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(12) United States Patent (10) Patent No.: US 6,472,422 B2 Kozikowski Et Al

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(12) United States Patent (10) Patent No.: US 6,472,422 B2 Kozikowski Et Al 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 COCAINE Clarke, R.L., et al., “Compounds Affecting the Central Nervous System.4.3B-Phenyltropane-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 Sodium 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.
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