III IIII US005506359A United States Patent 19 11 Patent Number: 5,506,359 Madras et al. 45) Date of Patent: Apr. 9, 1996 (54) COCAINE ANALOGUES AND THEIR USE AS ne-Releasing Effects of H-3-CFT (WIN35,428): A Poten COCANE DRUG THERAPES AND tial Brain Imaging Ligand for Dopamine Transporter or THERAPEUTIC AND MAGNGAGENTS Cocaine . " Soc. Neuro. Abs., 16:309.5 (1990). FOR NEURODEGENERATIVE DISORDERS Clarke et al. "(2-exo-3-endo)-2-Aryltropane-3-carboxylic Esters, a (75) Inventors: Bertha K. Madras, Newton; Peter New Class of Narcotic Antagonists' J. Med. Chem, Meltzer, Lexington, both of Mass. 21:1235-1242 (1978). Clarke et al. "Compounds Affecting the Central Nervous 73) Assignee: President and Fellows of Harvard System. 4.3B-Phenyltropane-2-carboxylic Esters and Ana College, Cambridge, Mass. logs' J. Med. Chem., 16:1260-1267 (1973). Cline et al. "Behavior Effects of Novel Cocaine Analogs: A 21 Appl. No.: 111,141 Comparison with in Vivo Receptor Binding Potency' J. Pharm. & Exp. Therapeutics, 260:1174-1179 (1992). 22 Filed: Aug. 24, 1993 Daum et al. "Compounds Affecting the Central Nervous System. 3. 3?-Phenyltropan-2-ols' J. Med. Chem., Related U.S. Application Data 16:667-670 (1973). 63 Continuation-in-part of Ser. No. 934,362, Aug. 24, 1992, Elmaleh et al. “N-C-11 abandoned. -Methyl-2B-Carbomethoxy-3B-Phenyl Tropane C-11) PT) and Glucose Utilization in a Primate Model of Hun (51) Int. Cl. ...................................... CO7) 451/02 tington's Disease” J. Nuclear Med. Abs., 32:552 (1991). 52 U.S. Cl. ................. 546/130; 54.6/128; 54.6/129 Elmaleh et al. "Preparation and In Vivo Imaging of (58) Field of Search ..................................... 54.6/129, 130, N-C-11-Methyl-2-Carbomethoxy-3-Phenyl Tropane 54.6/128; 514/304 (IC-11 PT) in Monkey Brain' J. Nuclear Med. Abs., 32:1009 (1991). 56 References Cited Elmaleh et al. "PET Imaging Probes for the Cocaine Recep U.S. PATENT DOCUMENTS tors: A Walidation Study in a Nonhuman Primate Model' J. Nuclear Med. Abs., 33:946 (1992). 2,799,680 7/1957 Fromer ................................. 260f294.7 Goodman et al. "Radioiodinated 3,452,029 6/1969 Childress et al........................ 260/292 2B-Carbomethoxy-3B-(4-Chlorophenyl)-8-(3E-and 3,813,404 5/1974 Clarke et al. ........................... 260/292 3Z-Iodopropen-2-YL)Nortropanes: Synthesis of Potential 4,393,069 7/1983 Langbein et al........................ 424/265 Radioligands for Mapping Cocaine Receptor..." J. Nuclear 5,128,118 7/1992 Carroll et al. ........................... 424/1.1 Med. Abs., 33:890 (1992). OTHER PUBLICATIONS Hantraye et al. "Dopamine Fiber Detection by 'C-CFT and PET in a Primate Model of Parkinsonism' Clin. Neu Balster et al. "Potent Substituted-33-phenyltropane Ana rosci. and Neuropath., 3:265-268 (1992). logs of Cocaine have Cocaine-like Discriminative Stimulus Hillier “WIN-35,428" Drugs of the Future, 5:459-460 Effects' Drug and Alcohol Dependence, 29:145-151 (1991). (1980). Boja et al. "Isothiocyanate Derivatives of Cocaine: Irrevers Horn "Dopamine Uptake: A Review of Progress in the Last ible Inhibition of Ligand Binding at the Dopamine Trans Decade' Progress in Neurobiology, 34:387-400 (1990). porter' Molecular Pharmacology 39:339–345 (1991). Innis et al. "Single Photon Emission Tomography Imaging Boja et al. "New, Potent Cocaine Analogs: Ligand Binding of Monoamine Reuptake Sites in Primate Brain with 'I) and Transport Studies in Rat Striatum' European J. of CIT' Eur. J. of Pharmacol., 200:369-370 (1991). Pharmacology, 184:329-332 (1990). Kaufman et al. "Severe Depletion of Cocaine Recognition Brownell et al. "Glucose Utilization and N-C-11-Me Sites Associated With the Dopamine Transporter in thyl-2 Carbomethoxy-3-Phenyl Tropane (IC-11)PT) Stud Parkinson's-Diseased Striatum' Synapse, 9:43–49 (1991). ies of the Primate Model of Huntington's Disease” J. Kitayama et al. "Dopamine Transporter Site-Directed Muta Nuclear Med. Abs., 32:981 (1991). tions Differentially Alter Substrate Transport and Cocaine Canfield et al. "Autoradiographic Localization of Cocaine Binding” Proc. Natl. Acad. Sci., 89:7782-7785 (1992). Binding Sites by HCFT (HWIN35,428) in the Monkey Kline, Jr. et al. "Synthesis of 3-Arlecgonine Analogues as Brain" Synapse, 6:189-195 (1990). Inhibitors of Cocaine Binding and Dopamine Uptake” J. Carroll et al. "Probes for the Cocaine Receptor. Potentially Med. Chem., 33:2024-2027 (1990). Irreversible Ligands for the Dopamine Transporter'J. Med. Chem., 35:1813-1817 (1992). (List continued on next page.) Carroll et al. "Cocaine Receptor: Biochemical Characteriza tion and Structure-Activity Relationships of Cocaine Ana Primary Examiner-C. Warren Ivy logues at the Dopamine Transporter' J. Med. Chem., Assistant Examiner-Evelyn Huang 35:969-981 (1992). Attorney, Agent, or Firm-Fish & Richardson Carroll et al. "Synthesis, Ligand Binding, QSAR, and 57 ABSTRACT COMFA Study of 3B-(p-Substituted phenyl)tropane-2-carboxylic Acid Methyl Esters' J. Med. Disclosed are benztropine and CFT analogs useful for imag Chem., 34:2719-2725 (1991). ing of cocaine receptors and treatment of cocaine abuse. Carroll et al. "Synthesis and Ligand Binding of Cocaine Also disclosed are analogs useful for imaging and treatment Isomers at the Cocaine Receptor" J. Med. Chem., of Parkinson's disease. 34:883-886 (1991). Chen et al. "In Vivo Binding, Internalization, and Dopami 13 Claims, 18 Drawing Sheets 5,506,359 Page 2 OTHER PUBLICATIONS High-Affinity SPECT Radiotracer of Monoaminie Reuptake Leete "2-Carbomethoxy-3-tropinone: An Advanced Inter Sites in Brain' J. Med. Chem., 34:3144-3146 (1991). mediate in the Biosynthesis of Cocaine” J. Amer. Chem. Patel et al. "A Cocaine Analog and a GBR Analog Label the Soc., 83:6727-6728 (1983). 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"Pharmacology of New Tropan Derivatives' tuted Tropane Derivatives. High-Affinity Ligands for the Pharm. Ther., 32:327-337 (1987). Cocaine Receptor" J. Med. Chem., 34:1728-1731 (1991). Cutting W. C. in "The actions and uses of drugs. Handbook Milius et al., “[3H]-CFT, A High-Affinity Probe for the of Pharmacology. Appleton-Century-Crofts N.Y. 1969. Cocaine Receptor' Amer. Chem. Soc. Abstract, 199:1 Van der Zee et al., "A comparison of the inhibitory effects of (1990). aromatic substituted benzhydryl . into synaptosomal Neumeyer et al. “123) preparations of the rat brain”, Neuropharmacology, 17(7), -2B-Carbomethoxy-3B-(4-iodophenyl) tropane: 483-90, 1978. U.S. Patent Apr. 9, 1996 Sheet 1 of 18 5,506,359 H COCAINE ICso(moles/liter) 109 10:10 10:10 109 10-8 107 106 105 IC (moles/liter) CH CO2CH3 F HCFT H FIG. A H U.S. Patent Apr. 9, 1996 Sheet 2 of 18 5,506,359 CAUDATE-PUTAMEN 1000 00 10 RELATIVE POTENCY DOPAMINE UPTAKE OO OO O . 1 10 100 000 RELATIVE POTENCY HCFTBINDING FIG. 1B U.S. Patent Apr. 9, 1996 Sheet 3 of 18 5,506,359 I it it ly it in in i i if it it is NUCLEUS ACCUMBENS 1000 100 10 RELATIVE POTENCY DOPAMINEUPTAKE ms 001 001 01 1 10 100 1000 RELATIVE POTENCY HCFTBINDING FIG. 1C U.S. Patent Apr. 9, 1996 Sheet 4 of 18 5,506,359 OOO CAUDATE-PUAMEN 100 RELATIVE POTENCY STIMULANT EFFECT 0.1 0.01 0.01 0.1 1 10 100 1000 HCFTBINDING RELATIVE POTENCY FIG. 2A U.S. Patent Apr. 9, 1996 Sheet 5 of 18 5,506,359 000 CAUDATE-PUTAMEN 100 RELATIVE POTENCY SELF-ADMINISTRATION 1 0.1 0.01 0.01 0.1 1 10 100 1000 HCFTBINDING RELATIVE POTENCY FIG. 2B U.S. Patent Apr. 9, 1996 Sheet 6 of 18 5,506,359 HSWESIGSNOSN|XHwd[,] TOHINOOKONUDNU ENITESWEENITESWE TOC|N|ZWWHN|WOOO.. U.S. Patent Apr. 9, 1996 Sheet 7 of 18 5,506,359 FIG. 4a-A xxxx FIG. 4a-B rerorcorror FG. Aa-C - U.S.