Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-24
2002-09-10
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S234000
Reexamination Certificate
active
06448249
ABSTRACT:
The present invention relates to a substituted triazolo-pyridazine derivative, to its use in therapy, to compositions containing it and to a process for its manufacture.
We have now discovered that it is possible to obtain medicaments which have cognition enhancing effects which may be employed with less risk of proconvulsant effects previously described with benzodiazepine receptor partial or full inverse agonists. Inverse agonists which are inverse agonists for the &agr;5 receptor and are relatively free of activity at a &agr;1, &agr;2, and &agr;3 receptor binding sites are preferred.
European Patent Applications 0085840 and 0134946 describe related series of 1,2,4-triazolo[3,4-a]phthalazine derivatives which are stated to possess antianxiety activity. However, there is no disclosure nor any suggestion in either of these publications of the compounds of the present invention, nor that the compounds disclosed in the Applications have any cognition enhancing properties.
The present invention provides a compound which is:
3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine.
Cognition enhancement can be shown by testing the compound in the Morris watermaze as reported by McNamara and Skelton, Psychobiology, 21:101-108. The functional efficacy at the various receptor subtypes can be calculated using the method disclosed in WO-A-9625948.
Thus, for example, the compound of the present invention can be used in a variety of disorders of the central nervous system. Such disorders include delirium, dementia and amnestic and other cognitive disorders. Examples of delirium are delirium due to substance intoxication or substance withdrawal, delirium due to multiple etiologies and delirium NOS (not otherwise specified). Examples of dementia are: dementia of the Alzheimer's type with early onset which can be uncomplicated or with delirium, delusions or depressed mood; dementia of the Alzheimer's type, with late onset, which can be uncomplicated or with delirium, delusions or depressed mood; vascular dementia which can be uncomplicated or with delirium, delusions or depressed mood; dementia due to HIV disease; dementia due to head trauma; dementia due to Parkinson's disease; dementia due to Huntington's disease; dementia due to Pick's disease; dementia due to Creutzfeld-Jakob disease; dementia which is substance-induced persisting or due to multiple etiologies; and dementia NOS. Examples of amnestic disorders are amnestic disorder due to a particular medical condition or which is substance-induced persisting or which is amnestic disorder NOS.
The invention also provides pharmaceutical compositions comprising the compound of this invention and a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums or surfactants such as sorbitan monooleate, polyethylene glycel, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of the compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions a homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
The present invention further provides the use of the compound of the present invention in the manufacture of a medicament for the enhancement of cognition, preferably in a human suffering from dementing illness such as Alzheimer's disease.
For the enhancement of cognition, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.01 to 100 mg/kg per day, and especially about 0.01 to 5 mg/kg of body weight per day. The compound may be administered on a regimen of 1 to 4 times per day. In some cases, however, dosage outside these limits may be used.
It is preferred that the compound of the present invention be ground, for example using a pestle and mortar or industrial equivalent thereto, to a particle size of between 1 and 10 &mgr;M, and preferably less than 5 &mgr;M, before formulation. The compound may be micronised or sonicised by methods known in the art or nanonised, for example by methods disclosed in U.S. Pat. No. 5,145,684.
The present invention also provides a process for the production of the compound of the present invention, which comprises reacting a methylating reagent, such as lithium hexamethyldisilazide with 3-(5-methylisoxazol-3-yl)-6-(1H-1,2,3-triazol-5-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine.
The reaction is generally carried out in a solvent such as DMF, generally at a temperature below 0° C. with warming to about room temperature and generally under an inert gas such as nitrogen. The reaction mixture is generally allowed to stand for 4-12 hours. The desired product is generally purified from other reaction products by a conventional separation technique such as preparative HPLC.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in
Protective Groups in Organic Chemistry
, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts,
Protective Groups in Organic Synthesis
, John Wiley & Sons 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The compound in accordance with this invention potently inhibit the binding of [
3
H]-flumazenil to the benzodiazepine binding site of human GABA
A
receptors containing the &agr;5 subunit stably expressed in Ltk
−
cel
Carling William Robert
Ladduwahetty Tamara
MacLeod Angus Murray
Merchant Kevin John
Moore Kevin William
Lee Shu Muk
Merck Sharp & Dohme Ltd.
Morris Patricia L.
Thies J. Eric
Winoker Melvin
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