NO179358B - Use of substituted benzofuranyl piperidines as nootropics - 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 present invention relates to the use of 4-(7-bromo-5-methoxy-benzofuran-2-yl)-piperidine with the formula I

or one of its pharmaceutically usable salts for the manufacture of a medicament for the treatment of the degeneration of nerve cells occurring in degenerative nerve diseases, as well as a nootropic.

Pharmaceutically usable salts of 4-(7-bromo-5-methoxy-benzofuran-2-yl)piperidines are in particular their pharmaceutically usable salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochloride, hydrobromide, sulphate, hydrogen sulfate or phosphate or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, for example methanesulfonate, benzenesulfonate, p-toluenesulfonate or N-cyclohexylsulfamate (cyclamate).

4-(7-Bromo-5-methoxy-benzofuran-2-yl)piperidine and its pharmaceutically usable salts are known, and for example described in DE-2653147. They inhibit in the rat, after being given subcutaneously in doses from about 10 to about 50 mg/kg, the reception of noradrenaline in the heart and monoamine oxidase and their compliance with what is proposed as antidepressant agents for the treatment of depression, for example in Drugs of the future 10, 371-373 (1985).

The invention is based on the surprising finding that 4-(7-bromo-5-methoxy-benzofurean-2-yl)piperidines and its pharmaceutically usable salts also show pronounced nootropic effects and a pronounced delaying effect on the degeneration of the nerve cells, which occurs, for example, in Alzheimer's and Parkinson's diseases. Thus, in mice, they provide a safe protection against the memory-loss effect of a cerebral electroshock and a significant improvement in memory performance. Thus, after follow-up with a dose of approx. 0.1 to approx. 3 mg/kg p.o. compared to the carrier alone, a highly significant extension of the residence time in the bright test box part (carrier: 10.4 s; 3.0 mg/kg active substance in the form of its hydrochloride: 3.8 ± 7.9 s; p < 0.0002). From J. Neural Transm. 1.82.83 (1989) it is also known that brofaromine in the EEG leads to comparable effects as physiostigmine. Furthermore, brofaromine in WO-89/03692 was proposed for the treatment of premenstrual syndrome due to its mono-amine oxidase inhibitory properties.

Moreover, in a one-way active avoidance test, which is carried out on 27-month-old rats, they facilitate learning the avoidance task after oral administration of a dose of from 0.3 to 3.0 mg/kg, i.e. the number of learning trials necessary for achievement is reduced of 5 consecutive active avoidance reactions over vehicle in a significant way (vehicle: 21.7 ± 4.5; 3.0 mg/kg active substance in the form of its hydrochloride: 10.2 ± 1.8; p < 0 .05). This effect occurs at doses significantly lower than the oral ED50 of brofaromine for the selective and reversible MAO inhibition in the rat (21 mg/kg, Eur. J. Pharmacol. 169, 200 (1989)).

Because of these properties, 4-(7-bromo-5-methoxy-benzofuran-2-yl)-piperidines and its pharmaceutically usable salts are well suited for delaying the degeneration of nerve cells that occurs in degenerative nerve diseases such as Alzheimer's and Parkinson's diseases, so as well as for the treatment of diseases affected by nootropic treatment, for example in case of insufficient cerebral performance as in various origins and causes, in particular for memory disorders as in senile dementia, multi-infarct dementia or dementia of the Alzheimer type, moreover from stroke as well as from the consequences of brain trauma and apoplexy.

The proposed nootropic drug active substances according to the invention can be given enterally or parenterally, preferably orally or intravenously. The recommended daily dose is for example from about 0.6 to about 18 mg/kg respectively from about 40 to about 1250 mg/70 kg, preferably from about 2 to 8 mg/kg respectively about 150 to 600 mg/70 kg, for example from approx. 2.5 to approx. 6 mg/kg, respectively approx. 175 to 420 mg/70 kg, which can necessarily be given in two to four single doses, for example from approx. 0.3 to approx. 6 mg/kg, respectively approx. 20 to 400 mg/70 kg, preferably from about 2 to about 4 mg/kg, respectively about 150 to 300 mg/70 kg, for example from about 2.5 to about 3.2 mg/kg, respectively about 175 to 225 mg/70 kg.

The nootropic pharmaceutical preparations of the invention are preferably those which contain the pharmacological active substance alone or together with a pharmaceutically usable carrier material in a unit dose form for enteral use, such as oral or rectal, and parenteral use in warm-blooded animals.

The nootropic pharmaceutical preparation produced according to the invention contains, for example, from about 1056 to about 8056, preferably from about 2056 to about 6056, of the active ingredient. Pharmaceutical preparations according to the invention for enteral or parental use are, for example, in dosage unit forms such as dragees, tablets, suppositories or ampoules. These are produced by known methods, for example by means of conventional mixing, granulating, coating, dissolving or lyophilization methods. In this way, pharmaceutical preparations for oral use can be obtained, where the active substance is combined with solid carrier substances, a resulting mixture is possibly granulated and the mixture or the granulate is, when desired or necessary, processed by adding suitable excipients

<5to tablets or dragon cores.

Suitable carriers are in particular fillers such as sugar, for example lactose, sucrose, mannose or sorbitol, cellulose preparations and/or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch pastes, and the use of, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, when desired blowing agents such as the above-mentioned starches, further carboxymethyl starches, cross-linked polyvinylpyrrolidones, agar, alginic acids or a salt thereof such as sodium alginate, auxiliaries are primarily flow, flow regulating and lubricants for for example silicic acid, talc, stearic acid or salts thereof such as magnesium or calcium stearate and/or polyethylene glycol. The dragon cores are equipped with suitable, possibly enteric-resistant coatings, which contain, among other things, concentrated sugar solutions, possibly gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or for the production of enteric-resistant coatings, it is used solutions of suitable cellulose preparations such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. The tablets or dragé coatings can be added with dyes or pigments, for example for identification or as characteristics for different active agent doses.

Other orally usable pharmaceutical preparations are suppositories—capsules of gelatin, as well as soft, resealable capsules of gelatin and an emollient such as glycerin or sorbitol. The capsules can contain active substances in the form of a granule, for example in a mixture with fillers such as lactose, binders such as starch and/or lubricants such as talc or magnesium stearate and possibly stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as fatty oils, paraffin oil or liquid polyethylene glycols, where stabilizers may be added.

As rectally usable pharmaceutical preparations, for example, suppositories come into consideration, which consist of a mixture of the active ingredient with a suppository base. Natural and synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols are suitable as suppository base material. Furthermore, gelatin rectal capsules can also be used, consisting of a mixture of the active ingredient with a base substance. Liquid triglyceride, polyethylene glycol or paraffin hydrocarbons are suitable as base material.

To be given parenterally, aqueous solutions of an active substance in water-soluble form are suitable, for example a water-soluble salt, for without suspensions of the active substance that correspond to oil-based injection suspensions where suitable lipophilic solvents or carriers such as fatty oils such as sesame oil or synthetic fatty acid esters are used for for example ethyl oleate or triglyceride or water-based injection suspensions containing viscosity-increasing substances such as sodium carboxymethyl cellulose, sorbitol and/or dextran and possibly also stabilizers.

The following examples serve as an illustration of the invention; temperatures here indicated in degrees Celsius and pressure in millibars.

Pharmacological example 1: Protection against the amnesiogenic effect of a cerebral electroshock in mice.

It is a fact of clinical experience that cerebral electroshock treatment leads to regressive amnesia; the ability to remember events immediately before the electroshock is destroyed. Neither the biochemical mechanism nor the way the treatment affects the physiological processes is known. There is still no doubt that the electric shock affects the memory process in one way or another. The time dependence of the retroactive amnesia (the further back the information access is, the smaller the effect) speaks for an impact on a time-limited process, which probably concerns the earliest fixation of memory traces or the fixation of the memory content. It is therefore assumed that drugs that have a beneficial influence on the fixation of the memory traces facilitate the effect of the electroshock-induced memory loss, for example by shortening the time period for which the fixation of the memory trace is destroyed and thereby reducing the extent of the memory loss. In animal experiments, electroshock-induced amnesia can be determined when the cerebral electroshock is delivered within seconds of training. In the present case, this consists of a passive avoidance task.

Experimental setup: A large brothel (35 x 20 x 10 cm) is connected to a smaller brothel (10 x 10 x 10 cm) through a sliding door. The smaller brothel is lit from above with a 100 watt incandescent lamp and the large brothel is dark. The floor in both parts of the brothel consists of an electrically conductive grid.

Methodology: The experimental animals are placed individually in the bright brothel. Since the mice have a natural preference for dark surroundings, most of the experimental animals immediately go to the dark brothel. As soon as all test animals are here, the sliding door is closed and followed by a foot shock (1 mÅ, 5 seconds).

The experimental animals are then immediately taken out and after 24 hours again put in the bright box part. The time the test animals hesitate before entering the dark brothel is measured. Generally, most of the test animals remain in the bright brothel for the same reflection time (150 seconds), which means that practically all the test animals have mastered the learning task.

If the foot shock phase of the learning process is immediately followed by a cerebral electroshock (14 mA, 0.2 seconds, 150 Hz), the ability to remember the foot shock is destroyed. In this model, 4-(7-bromo-5-methoxy-benzofuran-2-yl)piperidines in the form of their hydrochloride have a clear amnesia-preventing effect after oral administration 60 minutes before the cerebral electroshock.

Measurement results:

Conclusion:

The active ingredient is effective at 0.3, 1.0 and 3.0 mg/kg p.o. The strongest effect was observed at 3.0 mg/kg p.o.; the average stay time in the bright brothel was then 38.8 ± 7.9 seconds (p < 0.0002). At 30.0 mg/kg p.o. no significant effect was measured. In relation to the residence time after the carrier alone (10.4 seconds), this shows a statistically significant extension by a factor of 3.7.

Pharmacological example 2: Effect of chronic treatment on the learning ability of old rats.

A certain weakening of higher mental functions, which can be observed in everyone when storing and utilizing information, is noticeable in both humans and animals and is a consequence of the natural aging process. In animals, the impairment can be determined by the ability to gather information and to take advantage of it. Old laboratory animals are, in accordance with this, usable model objects for the investigation of age-related cognitive malfunctions, and in particular of drug active substances on age-related memory performance.

Test device<g>: The test device consists of two equal brothel parts A and B (both 20 x 20 x 30 cm) connected to each other through a door (12 x 16 cm) and equipped with an electrically conductive grid at the bottom. The learning experiment consists of the test animals being placed in brothel A and after 10 seconds they are exposed to a foot shock. The test animal can avoid this by going to brothel B. The learning in this active one-way avoidance task is continued for so long that the test animals avoid the electric shock 5 times in a row in this way.

Procedure: Old rats (age at the start of the experiment: 27 months) are treated daily orally with 0.3, 1.0, 3.0 and 30 mg/kg of the test substance. A control group is given vehicle. 60 minutes after the treatment, the experimental animals are exposed to the above-mentioned training. The next learning attempt follows 4 hours later.

Measurement results:

Conclusion. salary:

A dose of 0.3 and 3.0 mg/kg p.o. of the active substance reduces the required learning trials to learn the active avoidance task in a statistically significant way to 4756 of the control values.

Formulation example 1:

Tablets, each containing 200 mg of 4-(7-bromo-5-methoxy-benzofuran-2-yl)piperidines or a salt, for example the hydrochloride thereof, may be prepared as follows:

Composition (10,000 tablets!

The active substance is mixed with the lactose and 292 g of potato starch, the mixture was moistened with an alcohol solution of the gelatin and granulated through a sieve. After drying, the rest of the potato starch, magnesium stearate, talc and silicon dioxide are added and the mixture is pressed into tablets, each with a weight of 295.0 mg and an active substance content of 50.0 mg, which, if desired, can be equipped with a dividing sheet for better adaptation of the dosage.

Formulation example 2: Lacquer tablets each containing 400 mg of 4-(7-bromo-5-methoxy-benzofuran-2-yl)piperidines or a salt thereof, for example the hydrochloride, can be prepared as follows:

Composition (for 1000 varnish tablets)

The active substance, the lactose and 40 g of corn starch were mixed and moistened with a paste made from 15 g of corn starch and water (while heating). The granulate was dried, the rest of the cornstarch, talc and calcium stearate were added and mixed with the granulate. The mixture was pressed into tablets (weight: 580 mg) and coated with a solution of the hydroxypropylmethyl cellulose and shellac in methylene chloride; final weight for the varnish tablets: 583 mg.

Formulation example 3: Gelatin suppositories each containing 500 mg of 4-(7-bromo-5-methoxy-benzofuran-2-yl)piperidines or a salt thereof, for example the hydrochloride, can for example be prepared as follows:

Composition (for 1000 capsules)

The sodium lauryl sulfate was sieved into the lyophilized active substance through a sieve with a mesh size of 0.2 mm. Both components were thoroughly mixed. Next, the lactose was sieved through a sieve with a mesh size of 0.6 mm, and then the microcrystalline cellulose was sieved through a sieve with a mesh size of 0.9 mm. This was then mixed thoroughly for 10 minutes. Finally, the magnesium stearate was sieved through a sieve with a mesh size of 0.8 mm. After 3 minutes of further mixing, the resulting mixture was filled into gelatin capsules of appropriate size. Formulation example 4: A 5% injection or infusion solution of 4-(7-bromo-methoxy-benzofuran-2-yl)piperidines or one of its salts, for example the hydrochloride, can for example be prepared as follows:

Composition (for 1000 and 400 ampoules respectively)

The active substance and the sodium chloride were dissolved in 1000 ml of water and filtered through a microfilter. The buffer solution was added and it was topped up with water to 2500 ml. For the production of dosage units, glass ampoules, each of 1.0 or 2.5 ml, were filled, each containing 50 and 125 mg of active ingredient.

Claims (1)

1. Use of 4-(7-bromo-5-methoxy-benzofuran-2-yl)piperidine of formula I or one of its pharmaceutically usable salts for the manufacture of a medicament for the treatment of degenerative nerve diseases caused by degeneration of nerve cells as well as nootropics.