Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-14
2002-08-20
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S290000, C546S094000
Reexamination Certificate
active
06436954
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to benzo[b]quinolizidines, be U[f]indolizidines, and ring-expanded derivatives thereof, which are useful for the treatment of neurodegenerative states and diseases associated with memory impairment. The invention also relates to pharmaceutical compositions comprising these compounds, and to methods of treating or controlling the symptoms of Alzheimer's disease, senile dementia, or other conditions associated with the impairment of memory. The compounds of this invention are weak inhibitors of neural acetylcholinesterase in vitro. The compounds of this invention also protect rodents against scopolamine-induced amnesia without inducing psychomotor or behavioral deficits.
BACKGROUND OF THE INVENTION
Impairment of cognition and memory is associated with numerous diseases. The most widely known is Alzheimer's disease, which is associated with extensive loss of specific neuronal subpopulations in the brain (Sims, N. R., et al. (1987)
Annals of Neurology
21:451; Katzman, R. (1986)
New England Journal of Medicine
314:964). The biochemical and cellular changes which lead to neuronal loss remain unknown. Proposed causes include environmental factors, (Perl, D. P. (1985)
Environmental Health Perspective
63:149; Katzman, R. (1986)), including metal toxicity, (Perl, D. P., et al. (1980)
Science
208:297), defects in &bgr;-amyloid protein metabolism; (Shoji, M., et al. (192)
Science
253:126
; Assoc. Disord
. 6:7; Kosik, K. S. (1992)
Science
256:780; Selkoe, D. J. (1991)
Neuron
6:487; Hardy, H. and Allsop, D. (1991)
Trends in Pharmacological Science
12:383; Varghese, J., et al., 1997
, Annual Reports in Medicinal Chemistry
32:11), and abnormal calcium homeostasis and/or calcium activated kinases. (Mattson, M. P., et al. (1992)
Journal of Neuroscience
12:376; Borden, L. A., et al. (1991)
Neurobiology of Aging
13:33; Peterson, E., et al. (1989)
Annals of New York Academy of Science
568:262; Peterson, C., et al. (1988)
Neurobiology of Aging
9:261; Peterson, C., et al. (1986)
Proceedings of the National Academy of Science
83:7999).
Tacrine hydrochloride (COGNEX) was the first drug approved for the treatment of Alzheimer's Disease. Tacrine is a complex pharmacological agent (Cacabelos, R., et al.,
Drugs of Today
1994, 30, 295) which among other properties is a potent inhibitor of acetylcholinesterase (AcChE), and an even more potent inhibitor of the butyrylcholinesterase family of enzymes (Maayani, S., et al.,
Biochem. Pharmacol
. 1974, 23, 1263-1281). Tacrine is generally considered to be a postsynaptic agent (Hershenson, F. M. in
New Leads and Targets in Drug Research
, Alfred Benzon Symposium 33, pages 354-363, ed. P. Krogsgaard-Larsen, S. Brogger, H. Kofod; Munksgaard, Copengagen, 1992). Other synaptic AcChE inhibitors include the tacrine analogs, physostigmine (
Drugs of the Future
1991, 16, 33; ibid. 1994, 19, 343, 656) and physostigmine derivatives, E-2020 (
Drugs of the Future
1991, 16, 33; ibid. 1994, 19, 343, 656), and huperzine A (
Drugs of the Future
1991, 16, 33; ibid. 1994, 19, 343, 656).
Tacrine belongs to the well-known structural class of aminopyridines (Osterrieder, W. Br.
J. Pharmac
. 1987, 92, 521; Edwards, G. and Weston, E. H. in
Receptor Data for Biological Experiments, p
. 194, Ellis Horwood, N.Y., 1991) which are potassium channel blockers. The deficiency of tacrine as a drug is related to its liver toxicity and peripheral cholinomimetic actions (Manning, F. C. American
Family Physician
1994, 50, 819).
Many analogs of tacrine have been prepared (
Drugs of the Future
1991, 16, 33; ibid. 1994, 19, 343, 656; McKenna, M., et al.,
J. Med. Chem
. 1997, 40, 351-3523). Because the 4-aminoquinoline portion of tacrine is generally believed to be important for binding of the drug to the active site of AcChE (Silman, I., et al.,
Biochem. Soc. Trans
., 1994, 22, 745-749), most of these are structurally related to the parent compound, and tend to exhibit some of the same toxicological problems as tacrine. Consequently, there remains a great need for alternative drugs, less structurally related to tacrine, for the treatment of memory impairment such as is associated with Alzheimer's disease.
The systematic name for the benzo[b]quinolizidine ring system is 1,3,4,6,11,11a-hexahydro-2H-benzo[b]quinolizine. Although the parent ring system has been known for some time, derivatives with an amino group at C-11 were not previously known.
With respect to 11-oxygenated derivatives, the C-11 ketone (1,3,4,11a-tetrahydro-2H-benzo[b]quinolizin-11(6H)-one) is known (G. Gonzalez Trigo and J. Alvarez-Builla,
An. Quim., Ser. C
, 1980, 76: 12-15), as is the 8,9-dimethoxy derivative (Sugimoto, Yakugaku Zasshi (
J. Pharm. Soc. Japan
), 1956, 76, 1045
; Chem. Abstr
. 1957, 3598). The 11-hydroxy derivative (1,3,4,6,11,11a-hexahydro-2H-benzo[b]quinolizin-11-ol) is known (G. Gonzalez Trigo and J. Alvarez-Builla, loc. cit.), as are some 11-aryl and 11-aminoalkyl derivatives (G. E. Hardtnann, U.S. Pat. No. 3,408,352; W. Houlihan and J. Nadelson, U.S. Pat. 3,824,244 and 3,892,752) and the 8,9-dimethoxy derivative (S. Kupchan et al.,
J. Org. Chem
., 1966, 31:1713-1716).
The systematic name for the benzo[f]indolizidine ring system is 1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinoline. Although the parent ring system has been known for some time, derivatives with an amino group at C-10 have not been reported previously.
With respect to 11-oxygenated derivatives, 1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinolin-10-ol is known (Totleben, M. J., et al.,
J. Org. Chem
., 1997, 62:7319-7323; Rigo, B.; Kolocouris, N.
J. Heterocyclic. Chem
. 1983, 20:893-898), as is the 7,8-dimethoxy derivative, and the 10-O-acetate ester thereof (Knefeli, F., et al.,
Arch. Pharm
., 1983, 316:773-781).
A few 3-keto derivatives of the 10-hydroxy compound are also known (Rigo, B., and Kolocouris, N., loc. cit.,; Kubo, A., et al.,
Heterocycles
, 1966, 42:195-211.
SUMMARY OF THE INVENTION
In general this invention relates to benzoquinolizidines, benzoindolizidines, and ring-expanded derivatives thereof, and to pharmacological compositions containing these compounds. The compounds of the present invention are benzoquinolizidines, benzoindolizidines, and ring-expanded derivatives of the general formula:
wherein m, n, p, R
1
, R
3
, R
4
, R
6
and R
7
are as defined further below.
The compounds of this invention are expected to be useful for enhancing cognition, and for treating or controlling the symptoms of memory impairment in senile dementia, Alzheimer's disease, or similar conditions. Although some of these conditions may be associated with decreased availability of acetylcholine, and although the compounds of this invention are in general weak inhibitors of acetylcholinesterase, the present invention is not limited with regard to any specific mechanism of action, nor are the memory-enhancing properties of the compounds of the invention attributed to any specific mechanism.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides benzoquinolizidines, benzoindolizidines, and ring-expanded derivatives thereof, wherein a tetrahydroisoquinoline is fused to a pyrrolidine, piperidine, azepine or azocine ring. These compounds are of the general formula:
wherein n=1 to 4, and each R
1
independently may be hydrogen, halo, or optionally substituted alkyl or cycloalkyl, aryl, arylalkyl, haloalkyl, haloalkoxy, hydroxy, alkoxy, trifluoromethyl, cyano, carboalkoxy, alkanoyl, aroyl, or alkylsulfonyl;
wherein R
2
=OR
5
or NR
6
R
7
, and R
5
is hydrogen, optionally substituted alkyl or cycloalkyl, alkanoyl, aroyl, aryl, arylalkyl, alkylaryl, haloalkyl, or haloalkoxy, and R
6
and R
7
may each independently be hydrogen, optionally substituted alkyl or cycloalkyl, aryl, arylallyl, alkylaryl, aroyl, alkanoyl, alkylaroyl, or arylalkanoyl, or NR
6
R
7
may be azetidino, pyrrolidino, piperidino, or morpholino;
wherein p=1
Regan Ciaran
Szmuszkovicz Jacob
American Biogenetic Sciences Inc.
Desai Rita
Morgan & Finnegan , LLP
Rotman Alan L.
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