Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1995-01-17
2002-12-10
Low, Christopher S. F. (Department: 1653)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S019300, C562S445000, C568S818000, C548S496000
Reexamination Certificate
active
06492531
ABSTRACT:
BACKGROUND OF THE INVENTION
Cholecystokinin (CCK) is a neuropeptide with a widespread distribution in brain. CCK receptors are classified into two types; CCK
A
and CCK
B
, both of which are present in brain (Woodruff, G. N. and Hughes, J., 1991,
Ann. Rev. Pharmacol.
31, 469-501).
CI-988, the chemical name is: [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1
3,7
]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino)-4-oxobutanoic acid, and the structure is:
It is a potent CCK
B
antagonist with high selectivity for CCK
B
receptors (Hughes, J., et al, 1990,
Proc. Natl. Acad. Sci.,
USA, 87 6728-6732). CCK
B
antagonists have been shown to have anxiolytic-like activity in animal models of anxiety (Hughes, J., et al,
Proc. Natl. Acad. Sci.,
USA, 87, 6728-6732; Singl, L., Lewis, A. S., Field, M. J., Hughes, J., and Woodruff, G. N., 1991,
Proc. Natl. Acad. Sci.,
USA, 88, 1130-1133), suggesting a physiological role for CCK in anxiety. It has also been suggested that CCK may be involved in the control of food intake and in analgesic responses (Woodruff, G. N. and Hughes, J., 1991,
Ann. Rev. Pharmacol.
31, 469-501).
The above compound and other CCK antagonists have been described in EPA 0405537. These antagonists are also described in U.S. application Ser. No. 07/629,809, filed Dec. 19, 1990, now U.S. Pat. No. 5,278,316 the disclosure of which is hereby incorporated by reference.
Other CCK antagonists have been described in U.S. application Ser. No. 07/726,656, now U.S. Pat. No. 5,331,006; Ser. No. 07/726,655, now abandoned; application Ser. Nos. 07/839,647; 07/726,654 now U.S. Pat. Nos. 5,244,915, 5,397,788, and 5,523,306; Ser. No. 07/726,653 now U.S. Pat. No. 5,340,825; Ser. No. 07/726,652 now U.S. Pat. No. 5,264,419; and, Ser. No. 07/726,651 now U.S. Pat. No. 5,244,905, the disclosures of which are also hereby incorporated by reference.
The above patents and applications cover the compounds of the instant invention, methods for preparing them, and several uses thereof.
The above references do not disclose the use of CCK
B
antagonists for treating cognitive disorders.
The present invention concerns medical methods of treatment. More particularly, the invention concerns the use of CCK-B ligands for the treatment of the symptoms of cognitive decline or deficiencies such as in the loss of memory or in an elderly patient suffering from Alzhemier's disease.
Disorders of cognition are generally characterized by symptoms of forgetfulness, confusion, memory loss, attentional deficits and/or, in some cases, affective disturbances. These symptoms may arise as a result of the general aging process and/or from organic brain disease, cerebrovascular disease, head injury or developmental or genetic defects.
The general decrease in cognitive function which accompanies the aging process is well known. The same phenomenon has been observed and documented in many lower mammals, including those routinely employed in pharmacological testing programs for screening and predicting usefulness for particular drugs in higher animals, including humans.
Although disorders of cognition often accompany the general aging process, presenile and senile primary degenerative dementia are the most common accepted causes of mental deterioration in the elderly. It has been estimated that at least ten percent of persons over sixty years of age will eventually suffer severe mental deterioration. A much larger number will experience cognitive decline of sufficient severity to impede their activities.
SUMMARY OF THE INVENTION AND DETAILED DESCRIPTION
The present invention relates to a novel therapeutic use of known compounds, CCK
B
antagonists, their derivatives, and pharmaceutically acceptable salts. The present invention concerns a method for treating cognitive disorders in a mammal in need of such treatment.
This invention provides a method of treating disorders of cognition using CCK
B
receptor antagonists. The results presented herein indicate that such compounds improve basal cognition and inhibit the impairments in performance caused by cholinergic deficits. Thus the compounds with CCK-B receptor antagonist activity are expected to be useful in diseases such as senile cognitive decline, Alzheimer's disease, myasthenia gravis, tardive dyskinesia and dementia associated with Down's syndrome or Parkinson's disease.
The treatment comprises administering in unit dosage form an amount effective to treat the cognitive disorder of a CCK
B
antagonist or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.
Preferred compounds include but are not limited to:
1. [1S-[1&agr;,2&bgr;[S*[S*(E)]],4&agr;]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid,
2. [1S-[1&agr;,2&bgr;[S*(S*)],4&agr;]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]methylamino]-1-phenylethyl]amino]-4-oxobutanoic acid,
3. [1S-[1&agr;,2&bgr;[S*(S*)],4&agr;]]-4-[[2-[[3-(1H-indol-3-yl-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]-hept-2-yl)amino]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid,
4. [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo[3.3.1.1
3,7
]dec-2-ylsulfonyl)amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid,
5. [R-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo[3.3.1.1
3,7
]dec-2-ylsulfonyl)amino]propyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
6. [1R-[1&agr;[R*(S*)],2&bgr;]] and [1S-[1&agr;[S*(R*)],2&bgr;]]-4-[[2-[[2-[[[(2-fluorocyclohexyl)oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
7. [1R-(1&agr;[R*(S*)],2&bgr;]] and [1S-[1&agr;[S*(R*)],2&bgr;]]-4-[[2-[[2-[[[(2-fluorocyclohexyl)oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]methylamino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
8. [1R-[1&agr;[R*(S*)],2&bgr;]] and [1S-[1&agr;[S*(R*)],2&bgr;]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[[2-(trifluoromethyl)cyclohexyl]oxy]carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
9. [1R-[1&agr;[R*(S*)],2&bgr;]] and [1S-[1&agr;[S*(R*)],2&bgr;]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[[2-(trifluoromethyl)cyclohexyl]oxy]carbonyl]amino]propyl]methylamino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
10. [R-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1
3,7
]dec-2-yloxy)carbonyl]amino]propyl]methylamino]-3-phenylpropyl]amino]-4-oxobutanoic acid,
11. [1S-[1&agr;,2&bgr;[S*(R*)],4&agr;]]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-[[1-oxo-3-(1H-tetrazol-5-yl)propyl]amino]-1-(phenylmethyl)ethyl]amino]ethyl]carbamic acid, 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl ester,
12.
Anderson Elizabeth M.
Ashbrook Charles
Low Christopher S. F.
Lukton David
Warner-Lambert & Company
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