DE3340629A1 - Base-substituted 2,6-dimethoxybenzamides, their acid addition salts, medicaments containing these and process for their preparation - Google Patents

Abstract

The invention relates to base-substituted 2,6-dimethoxybenzamides of the general formula (I) <IMAGE> in which R denotes hydrogen or bromine, and their acid addition salts. The compounds are prepared by reaction of a 2,6-dimethoxybenzoic acid derivative with 3-amino-8-benzylnortropane and are neuroleptically active.

Description

Basic substituted 2,6-dimethoxibenzamides, whose acid

addition salts, medicaments containing them and processes for their preparation From J. Med. Chem. 25, 1280-1286 (1982) and EU-PS No. 4,831 are 2,6-dimethoxibenzamide derivatives of the structure known, in which R1 is an alkyl radical having 1 to 3 carbon atoms and R2 and R3 are hydrogen, chlorine or bromine.

A dopamine receptor blocking effect is attributed to these compounds. One of these compounds, namely the S - (-) - enantiomer of the formula is in clinical investigation for antipsychotic effects.

It has now been found that structurally opposite, basic substituted 2,6-dimethoxibenzamides have interesting therapeutic properties. The invention relates to new basic substituted 2,6-dimethoxibenzamides, which differ from the known compounds by a different basic molecule part, of the general formula (I) and their physiologically acceptable acid addition salts, in which R is a hydrogen atom or a bromine atom.

The invention also relates to the preparation of the new compounds. The manufacturing process is characterized in that a 2,6-dimethoxibenzoic acid derivative of the general formula (II) in which R has the abovementioned meaning and Y is a chlorine or bromine atom or an ethoxicarbonyloxi or l-imidazolyl group, is reacted with 3-amino-8-benzylnortropane and the end product obtained is optionally converted into an acid addition salt.

When using dimethoxibenzoyl halides of the general formula II, the calculated amount of acylating agent or an excess is used of it and expediently works in the presence of an acid-binding substance such as e.g.

Dicycloherylethylamine, sodium carbonate, potassium carbonate, calcium oxide or preferably triethylamine. Although solvents can be dispensed with, is to be carried out in inert solvents such as chloroform, toluene, nitromethane, Tetrahydrofuran, dimethylformamide or preferably methylene chloride are advantageous. The reaction temperature can be varied within wide limits. Temperatures are appropriate around 200C or below.

The acylation of 3-ainino-8-benzylnortropane using a carboxylic acid imidazolide takes place in such a way that the corresponding 2,6-dimethoxibenzoic acid initially with Carbonyldiimidazole and then reacted with the amine. One uses the calculated amount of the carboxylic acid and equivalent amounts of carbonyldiimidazole. The reaction takes place in inert solvents. Tetrahydrofuran has proven to be particularly favorable proven. The reaction temperature is variable within limits. The response will be on best done at 0 to 10C.

The acylation of 3-amino-8-benzyl-nortropane using a mixed Anhydride can also be done in a one-pot process. This is done using 2,6-dimethoxibenzoic acid initially reacted with chlorocarbonic acid ester at low temperatures. The reaction with the amine then takes place in the same reaction medium. The reaction temperature is critical. Temperatures around OOC have proven to be particularly favorable. the Choice of solvents is not critical. Acetone or methylene chloride have proven effective.

The reaction products obtained by the process are from the Reaction approaches isolated using known methods. If necessary, can the raw products obtained using special processes, e.g. through Column chromatography be cleaned before they are in the form of the Bases or suitable acid addition compounds crystallized.

The 3-amino-8-benzyl-nortropane required for the process can according to according to the information provided by N.J. Harper et al, J. Med. Chem.

7, 729-732 (1964).

The 2,6-dimethoxibenzamides according to the invention of the general formula I can in the usual way in their physiologically acceptable acid addition salts be convicted. Acids suitable for salt formation are, for example, hydrochloric acid, Hydrobromic acid, hydriodic acid, hydrofluoric acid, sulfuric acid, Phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, Valeric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, Tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, Phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, 8-chlorotheophylline.

The new compounds of general formula I show the typical Effects of neuroleptics and should therefore be used as CNS depressants will.

The compounds were tested in the apomorphine climbing test on mice (B. Costall et al., Europa J. Pharmacol. 50, 39 ff (1978), modified). They show strong apomorphine antagonistic effects similar to those mentioned above In some cases, considerably outperform comparison compounds.

These properties leave the prior art neuroleptic Expect effects on humans. The properties were due to the close structural relationship with the compounds known from EU-PS No. 4,831 surprising and not foreseeable. Statements about side effects such as sedation or motor coordination disorder could be done with the help of the following test arrangements: The motility measurement on mice according to T.H. SVENSSON and G. WIIEME, Psychopharmacol.

(Berlin) 14, 157 ff (1969), modified, gives indications of sedation. The ataxia test on the rotating rod (Rotarod) in mice according to N.W. DWiUSI and T.S. MIYA, J. Amer. Pharm. Assoc.

Sci. Ed. 46, 208 ff (1957), modified, allows statements to be made about disturbances of motor coordinationO The dyskinetic effects are among the most bothersome side effects of neuroleptics. Parkinson's-like phenomena such as tremor and rigor are also included and akinesia, but also dyskinesia in the mouth, tongue and throat area.

Investigation of such symptoms in animal models is on with haloperidol sensitized rhesus monkeys possible, such animals show after administration of neuroleptics, which have extrapyramidal motor effects in humans, typical dyskinesias in the mouth and tongue area (according to J.

Liebmann and R. Neale, Psychopharmacology 68: 25-29 (1980), modified).

The compounds to be protected behave with regard to the side effects cheaper than the comparison substances. For the biochemical characterization of the The above compounds were used for binding studies in rats. This is how the substances became in the 3H spiroperidol binding test on synaptosome preparations from rat brain 5Striatum) after J. Creese, D.R.

Burt and S.H. Snyder, Science 188, 1217 (1975).

They show something comparable to the compounds of the prior art or better attachment behavior and are thus characterized as effective neuroleptics. In addition, studies were carried out on α-adrenergic and α-adrenolytic properties with the help of tritiated 2- [2- (2 ', 6'-dimethoxy-phenoxy) -ethyl-aminomethyl] -benzodioxane hydrochloride, an a-adrenergic antagonist. In this binding test show the invention Compounds compared to the previously known 2,6-Dimethoxy-benzamides superior properties (D.C. U'Prichard, D.A. Greenberg and S.H. Snyder, Mol. Pharmacol. 13, 454 ff (1977)). Investigations on muscarinic anticholinergic binding properties were tested in binding tests with tritiuin-labeled D-quinuclidinyl benzilate according to Yamamura and S.H. Snyder, Proceed. Nat. Acad. Sci. USA, 71, 1725-1729 (1974). Here the substances according to the invention show stronger anticholinergic binding properties than the derivatives of EU PS No. 4 831.

The compounds of the general formula I according to the invention can be used alone or in combination with other active ingredients. Suitable Application forms are, for example, tablets, capsules, suppositories, solutions, juices, Emulsions or dispersible powders. Corresponding tablets can, for example by mixing the active ingredient (s) with known auxiliaries, for example inert diluents such as calcium carbonate, calcium phosphate or milk sugar, Disintegrants such as corn starch, alginic acid, binders such as starch or gelatin, Lubricants such as magnesium stearate or talc and / or means for achieving one Depot effect such as carboxy polymethylene, carboxy methyl cellulose, cellulose acetate phthalate or polyvinyl acetate.

The new compounds of general formula I can enteral or can be used parenterally. When administered orally, single doses have become of 0.5-10 mg, preferably 1-5 mg, have been found to be expedient.

The following examples illustrate the invention in a non-limiting manner Way.

Example 1 N- (8-Benzvl-3-nortropanvl) -2. 6-dimethoxibenzamide 1.8 g of 2,6-dimethoxibenzoic acid (10 mol) are mixed with 1.75 ml of oxalyl chloride in 30 ml Methylene chloride at OOC within 3.5 hours into the corresponding acid chloride convicted.

The solvent is distilled off. The residue is dissolved in 20 ml of absolute methylene chloride and added dropwise to a solution of 2.2 g (10 m mol) 3-Amino-8-benzylnortropane, 4.1 ml of triethylamine and 30 ml of absolute methylene chloride under ice cooling. The reaction is allowed to continue for 2 hours and is worked up.

For this purpose, the solution is mixed with 50 ml of methylene chloride and three times washed with 50 ml of water each time. The organic phase is separated off over sieve04 dried and concentrated. The residue, dissolved in 100 ml of ethyl acetate / methanol (8: 2), is purified over 400 g of silica gel. The clean base is then made from ether recrystallized.

2.2 g of white crystals with a melting point of 157 ° C. are obtained in this way in a yield of 57.9 of theory.

C23H28N203 calcd. C 72.60 H 7.42 N 7.36 (380.47) found. C 72.46 H 7.48 N 7.30 Example 2 N- (8-Benzyl-3-nortropanyl) -2. 6-dimethoxy - 3-bromobenzamide 2.6 g of 2,6-dimethoxy-5-bromobenzoic acid (10 mol) are mixed with 1.75 ml of oxalyl chloride in 30 ml of methylene chloride at OOC within 3.5 hours in the corresponding Acid chloride transferred. The solvent is distilled off and the residue is dissolved one in 20 ml of absolute methylene chloride and dripped it at room temperature to a Solution of 2.2 g (10 mol) of 3-amino-8-benzylnortropane, 3.6 ml of triethylamine and 30 ml of methylene chloride. The reaction is allowed to continue for 2 hours and then worked up. the To this end, the solution is mixed with 100 ml of methylene chloride, three times with 100 ml of water washed, the organic phase is separated off, dried over MgS04 and constricted. The residue, dissolved in ethyl acetate / methanol (80/20), is poured over 150 g of silica gel filtered. The clean base is after concentration from ether / diisopropyl ether several times crystallized, 2.6 g are obtained in a yield of 62.9 r with a melting point from 167-168 ° C.

C23H27BrN203 calcd. C 60.13 H 5.92 N 6.20 Br 17.40 (459.38) found C 60.31 H 5.90 N 6.21 Br 17.19 Pharmaceutical Formulation Examples a) Dragees 1 tablet core contains: active ingredient according to the present invention 2.0 mg lactose 28.5 mg corn starch 17.0 mg gelatin 2.0 mg magnesium te arate 50.0 mg Preparation: The mixture of Active ingredient with lactose and corn starch is made with a 10% aqueous gelatin solution Granulated through a sieve with 1 mm mesh size, dried at 40 ° C and again driven through a sieve. The granules obtained in this way are mixed with magnesium stearate and pressed.

The cores obtained in this way are covered in the usual way with a shell, made with the help of an aqueous suspension of sugar, titanium dioxide, talc and gum arabic is applied. The finished coated tablets are polished with beeswax. Final dragée weight: 100 mg.

b) tablets active ingredient according to the present invention 2.0 mg lactose 55.0 mg Corn starch soluble starch magnesium stearate 38.0 mg 4.0 mg 1.0 mg 100.0 mg Manufacture: Active ingredient and magnesium stearate are combined with a aqueous solution of the soluble starch granulated, the granules dried and intimately mixed with milk sugar and corn starch.

The mixture is then compressed into tablets weighing 100 mg, which contain 2 mg of active ingredient.

c) Suppositories 1 suppository contains: active ingredient according to the present Invention 1.0 mg suppository masses 1699.0 mg Production: The finely powdered substance is melted and cooled to 400C with the help of an immersion homogenizer Stir in suppository mass. The mass is poured into slightly pre-cooled molds at 350C.

d) Ampoules of active ingredient according to the present invention 2.0 mg of sodium chloride 18.0 mg distilled water ad 2.0 ml Preparation: active ingredient and sodium chloride are dissolved in water, the solution is filtered free of suspended particles and Filled in 2 cc ampoules under aseptic conditions. Last are the ampoules sterilized and sealed.

Each ampoule contains 2 mg of active ingredient.

Claims (6)

PATENT CLAIMS Basically substituted 2,6-dimethoxibenzamides of the general formula (I) in which R is a hydrogen or bromine atom and also their acid addition salts. 2. Process for the preparation of compounds according to claim 1, characterized in that a 2,6-dimethoxibenzoic acid derivative of the general formula (II) in which R has the abovementioned meaning and Y is a chlorine or bromine atom or an ethoxicarbonyl or imidazolyl group, reacts with 3-amino-8-benzylnortropane and optionally converts the compound obtained into its acid addition salts. 3. Pharmaceutical preparations, characterized in that she one or more compounds according to claim 1 in addition to customary auxiliaries and carriers contain. 4. Process for the production of pharmaceutical preparations according to Claim 3, characterized in that one compounds according to claim 1 with usual galenic excipients and carriers for common pharmaceutical dosage forms processed. 5. Compounds according to claim 1 for use in the manufacture of drugs with neuroleptic action. 6. Use of compounds according to claim 1 for the preparation of Medicines with a neuroleptic effect.