Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-06
2003-12-30
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S132000
Reexamination Certificate
active
06670375
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to tropane analogs of cocaine and their use as inhibitors of monoamine reuptake.
BACKGROUND OF THE INVENTION
Cocaine dependence is a problem of national significance. To date no cocaine pharmacotherapy has been reported. Cocaine is a potent stimulant of the mammalian central nervous system. Its reinforcing properties and stimulant effects are associated with its propensity to bind to monoamine transporters, particularly the dopamine transporter (DAT). (Kennedy, L. T. and I. Hanbauer (1983),
J. Neurochem.
34: 1137-1144; Kuhar, M. J., M. C. Ritz and J. W. Boja (1991),
Trends Neurosci.
14: 299-302; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989),
J. Pharmacol. Exp. Ther.
251: 131-141; Madras, B. K., J. B. Kamien, M. Fahey, D. Canfield, et al. (1990),
Pharmacol Biochem. Behav.
35: 949-953; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986),
Biochem. Pharmacol.
35: 1123-1129; Ritz, M. C., R. J. Lamb, S. R. Goldberg and M. J. Kuhar (1987),
Science
237: 1219-1223; Schoemaker, H., C. Pimoule, S. Arbilla, B. Scatton, F. Javoy-Agid and S. Z. Langer (1985),
Naunyn
-
Schmiedeberg's Arch. Pharmacol.
329: 227-235.) It also binds with substantial potency to serotonin transporters (SERT) and norepinephrine transporters.
Structure activity relationship (SAR) studies have largely focused on a series of cocaine analogs. Among the more potent of these congeners at
3
H-cocaine binding sites in striatum (Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989),
J. Pharmacol. Exp. Ther.
251: 131-141; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986),
Biochem. Pharmacol.
35: 1123-1129) is (1R)-3&bgr;-(4-fluorophenyl)tropane-2&bgr;-carboxylic acid methyl ester, (WIN35,428 or CFT) (Kaufman, M. J. and B. K. Madras (1992),
Synapse
12: 99-111; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989),
J. Pharmacol. Exp. Ther.
251: 131-141) reported in 1973 (Clarke, R. L., S. J. Daum, A. J. Gambino, M. D. Aceto, et al. (1973),
J. Med. Chem.
16: 1260-1267). This compound was subsequently radiolabeled to provide a selective probe for the DAT in primate brain. (Canfield, D. R., R. D. Spealman, M. J. Kaufman and B. K. Madras (1990),
Synapse
6: 189-195; Kaufman, M. J. and B. K. Madras (1991),
Synapse
9: 43-49; Kaufman, M. J., R. D. Spealman and B. K. Madras (1991),
Synapse
9: 177-187.)
Among the most potent tropane inhibitors of monoamine binding sites in striatum are 3&bgr;-{4-(1-methylethenyl)-phenyl}-2&bgr;-propanoyl-8-azabicyclo(3.2.1)octane and 3&bgr;-(2-naphthyl)-2&bgr;-propanoyl-8-azabicyclo(3.2.1)octane, (Bennett, B. A., C. H. Wichems, C. K. Hollingsworth, H. M. L. Davies, C. Thornley, T. Sexton and S. R. Childers (1995),
J. Pharm. Exp. Ther.
272: 1176-1186; Davies, H. M. L., L. A. Kuhn, C. Thornley, J. J. Matasi, T. Sexton and S. R. Childers (1996),
J. Med. Chem.
39: 2554-2558) (1R)-RTI55 (&bgr;CIT), (Boja 1991; Boja, J. W., A. Patel, F. I. Carroll, M. A. Rahman, et al. (1991),
Eur. J. Pharmacol.
194: 133-134; Neumeyer, J. L., S. Wang, R. A. Milius, R. M. Baldwin, et al. (1991),
J. Med. Chem.
34: 3144-3146) (1R)-RTI121, (Carroll, F. I., A. H. Lewin, J. W. Boja and M. J. Kuhar (1992),
J. Med. Chem.
35: 969-981.) and (1R)-3&bgr;-(3,4-di-chlorophenyl)-tropane-2&bgr;-carboxylic acid methyl ester (O-401), (Carroll, F. I., M. A. Kuzemko and Y. Gao (1992),
Med. Chem Res.
1: 382-387; Meltzer, P. C., A. Y. Liang, A.-L. Brownell, D. R. Elmaleh and B. K. Madras (1993),
J. Med. Chem.
36: 855-862)
SAR studies of the binding of these agents and their effects on monoamine transporter function have been reported. (Blough, B. E., P. Abraham, A. H. Lewin, M. J. Kuhar, J. W. Boja and F. I. Carroll (1996),
J. Med. Chem.
39: 4027-4035; Carroll, F. I., P. Kotian, A. Dehghani, J. L. Gray, et al. (1995),
J. Med. Chem.
38: 379-388; Carroll, F. I., A. H. Lewin, J. W. Boja and M. J. Kuhar (1992),
J. Med. Chem.
35: 969-981; Carroll, F. I., S. W. Mascarella, M. A. Kuzemko, Y. Gao, et al. (1994),
J. Med. Chem.
37: 2865-2873; Chen, Z., S. Izenwasser, J. L. Katz, N. Zhu, C. L. Klein and M. L. Trudell (1996),
J. Med. Chem.
39: 4744-4749; Davies, H. M. L., L. A. Kuhn, C. Thornley, J. J. Matasi, T. Sexton and S. R. Childers (1996),
J. Med. Chem.
39: 2554-2558; Davies, H. M. L., Z.-Q. Peng and J. H. Houser (1994),
Tetrahedron Lett.
48: 8939-8942; Davies, H. M. L., E. Saikali, T. Sexton and S. R. Childers (1993),
Eur. J. Pharmacol. Mol. Pharm.
244: 93-97; Holmquist, C. R., K. I. Keverline-Frantz, P. Abraham, J. W. Boja, M. J. Kuhar and F. I. Carroll (1996),
J. Med. Chem
39: 4139-4141; Kozikowski, A. P., G. L. Araldi and R. G. Ball (1997),
J. Org. Chem.
62: 503-509; Kozikowski, A. P., M. Roberti, L. Xiang, J. S. Bergmann, P. M. Callahan, K. A. Cunningham and K. M. Johnson (1992),
J. Med. Chem.
35: 4764-4766; Kozikowski, A. P., D. Simoni, S. Manfredini, M. Roberti and J. Stoelwinder (1996),
Tetrahedron Lett.
37: 5333-5336; Meltzer, P. C., A. Y. Liang, A.-L. Brownell, D. R. Elmaleh and B. K. Madras (1993),
J. Med. Chem.
36: 855-862; Meltzer, P. C., A. Y. Liang and B. K. Madras (1994),
J. Med. Chem.
37: 2001-2010; Meltzer, P. C., A. Y. Liang and B. K. Madras (1996),
J. Med. Chem.
39: 371-379; Newman, A. H., A. C. Allen, S. Izenwasser and J. L. Katz (1994),
J. Med Chem.
37: 2258-2261; Newman, A. H., R. H. Kline, A. C. Allen, S. Izenwasser, C. George and J. L. Katz (1995),
J. Med. Chem.
38: 3933-3940; Shreekrishna, V. K., S. Izenwasser, J. L. Katz, C. L. Klein, N. Zhu and M. L. Trudell (1994),
J. Med. Chem.
37: 3875-3877; Simoni, D., J. Stoelwinder, A. P. Kozikowski, K. M. Johnson, J. S. Bergmann and R. G. Ball (1993),
J. Med. Chem.
36: 3975-3977.)
Binding of cocaine and its tropane analogs to monoamine transporters is stereoselective. As example (1R)-(−)-cocaine binds at the dopamine transporter about 200-fold more potently than the unnatural isomer, (1S)-(+)-cocaine. (Kaufman, M. J. and B. K. Madras (1992),
Synapse
12: 99-111; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989),
J. Pharmacol. Exp. Ther.
251: 131-141; Madras, B. K., R. D. Spealman, M. A. Fahey, J. L. Neumeyer, J. K. Saha and R. A. Milius (1989),
Mol. Pharmacol.
36: 518-524; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986),
Biochem. Pharmacol.
35: 1123-1129; Ritz, M. C., R. J. Lamb, S. R. Goldberg and M. J. Kuhar (1987),
Science
237: 1219-1223.)
Also, only the R-enantiomers of cocaine have been found active in a variety of biological and neurochemical measures. (Clarke, R. L., S. J. Daum, A. J. Gambino, M. D. Aceto, et al. (1973),
J. Med. Chem.
16: 1250-1267; Kaufman, M. J. and B. K. Madras (1992),
Synapse
12: 99-111; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989),
J. Pharmacol. Exp. Ther.
251: 131-141; Madras, B. K., R. D. Spealman, M. A. Fahey, J. L. Neumeyer, J. K. Saha and R. A. Milius (1989),
Mol. Pharmacol.
36: 518-524; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986),
Biochem. Pharmacol.
35: 1123-1129; Ritz, M. C., R. J. Lamb, S. R. Goldberg and M. J. Kuhar (1987),
Science
237: 1219-1223; Sershen, H., M. E. A. Reith and A. Lajtha (1980),
Neuropharmacology
19: 1145-1148; Sershen, H., M. E. A. Reith and A. Lajtha (1982),
Neuropharmacology
21: 469-474; Spealman, R. D., R. T. Kelleher and S. R. Goldberg (1983),
J. Pharmacol. Exp. Ther.
225: 509-513.) Parallel stereoselective behavioral effects have also been observed. (Bergman, J., B. K. Madras, S. E. Johnson and R. D. Spealman (1989),
J. Pharmacol. Exp. Ther.
251: 150-155; Heikkila, R. E., L. Manzino and F. S. Cabbat (1981),
Subst. Alcohol Actions/Misuse
2: 115-121; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986),
Biochem. Pharmacol.
35: 1123-1129; Spealman, R. D., R. T. Kelleher and S. R. Goldberg (1983),
J. Pharmacol. Exp. Ther.
225: 509-513; Wang, S., Y. Gai, M. Laruelle, R. M. Baldwin, B. E. Scanlet, R. B. Innis and J.
Blundell Paul
Chen Zhengming
Madras Bertha K.
Meltzer Peter C.
Butler, Esq. Gregory B.
Edwards & Angell LLP
Lambkin Deborah C.
Neuner, Esq. George W.
Organix Inc.
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