WO2016144860A1 - Faah inhibitors for the treatment or prevention of nausea - Google Patents

Abstract

The present disclosure relates to compound 1 and compositions comprising compound 1. The disclosure also provides methods of using compound 1 and compositions comprising compound 1 in the treatment or prevention of various disorders, including nausea and vomiting.

Description

FAAH INHIBITORS FOR THE TREATMENT OR PREVENTION OF NAUSEA

CLAIM OF PRIORITY

[0001] This application claims priority to United States Provisional Application Serial Nos.

62/129,440, filed on March 6, 2015 and 62/181,990, filed on June 19, 2015. The entire

contents of the aforementioned applications are herein incorporated by reference.

TECHNICAL FIELD

[0002] The present disclosure relates to IW-7229, an indole ketoamide, useful for inhibition

of the enzyme Fatty Acid Amide Hydrolase (FAAH). The disclosure also provides methods

of using the compositions in the treatment of various disorders.

BACKGROUND

[0003] The endocannabinoid (eCB) system has been implicated in a variety of processes

including cell signaling, memory encoding, compensatory mechanisms, and

immunosuppressant and anti-inflammatory responses. The eCB system comprises at least

two receptors: the CB1 cannabinoid receptor, widely distributed in the brain, and present in

some peripheral organs, and the CB2 receptor, found principally in the periphery and immune

cells and in some regions of the brain. The endogenous agonists of these receptors are the

endogenous cannabinoids (eCBs), a family of lipids comprising the fatty acid anandamide

(AEA) as well as other fatty acid amides.

Endocannabinoid-degrading enzymes, including fatty acid amide hydrolase (FAAH), are

responsible for cleaving and deactivating eCBs in vivo. FAAH is an integral membrane

protein that is expressed in high levels in several brain regions, especially in the neurons of

the hippocampus, cerebellum, neocortex and olfactory bulb. FAAH is the principal enzyme

responsible for the hydrolysis of AEA in vivo and is also capable of hydrolyzing a wide

variety of other substrates. It is known that inhibiting FAAH can lead to increases in fatty

acid amides, including AEA, which could enhance cannabinoid signals within the eCB

system. In the past decades, an emerging body of research has suggested that cannabinoid

and the endocannabinoid system may have a role in the control of nausea and vomiting. It is

postulated that this system may act by stimul ti CB1 d CB2 receptors located in the vagal complex of the brainstem. Two orally administered synthetic cannabinoids, nabilone and dronabinol, have been approved as therapies for refractory CINV, supporting a possible role for enhanced activation of the endogenous cannabinoid system in the management of CINV.

SUMMARY

[0004] The compound of the instant disclosure (compound 1) and its

pharmaceutically acceptable salts thereof are useful as FAAH inhibitors.

1

[0005] A further aspect of the disclosure includes compound 1 described herein and its pharmaceutically acceptable compositions are useful in methods for treating or lessening the severity of a variety of diseases or disease symptoms, including nausea and vomiting.

[0006] The invention also relates to methods for the treatment or prevention of nausea; acute nausea; anticipatory nausea; chemotherapy-induced nausea; chemotherapy-induced anticipatory nausea; radiation-induced nausea; radiation-induced anticipatory nausea; post- operative nausea; post-operative anticipatory nausea; vomiting; chemotherapy-induced vomiting; radiation-induced vomiting; and post-operative vomiting; hyperemesis; pregnancy- induced nausea; pregnancy-induced vomiting (“morning sickness”); nausea or anticipatory nausea induced by motion; vomiting induced by motion (“motion sickness,” such as that induced by traveling in a car, bus, train, airplane or boat); nausea or anticipatory nausea induced by a viral or bacterial infection; vomiting induced by a viral or bacterial infection; nausea induced by Meniere’s Disease; vomiting induced by Meniere’s Disease; nausea or anticipatory nausea induced by migraine headaches; vomiting induced by migraine headache; nausea induced by vertigo (e.g., benign paroxysmal positional vertigo, or vertigo caused by vestibular neuronitis or labyrinthitis); vomiting induced by vertigo (e.g., benign paroxysmal positional vertigo, or vertigo caused by vestibular neuronitis or labyrinthitis); vomiting resulting from gastroparesis (e.g., idiopathic gastroparesis or diabetic gastroparesis); nausea resulting from gastroparesis (e.g., idiopathic gastroparesis or diabetic gastroparesis); vomiting resulting from use of a pharmaceutical substance (e.g., from the use of a pharmaceutical substance including but not limited to opioids, antibiotics or anti-depressants); or nausea resulting from use of a pharmaceutical substance (e.g., from the use of a pharmaceutical substance including but not limited to opioids, antibiotics, anti-depressants or other pharmaceutical substances such as acetaminophen, bendamustine hydrochloride, hydrocodone bitartrate, bretylium tosylate, ceftibuten, ceftriaxone, cephadrine, cetirizine, cephradine, cetirizine, clonidine, clozapine, colestipol, conivaptan, dantrolene, desflurane, dibucaine, doxorubicin, fentanyl, fibrinogen, flurbiprofen, forpropofol, furosemide, linezolid, liotrix, L-ornithine-L-aspartate, mepacrine, mephenesin, methocarbamol, metolazone, miltefosine, minoxidil, mosapride, norethindrone, noscapine, paregoric, penfluridol, pentoxifylline, piperacillin, thioguanine, triazolam, velaglucerase alfa or yohimbine ), by using compound 1 or a pharmaceutical composition comprising compound 1, either alone or in combination therapy.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the effect of compound 1 (3, 10, 30 or 100 mg/kg) and vehicle (ig) administered 120 min prior to the conditioning trial, against the number of conditioned gaping responses (acute nausea).

Figure 2 illustrates the mean cumulative amount of saccharin solution consumed (mL) during a one-bottle consumption test which was measured at 15, 30, 60, 120, 240 and 360 min. after introduction of the bottle to fluid-restricted rats as described in Example 7.

Figure 3 illustrates the effect of compound 1 (10, 30 or 100 mg kg^-1 ig) and vehicle (ig) administered 120 min prior to the anticipatory nausea test, against the number of conditioned gaping responses (anticipatory nausea).

Figure 4 illustrates the effect of compound 1 (10, 30 or 100 ig mg kg^-1) and vehicle (ig) on the locomotor activity test, given after the anticipatory nausea test.

Figure 5 illustrates the effect of compound 1 (10 mg/kg) and vehicle (ig) administered 120 min. prior to the conditioning trial, along with SR 1411716 (1 mg/kg) or VEH (i.p.). administered 30 min. prior to the conditioning trial, on the number of conditioned gaping responses.

Figure 6 illustrates the mean cumulative amount of saccharin solution consumed (mL) during a one-bottle consumption test which was measured at 15, 30, 60, 120, 240 and 360 min. after introduction of the bottle to fluid-restricted rats as described in Example 10.

Figure 7 illustrates the effect of compound 1 (10 mg/kg, ig) or vehicle (ig) administered 120 min prior to the anticipatory nausea test and 90 min prior to pretreatment with SR141716 (2.5 mg/kg, ip) against the number of conditioned gaping responses (anticipatory nausea).

Figure 8 illustrates the effect of compound 1 (10 mg/kg, ig) and vehicle (ig) administered 120 min. prior to the anticipatory nausea test and 90 min. prior to pretreatment with

SR141716 (2.5 mg/kg, ip) on the locomotor activity test, given after the anticipatory nausea test.

DETAILED DESCRIPTION

[0007] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulae. While the invention will be described in conjunction with the disclosed embodiments, it will be understood that they are not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present invention as defined by the claims. The present invention is not limited to the methods and materials described herein but include any methods and materials similar or equivalent to those described herein that could be used in the practice of the present invention. In the event that one or more of the incorporated literature references, patents or similar materials differ from or contradict this application, including but not limited to defined terms, term usage, described techniques or the like, this application controls.

Description of Exemplary Compounds:

Definitions and general terminology

[0008] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed. (1994). Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, 5th Ed., Smith, M. B. and March, J., eds. John Wiley & Sons, New York: 2001, which are herein incorporated by reference in their entirety.

[0009] As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention. The phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. If a substituent radical or structure is not identified or defined as“optionally substituted”, the substituent radical or structure is not substituted. As it will be apparent to one of ordinary skill in the art, groups such as–H, halogen,–NO₂,–CN,–OH,–NH₂ or– OCF₃ would not be substitutable groups.

[0010] The phrase“up to”, as used herein, refers to zero or any integer number that is equal to or less than the number following the phrase. For example, optionally substituted with“up to 3” means substituted with 0, 1, 2, or 3 substituents. As described herein, a specified number range of atoms includes any integer therein. For example, a group having from 1–4 atoms could have 1, 2, 3 or 4 atoms. It will be understood by one of ordinary skill in the art that when a group is characterized as substituted (as opposed to optionally substituted) with, e.g.,“up to 3” substituents, it can only be substituted with 1, 2 or 3 substituents.

[0011] When any variable occurs more than one time at any position, its definition on each occurrence is independent from every other occurrence.

[0012] Selection of substituents and combinations envisioned by this disclosure are only those that result in the formation of stable or chemically feasible compounds. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation. The term“stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions that allow for their production, detection, and, in some embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 25 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0013] A compound, such as the compounds of the invention or other compounds herein disclosed, may be present in its free form (e.g., an amorphous form or polymorphs). Under certain conditions, compounds may also form salts, and/or other multi-component crystalline forms (e.g., solvates (e.g., hydrates) and co-crystals). As used herein, the term co-form is synonymous with the term multi-component crystalline form. When one of the components in the co-form has clearly transferred a proton to the other component, the resulting co-form is referred to as a“salt”. When both compounds in a multi-component crystalline form are independently solids at room temperature, the resulting co-form is referred to as a“co- crystal”. In co-crystals, no proton transfer takes place between the different components of the co-form. The formation of a salt or a co-crystal is determined by how large is the difference in the pKas between the partners that form the mixture. As used herein, a “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein (or its salts or co-crystals). A“hydrate” is a particular type of solvate in which the solvent is water. Examples of solvents that can form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, tetrahydrofuran (THF), dichloromethane (DCM), N,N-dimethylformamide (DMF).

[0014] Unless only one of the isomers is drawn or named specifically, structures depicted herein are also meant to include all stereoisomeric (e.g., enantiomeric, diastereomeric, atropoisomeric and cis-trans isomeric) forms of the structure, for example, the R and S configurations for each asymmetric center, Ra and Sa configurations for each asymmetric axis, (Z) and (E) double bond configurations, and cis and trans conformational isomers. Therefore, single stereochemical isomers as well as racemates, and mixtures of enantiomers, diastereomers, and cis-trans isomers (double bond or conformational) of the present compounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the disclosure.

[0015] The present disclosure also embraces isotopically labeled compounds that are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Certain isotopically labeled compounds of the present invention (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron-emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0016] The terms“aliphatic” or“aliphatic group”, as used herein, mean a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1–20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1–10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1–8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1–6 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1–4 aliphatic carbon atoms and in yet other embodiments, aliphatic groups contain 1–3 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples of aliphatic groups include, but are not limited to: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, sec- butyl, tert-butyl, butenyl, propargyl, acetylene and the like.

[0017] The term“alkyl”, as used herein, refers to a saturated linear or branched-chain monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group contains 1–20 carbon atoms (e.g., 1–20 carbon atoms, 1–10 carbon atoms, 1–8 carbon atoms, 1–6 carbon atoms, 1–4 carbon atoms or 1–3 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like.

[0018] The term“alkenyl” refers to a linear or branched-chain monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon, sp² double bond, wherein the alkenyl radical includes radicals having“cis” and“trans” orientations, or alternatively, “E” and“Z” orientations. Unless otherwise specified, an alkenyl group contains 2–20 carbon atoms (e.g., 2–20 carbon atoms, 2–10 carbon atoms, 2–8 carbon atoms, 2–6 carbon atoms, 2– 4 carbon atoms or 2–3 carbon atoms). Examples include, but are not limited to, vinyl, allyl and the like.

[0019] The term“alkynyl” refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. Unless otherwise specified, an alkynyl group contains 2–20 carbon atoms (e.g., 2–20 carbon atoms, 2–10 carbon atoms, 2–8 carbon atoms, 2–6 carbon atoms, 2–4 carbon atoms or 2–3 carbon atoms). Examples include, but are not limited to, ethynyl, propynyl, and the like.

[0020] The term“carbocyclic” refers to a ring system formed only by carbon and hydrogen atoms. Unless otherwise specified, throughout this disclosure, carbocycle is used as a synonym of“non-aromatic carbocycle” or“cycloaliphatic”). In some instances, the term can be used in the phrase“aromatic carbocycle”, and in this case it refers to an“aryl group” as defined below.

[0021] The term“cycloaliphatic” (or“non-aromatic carbocycle”,“non-aromatic

carbocyclyl”,“non-aromatic carbocyclic”) refers to a cyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic, and which has a single point of attachment to the rest of the molecule. Unless otherwise specified, a cycloaliphatic group may be monocyclic, bicyclic, tricyclic, fused, spiro or bridged. In one embodiment, the term“cycloaliphatic” refers to a monocyclic C₃–C₁₂ hydrocarbon or a bicyclic C₇–C₁₂ hydrocarbon. In some embodiments, any individual ring in a bicyclic or tricyclic ring system has 3–7 members. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of aliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,

cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

[0022] The term“cycloaliphatic” also includes polycyclic ring systems in which the non- aromatic carbocyclic ring can be“fused” to one or more aromatic or non-aromatic carbocyclic or heterocyclic rings or combinations thereof, as long as the radical or point of attachment is on the non-aromatic carbocyclic ring.

[0023] The term“heterocycle” (or“heterocyclyl” or“heterocyclic”), as used herein, refers to a ring system in which one or more ring members are an independently selected heteroatom, which is completely saturated or that contains one or more units of unsaturation but which is not aromatic, and which has a single point of attachment to the rest of the molecule. Unless otherwise specified, through this disclosure, heterocycle is used as a synonym of“non- aromatic heterocycle”. In some instances the term can be used in the phrase“aromatic heterocycle”, and in this case it refers to a“heteroaryl group” as defined below. The term heterocycle also includes fused, spiro or bridged heterocyclic ring systems. Unless otherwise specified, a heterocycle may be monocyclic, bicyclic or tricyclic. In some embodiments, the heterocycle has 3–18 ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur or nitrogen, and each ring in the system contains 3 to 7 ring members. In other embodiments, a heterocycle may be a monocycle having 3–7 ring members (2–6 carbon atoms and 1–4 heteroatoms) or a bicycle having 7–10 ring members (4–9 carbon atoms and 1–6 heteroatoms). Examples of bicyclic heterocyclic ring systems include, but are not limited to: adamantanyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza- bicyclo[2.2.2]octyl.

[0024] As used herein, the term“heterocycle” also includes polycyclic ring systems wherein the heterocyclic ring is fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or with combinations thereof, as long as the radical or point of attachment is in the heterocyclic ring.

[0025] Examples of heterocyclic rings include, but are not limited to, the following monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3- tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3- thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1- tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4- thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl; and the following bicycles: 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and 1,3-dihydro- imidazol-2-one.

[0026] As used herein, the term“aryl” (as in“aryl ring” or“aryl group”), used alone or as part of a larger moiety, as in“aralkyl”,“aralkoxy”,“aryloxyalkyl”, refers to a carbocyclic ring system wherein at least one ring in the system is aromatic and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aryl group may be monocyclic, bicyclic or tricyclic and contain 6–18 ring members. The term also includes polycyclic ring systems where the aryl ring is fused with one or more aromatic or non- aromatic carbocyclic or heterocyclic rings, or with combinations thereof, as long as the radical or point of attachment is in the aryl ring. Examples of aryl rings include, but are not limited to, phenyl, naphthyl, indanyl, indenyl, tetralin, fluorenyl, and anthracenyl. An optionally substituted“aralkyl” can be substituted on both the alkyl and the aryl portion. For instance, unless otherwise indicated, as used in this disclosure, an optionally substituted aralkyl is attached to the rest of the molecule through the alkyl chain and optionally substituted in the aryl portion. The same principle applies, for example, to a substituted aralkoxy, which would be attached to the rest of the molecule through the oxygen of the alkoxy and substituted on the aryl portion. A substituted aryloxyalkyl would be attached to the rest of the molecule through the alkyl chain and substituted on the aryl ring, which in turn would be attached to the alkyl chain through an oxygen atom.

[0027] The term“heteroaryl” (or“heteroaromatic” or“heteroaryl group” or“aromatic heterocycle”) used alone or as part of a larger moiety as in“heteroaralkyl” or

“heteroarylalkoxy” refers to a ring system wherein at least one ring in the system is aromatic and contains one or more heteroatoms, wherein each ring in the system contains 3 to 7 ring members and which has a single point of attachment to the rest of the molecule. Unless otherwise specified, a heteroaryl ring system may be monocyclic, bicyclic or tricyclic and have a total of five to fourteen ring members. In one embodiment, all rings in a heteroaryl system are aromatic. Also included in this definition are heteroaryl radicals where the heteroaryl ring is fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or combinations thereof, as long as the radical or point of attachment is in the heteroaryl ring. A bicyclic 6,5 heteroaromatic system, as used herein, for example, is a six-membered heteroaromatic ring fused to a second five-membered ring wherein the radical or point of attachment is on the six-membered ring. [0028] Heteroaryl rings include, but are not limited to the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, and the following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl, benzopyrazinyl, benzopyranonyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

[0029] As used herein,“cyclo” (or“cyclic”, or“cyclic moiety”) encompasses mono-, bi- and tri-cyclic ring systems including cycloaliphatic, heterocyclic, aryl or heteroaryl, each of which has been previously defined.

[0030]“Fused” bicyclic ring systems comprise two rings which share two adjoining ring atoms.

[0031]“Bridged” bicyclic ring systems comprise two rings which share three or four adjacent ring atoms. As used herein, the term“bridge” refers to a bond or an atom or a chain of atoms connecting two different parts of a molecule. The two atoms that are connected through the bridge (usually but not always, two tertiary carbon atoms) are referred to as“bridgeheads”. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,

bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl.

[0032]“Spiro” bicyclic ring systems share only one ring atom (usually a quaternary carbon atom).

[0033] The term“ring atom” refers to an atom such as C, N, O or S that is part of the ring of an aromatic group, a cycloaliphatic group or a heteroaryl ring. A“substitutable ring atom” is a ring carbon or nitrogen atom bonded to at least one hydrogen atom. The hydrogen can be optionally replaced with a suitable substituent group. Thus, the term“substitutable ring atom” does not include ring nitrogen or carbon atoms which are shared when two rings are fused. In addition,“substitutable ring atom” does not include ring carbon or nitrogen atoms when the structure depicts that they are already attached to one or more moiety other than hydrogen and no hydrogens are available for substitution.

[0034]“Heteroatom” refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocyclic or heteroaryl ring, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl).

[0035] In some embodiments, two independent occurrences of a variable may be taken together with the atom(s) to which each variable is bound to form a 5–8-membered, heterocyclyl, aryl, or heteroaryl ring or a 3–8-membered cycloalkyl ring. Exemplary rings that are formed when two independent occurrences of a substituent are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of a substituent that are bound to the same atom and are taken together with that atom to form a ring, where both occurrences of the substituent are taken together with the atom to which they are bound to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the group is attached to the rest of the molecule by a single point of attachment; and b) two independent occurrences of a substituent that are bound to different atoms and are taken together with both of those atoms to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the ring that is formed has two points of attachment with the rest of the molecule.

[0036] For example, where a phenyl group is substituted with two occurrences of R_o as in Formula D1:

,

these two occurrences of OR_o are taken together with the carbon atoms to which they are bound to form a fused 6-membered oxygen containing ring as in Formula D2:

.

[0037] It will be appreciated that a variety of other rings can be formed when two independent occurrences of a substituent are taken together with the atom(s) to which each substituent is bound and that the examples detailed above are not intended to be limiting.

[0038] In some embodiments, an alkyl or aliphatic chain can be optionally interrupted with another atom or group. This means that a methylene unit of the alkyl or aliphatic chain can optionally be replaced with said other atom or group. Unless otherwise specified, the optional replacements form a chemically stable compound. Optional interruptions can occur both within the chain and/or at either end of the chain; i.e., both at the point of attachment(s) to the rest of the molecule and/or at the terminal end. Two optional replacements can also be adjacent to each other within a chain so long as it results in a chemically stable compound. Unless otherwise specified, if the replacement or interruption occurs at a terminal end of the chain, the replacement atom is bound to an H on the terminal end. For example, if –CH₂CH₂CH₃ were optionally interrupted with–O–, the resulting compound could be –OCH₂CH₃,–CH₂OCH₃, or–CH₂CH₂OH. In another example, if the divalent linker –CH₂CH₂CH₂– were optionally interrupted with–O–, the resulting compound could be –OCH₂CH₂–,–CH₂OCH₂–, or–CH₂CH₂O–. The optional replacements can also completely replace all of the carbon atoms in a chain. For example, a C₃ aliphatic can be optionally replaced by–N(R^$)–,–C(O)–, and–N(R^$)– to form–N(R^$)C(O)N(R^$)– (a urea).

[0039] In general, the term“vicinal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.

[0040] In general, the term“geminal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom.

[0041] The terms“terminally” and“internally” refer to the location of a group within a substituent. A group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure. Carboxyalkyl, i.e., R^XO(O)C–alkyl, is an example of a carboxy group used terminally. A group is internal when the group is present in the middle of a substituent at the end of the substituent bound to the rest of the chemical structure. Alkylcarboxy (e.g., alkyl–C(O)O– or alkyl–O(CO)–) and alkylcarboxyaryl (e.g., alkyl–C(O)O–aryl– or alkyl–O(CO)–aryl–) are examples of carboxy groups used internally. [0042] As described herein, a bond drawn from a substituent to the center of one ring within a multiple-ring system (as shown below), represents substitution of the substituent at any substitutable position in any of the rings within the multiple ring system. For example, formula D3 represents possible substitution in any of the positions shown in formula D4:

[0043] This also applies to multiple ring systems fused to optional ring systems (which would be represented by dotted lines). For example, in Formula D5, X is an optional substituent both for ring A and ring B.

[0044] If, however, two rings in a multiple ring system each have different substituents drawn from the center of each ring, then, unless otherwise specified, each substituent only represents substitution on the ring to which it is attached. For example, in Formula D6, Y is an optional substituent for ring A only, and X is an optional substituent for ring B only.

D6 [0045] As used herein, the terms“alkoxy” or“alkylthio” refer to an alkyl group, as previously defined, attached to the molecule, or to another chain or ring, through an oxygen (“alkoxy,” e.g., O-alkyl) or a sulfur (“alkylthio,” e.g., S-alkyl) atom. The terms C_n–m “alkoxyalkyl”, C_n–m“alkoxyalkenyl”, C_n–m“alkoxyaliphatic”, and C_n–m“alkoxyalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more alkoxy groups, wherein the total number of carbons between the alky and alkoxy, alkenyl and alkoxy, aliphatic and alkoxy or alkoxy and alkoxy, as the case may be, is between the values of n and m. When these moieties are optionally substituted they can be substituted in either of the portions on both sides of the oxygen or sulfur. For example, an optionally substituted C₄ alkoxyalkyl could be, for instance, -CH₂CH₂OCH₂(Me)CH₃ or -CH₂(OH)O CH₂CH₂CH₃; a C₅ alkoxyalkenyl could be, for instance,

r

=CHCH₂CH₂OCH₂CH₃.

[0046] The terms“aryloxy”,“arylthio”,“benzyloxy” or“benzylthio”, refer to an aryl or benzyl group attached to the molecule, or to another chain or ring, through an oxygen (“aryloxy”,“benzyloxy,” e.g.,–O–Ph,–OCH₂Ph) or sulfur (“arylthio,” e.g.,–S–Ph,–S– CH₂Ph) atom. For instance, the terms“aryloxyalkyl”,“benzyloxyalkyl”“aryloxyalkenyl” and“aryloxyaliphatic” mean alkyl, alkenyl or aliphatic, as the case may be, substituted with one or more aryloxy or benzyloxy groups, as the case may be. In this case, the number of atoms for each aryl, aryloxy, alkyl, alkenyl or aliphatic will be indicated separately. Thus, a 5–6-membered aryloxy(C_1–4alkyl) is a 5–6 membered aryl ring, attached via an oxygen atom to a C_1–4 alkyl chain which, in turn, is attached to the rest of the molecule via the terminal carbon of the C_1–4 alkyl chain.

[0047] An optionally substituted“aralkyl” can potentially be substituted on both the alkyl and the aryl portion. Unless otherwise indicated, as used in this disclosure, an optionally substituted aralkyl is attached to the rest of the molecule through the alkyl chain and optionally substituted in the aryl portion. The same principle applies, for example, to a substituted aralkoxy, which would be attached to the rest of the molecule through the oxygen of the alkoxy and substituted on the aryl portion. A substituted aryloxyalkyl would be attached to the rest of the molecule through the alkyl chain and substituted on the aryl ring, which in turn would be attached to the alkyl chain through an oxygen atom. For example, an optionally substituted 6-membered aryloxy(C₃alkyl) group could be, for instance,–

(CH₃)₂CH₂– [p-(MeO)-Ph]; an optionally substituted 6-membered heteroaryloxy(C₄alkyl) could, for instance, be–CH₂CH₂CH₂–O-(3-F-2-pyrydyl) or–CH(CH₃)–O–CH₂CH₂–(5,6- dimethyl-1,3-pyrimidine). If the alkyl chain on the“aralkyl” group is also substituted that will be specifically indicated. For instance an optionally substituted 6-membered

heteroaryloxy(C₄alkyl) that is also optionally substituted on the alkyl would be referred to as “an optionally substituted 6-membered heteroaryloxy(C₄alkyl), wherein said C₄ alkyl chain is optionally substituted.” An example of this latter group could be 5, 6-dimethyl-1,3- pyrimidine–O–CF(CH₃)–CH(OH)CH₂, wherein the alkyl chain is substituted with F and with –OH.

[0048] As used herein, the terms“halogen” or“halo” mean F, Cl, Br, or I. [0049] The terms“haloalkyl”,“haloalkenyl”,“haloaliphatic”, and“haloalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more halogen atoms. For example, a C_1–3 haloalkyl could be CFHCH₂CHF₂ and a C_1–2 haloalkoxy could be– OC(Br)HCHF₂. This term includes perfluorinated alkyl groups, such as–CF₃ and–CF₂CF₃.

[0050] As used herein, the term“cyano” refers to–CN or–C^N.

[0051] The terms“cyanoalkyl”,“cyanoalkenyl”,“cyanoaliphatic”, and“cyanoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more cyano groups. For example, a C_1–3 cyanoalkyl could be–C(CN)₂CH₂CH₃ and a C_1–2 cyanoalkenyl could be =CHC(CN)H₂.

[0052] As used herein, an“amino” group refers to–NH₂.

[0053] The terms“aminoalkyl”,“aminoalkenyl”,“aminoaliphatic”, and“aminoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more amino groups. For example, a C_1–3 aminoalkyl could be–CH(NH₂)CH₂CH₂NH₂ and a C_1-2 aminoalkoxy could be–OCH₂CH₂NH₂.

[0054] The terms“hydroxyl”or“hydroxy” refer to–OH.

[0055] The terms“hydroxyalkyl”,“hydroxyalkenyl”,“hydroxyaliphatic”, and

“hydroxyalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more–OH groups. For example a C_1–3 hydroxyalkyl could be–

CH₂(CH₂OH)CH₃ and a C₄ hydroxyalkoxy could be–OCH₂C(CH₃)(OH)CH₃.

[0056] As used herein, an“aroyl” or“heteroaroyl” refers to a–C(O)-aryl or a–C(O)- heteroaryl. The aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.

[0057] As used herein, a“carbonyl”, used alone or in connection with another group refers to C(O)– or–C(O)H. For example, as used herein, an“alkoxycarbonyl,” refers to a group such as–C(O)O(alkyl).

[0058] As used herein, an“oxo” refers to =O, wherein oxo is usually, but not always, attached to a carbon atom (e.g., it can also be attached to a sulfur atom forming a sulfoxide or a sulfone). An aliphatic chain can be optionally interrupted by a carbonyl group or can optionally be substituted by an oxo group, and both expressions refer to the same: e.g.,–CH₂- C(O)-CH₃. [0059] As used herein, in the context of resin chemistry (e.g., using solid resins or soluble resins or beads), the term“linker” refers to a bifunctional chemical moiety attaching a compound to a solid support or soluble support.

[0060] In all other situations, a“linker”, as used herein, refers to a divalent group in which the two free valences are on different atoms (e.g., carbon or heteroatom) or are on the same atom but can be substituted by two different substituents. For example, a methylene group can be a C₁ alkyl linker (–CH₂–) which can be substituted by two different groups, one for each of the free valences (e.g., as in Ph–CH₂–Ph, wherein methylene acts as a linker between two phenyl rings). Ethylene can be a C₂ alkyl linker (–CH₂CH₂–) wherein the two free valences are on different atoms. The amide group, for example, can act as a linker when placed in an internal position of a chain (e.g.,–CONH– ). A linker can be the result of interrupting an aliphatic chain by certain functional groups or of replacing methylene units on said chain by said functional groups. E.g., a linker can be a C_1–6 aliphatic chain in which up to two methylene units are substituted by–C(O)– or–NH– (as in–CH₂–NH–CH₂–C(O)– CH₂– or– CH₂–NH–C(O)–CH₂–). An alternative way to define the same–CH₂–NH–CH₂– C(O)–CH₂– and– CH₂–NH–C(O)–CH₂– groups is as a C₃ alkyl chain optionally interrupted by up to two–C(O)– or–NH– moieties. Cyclic groups can also form linkers: e.g., a 1,6- cyclohexanediyl can be a linker between two R groups, as in

[0061] Divalent groups of the type =CH–R or =C–R₂, wherein both free valences are in the same atom and are attached the same substituent, are also possible. In this case, they will be referred to by their IUPAC accepted names. For instance, an alkylidene (such as, for example, a methylidene (=CH₂) or an ethylidene (=CH–CH₃)) would not be encompassed by the definition of a linker in this disclosure.

[0062] The term“protecting group”, as used herein, refers to an agent used to temporarily block one or more desired reactive sites in a multifunctional compound. In certain embodiments, a protecting group has one or more, or preferably all, of the following characteristics: a) reacts selectively in good yield to give a protected substrate that is stable to the reactions occurring at one or more of the other reactive sites; and b) is selectively removable in good yield by reagents that do not attack the regenerated functional group. Exemplary protecting groups are detailed in Greene, T.W., Wuts, P.G. in Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference. The term“nitrogen protecting group”, as used herein, refers to an agents used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound. Preferred nitrogen protecting groups also possess the characteristics exemplified above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T.W., Wuts, P.G. in Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.

[0063] As used herein, the term“displaceable moiety” or“leaving group” refers to a group that is associated with an aliphatic or aromatic group as defined herein and is subject to being displaced by nucleophilic attack by a nucleophile.

[0064] As used herein,“amide coupling agent” or“amide coupling reagent” means a compound that reacts with the hydroxyl moiety of a carboxy moiety thereby rendering it susceptible to nucleophilic attack. Exemplary amide coupling agents include DIC

(diisopropylcarbodiimide), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide), DCC (dicyclohexylcarbodiimide), BOP (Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate), pyBOP ((Benzotriazol-1-yloxy)tripyrrolidinophosphonium

Hexafluorophosphate), etc.

[0065] The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound’s identity.

[0066] In one aspect, the invention relates to compound 1 or pharmaceutically acceptable salts thereof.

Methods of preparing the compounds:

[0067] Compound 1 may be prepared according to the schemes and examples depicted and described in International Application PCT/US2011/066972 published as WO 2012/088469 (see“general route 3” beginning on p.63 and“compounds prepared according to general route 3” beginning on p.119), which is incorporated by reference herein in its entirety.

Unless otherwise specified, the starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available compounds or prepared using well-known synthetic methods. Pharmaceutically acceptable salts:

[0068] The phrase“pharmaceutically acceptable salt,” as used herein, refers to

pharmaceutically acceptable organic or inorganic salts of compound 1. For use in medicine, the salts of compound 1 will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of compound 1 or of its pharmaceutically acceptable salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.

[0069] Pharmaceutically acceptable salts compound 1 include those derived from suitable inorganic and organic acids and bases. In some embodiments, the salts can be prepared in situ during the final isolation and purification of compound 1. In other embodiments the salts can be prepared from the free form of compound 1 in a separate synthetic step.

[0070] The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al.,

"Pharmaceutical Salts," J. Pharm. Sci., 1977:66:1–19, incorporated herein by reference in its entirety.

Pharmaceutical compositions and methods of administration:

[0071] Compound 1 and its pharmaceutically acceptable salts, thereof, may be formulated as pharmaceutical compositions or“formulations”.

[0072] In a second aspect, the invention comprises a pharmaceutical composition comprising compound 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or adjuvant. In a further embodiment, the pharmaceutical composition further comprises at least one additional therapeutic agent. In other embodiments, the

pharmaceutical composition further comprises an additional therapeutic agent which is chosen from the group consisting of painkillers, non-steroidal anti-inflammatory drugs (NSAIDs), cannabinoid receptor agonists, opiate receptor agonists, anti-infective agents, sodium channel blockers, N-type calcium channel blockers, local anesthetics, VR1 agonists and antagonists, agents used for migraines, topical agents used in the treatment of localized pruritus, anti-inflammatory and/or immunosuppressive agents, agents designed to treat tobacco abuse (e.g., nicotine receptor partial agonists and nicotine replacement therapies), ADD/ADHD agents, agents to treat alcoholism, such as opioid antagonists, agents for reducing alcohol withdrawal symptoms such as benzodiazepines and beta-blockers, antihypertensive agents such as ACE inhibitors and Angiotensin II Receptor blockers, Renin inhibitors, vasodilators, agents used to treat glaucoma such as direct-acting Miotics

(cholinergic agonists), indirect acting Miotics (cholinesterase inhibitors), Carbonic anhydrase inhibitors, selective adrenergic agonists, Osmotic diuretics, antidepressants such as SSRIs, tricyclic antidepressants and dopaminergic antidepressants, anti-emetic agent such as dopamine receptor antagonists, cognitive improvement agents, acetylcholinesterase inhibitors, anti-emetic agents (e.g., 5HT3 antagonists), neuroprotective agents,

neuroprotective agents currently under investigation, antipsychotic medications, agents used for multiple sclerosis, disease-modifying anti-rheumatic drugs (DMARDS), biological response modifiers (BRMs), COX-2 selective inhibitors, COX-1 inhibitors,

immunosuppressives, PDE4 inhibitors, corticosteroids, histamine H1 receptor antagonists, histamine H2 receptor antagonists, proton pump inhibitors, leukotriene antagonists, 5- lipoxygenase inhibitors, nicotinic acetylcholine receptor agonists, P2X3 receptor antagonists, NGF agonists and antagonists, NK1 and NK2 antagonists, NMDA antagonists, potassium channel modulators, GABA modulators, anti-cancer agents such as tyrosine kinase inhibitors, anti-hyperlipidemia drugs, appetite suppressing agents, anti-diabetic medications such as insulin, GI (gastrointestinal) agents, and serotonergic and noradrenergic modulators.

[0073] A typical formulation is prepared by mixing compound 1, or a pharmaceutically acceptable salt, solvate, co-crystal or pro-drug thereof, and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which compound 1 is being formulated. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (e.g., GRAS—Generally Regarded as Safe) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc., and mixtures thereof. The formulations may also include other types of excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or slow release) preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of compound 1 or aid in the manufacturing of the

pharmaceutical product (i.e., medicament).

[0074] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (e.g., compound 1, a pharmaceutically acceptable salt, solvate, co-crystal or pro-drug thereof, or a stabilized form of the compound, such as a complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. A compound having the desired degree of purity is optionally mixed with

pharmaceutically acceptable diluents, carriers, excipients or stabilizers, in the form of a lyophilized formulation, milled powder, or an aqueous solution. Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers. The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8.

[0075] Compound 1 or a pharmaceutically acceptable salt thereof is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen. Pharmaceutical formulations of compound 1, or a pharmaceutically acceptable salt, solvate, co-crystal or pro-drug thereof, may be prepared for various routes and types of administration. Various dosage forms may exist for the same compound, since different medical conditions may warrant different routes of administration. The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total composition (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ^g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur. As a general proposition, the initial pharmaceutically effective amount of the inhibitor administered will be in the range of about 0.01–300 mg/kg per dose, about 0.1 to 60 mg/kg of patient body weight per day, about 0.3 to 45 mg/kg/day, or about 1 to 25 mg/kg/day.

[0076] In some embodiments, the pharmaceutically effective amount of the inhibitor will be administered once daily, twice daily, three times daily. In some embodiments, the pharmaceutically effective amount of the inhibitor will be administered immediately prior to or immediately following chemotherapy. In some embodiments, the pharmaceutically effective amount of the inhibitor will be administered immediately prior to or immediately following radiation therapy. In some embodiments, the pharmaceutically effective amount of the inhibitor will be administered following chemotherapy. In some embodiments, the pharmaceutically effective amount of the inhibitor will be administered following a surgical procedure.

[0077] The term“therapeutically effective amount” as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The therapeutically or pharmaceutically effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, cure or treat the disease or disorder or one or more of its symptoms.

[0078] The term“prophylactically effective amount” refers to an amount effective in preventing or substantially lessening the chances of acquiring a disease or disorder or in reducing the severity of the disease or disorder or one or more of its symptoms before it is acquired or before the symptoms develop. Roughly, prophylactic measures are divided between primary prophylaxis (to prevent the development of a disease) and secondary prophylaxis (whereby the disease has already developed and the patient is protected against worsening of its severity).

[0079] The pharmaceutical compositions of compound 1 will be formulated, dosed, and administered in a fashion, i.e., in amounts, concentrations, schedules, courses, vehicles, and route(s) of administration consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular human or other mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners, such as the age, weight, and response of the individual patient.

[0080] Acceptable diluents, carriers, excipients, and stabilizers are those that are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride;

hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol;

cyclohexanol; 3-pentanol; and m-cresol); proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN^TM, PLURONICS^TM or polyethylene glycol (PEG). The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, e.g., hydroxymethylcellulose or gelatin- microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano- particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in

Remington's: The Science and Practice of Pharmacy, 21^st Edition, University of the Sciences in Philadelphia, Eds., 2005 (hereafter“Remington’s”).

[0081]“Controlled drug delivery systems” supply the drug to the body in a manner precisely controlled to suit the drug and the conditions being treated. The primary aim is to achieve a therapeutic drug concentration at the site of action for the desired duration of time. The term “controlled release” is often used to refer to a variety of methods that modify release of drug from a dosage form. This term includes preparations labeled as“extended release”,“delayed release”,“modified release” or“sustained release”. [0082]“Sustained-release preparations” are the most common applications of controlled release. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound, wherein the matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No.3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid- glycolic acid copolymers, and poly-D-(-)-3-hydroxybutyric acid.

[0083]“Immediate-release preparations” may also be prepared. The objective of these formulations is to get the drug into the bloodstream and to the site of action as rapidly as possible. For instance, for rapid dissolution, most tablets are designed to undergo rapid disintegration to granules and subsequent disaggregation to fine particles. This provides a larger surface area exposed to the dissolution medium, resulting in a faster dissolution rate.

[0084] Implantable devices coated with compound 1 are another embodiment of the present invention. Compound 1 may also be coated on implantable medical devices, such as beads, or co-formulated with a polymer or other molecule, to provide a“drug depot”, thus permitting the drug to be released over a longer time period than administration of an aqueous solution of the drug. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos.6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or

combinations thereof to impart controlled release characteristics in the composition.

[0085] The formulations include those suitable for the administration routes detailed herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington’s. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. [0086] The terms“administer”,“administering” or“administration” in reference to a compound, composition or formulation described herein mean introducing the compound into the system of the animal in need of treatment. When a compound of the invention is provided in combination with one or more other active agents,“administration” and its variants are each understood to include concurrent and/or sequential introduction of the compound and the other active agents.

[0087] The compositions described herein may be administered systemically or locally, e.g.: orally (e.g., using capsules, powders, solutions, suspensions, tablets, sublingual tablets, sublingual films and the like), by inhalation (e.g., with an aerosol, gas, inhaler, nebulizer or the like), to the ear (e.g., using ear drops), topically (e.g., using creams, gels, liniments, lotions, ointments, pastes, transdermal patches, etc.), ophthalmically (e.g., with eye drops, ophthalmic gels, ophthalmic ointments), rectally (e.g., using enemas or suppositories), nasally, buccally, vaginally (e.g., using douches, intrauterine devices, vaginal suppositories, vaginal rings or tablets, etc.), via an implanted reservoir or the like, or parenterally depending on the severity and type of the disease being treated. The term“parenteral” as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

[0088] The pharmaceutical compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [0089] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution-retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Tablets may be uncoated or may be coated by known techniques, including microencapsulation, to mask an unpleasant taste or to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. A water soluble taste-masking material such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose may be employed.

[0090] Formulations of compound 1 that are suitable for oral administration may be prepared as discrete units such as tablets, pills, troches, lozenges, erodible and dissolvable films, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs. Formulations of a compound intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.

[0091] Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.

[0092] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0093] Compound 1 can also be in microencapsulated form with one or more excipients as noted above.

[0094] When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.

[0095] Sterile injectable forms of the compositions described herein (e.g., for parenteral administration) may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di- glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of injectable formulations.

[0096] Oily suspensions may be formulated by suspending compound 1 in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as butylated hydroxyanisol or alpha- tocopherol.

[0097] Aqueous suspensions of compound 1 contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g.,

polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

[0098] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0099] In order to prolong the effect of compound 1, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsuled matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled.

Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot-injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. [00100] The injectable solutions or microemulsions may be introduced into a patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS^TM model 5400 intravenous pump.

[00101] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers, such as cocoa butter, beeswax, polyethylene glycol or a suppository wax that are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Other formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays.

[00102] The pharmaceutical compositions of compound 1 described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the ear, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[00103] Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches may also be used. [00104] For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[00105] For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or, preferably, as solutions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as

benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum. For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations may be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w. When formulated in an ointment, the active ingredients may be employed with either an oil-based, paraffinic or a water-miscible ointment base.

[00106] Alternatively, the active ingredients may be formulated in a cream with an oil- in-water cream base. If desired, the aqueous phase of the cream base may include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.

[00107] The oily phase of emulsions prepared using compound 1 may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. A hydrophilic emulsifier may be included together with a lipophilic emulsifier which acts as a stabilizer. In some embodiments, the emulsifier includes both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulations. Emulgents and emulsion stabilizers suitable for use in the formulation of compound 1 include Tween^TM-60, Span^TM-80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.

[00108] The pharmaceutical compositions may also be administered by nasal aerosol or by inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance

bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. Formulations suitable for intrapulmonary or nasal administration have a mean particle size, for example, in the range of 0.1 to 500 microns (including particles with a mean particle size in a range between 0.1 and 500 microns in micron increments such as 0.5, 1, 30, 35 microns, etc.), and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.

[00109] For use, the pharmaceutical composition (or formulation) may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

[00110] The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.

Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as recited herein, or an appropriate fraction thereof, of the active ingredient. [00111] In another aspect, compound 1 or a pharmaceutically acceptable salt thereof may be formulated in a veterinary composition comprising a veterinary carrier. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials that are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

Therapeutic Methods:

[00112] The terms,“disease”,“disorder”, and“condition” may be used

interchangeably here to refer to a condition where an increase in the concentration of an endogenous cannabinoid (eCB) might be beneficial or a condition that can be treated by a FAAH inhibitor.

[00113] As used herein, the terms“subject” and“patient” are used interchangeably. The terms“subject” and“patient” refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a“mammal” including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more preferably a human. In one embodiment, the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject is a“human”.

[00114] The term“biological sample”, as used herein, includes, without limitation, in vivo or ex vivo cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; blood, saliva, urine, feces, semen, tears, lymphatic fluid, ocular fluid, vitreous humor or other body fluids or extracts thereof.

[00115] “Treat”,“treating” or“treatment” with regard to a disorder or disease refers to alleviating or abrogating the cause and/or the effects of the disorder or disease. As used herein, the terms“treat”,“treatment” and“treating” refer to the reduction or amelioration of the progression, severity and/or duration of a condition wherein an increase in the concentration of eCB might be beneficial or that can be treated with a FAAH inhibitor, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of said condition, resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound or composition of the invention). In specific embodiments, the terms“treat”,“treatment” and“treating” refer to the amelioration of at least one measurable physical parameter of condition wherein an increase in the

concentration of eCB might be beneficial or a condition that can be treated with a FAAH inhibitor. In other embodiments the terms“treat”,“treatment” and“treating” refer to the inhibition of the progression of said condition, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both.

[00116] As used herein, the terms“prevent”,“preventing” and“prevention” with regard to a disorder or disease refer to averting the cause and/or effects of a disease or disorder prior to the disease or disorder manifesting itself. The terms“prophylaxis” or “prophylactic use”, as used herein, refer to any medical or public health procedure whose purpose is to prevent, rather than treat or cure a disease. As used herein, the terms“prevent”, “prevention” and“preventing” refer to the reduction in the risk of acquiring or developing a given condition, or the reduction or inhibition of the recurrence or said condition in a subject who is not ill, but who has been or may be near a person with the disease.

[00117] The term“chemotherapy” refers to the use of medications, e.g., small molecule drugs or biologics (e.g., therapeutic antibodies or therapeutic proteins) for treating a disorder or disease. In some embodiments, chemotherapy is used to treat cancer or other proliferative disorders.

[00118] The term“chemoprophylaxis” refers to the use of medications, e.g., small molecule drugs (rather than e.g.,“vaccines”) for the prevention of a disorder or disease.

[00119] In one embodiment, the methods of the invention are a preventative or“pre- emptive” measure to a patient, preferably a human, having a predisposition to developing a condition or symptom that can be improved by an increase in the concentration of an eCB or treated with a FAAH inhibitor.

[00120] Also described are methods for treating or preventing various disorders with a composition that includes any of the various embodiments of compound 1. Among the disorders or symptoms that can be treated or prevented are:

[00121] The compounds and compositions herein described can be used alone or in combination therapy for the treatment of nausea and vomiting diseases or disorders: e.g., nausea, anticipatory nausea, chemotherapy-induced nausea, radiation-induced nausea, post- operative nausea, vomiting, chemotherapy induced vomiting, radiation-induced vomiting and post-operative vomiting, hyperemesis, pregnancy-induced nausea, pregnancy-induced vomiting (“morning sickness”), nausea or anticipatory nausea induced by motion, vomiting induced by motion (“motion sickness,” such as that induced by traveling in a car, bus, train, airplane or boat), nausea or anticipatory nausea induced by a viral or bacterial infection, vomiting induced by a viral or bacterial infection, nausea or anticipatory nausea induced by Meniere’s Disease, vomiting induced by Meniere’s Disease, nausea or anticipatory nausea induced by migraine headaches, vomiting induced by migraine headache, nausea or anticipatory nausea induced by vertigo (e.g., benign paroxysmal positional vertigo, or vertigo caused by vestibular neuronitis or labyrinthitis), or vomiting induced by vertigo (e.g., benign paroxysmal positional vertigo, or vertigo caused by vestibular neuronitis or labyrinthitis); vomiting resulting from gastroparesis (e.g., idiopathic gastroparesis or diabetic gastroparesis); nausea resulting from gastroparesis (e.g., idiopathic gastroparesis or diabetic gastroparesis); vomiting resulting from use of a pharmaceutical substance (e.g., from the use of a pharmaceutical substance including but not limited to opioids, antibiotics or anti- depressants); or nausea resulting from use of a pharmaceutical substance (e.g., from the use of a pharmaceutical substance including but not limited to opioids, antibiotics, anti- depressants or other pharmaceutical substances such as acetaminophen, bendamustine hydrochloride, hydrocodone bitartrate, bretylium tosylate, ceftibuten, ceftriaxone, cephadrine, cetirizine, cephradine, cetirizine, clonidine, clozapine, colestipol, conivaptan, dantrolene, desflurane, dibucaine, doxorubicin, fentanyl, fibrinogen, flurbiprofen, forpropofol, furosemide, linezolid, liotrix, L-ornithine-L-aspartate, mepacrine, mephenesin,

methocarbamol, metolazone, miltefosine, minoxidil, mosapride, norethindrone, noscapine, paregoric, penfluridol, pentoxifylline, piperacillin, thioguanine, triazolam, velaglucerase alfa or yohimbine ), by using compound 1 or a pharmaceutical composition comprising compound 1, either alone or in combination therapy.

[00122] In some embodiments, the compound and composition herein described can be used alone or in combination therapy for the treatment of nausea and vomiting diseases or disorders: e.g., nausea, anticipatory nausea, chemotherapy-induced nausea, radiation-induced nausea, post-operative nausea, vomiting, chemotherapy induced vomiting, radiation-induced vomiting, post-operative vomiting.

[00123] Compound 1 and compositions comprising compound 1 are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including, without limitation, dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs and cattle. [00124] In another embodiment, the invention provides a method of inhibiting FAAH in a biological sample, comprising contacting said biological sample with compound 1 or a composition comprising compound 1. Use of a FAAH inhibitor in a biological sample is useful for a variety of purposes known to one of skill in the art. Examples of such purposes include, without limitation, biological assays and biological specimen storage.

Combination Therapies:

[00125] The compounds and pharmaceutical compositions described herein can be used in combination therapy with one or more additional agents (e.g., therapeutic agents). For combination treatment with more than one active agent, where the agents active agents are in separate dosage formulations, the active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.

[00126] When co-administered with other agents, e.g., when co-administered with another pain medication, an“effective amount” of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound described herein being used. In cases where no amount is expressly noted, an effective amount should be assumed. For example, compounds described herein can be administered to a subject in a dosage range from between about 0.001 to about 100 mg/kg body weight/day, from about 0.001 to about 50 mg/kg body weight/day, from about 0.001 to about 30 mg/kg body weight/day, from about 0.001 to about 10 mg/kg body weight/day.

[00127] When combination therapy is employed, an effective amount can be achieved using a first amount of compound 1 or a pharmaceutically acceptable salt, solvate (e.g., hydrate), co-crystal or pro-drug thereof and a second amount of an additional suitable therapeutic agent (e.g., an agent to treat pain).

[00128] In one embodiment of this invention, compound 1 and the additional therapeutic agent, are each administered in an effective amount (i.e., each in an amount which would be therapeutically effective if administered alone). In another embodiment, compound 1 and the additional therapeutic agent, are each administered in an amount which alone does not provide a therapeutic effect (a sub-therapeutic dose). In yet another embodiment, compound 1 can be administered in an effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose. In still another embodiment, compound 1 can be administered in a sub-therapeutic dose, while the additional therapeutic agent, for example, a suitable cancer-therapeutic agent is administered in an effective amount.

[00129] As used herein, the terms“in combination” or“co-administration” can be used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). The use of the terms does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.

[00130] Co-administration encompasses administration of the first and second amounts of the compounds in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, a capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each. In addition, such co-administration also encompasses use of each compound in a sequential manner in either order. When co- administration involves the separate administration of the first amount of compound 1 and a second amount of an additional therapeutic agent, the compounds are administered sufficiently close in time to have the desired therapeutic effect. For example, the period of time between each administration that can result in the desired therapeutic effect, can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile. For example, compound 1 and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other.

[00131] More specifically, a first therapy (e.g., a prophylactic or therapeutic agent such as a compound described herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks subsequent to) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anti- cancer agent) to a subject. [00132] Additional therapeutic agents that can be combined with compounds described herein include, without limitation:

[00133] FAAH inhibitors: e.g., OL-135, LY2183240, URB-597, CAY-10402, PF-750, BMS-469908, SSR-411298, TK-25, PF-04457845, PF-3845, SA-47, JNJ-245, JNJ-28833155 and JNJ-1661010;

[00134] painkillers such as acetaminophen or paracetamol;

[00135] non-steroidal anti-inflammatory drugs (NSAIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenhufen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives

(indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (meclofenamic acid, mefe-namic acid, and tolfenamic acid), biphenyl-carboxylic acid derivatives, oxicams (isoxicam, meloxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone), and COX-2 inhibitors, such as the coxibs (celecoxib, deracoxib, valdecoxib, rofecoxib, parecoxib and etoricoxib);

[00136] other pain relieving agents such as gabapentin, topical capsaicin, tanezumab, esreboxetine;

[00137] opiate receptor agonists such as morphine, propoxyphene (Darvon^TM), tramadol, buprenorphin;

[00138] cannabinoid receptor agonists such as dronabinol, nabinol, ^9-THC, CP- 55940, WIN-55212-2, HU-210;

[00139] anti-infective agents;

[00140] sodium channel blockers such as carbamazepine, mexiletine, lamotrigine, pregabalin, tectin, NW-1029, CGX-1002;

[00141] N-type calcium channel blockers such as ziconotide, NMED-160, SPI-860; serotonergic and noradrenergic modulators such as SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram; [00142] local anesthetics such as ambroxol, lidocaine;

[00143] VR1 agonists and antagonists such as NGX-4010, WL-1002, ALGRX-4975, WL-10001, AMG-517;

[00144] fatty acid amides such as anandamide (AEA), oleoylethanolamide (OEA), palmitoylethanolamide (PEA) and linoleoyl ethanolamide (LEA);

[00145] agents used for migraines, such as sumatriptan, zolmitriptan, naratriptan, eletriptan, rauwolscine, yohimbine, metoclopramide;

[00146] topical agents used in the treatment of localized pruritus: e.g.,

camphor/menthol lotions or creams containing 0.125 to 0.25% menthol, doxepin (e.g., Sinequan^TM, Zonalon^TM), phenol (e.g., Cepastat®, Chloraseptic® gargle, Ulcerease), 0.5 to 2%, pramoxine (e.g., Anusol^TM ointment, Proctofoam-NS, Tronolane^TM Cream, Tucks^TM Hemorrhoidal), eutectic mixture of local anesthetics (EMLA), and corticosteroids;

[00147] anti-inflammatory and/or immunosuppressive agents such as methotrexate, cyclosporin A (including, for example, cyclosporin microemulsion), tacrolimus, corticosteroids, statins, interferon beta, Remicade^TM (infliximab), Enbrel^TM (etanercept) and Humira^TM (adalimumab);

[00148] agents designed to treat tobacco abuse: e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename Zyban™) and nicotine replacement therapies;

[00149] ADD/ADHD agents: e.g., Ritalin™ (methylphenidate hydrochloride), Strattera™ (atomoxetine hydrochloride), Concerta™ (methylphenidate hydrochloride) and Adderall™ (amphetamine aspartate; amphetamine sulfate; dextroamphetamine saccharate; and dextroamphetamine sulfate);

[00150] agents to treat alcoholism, such as opioid antagonists (e.g., naltrexone (also known under the tradename ReVia M) and nalmefene), disulfiram (also known under the tradename Antabuse™), and acamprosate (also known under the tradename Campral™));

[00151] agents for reducing alcohol withdrawal symptoms such as benzodiazepines, beta-blockers, clonidine, carbamazepine, pregabalin, and gabapentin (Neurontin™);

[00152] antihypertensive agents: e.g., ACE inhibitors and Angiotensin II Receptor blockers such as benazepril , captopril , enalapril , fosinopril , lisinopril, candesartan , eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, renin inhibitors such as aliskiren, vasodilators such as minoxidil;

[00153] agents used to treat glaucoma: e.g., direct-acting miotics (cholinergic agonists), indirect acting miotics (cholinesterase inhibitors), carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide, brinzolamide, dorzolamide, selective adrenergic agonists (e.g., apraclonidine, brimonidine), beta-blockers (timolol, betaxolol, carteolol, levobetaxolol, levobunolol, metipranolol), osmotic diuretics (e.g., glycerin, mannitol);

[00154] antidepressants: e.g., SSRIs (e.g., fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine), tricyclic antidepressants (e.g., imipramine, amitriptiline, chlomipramine and nortriptiline), dopaminergic antidepressants (e.g., bupropion and amineptine), SNRIs (e.g., venlafaxine and reboxetine);

[00155] cognitive improvement agents: e.g., donepezil hydrochloride (Aricept™) and other acetylcholinesterase inhibitors;

[00156] anti-emetic agents: e.g., 5HT3 antagonists such as dolasetron, ondansetron, granisetron, tropisetron, palonosetron, mirtazapine and metoclopramide; NK1 receptor antagonists such as aprepitant or casopitant; dopamine receptor antagonists such as droperidol, olanazapine, alizapride, prochlorperazine or domperidone; antihistamines such as cyclizine, diphenylhydramine, dimenhydrinate, doxylamine, meclizine, promethazine or hydroxyzine; Cannabinoids such as dronabinol, nabilone or sativex; benzodiazepines such as midazolam, lorazepam; anticholinergics such as hyoscine; steroids such as dexamethasone; other anti-emetic agents such as trimethobenzamide, ginger, emetrol, propofol, peppermint, muscimol or ajwain;

[00157] neuroprotective agents: e.g., memantine, L-dopa, bromocriptine, pergolide, talipexol, pramipexol, cabergoline, neuroprotective agents currently under investigation including anti-apoptotic drugs (CEP 1347 and CTCT346), lazaroids, bioenergetics, antiglutamatergic agents and dopamine receptors. Other clinically evaluated neuroprotective agents are, e.g., the monoamine oxidase B inhibitors selegiline and rasagiline, dopamine agonists, and the complex I mitochondrial fortifier coenzyme Q10;

[00158] antipsychotic medications: e.g., ziprasidone (Geodon™), risperidone

(Risperdal™), and olanzapine (Zyprexa™);

[00159] agents used for multiple sclerosis such as beta-interferon (e.g., Avonex™, Betaseron™) baclofen and Copaxone™;

[00160] disease-modifying anti-rheumatic drugs (DMARDS) such as methotrexate, azathioptrine, leflunomide, pencillinamine, gold salts, mycophenolate mofetil,

cyclophosphamide, CP-690,550; biological response modifiers (BRMs) such as Enbrel™, Remicade™, IL-1 antagonists; NSAIDS such as piroxicam, naproxen, indomethacin, ibuprofen and the like; COX-2 selective inhibitors such as Celebrex^TM; COX-1 inhibitors such as Feldene™; immunosuppressives such as steroids, cyclosporine, tacrolimus, rapamycin and the like;

[00161] PDE4 inhibitors such as theophylline, drotaverine hydrochloride, cilomilast, roflumilast, denbufylline, rolipram, tetomilast, enprofylline, arofylline, cipamfylline, tofimilast, filaminast, piclamilast, (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2- phenylethyl]pyridine, mesopram, N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5- hydroxy-1H- -indol-3-yl]-2-oxoacetamide, CDC-801 (Celgene), CC-1088 (Celgene), Lirimilast, ONO-6126 (Ono), CC-10004 (Celgene) and MN-001 (Kyorin), ibudilast and pentoxifylline, for use in treating inflammation, lung disorders and as bronchodilators;

[00162] corticosteroids such as betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone;

[00163] histamine H1 receptor antagonists such as bromopheniramine,

chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdiazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, desloratadine, fexofenadine and levocetirizine;

[00164] histamine H2 receptor antagonists such as cimetidine, famotidine and ranitidine;

[00165] proton pump inhibitors such as omeprazole, pantoprazole and esomeprazole;

[00166] leukotriene antagonists and 5-lipoxygenase inhibitors such as zafirlukast, montelukast, pranlukast and zileuton;

[00167] nicotinic acetylcholine receptor agonists such as ABT-202, A-366833, ABT- 594; BTG-102, A-85380, CGX1204;

[00168] P2X3 receptor antagonists such as A-317491, ISIS-13920, AZD-9056; [00169] NGF agonists and antagonists such as RI-724, RI-1024, AMG-819, AMG- 403, PPH 207;

[00170] NK1 and NK2 antagonists such as DA-5018, R-116301; CP-728663, ZD- 2249;

[00171] NMDA antagonist such as NER-MD-11, CNS-5161, EAA-090, AZ-756, CNP-3381; potassium channel modulators such as CL-888, ICA-69673, retigabine;

[00172] GABA modulators such as lacosamide and propofol;

[00173] anti-cancer agents such as tyrosine kinase inhibitors imatinib

(Gleevec™/Glivec™) and gefitinib (Iressa™);

[00174] anti hyperlipidemia drugs such as statins, ezetimibe, niacin and bile acid sequestrants;

[00175] appetite suppressing agents: e.g., sibutramine, taranabant, rimobamant;

[00176] anti-diabetic medications such as insulin, tolbutamide (Orinase™), acetohexamide (Dymelor™), tolazamide (Tolinase™), chlorpropamide (Diabinese™), glipizide (Glucotrol™), glyburide (Diabeta™, Micronase™, Glynase™), glimepiride (Amaryl™), gliclazide (Diamicron™), repaglinide (Prandin™), nateglinide (Starlix™), pramlintide (Symlin™) and exenatide (Byetta™);

[00177] serotonergic and noradrenergic modulators such as SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram, flibanserin; and

[00178] GI agents: e.g., laxatives (e.g., lubiprostone (Amitiza™), Fybogel®, Regulan®, Normacol® and the like), a gastrointestinal agent used for the treatment of idiopathic chronic constipation and constipation-predominant IBS, GI motility stimulants (e.g., domperidone, metoclopramide, mosapride, itopride), antispasmodic drugs (e.g., anticholinergics such as hyoscyamine or dicyclomine); anti-diarrheal medicines such loperamide (Imodium™) and bismuth subsalicylate (as found in Pepto Bismol™ and Kaopectate™), GCC (Guanylate Cyclase C) agonists (e.g., linaclotide), 5HT4 agonists (e.g., tegasarod), 5HT3 antagonists (e.g.,alosetron, ramosetron, ondansetron).

EXAMPLES General analytical techniques

[00179] LC/MS was run on a Waters Acquity system using a Polar C18 column, and 5 to 60 % acetonitrile/water over 5 min. The ionization method for the MS was electrospray.

[00180] Automated column chromatography was run using an ISCO system. One of the Companion, Combiflash, or Combiflash Rf was used in each case.

[00181] Microwave reactions were run on a Personal Chemistry Optimizer, at 0–240 oC, a power of 0–300 W and a pressure of 0–21 bar.

[00182] HPLC for purification was run on a Varian Prepstar instrument using the following conditions:

Solvent A: 0.1% Trifluoroacetic acid in water

Solvent B: 0.1% Trifluoroacetic acid in acetonitrile

[00183] All references provided in the Examples are herein incorporated by reference in their entirety. As used herein, all abbreviations, symbols and conventions are consistent with those used in the contemporary scientific literature. See, e.g., Janet S. Dodd, ed., The ACS Style Guide: A Manual for Authors and Editors, 2^nd Ed., Washington, D.C.: American Chemical Society, 1997, herein incorporated by reference in its entirety.

Biological Assays:

Example 1: FAAH Inhibition Using Rat and Human Brain Homogenate Assays: [00184] The ability of compound 1 to inhibit FAAH was measured in human whole cell and human and rodent brain homogenates as described herein.

A. FAAH Rat Brain Membrane (RBM) Homogenate Preparation

[00185] Adult rats (Charles River CD strain, female, 200 g) were anaesthetized with isofluorane and rapidly decapitated. Each brain was quickly removed and chilled in tubes (3 brains per tube) on ice. About 25 mL of“homogenization buffer” (20 mM HEPES buffer, pH 7.0, with 1 mM MgCl₂) was added to 15 to 20 g of brain. The brains were homogenized on ice for 1 minute using an Omni GLH homogenizer (Omni International, Marietta, Georgia). The homogenates were then transferred to three centrifuge tubes and centrifuged at 36,500g for 20 minutes at 4 °C. The supernatant was discarded and each pellet was re- suspended in 25 mL homogenization buffer. The re-suspended material was again centrifuged (36,500g, 20 minutes at 4 °C). Pellets were combined by re-suspension in 10 mL of homogenization buffer and incubated in a 37 ^oC water bath for 15 minutes. The tubes were then placed on ice for 5 minutes followed by centrifugation at 36,500 g for 20 minutes at 4 °C. The supernatant was discarded and the membrane pellets were then re-suspended in 40 mL of“re-suspension buffer” (50 mM Tris-HCl buffer, pH 7.4, containing 1 mM EDTA and 3 mM MgCl₂). A Bradford Protein assay was performed to determine protein concentration. The protein was aliquotted into screw cap Cryo tubes each containing ~ 400 ^L, flash-frozen in liquid nitrogen and stored at–80 ^oC until used for the assay. A similar protocol was used to obtain brain membrane homogenates from mice

B. FAAH Human Brain Membrane (HBM) Homogenate Preparation.

[00186] Brain cerebral cortex tissue (ABS, Inc.) from 3 human donors (2 females, 1 male; 63–85 years old) was collected previously and flash-frozen in liquid nitrogen within 4 hours post-mortem interval. Tissue was stored at -80°C. Serology was negative for a defined list of infectious agents. Brain cortex samples (equal amounts from 3 donors pooled as 10 g total) were homogenized as described below.

[00187] All tissue samples were handled following Centers for Disease Control Biosafety Level 2 (BL-2) procedures for working with bio-hazardous materials by trained personnel in BL-2 certified laboratories. Brain tissue was thawed in ice-cold homogenization buffer 20 mM HEPES (pH 7.0), 1 mM MgCl₂. Approximately 4 mL of buffer was used per gram of tissue. Human brain tissue was homogenized in buffer in an ice-cold mortar with a pestle. Homogenates were centrifuged at 36,500 x g for 20 minutes at 4°C. Supernatants were discarded. Pellets were re-suspended and homogenized in ice-cold homogenization buffer as before. The tubes were capped and incubated upright in a 37°C water bath for 15 minutes followed by incubation on ice for 5 min. The tubes were centrifuged as before. The brain membrane microsome pellets were re-suspended using ice-cold re-suspension buffer (50 mM Tris-HCl buffer, pH 7.4, containing 1 mM EDTA and 3 mM MgCl₂). Protein concentrations of the brain microsome suspensions were determined using BioRad protein assay kit (BioRad). The protein was aliquotted and flash frozen as 0.2 mL aliquots in liquid nitrogen and stored at -80°C until use.

C. Determination of FAAH Activity

[00188] FAAH activity was assayed in the respective homogenates described herein (Rat brain, Mouse brain or Human brain) with compound 1 using a modification of the method of Omeir et al. (1995 Life Sci.56:1999) and Fowler et al. (1997 J. Pharmacol. Exp. Ther.283:729). For the assay of FAAH activity in rat brain membrane (RBM) homogenates, RBM homogenates (7 ^g protein in 20 ^L final volume of 10 mM Tris pH 6.5) were mixed with 180 ^L of a mixture of the following: 2.0 ^M unlabelled anandamide (AEA), 0.03 ^Ci radio labeled anandamide [ethanolamine 1-³H] (40-60 Ci/mmol; product number ART-626, American Radiolabelled Chemicals, St. Louis, MO), 1 mg/mL Bovine Serum Albumin (fatty acid-free BSA, electrophoresis grade, Sigma, St. Louis, MO), 10 mM Tris-HCl (pH 6.5), and 1 mM EDTA in the presence and absence of test compounds (vehicle was DMSO at a final concentration of 1%) and incubated for 10 minutes at 37 ^C. Samples were placed on ice to terminate the reactions.

[00189] The ³H-ethanolamine product and un-reacted ³H-anandamide substrate were then separated by either: (1) using chloroform/ methanol extraction or (2) passing the reaction mixture through a glass fiber filter containing activated charcoal. Samples were extracted with chloroform/methanol by adding 0.4 mL of chloroform/methanol (1:1 v/v), vigorously mixing the samples, and separating the aqueous and organic phases by centrifugation.

Radioactivity (corresponding to FAAH-catalyzed breakdown of ³H-anandamide) found in aliquots (0.2 mL) of the aqueous phase was determined by liquid scintillation counting with quench correction. IC₅₀ values were determined as described by Jonsson et al. (2001 Br. J Pharmacol.133:1263). Alternatively, reactions were purified using a modification of the solid-phase extraction method described by Wilson et al (2003 Anal. Biochem.318 : 270). This method was modified as follows: after reactions were incubated at 37 ^C for 10 minutes and chilled on ice, the reaction mixtures were acidified by adding 10 ^L of sodium phosphate solution [0.5M (pH 2.0)]. Next, 90 ^L aliquots of the acidified reaction mixtures were applied to activated charcoal (that had been previously washed with methanol as described by Wilson et al. (supra)) containing 80 ^L of water on top of a glass fiber filter, centrifuged, and the radioactivity in the eluate was counted as described previously by Wilson et al. (supra).

[00190] FAAH activity using human homogenates was assayed based on methods adapted from Omeir et al 1995 (1) with modifications by Fowler et al.1997 (supra).

Separation of ³H-product and [³H]-ethanolamine product was based on modifications of Wilson et al.2003 (supra). FAAH assays were conducted in 0.2 mL (volume final) of reaction buffer per well [10 mM Tris (pH 7), 1 mM EDTA, 0.1% fatty acid free BSA (Sigma catalog # A0281), 0.5 ^M anandamide (Cayman catalog # 90050), 70,000 dpm of anandamide-(ethanolamine-1-[³H]) (60 Ci/mmol, radiochemical purity >99%, American Radiolabeled Chemicals, Inc., catalog # ART 626)] in the presence and absence of test compounds (vehicle is DMSO at a final concentration of 1%). Reactions were initiated by adding 12.5 ^g of brain microsome. Reactions were conducted at 37 °C for 10 min. The reactions were terminated by chilling the plates on ice and adding 20 ^L of 0.5M of potassium phosphate buffer (adjusted to pH 2.1 with phosphoric acid). [³H]-ethanolamine product and un-reacted [³H]-anandamide substrate were separated by passing the reaction mixture through a glass fiber filter containing activated charcoal, and the radioactivity in the eluate was counted as described previously by Wilson et al. (supra).

[00191] The known FAAH inhibitors, 3'-(aminocarbonyl)biphenyl-3-yl

cyclohexylcarbamate (URB597), [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3- yl]acetic acid (indomethacin) and 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid (Ketorolac) were used as controls in these assays. Compound 1 had an activity of less than 100 nM in both the human brain and rat brain extract.

Example 2: Whole cell anandamide hydrolysis assay:

[00192] FAAH activity was assayed in whole cells using methods disclosed previously (Maccarone et al., 1998 J Biol. Chem.273:32332 and Bisogno et al., 1997 J Biol. Chem. 272:3315). In addition to the cell lines described in Maccarone et al. and Bisogno et al., MCF7 (ATCC designation HTB-22) and T84 (ATCC designation CCL-248) cell lines were also used in these assays.

A. HeLa cell transfection with human FAAH-1

[00193] cDNA expression clone for human FAAH-1 (in pcDNA3 vector) (Genbank Accession U82535; obtained from Benjamin Cravatt, Scripps Research Institute, La Jolla, California) was linearized by digestion with Bg1II (New England Biolabs) and transfected by calcium phosphate into human HeLa cells (ATCC catalog #CCL-2). The HeLa cell line was selected as a host because it does not express FAAH or exhibit FAAH activity such that all subsequent activity can be attributed to the transfected gene. Following transfection, a stable HeLa-derived clone, designated 5c5, was isolated by single colony purification and expanded and maintained in modified Eagles medium (MEM; VWR catalog # 45000-300) containing 10% fetal bovine serum (FBS), 2 mM L-glutamine, and 0.5 mg/mL G-418 (Sigma catalog # G5013).

B. FAAH whole cell activity assay

[00194] Clone 5c5 (50,000 cells in 150 ^L) was seeded into 96-well plates and incubated overnight (5% CO₂, 37 °C). Media was carefully replaced with 180 ^L

DMEM/F12 medium (VWR catalog # 45000-350) containing 15 mM HEPES, pH 7.4 and 0.1% fatty acid free BSA (Sigma catalog # A0281). Then, 2 ^L of 100x desired final concentrations of certain exemplary compounds described herein were made up in DMSO, added to wells containing cells, and plates were incubated at 37 °C for 10 min. Next, 20 ^L of 5 ^M anandamide (Cayman catalog # 90050) spiked with 8 ^Ci of anandamide- (ethanolamine-1-[³H]) (American Radiolabeled Chemicals, Inc., catalog #ART 626) was added to the cells and the plates were incubated for an additional 15 min at 37 °C. The reactions were terminated by chilling the plates on ice and adding 20 ^L of 0.5M of potassium phosphate buffer (adjusted to pH 2.1 with phosphoric acid).

[00195] The acidified reactions were transferred to 96-well filter plates (0.25 mL capacity/well, 1.2 micron glass fiber pre-filter packed above 0.65 micron pore-size PVDF membrane, Millipore catalog MSFCN6B50) containing 25 ^L charcoal (neutral activated carbon, Fisher Scientific catalog C170-500) per well. Prior to the assay, charcoal was measured and loaded onto the plate using an aluminum 96-well column loading device (Millipore catalog MACL09625). The filter plate was assembled over an empty 96-well plate (Costar) using a centrifuge alignment frame (Millipore catalog MACF09604) to allow for collection of the filtrate in the receiver plate. The charcoal glass-fiber filter plates were pre- washed with methanol by centrifugation 650 x g for 10 min). Next, 80 ^L of water was added to the wells of the pre-washed 96 well charcoal filter plate. Then, 90 ^L of the acidified reaction mixture was added to the water in the wells of the charcoal plate. The samples were centrifuged as above. The substrate remained bound to the charcoal, whereas the [³H]-ethanolamine product formed flowed through and was transferred to the microplates containing scintillation cocktail and quantified in a micro-plate scintillation counter (Perkin- Elmer Microbeta). Control reactions with either no cells or cells treated with DMSO alone were performed in triplicate and used to define background (no cells) and 100% activity (DMSO alone).

[00196] Following subtraction of background radioactivity, data were expressed as percent inhibition relative to 100% activity and fit with a nonlinear regression curve using GraphPad Prism Software (GraphPad Software Inc). IC₅₀ values were calculated from the resulting dose-response curves constrained at top and bottom to 100% and 0. Compound 1 had a whole cell activity of less than 100 nM.

Example 3: Human CB1 Cannabinoid Receptor Assay [00197] Binding assays were used to characterize potential CB1 receptor binding affinity for compound 1.

A. CB1 Clones

[00198] cDNA expression clones for human CB1 (hCB1, Genbank Accession No. AY225225) expressed in vector pcDNA3.1+ were purchased from UMR cDNA Resource Center, Rolla, MO (Clone ID CNR01L000 for hCB1).

B. Stable and Transient Transfection [00199] Stable, HEK-293-derived cell lines that recombinantly express hCB1 were established. In brief, the clone hCB1 (CNR1L) was transfected into human embryonic kidney cells (HEK-293) using Lipofectamine 2000 (Gibco, Cat# 11668-019) according to the manufacturer’s protocol. Transfected clones were isolated by single colony purification and clones were screened for receptor expression using a whole cell, ³H-CP 55,940 radioligand binding assay. HEK-293 stable cells were maintained in Dulbecco’s modified Eagles medium (DMEM) containing 10% fetal bovine serum, 2 mM L-glutamine and 0.5mg/mL G-418. C. Human CB1 Cannabinoid Receptor Radioligand Binding Assay [00200] Membranes were isolated from transfected cells as follows. Monolayers of cultured cells were washed twice with phosphate-buffered saline (PBS). Cells were scraped into 20 mM HEPES, pH 7.4, 10 mM EDTA containing complete cocktail protease inhibitors (Roche, Catalog # 11697498001) and were homogenized by an electric-powered mechanical probe homogenizer (Omni GLH; probe G7-195S) for 40 seconds at 7000 rpm. Homogenates were centrifuged 10 minutes at 1000 x g at 4°C. The supernatant was collected and was centrifuged for 1 hour at 40,000 x g. The supernatant was then decanted and the resulting pellet was resuspended in 20 mM HEPES, pH 7.4, 5 mM MgCl₂, 1 mM EDTA, 10% sucrose with complete cocktail protease inhibitors. Protein concentration of membrane suspensions were measured by Bradford Protein Assay using bovine serum albumin as the standard (BioRad catalog #500-0006). Protein concentrations of membrane suspensions were adjusted with the final buffer in the range of 5 to 10 mg/mL and were stored at -80°C until further use.

D. Cannabinoid receptor radioligand binding assay [00201] Radioligand binding assays were performed by incubating membranes (2-10 ug protein) prepared from HEK-293 cells expressing recombinant human cannabinoid receptor, CB1, at room temperature with 0.5 nM cannabinoid receptor agonist, [³H]-CP 55,940 (Perkin Elmer, catalog # NET1051) in 0.2 mL of binding buffer (50 mM Tris-HCl, pH 7.5, 5 mM MgCl₂, 2.5 mM EDTA) and 0.1 % fatty acid free bovine serum albumin (Sigma Cat. # A0821) for 90 minutes. A rapid filtration technique using Millipore FB filter plates (Catalog # MADVNOB) and filtration apparatus (Millipore system Catalog

MAVM0960R) with vacuum aspiration was used to harvest and rinse labeled membranes (8 times with 0.2 mL of chilled binding buffer). The radioactivity bound to the filters was counted with 0.05 mL of liquid scintillant (UltraGold MV, PerkinElmer catalog # 6013159) in a scintillation counter (Perkin Elmer Microbeta instrument). Nonspecific binding was determined in the presence of unlabeled 1 uM CP 55,940 (Sigma Aldrich, catalog # C1112). Binding data were analyzed using GraphPad Prism (GraphPad Software, Inc. San Diego, CA). Human CB1 activity for compound 1 above 50% at 1 μM and greater than 75% above 10 μM.

[00202] In some embodiments, compound 1 displays a decreased affinity for binding to the CB1 receptor. In some embodiments, compounds of the invention displayed a decreased affinity for binding to the CB1 receptor when compared to other known FAAH inhibitors. In some embodiments, compounds of the invention displayed a decreased affinity for binding to the CB1 receptor when compared to other known FAAH inhibitors having similar structures.

[00203] In some embodiments, compounds of the invention show increased selectivity for binding to FAAH relative to their binding to the CB1 receptor.

Example 4. Nonclinical Safety Profile Determination

[00204] The safety profile of the compounds can be evaluated in nonclinical toxicology studies in rodents and non-rodents. Male and female animals are administered test compound in a vehicle by an appropriate route (e.g., oral, intramuscular, intravenous) once daily for, e.g., 14 or 28 consecutive days. Additional animals receive the vehicle only and serve as the vehicle control group. Clinical observations, changes in body weights and feed consumption, ophthalmic and clinical pathology (hematology, clinical chemistry, coagulation) parameters are evaluated in each animal during the in life portion of the study. In rodents, toxicokinetic evaluations for systemic exposure determinations are conducted on separate groups of animals at each dose level of the test compound. In non-rodents, toxicokinetic evaluations are conducted on the same animals used for toxicity evaluations. Additional groups of animals can be included to assess recovery from any findings. At the end of the dosing and recovery periods, necropsy examinations are performed and organ weights, macroscopic and microscopic evaluations are conducted. Results are compared to vehicle control values using statistical analyses where appropriate. Results are used to determine the no-observed-adverse-effect-level (NOAEL) and toxicity profile in the test species.

Example 5. hERG-related compound toxicity

[00205] Human ether-a-gogo-related (hERG) ion channel encodes the inward rectifying voltage gated potassium channel in the heart and has a major role during the repolarization of the cardiac action potential. It is well established that blockade of this ion channel can lead to potentially lethal arrhythmias. hERG pre-clinical safety data is often used by regulatory agencies in elucidate the toxicity profile of certain compositions.

Compound 1 was tested for their ability to inhibit hERG ion channels.

hERG Testing Methods

[00206] a. hERG-CHO Culture Conditions

Media components include F12 Nutrient Mixture (Ham) with GlutaMAX^TM

(Invitrogen, Cat# 31765), Fetal Bovine Serum, Certified (Invitrogen, Cat# 16000-044– not heat activated), and Geneticin® Selective Antibiotic (Invitrogen, Cat# 10131-027).

One vial of frozen cells, at 1.62x10⁶ cells are thawed into a T150 flask (BD Falcon 355001) with 40 mL of pre-warmed complete media. Cells are cultured at 37 °C, 5% CO₂ for four hours prior to gently changing media. 99% of cells appear attached at this time point.

The flask is media changed at 24 hours post-thaw, the cells are imaged, media changed, and returned to the incubator. At this point, the cells appear healthy and about 25% confluent in the flask. Cells are typically passed 24-48 hours after thaw according to the following intervals and densities below. Cells are incubated at 30 °C for 48 hours prior to assay.

b. hERG Voltage testing conditions

[00207] Using an automated patch clamp apparatus (IonWorks^HT), a three pulse protocol was applied by stepping from a holding potential of -80mV to +40mM for 2s, to activate hERG channels. The membrane voltage was then stepped back to -50mV for 2s to evoke a tail current prior to returning to the holding potential for 1s. This sequence was repeated a further two times. This voltage protocol was applied prior to drug (Pre compound) and after 600s in the presence of drug (Post compound). [00208] The amplitude of the hERG tail current was calculated by measuring the difference between the maximum current on stepping to -50mV of the third pulse (i.e. peak of the outward hERG tail current) and the current measured immediately prior to activation of any hERG current. This parameter was assessed before (pre tail current amplitude) and after 600 s incubation (post tail current amplitude) in drug. In order to assess the amount of block produced by test compounds, the data was first filtered using the IonWorks™ software to exclude any cells where the seal resistance was less than 50MOhm. The remaining data was then exported to an excel compatible data file and only currents with tail currents greater than 250pA were analyzed. The post/pre tail current amplitude ratio for the third pulse was calculated for each drug and control, and presented as percent inhibition. Compound 1 provided an inhibition % less than 25% at both 1 μM and 10 μM.

[00209] In some embodiments, compound 1 displayed decreased inhibition of the hERG channel. In some embodiments, compound 1 displayed a decreased inhibition of the hERG channel when compared to other known FAAH inhibitors. In some embodiments, compound 1 displayed a decreased inhibition of the hERG channel when compared to other known FAAH inhibitors having similar structures.

Example 6. Pharmacokinetic studies

[00210] Pharmacokinetic studies were conducted to determine absorption and distribution profiles of the disclosed compounds which were orally administered to rats. a. Compound administration and blood preparation

[00211] Compound 1 was formulated in a 1% DMA / 99% Vitamin E TPGS vehicle. Prepared compounds were dosed via oral gavage (PO). Following the appropriate

pretreatment time of 2 hours, rats were anesthetized with isoflurane gas. Blood was collected into tubes containing EDTA via retro-orbital eye bleed. Whole blood was spun in a micro- centrifuge at approximately 13,000 rpm for 5 minutes at room temperature. Separated plasma was subsequently aliquoted into eppendorf tubes. Samples were stored at -80 ^oC until prepped for analysis.

b. FAAH Plasma Sample Preparation

[00212] Plasma samples were thawed and the required amount of plasma for standards, blanks and dilutions were made. The dilutions were prepared before plating. Preparation of crash solution included cold acetonitrile + 0.1% formic acid and 25 ng/mL of a FAAH inhibitor used as internal standard. solvent standards of the FAAH inhibitor being studied were preparation at 10, 30, 100, 300, 1000, 3000, 10000, 30000, 100000, and 300000 ng/mL in DMSO. Then a plasma standard curve was generated from the solvent standards (final concentrations of standards in plasma were: 0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000 ng/mL). 50 μL of each plasma sample/dilution, standard, or blank was transferred into 96- well plates. To each well, 200 μL of cold crash solution was added. The plate was covered and gently vortexed. The plate was centrifuged at 3500 rpm, 4^C for 10 min. 200 μL of each supernatant was transferred into new plates. The plates were dried under nitrogen in a TurboVap at 55^C. The sample in each well was re-suspended with 100 μL of 30% acetonitrile, covered and vortexed gently. The well solutions were analyzed by the

LC/MS/MS conditions and specifications below.

c. LC/MS/MS Conditions:

[00213] HPLC column was a Clipeus C8, 2.1x 30 mm, 5 μm, with Basic 8 guard column using 20 μL injections. Mobile phase used was mobile phase A: 0.1% Formic Acid in water and mobile phase B: 0.1% Formic Acid in 85:10:5 ACN: IPA: H₂O. The flow rate for the run was 0.5 mL/min and the gradient for the 4 minute total run time was: 0.0 minutes 35% B; 0.5 minutes 35% B; 1.5 minutes 95% B; 2.3 minutes 95% B; and 2.4 minutes 35% B. Compound 1 provided a plasma PK level greater than 1000 nM at 2 hours in rats.

[00214] In some embodiments, compound 1 displayed an increase in plasma exposure (i.e. absorption and distribution). In some embodiments, compound 1 displayed an increase in plasma exposure when compared to other known FAAH inhibitors. In some embodiments, compound 1 displayed an increase in plasma exposure when compared to other known FAAH inhibitors having similar structures.

Example 7. Effect of Compound 1 on Acute Nausea

Compound 1, a fatty acid amide hydrolase (FAAH) inhibitor, was evaluated to interfere with acute nausea (AN), using a rat model of acute nausea (conditioned gaping reactions to a lithium chloride-paired flavour). Rats were surgically implanted with an intraoral cannula. Following recovery, they underwent a conditioning trial in which they were pretreated with compound 1 (3, 10, 30 or 100 mg/kg, ig) or vehicle 120 min prior to placement in the taste reactivity (TR) chamber. Rats received a 2 min infusion of 0.1 % saccharin (video taped) and were then injected with lithium chloride (LiCl). At test, rats were returned to the TR chamber and again infused with 0.1 % saccharin for 2 min (video taped). The orofacial reactions (conditioned gaping) were later scored.

As depicted in Figure 1, compound 1 (10, 30 mg/kg or100 mg/kg) significantly reduced conditioned gaping reactions to a lithium chloride-paired flavour (a rat model of acute nausea). These effects occurred without impairing learning (3, 10, 30 mg/kg), however at 100 mg/kg, compound 1 interfered with conditioned taste avoidance, a measure of flavour- illness associated learning (See Figure 2). Example 8. Effect of Compound 1 on Expression of Anticipatory Nausea in Rats

Compound 1, a fatty acid amide hydrolase (FAAH) inhibitor, was evaluated to interfere with anticipatory nausea (AN), using a rat model of contextually-elicited conditioned gaping reactions.

Following four pairings of a novel context with lithium chloride (LiCl), the rats were given a test for anticipatory nausea. On the test trial they received intragastric pretreatments of vehicle (VEH) or compound 1 (10, 30 or 100 mg/kg). Immediately following the anticipatory nausea test, rats were given a 15 min locomotor activity test to assess whether the drug produced any motoric impairments.

As illustrated in Figure 3 and Figure 4, compound 1 (10 or 30 mg/kg, but not 100 mg/kg) reduced contextually-elicited gaping reactions, without producing any locomotor effects at the effective doses. Example 9. Ability of SR141716 (1 mg/kg) to block the Compound 1 (10 mg/kg)- induced suppression of Acute Nausea in Rats

SR 1411716 , a CB₁ receptor antagonist, was evaluated for blocking the suppressive effect of Compound 1 (10 mg/kg, ig) on acute nausea, using a rat model of acute nausea.

Rats were surgically implanted with an intraoral cannula. Following recovery, they received a single conditioning trial in which they were pretreated with Compound 1 (10 mg/kg, ig) or VEH 120 min. prior to placement in the taste reactivity (TR) chamber. Additionally, SR141716 (1 mg/kg, ip) or VEH was administered 30 min prior to placement in the TR chamber. In the TR chamber, rats received a 2 min infusion of 0.1 % saccharin (video taped) and were then injected with lithium chloride (LiCl). At test, rats were returned to the TR chamber and again infused with 0.1 % saccharin for 2 min (video taped). The orofacial reactions (conditioned gaping) were later scored.

As shown in Figure 5 and Figure 6, SR141716 blocked the suppression of conditioned gaping reactions to a lithium chloride-paired flavour (a rat model of acute nausea) induced by Compound 1. This indicated a CB₁ receptor mediated mechanism of action for Compound 1. These effects occurred in the absence of any impact on conditioned taste avoidance.

Example 10. Ability of SR1411716 (2.5 mg/kg) to block the Compound 1 (10 mg/kg) induced suppression of Anticipatory Nausea (AN) in Rats

SR141716, a CB₁ receptor antagonist, was evaluated for blocking the effect of compound 1 to interfere with AN, using a rat model of contextually-elicited conditioned gaping reactions. The potential of IW7229 (10 mg/kg, ig) to reduce AN and modify locomotor activity was evaluated. Additionally, we evaluated whether this effect was mediated by the CB₁ receptor. Following 4 pairings of a novel context with lithium chloride (LiCl), the rats were given a test for AN. On the test trial they received a pretreatment of either vehicle (VEH) or

Compound 1 (10 mg/kg, ig), followed by an additional pretreatment of either VEH or SR141716 (2.5 mg/kg, ip). Immediately following the AN test, rats were given a 15 min locomotor activity test to assess whether the drug produced any motoric impairments.

As illustrated in Figure 7 and Figure 8, Compound 1 (10 mg/kg) reduced contextually-elicited gaping reactions and the effect was blocked by administration of SR141716, without producing any locomotor effects. This indicated that Compound 1 (10 mg/kg) has therapeutic potential as a treatment for AN, exerting its action at the CB₁ receptor, without producing any locomotor effects.

OTHER EMBODIMENTS

[00215] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims.

Claims

CLAIMS We claim:

1. A method for the treatment or prevention of nausea comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of compound 1 or a composition comprising compound 1.

2. The method of claim 1, wherein the composition comprising compound 1 further comprises at least one additional therapeutic agent.

3. The method of claim 2, wherein the additional therapeutic agent is chosen from the group consisting of painkillers, non-steroidal anti-inflammatory drugs (NSAIDs), cannabinoid receptor agonists, opiate receptor agonists, anti-infective agents, sodium channel blockers, N-type calcium channel blockers, local anesthetics, VR1 agonists and antagonists, agents used for migraines, topical agents used in the treatment of localized pruritus, anti- inflammatory and/or immunosuppressive agents, agents designed to treat tobacco abuse (e.g., nicotine receptor partial agonists and nicotine replacement therapies), ADD/ADHD agents, agents to treat alcoholism such as opioid antagonists, agents for reducing alcohol withdrawal symptoms such as benzodiazepines and beta-blockers, antihypertensive agents such as ACE inhibitors and Angiotensin II Receptor blockers, Renin inhibitors, vasodilators, agents used to treat glaucoma such as direct-acting Miotics (cholinergic agonists), indirect-acting Miotics (cholinesterase inhibitors) or Carbonic anhydrase inhibitors, selective adrenergic agonists, Osmotic diuretics, antidepressants such as SSRIs, tricyclic antidepressants, dopaminergic antidepressants, cognitive improvement agents, acetylcholinesterase inhibitors, anti-emetic agents (e.g., 5HT3 antagonists), neuroprotective agents, neuroprotective agents currently under investigation, antipsychotic medications, agents used for multiple sclerosis, disease- modifying anti-rheumatic drugs (DMARDS), biological response modifiers (BRMs), COX-2 selective inhibitors, COX-1 inhibitors, immunosuppressives, PDE4 inhibitors, corticosteroids, histamine H1 receptor antagonists, histamine H2 receptor antagonists, proton pump inhibitors, leukotriene antagonists, 5-lipoxygenase inhibitors, nicotinic acetylcholine receptor agonists, dopamine receptor antagonists, P2X3 receptor antagonists, NGF agonists and antagonists, NK1 and NK2 antagonists, NMDA antagonist, potassium channel modulators, GABA modulators, anti-cancer agents such as tyrosine kinase inhibitors, anti-hyperlipidemia drugs, appetite suppressing agents, anti-diabetic medications such as insulin, GI (gastrointestinal) agents, serotonergic and noradrenergic modulators and fatty acid amides (e.g., AEA, OEA, PEA and LEA).

4. The method according to claim 2, wherein the additional therapeutic agent is an anti- emetic agent.

5. The method according to claim 4, wherein the anti-emetic agent is a 5HT3 antagonist such as dolasetron, ondansetron, granisetron, tropisetron, palonosetron, mirtazapine and metoclopramide; a NK1 receptor antagonist such as aprepitant or casopitant; a dopamine receptor antagonists such as droperidol, olanazapine, alizapride, prochlorperazine or domperidone; an antihistamine such as cyclizine, diphenylhydramine, dimenhydrinate, doxylamine, meclizine, promethazine or hydroxyzine; a Cannabinoid such as dronabinol, nabilone or sativex; benzodiazepines such as midazolam, lorazepam; an anticholinergic such as hyoscine; steroids such as dexamethasone; or other anti-emetic agent such as

trimethobenzamide, ginger, emetrol, propofol, peppermint, muscimol or ajwain.

6. The method according to claims 1-5, wherein the nausea is acute nausea.

7. The method according to claims 1-5, wherein the nausea is anticipatory nausea.

8. The method according to claims 1-5, wherein the nausea is chemotherapy-induced nausea.

9. The method according to claims 1-5, wherein the nausea is chemotherapy-induced anticipatory nausea.

10. The method according to claims 1-5, wherein the nausea is radiation-induced nausea.

11. The method according to claims 1-5, wherein the nausea is radiation-induced anticipatory nausea.

12. The method according to claims 1-5, wherein the nausea is post-operative nausea.

13. The method according to claims 1-5, wherein the nausea is post-operative anticipatory nausea.