DK146180B - METHOD OF ANALOGUE FOR THE PREPARATION OF METHYLAMINE DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. - Google Patents

Description

U6180

The present invention relates to an analogous process for the preparation of novel methylamine derivatives of the general formula n "C3H7

R- C-N (CHO) I

Wherein R is n-propyl, isopropyl, isobutyl or allyl, and n is 0 or 1, or pharmaceutically acceptable acid addition salts thereof, characterized in that an alcohol of the general formula n C3H7 ___

R -; C-NH-CH 2 - (CH 2) n-CH 2 OH II

n-C 3 H 7 wherein R and n are as defined above, or an acid addition salt thereof is reacted with a suitable cyclizing agent in a solvent or in the absence of a solvent, whereupon the methylamine derivative formed is optionally reacted with an organic or inorganic acid to form of a pharmaceutically acceptable acid addition salt.

The pharmaceutically acceptable acid addition salts of the compounds of formula I are those of inorganic acids, e.g. hydrochloric acid, or of organic acids in which the free carboxyl group is attached to a saturated or unsaturated aliphatic group, an aromatic group or an aralkyl group which may optionally contain another carboxyl group, e.g. fumaric acid.

As further explained below, the methylamine derivatives of formula I and their pharmaceutically acceptable acid addition salts have pharmacological properties which must make them particularly useful in the treatment of Parkinson's disease and in the correction of extrapyramidal disorders caused by neuroleptics.

146180 2

One can treat Parkinson's disease and correct extrapyramidal disorders caused by neuroleptics by administering an effective dose of at least one compound of formula I or a pharmaceutically acceptable acid addition salt thereof to the affected patient.

The daily dose is preferably between 10 and 60 mg of active ingredient in a human with a body weight of approx. 60 kg.

In the cyclization of the compounds of formula II, these can be used in the form of acid addition salts, such as e.g. hydrochlorides.

The cyclization may be carried out a) in the absence or presence of a solvent such as benzene using a suitable agent such as chlorosulfonic acid, b) in a solvent such as acetonitrile or benzene using a suitable agent such as triphenylphosphine. bromide, and in the presence of an organic base such as triethylamine, or c) in a solvent such as benzene using a suitable agent such as phosphoric anhydride.

The compounds of formula II can be prepared by reacting an ester of the general formula n-C-H, CH, - (CHO) -CO-R., 377 yr 2 2 n 2 1

R-C-NH III

n-C 3 H 7 wherein R and n have the meanings set forth above and R 2 represents a straight or branched alkyl group of 1-4 carbon atoms, with a suitable reducing agent, e.g. lithium aluminum hydride, in an inert and anhydrous medium such as ethyl ether.

Furthermore, the compounds of formula II wherein n is 0 may be prepared by reacting a methylamine derivative of the general formula n-C

R-C-NH 4, IV

wherein n is as defined above with ethylene oxide in the presence of a suitable catalyst, e.g. boron trifluoride, which is preferably used in the form of an etherate. Reaction 5 is carried out while heating the reactants to a temperature preferably between 170 and 200 ° C.

The compounds of formula III may be prepared by heating a methylamine derivative of the general formula IV with an appropriate amount of a halogenated compound of the general formula

Hal-CH2- (CH2) n -CO2R; L V

wherein R 2 and n have the meanings given above and Hal represents a chlorine, bromine or iodine atom, in a suitable medium, e.g. ethanol, and in the presence of a basic agent, e.g.

Sodium bicarbonate.

The compounds of formula IV are known compounds which are also described in British Patent Specification No. 1,467,739.

The above-mentioned methylamine derivatives have valuable pharmacological properties as mentioned above which may render them useful in human and veterinary therapy.

In particular, the compounds of this 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.

Furthermore, at doses that completely suppress neuroleptic-induced catatonia and catalepsy, the compounds of the present invention do not affect the antiamphetamine effect of neuroleptics on rats and anti-apomorphine action on dogs. Furthermore, regardless of the dosage size, the compounds of the present invention have no emetic effect on dogs and are not cholinolytic agents.

These pharmacological properties taken together make the compounds of formula I useful for the treatment of Parkinson's disease and for the correction of extrapyramidal disorders caused by neuroleptics.

Compounds which are trisubstituted on the methylamine moiety but unsubstituted on the nitrogen atom are already known to exhibit central noradrenergic and central dopaminergic properties which make them useful in the treatment of Parkinson's disease and in the correction of extrapyramidal disorders caused by neuroleptics.

These compounds are described in British Pat.

15,467,739.

However, these known trisubstituted methylamine derivatives have a more powerful tremor-inducing effect than the compounds of the present invention. It is desirable that the tremor-inducing effect be as small as possible, since tremors are the first sign of motor stimulation which is an undesirable side effect as it often induces mental and physical fatigue. In people suffering from depression, this can lead to severe worsening of the condition.

Furthermore, the compounds of the present invention are more advantageous than amantadine, i.e. 1-amino-adamantane, a product widely used to treat Parkinson's disease.

Although the pharmacological spectrum of the compounds of the present invention is very similar to the spectrum of amantadine, pharmacological tests performed with the compounds of the present invention and amantadine 30 have shown marked differences. When comparing the doses of the compounds of the present invention and of amantadine for a particular efficiency, it has e.g. It has been found that the effective dose is always relatively more distant from the toxic dose of the compounds of the present invention than of amantadine. In other words, the safety margin of the compounds of the present invention is greater than that of amantadine.

The development of new anti-Parkinson's agents is extremely important, 5 as the treatment is of long duration and changing use of various products is necessary.

From this point of view, the compounds of the present invention are valuable supplements to the Committee.of the available anti-Parkinson's agents, as there is currently no ideal remedy for the treatment of this disease, as explained above.

The Ν, dis-disubstituted derivative which has shown the most valuable properties as anti-Parkinson's agent is N, N-trimethylene-1,1-di-n-propyl-n-butylamine, which can be used in form of the free base or in the form of a pharmaceutically acceptable acid addition salt such as the hydrochloride or fumarate.

The central dopaminergic activity of the compounds of this invention is listed below for some of these compounds, together with the action of amantadine. The compounds were tested in the form of the hydrochlorides. The following compounds were: N, N-trimethylene-1,1-di-n-propyl-n-butylamine, HCl (Compound 1), N, N-ethylene-1,1-di-n-propyl-n-butylamine , HCl (Compound 2).

In the following experiments, the compound number refers to the hydrochloride.

25 I. Inhibition of reserpine-induced and neuroleptic-induced catatonia (dopaminergic properties).

1. Inhibition of reserpine-induced catatonia.

The test used for the study is similar to the test described in British Patent Specification No. 1,467,739.

146180 6

The results obtained with the above-mentioned compounds and amantadine are listed below in Table X. The results are expressed according to the same scoring system, from 0 to 4, as set out in the above-mentioned British patent.

Table I.

Compound Administered dose Inhibition of reserve in mg / kg pin-induced catatonia 16 4 2 6 2 10 Amantadine 100 4 2. Inhibition of neuroleptic induced catatonia.

The test used for this study is similar to the test described in British Patent Specification No. 1,467,739.

The results obtained with the above compounds as well as with amantadine are set forth in the following Table II. The point system was the same as used above in Table I.

Table II.

Compound Managed dose Inhibition of neuro- in mg / kg leptic induced catatonia 20 1 6 4 2 6 1

Amantadine 100 4

Complementary experiments have shown that compound 1 at a dose as low as 3 mg / kg has an inhibition index of neuroleptically induced catatonia of 2.

7 148180 II. Tremor-Inducing Effect In this experiment, the above-mentioned compound # 1 and the compound known from British Patent No. 1,467,739 are inherited from 1,1-di-n-propyl-n-butylamine hydrochloride.

Five groups of 10 rats are administered the test compound orally in an amount of 0.031 mmol / kg.

30 minutes after administration, the number of tremor animals is counted and the following ratios are calculated: reserpine-induced catatonia number of tremor-10 animals The reserpine-induced catatonia is expressed using the above-mentioned scoring system, ranging from 0 to 4.

The results are shown in the following Table III.

Table III

Compound Reserpine Induced Catatonic Number of Animals with Tremor 15 1 3/6 = 0.50 1,1-di-n-propyl-n-butylamine hydrochloride (known) 4/10 = 0.40

It is apparent from the results set forth above that the compounds of the present invention have a significantly better effect than the known compounds.

III. Acute toxicity

The acute toxicity LD, -q was determined in mice by oral route using the same method as described in British Patent Specification No. 1,467,739, 8 U6180 The following results were obtained with the subject compounds and amantadine:

Compound LD, .q ^ 1 65 5 2> 150

Amantadine 1050

The LDj-0 / ED20_3q index of the compounds in question was compared with the corresponding index of amantadine.

In this index, ED20-30 ^ means an e ^^ e ^ t ^ ve dose to achieve 20 to 30% of catatonia inhibition. The following results were found:

Connection Index 2> 25

Amantadine 21 15 This result shows that the compound in question is more advantageous than amantadine because it has a greater safety margin.

Likewise, the index LD 2 q / ED 2 q0 was determined for the compounds and amantadine.

The following results were obtained:

Compound Index 1 10.8

Amantadine 10

This result again shows that the compound in question has a greater safety margin than amantadine.

In the therapeutic use of the subject compounds, they are usually administered in the form of a pharmaceutical or veterinary composition in a dosage unit form corresponding to the dosage unit.

U618G

and containing a compound as an active ingredient together with a pharmaceutical carrier or excipient therefor. In 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. The composition may alternatively be provided as a suppository for rectal administration or a solution or suspension for parenteral administration.

The dosage unit form composition may contain from 5 to 50 mg, preferably from 5 to 20 mg, of the active ingredient per day. dose unit by oral administration, from 5 to 100 mg of active ingredient per day. per unit dose by rectal administration or from 1 to 20 mg of active ingredient per day. dose unit by parenteral administration.

The therapeutic compositions are prepared by bringing 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 thereof. Examples of suitable carriers or excipients are talc, magnesium stearate, milk sugar, sucrose, carboxymethyl cellulose, starches, kaolin, levitate and cocoa butter.

The following examples illustrate the process of the invention.

Example 1

Preparation of N, N-Ethylene-1,1-di-n-propyl-n-butylamine a) Ethyl 2- (1,1-di-n-propyl-n-butylamino) -ethanoate.

Into a 500 ml three-necked flask equipped with a mechanical stirrer and a capacitor are added 23.6 g (0.15 mol) of 1,1-di-n-propyl-30 n-butylamine, 16.8 g of sodium bicarbonate and 300 ml of ethanol. .

To this mixture is then added 28.4 g (0.17 mole) of ethyl bromoacetate and refluxed for 20 hours. Then 200 ml of ether is added and the resulting base is added

IQ

falls are separated. The solution is concentrated and the oil thus obtained is distilled under reduced pressure.

In this way, 22.9 g of ethyl 2- (1,1-di-n-propyl-n-butylamino) ethanate are obtained. Kp. 90-92 ° C below 0.3 mm Hg. Yield 5 63%.

b) N- (2-Hydroxyethyl) -1,1-di-n-propyl-n-butylamine.

To a suspension of 7.6 g (0.2 mole) of lithium aluminum hydride in 15 ml of ether is added 22.8 g (0.094 mole) of ethyl 2- (1,1-di-n-propyl-n-butylamino) ethanate dissolved in 50 ml of ether. The mixture is heated at reflux for 20 hours and then hydrolyzed by the addition of ice. The precipitate thus obtained is filtered off and washed with ether and the solvent is evaporated off under vacuum.

This gives 17.8 g of N- (2-hydroxyethyl) -1,1-di-n-15-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 above-obtained amine in 150 ml of ethanol is added 1.9 ml of concentrated hydrochloric acid. After removal of the solvent in vacuo, the oil thus obtained is taken up in 100 ml of isopropyl ether. The desired precipitated hydrochloride is separated and then recrystallized from 150 ml of ethyl acetate.

This gives 2.7 g of N- (2-hydroxyethyl) -1,1-di-n-25-propyl-n-butylamine hydrochloride. Mp. 157 ° C. Yield 60%.

d) N, N-Ethylene-1,1-di-n-propyl-n-butylamine.

In a 250 ml three-neck flask containing 15 g (0.063 mol) of the above-prepared N- (2-hydroxyethyl) -1,1-di-n-propyl-n-butylamine hydrochloride is slowly added with stirring 15 ml fresh distilled chlorosulfonic acid. During the addition, a strong exothermic reaction is observed. The mixture is further heated to 80 ° C and, using a water air pump, partial vacuum is provided in the flask. Under these conditions, the heating is maintained at a temperature of 80 ° C for one hour, and then the mixture is heated to 140 ° C under atmospheric pressure for 90 minutes. The viscous mixture 5 is 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 sodium hydroxide solution. The mixture is then subjected to steam distillation and 500 ml of distillate are collected. After addition of 100 ml of sodium hydroxide solution, the basic part of the distillate is extracted with ether. The ether is evaporated in vacuo and the residual oil is distilled off.

In this way, 8.7 g of N, N-ethylene-1,1-di-n-propyl-n-butylamine are isolated in the form of a colorless liquid. Kp. 103-104 ° C under 18 mm Hg. Yield 76%.

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.

Into a 50 ml flask equipped with several feed pipes, a mechanical stirrer, a reflux condenser, a thermometer 20 and a submerged tube by adding nitrogen and ethylene oxide, 0.2 ml of boron trifluoride in the form of the etherate and 10 g of 1,1 n-propyl-n-butylamine. The apparatus is rinsed with nitrogen and the reaction medium heated with stirring to 160 ° C by means of an oil bath. Ethylene oxide is then continuously bubbled through the reaction medium for 4 hours, carefully maintaining the reaction temperature of 180-200 ° C. The flask is rinsed with nitrogen before cooling and the reaction mixture is acidified with 20 ml of 36% hydrochloric acid. After cooling to 0 ° C, the mixture is kept at this temperature for 2 hours, then suction filtered and dried to constant weight.

This gives 5 g of N- (2-hydroxyethyl) -1,1-di-n-propyl-n-butylamine hydrochloride. Mp. 175 ° C.

B) N, N-Ethylene-1,1-di-n-propyl-n-butylamine. .

Using the procedure of Example 1 and the compound prepared under a) above, N, N-ethylene-1,1-di-n-propyl-n-butylamine is prepared.

Example 3

Preparation of N, N-trimethylene-1,1-di-n-propyl-n-butylamine hydrochloride.

a) Methyl 3- (1,1-di-n-propyl-n-butylamino) propanoate.

A solution of 28.4 g (0.33 mol) of methyl acrylate in 60 ml of methanol is heated at reflux for 48 hours together with 47.1 g (0.3 mol) of 1,1-di-n-propyl-n-butylamine. . After distilling off the methanol under vacuum, the resulting liquid is distilled.

This gives 61 g of methyl 3- (1,1-di-n-propyl-n-butyl-amino) propanoate. Kp. 97-98 ° C below 0.4 mm Hg. Yield 82%.

b) N- (3-Hydroxy-n-propyl) -1,1-di-n-propyl-n-butylamine.

Into a 500 ml three-neck flask equipped with a mechanical stirrer, a condenser and a dropper funnel are added 3.8 g (0.17 mol) of lithium aluminum hydride and 130 ml of dry ether. To this mixture is slowly added 12.2 g (0.05 mole) of the above-prepared methyl 3- (1,1-di-n-propyl-n-butylamino) propanoate. The reaction medium is heated at reflux for 12 hours and then hydrolyzed. The precipitate formed is washed with ether, the ether is evaporated and the oil thus obtained is distilled off.

In this way 14.9 g of N- (3-hydroxy-n-propyl) -1,1-di-n-propyl-n-butylamine is obtained in the form of a colorless liquid. Kp. 107-108 ° C below 0.4 mm Hg. Yield 85%. The hydrochloride melts at 121-122 ° C.

C) N, N-Trimethylene-1,1-di-n-propyl-n-butylamine.

Into a 500 ml three-necked flask equipped with a mechanical stirrer, a submerged thermometer, a droplet funnel and a calcium chloride trap are added 18.3 g (0.07 mole) of triphenylphosphine, 150 ml of acetonitrile and 50 ml of ethyl ether. The mixture is cooled to 0 ° C and then 11.2 g (0.07 mol) of bromine is added dropwise with stirring. Then, 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 and then 19.4 ml ( 0.14 mole) of anhydrous triethylamine, keeping the reaction medium at a temperature of approx. 0 ° C. The mixture is allowed to stand for 12 hours at room temperature and the precipitate formed is separated and washed with ether. To the filtrate are added 100 ml of water and 30 ml of concentrated hydrochloric acid and the solvent is evaporated under vacuum.

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

From the aqueous solution made basic by the addition of sodium hydroxide, the organic portion is continuously extracted for 48 hours with methylene chloride. The solvent is removed and the residue is distilled under reduced pressure.

In this way, N, N-trimethylene-1,1-di-n-propyl-n-20-butylamine is obtained in the form of a colorless liquid. Kp. 112-115 ° C under 14 mm Hg. Yield 57%.

d) N, N-Trimethylene-1,1-di-n-propyl-n - butylamine, hydrochloride.

A solution of 6.9 g of the above obtained amine in dry ether is treated with ether saturated with gaseous hydrogen chloride to pH 3 to 4. The precipitate is separated, washed with ether and dried.

In this way, N, N-trimethylene-1,1-di-n-propyl-n-butylamine hydrochloride is obtained in the form of colorless crystals, m.p. 92-93 ° C. Yield 87%.