US0074.02687B2

(12) United States Patent (10) Patent No.: US 7.402,687 B2 Stack et al. (45) Date of Patent: Jul. 22, 2008

(54) DIHYDROBENZOFURAN DERIVATIVES AND 6,419,958 B2 7/2002 Sherman et al. USES THEREOF 6,444,708 B2 9/2002 Rudolph et al. 6,765,008 B1 7, 2004 Chen (75) Inventors: Gary Paul Stack, Ambler, PA (US); 7,045,545 B1 5, 2006 Briner et al. 2002/0183395 A1 12/2002 Argentieri et al. Jianyao Wang, Monmouth Junction, NJ 2004.0029949 A1 2/2004 Argentieri et al. (US); William Demaio, Collegeville, PA 2004/0235856 A1 1 1/2004 McMurray et al. (US); Ronald Jordan, Richboro, PA 2005, 0124692 A1 6/2005 Gross et al. (US); John Chuck Lem Erve, 2005.01434.52 A1 6/2005 Gross et al. Eagleville, PA (US); Rasmy Elsayed 2005/0261347 A1 11/2005 Gross et al. Talaat, West Chester, PA (US); Matthew 2006,008.9405 A1 4/2006 Zhou John Hoffmann, Pottstown, PA (US) 2006/01 11438 A1 5/2006 Gontcharov et al. 2006/0241172 A1 10/2006 Zhou et al. (73) Assignee: Wyeth, Madison, NJ (US) 2006/0241176 A1 10/2006 Stacket al. 2006, O246551 A1 11/2006 Stacket al. (*) Notice: Subject to any disclaimer, the term of this 2006, O247 276 A1 11/2006 Gross et al. 2006/0252825 A1 11/2006 Tadayon et al. patent is extended or adjusted under 35 2006/0258639 A1 11/2006 Logue et al. U.S.C. 154(b) by 96 days. 2006/0258711 A1 11/2006 Rosenzweig-Lipson 2006/0258712 A1 11/2006 Jacobson (21) Appl. No.: 11/409,479 2006/0258713 A1 11/2006 Rosenzweig-Lipson 2006/0258714 A1 11/2006 Heffernan et al. (22) Filed: Apr. 21, 2006 2006/0258715 A1 11/2006 Jandura et al. 2006/0258739 A1 11/2006 Ai et al. (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2006/0241176A1 Oct. 26, 2006 WO WO 2006/OOO902 5, 2006 Related U.S. Application Data OTHER PUBLICATIONS (60) Provisional application No. 60/674,150, filed on Apr. U.S. Appl. No. 1 1/787,929, Yu et al. 22, 2005. U.S. Appl. No. 1 1/787,860, Gontcharov et al. U.S. Appl. No. 1 1/726.941, Rosenzweig-Lipson. (51) Int. Cl. Allison, et al., Am. J. Psychiatry, 156: 1686-96, 1999. C07D 407/12 (2006.01) (52) U.S. Cl...... 549/419; 549/424; 549/425; (Continued) 549/467 Primary Examiner Patricia L. Morris (58) Field of Classification Search ...... 549/419, (74) Attorney, Agent, or Firm—Julie Anne Knight; Andrea L. 549/424, 425, 467 See application file for complete search history. C. Robidoux: Choate, Hall & Stewart LLP (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS Compounds of formula I are described herein which are ago 2,554,736 A 1 1/1951 Haefliger et al. nists or partial of the Subtype of brain 3,912,743 A 10, 1975 Christensen et al. receptors. 4,007,196 A 2f1977 Christensen et al. 4,085,225 A 4, 1978 Welle et al. 4,136,193 A 1/1979 Bogeso et al. 4,210,754 A 7, 1980 Burkard et al. 4,229,449 A 10, 1980 Melloni et al. 4,314,081 A 2/1982 Molloy et al. 4.478,836 A 10, 1984 Mouzin et al. 4,535,186 A 8, 1985 Husbands et al. 4,536,518 A 8, 1985 Welch et al. RE34,712 E 8/1994 Boegesoe et al. 5,384.330 A 1/1995 Dieter et al. 5,565.483. A 10, 1996 Hewawasam et al. 5,668,145 A 9/1997 Bright 5,705,646 A 1/1998 Bright et al. 5,712.303 A 1/1998 Faraci et al. 5,916,923 A 6/1999 Rudolph et al. 6,090,803 A 7/2000 Failli et al. orpharmaceutically acceptable salts thereof, wherein each of 6,096,735 A 8/2000 Ogawa et al. R", R. R. R. R. R', and n are as defined herein. Such 6,096,736 A 8/2000 Ogawa et al. compounds, and compositions thereof, are useful for treating 6,194.407 B1 2/2001 Failli et al. a variety of central nervous system disorders such as Schizo 6,218,397 B1 4/2001 Chen phrenia. 6,274,171 B1 8, 2001 Sherman et al. 6,403,120 B1 6, 2002 Sherman et al. 8 Claims, No Drawings US 7,402.687 B2 Page 2

OTHER PUBLICATIONS Lassen, Eur: J. Pharmacol, 47: 351, 1978. Laursen, et al., Acta Psychiat. Scand. 71: 249, 1985. Battegay, et al., Neuropsychobiology, 13:31, 1985. Lowry, et al., J. Biol. Chem., 193: 265, 1951. Bishop, et al., Expert Opin. Ther: Patent, 13: 1691-1705, 2003. Masand, “Weight gain associated with psychotropic '. Exp. Bundgaard (ed), Design of Prodrugs, Elsevier, Ch. 1 (p. 1-92), Opin. Pharmacother. I: 377-89, 2000. Ch.4(p. 157-176), Ch.5(p. 177-198), and Ch.6(199-241), 1985. Mendell, et al., N. Engl. J. Med., 348: 1243-55, 2003. Bundgaard, et al., Journal of Delivery Reviews, 8: 1-38, 1992. Millan, et al., Neuropharmacology, 37: 953-55, 1998. Bundgaard, J. of Pharmaceutical Sciences, 77: 285-298, 1988. Moret, et al., Neuropharmacology, 24: 1211-19, 1985. Christensen, et al., Eur: J. Pharmacol., 41: 153, 1977. Robertson, et al., J. Med. Chem., 31: 1412, 1988. Cowen, et al., Human Psychopharmacology, 10: 385-91, 1995. Rosenzwieg-Lipson, et al., “Antiobesity-like effects of the selective DiGiovanni, et al., Synapse, 35:53-61, 2000. 5-HT2C way”, ASPET abstract, 2000. DiMatteo, et al., Neuropharmacology, 37: 265-272, 1998. Whitaker, Spectrum Life Sciences Decision Resources, 2: 1-9, 2000. DiMatteo, et al., Neuropharmacology, 38: 1195-1205, 1999. Wilen, et al., Tetrahedron, 33: 2725-2736, 1977. Dufour, et al., Int. Clin. Psychopharmacol. 2: 225, 1987. Widder, et al (ed.), Methods in Enzymolgoy, Academic Press, Fox, et al., Experimental Neurology, 151: 35-49, 1998. 112:56-67, 1985. Hassan, et al., Brit J. Clin. Pharmacol. 19: 705, 1985. International Search Report PCT/US2006/015192. US 7,402,687 B2 1. 2 DHYDROBENZOFURANDERVATIVES AND SUMMARY OF THE INVENTION USES THEREOF The present invention relates to 5-HT, agonists and uses CROSS REFERENCE TO RELATED thereof. The compounds of the present invention are useful, APPLICATIONS for example, to treat Schizophrenia and the concomitant mood This application claims priority to U.S. Provisional Patent disorders and cognitive impairments of schizophrenia. In cer Application Ser. No. 60/674,150, filed Apr. 22, 2005, the tain embodiment, compounds of the present invention are less entirety of which is hereby incorporated herein by reference. likely to produce the body weight increases associated with 10 current atypical antipsychotics. The compounds of the FIELD OF THE INVENTION present invention are also useful for the treatment of obesity and its comorbidities. The present invention relates to 5-HT2 agonists, In certain embodiments, the present invention provides a processes for their preparation, and uses thereof. compound of formula I: 15 BACKGROUND OF THE INVENTION

Schizophrenia affects approximately 5 million people. The most prevalent treatments for Schizophrenia are currently the atypical antipsychotics, which combine (D) and serotonin (5-HT) receptor antagonism. Despite the reported improvements in efficacy and side-effect liability of atypical antipsychotics relative to typical antipsychotics, these compounds do not appear to adequately treat all the symptoms of Schizophrenia and are accompanied by prob 25 lematic side effects, such as weight gain (Allison, D. B., et. al., Am. J. Psychiatry, 156: 1686-1696, 1999; Masand, P. S., Exp. Opin. Pharmacother. I: 377-389, 2000; Whitaker, R., Spectrum Life Sciences. Decision Resources. 2:1-9, 2000). Atypical antipsychotics also bind with high affinity to 30 5-HT, receptors and function as 5-HT2 receptor antagonists or pharmaceutically acceptable salts thereof, wherein: or inverse agonists. Weight gain is a problematic side effect each re-independently represents a single or double bond, associated with atypical antipsychotics Such as and provided that both -r-groups do not simultaneously rep , and it has been Suggested that 5-HT, antago resent a double bond; nism is responsible for the increased weight gain. Conversely, 35 stimulation of the 5-HT, receptor is known to result in R" is hydrogen, lower alkyl, or C(O)R; decreased food intake and body weight (Walsh et. al., Psy R is hydrogen or lower alkyl: chopharmacology 124: 57-73, 1996; Cowen, P. J., et. al., R’ is hydrogen, OH, or —OS(O)OH: Human Psychopharmacology 10: 385-391, 1995; Rosenz R is hydrogen, halogen, methyl, methoxy, OH, or —OS weig-Lipson, S., et. al., ASPET abstract, 2000). 40 Several lines of evidence support a role for 5-HT, recep (O),OH: toragonism or partial agonism as a treatment for Schizophre R" is hydrogen, OH, or —OS(O).OH: nia. Studies suggest that 5-HT, antagonists increase synap R" and Rare each hydrogen or are taken together to forman tic levels of dopamine and may be effective in animal models OXO moiety; of Parkinson's disease (Di Matteo, V., et. al., Neuropharma 45 RandR are each hydrogen or are taken together to forman cology 37: 265-272, 1998; Fox, S. H., et. al., Experimental OXO moiety; Neurology 151: 35-49, 1998). Since the positive symptoms of each R is independently halogen or lower alkyl: Schizophrenia are associated with increased levels of dopam ine, compounds with actions opposite to those of 5-HT, each R" is independently hydrogen, —OH, or —OS(O)OH, antagonists, such as 5-HT2, agonists and partial agonists, 50 wherein at least one of R,R, and Ris-OH or OS(O), should reduce levels of synaptic dopamine. Recent studies OH; and have demonstrated that 5-HT2, agonists decrease levels of n is one or two. dopamine in the prefrontal cortex and nucleus accumbens In certain other embodiments, the invention relates to (Millan, M. J., et. al., Neuropharmacology 37: 953-955, methods for treating a patient Suffering from Schizophrenia, 1998; Di Matteo, V., et. al., Neuropharmacology 38: 1195 55 schizophreniform disorder, schizoaffective disorder, delu 1205, 1999; Di Giovanni, G., et. al., Synapse 35: 53-61, sional disorder, Substance-induced psychotic disorder, 2000), brain regions that are thought to mediate critical antip L-DOPA-induced psychosis, psychosis associated with sychotic effects of drugs like clozapine. However, 5-HT, Alzheimer's dementia, psychosis associated with Parkin agonists do not decrease dopamine levels in the striatum, the son's disease, psychosis associated with Lewy body disease, brain region most closely associated with extrapyramidal side 60 dementia, memory deficit, intellectual deficit associated with effects. In addition, a recent study demonstrates that 5-HT, Alzheimer's disease, bipolar disorders, depressive disorders, agonists decrease firing in the Ventral tegmental area (VTA). mood episodes, anxiety disorders, adjustment disorders, eat but not in the substantia nigra. The differential effects of ing disorders, epilepsy, sleep disorders, migraines, sexual 5-HT agonists in the mesolimbic pathway relative to the dysfunction, Substance abuse, addiction to and vari nigrostriatal pathway Suggest that 5-HT2, agonists have lim 65 ous other drugs, including cocaine and , gastrointes bic selectivity, and will be less likely to produce extrapyra tinal disorders, obesity, or a central nervous system deficiency midal side effects associated with typical antipsychotics. associated with trauma, stroke, or spinal cord injury that US 7,402,687 B2 3 includes administering to the patient a therapeutically effec tive amount of a compound of formula I, or a pharmaceuti cally acceptable salt thereof. In still other embodiments, the invention relates to compo sitions comprising a compound of formula I or a pharmaceu tically acceptable salt thereof, and one or more pharmaceuti cally acceptable carriers, excipients, or diluents.

DETAILED DESCRIPTION OF THE INVENTION 10

1. Compounds and Definitions: The present invention relates to compounds that are ago nists or partial agonists of the 2C Subtype of brain serotonin 15 receptors. or pharmaceutically acceptable salts thereof, wherein: The term “lower alkyl, as used herein, refers to a hydro each ----independently represents a single or double bond, carbon chain having up to 4 carbon atoms, preferably 1 to 3 provided that both =rgroups do not simultaneously rep carbon atoms, and more preferably 1 to 2 carbon atoms. The resent a double bond; term “alkyl includes, but is not limited to, straight and R" is hydrogen, lower alkyl, or C(O)R; branched chains such as methyl, ethyl, n-propyl, isopropyl. R is hydrogen or lower alkyl: n-butyl, isobutyl, sec-butyl, or t-butyl. R’ is hydrogen, OH, or —OS(O).OH: The terms “halogen' or “halo.” as used herein, refer to R is hydrogen, halogen, methyl, methoxy, -OH, or OS chlorine, bromine, fluorine or iodine. 25 (O),OH: The terms “effective amount” and “therapeutically effec R" is hydrogen, OH, or —OS(O).OH: tive amount, as used herein, refer to the amount of a com R" and Rare each hydrogen or are taken together to forman pound of formula I that, when administered to a patient, is OXO moiety; effective to at least partially treat a condition from which the R and Rare each hydrogen or are taken together to forman patient is suffering from. Such conditions include, but are not 30 OXO moiety; limited to, schizophrenia, schizoaffective disorder, schizo each R is independently halogen or lower alkyl, phreniform disorder, L-DOPA-induced psychosis, bipolar each R" is independently hydrogen, —OH, or —OS(O)OH, disorder, obesity, obsessive compulsive disorder, depression, wherein at least one of R,R, and Ris-OH or OS(O) panic disorder, sleep disorders, eating disorders, and epilepsy. 35 OH; and The term “pharmaceutically acceptable salts' or “pharma n is one or two. ceutically acceptable salt” refers to salts derived from treating As defined generally above, each -r-independently repre a compound of formula I with an organic or inorganic acid sents a single or double bond, provided that both =rgroups Such as, for example, acetic, lactic, citric, cinnamic, tartaric, do not simultaneously represent a double bond; RandR are Succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, 40 each hydrogen or are taken together to form an oxo moiety; propionic, hydrochloric, hydrobromic, phosphoric, nitric, and RandR are each hydrogen or are taken together to form Sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, an oxo moiety. It will be appreciated that when a ----group toluenesulfonic, Salicylic, benzoic, or similarly known represents a double bond, then the corresponding RandR' or acceptable acids. In certain embodiments, the present inven RandRpair must represent a single hydrogen. Accordingly, tion provides the hydrochloride salt of a compound of for 45 compounds of formula I are contemplated Such that Valency mula I. permits. The term “patient, as used herein, refers to a mammal. In In certain embodiments, the n group of formula I is 1. certain embodiments, the term “patient’, as used herein, In other embodiments, the n group of formula I is 2. refers to a human. As defined generally above, the R' group of formula I is R' 50 is hydrogen, lower alkyl, or—C(O)R, wherein R is hydrogen The terms “administer,” “administering,” or “administra or lower alkyl. In certain embodiments, the R' group of for tion, as used herein, refer to either directly administering a mula I is hydrogen. In other embodiments, the R' group of compound or composition to a patient, or administering a formula I is lower alkyl. In still other embodiments, the R' prodrug derivative or analog of the compound to the patient, group of formula I is methyl. According to another aspect, the which will forman equivalent amount of the active compound 55 R" group of formula I is C(O)R wherein R is hydrogen or or substance within the patient’s body. methyl. The terms “treat' or “treating,” as used herein, refers to In certain embodiments, the R group of formula I is fluoro partially or completely alleviating, inhibiting, preventing, or chloro. In other embodiments, the R group of formula I is ameliorating and/or relieving the condition. 60 fluoro. The terms “suffer or “suffering as used herein refers to In certain embodiments, the R group of formula I is —OH one or more conditions that a patient has been diagnosed with, and the R' group is hydrogen. In other embodiments, the R or is Suspected to have. group is hydrogen and the R group of formula I is OH. In still other embodiments, both of the R and R' groups of 2. Description of Exemplary Compounds: 65 formula I are —OH. In certain embodiments, the invention relates to a com In certain embodiments, each R group of formula I is pound of formula I: independently halogen or methyl. In other embodiments, US 7,402,687 B2 5 6 each R group of formula I is independently a halogen group. In still other embodiments, both R groups of formula I are -continued chloro.

I-e In certain embodiments, at least one of the R. R. and R' groups of formula I is —OS(O)OH. According to another 5 aspect, the present invention provides a compound of any of formulae I-a, I-b, I-c, I-d, and I-e:

10 I-a

15

orpharmaceutically acceptable salts thereof, wherein each of 2O R. R. R', and R is as defined above and in classes and subclasses described herein. In certain embodiments, the -r-moiety of formula I is a double bond. In other embodiments, the present invention I-b R2 25 provides a compound of formula I-f

F 2 I-f NH2 R R3 to--o O 30 O RX RX N NH 21 R4 O N X 35 (Ry)1-3 R 21 I-c R2

F 40 NH2 R4 O orpharmaceutically acceptable salts thereof, wherein each of R. R. R. R', and R is as defined above and in classes and RX RX subclasses described herein. According to one aspect of the present invention, RandR O O 45 are taken together to form an oxo moiety. According to W-O another aspect, R and Rare taken together to form an oxo HO 1. \ O moiety. In certain embodiments, the present invention pro I-d 50 vides a compound of formula I-g or I-h: R2

F

R4 O O NH2 55

RX RX O 60

OFSFOf h 65 US 7,402,687 B2 7 8 According to yet another embodiment, the present inven -continued tion provides a compound of formula III:

III R2

F NH2 10 HO O

R 21 RX

15 six (R)-3 orpharmaceutically acceptable salts thereof, wherein each of R. R. R. R', and R is as defined above and in classes and subclasses described herein. In other embodiments, the present invention provides a or pharmaceutically acceptable salts thereof, wherein each compound of formula I': R. R. and Rare as defined generally above and in classes and subclasses described above and herein. According to yet another embodiment, the present inven tion provides a compound of formula IV: 25

I IV R2

F 30 NH2 R4 O

RX RX 35

HO

40 or pharmaceutically acceptable salts thereof, wherein each R, R and Rare as defined generally above and in classes and subclasses described above and herein. orpharmaceutically acceptable salts thereof, wherein each of According to yet another embodiment, the present inven R", n, R. R. R. R. and R is as defined above and in classes tion provides a compound of formula V: and subclasses described herein. 45 According to another embodiment, the present invention provides a compound of formula II: R2 V

50 F II OH NH2 R4 O F R RX NH2 55 R4 O

R RX 21 OH 60 S X (R)-3 or pharmaceutically acceptable salts thereof, wherein each R. R. and R are as defined generally above and in classes and subclasses described above and herein. or pharmaceutically acceptable salts thereof, wherein each 65 R. R. and R are as defined generally above and in classes According to yet another embodiment, the present inven and subclasses described above and herein. tion provides a compound of formula VI: US 7,402,687 B2 10 or a pharmaceutically acceptable salt thereof, wherein each R", R. R. R. R. and R” areas defined above for compounds VI of formula I and in classes and Subclasses as described above R2 and herein. According to another embodiment, the present invention F provides a compound of formula Ic or Id: NH2 R4 O

Ic R RX 10

OH

15 or pharmaceutically acceptable salts thereof, wherein each R, R and Rare as defined generally above and in classes and subclasses described above and herein. Compounds of the present invention contain asymmetric carbon atoms and thus give rise to stereoisomers, including Id enantiomers and diastereomers. Accordingly, it is contem plated that the present invention relates to all of these stere oisomers, as well as to mixtures of the Stereoisomers. Throughout this application, the name of the product of this 25 invention, where the absolute configuration of an asymmetric center is not indicated, is intended to embrace the individual Stereoisomers as well as mixtures of stereoisomers. In certain embodiments of the invention, compounds having an abso lute (R) configuration are preferred. 30 In certain embodiments, the present invention provides a compound of formula Ia or Ib: or a pharmaceutically acceptable salt thereof, wherein each Ia 35 R", R. R. R', and Rare as defined above for compounds of formula I and in classes and Subclasses as described above and herein. Where an enantiomer is preferred, it may, in some embodi ments be provided substantially free of the corresponding 40 enantiomer. Thus, an enantiomer Substantially free of the corresponding enantiomer refers to a compound which is isolated or separated via separation techniques or prepared free of the corresponding enantiomer. “Substantially free, as used herein, means that the compound is made up of a sig 45 nificantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments of the invention, the compound is made up of at least about 99% by weight of a preferred enantiomer. Preferred enantiomers 50 may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid Ib chromatography (HPLC) and the formation and crystalliza tion of chiral salts or prepared by methods described herein. See, for example, Jacques, et al., Enantiomers, Racemates 55 and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, N.Y., 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame 60 Press, Notre Dame, Ind. 1972). It is recognized that atropisomers of the present com pounds may exit. The present invention thus encompasses atropisomeric forms of compounds of formula I as defined above, and in classes and Sublicasses described above and 65 herein. Exemplary compounds of formula I are set forth in Table 1, below. US 7,402,687 B2 11 12

TABLE 1. TABLE 1-continued Exemplary Compounds of Formula I: Exemplary Compounds of Formula I: F F O NH2 NH2 O

HO O 10 C C

C C

OH I-5 I-1 15

F O NH2 OH O

F C C O NH2 25 O OH

C C OH I-6 30

I-2

35 OH

F F NH2 O NH2 40 O O C C C C

45 OH HO I-3 OH I-7

50

F F O NH2 55 NH2 O O C C C C 60

HO OH OH I-4 OH 65 US 7,402,687 B2 13 14

TABLE 1-continued TABLE 1-continued Exemplary Compounds of Formula I: Exemplary Compounds of Formula I: OH F F NH2 O N NH2 O O 10 C C C C

HO OH 15 OH OH I-12 I-9 F O NH2 O O C C

25

I-13

OH

30 F OH O NH2 O F O 35 C C O

C C I-14 40 F HO - O

O O NH2 O I-10 O 45 C C

50 OH I-15

OH OH O F F N NH2 55 NH2

O O

C C C C 60

I-11 O 65 I-16 US 7,402,687 B2 15 16 each R is independently halogen or lower alkyl: TABLE 1-continued each R is independently hydrogen, OH, - OS(O),OH, or –OGlu; Exemplary Compounds of Formula I: each Glu is a glucuronyl moiety; and O n is one or two: F provided that at least one of R', R, R', and R contains a NH2 glucuronyl moiety. As defined generally above, each -r-independently repre O sents a single or double bond, provided that both -r-groups 10 do not simultaneously representa double bond; RandR are C C each hydrogen or are taken together to form an oxo moiety; and RandR are each hydrogen or are taken together to form an oxo moiety. It will be appreciated that when a regroup HO represents a double bond, then the corresponding RandR' or I-17 15 RandR'pair must represent a single hydrogen. Accordingly, compounds of formula VII are contemplated such that O Valency permits. F The compounds of the present invention are also useful for the study of 5-HT2, agonists or partial agonists in biological O NH2 and pathological phenomena and the comparative evaluation O of 5-HT, agonists or partial agonists. The present compounds were discovered as a result of C C metabolic studies of 5-HT2, agonists or partial agonists. O Without wishing to be bound by theory, it is believed that the 25 present compounds are metabolites of 5-HT2, agonists or HO-S-O partial agonists, such as those described in U.S. patent appli O cation Ser. No. 10/970,714, filed Oct. 21, 2004, and PCT I-18 publication number WO2005/044812, the entirety of which is hereby incorporated herein by reference. Accordingly, the 30 present compounds are also useful for conducting the effects In addition to the compounds described above, the present of such 5-HT2, agonists or partial agonists in vivo or in vitro. invention also provides compounds of formula VII useful as As used herein, the term “prodrug” refers to a derivative of prodrugs of 5-HT, agonists or partial agonists of formula I. a parent drug molecule that requires transformation within as defined herein. These compounds have the general formula the body in order to release the active drug, and that has VII: 35 improved physical and/or delivery properties over the parent drug molecule. Prodrugs are designed to enhance pharmaceu tically and/or pharmacokinetically based properties associ VII ated with the parent drug molecule. The advantage of a pro drug lies in its physical properties, such as enhanced water 40 solubility for parenteral administration at physiological pH compared to the parent drug, or it enhances absorption from the digestive tract, or it may enhance drug stability for long term storage. In recent years several types of bioreversible derivatives have been exploited for utilization in designing 45 prodrugs. Using esters as a prodrug type for drugs containing carboxyl or hydroxyl function is known in the art as described, for example, in “The Organic Chemistry of Drug Design and Drug Interaction” Richard Silverman, published by Academic Press (1992). 50 As used herein, the term “glucuronyl moiety” refers to a or a pharmaceutically acceptable salt thereof, wherein: group having the structure: each -r-independently represents a single or double bond, provided that both =rgroups do not simultaneously rep resent a double bond; 55 R" is hydrogen, —C(O)R, -Glu, —C(O)Glu, or C(O) OGlu; HO R is hydrogen or lower alkyl: HO OH R’ is hydrogen, OH, OS(O),OH, or —OGlu; 60 R is hydrogen, halogen, methyl, methoxy, -OH,-OS(O), OH OH, or OGlu: R" is hydrogen, OH, OS(O),OH, or —OGlu; R" and Rare each hydrogen or are taken together to forman wherein the wavy line depicted designated the point of attach OXO moiety; 65 ment to a compound of formula VII. Rand Rare each hydrogen or are taken together to forman In certain embodiments, then group of formula VII is 1. OXO moiety; In other embodiments, the n group of formula VII is 2. US 7,402,687 B2 17 As defined generally above, the R' group of formula VII is hydrogen, —Glu, or —C(O)OGlu. In certain embodiments, -continued IXa the R' group of formula VII is hydrogen. In other embodi R2 OH ments, the R' group of formula I is —Glu. In still other HO embodiments, the R' group of formula I is —C(O)OGlu. F OH In certain embodiments, the R group of formula VII is H fluoro or chloro. In other embodiments, the R group of for N mula VII is fluoro. R4 O O OH O In certain embodiments, the R group of formula VII is 10 —OH and the R group is hydrogen. In other embodiments, R 21 RX O the R group is hydrogen and the R group of formula VII is –OH. In still other embodiments, both of the R and R' S X groups of formula VII are —OH. (R)-3 In certain embodiments, the R group of formula VII is 15 IXb —OGlu and the R'group is hydrogen. In other embodiments, R2 the R group is hydrogen and the R group of formula VII is F OH - OGlu. H N O OH In certain embodiments, each R group of formula VII is independently halogen or methyl. In other embodiments, -Nes? Y1 each R group of formula VII is independently a halogen O O group. In still other embodiments, both R groups of formula RX 21 RX OH VII are chloro. According to another embodiment, the present invention 25 N X O OH provides a compound of formula VIII: (R)-3

VIII HO or pharmaceutically acceptable salts thereof, wherein each OH 30 R. R. R. and R are as defined generally above and in classes and Subclasses described above and herein. HO OH According to yet another embodiment, the present inven tion provides a compound of formula X:

35

40

45 or pharmaceutically acceptable salts thereof, wherein each R. R', and Rare as defined generally above and in classes OH and subclasses described above and herein. 50 According to yet another embodiment, the present inven OH tion provides a compound of formula IX, IXa, or IXb: or pharmaceutically acceptable salts thereof, wherein each IX 55 R. R', RandR areas defined generally above and in classes R2 and subclasses described above and herein.

F OH 3. General Methods of Providing the Present Compounds: H Compounds of the present invention are prepared accord N OH ing to the methods described in detail in U.S. patent applica R4 O 60 tion Ser. No. 10/970,714, filed Oct. 21, 2004, (WO 2005/ O 044812), the entirety of which is hereby incorporated herein RX RX OH by reference. The stereoisomers of the present invention are 21 prepared by the stereoselective processes described in U.S. provisional patent application Ser. No. 60/621,023, filed Oct. N X O OH 65 21, 2004, and U.S. provisional patent application Ser. No. 60/621,024, filed Oct. 21, 2004, the entirety of both of which is hereby incorporated herein by reference. US 7,402,687 B2 19 20 Compounds of formula VII are prepared in general by Scheme 1 above depicts a general method for preparing methods known to one of ordinary skill in the art and, for compounds of formula VIII. As shown above, the hydroxyl example, by the methods described in general Schemes, compound 1 is treated with a Suitably protected glururonidate below. compound 2 having a suitable leaving group to enable the desired coupling to form3. For compounds of formula 2, each of PG, PG, and PG is a suitable hydroxyl protecting group. Scheme 1 Suitable hydroxyl protecting groups are well known in the art OH and include those described in detail in Protecting Groups in F Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 N NH 10 edition, John Wiley & Sons, 1999, the entirety of which is NR incorporated herein by reference. Examples of suitable 21 O hydroxyl protecting groups further include, but are not lim -- ited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, R RX arylalkyl ethers, and alkoxyalkyl ethers. Examples of Such 21 15 esters include formates, acetates, carbonates, and Sulfonates. Specific examples include formate, benzoyl formate, chloro N X acetate, trifluoroacetate, methoxyacetate, triphenylmethoxy (R)-3 acetate, p-chlorophenoxyacetate, 3-phenylpropionate, 1 4-oxopentanoate, 4.4-(ethylenedithio)pentanoate, pivaloate O (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, O Ll p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates Such PG|O as methyl, 9-fluorenylmethyl, ethyl, 2.2.2-trichloroethyl, Her 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include tri PGPO OPG 25 methylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphe OPG3 nylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl 2 ethers include methyl, benzyl, p-methoxybenzyl, 3,4- PGO dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl OPG2 ethers or derivatives. Alkoxyalkyl ethers include acetals such 30 as methoxymethyl, methylthiomethyl. (2-methoxyethoxy) PGO OPGl methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxym ethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4- O O dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-haloben Zyl. 2,6-dichlorobenzyl, p-cyanobenzyl, 2- and 4-picolyl. I will be understood that each of PG, PG, and PG may be different or the same. In certain embodiments, each of PG, PG, and PG is the same such that they are removed by the same conditions. The removal of these protecting groups, also known as “deprotection', is achieved by methods known in the art, including those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3" edition, John Wiley & Sons, 1999. For compounds of formula 2, the PG' group is a suitable carboxylate protecting group. Such protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. protein G. M. Wuts, 3' edition, John Wiley & Sons, 1999, the entirety OH of which is incorporated herein by reference. Suitable car OH 50 boxylate protecting groups further include, but are not limited HO OH to. Substituted Caliphatic esters, optionally Substituted aryl esters, silyl esters, activated esters, amides, hydrazides, and the like. Examples of such ester groups include methyl, ethyl, O O propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl wherein

55 each group is optionally Substituted. After coupling the glucoronidate compound 2 with the compound 1, a protected compound 3 is obtained. This com pound is then deprotected to form compounds of formula VIII. 60 It will be appreciated that in certain circumstances, it will be advantageous to remove all protecting groups at the same time. In such situations, the choice of PG, PG, PG, and PG' will be such that each protecting group is removed under the same conditions, e.g. by treatment with acid or base, by 65 reduction, or by ultra-violet light, to name but a few. Such choice of protecting groups is well known to one of ordinary skill in the art. US 7,402,687 B2 21 22 Compounds of formula IX and X are prepared in a sub American Psychiatric Association (1994), incorporated stantially similar manner to that described in Scheme 1, above herein by reference in its entirety. and by methods known to one of ordinary skill in the art. In certain embodiments, compounds of the present inven tion are administered in combination with one or more anti 4. Uses, Formulation and Administration 5 psychotic agents. Such anti-psychotic agents are well known Compounds of the present invention have affinity for and in the art and include clozapine (e.g., CloZaril(R), agonist or partial agonist activity at the 2C Subtype of brain (e.g., Risperidal(R), olanzapine (e.g., ZyprexaR), serotonin receptors and are thus of interest for the treatment of (e.g., Seroquel(R), (e.g., Geodon(R), , a variety of disorders and/or the alleviation of one or more amisulpiride, , fluiphenazine, associated symptoms. Such disorders associated with modu 10 (e.g., Haldol.R.), , , molindone, per lations of the 2C subtype of brain serotonin receptors are phenazine, , seroquel, Sulpiride, , thio described in detail below. The present invention contemplates thixene, , and to name a few. that compounds of the present invention are associated with a The combination of a compound of the present invention rapid . In addition, compounds of the present with one or more anti-psychotic agents is useful for treating invention lack the side-effect of sexual dysfunction. 15 Schizophrenia including paranoid type, disorganized type, Compounds of the present invention are useful for treating catatonic type, and undifferentiated type, Schizophreniform one or more psychotic disorders, as described herein, without disorder, schizoaffective disorder, delusional disorder, Sub causing diabetogenesis. Diabetogenesis is a side-effect asso stance-induced psychotic disorder, and psychotic disorder ciated with agents. Without wishing to not otherwise specified; L-DOPA-induced psychosis: psy be bound by any particular theory, it is believed that the chosis associated with Alzheimer's dementia; psychosis diabetogenesis associated with atypical antipsychotic agents associated with Parkinson's disease; psychosis associated results from the fact that those agents are 5-HT, antagonists. with Lewy body disease; bipolar disorders such as bipolar I As described herein, the present compounds are 5-HT2, ago disorder, bipolar II disorder, and cyclothymic disorder; bipo nists, or partial agonists, and therefore are not associated with diabetogenesis. lar mania, dementia, and depression with psychotic features. 25 In some embodiments, these combinations are useful in the Compounds of the present invention are useful for treating treatment of bipolar disorder, including for example treating one or more psychotic disorders such as Schizophrenia the cycling between bipolar depression and bipolar mania. including paranoid type, disorganized type, catatonic type, In other embodiments, administration of a compound of and undifferentiated type, schizophreniform disorder, the present invention with an anti-psychotic agent provide schizoaffective disorder, delusional disorder, substance-in 30 anti-psychotic benefits while eliminating or minimizing cer duced psychotic disorder, and psychotic disorder not other tain side affects (e.g., akathisia, dystonia, Parkinsonism dys wise specified; L-DOPA-induced psychosis; psychosis asso kinesia and late dyskinesia and the like) typically observed ciated with Alzheimer's dementia; psychosis associated with when the anti-psychotic agent(s) is/are taken alone. Parkinson's disease; and psychosis associated with Lewy In other embodiments, compounds of the present invention body disease. 35 are useful for treating one or more depressive disorders such Compounds of the present invention are also useful for as major depressive disorder, seasonal affective disorder, dys treating symptoms related to psychotic disorders of the thymic disorder, Substance-induced mood disorder, depres Schizophrenic types, including the so called “positive' and sive disorder not otherwise specified, and treatment resistant “negative' symptoms of Schizophrenia. These symptoms depression. include for example hallucinations, delusions, paranoia, 40 Another aspect of the present invention provides a method anxiety, agitation, excessive aggression, tension, thought dis for treating one or more mood episodes such as major depres order, blunted affect, and social or emotional withdrawal in sive episode, manic episode, mixed episode, and hypomanic psychotic patients. Other symptoms often associated with episode; and adjustment disorders such as adjustment disor psychotic disorders include cognition disorders or deficits ders with anxiety and/or depressed mood. Such as poor attention and impaired function, depression, 45 Compounds of the present invention are also useful for Suicide, metabolic syndrome, and Substance abuse. Thus, treating symptoms related to depressive disorders including another embodiment of the present invention provides a Somatic symptoms Such as neuropathic pain and sexual dys method for treating one or more symptoms associated with a function. Other Somatic symptoms include hopelessness, psychotic disorder. helplessness, anxiety and worries, memory complaints with In other embodiments, the present compounds are useful 50 or without objective signs of cognitive impairment, loss of for treating anxiety disorders such as panic attack, agorapho feeling of pleasure (anhedonia), slowed movement, irritabil bia, panic disorder, specific phobia, social phobia, Social ity, and lack of interest in personal care, Such as poor adher anxiety disorder, obsessive compulsive disorder, posttrau ence to medical or dietary regimens. matic stress disorder, acute stress disorder, generalized anxi In certain embodiments, the present invention provides a ety disorder, separation anxiety disorder, Substance-induced 55 method of treating sexual dysfunction related to depression. anxiety disorder, and anxiety disorder not otherwise speci In other embodiments, the present invention provides a fied. method of treating sexual dysfunction associated with admin According to another embodiment, the present compounds istering a serotonin (SRI) for treating a are useful for treating bipolar disorders. Such bipolar disor depressive or other disorder. Such methods of treating sexual ders include bipolar I disorder, bipolar II disorder, and 60 dysfunction are described in detail below. cyclothymic disorder; bipolar mania, dementia, and depres In certain embodiments, compounds of the present inven sion with psychotic features. The present compounds are also tion are administered in combination with one or more anti useful for treating (including the preventing) of cycling that depressive agents. Suitable agents include, for may occur between bipolar depression and bipolar mania. example, serotonin reuptake inhibitors (SRIs), norepineph A more complete description of the aforementioned mental 65 rine reuptake inhibitors (NRIs), combined serotonin-norepi disorders can be found in the Diagnostic and Statistical nephrine reuptake inhibitors (SNRIs), monoamine oxidase Manual of Mental Disorders, 4" edition, Washington, D.C., inhibitors (MAOIs), reversible inhibitors of monoamine oxi US 7,402,687 B2 23 24 dase (RIMAS), phosphodiesterase-4 (PDE4) inhibitors, cor , and , and pharmaceu ticotropin releasing factor (CRF) antagonists, alpha.-adreno tically acceptable salts thereof. receptor antagonists or other compounds including atypical Suitable reversible MAOIs for administering in combina . Additional antidepressants for administering tion with compounds of the present invention include: in combination with compounds of the present invention (4-chloro-N-2-(4-morpholinyl)-ethylbenza include triple uptake inhibitors such as DOV 216303 and mide: See U.S. Pat. No. 4,210,754, incorporated herein by DOV 21947. . . ; melatonin agonists such as agomelotine, reference in its entirety), selegiline, and pharmaceutically super neurotransmitter uptake blockers (SNUBs; e.g., acceptable salts thereof. NS-2389 from GlaxoSmithKline and Neurosearch; (R)- Suitable SNRIs for administering in combination with DDMA from Sepracor), and/or substance P/neurokinin 10 compounds of the present invention include (see receptor antagonists (e.g., aprepitant/MK-869 from Merck; U.S. Pat. No. 4,535,186, incorporated herein by reference in NKP-608 from Novartis; CPI-122721 from ; R673 its entirety; see also U.S. Pat. Nos. 5,916,923, 6,274,171, from Roche; TAK637 from Takeda; and GW-975.99 from 6,403,120, 6.419,958, 6.444,708, each of which is incorpo GlaxoSmithKline). rated herein by reference in its entirety), and pharmaceuti Another class of antidepressantagents for administering in 15 cally acceptable salts and analogs, including the O-desmeth combination with compounds of the present invention are ylvenlafaxine succinate salt; (N,N-diethyl-2- noradrenergic and specific antidepressants aminomethyl-1-phenylcyclopropanecarboxamide; see U.S. (NaSSAs). A suitable example of a NaSSA is mirtazepine. Pat. No. 4.478,836; Moret et al., Neuropharmacology Suitable NRIs for administering in combination with com 24:1211-19, 1985, each of which is incorporated herein by pounds of the present invention include tertiary amine tricy reference in its entirety); (available from Bristol clics and secondary amine . Suitable examples of Myers Squibb and Dr. Reddy Labs Inc.); dulloxetine; and tertiary amine tricyclics include: , clomi pharmaceutically acceptable salts thereof. pramine, , (See U.S. Pat. No. 2,554,736, Suitable CRF antagonists for administering in combina incorporated herein by reference in its entirety) and trimi tion with compounds of the present invention include those pramine, and pharmaceutically acceptable salts thereof. Suit 25 compounds described in International Patent Specification able examples of secondary amine tricyclics include: amox Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO apine, , , and 94f13676 and WO94f13677. , and pharmaceutically acceptable salts thereof. Suitable atypical antidepressants for administering incom bination with compounds of the present invention include: Another NRI or administering in combination with com 30 (WellbutrinTM: (..+-)-1-(3-chlorophenyl)-2-(1,1- pounds of the present invention is (EdromaxTM: dimethylethyl)amino-1-propanone), , nefazodone, 2-.alpha.-(2-ethoxy)phenoxy-benzylmorpholine, usually and , and pharmaceutically acceptable administered as the racemate; See U.S. Pat. No. 4,229,449, salts thereof. Another Suitable atypical antidepressant is incorporated herein by reference in its entirety). Sibutramine. Suitable SSRIs or administering in combination with com 35 Particular antidepressants for administering in combina pounds of the present invention include: (1-3- tion with compounds of the present invention include, but are (dimethylamino)propyl-(4-fluorophenyl)-1,3-dihydr-o-5- not limited to, , alaproclate, , aminep isobenzofurancarbonitrile; See U.S. Pat. No. 4,136, 193; tine, amitriptyline, amitriptyline/ combina Christensen et al., Eur:J. Pharmacol.41:153, 1977; Dufour et tion, , aprepitant, atipamezole, aZamianserin, al., Int. Clin. Psychopharmacol. 2:225, 1987; Timmerman et 40 baZinaprine, befuraline, , binodaline, bipenamol. al., ibid., 239, each of which is incorporated herein by refer brofaromine, buproprion, , cericlamine, ciano ence in its entirety); (N-methyl-3-(p-trifluorom pramine, cimoxatone, citalopram, clemeprol, , ethylphenoxy)-3-phenylpropylamine, marketed in the hydro , dazepinil, deanol, , desipramine, chloride salt form and as the racemic mixture of its two O-desmethylvenlafaxine, , dothiepin, doxepin, isoforms; see, for example, U.S. Pat. No. 4.314,081; Robert 45 droxidopa, dulloxetine, elZasonan, enefexine, , son et al., J. Med. Chem. 31:1412, 1988, each of which is , estazolam, , femoxetine, fengab incorporated herein by reference); fluoxetine/olanzapine in ine, fezolamine, , fluoxetine, , combination; fluvoxamine (5-methoxy-1-4-(trifluorom , idazoxan, imipramine, , , ethyl)phenyl-1-pentanone O-(2-aminoethyl)oxime: See , , levoprotiline, , U.S. Pat. No. 4,085,225; Claassen et al., Brit. J. Pharmacol. 50 , maprotiline, , , 60:505, 1977: De Wilde et al., J. Affective Disord. 4:249, , , milnacipran, , mirtazap 1982; Benfield et al., Drugs 32:313, 1986, each of which is ine, moclobemide, montirelin, nebracetam, , nefo incorporated herein by reference in its entirety); Zodine, nemititide, , , norfluoxetine, (trans-(-)-3-(1,3-benzodioxol-5-yloxy)methyl-4-(4-fluo nortriptyline, orotirelin, , paroxetine, pheneizine, rophenyl)piperidine: See U.S. Pat. No. 3,912,743: U.S. Pat. 55 , pirlindone, pizotyline, protryptiline, reboxetine, No. 4,007, 196; Lassen, Eur: J. Pharmacol. 47:351, 1978; , , rolipram, selegiline, sercloremine, Ser Hassan et al., Brit. J. Clin. Pharmacol. 19:705, 1985; Laursen traline, , Sibutramine, Sulbutiamine, Sulpiride, et al., Acta Psychiat. Scand. 71:249, 1985: Battegay et al., , , thoZalinone, thymoliberin, tianept Neuropsychobiology 13:31, 1985, each of which is incorpo ine, tiflucarbine, , , , tomoxet rated herein by reference in its entirety); , (1S-cis)- 60 ine, tranylcypromine, traZodone, trimiprimine, Venlafaxine, 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1- Veralipride, , Viloxazine, Viqualine, naphthylamine hydrochloride: See U.S. Pat. No. 4,536,518, and Zometrapine, and pharmaceutically acceptable salts incorporated herein by reference in its entirety); escitalopram thereof, and St. John's wortherb, or Hypencuin perforatum or (see U.S. Pat. RE34,712); and pharmaceutically acceptable extracts thereof. salts thereof. 65 Suitable classes of anti-anxiety agents for administering in Suitable MAOIs for administering in combination with combination with compounds of the present invention compounds of the present invention include: isocarboxazid, include 5-HT agonists or antagonists, especially 5-HT US 7,402,687 B2 25 26 partial agonists, neurokinin recepter (NK) antagonists (e.g., of formula I in combination with an SSRI. In certain embodi saredutant and osanetant) and corticotropin releasing factor ments, the SSRI is fluoxetine, Venlafaxine, paroxetine, dulox (CRF) antagonists. Suitable 5-HT, receptor agonists or etine, or Sertraline. antagonists that may be used in the present invention include, According to another embodiment, compounds of the in particular, the 5-HT, receptor partial agonists , present invention are useful for treating a variety of eating , gepirone and , and pharmaceutically disorders. In certain embodiments, the eating disorder is acceptable salts thereof. An example of a compound with hyperphagia, bulimia oranorexia nervosa. In certain embodi 5-HT, /partial agonist activity ispindolol. ments, compounds of the present invention are useful for new 5HT agonists Variza, alnespirone, gepirone, sune treating gastrointestinal disorders, such as malfunction of pitron, MKC242, villazodone, eptapirone, and ORG12962 10 gastrointestinal motility or intestinal propulsion. Compounds from Organon; new 5HT antagonists such as robalZotan; of the present invention are also useful in connection with new 5-HT agonists Such as elZasonan; new 5HT antago weight loss or control (e.g., reduction in calorie or food nists such as YM-992 (from Yamanouchi Pharmaceuticals) intake, and/or appetite Suppression). Such methods are par and nemifitide. ticularly useful for treating obesity with its consequent According to the present invention, the inventive combina 15 comorbidities including diabetes insipidus, Type II diabetes, tions may be administered in conjunction with one or more cardiovascular disease, hypertension, hyperlipidemia, stroke, other agents that is useful intreating depression or other mood osteoarthritis, sleep apnea, gallbladder disease, gout, some disorders. Alternatively or additionally, inventive combina cancers, Some infertility, and early mortality. tions may be administered with one or more other pharma In certain embodiments, compounds of the present inven ceutical agents active in treating any other symptom or medi tion are administered in combination with one or more anti cal condition present in the mammal that is related or obesity agents. Such anti-obesity agents are known in the art unrelated to the depression or mood disorder being experi and include apolipoprotein-B secretion/microsomal triglyc enced by the mammal. Examples of Such pharmaceutical eride transfer protein (apo-B/MTP) inhibitors, 11B-hydroxy agents include, for example, anti-angiogenic agents, anti steroid dehydrogenase-1 (11 (B-HSD type 1) inhibitors, neoplastic agents, anti-diabetic agents, anti-infective agents, 25 PYY, and analogs thereof, MCR-4 agonists, cholecystoki pain-relieving agents, anti-psychotic agents, gastrointestinal nin-A (CCK-A) agonists, monoamine reuptake inhibitors agents, etc., or combinations thereof. Other pharmaceutical (such as Sibutramine), sympathomimetic agents, R3 adrener agents useful in the practice of the present invention include, gic receptoragonists, dopamine agonists (such as bromocrip for example, adjunctive therapies typically used to enhance tine), melanocyte-stimulating hormone receptor analogs, the effects of an antidepressant. Such adjunctive agents may 30 cannabinoid 1 receptor antagonists (e.g., rimonabant), mela include, for instance, mood stabilizers (e.g., lithium, Valproic nin concentrating hormone antagonists, (the OB pro acid, carbamazepine, etc.); , stimulants (e.g., meth tein), analogs, leptin receptoragonists, antago ylphenidate, dextroamphetamine, etc.); or thyroid augment nists, lipase inhibitors (such as tetrahydrolipstatin, i.e. ing agents (e.g., Ts); anti-psychotics, anti-anxiety agents orlistat), anorectic agents (such as a agonist), Neu (e.g., ), and/or agents that relieve sexual dys 35 ropeptide-Y receptor antagonists, thyromimetic agents, function (e.g., buspirone, which also has anti-anxiety effects; dehydroepiandrosterone oran analog thereof, glucocorticoid dopaminergic agents such as amantadine, pramipexole, receptor agonists or antagonists, receptor antagonists, bupropion, etc.). binding protein antagonists, -like pep As 5-HT, modulators, compounds of the present inven tide-1 receptor agonists, ciliary neurotrophic factors (such as tion are useful for treating a variety of disorders. Such disor 40 Axokine'), human agouti-related proteins (AGRP), ghrelin ders include premenstrual syndrome (PMS), premenstrual receptor antagonists, histamine 3 receptor antagonists or dysphoric disorder (PMDD), motion or motor disorders such inverse agonists, and receptor agonists. as Parkinson's disease; chronic fatigue syndrome, anorexia In other embodiments, a compound of the present inven nervosa, disorders of sleep (e.g., sleep apnea), and mutism. tion is administered in combination with an anti-obesity agent 45 selected from orlistat, Sibutramine, , ephedrine, Premenstrual dysphoric disorder, or PMDD, is a severe leptin, rimonabant, pseudoephedrine, PYY3.36 or an analog form of PMS. Like PMS, PMDD typically occurs the week thereof, and 2-oxo-N-(5-phenylpyrazinyl)spiro-isobenzofu before the onset of menstruation and disappears a few days ran-1 (3H), 4-piperidine-1-carboxamide. According to after. PMDD is characterized by severe monthly mood Swings and physical symptoms that interfere with everyday another aspect of the invention, a compound of the present 50 invention is administered in combination with an anti-obesity life, especially a woman’s relationships with her family and agent in conjunction with typical treatments for obesity Such friends. PMDD symptoms go far beyond what are considered as exercise and a sensible diet. manageable or normal premenstrual symptoms. According to another embodiment, a compound of the PMDD is a combination of symptoms that may include present invention is administered in combination with one or irritability, depressed mood, anxiety, sleep disturbance, diffi 55 more agents for treating diabetes and associated conditions. culty concentrating, angry outbursts, breast tenderness and In certain embodiments, a compound of the present invention bloating. The diagnostic criteria emphasize symptoms of is administered in combination with one or more such agents depressed mood, anxiety, mood Swings or irritability. The including and insulin analogs (e.g., LysPro Insulin); condition affects up to one in 20 American women who have GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36) NH; sul regular menstrual periods. According to another embodi 60 fonylureas and analogs thereof: chlorpropamide, glibencla ment, the present invention provides a method for treating one mide, tolbutamide, tolaZamide, acetohexamide, Glypizide R. or more symptoms associated with PMDD. glimepiride, repaglinide, meglitinide; biguanides: met Selective serotonin reuptake inhibitors (SSRIs) are the cur formin, phenformin, buformin; “2-antagonists and imidazo rent preferred method for treating symptoms associated with lines: midaglizole, isaglidole, deriglidole, idazoxan, efar PMDD. According to another aspect, the present invention 65 oxan, fluparoxan; other insulin secretagogues: linogliride, provides a method for treating PMDD, or one or more symp A-4166; glitaZones: ciglitaZone, ActoSR) (pioglitaZone), toms associated with PMDD, by administering a compound englitaZone, troglitaZone, darglitaZone, Avandia(R) US 7,402,687 B2 27 28 (BRL49653); fatty acid oxidation inhibitors: clomoxir, eto associated with prostatitis, prostatic hypertrophy, interstitial moxir; glucosidase inhibitors: acarbose, miglitol, emiglitate, cystitis, urinary tract infections or vaginitis. The methods of voglibose, MDL-25,637, camiglibose, MDL-73,945: this invention may also be used to assist in inhibition or 13-agonists: BRL 35135, BRL 37344, RO 16-87.14, ICI correction of the conditions of Frequency-Urgency Syn D7114, CL 31 6.243; or phosphodiesterase inhibitors: L-386, drome, and lazy bladder, also known as infrequent voiding 398. syndrome. In other embodiments, a compound of the present inven Compounds of the present invention may also be used to tion is administered in combination with one or more lipid treat, prevent, inhibit, or limit the urinary incontinence, uri lowering agents: benfluorex: Vanadate and Vanadium com nary instability or urinary urgency associated with or result plexes (e.g., Nagiivan R) and peroxovanadium complexes; 10 ing from administrations of other medications, including antagonists; glucagon antagonists; gluconeogenesis diuretics, vasopressin antagonists, anticholinergic agents, inhibitors; somatostatin analogs; antilipolytic agents: nico sedatives or hypnotic agents, narcotics, alpha-adrenergicago tinic acid, acipimox, WAG 994, (Symlin'), AC nists, alpha-adrenergic antagonists, or calcium channel 2993, nateglinide, aldose reductase inhibitors (e.g., Zopolr blockers. estat), glycogen phosphorylase inhibitors, Sorbitol dehydro 15 Compounds of the present invention are useful for induc genase inhibitors, Sodium-hydrogen exchanger type 1 (NNE ing or assisting in urinary bladder control or preventing or 1) inhibitors and/or cholesterol biosynthesis inhibitors or treating the maladies described herein in humans in need of cholesterol absorption inhibitors, especially a HMG-CoA Such relief, including adult and pediatric uses. They may also reductase inhibitor, or a HMG-CoA synthase inhibitor, or a be utilized for veterinary applications, particularly including HMG-CoA reductase or synthase gene expression inhibitor, a canine and feline bladder control methods. If desired, the CETP inhibitor, a bile acid sequesterant, a fibrate, an ACAT methods herein may also be used with farm animals, such as inhibitor, a squalene synthetase inhibitor, or an anti-oxidant. ovine, bovine, porcine and equine breeds. In other embodiments, a compound of the present invention is According to the present invention, compounds of the administered in combination with one or more naturally present invention may be administered alone to modulate occurring compounds that acts to lower plasma cholesterol 25 bladder activity, or alternatively may be administered in com levels. Such naturally occurring compounds are commonly bination with (whether simultaneously or sequentially) one or referred to as nutraceuticals and include, for example, garlic more other pharmaceutical agents useful in the modulation of extract, Hoodia plant extracts, and niacin. bladder activity. Alternatively or additionally, the compounds In certain embodiments, compounds of the present inven of the present invention may be administered in combination tion are useful for inducing, assisting or maintaining desirable 30 with one or more other pharmaceutical agents useful in the bladder control in a mammal. The methods are particularly treatment or prevention of one or more other symptoms, useful for treating a mammal that is experiencing or suscep disorders, or diseases suffered by the individual in need of tible to bladder instability or urinary incontinence. Inventive bladder activity modulation. methods include prevention, treatment or inhibition of blad Other pharmaceutical agents useful in the modulation of der-related urinary conditions and bladder instability, includ 35 bladder activity, and particularly for treatment, prevention, ing idiopathic bladder instability, nocturnal enuresis, noc inhibition, and/or amelioration of urinary incontinence, turia, Voiding dysfunction and urinary incontinence include, for example, desmopressin acetate (available as (including, for example, stress incontinence, urge inconti DDAVPR Nasal Spray and DDAVPR tablets from Aventis nence, and/or mixed incontinence). Also treatable or prevent Pharmaceuticals), as well as a desmopressin acetate rhinal able by administration of a compound of this invention is 40 tube (available from Ferring Pharmaceuticals Inc.). Other bladder instability secondary to prostate hypertrophy, as is a products include, for example, tolterodine tartrate (available method for enhancing urethral tone and reducing undesirable as DetrolTM tablets from Pharmacia & Upjohn), oxybutinin urine leakage even in an otherwise healthy person. For chloride (available in the form of Ditropan R tablets and syrup example, the inventive methods are applicable to alleviating and Ditropan XLR extended release tablets from ALZA Phar urine leakage often occurring in women during the first year 45 maceuticals), propanthaline bromide (available in tablet form after childbirth. from Roxane Laboratories, Inc.), hyoscyamine and hyos In other embodiments, the present compounds are useful cyamine sulfate (available, respectively, as CystopazR) tablets for treating urine retention or detrusor sphincter dyssynergia. and Cystopaz-M(R) timed release capsules from PolyMedica Patients suffering from urine retention include those suffering Pharmaceuticals (U.S.A.), Inc.), hyoscyamine hydrobro from spinal cord injuries or male patients with benign pros 50 mide, flavoxate HCl (available in Urispas(R) 100 mg tablets tatic hyperplasia. from ALZA Pharmaceuticals), imipramine HCl (available in According to the present invention, a compounds of the 10 mg, 25 mg and 50 mg tablets from Geneva Pharmaceuti present invention is also useful in promoting the temporary cals, Inc.), phenylpropanolamine, midodrine HCl (available delay of urination whenever desirable. Such compounds may in 2.5 mg and 5 mg Proamatine(R) tablets from Shire US Inc.), be utilized in accordance with the present invention to stabi 55 HCl (available as Dibenzyline(R) capsules lize the bladder in any applicable context. Inventive methods from WellSpring Pharmaceuticals Corporation), and therefore may be utilized to allow a recipient to control the HCl (available in Minipress(R capsules from Pfizer Inc.). urgency and frequency of urination. Each of these medicaments may be administered in the phar In some embodiments of the invention, compounds of the maceutically effective amounts and regimens known in the present invention are administered to a mammal in need 60 art, including those listed in the Physicians’ Desk Reference, thereof for the treatment, prevention, inhibition and/or ame 55 Edition, 2001, published by Medical Economics Com lioration of urge urinary incontinence (also known as bladder pany, Inc. at Monvale, N.J.07645-1742, the relevant portions instability, neurogenic bladder, voiding dysfunction, hyper of which are incorporated herein by reference. active bladder, detrusor overactivity, detrusor hyper-reflexia Yet other pharmaceutical agents that can act to modulate or uninhibited bladder) or mixed urinary incontinence. Inven 65 bladder activity include, for example, other regulators of the tive uses include, but are not limited to, those for bladder 5HT, receptor. For example, United States Patent Applica activities and instabilities in which the urinary urgency is tion 2004/0235856 (previously incorporated herein by refer US 7,402,687 B2 29 30 ence in its entirety) describes a variety of 5HT, receptor (“DSM-IV), which was prepared by the Task Force on modulators that are useful in accordance with the practice of Nomenclature and Statistics of the American Psychiatric the present invention. Additional 5HT agonists are exem Association. The criteria for substance dependence set forth plified in Bishop et al., Expert Opin. Ther. Patent 13:1691 in DSM-IV is a pattern of substance use, leading to clinically 1705, 2003, the entire contents of which are incorporated significant impairment or distress as manifested by at least herein by reference. three selected from the following group, occurring at any time Still other pharmaceutical agents that can act to modulate within the same twelve month period: (1) tolerance as defined bladder activity include, for example, modulators of one or by either (a) a need for substantially increased amounts of the more KCNO potassium channels. In some embodiments of substance to achieve the desired effect; or (b) substantially the present invention, compounds of the present invention are 10 diminished effect with continued use of the same amount of administered in conjunction with one or more agonists of the substance; (2) withdrawal, as demonstrated by either (a) KCNQ 2/3 or KCNQ3/5. Such KCNQ modulators include, the characteristic withdrawal syndrome for the specific sub for example, compounds described in U.S. Pat. No. 5,384.330 stance; or (b) the same, or a closely related Substance is taken and those described in U.S. Pat. No. 5,565,483, as well as to relieve or avoid withdrawal symptoms; (3) the substance is those described in U.S. Patent Application Ser. No. 2002/ 15 often taken in larger amounts or over alonger period then was 0183395; and U.S. Patent Application Ser. No. 2004/ intended; (4) there is a persistent desire or unsuccessful 0029949. The entire contents of each of these patents and efforts to cut down or control substance use; (5) a great deal of patent applications is incorporated herein by reference. In time is spent in activities to obtain the Substance, use the Some embodiments of the present invention, compounds of Substance, or recover from its effects; (6) important Social, the present invention are administered with retigabine. occupational or recreational activities are given up or reduced In some embodiments of the present invention, compounds because of Substance use; and (7) the Substance use is con of the present invention are administered in conjunction with tinued despite knowledge of having a persistent or recurrent one or more compounds which act as vasopressin agonists physical or psychological problem that is likely to have been including, but not limited to those described in U.S. Pat. No. caused or exacerbated by the Substance. Substance depen 6,194,407 (Failliet al.), U.S. Pat. No. 6,090,803 (Failliet al.), 25 dence can be with physiological dependence; that is evidence U.S. Pat. No. 6,096,736 (Ogawa et al.), and U.S. Pat. No. of tolerance or withdrawal is present, or without physiologi 6,096,735 (Ogawa et al.). cal dependence, where no evidence of tolerance or with In general, it will often be desirable in accordance with the drawal is present. Four of the conditions set forth in DSM-IV present invention to administer one or more compounds of the include remission. These types of remission are based on the present invention in conjunction with one or more alpha 30 interval of time that has elapsed since the cessation of depen adrenergic receptor agonists and/or one or more other sym dencies and whether there is continued presence of one or pathomimetic drugs. more of the symptoms included in the criteria for dependen According to the present invention, compounds of formula cies. I may be used to treat, prevent, or alleviate dependence, In certain embodiments, compounds of the present inven withdrawal, or symptoms thereof for any of a variety of 35 tion are useful for treating alcoholism (e.g., alcohol abuse, Substances including, for example, recreational Substances addiction and/or dependence including treatment for absti (e.g., alcohol, tobacco for example, nicotine), pharmaco nence, craving reduction and relapse prevention of alcohol logic agents (e.g., pain relievers for example, Vicodin(R), intake) and/or tobacco abuse (e.g., Smoking addiction, cessa Lortab(R), LorcetR), PercocetR), Percodan R, Tylox R, Hydro tion and/or dependence including treatment for craving codone, OxyContin R, methadone, , etc., tranquil 40 reduction and relapse prevention of tobacco Smoking). izers, stimulants, or sedatives), and illicit drugs (e.g., mari In evaluating Substance abuse in accordance with the juana, heroine, cocaine, ecstasy, LSD. PCP. present invention, reference may be made, for example, to the methamphetamine, etc.). National Survey on Drug Use and Health (NSDUH), which The term “substance abuse', as used herein, may be obtains information on nine different categories of illicit drug defined with reference to criteria set form in the Diagnostic 45 use: marijuana, cocaine, heroin, hallucinogens, inhalants, and and Statistical Manual of Mental Disorders, 4" Ed. (1994) nonmedical use of prescription-type pain relievers, tranquil (“DSM-IV), which was prepared by the Task Force on izers, stimulants, and sedatives. In these categories, hashish is Nomenclature and Statistics of the American Psychiatric included with marijuana, and crack is considered a form of Association. A feature of Substance abuse is a maladaptive cocaine. Several drugs are grouped under the hallucinogens pattern of Substance use manifested by recurrent and signifi 50 category, including LSD. PCP peyote, , mush cant adverse consequences related to the repeated use of rooms, and “Ecstasy” (MDMA). Inhalants include a variety substances. As recited in the DSM-IV, substance abuse is of Substances, such as amyl nitrite, cleaning fluids, gasoline, defined as maladaptive pattern of Substance abuse leading to paint, and glue. The four categories of prescription-type drugs clinicallyl significant impairment or distress, as manifested by (pain relievers, tranquilizers, stimulants, and sedatives) cover one (or more) of the following, occurring within a 12-month 55 numerous drugs available through prescriptions and some period: (1) recurrent Substance use resulting in a failure to times illegally “on the street.” Methamphetamine is consid fulfill major role obligations at work, school, or home; (2) ered a type of stimulant. Respondents are asked to report only recurrent Substance use in situations in which it is physically uses of drugs that were not prescribed for them or drugs they hazardous; (3) recurrent Substance-related legal problems; took only for the experience or feeling they caused. Over-the and (4) continued Substance use despite having persistent or 60 counter drugs and legitimate uses of prescription drugs are recurrent Social or interpersonal problems cause or exacer not included. NSDUH reports combine the four prescription bated by the effects of the substance. In addition, the DMS-IV type drug groups into a category referred to as “any psycho requires that the symptoms of substance abuse do not meet the therapeutics.” criteria for Substance dependence. The NSDUH categorizes alcohol abuse through use of The term “substance dependence', as used herein, may be 65 questions about the frequency of the consumption of alco defined with reference to criteria set form in the Diagnostic holic beverages, such as beer, wine, whiskey, brandy, and and Statistical Manual of Mental Disorders, 4" Ed. (1994) mixed drinks. An extensive list of examples of the kinds of US 7,402,687 B2 31 32 beverages covered is given to respondents prior to the ques toms are not due to a general medical condition and are not tion administration. A "drink' is defined as a can or bottle of better accounted for by another medical disorder. beer, a glass of wine or a wine cooler, a shot of liquor, or a The discontinued or reduction in use of ethanol (ethanol mixed drink with liquor in it. Times when the respondent only containing beverages) results in the onset of ethanol with had a sip or two from a drink are not considered as consump 5 drawal conditions. Ethanol withdrawal conditions are char tion. For this report, estimates for the prevalence of alcohol acterized by Symptoms that begin when blood concentrations use are reported primarily at three levels defined for both of ethanol decline sharply, within 4 to 12 hours after ethanol use has been stopped or reduced. These ethanol withdrawal males and females and for all ages as follows: symptoms include craving for ethanol; autonomic hyperac Current use—At least one drink in the past 30 days (includes 10 tivity (such as Sweating or pulse rate greater than 100); hand binge and heavy use). tremor; insomnia; nausea; Vomiting; transient visual, tactile, or auditory hallucinations or illusions; psychomotor agita Binge use-Five or more drinks on the same occasion at least tion; anxiety; and grand mal seizures. These symptoms often once in the past 30 days (includes heavy use). cause clinically significant distress or impairment in Social, Heavy use-Five or more drinks on the same occasion on at 15 occupational, or other important areas of functioning. The least 5 different days in the past 30 days present invention is most preferably used to alleviate one or more symptoms attributed to ethanol withdrawal when such The NSDUH also characterizes the use of tobacco prod symptoms are not due to a general medical condition and are ucts, including cigarettes, chewing tobacco, Snuff, cigars, and not better accounted for by another medical disorder. pipe tobacco. For analytic purposes, data for chewing tobacco According to another embodiment, a compound of the and Snuffare combined as "smokeless tobacco. Cigarette use present invention is administered in combination with one or is defined as Smoking part or all of a cigarette. Questions to more agents useful for treating Substance abuse. In certain determine nicotine dependence among current cigarette embodiments, a compound of the present invention is admin smokers also are included in NSDUH. Nicotine dependence istered in combination with one or more agents to treat is based on criteria from the Nicotine Dependence Syndrome 25 tobacco abuse. Such agents include nicotine receptor partial Scale (NDSS) or the Fagerstrom Test of Nicotine Depen agonists bupropion hypochloride (ZybanTM) and nicotine dence (FTND). replacement therapies. In other embodiments, compounds of the present invention According to yet another embodiment, a compound of the are useful for treating withdrawal from drug addiction includ present invention is administered in combination with one or ing addiction to nicotine, alcohol, and other Substances of 30 more agents to treat alcoholism, Such as opioid antagonists abuse. Individuals often suffer the symptoms of nicotine (e.g., naltrexone, ReViatM), nalmefene, disulfiram (Ant withdrawal as a consequence of the discontinued use of abuseTM), and acamprosate (CampralTM). tobacco in any form, including, but not limited to Smoking of In certain embodiments, a compound is administered in cigarette, cigar, or pipe tobacco, or the oral or intranasal combination with one or more agents for reducing alcohol ingestion of tobacco or chewing tobacco. Such oral or intra 35 withdrawal symptoms such as benzodiazepines, beta-block nasal tobacco includes, but is not limited to Snuff and chewing ers, , carbamazepine, , and tobacco. The cessation of nicotine use or reduction in the (NeurontinTM). In other embodiments of the invention, amount of nicotine use, is often followed within 24 hours by therapy utilizing compounds of the present invention is symptoms including dysphoric, depressed mood; light-head administered concomitantly with, in connection with, and/or edness; insomnia; irritability, frustration or anger, anxiety; 40 Subsequent to an educational and/or behavioral modification nervous tremor, difficulty concentrating; restlessness; program to enhance continued abstinence from Substance decreased heart rate; increased appetite or weight gain; and dependence or abuse. The method of the present invention the craving for tobacco or nicotine. These symptoms often may be particularly useful in treating symptoms of with cause clinically significant distress or impairment in Social, drawal often observed in rehabilitation or other treatment occupational, or other important areas of functioning. 45 programs. Therefore, the programs can be more effective by The discontinued or reduction in administration of an focusing on educational and behavioral modification goals, opioid, typically self-administration, through injection or further reducing the incidence of program non-completion. orally, through Smoking or intranasal ingestion, often results In certain embodiments, compounds of the present inven in the presence of a characteristic opioid withdrawal condi tion are useful for treating one or more intellectual deficit tion. This withdrawal condition can also be precipitated by 50 disorders comprising administering a compound of the administration of an opioid antagonist Such as naloxone or present invention. In other embodiments. Such intellectual maltrexone after opioid use. Opioid withdrawal is character deficit disorders include dementia, such as dementia of aging, ized by symptoms that are generally opposite to the opioid vascular dementia, mild cognitive impairment, age-related agonist effects. These withdrawal symptoms may include cognitive decline, and mild neurocognitive disorder, Alzhe anxiety; restlessness; muscle aches, often in the back and 55 imer's disease, and memory deficit, attention deficit disorders legs; craving for opioids; irritability and increased sensitivity (ADD, also known as Attention Deficit Hyperactivity Disor to pain; dysphoric mood; nausea or Vomiting; lacrimation; der or ADHD) in both children and adults. In certain embodi rhinorrhoea; papillary dilation; piloerection; Sweating; diar ments, the present invention provides a method of treating rhea, yawning; fever, and insomnia. When dependence is on ADD and/or ADHD in a pediatric patient comprising admin short-acting opioids, such as heroin, withdrawal symptoms 60 istering to said patient a compound of formula I or pharma usually occur within 6-24 hours after the last dose, while with ceutical composition thereof. longer-acting opioids, such as methadone, symptoms may In other embodiments, the present invention provides a take 2-4 days to emerge. These symptoms often cause clini method of treating one or more cognition disorders. Accord cally significant distress or impairment in Social, occupa ing to another aspect, the cognition disorder is a learning tional or other important areas of functioning. The present 65 disorder. Such learning disorders are known in the art and invention is most preferably used to alleviate one or more include autism, dyslexia, Asperger's syndrome, a neurobio symptoms attributed to opioid withdrawal when Such symp logical disorder similar to autism and characterized by seri US 7,402,687 B2 33 34 ous deficits in Social and communication skills; specific and vaginismus; and/or HSDD characterized by a woman learning disability, a disorder in one or more of the basic who has no or little desire to be sexual, and has no or few psychological processes involved in understanding or in sexual thoughts or fantasies. using spoken or written language, which may manifest itself According to another embodiment, a compound of the in an imperfectability to listen, think, speak, read, write, spell 5 present invention is administered in combination with one or or to do mathematical calculations; dysgraphia, a disorder more agents for treating male sexual dysfunction (e.g., male that causes difficulty with forming letters or writing within a erectile dysfunction). Such agents are known in the art and defined space; dyscalculia, a disorder that causes people to include a dopaminergic agent (e.g. D2, D3 or D4 agonists and have problems doing arithmetic and grasping mathematical ); an NPY () (preferably an concepts; dyspraxia, a problem with the body’s system of 10 NPY-1 and/or NPY-5 inhibitor); a melanocortin receptorago motion that interferes with a person’s ability to make a con nist or modulator or melanocortin enhancer; an NEP inhibi trolled or coordinated physical response in a given situation; tor; a PDE inhibitor (preferably, a coMP PDE-5 inhibitor); a visual perceptual deficit, difficulty receiving and/or process antagonist or modulator, and a soluble ing accurate information from the sense of sight, although secreted endopeptidase inhibitor (SEPi). In certain embodi there is nothing wrong with vision; and auditory perceptual 15 ments, a compound of the present invention is administered in deficit, difficulty receiving accurate information through combination with one or more agents for treating male sexual auditory means, even though there is no problem with hear dysfunction Such as alprostadil or sildenafil. ing. According to yet another embodiment, a compound of the In certain embodiments, the present invention provides a present invention is administered in combination with one or method for treating one or more impulsivity disorders (e.g. more agents for treating female sexual dysfunction. Such borderline personality disorder), disruptive behavior disor agents are known in the art and include receptor ders, or impulse control disorders. In certain embodiments, modulators (e.g., estrogen agonists and/or estrogen antago the present invention provides a method for treating nists); testosterone replacement agents, testosternone Tourette's syndrome (TS), an inherited, neurological disorder (Tostrelle), dihydrotestosterone, dehydroepiandrosterone characterized by repeated and involuntary body movements 25 (DHEA), a testosterone implant; egdehydroandrostendione, (tics) and/or uncontrollable Vocal sounds. estrogen, estrogen, medroxyprogesterone, medroxyprogest According to another aspect, the present invention pro erone acetate (MPA), a combination of estrogen and a methyl vides a method for treating one or more behavioral addictions testosterone hormone replacement therapy agent; Premarin, and addictive disorders. Behavioral addictions and addictive Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, Elleste disorders result from the intoxication one senses from the 30 Solo, Estring, Eastraderm TTS, Eastraderm Matrix, Derm release of brain chemicals (e.g., serotonin, adrenaline, epi estril, Premphase, Preempro, Prempak, Premique, Estratest, nepherine, etc.) during certain activities. Such disorders are Estratest HS, Tibolone, a dopaminergic agent; eg apomor known in the art and include gambling, sex addiction, eating phine or a selective D2, D3 or D2/Dagonist such as, prami disorders, spending addiction, rage/anger, workaholism, pexole and ropirinol, a NPY (neuropeptide Y) inhibito: ega exercise addiction, risk taking addictions, and perfectionism 35 NPY (neuropeptide Y) inhibitor such as a NPY1 or NPY5 to name a few. inhibitor, preferably NPY1 inhibitor, a melanocortin or a melanocortin enhancer, eg melanotan II, In certain embodiments, a compound of the present inven PT-14, PT-141, a NEP (neutral endopeptidase) inhibitor; a tion is administered in combination with one or more cogni PDE (phosphodiesterase) inhibitor, eg sildenafil, and/or a tive improvement agents. Such agents are well known in the 40 bombesin receptor modulator. art and include donepezil hydrochloride (AirceptTM) and According to the present invention, compounds of the other acetylcholinesterase inhibitors; galantamine, neuropro present invention are useful for treating any of a variety of tective agents (e.g., ); ADD/ADHD agents (e.g., different types of pain experienced by mammals, such as methylphenidate (Ritalin'"), (StratteraTM), humans. For example, the compounds of the present inven methylphenidate, sustained release (ConcertaTM) and 45 tion may be used to treat treating acute pain (short duration) or /dextroamphetamine (AdderallTM). chronic pain (regularly reoccurring or persistent), whether According to another aspect, the present invention pro centralized or peripheral. vides a method for treating sexual dysfunction comprising Examples of pain that can be acute or chronic and that can administering a compound of the present invention. In certain be treated in accordance with the methods of the present embodiments, the sexual dysfunction is associated with a 50 invention include inflammatory pain, musculoskeletal pain, depressive disorder. In other embodiments, the sexual dys bony pain, lumbosacral pain, neck or upper back pain, vis function is associated with treatment of a disorder by admin ceral pain, Somatic pain, neuropathic pain, cancer pain, pain istration of a serotonin reuptake inhibitor. Compounds of the caused by injury or Surgery Such as burn pain, or headaches present invention are useful for treating sexual dysfunction in Such as migraines or tension headaches, or combinations of the male and in the female. Such disorders include male 55 these pains. One skilled in the art will recognize that these erectile dysfunction (MED) and female sexual dysfunction pains may overlap one another. For example, a pain caused by (FSD), e.g. female sexual arousal disorder (FSAD). inflammation may also be visceral or musculoskeletal in In other embodiments, the present invention provides a nature. method for treating one or more disorders associated with In one embodiment of the present invention, one or more sexual dysfunction including: HSDD, characterized by a defi 60 compounds of the present invention is/are administered in ciency, or absence of sexual fantasies and desire for sexual mammals to treat chronic pain Such as neuropathic pain asso activity: FSAD, characterized by a persistent or recurrent ciated for example with damage to or pathological changes in inability to attain, or to maintain until completion of the the peripheral or central nervous systems; cancer pain; vis sexual activity, an adequate lubrication-Swelling response of ceral pain associated with for example the abdominal, pelvic, sexual excitement; FOD characterized by persistent or recur 65 and/or perineal regions or pancreatitis; musculoskeletal pain rent delay in, or absence of orgasm following a normal sexual associated with for example the lower or upper back, spine, excitement phase; Sexual Pain Disorders such as dyspareunia fibromylagia, temporomandibular joint, or myofascial pain US 7,402,687 B2 35 36 syndrome; bony pain associated with for example bone or accordance with the present invention may be with or without joint degenerating disorders such as osteoarthritis, rheuma peripheral or central sensitization. toid arthritis, or spinal Stenosis; headaches such migraine or The present invention also provides use of the compounds tension headaches; or pain associated with infections such as of the present invention to treat acute and/or chronic pains HIV, sickle cell anemia, autoimmune disorders, multiple scle associated with female conditions, which may also be rosis, or inflammation Such as osteoarthritis or rheumatoid referred to as female-specific pain. Such types of pain include arthritis. those that are encountered solely or predominately by In some embodiments, the compounds of the present females, including pain associated with menstruation, ovula invention are used to treat chronic pain that is neuropathic tion, pregnancy or childbirth, miscarriage, ectopic pregnancy, pain, visceral pain, musculoskeletal pain, bony pain, head 10 retrograde menstruation, rupture of a follicular or corpus ache, cancer pain or inflammatory pain or combinations luteum cyst, irritation of the pelvic viscera, uterine fibroids, thereof, in accordance with the methods described herein. adenomyosis, endometriosis, infection and inflammation, Inflammatory pain can be associated with a variety of medical pelvic organ ischemia, obstruction, intra-abdominal adhe conditions such as osteoarthritis, rheumatoid arthritis, Sur sions, anatomic distortion of the pelvic viscera, ovarian gery, or injury. Neuropathic pain may be associated with for 15 abscess, loss of pelvic Support, tumors, pelvic congestion or example diabetic neuropathy, peripheral neuropathy, post referred pain from non-gynecological causes. herpetic neuralgia, trigeminal neuralgia, lumbar or cervical In certain embodiments, a compound of the present inven radiculopathies, fibromyalgia, glossopharyngeal neuralgia, tion is administered in combination with a pain relieving reflex sympathetic dystrophy, casualgia, thalamic syndrome, agent. Examples of pain relieving agents that may be admin nerve root avulsion, or nerve damage cause by injury result istered with compounds of the present invention include, but ing in peripheral and/or central sensitization Such as phantom are not limited to, analgesics such as non-narcotic analgesics limb pain, reflex sympathetic dystrophy or postthoracotomy or narcotic analgesics; anti-inflammatory agents such as non pain, cancer, chemical injury, toxins, nutritional deficiencies, steroidal anti-inflammatory agents (NSAIDs), steroids or or viral or bacterial infections such as shingles or HIV, or anti-rheumatic agents; migraine preparations such as beta combinations thereof. Inventive treatment methods further 25 adrenergic blocking agents, ergot derivatives, or isomethep include treatments in which the neuropathic pain is a condi tene; antidepressants such as amitryptyline, tion secondary to metastatic infiltration, adiposis dolorosa, desipramine, or imipramine; anti-epileptics such as gabapen burns or central pain conditions related to thalamic condi tin, carbamazepine, topiramate, Sodium valproate or pheny tions. loin, C agonists; or selective serotonin reuptake inhibitors/ Neuropathic pains described above may also be, in some 30 selective norepinepherine uptake inhibitors, or combinations circumstances, classified as “painful Small fiber neuropa thereof. thies' such as idiopathic Small-fiber painful sensory neuropa One skilled in the art will recognize that some agents thy, or “painful large fiber neuropathies” such as demylinat described herein act to relieve multiple conditions such as ing neuropathy or axonal neuropathy, or combinations pain and inflammation, while other agents may just relieve thereof. Such neuropathies are described in more detail, for 35 one symptom Such as pain. A specific example of an agent example, in the J. Mendell et al., N. Engl. J. Med. 2003, having multiple properties is aspirin, where aspirin is anti 348: 1243-1255, which is hereby incorporated by reference in inflammatory when given in high doses, but at lower doses is its entirety. just an analgesic. The pain relieving agent may include any combination of the aforementioned agents, for example, the In another embodiment, the compounds useful in the 40 pain relieving agent may be a non-narcotic analgesic in com present invention may be administered to totally or partially bination with a narcotic analgesic. inhibit a neuropathic pain condition from developing. For Non-narcotic analgesics useful in the practice of the example, compounds of the present invention may be admin present invention include, for example, Salicylates Such as istered to a mammal who is at risk for developing a neuro aspirin, ibuprofen (MotrinR), Advil(R), ketoprofen (Orudis(R), pathic pain condition Such as a mammal who has contracted 45 naproxen (NaprosynR), acetaminophen, indomethacin or shingles or a mammal who is being treated for cancer. combinations thereof. Examples of narcotic analgesic agents In one embodiment, the compounds useful in the present that may be used in combination with compounds of the invention may be administered prior to or during a Surgical present invention include opioid analgesics Such as fentenyl, procedure to partially or totally inhibit development of pain Sufentanil, morphine, hydromorphone, codeine, oxycodone, associated with the Surgical procedure. 50 buprenorphine or pharmaceutically acceptable salts thereof As mentioned previously, the methods of the present inven or combinations thereof. Examples of anti-inflammatory tion may be used to treat pain that is somatic and/or visceral agents that may be used in combination with compounds of in nature. For example, Somatic pain that can be treated in the present invention include but are not limited to aspirin; accordance with the methods of the present invention ibuprofen, ketoprofen; naproxen; etodolac (Lodine(R): includes pain associated with structural or soft tissue injury 55 COX-2 inhibitors such as celecoxib (CelebrexR), rofecoxib experienced during Surgery, dental procedures, burns, or trau (Vioxx(R), Valdecoxib (Bextra(R), parecoxib, etoricoxib matic body injuries. Examples of visceral pain that can be (MK663), deracoxib. 2-(4-ethoxy-phenyl)-3-(4-methane treated in accordance with the methods of the present inven Sulfonyl-phenyl)-pyrazolo 1.5-b]pyridazine, 4-(2-oxo-3- tion include those types of pain associated with or resulting phenyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide, dar from maladies of the internal organs such as ulcerative colitis, 60 bufelone, flosulide, 4-(4-cyclohexyl-2-methyl-5-oxazolyl)- irritable bowel syndrome, irritable bladder, Crohn's disease, 2-fluorobenzenesulfonamide), meloxicam, nimeSulide, rheumatologic (arthralgias), tumors, gastritis, pancreatitis, 1-Methylsulfonyl-4-(1,1-dimethyl-4-(4-fluorophenyl)cyclo infections of the organs, or biliary tract disorders, or combi penta-2,4-dien-3-yl)benzene, 4-(1.5-Dihydro-6-fluoro-7- nations thereof. One skilled in the art will also recognize that methoxy-3-(trifluoromethyl)-(2)-benzothiopyrano (4.3-c) the pain treated according to the methods of the present inven 65 pyrazol-1-yl)benzenesulfonamide, 4.4-dimethyl-2-phenyl tion may also be related to conditions of hyperalgesia, allo 3-(4-methylsulfonyl)phenyl)cyclo-butenone, 4-Amino-N- dynia, or both. Additionally, chronic pain to be treated in (4-(2-fluoro-5-trifluoromethyl)-thiazol-2-yl)-benzene US 7,402,687 B2 37 38 sulfonamide, 1-(7-tert-butyl-2,3-dihydro-3,3-dimethyl-5- pharmaceutically acceptable carriers, excipients, or diluents. benzo-furanyl)-4-cyclopropyl butan-1-one, or their physi Such compositions are prepared in accordance with accept ologically acceptable salts, esters or Solvates; Sulindac (Cli able pharmaceutical procedures. Such as, for example, those norilR); diclofenac (VoltarenR); piroxicam (FeldeneR): described in Remingtons Pharmaceutical Sciences, 17th edi diflunisal (DolobidR), nabumetone (RelefenR), oxaprozin tion, ed. Alfonoso R. Gennaro, Mack Publishing Company, (Day proR), indomethacin (Indocin R); or steroids such as Easton, Pa. (1985), which is incorporated herein by reference Pediaped(R) prednisolone sodium phosphate oral solution, in its entirety. Pharmaceutically acceptable carriers are those Solu-MedrolR) methylprednisolone sodium succinate for carriers that are compatible with the other ingredients in the injection, Prelone(R) brand prednisolone syrup. formulation and are biologically acceptable. Further examples of anti-inflammatory agents that may be 10 The compounds of formula I or VII can be administered used for treating pain, for example associated with rheuma orally or parenterally, neat, or in combination with conven toid arthritis, in accordance with the present invention include tional pharmaceutical carriers. Applicable solid carriers can naproxen, which is commercially available in the form of include one or more Substances that can also act as flavoring EC-NaprosynR) release tablets, NaprosynR), AnaproxR) and agents, lubricants, solubilizers, Suspending agents, fillers, AnaproxR DS tablets and NaprosynR suspension from 15 glidants, compression aids, binders, tablet-disintegrating Roche Labs, Celebrex R brand of celecoxib tablets, Vioxx(R) agents, or encapsulating materials. In powders, the carrier is a brand of rofecoxib, Celestone(R) brand of betamethasone, finely divided solid that is in admixture with the finely divided Cupramine(R) brand penicillamine capsules, DepenR brand active ingredient. In tablets, the active ingredient is mixed titratable penicillamine tablets, Depo-MedrolR brand of with a carrier having the necessary compression properties in methylprednisolone acetate injectable suspension, AravaTM Suitable proportions and compacted in the shape and size leflunomide tablets, AZulfidine EN-tabs(R brand of sulfasala desired. The powders and tablets preferably contain up to zine delayed release tablets, FeldeneR brand piroxicam cap 99% of the active ingredient. Suitable solid carriers include, sules, Cataflam(R) diclofenac potassium tablets, Voltaren R. for example, calcium phosphate, magnesium Stearate, talc, diclofenac sodium delayed release tablets, Voltaren R-XR Sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cel diclofenac sodium extended release tablets, or Enbrel Reta 25 lulose, Sodium carboxymethyl cellulose, polyvinylpyrroli nerecept products. dine, low melting waxes and ion exchange resins. Examples of yet other agents used to treat inflammations, Liquid carriers can be used in preparing Solutions, Suspen especially rheumatoid arthritis, include immunosuppressants sions, emulsions, syrups and elixirs. The active ingredient can such as GengrafTM brand cyclosporine capsules, Neoral(R) be dissolved or Suspended in a pharmaceutically acceptable brand cyclosporine capsules or oral Solution, or Imuran R. 30 liquid carrier Such as water, an organic solvent, a mixture of brand azathioprine tablets or IV injection: Indocine(R) brand both, or a pharmaceutically acceptable oil or fat. The liquid indomethacin capsules, oral suspension or suppositories: carrier can contain other suitable pharmaceutical additives Plaquenil R) brand hydroxychloroquine sulfate; or Remi Such as, for example, solubilizers, emulsifiers, buffers, pre cade(R) infliximab recombinant for IV injection; or gold com servatives, Sweeteners, flavoring agents, Suspending agents, pounds such as auranofin or MyochrisyineR gold sodium 35 thickening agents, colors, viscosity regulators, stabilizers or thiomalate injection. osmo-regulators. Suitable examples of liquid carriers for oral As 5-HT, modulators, compounds of the present inven and parenteral administration include water (particularly con tion are useful for treating a variety of disorders. Such disor taining additives as above, e.g. cellulose derivatives, prefer ders include premenstrual syndrome, motion or motor disor ably sodium carboxymethyl cellulose solution), (in ders such as Parkinson's disease and epilepsy; migraines, 40 cluding monohydric alcohols and polyhydric alcohols e.g. chronic fatigue syndrome, anorexia nervosa, disorders of glycols) and their derivatives, and oils (e.g. fractionated coco sleep (e.g., sleep apnea), and mutism. nut oil and arachis oil). For parenteral administration, the In other embodiments, compounds of the present invention carrier can also be an oily ester Such as ethyl oleate and are useful for treating one or more central nervous system isopropyl myristate. Sterile liquid carriers are used in sterile deficiencies associated, for example, with trauma, stroke, and 45 liquid form compositions for parenteral administration. The spinal cord injuries, neurodegenerative diseases or toxic or liquid carrier for pressurized compositions can be haloge infective CNS diseases (e.g., encephalitis or meningitis), or nated hydrocarbon or other pharmaceutically acceptable pro Parkinson's disease. The compounds of the present invention pellant. can therefore be used to improve or inhibit further degrada Liquid pharmaceutical compositions that are sterile solu tion of central nervous system activity during or following the 50 tions or Suspensions can be administered by, for example, malady or trauma in question. Included in these improve intramuscular, intraperitoneal or Subcutaneous injection. ments are maintenance or improvement in motor and motility Sterile solutions can also be administered intravenously. skills, control, coordination and strength. Compositions for oral administration can be in either liquid or solid form. 5. Pharmaceutically Acceptable Compositions 55 The compounds of formula I or VII can be administered In other embodiments, the invention relates to composi rectally or vaginally in the form of a conventional Supposi tions comprising at least one compound of formula I or VII, or tory. For administration by intranasal or intrabronchial inha a pharmaceutically acceptable salt thereof, and one or more lation or insufflation, the compounds of formula I or VII can pharmaceutically acceptable carriers, excipients, or diluents. be formulated into an aqueous or partially aqueous solution, Such compositions include pharmaceutical compositions for 60 which can then be utilized in the form of an aerosol. The treating or controlling disease states or conditions of the compounds of formula I can also be administered transder central nervous system. In certain embodiments, the compo mally through the use of a transdermal patch containing the sitions comprise mixtures of one or more compounds of for active compound and a carrier that is inert to the active com mula I or VII. pound, is non-toxic to the skin, and allows delivery of the In certain embodiments, the invention relates to composi 65 agent for systemic absorption into the blood stream via the tions comprising at least one compound of formula I or VII, or skin. The carrier can take any number of forms such as creams a pharmaceutically acceptable salt thereof, and one or more and ointments, pastes, gels, and occlusive devices. The US 7,402,687 B2 39 40 creams and ointments can be viscous liquid or semisolid To evaluate the affinity of various compounds of formula I emulsions of either the oil-in-water or water-in-oil type. for activity at the 5-HT2C receptor, a CHO (Chinese Hamster Pastes comprised of absorptive powders dispersed in petro Ovary) cell line transfected with the cDNA expressing the leum or hydrophilic petroleum containing the active ingredi human 5-hydroxytryptamine-2C (h5-HT) receptor is main ent can also be suitable. A variety of occlusive devices can be used to release the active ingredient into the blood stream tained in DMEM (Dulbecco's Modified Eagle Media) sup Such as a semipermeable membrane covering a reservoir con plied with fetal calf serum, glutamine, and the markers: gua taining the active ingredient with or without a carrier, or a ninephosphoribosyl transferase (GTP) and matrix containing the active ingredient. Other occlusive hypoxanthinethymidine (HT). The cells are allowed to grow devices are known in the literature. 10 to confluence in large culture dishes with intermediate Preferably the pharmaceutical composition is in unit dos changes of media and splitting. Upon reaching confluence, age form, e.g. as tablets, capsules, powders, Solutions, Sus the cells are harvested by scraping. The harvested cells are pensions, emulsions, granules, or Suppositories. In Such form, Suspended in half Volume of fresh physiological phosphate the composition is sub-divided in unit dose containing appro buffered saline (PBS) solution and centrifuged at low speed priate quantities of the active ingredient; the unit dosage 15 (900xg). This operation is repeated once. The collected cells forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled Syringes or Sachets con are then homogenized with a polytron at setting #7 for 15 sec taining liquids. The unit dosage form can be, for example, a in ten volumes of 50 mM Tris.HCl, pH 7.4 and 0.5 mM capsule or tablet itself, or it can be the appropriate number of EDTA. The homogenate is centrifuged at 900xg for 15 minto any such compositions in package form. remove nuclear particles and other cell debris. The pellet is The amount of compound of formula I or VII provided to a discarded and the supernatant fluid recentrifuged at 40,000xg patient will vary depending upon what is being administered, for 30 min. The resulting pellet is resuspended in a small the purpose of the administration, such as prophylaxis or volume of Tris.HCl buffer and the tissue protein content is therapy, the state of the patient, the manner of administration, determined in aliquots of 10-25 uL volumes. Bovine Serum and the like. In therapeutic applications, compounds of for 25 Albumin (BSA) is used as the standard in the protein deter mula I are provided to a patient Suffering from a condition in mination by the method of Lowry et al., (J. Biol. Chem. an amount Sufficient to treat or at least partially treat the symptoms of the condition and its complications. An amount 193:265 (1951). The volume of the suspended cell mem adequate to accomplish this is a “therapeutically effective branes is adjusted with 50 mM Tris.HCl buffer containing: amount’ as described previously herein. The dosage to be 30 0.1% ascorbic acid, 10 mM pargyline and 4 mM CaCl to give used in the treatment of a specific case must be subjectively a tissue protein concentration of 1-2 mg per ml of suspension. determined by the attending physician. The variables The preparation membrane suspension (many times concen involved include the specific condition and the size, age, and trated) is aliquoted in 1 ml volumes and stored at -70 C until response pattern of the patient. The treatment of Substance used in Subsequent binding experiments. abuse follows the same method of subjective drug adminis 35 Binding measurements are performed in a 96 well micro tration under the guidance of the attending physician. Gener titer plate format, in a total volume of 200 uL. To each well is ally, a starting dose is about 5 mg per day with gradual added: 60 uL of incubation buffer made in 50 mM Tris.HCl increase in the daily dose to about 150 mg per day, to provide buffer, pH 7.4 and containing 4 mM CaCl; 20 uL of 'I the desired dosage level in the patient. DOI (S.A., 2200 Ci/mmol, NEN Life Science). In certain embodiments, the present invention is directed to 40 prodrugs of compounds of formula I. The term “prodrug. as The dissociation constant, K, of 'I DOI at the human used herein, means a compound that is convertible in vivo by serotonin 5-HT, receptor is 0.4 nM by saturation binding metabolic means (e.g. by hydrolysis) to a compound of for with increasing concentrations of' I DOI. The reaction is mula I. Various forms of prodrugs are known in the art such as initiated by the final addition of 100 uL of tissue suspension those discussed in, for example, Bundgaard, (ed.), Design of 45 containing 50 ug of receptor protein. Nonspecific binding is Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in measured in the presence of 1 uM unlabeled DOI added in Enzymology, Vol. 4, Academic Press (1985); Krogsgaard 20.0 uL volume. Test compounds are added in 20.0 uL. The Larsen, et al., (ed). "Design and Application of Prodrugs, mixture is incubated at room temperature for 60 min. The Textbook of Drug Design and Development, Chapter 5, 113 incubation is stopped by rapid filtration. The bound ligand 191 (1991), Bundgaard, et al., Journal of Drug Delivery 50 receptor complex is filtered off on a 96 well unifilter with a Reviews, 8:1-38(1992), Bundgaard, J. of Pharmaceutical Sci Packard RFiltermate 196 Harvester. The bound complex ences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) caught on the filter disk is dried in a vacuum oven heated to Prodrugs as Novel Drug Delivery Systems, American Chemi 60° C. and the radioactivity measured by liquid scintillation cal Society (1975), each of which is hereby incorporated by with 40 uL Microscint-20 scintillantina Packard TopCount(R) reference in its entirety. 55 equipped with six (6) photomultiplier detectors. EXAMPLES Specific binding is defined as the total radioactivity bound less the amount bound in the presence of 1 uM unlabeled Biological Assays DOI. Binding in the presence of varying concentrations of 60 test drugs is expressed as percent of specific binding in the The ability of the compounds of this invention to act as absence of drug. These results are then plotted as log 96 bound 5-HT agonists and partial agonists is established using sev VS log concentration of test drug. Nonlinear regression analy eral standard pharmacological test procedures; Such proce sis of data points yields both the ECs and the K values of test dures are provided below. In the test procedures, 5-HT stands compounds with 95% confidence limits. Alternatively, a lin for 5-hydroxytryptamine, mCPP stands for meta-chlorophe 65 ear regression line of decline of data points is plotted, from nylpiperazine, and DOI stands for 1-(2,5-dimethoxy-4-io which the ECso value can be read off the curve and the K, dophenyl)isopropylamine. value determined by Solving the following equation: US 7,402,687 B2 41 42

TABLE 3 C Ki = 50 1 + Lf KD ECso Data for Reference Compounds: Compound ECso 5-HT O.5 nM where L is the concentration of the radioactive ligand used DOI O.5 nM and the K is the dissociation constant of the ligand for the mCPP 5.4 nM receptor, both expressed in nM. 10 The following K.’s (95% confidence interval) are provided The entire disclosure of each patent, patent application, for various reference compounds in Table 2, below: and publication cited or described in this document is hereby incorporated by reference. TABLE 2 While we have presented a number of embodiments of this 15 invention, it is apparent that our basic construction can be K. Data for Reference Compounds altered to provide other embodiments which utilize the com Compound K pounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by Ritanserin 2.0 (1.3-3.1) nM 94.8 (70.7-127.0) nM the appended claims rather than by the specific embodiments Mianserin 2.7 (1.9-3.8) nM which have been represented by way of example. Clozapine 23.2 (16.0-34.0) nM Methiothepin 4.6 (4.0-6.0) nM We claim: 6.3 (4.6–8.6) nM 1. A compound of formula VII: Loxapine 33.0 (24.0-47.0) nM mCPP 6.5 (4.8-9.0) nM DOI 6.2 (4.9-8.0) nM 25

VII

The ability of the compounds of formula I to produce an agonist response at brain 5-HTC is assessed by determining their effect on calcium mobilization using the following pro 30 cedure: CHO cells stably expressing the human 5-HT, receptor are cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum and non-essential amino acids. Cells are plated at a density of 40 K cells/well in 96-well clear-bottom black-wall plates 24 35 hours prior to the evaluation of 5-HT, receptor-stimulated calcium mobilization. For calcium studies, cells are loaded with the calcium indicator dye Fluo-3-AM in Hank's buffered saline (HBS) for 60 minutes at 37° C. Cells are washed with or a pharmaceutically acceptable salt thereof, wherein: HBS at room temperature and transferred to the fluorometric 40 each -r-independently represents a single or double bond, imaging plate reader (FLIPR, Molecular Devices, Sunnyvale, provided that both -r-groups do not simultaneously Calif.) for acquisition of calcium images. Excitation at 488 represent a double bond; nm is achieved with an Argon ion laser and a 510-560 nm R" is hydrogen, —C(O)R, -Glu, —C(O)Glu, or C(O) emission filter is used. Fluorescence images and relative OGlu; 45 R is hydrogen or lower alkyl: intensities are captured at 1 second intervals and cells were R’ is hydrogen, -OH,-OS(O),OH, or —OGlu; stimulated by addition of agonist after 10 baseline measure R is hydrogen, halogen, methyl, methoxy, -OH, - OS ments using the internal fluidics module of the FLIPR. An (O) OH, or - OGlu: increase in fluorescence counts corresponds to an increase in R" is hydrogen, -OH,-OS(O),OH, or —OGlu; intracellular calcium. 50 R" and Rare each hydrogen or are taken together to form For the evaluation of agonist pharmacology the calcium an oxo moiety; changes in response to different concentrations of agonist are R and Rare each hydrogen or are taken together to form determined using a maximum minus minimum calculation of an oxo moiety; the raw fluorescence count data. Calcium changes are then each R is independently halogen or lower alkyl: expressed as a percentage of the response observed with a 55 each R is independently hydrogen, OH, - OS(O),OH, maximally effective concentration of 5-HT. ECso values are or —OGlu; estimated by non-linear regression analysis of the log-con each Glu is a glucuronyl moiety; and centration% maximum 5-HT response curves using the 4-pa n is one or two: rameter logistic function. In certain embodiments, com provided that at least one of R. R. R. and R contains a pounds of the present invention provide an ECso of sabout 60 glucuronyl moiety. 1000 nM. In other embodiments, compounds of the present 2. The compound according to claim 1, wherein R' is -Glu, invention provide an ECso of sabout 100 nM, in yet other - C(O)Clu, or - C(O)OGlu. embodiments sabout 20 nM, in still other embodiments 3. The compound according to claim 1, wherein R is sabout 5 nM, and certain embodiments sabout 2 nM. 65 —OH and R is hydrogen. The following ECsos are provided for various reference 4. The compound according to claim 1, wherein R is compounds in Table 3, below —OH and R is hydrogen. US 7,402,687 B2 43 44 5. The compound according to claim 1, wherein R is —OGlu and R is hydrogen. -continued 6. The compound according to claim 1, wherein said com pound is of formula VIII: IXb 5 R2

VIII F OH HO H OH N O OH HO OH 10 R. O r O O R RX OH O O 21

15 (R)-3

2O or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 1, wherein said com pound is of formula X or a pharmaceutically acceptable salt thereof. 25 7. The compound according to claim 1, wherein said com pound is of formula IX, IXa, or IXb:

IX 30

R2 X

F OH H N OH R4 O 35 O RX 21 RX OH N X O OH 40 (R)-3 IXa R2 OH F HO HO OH OH H 45 OH N R4 O O OH O R RX 21 O 50 N X or a pharmaceutically acceptable salt thereof.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 7,402,687 B2 Page 1 of 1 APPLICATIONNO. : 1 1/409479 DATED : July 22, 2008 INVENTOR(S) : Stack et al.

It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Title Page Item 75) On Page 1, under Inventors please delete William Demaio and replace with William DeMaio.

Signed and Sealed this Fourteenth Day of October, 2008 WDJ

JON. W. DUDAS Director of the United States Patent and Trademark Office