DE2822360A1 - 1-Adamantyl-piperidine derivs. - useful as CNS stimulants and tremorine antagonists - Google Patents

Abstract

Piperidine derivs. of formula (I) and their acid-addn. salts are new (where A is opt. substd. adamantyl; Z is CAr1Ar2 or CHCHAr1Ar2; Ar1 and Ar2 are phenyl opt. monosubstd. by halogen or alkyl). Cpds. (I) relieve tremors associated withextrapyramidal disorders (e.g., Parkinsonism) and increase motility; some also have an antagonistic action against haloperidol, phenolthiazine, etc. They have lower toxicity and higher antitremorine activity than amphetamine and are free of its undesirable side-effects. A typical cpds. is 1-(1-adamantyl)-4,4-diphenylpiperidine. In an example, this is prepd. from 1-(1-adamantyl)-3-benzoyl-4-hydroxy-4-phenylpiperidine and benzene.

Description

Piperidinoadamantanes, process for their preparation

and medicines containing them The invention relates to Piperidinoadamantanes and their salts, processes for their preparation and containing them Drug.

Aminoadamantanes are according to the German patent documents DT-AS 1 468 769 and DT-AS 1 792 282 known as Virustatica, you will also receive a Effect as an anti-Parkinson agent (DT-OS 2 219 256) attributed. From the British Patent specification GB-PS 1 313 781 and the German Offenlegungsschrift DT-OS 2 139 085 and US Pat. No. 2,739,968 are piperidine derivatives known that are said to have a variety of effects, such as a stimulating one Effect on the central nervous system, a spasmolytic and analgesic effect as well as antihistamine and antiacetylcholine activity at the same time. Against it was now found that certain piperidinoadamantanes and their acid addition salts pharmacologically have uniform properties.

The invention relates to piperidinoadamantanes of the general formula I where A denotes an optionally substituted adamantyl radical and Z denotes the grouping or in which R1 and R2 independently represent a hydrogen atom, a halogen atom or an alkyl group, represents 1 and their acid addition salts.

Adamantyl-1-, adamantyl-2-, Adamantyl-1-methyl-, 5, 5-dimethyl-adamantyl-1-residue, preferably the adamantyl-1-residue, into consideration.

The alkyl groups R1 and R2 are straight-chain or branched alkyl radicals with 1 to 4 carbon atoms in question.

Straight-chain alkyl radicals are the methyl, ethyl, propyl or butyl radical, of which the methyl radical is preferred. Branched alkyl radicals are e.g. the isopropyl, Isobutyl, sec-butyl or tert-butyl radical, of which the isopropyl radical is preferred is. The halogen substituents R1 and R2 are fluorine, chlorine, bromine, in particular Chlorine. The substituents R1 and R2 are preferably identical and in the p position.

All acid addition salts come into consideration as salts. Mentioned especially let the pharmacologically tolerable salts be those commonly used in galenics inorganic and organic acids. Pharmacologically incompatible salts become converted into pharmacologically acceptable salts by methods known to the person skilled in the art. Suitable pharmacologically acceptable acid addition salts are, for example water-soluble and water-insoluble salts, such as the hydrochloride 'hydrobromide, hydroiodide, Phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate (2- (4-hydroxybenzoyl3-benzoate), Fendizoate (o - [(2'-Hydroxy-4-biphenylyl) carbonyl] benzoate), propionate, butyrate, Sulphosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate (4,4'-diamino-stilbene-2,2'-disulfonate) 1 embonate (1,1'-methylene-bis-2-hydroxy-3-naphthoate), Metembonate, stearate, tosilate (p-toluenesulfonate), 2-hydroxy-3-naphthoate, 3-hydroxy = y-2-naphthoate 7 Nesilate (nethanesulfonate).

Embodiments of the invention are piperidinoadamantanes of the general formula Ia or Ib wherein R1, R2 and A have the meaning given above, and their pharmacologically acceptable salts.

Preferred compounds of the general formulas Ia and Ib are those in which R1 and R represent a hydrogen atom, a chlorine atom or a methyl group and A has the meaning given above. Of particular interest among the preferred Compounds are those in which A is an adamantyl-1 group and R1 and R2 are hydrogen mean. The preferred compounds also include the corresponding pharmacologically compatible salts.

Selected representatives are 1-Adamantyl-tl) -e-diphenylmethyl-piperidine, 1-Adamantyl- (i) -4, 4-diphenyl-piperidine and their pharmacologically acceptable Salts.

The invention also relates to a process for the preparation of the piperidinoadamantanes I or the embodiments Ia and Ib, characterized in that a) a piperidine of the general formula II in which Z has the meaning given above, adamantylated or b) a 4-hydroxypiperidine of the general formula III Ri is a hydrogen atom or a Group and A and R1 have the meaning given above, with a benzene of the general formula IV in which R1 has the meaning given above, is reacted in the presence of a Friedel-Crafts catalyst and, if appropriate, subsequently converting a salt obtained into the free base or other salts or the free base into salts.

The adamantylation of the piperidines II takes place according to methods like them are known to those skilled in the art for the N-alkylation of piperidines. For example the piperidines II with an adamantylating agent, such as a corresponding one Adamantyl halide, preferably bromide, adamantyl sulfonate, preferably tosylate, or adamantyl sulfate in inert solvents such as ketones, e.g. acetone, methyl ethyl ketone, Alcohols, e.g. methanol, ethanol, isopropanol, using an auxiliary base, such as potassium carbonate, sodium carbonate, triethylamine, at temperatures up to the boiling point ture of the solvent treated. Alternatively, they can be shared by common Melting the components together, which is preferred.

The 4-hydroxypiperidines III are reacted with the benzenes TV according to methods known to the person skilled in the art. In general, the Friedel-Crafts catalyst presented in the benzene IV and then the piperidine derivative III, dissolved in the same or another suitable solvent, slowly added. The addition takes place advantageously at temperatures from 30 to / 000C. However, the reaction can also be carried out so that the piperidine derivative III is added to the benzene IV and the Friedel-Crafts catalyst is added at room temperature, wherein Warming occurs. The implementation is then carried out by further heating, if necessary brought to an end. After the end of the reaction, the reaction product is in each case in the usual way Way worked up.

Acid addition salts are obtained by dissolving the free base in a suitable solvent, e.g. acetone, water, a low molecular weight aliphatic Alcohol (ethanol, isopropanol) or ether (diethyl ether, tetrahydrofuran), which the contains the desired acid, or to which the desired acid is then added. The salts are obtained by filtering, precipitating with a nonsolvent for that Addition salt or obtained by evaporation of the solvent.

The salts obtained, e.g. the hydrochloride, can be neutralized be converted into the free base with aqueous sodium or potassium hydroxide, which then by solvent extraction with a suitable, immiscible with water, Solvents such as chloroform, dichloromethane, ether, benzene, toluene, cyclohexane etc., is won. The free bases can also be obtained by neutralizing an acid addition salt with sodium methylate in methanol and isolation of the base by known methods be won. Salts can too by conversion into the base and further conversion with an acid into other salts, e.g. pharmacologically acceptable Acid addition salts are converted The starting compounds of the formula II or Corresponding adamantylating agents are known or can be prepared according to known ones Represent methods such as those in British patent specification GB-PS 1 313 781, the German Offenlegungsschriften DT-OS 2 139 085, DT-OS 2 303 305, U.S. Patent No. 2,739,968.

The starting compounds of the formula III can be known per se Way to be made. For example, they are implemented by implementing an appropriate Adamantylamine salt with an optionally substituted acetophenone and paraformaldehyde analogous to the German patent specification DT-PS 820 141 or

C. Podesva and C. Solomon, J. Med.Chem. 11 (1968) 634 and subsequent treatment of the condensation products with alkalis. On the other hand, they are by adamantylation of piperidinols of the general formula V in which R3 and R4 have the meaning given above, obtained with intermediate protection of the hydroxyl group.

The adamantylation takes place according to known, already further methods described above. For the intermediate protection of the hydroxyl group there are ether groups, which then include the oxygen atom of the hydroxyl group, for example as alkoxy groups with 1 to 5, preferably 1 to 2, carbon atoms are present, or acyl groups, such as alkanoyl groups, preferably with 2 to 5 carbon atoms, e.g. the acetyl group, into consideration, which are split off in the usual way.

Piperidinols V are known to the person skilled in the art or can be prepared according to known Processes are produced, for example, in the German Offenlegungsschriften DT-OS 2 040 231 and 1 695 256, the German patent specification DT-PS 1 289 845, the British patent specification GB-PS 895 309 and the American patent specification US-PS 3,438,991.

Preferred starting compounds are those whose reactions are too the preferred embodiments and the selected representatives.

The piperidinoadamantanes of the general formula I or the embodiments and their pharmacologically acceptable salts have valuable properties that make them commercially exploitable. For example, the connections and the unfold pharmacologically, i.e. biologically compatible, salts have pronounced effects the central nervous system (= CNS).

The CNS effectiveness of the piperidinoadamantanes and the pharmacological compatible salts extends, for example, to central stimulation, the abolition of the tremor as it occurs in diseases of the extrapyramidal system occurs in mammals, increase in motility. In addition, some representatives show an antagonistic effect against haloperidol, phenothiazine etc.

The excellent and broad pharmacological activity of the compounds enables its use in both human and veterinary medicine, whereby they are used to prevent symptoms or to treat symptoms that have already occurred can be used.

The indications for the human medical field are for men and in women, for example, Parkinson's disease and other extrapyramidal disorders System called.

So far, e.g. Amphetamine used. However, this connection has the property that it is only is short-term k-effective and shows a negative post-phase. With further treatment a dose increase is necessary, showing signs of dependence or even of addiction, which puts the therapeutic value of amphetamine in question is posed.

The new compounds according to the invention now turn out to be the connection the prior art, the amphetamine, superior, e.g. they are less toxic, show no increase in toxicity and no tachyphylaxis symptoms when kept in groups, but have a considerably higher tremoric antagonism.

Furthermore, the new compounds according to the invention cause in contrast to amphetamine no stronger blood pressure increases and no general sympathetic stimulation.

The main indications for veterinary medicine are Stimulation or resolution of spasms into consideration For example, higher animals, like farm animals and pets.

The medicaments are produced by methods known per se. As a medicinal product, the new compounds can be used as such or, if necessary, in Can be used in combination with suitable pharmaceutical carriers. Contain the new pharmaceutical preparations in addition to the active ingredients phar- = azeitisehe Carriers; the active ingredient content of these mixtures is from 5 to 95, preferably 25 to 75 percent by weight of the total mixture.

In accordance with the invention can be used in human and veterinary medicine Area where the active ingredients can be used in any form, e.g. systemically provided that the training or maintenance of sufficient Blood or tissue levels or local concentrations of active ingredient is guaranteed. This can be done either by oral, rectal or parenteral administration in appropriate doses can be achieved. The pharmaceutical preparation of the active ingredient is advantageously located in the form of unit doses tailored to the desired administration. A unit dose can be, for example, a T-tablet, a dragee, a capsule, a Suppository or a measured volume of a powder, a granulate, a Solution, emulsion, suspension, sol or gel.

"Elnaeitdose" in the sense of the present invention is a physically determined unit that is an individual amount of the active ingredient in combination with a pharmaceutical carrier contains understood, their Active ingredient content a fraction or a multiple of a therapeutic single dose is equivalent to. A single dose preferably contains the amount of active ingredient required for is administered to an application and is usually a whole, half, corresponds to a third or a quarter of the daily dose.

If only a fraction for a single therapeutic administration 1 such as half or a quarter of the unit dose needed is the unit dose advantageously divisible, e.g. in the form of a tablet with a breaking notch.

The pharmaceutical preparations = contain according to the invention, If they are available in unit doses and are intended for application to humans, for example are, about 0.5 to 50 mg, advantageously 1 to 30 mg and especially 2 to 20 mg of active ingredient.

In general it has been used in both human and veterinary medicine Proven to be advantageous, the active ingredient or ingredients when administered orally in a daily dose from about 5 to about 100, preferably 10 to 60, especially 15 to 45 mg, optionally in the form of several, preferably 1 to 3, individual doses to achieve the desired Deliver results. A single dose contains the active ingredient (s) in large quantities from about 1 to about 30, preferably 2 to 20, especially 5 to 15 mg.

The therapeutic administration of the pharmaceutical preparation In the case of long-term medication, generally takes place at fixed times, such as 1 to 4 times a day, e.g. after meals and / or in the evening. In acute cases the medication takes place at varying times. Under certain circumstances it may be necessary to deviate from the dosages mentioned in Depending on the type, body weight and age of the object to be treated, the type and severity of the disease, the type of preparation and application of the drug and the period or interval within which the administration he follows. So in some cases it may be sufficient with less than the above mentioned amount of active ingredient, while in other cases the above The amount of active ingredient must be exceeded. The determination of the required The person skilled in the art can based on optimal dosage and type of application of the active ingredients his expertise at any time.

The pharmaceutical preparations generally consist of those according to the invention Active ingredients and non-toxic, pharmaceutically acceptable drug carriers, as an admixture or. Thinners in solid, semi-solid or liquid In the form or as a coating, for example in the form of a capsule, a tablet coating, a bag or other container for the therapeutically active ingredient come into use. A carrier can e.g.

as a mediator for drug uptake by the body, as Formulation auxiliaries, as sweeteners, as flavorings2, as colorants or serve as a preservation center.

For oral use, e.g. tablets1 dragees, hard and soft Capsules, e.g. made of gelatin, dispersible powders, granulates, aqueous and oily Suspensions, emulsions, solutions or syrups come.

Tablets can contain inert diluents, e.g. calcium carbonate, Calcium phosphate, sodium phosphate or lactose; Granulating and distributing agents, e.g. corn starch or alginates; Binders such as starch, gelatin or acacia gum; and lubricants such as aluminum or magnesium stearate, talc or silicone oil. They can also be provided with a coating that is also designed in this way -may cause delayed dissolution and absorption of the drug in the gastrointestinal tract and thus e.g. better compatibility, protraction or retardation is achieved. Gelatine capsules can contain the medicinal substance mixed with a solid, e.g. calcium carbonate or kaolin, or an oily, e.g. olive, peanut joder Paraffin oil, contain thinners. ; l: Aqueous suspensions can be suspending agents, e.g. sodium carbonate methyl cellulose, methyl cellulose, hydroxypropyl cellulose, N, atrium alginate, Polyvinylpyrrolidone, gum tragacanth or gum acacia; - Disp ergi and- wetting agents el, e.g. Polyo = cy ethylene stearate, heptadecaethylene oxycetanol, polyoxyethylene sorbitol monooleate, Polyoxyethylene sorbitan monooleate or lecithin; Preservatives, e.g. methyl or propyl hydroxybenzoate; Flavoring agents; Sweeteners, e.g. sucrose, lactose, Contains sodium cyclamate, dextrose, invert sugar syrup.

Oily suspensions can e.g. peanut, oval, sesame, coconut or Paraffin oil and thickeners, such as e.g. Bi.emenwax, paraffin wax or cetyl alcohol, contain; also sweeteners, flavorings and antioxidants.

The medicinal substances can be dispersed in water and granules in a mixture with dispersing, wetting and suspending agents, e.g. those mentioned above, as well as with sweeteners1 Flavors and colors contain emulsions e.g. olive, peanut or paraffin oil in addition to emulsifying agents such as acacia gum, Traganth gunni, phosphatides, sorbitan monooleate, polyox, väthylensorbitaDmonooleaf, and contain sweeteners and flavorings.

For rectal application of the drugs, suppositories are used that with the help of binders that melt at the rectal temperature, for example cocoa butter or polyethylene glycols.

Sterile injectables are used for the parenteral application of the medicinal substances aqueous suspensions, isotonic saline solutions or other solutions that disperse or wetting agents and / or pharmacologically acceptable diluents, e.g. Propylene or butylene glycol.

Powders and sprays can be used with the usual active ingredient (s) Contain carriers, e.g. 3. Lactose, Taikum, silicic acid, Alu = iiniumhydroid, Calcium silicate and polyamide powder or mixtures of these substances. Sprays can also common propellants such as chlorofluorocarbons.

The active ingredient (s) can optionally be combined with one or more of the above-mentioned carriers are also in microencapsulated form.

In addition to the piperidinoadamantanes according to the invention, the pharmaceutical Preparations for example one o, the several pharmacologically active ingredients from other drug groups, for example mild stimulants such as Caffeine; Analgesics such as aminophenazone, acetylsalicylic acid, d-propoxyphene; Antidepressants, such as dibenzepin, doxepin, maprotilin, amitriptyline, nortriptyline, melitracen; Tranquilizers, such as benzodiazepines, e.g. diazepam, chlordiazepoxide, meprobamate; cerebral circulation-promoting Agents and / or nutrients such as glutamic acid, vitamins or their combinations.

Another object of the invention is a method of treatment of mammals suffering from primary or secondary disorders of the central nervous system -suffering, which is characterized by the fact that one is given to the infected mammal ZWS-effective and pharmacologically acceptable amount of one or more according to the invention Piperidinoadamantane and / or their pharmacologically acceptable salts administered.

The following examples serve to illustrate the invention.

Temperatures are given in OC, m.p. means melting point, b.p. means boiling point.

Examples Example 1 i- (Adamantyl 3-benzoyl-4-hydroxy-4-phenylpiperidine 33.2 g of CJ (adamantyl-1-amino) propiophenone hydrochloride, 103 ml in sodium hydroxide solution and 450 ml of ethanol are stirred for 2 days at room temperature, the precipitate is filtered off and dried. Yield 12.7g. Mp (from ethanol) 1481490.

Example 2 1- (Adamantyl-1) -4, 4-diphenylpiperidine a) 3 g of i- (Adamantyl-1) -3-benzoyl-4-hydroxy-4-phenylpiperidine, 4.8 g anhydrous aluminum chloride and 100 ml absolute benzene are 2 1/2 hours refluxed with stirring, poured onto ice and made alkaline with 6N sodium hydroxide solution.

The organic phase is collected, dried over sodium sulfate and concentrated to a dark viscous residue. Rub 50 ml of petroleum ether through 1 filtered, the filtrate is mixed with 10 ml of methanol and ethereal hydrochloric acid, whereby 500 mg of the title compound crystallize out as the hydrochloride. M.p. 312-3140 (under sintering).

b) i g 414-diphenylpiperidine and 1.06 g l-bromoadamantane are im closed vessel heated to 240 for 5 hours, after cooling in 70 ml boiling Dissolved methanol and filtered hot; the filtrate is made with ethereal hydrobromic acid offset and narrowed. The residue is stirred thoroughly with ether and filtered and recrystallized from ethanol. The hydrobromide of the title compound thus obtained melts> 3200.

By treating the methanolic solution of the hydrobromide with aqueous Sodium hydroxide solution gives the free base.

Mp (from n-hexane) 162-163 °.

Example 3 1- (Adamantyl-1) -4-diphenylmethylpiperidine 4 g of 4-diphenylmethylpiperidine and 3.6 g of 1-bromoadamantane are heated to 2500 in a closed vessel for 5 hours, the reaction mixture dissolved in 100 ml of methanol at the boiling point and over activated charcoal filtered off. 60 ml of ethereal hydrobromic acid are added to the filtrate, concentrated to 30 ml and the crystallized hydrobromide of the title compound collected.

Yield 2.8 g; M.p.> 3050.

The free base is obtained by treating the methanolic solution of the hydrobromide with aqueous sodium hydroxide solution, extraction with ether and concentration of the Ether phase.

Yield 0.9 g; Mp. 1290 (after recrystallization from n-hexane / ether).

The methanesulfonate (from water) melts at 275-278 °.

Example 4 Tablets Ingredients: Amount: 1. 1-Adamantyl-4-diphenylmethyl-piperidine methanesulfonate 10 kg 2. Milk sugar 75 kg 3. Corn starch 80 kg 4. Highly dispersed silica 3 kg 5. Sodium lauryl sulfate 4 kg 6. Polyvinylpyrrolidone avg. M-G. 25,000 5 kg 7. Sodium carboxymethyl cellulose 16 kg 8. Talc 5 kg 9. Magnesium stearate 2 kg 200 kg The specified amounts of the under 1 to 5 listed ingredients are sieved and mixed. 6 will be in 20 1 water is dissolved and the powder mixture is moistened well with this solution. the The moist mixture is granulated through a sieve with a mesh size of 1.2 mm. After this To dry the granulate, 7, 8 and 9 are mixed in. The finished mixture will be too Compressed tablets with a diameter of 8 mm and a weight of 200 mg.

Instead of 1-adamantyl-diphenylmethyl-piperidine-methanesulphonate can also use another compound according to the invention, e.g. 1-adamantyl-4,4-diphenyl-piperidine, can be used in the form of a salt.

Example 5 Capsules Ingredients: Amount: 1. 1-Adamantyl-4-diphenylmethyl-piperidine methanesulfonate 10 kg 2. Lactose sugar, spray-dried 210 kg The specified amounts of the under 1 and 2 ingredients listed are mixed and placed in capsule size 3 capsules bottled.

Instead of 1-adamantyl-4-diphenylmethyl-piperidine-methanesulphonate can also another compound according to the invention, e.g. 1-adamantyl-4,4-diphenyl-piperidine, can be used in the form of a salt.

Example 6 Ampoules Ingredients: Amount: 1. 1-Adamantyl-4-diphenylmethyl-piperidine methanesulfonate 2.5 kg 2nd sodium chloride 51.5 kg 3rd dist. Water ad 600 ltr.

The ingredients listed under 1 and 2 are distilled in 550 liters Dissolved water and made up to 600 l with distilled water. The solution will be filtered through a membrane filter with a pore diameter of 0.1 / u, in 5 ml ampoules bottled and sterilized at 1000 for 1 hour.

Claims (10)

Claims 1. Piperidinoadamantanes of the general formula I where A denotes an optionally substituted adamantyl radical and Z denotes the grouping or in which R1 and R2 independently represent a hydrogen atom, a halogen atom or an alkyl group, and their acid addition salts. 2. Piperidinoadamantanes of the general formula Ia wherein R1, R2 and A have the meaning given above, and their pharmacologically acceptable salts. 3. Piperidinoadamantanes of the general formula Ib wherein Rt, R2 and A have the meaning given above, and their pharmacologically acceptable salts. 4. Compounds according to claim 2 or 3, in which R1 and R2 are a hydrogen atom, represent a chlorine atom or a methyl group and A has the meaning given above and their pharmacologically acceptable salts. 5. Compounds according to claim 4, in which A is an adamantyl-1 group and R1 and R2 represent a hydrogen atom, and their pharmacologically acceptable ones Salts. 6. I-Adamantyl- (i) 4-diphenylmethyl-piperidine and its pharmacological compatible salts. 7.1 Adamant; yl- (I) -4,4-diphenyl-piperidine and its pharmacological compatible salts. 8, medicaments containing one or more compounds according to claim 1 to 7. 9. Use of piperidinoadamantanes according to claim 1 to 7 in the fight against disorders of the central nervous system. 10. Process for the preparation of the piperidinoadamantanes I or the embodiments Ia and Ib, characterized in that a) a piperidine of the general formula Ii in which Z has the meaning given above, adamantylated or b) a 4-hydroxypiperidine of the general formula III wherein R3 is a Group, R4 is a hydrogen atom or a group and A and R1 have the meaning given above, with a benzene of the general formula TV in which R1 has the meaning given above, is reacted in the presence of a Friedel-Crafts catalyst and, if appropriate, subsequently converting a salt obtained into the free base or other salts or the free base into salts.