NZ622480B2 - Meta-substituted biphenyl peripherally restricted faah inhibitors - Google Patents

Abstract

The present disclosure provides methods of making and using peripherally restricted inhibitors of fatty acid amide hydrolase (FAAH). The present disclosure provides compounds of formula I and compositions that suppress FAAH activity and increases anandamide levels outside the central nervous system (CNS). The present disclosure also sets forth methods for inhibiting FAAH as well as methods for treating conditions such as, but not limited to, pain, inflammation, immune disorders, dermatitis, mucositis, the over reactivity of peripheral sensory neurons, neurodermatitis, and an overactive bladder. Accordingly, the disclosure also provides compounds, methods, and pharmaceutical compositions for treating conditions in which the selective inhibition of peripheral FAAH (as opposed to CNS FAAH) would be of benefit. In one embodiment the compound is [3-(3-carbamoylphenyl}-5 –hydroxy-phenyl] N- cyclohexylcarbamate. (CNS). The present disclosure also sets forth methods for inhibiting FAAH as well as methods for treating conditions such as, but not limited to, pain, inflammation, immune disorders, dermatitis, mucositis, the over reactivity of peripheral sensory neurons, neurodermatitis, and an overactive bladder. Accordingly, the disclosure also provides compounds, methods, and pharmaceutical compositions for treating conditions in which the selective inhibition of peripheral FAAH (as opposed to CNS FAAH) would be of benefit. In one embodiment the compound is [3-(3-carbamoylphenyl}-5 –hydroxy-phenyl] N- cyclohexylcarbamate.

Description

META-SUBSTITUTED BIPHENYL PERIPHERALLY RESTRICTED FAAH INHIBITORS CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims ty to, and the benefit of, U.S. Provisional application Serial No. 61/525,636 filed August 19, 2011, the disclosure of which is incorporated herein by reference in its entirety.

STATEMENT AS TO RIGHTS TO IONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] This invention was made with U. S. Government support under Grant Nos.

AA017538, DA012413, and DA012447, awarded by the National Institutes of Health. T he U.S. Government has certain rights in this ion.

BACKGROUND OF THE INVENTION

[0003] The reference to any prior art in this specification is not, and should not be taken as an acknowledgement or any form of suggestion that such art forms part of the common general knowledge at it relates to the claims defining the invention.

Anandamide, the naturally occurring amide of arachidonic acid with ethanolamine, meets all key criteria of an endogenous inoid substance (Devane, W.A. et al. Science, 258, 1946-1949 (1992)): it is released upon demand by stimulated neurons (Di Marzo, V. et al., Nature, 372, 686-691 (1994); Giuffrida, A. et al., Nat. Neurosci., 2, 358-363 (1999)); it activates cannabinoid receptors with high affinity (Devane, W.A. et al. e, 258, 1946- 1949 ) and it is rapidly eliminated through a two-step s consisting of carriermediated transport followed by intracellular hydrolysis (Di Marzo, V. et al., , 372, 686-691 ; Beltramo, M. et al., FEBS Lett., 403, 263-267 ). Anandamide ysis is catalyzed by the enzyme fatty acid amide hydrolase (FAAH), a membranebound serine hydrolase (Cravatt, B.F. et al., Nature, 384, 83-87 (1996); Patricelli, M.P. et al., Biochemistry, 38, 9804-9812 (1999)) (WO 98/20119) (U.S. Patent No. 6,271,015) that also cleaves other bioactive fatty ethanolamides, such as oleoylethanolamide - octadecenamide)) guez de Fonseca, F. et al. Nature, 414, 209-212 (2001)) and palmitoylethanolamide (Calignano, A. et al., Nature, 394, 277-281 (1998)). Mutant mice lacking the gene encoding for FAAH cannot metabolize anandamide (Cravatt, B.F. et al., normal, show signs of enhanced rnide activity at cannabinoid receptors, such as reduced pain sensation (Cravatt, BF. et al., Proc, Natl. Acarz’. Sci. U. S. A“, 98, 93719376 (200D). This suggests the possibility that drugs ing FAAH may heighten the tonic actions of anandaniide, while possibly avoiding the multiple, often unwanted effects l4'! produced by Ail—THC and other direct—acting cannabinoid agonists l, W., et al., Lancet, 352, 161 l--l6l6 {1998); Chaper‘on, F., et al, Crit. Rev. Njurobiol, 13, 1 (1999)). llltltldj l’ain perception can he effectively controlled by neurotransmitters that operate within the Ci S. This: modulation has been well characterized in the dorsal horn of the spinal cord, where inipulses carried by noeiceptive (pain—sensing) fibers are processed before they l 0 are transmitted to the brain. In addition to these central mechanisms, intrinsic control of pain transmission can occur at terminals of afferent nerve fibers outside the CNS One ent example of eral regulation is provided by the endogenous opioids, which are released from ted immune cells during inflammation and inhibit pain initiation by interacting with opioid receptors localized on sensory nerve endingsl’2. l 5 llllltlf’il It has been proposed that endocannabinoid mediators might serve an analogous firnetion to that of the opioids, because pharmacological activation of peripheral (Bl and C32 cannabinoid receptors ts pain~related behaviorsj" While genetic tion of CB; receptor expression in primary nocrceptrve neurons exacerbates such hehavrors . Moreover: there is evidence that clinical conditions associated with neuropathic pain or inflammation, such as complex regional pain syndrome and arthritis, may be accompanied by peripheral ( ‘ elevations in the levels ot the endocannabinoid anandamide)’J (' , Another major. . , v a . . , . endocannabinoid ligand, hidonoylglycerol (ZAG), has also been implicated in . . . . . a , 8.11 micrceptive Signaling outsrde the CNS ’ . liltllldl Much attention has been directed toward the role of anandaniide in pain. h/lethods M U: of t eating pain by administering anandamide and toylethanolarnide are disclosed in US. Patent Application Publication No: 23020173550. Methods of treating pain by administering inhibitors of FAAH are disclosed in US Patent Application Publication Nos. 200401 2175 l8 and 2003084894,, Methods of treating pain by administering inhibitors of mide transport are sed in US. Patent ation ation No 29330149082. (14‘ llltltlfl Although these findings suggest that the endocannabinoid system serves an ant function in the peripheral regulation ofnoeiception, they offer no definitive insight on the identity of the endogenous ligand, or ligands, involved in this on Thus there exists a need related to an understanding, at a molecular level, oi‘the intrinsic mechanisms that control pain initiation in order to identify new analgesic agents devoid ol’central side effects. Surprisingly, the present invention satisfies this as well as many other needs by identifying, characterizing and making brain~impermeant tors of the anandamide~ degrading enzyme, FAAl—l, with the aim of magnifying the actions of peripheral anandamide and unnrasking their possible role in the control of emerging pain signals”. Another need in the field of ping and therapeutically using FAAH inhibitors is related to the ability of these inhibitors to modulate endogenous cannahinoid systems Within the CNS system to cause unwanted psychotropic or mood-altering effects. The present invention also surprisingly satisl'ies these and other needs by providing peripherally restricted FAAH l0 inhibitors and s of their use in the ent of a variety of conditions, including pain and/or mation 13398} The following references may provide background information for the field to which the present invention pertains. The disclosure of each reference is hereby incorporated by reference in its entirety for all purposes, (1) Stein, C Schafer, M,, 6;: Machelska, ll, Attacking pain at its source: new perspectives on s. Nat Med 9 (8), 08 (2003); 2) Stein, C. 8;. r, C, Opioids and sensory nerves. l-landh Exp Pharmacol (194), 49545 l S ; 3) Calignano, A, La Rana, G, Giuilrida, Ar, & Piornelli, l1, Control of pain initiation by endogenous cannahinoids. Nature 394 (6690), 277—2181 (l 998); 4) laggar, 8.1}, Sellaturay, 8., & Rice, AS, The endogenous cannabinoid anandamide, but not the CBZ ligand palmitoylethanolamide, prevents the owisceral ~r‘etlexia associated with inflammation of the rat urinary bladder, Neurosci Lett 253 (2) l23—l26 (1998); 5) Nacl<ley, AG, Suplita, R.L., 2nd, at Hohmann, A6,, A peripheral cannahinoid mechanism suppresses spinal t‘os protein expression and pain behavior in a rat model of inflammation. Neuroscience l l? (3), 0 (2003); 6) Dziadulewicz, ER et al., Naphtlralen-l-yl—(él— N U: pentyloxynaphthalen—l—yl)metlianone: a potent, orally bioavailable human CBl/CB2 dual agonist with antihyperalgesic properties and cted central s system penetration. J Med Chem 50 (16), 3851-3 8:36 (2007); 7) Anand, R, Whiteside, C1,, Fowler, Cl, & n, AG, Targeting CB2 receptors and the cndocannabinoid system for the ent of pain. Brain Res Rev ('50 (1), 6 (2009’); 8) Agarwal, N. et al., Cannahinoids mediate analgesia largely via peripheral type l cannabinoid receptors in nociceptors. Nat Neurosci 10 (7), 870379 (2007); 9) Kaul’rnann, 1. et al., Enhanced arrandarnide plasma levels in ts with complex regional pain syndrome following traumatic injury: a preliminary report. Eur Surg Res 43 (4), 325-329 (2939); 1(3) Richardson, D. et al., Characterisation of the cannahinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and 111eun121toid a1thri‘1is.Arth1itis Res T11e1 11)1),R431’2()()8) ll) Mitrirattanaktd, S. e1211., Site~ spec111cinere=ases in1.1er1phera1 cannahinoid re'cep‘tors and their endogenous ligandsin a modei of neuropathic pain Pain 1216 11—3), 1021 114 2006); 12) Schioshurg, JE, Kinsey, 3.13., & Lichtnian, A11, Targeting fatty acid amide hydrolase I) to treat pain and inflammation. AAPS J ll (11.39—5115111213139); 13) Kathunia, S et al. Modulation of anxiety through hiockade 111.11121nda1111de hydrolysis Nat Med 9111), 76—812003), 14) Piomelii, D. 1;! 211.. Pharrnacologicai profiie of the seiectiye EAAH inhihitor KIDS—4103 (URB597). CNS Drug Rey 12 (1), 21-38 (2006); 15 flapper, J .R. et 211., A second generation ofcarbaniate- based fatty acid amide hydroiase tors with improved activity in Vivo.7’he1an11;dCh=rr1 4 (9), 513 (21009); 16) Aiexander, JP. & Cravatt, BE... Mechanism of carbainate vation of FAAH: implications for the design of covaient inhibitors and in V1VO functiona1 probes 101' enzymes. Chem Biol 12 (ll), 1179—1187 (2005); 17:1 Loscher, W. & ha, 11., Blood—brain harrier active efflux transporters: ATP~hinding cassette gene farniiy fl2 (l), 12131321), 18) Cravatt, BE. etal..\upcrscns1t1uty to anandainide and enhanced endogenous cannabinoid signaiing in mice 1ael<ing fatty acid amide hydrolase.

Proc Naii Acad Sci U S A 98 ('16), 9371—9376 (2001); 19) Starowicz, 141., Nigam, S., & Di ivlarzo. ‘17., Biochemistry and coiogy of endovaniiloids. Pharrnacoi Ther 114 (1), 13— 33 (2007 ); 2(3) LD\/1;11n.l., La Rana, G, Russo, R., Cahgnano, A, 8; lii, 13., The search 101' the pa11nitoylet11anolan1ide receptor. Life Sci 77 (14), 1685 11198 (2005); 21) Sager, D.R., Kendall, 13,131., & Chapman, V., Inhibition of fatty acid amide hydroiase produces 1313AR—aipha—1nediated analgesia in a rat model of inflammatory pain. Br J Pharniacoi 155 (8), 1297-1306 (21.31.38); 22) Coderre, '11]. 8; Meizack, R, The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin— induced tissue injury. J N’eurosci 12 (9), 3665—3670 ; 23) 11mg. 3!. & Sorkin, 1;.S., Eornialin-evoked ty in identified y afferent fibers: systeniic iidocaine suppresses 2 activity. Pain 64 1'2), 345355 11996:;1 24:1 Bennett 13.1.61; ’.K., A peripheral rr1o11onenropathy1n rat that produces disorders 1111121111 sensation like those 5een in man Pain 33 (l), 87—107 ; 25) Ahiuwalia, J., Yaqoob, 191.. Urban, 1;., Bevan, 8., & Nagy, 1., Activation of eapsaiein-sensitive pri1na1y sensory neurones induces anandarnide production and reiease. J Neurochem 84 (3), 585—591 12003); 26) Liu, J. et 211., A biosynthetic pathway for anandarnide. Proc Natl Acad Sci U S A 103 (36), 133451335012006);27) Hohniann, AG. 6;: Herirenhain, M., Localization of eentrai inoid CBl receptor messenger RNA in neuronai subpopuiations of rat dorsai root ganglia: a double~lahel in situ hybridization study. Neuroscience 91’) (3), 923—931 (1999); 28) Hohrnann, AG. <9 1—lerkenha1n, M., Cannabinoid receptors undergo axonal flow in y nerves. Neuroscience 92 14), 1171' 12175 (1999); 29) Richardson, 3D,. Kilo, 8., & aves, K.M., Cannabinoids reduce hyperalgesia and infiarrirnation via interaction with peripheral CBl receptors. Pain 75 (l ), l 1 1—1 19 ; 30) Mackie, K Carinahinoid receptors as therapeutic targets. Annu Rev Pharmacol ’l'oxicol 46, 101-—122 ; 31) Lo‘v’erine, J. et a1, Rapid broad-spectrum analgesia through activation ofperoxisome proliferator—activated receptor—alpha. J Pharmacol Exp Ther 319 (3), l051—1061 (2006); 32) Guindon, J. 8: nn, AG, Cannahinoid CBZ receptors; a therapeutic target for the treatment of inflammatoiy and neuropathic pain. Br J Pharmacol 153 (2), 319-334 (2008); 33) Cravatt, BF. et al., Functional disassoeiatiori of the central and peripheral fatty acid amide signaling systems. Proc Natl Acad Sci U S A 101 (29), l0 10821—10826 (2004);3=4) Lever, U. et al, localization of the endocannahinoiddegrading enzyme fatty acid amide hydrolase in rat dorsal root ganglion cells and its regulation after peripheral nerve injury. J Neurosci 29 (12), 3766—3780 (2009); 35:) Tegeder, J. et al, eral opioid analgesia in experimental human pain models, Brain 126 (Pt 5), l092—l 102 (2003); 36) King, AR. et a1, URB602 inhibits inonoacylglyceroi lipase and selectively blocks 2x-arachidonoylglycerol degradation in intact brain slices. Chem Biol l4 (l2), l357-— l365 (2007); 37) ta, CL, Ahmed, F, & Fiomeili, 1)., identification ot‘hiosynthetic precursors for the endocannabinoid anandamide in the rat hrain. J Lipid Res 49 (l), 4867 ; 38) Fegley, D. et al., Characterization of the fatty acid arnide ase inhibitor cyclohexyl carbarnic acid 3'~carbarnoyhhiphenyl—3—yl ester (EJ133597): effects on mide and oiei’iyiethanolamide deactivation. J Pharmacol Exp Ther 3 i 3 t 1), 352—358 (2005); 39) Cadas, H di Tomaso, F, 84: Piomelii, 1)., Occurrence and biosynthesis of endogenous cannabinoid precursor, N—arachidonoyl phosphatidylethanolarnine, in rat brain. J ci l7 (4), 1226—1242 (1997); 40) Hargreaves, K, Dunner, R., Brown, F Flores, (3,, Sr Joris, J.. A new and sensitive method for measuring thermal nocieeption in cutaneous hyperaigesia. Pain 32 (l), was (1988).

BRIEF SUMMARY OF THE ENVENTION {6609} in a first aspect, the ii'ivention provides compounds, and iaeeutical compositions of the compounds, having Formula 1: (R5)Hl Formula 1 In Formula 1, R1 is selected from the group consisting of hydrogen, hydroxy and the physiologically hydrolyzable esters thereof, ~Sl>l, y and the physiologically Ur liydrolysable esters thereof, a hydroxy lower (Ci--C3)all<yl (cg, --ClrleH, “CHZCHMH, and Cllt:Ol-l)(3l-lg) and the physiologically hydrolyzable esters thereof, ~NR7RS, and ~Nl—lSOgR9; wherein R7 and R8 are independently selected from hydrogen or unsubstituted tCfi—Cfialkyl and R9 is hydrogen, methyl, ethyl, tritluorornethyl or trifluoroethyl; R2 and R3 are independently hydrogen or tuted or unsubstituted (C; --Cg)all§yl; each R4 is ll) independently hydrogen or substituted or unsubstituted (C1-C3)all{yi and n is an r from 0 "to 4; each R5 is ndently hydrogen, halogen, hydroxy and the physiologically yzable esters f, carboxy and the physiologically hydrolysable esters thereof, liydroxyl-ttj} --C3)alkyl and the physiologically hydrolyzable esters thereof, --(C~,~C3)alkoxy, or 21, and R20 and R21 are independently ed from hydrogen or (C1—C313alkyl; rn is an integer from O to 3; R6 is a exyl, eyclopentyl, cyclobutyl or tetrahydropyran—4—yl which may be substituted or unsubstituted. Also included are the pharmaceutically acceptable salts thereof. in some embodiments, In and n are each 0, R2 and R3 are each H; and Re1 is hydroxy, carhoxy, hydroxyrnetl'iyl, or hydroxyethyl; and R6 is cyclohexyl. In some embodiments, the cyclohexyl is substituted or unsubstituted. Also include are the physiologically acceptable esters thereof. The compounds set forth herein have the advantageous property of being peripherally cted FAAH inhibitors with accordingly reduced potential for side—effects on the central neiyous system. {6616} in a second aspect, the invention provides pharmaceutical compositions sing a therapeutically effective amount of the compounds according to the invention. The compositions can be formulated for any route of administration including the oral and parenteral routes. in addition, the itions may be in a unit dose . {bill l} in a third aspect, the invention provides a method of treating a subject in need of a erally restricted FAAH inhibitor (eg, a FAAl—i inhibitory compound according to the invention), in preferred embodiments, the subject is a human. in some embodiments, the need is with respect to a ent for pain, inflammation, or an immune disorder of the subject, in some embodiments, the pain can be noeiceptive, inflammatory, or neuropathic pain. Preferably, the peripherally restricted FAAl—i inhibitory compound is a compound of the invention. it) {8912} in a fourth aspect, the invention provides a method of enhancing the peripheral activity of an endogenously produced (Le, an endtwannabinoid such as anandamide, N— arachidonoyl dopamine) or exogenously provided cannabinoid fatty acid amide in a subject by administering a compound according to the invention. Preferably, the fatty acid amide is anandan'iide, N—aracl'iidt‘inoyl dopai'nine, oleoylethanolamide, stearoylethanolamide, or palmitoylethanolamide. Where the fatty ethanolan‘ride is exogenousiy provided, the fatty acid ethanolamide can be administered to the subject before, after, or contemporaneous with the administration of the compound according to the invention. in some embodiments, the subject is in need of treatment for pain, inflammation, or an immune disorder. in preferred embodiments, the pain can be nociceptive, inflammatory, or neuropathic pain. 13313} in a fifth aspect, the invention provides a pharmaceutical composition for treating a condition selected from dermatitis, mucositis, or the over vity of peripheral sensory neurons, neurodermatitis, overactive bladder, or cough wherein said composition rises a compound according to the invention and a ceuticaliy able excipient. In some embodiments of any of the above, the condition is a chemical, drug-- or ion-vinduced pathology. ingly, in this aspect the ion also provides methods of treating a condition selected from dermatitis, mucositis, or the over reactivity of peripheral sensory neurons, neurodermatitis, overactive r, or cough pain and/or inflammation by administering to a mammal in need thereof, a therapeutically effective amount of a compound ing to the invention, BRIEF DESCRH’TION OF THE BRA'WINGS {6614} Figure 1 Effects of oral administration of compound 1 on can‘ageenart~induced edema. Compound 1 reduced the difference between the paw volume of male CDl mice, measured at each time point, and the basal paw volume ed immediately before carrageenan injection. Results are expressed as mean ± SEM (n = 6, each group), * p<0.05, *** p<0.001 vs. vehicle.

Figure 2 Effects of oral administration of compound 1 on carrageenan-induced hyperalgesia. In the mechanical hyperalgesia test, compound 1 increased the withdrawal old measured on the inflamed ipsilateral paw at different time points after oral drug stration. Results are sed as mean ± SEM (n = 6, each group), *** p<0.001 vs. vehicle.

Figure 3 Effects of oral administration of compound 1 on carrageenan-induced hyperalgesia. In the thermal hyperalgesia test, compound 1 increased the withdrawal threshold measured on the inflamed teral paw at different time points after oral drug administration. Results are expressed as mean ± SEM (n = 6, each group), *** p<0.001 vs. vehicle.

DETAILED PTION OF THE INVENTION 1. General

[0017] The present invention provides methods of making and using peripherally cted inhibitors of fatty acid amide hydrolase (FAAH). T he present invention provides compounds that suppress FAAH activity and increases anandamide levels outside the central nervous system (CNS). Despite their ve inability to access the brain, such compounds are useful in attenuating behavioral responses indicative of persistent pain in rodent models of inflammation. T he present invention also sets forth methods for inhibiting FAAH as well as methods for treating conditions such as, but not limited to, pain, inflammation, immune ers, dermatitis, mucositis, the over reactivity of peripheral sensory s, ermatitis, and an overactive bladder. Accordingly, the ion also provides compounds, s, and pharmaceutical compositions for treating conditions in which the selective inhibition of peripheral FAAH (as opposed to CNS FAAH) would be of benefit. 2. Definitions It is noted here that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference and the word “comprise” and its variations, such as “comprises” and “comprising”, means including, but not limited to, er follows the word, unless the context clearly dictates otherwise.

"FAAH" denotes a mammalian Fatty Acid Amide ase and includes, but is not limited to, the human, rat, and mouse forms of the enzyme. U.S. Patent No. 6,271,015 discloses isolated and purified forms of FAAH. In one set of embodiments, the FAAH IC50 of the subject compounds is defined according to inhibition of the rat enzyme under physiologically relevant conditions. Fatty Amide llydrolases (FAAHS) (Deutsch, D.G., et al., Prostagiandins .Ijieakot. ESSQi’Zf. Fatty Acid, 66, 201—21 0 (2002)) are enzymes responsible for the degradation of lipid ethanolarnides, (Fowler, C. J}, et al., Biochem. Pharmaco]. 6‘2, 517-- 526 (200M; Patricelli, M. R, et al. Vitam. Harm, 62. 4 (2001)) eg. anandanride (ABA, 1, Figure l), (Devane, W. A., et al., e 258, ”464949 (l992)) oleoylethanotamide, (Rodriguez de Fonseca, l3., et al. Nature n) 414-, 1209—212 (2001); Fu, l et al., Nature (London) 425, 90-93 (2003)) and palmitoylethanolarnide, nano, A, et al. Nature (London) 394, 2 7—28l (l 998); t, Dix/l, et al., Curr. Med. Chem. 9, 663— it) 674 (2002,) a biochemical process which, along with selective transport into cells in the case ofAEA, (Di Marzo, V., Nature (London) 372, 686-691 {1994); Beltrama, M., et al., Science 277, 10944097 (1997); Piornelli, 1)., et al., Proc. Natl. Acad. Sci. [./’.S./l. (2002)) brings about the cessation of the cellular effects of these autacoids. Owing to the various and in'rportant physiological roles of fatty acid ethanolamides, classes of small—molecule compounds able to block rl or FAAHs but not bind to other endocannabinoid—metabolizing enzymes, eg. rnonoglyceride lipase (M61), (Din‘n, TR, et al., Proc. M10. Acad. Sci. USA. 99, 10819 ,1 0824 (2002)) or cannabinoid receptors, would be ageous both as ph armacologicai tools and as prototypes for drug development ts (Piomelli, i1, et al. fiends Pimrmacoi.

Sci. 2l, 2l8—224 (2000); Bisogno, T., et at, Curr. Pharm. Des. S 533—547 (2002); Yarnell A, Chem. Eng. News 80(49), 32 (2002); Smith, A, Nat. Rev. Dng Discov. 2, 92 (2003); Wendeler, M., et al. Angew. Chem. Int. Ed 42, 293 8—294l (2003)). {0020} The term “pharmaceutically acceptable carrier” encompasses any of the standard pharmaceutical rs, buffers and excipients, including phosphate—lniffered saline solution, water, and em ulsions (such as an oil/water or water/oil on), and s types of wetting agents and/or adjuvants. Suitable pharmaceutical carriers and their formulations are described in Remington‘s ceutical Sciences (Mack Publishing Co., Easton, 19th ed. l995). Preferred pharmaceutical carriers depend upon the intended rnode of adn'rinistration of the active agent. ’l‘ypical modes of administration are described below. {0021} The term “effective amount” means a dosage sufficient to e a d result with respect to the indicated er, condition, or mental state. The desired result may comprise a subjective or objective improvement in the recipient of the dosage. With respect to pain, the improvement may be decreased sign or symptom of pain. {0022} The terms “treatment”, “therapy” and the like include, but are not limited to, methods and manipulations to produce beneficial changes in a recipient’s health status. The changes: can be either subjective or ive and can relate to features such as symptoms or signs of the e, disorder or condition being treated. For example, if the patient notes decreased pain, then successful treatment of pain has ed. For example, if a decrease in the amount of swelling has occurred, then a beneficial treatment of inflammation has occurred. Similarly, if the clinician notes objective s, such as improved range of motion, then treatment for a pain or inflammation which had been impairing the motion has also been beneficial, ting the de ,erioration of a recipient's status is also included by the term. {8923} Therapeutic benefit includes any ofa number ofsubjective or ive factors ll) indicating a beneficial response or improvement of the condition being treated as discussed herein. 13324} "Phannaceuticallywacceptable” or peutically-acceptable” refers to a substance which does not interfere with the effectiveness or the biological activity of the active ingredients and which is not toxic to the hosts in the amounts used, and which hosts maybe either humans or animals to which it is to be administered. {6025} “'l‘herapeuticallyneffective amount” refers to the amount of an active agent sufficient to induce a desired biological or clinical result. That result may be alleviation of the signs, symptoms, or causes of a disease, or any other desired tion of a biological system, The term “thera )eutically effective amount” is used herein to denote any amount of the ation which causes a substantial improvement in a disease, disorder or condition when administered to a subject. The amount will vary with the condition being treated, the stage of advancement of the condition, and the type and tration of formulation applied.

Appropriate amounts in any given instance. will be readily apparent to those skilled in the art or e of determination by routine experimentation. {@926} A “prophylactic treatment” is a treatment administered to a t who does not exhibit signs of a neurological or psychological disorde or condition or exhibits only early or slight signs of such a disorder or condition, n treatment is administered for the purpose of decreasing the risk of developing a pathology or worsening of disorder or condition. The compounds of the invention may be given as a prophylactic treatment to prevent undesirable or unwanted anxiety or panic attacks, or to reduce the level of anxiety should worsening occur. {@927} The term "subject" as used herein includes any , including, but not limited to, mammals leg, rat, mouse, cat, dog) including humans to which a treatment is to be given. {@923} As used herein, the term "hydrocarbyl" refers to a (Ci-Cg) hydrocarbon radical that is a (Cl—Cg)allryl, lalkenyl, )e§,rcloallryl, (C3—C3)eycloalkenyl, (C1-i:lg)l1€l7€l"02tll<yl, (Ci—Cgfiieteroalkenyl, (C3ng)heterocycloalkyl, or (C3' ‘ rocychjalkenyl radical. J‘s/lore preferably, the hydrocarbyl in each instance is either a substituted or unsubstituted (C1 to C6), (C1 to Cg), or (C1 to Cfihydrocarbyl, and more preferably still an unsubstituted ((31 to C3)alkyl. Still more preferably the hydrocarbyl in each instance is methyl or ethyl or trifluoroniethyl. The term “hydrocarbyl” also includes those groups having up to l, 2, or 3 atoms of a arbyl group as set forth above replaced by a heteroatom with the proviso that the heteroatoms of the hydrocarbyl are not contiguous to each other and the arbyl ll) is not attached to the remainder of the compound by a atom of the hydrocarbyl. {6629} As used herein, the term "alkyl", by itself or as part of another tuent, means, unless otherwise stated, a straight or branched chain , saturated, hydrocarbon radical, having the number of carbon atoms designated (if). (C1—C6) means one to six s). Examples of alkyl groups include methyl, ethyl, yl, isopropyl, l, t—hutyl, isobutyl, secvbutyl, n-pentyl, n--hexyl, n--heptyl, n-voctyl, and the like. {693%} As used herein, the term “’alkoxy” represents an alkyl moiety joined to the remainder of the molecule by the oxygen atom of the alkoxy. Accordingly, examples of alkoxy would include, hut not he limited to, methoxy, ethoxy, propoxy and the like. {6631} As used herein, the term “carboxy” or “carboxyl” refers to a compound having the general formula R-COOH wherein R is an organic molecule such as alkyl. Examples of carboxy include ~COOl-l; —Cl—l2~COOH, and —CH3—CH3-COOH. {6632} The term "alkenyl" is derived from the name of the corresponding alkyl group but differs in sing one or more double bonds, Similarly, "alkynyl" groups are named with respect to their corresponding alkyl group but differ in possessing one or more triple bonds.

Non—limiting examples of such unsaturated allrenyl groups and allgynyl groups include Vinyl, 2—propenyl, crotyl, 2~isopentenyl, 2—(butadienyl), 2,4—pentadienyl, 3—(_ 1,4—pentat’lienyl), ethynyl, l-- and 3--propynyl, ynyl, and the higher homologs and isomers. illll33§ As used herein, the term "heteroalkyl" derives its name from the corresponding alkyl group but differs in containing one, two, or three heteroatoms independently selected from N, O, and S each substituting fora carbon of an alkyl group. The heteroatorn en and sulfur atoms are optionally oxidized, and the en atoms) are optionally quaternized. A heteroalkyl group is attached to the remainder of the molecule through a carbon atom of the heteroalkyl group and the heteroatonis of the alkyl are not contiguous with r heteroatom. {8934} The term "heteroallrerrylfl derives its name from the corresponding alkenyl group but differs in having 19 2,9 or 3 heteroatoms substituting for a carbon of the alkenyl group. The heteroatorn nitrogen and sulfur atoms are optionally oxidized, and the nitrogen s) are optionally quaternized. A heteroatorn can form a double bond with a carbon atom. A heteroalkenyl group is attached to the remainder of the le through a carbon atom of the hydrocarbyl and the heteroatoms of the hydrocarhyl are not contiguous with another heteroatom. ll) {8935} As used herein, the term "cycloalh’yl" refers to a saturated niorrocycllc arbon radical comprising from about 3 to about 8 carbon atoms, and more preferably 3 to 6 carbon atoms. The term "cycloalhenyl" refers to monocyclicj non-aromatic hydrocarbon l comprising from about 5 to about 6 carbon atoms and having at least one double bond.

Exemplary cycloalkyl groups and cycloallcenyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyln cycloheptavl, 3—dienyl, and the like, {6936} As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated nionocyclic hydrocarbon radical sing from about 3 to about 8 carbon atoms, and more preferably 3 to 6 carbon atoms in which l, 2 or 3 of the carbon atoms are independently replaced by a heteroatorn independently ed from 0, N9 or S. Nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atorn(s) are optionally quaternized. r ulfur may be in the thio, s'ultinyl or sulfonyl oxidation state. The term "heterocycloalhenyl refers to heterocycloalkyl group having at least one double bond. A heterocyeloalkyl or heterocyeloalkenyl group is attached to the remainder of the molecule through a carbon atom, ‘espectively, of the heterocycloalkyl or cycloalhenyl group; and the heteroatorns of the heterocycloalkyl or heterocyeloalkenyl are not cr’jntiguous with another heteroaton'r of the heterocycloallryl or heterocycloallren yl. lllll37§ As used herein” the term "heteroatorn" is meant to include oxygen (0), nitrogen (N), and sulfur (8)). llllliil’il As used herein, the term "halogen” or "halo" refers to iodine (I), bromine (Br), chlorine (Cl), and/or fluorine (F), } The above hydrocarbylfl alkyl, alkenylfl cycloalkyl, lkeriyl, heteroalkyl, alkenyl, cycloheteroalkyl, and cycloheteroalkenyl radicals can each be substituted with one, two or three tuents independently selected front unsubstituted (C1-C6) or (CE— C3)all<yl, tituted (Cl-C36) or (C1—C313alkoxy, unsubstituted arnino, unsubstituted (C1—C6) or t ijg) all<ylamino, di— unsubstituted (C1—C6) or (Cngalkylaniino, hydroxy, halo, unsubstituted carboxarnido, unsubstituted (Cr-Cg) or (C,--Cfiallrylcarboxamido, oxo, and nitro. Non—limiting examples of alkoxy groups e methoxy, ethoxy, t—butoxy, cyclopentyloxy, u’ironiethoxy, and the like As used herein, the term “oxo” refers to =0 As used herein, the term ”amino" refers to ~NH2. in some embodiments, each of the liydrocarbyl groups is unsubstituted. in some embodiments, each of the hydrocarbyl, allryl, allteriyl, cycloalltyl, cycloalkenyl, heteroalkyl, heteroalkenyl, cycloheteroalkyl, and cycloheteroalhenyl groups are unsubstitute' . {6646} A peripherally restricted compound is one which poorly penetrates the blood brain barrier or is extruded more rapidly from the brain. Accordingly, a peripherally restricted compound ing to the invention can be administered at s which inhibit FAAl—i activity in the periphery to a far greater extent than centrally (egg in brain); In some embodiments the FAAH inhibitor according to the invention has a subcutaneously, intravenously, or orally administered EDSQ tor inhibiting peripheral FAAH activity (eg, liver) which is no more than ’75:, l/8, or l/lt’) oi" the EDsg for inhibiting brain FAAl‘l activity in the mouse Preferably, the peripherally restricted FAAH inhibitor is one which reduces FAAl-l activity in the periphery by at least 3, 4, 5,, 7—, 8—fold, or 10~iold more than it reduced FAAl‘l activity centrally (egr, in the brain) of the test mammal. For instance, FAAH activity levels in the ery can be inhibited by 80% (20% of the ne or bited level of FAAH activity remains) While central FAAH activity would be inhibited by 10% (90% of the baseline or uninhibited level of FAAH activity remains) providing for a 8096/1096 or 8—fold difference in FAAH inhibition.

N Us {6641} A “physiologically cleavable ester” or ologically hydrolysabie ester” is one which is a substrate for carboxyesterases in vivo. Physiologically cleavable esters are typically y hydrolyzed such that the concentration of the corresponding alcohol or acid released by the hydrolysis comes to ch or exceed that of the ester in blood or plasma.

For instance, a physiologically ble es ,er is one which is rapidly hydrolyzed to the corresponding alcohol and acid in vivo with a. half time of less than 1/2, l, 2., 3 or 4 hours at a therapeutically nt dosages. See eg, Bundgaard, l-lr, Ed Design of Prodrugs (Elsevier Science Publishers, Amsterdam l 985). A physiologically cleavable ester reters to those esters which retain” upon hydrolysis of the ester bond, the biological effectiveness and properties of the carboxylic acid or alcohol and are not biologically or otherwise undesirable.

For a description ot‘pharrnaceutically acceptable esters as prodrugs, see Bundgaard, H, supra. These esters are typically formed from the reaction ot‘a corresponding carboxylic acid (X~CO;H) or an alcohol (XUOH‘), respectively, with a compound according to the invention which respectively is an alcohol or acid, X can be a substituted or unsubstituted hydrocarbyl, C3)all<yl, a (C1 to (Z6)all<yl (egw ethyl), aryl, heteroaiyl, cycloallcyl, alkenyl, cycloalkenyl, heteroalkyl, heteroalkenyl, cyclohetert‘ialkyl, and cycloheteroalkenyl radical, ceutically acceptable alcohols and acids are contemplated (e.g., ethanol, benzoic acid). .>. unds l0 {6642} The present application provides peripherally restricted FAAH inhibitors of Formula, l. These inhibitors retain a, FAAH inhibitory activity and are peripherally cted which is highly advantageous because these tors do not substantially form reactive benzoquinones when metabolized in a mammalian subject, {6643} in some embodiments, the peripheral pre ”erence of the FAAH inhibitors is l5 specifically conferred by certain meta-substituents on the proximal phenyl of the yl moiety. in some embodiments, rneta—substituents include the yl, hydroxyinethyl, and carboxyl group as well as the ysable esters thereotl in certain embodiments, the meta— substituents are hydroxyl. ln other embodiments, the niet~substituents are yinethyl. In yet other embodiments, the meta~snbstitnents are carbonyl. {@944} In certain embodiments, the present invention provides compounds are according to the formula: Formula l, 2012/051478 ln Formula I, R1 is selected from the group consisting of hydrogen, y and the physiologically l'iydrolyzable esters thereof, ~SH, carboxy and the pl’iysiologically hydrolysable esters thereof, hydroxy ((i1~C3)all<y'l (e.g,, CHZOH and — CH2CH20H) and the logically hydrolyzable esters thereof, NR’R8 and --NHSO2R9; wherein R7 and R8 are independently selected from hydrogen or ((31—C3)all(yl and R9 is selected from hydrogen, methyl, ethyl, trilluorontethyl or tritluoroethyl; R2 and R3 are independently selected from en or tuted or unsubstituted (C; --C3)alkyl; each R4 is independently a hydrogen, a substituted or unsubstituted (Cnghlkyl and n is an integer from t) to 4; each R5 is independently hydrogen, halogen, hydroxy and the logically hydrolyzable esters thereof, carboxy and the physiologically hydrolysable esters thereof, hydroxyl—(C j —C3)all<yl and the physiologically hydrolyzable esters thereof, "(Cg --€;‘,3)all{oxy, or "NRZORzl; and R20 and R21 are independently ed from hydrogen or (C;,—(Z3)all(y'l; m is an integer from t} to 3: R6 is an unsubstituted or substituted cyclohexyl, entyl, cyclobutyl or tetrahydropyran~4~yl.

Also included are the pharmaceutically able salts thereof. {6645} In some embodiments of the above compounds, in and n are each (i, and R2 and R3 are each It. {8946} In further embodiments of any of the above compounds, RE is hydroxy, carboxy, or hydroxyinethyl. {6647} In some embodiments, R1 hydrogen, ln “eitain embodiments, R1 is hydroxy or the physiologically hydrolyzable esters thereof. In other embodiments, R] is ~SH. in still other en'ibodin'ients, R1 is carboxy or the physiologically hydrolysable esters thereof. In n embodiments, R1 is hydroxyl~(C;—C3)alkyl. In other embodiments, RI is ~CH20H or v---CH3CH20H or the physiologically hydrolyzable esters thereof. In certain embodiments, R1 is —NR7R8. In other embodiments, R1 is ~NI‘lS()2R9. In some of these embodiments, R7 and R8 are independently en or (C1—C313alkyl, In some embodiments, R7 and R8 are independently methyl, ethyl, propyl, isopropyl, butyl, t—butyl, isobutyl, n—butyl, pentyl, hexyl, heptyl, or octyl. In certain embodiments, R9 is hydrogen, methyl, ethyl, tritl'uoromethyl or trifl uoroeth yl. {664$} In still further ments of any of the above compounds, R6 is substituted or unsubstituted. In still further ments of any of the above compounds, R” is cyclohexyl. {6049} In yet further embodiments of any of the above compounds, the exyl is unsubstituted. {0050} In still further embodiments, the compound is a physiologically acceptable ester of any of the above. {0051} In still further embodiments ot‘any of the above, R7] and R8 are each II and R9 is methyl, ethyl, trifluorometbyl or tritiuoroethyl; 13352} In other embodiments of the compounds of Formula I, m is (l and n is (I, l, 2, 3, or 4. In other further embodiments, in is l and n is I}, l, 2, 3, or 4. In still other embodiments, m is 2 and n is O, l, 2, 3, or 4. In yet still other embodiments, m is 3, and n is O, l, 2, 3, or 4.

In some further ments, the sum of m and n is l), l, 2, or 3. In still further embodiments, of each of the above, each RE, R2, R3, R4, R6, R7, and R,8 member is also unsubstituted. {@653} In some embodiments, R1 is hydroxy or a xyt<C1—C3)all<yl group or a physiologically hydrolysable ester of the hydroxyl or hydroxy(Q—C3)alhyl group, In certain embodiments, R1 has the formula begun”, (meow, unnl‘), nl”, - crimson/(0)1210 — :tuicrisioiconmi, —cu(_Ct»rsi(Oiconw. In , crucrrxmconm , these formula, Rm is substituted or unsubstituted bydroearbyl. In other embodiments, R10 is substituted or tituted allgyl, alkenyl, cycloalkyl, heteroallqul, heterocyeloalkyl, heteroalkenyl, heterocycloalkenyl, and cycloalkenyl. In other embodiments, R1‘0 issubstituted or unsubstituted ((:i1-C3)Elll(§’l. In still other embodiments, R10 is methyl, ethyl, propyl, or tritiuoromethyl. In yet other ments, Rm is a tuted or unsubstituted (C1—C3) hydrocarbyl selected from the group consisting of alkenyl, cycloalkyl, heteroalkyl, heterocycloalhyl, heteroalkenyl, eycloalhenyl, and eycloalhenyl. In further of these embodiments, m is 0 and n is 0, l, 2; m is l and n is 0, l, or 2; or m is 2 and n is t), l, or ‘2, {6654} Preferably, in the case where R1 is a carboxy group or physiologically ysable ester thereof, R1 is ----C02H, or --CO21{10 wherein R” is substituted or tituted hydrocerbyl, more preferably, substituted or unsubstituted alltyl, allcenyl, cycloallt’yl, heteroalkyl, heterocyeloulkyl, heteroalkenyl, eyeloalkenyl, and eyeloalkenyl and still more pie ‘erably, substituted or unsubstituted (Cr-Cgalhyl leg, methyl, ethyl, propyl, trifluoroinethyl) or a substituted or unsubstituted (C1-C3) hydroearbyl selected from alkenyl, cycloelkyl, heteroalkyl, cycloulkyl, heteroalkenyl, beterocycloallcenyl, and cycloalkenyl. In further of these embodiments, m is l) and n is I), l, 21; m is l and n is O, l, or 2.; or m is 2 and n is 0, l, or 2. {0055} In thither embodiments that are applicable to any of the above, R2 and R3 are hydrogen, In further oftbese embodiments, in is (l and n is 0, I, or 2; m is l and n is 0, l, or 2; or in is 2 and n is 0, l, or 2. in further of these embodiments, In is (l and n is t), l, 2; m is l and n is 0, l, or 2' or m is 2 and n is 0 l or 2. 9 7 D {8956} in further embodiments that are able to any of the above, R1 is y and at least one of R? and R3 is hydrogen. In still further embodiments of such, both of R2 and R3 are hydrogen. In other embodiments in which R1 is hydroxy, R2 and R3 are independently selected from substituted or unsubstituted (C1—C33alkyll (e.g., methyl, ethyl, propyl), and H. ln r ofthese embodiments, rn is {l and n is 0, l, 2; m is l and n is 0, l, 2; or in is 2 and n is 0, l, 2, {6057} in yet still further embodiments that are applicable to any of the above, R6 is substituted or unsubstituted cyclol'iexyl. Substituen ts for the eyelohexyl include alkyl (e.g., methyl, ethyl), halo (F, Cl, I, Br and preferably F or Cl), and trifluoromethyl. in yet other of these embodiments, m is 0 and n is (l, l, 2; m is l and n is 0, l, 2; or In is 2 and n is t), l, 2. illlliidl In a ularly preferred embodiment, R1 is hydroxy or hydroxy (CVCQaElryl or a physiologically hydrolyzable ester thereof in which the hydrolysis releases the ponding compound wherein R1 is hydroxyl or hydroxy(C;“Cgalkyl, R6 is unsubstituted cyclohexyl, n1 is t) and n is 0, l, or 2; or m is l and n is t), l, or 2 or m is 2 and n is t), l, or 2 in still further embodiments, R2 and R3 are each ll. in some embodiments of such the ester is of the formula 0&0)ng wherein R10 is substituted or unsubstituted l'iydroearbyl, more preferably, substituted or unsubstituted alkyl, ullrenyl, cycloulkyl, heteroalkyl, heterocyeloalkyl, heteroalkenyl, heterocycloalkenyl, and cycloallrenyl and still more preferably, substituted or unsubstituted (Ch—Cgallryl (ego, methyl, ethyl, propyl, trifluoromethyl) or a substituted or unsubstituted (Cng) hydrocarbyl selected from alkenyl, cycloalkyl, alkyl, heterocycloulkyl, heteroallrenyl, heterocyeloalkenyl, and cycoallrenyl. In some further ments, R10 is tituted hydrocarbyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted cycloalkyl, unsubstituted heteroztlkyl, unsubstituted heterocyeloulkyl, unsubstituted heteroalkenyl, unsubstituted heteroeyeloalkenyl, or unsubstituted cycoalkenyl; or unsubstituted (C1--ng)a,llq¢l (eg, methyl, ethyl, propyl, trifluorornethyl) or unsubstituted (C1-C3) hydroearbyl ed from allrenyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heteroalkenyl, heterocycloulkenyl, and cycoalkenyl. {66559} In some embodiments of formula (l), R5 is independently hydrogen, halogen, hydroxy and the physiologically hydrolyzable esters thereof, y and the physiologically hydrolysuble esters thereof, hydroxyl—(C; l(yl and the physiologically hydrolyzuble ~ ~ -~ , , —(_C1—t_t,3)all<oxy, or R71; and R“b and R“ are independently selected troni. "l v ’,7( 17 7‘ "1 esters thereof, hydrogen or 3)alkyl. In some other embodiments, R5 is independently selected from hydrogen or halogen. In certain embodiments, R5 is independently en, n, or hydroxy and the physiologically hydrolyzable esters thereof, In other embodiments, R5 is ndently hydroxy and the physiologically hydrolyzable esters thereof, carboxy and the physiologically hydrolysable esters thereof, yl—(Ci—Cg)alkyl and the physiologically hydrolyzable esters thereof, or —(Cl—C 3)all<o>; y. In yet other ernbodirnents, R5 is hydroxy and the physiologically hydrolyzable esters f. in still other embodiments, R5 is carboxy and the physiologically hydrolysable esters thereof. In other embodiment, R5 is hydroxyl—(Ci— Cgallt’yl and the physiologically hydrolyzable esters thereof. In some embodiments, R5 is — I0 (Ci—C3)a,lkoxy. In some other embodiments, RS is —l“‘lRZORZ1 and R20 and RZ1 are independently selected from hydrogen or (Cy-Cgalkyl. in some embodiments, R5 is l‘tIRZOR21 and R20 and R21 are hydrogen. In still other embodiments, R5 is as bed herein and m is l. {6669} In some embodiments of formula (I), R5 is independently ~(C1~C3)all<oxy or — NR2”R21; and R20 and R2] are independently selected from hydrogen or (Cy-Cflalkyl. In other embodiments of formula (I), R5 is independently hydrogen, halogen, hydroxy and the logically liydrolyzable esters thereof, or carboxy and the physiologically hydrolysable esters thereof. In some embodiments of a (I), R5 is independently hydrogen, hydroxy and the physiologically hy drolyzable esters thereof, carboxy and the physiologically hydrolysable esters thereof, or hydroxyl~(_Cl-C3)allcyl and the pl'rysiologically hydrolyzablet esters thereof, {6961} In some embodiments, R5 is hydroxyl. In certain embodiments, R5 is hydroxyl and m is l. In some embodiments, R5 is COOH. In certain other embodiments, R:3 is COQH and m is l. In some other irnents, R5 is CI‘IZOH. In some embodiments, R5 is CHZOII and m is I, In some other embodiments, R5 is OCH}. In other ments, R5 is OCH; and in is l. In certain embodiments, R5 is (7H3. In certain other embodiments, R5 is CH; and m is l.

In some ments, R5 is F. In certain embodiments, R5 is F and m is 1. In other embodiments, R3 is NHZ In some other embodiments, R3 is NHZ and I‘D is l, {6662} In a particularly preferred embodiment, the compound has a formula selected from the group consisting of: {6663} In furthe ' embodiments? the above compound is prwided as a, physiologiea} 1y hydrolysable ester as described above. {@964} In preferred embodiments of any of the abnve eornpnunds are erally restricted its compounds {@865} In some embodiments, the present invention prevides a corripetmd having the following structure: 13366} In other embodiments, the present invention es a compound having the fniiowing structure: {@967} In some ether embodiments, the t invention provides a compound having the following structure: (0mm {6668} In certain embodiments, the present invention provides a nd having the fniiowing structure: 0 [54 V‘ \an {s,2 <R“)n $3669} In some embodiments, the present invention provides a compound having the following structure: {697%} In other ments? the present invention provides a, compound having the following structure: KyiiW/o “wk/J , v t {6671} In some oth er embodiments? the present ion provides a compound having the following structure: (Rom £3672} In yet other embodiments, the present invention provides a compound having the following structure: {6673} In certain embodiments? the present invention provides a compound having the ing structure: 13374} In other embodiments, the present invention provides a compound having the foilowing structure: {@975} In some embodiments; the present invention provides a compound having the ing structure: {6676} In some other ments, the present invention provides a con'rpound having the following structure: {6677} In yet other enibodinientsa the present invention es a compound having the following structure: N O {6678} In some embodiments, the present invention provides a compound having the foiiowing structure: N O 13379} In other ments, the present invention provides a compound having the fi‘fliowing structure: {@988} In certain embodiments, the present invention provides a compound having the following structure: CH3 . {6981} In some ments, the present invention provides a nd having the , following structure: {@982} In certain other embodiments, the present invention provides at compound having the following structure: it) N342 {6683} In some embodiments, the present invention provides a compound having the ing structure: {@984} In some ether embodiments, the present invention provides a compound having the foiiowing ure: 13385} In yet other embodiments, the present invention provides a, compound having the foitewing structure: {66%} In some embodiments, the t in ventiotr provides a cempound having the foliowing structure: it OH {@987} in other embodiments, the present invention provides a compound having the following structure: 13388} in some other embodiments, the present invention provides a pharmaceutical composition comprising a compound, as set forth above, with a pharmaceutically acceptable ent. in yet other embodin'ients, the present invention provides a pharmaeeutical composition comprising a pharmaceutically acceptable salt of a compound, as set forth above. ln other embodiments, the present invention provides a ment for ng a ll} e or condition as set forth herein wherein the rnedicarnent includes a compounds as set forth herein. {6689} nds of the invention may contain one or more tric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereonieric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the inventive compounds. {$6596} Compounds of the invention include any diastereoisomers or pairs of any enantiomers. Diastereomers for example, can be obtained by fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof. The enantioniers may be separated into dual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent. {8991} Alternatively, any enantiomer of such a compound of the invention may be obtained by stereospecific synthesis using optically pure starting materials of known configuration. {@992} The compounds of the present invention may have unnatural ratios of atomic isotopes at one or more of their atoms, For example, the compounds may be radiolabeled with isotopes, such as tritium or carbon—l4. All isotopic variations of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention #3693} The instant compounds may be isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Such acids may include hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic and the like. in addition, certain compounds containing an acidic tunction can be in the form of their inorganic salt in which the counterion can be selected from sodium, ium, m, calcium, magnesium and the like, as well as from organic bases. The term "pharmaceutically able salts" refers to salts prepared from pharrnaceutically acceptable non~toxic bases or acids including inorganic bases or acids and organic bases or acids, {66%} The invention also encompasses prodrugs of the present nds, which on administration undergo chemical conversion by metabolic processes before becoming active cological substances. In general, such gs will be derivatives of the t compounds that a e eadily convertible in vivo into a functional nd of the invention.

Conventional procedures for the selection and preparation of suitable prodiug derivatives are bed, for e, in "Design of Prodrugs", ed. l-l. Bundgaard, Elsevier, 1985. The ion also encompasses active metabolites of the present compounds, {@6595} Some of the compounds described herein contain olefinic double bonds, and unless specified ise, are meant to include both E and Z geometric isomers. {@896} Some of the compounds described herein may exist with ent points of attachment of en, referred to as tautorners. Such an example maybe a ketone and its enol form known as ketowenol tautomers, The dual tautomers as well as mixture thereof are encompassed by the inventive as. 4. High throughput FAAH inhibition Assays {@897} The assays for compounds described herein are amenable to high throughput screening. Preferred assays thus detect binding of the inhibitor to FAAH or the release of a reaction product (e.g fatty acid amide or ethanolamine) produced by the hydrolysis of a substrate such as oleoylethanolamide or anandarnide. The substrate may be labeled to facilitate detection of the released reaction products. High throughput assays for the presence, absence, or quantification of particular reaction products are well known to those of skill in the art. Thus, for example, US. Patent No 5,559,410 discloses high hput screening methods for proteins, and US. Patents: No. 220 and No. 5,54l,(}61 disclose high throughput methods of screening for 1igand/antibody binding. {96598} in addition, high throughput screening systems are commercially available (see, e.g., : Corp, Hopkinton, MA; Air nical industries, Mentor, OH; Beckman instruments, Inc. Fullerton, CA; Precision Systems, lnc., Natick, MA, etc). These systems l \ lly te entire procedures including all sample and reagent pipettin g, liquid dispensing, ti nied incubations, and final readings of the microplate in or(s) appropriate for the assay. 'l‘hese configurable systems provide high throughput and rapid start up as well as a high degree oftlexibility and customization. The manufacturers of such systems provide etailed protocols the various high throughput. Thus, for example, Zymark Corp. provides technical bulletins describing ing systems for detecting the modulation of gene transcription, ligand binding, and the like.

. Mechanism of Activity {6&9} Peripheral cannahinoid receptors exert a powerful inhibitory control over pain initiation, but the endogenous cannabinoid signal that normally engages this intrinsic 2 \ analgesic mechanism is unknown. it has been found that nd UR8937, set forth in the Examples below, which is a novel peripherally restricted inhibitor of fatty acid amide hyd ‘olase (FAAH), the enzyme responsible for the degradation of the endocannabinoid anandamide, suppressed FAAH activity and sed anandamide levels outside the central nervous system (CNS). 1 t is worth noting that UR8937 was {mind to be surprisingly b.) U: susceptible to a transport system mediated extrusion from brain. Despite a surprising relative inability to access brain and spinal cord, URB‘B? ated oral responses tive of persistent pain in rodent models of inllan'rmation and peripheral nerve injury, and suppresses noxious stimulus—evoked neuronal activation in spinal cord regions implicated in nociceptive processing. Cl}, receptor blockade prevents these ef ects. The results indicated 'VJ that anandamide—mediated signaling at peripheral CB; receptors ls the ission of pain information to the CNS. Accordingly, relatively l3rain~impermeant FAAH inhibitors, which strengthen this gating mechanism, offer a net ’ ch to pain therapy (see, US. ional Patent Application Serial No. til/368,500, tiled on July 28, 2010, which is incorporated herein by reference in its ty for all purposes, and specifically with respect to methods of assaying EAAH inhibitors for their biological and pharmaceutical properties, and the pharmacological properties of peripherally restricted FAAH tors in general). {8138} Pain perception can ' e effectively controlled by neurotransmitters that operate Within the CNS. This modulation has been well characterized in the dorsal horn of the spinal cord; where impulses carried by nociceptiye (pairr~serrsing) fibers are processed before they are transmitted to the brain. in on to these central isms, intrinsic control of pain transmission can occur at terminals of afferent nerve fibers outside the CNS: One prominent e of peripheral regulation is provided by the endogenous opioids, which are ed from activated immune cells during inflammation and inhibit pain initiation by interacting if} with opioid receptors localized on sensory nerve endings. {6161} A peripherally restricted FAAH tor is a FAAl—l inhibitor that does not y enter the CNS and thus principally intenupts anandamide deactivation only in peripheral tissues. Despite this restricted range of action, peripherally restricted FAAl—l inhibitors cause marked an tinociceptive effects in rodent models of acute and persistent pain, which are ted by C81 cannabinoid receptor blockade. These findings indicate that inhibition of peripheral FAAH ty magnifies an endogenous analgesic mechanism which regulates the transmission of emerging ptiye inputs to the spinal cord and the brain. The mechanism is likely to be mediated by anandamide or another endo enous fatty acid amide cannabinoid. {6162} Peripheral anandamide signaling is thought to serve as a diffuse paracrine system that modulates the intensity of pain stimuli as they arise in damaged tissues. For e, s generated by inflammation and neural injury can trigger the local release of anandaniide. r, membrane depolarization and activation of TRPV—l channels each stimulates anandamide production in cultures of sensory neurons; while activation of the pro— inflammatory or, ike receptor 4, causes a similar effect in macrophages. These signals, and others yet to be identified, may contribute to the elevations in peripheral anandamide documented in animal models of spinal nerve injury and inflammation as well as in painful human conditions such as complex regional pain syndrome and arthritis. Also, though ularly abundant in the brain, CB} receptors are broadly distributed throughout mammalian tissues and organs. in particular, they are expressed in large—sized y sensory neurons and are transported to peripheral nerve endings, Where they may be both necessary to maintain normal pain thresholds and sufficient to exert marked antinociceptive effects. CB; receptors on pain—sensing als may mediate the analgesic actions of locally produced anandamide, and might also be implicated in the anti—inflammatory activity of this lipid mediator through their inhibitory influence on the release of excitatory neuropeptides.

Nevertheless, it is reasonable to assume that other cannabinoid and cannabinoid-like receptors also contribute, directly or indirectly, to anandarnide signaling in response to injury, Two likely candidates are C33 receptors, which can be activated either by anandamide, or :3- AG, and typed some proliferator—activated receptors, which are activated by PEA and (J! other lipid—derived mediators. These receptors and their endogenous ligands are present in peripheral sensory neurons and immune cells, and have been implicated in the modulation of naciception and inflammation. lli‘ltlftl Mutant mice in which FAAl—l is selectively deleted in non—neuronal cells, but is preserved in peripheral and central neurons, display a striking phenotype in which normal ll) nociceptive transmission is accompanied by reduced responsiveness to proinflammatory triggers. A possible explanation for this finding, which is tent with the present results, is that the signaling activity of anandarnide at peripheral nociceptors is regulated by FAAH localized to the nociccptors lves, rather than to neighboring non—neural cells, This is consistent with the observation that peripheral axotomy s FAAH sion in large-v l5 sized sensory neurons, a se that is expected to expand the colocalization of FAAl-l with C31 receptors, {6164} Direct—acting ts of opioid ors exert nd analgesic effects in animal and human experimental pain models. The results set forth herein show that is possible to achieve significant sia also by magnifying the activity of an anandarnide—based mechanism involved in maintaining nociceptive stasis, The present invention provides methods for the intrinsic control of pain which can be exploited eutically. The present invention also provides methods for developing effective .esics largely devoid ofcentral side effects, The present invention t‘urtl'rer provides effective analgesics largely devoid of central side effects. l\) Ur 6. Methods {6195] The cornpounds and compositions set forth herein are useful for treating disorders in which peripheral FAAH inhibition is desirable, Such disorders include, but are not limited to, pain, inflammation, auto-immune disorders, obesity, eating disorders, and appetite control, metabolic disorders, liver steatosis and asthma. Certain compositions and compounds set in») , ~—.- forth herein offer a significant advantage over peripherally restricted FAAH inhibitors, such as the compound URBQST’, which may form a toxic uinone moiety h liver oxidation of the parauhydroxybiphenyl moiety.

DJ ,m t../ {@186} In some embodiments, the present invention provides s of treating disorders including, but are not limited to, pain, inflammation, auto—immune disorders, obesity, eating disorders, and appetite control, metabolic disorders, liver steatosis and asthma, wherein the methods includes administering to a patient in need thereof a ceutical ition having a compound as set forth herein. In other embodiments, the present invention provides methods of treating pain, wherein the methods includes administering to a patient in need f a, pharmaceutical composition having a compound as set forth herein, in some other embodiments, the present ion provides methods of treating inflammation, wherein the methods includes administering to a patient in need thereof a pharmaceutical composition l0 having a compound as set forth herein. In some embodiments, the present invention provides methods of treating an auto—immune disorder, n the methods includes administering to a t in need thereof a pharmaceutical composition having a compound as set forth , in some other embodiments, the present invention provides methods of treating obesity, wherein the methods includes administering to a patient in need thereof a pharmaceutical composition having a compound as set forth herein. in yet other ments, the present invention provides methods of treating an eating disorder, wherein the methods includes adminis cling to a patient in need f a pharmaceutical composition having a. compound as set forth herein. in still other ments, the present invention provides methods of treating appetite l, wherein the methods includes administering to a patient in need thereof a pharmaceutical composition having a nd as set forth herein, in certain embodiments, the present ion es methods of treating a lic disorder, wherein the methods includes administering to a patient in need thereof a pharmaceutical composition having a compound as set forth herein. In some embodiments, the present invention provides methods of treating liver steatosis, wherein the methods includes administering to a patient in need thereof a pharmaceutical composition having a compound as set forth herein. In some other embodiments, the t invention provides methods of treating asthma, n the methods includes administering to a patient in need thereof a, pharmaceutical composition having a compound as set forth herein.

{MN} The present invention also sets forth s wherein FAAH inhibitors greatly accelerate the rate and quality of wound healing. The term wounds as used herein is exemplified but not lirnited to skin injury. Other types of , as contemplated herein, can involve damage or injury to an internal tissue or organ such as the lung, kidney, heart, gut, tendon or liver. The wounds may be acute (such as, but not limited to, penetrative injuries, burns, nerve damage or elective surgery) or c (such as, but not limited to, diabetes, decubitus ulcerations) or occur in healing-compromised individuals (such as, but not d to, elderly individuals, persons treated with GCs, the malnourished). The wounds may result from trauma, overuse of tissues, surgery, or e, ing injurie‘ to l organs, the extremities, and skin. in some embodiments, the compounds and compositions set forth herein have wound—healing properties. In certain embodiments, the compounds and ositions set forth herein are useful for accelerating the healing of surgical wounds, ic ulcers and, or, pressure ulcers. {6168} Accordingly, in some embodiments, the present invention provides a method of accelerating the rate or the quality of healing of wounds or tissue es in a t in need if} thereof, said method comprising administering to the subject a therapeutically effective doses of a globally acting and/or erally restricted FAAl—l inhibitor. For instance, the g can cut the time it takes a wound to heal by 25%, 4' %, 69% as compared to an untreated or control wound (eg, l, 2, 3, 4, 5, o, '7, S or 9 days less than a control or untreated wound).

For instance, the improved quality of healing can provide for a greater re ,ention of function in the wounded tissue or site of injury. in some embodiments, the administering can he topical, local, systemic, oral, subcutaneous, transdermal, rectal, by inhalation, intranasal, intravenous, intramuscular or intra—peritoneal. in any of the above embodiments, the wound or tissue injury can be an acute wound or injury or may be ed from the group consisting of a penetrative , a burn, neiye damage, a surgical wound, an injury to an internal organ, a skin injury. in yet more embodiments, the wound or tissue injury can be an acute, chronic, or recurring condition selected from the group consisting of vascular or tissue injurie‘ associated with metabolic diseases (eg, diabetes, hyperuricemia, osis‘), ' une conditions (eg, vasculitis, hypodermis gangrenosum, etc..), degenerative lesions (eg, decubitus,diseases of the connective tissue such as rheumatoid arthritis, systemic lupus N U: eiythematosus, seieroderma, mixed connective tissue disease, etc”), lesions caused by infectious diseases (e.g., viral, bacterial, fungal, mixed), cancer lesions (squamous cell carcinomas, melanomas, sltin metastases, etc), and hen'iatological lesions (cryoglobulinernia, thrombocytosis, proliferative disorders, etc). The wound or injury can be a penetrating wound or injury to an internal organ. The injured organ may include, but not be limited to, the liver, intestine, stomach, heart, lung, pancreas, kidney, eye, ear, muscle, or bladder. in some further embodiments of such, the FAAH inhibitors are stered to post—surgical patients to promote wound healing. 13199} in still other embodiments, the FAAH inhibitor as set forth herein are formulated for topical administration as a cream, gel, cataplasm, , liniment, milk, lotion, emulsion, 2012/051478 spray, collyrium, drops, powder. The FAAH inhibitor can also be incorporated into a ng or surgical implant (cg, stent, artificial replacement for ajoint, suture). in other embodiments, the FAAH inhibitor is formulated for systemic stration as an injectafble solution or a, suppository or for oral administration. The EAAH inhibitor can also be ated as a as suspension, syrup, tablets, capsules, or pill. ltllllll in other ernhodimen ts, the ts to be treated by the methods set forth herein are chronic wound patients (cg, subjects with diabetes or pressure ulcers l'bed sores’] to whom the treatment may be given systemically or' locally). In other embodiments, the administering is prophylactic. For ce, an overuse injury to muscle or tendon may be prevented, if) elayed or avoided by administering a FAAH inhibitor to the subject during and/or before the period of overuse, in some embodiments, the invention provides methods wherein stering the nds and compositions, as set forth herein, results in a rate of healing which exceeds the rate at which an overuse injury would heal in the absence of the administration of the compounds and compositions set forth herein. 7. Pharmaceutical compositions itillll The invention also provides pharmaceutical compositions of the above peripherally restricted FAAH inhibitory compounds, The term ”composition", as in pharmaceutical composition, is intended to encompass a t comprising the active ient(s), and the inert ient(s) that make up the carrier, as well as any product which s, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a con'rpound of the present invention and a pharmaceutically acceptable carrier. The term i\.) U: “pharmaceutical composition” indicates a ition suitable for pharmaceutical use in a, subject, including an animal or human. A pharmaceutical composition generally ses an effective amount of an active agent and a pharmaceutically acceptable carrier. {till 2} The compositions include itions suitable for oral, rectal, topical, parenteral (including aneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary 'vJ C) (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend in part on the nature and severity of the conditions being treated and on the nature of the active. ingredient, An exemplary route of administration is the oral route.

The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well—imown in the art of pharmacy.

DJ \ {@133} in practical use, the compounds of the invention can be ed as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation d for administration, e.g,, oral or parenteral ding intravenous). in preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, vatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. {6114} Because of their ease of administration, s and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by rd aqueous or nonaqueous techniques.

Such compositions and preparations can contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 12 percent to about 60 percent of the weight of the unit, The amount of active compound in such therapeutically useful compositions is such that a. therapeutically effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray, {6115} The tablets, pills, capsules, and the like may also contain a binder such as gum anth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; ’ disintegrating agent such as corn starch, potato starch, alginic acid; a ant such as N U‘: magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin, When a dosage unit form is a capsule, it may contain, in on to materials of the above type, ' liquid carrier such as a fatty oil. el Various other als may be present as coatings or to modify the al form of the dosage unit. For instance, s may be coa ,ed with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, e as a sweetening agent, methyl and propylparabens as preservatives, a dye and a ing such as cherry or orange flavor.

To prevent breakdown during transit through the upper portion of the GI tract, the composition may be an enteric coaed formulation, {@117} With respect to formulations with respect to any variety of routes of administration, methods and lormulations for the administration of drugs are disclosed in Remington’s Pharmaceutical es, l7th Edition, (Gennaro et al. Eds Mach Publishing Co, l985).

Remington‘s Pharmaceutical es, o AR ed. Zlitli edition, 2000: Williams & s PA, U SA. ltllllil Solid pharmaceutical exeipients suitable for use with the present ion include starch, cellulose, tale, glucose, lactose, e, gelatin, malt, rice, flour, chall<, silica gel, magnesium te, sodium te, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from water, ethanol, l \ glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (erg, peanut oil, soybean oil, mineral oil, sesame oil, and the like).

Preferred liquid rs, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols. ll. Administration l 5 lull?“ The compounds set forth herein can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (eg, transdermal, intranasal or by suppository) or parenteral (eg, intramuscular, intravenous or subcutaneous).

Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate 2 \ composition and are comprised of, in general, a nd as set forth herein in combination with at least one ceutically acceptable excipient. Acceptable excipients are non—toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient.

Such excipient maybe any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is lly available to one of skill in the art.

M U: {9129} The compounds of the invention may also be stered erally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as ypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereofin oils. Under ordinary conditions of storage and use, th se preparations contain a preservative to prevent the growth of microorganisms.(D (14‘ 131le The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous ation of sterile injectable solutions or dispersions. in all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. it must be stable under the conditions of manufacture and storage and must be preserved against the inating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg. glycerol, propylene glycol and liquid polyetl'rylene glycol), suitable mixtures thereof, and vegetable oils. {0122} The compounds of the invention can be effective over a wide dosage range. For example, in the ent of adult humans, disages from about 10 to about lOOO mg, about l00 to about 500 mg or about 1 to about loll rng may be , Doses ofthe 0.05 to about 100 mg, and more preferably from about 0.1 to about lOO mg, per day may e used, A most preferable dosage is ' bout 0.l mg to about 70 mg per day. in choosing a regimen for patients, it may frequently be necessary to begin with a dosage of from about 2 to about 70 mg per day if) and when the condition is under control to reduce the dosage as low as from about 0.1 to about 10 mg per day. For example, in the treatment of adult humans, dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used. The exact disage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge. {0123} Generally, the compounds of the present invention can be dispensed in unit dosage form comprising ably from about 0.1 to about lOO mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage, Usually, dosage forms suitable for oral. nasal, ary or transdermal administration se from about 0.001 mg to about 100 mg, preferably from about 0.01 mg to about 50 mg of the compounds admixed with a aceutically acceptable carrier or diluent. For e and use, these preparations preferably contain a preservative to prevent the growth of microorganisms. {0124} Administration of an appropriate amount the ate compound may be by any means known in the art such as, for example, oral or rectal, parenteral, intraperitoneal, enous, subcutaneous, subderinal, intranasal, or intram uscular. in some embodiments, administration is transdermal. An appropriate amount or dose of the candidate compound may be determined empirically as is known in the art. An appropriate or therapeutic amount is an amount sufficient to provide the desired therapeutic effect (cg, treat or alleviate pain or treat or red uee inflammation). The candidate compound can be administe ed as often as ’equired to alleviate the pain or reduce the mation, for example, hourly, every six, eight, twelve, or eighteen hours, daily, or weekly. in some of the s set forth herein, the methods includes stering a therapeutically effective amount ofa compounds which is set forth herein. {@125} Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the packaged nucleic acid suspended in diluents, such as water, saline or PEG 400; (b) capsules, s or tablets, each containing a ermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate ; and (d) le emulsions. Tablet forms can include one or more of lactose, sucrose, tol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, n, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, tillers, s, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharrnaceutically compatible carriers, Lozenge forms can comprise the active ingredient in a flavor, e.g., e, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucr "ise and acacia emulsi‘rns, gels, and the like containing, in addition to the active ingredient, rs known in the art {6126} lnjection solutions and suspensions can be prepared from sterile powders, granules, and s of the kind previously described. ations suitable for parenteral administration, such as, for example, by intraarticular (in nts), intravenous, intramuscular, errnal, intraperitoneal, and subcutaneous routes, include aqueous and non—aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non—aqueous sterile suspensions that can include suspending , solubilizers, ning agents, stabilizers, and preservatives. {6127} With respect to transderinal routes of administration, methods for transdermal administration ofdrugs are disclosed in Remington's Pharmaceutical Sciences, Gennaro AR ed. 20th edition, 2000: ms & s PA, USA. Dermal or skin patches are a preferred N Y): means for transdermal ry of the compounds of the invention. Patches preferably provide an absorption enhancer such as DMSO to increase the absorption of the compounds.

Other methods for transderrnal drug delivery are disclosed in US Patents No. 0l2, 6,26l ,595, and 6,26l,595. Each of which is incorporated by reference in its entirety. {9128} Preferred patches include those that control the rate of drug delivery to the skin.

Patches may provide a variety of dosing systems including a reservoir system or a monolithic system, respectively. The reservoir design may, for example, have four layers: the adhesive layer that directly contacts the skin, the control membrane, which controls the diffusion of drug molecules, the reservoir of drug molecules, and a water—resistant backing, WO 28570 El3129l Such a design delivers uniform amounts of the drug over a specified time period, the rate of delivery has to be less than the saturation limit of different types of Skill. {813%} The monolithic design, for example, typically has only three layers: the adhesive layer, a polymer matrix containing the compound, and a waterproof backing. This design brings a saturating amount of drug to the skin. Thereby, delivery is controlled by the skin.

As the drug amount decreases in the patch to below the saturating level, the delivery rate falls. {6131} Compounds of the invention may be used in ation with other compounds of the invention or with other drugs that may also be useful in the treatment, tion, l0 suppression ofpain, intlarnn'iation, or immune disorders. ln one embodiment, the second drug is not a FAAH inhibitor and is ed toward the same disorder as the FAAH inhibitor.

Such other drugs may be administered, by a. route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the invention. When a compound of the invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form ning such other drugs and the nd is preferred.

When used in combination with one or more other active ingredients, the compound ofthe present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ients, in addition to the compounds disclosed ahove. £3132} in the pharmaceutical compositions of the present ion for oral, sublingual, subcutaneous, intramuscular. enous, transderinal, local or rectal stration, the active principle, by itself or in association with another active principle, can be administered to animals and humans in unit forms of administration mixed with conventional pharmaceutical carriers. The appropriate unit forms of administration e oral forms such as tablets, gelatin capsules, powders, granules and ons or suspensions to be taken orally, sublingual and buccal forms of administration, aerosols, implants, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms ot'adrninistration and rectal forms of administration. {$133} in othe embodiments, the pharmaceutical compositions of the present invention, the active principle or active principles are generally formulated in dosage units. The dosage unit contains from 0.5 to } mg, advantageously from 1 to Silt} mg and preterahly from 2 to 209 mg of FAAH inhibitor per dosage unit for daily administration. {01.34} In some embodiments, the present invention sets forth methods wherein the methods include administering a pharmaceutical composition having a dosage unit of a compound which is set forth herein, 1n other ments, the present invention sets forth pharmaceutical compositions having a dosage unit of a compound which is set forth herein.

The dosage unit contains from 0.5 to 1000 mg, advantageously from 1 to 500 mg and preferably from 2 to 200 mg of a compound which is set forth herein In n embodiments, the dosage unit is for daily administration. in othe ' embodiments, the dosage unit is for weekly administration. In still other ments, the dosage unit is for monthly administration. in still other embodiments, the dosage unit is for an irregular administration. 1n some embodiments, the dosage unit includes 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1,, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7., 1.8, 1.9., 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 10.0, 11, 12, 13,14,15,16,17,18,l9, 20, 21, 22, 23 24, 25, 26, 2'7, 28, 29, 30, 31, 32, 33, 34 35, 36 37 38, 3"), 40, 41, 42,43,414, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 11,5, 120, 1215, 130, 135, 140, 145, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, (350, 700, 750, 800, 850, 900, 950, 975, or 1000 mg ofa compound which is set forth herein. 9. Methods of Treatment 3. Control of Pain 1111351 In some embodiments, the compounds set forth herein may be administered to al1eviate or treat pain in a subject. The treatment may be prophylactic or t1'ierapeutic. The treatment may be administered to a human subject. The compounds and compositions of the ion maybe administered solely for the purposes of reducing the severity or frequency or extent of pain. The ent may be administered in a combination therapy with another pain er or nf1ammatory agent. In some embodiments, the pain can be a neuropathic pain selected from the group consisting of post trigeminal neuralgia, neuropathic low back pain, peripheral or polyneuropatliic pain, complex regional pain me (causalgia and reflex sympathetic dystrophy), diabetic neuropathy, toxic neuropathy, and chronic neuropathy caused by chemotherapeutic agents. 1n other embodiments, the pain is renal and liver colic pain or iibromyalgia. In some neuropathic pain embodiments, the primary lesion or dysfunction of the nervous system is caused by a mechanical injury to a nerve of the subject. 1n a further embodiment, the mechanical injury is due to compression of a nerve, transection of nerve, causalgia, spinal cord , post surgical pain, phantom limb pain, or scar formation in the subj ect. {01361 In other embodin'ients, the pain is a pain caused by inflammation or injury ofa . 1nf1ammatory pain develops in response to tissue damage occurring from the s stimuli. In se to the tissue injury, cytokines and other mediators are released which strengthen nociception. As a result primary hyperalgesia (increased sensitivity to pain) occurring in the area of injury and a secondary hyperalgesia occurring in the tissue surrounding the injury ensue. The hyperalgesia suhsides with the inflammation as the tissue is healed. In some r embodiments, the inflammation is associated with pulmonary edema, kidney stones, minor injuries, wound healing, skin wound healing, tis, candidiasis, lumbar spondylanhrosis, lumbar spondylartl'irosis, vascular diseases, migraine headaches, sinus headaches, tension headaches, dental pain, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin’s disease, sclerodoma, rheumatic “ever, type i diabetes, type II diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Beheet’s syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after , or myocardial ischemia, or osteoarthritis. 1). Control of lnl‘lammatinn {@137} in some ir ents, the compounds of Formula l may he administered to alleviate inflammation in a subject. The treatment may be prophylactic or therapeutic. The treatment may be administered to a human subject. The nds and compositions of the invention may be administered solely for the purposes of reducing the ty or frequency or extent of the mation; The treatment maybe administered in a, combination therapy with r pain reliever or anti--inflammatoi,4r agent. lilo Examples 2 \l 21. Example l {@138} s for Screening Centipeunrls fer Antineeiecptive Activity: s for screening FAAH inhibitors for an antinociceptive effect are well known to one of ordinary in the art. For instance, the test compounds can be administered to the subject animals in the mouse hot—plate test and the mouse formalin test and the nociceptive reactions to thermal or chemical tissue damage measured, See also U.8. Patent No. 6,326,156 which s methods of screening for antinoeiceptive activity. See Cravatt et al. Proc. 1 or]. Acad. Sci.

USA. l 49376 (200l). h. Example 2 {8139} The Pharmacological Profile ofPeripherally Restricted FAAH Inhibitors: U») , {@146} Materials and Methods include the ing {6147” Enzyme assays: Standard FAAH and rnonoacylgiycerol lipase assays were conducted as described (Clapper, JR. et al., A second generation of carbamate—hased fatty 4i.) acid amide hydrolase inhibitors with improved activity in VlVO. ChemMedChem 4 (9), 1505-- lS l 3 (2009); King, AR, et ai,, URBoOZ inhibits n'ionoacyl glycerol lipase and selectively blocks Z—arachidonoyl glycerol degradation in intact brain slices. Chem Biol 14- (l 2), 1357' 1365 (2007),), using as ates aiia,ndainide (a gift of the National institute on Drug Abuse) and 2—oleoyl—sn—glycerol (Nu—Check Prep, Elysian, MN), respectively. {6142} Tissue analyses: Tissue extractions and liquid chromatograpl'iy/nrass spectrometry analyses of endocannabinoids was performed as described (Astarita, G, Ahmed, F & l’iomelli, D, identification of biosynthetic sors for the endocannabinoid anandamide in the rat brain. J Lipid Res 49 (l), 48—.37 (2008)). {8143} Carrageenarninduced inflammation in mice: Peripheral inflammation was d by iritraplantar (irpiy) ion of the polysaccharide ageenan (ipl. l% weight vol"E in sterile water, 20 3.1L) into the left hind paw of male CD1 rnice. Carrageenarntreated mice received compound 1 (it), 30 ing/lrg, per os) just before intraplantar injection of carrageenan. {8144} oral tests: Nocii‘ensive responses were measured elicited by intraplantar injection of carrageenan in male CDi l.,t_iVerme, l La Rana, 8,, Russo, R Calignano, A., & Piornelli, D, The search for the paimitoylethanolamide receptor. Life Sci ‘7’!" .1 .1 (14), 1685—1698 (2mm } Chemicals [3 l-l]—Anandarnide was purchased from American Radiolabeied Chemicals, lnc. (St. Louis, MO), Anandamide, [Elia—anaiidanride and PEA were synthesized in the laboratory(Fegley, D. et 1211., Characterization of the fatty acid amide hydrolase tor cyclohexyl carbarnic acid 3‘—carbanioyl—biphenyhfa—yl ester (URBSW): effects on anandamide and oleoylethamilamide deactivation. J Pharmacol Exp Ther 3 l3 (1,"), 352—358 (2005)), N— exyl biphenyl—3—ylacetarnide was donated by Kadmus Pharmaceuticals inc, {6146} Animals Male Swiss Webster and CDl mice es River, 20—30 g) were used, Mice were group—housed in standard cages at room temperature on a l2112 h iight:dark cycle with unlimited access to water and rd chow pellets, Wistar rats were typically used for the FAAH studies. All experiments met the National institutes of Health guidelines for the care and use of laboratory animals, were approved by the institutional Animal Care and Use Committee of the University of California, lrvine, and the University of Georgia, Athens, and were in compliance with the European Community Council Directive 86 (609) EEC and the experimental protocol was carried out in ance with ltalian regulations (Dis 116/92). {8147} Tissue extractions Mice were sacrificed with isoflurane and tissues were collected and immediately frozen in liquid en Frozen s v ’ere weighed and homogenized in methanol (_ l ml.) containing HQ—anandamlde, l)l3A, l""12H3]~2~AG, and ,z‘v’écyclohexyl biphenyl-B--ylacetarnide as internal standards. Analytes were extracted with chloroform (2. vol) and washed with water (l vol). Organic phases were collected and dried under nitrogen.

For other es the organic extract was fractionated by open—bed silica gel column chromatography, as dest:i‘lbed(Cadas, ll, dl so, E, 8; Piomelli, ll, Occurrence and biosynthesis of endogenous cannabinoid precursor, N--arachidonoyl phosphatidylethanolamine, in rat brain. J Neurosci l7 (4}, l226—l 242 }. Brietly, the extract was dissolved in chloroform and loaded onto small glass columns packed with Silica Gel G ((3025; 230 40f.) Mesh AS'l‘lVl; an, n, NJ). Anandamide, PEA and 2--AG were eluted with chloi'oform/niethanol (9:1, vol/vol). {614$} Scrum extractions Trunk blood was collected from decapitated mice, allowed to clot and placed on ice, The clotted blood was centrifuged at l8,000 x g for it) min at 4"‘C and l 5 the serum was transferred to glass vials and diluted with distilled water to 1 ml... Proteins were itated with ice~cold acetone (_ 1 ml...) containing N—cyclohexyl biphenyl~3~ ylacetamide as an internal standard, and the precipitate was removed by centrifugation at 30310 X g for l0 min at 49C. The samples 1 etc dried under nitrogen to remove acetone, and extracted with chloroform/methanol as described above, 0 {6149} Drug preparation for in viva experiments Drugs were dissolved in polyethylene glycol 400/Tween—8ll/saline (1/ l/18; by volume) and administered by ip. (S—l 0 mL—lrg'j‘).

Alternatively, drugs were dissolved in polyetl'iylene glycol een—till/saline ( lO/l 0/80; by volume) and administered per os (l l) and 30 mgr/Kg). {6156} Behavioral tests Paw ertlema was induced in mice by injection into the right hind paws of St} uL of sterile saline containing 1% h—carrageenan. Paw volumes were measured using a plethysrnometer (Ugo Basile, Milan, . Vehicle or compound 1 (l0 and 30 mg kg, per os) were administered immediately before carrageenan. The increase in paw volume (mL) was evaluated as the difference between the paw volume measured at each time point and the basal paw volume measured ately before carrageenan ion. is») , ~—.- Mechtmicai hyperaigesia — Mechanical hyperalgesia was determined by ing the latency in seconds to withdraw the paw away from a constant mechanical pressure exerted onto the dorsal surface. A l5 0' calibrated glass cylindrical rod (diameter ll) mm) chambered to a cortical point (diameter : 3 mm) was used to exert the mechanical force. The weight was suspended ally n two rings attached to a stand and was free to move vertically. A cutoff time of lSG s V’ES used. Withdrax 'al old was measured on the inflamed ipsilateral paw at different time points after oral drug administration. Six mice were included in each experimental group. 'l‘ln‘ee determinations were made on each mice resulting in a total of 18 measurements. l hutgzzeraigesia was assessed as described (:l-lai'greaves, K, Dubner, R, Brown, F Flores, C., & Joris, 3., A new and ive method for measuring thermal ption in cutaneous hyperalgesia. Pain 32. (l), 77-88 (l988)), ing the latency to withdraw the hindpaw from a focused beam of radiant heat (thermal intensity: infrared 3.0) applied to the plantar surface using a plantar test apparatus (Ugo Basile, ltaly).

The cutoff time was set at 30 s, Withdrawal latency was measured on the inflamed ipsilateral pat ' at different time points after oral drug administration. Six mice were included in each experimental group. Three determinations were made on each mice resulting in a total of 18 rernents. {615]} Statistical Analyses: ,esults are expressed as the mean :t: sent. Statistical significance was determined by Students 5 test, one—way, or two—way analysis of variance (ANOVA) followed by Bonferroni post her: test when appropriate. Post hoc comparisons that did not meet the equal variance assumption were corrected by fractional adjustment of the degrees of freedom. Analyses were performed using SPSS statistical software ( n 17.0; SPSS incorporated, o, lls, USA). {6152} General analytical methods: y’is analyses of compounds were run on a Waters ACQUI’l‘Y UPLC/MS instrument ting of a SQD Single Quadropole Mass Spectrometer equipped with an electrospray ionization interface and a pliotodiode array detector. The analyses were performed on an ACQUITY UPLC BEH (318 column (50x2.1mmll), particle size 1.77pm) with a VanGuard BEH Cl8 pre—column (Slemmli‘L E\) Ur particle size lining). The mobile phases were 10 mM ammonium acetate at pH 5 adjusted with acetic acid (A) and 10 mM ammonium acetate in acetrmitrile—water (95:55) at pH 5 (B).

Electrospray ionization in positive and negative mode was used in the mass scan range l00~ SlilDa. £3153} NMR experiments were run on a Bruker Avance lit 400 system (400.13 MHZ for 3 0 1H), equipped with a T331 inverse probe and Iii—gradients. Unless indicated, a were acquired at 390 K using deuterated diniethylsulfoxyde SO"6£6) and deuterated chloroform (CDCh) as solvents. c. Example 3 {(3154} Synthesis of i3—(3—earhamoylphenyl)~5~hydroxy—phenyl} N—eyclohenyiearhaina‘te (Compound 1). nd 1 was synthesized as described in the following Scheme: 11) -1‘12 3) t—BUONa K2003 BnOH F NBr mm»_ E3110 on1‘1 (3/3/31:Pd GAGE BnO \J I: anh. DMF ‘ \ EGME.H20, 3:1 NH: r ér den 1 11 HE C) Pct/C 10% ‘\ 1 d) chexNCO cyclohexene HO ‘ / _O (2116? :3“, E dioxane, 80°C 0 N H2 1 O H 13/V Compound 1 {@155} Step l: l,3—diher1zyloxy—5—bromo—henzene (11): In a 1L round bottomed flask, U1 equipped with a magnetic stirrer and under nitrogen here: 200 mL of anhydrous diniethylformamide (DMF) were loaded followed by the on oi‘t—BuflNa (5 eq., 207.3 mmol, 199 g) and, subsequently, henzyl alcohol (5 eq., 207.3 mmol, 21.3 11111). After 10 min, I (l eqw =4] .5 mmol /l 8 1111‘1 was added and the reaction r11ixtu1e was heated at 9{‘1".C After 311, the reaction mixture was cooled to room temperature and slowly erred, under l0 stirring in a 3L flask containing 600 mL of water and 500 mL olz’; o1: 1-11 ,-.._r :1? LACE-1 (M'l'BE). After 3{‘1 min, the organic phase was separated, washed with water (400 1111;) and dried over Na:$04. Evaporation of the solvent gave 11 as yellow oil that crystallized after cooling overnight at 49013. The solid was treated with l80 mL of l-l then filtered and washed with 30 mL of eold MeOH (l l 5; 7728/11 yield). H NMR (400 MHZ 1;DCl3) 8 7.5 l5 7.3l (m, 10H)? 6.80 (d, J: 2.2 Hz, 2H)? 6.57 (t? J: 21.2 Hz lH), 5.03 (5,413), MS (E81): 367(M-H)”, 369 ”. $3156} Step 2:3—(35dtbehzvlosyphenvirhenzamide (Ill): To a solution of 1,3— dibenzyloxy—Sbroom—benzene (H) (led, 29.8 mmol, l 1.0 g) in e ‘\ (EGME) (152 mil) in a, 500 rnL round bottomed flask, water (_541 1111;) was added drop wise, followed by the addition of Kit); 1f2 err, 59.6 mrnol: 8.2 gx 3-- carbamoylhenzeneboronie acid (I 5 eq 447 mmol 74 g) and Pdt 025113)} (1.29/11, 0.36 hiinol, 8{‘13 111g) Ehe 1eaetio11 mixturewas st1rred at 60°Cfor 20 mm [hen 100 ml of water were added and a precipitate was formed which was filtered and washed with water (50 mL). The title compound was recrystallized from 350 mL of a 5:2 mixture of MeQH/Tl-lF (8.5 g, 70% yield). 1n valR(4l)l)1»11-lz, persona) 5 8.15 (1,}: , 111), 8.12 (bs, 11-1), 7.87 {4:1,}: 78 Hz, 1H), 7.83 (11.7: 7.8 Hz, in), 7.61 — 7.30 (m, 121:1), 7.00 (a, J: 2.2 Hz, 2H), 6.73 a, J: 12.2 Hz, 111), 5.19 (s, 411). Ms (use: 410 (MHHY, 408 (M—H)". {6157} Step 3: 3{3,5~dihj,idroxyphenyl)henzamide (IV): To a sus ension of 3—8.5— dibenzyloxyphenyl)benzamide 111 (8.5 g, 29.8 mmol) in 260 rnL oi‘dioxane, in a 500 rnL three necked round bottomed flash, 80 ml. ot'eycloh exene were added and the mixture was heated at 50°C for 15 min to ensure complete dissolution of the solids. The mixture was then cooled to room temperature and 2 g of Pd/C 10% were added. The reaction mixture was heated at 80°C for 2h and an additional amount of2 g of Pct/C were then added. After 211, the l0 mixture was cooled down to room temperature, then filtered through a small pad ofeelite and washed with 11.11) rnl. of dioxane and 101) ml. of absolute ethanol. The clear solution was concentrated to dryness to afford 1V as a fluffy light yellow solid (4.8 g, quantitative). 11-1 NMR (400 MHZ, DMSOzdd) 5 9.38 (s, 211), 8.10 (17s, 111), 8.07 — 8.03 (m, 111), 7.83 (d, J: 7.8 Hz, 111), 7.68 (d, J: 7.8 Hz, 11—1), 7.50 (t, J: 7.7 Hz, 111), 738(175, 111), 6.55 (d, J: 2.1 Hz, 2H), 6.27 (t, J": 2.1 Hz, 13). MS (7581): 2.30 (WHEY, 228 (hi-H)". {6158} Step 4: [3{3x-oarbamoylphenyhnfi--hydroxy-phenyl] N-eyclohexylearbamate, Compound 1: To a on ,S-dihydroxypheny )henzamide IV (1 eq., 11.4 mmol, 2.6 g) in ous DMF (30 ml.) in a. 500 ml. round bottomed flask CuCl (1 eq., 11.4 rnmol, 1.1 g) was added. exyl isocyanate (1 eq., 11.4 rmnol, 1.45 mL) was then added and the mixture was stirred at room temperature for 39 min. To this solution, 200 mL of a mixture 01’39/15 aq. citric acid solution and 100 ml. of ethyl acetate (EtOAe) were then added. The organic phase was seaarated and dried over NagSOz. ation of the solvent gave a. crude, which was ed by column chromatography (cyelohexane/EtOAe) to afford compound 1 as white solid. The solid was re—dissolved in 75 ml. ofa 65:20:15 mixture of acetone/ethanol. To this solution 30 nil. of water were then added to give a precipitate which was filtered to afford compound 1 as white solid (1 . 17 g, 299/15 yield). jH NMR (400 MHZ, DMSO—dg) 5 9.86 (s, 1H), 8.13 (13s, 1H), 8.11 8.09 (m, 1H), 7.86 ((1,.27-77 Hz, 111), 7.75 (11,]: 7.7 Hz, 1H), 7.70 (d, J: 7.7 112,111), 7.53 (t, J: 7.7 Hz, 111), 7.41 (hs, 1H), 6.95 (t, J: 1.9 112, 111), 6.89 (t, J: l.9 Hz, 1H), 6.53 (d, J: 1.9 Hz, 111), 3.46 — 3.321 (m, 1H), 1.99 1.46 m, 611), 1.46 0.99 (m, 417). MS (1231): 355 (air-inf, 372 (Mi-N114)", 75 (M~1—I)‘. {6159} Synthesis of roxyw5{3.~(n7ethylearbanioyl)phehyllphenyl] N— cyelohexylcarbamate, Compound 2. Compound 2 was synthesized using a synthetic procedure analogous to the one previously described. 1H NMR (401) MHZ, Dl‘vlSsz’o) 5 9.79 (bs,1ll),8<7(q J4411121111807801111, 111) 782 (1.1 J.. 12 111),?u.4(c1,J:= 7.7 112, 111), 7.59 111.1: 7.9112, 1111,7531 (1,.1: 7.7 112, 1111,1198 — 5.92 (m, 111), 6.91 — 6.861311, 1111, 6.53 (1,..1': 2.1 112, 11111, 3.39 — 3.31 (m, 1111, 2.82 (d, J: 4.4 112, 3111, 1.90 — 1.48 1111, 511), 1.35 1.114.1111, 5111. Ms (E81): 369 (M+H), 386 (51min); 357 1111—111, 427 .5 (Mi-Acct). d. Example 4 lillfiiil Comparison of compounds according to the invention with other peripherally cted FAAH inhibitors for their y to inhibit FAAH in the periphery. Using r FAAH inhibition hioassay methods as described for URB937 above (see, also, Clapper et a1.

Nature Neuroscience l3:l265—7{) (2910)), which is incorporated herein by reference with respect to such FAAH hioassay methods, the hepatic and CNS FAAH inhibitory activities of the compounds following administration was compared to that of URB937. in particular, (1) Kim values were generated in Vitro using a FAAl-l, assay. Percent in vivo FAAH inhibition values for ('2) liver and (3) brain were determined, as follows. Mice received a l g dose lb of each compound by the intraperitoneal route, and were killed 2 h after administration.

Tissues were collected and FAAH ty was measured ex VlVD in tissue extracts ane on1 using the FAAH assay. Data are reportedin the Table 1 below.

FAAi-i FAAi-i 1 1 inhibition inhibition in iiver ' in brain ' cyciohexyi 2.5 55512.34?- 525+a4.

Linnea? 1-1 an.”11111.1 41111.1 UR8937 Compound 1 {6161} Based upon their peripheral and central FAAH activities, the ants have Ur surprisingly found that placement of a polar substituent on the meta position of the proximal biphenyl ring also provides a peripherally restricted inhibitor H. Compound l, and the other compounds of formula L also are ed to have an important practical advantage in that the metabolism of these compounds in VlVD is likely much less able to lead to the formation of a potentially toxic pai‘abenzoqtilnones. l 0 8 Example 5 FAAH FAAH : : : E leg inhibition inhibition COmpm‘m R:30 R31 R32 R33 (anl) in liver (%) in brain UR3937 H “3.0 i 8.0 _______________________________________ ARN1289 H ~42 i 2.5 ARN14427 H A .7 a 0,2 ARNO715 H 2.1 $05 ARNeTie H H CHaQH H 9.4 91.5 i 1.1 10.5 $1.5 1‘. Example 6 {6162} The activity of compounds of Formula 1 as peripherally restricted FAAH tors was found based in part on the polarity of the p-hydroxyphenyl moiety. it was found that this (J! moiety is a contributor to the peripheral segregation of UM3937, a model peripherally restricted FAAH inhihitor. Table 3 shows that analogs in which the R40 substitucnt was weakly polar or apolar compounds, eg. lc, id and le, were found to enter the brain after systemic stration in mice, whereas an analog in which R40 consisted of a polar amino group, e.g., compound if, was found to be largely excluded. {6163} Table 3: In vitro and in viva characterization of O—arylcarbamate FAAH inhibitors H 7.7 :15 ND. 96.2 i 0.4 (UR8597) :) OH 26.6 i 4.9_. , 91.7 i 0.7 ~31) i 8.0, .

(URBQS?) 1e OCHg 45.3 i 14.1 94.6 i 0.7 86.4 i 2.1 1d OH; 20.5 i 0.6 93.0 e 1.1 91.9 i 1.5 1e F 49.7 e 5.8 90.7 $1.2 89.7 $1.3 1f NH2 42.5 i 4.2 92.2 i 0.6 23.2 i 2.1 a i050 measured in membrane preparation of rat brain bFAAH inhibition measured ex vivo 1 it after a single injection in mice (1 mg~kg'1, i.p.). idle-1} The following es are provided for illustrative purposes, and are not intended to limit the scope of the invention as claimed herein. Any variations in the ified compounds, compositions, and, or, methods which occur to the skilled artisan are intended to fall within the scope of the present invention. Although the ing ion has been described in some detail by way of illustration and example for purposes ofclarity of 2012/051478 understanding, one of skiii in the art Wiii appreciate that certain changes and modifications may be ced within the scope of the appended claims. in addition, each reference provided herein is perated by reference in its entirety to the same extent as if each reference was individualiy incorpnrated by reference. Where a conflict exists between the instant application and a reference previded herein, the instant application shall dentinate.

Claims (34)

WHAT IS D IS:

1. A nd having the formula: wherein: R1 is selected from the group consisting of hydroxy and the physiologically hydrolyzable esters thereof, carboxy and the physiologically hydrolysable esters thereof, hydroxyl-(C1-C3)alkyl and the physiologically hydrolyzable esters thereof, and -NR7R8, wherein R7 and R8 are independently selected from hydrogen or (C1-C3)alkyl and R9 is selected from hydrogen, methyl, ethyl, trifluoromethyl or trifluoroethyl; and R5 is hydrogen; R1 is hydrogen; and R5 is carboxy and the physiologically hydrolysable esters thereof, or hydroxyl-(C1-C3)alkyl and the physiologically yzable esters thereof; R2 and R3 are independently ed from the group consisting of hydrogen and tituted (C1-C3)alkyl; each R4 is independently selected from the group consisting of hydrogen and unsubstituted (C1-C3)alkyl and n is an integer from 0 to 4; R6 is cyclohexyl, cyclopentyl, cyclobutyl or tetrahydropyranyl; or a pharmaceutically acceptable salt f.

2. The compound of claim 1, wherein R2 and R3 are each H.

3. The compound of claim 1 or claim 2, wherein R1 is hydroxy, carboxy, or hydroxymethyl.

4. The compound of claim 1, 2, or 3 wherein R6 is cyclohexyl.

5. The compound of claim 1, wherein, R7 and R8 are each H..

6. The compound of claim 1, wherein n is 0 or 1.

7. The compound of claim 1, wherein R1 is hydroxy or a physiologically hydrolysable ester f.

8. The compound of claim 7, n the logically hydrolysable ester is of the formula -OC(O)R10 and R10 is hydrocarbyl.

9. The compound of claim 1, wherein R1 is or –C(O)OR10, and R10 is hydrogen or hydrocarbyl.

10. The compound of claim 1, wherein R5 is COOH.

11. The compound of claim 1, wherein R5 is CH2OH.

12. The compound of claim 1, wherein the compound has the following formula:

13. The compound of claim 1, wherein the compounds has the formula:

14. The compound of claim 1, wherein the compounds has the formula:

15. The compound of any one of claims 1, 2, 4, 5, or 6, wherein R1 is hydrogen; and R5 is independently hydroxyl-(C1-C3)alkyl or the physiologically hydrolyzable ester thereof or carboxy or the physiologically ysable ester thereof.

16. The compound of any one of claims 1, 2, 4, 5, or 6, n R1 is hydroxy or the physiologically hydrolyzable esters f, carboxy or the physiologically hydrolysable esters thereof, hydroxyl-(C1-C3)alkyl or the logically hydrolyzable esters thereof, -NR7R8, R7 and R8 are independently selected from hydrogen or (C1-C3)alkyl; and R5 is hydrogen.

17. The compound of any one of claims 1, 2, 4, 5, or 6, wherein R5 is COOH or a physiologically hydrolyzable ester thereof.

18. The compound of any one of claims 1, 2, 4, 5, or 6, wherein R5 is CH2OH, or a physiologically hydrolyzable ester thereof.

19. The compound of claim 1, wherein the compounds has the a:

20. A pharmaceutical composition comprising a compound of any one of claims 1 to 19.

21. Use of a nd of any one of claims 1 to 19 in the manufacture of a medicament for inhibiting FAAH in a mammal in need thereof.

22. Use of claim 21 wherein the mammal is in need of treatment for a pain, an matory disorder, or an immune disorder.

23. Use of claim 22, wherein the pain is nociceptive, inflammatory, or neuropathic pain.

24. Use of claim 22, wherein the mammal has an inflammatory or immune disorder.

25. A pharmaceutical composition for selectively ting peripheral Fatty Acid Amide Hydrolase (FAAH), said composition comprising a compound of any one of claims 1 to 19 and a pharmaceutically acceptable excipient.

26. A pharmaceutical composition for treating a condition selected from pain, inflammation, and an immune disorder, said composition comprising a compound of any one of claims 1 to 19 and a pharmaceutically acceptable excipient

27. A pharmaceutical composition for treating a condition selected from dermatitis, mucositis, or the over vity of peripheral sensory neurons, neurodermatitis, tive bladder, or cough wherein said composition comprises a compound of any one of claims 1 to 19 and a pharmaceutically acceptable excipient.

28. The ition of clam 26, wherein the condition is a drug-induced or radiation-induced pathology.

29. Use of a compound of any one of claims 1 to 19 in the manufacture of a medicament for increasing peripheral levels of mide, oleoylethanolamide (OEA), palmitylethanolamide (PEA), or stearoylethanolamide (SEA), in a mammal.

30. A pharmaceutical composition for accelerating wound healing in a mammal in need thereof, said composition comprising a compound of any one of claims 1 to 19 and a pharmaceutically acceptable excipient.

31. Use of a compound of any one of claims 1 to 19 in the manufacture of a medicament for treating a condition ed from dermatitis, tis, or the over vity of peripheral sensory neurons, neurodermatitis, overactive bladder, or cough.

32. Use of a compound of any one of claims 1 to 19 in the manufacture of a medicament for rating wound healing in a mammal in need thereof.

33. Use of a compound of any one of claims 1 to 19 in the manufacture of a medicament for treating pain, an inflammatory disorder, or an immune disorder.

34. Use of claim 33, wherein the pain is nociceptive, inflammatory, or neuropathic pain