IE74906B1 - Substituted benzofuranyl-piperidine as nootropic - Google Patents

Abstract

4-(7-Bromo-5-methoxybenzofuran-2-yl)piperidine of the formula I <IMAGE> and its pharmaceutically utilisable salts can be used as pharmaceutical active ingredients for slowing down the degeneration of nerve cells associated with degenerative neurological disorders, and as nootropics for the treatment of disorders which respond to nootropic treatment.

Description

The invention relates to the use of 4-(7-bromo-5-methoxybenzofuran-2-yl)piperidine of formula I or of a pharmaceutically acceptable salt thereof, in the preparation of a nootropic agent and in the treatment of the degeneration of nerve cells that accompanies degenerative nerve disorders.

Pharmaceutically acceptable salts of 4-(7-bromo-5-methoxybenzofuran-2-yl)piperidine are especially its pharmaceutically acceptable salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, for example methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfamates (cyclamates). 4-(7-Bromo-5-methoxybenzofuran-2-yl)piperidine and its pharmaceutically acceptable salts are known. When administered subcutaneously to rats in a dose ranging from approximately 10 to approximately 50 mg/kg, they inhibit the uptake of noradrenaline into the heart and they inhibit monoamine oxidase, and they have therefore been proposed as active ingredients for antidepressant medicaments for the treatment of depression.

The invention is based on the surprising discovery that 4(7-bromo-5-methoxybenzofuran-2-yl)piperidine and its pharmaceutically acceptable salts have in addition pronounced nootropic activity and a pronounced retardant action on the degeneration of nerve cells, which occurs, for example, with ! Alzheimer's disease and Parkinson's disease. For example, in mice they provide reliable protection against the amnesio* genic effect of a cerebral electric shock and bring about a marked improvement in memory function. For example, following peroral administration of a dose of from approximately 0.1 to approximately 3 mg/kg p.o., a highly significant increase in the time which the mice spend in the illuminated compartment of the test cage was observed, as compared with the vehicle alone (vehicle: 10.4 s; 3.0 mg/kg of active ingredient in the form of the hydrochloride: 38.8 ± 7.9 sec; p < 0.0002).

Furthermore, in the one-way active avoidance test, which was carried out on 27-month-old rats, following peroral admini15 stration of doses of 0.3 and 3.0 mg/kg, they significantly facilitate learning of the avoidance task, as compared with the vehicle, that is to say, they reduced the number of learning attempts required to achieve five successive active avoidance reactions (vehicle: 21.7 ± 4.5; 3.0 mg/kg of active ingredient in the form of the hydrochloride: 10.2 ± 1.8; p < 0.05).

On account of these properties, 4-(7-bromo-5-methoxybenzofuran-2-yl)piperidine and its pharmaceutically acceptable salts are excellently suitable for retarding the degeneration of nerve cells that accompanies degenerative nerve disorders, such as Alzheimer's disease and Parkinson's disease, and for treating disorders that are responsive to treatment with nootropic agents, for example cerebral insufficiencies having * very varied origins and aetiologies, especially memory dis30 orders, such as senile dementia, multi-infarct dementia or * dementia of the Alzheimer type, and also stroke and the consequences of brain traumas or apoplexies.

The active ingredients for nootropic medicaments proposed according to the invention nay be administered enterally or parenterally, especially orally or intravenously. The recommended daily dose is, for example, from approximately 0.6 to approximately 18 mg/kg or from approximately 40 to approximately 1250 mg/70 kg, preferably approximately from 2 to 8 mg/kg or approximately from 150 to 600 mg/70 kg, for example from approximately 2.5 to approximately 6 mg/kg or approximately from 175 to 420 mg/70 kg, which may, if necessary, be divided into 2 to 4 single doses of, for example, from approximately 0.3 to approximately 6 mg/kg or from approximately 20 to approximately 400 mg/70 kg, preferably approximately from 2 to 4 mg/kg or approximately from 150 to 300 mg/70 kg, for example from approximately 2.5 to approximately 3.2 mg/kg or approximately from 175 to 225 mg/70 kg.

The nootropic pharmaceutical compositions provided according to the invention are preferably pharmaceutical compositions in unit dose form for enteral, such as oral, also rectal, and parenteral administration to (a) warm-blooded animal(s), the compositions comprising the pharmacological active ingredient on its own or together with a pharmaceutically acceptable carrier.

The nootropic pharmaceutical compositions provided according to the invention comprise, for example, from approximately 10 % to approximately 80 %, preferably from approximately 20 % to approximately 60 %, active ingredient. Pharmaceutical compositions according to the invention for enteral or parenteral administration are, for example, compositions in unit dose form, such as dragees, tablets, capsules or suppositories, and also ampoules. They are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. For example, pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture, and processing the mixture or granules, if desired or necessary after the addition of suitable excipients, to form tablets or dragee cores.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, such as the above-mentioned starches and also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable, optionally enteric coatings, there being used inter alia concentrated sugar solutions, which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colourings or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient.

Pharmaceutical compositions for oral administration are also hard gelatin capsules, and soft sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol. The hard gelatin capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and optionally stabilisers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it likewise being possible to add stabilisers.

Suitable rectally administrable pharmaceutical compositions are, for example, suppositories that consist of a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use gelatin rectal capsules, which contain a combination of the active ingredient with a base material. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration there are suitable, especially, aqueous solutions of an active ingredient in water-soluble form, for example in the form of a water-soluble salt, and also suspensions of the active ingredient, such as corresponding oily injection suspensions, there being used suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions that comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilisers.

The following Examples serve to illustrate the invention; temperatures are given in degrees Celsius, pressures in mbar.

Pharmacological Example 1: Protection against the amnesiogenic effect of a cerebral electric shock in mice It is an empirical clinical fact that cerebral electric shock treatment leads to retrograde amnesia; the ability to remem5 ber events immediately before the electric shock is impaired.

Neither the biochemical mechanism nor the nature of the psychological process affected by the treatment is known. However, there is virtually no doubt that the electric shock affects the recollection process in some way. The fact that 0 the retrograde amnesia is time-dependent (the greater the period of time that has elapsed since the information was absorbed, the less pronounced is the effect) suggests an influence on a time-limited process, which most probably concerns fixing the memory pathway or consolidating the contents of the memory. It is therefore to be assumed that medicaments that facilitate fixing of the memory pathway have an advantageous effect on amnesia brought about by the electric shock, for example they shorten the period of time during which fixing of the memory pathway is impaired and thus reduce the extent of the amnesia. In the animal experiment, amnesia induced by an electric shock can be observed when the cerebral electric shock is applied within a few seconds following the learning process, which in the present case is a passive avoidance task.

Experimental arrangement: A larger cage compartment (35 x 20 x 10 cm) communicates with a smaller cage compartment (10 x 10 x 10 cm) by means of a sliding door. The smaller cage compartment is illuminated from above by means of a 100 Watt light bulb; the larger cage compartment is dark.

The floor of both cage compartments consists of an electrically conductive grid.

Method: The test animals are placed individually in the illuminated cage compartment. Since mice have a natural preference for a dark environment, most of the test animals move spontaneously into the dark cage compartment. As soon as all the test animals are in that compartment, the sliding door is closed and an electric shock (1 mA, 5 sec) is administered to their feet.

The test animals are removed immediately, and 24 hours later they are again placed in the illuminated cage compartment.

The period of time for which the test animals hesitate before moving into the dark cage compartment is measured. In general, most of the test animals remain in the illuminated cage compartment for the entire observation period (150 sec), which means that virtually all the test animals have mastered the learning task.

If a cerebral electric shock (14 mA, 0.2 s, 150 Hz) is administered immediately after the foot-shock phase of the learning process, the test animals' ability to remember the foot shock is impaired. 4-(7-Bromo-5-methoxybenzofuran-2yl)piperidine in the form of the hydrochloride has a pronounced anti-amnesiogenic protective effect in this model when administered perorally 60 minutes prior to the cerebral electric shock.

Measurement results: Test compound Time in illuminated Signi ficance cage compartment 0.3 mg/kg p.o. active ing. 25.9 s p<0.01 3.0 mg/kg p.o. active ing. 38.9 s p<0.0002 30.0 mg/kg p.o. active ing. 14.5 s n. s. Vehicle on its own 10.4 s Conclusion: * The active ingredient is effective at 0.3, 1.0 and 3.0 mg/kg p.o.. The most pronounced activity is to be observed at 3.0 mg/kg p.o.; the average time spent in the illuminated cage compartment in that case is 38.8 ± 7.9 sec (p < 0.0002).

At 30.0 mg/kg p.o., no further significant activity is observed. As compared with the time spent in the illuminated cage compartment following administration of the vehicle on its own (10.4 s), this corresponds to a statistically highly TO significant increase, by a factor of 3.7.

Pharmacological Example 2: Action in the case of chronic treatment on the learning ability of elderly rats A certain deterioration in higher intellectual functions, noticeable especially in the storage and utilisation of T5 information, is a feature and a consequence of the natural ageing process in humans and animals. In animals, a decline in the ability to gather and utilise information can be observed. Elderly test animals are therefore useful test subjects for investigating age-related cognitive mal20 functions, and especially for studying the effect of active ingredients for medicaments on age-related memory dysfunctions.

Experimental arrangement: The experimental arrangement consists of two identical cage compartments A and B (each measuring 20 x 20 x 30 cm) which communicate by means of a / door (12 x 16 cm) and are provided with electrically conductive floor grids. The learning test consists in • placing the test animal in cage compartment A and, after seconds, subjecting it to an electric shock to its feet. 3Q The test animal can avoid this by moving into cage compartment B. Training in this active one-way avoidance task is continued until the test animal is able to avoid the electric shock in this manner five times in succession.

Method; Elderly rats (age at start of test: 27 months) are treated daily perorally with 0.3, 1.0, 3.0 and 30 mg/kg of the test compound. The vehicle is administered to a control group. 60 minutes after the treatment, the test animals are subjected to the above training. A further learning attempt takes place 4 hours later.

Measurement results: Test compound Number of learning attempts Signi f icance 0.3 mg/kg p.o. active ing. 15.6 ± 2.6 p<0.05 3.0 mg/kg p.o. active ing. 10.2 ± 1.8 p<0.02 Vehicle on its own 21.7 ± 4.5 Conclusion: Doses of 0.3 and 3.0 mg/kg p.o. of the active ingredient bring about a statistically significant reduction, to 47 % of the control value, in the number of learning attempts required to learn the active avoidance task.

Formulation Example 1: Tablets, each comprising 200 mg of 4S' ( 7-bromo-5-methoxybenzofuran-2-yl)piperidine or of a salt, for example the hydrochloride, thereof, can be prepared as 1 follows: Composition f 10 000 tablets') active ingredient lactose potato starch gelatin talc magnesium stearate silica (highly disperse) ethanol 2000.0 g 500.0 g 352.0 g 8.0 g 60.0 g 10.0 g 20.0 g g. s.

The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve.

After drying, the remaining potato starch, the magnesium stearate, the talc and the silica are mixed in and the mixture is compressed to form tablets which each weigh 295.0 mg and comprise 50.0 mg of active ingredient, and which may, if desired, be provided with dividing notches for finer adjustment of the dose.

Formulation Example 2: Film-coated tablets, each comprising 400 mg of 4-(7-bromo-5-methoxybenzofuran-2-yl)piperidine or of a salt, for example the hydrochloride, thereof, can be prepared as follows: 400.0 g 100.0 g 70.0 g 8.5 g 1.5 g 2.36 g 0.64 g q.s. q.s.

Composition (for 1000 film-coated tablets) active ingredient lactose corn starch talc calcium stearate hydroxypropylmethylcellulose shellac water methylene chloride The active ingredient, the lactose and 40 g of the corn starch are mixed, and the mixture is moistened with a paste, prepared from 15 g of corn starch and water (with heating), and granulated. The granules are dried, and the remaining corn starch, the talc and the calcium stearate are added and mixed with the granules. The mixture is compressed to form tablets (weight: 580 mg), which are coated with a solution of the hydroxypropylmethylcellulose and the shellac in methylene chloride; final weight of each film-coated tablet: 583 mg.

Formulation Example 3: Hard gelatin capsules, each containing 500 mg of 4-(7-bromo-5-methoxybenzofuran-2-yl)piperidine or of a salt, for example the hydrochloride, thereof, can be prepared, for example, as Composition f for 1000 caps active ingredient lactose microcrystalline cellulose sodium lauryl sulfate magnesium stearate follows: ulesl 500.0 g 250.0 g 30.0 g 2.0 g 8.0 g The sodium lauryl sulfate is added to the lyophilised active ingredient through a sieve having a mesh size of 0.2 mm. The two components are mixed intimately. Then, first the lactose is added through a sieve having a mesh size of 0.6 mm and y then the microcrystalline cellulose through a sieve having a mesh size of 0.9 mm. The mixture is mixed intimately again for 10 minutes. Finally, the magnesium stearate is added through a sieve having a mesh size of 0.8 mm. After further mixing for 3 minutes, hard gelatin capsules of a suitable size are each filled with 790 mg of the resulting formulation.

Formulation Example 4; A 5 % injection or infusion solution of 4—(7—bromo—5—methoxybenzofuran—2—yl)piperidine or of a salt, for example the hydrochloride, thereof can be prepared, for example, as follows: Composition ffor 1000 or 400 ampoules) active ingredient 125.0 g sodium chloride 22.5 g phosphate buffer pH = 7.4 300.0 g demineralised water ad 2500.0 ml The active ingredient and the sodium chloride are dissolved in 1000 ml of water and filtered through a microfilter. The buffer solution is added, and the mixture is made up to 2500 ml with water. To prepare unit dose forms, 1.0 or 2.5 ml are introduced into each glass ampoule, which then contains 50 or 125 mg, respectively, of active ingredient.

Claims (2)

CLAIMS :

1. The use of 4-(7-bromo-5-methoxybenzofuran-2-yl)piperidine of formula I or of a pharmaceutically acceptable salt thereof, in the 5 preparation of a medicament for treating the degeneration of nerve cells that accompanies degenerative nerve disorders, and as a nootropic agent.

2. Use according to claim 1, substantially as hereinbefore described.