NO124642B - - Google Patents

Description

Analogy methods for the production of oximeters

with effects on the central nervous system.

The invention relates to analogue methods for the production of new oximeters with an effect on the central nervous system and with the general formula II

and salts thereof with pharmacologically acceptable acids, in which formula R.^ represents hydrogen or methyl, represents a halogen atom, an alkyl-

or alkoxy group having 1 to 4 carbon atoms, a nitro or CF^ group, has the same meaning as R^ or means an amino group, m means 0 or 1, R^' and R^" together with the carbon atoms to which they are attached mean , a benzene ring, and n = 0 and A is a carbon-carbon bond, an oxygen or sulfur atom, or R^' and R^" each mean two hydrogen atoms, a hydrogen atom and one phenyl group, or a hydrogen atom and an alkyl group with 1 to 5 carbon atoms, and n-0 or 1, and A means a carbon-to-carbon bond, db oxygen or sulfur atom or a CHn group, R ' and R " cannot form part of a benzene ring or both can mean 2 hydrogen atoms when R^=H^, A is a carbon-to-carbon bond, and m=n=0.

The compounds produced according to the invention have interesting pharmacological properties. In particular, they have a very strong effect on the central nervous system which can be expressed both in an antidepressant effect, whether this is caused by mono-amine oxidase inhibition or not and in a sedative or anticonvulsant activity.

In particular, they have four bonds in which R^

means a hydrogen atom, strong activity.

The monoamine oxidase inhibitory activity of the compounds prepared according to the invention was found in experiments where the compounds to be investigated were administered intraperitoneally or orally to 5 male albino mice. One hour later, the animals were injected subcutaneously with tryptamine hydrochloride in an amount of 250 mg/kg. This amount caused no mortality in animals that had not received the compound to be tested, but caused mortality in the treated animals. 18 hours after the administration of tryptamine hydrochloride, it was determined how many treated animals had died. From the results, ED^Q was determined.

The antidepressant activity of the compounds prepared according to the invention was determined in the tetrabenazine test. In this test, the compound to be investigated was administered intraperitoneally or orally to 5 male albino mice. After 45 min. the animals were injected subcutaneously with 80 mg tetrabenazine. After another 45 min. the degree of ptosis was determined and compared with the ptosis of the animals that have only received tetrabenazine. From the results, ED(-q was determined.

The sedative effect of the compounds prepared according to the invention was found in the hexobarbital anesthesia test. In this test, the compound to be investigated was administered intravenously and orally, resp. 30 and 60 minutes before a dose of hexobarbital (30 mg/kg), which was just less than the anesthetic dose. Producing anesthesia was the criterion for the substance's activity. ED5Q was calculated from a series of experiments with different doses.

The anticonvulsant activity of the compounds prepared according to the invention against supramaximal electric shocks was determined in female mice for 30 min. after intraperitoneal administration or 60 min. after oral administration of the compounds to be investigated.

The effect of the compounds on the convulsive activity of a supramaximal intravenously administered dose of pentamethylenetetrazole (50 mg/kg) was also determined in female rats at 30 min. after intraperitoneal administration or 60 min. after oral administration of the compound.

The anti-depressant compounds produced according to the invention are particularly suitable for use in the therapy of neurotic and psychotic disorders, especially of the depressive syndrome and also for the treatment of psychosomatic disorders. The substances can therefore also be administered to depressive patients as a psychostimulant.

The sedative compounds are well suited for use as ataxia. The part is successfully used for the treatment of mild psychoneurotic conditions.

The anticonvulsant compounds can be used in the treatment of epileptic patients.

The compounds, when they have been brought into a suitable administration form, can be administered in the usual ways. They can be injected or administered orally or rectally. As forms of administration, it can therefore i.a. used: injection fluids, pills,

tablets, coated tablets, capsules, powders and the like.

The manner, amount and frequency with which the substance is to be administered to the patient may vary for each individual patient also in accordance with the degree of disturbance. Usually, general practitioners will have no difficulty in choosing the right therapy for a patient.

Dosage of Sedative and antidepressant compounds will usually range from 10 to 500 mg/day for adults. As a rule, an amount of from 10 to 150 mg will be satisfactory.

Anticonvulsants produced according to the invention will usually be administered in doses from 100 to 500 mg/day.

The compounds produced according to the invention can be processed into preparations according to usual pharmaceutical methods, e.g. by mixing an active substance with or dissolving it in solid or liquid carriers.

As such, ordinary carriers can be used, e.g. water give ort isotonic with blood, if desired, e.g. using table salt, glycerin, chalk, calcium phosphate, lactose, powdered sugar, calcium carbonate. As swelling agents in tablets and coated tablets, e.g. potato starch, corn starch, arrowroot (amylum marantae), carboxymethyl cellulose, gelatin and acacia gum.

Talc, magnesium stearate, calcium stearate and stearic acid can be used as lubricants. Mixtures to be administered orally may also contain flavourings, e.g.

sugar or vanilla extracts.

As preservatives, it can e.g. propyl-p-hydroxybenzoate and benzyl alcohol are used. The mixtures may also contain surfactants, e.g. mono-, di- and triesters of higher fatty acids.

As examples of pharmacologically tolerable acids, which can form salts with the compound, mention may be made of hydrohalic acids, e.g. hydrogen chloride, hydrogen bromide, in addition other inorganic acids, e.g. sulfuric acid, nitric acid, phosphoric acid and organic acids, e.g. citric acid, acetic acid, oxalic acid, fumaric acid, lactic acid, succinic acid, sulphamic acid, benzoic acid, tartaric acid and bile acid.

The compounds are produced according to the invention by methods known per se.

The methods according to the invention are characterized in that a compound of formula III

is reacted with a compound of formula IV or a salt thereof, in which formulas A, R^, R^', Rjjj m and n have the above meanings, and M means a hydrogen atom or an alkali metal atom, X means a halogen atom or a tosyloxy group, Y means a hydrogen atom or an acyl group, and.R^' has the same meaning as R,., but instead of an amino group means an acylamino group, and in the case of Y means an acyl group or R,.' contains an acyl group, this is split off by hydrolysis after the coupling reaction, or that a compound of formula V is reacted with a compound of formula VI in which A, R1, R^' , R-^"» Rjj> R^' m and n have the above meanings, or that a compound of formula III, where M is a hydrogen atom, is reacted with an imine of formula VII in which formula R^ means an alkoxycarbonyl or acyl group, which is split off by means of hydrolysis after the reaction, or that a compound of formula VIII

wherein A, R-j'» Rj"> Rjp R^i m and n have the above meanings, and X means a halogen atom or a tosyloxy group, is reacted with ammonia

or methylamirym and, if Rj-1 contains an acyl group, this is cleaved off by hydrolysis,

after which the amines formed are optionally converted to salts with pharmacologically acceptable acids.

The reaction can be carried out in a common solvent. As such, it can i.a. used: alcohols, e.g. methanol, ketones, e.g. acetone and methyl ethyl ketone and ethers, e.g. diplcsane, dimethyl ether, glycol ether. The removal of an acyl group Y can, for example, be carried out with KOH in alcohol, e.g. ethanol.

If M in formula III means a hydrogen atom, it may be advantageous to add an acid binder to the reaction mixture. As such, it can i.a. are mentioned: alcoholates, potassium carbonate and sodium carbonate, tertiary amines, pyridine and the like.

The temperature of the reaction mixture can vary within wide limits. Usually it will lie between 0 and 50°C.

The oximes of formula III can be obtained in the usual way from the corresponding aldehydes to ketones by means of hydroxylanine. The oximates may be prepared from the oximes by adding them, whether dissolved in alcohol or not, to a solution of sodium alcoholate or potassium alcoholate or sodium hydroxide or potassium hydroxide in alcohols.

The acylated amines of formula IV can be prepared by starting from the corresponding primary and secondary amine and an acid chloride dissolved in e.g. benzene.

The compounds can alternatively be prepared by reacting a compound of formula V

with a compound of formula VI

wherein A, R.^ R^' , R-<j>"> Rip R^> m and n have the above meanings.

The reaction is preferably carried out in a solvent at room temperature. Such solvents can be mentioned: alcohols, pyridines, dioxane, dimethylformamide, tetrahydrofuran and the like.

An alternative method for preparing compounds of formula II is that an oxime of formula III (M = H) is reacted with an imine of formula VII

in which formula R1' means an alkoxycarbonyl or acyl group which is split off by hydrolysis after the reaction. The dissolution can be carried out in a suitable solvent, e.g. in alcohols. The compounds of formula II can alternatively be obtained by reacting a compound of formula VIII

with ammonia or methylamine.

In formula VIII, A, R 1 , R 11 , R 1 , R 8 , m and n have the above meanings, and X means a halogen atom, preferably a bromine atom, or a tosyloxy group. The reaction can be carried out e.g. in alcohols. An acyl group present in R^' is cleaved off by hydrolysis after the reaction.

The starting materials of formula VIII can be obtained by reacting oximes of formula III (M = H) in the presence of an acid binder with a halogen compound of formula IX

wherein X has the same meaning as for formula VIII dg Hal is a halogen atom, preferably a bromine atom.

The method according to the invention will be explained in more detail below with reference to some examples. Example 1.

2-n-butyl-0-(2-amino-ethyl)-indanone-1-oxim. HCl.

A solution of 3.76 g of 2-n-butylinda-non-1 in 25 ml of ethanol was mixed with 3.0 g of 0-(2-aminoethyl)-hydroxylamine dihydrochloride and 10 ml of pyridine and then refluxed for 2 hours . The solvent was then distilled off in vacuo. The residue was mixed with 50 ml of water and then extracted with ether. The aqueous layer was then mixed with an excess of sodium hydroxide solution and again extracted with ether. The latter ether extract was dried over sodium sulfate, after which the solvent was removed in vacuo. The residue was neutralized

with alcoholic hydrochloric acid and the solution was removed in vacuo and the residue crystallized from a mixture of absolute ether and petroleum ether. This gave the hydrochloride of 2-n-butyl-0-(2-amino-ethyl)-indanone-1-oxime with m.p. approximately 100°C.

Example 2.

0-(2-amino-ethyl)-3-n-propylindanone-1-oxim. HCl.

0.030 mol of 3-n-propylindanone-1-oxime (5.64 g) was added to a solution of 0.120 mol of sodium (2.76 g) in 75 ml of ethanol supra. 0.060 mol of 2-bromoethylamine hydrobromide (12.3 g) was then added. This mixture was stirred at room temperature for 150 min. after first adding another 25 ml of ethanol supra. The mixture was then suctioned from the formed NaBr precipitate. The filtrate was evaporated in vacuo until it was free of solvent, after which the residue was dissolved in 50 ml of water +

50 ml of ether. The layers were separated and the ether layer was washed again

25 ml of water. The ether layer was then acidified with 60 ml of normal hydrochloric acid. The acidic aqueous layer was separated and then basified with 50 mL of 2 N NaOH and then extracted with 3 x 75 mL of ether. The combined ether extracts were evaporated in vacuo after drying over ^£30^. The resulting oil was dissolved in 10 ml of ethanol and adjusted to pH 4 with approximately 3.2 N alcoholic hydrochloric acid. After addition of the ethyl ether, the substance crystallized with m.p. 117-18°C.

Example J> .

O-(2-methylaminoethyl)-fluorenone-oxime hydrochloride.

0.300 mole of sodium (6.90 g) was dissolved

in 200 ml ethanol supra. 0.075 mol of fluorenone oxime (14.65 g) was added to the solution. 0.150 mol of 2-methylaminoethyl chloride hydrochloride (19.35 g) was then added. The mixture was stirred at room temperature for 25 hours. The mixture was then suctioned from the formed NaCl precipitate. The filtrate was evaporated in vacuo until it was free of solvent. The resulting oil was dissolved in 150 ml of water and 150 ml of ether and the aqueous layer was separated. The ether solution was then washed again three times with 50 ml of water. The ether layer was shaken with 150 ml of 2 N HCl solution and the acidic water layer

were separated. This aqueous layer was washed three times with 30 ml of ether and then made basic again with 200 ml of 2 N NaOH. The basic oil which was liberated was extracted three times with 50 ml of ether. The combined ether extracts were finally washed three times with 50 ml of water; after drying over Na 2 SO 4 , the ether was removed in vacuo. The resulting oil was dissolved in 4 mL absolute ethanol and acidified with approximately 4 N alcoholic hydrochloric acid to pH 6 to 7.

Ether was added to the alcoholic solution and a crystalline substance appeared. After this had been allowed to stand for an hour, it was suctioned off at 3°C, washed with some ether and dried in a vacuum over solid NaOH.

After two recrystallizations from a mixture of absolute alcohol and ether, a substance was obtained which melted at 183.5 - 184.5°C

Example ' 4a. Preparation of starting materials of formula VIII. 0-{(2-p-toluenesulfonyl-oxy)-ethyl}-1-indanone oxime.

1.92 g of p-toluenesulfonyl chloride was added to a solution of 1.70 g of 0-(2-hydroxyethyl)-1-indanone oxime (prepared from 1-indanone oxime and ethylene oxime under the action of lithium ethanolate) in 3 ol of pyridine with stirring and cooling in ice water The reaction mixture was stirred under cooling for an additional 30 minutes and then at room temperature for 90 minutes.

The reaction mixture was then poured

1 a mixture of 14 g of ice and 4.7 ml of concentrated hydrochloric acid. The precipitated substance was extracted three times with 15 ml of benzene.

The solution in benzene was washed with

2 N hydrochloric acid and then with dilute sodium carbonate solution. After drying the solution over sodium sulfate, the solvent was removed in vacuo and the residue was crystallized from naphtha. Temp. 76-78°C.

Example 4b.

0-(2-methylamino-ethyl)-1-indanone-oxime-HCl.

A suspension of 0.92 g of 0<1>{2(p-toluenesulfonyloxy)-ethyl}-1-indanone oxime and 10.65 ml of 35% aqueous methylamine was stirred at room temperature for 3 hours. 5 ml of ethanol was then added to the mixture which was then heated at 60 to 70°C with stirring for 3 hours and then stirred for a further 17 hours at room temperature. Excess methylamine and most of the solvent were then distilled off in vacuo. The residue was mixed with 5 ml of 2 N sodium hydroxide solution, and this mixture was extracted three times with 10 ml. ether... The extract was then extracted with 15 ml of 1 N hydrochloric acid. After adding 10 ml of 2N sodium hydroxide solution to the hydrochloric acid extract, the latter was extracted with 30 ml of chloroform. The chloroform extract was dried over sodium sulfate, after which the solvent was removed in vacuo. The resulting residue was dissolved in 1 ml of absolute ethanol, neutralized with 0.6 ml of ethanolic hydrochloric acid and this solution was mixed with 25 ml of abs. ether. From this mixture the above substance was formed in a crystalline form. Temp. after recrystallization from ethanol-ether was 177-178°C Example 5a.

3-fluoro-O-{2-(N-ethoxycarbonylamino)ethyl}-fluorenone oxime.

A solution of N-ethoxycarbonylethylenimine, formed by reacting 1.4 ml of ethyleneimine and 2.4 ml of ethyl chloroformate under the action of triethylamine in 30 ml of absolute benzene, was mixed with stirring with a warm (about 50°C) solution of 5 g of 3-fluoro-fluorenone oxime and 40 ml of ethyl acetate. The reaction mixture was then heated to boiling temperature with stirring and then stirred for 30 min. at this temperature. After standing at room temperature for 16 hours, water was added and the benzene-ethyl acetate layer was separated. This layer was washed three times with water and then dried over anhydrous sodium sulfate. After removing the solvent in vacuo, the crystalline residue was mixed with a little ethanol, in which unreacted fluorenone oxime does not dissolve well. The latter was sucked off, after which a substance with m.p. 93>5 - 94°C from the filtrate by selective crystallization.

Example 5b.

3- fluoro- 0-( 2- aminoethyl)- fluorenone- oxime- HCl.

0.3 g of the compound prepared according to example 5a was dissolved in 5 ml of ethanol by heating. This solution was mixed with 1.9 ml of 3 N sodium hydroxide solution and then boiled well for 1 hour. The reaction mixture was then diluted with 10 ml of water and extracted three times with diethyl ether. The ether extract was then extracted with 2.5 ml of a 1.2 N hydrochloric acid and then again with 1.8 ml of 3 N sodium hydroxide solution and again extracted with diethyl ether. The latter ether extract was dried over sodium sulfate and then evaporated in vacuo. The residue was dissolved in a little ethanol and then neutralized with alcoholic hydrochloric acid. As a result, ~é't "substance crystallized out which was sucked off and washed with a mixture of diethyl ether and ethanol" and dried in vacuo. M.p. 216-217.5°C with decomposition.

Example:. 6a..... 3- f luor- O- / £.- ( ethoxy- carbonylamino) ethyl/- f luorenone oxime.

A solution of 2.06 g of 2-bromo-N-(ethoxycarbonyl)-ethylamine in 6 ml of absolute ethanol. was added with stirring to a solution consisting of 1.95 g of 3-fluoro-fluorenone oxime and 10.24 g of sodium in 18 ml of absolute ethanol. The reaction mixture was stirred for a few hours and then left at room temperature for 24 hours. The mixture was then diluted with water and extracted with diethyl ether three times. The ether layer was dried over sodium sulfate. and the solvent was then removed in vacuo. By fractional crystallization of the residue from ethanol, a substance with m.p. 93.5-94°C.

Example 6b.

3~ fluoro- O-( 2- aminoethyl)- fluorenone- oxime. HCl.

0.3 g of the compound thus obtained was dissolved in 5 ml of ethanol by heating. The solution was mixed with 1.9 ml of 3 N sodium hydroxide solution and then boiled for well over 1 hour. The reaction mixture was then diluted with 10 ml of water and extracted with diethyl ether three times. The ether extract was then extracted with 2.5 ml of 1.2 N hydrochloric acid and then once more with water. The resulting acidic solution was made alkaline with 1.8 ml of 3 N sodium hydroxide solution and again extracted with ether. The last ether extract was dried over sodium sulfate and then evaporated in vacuo. The residue was dissolved in a little ethanol and then neutralized with alcoholic hydrochloric acid. As a result, a substance crystallized which was sucked off, washed with a mixture of diethyl ether and ethanol and dried in vacuo. Temp. 2l6-217°C during decomposition.

Example 7.

3- fluoro- O-( 2- aminoethyl)- fluorenone- oxime. HCl.

A solution of 4.91 g of the dihydrochloride of O-(2-aminoethyl)-hydroxylamine in 10 ml of water and a solution of 2.71 g of sodium acetate likewise in 10 ml of water were mixed with a hot (about 40°C ) solution of 5.94 g of 3-fluoro-fluorenone in 125 ml of ethanol. The mixture was then left at room temperature for 4 hours and then at approx. 70°C for 30 min. The solvent was then removed in vacuo. The resulting residue was dissolved in 200 ml of water and extracted twice with 50 ml of methylene chloride. An excess of sodium hydroxide solution was then added to the aqueous solution and the whole was extracted three times with 50 ml of methylene chloride. The extract was washed with water and dried over sodium sulfate. The solvent was then distilled off in vacuo, and the residue dissolved in 15 ml of ethanol was neutralized with alcoholic hydrochloric acid. As a result, the above substance began to crystallize. After adding some more ether to the crystallizing solution, the substance was sucked off after some time, washed with diethyl ether. and dried. Temp. 216-217.5°C.

According to method A: reaction of a compound of formula III with a compound of formula IV or according to method B: reaction of a compound of formula V with a compound of formula VI, the following substances were formed:

In the last three columns, + means active, - not active or essentially not active. If nothing is filled in a column R, R represents a hydrogen atom, - column A means a carbon-to-carbon bond. -

In the following tables, a comparison of some compounds produced according to the invention with known compounds is drawn up, the known compounds being known from French patent no. 1,500,629 and Chemical Abstract 6l, 10545 e - 10546 c (1964), as from the French patent is known antidepressant oximes and from the Chemical Abstract parasympatholytic and spasmolytic dialkylaminoethyl ketoximes. The compounds produced according to the invention have either an antidepressant effect which is significantly greater or a stronger and more selective anticonvulsant effect than the known compounds.

It is clear from this table that the compounds according to the invention are more active than the compounds used as a comparison.

Claims (1)

Analogous methods for the preparation of new oximeters with an effect on the central nervous system and with the general formula II and salts thereof with pharmacologically acceptable acids, in which formula R^ means hydrogen or methyl, R^ means a halogen atom, an alkyl or alkoxy group with 1 to 4 carbon atoms, a nitro or CF^ group, Rj.- has the same meaning as R^ or means an amino group, m means 0 or 1, R^' and R^" together with the carbon atoms to which they are attached, means a benzene ring, and n = 0 and A•is a carbon-to-carbon bond, an oxygen or sulfur atom, or R^' and R^" each mean 2 hydrogen atoms, a hydrogen atom and a phenyl group, or a hydrogen atom and an alkyl group of 1 to 5 carbon atoms, and n = 0 or 1, and A means a carbon to- -carbon bond, an oxygen or sulfur atom or a CHg group, since R^' and Ry cannot form part of a benzene ring or cannot both represent 2 hydrogen atoms when R^=H, A is a carbon-to- carbon bond, and m = n = 0, characterized in that a compound of formula III is reacted with a compound of formula IV or a salt thereof, in which formulas A, R^, R^', R^", Rjj > m and n have the above meanings, and M means a hydrogen atom or an alkali metal atom, X means a halogen atom or a tosyloxy group, Y means a hydrogen atom or an acyl group, and R,-' has the same meaning as R,_, but means instead of an amino group an acylamino group, and in case Y means an acyl group or R^' contains an acyl group, this is by hydrolysis after the coupling reaction, or that a compound of formula V is reacted with a compound of formula VI wherein A, R^, Rj'> ^3"» ^5* m °S n have the above meanings, or that a compound of formula III, where M is a hydrogen atom, is reacted with an imine of formula VII in which formula R^<1> means an alkoxycarbonyl or acyl group, which is cleaved off by means of hydrolysis after the reaction, or that a compound of formula VIII wherein A, R-j', R4» R5j m and n have the above meanings, and X means a halogen atom or a tosyloxy group, is reacted with ammonia or methylamine, and, if R,-' contains an acyl group, this is cleaved off by hydrolysis, after which the amines formed are optionally converted to salts with pharmacologically acceptable acids.