USOO6472422B2 (12) United States Patent (10) Patent No.: US 6,472,422 B2 Kozikowski et al. (45) Date of Patent: Oct. 29, 2002

(54) ANALOGS OF Clarke, R.L., et al., “Compounds Affecting the Central Nervous System.4.3B--2-carboxylic Esters (75) Inventors: Alan P. Kozikowski, Princeton, NJ and Analogs”,Journal of Medicinal Chemistry, vol. 16, No. (US); Gian Luca Araldi, Washington, 11, p. 1260–1267, (1973). DC (US) Clarke, R.L., et al., “In pursuit of analgetic agents. Hydro-1, 3-ethanoindeno2,1-cpyridines and homologs”,Journal of (73) Assignee: Georgetown University, Washington, Medicinal Chemistry, vol. 17, No. 10, pp. 1040–1046, DC (US) (1974). Engestoft, M., et al., “Synthesis and 5HT modulating activ (*) Notice: Subject to any disclaimer, the term of this ity of Stereoisomers of patent is extended or adjusted under 35 3-phenoxymethyl-4-phenylpiperidines, Acta Chemica U.S.C. 154(b) by 0 days. Scandinavica, vol. 50, pp. 164-169, (1996). Kozikowski, A.P., et al., “Chemistry and pharmacology of (21) Appl. No.: 09/769,774 the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton”, J. Med. (22) Filed: Jan. 25, 2001 Chem., vol. 41, pp. 1962–1969, (1998). (65) Prior Publication Data Lambrecht, G., et al., “Structure-activity relations of Sub Stituted aromatic piperidine derivatives. 1. Esters of 4-phe US 2002/005.5521A1 May 9, 2002 nyldihydroarecaidine”, Arch. Pharm. (Weinheim, Germany), (1975). Related U.S. Application Data Pandiarajan, K., et al., “ASSignment of the configuration of (63) Continuation of application No. 09/056,727, filed on Apr. 7, a Substituent in Saturated Six-membered ring compounds 1998, now Pat. No. 6,180,648. using the 13C chemical shifts of a Single epimer, Magnetic (60) Provisional application No. 60/042,775, filed on Apr. 7, Resonance in Chemistry, vol. 31, pp. 80-80, (1993). 1997. Reith, M.E., et al., "Structural requirements for cocaine congeners to interact with 3H batrachotoxinin in 20-alpha (51) Int. Cl." ...... A61K31/35; CO7D 315/00 -benzoate binding Sites on channels in mouse brain synaptosomes”, J. Biol. chem., (1986). (52) U.S. Cl...... 514/451; 549/425; 549/426; Reith, M.E., et al., “Structure activity relationships for 549/427; 549/428 cocaine congeners in inhibiting dopamine uptake into rat (58) Field of Search ...... 549/425, 426, brain Synaptic vesicles and bovine chromaffin granule 549/427, 428; 514/451 ghosts”, The Journal of Pharmacology and Experimental Therapeutics, vol. 271, No. 3, pp. 1444–1452, (1994). (56) References Cited Willcocks, K., et al., “The synthesis of 14C-3S, 4R-(4-fluorophenyl)-=3-(3.4-methylenedioxyphenoxym U.S. PATENT DOCUMENTS ethyl)piperidine hydrochloride (BRL 29060A), and mecha 3,912,743 A 10/1975 Christensen et al...... 546/197 nistic Studies using carbon-13 labeling”, J. Labelled Compa. 4,007,196 A 2/1977 Christensen et al...... 546/197 Radiopharm., vol. 33, No. 8, pp. 783–794, (1993). 4,877,799 A 10/1989 Drejer et al...... 514/317 * cited by examiner

5,208.232 A 5/1993 Jacobsen et al. .. 514/228.2 Primary Examiner-Ceila Chang 5,760,073 A * 6/1998 Urbahns et al...... 514/451 (74) Attorney, Agent, or Firm-Dana M. Gordon; Foley FOREIGN PATENT DOCUMENTS Hoag LLP DE 3441929 A1 5/1986 (57) ABSTRACT EP O 339 579 A2 11/1989 EP O 339 579 B1 7/1998 The invention provides a compound of formula (I): WO WO 93/081.66 * 4/1993 OTHER PUBLICATIONS (I) Wilkenson et al. “Electrostatic interactions and conforma tion of some thromboxane antagonists’ CA 110:88001 (1989).* Yamaguchi et al. “A highly Steroselective Michael reaction of Simple ester enolates toalpha-beta-unsaturated esters' CA 102:131516 (1985).* Pandiarajan et al.; XP-002074607, Magnetic Resonance in wherein R', R, R, and Y have any of the meanings defined Chemistry vol. 31(1): 80–89, (1993). in the Specification; as well a pharmaceutical composition “Chemical Abstracts”, vol. 109, No. 1, Beecham Group comprising a compound of formula I; intermediates and PLC, UK-Columbus, Ohio, (Jul. 4, 1988). methods useful for preparing a compound of formula I; and "Preparation of Arylpyridy carbinol derivaties as antidepres therapeutic methods for treating drug addiction, Parkinson's sants”, Beecham Group PLC, (1985). disease or depression comprising administering a compound “Preparation of Nicotinate ester derivatives as intermediates for antidepressants”, Chemical Abstracts, vol. 107, No. 15, of formula I, to a mammal in need of Such treatment. (Oct. 12, 1987). 11 Claims, 10 Drawing Sheets U.S. Patent Oct. 29, 2002 Sheet 1 of 10 US 6,472,422 B2

Figure 1

NCO2Me MeO2C 2 C Me- C ------Me-N y Me-N E 1 N s Sa '', Br Me H H w E. CO2Me 1, cis isomer (racernic) 2, trans isomer (racernic)

C C M. MeO2, O.a C. - "M Mos %sers and Me-N-MeO2C f H H 1 (racemic) (-)-3, old = -56 (+)-4, or = +56

C Me-N C - "ROHOCH % C - . HOCH . . F. f F (-)-9 (-)-5 (+)-6

C C AcOCH2 e. K AcOCH2 Me-N- Sesa Me-N-N F. F (-)-7 (+)-8

MeOC C MeO2C 2 C.al --ax-a--- RCs f H

U.S. Patent Oct. 29, 2002 Sheet 3 of 10 US 6,472,422 B2

Figure 3

C C C

MeO2C. e No e 11 16, minor SOmer 17, major somer 6a, R = n-Pr 17a, R = n-Pr 16b, R = CH2OH 17b, R = CH2OH U.S. Patent Oct. 29, 2002 Sheet 4 of 10 US 6,472,422 B2

Figure 4 CFs

NS CO2Me MeC2C,

MeN Me 8

NO2 CNS MeO2C, MeO2C, orsemes M 9 Me 2O

NH2 X nS 2. MeO2C. -- MeO2C. ( 22a-c, X = Br, l, N3 Me 2 M L X semes MeO2C. n 23a-b, X = NHAC or NHCOOEt Me Amide analogs

s Me es ZnCl, Med2C. Hiaasenees MeO2C. PoCl2(PPh3)2 Me 22 Me 24 isopropenyl derivative U.S. Patent Oct. 29, 2002 Sheet 5 of 10 US 6,472,422 B2

Figure 5

X X X Z MeO2C MeO2C. al re- it. alliame---

Me 25 26 27

4. a C Me 28 U.S. Patent Oct. 29, 2002 Sheet 6 of 10 US 6,472,422 B2

Figure 6

---art- de racemic material f 30a, x = O, cis isoner 31a, x - O trans isomer 29, X = O and CH2 30b, X = CH2 31b, X is CH2 U.S. Patent Oct. 29, 2002 Sheet 7 of 10 US 6,472,422 B2

Figure 7

X X X n a MeO2C, -- Meoc -- Meoc,

Me N 32 33 11, X = Cl U.S. Patent Oct. 29, 2002 Sheet 8 of 10 US 6,472,422 B2

Figure 8

C C

HMel MeO2C, memorale MeO2C, N N

32 CT3 4. U.S. Patent Oct. 29, 2002 Sheet 9 of 10 US 6,472,422 B2

Figure 9

MeO2C. OHC R-CH-PPh3 U.S. Patent Oct. 29, 2002 Sheet 10 Of 10 US 6,472,422 B2

Figure 10

X X n R 2 HO2C. --alm-mamma- N^Yo-e, Me 45 M. 46 US 6,472,422 B2 1 2 ANALOGS OF COCAINE Several others involving Steric hindrance, distinct but over lapping sites or multiple binding Sites in which at least one This application is a continuation of U.S. patent appli is required for both cocaine and dopamine binding. In cation Ser. No. 09/056,727, filed Apr. 7, 1998, now U.S. Pat. addition, a recent Study using rotating disk electrode 6,180,648, issued Jan. 30, 2001. Voltammetry, which is capable of monitoring uptake with a 50 msec resolution, Suggests that cocaine inhibits dopamine GOVERNMENT FUNDING uptake uncompetitively while competitively blocking Na' and Cli binding to the carrier. While these data have not The invention described herein was made with U.S. been validated using other experimental approaches, they Government support under grant DA11546 awarded by the further Support the idea that the cocaine and dopamine National Institutes of Health, National Institute on Drug binding Sites are unique. Abuse. N-Ethylmaleimide (NE) is capable of inhibiting about PRIORITY OF INVENTION 95% of the specific binding of Hmazindol, and the effect of 10 mM N-ethylmaleimide is completely prevented by 10 This application claims priority under 35 U.S.C. S119(e) 15 luM cocaine, while neither 300 uM dopamine nor from U.S. Provisional patent application Ser. No. 60/042, d-amphetamine afforded any Significant protection. 775, filed Apr. 7, 1997. Furthermore, a recent Study of the Structure of the dopamine transporter revealed that aspartate and Serine residues lying BACKGROUND OF THE INVENTION within the first and seventh hydrophobic putative membrane Cocaine abuse is one of the greatest concerns of the Spanning regions were critical for dopamine uptake, but leSS American public today, and has therefore become a focus of so for HICFT (WIN-35428) binding. For example, medical, Social and political leaders. Cocaine is one of the replacement of the serine residues at positions 356 and 359 most addictive Substances known, and addicts may lose their in the Seventh hydrophobic region by alanine or glycine ability to function at work or in interpersonal Situations. reduced HDA uptake, whereas HICFT (WIN-35428) Drug dependence and the great profits that are made 25 binding was less affected. More recent experiments with DA throughout the distribution network of cocaine have fueled and NE transporter chimeras show that transmembrane a rise in drug-associated crime in the United States and in domains 6-8 determine cocaine binding while domains Colombia. Although the incidence of casual cocaine use has 9-12 plus the carboxy tail are responsible for DA binding decreased Substantially in the last few years, the number of affinity. Thus, these data Support the hypothesis that a weekly users is rising. The rise has accompanied a change in Significant portion of the cocaine binding domain on the the chemical form often used to free base, or "crack,” and dopamine transporter is distinct from that of either dopamine the route of administration used from nasal to inhalation by or amphetamine. This distinction may be Sufficient to allow Smoking or intravenous injection. properly designed drugs to prevent cocaine binding without Psychological and behavioral approaches are important in inhibiting dopamine uptake. a treatment program because peer pressure and environmen 35 The most promising agents for treating cocaine abuse, tal cues are closely associated with a relapse to addiction. may be agents which possess the ability to mimic partially However, behavioral observations have identified a window the effects of cocaine, thereby helping to maintain individu of about ten weeks after cessation of cocaine use where the als in treatment programs while they slowly withdraw from cocaine. Such an agent would function like methadone, a Susceptibility to relapse is greatest. Clearly, there is a need 40 to increase the Success rate of outpatient detoxification drug widely used in the treatment of opiate abuse. A com programs through the development of pharmacological pound with methadone-type activity against cocaine abuse is agents that will assist during this critical period. likely to be a partial agonist of cocaine; namely, a Substance that elicits. Some of the same effects in the user as cocaine Currently a number of treatment Strategies are being itself, but without causing the same degree of euphoria. looked at using CNS agents developed for other indications. 45 The agents being tried include, among others, the indirect Ideally, the compound should have little or no abuse liability. dopamine agonist, , the direct agonist Thus there is currently a need for therapeutic agents that bromocriptine, the partial mu opiate receptor agonist, can be used to treat cocaine abuse. bupre norphine, and the tricyclic antidepressant, SUMMARY OF THE INVENTION . While these agents appear to depress either 50 Self-administration or cocaine "craving under certain The present invention provides a compound of formula circumstances, these Studies are Still in their early Stages and (I): the efficacy of Such treatments has not been established. The behavioral properties of cocaine, including its abili (I) ties to act as a reinforcer, are thought to Stem from its ability 55 to inhibit the reuptake of dopamine (DA). While cocaine also has the ability to act as an inhibitor of Serotonin and norepinephrine uptake as well as to bind to Sigma opiate and muscarinic receptors, the potencies of cocaine and analogs in self-administration studies correlate best with their DA 60 transporter inhibitor activities. Unfortunately, the precise mechanism by which cocaine inhibits dopamine uptake is wherein Still uncertain. Several laboratories have shown that cocaine Y is NR, -C(R')(R)- or -O-; inhibition of dopamine uptake into striatal SynaptoSomes is R" is -C(=O)0R, cyano, (C-C)alkyl, (C-C) consistent with a classic, fully competitive mechanism. 65 alkanoyl, (C-C)alkenyl, (C-C) alkynyl, or 1,2,4- However these data are also consistent with more complex oxadiazol-5-yl optionally substituted at the 3-position by W. models, including allosteric or partially competitive, and wherein any (C-C) alkyl, (C-C)alkanoyl, (C-C) US 6,472,422 B2 3 4 alkenyl, or (C-C)alkynyl may optionally be Substituted by agent (e.g. to identify, or evaluate the function of, neu 1, 2 or 3 Z, wherein each Z is independently halo, nitro, rotransmitter binding Sights in the brain of a mammal, Such cyano, hydroxy, (C-C)alkoxy, (C-C)acyloxy, C(=O) as a human). OR, C(=O)NRR, NR,R or S(=O), R.; and R is The invention also provides a method comprising binding (C-Co)aryl, 5-10 membered heteroaryl, (C-Co)aryl a compound of formula I to mammalian tissue comprising (C-C)alkyl, 5-10 membered heteroaryl(C-C)alkyl, dopamine receptors, in Vivo or in vitro, by contacting Said (C-C) arylcarbonyl, or 5-10 membered tissue with an amount of a compound of formula I effective heteroarylcarbonyl, wherein any aryl or heteroaryl Substitu to bind to Said receptors. Tissue comprising dopamine ent may optionally be substituted on carbon by 1, 2 or 3 Z; receptors with compounds of formula I bound thereto can be O used as a pharmacologic tool to identify potential therapeu R" is -CH2-, or -CHCH-, wherein R is attached to a tic agents for the treatment of diseases or conditions asso carbon at the ortho position of R; and R is (C-Co)aryl, ciated with dopamine function, by contacting the agents or 5-10 membered heteroaryl; with the tissue, and measuring the extent of displacement of R’ is hydrogen or (C-C)alkyl; the compound of formula I and/or binding of the agent. R" and R are independently hydrogen or (C-C)alkyl; 15 TiSSue comprising dopamine receptors with compounds of R is hydrogen, (C-C)alkyl, (C-C)alkanoyl, or formula I bound thereto can also be used generally to S(O).R., elucidate the physiological function of neurotransmitters. n is 0, 1 or 2; Wis (C-C)alkyl, or phenyl, optionally substituted by 1, BRIEF DESCRIPTION OF THE FIGURES 2, or 3 Z; FIGS. 1-10 Illustrate the synthesis of representative com R, to R are independently hydrogen or (C-C)alkyl; and pounds of the invention. R, is H., (C-C)alkyl, or phenyl; or a pharmaceutically acceptable Salt thereof. DETAILED DESCRIPTION OF THE Unexpectedly, it has been found that compounds of for INVENTION mula (I) can bind to the cocaine recognition site with an 25 The following definitions are used, unless otherwise affinity comparable to that of cocaine; additionally, the described: halo is fluoro, chloro, bromo, or iodo. Alkyl, compounds also act as potent inhibitors of dopamine uptake. alkoxy, alkenyl, alkynyl, etc. denote both Straight and It has been observed in drug discrimination Studies in rats, branched groups, but reference to an individual radical Such that Such compounds exhibit only weak cocaine- and as “propyl” embraces only the Straight chain radical, a amphetamine-like effects. The compounds of the invention branched chain isomer Such as "isopropyl being Specifi thus appear to partially mimic cocaine's discriminative cally referred to. Aryl denotes a phenyl radical or an stimulus effects. Of further note are the results obtained from ortho-fused bicyclic carbocyclic radical having about nine to intravenous drug Self-administration Studies carried out ten ring atoms in which at least one ring is aromatic. using rats. In these Studies, the animals trained to Self Heteroaryl encompasses a radical attached via a ring carbon administer cocaine failed to Self-administer the present 35 of a monocyclic aromatic ring containing five or six ring compounds. In locomotor activity Studies the compounds atoms consisting of carbon and one to four heteroatoms each were found to have weak motor effects. Com Selected from the group consisting of non-peroxide oxygen, pounds with these properties may be useful for treating drug sulfur, and N(X) wherein X is absent or is H, O, (C-C) abuse or for treating disorders wherein modulation of alkyl, phenyl or benzyl, as well as a radical of an Ortho-fused dopamine or Serotonin uptake is desired. 40 The invention also provides a pharmaceutical composi bicyclic heterocycle of about eight to ten ring atoms derived tion comprising a compound of formula I as described therefrom, particularly a benz-derivative or one derived by herein; or a pharmaceutically acceptable Salt thereof; in fusing a propylene, trimethylene, or tetramethylene diradical combination with a pharmaceutically acceptable diluent or thereto. carrier. 45 It will be appreciated by those skilled in the art that The invention also provides a method comprising treating compounds of the invention having a chiral center may exist drug (e.g. cocaine) addiction in a human by administering a in and be isolated in optically active and racemic forms. pharmaceutically effective dose of a compound of formula I; Some compounds may exhibit polymorphism. It is to be or a pharmaceutically acceptable Salt thereof. understood that the present invention encompasses any The invention also provides a method for treating a 50 racemic, optically active, polymorphic, or Stereoisomeric disease or condition in a mammal in which the activity of form, or mixtures thereof, of a compound of the invention, dopamine or Serotonin is implicated and modulation of which possess the useful properties described herein, it dopamine or Serotonin reuptake is desired (e.g. Parkinson's being well known in the art how to prepare optically active disease or depression), comprising administering a com forms (for example, by resolution of the racemic form by pound of formula I; or a pharmaceutically acceptable Salt 55 recrystallization techniques, by Synthesis, from optically thereof. active Starting materials, by chiral Synthesis, or by chro The invention also provides a compound of formula I; or matographic separation using a chiral Stationary phase) and a pharmaceutically acceptable Salt thereof; for use in medi how to determine the relevant pharmacological properties of cal therapy or diagnosis. the compound using the Standard tests described herein, or The invention also provides the use of a compound of 60 using other Similar tests which are well known in the art. formula I; or a pharmaceutically acceptable Salt thereof; to Specific values listed below for radicals, Substituents, and prepare a medicament useful for treating drug (e.g. cocaine) ranges, are for illustration only and they do not exclude other addiction, Parkinson's disease, or depression. defined values or other values within defined ranges for the The invention also provides a radiolabeled compound radicals and Substituents comprising a radionuclide and a compound of formula I; or 65 Specifically, (C-C)alkyl can be methyl, ethyl, propyl, a pharmaceutically acceptable Salt thereof, as well as meth isopropyl, butyl, iso-butyl, Sec-butyl, pentyl, 3-pentyl, or ods for using Such a radiolabeled compound as an imaging hexyl, (C-C)alkoxy can be methoxy, ethoxy, propoxy, US 6,472,422 B2 S 6 isopropoxy, butoxy, iso-butoxy, Sec-butoxy, pentoxy, W, wherein any (C-C)alkanoyl, (C-C)alkenyl, or 3-pentoxy, or hexoxy, (C-C)alkenyl can be vinyl or allyl, (C-C)alkynyl may optionally be substituted by 1, 2 or 3 Z, (C-C)alkynyl can be ethynyl, 1-propynyl, or 3-propynyl, wherein each Z is independently halo, nitro, cyano, hydroxy, (C-C)alkanoyl can be acetyl, propanoyl or butanoyl; (C-C)alkoxy, (C-C)acyloxy, C(=O)CR, C(=O) (C-C)acyloxy can be acetoxy, ethylcarbonyloxy or pro NRR, NRR, or S(=O).R.; and R is (C-Clio)aryl, 5-10 pylcarbonyloxy. Likewise, aryl can be phenyl, indenyl, or membered heteroaryl, (C-Co)aryl(C-C) alkyl, 5-10 naphthyl. Heteroaryl can be furyl, imidazolyl, tetrazolyl, membered heteroaryl(C-C)alkyl, (C-C)arylcarbonyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its or 5-10 membered heteroarylcarbonyl, wherein any aryl or N-oxide), indolyl, or quinolyl (or its N-oxide). heteroaryl Substituent may optionally be Substituted on A specific value for Y is NR; wherein R is hydrogen, carbon by 1, 2 or 3 Z; or R' is -CH2-, or -CHCH-, wherein (C-C)alkyl or (C-C)alkanoyl. R" is attached to a carbon at the orthoposition of R; and R' A specific value for R' is (C-C)alkyl, which may is (C-Co)aryl, or 5-10 membered heteroaryl; or a phar optionally be substituted by 1, 2 or 3 Z. Another specific maceutically acceptable salt thereof; provided that R is not value for R' is -C(=O)0R, cyano, (C-C)alkyl, (C-C) phenyl, when R is methoxycarbonyl, R is hydrogen, Y is alkanoyl, (C-C)alkenyl, (C-C) alkynyl, or 1,2,4- 15 NR, and R is methyl. oxadiazol-5-yl optionally substituted at the 3-position by W. Another specific group of compounds are compounds of Another specific value for R' is cyano, (C-C)alkyl, formula I wheren Y is -C(R')(R)-, or -O-;or a pharmaceu (C-C)alkanoyl, (C-C)alkenyl, (C-C)alkynyl, or 1.2, tically acceptable Salt thereof. 4-oxadiazol-5-yl optionally substituted at the 3-position by Another specific group of compounds are compounds of W. Another specific value for R' is (C-C)alkyl, (C-C) formula I wheren R is -C(=O)CR, cyano, (C-C)alkyl, alkenyl, or (C-C)alkynyl. Another specific value for R' is (C-C)alkanoyl, (C-C)alkenyl, (C-C)alkynyl, or 1.2, -C(=O)CR; wherein R is (C-C)alkyl. 4-oxadiazol-5-yl optionally substituted at the 3-position by A specific value for R is hydrogen. W; and R is (C-Clio)aryl, 5-10 membered heteroaryl, (Co-Co)aryl(C-C)alkyl, 5-10 membered heteroaryl A specific value for R is benzyl, wherein the phenyl ring 25 may optionally be substituted on carbon by 1, 2 or 3 Z. (C-C)alkyl, (C-C)arylcarbonyl, or 5-10 membered Another specific value for R is phenethyl, wherein the heteroarylcarbonyl, wherein any aryl or heteroaryl Substitu phenyl ring may optionally be Substituted on carbon by 1, 2 ent may optionally be substituted on carbon by 1, 2 or 3 Z; or 3 Z. Another specific value for R is 5-10 membered or R' is -CH2-, or -CHCH-, wherein R' is attached to a heteroaryl, or 5-10 membered heteroaryl(C-C)alkyl, carbon at the ortho position of R; and R is (C-Clio)aryl, wherein any heteroaryl Substituent may optionally be Sub or 5-10 membered heteroaryl; or a pharmaceutically accept stituted on carbon by 1, 2 or 3 Z. Another specific value for able salt thereof; provided that R is not phenyl, when R' is R is (C-Clio)aryl, (C-Clio)aryl(C-C)alkyl, or (Co-Clio) methoxycarbonyl, R is hydrogen, Y is NR and R is arylcarbonyl, wherein any aryl Substituent may optionally be methyl. A Specific group of compounds are compounds of formula substituted on carbon by 1, 2 or 3 Z. 35 I wherein R is -C(=O)CR, cyano, (C-C)alkyl, (C-C) Specifically R' and Rare each independently hydrogen. alkanoyl, (C-C) alkenyl, or (C-C)alkynyl, wherein any A specific value for R is hydrogen, (C-C)alkyl or (C-C)alkyl, (C-C)alkanoyl, (C-C)alkenyl, or (C-C) (C-C)alkanoyl. Another specific value for R is methyl or alkynyl may optionally be substituted by 1, 2 or 3 Z, wherein ethyl. Another specific value for R is hydrogen. each Z is independently halo, nitro, cyano, hydroxy, (C-C) A specific value for R is methyl or ethyl. 40 alkoxy, (C-C)acyloxy, C(=O)CR, C(=O)NRR, Aspecific group of compounds are compounds of formula NR,R or S(=O), R.; and R is phenyl which may I wheren R is 2,4-oxadiazol-5-yl, optionally substituted at optionally be substituted on carbon by 1, 2 or 3 Z. the 3-position by W. A preferred value for R is 4-chlorophenyl, Another specific group of compounds are compounds of 45 4-fluorophenyl, 4-methylphenyl, or 4-isopropenylphenyl. formula I wheren Ris-C(=O)CR, cyano, (C-C)alkyl, A preferred group of compounds are compounds of for (C-C)alkanoyl, (C-C)alkenyl, (C-C)alkynyl, or 1.2, mula I wherein R and R are in a trans configuration. 4-oxadiazol-5-yl optionally substituted at the 3-position by A preferred group of compounds are compounds of for W, wherein any (C-C)alkyl, (C-C)alkanoyl, (C-C) mula I wherein Y is NR; R is methoxycarbonyl, (C-C) alkenyl, or (C-C)alkynyl may optionally be Substituted by 50 alkyl, or acetoxymethyl; R’ is hydrogen; and R is 1, 2 or 3 Z, wherein each Z is independently nitro, cyano, 4-chlorophenyl, 4-fluorophenyl, 4-methylphenyl, or (C-C)alkoxy, (C-C)acyloxy, C(=O)CR, C(=O) 4-isopropenylphenyl; and R is methyl; or a pharmaceuti NR,R or S(=O), R.; and R is (C-C)aryl, 5–10 mem cally acceptable Salt thereof bered heteroaryl, (C-Co)aryl(C-C)alkyl, 5–10 mem A preferred compound is (+)-methyl 4f-(4- bered heteroaryl(C-C)alkyl, (C-Co)arylcarbonyl, or 55 5-10 membered heteroarylcarbonyl, wherein any aryl or chlorophenyl)-1-methylpiperidine-3C-carboxylate; or a heteroaryl Substituent may optionally be Substituted on pharmaceutically acceptable Salt thereof. carbon by 1, 2 or 3 Z; or R' is -CH-, or -CHCH-, Another preferred compound is (-) 4?-(4-chlorophenyl)- wherein R' is attached to a carbon at the ortho position of 1-methyl-3?-n-propylpipe ridine; or (+) 4?-(4- R; and R is (C-C)aryl, or 5-10 membered heteroaryl; 60 chlorophenyl)-1-methyl-3C-n-propylpiperidine, or a phar or a pharmaceutically acceptable Salt thereof, provided that maceutically acceptable Salt thereof. R is not phenyl, when R is methoxycarbonyl or Processes and intermediates useful for preparing com acetoxymethyl, R is hydrogen, Y is NR, and R is methyl. pounds of formula I are provided as further embodiments of Another specific group of compounds are compounds of the invention and are illustrated by the following proce formula I wheren R' is -C(=O)0R, cyano, (C-C)alkyl, 65 dures. (C-C)alkanoyl, (C-C)alkenyl, (C-C)alkynyl, or 1.2, As illustrated in FIG. 1, racemic piperidines 1 and 2 were 4-oxadiazol-5-yl optionally substituted at the 3-position by prepared Starting from hydrobromide using chem US 6,472,422 B2 7 8 istry similar to that reported by Plati for the synthesis of the lowed by chromatographic Separation of the resulting iso unsubstituted phenyl bearing piperidine analogs (Plati, J. T.; mers gives compound 18. Nitration of compound 19 with Ingberman, A. K.; Wenner, W. Pyrilindene Derivatives. III. nitronium tetrafluoroborate gives nitro compound 20, which Synthesis from Arecoline. J Org. Chem. 1957, 22, 261-265). can be reduced with Rany Ni to give 21. Treatment of Thus, the hydrobromide salt of arecoline was converted to amine 21 with HONO followed by copper(I) bromide, its free base by Sodium bicarbonate, and this intermediate potassium iodide or Sodium azide gives compounds 22a-c. Subjected to a Grignard reaction using Treatment of amine with acetyl chloride or ethyl chlorofor p-chlorophenylmagnesium bromide. A mixture of the cis mate gives amide 23a or carbamate 23b. Additionally, aryl and trans-disubstituted piperidines 1 and 2 was produced in iodide 22b can be treated with isopropenyl zinc chloride in a 75/25 ratio. The cis derivative was obtained by crystalli the presence of a palladium catalyst bis(triphenylphosphine) Zation of the crude material using EtOAc/hexane as . palladium(II) chloride to yield isoprenyl compound 24. The racemic trans piperidine was readily obtained by flash As shown in FIG. 5, compounds of formula I wherein R' chromatography of the mother liquor. is -CH2-, or -CHCH-, wherein R is also attached to a The cis ester was resolved by use of (+)- and (-)- carbon at the ortho position of R; and R is (C-Clio)aryl, dibenzoyltartaric acid to provide the pure enantiomers (-)-3 15 or 5-10 membered heteroaryl can be prepared from a and (+)-4 (Law, H., Leclerc, G. A.; Neumeyer, J. L. An corresponding compound wherein R' is-C(=O)0R. Treat efficient and inexpensive resolution of the potent dopamin ment of methyl amine 25 with 1-chloroethyl chloroformate ergic substance 3-(3-Hydroxyphenyl)-N-(1-propyl)- and methanol, followed by p-toluenesulfonyl chloride in piperidine (1)-3-PPP. Tetrahedron Asymm. 1991, 2, gives the tosyl amine 26. Reduction of the ester 989-992). An X-ray structure determination of the salt with lithium aluminum hydride followed by treatment with formed from (-)-dibenzoyltartaric acid and 1 was used to PBra and cyclization with AlCls gives tricyclic compound determine the absolute stereochemistry of (-)-3 which is 27 which can be deprotected by treatment with HBr/HOAc, depicted in FIG. 1. AS is apparent, the absolute Stereochem and converted to the methylamine 28 by reatment with with istry of the (-)-isomer corresponds to that found in the WIN Sodium hydroxide and formaldehyde, followed by reduction Series of Structures. 25 with sodium cyanoborohydride. The optically pure (+)- and (-)-cis esters were converted As illustrated in FIG. 6, compounds of formula I wherein to their respective alcohols (-)-5 and (+)-6 by lithium Y is -CH2- or -O- may be prepared from the appropriate aluminum hydride reduction, and these alcohols were acy dihydropyran-3-carboxylate or cyclohexenecarboxylate lated with acetic anhydride in the presence of pyridine to using procedures Similar to those described above for the give acetate derivatives (-)-7 and (+)-8. Compound 9, preparation of the corresponding compounds wherein Y is wherein R' is propyl, was prepared from alcohol 5 by NR. oxidation to the aldehyde followed by Wittig reaction and As illustrated in FIG. 7, a compound of formula I wherein catalytic . Compound 10 was prepared from R is (C-C)alkyl or (C-C)alkanoyl (33) can be prepared the cis piperidine (-)-3 by hydrogenolysis over 10% palla from a corresponding compound of formula I wherein R is dium on charcoal in methanol at atmospheric pressure. 35 methyl by treatment with ACECI in refluxing methanol to Because it was difficult to obtain Satisfactory crystals give amine 32, followed by alkylation or acylation of the from (t)-2 and dibenzoyltartaric acid, compounds (+)-11 amine using Standard conditions. and (-)-12 were prepared by the base-catalyzed epimeriza As shown in FIG. 8, a radiolabeled compound of formula tion of compounds (-)-3 and (-)-4 as shown in FIG. 2. The 40 I can be prepared by alkylation of an amine of formula 32 more active isomer (+)-11 was converted to the correspond with a radiolabeled compound (e.g. ICH). ing alcohol (+)-13 by reduction with lithium aluminum As shown in FIG.9, compounds of formula I wherein R' hydride in tetrahydrofuran. Acylation of alcohol (+)-13 with is (C-C)alkyl, (C-C)alkenyl, or (C-C)alkynyl can be acetic anhydride and pyridine gave the acetate (+)-14. The prepared using procedures similar to those described in n-propyl derivative (+)-15 was prepared by oxidation of 45 Kozikowski, A. P., Saiah, M. K. E., Johnson, K. M., and alcohol (+)-13 followed by Grignard reaction using Bergmann, J. S. (1995) Chemistry and biology of the ethyltriphenyl-phosphonium bromide, and Subsequent 2b-alkyl-3b-phenyl analogues of cocaine: Subnanomolar hydrogenation over 5% platinum on carbon. affinity ligands that Suggest a new pharmacophore model at As illustrated in FIG. 3, a compound of formula I wherein the C-2 position. J. Med Chem., 38,3086-3093. Reduction is Rf (C-C)alkyl and R' is -C(=O)0R or cyano can be 50 of ester 11 with DIBAL followed by oxidation gives alde prepared from a corresponding compound of formula I hyde 42. Treatment of compound 42 with a Grignard reagent wherein R is hydrogen by deprotonation followed by gives an alkene of formula 43, which can be reduced with alkylation. hydrogen over platinum on carbon to give an alkane of As illustrated in FIG. 4, compounds of formula I wherein formula 44. R is Substituted phenyl can be prepared using procedures 55 As illustrated in FIG. 10, a compound of formula I similar to those described in: Carroll, F.I., Gao, Y., Rahman, wherein R is oxadiazolyl can be prepared by conversion of M. A., Abraham, P., Parham, K., Lewin, A. H., Boja, J. W., the ester group in a compound of formula I wherein R is and Kuhar, M. J. (1991) Synthesis, ligand binding, QSAR -C(=O)CR to an acid, followed by acid chloride and CoMFA study of 3b-(p-substituted phenyl)tropane-2 formation, and reaction with the appropriate amide oxime as b-carboxylic acid methyl esters. J. Med. Chem., 34, 60 described in: Kotian, P., Mascarella, S. W., Abraham, P., 2719-2725; or Blough, B. E., Abraham, P., Lewin, A. H., Lewin, A. H., Boja, J. W., Kuhar, M. J., and Carroll, F. I. Kuhar, M.J., Boja, J. W., and Carroll, F. I. (1996) Synthesis (1996) Synthesis, ligand binding, and quantitative structure and transporter binding properties of 3b-(4'alkyl-, activity relationship study of 3b-(4'-substituted phenyl)-2b 4'-alkenyl-, and 4'-alkynylphenyl)nortropane-2b-carboxylic heterocyclic tropanes: evidence for an electrostatic interac acid methyl esters: Serotonin transporter Selective analogs.J. 65 tion at the 2b-position. J. Med Chem, 39, 2753–2763. Med. Chem., 39, 4027-4035. Treatment of arecoline with It is noted that many of the Starting materials employed in 4-trifluoromethylphenyl magnesium bromide in ether fol the Synthetic methods described above are commercially US 6,472,422 B2 10 available or are reported in the Scientific literature, and that The active compound may also be administered intrave certain compounds of formula I are useful as intermediates nously or intraperitoneally by infusion or injection. Solu to prepare other compounds of formula I. tions of the active compound or its Salts can be prepared in In cases where compounds are Sufficiently basic or acidic water, optionally mixed with a nontoxic Surfactant. Disper to form stable nontoxic acid or base Salts, administration of Sions can also be prepared in glycerol, liquid polyethylene the compounds as Salts may be appropriate. Examples of glycols, triacetin, and mixtures thereof and in oils. Under pharmaceutically acceptable Salts are organic acid addition ordinary conditions of Storage and use, these preparations Salts formed with acids which form a physiological accept contain a preservative to prevent the growth of microorgan able anion, for example, tosylate, methaneSulfonate, acetate, SS. citrate, malonate, tartarate, Succinate, benzoate, ascorbate, C.-ketoglutarate, and O-glycerophosphate. Suitable acid The pharmaceutical dosage forms Suitable for injection or infusion can include Sterile aqueous Solutions or dispersions addition Salts of inorganic acids may also be formed, includ or Sterile powders comprising the active ingredient which ing hydrochloride, Sulfate, nitrate, bicarbonate, and carbon are adapted for the extemporaneous preparation of Sterile ate Salts. injectable or infusible Solutions or dispersions, optionally Pharmaceutically acceptable Salts may be obtained using 15 encapsulated in liposomes. In all cases, the ultimate dosage Standard procedures well known in the art, for example by form must be sterile, fluid and stable under the conditions of reacting a Sufficiently basic compound Such as an amine with manufacture and Storage. The liquid carrier or vehicle can be a Suitable acid affording a physiologically acceptable anion. a Solvent or liquid dispersion medium comprising, for Alkali metal (for example, Sodium, potassium or lithium) or example, water, , a polyol (for example, glycerol, alkaline earth metal (for example calcium) Salts of carboxy propylene glycol, liquid polyethylene glycols, and the like), lic acids can also be made. vegetable oils, nontoxic glyceryl esters, and Suitable mix The compounds of formula I can be formulated as phar tures thereof. The proper fluidity can be maintained, for maceutical compositions and administered to a mammalian example, by the formation of liposomes, by the maintenance host, Such as a human patient in a variety of forms adapted of the required particle Size in the case of dispersions or by to the chosen route of administration, i.e., orally or 25 the use of Surfactants. The prevention of the action of parenterally, by intravenous, intramuscular, topical or Sub microorganisms can be brought about by various antibacte Cutaneous routeS. rial and antifingal agents, for example, parabens, Thus, the present compounds may be Systemically chlorobutanol, phenol, Sorbic acid, thimerosal, and the like. administered, e.g., orally, in combination with a pharmaceu In many cases, it will be preferable to include isotonic tically acceptable vehicle Such as an inert diluent or an agents, for example, Sugars, buffers or Sodium chloride. assimilable edible carrier. They may be enclosed in hard or Prolonged absorption of the injectable compositions can be Soft shell gelatin capsules, may be compressed into tablets, brought about by the use in the compositions of agents or may be incorporated directly with the food of the patient's delaying absorption, for example, aluminum monoStearate diet. For oral therapeutic administration, the active com and gelatin. pound may be combined with one or more excipients and 35 Sterile injectable Solutions are prepared by incorporating used in the form of ingestible tablets, buccal tablets, troches, the active compound in the required amount in the appro capsules, elixirs, Suspensions, Syrups, wafers, and the like. priate Solvent with various of the other ingredients enumer Such compositions and preparations should contain at least ated above, as required, followed by filtersterilization. In the 0.1% of active compound. The percentage of the composi case of Sterile powders for the preparation of Sterile inject tions and preparations may, of course, be varied and may 40 able Solutions, the preferred methods of preparation are conveniently be between about 2 to about 60% of the weight Vacuum drying and the freeze drying techniques, which of a given unit dosage form. The amount of active compound yield a powder of the active ingredient plus any additional in Such therapeutically useful compositions is Such that an desired ingredient present in the previously Sterile-filtered effective dosage level will be obtained. Solutions. The tablets, troches, pills, capsules, and the like may also 45 contain the following: binderS Such as gum tragacanth, For topical administration, the present compounds may be acacia, corn Starch or gelatin; excipients Such as dicalcium applied in pure form, i.e., when they are liquids. However, phosphate, a disintegrating agent Such as corn Starch, potato it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a Starch, alginic acid and the like; a lubricant Such as magne dernatologically acceptable carrier, which may be a Solid or sium Stearate; and a Sweetening agent Such as Sucrose, 50 fructose, lactose or aspartame or a flavoring agent Such as a liquid. peppermint, oil of wintergreen, or cherry flavoring may be Useful dosages of the compounds of formula I can be added. When the unit dosage form is a capsule, it may determined by comparing their in Vitro activity, and in vivo contain, in addition to materials of the above type, a liquid activity in animal models. Methods for the extrapolation of carrier, Such as a vegetable oil or a polyethylene glycol. 55 effective dosages in mice, and other animals, to humans are Various other materials may be present as coatings or to known to the art; for example, see U.S. Pat. No. 4,938,949. otherwise modify the physical form of the Solid unit dosage Generally, the concentration of the compound(s) of for form. For instance, tablets, pills, or capsules may be coated mula I in a liquid composition, Such as a lotion, will be from with gelatin, wax, shellac or Sugar and the like. A Syrup or about 0.1-25 wt-%, preferably from about 0.5–10 wt-%. The elixir may contain the active compound, Sucrose or fructose 60 concentration in a Semi-Solid or Solid composition Such as a as a Sweetening agent, methyl and propylparabens as gel or a powder will be about 0.1-5 wt-%, preferably about preservatives, a dye and flavoring Such as cherry or orange 0.5-2.5 wt-%. Single dosages for injection, infusion or flavor. Of course, any material used in preparing any unit ingestion will generally vary between 50-1500 mg, and may dosage form should be pharmaceutically acceptable and be administered, i.e., 1-3 times daily, to yield levels of about Substantially non-toxic in the amounts employed. In 65 0.5-50 mg/kg, for adults. addition, the active compound may be incorporated into Compounds of the invention may also be used as imaging Sustained-release preparations and devices. agents when labeled with a radionuclide. AS illustrated in US 6,472,422 B2 11 12 FIG. 9, the radionuclide (such as tritium, iodine-125, iodine A. H., Carroll, F. I. and Kuhar, M. J. (1991) Isothiocyanate 131, iodine-123, astatine-210, carbon-11, carbon-14, derivatives of cocaine: Irreversible of ligand binding at the nitrogen-13, fluorine-18) may be incorporated into, or dopamine transporter. Mol Pharmacol., 39, 339. attached directly to the core Structure, as by halogenation; or the radionuclide (such as Tc-99m, Re-186) may be attached B. Serotonin Transporter Binding to a linking group or bound by a chelating group which is Inhibition of Hibinding to the serotonin transporter can then attached to the compound of formula I directly, or by be assayed according to previously published methods: means of a linker. Radiolabeling techniques Such as these are routinely used in radiopharmaceutical chemistry. Boja, J. W., Rahman, M. A., Philip, A., Lewin, A. H., Radiolabeled compounds of the invention are generally Carroll, F. I. and Kuhar, M.J. (1991) Isothiocyanate deriva useful as imaging agents to diagnose neurological disease tives of cocaine: Irreversible of ligand binding at the dopam (e.g. a neurodegenerative disease) or a mental condition or ine transporter. Mol. Pharmacol., 39, 339. to follow the progression or treatment of Such a disease or C. Norepinephrine Transporter Binding condition in a mammal (e.g. a human). The radiolabeled compounds of the invention and can conveniently be used in Binding to the norepinephrine transporter can be assayed conjunction with imaging techniqueS Such positron emission 15 using a method described by Carroll, F. I., Grey, J., tomography (PET) or single photon emission computerized Abraham, P., Kuzemko, M. A., Lewin, A. H., Boja, J. W., tomography (SPECT). and Kuhar, M. J. (1993) 3-Aryl-2-(3'-substituted-1', 2', The pharmacological activity of compounds of the inven 4'-oxadiazole-5'-yl)tropane analogues of cocaine: Affinities tion can be demonstrated using Standard pharmacological at the cocaine binding site at the dopamine, Serotonin, and models which are known in the art, or can be demonstrated norepinephrine transporters. J. Med Chem., 36, 2886-2890. using the models that are described or cited hereinbelow. Representative compounds of the invention 1-15 were Uptake Studies tested for their ability to displace HIWIN-35428 binding A. HDopamine Uptake Studies from rat striatal membranes and to inhibit the high-affinity uptake of Hldopamine into rat striatal nerve endings 25 Inhibition of Hldopamine uptake can be determined (Synaptosomes) in accordance with protocols previously using the method of Boja, J. W., McNeil, R. M., Lewin, A. described by Boja et al. Mol Pharmacol. 1991,39,339. The H., Abraham, P., Carroll, F. I., and Kuhar, M. J. (1992) results of these assays are provided in Table 1. Selective dopamine transporter inhibition by cocaine ana logs. Neuroreport, 3,984. TABLE 1. B. HSerotonin Uptake Studies ICso Values for Compounds of Formula I in Inhibition of Hlserotonin uptake can be determined in HIWIN 35,428 Binding and in the Inhibition of fresh rat hind brain tissue. The assay can be conducted as HIDopamine Uptake described above, with Some modifications. The final tissue CH concentration will be approximately 2 mg/mL, and the final YN R 35 Hserotonin concentration will be 5.0 nM. Non-specific uptake of Hiserotonin can be defined using 1 uM citalo X pram.

H C. HINorepinephrine Uptake Studies 40 Inhibition of Hnorepinephrine uptake can be deter ICso(nM) ICso(nM) Compound HIWIN 35,428 H dopamine mined in fresh rat cortex. The assay can be conducted in a number R X binding uptake manner similar to that described for Hldopamine uptake Studies, with Some modifications. The final tissue concen cocaine 101.6 9.4 2391 11 tration will be approximately 10 mg/mL, and the final (+)-1 B-COMe Cl 53.7 1.9 37.8 7.9 45 (+)-2 C-COMe Cl 1968, 7.9 Hnorepinephrine concentration will be 5.0 nM. The non (-)-3 B-COMe Cl 24.8 1.6 85.23 - 2.6 specific uptake of Hnorepinephrine can be defined using (+)-4 B-COMe Cl 1362 - 125 SO92 172 1 uM desipramine. (-)-5 B-CHOH Cl 75.3 6.2 49.0 3.0 (+)-6 B-CH-OH Cl 442 32 Intravenous Safety (-)-7 B-CHOAc Cl 44.7 - 10.5 62.9 - 2.7 50 (+)-8 B-CHOAc Cl 928 - 43 2O27 82 Cocaine and a number of other tropane analogs are potent (-)-9 B-nPr Cl 3.0 - 0.5 8.3 - 0.6 inhibitors of norepinephrine re-uptake and possess local (-)-10 B-COMe H 769 19 anesthetic actions. These properties may indicate significant (+)-11 C-COMe Cl 57.3 8.1 34.6 3.2 potential for cardiovascular and central nervous System (-)-12 C-COMe Cl 653 38 1958 toxicity. (+)-13 C-CHOH Cl 240 - 18 683 - 47 55 (+)-14 C-CHOAc Cl 461 - 11 The test compounds with 10 uM or greater affinity for the (+)-15 Ci-nPr Cl 17.2 - O.S 23.2 - 22 dopamine transporter can be tested in rats for intravenous Safety according to the previously published procedure. Tella, S. R., Korupolu, G. R., Schindler, C. W., and Analog Binding at Neurotransporters Goldberg, S. R. (1992) Pathophysiological and pharmaco Determination of inhibitory binding potencies of ana 60 logues at dopamine, Serotonin, and norepinephrine trans logical mechanisms of acute cocaine toxicity in conscious porters can be carried out using Standard receptor binding rats. J. Pharmacol. Exp. Ther, 262,936–946. assays which are known in the art. Behavioral Testing

A. Dopamine Transporter Binding 65 A. Locomotor Activity Dopamine transporters can be assayed using the method The locomotor effects of compound 2 were evaluated described by Boja, J. W., Rahman, M.A., Philip, A., Lewin, using male Swiss Webster mice according to previously US 6,472,422 B2 13 14 published procedures: Izenwasser, S., Terry, P., Heller, B., testing. During drug Self-administration Sessions, food pel Witkin, J. M., and Katz, J. L. (1994) Differential relation lets were no longer delivered, and instead intravenous injec ships among dopamine transporter affinities and Stimulant tions of drugs were delivered by way of the catheter. Each potencies of various uptake inhibitors. Eur: J. Pharmacol. completion of 10 lever press responses (FR10) resulted in an 263, 277–283. i.V. infusion of cocaine (1 mg/kg/infusion) delivered over a Cocaine (10 mg/kg, i.p.) produced a significant (P<0.05) 1 Second period. increase in the distance traveled and Stereotypic behavior as Following approximately 3 weeks of cocaine Self compared to Saline control responses in Sprague-Dawley administration, the extinction test was done by Substituting rats. In contrast to cocaine, piperidine analog 2 (3-20 mg/kg saline (0.25 ml/kg) for cocaine for 5 days. Following i.p.) did not alter the distance traveled. However, piperidine extinction, re-acquisition of cocaine (1 mg/kg/infusion) Self 2 at 10 and 20 mg/kg doses produced a Small, Statistically administration was tested for 5 days. Following nonsignificant increase in Stereotypic time. The time-course re-acquisition of cocaine Self-administration, the Saline data indicate that this Small increase in Stereotypic behavior extinction test was repeated. Following this Second extinc is persistent at 90 minutes following the drug injection, tion test, Self-administration of piperidine analog 2 was while the Stereotypic response to cocaine showed a clear 15 Studied at doses of 1,3, and 0.3 mg/kg/infusion in that order. tendency to decline at this time period. Thus the Small Each dose was tested for five days. During all the behavioral responses to the piperidine analog appear to last re-acquisition test days, a priming infusion was given at the longer than that of cocaine. The motor effects of higher Start of the Session on each day. doses of the piperidine analog were not tested as these doses Cocaine maintained significantly (P<0.05) higher rates of produce convulsions. responding as compared to the responding during the Saline extinction test. The Substitution of Saline for cocaine led to B. Drug-discrimination a decline in the response rate. The Substitution of piperidine Compound 2 was evaluated in the drug discrimination analog 2 (0.3–3 mg/kg/infusion) for Saline failed to restore procedure described by: Callahan, P. M., Bryan, S. K., and the Self-administration responding. The number of infusions Cunningham, K. A. (1995) Discriminative stimulus effects 25 of the piperidine analog delivered at all of the doses tested of cocaine: antagonism by dopamine D1 receptor blockade were not significantly different from that of the saline in the amygdala. Pharmacol. Biochem. Behavi, 51, 759-766. extinction test. These data Suggest that the piperidine analog, In Substitution tests, amphetamine administration engen unlike cocaine, lackS positive reinforcing effects. In contrast, dered a dose-dependent and complete Substitution for the the piperidine analog 3 is cocaine-like in this test, as discriminative Stimulus effects of amphetamine, whereas evidenced by the fact that rats reliably self-administered this administration of the piperidine analog 2 resulted in a compound (0.125-0.5 mg/kg infusion). maximum of 53% amphetamine-lever responding. Response D. Effects of Test Compounds on Cocaine Self rates remained fairly stable acroSS all test doses of amphet Administration and Food Reinforcement amine and piperidine analog 2. 35 Cocaine (1.25-10 mg/kg) administration resulted in a The effect of pretreatment with test compound on cocaine dose-related increase in cocaine-appropriate responding, Self-administration can be Studied. Five minutes following whereas piperidine analog 2 (5 and 20 mg/kg) engendered a intravenous injection of test compounds, rats can be tested maximum of 40% cocaine-lever responding. Response rates for cocaine self-administration. The doses that fall on both following piperidine analog 2 (5 and 10 mg/kg) were 40 the ascending and the descending portions of the cocaine Substantially lower than those observed following cocaine dose-response function can be tested following pretreatment (10 mg/kg) administration. Co-administration of piperidine with test compounds. This allows for a determination of analog 2 (10 mg/kg) plus cocaine (1.25 and 5 mg/kg) did not whether there is a left- or rightward shift or downward shift significantly alter drug choice F(1.7)=1.35, p=0.28 or in the cocaine dose-response function. Compounds showing response rate performance F(1,7)=4.84, p=0.06 from that 45 overall reduction (downward shift) in cocaine self observed following administration of 1.25 and 5 mg/kg of administration can be further tested for the specificity of this cocaine alone (data not shown). This result is in contrast to effect. This can be done by studying the effect of test other dopamine uptake inhibitors that are known to cause a compound on non-drug reinforcerS Such as food. leftward Shift in cocaine's dose-response function. These PET Evaluation results Suggest that the piperidine analog differs from other 50 uptake inhibitors in lacking the potentiation of cocaine's The cis and trans isomers of 4-(4-chlorophenyl)-3- discriminative Stimulus effects. (carbomethoxy)piperidine were labeled via N-methylation. 'C-methyl iodide was bubbled into a solution of each of the C. Intravenous Drug Self-Administration piperidine isomers (1.5 mg free base in 0.3 cc DMSO) and Compounds 2 and 3 were evaluated using the intravenous 55 the mixtures were heated at 110° C. for 7 minutes. The drug Self-administration procedures described by: Tella, S. products were purified by HPLC on a C-18 cartridge eluted R., Ladenheim, B., Andrews, A. M., Goldberg, S. R., and with MeOH: phosphate/triethylamine buffer, pH 7.2 (60:40). Cadet, J. L. (1996) Differential reinforcing effects of cocaine The 'C-labeled drugs were produced in good radiochemical and GBR-12909: Biochemical evidence for divergent neu yield ~15% (GEOS). Radiochemical purities of the final roadaptive changes in the meSolimbic dopaminergic System. 60 products were>98% and specific activity were routinely J. NeuroSci., 16, 7416–7427. >2,000 mCl?umole EOS). Rats were initially trained to lever press for food pellets After passage through a 0.22 um filter, the Sterile products in Standard operant boxes. Following lever press training, were administered to three Rhesus monkeys and dynamic rats were implanted with polyvinyl chloride catheters into PET images were acquired over 90 minutes. Both isomers femoral veins under halothane anesthesia (2-3% in medical 65 accumulated rapidly in the striatum with the cis isomer grade oxygen) and were allowed to recover for an additional exhibiting greater nonspecific accumulation in the cortex. 7 days before initiation of i.v. drug self-administration Studies with low specific activity tracer showed reduced US 6,472,422 B2 15 16 striatal-to-cerebellar ratioS compared with high Specific mL), dried, and concentrated under reduced pressure. The activity preparations. When unlabeled CFT was adminis crude mixture was crystallized from EtOAc/hexane to afford tered 60 minutes after injection of the trans isomers, a the the title compound 1 (5.0 g, 22%) as a white solid. Selective decrease in the striatal activity was observed; Concentration of the mother liquor gave a mixture of consistent with in Vivo binding to the dopamine transporter. compounds 1 and 2 that was separated by flash chromatog These results establish that both the cis- and trans isomers raphy on Silica gel using ether/EtN 9/1 as eluent to give of 4-(4-chlorophenyl)-3-carbomethoxy-N-methylpiperidine additional title compound (total 12.4g, 56%); mp 98-99 C.; have high levels of Specific binding to striatal dopamine "H NMR (CDC1) & 1.74–1.86 (m, Hs), 2.07 (dt, H., transporter Sites. J=3.0 and 11.4 Hz), 2.28 (s, 3H), 2.35 (dd, H, J=3.6 and The 3-n-propyl derivative (-)-9 was found to have a 11.7 Hz), 2.66 (dq, H, J=3.9 and 12.0 Hz), 2.78 (dt, H., binding affinity of 3 nM. Thus compound 9 is 33-fold more J=3.6 and 12.0 Hz), 2.9-3.06 (m, H, and He), 3.18 (bd, potent than cocaine in binding affinity, and 29-fold more H., J=12.0 Hz), 3.52 (s, 3H), 6.2–6.35 (m, 4H); C NMR potent in its inhibition of dopamine uptake. The above (CDC1) & 26.42 (C), 41.27 (Cl), 46.06 (C), 46.53 (C.), results demonstrate that representative compounds of for 51.25 (C), 55.88 (C), 58.36 (C), 128.08 (C,C), 128.95 mula I possess Significant binding activity at the dopamine 15 (C,C), 131.79 (C), 141.54 (Co), 172.47 (C); MS m/z. receptor. Accordingly compounds of the invention may be (%) 267 (M', 7), 208 (14), 128 (6), 70 (29), 44 (100). useful as therapeutic agents for the treatment of drug abuse Compound 1 was dissolved in a methanolic Solution of (e.g. cocain addiction). Additionally, compounds of formula hydrochloric acid gas and the resulting Solid was triturated I, and in particular, compounds wherein R is hydrogen, may with ether to give compound 1.HCl: "H NMR (methanol-d) also possess activity as Serotonin reuptake inhibitors. & 2.05 (bd, 1H, J=4.0 Hz), 2.53 (bq, 1H, J=10.8 Hz), 2.94 Accordingly, compounds of formula I may also be useful for (s, 3H), 3.14–3.5 (m, 4H), 3.45 (s, 3H), 3.6–3.7 (m, 1H), inhibiting Serotonin reuptake, and thus for treating Parkin 3.78 (d. 1H, J=12.9 Hz), 7.22 (d. 2H, J=8.4 Hz), 7.35 (d. Son's disease or depression. 2H, J=8.4 Hz). The invention will now be illustrated by the following Example 2 non-limiting examples, wherein unless otherwise Stated: 25 (+)-cis-Methyl 4-(4-Chlorophenyl)-1-methylpiperidine-3- Starting materials were obtained from Aldrich Chemicals or carboxylate (2). from other commercial Suppliers, diethyl ether and cyclo Concentration of the mother liquor from Example 1 gave hexane were distilled from phosphorus pentoxide, tetrahy a mixture of compounds 1 and 2. Flash chromatography on drofuran was freshly distilled under nitrogen from Sodium Silica gel using ether/EtN 9/1 as eluent gave compound 2 benzophenone; infrared (“IR”) spectra were recorded on an (2.0 g, 18%); H NMR (benzene-d) & 1.4-1.5 (m, 1H), ATI Mattson Genesis spectrometer; proton H and carbon 1.62 (dq, 1H, J=3.9 and 12.6 Hz), 1.75 (dt, 1H, J=2.7 and 'C nuclear magnetic resonance (“NMR") spectra were 12.0 Hz), 2.06 (s, 3H), 2.0–2.15 (m, 1H), 2.54–2.63 (m, 1H), obtained with a Varian Unity Inova instrument at 300 and 2.68 (dt, 1H, J=4.2 and 11.7 Hz), 2.86-3.0 (m, 2H), 3.08 (s, 75.46 MHz; H chemical shifts (ö) are reported in ppm 3H), 6.87 (d. 2H, J–8.7 Hz), 7.07 (d. 2H, J=8.7 Hz); 'C downfield from internal TMS; C chemical shifts are 35 NMR (CDC1) & 33.1, 44.0, 46.1, 49.1, 51.5, 55.7, 58.1, referred to CDC1 (central peak, Ö=77.0 ppm), benzene-d 128.6, 128.7, 132.3, 1419, 1734; MS m/z (%)267 (M', 17), (central peak, 8=128.0 ppm), or DMSO-d (central peak, 208 (30), 128 (16), 114 (16), 43 (100). 8=39.7 ppm); when appropriate NMR assignments were Using a procedure Similar to that described in Example 1, made with the help of COSY, DEPT, and HETCOR experi the hydrochloride Salt of compound 2 was prepared: com ments, melting points were determined in Pyrex capillaries 40 pound 2 HCl: "H NMR (methanol-d) & 2.04–2.16 (m, 2H), with a Thomas Hoover Unimelt apparatus and are uncor 2.97 (s, 3H), 3.0–3.3 (m, 4H), 3.47 (s, 3H), 3.56-3.66 (m, rected; mass spectra were measured in the EI mode at an 1H), 3.7–3.8 (m, 1H), 7.25 (d. 2H, J=8.4 Hz), 7.34 (d. 2H, ionization potential of 70 eV, thin layer chromatography J=8.4 Hz). (“TLC) was performed on Merck silica gel 60Fs glass 45 Example 3 plates, column chromatography was performed using Merck (-)-Methyl 43-(4-chlorophenyl)-1-methylpiperidine-3,3- silica gel (60-200 mesh); each of compounds 1-15 gave carboxylate (3). Satisfactory combustion analysis, and the following abbre To a solution of compound 1 (6.4g, 24 mmol) in MeOH viations are used: DMSO=dimethylsulfoxide; ether=diethyl (200 mL) was added a solution of dibenzoyl-L-tartaric acid ether; THF=tetrahydrofliran; and DCM=dichloromethane. 50 (8.9 g, 24 mmol) in MeOH (100 mL). The resulting mixture EXAMPLES was stirred at room temperature for 5 hours, filtered, and the white precipitate washed with MeOH (20 mL). This tartrate Example 1 salt was treated with a saturated solution of NaHCO (150 (+)-cis-Methyl 4-(4-Chlorophenyl)-1-methylpiperidine-3- mL) and the mixture extracted with CHCl (3x100 mL). The carboxylate (1). 55 combined organic phases were washed with brine (150 mL), To a solution of 4-chlorophenylmagnesium bromide (166 dried, and concentrated under reduced pressure to afford the mL, 1.0 M in ether) in ether (700 mL) was added dropwise title compound (2.0 g) as a white solid: mp 98-99 C.; at -10° C. a solution of arecoline free base (12.9 g, 83 mmol, o,-56° (c 1.0, EtOH). obtained from the hydrobromide by treatment with sodium Using a procedure Similar to that described in Example 1, bicarbonate and extraction into methylene chloride) in ether 60 the hydrochloride Salt of compound 3 was prepared: com (300 mL). The mixture was stirred at -10° C. for 30 minutes, pound 3OHCl; C-130 (c 1.0, EtOH). then poured onto crushed ice and treated slowly with 10% Single Crystal X-Ray Analysis was preformed on the HCl (200 mL). The aqueous layer was separated, washed (-)-Dibenzoyltartrate of (3) as described below. A clear with ether (200 mL), and treated, while cooling in an ice rectangular 0.06x0.08x0.52 mm crystal, CHOC1N bath, with a saturated solution of sodium bicarbonate (100 65 CHOs, FW=626.04, was selected for data collection. mL). The mixture was extracted with ether (2x200 mL), and Data were collected on a computer controlled Siemens CCD the combined organic phases were washed with brine (200 1K area detector system with a Siemens PLATFORM goni US 6,472,422 B2 17 18 ometer using a Rigaku rotating anode Source and Gobel and 13.5 Hz), 3.0-3.1 (m, Ho), 3.14 (br d, H., J=11.4 mirrors (CuK radiation, 2-154178 A, T-295 K). Data Hz), 3.54 (dt, H., J=2.4 and 10.8 Hz), 3.70 (dd, H., J=3.3 collection nominally covered a hemisphere in reciprocal and 11.1 Hz), 7.24 (d. 2H, J=8.7 Hz), 7.29 (d. 2H, J=8.7 Hz); Space by combining Six Sets of exposures with different 20 'C NMR (CDC1) & 27.9 (C), 40.2 (C), 43.5 (C), 46.3 and (p angles: each exposure covered a range of 0.75 in Co. (C), 56.2 (C), 61.4 (Cs), 64.5 (Cs), 128.4 (C,C), 129.2 The crystal to detector distance was 5.09 cm, and coverage (C,C), 131.9 (C), 142.1 (Co.); MS m/z (%) 239 (M", of a unique set was 98% complete to 1.0 A resolution. The 6), 208 (6), 100 (16), 44 (100). crystal decay was monitored by repeating 50 of the initial frames at the end of data collection and was found to be Example 6 2.7%. A least-Squares refinement using 176 centered reflec (+)-4 B-(4-Chlorophenyl)-3 B-(hydroxymethyl)-1- tions within 16.2<20<34.4 gave the orthorhombic P222 methylpiperidine (6). cell, a =7.752(3), b=14.691 (5) c=27.502(8) A, with Using a procedure Similar to that described in Example 5, V=3132.2 (17) A, Z=4, and di-1,328 gm/cm. A total of except replacing the compound 3 used therein with com 8342 reflections were to 20=100, of which there were pound 4, the title compound 6 was prepared (82%) as a 2923 independent reflections. Corrections were applied for 15 colorless oil; C,-67 (c 1; EtOH). Lorentz and polarization effects. An empirical absorption Example 7 correction was applied using equivalent reflections (-)-3?-(Acetoxymethyl)-4 B(4-chlorophenyl)-1- (SADABS), u=1.577 mm. Max. and min. transmission methylpiperidine (7). were 0.44 and 0.88, respectively. The structure was solved To a solution of compound 5 (90 mg, 0.38 mmol) in by direct methods with the aid of the program SHELXT1 pyridine (2 mL) was added acetic anhydride (0.5 mL). The and refined on F with fall matrix least-squares. The 398 resulting Solution was Stirred at room temperature for 15 parameters refined include the coordinates and anisotropic hours, concentrated under reduced pressure, diluted with thermal parameters for all non-hydrogen atoms. Hydrogens EtOAc (30 mL), and washed with a saturated solution of were included using a riding model. The final R values for NHCl (2x20 mL). The organic solution was dried and the 2244 observed reflections with F-4o(F) were R=0.086 25 concentrated under reduced pressure to afford the title and wr(F)=0.208. The goodness of fit parameter was 1.07, compound (0.10 g, 95%) as a white solid: mp 76° C.; and final difference Fourier excursions were 0.41 and -0.27 o,-109° (c 0.75; EtOH); R, 0.6 (ether/Et,N 9.5/0.5); H eA-. The absolute configuration determination was based NMR (benzene-d) & 1.21 (brd, 1H, J=11.4 Hz), 1.52 (s, on a method Suggested by D. Rogers. The absolute structure 3H), 1.72 (dq, 1H, J=3.0 and 12.3 Hz), 1.6–1.7 (m, 1H), 1.86 parameter which should be near 0.0 for the correct choice of (dd, 1H, J=2.7 and 11.4 Hz), 2.0-2.1 (m, 1H), 2.09 (s, 3H), chirality and 1.0 for an incorrect choice was 0.04(6). The 2.40 (dt, 1H, J=3.9 and 11.4 Hz), 2.67 (brd, 1H, J=8.1 Hz), compound also contained a chiral anion, (-)- 2.91 (d. 1H, J=11.4 Hz), 3.90 (dd, 1H, J=4.5 and 10.8 Hz), dibenzoyltartaric acid. 4.47 (dd, 1H, J=9.6 and 10.5 Hz), 6.68 (d, 2H, J=8.4 Hz), Example 4 7.09 (d. 2H, J-84 Hz); 'C NMR (CDC1) & 20.8, 25.6, (+)-Methyl 43-(4-Chlorophenyl)-1-methylpiperidine-3 35 39.6, 41.9, 46.5, 56.2, 57.8, 62.5, 128.4,128.5, 1320, 141.5, f3-carboxylate (4). 170.9; MS m/z (%) 281 (M', 6), 238 (6), 208 (15), 142 (7), To the mixture of enantiomers derived from the mother 44 (100). liquor of Example 3 (4.2g, 15.7 mmol) in MeOH (150 mL) Example 8 was added a Solution of dibenzoyl-D-tartaric acid (5.8 g., (+)-3B-(Acetoxymethyl)-4 B-(4-chlorophenyl)-1- 15.7 mmol) in MeOH (50 mL). The resulting mixture was 40 methylpiperidine (8). Stirred at Oom temperature 5 hours, filtered, and the white Using a procedure Similar to that described in Example 7, precipitate was washed with MeOH (10 mL). This tartrate except replacing compound 5 used therein with compound salt was treated with a saturated solution of NaHCO (100 6, the title compound 8 was prepared (93%) as a white solid: mL) and the mixture extracted with CHCl (3x70 mL). The 45 of-107 (c 0.35; EtOH); MS m/z (%) 281 (M', 6). combined organic phases were washed with brine (150 mL), Example 9 dried, and concentrated under reduced pressure to afford the title compound (2.2 g) as a white solid: mp 98-99 C.; (-) 4-3-(4-chlorophenyl)-1-methyl-3?-n-propylpiperidine o,+56° (c 1.0, EtOH). (9). The hydrochloride Salt was prepared by dissolution of the Oxalyl chloride (0.19 mL) was dissolved in anhydrous 50 CHCl (15 mL), and the solution was cooled to -78 °C. free base of compound 4 in a methanolic Solution of HCl(g), Dimethyl sulfoxide (0.32 mL) was added, after 5 minutes, concentration, and final trituration of the crude Salt with alcohol 5 (0.5g, 2.08 mmol) was added in CHCl (5 mL), ether: o,+126° (c 1.0, EtOH). and Stirring was continued for 30 minutes. The reaction Example 5 mixture was quenched by adding EtN (2.84 mL), and the (-)-4B-(4-Chlorophenyl)-3 B-(hydroxymethyl)-1- 55 resulting Solution was warmed to room temperature, diluted methylpiperidine (5). with CHCl (30 mL), washed with NHCl (2x30 mL), To a solution of 3 (1.0 g, 3.7 mmol) in THF (30 mL) was dried, and concentrated under reduced pressure to provide added portionwise LiAIH (0.3 g, 7.5 mmol). The resulting the intermediate aldehyde (0.45 g, 91%) as a colorless oil mixture was Stirred at room temperature for 2 hours. A used in the next step without further purification: "H NMR saturated solution of Rochelle salt (30 mL) was added 60 (CDC1) & 1.9-2.0 (m, 1H), 2.10 (dt, 1H, J=2.4 and 11.4 Hz), followed by extraction with EtOAc (100 mL). The organic 2.29 (s.3H), 2.2-2.4 (m, 2H), 2.64-2.74 (m, 1H), 2.92 (dt, phase was washed with brine (100 mL), dried, and concen 1H, J=3.9 and 12.9 Hz), 3.0-3.1 (m, 1H), 3.28 (brid, 1H, trated under reduced pressure to afford the title compound J=11.4 Hz), 7.2 (d. 2H, J=8.4 Hz), 7.29 (d. 2H, J=8.4 Hz), (0.9 g, 98%) as a colorless oil: o,-70 (c 1.0, EtOH); H 8.7 (s, 1H), 'CNMR (CDC1) & 27.2,409, 46.5, 51.9, 55.9, NMR (CDCl3) & 1.64–1.84 (m, H, and Hs), 2.11 (dt, H., 65 57.0, 128.6, 128.7, 132.3, 140.6, 203.9. J=3.3 and 11.7 Hz), 2.29 (s.3H), 2.45 (dt, H, J=2.7 and 11.4 A solution of n-BuLi (2.28 mL, 1 M in hexane, 5.7 mmol) Hz), 2.55 (dq, Hs, J=4.2 and 12.6 Hz), 2.84 (dt, H, J=4.5 was dissolved in THF (10 mL) and cooled to 0° C. Ethyl US 6,472,422 B2 19 20 triphenylphosphonium bromide (2.1 g, 5.7 mmol) was added To a solution of compound 3 (0.5g, 1.87 mmol) in MeOH Slowly under nitrogen. The resulting yellow-orange Solution (6 mL) was added a 30% methanolic solution of sodium was stirred at 0°C. for 30 minutes, and the cooling bath was methoxide (0.04 mL). The resulting solution was stirred at removed. The crude aldehyde (0.45 g, 1.9 mmol) was added reflux for 24 hours and concentrated under reduced pressure. in THF (2 mL), and the reaction mixture was stirred for 15 CH2Cl and brine were added, and the organic layer was hours at room temperature, diluted with EtOAc (20 mL), and washed with brine. Concentration of the combined organic washed with a saturated solution of NHCl (2x30 mL). The phase afforded compound 3 and compound 11 in a 1:32 ratio organic phase was extracted with 10% HCl (3x10 mL). The (determined by GC-MS analysis). Purification of the crude combined aqueous phases were washed with EtOAc (30 product by Silica gel flash chromatography using ether/EtN mL), neutralized with a saturated solution of NaHCO, and extracted with CHCl (2x30 mL). The combined organic 9.8/0.2 as eluent afforded the title compound (0.43 g, 86%) phases were dried and concentrated under reduced pressure, as a colorless oil: o,+46 (c 1.0, EtOH). and the residue was purified by flash chromatography on The hydrochloride salt was prepared by dissolution of the silica gel using ether/EtN 9.5/0.5 as eluent to afford an free base in a methanolic Solution of HCl(g), resulting in a olefin intermediate as a mixture of cis and trans isomers (0.3 direct crystallization of the desired salt: o,+55° (c 0.5, g, 63%): MS m/z (%) 248 (M., 6), 57 (100). 15 EtOH); impa230° C. To a solution of the olefins (0.2g, 0.80 mmol) in cyclo hexane (20 mL) was added 5% Pt/C (0.2g). The mixture was Example 12 stirred at room temperature for 30 minutes under H. (40 psi). (-)-Methyl 4B-(4-Chlorophenyl)-1-methylpiperidine-3C.- The solution was filtered over celite and evaporated to carboxylate (12). dryneSS. The resulting colorleSS oil was purified by flash To a solution of compound 4 (0.4g, 1.49 mmol) in MeOH chromatography on Silica gel using ether/EtN 9.5/0.5 as (3 mL) was added a 30% methanolic solution of sodium eluent to afford the title compound 9 (0.19 g, 94%) as a methoxide (0.01 mL). The resulting solution was stirred at colorless oil: o,-84 (c 0.5, EtOH); H NMR (benzene reflux for 11 hours and concentrated under reduced pressure. d) & 0.71 (t, 3H, J=6.9 Hz), 0.75–1.0 (m, 2H), 1.2–1.4 (m, CH2Cl and a saturated solution of NHCl were added. The 2H), 1.52-1.65 (mn, 1H), 1.65-1.84 (m, 2H), 1.84-2.0 (m, 25 organic layer was washed with brine, dried over Sodium 2H), 2.14 (s.3H), 2.47 (dt, 1H, J=3.6 and 12.3 Hz), 2.7–2.84 Sulfate, and concentrated under reduced preSSure to afford (m, 1H), 6.77 (d. 2H, J=8.4 Hz), 7.15 (d. 2H, J=8.4 Hz); 'C compounds 4 and 12 in a 1:5.6 ratio (determined by GC-MS NMR (CDC1) & 14.0, 21.1, 25.4, 27.6, 40.2, 43.9, 46.8, analysis). Purification of the crude product by Silica gel flash 56.5,59.4,128.1,128.8, 1314, 142.9; MS m/z (%) 251 (M", chromatography using ether/EtN 9.8/0.2 as eluent afforded 8), 208 (8), 112 (24), 44 (100). the title compound (0.35 g, 85%) as a colorless oil: o,- The hydrochloride Salt was prepared by dissolution of the 50° (c 1.0, EtOH). free base in a methanolic Solution of HCl(g), concentration, Example 13 and final trituration of the crude Salt with ether: mp>230 C.; (+)-4 B-(4C chlorophenyl)-3C.-(hydroxymethyl)-1- o,-73° (c 0.25, EtOH); H NMR (methanol-d) & 0.78 methylpiperidine (13). (t, 3H, J=6.6 Hz), 0.9–1.1 (m, 2H), 1.28-1.5 (m, 2H), 35 Using a procedure Similar to that described in Example 5, 1.94–206 (m, 1H), 2.14–2.38 (m, 2H), 2.92 (s, 3H), except replacing the compound 3 used therein with com 3.04-3.4 (m, 3H), 3.54–3.7 (m, 2H), 7.24 (d. 2H, J=7.8 Hz), pound 11, the title compound was obtained (84%) as a 7.35 (d. 2H, J-7.8 Hz). colorless oil: o,+38 (c 0.5; EtOH); mp 148-150° C.; Example 10 H NMR (CDC1) & 1.4 (brs, OH), 1.7–2.1 (m, 5 H), 2.29 (-)-Methyl 1-Methyl-4B-phenylpiperidine-3,3-carboxylate 40 (dd, 1 H, J=5.4 and 10.5 Hz), 2.36 (s, 3 H), 2.95 (d. 1H, (10). J=10.8 Hz), 3.15 (d. 1H, J=10.8 Hz), 3.24 (dd, 1H, J=6.6 and A mixture of compound 3 (0.7 g, 2.61 mmol) and 10% 10.8 Hz), 3.41 (dd, 1H, J=3.0 and 10.8 Hz), 7.14 (d, 2 H, Pd/C (0.28 g) in MeOH (20 mL) was hydrogenated under 1 J=8.4 Hz), 7.27 (d. 2H, J=8.4 Hz). atm of H for 3 hours. The resulting mixture was filtered over celite and evaporated to dryneSS. The resulting pale 45 Example 14 yellow oil was purified by flash chromatography on Silica (+)-3B-(Acetoxymethyl)-4 B-(4-chlorophenyl)-1- gel using ether/EtN 9.5/0.5 as eluent to afford the title methylpiperidine (14). Using a procedure Similar to that described in Example 7, compound (0.6 g.98%) as a colorless oil: o,-54 (c 1; except replacing compound 5 used therein with compound EtOH); H NMR (CDC1,) & 1.76–19 (m, Hs), 2.09 (dt, 50 He, J=2.7 and 11.1 Hz), 2.29 (s.3H), 2.37 (dd, H., J=3.6 13, the title compound was obtained (80%) as a white solid: and 11.7 Hz), 2.70 (dq, H, J=3.9 and 12.3 Hz), 2.85 (dt, "H NMR (CDC1) & 1.7–1.9 (m,3H), 1.97 (s.3H), 1.95–2.1 H. J=3.9 and 11.7 Hz), 2.92-3.06 (m, H, and H), 3.18 (br (m, 1H), 2.1-2.3 (m, 2H), 2.35 (s, 3H), 2.95 (d. 1H, J=11.4 d, H., J=12.0 Hz), 3.50 (s.3H), 7.1–7.4 (m, 5H); 'C NMR Hz), 3.07 (d. 1H, J=9.6 Hz), 3.63 (dd, 1H, J=7.5 and 11.4 (CDC1) & 26.6, 41.8, 46.2, 46.6, 51.2, 55.9, 58.3, 126.1, Hz), 3.82 (dd, 1H, J=3.0 and 11.1 Hz), 7.12 (d. 2H, J=8.4 127.6, 128.0, 143.0, 172.7; MS m/z (%) 233 (M", 13), 232 55 Hz), 7.27 (d. 2H, J=8.4 Hz); C NMR (CDC1) & 20.7,344, (6), 174 (17), 70 (26), 44 (100). 41.0, 44.2, 46.4, 56.0, 59.3, 65.2, 128.7, 128.8, 132.2, 142.1, The hydrochloride Salt was prepared by dissolution of the 170.9. free base in a methanolic Solution of HCl(g), concentration, Example 15 and final trituration of the crude salt with ether:IC), 130° 60 (+) 4?-(4-chlorophenyl)-1-methyl-3C.-n-propylpiperidine (c 1.0, EtOH); mp 168-169° C.; H NMR (methanol-d) & (15). 2.0-2.1 (m, 1H), 2.5–2.7 (m, 1H), 2.95 (s, 3H), 3.1–3.5 (m, Using a procedure Similar to that described in Example 9, 4H), 3.42 (s, 3H), 3.6–3.7 (m, 2H), 3.7–3.85 (m, 1H), except replacing compound 5 used therein with compound 7.2-7.4 (m, 5H). 13, the title compound was obtained (70%) as a colorless oil: Example 11 65 o,+418 (c 1.0, EtOH); H NMR (CDC1) & 0.73 (t, 3H, (+)-Methyl 43-(4-chlorophenyl)-1-methylpiperidine-3? J=7.2 Hz), 0.8-1.0 (m, 1H), 1.0-1.2 (m, 2H), 1.2–1.4 (m, carboxylate (11). 1H), 1.65 (t, 1H, J=10.8 Hz), 1.7–1.9 (m, 3H), 1.9-2.15 (m, US 6,472,422 B2 21 22 2H), 2.32 (s, 3H), 2.93 (d. 1H, J=11.1 Hz), 3.05 (d. 1H, J=10.8 Hz), 7.10 (d. 2H, J=8.4 Hz), 7.25 (d, J=8.1 Hz); 'C NMR (CDC1) d 14.1, 19.7, 33.9, 35.0, 40.8, 46.5, 48.2, (v) Injection 2 (10 mg/ml) mg/ml 56.3, 61.6, 128.5, 129.0, 131.6, 143.8. Compound X (free acid form) 1.O.O The hydrochloride Salt was prepared by dissolution of the Monobasic sodium phosphate O.3 Dibasic sodium phosphate 1.1 free base in a methanolic Solution of HCl(g), concentration, Polyethylene glycol 400 2OO.O and final trituration of the crude salts with ether: o,+348 01 N. Sodium hydroxide solution C.S. (c 0.25, EtOH); mp 216° C. (EtOAc); H NMR (methanol (pH adjustment to 7.0–7.5) d) & 0.77 (t, 3H, J=6.9 Hz), 1.0-1.4 (m, 4H), 1.9-2.2 (m, Water for injection q.S. ad 1 mL 3H), 2.56 (q, 1H, J=10.8 Hz), 2.86 (t, 1H, J=12.6 Hz), 2.93 (s, 3H), 3.0–3.2 (m, 1H), 3.5–3.7 (m, 2H), 7.23 (d. 2H, J=8.4 Hz), 7.35 (d. 2H, J=8.4 Hz). 15 (vi) Aerosol mg/can Example 16 Compound X 2O.O The following illustrate representative pharmaceutical dos Oleic acid 1.O.O Trichloromonofluoromethane 5,000.0 age forms, containing a compound of formula I (Compound Dichlorodifluoromethane 10,000.0 X), for therapeutic or prophylactic use in humans. Dichlorotetrafluoroethane 5,000.0

The above formulations may be obtained by conventional (i) Tablet 1 mg/tablet procedures well known in the pharmaceutical art. All publications, patents, and patent documents are incor Compound X 1OO.O 25 porated by reference herein, as though individually incor Lactose 77.5 Povidone 15.O porated by reference. The invention has been described with Croscarmellose sodium 12.0 reference to various Specific and preferred embodiments and Microcrystalline cellulose 92.5 techniques. However, it should be understood that many Magnesium stearate 3.0 variations and modifications may be made while remaining within the Spirit and Scope of the invention. 3OO.O What is claimed is: 1. A compound of formula I:

(I) 35 R3 (ii) Tablet 2 mg/tablet R2 Compound X 2O.O Microcrystalline cellulose 41O.O R1 Starch SO.O Sodium starch glycolate 15.O Y Magnesium stearate 5.0 40 SOO.O wherein Y is -O-; R"is -C(=O)0R, cyano, (C-C)alkanoyl, (C-C) 45 alkynyl, or 1, 2, 4-oxadiazol-5-yl optionally Substituted at the 3-position by W, wherein any (C-C)alkanoyl, (iii) Capsule mg/capsule or (C-C)alkynyl may optionally be Substituted by 1, Compound X 1.O.O 2, or 3 Z. wherein each Z is independently halo, nitro, Colloidal silicon dioxide 1.5 cyano, hydroxy, (C-C)alkoxy, (C-C) acyloxy, Lactose 465.5 50 Pregelatinized starch 12O.O C(=O)0R, C(=O)NRR, NRRor S(=O), R.; and Magnesium stearate 3.0 R is (C-Clio)aryl, 5-10 membered heteroaryl, (C-C)aryl(C-C)alkyl, 5-10 membered het 6OOO eroaryl (C-C)alkyl, (C-Co)arylcarbonyl, or 5-10 membered heteroarylcarbonyl, wherein any aryl or 55 heteroaryl Substituent may optionally be Substituted on carbon by 1, 2 or 3 Z; or R" is -CH-, or -CHCH-, wherein R'is attached to a (iv) Injection 1 (1 mg/ml) mg/ml carbon at he ortho position of R; and Ris (C-Co) Compound X (free acid form) 1.O 60 aryl, or 5-10 membered heteroaryl; Dibasic sodium phosphate 12.0 R is hydrogen or (C-C)alkyl; Monobasic sodium phosphate O.7 Sodium chloride 4.5 R" and Rare independently hydrogen or (C-C)alkyl; 1.0 N Sodium hydroxide solution C.S. R is hydrogen, (C-C)alkyl, (C-C)alkanoyl, or S(O) (pH adjustment to 7.0–7.5) 2R, Water for injection q.S. ad 1 mL 65 n is 0, 1 or 2; Wis (C-C)alkyl, or phenyl, optionally substituted by 1, 2, or 3 Z; US 6,472,422 B2 23 24 R to R are independently hydrogen or (C-C) alkyland, (I) R, is H., (C-C alkyl, or phenyl; or a pharmaceutically acceptable Salt thereof. 2. The compound of claim 1 wherein R is -C(=O)0R, cyano, (C-C)alkyl, (C-C)alkanoyl, (C-C)alkenyl, (C-C)alkynyl, or 1,2,4-oxadiazol-5-yl optionally Substi tuted at the 3-position by W.; and R is (C-C)aryl, 5-10 membered heteroaryl, (C-Co)aryl(C-C)alkyl, 5-10 1O wherein membered heteroaryl(C-C)alkyl, (C-C)arylcarbonyl, Y is NR, -C(R')(R)-, or -O-; or 5-10 membered heteroarylcarbonyl, wherein any aryl or R" is -C(=O)CR, cyano, (C-C) alkyl, (C-C) heteroaryl Substituent may optionally be Substituted on alkanoyl, (C-C)alkenyl, (C-C)alkynyl, or 1,2,4- carbon by 1, 2 or 3 Z; or R' is -CH2-, or -CHCH-, wherein OXadiazol-5-yl optionally Substituted at the 3-position 15 by W, wherein any (C-C)alkyl, (C-C)alkanoyl, R" is attached to a carbon at the ortho position of R; and R (C-C)alkenyl, or (C-C)alkynyl may optionally be is (C-Co)aryl, or 5-10 membered heteroaryl. Substituted by 1, 2 or 3 Z, wherein each Z is indepen 3. The compound of claim 1 wherein R is -C(=O)0R, dently halo, nitro, cyano, hydroxy, (C-C)alkoxy, cyano, (C-C)alkanoyl, (C-C)alkynyl, or 1,2,4-oxadiazol (C-C)acyloxy, C(=O)CRC(=O)NRR, NR.R 5-yl optionally substituted at the 3-position by W. or S(=O).R.; and R is (C-Clio)aryl, 5–10 membered 4. The compound of claim 1 wherein R is cyano, heteroaryl, (C-C)aryl(C-C)alkyl. 5-10 membered (C-C)alkanoyl, (C-C)alkynyl, or 1,2,4-oxadiazol-5-yl heteroaryl(C-C)alkyl, (C-C)arylcarbonyl, or 5-10 membered heteroarylcarbonyl, wherein any aryl or optionally substituted at the 3-position by W. heteroaryl Substituent may optionally be Substituted on 5. The compound of claim 1 wherein R' is (C-C) carbon by 1, 2 or 3 Z; or alkynyl. 25 R" is -CH-, or -CHCH-, wherein R is attached to a 6. The compound of claim 1 wherein R' is -C(=O)0R; carbon at the orthoposition of R; and R is (C-Clio) and R is (C-C)alkyl. aryl, or 5-10 membered heteroaryl; 7. The compound of claim 1 wherein R is hydrogen. R’ is hydrogen or (C-C)alkyl; 8. The compound of claim 1 wherein R is (C-Clio)aryl, R" and R are independently hydrogen or (C-C)alkyl; (Co-Co)aryl(C-C) alkyl, or (Co-Co.)arylcarbonyl, R" is hydrogen, (C-C)alkyl, (C-C)alkanoyl, or S(O) wherein any aryl Substituent may optionally be Substituted 2R, on carbon by 1, 2 or 3 Z. n is 0, 1 or 2; 9. The compound of claim 1, 2, 3, or 8 wherein R is Wis (C-C)alkyl, or phenyl, optionally Substituted by 1, 4-chlorophenyl, 4-fluorophenyl, 4-methylphenyl, or 2, or 3 Z; 35 R to R are independently hydrogen or (C-C)alkyl; and 4-isopropenylphenyl. R, is H., (C-C)alkyl, or phenyl, or a pharmaceutically 10. The compound of claim 1, 2, 3, or 4 wherein R and acceptable Salt thereof; and a pharmaceutically accept R are in a trans configuration. able diluent or carrier. 11. A pharmaceutical composition comprising a com pound of formula I: k k k k k UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 6,472,422 B2 Page 1 of 1 DATED : October 29, 2002 INVENTOR(S) : Kozikowski, Alan P. et al.

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

Column 24 Line 12, replace “Y is NR", -C(R)(R)-, or -O-” with -- Y is -O---.

Signed and Sealed this Twenty-eighth Day of December, 2004 WDJ

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