Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-01-16
2000-09-12
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5462767, A61K 3144, C07D40100, C07D41300, C07D41700
Patent
active
061178896
DESCRIPTION:
BRIEF SUMMARY
This invention is in the area of 7-azabicyclo[2.2.1]heptane and -heptene derivatives and their method of manufacture and pharmaceutical use.
BACKGROUND OF THE INVENTION
Opiates, and in particular, morphine, are routinely administered for the treatment of moderate to severe pain. Agents that are less potent than morphine, such as codeine, mixed agonist-antagonist opioids, and non-opiate analgesics, including non-steroidal anti-inflammatory drugs (NSAIDS) are often used to relieve mild to moderate pain. Because of the well-known side effects of opiates, including chemical dependence and respiratory depression, there is a strong need for a non-opiate based analgesic for moderate to severe pain that would equal or exceed the potency of opiate analgesics, yet lack the serious side effects associated with the administration of opiates. Spande, et al., reported in 1992 that a potent nonopiate analgesic had been isolated from the skins of the Ecuadoran poison frog, Epipedobates tricolor. Spande, et al., 1992 J. Am. Chem. Soc., 114, 3475-3478. The structure of the compound was determined by mass spectroscopy, infrared spectroscopy, and nuclear magnetic resonance as exo-2-(2-chloro-5-pyridyl)-7-azabicyclo[2.2.1]heptane (see FIG. 1). The compound, which was named epibatidine, is the first member of the class of 7-azabicyclo[2.2.1]heptane compounds to be found in nature. Limited pharmacological evaluation of epibatidine indicated that it is approximately 500 times more potent than morphine in eliciting the Straub-tail response, and that this effect is not reversed by the opiate antagonist naloxone. In the hot plate analgesia assay, epibatidine is approximately 200 times as potent as morphine. It has also been determined that epibatidine has a negligible affinity for opiate receptors (1/8000 times that of morphine). Based on this data, it appears that epibatidine is a very potent analgesic that acts via a non-opiate mechanism. Since epibatidine was isolated from the skins of the Ecuadoran poison frog, its identification and characterization was not based on the synthesis of the compound. In fact, compounds in the family of 7-azabicyclo[2.2.1]-heptanes and -heptenes (also referred to as 7-azanorbornanes and 7-azanorbornenes, respectively) have historically been difficult to synthesize.
A possible entry into the 7-azabicyclo[2.2.1]-heptane and -heptene ring systems involves the construction of the bicyclic ring through the 2+4 cycloaddition of appropriately substituted 3-vinyl pyridine and pyrrole fragments, as indicated below. ##STR1## Unfortunately, pyrrole and its derivatives readily undergo substitution reactions upon treatment with dienophiles (Diels, O. and Alder, K., Ann. 1932 498, 1.), with only a few exceptions reported (Wittig, G., Angew Chem. 1957 69, 245). The partial aromatic character of pyrrole limits its reactivity as a diene and Michael-type addition products usually dominate. (Jones, R. A., The Chemistry of Heterocyclic Compounds, v.48 Pyrroles Wiley & Sons: New York. 1990.) Rate and yield enhancement of the Diels-Alder reaction between pyrroles and olefins have been obtained using Lewis acids (Donnini, G. P.; Just, G. J. Heterocycl. Chem. 1977, 14, 1423; Bansal, R. C.; McCulloch, A. W.; McInnes, A. G. Can. J. Chem. 1969, 47, 2391), and high pressures (Kotsuki, H.; Mori, Y; Nishizawa, H.; Masamitsu, O.; Matsuoka, K. Heterocycles, 1982, 19, 1915; Drew, M. G. B.; George, A. V.; Isaacs, is N. S.; Rzepa, H. S. T. C. S. Perkin Trans 1, 1985, 1277), but thus far these approaches have been limited in scope. The limitation in these reactions can often be traced to the inherent instability of the 7-azabicyclo[2-2.1]hept-2-ene products with respect to either retro-cycloaddition or retro-Mannich and re-aromatization pathways. This is especially true for cases where the resulting olefin is functionalized by electron-withdrawing groups. (Altenbach, H. J.; constant, D.; Martin, H. D.; Mayer, B.; Muller, M.; Vogel, E. Chem. Ber. 1991, 124, 791.) An alternative method for the synthesis of the 7-azanorbornane system
REFERENCES:
patent: 4835162 (1989-05-01), Abood
patent: 4910193 (1990-03-01), Buchheit
patent: 4940703 (1990-07-01), Baker et al.
patent: 4966916 (1990-10-01), Abood
patent: 4992436 (1991-02-01), Baker et al.
patent: 5104989 (1992-04-01), Cottrell et al.
patent: 5106853 (1992-04-01), Showell et al.
patent: 5124460 (1992-06-01), Humphrey
patent: 5128118 (1992-07-01), Carroll et al.
patent: 5219860 (1993-06-01), Chambers et al.
patent: 5227385 (1993-07-01), Caldwell et al.
patent: 5242927 (1993-09-01), Baker et al.
patent: 5242930 (1993-09-01), Baker et al.
patent: 5256671 (1993-10-01), Ladduwahetty et al.
patent: 5260293 (1993-11-01), Baker et al.
patent: 5288730 (1994-02-01), Baker et al.
patent: 5314899 (1994-05-01), Daly et al.
patent: 5324723 (1994-06-01), Baker et al.
patent: 5405853 (1995-04-01), Baker et al.
patent: 5426106 (1995-06-01), Kulagowski et al.
patent: 5432177 (1995-07-01), Baker et al.
patent: 5444074 (1995-08-01), Baker et al.
patent: 5451588 (1995-09-01), Baker et al.
patent: 5459270 (1995-10-01), Williams et al.
patent: 5461063 (1995-10-01), Kelleher et al.
Adamus, et al., "Phase I Clinical Trials with WAL2014, A New Muscarinic Agonist for the Treatment of Alzheimer's Disease," Life Sciences, 56:(11/12):883-890 (1995) (Elsevier Sciences, Ltd., Editors).
Ainsworth and Hackler, "Alkyl-1,3,4-oxadiazoles," J. Org. Chem., 31:3442-3444 (1966).
Altenbach, H.J., et al., "Synthesis and Photoelectron Spectra of 7-Azanorbornadiene and Related Compounds. An Analysis with Fragment Orbitals," Chem. Ber. vol. 124, p. 791 (1991).
Altenbach, H.J., et al., "7-Azanorbornadiene," Angew Chem. Int. Ed. Engl., vol. 21, No. 10, p. 778 (1992).
Badio, B. and Daly, J.W.; "Epibatidine. A potent analgetic and nicotinic agonist," FASEB Journal, 1994, 8(4-5):A875.
Badio and Daly, "Epibatidine, a Potent Analgetic and Nicotinic Agonist," Mol. Pharmacol., 45(1):563-569 (1994).
Bansal, R.C., McCulloch, A.W., and McInnes, A.G., "Influence of Lewis acids on the Diels-Alder reaction. Part I. An improved synthesis of 7-azanorbornadiene, 3-azaquadricyclaine, and azepine derivatives," Can. J. Chem., vol. 47, p. 2391 (1969).
Barber, A., Gottschlich, R., "Opioid Agonists and Antagonists: An Evaluation of Their Peripheral Actions in Inflammation," Medicinal Research Review, vol. 12, No. 5, pp. 525-562 (Sep. 1992).
Barnes, et al., "Tiotropium Bromide (Ba 679 BR), a Novel, Long-Acting Muscarinic Antagonist for the Treatment of Obstructive Airways Disease," Life Sciences, 56:(11/12):853-859 (1995) (Elsevier Science, Ltd., Editors).
Bhattacharya, S.N., et al., "Friedel-Crafts Sulphonylation of Bis(trimethylsilyl)acetylene: a Useful Route to Aryl Ethynyl Sulphones," Organomet. Chem. Synth., vol. 1, p. 145 (1970).
Broka, C.A., "Total Synthesis of Epibatidine," Tet. Lett., vol. 34, No. 20, pp. 3251-3254 (1993).
Burgen, "The Background of the Muscarinic System," Life Sciences, 56(11/12):801-806 (1995) (Elsevier Science, Ltd., Editors).
Burke, et al., "Construction of a Molecular Shape Analysis-Three Dimensional Quantitative Structure-Analysis Relationship for an Analog Series of Pyridobenzodiazepinone Inhibitors of Muscarinic 2 and 3 Receptors," J. Med. Chem., 37:3775-3788 (1994).
Clayton and Regan, "A Total Synthesis of (+/-) Epibatidine," Tetrahedron Letters, 34(46):7493-7496 (1993).
Cordone, R., et al., "p-Heterocyclic Complexes of Pentaammineosmium(II) and the Metal-Induced Cycloaddition of Pyrrole and Maleic Anhydride," J. Am. Chem. Soc., vol. 111, pp. 5969-5970 (1989).
Corey, E.J., et al., "Stereocontrolled Total Synthesis of (+)-and (-)-epibatidine," J. Org. Chem., vol. 58, No. 21 (Oct. 8, 1983) pp. 5600-5602.
Daly, J.W., Tokuyama, T., Fujiwara, T., Highet, R., and Karle, I.L., J. Am. Chem. Soc., vol. 102, p. 830 (1980).
Davis, A.P., and Whitham, G.H., "Ethynyl p-Tolyl Sulphone as an Acetylene Equivalent in Diels-Alder Reactions," J.C.S. Chem. Comm., p. 639 (1980).
Donnini, G.P., Just, G.J., "Diels-Alder Reactions of Pyrroles as an Entry to Substituted 3-Oxatropanes and Tetrasubs
Gonzalez Javier
Harman W. Dean
Huang Dao Fei
Shen Tsung-Ying
Kifle Bruck
Shah Mukund J.
University of Virginia
LandOfFree
7-Azabicyclo-[2.2.1]-heptane and -heptene derivatives as analges does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 7-Azabicyclo-[2.2.1]-heptane and -heptene derivatives as analges, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 7-Azabicyclo-[2.2.1]-heptane and -heptene derivatives as analges will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-96563