IE45732B1 - 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-ch2.

CH3-CH2-CH2^-N CH3-CH2-CH2 ^r wherein Rj represents hydrogen, propargyl or 2hydroxyethyl, Rg represents propargyl, 2-hydroxyethyl or 3-hydroxy-n-propyl or Rj and Rg, when they are taken together, represent methylene, ethylene, trimethylene, ethylidene or -CHg-CHg-O-CHg-CHg- with the proviso that when Rg represents 3-hydroxy-n-propyl then Rj represents hydrogen.

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 aralkyi radical which may optionally contain a second carboxyl group such as, for example, fumaric acid.

Depending on their chemical structure, the compounds of formula X 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 general formula I above, can be prepared by different procedures in accordance with their chemical structure.

Thus, the compounds of formula I wherein R^ represents hydrogen or propargyl and Rg represents propargyl, can be prepared by heating, in the presence of an alkaline agent, such as for example, sodium bicarbonate, an amine of the general formula: II or an acid addition salt thereof, such as for example the hydrochloride, in which Rg represents hydrogen or propargyl with an appropriate quantity of propargyl 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 obtian 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.

In accordance with known procedures and when it is desired to obtain N,N-dipropargy1-1,l-di-npropyl-n-butylamine, 1,l-di-n-propyl-n-butylamine is treated so that two molar equivalents of propargyl halide react with one molar equivalent of 1,1-di-n3 45733 propy1-n-butylamine.

It is well known that when N-propargy1-1,1di-n-propyl-n-butylamine is desired, there will be obtained a mixture containing, in addition to the desired monosubstituted compound, a certain proportion of N,N-dipropargyl-l,1-di-n-propyl-n-butylamine, even when the molar equivalents indicated above are employed.

Such mixtures of mono- and di-substituted 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 Ν-ω-hydroxyalkyl derivatives of formula I i.e. N-(2-hydroxyethyl)-, N,N-bis-(2-hydroxyethyl)- and N-(3-hydroxy-n-propyl)-1,1-di-n-propyl-n-butylamines may be obtained by treating, by means of an appropriate reducing agent, such as for example, lithium aluminium ’hydride, and in an inert and anhydrous medium, such as for example ethyl ether, an ester of the general formula: CH3-CH2-CH2^ ^H^CH^-CO^ CHg-CH2-CH2—C-N ch3-ch2-ch2X Xr5 III wherein Rj represents a straight- or branched-chain alkyl radical having from 1 to 4 carbon atoms, n represents 0 or 1 and Rg represents hydrogen or 2-hydroxyethyl with the proviso that when Rg represents 2-hydroxyethyl, n represents 0, to obtain the desired compound of formula I which may then be treated with an organic or inorganic acid to provide a pharmaceutically - 4 45732 acceptable acid addition salt of the said compound.

The compounds of formula I wherein R^ and Rg, when they are taken together, represent an ethylene, trimethylene or -CHg-CHg-O-CHg-CHg- radical, can be obtained in a solvent or in the absence of a solvent by reacting an appropriate cyclization agent with a methylamine derivative of the general formula: CH3-CH2-CH2 -C-N CHg-CHg-CH^ IV in which Rg represents hydrogen or the radical CHg-CHgOH and m represents 0 or 1 with the proviso that when Rg represents CHg-CHgOH, m represents 0, which provides the desired 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.

When Rg represents hydrogen, the compound of formula IV hereabove can also be used in the form of an addition salt such as for example the hydrochloride.

The cyclization operation which is involved in the aforesaid process can be effected: a) in the absence of a solvent or in the presence of a solvent, such as for· example benzene, by means of a suitable agent, such as for example chlorosulphonic acid, b) in a solvent such as for example acetonitrile or benzene, by means of a suitable agent such as for example triphenylphosphine bromide and in the presence of an organic base, such as for example triethylamine, c) in a solvent such as for example benzene, by means of a suitable agent, such as for example phosphoric anhydride.

The cyclization agent will be chosen in 5 accordance with the structure of the compound of formula IV, For example, chlorosulphonic acid or triphenylphosphine bromide can be used when in the compound of formula IV Rg represents hydrogen. Similarly, phosphoric anhydride could be used, for example with a compound of formula IV wherein Rg represents the radical CHg-CHgOH and m represents 0.

The compounds of formula I wherein R^ and Rg, when they are taken together, represent a methylene or ethylidene radical can be obtained by condensing 1,1-di-n-propyl-n-butylamine with formaldehyde or acetaldehyde respectively, the operation of condensation being carried out either in the absence of a solvent •or in the presence of a solvent, such as for example benzene, to provide the desired compound of formula I which may then be reacted, if desired, with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt.

A certain number of N-substituted methylamine derivatives of formula I can also be obtained in accordance with other methods than those already described herein.

The different procedures set out hereunder for the preparation of some compounds of formula I are also included in the present invention, in addition to the general methods described above for the preparation of the whole of the methylamine derivatives fi 45732 covered by Lhe Invention.

For example, the compounds of formula X in which R4 represents hydrogen and Rg represents propargyl can be prepared starting with a compound of the general formula: wherein A represents the group NH-CO-C=CH or N=CH-C=CH and reducing this compound: a) in an appropriate anhydrous medium, such as for example ethyl or butyl ether, with lithium aluminium hydride in the case where A represents NH-C0-C=CH b) in a solvent such as for example methanol, with sodium borohydride in the case' where A represents N=CH-C=CH 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.

On the other hand, N-(2-hydroxyethyl)-l,1di-n-propyl-n-butylamine can be obtained by reacting ethylene oxide with 1,1-di-n-propyl-n-butylamine, in the presence of an appropriate catalyst, such as for example boron trifluoride used preferably in the form of an etherate, to provide the desired compound of formula I which can then be treated with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt of this compound.

On the other hand, N-(2-hydroxyethyl)-1,1di-n-propyl-n-butylamine can be obtained by reacting ethylene oxide with 1,1-di-n-propyl-n-butylamine, in the presence of an appropriate catalyst, such as for example boron trifluoride used preferably in the form of an etherate, to provide the desired compound of formula X which can then be treated with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt of this compound.

The reaction in question will be effected by heating the reagents, preferably at a temperature between 171° and 200°C. Ν,N-bis-(2-hydroxyethyl)-1,1-di-n-propyln-butylamine can also be prepared by reacting under pressure a molar equivalent of 1,1-di-n-propyl-nbutylamine with two molar equivalents of an ethylene oxide, this reaction being undertaken in the presence 'of a strong acid, such as for example hydrochloric acid, and in an inert medium, such as for example methanol, to provide Lhe desired compound of formula I which can further be reacted with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt of the said compound.

The reaction in question will be effected by heating the reagents, for example at a temperature between 40° and 80°C, preferably at 50°C, and under pressure of 3 bars.

Likewise , N-(3-oxapentamethylene)-l,1-di-npropyl-n-butylamine can be prepared following other procedures than than mentioned hereabove. - 8 45732 Thus, this compound In question of formula I can also be obtained by heating 1,1-di-n-propyl-nbutylamtne or an acid addition salt thereof, for example the hydrochloride, with di-(2-chloroethyl) oxide in the presence of an alkaline agent, such as for example sodium carbonate, to provide the desired compound of formula I which can further be reacted with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt of this compound.

Furthermore, N-(3-oxapentanemethylene)-l,1di-n-propyl-n-butylamine can also be obtained by reacting, in an anhydrous ether, such as for example ethyl ether, 2-N-morpholino-2-n-propyl-valeronitrile with n-propyl magnesium bromide and further hydrolyzing the complex so formed to provide the desired compound of formula I which can then be reacted with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt of the said compound.

Amongst the compounds of formula II, that wherein Rg represents hydrogen is a known product having been described together with its process of preparation in British Patent No. 1,467,739 and Irish Patent No. 41032.

The other compound of formula II, namely that wherein Rg represents propargyl is in fact a compound of formula I for which two processes of preparation are described hereabove.

The compounds of formula II can be obtained by heating, in an appropriate medium, such as for example ethanol, and in the presence of an alkaline agent, such as for example sodium bicarbonate, 1,1-di-n-propyl-n-butylamine or N-(2-hydroxyethyl)1,1-di-n-propyl-n-butylamine with an appropriate quantity of a halogentated compound of the general formula: Hal-CH2-(CH2)n-CO2R5 VI in which Rg has the same meaning as in formula III n represents 0 or 1 and Hal represents an atom of chlorine, bromine or iodine which gives the desired compound of formula III.

Furthermore, the compounds of formula III in which Rg represents hydrogen and n represents 1 can also be prepared by heating in an inert medium, such as for example methanol, 1,1-di-n-propyl-n-butylamine with an acrylic acid ester of formula CH2=CH-C02Rg wherein Rg has the same meaning as in formula III to obtain the desired compound.

The compounds of formula IV are in fact compounds of formula I for which a process of preparation is described hereabove.

The compounds of formula V wherein A represents N=CH-C=CH can be prepared by condensing 1,1-di-n-propyln-butylamine with propiolic anhydride while the other compound of formula V namely that in which A represents NH-CO-C=CH can be obtained either in the absence of a solvent or in a solvent, such as for example benzene and in the presence of an acid acceptor, such as for example pyridine or 2,6-dimethyl-pyridine, by reacting 1,1-di-n-propyl-n-butylamine with propiolic chloride or bromide with propiolic anhydride.

With respect to 2-N-morpholino-2-n-propyl10 45732 valeronitrile, this can be obtained by reacting potassium cyanide with a mixture of morpholine hydrochloride and di-n-propylketone, the reaction being carried out in an appropriate medium such as for example methanol.

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 doses which completely suppress 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.

Amongst the N-substituted derivatives and N,N-di-substituted derivatives of the present invention that which has shown the most valuable properties for constituting an antiparkinsonian agent, i.s: Ν,Ν-trimethylene-l,l-di-n-propyl-n-butylami ne this compound being used in the form of their 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,N-trimethylene-l,l-di-n-propyl-n-butylamine (Compound 1) N-propargyl-1,l-di-n-propyl-n-butylami ne ( Compound 2) N,N-dipropargy1-1,1-di-n-propy-n-butylamine (Compound 3) N,N-ethylene-l,l-di-n-propyl-n-butylamine (Compound 4) N-methylene-1,i-di-n-propyl-n-butylamine (Compound 5) N-ethylidene-1,l-di-n-propyl-n-butylamine (Compound 6) N-(2-hydroxyethyl)-l,l-di-n-propyl-nbutylamine (Compound 7) N, N-bis-(2-hydroxyethy1)-1,l-di-n-propyl-nbutylamine (Compound 8) N-(3-hydroxy-n-propyl)-l,1-di-n-propyl-n30 butylamine (Compound 9) -12 45732 Ν,Ν—(3-oxapentamethylene)-l,1-di-n-propyl-nbutylamine (Compound 10) I. Inhibition of reserpine-induced and neurolepticinduced catatonia (dopaminergic properties) 1. Inhibition_of reserjHne-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, fromO to 4, as that set out in the above-cited British patent.

TABLE I Compound Dose administered in mg/kg Inhibition of reserpineinduced catatonia 1 6 4 2 6 1 3 15 2 4 6 2 5 5.5 4 6 6 4 7 13 3 8 15 1 9 14 2 10 8 1 Amantadine 100 4 Complementary trials have shown that at a dose as low as 3 mg/kg, the Index of Inhibition of reserpine-induced catatonia of Compund 1 is equal to 3. 2. Inhibition of neurolegtic-induced_catatonia The test performed for this purpose is identical to that described in British Patent No. 1,467,739.

The results obtained with 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 4 2 6 4 4 6 1 5 5.5 3 6 6 2 7 6.5 1 8 15 1 9 7 2 10 8 2 Amantadine too 4 Complementary tests have shown that Compound at a dose as low as 3 mg/kg have an index of inhibition of neuroleptic-induced catatonia equal to while Compound 4 at the dose of 12 mg/kg has an index equal to 3.

II. Acute toxicity The acute toxicity LD5Q was determined on mice by oral route 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 LD50 in mg/kg 65 >150 >150 >150 >150 120 150 140 250 Amantadine 1050 A comparison was made between the index LDgQ ED20-30 of the compounds of the invention with the corresponding index of amantadine.

In this index, ΕΟ2θ_2θ represents the effective dose to obtain 20 to 30% inhibition of the catatonia, this value being represented by the figure 1 in Tables I and II.

The following results were registered: Compound Index >25 >25 23 4S732 31 Amantadine 21 These results show that the compounds of the present invention are more advantageous than amantadine because they offer a greater safety margin.

Similarly, an index LDgQ was determined in comparison with amantadine.

The following results were registered: Compound Index . 10.8 27 Amantadine 10 These results again 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 pharamceutical 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 pharaceutical 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 - 16 4 5732 administration, or oi a solution ox· 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 co-pending Application No. 45730.

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

EXAMPLE 1 Preparation of N-ethylidene-l,1-di-n-propyl-n-butylamine Into a 25 ml two necked flask, were introduced 7.9 g (0.05 mol) of I,1-di-n-propyl-n-butylamine. To this product, 2.64 g (0.06 mol) of acetaldehyde were added slowly, the reaction medium being cold. After this operation, 5.6 g of potassium hydroxide in pellet form were introduced and stirring was maintained for one hour at room-temperature. The lower phase was separated out from the organic phase which was distilled under vacuum in the presence of 1 g of ground potassium hydroxide and under nitrogen atmosphere.

In this manner, 7.8 g of N-ethylidene-1,1di-n-propyl-n-butylamine were obtained in the form of a colourless liquid.

B.P. : 87°C under 13 mm Hg Yield : 85% EXAMPLE 2 Preparation of N-propargy1-1,1-di-n-propyl-n-butylamine hydrochloride a) N-Progargyl-l^l-di^n-grog^l-n^butylamine Over a period of 48 hours, a mixture constituted by 11.9 g (0.1 mol) of propargy bromide, 25 g of sodium bicarbonate, 250 ml of ethanol and 19.7 g (0.1 mol) of 1,1-di-n-propy1-n-butylamine was refluxed. After the insoluble fraction was filtered out and the ethanol evaporated off, the mixture was treated by means of a diluted solution of sodium hydroxide. The organic phase was extracted with ether and distilled using a spinning band Column.

In this manner, 10 g of N-propargyl-1,1-din-propyl-n-butylamine were isolated in the form of a pale yellow liquid.

B.P. : 94-96°C under 5 mm Hg Yield : 51% b) N-Progargyl-l^l-di-n-propyl^n^butylamine_hydrochloride By bubbling dry and gaseous hydrochloric acid through an ethereal solution of the amine so obtained, the desired hydrochloride was precipitated and was then filtered out and dried.

In this manner, N-propargyl-1,1-di-n-propyln-butylamine hydrochloride was obtained in the form of crystals.

M.P. : 154-155°C Quantative yield.

EXAMPLE 3 Preparation of N,N-dipropargyl-l,l-di-n-butylamine hydrochloride a) 2i2zPiE£2E21>l-di-n-gropyl^n-butylamine By continuing the distillation operation commenced in the above Example 2 with a view to obtaining N-propargyl-1,1-di-n-propyl-n-butylamine, the corresponding Ν,Ν-dipropargyl derivative was isolated.

In this manner, 3 g of N,N-dipropargyl-l,1di-n-propyl-n-butylamine were obtained in the form of a colourless liquid.

B.P. : 120°C under 5 mm Hg Yield : 13% b ) ii?iz2iEi2EaESyiziaiz2izSzE£2EZ2:Z2zb!iiYia5is® hydrochloride By bubbling dry gaseous hydrogen chloride through an ethereal solution of the amine thus obtained, the desired hydrochloride was precipitated.

In this manner, Ν,Ν-dipropargyl-l,1-di-n-propyl19 45732 n-butylamine hydrochloride was obtained in the form of colourless crystals.

M.P. : 177°C (decomposition) EXAMPLE 4 Preparation of N-(2-hydroxyethyl)-l,1-di-n-propyln-butylamine hydrochloride a) Ethy 1-2-( 1,l^di^n-groggl-n-buty lamino^ethanoate Into a 500 ml three-necked flask fitted with a mechanical'stirrer and a condenser, were introduced 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 were then added 28.4 g (0.17 mol) of ethyl bromo-acetate and, while stirring the whole was refluxed for 20 hours. After this operation, 200 ml of ether were added and the precipitate which formed was separated out. The solution was concentrated and the pil so obtained was distilled under reduced pressure.

In this manner, 22.9 g of ethyl 2-(l,l-di-n20 propyl-n-butylamino)-ethanoate were obtained.

B.P. : 90°-92°C under 0.3 mm Hg Yield : 63% To a suspension of 7.6 g (0.2 mol) of lithium aluminium hydride in 15 ml of ether, were added 22.8 g (0.094 mol) of 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, while cold, hydrolyzed by adding ice. The precipitate so obtained was filtered out, washed with ether and the - 20 45732 solvent was evaporated off under vacuum.

In this manner, 17.8 g of N-(2-hydroxyethyl)1,l-di-n-propyl-n-butylamine were obtained.

Yield : 94% c) N-(2-Hydroxyethj’l)-l^l-di-n-propyl-n-butylamine hydrochloride To a solution of 3.75 g (0.0187 mol) of the amine previously obtained in 150 ml of ethanol, were added 1.9 ml of concentrated hydrochloric acid.

After the solvent was eliminated under vacuum, the oil so obtained was taken up with 100 ml of isopropyl ether. The desired hydrochloride, which precipitated, was separated out and then recrystallized from 150 ml of ethyl acetate.

In this manner, 2.7 g of N-(2-hydroxyethyl)~ 1,l-di-n-propyl-n-butylamine hydrochloride were obtained.

M.P. : 157°C Yield : 60% EXAMPLE 5 Preparation of N-(3-oxapentamethylene)-l,l-di-n-propyln-butylamine hydrochloride or tri-n-propylmethylmorpholino hydrochloride Under vigorous stirring, a mixture of 39 g (0.25 mol) of 1,1-di-propyl-n-butylamine, 40 g of di-(2-chloroethyl) oxide and 26.5 g of sodium carbonate was refluxed for five days. The mixture was treated with water and the organic fraction was extracted with ether. The organic phase was dried over magnesium - 21 I sulphate evaporated under vacuum and distilled under reduced pressure.

In this manner, 25 g of N-(3-oxapentamethylene)1.1- di-n-propyl-n-butylamine were collected in the form of colourless liquid.

B.P. : 105-106°C (under 5 mm Hg) Yield : 44% b) N-(3-Oxagentamethylene^l^l-di-n^grogyl-n^butylamine hydrochloride A solution of 3 g of N-(3-oxapentamethylene)1.1- di-n-propyl-n-butylamine, previously obtained, in 15 ml of isopropanol was treated with 1.5 ml of concentrated hydrochloric acid (d = 1.19) and the desired hydrochloride was precipitated by adding 25 ml of isopropyl ether.

In- this manner, N-(3-oxapentamethylene)-l,ldi-n-progyl-q-butylamine hydrochloride was obtained in the form of brilliant and colourless crystals which sublimated between 140 and 150°C.

Yield : 80% ' EXAMPLE 6 Preparation of N,N-ethylene-l,1-di-n-propyl-n-butylamine In a 250 ml three necked flask containing 15 g (0.063 mol) of N-(2-hydroxyethy1)-1,1-di-n-propyln-butylamine hydrochloride, prepared as described hereabove, were slowly added, while stirring, 15 ml of freshly distilled chlorosulphonic acid. During the operation of addition, a strong exothermic reaction was observed. The mixture was further heated to 80°C and using a water pump, a partial vacuum was created in -2245732 the flask. Under these conditions, heating was maintained at 80°C for one hour and then, at atmospheric pressure the mixture was heated at 140°C for 90 minutes. The viscous mixture was stirred for 12 hours with 100 5 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 submitted to steam distillation and 500 ml of distillate were collected. After 100 ml of a sodium hydroxide solution were added, the basic fraction of the distillate was extracted with ether. The ether was evaporated off under vacuum and the residual oil was distilled.

In this manner, 8,7 g of N,N-ethylene-l,1di-n-propyl-n-butylamine were isolated in the form of a colourless liquid.

B.P. : 103-104°C under 18 mm Hg Yield : 76% EXAMPLE 7 Preparation of N-(3-hydroxy-n-propyl)-l,1-di-n-propyl20 n-butylamine hydrochloride a) M®thzl_3z£l.>.l;;di-n-2ropyl-n~butylamino)-propanoate A solution of 28.4 g (0.33 mol) of methyl acrylate in 60 ml of methanol was heated under reflux for 48 hours together with 47.1 g (0.3 mol) of 1,1-di25 n-propyl-n-butylamine. After the methanol was eliminated under vacuum, the liquid so obtained was distilled.

In this manner, 61 g of methyl 3-(1,1-di-npropyl-n-butylamino)-propanoate were obtained.

B.P. : 97-98°C under 0.4 mm Hg Yield : 82% b) N-(S-Hydroxy-n^grogj/l)-1^l^di-n-progyl^n-butylamine Into a 500-ml three necked flask fitted with a mechanical stirrer, a condenser and a dropping funnel were introduced 3.8 g (0.17 mol) of lithium aluminium hydride and 130 ml of dry ether. To this mixture were slowly added 12.2 g (0,05 mol) of methyl 3-(1,1-di-npropyl-n-butylamino)-propanoate, prepared as previously described. The reaction medium was heated under reflux for 12 hours and then hydrolyzed. The 10 precipitate which formed was washed with ether, the ether was evaporated off and the oil so obtained was distilled.

In this manner, 14.9 g of N-(3-hydroxy-npropyl)-! ,1-di-n-propyl-n-butylamine were collected in the form of a colourless liquid.

B.P. : 107-108°C under 0.4 mm Hg Yield : 85% c 1 5ς£5ς3ζ5£25Ζς2ςΕ£°ΕΖΙ 1 ς12.1ς5£ς2ςΕΞ2ΕΖΪς2ς^2£ς£25!£22 hydrochloride A solution of 10.2 g of the amine previously obtained in 150 ml of ethanol was treated with 5 ml of concentrated hydrochloric acid. The solution was concentrated to dryness and the oil so obtained was taken up with 100 ml of isopropyl ether. The precipitate which formed was separated out and recrystallized from 120 ml of ethyl acetate.

In this manner, 11.25 g of N-(3-hydroxy-npropyl)-! ,1-di-n-propyl-n-butylamine hydrochloride were obtained.

M.P. : 121-122°C Yield : 90% I EXAMPLE 8 Preparation of N,N-trimethylene-l,1-di-n-propyl-nbutylamine hydrochloride a) N^N-Trimethylene^l,l^di-n-propyl-n-butylamine Into a 500 ml three necked flask, fitted with a mechanical stirrer, a dip thermometer, a dropping funnel and a calcium chloride trap, were introduced 18.3 g (0.07 mol) of triphenylphosphine, 150 ml of acetonitrile and 50 ml of ethyl ether.

The mixture was cooled to 0°C and then 11.2 g (0.07mol) of bromine were added, drop-by-drop and while stirring. After this operation, a solution of 14 g (0.065 mol) of N-(3-hydroxy-n-propyl)-l,1-di-n-propyl-n-butylamine in 25 ml of acetonitrile was first added followed by 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 which formed was separated out and washed with ether. To the filtrate, 100 ml of water and 30 ml of concentrated hydrochloric acid were added and the solvents were evaporated out under vacuum. The precipitate was filtered off and washed first with 5% hydrochloric acid and then with water.

Prom the aqueous solution, made alkaline by adding sodium hydroxide, the organic fraction was continuously extracted for 48 hours with methylene chloride. The solvent was eliminated and the residue was distilled under reduced pressure.

In this manner, N,N-trimethylene-l,1-di-npropyl-n-butylamine was obtained in the form of a 48732 colourless liquid.

B.P. : 112-115°C under 14 mm Hg Yield : 57% 5 5££?rochloride A solution of 6.9 g of the amine, previously obtained, in dry ether, was treated with ether saturated with gaseous hydrogen chloride to pH 3 to 4. The precipitate was separated out, washed with ether and dried.

In this manner, Ν,Ν-trimethylene-l,l-di-npropyl-n-butylamine hydrochloride was obtained in the form of colourless crystals.

M.P. : 92-93°C 15 Yield : 87% EXAMPLE 9 Preparation' of'· ΙΓ-'methylen'e-I, l-di-n-propyl-n-butylamine Into a 1-litre three-necked flask, equipped with a mechanical stirrer and a Dean Stark apparatus fitted with a condenser, were introduced 300 ml of benzene, 120 ml of a 30% solution of formic aldehyde and 11 g (0.07 mol) of 1,1-di-n-butylamine. The mixture was heated on an oil-bath to eliminate the water by azeotropic distillation, the benzene solution was evaporated to dryness and the oil so obtained was distilled.

In this manner, 11 g of N-methylene-1,l-din-propyl-n-butylamine were obtained in the form of a colourless liquid.

B.P. : 85°C under 13 mm Hg EXAMPLE 10 Preparation of N-^-hydroxyethyl)-1,1-di-n-propyl-nbutylamine hydrochloride In a 50 ml flask fitted with several inlet tubes, a mechanical stirrer, a condenser for reflux, a thermometer and a dip tube for allowing the entry of nitrogen' or ethylene oxide, was introduced 0.2 ml of boron trifluoride in the form of etherate and 10 g of 1,1-di-n-propyl-n-butylamine. The apparatus was cleared with nitrogen and the reaction medium was heated, while stirring, to 160°C by means of an oilbath. After that, ethylene oxide was continuously bubbled through the reaction medium for 4 hours, care being taken to maintain the reaction temperature at 180°-200°C. The flask was cleared with nitrogen before cooling and the reaction mixture was acidifiid with 20 ml of 36% hydrochloric acid. After cooling to 0°C, the mixture was maintained at this temperature for 2 hours and then suction filtered and dried to constant weight.

In this manner, 5 g of N-(2-hydroxyethyl)1,1-di-n-propyl-n-butylamine hydrochloride were obtained.

M.P. : 175°C EXAMPLE 11 Preparation of N,N-bis-(2-hydroxyethyl)-1,1-di-n-propyln-butylamine hydrochloride In an enamelled bomb-apparatus fitted with a dip-thermometer, a manometer, an adjusted safety valve, were introduced at low temperature, 48.6 g (60 ml) of methanol, 74.8 g (84 ml) (0.85 mol) of liquid ethylene oxide, 2.5 g of 36% hydrochloric acid and 25 g (0.159 mol) of 1,1-di-n-propyl-n-butylamine. The bombapparatus was closed, cleared with nitrogen and immersed in a water-bath thermostated at 50° - 2°C (pressure about 2.8 bars). The reaction was maintained for 40 hours and then the pressure was lowered to atmospheric pressure. The apparatus was cleared with nitrogen and the reaction medium was concentrated in a rotary evaporator to constant weight (45 g). The oil so obtained was taken up with 300 ml of ethyl ether and the ethereal solution was washed with 50 ml of a 4% aqueous solution of sodium hydroxide and then with water. The organic fraction was dried over anhydrous sodium sulphate and then evaporated to dryness to obtain 39 g of an oil which crystallized at about 50°C. This solid was recrystallized by dissolving in 160 ml of heptane under reflux, suction filtered after 2 hours at -3°C and dried to constant weight.

In this manner, 34 g of N,N-bis-(2-hydroxyethyl )-1,1-di-n-propyl-n-butylamine hydrochloride were obtained.

M.P. : 64°C · Yield : 87% f EXAMPLE 12 Preparation of N-(3-oxapentamethylene)-l,1-di-n-propyln-butylamlne hydrochloride a) ίίζ?ζΜ°ΣΕί)2ϋ22ζ5ζ2ζΕΕθΕΣ·1·ΣϊΕΐΕϊΕΕϊ£Εϊ·'·θ A solution of 43.5 g (0.5 mol) of morpholine in 200 ml of methanol was treated with 40 ml of iced and concentrated hydrochloric acid. To the solution of morpholine hydrochloride so obtained were added 57 g (0.5 mol) of di-n-propyl ketone and 100 ml of methanol and the resulting mixture was added to a suspension of 36 g of potassium cyanide in 400 ml of methanol. The reaction medium was stirred for 3 hours at room-temperature and then heated to 50°C for 12 hours. The precipitate which formed was filtered out, the methanol was evaporated off under vacuum and the oil so obtained was taken up with 100 ml of distilled water. The organic phase was extracted with ether, the ether was evaporated off and the residue was distilled under reduced pressure.

In this manner, N-2-morpholino-2-propylv'aleronitrile was obtained in the form of a colourless liquid.

Yield : 17% B.p. : 137-14O°C (under 3.5 mm Hg) b) 2z£2z2iSEE2£2S2£ilZ]:£2S2z2alz5iz22E£oEZi“2“62^Z^a5i^2e To a solution of propyl magnesium bromide, prepared from 1.1 g of magnesium turnings, from 5,6 g of propyl bromide and from 60 ml of dry ethyl ether, were added at room-temperature and while stirring, 8.4 g (0,04 mol) of 2-N-morpholino-2-n-propyl-valeronitrile previously obtained, in 30 ml of anhydrous ether.

The reaction mixture was refluxed for 2 hours and then, while cold, 30 ml of distilled water were added. The ether was separated out, dried over magnesium sulphate and evaporated off under vacuum. The resulting residue was distilled under reduced pressure.

I In this manner, N-(3-oxapentamethylene)-i,1di-n-propyl-n-butylamine was obtained.

Yield : 65% B.P. : . 96-97°C (under 4 mm Hg) c) ^(S^Oxagentamethylene)-1,l-di-n^propyl-n-butylamine hydrochloride A solution of 4.5 g of N-(3-oxapentamethylene)10 1,1-di-n-propyl-n-butylamine in 23 ml of isopropanol was treated with 2.3 ml of concentrated hydrochloric acid (d = 1.19). By adding 37.5 ml of isopropyl ether, the desired hydrochloride was precipitated.

In this manner, N-(3-oxapentamethylene)-l,l15 di-n-propyl-n-butylamine hydrochloride was obtained. Sublimation : between 140 and 150°C.

EXAMPLE 13 Preparation of N-(3-oxapentamethylene)-l,1-di-npropyl-n-butylamine hydrochloride a) N-(.3-0xagentamethylene}-l±l=di-n-grogyl-n2butylamine A solution of 5 g (about 0.02 mol) of N,N-bis(2-hydroxyethyl)-1,1-di-n-propyl-n-butylamine, prepared as previously described, in 50 ml of benzene was heated under reflux for 5 hours in the presence of .6 g (0.04 mol) of phosphoric anhydride. The mixture was stirred with 20 ml of distillc>d water and then separated from the aqueous phase which was treated with a siluted solution of sodium hydroxide and further extracted with ether.

In this manner, N-(3-oxapentamethylene)-l,130 45732 di-n-propyl-n-butylaine was obtained.

B.P, : 256°C (under 750 mm Hg) b) ίζ£5ζθϊ2Ε®Πίbyi®S®2zi±lz^izSzEE2Ey£z2zbE£Σΐ2ί?ΐ2® hydrochloride A solution of 4 g of N-(3-oxapentamethylene)1,1-di-n-propyl-n-butylamine in 20 ml of isopropanol was treated with 2 ml of concentrated hydrochloric acid (d = 1.19) and then 33 ml of isopropyl ether were added.

In this manner, N-(3-oxapentamethylene)-1,1di-n-propyl-n-butylamine hydrochloride was obtained which sublimated between 140 and 150°C.

Claims (38)

1. Methylamine derivatives corresponding to the general formula: ch 3 -ch 2 -ch 2 \ ^r x CH„-CH„-CH O -C-N 3 2 7 \ ch 3 -ch 2 -ch 2 r 2 and the pharmaceutically acceptable acid addition salts thereof wherein R^ represents hydrogen, propargyl or 2-hydroxyethyl, R 2 represents propargyl, 2-hydroxyethyl or 3-hydroxy-n-propyl or R^ and Rg, when they are together, represent methylene, ethylene,trimethylene, ethylidene or -CHg-CHg-O-CHg-CHg- with' the proviso that when.Rg'represents 3-hydroxy-n-propyl then R^ represents hydrogen.

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

3. Ν,Ν-Dipropargyl-l,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof.

4. N-Ethylidene-1,l-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof.

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

6. N,N-Ethylene-1,l-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof.

7. N-(2-Hydroxyethyl)-1,1-di-n-propyl-n32 1 4 5 7 3 2 butylamine and the pharmaceutically acceptable aeid addition salts thereof.

8. N-(3-Hydroxy-n-propyl)-l,1-di-n-propyln-butylamine and the pharmaceutically acceptable acid 5 addition salts thereof.

9. N,N-(3-0xapentamethylene)-l,1-di-n-propyln-butylamine and the pharmaceutically acceptable acid addition salts thereof.

10. Methylamine derivatives according to iq Claims 1 to 9 wherein the pharmaceutically acceptable acid addition salt is the hydrochloride or the fumarate.

11. Process for preparing methylamine derivatives according to Claim 1 wherein Rj represents 15 hydrogen or propargyl and Rg represents propargyl, whereby an amine of the general formula : ch 3 -ch 2 -ch CH 3 -CH 2 -CH 2 -C-NHR 3 CH 3 -CH 2 -CH 2 ' z ^ X or an acid addition salt thereof, in whieh Rg represents hydrogen or propargyl, is heated in the presence of an 2q alkaline agent, with an appropriate quantity of propargyl chloride or bromide or iodide, this reaction being undertaken either without any solvent or in the presence of a solvent, to obtain the required methylamine derivative which may then be reacted with an 22 organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said derivative.

12. Process according to Claim 11 wherein the alkaline agent is sodium bicarbonate. I

13. Process according to Claim 11 wherein the solvent is ethanol.

14. Process according to Claim 11 wherein the acid addition salt of the starting compound is the 5 hydrochloride.

15. Process for preparing methylamine derivatives according to Claim 1 wherein R^ represents hydrogen or 2-hydroxyethyl and Rg represents 2-hydroxyethyl or 3-hydroxy-n-propyl with the proviso that when / 10 R 2 re P resents 3-hydroxy-n-propyl, R^ represents hydrogen whereby an esier of the general formula: wherein R^ represents a straight- or branched-chain alkyl radical having from 1 to 4 carbon atoms, n represents 15 0 or 1 and Rg represents hydrogen or 2-hydroxyethyl with the proviso that when Rg represents 2-hydroxyethyl, n represents 0, is treated, by means of an appropriate reducing agent and in an inert and anhydrous medium, to obtain the required methylamine derivative which may 2o then be reacted with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said derivative.

16. Process according to Claim 15 wherein the reducing agent is lithium aluminium hydride. 25

17. Process according to Claim 15 wherein the inert medium is ethyl ether. 34 45732

18. Process for preparing methylamine derivatives according to Claim 1 wherein R^ and Rg, taken together, represent an ethylene, trimethylene or -CHg-CHg-O-CHg-CHg- radical, whereby an appropriate cyclization agent is reacted, in a solvent or in the absence of a solvent, with a compound of the general formula: lu lu ia la in which R g represents hydrogen or the radical CHg-CHgOH and m represents 0 or 1, with the proviso that when R g represents CHg-CHgOH, m represents 0, with an acid addition salt of this compound wherein R g represents hydrogen, which provides the required methylamine derivative which may then be reacted with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt of the said derivative.

19. Process according to Claim 18 wherein the solvent is benzene or acetonitrile.

20. Process according to Claim 18 wherein the cyclization agent is chlorosulphonic acid, triphenylphosphine dibromide or phosphoric anhydride.

21. Process according to.C.laim 18 wherein the acid addition salt of the starting compound is the hydrochloride.

22. Process for preparing methylamine derivatives according to Claim 1 wherein R^ and Rg, taken together, represent methylene or ethylene whereby 1,1-di-n-propyl-n-butylamine is condensed with formaldehyde or acetaldehyde respectively, the operation of condensation being carried out either in the absence of a solvent or in the presence of a solvent, to obtain the required methylamine derivative which may then be reacted, if desired, with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said derivative.

23. Process according to Claim 22 wherein the solvent is benzene.

24. Process for preparing methylamine derivatives according to Claim 1 wherein Rj represents hydrogen and Rg represent propargyl, whereby a compound of the general formula: ch 3 -ch 2 -ch 2 \^ CH 3 -CH 2 -CH 2 - C-A ch 3 -ch 2 -ch 2 ^ wherein A represents the group NH-CO-C=CH or N=CH-C=CH is reduced: a) in an appropriate anhydrous medium with lithium aluminium hydride in the case where A represents NH-CO-C=CH b) in a solvent with sodium borohydride in the case where A represents N=CH-CH=CH 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.

25. Process according to Claim 24 wherein the appropriate medium is ethyl ether. 36 45732

26. Process according to Claim 24 wherein the solvent is methanol.

27. Process for preparing the methylamine derivative according to Claim 1 wherein Rj represents hydrogen and R 2 represents 2-hydroxyethyl, whereby ethylene oxide is reacted, in the presence of an appropriate catalyst, with 1,1-di-n-propyl-n-butylamine to obtain the required methylamine derivative which may then be treated with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said derivative.

28. Process according to Claim 27 wherein the catalyst is boron trifluoride.

29. Process according to Claim 27 wherein boron trifluoride is in the form of an etherate.

30. Process according to Claim 27 wherein the reaction is carried out at a temperature between 170° and 200°C.

31. Process for preparing the methylamine derivative according to Claim 1 wherein Rj and R 2 , which are identical, each represent 2-hydroxyethyl, whereby a molar equivalent of 1,1-di-n-propyl-n-butylamine is heated under pressure with two molar equivalents of ethylene oxide, this reaction being carried out in the presence of a strong acid and in an inert medium, to obtain the required compound of formula I which may then be treated with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said derivative.

32. Process according to Claim 31 wherein the reaction is carried out at a temperature between 40° and 80°C.

33. Process according to claim 31 wherein the 5 pressure is 3 bars.

34. Process according to Claim 31 wherein the strong acid is hydrochloric acid.

35. Process according to Claim 31 wherein the inert medium is methanol. 10

36. Process for preparing the methylamine derivative according to Claim 1 wherein R^ and Rg, taken together, represent -CHg-CHg-O-CHg-CHg- whereby 1,1-di-n-propyl-n-butylamine or an acid addition salt thereof is heated with di-(2-chloroethyl) oxide in 15 the presence of an alkaline agent, to obtain the required methylamine derivative which may be treated with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the V , said derivative. 2o

37. Process for preparing the methylamine derivative according to Claim 1 wherein R^ and Rg, taken together,, represent -CHg-CHg-O-CHg-CHg- whereby 2-N-morpholino-2-n-propyl-valeronitrile is reacted, in an anhydrous ether, with n-propyl magnesium bromide and 25 the complex so formed is hydrolized to obtain the required methylamine derivative which may then be treated with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt of the said derivative. - 38 I

38. 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 13.