Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-08
2002-05-21
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S499000
Reexamination Certificate
active
06391873
ABSTRACT:
BACKGROUND
Conventional benzodiazepine anxiolytics are often associated with adverse effects such as motor impairment, excessive sedation, tolerance for the therapeutic effect, physical dependence, abuse liability, cognitive impairments, or toxic effects in overdose. The benzodiazepine of the present invention is useful for treating acute and chronic anxiety disorders (including but not limited to generalized anxiety disorder, panic disorder, social and other phobias, post-traumatic stress disorder, acute anxiety crises) and is not only rapid acting and efficacious in mild-to-severe anxiety disorders and effective when given daily (as once daily, b.i.d. or t.i.d) but shows either no, or substantially less, of the above mentioned adverse side effects.
SUMMARY OF THE INVENTION
The present invention relates to 7-Chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][1,4]benzodiazepin-6-one (I)
and pharmaceutically acceptable acid addition salts thereof.
This compound and its salts are novel and have valuable pharmacodynamic properties. They are therefore suitable for therapeutic purposes, especially for anxiolytic and/or anticonvulsant purposes and/or for the non-sedative treatment of insomnia across a dose range in which no appreciable sedation and/or motoric impairment occurs.
Objects of the present invention are the above mentioned compound and salts thereof per se and as therapeutically active substances, their manufacture and their use for therapeutic purposes or for the production of corresponding medicaments, as well as medicaments containing the above compound or a salt thereof and the production of such medicaments.
DETAILED DESCRIPTION OF THE INVENTION
The compound of the invention and its pharmaceutically acceptable acid addition salts can be manufactured, for instance, according to the synthesis path depicted in Reaction Scheme 1
The benzodiazepine according to the present invention exhibits high affinity in vitro binding to benzodiazepine receptors, as well as rapid onset and robust therapeutic effects in such indications as anxiety disorders, insomnia, mood disorders, psychotic symptoms and disorders, and convulsive disorders (see: Hollister, L. E. et al., Clinical uses of benzodiazepines.
J. Clin. Psychopharmacol.
13 (Suppl. 1): 1S-169S, 1993).
In particular, the benzodiazepine of the present invention is useful for treating acute and chronic anxiety disorders (including but not limited to generalized anxiety disorder, panic disorder, social and other phobias, post-traumatic stress disorder, acute anxiety crises) and is not only rapid acting and efficacious in mild-to-severe anxiety disorders and effective when given daily (as once daily, b.i.d. or t.i.d) but shows either no, or substantially less, adverse effects of the sorts characteristic of the known conventional benzodiazepine anxiolytics, such as motor impairment, excessive sedation, tolerance for the therapeutic effect, physical dependence (and the resultant withdrawal symptoms), abuse liability (i.e., psychological dependence), cognitive impairments, drug interactions due to different causes (especially interaction with ethanol or with substances commonly used within that patient population), or toxic effects in overdose (due either to exaggerated pharmacological effects or to non-specific effects of the compound itself at high doses). The pharmacological profile of the compound according to the present invention involves a clear separation between the therapeutic dose range and the doses producing adverse effects based on the results obtained in animals.
The preclinical pharmacological profile of the compound of the present invention for treatment of anxiety disorders, and/or treatment of convulsions and/or non-sedative treatment of sleep disorders involves no, or only minimal motor impairment, in a standard test of motor performance in animals (e.g. rotarod test in mice with motor function evaluated in the same animals at different time points up to 1 hour after intravenous injection). It has been shown for the compound of the present invention that the ED
50
(or doses producing impairment in 50% of the animals) for a rotarod deficit is greater than about 10 mg/kg i.v., and this is consistently observed at different time points across the entire period of measurement. Moreover, the pharmacological profile of the compound of the present invention involves a very high affinity in vitro binding to the benzodiazepine receptor (
3
H-flumazenil in vitro binding assay using homogenized rat cortex) with a pK
i
value of 9.1 together with a potent anxiolytic-like effect in a mouse model of anxiety.
The compound of the present invention has shown, in the pre-clinical stage, further advantages which overcome several problems typical of the known conventional products. For example, not only is it active in a mouse model of anxiety but additionally it has shown low ethanol interaction in mice, minimal withdrawal signs in chronically treated mice subsequently challenged with a benzodiazepine receptor antagonist (e.g., sarmazenil), minimal reduction (so-called tolerance) of the anxiolytic effect in mice after chronic treatment, or minimal cognitive impairment in rats. In addition, low doses of the benzodiazepine of the present invention are active in an animal model of anxiety and show anticonvulsant effects in animals (for paradigm examples see: Martin & Haefely, Drugs used for the treatment of anxiety and sleep disorders. In:
Principles of Pharmacology: Basic Concepts and Clinical Applications,
edited by P. Munson et al., New York: Chapman & Hall, 1995, pp. 243-277). Moreover, the benzodiazepine according to the present invention produces minimal or no inhibition of cytochrome P450 isoenzymes, thus reducing the risk of drug-drug interactions due to metabolic cause.
The affinity of the compound of the invention to the central benzodiazepine receptors was established in vitro according to the methods described in
Nature
294, 763-765 (1981) and
J. Neurochemistry
37, 714-722 (1981). According to these methods, the inhibition of the binding of tritiated flumazenil to the specific benzodiazepine receptors in the cortex of rats by the respective test substance is determined. The affinity was calculated as pK
i
(for background information on pK
i
see: Cheng, Y. and W. H. Prusoff, Relationship between the inhibition constant (K
i
) and the concentration of inhibitor which causes 50 percent inhibition (IC
50
) of an enzymatic reaction.
Biochem. Pharmac.
22: 3099-3108, 1973) as the measure of the specific binding of tritiated flumazenil to specific benzodiazepine receptors in the cortex of rat.
The motor impairing properties of the compound of the invention can be determined, for example, in the rotating rod test (rotarod test). Mice (Ibm: MORO (SPF); RCC Ltd., 4414 Füllinsdorf, Switzerland) weighing about 20-30 g are used for this test. These mice were housed in Macrolon® type I cages for one or more days following arrival in the laboratory colony (12:12 hour light-dark cycle). They have free access to a standard rodent diet (Kliba Mühlen, Kaiseraugst, Switzerland) and tap water in the home cage up to testing. They are brought into the test laboratory at least 30 min before the test which was done during the light portion of the day-night cycle. In the rotating rod test the animals are placed on a horizontally arranged, smooth metal rod having a diameter of 3 cm, which is rotated at 2 revolutions per min. Initially, the animals are given the opportunity of familiarizing themselves with the test situation for at least 30 sec. Subsequently, those animals which succeed in remaining on the rod for at least 1 min are selected for use in the test. These selected animals are then given the test preparations intravenously in different dosages. At various points in time post-injection, it is then determined whether the animals are able to remain wallking on the rod for a minimum period (minimum period of 10 sec at time points 15 sec. 30 sec. 1 min and 2 mi
Hoffmann-Emery Fabienne
Hunkeler Walter
Jenck François
Martin James Richard
Sleight Andrew
Dawson Arthur D.
Hoffman-La Roche Inc.
Johnston George W.
Reamer James H.
Rocha-Tramaloni Patricia S.
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