Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-05-25
2000-07-11
Krass, Frederick
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514879, A01N 4342
Patent
active
060873728
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB97/03232 filed Nov. 26, 1997.
The present invention provides a method of treatment for enhancing cognition (for example in the treatment of dementing illnesses such as Alzheimer's disease), the manufacture of medicaments useful for such treatment, pharmaceutical compositions and compounds.
A number of dementing illnesses and cognition deficit states are characterised by poor and often a progressive deterioration in the cognition of the sufferer. It would clearly be desirable to enhance cognition in subjects desirous of such treatments. International Patent Application No. PCT/GB 96/00377 discloses that certain GABA.alpha..sub.5 receptor inverse agonists (".alpha.5 inverse agonists") may be used to enhance cognition without producing convulsions. Also by choosing an as inverse agonist that does not have significant (.alpha..sub.1, .alpha..sub.2, or .alpha..sub.3 agonism it is possible to avoid benzodiazepine receptor activity such as that associated with marked anxiolytic, sedative or anti-depressive effects.
U.S. Pat. No. 4,312,870 ("the U.S. Patent") disclosed broad groups of 2-aryl-pyrazolo[4,3-c]quinolin-3-(1 and 3H)-ones which were said to be useful in the treatment of anxiety and depression. Certain of the compounds disclosed in the U.S. Patent have been tested further, see for example Yokoyama et al., J. Med. Chem., 1982, 25, 337-339 and Bennett, Physiology & Behaviours, 1987, 41, 241-245. The Yokoyama paper disclosed that the compounds of the formula (I): ##STR1## wherein R is (a) hydrogen, (b) chlorine or (c) methoxy have an order of magnitude greater affinity for the benzodiazepine receptors than diazepam with 3a being a potent benzodiazepine antagonist, 3b being diazepam-like and 3c acting as an agonist (diazepam-like) at lower doses and antagonist at higher doses. The latter, more detailed paper by Bennett concludes that compounds Ib offers the potential for effective anxiolytic therapy (having been employed clinically) and that compound Ia could be used for the treatment of benzodiazepine overdose. Compound Ic was shown to be only half as effective as related compounds in producing anti-conflict effects.
Subsequently the skilled worker is aware that none of the compounds of formula I proved to be acceptable as marketed medicaments (from which the skilled worker could conclude that the compounds of formula Ia and Ib cause unacceptable side effects or lack of clinical efficacy). Finally, the assignee of the U.S. Patent demonstrated the lack of value attributed to the compounds by them by not paying the patent renewal fees on the UK equivalent of the U.S. Patent by 1994.
Clearly, in view of what the skilled worker knows about the compounds of the U.S. Patent, the skilled worker would not investigate their behaviours further. However, most surprisingly, it has been found that 2-(4-methoxyphenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one and its pharmaceutically acceptable salts are useful for the treatment of conditions requiring the enhancement of cognition such as those indicated hereinbefore.
Accordingly, the present invention provides a method of treatment of a condition requiring the enhancement of cognition in a subject which comprises administering to the subject in need thereof a cognition enhancing amount of 2-(4-methoxyphenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one or a pharmaceutically acceptable salt thereof.
The method will be applied to a mammal, most aptly to a human, preferably to a human suffering from a dementing illness and most preferably to a human suffering from Alzheimer's disease.
It is a great advantage that the method of this invention leads to the enhancement of cognition without being convulsant. Other advantages include not being sedative. In addition, anxiolytic and anti-depressive effects are not prominent. It is believed that 2-(4-methoxyphenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one and its pharmaceutically acceptable salts are able to achieve this desirable end by virtue of being a GABA.sub.A .alpha..sub.5 inverse agonist without possessing major a
REFERENCES:
patent: 4312870 (1982-01-01), Yokoyama
patent: 4595684 (1986-06-01), Bennett
patent: 4740512 (1988-04-01), Yokoyama
patent: 5484793 (1996-01-01), Dood et al.
International Search Report --Mar. 6, 1998.
Bennett, D. A., "Pharmacology of the Pyrazolo-Type Compounds: Agonist, Antagonist and Inverse Agonist Actions," Physiology & Behavior, vol. 41, (1987), pp. 241-245.
Dawson Gerard Raphael
MacLeod Angus Murray
Seabrook Guy Ralph
Jagoe Donna
Krass Frederick
Lee Shu M.
Merck Sharp & Dohme Ltd.
Rose David L.
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