GB1565021A - Pharmaceutical compositions containing alkylamine deratives - Google Patents

Abstract

The methylamine derivatives of general formula: <IMAGE> and their non-toxic addition salts, in which R represents n-propyl, isopropyl, isobutyl or allyl, are obtained by reducing the corresponding isocyanate by means of lithium aluminium hydride in an inert and anhydrous medium and then reacting the base obtained with an acid to produce a non-toxic addition salt.

Description

(54) PHARMACEUTICAL COMPOSITIONS CONTAINING ALKYLAMINE DERIVATIVES (71) We, LABAZ, of 39 Avenue Pierre ler de Serbie, F-75008 Paris, France, a French body corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to pharmacologically active derivatives of methylamine and their pharmaceutically acceptable acid addition salts and is concerned with the use of such compounds in the treatment of Parkinson's disease and the correction of extra- pyramidal disturbances provoked by neuroleptics.

In U.S. Patent No. 3,067,101, it is disclosed that the hypertension in humans can be controlled by the administration of chemical compounds represented by the general tormula:

or pharmaceutically acceptable add addition salts thereof, wherein R1 is a member of the group consisting of hydrogen, methyl, ethyl and propyl R2 is a member of the group consisting of alkyl and alkenyl radicals having from 1 to 7 carbon atoms, the sum of the carbon atoms in Rl and R2 being greater than 1, and R1 and R2 when taken together form a tetramethylene group; R, and R4 are alkyl groups having from 1 to 4 carbon atoms, the sum of the carbon atoms in R3 and R4 being less than 8; and R6 is a member of the group consisting of lower alkyl, lower alkenyl and lower alkynyl radicals having from 2 to 4 carbon atoms, the acetyl radical and the a-hydroxyethyl radical.

It has now been found that four particular methylamine derivatives falling within the very broad class of compounds defined by the foregoing general formula but not specifically disclosed in the said U.S. Patent are particularly effective in the treatment of Parkinson's disease and the correction of extra-pyramidal disturbances provoked by neuroleptics.

As a result of in vivo laboratory tests on animals, N,N-dimethyl-l,l-di-n-propyl- n-butylamine, N - ethyl - 1,1 - di n - propyl - n - butylamine, N-allyl-1,1-di-n propyl-n-butylamine and N - methyl - N - ethyl - 1,1 - di - n- propyl - n - butylamine as well as pharmaceutically acceptable acid addition salts thereof were quite unexpectedly found to present an inhibitory action on reserpine-induced and neuroleptic- induced catatonia and catalepsy and are therefore likely to provide therapeutically valuable agents for treating Parkinson's disease and for correcting extra-pyramidal disturbances provoked by neuroleptics.

These properties are very surprising because there is nothing in the above cited U.S. Patent which could even remotely suggest the particular activities which in the light of the present invention can be attributed to N,N-dimethyl-1,1-di-n-propyl-n- butylamine, N-ethyl-1,1-di-n-propyl-n-butylamine, N-allyl-l, l-di-n-propyl-n-butylamine and N-methyl-N-ethyl-1,1-di-n-propyl-n-butylamine as well as pharmaceutically acceptable acid addition salts thereof.

The four methylamine derivatives referred to above were even found to exhibit a more pronounced inhibitory action on reserpine-induced and neuroleptic-induced catatonia and catalepsy than other compounds included within the general formula of U.S.

Patent No. 3,067,101 such as N-isopropyl-1,1-di-n-propyl-n-butylamine and N,N-di- methyl-l-n-propyl-l-isobutyl-n-butylamin Further investigations have shown that methylamine derivatives having a chemical structure similar to that of N,N-dimethyl-1,1-di-n-propyl-n-butylamine, N-ethyl-l,l- di-n-propyl-n-butylamine, N-allyl-1,1-di-n-propyl-n-butylamine and N-methyl-N-ethyl- 1,1-di-n-propyl-n-butylamine but falling outside the scope of U.S. Patent No. 3,067,101 are also affective in the treatment of Parkinson's disease and the correction of extrapyramidal disturbances provoked by neuroleptics.

The four methylamine derivatives specified above as well as the other related methylamine derivatives referred to are defined by the general formula I given hereinafter.

Consequently, in accordance with the invention there is provided a pharmaceutical or veterinary composition comprising as an essential active ingredient, at least one methylamine derivative represented by the general formula:

or a pharmaceutically acceptable acid addition salt thereof, wherein R1 and R, each represent a hydrogen atom or a straight- or branched-chain alkyl radical containing from 1 to 3 carbon atoms, R3 represents a straight- or branched-chain alkyl, alkenyl or alkynyl radical containing from 3 to 7 carbon atoms and Am represents the radical:

in which, R4 represents hydrogen, methyl, a straight- or branched-chain alkynyl radical containing 2 to 5 carbon atoms or an -hydroxyalkyl radical containing from 2 to 5 carbon atoms, R represents methyl, ethyl, allyl, a straight- or branched-chain alkynyl radical having from 2 to 5 carbon atoms or an lo-hydroxyalkyl radical containing from 2 to 5 carbon atoms with the proviso that when R4 represents hydrogen and R5 represents ethyl or allyl or when R4 represents methyl and R, represents methyl or ethyl then, R2 represents n-propyl, Rz represents a straight- or branched-chain alkyl radical containing 4 or 5 carbon atoms or an w-hydroxyalkyl radical containing from 2 to 5 carbon atoms, R7 represents a straight- or branched-chain alkyl, alkenyl or alkynyl radical con taining from 1 to 5 carbon atoms or an -hydroxyalkyl radical containing from 2 to 5 carbon atoms, or R6 and R7 when they are taken together represent an ethylene, trimethylene, pentamethylene or hexamethylene radical, an alkylidene radical containing from 1 to 5 carbon atoms or the radical ZH2 < H2+CH2 < Hn, Rl, R2 and R, being such that the trisubstituted methylamine radical possesses no more than 13 carbon atoms, in association with an appropriate pharma ceutical carrier or excipient therefor other than ordinary tap water or a common organic solvent.

The pharmaceutically acceptable acid addition salts of the compounds of formula I can be 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, it desired, at appropriate stages by methods known to those skilled in the art to obtain the respective individual isomers.

A preferred class of compounds of formula I can be represented by the following general formula:

wherein R'2 represents n-propyl, isopropyl, isobutyl or allyl, R'4 represents hydrogen, methyl, propargyl or 2-hydroxyethyl, R'6 represents methyl, ethyl, allyl, propargyl, 2-hydroxyethyl or 3-hydroxypropyl or R'4 and R', when they are taken together, represent a methylene, ethylene, trimethylene ethylidene or the radical KH2KH24KH2KH2 with the provisos that when R'4 represents methyl and Rts represents methyl or ethyl or when R'4 represents hydrogen and R'6 represents ethyl or allyl then R'2 represents n-propyl and pharmaceutically acceptable acid addition salts thereof.

The pharmaceutical or veterinary composition of the invention will normally be administered in the form of 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.

In accordance with another aspect of the present invention there is provided a method of treating Parkinson's disease and of correcting extra-pyramidal disturbances provoked by neuroleptics in a non-human subject, which method comprises the administration at an effective dose to the subject so affected of at least one compound of formula I or a pharmaceutically acceptable acid addition salt thereof.

Daily dosage will preferably be between 10 and 60 mg of active principle for a human being weighing 60 kg.

The compounds of general formula I above, can be prepared by different procedures in aocordance with their chemical structure: Thus, the compounds of formula I wherein Rl, R2 and R3 have the meaning given therein, Rr represents hydrogen, methyl or an alkynyl radical, R, represents methyl, ethyl, allyl or an alkynyl radical, RG represents an alkyl radical and R7 represents an alkyl, alkenyl or alkynyl radical, can be prepared by heating, in the presence of an alkaline agent, such as for example, sodium bicarbonate, an amine of the general formula:

or an acid addition salt thereof, such as for example, the hydrochloride, in which R1, R2 and R, have the same meaning as in formula I and R8 represents hydrogen, methyl, an alkyl radical having 4 or 5 carbon atoms or an alkynyl radical having from 2 to 5 carbon atoms, with an appropriate quantity of an halide of the general formula: EUX III wherein Re represents a branched- or straight-chain alkyl, alkenyl or alkynyl radical having from 1 to 5 carbon atoms and X represents chlorine, bromine or iodine, 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.

In accordance with known chemical procedures and when it is desired to obtain a compound of formula I having two identical substituents on the nitrogen atom, the appropriate compound of formula II i.e. a compound of formula II wherein RX, Re and Re have the desired meaning and Re represents hydrogen, is treated so that two molar equivalents of the halide of formula III react with one molar equivalent of the compound of formula II.

Likewise, when it is desired to obtain a compound of formula I having a hydrogen atom on the nitrogen atom, the appropriate compound of formula II i.e. a compound of formula II wherein Re, Ra and Ra have the desired meaning and Ra represents hydrogen is treated so that one molar equivalent of the halide of formula III, reacts with one molar equivalent of the compound of formula II.

It is well known that when a compound of formula I which is mono-substituted on the nitrogen atom is desired, there will be obtained a mixture containing, in addition to the desired monosubstitutod compound, a certain proportion of the corresponding compound of formula I which is disubstituted on the nitrogen atom, even when the molar equivalents indicated above are employed.

Similarly, a certain amount of compound mono-substituted on the nitrogen atom will be formed when the corresponding compound di-substituted on the nitrogen atom is desired.

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 compounds of formula I in which Re represents hydrogen and Re represents an -hydroxyalkyl radical or wherein R7 represents an alkyl, alkenyl or alkynyl radical or an # hydroxyaLkyl radical and Re represents an w-hydroxyaLkyl radical 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:

wherein Re, Re and Ra have the same meaning as in formula I, R1o represents a straight- or branched-chain alkyl radical having from 1 to 4 carbon atoms, n represents 0, 1, 2 or 3 and Raa represents hydrogen, a branched- or straight-chain alkyl, alkenyl or alkynyl radical having from 1 to 5 carbon atoms or a radical of the formula CH,--(CH,),,-COR,, wherein n represents 09 1, 2 or 3 and Rlo has the same meaning as given above, to obtain the desired compound of formula I.

The compounds of formula I wherein Re, Ra and Raa have the meaning given therein and Re and Ra, when they are taken together, represent an ethylene, trimethylene, pentamethylene or hexamethylene radical or the radical -CH2-CH2-O-CH2-CH2- 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:

in which Re, Re and Ra have the same meaning as in formula I, m represents 4 1, 3 or 4 and Rlz represents hydrogen or the radical CH2CH2OH, with the proviso that when Re represents CHH,OH, m represents 0, which provides the desired compound of formula I.

When R,, represents hydrogen, the compound of formula V 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 chloro sulphonic 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 accordance with the structure of the compound of formula V. For example, chlorosulphonic acid or triphenylphosphine bromide can be used when in the compound of formula V Re, Re and Ra each represent an alkyl radical and RIO represents hydrogen. Similarly, phosphoric anhydride could be used, for example with a compound of formula V wherein Re, R and Re each represent an alkyl radical, R,, represents the radical CH2HaOH and m represents 0.

The compounds of formula I wherein Ra, Ra and Era have the meaning given therein and Re and R,, when they are taken together, represent an alkylidene radical having from 1 to 5 carbon atoms can be obtained by condensing a methylamine derivative of the general formula:

wherein Re, Re and Re have the same meaning as in formula I, with an aldehyde or a ketone of the general formula:

wherein Re, represents hydrogen or a straight- or branched-chain alkyl, alkenyl or alkynyl radical, having from 1 to 4 carbon atoms and Rl represents hydrogen or a straight- or branched-chain alkyl, alkenyl or alkynyl radical having from 1 to 4 carbon atoms, 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.

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 the preparation of the whole of the methylamine derivatives covered by the invention.

For example, the compounds of formula I wherein Re, Ra and Re have the meaning cited therein, Re represents hydrogen and Re represents methyl, can also be prepared by reducing, with lithium aluminium hydride, an isocyanate of the general formula:

wherein Re, Ra and Re have the same meaning as in formula I to provide the required methylamine derivative of formula I.

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

Likewise, the compounds of formula I in which Re, R2 and Ra have the meaning cited therein, Re represents hydrogen and R, represents methyl or alkynyl radical can be prepared starting with a compound of the general formula:

wherein Ra, Ra and Ra have the meaning given in formula I and A represents the group NHCOR1\5 or N=CH-Raa in which R15 represents hydrogen or an alkynyl radical having from 1 to 4 carbon atoms 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-CO-R1.5 b) in a solvent such as for example methanol, with sodium borohydride in the case where A represents N=CHRls to provide the required compound of formula I.

The compounds of formula I wherein Rl, R2 and R, have the meaning cited therein, Rt represents methyl, Ra represents methyl or wherein R, represents an alkyl radical and R, represents methyl can also be obtained by heating a methylamine derivative of the general formula:

or an acid addition salt thereof, for example the hydrochloride, wherein Ra, R2 and R, have the same meaning as in formula I and R16 represents hydrogen, methyl, or a straight- or branched-chain alkyl radical having 4 or 5 carbon atoms, in the presence of formic aldehyde and formic acid to give the desired compound of formula I.

On the other hand, the compounds of formula I wherein Ra, R, and Ra have the meaning cited therein, R represents hydrogen and R5 represents 2-hydroxyethyl can be obtained by reacting ethylene oxide with a methylamine derivative of general formula VI, 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.

The reaction in question will be effected by heating the reagents, preferably at a temperature between 1700 and 200 C.

The compounds of formula I wherein R1, R2 and Ra have the meaning cited therein and R4 and Ra, which are identical, each represent an , > hydroxyalkyl radical can also be prepared by reacting under pressure a molar equivalent of a methylamine derivative of the general formula VI with two molar equivalents of an alkylene oxide of the general formula

wherein R17 represents hydrogen or an alkyl radical having from 1 to 3 carbon atoms, 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 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 the said compound.

The reaction in question will be effected by heating the reagents, for example at a temperature between 400 and 80 C, preferably at 50 C and under pressure of 3 bars.

Likewise, the compounds of formula I wherein Rl, R2 and Ra have the meaning cited therein and R and R,, when they are taken together, represent the radical -CH2-CH2-OCH2-CH2- can can be prepared following other procedures than those mentioned hereabove namely: a) by heating a methylamine derivative of formula VI 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, or b) by reacting in an anhydrous ether, such as for example ethyl ether, a morpholine derivative of the general formula:

wherein R1, and Rls, which can be the same or different, each represent a straight- or branched-chain alkyl radical having from 3 to 6 carbon atoms with an organs magnesium derivative of the general formula: R2 Mg Br XIII in which R2 has the same meaning as in formula I and further hydrolyzing the com plex so formed to provide the desired compound of formula I.

The compounds of formula I prepared in accordance with any one of the above cited processes can be reacted with an organic or inorganic acid so as to provide a pharmaceutically acceptable acid addition salt thereof.

Amongst the compounds of formula II, those wherein R8 represents hydrogen are in fact compounds represented by formula VI hereabove. These compounds are known products having been described together with their process of preparation in British Patent No. 1,467,739.

The other compounds of formula II, are in fact compounds of formula I for which several processes of preparation are described hereabove.

The compounds of formula IV 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, a methylamine derivative of the general formula:

wherein R, R2 and R3 have the same meaning as given above and R20 represents hydrogen or a branched- or straight-chain alkyl, alkenyl or alkynyl radical having from 1 to 5 carbon atoms with an appropriate quantity of a halogenated compound of the general formula: HalCH2 (CH2)nC02Rlo XV in which n and Rao have the same meaning as in formula IV and Hal represents chlorine, bromine or iodine which gives the desired compound of formula IV.

The compounds of formulae V, X and XIV are either compounds of formula I or compounds which can be obtained in accordance with a process described hereabove while the compounds of formula VIII are also known products having been described together with their process of preparation in British Patent No. 1,467,739.

The compounds of formula IX wherein A represents N=CH-Raa are in fact compounds of formula I for which a process of preparation is described hereabove while those in which A represents NH-C(#Ras can be prepared 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 a methylamine derivative of formula VI with a halide or an anhydride of the general formula:

in which R" has the same meaning as in formula IX and Raa represents an atom of chlorine, bromine or a radical O--COO-R,, wherein Rls has the same meaning as in formula IX, to provide the required compound.

The nitriles of formula XII can be obtained by reacting potassium cyanide with a mixture of morpholine hydrochloride and a ketone of the general formula:

in which R,S and R,g have the same meaning as in formula XII, the reaction being carried out in an appropriate medium, such as for example methanol.

As mentioned above, 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 neurolepticinduced 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.

Compounds which are tri-substituted on the methylamine moiety but not substituted on the nitrogen atom are already known as possessing central noradrenergic and cenual dopaminergic properties which are likely to be used in the treatment of Parkinson's disease and for the correction of extra-pyramidal disturbances provoked by neuroleptics.

Such compounds have been described in British Patent No. 1,467,739.

Likewise, it has been found that compounds which are di-substituted on the methylamine moiety but having no substitution on the nitrogen atom, such as l-n- propyl-n-butylamine, also possess the required qualities to be used as anti-parkinsonian agents.

However, the di-substituted these compounds 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 the case of some compounds of the invention 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-l,l-di-n-propyl-n-butylamine (Compound 1) N,N-dimethyl-l,l-di-n-propyl-n-butylannine (Compound 2) N,N-trimethylene-l,1-di-n-propyl-n-butylarnine (Compound 3) N-methyl-l-n-propyl-l-isopropyl-n-butylamine (Compound 4) N-rnethyl-l-n-propyl-l-isobuyl-n-butylamine (Compound 5) N-methyl- 1-n-propyl- 1-allyl-n-butylamine (Compound 6) N-ethyl-l,l-di-n-propyl-n-butylamine (Compound 7) N-allyl-l,l-di-n-propyl-n-butylamine (Compound 8) N-propargyl-l,1-di-n-propyl-n-butylamine (Compound 9) N-methyl-N-ethyl-l,l-di-n-propyl-n-butylamine (Compound 10) N,N-dipropargyl-l,l-di-n-propyl-n-butylamine (Compound 11) N,Nethylene-l,l-di-n-propyl-n-butylamine (Compound 12) N-methylene-l,l-di-n-propyl-n-butylamine (Compound 13) Nethylidene 1,Idi-n-propyl-n-butylamine (Compound 14) N-(2-hydroxyethyl)-1,1-di-n-propyl-n-butylarnine (Compound 15) N,N-bis-(2-hydroxyethyl)- 1, 1-:li-n-prnpyl-n-butylamine (Compound 16) NC3-hydroxy-n-propyl)-1,1-di-n-propyl-n-butylamine (Compound 17) N,N < 3-oxapentamethylene)-1,1 di-n-propyl-n-butylamine (Compound 18) I. Inhibition of reserpine-induced and neuroleptic-induced 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 abovecited British Patent.

TABLE I Dose administered Inhibition of reser Compound in mg/kg pine induced catatonia 1 6 4 2 6 4 3 6 4 4 6 4 5 6.5 3 6 5 2 7 6 2 8 6 2 9 6 1 10 6.5 2 11 15 2 12 6 2 13 5.5 4 14 6 4 15 13 3 16 15 1 17 14 2 18 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 Compound 3 is equal to 3.

2. Inhibition of neuroleptic-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 Dose adminstered Inhibition of neuro Compound in mg/kg leptic-induced catatonia 1 6 3 2 6 4 3 6 4 4 4 6 3 5 6.5 4 6 5 2 7 6 4 8 6 4 9 6 4 10 6.5 2 12 6 1 13 is 3 14 6 2 15 6.5 1 16 15 1 17 7 2 18 8 2 Amantadine 100 4 Complementary tests have shown that Compounds 2 and 3, at a dose as low as 3 mg/kg have an index of inhibition of neuroleptic-induced catatonia equal to 2 while Compound 12 at the dose of 12 mg/kg has an index equal to 3.

II. Acute toxicity The acute toxicity LD50 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 comZ parison with amantadine: Compound LDsn in mg/kg 1 100 3 65 4 > 150 6 170 7 100 8 130 9 > 150 10 > 120 11 > 150 12 > 150 13 > 150 14 120 15 150 17 140 18 250 Amantadine 1050 A comparison was made between the index LD50 ED20-30 of the compounds of the invention with the corresponding index of amantadine.

In this index, ED2o 30 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 9 > 25 12 > 25 15 23 18 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 LD50 EDloo was determined in comparison with amantadine.

The following results were registered: Compound Index 1 16.5 3 10.8 4 > 25 7 16.5 8 21 13 27 14 20 Amantadine 10 These results again show that the compounds of the present invention offer a greater safety margin than amantadine.

III. Determination of the inhibition of the monoamine oxidase For this purpose, the following test was performed: Two rats weighing 190 and 200 g respectively were sacrificed by decapitation. The livers were rapidly removed, cut in a hypertonic medium and pounded; the homogenate was purified by fractional centrifugation and the fraction of mitochondrias was collected.

The inhibition of the monoamine oxidase by the compound under study was measured by polarography.

Into the measuring cell, the following solutions were introduced: a) 1.1 ml of a 0.1 molar phosphate buffer-solution (pie=7.4) to which a 0.005 molar solution of potassium cyanide was added.

b) 0.01 ml or a 0.5 molar aqueous solution of the compound under study. The final concentration in this product in the cell was 0.00333 met c) 0.1 ml of the suspension of mitochondrias previously prepared namely 12.5 mg of protein.

Three minutes after this operation, the reaction was initiated by adding 0.2 ml of a 0.05 molar solution of serotoninecreatine sulphate in a phosphate buffer-solution, the final concentration in amine in the cell being 0.00666 mol.

The titer in mitochondrias was calculated in accordance with the method of Biuret, the bovine albumin being taken as the protein of reference. Similar tests were also undertaken with 0.02, 0.04, 0.06, 0.08 and 0.10 ml of the 0.5 molar solution of the compounds under study.

The following results show the percentage of inhibition of the monoamine oxidase by a compound of the invention in comparison with the inhibitory action of two methylamine derivatives unsubstituted on the nitrogen atom, these two derivatives being studied under the same conditions: TABLE l,l-di-n-propyl- N-methyl-l,l-di- l-n-propyl-k n,n-butylamine n-propyl-n M1 of butylamine hydro- butylamine inhibitor hydrochloride chloride hydrochloride 0.01 22 1.5 3 0.02 25 6 1.5 0.04 35.5 11.5 3 0.06 44 11.5 0 0.08 48 14.5 0 0.10 54 14.5 3 These results show that the inhibitory action on the monoamine oxidase is very marked in the case of l-n-propyl-n-butylamine hydrochloride, weak in the case of l,l-di-n-propyl-n-butylamine hydrochloride and practically nil in the case of N-methyl l,l-di-n-propyl-n-butylamine hydrochloride.

The following Examples 1 to 21 illustrate the preparation of compounds which may be employed in the invention, whilst Example 22 describes a pharmaceutical composition in accordance with the invention.

EXAMPLE 1 Preparation of N-methyl- 1, 1-di-n-propyl-n-butylamine hydrochloride a) N-Methyl- 1 ,1i-n-propyi-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 l,l-di-n-propyln-butylisocyanate in 20 ml of dry ether.

The operation of addition was carried out over a period of 30 minutes at roomtemperature 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-n-propyl-n-butylamine were obtained in the form of a colourless liquid.

B.P.: 84"C under 13 mm Hg.

Yield: 94% b) N-Methyl-1,1-di-n-propyl-n-butylamine hydrochloride By bubbling dry gaseous hydrogen chloride through the ethereal solution of the amine previously obtained, N-methyl-l,l-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 starting-products, the compound hereunder was prepared: Compound Melting point "C N-Methyl-l-n-propyl-1-isopropyl-n- butylamine hydrochloride 144--145 (Yield: 80%) EXAMPLE 2 Preparation of N-methyl-l,l-di-n-propyl-3-buten-1-ylamine fumarate First 1,1-di-n-propyl-3-buten-1-ylisocyanate was prepared by reacting bromine and 2,2-di-n-propyl-4-penten-1-ylamide in the presence of sodium hydroxide. The desired product was obtained in the form of a colourless liquid boiling at 7820C under 5 mm Hg. The isocyanate so obtained was then reduced by means of lithium aluminium hydride to provide without purification, N-methyl- 1,1 -di-n-propyl-3 -buten- 1-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 were washed with acetone and dried.

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

M.P.: 149 C Yield: 91% EXAMPLE 3 Preparation of N-methyl- 1-n-p ropyl- 1-isobutyl-n-butylamine hydrochloride a) N-Atthyl-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-1-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 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-propyl-l-isobutyl-n-butylamine were obtained in the form of a colourless liquid.

BY.: 860C under 12 man Hg Yield: 34% b) N-Methyl-l-n-propyl-l-isobutyl-n-butylamine hydrochloride In 150 mi 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-methyl-1-n-propyl-1-isobutyl-n-butylamine hydrochloride were obtained.

Yield: 61% AtP.: 139"C By following the same procedure as that described hereabove but using the appropriate starting-products, the compound hereunder was prepared: Compound MY. "C N-Methyl-l,l-di-n-propyl-n-butylamine hydrochloride 133-134 EXAMPLE 4 Preparation of N-ethylidene-l,l-di-n-propyl-n-butylamine Into a 25-ml twonecked flask, were introduced 7.9 g (0.05 mol) of l,l-di-n propyl-n-butylamine. To this product, 2.64 g (0.06 mol) of acetaldehyde were added dowry, 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-l,1-di-n-propyl-n-butylamine were obtained in the form of a colourless liquid.

B.P.: 87"C under 13 mm Hg Yield: 850/, EXAMPLE 5 Preparation of N-ethyl-1,1-di-n-propyl-n-butylamine hydrochloride a) N-Ethyl- 1, ldi-n-propyi-n-butylamine Into a 500-ml three-necked flask, fitted with a mechanical stirrer and a condenser, were introduced 17.6 g (0.096 mol) of N-ethylidene-1,1-di-n-propyl-n-butylamine, prepared as described hereabove, and 150 ml of methanol. To this solution when cooled, 7.6 g (0.2 mol) of sodium borohydride were added slowly and while stirring.

After this operation, the mixture was maintained at a temperature of 5"C for 30 minutes and then progressively heated under reflux. Thirty minutes later, the methanol was evaporated off under vacuum and 200 ml of water were added to the residue so obtained followed by 100 ml of a solution of sodium hydroxide (di=1.38). The organic fraction was extracted with ether and the solution was distilled under reduced pressure.

In this manner, 11.8 g of N-ethyl-l,l-di-n-propyl-n-butylamine were collected in the form of a colourless liquid.

B.P.: 8081 C under 11 to 12 mm Hg Yield: 69% b) N-Ethyl-l,l-di-n-propyl-n-butylamine hydrochloride By bubbling dry gaseous hydrogen chloride through an ethereal solution of the amine previously prepared, N-ethyl-l,lZi-n-propyl-n-butylamine hydrochloride precipitated.

M.P.: 19(1910C Quantitative yield.

EXAMPLE 6 Preparation of Nethyl-l,l-di-n-propyl-n-butylamine hydrochloride a) N-Acetyl-l, l-di-n-propyl-n-butylamine To a solution of 7.85 g (0.05 mol) of 1,1-di-n-propyl-n-butylamine in 5.3 g of pyridine, 3.9 g of acetyl chloride were slowly added. The mixture was heated to 80"C for 3 hours and then poured into 60 ml of iced water. The precipitate so obtained was separated out, washed with water and dried.

In this manner, 7 g of N-acetyl-l,l-di-n-propyl-n-butylamine were obtained after recrystallisation from heptane.

M.P.: 91"C Yield: 70%.

b) N-Ethyl-1, 1-di-n-propyi-n-butylamine hydrochloride To a suspension of 1.9 g of lithium aluminium hydride in 80 ml of butyl ether, were added, while stirring, 4 g (0.02 mol) of the N-acetylated derivative previously obtained, dissolved in 20 ml of butyl ether. The mixture was progressively heated under reflux which was maintained for 5 hours. After hydrolysis by adding ice, the ethereal fraction was separated out and washed twice with 70 ml of a 10%-hydro- chloric acid solution. From the aqueous fraction, the hydrochloride of the desired amine was extracted with methylene chloride and the solution evaporated under vacuum.

In this manner, 3 g of N-ethyl-1,1 < Ii-n-propyl-n-butylamine hydrochloride were obtained in the form of colourless crystals.

PULP.: 19e191"C Yield: 67% By following the same procedure as that described hereabove but using the appropriate starting products, the compound hereunder was prepared: Compound M.P. "C N-Methyl-l,l-di-n-propyl-n-butylamine hydrochloride 133-134 EXAMPLE 7 Preparation of N-allyl-l,l-di-n-propyl-n-butylamine hydrochloride a) N-Anyl-1,1-di-n-proyl-n-butylamine A mixture constituted by 12.1 g of allyl bromide, 25 g of sodium bicarbonate, 250 ml of ethanol and 19.35 g (0.1 mol) of l,l-di-n-propyl-n-butylamine hydrochloride was refluxed for 48 hours. After separation of the insoluble fraction, the ethanol was evaporated out under vacuum and the oil so obtained was treated with 50 ml of a 10%-sodium hydroxide solution and 200 ml of ether. The organic phase was separated out and distilled under reduced pressure.

In this manner, 9 g of N-allyl-1,1-di-n-propyl-n-butylamine were obtained in the form of a slightly coloured liquid.

B.P.: 116"C under 20 mm Hg Yield: 89% b) N-Allyl-l,l-di-n-propyl-n-butylamine hydrochloride By bubbling dry gaseous hydrogen chloride through an ethereal solution of the amine so prepared, the desired hydrochloride was precipitated and then filtered out and dried.

In this manner, N-allyl-l,l-di-n-propyl-n-butylamine hydrochloride was obtained in the form of colourless crystals.

AtP.: 194--195"C Quantitative yield.

EXAMPLE 8 Preparation of N-propargyl-l, l-di-n-propyl-n-butylamine hydrochloride a) N-Propargyl-l,lZi-n-propyl-n-butylamine Over a period of 48 hours, a mixture constituted by 11.9 g (0.1 mol) of propargyl bromide, 25 g of sodium bicarbonate, 250 ml of ethanol and 19.7 g (0.1 mol) of l,l-di- n-propyl-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-l,l-di-n-propyl-n-butylamine were isolated in the form of a pale yellow liquid.

B.P.: P4--96"C under 5 mm Hg Yield: 51% b) N-Propargyl-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-l,l-di-n-propyl-n-butylamine hydrochloride was obtained in the form of crystals.

M.P.: 15A 155"C Quantitative yield.

By following the same procedure as that described hereabove but using the appropriate starting-products, the compound hereunder was prepared: Compound M.P. "C N-Methyl-l,lZi-n-propyl-n-butylamine hydrochloride 133-134 EXAMPLE 9 Preparation of N,N-dipropargyl-l,l-di-n-propyl-n-butylamine hydrochloride a) N,N-Dipropargyl-l,l-di-n-propyl-n-butylamine By continuing the distillation operation commenced in the above Example 10 a) with a view to obtaining N-propargyl-l,l-di-n-propyl-n-butylamine, the corresponding N,N-dipropargyl derivative was isolated.

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

B.P.: 1200C under 5 ram Hg Yield: 13% b) N,N-Dipropargyl-1, 1 -di-n-propyl-n-butylamine hydrochloride By bubbling dry gaseous hydrogen chloride through an ethereal solution of the amine thus obtained, the desired hydrochloride was precipitated.

In this manner, N,N-dipropargyl-l,l-di-n-propyl-n-butylamine hydrochloride was obtained in the form of colourless crystals.

M.P.: 177"C (decomposition) By following the same procedure as that described above but using the appropriate starting-products, the compound hereunder was prepared: Compound M.P. "C N,N-Dimethyl-l,1-di-n-propyl-n-butylamine hydrochloride 228-229 EXAMPLE 10 Preparation of N,N-dimethyl-l,l-di-n-propyl-n-butylamine hydrochloride a) N,N-Dimethyl-l,l-di-n-propyl-n-butylamine Over a period of 6 hours, 40 mi of a 30%-solution of formic aldehyde and 15.7 g (0.01 mol) of l,l-di-n-propyl-n-butylamine, were heated under reflux. After this operation, 40 ml of nure formic acid were added and heating was maintained for 7 hours. After the solution was concentrated, the oil so obtained was treated with a diluted and iced solution of sodium hydroxide. The organic fraction was extracted with ether, dried over magnesium sulphate, concentrated under vacuum and distilled under reduced pressure.

In this manner, 16 g of N,N-dimethyl-l,l-di-n-propyl-n-butylamine were collected in the form of a colourless liquid.

B.P.: F97 C under 15 mm Hg Yield: 86 /O b) N,N-Dimethyl-l,lli-n-propyl-n-butylamine hydrochloride By bubbling gaseous dry hydrogen chloride through an ethereal solution of the amine previously obtained, the desired hydrochloride was precipitated.

In this manner, N,N-dimethyl-1, ldi-n-propyl-n-butylamine hydrochloride was obtained in the form of colourless crystals.

M.P.: 228--2299C (with sublimation) Quantitative yield.

EXAMPLE 11 Preparation of N-ethyl-N-methyl-l,ldi-n-propyl-n-butylarnine hydrochloride a) N-Ethyl-N-methyl-l,l-di-n-propyl-n-butylamine Over a period of 5 hours, a mixture of 11.3 g (0.061 mol) of N-ethyl-l,l-di-npropyl-n-butylamine, 10 ml of a 30%-aqueous solution of formic aldehyde and 9.4 ml of formic acid was refluxed. To the reaction medium was added 10 ml of concentrated and iced hydrochloric acid and the solution was then concentrated under vacuum. The oil so obtained was taken up with 100 ml of water and 30 ml of a concentrated sodium hydroxide solution. The organic fraction was extracted with ether and distilled under reduced pressure using a spinning band column.

In this manner, 10 g of N-ethyl-N-methyl-l,ldi-n-propyl-n-butylamine were isolated in the form of a colourless liquid.

B.P.: 92"C under 11 mm Hg Yield: 83% b) N-Ethyl-N-methyl-l,l-di-n-propyl-n-butylamine hydrochloride To a solution of 7 g (0.035 mol) of the amine in 100 ml of ethanol, were added 5 ml of concentrated hydrochloric acid. The solution was concentrated to dryness and the oil so obtained was taken up with 50 ml of isopropyl ether. The precipitate was separated out and dried under vacuum at 50"C in the presence of phosphoric anhydride and potassium hydroxide. The dry product so obtained was then recry stallized from 100 ml of methylethylketone.

In this manner, 5 g of Nethyl-N-methyl-l,lZi-n-propyl-n-butylamine hydro chloride were obtained in the form of colourless crystals which sublimated at about 20000.

Yield: 61% EXAMPLE 12 Preparation of N-(2-hydroxyethyl)-1,1-di-n-propyl-n-butylamine hydrochloride a) Ethyl 2-(1, 1 di-n-propyl-n-butylamino)-ethanoate Into a 50Sml three-necked flask fitted with a mechanical stirrer and a condenser, were introduced 23.6 g (0.15 mol) of l,l-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 bromoacetate 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 oil so obtained was distilled under reduced pressure.

In this manner, 22.9 g of ethyl 2-(1,1-di-n-propyl-n-butylamino)-ethanoate were obtained.

BY.: 9992 C under 0.3 mm Hg Yield: 63% b) N"(2-Hydroxyethyl)-l,l-di-n-propyl-n-butylamine To a suspension of 7.6 g (0.2 mol) of lithium aluminium hydride in 15 ml of ether, were added 22.8 g (0.0g4 mol) of ethyl 2-(l,l-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 solvent was evaporated off under vacuum.

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

Yield: 94% c) N-(2-Hydroxyethyl)-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 vaccum, 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,ldi-n-propyl-n-butylamine hydrochloride were obtained.

AtP.: 1570C Yield: 60% EXAMPLE 13 Preparation of N-(3-oxapentamethylene)-1,1-di-n-propyl-n-buwlamine hydrochloride or tri-n-propylmethylmorpholine hydrochloride a) N-(3-Oxapentamethylene)-l,l-di-n-propyl-n-butylamine Under vigorous stirring, a mixture of 39 g (0.25 mol) of l,l-dipropyl-n-butyl amine, 40 g of di-(2whloroethyl) 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 sulphate evaporated under vacuum and distilled under reduced pressure.

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 l,l-di-n-propyl-nbutylamine. After the methanol was eliminated under vacuum, the liquid so obtained was distilled.

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

B.P.: 97--98"C under 0.4 mm Hg Yield: 8201,0 b) N-(3-Hydroxy-n-propyl)-1, 1-di-n-propyl-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-n-propyl-n-butylamino)-propanoate, prepared as previously described.

The reaction medium was heated under reflux for 12 hours and then hydrolyzed. The 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-n-propyl)-1,1-di-n-propyl-n-butylamine were collected in the form of a colourless liquid.

B.P.: 107-1080C under 0.4 mm Hg Yield: 85% c) N-(3-Hydroxy-n-propy1)-1, l-di-n-propyl-n-butylamine 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. The precipitate which formed was separated out and recrystallized from 120 ml of ethyl acetate.

In this manner, 11.25 g of NK3-hydroxy-n-propyL)-1,1-di-n-propyl-n-butylamine hydrochloride were obtained.

M.P.: 121122 C Yield: 90% EXAMPLE 16 Preparation of N,N-trimethylene- 1, ldi-n-propyl-n-butylamine hydrochloride a) N,N-Trimethylene-l,l-di-n-propyl-n-butylarnine Into a 500oral 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 (0.07 mol) of bromine were added, drop bydrop and while stirring. After this operation, 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 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.

From 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,l-di-n-propyl-n-butylamine was obtained in the form of a colourless liquid.

B.P.: 112--115"C under 14 mm Hg Yield: 57% b) N,N-Trimethylene-1, 1 -di-n-propyl-n-b utylamine hydrochloride 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, N,N-trirnethylene-l,l-di-n-propyl-n-butylamine hydrochloride was obtained in the form of colourless crystals.

M.P.: 92--93"C Yield: 87 /ó EXAMPLE 17 Preparation of N-methylene-l,l-di-n-propyl-n-butylamine Into a l-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 l,l-di-n-propyl-n-butyl- amine. 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-l,l-di-n-propyl-n-butylamine were obtained in the form of a colourless liquid.

B.P.: 85"C under 13 mm Hg EXAMPLE 18 Preparation of N-(2-hydroxyethyl) - 1, 1-li-n-propyi-n-butylamine 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 l,l-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 oil-bath. After that, ethylene oxide was continuously bubbled through the reaction medium for 4 hours, care being taken to maintain the reaction temperature at 1800-2000C. The flask was cleared with nitrogen before cooling and the reaction mixture was acidified 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.

AtP.: 175"C EXAMPLE 19 Preparation of N,N-bis-(2-hydroxyethyl)- 1, 1-di-n-propyl-n- butylamine hydrochloride In an enamelled boml:-apparatus fitted with a dipthermometer, 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 l,l-di-n-propyl-n-butylamine. The bombXapparatus was closed, cleared with nitrogen and immersed in a water-bath thermostated at 500 + 20C (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 40%-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, suctionfiltered after 2 hours at - 50C 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% EXAMPLE 20 Preparation of N-(3-Oxapentamethylene)-l,l-di-n-propyl-n- butylamine hydrochloride a) N-2-Morpholino-2-n-propyl-valeronitrile 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-n-propyl-valeronitrile was obtained in the form of a colourless liquid.

Yield: 17% B.P.: 137-1400C (under 3.5 mm Hg) b) N-(3-Oxapentamethylene)-l,l-di-n-propyl-n-butylamine 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.

In this manner, N-(3-oxapentamethylenefl,l-di-n-propyl-n-butylamine was obtained.

Yield: 65 B.P.: 96 97^C (under 4 mm Hg) c) N-(3-Oxapentamethylene)-1,1-di-n-propyl-n-buylamine hydrochloride A solution of 4.5 g of N-(3-oxapentamethylene)-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)-1,1-di-n-propyl-n-butylamine hydro chloride was obtained.

Sublimation : between 140 and 150 C.

EXAMPLE 21 Preparation of N-(3-oxapentamethylene)-l, I-di-n-propyl-n-butylamine hydrochloride a) N-(3-Oxapentamethylenef lal-di-n-propyl-n-butylamine 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 5.6 g (0.04 mol) of phosphoric anhydride. The mixture was stirred with 20 ml of distilled water and then separated from the aqueous phase which was treated with a diluted solution of sodium hydroxide and further extracted with ether.

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

B.P.: 256"C (under 750 mm Hg) b) N-(3-Oxapentamethylene)-l,l-di-n-propyl-n-butylamine hydrochloride A solution of 4 g of Nd3-oxapentamethylene)-1,1-di-n-propyl-n-butylamine in 20 ml of isopropanol was treated with 2 ml of concentrated hydrochloric acid (d!=l.l9) and then 33 ml of isopropyl ether were added In this manner, N-(3oxapentamethylene)-1, 1di-n-propyl-n-butylamine hydro chloride was obtained which sublimated between 140 and 1500C.

EXAMPLE 22 A hard-gelatin capsule containing the following ingredients was prepared in accordance with known pharmaceutical techniques: Ingredients mg N-methyl-1, 1di-n-propyl-n-buty1amine hydrochloride 15 Milk sugar 50 65 Some of the methylamine derivatives embraced by general formula I are believed to be novel compounds.

Thus in our copending Application No. 18083/78 (Serial No. 1,565,022) there are described and claimed methylamine derivatives represented by the general formula:

and the pharmaceutically acceptable acid addition salts thereof, wherein R represents propyl, isopropyl, isobutyl or allyl, whilst in our copending Application No.

46520/78 (Serial No. 1,565,023) there are described and claimed methylamine derivatives represented by the general formula:

and the pharmaceutically acceptable acid addition salts thereof, wherein Re represents hydrogen, propargyl or 2-hydroxyethyl, Re represents propargyl, 2-hydroxyethyl or 3-hydroxy-n-propyl or Re and R,, when they are together, represent methylene, ethylene, trimethylene, ethylidene or CHaH,-OCHaCHHa- with the proviso that when Ra represents 3-hydroxy-n-propyl, then Re represents hydrogen.

WHAT WE CLAIM IS: 1. A pharmaceutical or veterinary composition comprising as an essential active ingredient at least one compound represented by the general formula:

or a pharmaceutically acceptable acid addition salt thereof, wherein Re and Re each represent a hydrogen atom or a straight- or branched-chain alkyl radical containing from 1 to 3 carbon atoms, Ra represents a straight- or branched-chain alkyl, alkenyl or alkynyl radical containing from 3 to 7 carbon atoms and Am represents the radical:

m wtuct, Re represents hydrogen, methyl, a straight- or branched-chain alkynyl radical containing 2 to 5 carbon atoms or an -hydroxyalkyl radical containing from 2 to 5 carbon atoms, Re represents methyl, ethyl, allyl, a straight- or branched-chain alkynyl radical having from 2 to 5 carbon atoms or an #-hydroxyalkyl radical containing from 2 to 5 carbon atoms with the proviso that when Re represents hydrogen and Re represents ethyl or allyl or when Re represents methyl and Ra represents methyl or ethyl then Re represents n-propyl, Re represents a straight- or branched-chain alkyl radical containing 4 or 5 carbon atoms or an w-hydroxyalkyl radical containing from 2 to 5 carbon atoms, R, represents a straight- or branched-chain alkyl, alkenyl or alkynyl radical containing from 1 to 5 carbon atoms or an -hydroxyalkyl radical containing from 2 to 5 carbon atoms, or R, and Re, when they are taken together, represent an ethylene, trimethylene, pentamethylene or hexamethylene radical, an alkylidene radical containing from 1 to 5 carbon atoms or the radical

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (20)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   Some of the methylamine derivatives embraced by general formula I are believed to be novel compounds.

   Thus in our copending Application No. 18083/78 (Serial No. 1,565,022) there are described and claimed methylamine derivatives represented by the general formula:

   and the pharmaceutically acceptable acid addition salts thereof, wherein R represents propyl, isopropyl, isobutyl or allyl, whilst in our copending Application No.

   46520/78 (Serial No. 1,565,023) there are described and claimed methylamine derivatives represented by the general formula:

   and the pharmaceutically acceptable acid addition salts thereof, wherein Re represents hydrogen, propargyl or 2-hydroxyethyl, Re represents propargyl, 2-hydroxyethyl or 3-hydroxy-n-propyl or Re and R,, when they are together, represent methylene, ethylene, trimethylene, ethylidene or CHaH,-OCHaCHHa- with the proviso that when Ra represents 3-hydroxy-n-propyl, then Re represents hydrogen.

   WHAT WE CLAIM IS: 1. A pharmaceutical or veterinary composition comprising as an essential active ingredient at least one compound represented by the general formula:

   or a pharmaceutically acceptable acid addition salt thereof, wherein Re and Re each represent a hydrogen atom or a straight- or branched-chain alkyl radical containing from 1 to 3 carbon atoms, Ra represents a straight- or branched-chain alkyl, alkenyl or alkynyl radical containing from 3 to 7 carbon atoms and Am represents the radical:

   m wtuct, Re represents hydrogen, methyl, a straight- or branched-chain alkynyl radical containing 2 to 5 carbon atoms or an -hydroxyalkyl radical containing from 2 to 5 carbon atoms, Re represents methyl, ethyl, allyl, a straight- or branched-chain alkynyl radical having from 2 to 5 carbon atoms or an #-hydroxyalkyl radical containing from 2 to 5 carbon atoms with the proviso that when Re represents hydrogen and Re represents ethyl or allyl or when Re represents methyl and Ra represents methyl or ethyl then Re represents n-propyl, Re represents a straight- or branched-chain alkyl radical containing 4 or 5 carbon atoms or an w-hydroxyalkyl radical containing from 2 to 5 carbon atoms, R, represents a straight- or branched-chain alkyl, alkenyl or alkynyl radical containing from 1 to 5 carbon atoms or an -hydroxyalkyl radical containing from 2 to 5 carbon atoms, or R, and Re, when they are taken together, represent an ethylene, trimethylene, pentamethylene or hexamethylene radical, an alkylidene radical containing from 1 to 5 carbon atoms or the radical

   -CH,-CH,-O-CH,-CHL-, Ra, Ra and Ra being such that the trisub stituted methylamine radical possesses no more than 13 carbon atoms, in association with a pharmaceutical carrier or excipient therefor other than ordinary tap water or a common organic solvent.
2. 2. A pharmaceutical or veterinary composition comprising as an essential active ingredient at least one compound represented by the general formula:

   or a pharmaceutically acceptable acid addition salt thereof, wherein R'2 represents n-propyl, isopropyl, isobutyl or allyl, R'4 represents hydrogen, methyl, propargyl or 2-hydroxyethyl, R'5 represents methyl, ethyl, allyl, propargyl,2-hydroxyethyl or 3hydroxypropyl or R'4 and R'5, when they are taken together, represent a methylene, ethylene, trimethylene, ethylidene or the radical Ha-C1IaO#HaHa with the provisos that when R'4 represents methyl and R', represents methyl or ethyl or when R'4 represents hydrogen and R'5 represents ethyl or allyl then R', represents n-propyl, in association with a pharmaceutical carrier or excipient therefor other than ordinary tap water or a common organic solvent.
3. 3. A pharmaceutical or veterinary composition comprising as an essential active ingredient N,N-dimethyl-l,l-di-n-propyl-n-butylamine or pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or excipient therefor other than ordinary tap water or a common organic solvent.
4. 4. A pharmaceutical or veterinary composition comprising as an essential active ingredient Methyl-1,1-di-n-propyl-n-butylamine or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or excipient therefor other than ordinary tap water or a common organic solvent.
5. 5. A pharmaceutical or veterinary composition comprising as an essential active ingredient N-allyl-1,1-di-n-propyl-n-butylamine or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or excipient therefor other than ordinary tap water or a common organic solvent
6. 6. A pharmaceutical or veterinary composition comprising as an essential active ingredient N-methyl-N-ethyl-l,l-di-n-propyl-n-butylamine or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or excipient therefor other than ordinary tap water or a common organic solvent.
7. 7. A pharmaceutical or veterinary composition comprising as an essential active ingredient N,N-trimethylene-l,l-di-n-propyl-n-butylarnine or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or excipient therefor other than ordinary tap water or a common organic solvent.
8. 8. A pharmaceutical or veterinary composition comprising as an essential active ingredient N-methyl-l,l-di-n-propyl-n-butylamine or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or excipient therefor other than ordinary tap water or a common organic solvent.
9. 9. A pharmaceutical or veterinary composition comprising as an essential active ingredient N-methyl-l-n-propyl-l-isopropyl-n-butylamine or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or excipient therefor other than ordinary tap water or a common organic solvent.
10. 10. A pharmaceutical or veterinary composition comprising as an essential active ingredient N-methyl-1-n-propyl-1-isobutyl-n-butylamine or a pharmaceutically acceptable addition salt thereof, in association with a pharmaceutical carrier or excipient therefor other than ordinary tap water or a common organic solvent.
11. 11. A pharmaceutical or veterinary composition comprising as an essential active.

    ingredient N-methylene-l,l-di-n-propyi-n-butylamine or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or excipient therefor other than ordinary tap water or a common organic solvent.
12. 12. A pharraaceutical or veterinary composition comprising as an essential active ingredient N-ethylidene-l,l-di-n-propyl-n-butylamin or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or excipient therefor other than ordinary tap water or a common organic solvent.
13. 13. A pharmaceutical or veterinary composition as claimed in any preceding claim wherein the pharmaceutically acceptable acid addition salt is the hydrochloride or the fumarate.
14. 14. A composition as claimed in any preceding claim wherein the composition is in a dosage unit form.
15. 15. A composition as claimed in Claim 14, wherein the dosage unit is in a form intended for oral administration.
16. 16. A composition as claimed in Claim 14, wherein the dosage unit is in a form intended for parenteral administration.
17. 17. A composition as claimed in Claim 14, wherein the dosage unit is in a form intended for rectal administration.
18. 18. A pharmaceutical composition substantially as described in the foregoing Example 22.
19. 19. A method of treating Parkinson's disease or of correcting extra-pyramidal disturbances provoked by neuroleptics in a non-human subject in the need of such treatment, comprising the administration to said non-human subject of an effective dose of at least one compound or salt as claimed in Claim 1.
20. 20. A method of treating Parkinson's disease or of correcting extra.pyramidal disturbances provoked by neuroleptics in a non-human subject in need of such treatment, comprising the administration to said non-human subject of an effective dose of at least one compound or a pharmaceutically acceptable acid addition salt thereof, the said compound being selected from N,N-dimethyl-l,l-di-n-propyl-n-butylamine, N-ethyl-l,l-di-n-propyl-n-butylamine, N-allyl-1,1-di-n-propyl-n-butylamine, N-methyl Nethyl-l,l-di-n-propyl-n-butylamine, N,N - trimethylene - 1,1 - di - n - propyl - n butylamine, N - methyl - 1,1 - di - n - propyl - n - butylamine, N-methyl-1-n-propyl- 1-isopropyl-n-butylamine, N-methyl-l-n-propyl-l-isobutyl-n-butylamine, N-methylene 1, 1-di-n-propyl-n-butylarine and N-ethylidene-l,l-di-n-propym-butylamine