SE452763B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE DI-N-PROPYL-METHYLAMINE DERIVATIVES - Google Patents

Description

452 763 may have a second carboxyl group, such as e.g. fumaric acid.

Depending on the chemical structure, the compounds of formula I have an isomeric center and can thus be prepared as optical isomers, or mixtures of these isomers. The isomer mixtures can, if desired, at appropriate stages of operation and by methods well known to one skilled in the art be subdivided to give the respective individual isomers.

As described in more detail below, it has been found that the methylamine derivatives of formula I and the pharmaceutically acceptable acid addition salts thereof have pharmacological properties which probably make them particularly suitable in the treatment of Parkinson's disease and in counteracting extrapyramidal disorders caused by neuroleptics.

Accordingly, there is provided a method of treating Parkinson's disease and counteracting extrapyramidal disorders caused by neuroleptics, which method comprises administering to the patient thus effective an effective dose of at least one compound of formula I or a pharmaceutically acceptable acid addition salt thereof. .

The daily dose is preferably between 10 and 60 mg of active ingredient for a human weighing 60 kg.

Compounds of formula I can be prepared in a solvent or in the absence of solvent by reacting a suitable cyclizing agent with an alcohol of the general formula: n ~ C3H7 X CH2- (cH2) n-cH2oH R C-NH II \ n-C3H7 wherein R and n represent the same as in formula I, or with an acid addition salt of this compound, which gives the desired methylamine derivative which can then be reacted with any organic or inorganic acid to a pharmaceutically acceptable acid addition salt of the derivative. The cyclization reaction which takes place in said process can be carried out: a) in the absence of a solvent or in the presence of a solvent, such as e.g. benzene, by means of a suitable agent, such as e.g. chlorosulfonic acid, b) in a solvent, e.g. acetonitrile or benzene, by means of a suitable agent, eg triphenylphosphine bromide, and in the presence of an organic base, e.g. triethylamine, c) in a solvent, e.g. benzene, by means of a suitable agent, such as e.g. phosphoric anhydride.

The compounds of formula II may be prepared by treatment with any suitable reducing agent, such as, for example, lithium aluminum hydride, and in any inert and anhydrous medium, such as, for example, ethyl ether, of an ester of the general formula: n-C 3 H 7 /// CH 2 - ( CH 2) n -CO 2 R 1 R --- C ~ NH III n-C 3 H 7 wherein R and n have the same meaning as in formula I above, and R 1 represents a straight chain or branched alkyl radical having 1 to 4 carbon atoms, to the desired compound.

According to another method, the compounds of formula II, wherein n is 0, can be obtained by reacting ethylene oxide with a methylamine derivative of the general formula: n-C 3 H 7 R 1 -c-NH 2 Iv n-C 3 H 7 wherein n has the same meaning as in formula I above, in the presence of any suitable catalyst, such as e.g. boron trifluoride, preferably used in the form of an ether, to give the desired compound of formula II. The reaction in question takes place when the reagents are heated, preferably to a temperature between 170 and 200 ° C.

The compounds of formula III can be prepared by adding in a suitable medium, e.g. ethanol, and in the presence of an alkaline agent, e.g. sodium bicarbonate, heats a methylamine derivative of the above formula IV together with a suitable amount of a halogenated compound of the general formula: Hal-CH 2 - (CH 2) n -CO 2 R 1 'V wherein n and R 1 represent the same as above and Hal represents a chloro-, bromine or iodine atom, thereby forming the desired compound.

The compounds of formula IV are all known compounds which together with methods for their preparation are described in British Patent Specification 1 467 739 »As mentioned above it has been found that the methylamine derivatives according to the invention have valuable pharmacological properties which probably make them useful in human therapy. and the veterinary therapy.

In particular, it has been found that the compounds of the invention have central noradrenergic and central dopaminergic properties. These latter properties are evidenced by an inhibitory effect on reserpine-induced and neuroleptic-induced catatonia and catalepsy.

In addition, it has been found that the compounds of the invention, in doses which completely counteract neuroleptic-induced catatonia and catalepsy, do not affect the antiamphetamine effects of neuroleptics on rats and their antiapomorphine effects on dogs. Furthermore, the compounds of the invention do not have emetic effects on dogs in any doses, and they are not cholinolytic agents.

Together, these pharmacological properties probably mean that the compounds of formula I can be used to advantage in the treatment of Parkinson's disease and to counteract extrapyramidal disorders caused by neuroleptics. The compounds of the invention are more advantageous than amantadine, i.e. 1-amino-adamantane, a product commonly used in the treatment of Parkinson's disease. Although the compounds of the invention have a pharmacological spectrum very similar to that of amantadine, pharmacological tests performed with the compounds of the invention have shown marked differences in comparison with amantadine. For example, comparisons between doses of the compounds of the invention and of amantadine with a certain efficiency have shown that the active dose in question is proportionally always further away from the toxic dose in the case of the compounds of the invention than in the case of amantadine. In other words, the compounds of the invention provide a broader margin of safety than amantadine.

The search for new agents for Parkinson's disease is of primary importance, as the treatment is long-term and alternating use with different products is necessary. From this point of view, the compounds of the invention will be a valuable addition to the agents useful for Parkinson's disease, since it at present there is no agent which is ideal in the treatment of this disease, as explained above. The N, N-di-substituted derivative of the present invention which has been found to have the best properties as an antiparkinsonian agent is: 'N, N-trimethylene-1,1-di-n-propyl-n-butylamine to which compound is added in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt, such as, for example, the hydrochloride or fumarate.

Central dopaminergic action of the compounds of the invention is shown below for two of the compounds of the invention in comparison with amantadine. The compounds were preferably tested in the form of a pharmaceutically acceptable acid addition salt. They were as follows: 452,763 N, N-trimethylene-1,1-di-n-propyl-n-butylamine (Compound 1) N, N-ethylene-1,1-di-n-propyl-n-butylamine (Compound 2) I. Inhibition of reserpine-induced and neuroleptic-induced catatonia (dopaminergic properties) 1- l “ÉïÉeÉïE9_a! EeâeEPÅninÉ “EeEaÉ EaEëÉ ° Ei The experiments performed for this purpose were identical to those described in British Patent Specification 1,467,739.

The results obtained with the above-mentioned compounds of the invention, compared with amantadine, are shown in Table I below.

The results are given according to the same scoring system, from 0 to 4, which appears in the above-mentioned patent specification.

Table I Administered dose Inhibition of reserve compound mg / kg pin-induced catatonia 1 6 2 6 Amantadine 100 2 'ÃnÉiÉešiE9_aY 2eEr21ÉPÉíÉainÉuEeEaÉ ÉaÉaÉ ° Ei The experiments performed for this purpose were identical to the one described in the patent.

The results obtained with the compounds of the invention, listed above, in comparison with amantadine are shown in Table II below.

The scoring system was the same as in Table I above.

Table II Administered dose Inhibition of neuroleptic Compound mg / kg cainduced catatonia 1 6 4 2 6 1 Amantadine 100 4. for neuroleptic - induced catatonia equal to 2.

II. Acute toxicity The acute toxicity LD50 was determined in mice by oral administration using the method described in British Patent Specification 1,467,739. The following results were noted with the compounds of the invention in comparison with amantadine: IJ_D50_i_a1 / _ks 1 65 2> 150 Amantadine 1050 _ "N.. Lnso A comparison was made between the index ED20_3O for the compounds of the invention and the corresponding index for amantadine.

In this index, ED2O_3o represents the effective dose to obtain 20-30% inhibition of catatonin. The following results were noted: Compound Index 2> 25 Amantadine 21 The result shows that the compound of the present invention is more advantageous than amantadine because it provides a wider safety margin.

LD ED compared to amantadine. The following results were recorded: Compound Index 1 10.8 Amantadine The result again shows that the compound according to the invention provides a wider safety margin than amantadine. 452 ie: In therapeutic use, the compounds of the invention are usually administered in the form of a pharmaceutical or veterinary composition in the form of a unit dose suitable for the desired mode of administration, the compositions having as active ingredient a compound of the invention together with a farm - carrier or excipient thereof. For oral administration, the composition may be in the form of e.g. a coated or uncoated tablet, a hard or soft gelatin capsule, a suspension or a syrup. Alternatively, the composition may take the form of suppositories for rectal administration, or a solution or suspension for parenteral administration.

In unit dosage form, the composition may contain from 5 to 50 mg, preferably from 5 to 20 mg, of the active compound per unit dose for oral administration, from 5 to 100 mg of active compound per unit dose for rectal administration, or from 1 to 20 mg. mg active compound per unit dose for parenteral administration.

The therapeutic compositions of the invention are prepared by combining at least one of the compounds of formula I or a pharmaceutically acceptable acid addition salt thereof with at least one suitable carrier or excipient therefor. Examples of suitable carriers or excipients are talc, magnesium stearate, milk sugar, sucrose, carboxymethylcellulose, starch, kaolin, levilite and cocoa butter.

The following examples illustrate the preparation of the compounds of the invention.

Example 1. HI Preparation of N, N-ethylene-1,1-di-n-propyl-n-butylamine a) Ethyl 2- (1,1-di-n-propyl-n-butylamino) -ethanoate In a A 500 ml three-necked flask equipped with a mechanical stirrer and condenser was charged with 23.6 g (0.15 mol) of 1,1-di-n-propyl-n-butylamine, 16.8 g of sodium bicarbonate and 300 ml of ethanol. To this mixture was then added 28.4 g (0.17 mol) of ethyl bromoacetate and the whole was heated to reflux for 20 hours with stirring. Then 200 ml of ether were added and the precipitate which formed was separated. The solution 452 763 was concentrated and the oil thus obtained was distilled under reduced pressure.

There was thus obtained 22.9 g of ethyl 2- (1,1-di-n-propyl-n-butylamino) -ethanoate.

Boiling point = 90-92 ° C at 0.3 mm Hg Yield = 63%. b) N- (2-hydroxyethyl) -1,1-di-n-propyl-n-butylamine To a suspension of 7.6 g (0.2 mol) of lithium aluminum hydride in 15 ml of ether was added 22.8 g (0.094 mol ) ethyl 2- (1,1-di-n-propyl-n-butylamino) -ethanoate dissolved in 50 ml of ether. The mixture was heated under reflux for 20 hours and then hydrolyzed in the cold state by the addition of ice. The precipitate thus obtained was filtered off, washed with ether and the solvent was evaporated in vacuo.

There was thus obtained 17.8 g of N- (2-hydroxyethyl) -1,1-di-n-propyl-n- -butylamine.

Yield: 94% c) N- (2-hydroxyethyl) -1,1-di-n-propyl-n-butylamine hydrochloride To a solution of 3.75 g (0.0187 mol) of the previously prepared amine in 150 ml of ethanol was added 1.9 ml of concentrated hydrochloric acid.

Then the solvent was removed in vacuo and the oil thus obtained was taken up in 100 ml of isopropyl ether. The desired hydrochloride, which precipitated, was separated and then recrystallized from 150 ml of ethyl acetate.

There was thus obtained 2.7 g of N- (2-hydroxyethyl) -1,1-di-n-propyl-n- -butylamine hydrochloride. melting point = 17 ° C Yield: 60% d) N, N-ethylene-1,1-di-n-propyl-n-butylamine In a 250 ml three-necked flask containing 15 g (0.063 mol) of N- (2-hydroxyethyl) -1,1-Di-n-propyl-n-butylamine hydrochloride, prepared as described above, was introduced slowly and with stirring 15 ml of freshly distilled chlorosulfonic acid. During the addition, a strong exothermic reaction was observed. The mixture was further heated to 80 ° C, and by means of a water pump a partial vacuum was maintained in the flask.

Under these conditions, heating was continued at 8006 for 1 hour, and then the mixture was heated at 140 ° C for 90 minutes at atmospheric pressure. The viscous mixture was stirred for 12 hours with 100 ml of distilled water and then poured into a flask containing 300 ml of water and 100 ml of a sodium hydroxide solution. The mixture was then subjected to steam distillation and 500 ml of distillate was collected. After 100 ml of sodium hydroxide solution was added, the basic fraction of the distillate was extracted with ether. The ether was evaporated in vacuo and the residual oil was distilled.

In this way, 8.7 g of N, N-ethylene-1,1-di-n-propyl-n-butylamine were isolated as a colorless liquid.

Boiling point: 10-140 ° C at 18 mm ng Yield: 76% In the same manner as described above, but with suitable starting materials, the following compounds were prepared: Compound N, N-ethylene-1-n-propyl-1-isopropyl-n-butylamine N, N-ethylene-1-n-propyl-1-isobutyl-n-butylamine N, N-ethylene-1-n-propyl-1-allyl-n-butylamine Example 2 Preparation of N, N-ethylene-1, 1-di-n-propyl-n-butylamine a) N- (2-hydroxyethyl) -1,1-di-n-propyl-n-butylamine hydrochloride In a 50 ml flask equipped with several inlet pipes, mechanical stirrer, cooler for reflux, thermometer and a dip tube for supplying nitrogen or ethylene oxide, 0.2 ml of boron trifluoride in the form of the etherate and 10 g of 1,1-di-n-propyl-n-butylamine were introduced. The device was vented with nitrogen, and the reaction medium was heated with stirring to 160 ° C on an oil bath. Thereafter, ethylene oxide was continuously bubbled through the reaction medium for 4 hours, taking care to maintain the reaction temperature at 180-200 ° C. The flask was purged with nitrogen before cooling, and the reaction mixture was acidified with 20 ml of 36% hydrochloric acid. After cooling to M 452 vase 0OC, the mixture was kept at this temperature for 2 hours, after which it was suction filtered and dried to constant weight.

There was thus obtained 5 g of N- (2-hydroxyethyl) -1,1-di-n-propyl-n-butylamine hydrochloride. melting point = 17 ° C b) N, N-1,1-di-n-propyl-n-butylamine This compound was prepared in the same manner as described in Example 1 above.

Exemgel 3.

Preparation of N, N-trimethylene-1,1-di-n-propyl-n-butylamine hydrochloride a) Methyl 3- (1,1-di-n-propyl-n-butylamino) -pronanoate A solution of 28.4 g (0.33 mol) of methyl acrylate in 60 ml of methanol were heated under reflux for 48 hours together with 47.1 g (0.3 mol) of 1,1-di-n-propyl-n-butylamine. After the methanol was removed in vacuo, the liquid thus obtained was distilled off.

There was thus obtained 61 g of methyl 3- (1,1-di-n-propyl-n-butylamino) -propanoate.

Boiling point = 97-9 ° C at 0.4 mm ng Yield: 82% b) N- (3-hydroxy-n-propyl) -1,1-di-n-propyl-n-butylamine In a 500 ml three-necked flask , equipped with a mechanical stirrer, condenser and dropping funnel, 3.8 g (0.17 mol) of lithium aluminum hydride and 130 ml of dry ether were introduced. To this mixture was slowly added 12.2 g (0.05 mol) of methyl 3- (1,1-di-n-propyl-n-butylamino) -propanoate, prepared as previously described. The reaction medium was heated under reflux for 12 hours, after which it was hydrolyzed. The precipitate formed was washed with ether, the ether was evaporated and the oil thus obtained was distilled.

In this way, 14.9 g of N- (3-hydroxy-n-propyl) -1,1-di-n--propyl-n-butylamine were collected in the form of a colorless liquid. 452 763 12 xok point = 107-1oa ° c via 0.4 mm ng Yield: 85% melting point of the hyarochlorine = 121-122 ° cc) N, N-trimethylene-1,1-di-n-propyl-n-butylamine I a 500 ml three-necked flask equipped with a mechanical stirrer, immersion thermometer, dropping funnel and a calcium chloride lock was charged with 10.3 g (0.07 mol) of triphenylphosphine, 150 ml of acetonitrile and 50 ml of ethyl ether. The slurry was cooled to 0 ° C, after which 11.2 g (0.07 mol) of bromine were added dropwise and with stirring. After this was done, first a solution of 14 g (0.065 mol) of N- (3-hydroxy-n-propyl) -1,1-di- -n-propyl-n-butylamine in 25 ml of acetonitrile was added and then 19.4 ml (0.14 mol) of anhydrous triethylamine while maintaining the reaction medium at a temperature of about 0 ° C. The mixture was allowed to stand for 12 hours at room temperature and the precipitate formed was separated and washed with ether. To the filtrate were added 100 ml of water and 30 ml of concentrated hydrochloric acid, and the solvents were evaporated in vacuo.

The precipitate was filtered off and washed first with 5% hydrochloric acid and then with water.

From the aqueous solution, which was made alkaline by the addition of sodium hydroxide, the organic fraction was continuously extracted with methylene chloride for 48 hours. The solvent was removed and the residue was distilled off under reduced pressure.

There was thus obtained N, N-trimethylene-1,1-di-n-propyl-n-butylamine as a colorless liquid.

Boiling point = 112-115 ° C at 14 mm Hg Yield: 57% In the same manner as above, but using suitable starting materials, the following was prepared: Compound N, N-trimethylene-1-n-propyl-1-isopropyl-n- butylamine N, N-trimethylene-1-n-propyl-1-isobutyl-n-butylamine N, N-trimethylene-1-n-propyl-1-allyl-n-butylamine (f. 13 se 452 vas d) N, N-trimethylene-1,1-di-n-propyl-n-butylamine hydrochloride A solution of 6.9 g of the previously prepared amine in dry ether was treated with ether saturated with hydrogen chloride gas to pH 3-4. The precipitate which separated was washed with ether and dried.

There was thus obtained N, N-trimethylene-1,1-di-n-propyl-n-butylamine hydrochloride in the form of colorless crystals. Melting point = 92-93 ° C Yield: 87%

Claims (1)

A process of analogy for the preparation of novel di-n-propyl-methylamine derivatives of the general formula nC H 3 7 \\\ n --cN (cn2) n 1 n ~ C3H7 and the The pharmaceutically acceptable acid addition salts thereof, wherein R represents n-propyl, isopropyl, isobutyl or allyl and n is 0 or 1, characterized in that a suitable cyclizing agent is reacted in a solvent or in the absence of any solvent with an alcohol of the general formula n -C 3 H 7 R - C-NH-CH 2 - (GHz) n -cnzon II n-C 3 H 7 wherein R and n have the same meaning as above, or with an acid addition salt of this compound, which gives the desired methylamine derivative which can then be reacted with any organic or inorganic acid to a pharmaceutically acceptable acid addition salt of the derivative. ~ li