IE45731B1 - Methylamine derivatives and process for preparing the same - Google Patents

Description

. The present invention relates to novel pharmacologically active derivatives of methylamine, to pharmaceutically acceptable acid addition salts thereof and to processes for preparing said derivatives The novel methylamine derivatives with which the invention is concerned are represented by the general formula: ch3-ch2-ch R-C-NHCH, I / 3 CH3-CH2-CH2/ wherein R represents n-propyl, isopropyl, isobutyl or allyl.

The invention also includes within its scope the pharmaceutically acceptable acid addition salts of the compounds of formula I such as the acid addition salts obtained with an inorganic acid, for example, hydrochloric acid, or with an organic acid in which the free carboxyl is attached to a saturated or unsaturated aliphatic radical, or an aromatic or aralkyl radical which may optionally contain a second carboxyl group such as, for example, fumaric acid.

Depending on their chemical structure, the compounds of formula I possess one or more isomeric centres and thus can be produced as optical isomers, or mixtures of these isomers. The mixtures of these isomers can be resolved, if desired, at appropriate stages by methods known to those skilled in the art to obtain the respective individual isomers.

The compounds of formula I can be prepared by heating, in the presence of an alkaline agent, such as - 2 45731 for example, sodium bicarbonate, an amine of the general formula: ch3-ch2-ch2^ R-C“NH„ II CH3-CH2“CH2 or an acid addition salt thereof, such as for example the hydrochloride, in which R has the same meaning as given above with methyl chloride or bromide or iodide, this reaction being undertaken either without any solvent or in the presence of a solvent, such as for example ethanol, to obtain the required compound of formula I which may then be reacted with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said compound.

It is well known that when the compounds of formula I, which are mono-substituted on the nitrogen atom, will be so prepared there will be obtained a mixture containing, in addition to the desired monosubstituted compound, a certain proportion of the corresponding disubstituted compound.

Such mixtures of mono-and disubstituted derivatives can be separated out by known techniques, for example by fractional distillation of the reaction mixture containing them or by fractional crystallization from their salts.

The N-substituted methylamine derivatives of formula I can also be obtained in accordance with other methods than that already described herein.

The different procedures set out hereunder for the preparation of the compounds of formula I are also included in the present invention, in addition to the method described above.

For example, the compounds of formula I can also be prepared by reducing, with lithium aluminium hydride, an isocyanate of the general formula: ch3-ch2-ch2X^ R-C-N=C=O III CHg-CHg-CHg·^ wherein R has the same meaning as in formula I to provide the required methylamine derivative of formula I, which can further be treated with an organic or inorganic acid to give a pharmaceutically acceptable acid salt.

The reduction in question can be effected in an inert and anhydrous medium such as for example ethyl ether.

Likewise, the compounds of formula X can be prepared starting with a compound of the general formula: ch3-ch2-ch R-C-A IV CHg-CHg-CHg^ wherein R has the meaning given in formula X and A 0 represents the group || or N=CH„ and reducing NH-CH ά this compound: a) in an appropriate anhydrous medium, such as for example ethyl or butyl ether, with lithium θ aluminium hydride in the case where A represents NH-CH. b) in a solvent such as for example methanol, with sodium borohydride in the case where A represents N=CH2, to provide the required compound of formula I which can then be treated, if desired, with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt of this compound.

The compounds of formulae II and III are known products having been described together with their process of preparation in British Patent No. 1,467,739 and Irish Patent No. 41032.

The compounds of formula IV wherein A represents N=CH2 can be obtained by condensing an amine of formula II with formaldehyde, the operation of condensation being carried out either in the absence of solvent or in the presence of a solvent, such as for example benzene.

Besides, the compounds of formula IV wherein 0 A represents || can be prepared either in the NH-CH presence of an acid acceptor, such as for example pyridine or 2,6-dimethyIpyrldine, by reacting an amine of formula II with formic anhydride.

It has been discovered that the methylamine derivatives of the invention possess valuable pharmacological properties which are likely to render them useful in human and veterinary therapy.

In particular, it has been found that the compounds of the invention present central noradrenergic and central dopaminergic properties. These latter properties manifest themselves by an inhibitory action on reserpine-induced and neuroleptic-induced catatonia and catalepsy.

Furthermore, at dcj£?s which completely suppress - 5 neuroleptic induced catatonia and catalepsy, it was observed that the compounds of the invention do not influence the anti-amphetamine effects of the neuroleptics in the rat and their anti-apomorphine effects in the dog. Furthermore, the compounds of the invention have no emetic action in the dog at any doses and are not cholinolytic agents.

These pharmacological properties taken as a whole are likely to render the compounds of formula I useful in treating Parkinson's disease as well as for correcting extra-pyramidal disturbances provoked by neuroleptics.

The N-substituted derivative of the present invention which has shown the most valuable properties for constituting an antiparkinsonian agent is: N-methyl-1,1-di-n-propyl-n-butylamine this compound being used in the form of its free base or in the form of a pharmaceutically acceptable acid addition salt such as, for example, the hydrochloride or the fumarate.

The central dopaminergic activity found in the compounds of the present invention is illustrated hereunder in comparison with amantadine. These compounds were preferably studied in the form of a pharmaceutically acceptable acid addition salt. They are the following: N-methyl-1,1-di-n-propyl-n-butylamine (Compound 1) N-methyl-l-n-propyl-l-isopropyl-n-butylamine (Compound 2) 4S731 N-methyl-l-n-propyl-l-isobutyl-n-butylamine (Compound 3) N-methyl-l-n-propyl-l-allyl-n-butylamine (Compound 4) I. Inhibition of reserpine-induced and neurolepticinduced catatonia (dopaminergic properties) 1. Inhibition_of_reserpine-induced_catatonia The test undertaken for this purpose is identical to that described in British Patent No. 1,467,739.

The results obtained with the compounds of the invention listed hereabove as well as with amantadine are given in Table I hereunder.

These results are expressed according to the same scoring system, from 0 to 4, as that set out in the above-cited British Patent.

TABLE I Compound Dose administered in mg/kg Inhibition of reserpine-induced catatoniE 1 6 4 2 6 4 3 6.5 3 4 5 2 Amantadine 100 4 - 7 2. Inhibition_of_neuroleptie-induced catatonia The test performed for this purpose is identical to that described in British Patent No. 1,467,739.

The Results obtained with the compounds listed above in comparison with amantadine are set out in the following Table II.

The scoring system was that used hereabove for Table I.

TABLE II Compound Dose administered in mg/kg Inhibition of neuroleptic-induced catatonia 1 6 3 2 6 3 3 6.5 4 4 5 2 Amantadine 100 4 II. Acute toxicity The acute toxicity LDgg was determined on mice by oral rqute using the same method as that described in British Patent No. 1,467,739.

The following results were recorded with compounds of the invention in comparison with amantadine: Compound 11>5θ in mg/kg 100 >150 170 Amantadine 1050 A comparison was made between the index LDjED 100 - 8 45731 of the compounds of the invention with the corresponding index of amantadine.

In this index, Εϋ^θθ represents the effective dose to obtain 100% inhibition of the catatonia, this value being represented by the figure 4 in Tables I and II.

The following results were registered in comparison with amantadine: Compound Index ’ 16.5 >25 Amantadine 10 These results show that the compounds of the present invention offer a greater safety margin than amantadine.

It will be appreciated that for therapeutic use the compounds of the invention will normally be administered in the form of a pharmaceutical or veterinary composition in a dosage unit form appropriate to the required mode of administration, the composition comprising as active ingredient a compound of the invention in association with a pharmaceutical carrier or excipient therefor. For oral administration, the composition may take the form of, for example,· a coated or uncoated tablet, a hard- or soft-gelatin capsule, a suspension or a syrup. The composition may alternatively take the form of a suppository for rectal administration, or of a solution or suspension for parenteral administration.

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

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

Pharmaceutical and veterinary compositions . containing as an essential ingredient a compound ‘ selected from inter alia the methylamine derivatives of formula I and the pharmaceutically acceptable acid addition salts thereof are claimed in our copending Application No. 45730.

The following Examples illustrate the preparation of the compounds of the invention together with a suitable therapeutic composition: EXAMPLE 1 Preparation of N-methyl-1,1-di-n-propyl-n-butylamine hydrochloride a) N-Methyl-l^l-di^n-propyl-n-butylamine To a suspension of 1.9 g (0.05 mol) of lithium aluminium hydride in 60 ml of anhydrous sulphuric ether was added a solution of 3.66 g (0.02 mol) of 1,1-di-npropyl-n-butylisocyanate in 20 ml of dry ether. 43731 The operation of addition was carried out over a period of 30 minutes at room-temperature after which the reaction medium was heated under reflux for 3 hours. After hydrolysis, first with ether saturated with water and then with water, the organic fraction was separated out. The organic phase was dried over magnesium sulphate and distilled under reduced pressure.

In this manner, 3.2 g of N-methyl-1,1-di-npropyl-n-butylamine were obtained in the form of a colourless liquid.

B.P. : 84°C under 13 mm Hg Yield : 94% b) N^Methyl-l^l-di-n^progyl-n-butylamine-hydrochloride By bubbling dry gaseous hydrogen chloride through the ethereal solution of the amine previously obtained, N-methyl-1,1-di-n-propyl-n-butylamine hydrochloride was precipitated in the form of colourless crystals.

M.P. : 133-134°C Yield : 90% By following the same procedure as that described hereabove but using the appropriate startingproducts, the compound hereunder was prepared: Compound _ ,. Melting point °C N-Methyl-l-n-propyl-1isopropyl-n-butylamine 144-145 hydrochloride (Yield : 80%) EXAMPLE 2 Preparation of N-methyl-1,l-di-n-propyl-3-buten-l-ylamine fumarate First 1,l-di-n-propyl-3-buten-l-ylisocyanate was prepared by reacting bromine and 2,2-di-n-propyl-4buten-l-ylamide in the presence of sodium hydroxide.

The desired product was obtained in the form of a colourless .liquid boiling at 79-82°C under 5 mm Hg.

The 2,2-di-n-propyl-4-buten-l-ylamide so obtained was then reduced by means of lithium aluminium hydride to provide without purification, N-methyl-1,1-di-npropyl-3-buten-l-ylamine in a yield of 89%.

To a solution of 2.32 g (0.02 mol) of fumaric acid in 400 ml of acetone, were added under stirring 3.38 g (0.02 mol) of the amine, prepared hereabove, dissolved in 30 ml of acetone.

Stirring was maintained for one hour after which the colourless crystals which precipitated were separated out. They v/ere washed with acetone and dried.

In this manner, 5.2 g of N-methyl-1,1-di-npropyl-3-buten-l-ylamine fumarate were obtained.

M.P. : 149°C Yield : 91% EXAMPLE 3 Preparation of N.methyl-l-n-propyl-l-isobutyl-nbutylamine hydrochloride a) N-Methyl-l-n^propyl^l-isobutyl-n-butylamine In a one litre three-necked flask, equipped with a condenser of the Dean Stark type, were^placed 30 g (0.175 mol) of 1-n-propyl-l-isobutyl-n-butylamine, 150 ml of 30 % formol and 400 ml of benzene. The mixture was refluxed for 5 hours so as to eliminate by azeotropic distillation about 100 ml of water. After evaporating the benzene under vacuum, the oil so obtained was taken up in 250 ml of methanol and, at a temperature of 10°C, 13.3 g (0.35 mol) of sodium borohydride were added by small fractions. The temperature of the mixture was maintained at 10°C during the operation of addition of the hydride and stirring was maintained for 30 minutes at this temperature. The reaction medium was refluxed for one hour and the methanol was then evaporated off under vacuum. To the product so obtained, 200 ml of distilled water and 100 ml of a concentrated solution of sodium hydroxide were added. The organic fraction ι was extracted with ether and dried over magnesium sulphate. The ether was evaporated out under vacuum and the residual liquid was distilled using a column.

In this manner, 11 g of N-methyl-l-n-propyl1-isobutyl-n-butylamlne were obtained in the form of a colourless liquid.

B.P. : 86°C under 12 mm Hg Yield : 34% b) N^MethYl-l-n-grogyl-l-isobutyl-n-buty1amine_hydr02 chloride In 150 ml of absolute ethanol, 10.4 g of the amine previously obtained were dissolved and the resulting solution was treated by means of 5.6 ml of concentrated hydrochloric acid and evaporated to dryness.

The oil so obtained was taken up in 50 ml of hexane and the desired hydrochloride crystallized when cold. It was separated out and recrystallized in isopropyl ether. In this manner, 7.5 g of N-methyl1-n-propyl-l-isobutyl-n-butylamine hydrochloride were obtained.

Yield : 61% M.P. : 139°C By following the same procedure as that described hereabove but using the appropriate startingproducts, the compound hereunder was prepared: Compound M.P. °C N-Mehtyl-1,1-di-n-propyl-n- butylamine hydrochloride 133-134 EXAMPLE 4 A hard-gelatin capsule containing the following ingredients was prepared in accordance with known pharmaceutical techniques: Ingredients mg N-methy1-1,1-di-n-propyl-n- butylamine hydrochloride 15 Milk sugar 50

Claims (16)

1. Methylamine derivatives corresponding to the general formula: ch 3 -ch 2 -ch 2 R-C-NHCH, / CH 3 -CH 2 -CH 2 / and the pharmaceutically acceptable acid addition salts thereof wherein R representsn-propyl, isopropyl, isobutyl or allyl.

2. N-Methyl-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof.

3. N-Methyl-l-n-propyl-l-isopropyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof.

4. N-Methyl-l-n-propyl-l-isobutyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof.

5. N-Methyl-l-n-propyl-l-ally1-n-butylamine and the pharmaceutically acceptable acid addition salts thereof.

6. Methylamine derivatives according to Claims 1 to 5 wherein the pharmaceutically acceptable acid addition salt is the hydrochloride or the fumarate

7. Process for preparing methylamine derivatives according to Claim 1, whereby an amine of the general formula: ch 3 -ch 2 -ch 2S ^ R-C-NH n ch 3 -ch 2 -ch 2 15 ¢7 or an acid addition salt thereof, in which R has the same meaning as in Claim 1 is heated, in the presence of an alkaline agent with methyl chloride or bromide, this reaction being undertaken either without any 5 solvent or in the presence of a solvent, to obtain the required methylamine derivative which may then be reacted with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said derivative. 10

8. Process according to Claim 7 wherein the alkaline agent is sodium bicarbonate.

9. Process according to Claim 7 wherein the solvent is ethanol.

10. Process according to Claim 7 wherein the la acid addition salt of the starting compound is the hydrochloride.

11. Process for preparing methylamine derivatives according to Claim 1 whereby an isocyanate of the general formula: 20 CH 3 -CH 2 -CH R-C-N=C=0 ch 3 -ch 2 -chz /Z wherein R has the same meaning as in Claim 1, is reduced with lithium aluminium hydr.ide in an anhydrous and inert solvent to obtain the required methylamine derivative which may then be reacted, if desired, with 25 an organic or inorganic ac.id to provide a pharmaceutically acceptable acid addition salt of the said derivative. 16 A57 31

12. Process according to Claim 11 wherein the inert medium is ethyl ether.

13. Process for preparing methylamine derivatives according to Claim 1, whereby a compound of the general formula: ch 3 -ch 2 -ch 2 \ R-C-A ch 3 -ch 2 -ch 2 X wherein R has the same meaning as in Claim 1 and A 0 represents the group or N=CH 2 is reduced: a) in an appropriate anhydrous medium with lithium aluminium hydride in the case where A represents b) in a solvent with sodium borohydride in the case where A represents N=CH 2 , to obtain the required methylamine derivative which may then be treated, if desired, with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said derivative.

14. Process according to Claim 13 wherein the appropriate medium is ethyl ether.

15. Process according to Claim 13 wherein the solvent is methanol.

16. Process for preparing a methylamine derivative or a salt thereof according to Claim 1 substantially as described in any one of the foregoing Examples 1 to 3.