aryl group. The term "alkaminoalkyl nocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phos refers to an alkyl, alkenyl, or alkynyl group bound to a phonato, phosphinato, cyano, amino (including alkyl amino, nitrogen atom that is also bound to an alkyl group. dialkylamino, arylamino, diarylamino, and alkylarylamino), 0107 The term “amide" or “aminocarboxy” includes acylamino (including alkylcarbonylamino, arylcarbony compounds or moieties that contain a nitrogen atom that is lamino, carbamoyl and ureido), amidino, imino, Sulfhydryl, bound to the carbon of a carbonyl or a thiocarbonyl group. alkylthio, arylthio, thiocarboxylate, Sulfates, alkylsulfinyl, The term includes "alkaminocarboxy' groups that include Sulfonato, Sulfamoyl, Sulfonamido, nitro, trifluoromethyl, alkyl, alkenyl, or alkynyl groups bound to an amino group cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or bound to a carboxy group. It includes arylaminocarboxy heteroaromatic moiety. groups that include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or 0115 The term "heteroatom' includes atoms of any ele thiocarbonyl group. The terms “alkylaminocarboxy,”“alk ment other than carbon or hydrogen. Preferred heteroatoms enylaminocarboxy,”“alkynylaminocarboxy, and “arylami are nitrogen, oxygen, Sulfur and phosphorus. nocarboxy' include moieties wherein alkyl, alkenyl, alkynyl 0116. In certain embodiments, the ester group or the and aryl moieties, respectively, are bound to a nitrogen atom metabolite reducing moiety (EG or MR) does not substan which is in turn bound to the carbon of a carbonyl group. tially effect the biological activity of the therapeutic com US 2006/0009465 A1 Jan. 12, 2006 pound. Alternatively, in certain other embodiments the ester the receptor and agents that up-regulate (i.e., induce) the group or the metabolite reducing moiety (EG or MR) Synthesis or production of the receptor. Significantly effects the biological activity of the therapeutic compound. In one embodiment, the ester group or the 0127. The language “compounds that antagonize” a metabolite reducing moiety (EG or MR) decreases the receptor, e.g., a 5-HT, receptor, is intended to include biological activity of the therapeutic compound. Alterna compounds that inhibit the activity of the receptor and tively, in an another embodiment of the invention, the ester agents that down-regulate (i.e., inhibit) the Synthesis or group or the metabolite reducing moiety (EG or MR) production of the receptor. improves the biological activity of the therapeutic com 0128. The terms “modification” or “modifies” include pound. controlling or adjusting physical or chemical parameters, 0117. When the ester is a methyl or an ethyl ester, the e.g., the half-life, of the therapeutic compound in Vivo by formulation of the therapeutic compound is formulated to changing one or more factors, e.g., the lipophilicity, elec Sufficiently treat the target disorder. In addition, formula tronic properties and/or Steric Size of the metabolite reducing tions of the therapeutic compound can be used to provide moiety, e.g., ester group. controlled in Vivo adsorption of the therapeutic compound 0129. The language “spacer molecule,”“SP,”“SP,” or over a discrete period of time. “SP” includes molecules or moieties that are positioned within the compound to allow the compound to perform its 0118. In certain embodiments of the invention, the com intended function. In certain embodiments, the Spacer mol pound containing the metabolism reducing group, e.g., an ecule may be present. Alternatively, in certain other embodi ester group, is more active as a therapeutic agent for treating ments, the Spacer molecule may not be present. In certain disorders than the corresponding compound without the this embodiments, the Spacer molecule may be (CH), where m group, e.g., due to a reduction in the production of the is an integer number Selected from 1 to 20. In addition, the wake-promoting metabolite. In another embodiment of the Spacer molecule, e.g., the (CH), linker to an ester or a invention, the compound containing the ester group, is more carboxylic acid group, can be Substituted with one or more active as a therapeutic agent for treating disorders than the Substituents. In one embodiment, the Spacer molecule is corresponding acid. In other embodiments, the correspond mono-Substituted. In another embodiment of the invention, ing acid of the ester is not a therapeutically active agent for the Spacer molecule is disubstituted. In particular embodi treating disorders. ments, the linkers of the invention may be geminally 0119. One skilled in the art would recognize that the ester dialkylated, e.g., gem-dimethylated; singly Substituted with groups, as described above, could be extended to thioesters. a Substituent other than a noncyclic alkyl group, e.g., a Labile amides may also be used in replacement of the ester heteroatom; or a cyclic Substituent wherein one or more of group, wherein the in Vivo hydrolysis would be performed the carbons of the Spacer molecule is contained in the ring, by peptidases in the CNS. e.g., heterocycle (e.g., tetrahydropyran or tetrahydrofuran), or cyclic alkyl, e.g., cyclopropyl. However, the Substitution 0120) The language “biological activity” includes activ of the Spacer molecule is independent of the Substitution ity associated with the intended biological function of the elsewhere in the molecule. compounds of the present invention, e.g., treating a sleep disorder. 0.130. In particular, the therapeutic compound of the invention may comprise the formula: 0121 The language “modulate a target” or “modulation of a target' includes the act of agonizing or antagonizing a receptor or group of receptors of a target disorder. Thus, a wherein TZ is a traZOdone compound, EG is an ester group compound that agonizes or antagonizes a receptor or group that modifies the half-life of the therapeutic compound, SP of receptorS is referred to herein as a target modulator, e.g., is a Spacer molecule, and n is 0 or 1. Sleep disorder target modulator. 0131. In certain embodiments of the invention, the thera 0122) The language “target modulator” includes com peutic compound has a favorable biological property. In one pounds or compositions, e.g., pharmaceutical compositions, embodiment of the invention, the invention is a method of which are used to modulate a target, e.g., a sleep disorder treating a sleep disorder. The method comprises administer target. ing an effective amount of a traZOdone compound, Such that the Sleep disorder is treated, wherein the traZodone com 0123 The term “target' includes a receptor or group of pound has a favorable biological property (FBP). receptors that have been identified as useful point of action for a therapeutic compound, e.g., Sleep disorder target. 0132) The language “favorable biological property (FBP)” includes one or more biological properties that allow 0.124. The language “receptor” includes specific sites of the compound to perform its intended function in an binding or action within a is Subject, associated or respon enhanced manner. Examples of favorable biological prop Sible for the activity of the target disorder, e.g., a 5-HT2A erties include but are not limited to induction of a discrete receptor. Sleep or State, activity of the therapeutic compound 0.125 The language “group of receptors' includes two or for a discrete period of time, penetration through the blood more receptors that may comprise the Same receptor type or brain barrier into the CNS, modulation of the half-life of the may comprise two or more receptor types. therapeutic compound, in Vivo hydrolysis of the ester by esterases that allows Sequestration of the therapeutic com 0.126 The language “compounds that agonize” a receptor pound in the CNS, reduction of the formation of a wake is intended to include compounds that induce the activity of promoting metabolite, e.g., m-CPP, an alteration of charge, US 2006/0009465 A1 Jan. 12, 2006 an alteration of pharmacology-kinetics, an alteration of log administering to a Subject an effective amount of a thera P by a value of 0.25 or more, increased receptor selectivity, peutic compound, Such that the Sleep disorder is treated, reduced peripheral half-life, the ability to increase dosage, wherein the therapeutic compound is as described above and increased peripheral elimination, increased elimination from comprises one of the following formulae: the CNS, decreased anti-muscarinic activity, decreased anti cholinergic, and any combination thereof. It should be understood that the language “FPB' is intended to include a Single property or a combination of two or more properties. In particular embodiments of the invention, the therapeutic wherein TZ is a trazodone compound, MR is a metabolite compound induces a discrete Sleep or hypnotic State by reducing moiety that reduces the formation of wake pro penetration into the CNS. In certain embodiments of the moting metabolites, EG is an ester group that modifies the invention, the FBP includes increased concentration within half-life of the therapeutic compound, SP, SP and SP are the CNS for a discrete period of time as a result of a slower Spacer molecules, n, q, and r are independently 0 or 1, and rate of conversion to the corresponding carboxylic acid by in r and q are 0 when MR is the ester group that modifies the vivo esterase activity within the CNS as compared with the half-life of the therapeutic compound (i.e., EG=MR Such periphery. that EG also reduces the formation of the wake-promoting 0133. In certain embodiments, wherein the therapeutic metabolite). compound is active for a discrete period of time, the FBP is 0.138 Another embodiment of the invention is a sleep a reduced ability of the subject to form a tolerance to the disorder target modulator comprising the formula: therapeutic compound. The language “tolerance' includes the natural tendency of a Subject to become leSS affected by continued administration of a particular therapeutic com wherein TZ is a trazodone compound, MR is a metabolite pound due to repeated exposure to the compound. It should reducing moiety that reduces the formation of wake pro be noted that tolerance is typically increased coincident with moting metabolites, EG is an ester group that modifies the the increased time that a compound is present in its active half-life of the therapeutic compound, SP and SP are State within the Subject. Reduced tolerance would coincide Spacer molecules, n, q, and r are independently 0 or 1, and with increased therapeutic effectiveness. r and q are 0 when MR is the ester group that modifies the 0134) The language “discrete sleep or hypnotic state' half-life of the therapeutic compound. includes a State of Sedated consciousness that is induced by the presence of active therapeutic compound of the inven 0.139. In another embodiment of the invention, a sleep tion, for a defined period of time. This is in contrast to the disorder target modulator comprises the formula: lingering hangover effect resulting from the existing treat ments, e.g., anti-histamines, used for their effect that maintain active drug concentrations for extended peri wherein TZ is a traZOdone compound, EG is an ester group ods of time in the periphery. that modifies the half-life of the therapeutic compound, SP is a Spacer molecule, and n is 0 or 1. 0135 The language “discrete period of time” includes a defined period of time in which the therapeutic compound is 0140. In accord with the invention, particular embodi active, and depends upon the physical and reactive proper ments of the therapeutic compound used for treating disor ties of the ester group. In one embodiment of the invention, ders are: the half-life of the therapeutic compound is 1 to 8 hours. In a preferred embodiment, the half-life of the therapeutic compound is 4 to 6 hours. It should be understood that C ranges within these half-life values is intended to be within O OR the Scope of this invention. 0.136 The term “sequestration” includes having (l)b enhanced concentration in the CNS and more rapid elimi nation from the periphery. The product of hydrolysis can exit the brain by various carboxylate excretion mechanisms, possibly at a slower rate than from the periphery producing - a CNS sequestration of the carboxylate for a defined, or C discrete, period of time. In one embodiment of the invention, elimination of the hydrolyzed carboxylate-containing metabolite occurs predominately by excretion through the kidneys, due to enhanced polarity of the metabolite, either as r O , and the free carboxylate or after Phase II further metabolism. In NS another embodiment, elimination occurs predominantly by N metabolism in the liver, e.g. hydrolysis of the ester followed \ N O by glucuronidation, and excretion into the bile. In certain y- N embodiments, the brain assists in the elimination from the O CNS though various active transport mechanisms. 0.137 Another embodiment of the current invention is a method of modulating a sleep disorder target comprising US 2006/0009465 A1 Jan. 12, 2006

positions or more than one MR group may be attached at -continued multiple positions). In certain embodiments, MR is alkyl. In O OR Cl particular embodiments, the therapeutic compound of the invention is selected from the compounds listed in Table 2.

TABLE 2

Structure Series #

N 18d-Oxa 21 2 \, late N wherein a=0 through 5, b=0 through 5, b=0 through 5, and S isk R is any group which imparts properties to the therapeutic O compound to promote penetration into the CNS, reduction COPr of the formation of wake-promoting metabolites, and/or to C2H2O4 ( modify the half-life of the compound. In preferred embodi ments of the invention, a-0 or 1, b=0 or 1; and c=0 or 1. N 0141 Additional particular embodiments of the therapeu tic compound used for treating disorders are:

C Cl

N 18f-oxa 21 2 \, late N S isk O wherein MR is a metabolite reducing moiety that reduces the COpen formation of wake-promoting metabolites. MR is selected and positioned along the dotted line shown above Such that C2H2O4 K the compound is capable of performing its intended func N tion. 0142. In yet another particular embodiment, the thera peutic compound used for treating disorders can have the formula: C

(SP)-EG N 19d-Oxa 21 2 \, late N N isk O

C2H2O4 N 0143 wherein MR is a metabolite reducing moiety that reduces the formation of wake-promoting metabolites, EG is Co.N an ester group that modifies the half-life of the therapeutic compound, SP is a Spacer molecule, q is 0 or 1, and X is H or Cl, such that MR is selected and positioned along the dotted line shown above Such that the compound is capable of performing its intended function. It should be understood that MR can be one or more groups, i.e., functional moieties, Cl which can be attached at multiple positions along the dotted line (e.g., a single MR group may be attached at multiple US 2006/0009465 A1 Jan. 12, 2006 17

TABLE 2-continued TABLE 2-continued

Structure Series # Structure Series # 19f-oxa late 18a-HCI

N

cypenO2C

Cl

N/A

N/A

COiPr Cl

N/A

19a-HCI

C Cl US 2006/00094.65 A1 Jan. 12, 2006 18

TABLE 2-continued TABLE 2-continued

Structure Series # Structure Series # — -

rN N/A 7O NN

OiPr

N/A

Ocypen O N/A O N/A 7 NN 7 NN US 2006/00094.65 A1 Jan. 12, 2006 19

TABLE 2-continued TABLE 2-continued

Structure Series # Structure Series # Z \ N/A Free base / KXC O or

Cl OiPr Z \ N/A a \ N/A W

CI OiPr US 2006/0009465 A1 Jan. 12, 2006 2O

TABLE 2-continued TABLE 2-continued

Structure Series # Structure Series #

Free base N/A

Cl

N/A N/A

N/A N/A US 2006/0009465 A1 Jan. 12, 2006 21

TABLE 2-continued TABLE 2-continued

Structure Series # Structure Series #

N/A N/A

Ocypen

N/A N/A

OiPr

N/A N/A US 2006/0009465 A1 Jan. 12, 2006 22

EXAMPLE 1. TABLE 2-continued 0149 Several synthetic protocols for compounds of the Structure Series # invention and intermediates thereto are described below and N/A depicted in the corresponding Schemes, shown below. 0150 Compound 1. Compound 1 was synthesized fol lowing the Similar procedure reported by Lis, R., Marisca, A. J. A Convenient Synthesis of N-Aryl-N'-Benzyl-1,2- Ethanediamines. Synth. Commun. 1988, 18, 45-50.

OCH

Br HO NH Br COOEt Cl EtN, DMF

NH 0144. Another embodiment of the invention is a pharma ceutical composition comprising a therapeutic compound as prepared according to the methodology of this invention, and a pharmaceutically acceptable carrier. 0145. In another embodiment, the invention is intended Cl to include any novel compounds described herein. 1. 0146 Additionally, the compounds described above are intended to include analogs containing art-recognized Sub Stituents that do not significantly effect the analogs ability OCH to perform its intended function. Furthermore, any novel Synthesis of the compounds of the invention described herein, is also intended to be included within the Scope of the present invention. 0147 Assays can be used to design and/or select com pounds useful within the present invention. The SCORE method, described in Example 2, would be an example of -C, Such an assay. Multiple assay components, Such as total Sleep time, cumulative nonREM sleep profile, maximum CC nonREM sleep bout length, average nonREM sleep bout length, nonREM sleep time, nonREM onset of action pro file, sleep latency, REM sleep time, REM sleep bout length, cumulative REM sleep profile, maximum wake bout length, average wake bout length, locomotor activity, locomotor C. activity intensity, body temperature, and drinking are used to 2 R1 = COOEt, R = H define compounds that would be useful in the present 3 R = H, R2 = COOEt invention. For example, in determining therapeutic com pounds that would be useful as Sedatives or wake-promoting compounds, all of the components listed above would be used in determining a preferred therapeutic compound. therapeutic compounds would use the com 0151 Compound 2 and 3. Compound 1 (19.5 g, 60.93 ponents of total Sleep time, cumulative nonREM sleep mmol) and ethyl 2,3-dibromopropionate (30.2 g, 117.36 profile, maximum nonREM sleep bout length, REM sleep mmol) were dissolved in DMF (55 mL). Triethylamine (32.5 time, REM sleep bout length, locomotor activity, locomotor mL, 234.72 mmol) was added to give a slurry, which then activity intensity, and body temperature for determination of was heated in an oil bath at 110° C. for 17 h. The reaction preferred therapeutic compounds. was cooled to room temperature and 1 NNaOH (80 mL) was added. The resulting solid was collected by filtration and EXEMPLIFICATION OF THE INVENTION crystallized from 2-propanol to give 9.2 g of compound 3. 0.148. The invention is further illustrated by the following The mother liquor was then concentrated and purified by examples that should not be construed as limiting. Com column chromatography (silica) to give compound 2 (4.1 g). pounds described herein may be obtained through art rec Compound 2 and 3 were confirmed by H-NMR, C-NMR ognized Synthesis Strategies. and LC-MS. US 2006/0009465 A1 Jan. 12, 2006 23

0154) 2-(3-chloropropyl)-1,2,4-triazo4,3-alpyridin 3(2H)-one(7). A mixture of 1,2,4-triazo4,3-alpyridin OCH3 3(2H)-one (6), 1.35 g, 10 mmol), 1-bromo-3-chloropropane (4.13 g, 26 mmol) and potassium carbonate (2.07 g., 15 mmol) in MeCN ( 15 mL) was refluxed for 8 h. After removal of the insoluble material by filtration, the filtrate was concentrated and the residue was extracted with CHCl (150 mL). After evaporation of the solvent, the residual -C, material was purified by column chromatography (EtOAC/ TFA Heptane, 1:2) to give 2-(3-chloropropyl)-1,2,4-triazo4,3-a CC pyridin-3(2H)-one, compound 7 (1.47 g., 70%). Compound C. 7 was confirmed by H-NMR and LC-MS. 2 R = COOEt, R = H 3 R = H, R2 = COOEt N| H | C C. NEt3/Xylene 4 N2N N CN R2 N-sk \- C O C 5

Cl 4 R1 = COOEt, R = H 5 R1 = H, R2 = COOEt 21 2N N N isk 0152 Compound 5. Compound 2 (2.1 g, 5 mmol) and O methoxybenzene (1.1 g, 10 mmol) were added to a 5% solution of HSO in CFCOOH (12 mL). After the reaction was heated at 60° C. for 40 h, water (5 mL), 1 N. NaOH (10 mL, saturated NaHCO (10 mL), and CHCl (150 mL) were added. The organic layer was separated and dried (Na2SO) CN COOEt and the Solvent was removed to give compound 5 (760 mg, 60%). Compound 5 was confirmed by H-NMR and LC MS. 0153 Compound 4. Compound 4 was prepared from compound 2 in 75% yield following the same procedure as Cl that for compound 5. 15

21 2 N\, Br Cl N H - Y Y - N isk KCO/CH3CN 0155 Compound 15. Compound 6, 1.45 g, 6.9 mmol) O and 1-(3-chlorophenyl)-2-carbethoxypiperazine (5) (1.75 g, 6 6.9 mmol) and triethylamine (2 mL, 14.4 mmol) were taken up in Xylene (20 mL) and refluxed for 12 h. After cooling to room temperature, the Solution was washed with water and N evaporated under reduced pressure. The residue was dis CN isk \- solved in EtOAc (100 mL), washed with brine and dried O C (Na2SO), and was purified by column chromatography 7 (EtOAC/Heptane, 2:3) to give the compound 15 (1.65 g, 65%). Compound 15 was confirmed by H-NMR and LC MS. US 2006/0009465 A1 Jan. 12, 2006 24

4-Y2N 21 2N N N N N S isk { l O N 2-Propanol N COOEt (i) Aq. NaOH/MeOH C D NaH (cat) C r (ii) Aq. HCI N COOEt N

C Cl 15 14

4-Y2N 21 2N N N-sk N -K O O

COOH

N COOPir N HC

Cl Cl 19d 18a

0156 Compound 19d. Sodium hydride (60% dispersion 0158 Compound 18a-HC1. Compound 14 (1.2 g, 2.7 in mineral oil, about 60 mg) was added to a stirred Solution mmol) was dissolved in MeOH (20 mL) and an aqueous of 15 (2.2g, 4.95 mmol) in 2-propanol (15 mL). After 12 h, solution of NaOH (2N) was added. The reaction was the Solvent was removed under Vacuum. The residue was refluxed for 2 h and was cooled to room temperature. The then dissolved in EtOAc (100 mL), washed with brine, dried Solvents were removed and the residue was purified by using (Na2SO4), and purified by column chromatography preparative HPLC to give the sodium salt of 18a. The (EtOAC/Heptane, 1:2) to give the compound 19d (1.58 g, sodium salt was dissolved in MeOH (10 mL) and aqueous 70%/o). Compound 19d was confirmed by H-NMR and HCl (3 mL, 1 N) was added and stirred for 45 minutes. The LC-MS. Solution was concentrated to give the compound 18a-HCl and was confirmed by H-NMR, LC-MS and elemental analysis. Oxalic acid 9d -e- 19d-Ox EtOH Trazodone with gem-dimethyl bridge 0159) O157 Compound 19d-Oxalate. A solution of oxalic acid (150 mg, 1.68 mmol) in ethanol (1 mL) was added to a stirred solution of compound 19d (770 mg, 1.68 mmol) in O ethanol (1.25 mL) in one aliquot. The mixture became solid at the end of the addition and ethyl acetate (2 mL) was added 21 NN NH arxis K2CO3, DMF to facilitate Stirring. After 1 h of Stirring, the Solid was - 150° C. collected by suction and washed with ethyl acetate (5 mL). S N 2 After drying, the oxalate salt 19d-OX was obtained as white powder (730 mg, 85%). 'H-NMR and elemental analyses were consistent with the Structure. US 2006/0009465 A1 Jan. 12, 2006 25

-continued Scheme Ia Synthetic Route to Trazodone Analogs Esters on Piperidine Ring ---, OCH N =l 3 -C, Br 0160 Compound 3. A mixture of 1,2,4-triazolo(4,3-a)py ridin-3(2H)-one (11.2g, 82.88 mmol) (1), 1,3-dichloro-2,2- C NH Br COOEt dimethyl propane (2), and KCO (23.0g, 21.71 mmol.) in EtN, DMF DMF (100 mL) was stirred at 150° C. for 48 hours. Product NH 3 (5.4 g, 27% yield) was isolated by silica gel column purification and confirmed by H-NMR, LC-MS.

C 1.

O C 21 A / DBU, DMF/150° C. — / \ OCH N N HN N 3 \ /

R 4 CHO R = H, CF, Cl N R1 H2SO4 ---

N 2 TFA

C 2 R1 = COOEt, R = H 3 R1 = H, R2 = COOEt

H

NEt3/Xylene CN R2 0161 Compound 5. Compound 3 (1.0 equivalent) was dissolved in DMF (25 mL). The amine (4) (1.5 equivalent) N and 1,8-diazabicyclo5.4.0]undec-7-ene (DBU, 1.5 equiva CN isk \- lent) were added to the Solution, and the Solution was heated Cl O C to 150° C. for 48 h. Product 5, (12% to 20% yield) was 4 R1 = COOEt, R = H isolated after Silica gel column chromatography and con 5 R = H, R2 = COOEt firmed by H-NMR, LC-MS.

US 2006/0009465 A1 Jan. 12, 2006

-continued -continued OCH O Cl 2N1ls NN DBU,7 DMF/150° C., 48 h. CHO N o HN N NH \ / 3 R

NH 4 R = H, CH, Cl

C 1.

Scheme Ic -N N Synthetic Route to Gem-Dimethyl O N Derivatized Trazodone Analogs ls R

4NN NH C K2CO3, DMF N N -- He o 150° C., 48 h. 5 S N 2 R = H, CF, Cl 1.

Scheme II Synthetic Route to Trazodone Analogs: Esters Adjacent to the Piperidine Ring -s,COEt 1) Base N C N N NNat --- N 2) Deprotect N COEt N N Sk N N ( \ Cl N N ( O O O O 22 23 NH2

(Note: 24 can be obtained from the synthesis of 1. If 24 forms a cyclic aminal NH with 23, that does not equilibrate to allow the reduction to 25, then preforming the NaBHCN piperidine ring (31) and 1) reducing the enamine obtained with 23, or 2) alkylating with an C-halo ester analog of 23 could be tried.) C 24 US 2006/0009465 A1 Jan. 12, 2006 28

-continued

e N N- \ Y e O COR o N N- N N Ester Interchange Y or NaOH O COEt

e N N NH N N \N Br C Y COE D NH Cl O '''t Br/Refs. 1 & 2 27 R = H, isopropyl, isobutyl, cyclopentyl N C N 25

Cl 26

0162 References: 1) G. B. Phillips et al., J. Med. Chem., 1999, 42, 1587-1603.3) M. Giannangeli et al., J. Med Chem., 1992, 35, 743-750. 2) G. Le Bihan et al., J. Med. Chem., 1999, 42,336-345.

Scheme III Synthetic Route to Trazodone Analogs: Homologated Esters Adjacent to the Piperidine Ring

21 e NYN' B1N1 Norbs 21 e NY N isk N isk O O OTBS 28 1) BuNF 2) Oxidize US 2006/0009465 A1 Jan. 12, 2006

-continued

RO n1N 21 2N /N CO2Et 21 2N N COEt RO O N O N isk \ -e-Base N isk \ { O H O H 3O 29 H ) N (Note: 31 can be obtained by alkylating 1 with 1,2-dibromoethane followed by deprotection)

Cl 31 (m-CPP)

O- e- SN N '' N '' O COEt O r. N Ester Interchange or NaOH Ho

N D N)

C C 32 33 R = H, isopropyl, isobutyl, cyclopentyl

Scheme IV Synthetic Route to Cyclopropyl and Gem-Dimethyl Derivatized Trazodone Analogs

Br |

HerNBS, CC14 N1 N Cl benzoylrt peroxide Cl 21 2 N\, /N 1. Ref. 1 2 NGNagel O N Aldrich S N Sk O 3 Cl Lancaster 4 US 2006/0009465 A1 Jan. 12, 2006

-continued OCH3 H HCO N Note: Compounds 5 are either available from Aldrich, TCI, NH or are literature compounds. 2 N-1N N 6: From previous EtOC (H2C)- 1) trazodone analogs synthesis 2) EtOC (H2C)- Br Br 5 3) H2SO4/TFA or EtOH 7 n = 0, 1 o, morp n = 0, 1 o, m, or p Y

N N N N N N N N N / / f N N N O O O

H2 (3 atm.), PtCl2 1) CHI, Zn-Cu se- se N AcOH, 50° N 2) Ester interchange N Parr Apparatus Ref. 4 Refs. 2 & 3 R = H, isopropyl, isobutyl, cyclopentyl -CN -CN -CN 1O 9 8 n = 0, 1 n = 0, 1 n = 0, 1 o, m, or p o, m, or p o, m, or p

0163) References: 1) Stoller, A. et al, Tetrahedron Lett. interfered with nonREM sleep for 2-3 hours and REM sleep (1990), 31(3), 361-4. 2) Motherwell, W. B. et al., Contemp. for 7 hours post-treatment. These effects were followed by Org. Synth. (1994), 1(4), 219–241. 3) Simmons, H. E. et al., a rebound hypersomnolence. The temporal course of m-CPP Org. React. (1973), 20, 1. 4) Woodworth, C. W. et al, Chem. effects on Sleep-wakefulneSS provide working evidence that Comm. (1968), 569-570. the initial efficacy and duration of TraZOdone action on Sleep-wake may be greatly enhanced by inactivating the EXAMPLE 2 m-CPP component of Trazodone metabolism through medicinal chemistry modification of the Trazodone mol Comparison of Trazodone and Trazodone ecule. Metabolite Using SCORE-200TM 0164. Sleep-wakefulness, locomotor activity and body 0.165. The general experimental conditions utilized in temperature were monitored in Male Wistar rats treated with testing the compounds of the invention for their utility Trazodone (10 mg/kg, n=7) and the principal metabolite of treating sleep disorders are described below. Trazodone, m-CPP (3 mg/kg, n=6 and lo mg/kg, n=7). 0166) I. Animals & Surgery. Trazodone was administered at CT-18 (6 hours after lights off). The Trazodone metabolite m-CPP was administered at 0167 Adult, male Wistar rats (250 g at time of Surgery, CT-5 (5 hours after lights-on). Trazodone disrupted sleep Charles River Laboratories) were anesthetized (Nembutal, during the first hour but was highly Soporific in Subsequent 62 mg/kg) and Surgically prepared with a cranial implant to hours. Trazodone Sleep effects were characterized by permit chronic electro-encephalogram (EEG) and elec increased nonREM sleep time and increased sleep continu tromyogram (EMG) recording. Body temperature and loco ity, but without evidence of REM sleep inhibition, rebound motor activity were monitored via a miniature transmitter insomnia, or disproportional locomotor activity changes. By (Minimitter) Surgically placed in the abdomen. The cranial contrast, the Trazodone metabolite m-CPP significantly implant consisted of Stainless Steel Screws (two frontal+3.2 US 2006/0009465 A1 Jan. 12, 2006

AP from bregma, +2.0 ML and two occipital -6.9AP, +5.5 IV. Treatments and Study Design. ML) for EEG recording. Two Teflon-coated stainless steel wires were positioned under the nuchal trapezoid muscles 0170 A. Timing of treatment Compounds were admin for EMG recording. All leads were soldered to a miniature istered at CT-18, the peak of the activity-dominated period, connector prior to Surgery, and gas Sterilized in ethylene in order to ensure (i) prior wakefulness was Sufficient to oxide. The implant assembly was affixed to the skull with interact positively with hypnotic-drug effects, and (ii) Suf dental acrylic. A minimum of three weeks was allowed for ficient time was allowed to view the time course of the Surgical recovery. treatment effect before lights-on (6 hours post-treatment). The Trazodone metabolite m-CPP was administered at CT-5, II. Recording Environment. the middle of the rodent rest-phase of the daily sleep-wake 01.68 Each rat was permanently housed in its own indi rhythm, in order to ensure (i) maximum assay Sensitivity to vidual recording cage located within Separate, ventilated the wake-promoting effects of the compound, and (ii) maxi compartments of custom-designed Stainless Steel cabinets. mum assay Sensitivity to compound effects on REM sleep. Each Nalgene microisolator cage was enhanced with a 0171 B. Vehicle and route of administration. Compounds filter-top riser and low-torque Swivel-commutator. Food and were suspended in sterile 0.25% methylcellulose (1 ml/kg). water were available ad libitum. A 24-hr light-dark cycle (12 Treatments were administered as an intraperitoneal bolus. hours light, 12 hours dark) was maintained throughout the Study using 4-watt fluorescent bulbs 5 cm from the cage. 0172 C. Study design and controls. A parallel group Animals were undisturbed for at least 36 hours before and Study design was employed. Vehicle controls were drawn after treatments. from a large pool (N>200): a subset of the pooled vehicle controls was Selected, based on computerized matching with III. Automated Physiological Monitoring. the 24-hour pre-treatment baseline of the active treatment 0169 Sleep and wakefulness were determined using grOup. “SCORE-2000TM”—an internet-based sleep-wake and physiological monitoring System. The System monitors 0173 D. Drugs tested. Trazodone and the Trazodone amplified EEG (bandpass 1-30 Hz; digitization rate 400 Hz), metabolite m-CPP were tested for this proof of principle integrated EMG (bandpass 10-100 Hz), body temperature Study. Trazodone was administered at 10 mg/kg. The TraZ and non-specific locomotor activity (LMA) via telemetry, odone metabolite m-CPP was administered at 3 mg/kg and and drinking activity, continuously and Simultaneously. 10 mg/kg. Arousal states were classified on-line as NREM sleep, REM V. Results Sleep, wake, or theta-dominated wake every 10 Seconds using EEG feature extraction and pattern-matching algo 0174 Trazodone (10 mg/kg IP, n=7) interfered with sleep rithms. The classification algorithm uses individually-taught during the initial 2 hours post-treatment but markedly and EEG-arousal-state templates, plus EMG criteria to differen significantly increased nonREM sleep time (FIG. 1) and tiate REM sleep from theta-dominated wakefulness, plus sleep bout duration for 2-3 hours thereafter (FIG. 2), and behavior-dependent contextual rules (e.g., if the animal was increased sleep consolidation in the initial 2-3 hours of the drinking, it was awake). Drinking and locomotor activity Subsequent Subjective day (lights-on phase of the LD 12:12 (LMA) were recorded as discrete events every 10 seconds, light-dark cycle). Trazodone produced no evidence of while body temperature was recorded each minute. Loco rebound insomnia, disproportional motor inhibition, or motor activity was detected by a telemetry receiver (Mini adverse thermoregulatory events post-treatment. The Sleep mitter, Sunriver, Oregon) beneath the cage. Telemetry mea consolidating effects of Trazodone were especially notewor Sures (LMA and body temperature) were not part of the thy, as they were more robust in magnitude when compared Scoring algorithm; thus, Sleep-scoring and telemetry data to comparable treatment with contemporary were independent measures. Sedative hypnotics Such as Zolpidem. US 2006/00094.65 A1 Jan. 12, 2006 32

TOTAL SLEEP(NREM+REM)

g C5 60 - s

1. l l iN N i l Y igh it Na Aa 4. , , is 30 Yr. 3. s ; J

12:00 O:00 12:00 0:00 12:00 O:00 CRC N TIME - (A) Control (n=7) * P C 0.050 - (B) Trazodone-10 (n=7) Figure 1. Effect of Trazodone (10 mg/kg IP) on total sleep time in the rat. Data are plotted as hourly averages (meant SEM). Data are plotted 30 h before and after treatment (red triangle). Note the initial interference of sleep followed by a robust soporific effect relative to vehicle. US 2006/00094.65 A1 Jan. 12, 2006 33

LONGEST SLEEP-BOUT each hour

30

co l, Y 5 20 2s A Ni 7 A ' ' '. AA 's YX 'NNA W1 i 1C r N NN Y se-A24-Y1. Nissys A.

* 12:00 0:00 12:00 0:00 12:00 0:00 CRC TIME - (A) Control (n=7) * P C 0.050 - (B) Trazodone-10 (n=7) Figure 2. Effect of Trazodone (10 mg/kg IP) on sleep bout-length (sleep consolidation) in the rat. Data are plotted as hourly averages (meant SEM). Data are plotted 30 h before and after treatment (red triangle). Note the robust increase in sleep consolidation following treatment (arrow).

NREMSLEEP

g 6 2 92 Sh S y 5 \ \ 4. 40 f

s isA /AVNAA 4. - At s2 Y-M ^,I - S - 20 , ..is W t

O:OO 12:00 O:00 12:00 O:00 12:00 CIR AN TIME - (A) Methylcellulose vehicle 1 ml/kg IP (n=7) * P a 0.025 - (B) mm-CPP 10mg/kg IP (n=7) Figure 3. Effect of m-CPP (10 mg/kg IP) on nonREM sleep in the rat. Data are plotted as in Figure 1. Note the initial interference of sleep and subsequent rebound hypersomnolence (hypersomnolence denoted by arrow). US 2006/00094.65 A1 Jan. 12, 2006 34

20 REM SLEEP

0:00 12:00 O:00 12:00 O:00 12:00 CR ANTME - (A) Methylcellulose vehicle 1 ml/kg IP (n=7) * P C 0.025 - (B) mm-CPP 10mg/kg IP (n=7) Figure 4. Effect of m-CPP (10 mg/kg IP) on REM sleep in the rat. Data are plotted as in Figure 1. Note the virtual elimination of REM sleep post-treatment (arrow). US 2006/0009465 A1 Jan. 12, 2006 35

0175. The Trazodone metabolite m-CPP (3 mg/kg IP, increased, and drug carry-over will be decreased, through n=6, and 10 mg/kg IP, n=7) strongly and dose-dependently inactivation of the Trazodone metabolite m-CPP. interfered with sleep 2-3 hours post-treatment. Interference with Sleep was characterized by a dose-dependent reduction EXAMPLE 3 in nonREM sleep time lasting 2-3 hours post-treatment, and a marked dose-dependent reduction in REM sleep lasting up Comparison of Trazodone and Trazodone Analog to7 hours post-treatment at the higher dose. Sleep interfer Using SCORE-2000TM ence caused by m-CPP was followed by rebound hyperSom nolence reflected in both nonREM sleep and sleep bout 0177 Sleep-wakefulness, locomotor activity and body length measures. The timecourse of Sleep interference temperature were monitored in Male Wistar rats treated with (increased waking) caused by m-CPP correlated very Trazodone (30 mg/kg, n=9) and HY-2725 (I9) (30 mg/kg, Strongly with the initial interference of Sleep following n=8). The general experimental conditions utilized in testing Trazodone treatment (noted above). In addition, the rebound the compounds of the invention for their utility treating Sleep hypersomnolence caused by m-CPP correlated very strongly disorders are described in Example 2. with the timecourse of carryover effects following Traz Results odone administration (noted above). Taken together, it is likely that the delayed onset of TraZOdone-induced sleep is 0.178 Trazodone initially interferes with sleep (FIG. 5: caused in part or completely by the Sleep-interference char arrow; lower plot) whereas HY-2725 has a more rapid acteristics of the Trazodone metabolite m-CPP. It is further Soporific onset of action and does not interfere with Sleep likely that the Soporific carryover effects of Trazodone are (FIG. 2: upper plot). The initial interference in sleep after caused in part or completely by the rebound hyperSomno trazodone treatment is believed to be caused by the forma lence induced by the Trazodone metabolite m-CPP. tion of the TraZOdone metabolite m-CPP. HY-2725 is designed to reduce or eliminate the formation of this V. Conclusions metabolite. 0176 Trazodone has considerable potential as a sedative hypnotic if the undesirable effects of the Trazodone metabo 0179 FIG. 6 demonstrates that Trazodone treatment (tri lite m-CPP (sleep interference, rebound hypersomnolence, angle) inhibits REM sleep (FIG. 6: arrows, lower plot), REM sleep inhibition and sympathomimetic effects) could whereas HY-2725 does not inhibit REM sleep. be inactivated through medicinal chemistry modification of 0180. In addition, HY-2725, a cyclopentyl ester analog, the Trazodone molecule. On the basis of the data from this potently and dose-dependently increases Sleep consolidation study, it is anticipated that the efficacy of Trazodone will be after treatment (FIG. 7: triangle). US 2006/00094.65 A1 Jan. 12, 2006 36

Figure 5

NREM SLEEP

80

6

40

20 Q

18O MINUTES AFTER TREATMENT - (A) Methylcellulose vehicle 1 ml/kg PO (n=10) - (B) HY2725: 30mg/kg PO CT-18 (n=8)

NREM SEEP

Ar 120 18O MINUTES AFTER TREATMENT - (A) Methylcellulose vehicle 1 ml/kg PO (n=10) P C 0.025 - (B) Trazodone: 30 mg/kg PO CT-18 (n=9) US 2006/00094.65 A1 Jan. 12, 2006 37

Figure 6

2 REMSLEEP

12:00 0:00 12:00 0:00 O:00 CIRC NTIME -- (A) Methylcellulose vehicle 1 ml/kg PO (n=10) P C 0.025 - (B) HY2725:30mg/kg PO CT-18 (n=8)

REM SLEEP

CRC N TIME - (A) Methylcellulose vehicle 1 ml/kg PO (n=10) * P C 0,025 - (B) Trazodone: 30mg/kg PO CT-18 (n=9) US 2006/00094.65 A1 Jan. 12, 2006 38

Figure 7

LONGEST SEEP-BOUT each hor

O:OO 12:00 O:00 CRC N TIME - (A) Methylcellulose vehicle 1 ml/kg PO (n=7) * PC 0.025 - (B) HY2725: 56 mg/kg PO (n=7) - (C) HY2725: 30 mg/kg PO (n=8) US 2006/0009465 A1 Jan. 12, 2006 39

0181. Several interesting SCORE components deter effects of the Trazodone metabolite m-CPP (sleep interfer mined for the parent Trazodone compound and Compound ence, rebound hyperSomnolence, REM sleep inhibition and 19fare shown below. Compound 19f shows not initial sleep Sympathomimetic effects) could be inactivated through interference and no REM sleep inhibition, whereas Traz medicinal chemistry modification of the Trazodone mol odone shows Significant initial Sleep interference and Sig ecule. On the basis of the data from this study, including the nificant REM sleep inhibition. In addition the duration of experimental results obtained for Compound 19f, it is antici action of 19f is significantly decreased as compared with pated that the efficacy of Trazodone will be increased, and Trazodone. drug carry-over will be decreased, through inactivation of 0182 Summary of Findings using the SCORE-2000TM the Trazodone metabolite m-CPP. Sleep-Wake Assay: EXAMPLE 4

Compound Determination of Activity of Carboxylic Acid TRAZODONE 19f Derivatized Trazodone Compound Initial Sleep Interference ------None 0.184 Sleep-wakefulness, locomotor activity and body REM Sleep Inhibition ------None temperature were monitored in Male Wistar rats treated with Increase Sleep Consolidation ------Increase Sleep Time ------HY-2724 (a) (30 mg/kg, n=7). The general experimental Rebound Insomnia None None conditions utilized in testing the compounds of the invention Disproportional Motor Inhibition None None for their utility treating sleep disorders are described in Body Temp (CV) Adverse Event Yes No Example 2. Duration of Action 7-9 h 5-6 h Results 0185 FIG. 8 shows that the acid (L9a) form of HY-2725 Conclusions (9f, cyclopentyl ester) is ineffective in increasing Sleep and 0183 AS discussed in Example 2, Trazodone has consid sleep consolidation. HY-2724 was inactive on sleep-wake erable potential as a Sedative hypnotic if the undesirable fulness in all measured variables. US 2006/00094.65 A1 Jan. 12, 2006 40

Figure 8

AVERAGE SLEEP-BouTeach hour

12:00 O:00 CRC TIME - (A) Methylcellulose vehicle 1 ml/kg PO (n=10) P C 0.025 - (B) HY2724:30mg/kg PO CT-18 (n=7) US 2006/0009465 A1 Jan. 12, 2006

Conclusions 0186 On the basis of the data from this study, it would appear that the corresponding acid becomes inactive once metabolized from the ester to the acid form, e.g., by (SP)-EG esterases. This “deactivation” of the active compound

should provide an ability to sufficiently control (modify) the half-life of the ester derivatized compounds. EXAMPLE 5 5-HT, Binding Study wherein MR is a metabolite reducing moiety that reduces the 0187 Binding assays were performed on Trazodone, formation of wake-promoting metabolites, MR is attached to HY-2725 (19f), HY-2650 (19d) and HY-2724 (19a), a carbon along the dotted line shown, EG is an ester group described above, using both rat and human 5-HYA receptor. that modifies the half-life of the trazodone compound, SP is The results are shown in Table 3. a Spacer molecule, q is 0 or 1, X is H or Cl. 0188 The binding studies against the 5-HT, receptor, 130. The method of claim 129, wherein said spacer indicate binding affinity, and therefore the results of the molecule is (CH), where m is an integer Selected from 1 binding assays are an indication of the activity of the to 20. compound. 131. The method of claim 129, wherein said trazodone compound containing MR is more effective as a therapeutic 0189 Table 3 shows rat and human 5-HT2A receptor agent for treating a sleep disorder than the corresponding binding for the above-identified compounds. Soporific effi compound without the MR. cacy and Sleep consolidation paralleled binding affinity at 132. The method of claim 129, wherein said trazodone 5-HT for HY-2725, HY-2650 and HY-2724. Although compound containing Said EG is more effective as a thera HY-2725 binding affinity is shown as less than that of peutic agent for treating a sleep disorder than the corre Trazodone, however, the HY2725 compound used was a sponding compound without the EG. racemic mixture of two isomers. Thus, the effective binding 133. The method of claim 129, wherein said trazodone affinity of HY-2725 may be equal or nearly equal to that of compound containing EG is more effective as a therapeutic Trazodone. It is hypothesized that HY-2725 Soporific effi agent for treating a sleep disorder than the corresponding cacy is superior to Trazodone because HY-2725 does not acid of said EG. produce the metabolite m-CPP. 134. The method of claim 129, wherein said trazodone compound containing the corresponding acid of EG is not a TABLE 3 therapeutically effective agent for treating a sleep disorder. 135. The method of claim 129, wherein said wake pro 5HT2a (Ki nM moting metabolite is m-CPP. Compound Side-Chain Rat Human 136. The method of claim 129, wherein the trazodone compound induces a discrete Sleep or hypnotic State by Trazodone Ole 8.11 286 HY-2725 cyclopentyl 18.7 757 penetration into the Central Nervous System (CNS). HY-26SO isapropyl 50.3 2,103 137. The method of claim 129, wherein the sleep disorder HY-2724 acid 989 >10,000 is Selected from the group consisting of insomnia, hyper Somnia, narcolepsy, Sleep apnea Syndromes, parasomnia, restleSS leg Syndrome, and circadian rhythm abnormality. INCORPORATED BY REFERENCE 138. The method of claim 137, wherein the sleep disorder is insomnia. 0190. The entire contents of all patents, published patent 139. The method of claim 137, wherein the sleep disorder applications and other references cited herein are hereby is hyperSomnia. expressly incorporated herein in their entireties by reference. 140. The method of claim 137, wherein the sleep disorder Equivalents is narcolepsy. 141. The method of claim 137, wherein the sleep disorder 0191 Those skilled in the art will recognize, or be able to is Sleep apnea Syndrome. ascertain, using no more than routine experimentation, many 142. The method of claim 137, wherein the sleep disorder equivalents to specific embodiments of the invention is parasomnia. described specifically herein. Such equivalents are intended 143. The method of claim 137, wherein the sleep disorder to be encompassed in the Scope of the following claims. is restleSS leg Syndrome. 144. The method of claim 137, wherein the sleep disorder is circadian rhythm abnormality. 145. The method of claim 144, wherein the circadian 1.-128. (canceled) rhythm abnormality is Selected from the group consisting of 129. A method of treating a sleep disorder, comprising jet lag, Shift-work disorders, and delayed or advanced sleep administering to a Subject an effective amount of a traZodone phase Syndrome. compound, Such that the Sleep disorder is treated, wherein 146. The method of claim 129, wherein the trazodone Said traZodone compound is represented by the formula: compound is administered orally. US 2006/0009465 A1 Jan. 12, 2006 42

147. The method of claim 129, further comprising admin istering the traZodone compound in a pharmaceutically -continued acceptable vehicle. C 148. The method of claim 129, wherein MR is one or O OR more moieties that are attached at one or more positions 's- , and along the dotted line. (l)b 149. The method of claim 148, wherein MR is a single \ /s N moiety that is attached at multiple positions. N 150. The method of claim 148, wherein MR is more than - one moiety attached at multiple positions. y 151. The method of claim 129, wherein MR is an alkyl O R C grOup. 152. The method of claim 129, wherein MR is selected r ( )e from the MRS represented in the compounds listed in Table 2. NS N 153. The method of claim 152, wherein MR is selected \ N S. from a methyl, a geminal dimethyl, a cyclopropyl, a COOH, a COO-ethyl, a COO-isopropyl, a COO-cyclopentyl, a X---n- Nu COO-pentyl, a cycloheptyl, and a benzyl group. O 154. The method of claim 149, wherein MR is cyclopro wherein a, b, and care, independently, Selected from 0, 1, 2, pyl. 3, 4, and S. and R is any group which imparts properties to 155. A method of treating a sleep disorder, comprising the traZodone compound to promote reduction of formation administering to a Subject an effective amount of a traZodone of wake-promoting metabolites, and modification to the compound, Such that the Sleep disorder is treated, wherein half-life of the compound. Said traZodone compound is represented by the formula: 157. The method of claim 156, wherein a is 0 or 1. 158. The method of claim 156, wherein b is 0 or 1. 159. The method of claim 156, wherein c is 0 or 1. C 160. The method of claim 156, wherein R is selected from the group consisting of hydrocarbons and perfluorocarbons. 161. The method of claim 160, wherein the hydrocarbons

are Selected from the group consisting of linear; branched; cyclic; aromatic, and a combination of Saturated or unsat urated aliphatic and aromatic, wherein further the hydrocar bons are optionally substituted with O, N, S, or halogen and may additionally include one or more centers of chirality. 162. The method of claim 160, wherein the hydrocarbons contain from 1 to 20 carbons. wherein MR is Selected from a geminal dimethyl, a cyclo 163. The method of claim 156, wherein R is selected from propyl, a COOH, a COO-ethyl, a COO-isopropyl, a COO the group consisting of a methyl, an ethyl, an n-propyl, an cyclopentyl, a COO-pentyl, a cycloheptyl, and a benzyl isopropyl, a t-butyl, an isobutyl, a cyclopentyl, a cyclohexyl, grOup. a cycloheptyl, and a benzyl group. 156. A method of treating a sleep disorder, comprising 164. The method of claim 163, wherein R is a cyclohexyl administering to a Subject an effective amount of a traZodone grOup. compound, Such that the Sleep disorder is treated, wherein 165. The method of claim 163, wherein R is a cyclopentyl Said traZodone compound is Selected from the group con grOup. Sisting of: 166. The method of claim 163, wherein R is a cycloheptyl grOup. 167. The method of claim 163, wherein R is an isobutyl Cl grOup. 168. The method of claim 163, wherein R is an ethyl grOup. 169. The method of claim 163, wherein R is a methyl grOup. 170. The method of claim 163, wherein R is an n-propyl grOup. 171. The method of claim 163, wherein R is an isopropyl grOup. 172. The method of claim 163, wherein R is a t-butyl grOup. RO 173. The method of claim 163, wherein R is a benzyl grOup. US 2006/0009465 A1 Jan. 12, 2006 43

174. The method of claim 163, wherein R is a bulky 186. The compound of claim 185, wherein MR is selected alcohol. from methyl, geminal dimethyl, cyclopropyl, COOH, COO 175. The method of claim 174, wherein the bulky alcohol ethyl, COO-isopropyl, COO-cyclopentyl, COO-pentyl a is selected from the alcohols listed in Table 1. cycloheptyl, and benzyl. 176. A method of treating a sleep disorder, comprising 187. The compound of claim 181, wherein MR is cyclo administering to a Subject an effective amount of a traZodone propyl. compound, Such that the Sleep disorder is treated, wherein 188. A compound represented by the formula: Said traZodone compound is represented by the formula:

C

N CN sk \ . R1 O N

( N)- wherein MR is Selected from a geminal dimethyl, a cyclo Cl, propyl, a COOH, a COO-ethyl, a COO-isopropyl, a COO cyclopentyl, a COO-pentyl, a cycloheptyl, and a benzyl grOup. wherein R and R are, independently, Selected from H, 189. A compound selected from: COO-isopropyl, and COO-cyclopentyl, provided that at least one of R and R is not H. 177. The method of claim 176, wherein one of R and R. C is H. 178. A compound of the formula:

(SP)-EG

C

O OR wherein MR is a metabolite reducing moiety that reduces the re- , and formation of wake-promoting metabolites, MR is attached to (l)b a carbon along the dotted line shown, EG is an ester group \ N N that modifies the half-life of the trazodone compound, SP is a Spacer molecule, q is 0 or 1, X is H or Cl. - 179. The compound of claim 178, wherein said wake promoting metabolite is m-CPP. O C 180. The compound of claim 178, wherein said spacer molecule is (CH), where m is an integer Selected from 1 to 20. 181. The compound of claim 178, wherein MR is one or more moieties attached at one or more positions along the dotted line. 182. The compound of claim 181 wherein MR is a single moiety that is attached at multiple positions. 183. The compound of claim 181, wherein MR is more than one moiety attached at multiple positions. wherein a, b, and c, are, independently Selected from 0, 1, 2, 184. The compound of claim 178, wherein MR is an alkyl 3, 4, and 5, and R is any group which imparts properties to grOup. the traZodone compound to promote reduction of formation 185. The compound of claim 178, wherein MR is selected of wake-promoting metabolites, and modification to the from the MRS represented in the compounds listed in Table half-life of the compound. 2. 190. The compound of claim 189, wherein a is 0 or 1. US 2006/0009465 A1 Jan. 12, 2006 44

191. The compound of claim 189, wherein b is 0 or 1. 204. The compound of claim 196, wherein R is an 192. The compound of claim 189, wherein c is 0 or 1. isopropyl group. 193. The compound of claim 189, wherein R is selected 205. The compound of claim 196, wherein R is a t-butyl from the group consisting of hydrocarbons and perfluoro grOup. carbons. 206. The compound of claim 196, wherein R is a benzyl 194. The compound of claim 193, wherein the hydrocar grOup. bons are Selected from the group consisting of linear; 207. The compound of claim 178, wherein said compound branched; cyclic; aromatic, and a combination of Saturated is formulated to provide controlled in vivo absorption of the or unsaturated aliphatic and aromatic, wherein further the compound over a discrete period of time. hydrocarbons are optionally substituted with O, N, S, or 208. A compound having the formula: halogen and may additionally include one or more centers of chirality. 195. The compound of claim 193, wherein the hydrocar bons contain from 1 to 20 carbons. N 196. The compound of claim 189, wherein R is selected from the group consisting of a methyl, an ethyl, an n-propyl, CN isk \- R1 an isopropyl, an n-butyl, a t-butyl, a cyclopentyl, a cyclo O N hexyl, a cycloheptyl, and a benzyl group. 197. The compound of claim 196 wherein R is a cyclo hexyl group. ( N)- 198. The compound of claim 196, wherein R is a cyclo pentyl group. 199. The compound of claim 196, wherein R is a cyclo Cl, heptyl group. 200. The compound of claim 196, wherein R is an isobutyl group. wherein R and R2 are, independently, Selected from H, 201. The compound of claim 196, wherein R is an ethyl COO-isopropyl, and COO-cyclopentyl, provided that at grOup. least one of R and R is not H. 202. The compound of claim 196, wherein R is a methyl 209. The compound of claim 208, wherein one of R and grOup. R is H. 203. The compound of claim 196, wherein R is an n-propyl group.