CA1078837A - Active derivatives of methylamine, therapeutic compositions containing the same and processes for preparing the said derivatives and compositions - Google Patents
Active derivatives of methylamine, therapeutic compositions containing the same and processes for preparing the said derivatives and compositionsInfo
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- CA1078837A CA1078837A CA338,050A CA338050A CA1078837A CA 1078837 A CA1078837 A CA 1078837A CA 338050 A CA338050 A CA 338050A CA 1078837 A CA1078837 A CA 1078837A
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- butylamine
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Abstract
ABSTRACT OF THE DISCLOSURE:
n-Butylamine derivatives having the general formula:
I
and the pharmaceutically acceptable acid addition salts thereof wherein R4 represents hydrogen, propargyl or 2-hydroxyethyl, R5 represents methyl, propargyl, 2-hydroxyethyl, 3-hydroxy-n-propyl or R4 and R5, when they are taken together, represent methylene, ethylene, trimethylene, ethylidene or -CH2-CH2-O-CH2-CH2- and R2 is such that :
- when R4 repsesents hydrogen and R5 represents methyl, R2 represents n-propyl, isopropyl, isobutyl or allyl - when R4 represents hydrogen and R5 represents propargyl, 2-hydroxyethyl or 3-hydroxy-n-propyl or when R4 and R5 are identical and each represent propargyl or 2-hydroxyethyl or when R4 and R5 are taken together and represent methylene, ethylene, trimethylene, ethylidene or -CH2-CH2-O-CH2-CH2-, then R2 represents n-propyl.
These derivatives present central noradrenergic and central dopaminergic properties which make them useful in treating Parkinson's desease as well as for correcting extra-pyramidal disturbances provoked by neuroleptics.
n-Butylamine derivatives having the general formula:
I
and the pharmaceutically acceptable acid addition salts thereof wherein R4 represents hydrogen, propargyl or 2-hydroxyethyl, R5 represents methyl, propargyl, 2-hydroxyethyl, 3-hydroxy-n-propyl or R4 and R5, when they are taken together, represent methylene, ethylene, trimethylene, ethylidene or -CH2-CH2-O-CH2-CH2- and R2 is such that :
- when R4 repsesents hydrogen and R5 represents methyl, R2 represents n-propyl, isopropyl, isobutyl or allyl - when R4 represents hydrogen and R5 represents propargyl, 2-hydroxyethyl or 3-hydroxy-n-propyl or when R4 and R5 are identical and each represent propargyl or 2-hydroxyethyl or when R4 and R5 are taken together and represent methylene, ethylene, trimethylene, ethylidene or -CH2-CH2-O-CH2-CH2-, then R2 represents n-propyl.
These derivatives present central noradrenergic and central dopaminergic properties which make them useful in treating Parkinson's desease as well as for correcting extra-pyramidal disturbances provoked by neuroleptics.
Description
10~7883~7 This application is a division of appllcation No 279,749 filed on June 2, 1977.
The pLesent invention relates to novel pharmacological-ly active derivatives of n-butylamine,to pharmaceutically acceptable acid addition salts thereof and to processes for preparing said derivatives.
The novel n-butylamine derivatives with which the invention is concerned are represented by the general formula:
CH3-CH2 CH2 R5 ~
wherein R4 represents hydrogen, propargyl or 2-hydroxyethyl, R5 represents methyl, propargyl, 2-hydroxyethyl, 3-hydroxy-n-propyl or R4 and R5, when they are taken ~gether, represent methylene, ethylene, trimethylene, ethylidene or -CH2-CH2-0-CH2-CH2- and R2 is such that:
- when R4 represents hydrogen and R5 represents methyl, R2 represents n-propyl, isopropyl, isobutyl or allyl - when R4 represents hydrogen and R5 represents propargyl,
The pLesent invention relates to novel pharmacological-ly active derivatives of n-butylamine,to pharmaceutically acceptable acid addition salts thereof and to processes for preparing said derivatives.
The novel n-butylamine derivatives with which the invention is concerned are represented by the general formula:
CH3-CH2 CH2 R5 ~
wherein R4 represents hydrogen, propargyl or 2-hydroxyethyl, R5 represents methyl, propargyl, 2-hydroxyethyl, 3-hydroxy-n-propyl or R4 and R5, when they are taken ~gether, represent methylene, ethylene, trimethylene, ethylidene or -CH2-CH2-0-CH2-CH2- and R2 is such that:
- when R4 represents hydrogen and R5 represents methyl, R2 represents n-propyl, isopropyl, isobutyl or allyl - when R4 represents hydrogen and R5 represents propargyl,
2-hydroxyethyl or 3-hydroxy-n-propyl or when R4 and R5 are identical and each represent propargyl or 2-hydroxyethyl or when R4 and R5 are taken together and represent methylene, ethylene, trimethylene, ethylidene or -CH2-CH2-0-CH2-CH2-, then R2 represents n-propyl.
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, hydrochlorid acid, or with an - organic acid in which the free carboxyl is attached to a saturated or unsaturated aliphatic radical, or an aromatic or aralkyl radical which may optionally contain a second carboxyl group such as, for example, fumaric acid.
.~ .
Depending on their chemical structure, the compounds of formula I possess one or more isomeric centres and thus can be produced as optical isomers, or mixtures of these isomers.
The mixtures of these isomers can be resolved, if desired, at appropriate stages by methods known to those skilled in the art to obtain the respective individual isomers.
The compounds of general formula I above, can be prepared by different procedures in accordance with thelr chemical structure:
Thus, the compounds of ~ormula I wherein R~ has the meaning given therein~R4 represents hydrogen and R5 represents methyl as well as N propargyl- and N,N-dipropargyl-l~ di-n-butylamines, 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 thereof, such as for example the hydro-chloride, in which R represents n-propyl, isopropyl, isobutyl or allyl when R7 represents hydrogen or`in which R represents n-propyl when R7 represents propargyl with an appropriate quantity of a halide of the general formula :
wherein R~ represents methyl or propargyl and X represents a chlorine, bromine or iodine atom, this reaction being undertaken either without any solvent or in the presence of a solvent, such as for example ethanol, to obtain the required compound of formula I which may then be reacted with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said compound.
In accordance with known procedures and when it is : .. . : ~ ~ .
desired to obtain N,N-dipropargyl~ di-n-propyl-n-butylamine, l,l-di-n-propyl-n-butylamine is treated so that two molar equivalents of propargyl halide react with one molar equivalent of l,l-di-n-propyl-n-butylamine.
Like~ise, when it is desired to obtain a compound of formula I having a hydrogen atom Qn the nitrogen atom, the appropriate compound of formula II wherein Rl has the desired meaning and R7 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 monosubstituted 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-sub-stituted on the nitrogen atom will be formed when the corres-ponding compound di-substituted on the nitrogen atom is desired Such mixture 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 N-~-hydroxyalkyl derivatives of formula I i.e. N-(2-hydroxyethyl)-, N,N-bis-(2-hydroxyethyl)-and N-(3-hydroxy-n-propyl)-l,l-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 :
. . .
71~1~37
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, hydrochlorid acid, or with an - organic acid in which the free carboxyl is attached to a saturated or unsaturated aliphatic radical, or an aromatic or aralkyl radical which may optionally contain a second carboxyl group such as, for example, fumaric acid.
.~ .
Depending on their chemical structure, the compounds of formula I possess one or more isomeric centres and thus can be produced as optical isomers, or mixtures of these isomers.
The mixtures of these isomers can be resolved, if desired, at appropriate stages by methods known to those skilled in the art to obtain the respective individual isomers.
The compounds of general formula I above, can be prepared by different procedures in accordance with thelr chemical structure:
Thus, the compounds of ~ormula I wherein R~ has the meaning given therein~R4 represents hydrogen and R5 represents methyl as well as N propargyl- and N,N-dipropargyl-l~ di-n-butylamines, 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 thereof, such as for example the hydro-chloride, in which R represents n-propyl, isopropyl, isobutyl or allyl when R7 represents hydrogen or`in which R represents n-propyl when R7 represents propargyl with an appropriate quantity of a halide of the general formula :
wherein R~ represents methyl or propargyl and X represents a chlorine, bromine or iodine atom, this reaction being undertaken either without any solvent or in the presence of a solvent, such as for example ethanol, to obtain the required compound of formula I which may then be reacted with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said compound.
In accordance with known procedures and when it is : .. . : ~ ~ .
desired to obtain N,N-dipropargyl~ di-n-propyl-n-butylamine, l,l-di-n-propyl-n-butylamine is treated so that two molar equivalents of propargyl halide react with one molar equivalent of l,l-di-n-propyl-n-butylamine.
Like~ise, when it is desired to obtain a compound of formula I having a hydrogen atom Qn the nitrogen atom, the appropriate compound of formula II wherein Rl has the desired meaning and R7 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 monosubstituted 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-sub-stituted on the nitrogen atom will be formed when the corres-ponding compound di-substituted on the nitrogen atom is desired Such mixture 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 N-~-hydroxyalkyl derivatives of formula I i.e. N-(2-hydroxyethyl)-, N,N-bis-(2-hydroxyethyl)-and N-(3-hydroxy-n-propyl)-l,l-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 :
. . .
71~1~37
3 2 2 \ / 2 ~ 2)n 2 9 CH3-CH2-CH2 / C-N \ IV
CH3-CH2-CH2 Rlo wherein Rg represents a straight- or branched-chain alkyl radical having Erom 1 to 4 carbon atoms, n represents 0 and 1 and Rlo represents hydrogen or 2-hydroxyethyl with the proviso that when Rlo 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 pharma-ceutically acceptable acid addition salt of the said compound.
The compounds of formula I wherein R2 has the meaning cited thereinl R4 represents hydrogen and R5 represents methyl can also be obtained by heating a n-butylamine derivative of the general formula :
CH3-CH2 CH2\
R7C-NHR15 X , .
CH3-C~2 CH2 or an acid addition salt thereofl for example the hydrochloride, :
wherein R2 has the same meaning as in formula I and Rl~ represents ~ .7n ~ ~ ~d~
hydrogen, in the presence of formic aldehyde and~-~a~L~_~xk5 to give the desired compound of formula I which can then be reacted with an organic or inorganic acid to provide a pharma-ceutically acceptable acid addition salt of this compound.
The compounds of formula I wherein R2 represents n-propyl and R4 and R5, when they are taken together, represent an ethylene, trimethylene of -CH2-CH2-0-CH2-CH2- radical, can be obtained in a solvent or in the absence of a solvent by reacting an appropriate cyclization agent with a n-butylamine ~
derivative of the general formula : :
CH3-CH2-CH2 \ / cH2-(CH2)m-CH20H
CH3-CH2-CH2/C-N~
CH3-CH2-CH2 Rll : , - , ., :' ' ' ~' .
in which Rll represents hydrogen or the radical CH2-CH20H
and m represents 0 or 1 with the proviso that when Rll represents CH2-CH20H, 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 pharmaceuticall~ acceptable acid addition salt of the said compound.
When Rll 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 chlorosulphonic acid, b) in a solvent such as for example acetonitrile or benzene, by means OL 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 cylization 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~Rg represents hydrogen.
Similarly, phosphoric anhydride could be used, for example with a compound of formula V wherein R11 represents the radical CH2-CH20H and m represents ~.
The compounds of formula I wherein R2 represents n-propyl and R4 and R5, when they are taken together, represent ~)7~337 a methylene or ethylidene radical can be obtained by condensing l,l-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 prcvide the desired compound of formula I which may then be reacted, if desired, with an organic or inorganic acid to provide a phar~aceutically acceptable acid addition salt.
A certain number of N-substituted n-butylamine deriva-tives 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 n-butylamine derivatives covered by the invention.
For example, the compounds of formula I wherein R2 has the meaning cited therein, R4 represents hydrogen and R5 represents methyl, can also be prepared by reducing, with lithium aluminium hydride, an isocyanate of the general formula :
CH3--CH2 CH2 \
R2~ --C-N=C=OVIII
wherein R2 has the same meaning as in formula I to provide the required methylamine derivative oE formula I, which can further be treated with an organic or inorganic acid to give a pharma-ceutically acceptable acid addition salt~
The reduction in question can be effected in an inert and anhydrous medium such as for example ethyl ether.
Like wise, the compounds of formula I in which R2 has the meaning cited therein, R4 represents hydrogen and R5 represents methyl as well as N-propargyl-l,l-di-n-propyl-n-~78~3~7 butylamine can be prepared starting with a compound of the general formula :
CH3-CEI2-CH2\
wherein R2 has the meaning given in formula I and A represents the group NH-C0-R14 or N=CH-R14 in which R14 represents hydrogen or ethynyl and reducing this compound:
a) in an appropriate anhydrous medium, such as Eor example ethyl or butyl ether, with lithium aluminium hydride in the case where A represents NH-CO-R14 ~
b) in a solvent such as for example methanol, with sodium borohydride in the case where A represents 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~-1,1-di-n-propyl-n-bu~ylamine can be obtained by reacting ethylene oxide with l,l-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 inosganic acid to obtain a pharmaceutically acceptable acid addition salt of this compound.
The reaction in question will be effected by heating the reayents , preferably at a temperature between 171 and ~ : -200C.
N,N-bis-(2-hydroxyethyl)-1,1-di-n-butylamine can also be prepared by reacting under pressure a molar equivalent of :~
l,l-di-n-propyl-n-butylamine with two molar equivalents of ~)7~37 an ethylene oxide, this reaction being undertaken in the presenee of a strong acid, such as for example hydroehloric 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 aeid to obtain a pharma-ceuticall~ acceptable acid addition salt o the said compound.
The reaction in question will be effected by heating the reagents, for example at a temperature between 40 and 80C, preferably at 50C and under pressure of 3 bars.
1~ ~ikewise, N-~3-oxapentamethylene)-1,1-di-n-propyl-n-butylamine can be prepared fQllowing other procedures than that mentioned hereabove.
Thus, this eompound in question of formula I can also be obtained by heating l,l-di-n-propyl-n-butylamine or an acid addition salt thereof, for example the hydroehloride, with di-(2-ehloroethyl) oxide in the presence o an alkaline agent, sueh as for example sodium carbonate, to provide the desired compound of formula I which can further be reacted with an ~ organic or inorganie aeid ~ obtain a pharmaceutically accept-able aeid addition salt of this eompound.
Furthermore, N-(3-oxapentanemethylene)-1,1-di-n-propyl-n-butylamine ean also be obtained by reaeting, in an anhydrous ether, sueh as for example ethyl ether, 2-N-morpholino-2-n-propyl-valeronitrile with n-propyl magnesium bromide and further hydrolyzing the eomplex so formed to provide the desired compound of formula I which ean then be reaeted with an organie or inorganie aeid to obtain a pharmaceutically acceptable aeid addition salt of the said eompound.
Amongst the eompounds of formula II, those wherein R4 represents hydrogen are known produets having been deseribed together with their process of preparation in Canadian Patent N 1,056,730. -.
.. . , ".
.
~Im~7 The other compound of formula II, namely that wherein R4 represents propargyl is in fact a compound of formula I
for which several processes of preparation are described here-above.
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, l,l-di~n-propyl-n-butylamine or N-(2-hydroxyethyl)-l,l-di-n-propyl-n-butylamine with an appropriate quantity of a halogenated compound of the general formula :
Hal-cH2-(cH2)n-co2R9 XIV
in which R5 has the same meaning as in formula IV n represents 0 or 1 and Hal represents an atom of chlorine, bromine or iodine which gives the desired compound of formula IV.
Furthermore, the compounds of formula IV in which Rlo represents hydrogen and n represents 1 can also be prepared by heating in an inert medium, such as for example methanol, l,l-di-n-propyl-n-but~lamine with an acrylic acid ester of formula CH2=CH-C02Rg wherein Rg has the same meaning as in formula IV to obtain the desired compound.
The compounds of formula V are in fact co~pounds of formula I for which a process of preparation is described hereabove while the compounds of formula VIII are also known products having been described together with their prQCeSs of preparation in Canadian Patent N 1,056,730.
The compound of formula IX wherein A represents N=CH2 is in fact a compound of formula I for which a process of preparation is described hereabove. The other compound of formula IX wherein A represents N=CH-R14 can be prepared in accordance with the same procedure.
The compounds of formula IX wherein A represents NH-C0-R14 can be prepared either in the absence of a solvent , _ g _ . .
~'7~ill5137 or in a solven~, such as for example benzene and in the presence of an acid acceptor, such as Eor example pyridine or 2,6 dimethyl-pyridine, by reacting l,l-di-n-propyl-n-butylamine with a halide or an anhydride of the general formula:
R14-C0-Rlg in which R14 has the same meaning as in formula IX and Rlg represents an atom of chlorine, bromine or the radical 0-C0-R14 wherein R14 has the same meaning as in formula IX, to provide the required compound.
With respect to 2-N-morpholino-2-n-propyl-valeronitrile, this can be obtained b~ 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 n-butylamine deriva-tives 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 neurolepticinduced 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 chlolinolytic 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 .
- - .
g~ 78~3~7 :
disturbances provoked by neuroleptics.
Compounds which are tri-substituted on the butyl-amine moiety but not substituted on the nitrogen atom are already known as possessing central noradrenergic and central dopaminergic properties which are likely to be used in the treatment of Parkinson's disease and for the correction of extra-pyramidaldisturbancesprovoked by neuroleptics.
Such compounds have been described in Canadian Patent ~o 1,506,730. -Likewise, it has been found that compounds which are di-substituted on the butylamine moiety but having no substitution on the nitrogen atom, such as l-n-propyl-n-butyl-amine, also possess the required qualities to be used as anti-parkinsonian agents.
However, the di-substituted and tri-substituted derivatives of butylamine which are not substituted on the nitrogen atom in question exert, ~ various degrees, an inhibitory action on the monoamine oxidase.
In clinical use, this inhibitory action can manifest - itself by undesirable side-effects such as tachycardia, paroxystic hypotension and hypertension.
However, it has been discovered, very surprisingly, that at the same concentrations the compounds of the invention exert an inhibitory action on the monoamine oxidase which is much weaker than the inhibitory action presented by the di-and tri-substituted derivatives of methylamine cited hereabove, this inhibitory action being even nil in some cases.
This entirely unexpected advantage presented by the N-substituted derivatives of butylamine of the inven-tion ;~
- in comparison with the di- and tri-substituted derivatives of methylamine which are not substituted on the nitrogen atom is likely to render the compounds of the invention more advantageous ~ID781~37 than the derivatives which are unsubstituted on the nitrogen atom.
The compounds of the invention are also more advantage-ous than amantadine i.e. l-amino-adamantane, a product ~hich is widely used in the treatment of Parkinson's disease.
Although the pharmacological spectrum of the compounds of the invention is very similar to that o amantadine, pharmacological tr`ials performed with the compounds of the invention have revealed marked diferences in comparison with ;
amantadine. For example, when comparing the doses of the compounds of the invention and of amantadine which have a certain degree of activity, it has been observed that the active dose in question is always proportionally farther from the toxic dose in the case of the compounds of the invention than in the case of amantadine. In other words, the safety margin offered by the compounds of the invention is superior to that o amantadine.
The search for new antiparkinsonian agents is of primary importance since the treatment is of long duration and the alternating use of diferent products is necessary.
From this point o view, the compounds o the invention will constitute valuable additions to the available antiparkinsonian agents, since at present there is no ideal agent or the treatment of this disease as explained hereabove.
The N-substituted derivatives and N,N-substituted derivatives of the present invention which have shown the most valuable properties for constituting antiparkinsonian agents, are : -N-methyl-l,l-di-n-propyl-n-butylamine N,N-trimethylene-l,l-di-n-propyl-n-butylamine these compounds being used in the form of their free base or in these compounds being used in the form of their free - . : .
~ .
~V78837 base or in the form o~ a pharmaceutically acceptable acid a addition salt such as, for example, the hydrochloride or the ~umarate.
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 amantadien. These compounds were preEerably studied in the form o~ a pharmaceutically acceptable acid addition salt.
They are the following:
N-methyl~l,l-di-n-propyl-n-butylamine (Compound 1) N,N-trimethylene-l,l-di-n-propyl-n-butylamine(compound 2) N-methyl-l-n-propyl-l-isopropyl-n-butylamine (Compound 3) ~-N-methyl-l-n-propyl-l-isobutyl-n-butylamine (Compound 4) N-methyl-l-n-propyl-l-allyl-n-butylamine (Com~ound S) N-propargyl-l,l-di-n-propyl-n-butylamine ~Compound 6) N,N-dipropargyl-l,l-di-n-propyl-n-butylamine (Compound 7) N,N-ethylene-l,l-di-n-propyl-n-propyl-n-butylamine (Compound 8) N-methylene-l,l-di-n-propyl-n-butylamine (Compound 9) N-ethylidene-l,l-di-n-propyl-n-butylamine (Compound 10) N-(2-hydroxyethyl)-ljl-di-n-propyl-n-butylamine (Compound 11) N,N-bis-(2-hydroxyethyl)-1,1-di-n-propyl-n-butylamine (Compound 12) N-(3-hydroxy-n-propyl)-1,1-di-n-propyl-n-butylamine (Compound 13) N,N-(3-oxapentamethylene)-1,1-di-n-propyl-n-butylamine (Compound 14 I. Inhibition of reserpine-induced and neuroleptic-induced catatonia (dopaminergic properties) 1. Inhlbitlon of_reser~ine-lnduced catatonia The test undertaken for this purpose is identical to that described in Canadian Patent No 1,506,730 The results obtained with the compounds of the invention listed hereabove as well as with amantadine .
. : , ~ ~' 3l~7~3~37 are given in Table I hereunder.
These results are expressed according to the same scoring system, from 0 to 4, as that set out in the above-cited Canad1an Patent.
TABLE I
_ ~
Dose adminis- Inhibition of reserpine ~ ~ ;
" ' ~ ' ~' . ' ~" .
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 2 is equal`to 3.
2. Inhibition of neurole~tic-induced catatonia __________ ___ ______ _______________ ____ The test performed for this purpose is identical to . that described in Canadian Patent No 1,506,~30.
The results obtained with compounds listed above in ' comparison with amantadine are set out in the following .- 14 - . :
, , , , ,., , ~, .. , . . . , . . :
~71~337 Table II.
The scoring system was that used hereabove for Table.I.
TABLE I I
_ .
C d Dose adminis- Inhibition of neurolep-.
ompoun tered in mg/kg tic-induced catatonia 6 ; 3 ~- -10 ~L~i - I ~
.... ~ :
~
, Complementary tests have shown that Compounds 2 at a dose as low as 3 mg/kg have an index of inhibition of neuroleptic-induced catatonia equal to 2 while Compound 8 at the dose o 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 Canadian Patent No 1,056,730.
The following ~esults were recorded with compounds of the invention in comparison with amantadine:
. - 15 -.
: .
8~33'7 Compound LD50 in mg/kg 3 > 150 6 > 150 7 > 150 8 > 150 9 > 150 1~ 250 Amantadine 1050 A comparison was made between the index LD50 of the compounds of the invention with the corres-ponding index of amantadine.
In this index~ ED20-3o represents the effective dose to obtain 20 to 30% inhibition of the catatonla, this value being represented by the figure 1 in Tables I and II.
The following results ~ere registered:
Compound Index 6 `> 25 8 ~ 25 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 was determined in comparisOn with amantadine. D
The following results were registered:
Compound Index 1 16.5 2 10.8 3 > 25 10Amantadine 10 These results again show that the compounds of the present invention ofEer 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 (pH = 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 mol.
c) 0.1 ml of the suspension of mitochondrias previously prepared namely 12.5 mg of proteine.
Three minutes after this operation, the reaction was .
, )7~337 initiated by adding 0.2 ml of a 0.05 molar solution of serotonine-creatine 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 reerence.
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 10 compounds unde:r 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 o~ two methyl-amine.derivatives unsubstituted on the nitrogen atom, these two derivatives being studied under the same conditions:
TABLE
Ml of l-n-propyl-n- l,l-di-n-propyl- n-methyl-l,l-di-n-h-b t butylamine n-butylamine propyl-n-butylamine . ln 1 1 or hydrochloride hydrochloride hydrochloride . .
_ .
: 0.01 22 1.5 3 .02 25 6 1.5 0.04 35.5 11.5 .
. 0.06 44 11.5 0 0.08 48 14.5 0 .
0.1.0 54 14.5 3 i These results show that the inhibitory action on the mono-amine 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 hydro-- chloride.
.
, ' , .
~7~837 It Will be appreciated that ~or therapeutic use the compounds of the invention will normally be administered in the form of a pharmaceutical or veterinary composition in a dosage unit form appropriate to the required mode of administra-tion, the composition comprising as active ingredient a compound of the invention in association with a pharmaceutical carrier or excipient therefor. For oral administrationr 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 Erom 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.
The following Examples illustrate the preparation - of the compounds of the invention together with a suitable therea thereapeutic composition :
Preparation of N-methyl-l,l-di-n-propyl-n-butylamine hydro-- chloride a) N-Methyl-l~l-dl-n-propyl-n-butylamine ~)7~337 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 9 (0.02 mol) of l,l-di-n-propyl-n-butylisocyanate in 20 ml of dry ether.
The operation of addition was carried out over a period of 30 minutes at room-tempera-ture aEter which the reaction medium was heated under reflux for 3 hours. After hydrolysic 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 9 of N-methyl-l,l-di-n-propyl-n-butylamine were obtained in the form of a colourless liquid.
B.P. : 84C under 13 mm Hg.
Yield : 94~
b) N-Methyl-l,l-dl-n-~ro~yl-n-butylamine_hydrochlorlde 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. : 133-134C
Yield : 90~
By following the same procedure as that described hereabove but using the appropriate starting-products, the compound hereunder was prepared:
~ Melting point C
N-Methyl-l-n-propyl-l-isopropyl-n-butylamine hydrochloride 144-145 (Yield : 80~) Preparation of N-methyl-l,l-di-n-propyl-3-buten-1-ylamine fumarate .,:, . ~
: ................... . - . . : ~ .
71 3~3~
First 1,1-di-n-propyl-3-buten-1-ylisocyanate was prepared by reacting bromine and 2,2-di n-propyl-4-buten-1-ylamide in the presence of sodium hydroxide. The desired product was obtained in the form of a colourless liquid boiling at 79-82C
under 5 mm Hg. The 2,2-di-n-propyl-4-buten-1-~Ylamide so obtained was then reduced by means of lithium aluminium hydride to provide without purification, N-methyl-l,l-di-n-propyl-3-buten-l-ylamine in a yield of 89%.
To a solution of 2.32 g (0.02 mol) of fumaric acid in 400 ml of acetone, were added under stirring 3.38 g (0.02 mol) of the amine, prepared hereabove, dissolved in 30 ml of acetone.
Stirring was maintained for one hour after which the colourless crystals which precipitated were separated out.
They 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. : 149C
Yield : 91%
- Preparation of N-methyl-l-n-propyl-l-isobutyl-n-butYlamine hydrochloride a) N-Me_hyl-l-n-ero~yl-l-i_obutyl-n-butylamine ~n a one-litre three-necked flask, equipped with a condenser of the Dean Stark type, were placed 30 g (0.175 mol) of l-n-propyl-l-isobutyl-n-butylamine, 150 ml of 30%
formol and 400 ml of benzene. The mixture was refluxed for 5 hours so as to eliminate by azeotropic distillation about 100 ml of water. After evaporating the benzene under vacuum, the oil so obtained was taken up in 250 ml of methanol and, at a temperature of 10C, 13.3 g (0.35 mol) of sodium borohydride were added by small fractions. The ~ .
~7~337 temperature of the mixture was maintained at 10C 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, 200ml of distilled water and 100 ml of a concentrated solution of sodium hydroxide were addedO The organic ~raction 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-meth~l-l-n-propyl-l-isobutyl-n-butylamine were obtained in the form of a colourless liquid.
B.P. : 86C under 12 mm Hg Yield : 3~
b) N-Methyl-l-n-~roeyl-l-lsobutyl-n-butylamine hydrochloride In 150 ml of absolute ethanol, 10O4 g of the amine previously obtained were dissolved and the resulting solution was treated by means 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 llydrochloride crystallized when cold.
It was separated out and recrystallized ïn isopropyl ether~
In this manner, 7.5 g of N-methyl-l-n-propyl-l-isobutyl-n-butylamine hydrochloride were obtained.
Yield : 61%
M.P. : 139C
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 ~ 22 -~)7~7 Preparation of N-ethylidene-l,l-di-n-propyl-n-but~lamine Into a 25-ml two-necked 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 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-l,l-di-n--propyl-n-butylamine were obtained in the form of a colourless liquid.
B.P. : 78C under 13 mm Hg Yield : 85%
Preparation of N-methyl-l,l-di-n-propyl-n-butylamine hydro-chloride a) N-formyl-l,l-di-n-pro~yl-n-butylamine To a solution of 7.85 g (0.05 mol) of l,l-di-n-propyl-n-butylamine in 5.3 g of pyridine, 3.3 g of formyl chloride were slowly added. The mixture was heated to 80C 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, formyl-l,l-di-n-propyl-n-butylamine were obtained after recrystallization from heptane.
b) N-Methyl-l,l-di-n-~ro~yl-n-but~lamine hydrochloride _____ ___ _______ __ _______ ________ ___________ to a suspension of 1.9 g of lithium aluminium hydride 30in 80 ml of butyl ether, were added, while stirring, 3.7 g ~0.02 mol) of the N-formylated derivative previously obtained, dissolved in 20 ml-of butyl ether. The mixture was - 23 - ;~
. , ~
progressively heated under reElux 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~-hydrochloric 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, N-methyl-l,l-di-n-propyl-n-butylamine hydrochloride were obtained in the form of colourless crystals.
M.P. : 133~134C
Preparation of N-propargyl-l,l-di-n-propy~ -butylamine hydrochloride a) N-Pro~ar~yl-l~l-di-n-~ro~yl-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 ~0 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 9 of N-propargyl-l,l-di-n-propyl-n-butylamine were isolated in the form of a pale yellow liquid.
B.P. : 94-96C under 5 mm Hg Yield : 51%
b) N-Propargyl-lLl-di-n-propyl-n-butylamine hydrochloride _____ __ ___ _______ __ _______ ________ ___________ By bubbling dry and gaseous hydrochloric acid - through an ethereal solution of the amine so obtained, the .. ~ - .. . , -f~
~1~7~}~37 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. : 154 155C
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~ di-n-propyl-n-butylamine hydrochloride 133-134 Preparation of N,N-dipropar~y~ l-di-n-pr~pyl-n-butylamine hydrochloride a) NLN-Dl~ropar~yl-lLl-dl-n-2ro~yl-n-butylamine By continuing the distillation operation commenced in the above Example 6 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 9 of N,N-dipropargyl-l,l-di-n-propyl-n-butylamine were obtained in the form o~ a colourless liquid.
B.P. : 120C under 5 mm Hg Yield : 13%
b) NLN-Di~ropar~yl-l,l-dl-n-~ro~yl-n-butylam_ne 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. : 177C (decomposition) .. ., ' . .
`~
EXAMPL,E 8 Preparation o~ N-~2-hydroxyethyl)-1,1-di-n~propyl-n-butylamlne hydrochloride -a) Ethyl 2-(lLl-di-n-~ro~yl-n-butylamlnol-ethanoate Into a S00 ml 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 (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 Qut. The solution was concentrated and the oil so obtained was distilled undeL reduced pressure.
In this manner, 22.9 g of ethyl 2-(1,1-di-n-propyl-n-butylamine)-ethanoate were obtained.
B.P. : 90-92C under 0.3 mm Hg Yield : 63%
b) N-(2-Hydroxyethyl)-l,l-di-n-ero~yl-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 (0.094 mol~ of ethyl 2-(1,1-di-n-propyl-n-butylamino)-etha-noate dissolved in 5Q 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-hydroxyethyl)-1,1-di-n-propyl-n-butylamine were obtained.
Yield : 94%
c) N-(_-Hydroxyethyl~-lLl-di-n-~ro~yl-n-butylamine hydrochloride 30 - - 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 hvdrochloric acid. After the solven~ 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 o ethyl acetate.
In this manner, 2.7 g of N~ hydroxyethyl)-l,l-di-n-propyl-n-butylamine hydrochloride were obtained.
M.P. : 157C
Yield : 60 Preparation of N-(3-oxa~enta~eth~lene)-1,1-di-n-propyl-n-butylamine a) N-~3_0xa~entamethylenel-lLl-dl-n-pro~yl-n-butylamine Under vigorous stirring, a mixture of 39 g (0.25 mol) of l,l-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 sulphate evaporated under vacuum and distilled under reduced pressure.
In this manner, 25 g of N-(3-oxapentamethylene)~l,l-di-n-propyl-n-butylamine were collected in the form of colourless liquid.
B.P. : 105-106C (under 5 mm Hg) Yield : 44%
b) N-l3-OxapentamethyleneL-l l-di-n-eropyl-n-butylamine hydro-, __ _____ ________ __ _ __L____------ ---- -------------- ------chloride ________ 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 hydro-chloric acid (d = 1.19) and the desired hydrochloride was precipitated by adding 25 ml of isopropyl ether.
In this manner, N-(3-oxapentamethylene)-1,1-di-n-.
3~
propyl~n-butylamine hydrochloride was obtained in the form of brillant and colourless crystals which sublimated between 140 and 150C.
Yield : 80%
Preparation of N,N-ethylene-l,l-di-n-propyl-n butylamine In a 250~ml three~necked flask containing 15 g ~0.063 mol~ of N-(2-hydroxyethyl)-1,1-di-n propyl-n-butyl~
amine 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 80C and using a water pump, a partial vacuum was created in the flask. Under these conditions, heating was maintained at 80C for one hour and then, at atmospheric pressure the mixture wàs heated at 140C for 90 minutes. The viscous mixture was stirred for 12 hours with 100 ml of distilled water and then poured into a flask containing 300 ml of water and 100 ml of a sodium hydroxide solution. The mixture was then 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,l-di-n-propyl-n-butylamine were isolated in the form of a colourless liquid.
B.P. : 103 104C under 18 mm Hg Yield : 76~
_~earation of N-~3-hydroxy-n-propyl~-1,1-di-n~r~y~-n-butylamine hydrochloride '' . ' . . . ' ., '. ' ' : : :' : ', a) Methyl 3-~lLl-dl-n-ero~yl-n-butylaminol-~ro~anoate A solution of 28 . 4 g (O . 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-n-butyl-amine. After the methanol was eliminated under vacuum, the liquid so obtained was distilled.
In this manner, 61 9 of methyl 3-[1,1-di-n-propyl-n-butylamino)-propanoate were obtained.
B.P. : 97-98C under 0.4 mm Hg Yield : 82~
b) N-13-Hydroxy-n-~ro~yl~-lLl-di-n-~ro~yl-n-butylamlne Into a 500-ml three-necked flask itted with a me mechanical stirrer, a condenser and a dropping-~unnel 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-butyl-amino)-propanoatel 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 oE~ and the oil so obtained was distilled.
In this manner, 14.9 9 of N-(3-hydroxy-n-propyl)-l,l-di-n-propyl-n-butylamine were collected in the form of a colourless liquid.
B.P. : 107-108C under 0.4 mm Mg Yield : 85%
c) N-~3-Hydroxy-n-ero~ylL-l,l_dl_n_~ro~yl-n-butylamine hydroc_loride 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 concen-trated to dryness and the oil so obtained was taken up 83~
with 100 ml o~ 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-n-propyl)-l,l-di-n-propyl-n-butylamine hydrochloride were ~btained.
M.P. : 121-12~C
Yield : 90%
Preparation of N,N-trimethylene-l,l-di-n-propyl-n-butylamine hydrochloride a) N~N-Trimethylene-lLl-dl-n-~ro~l-n-butylamlne Into a 500-ml three-necked flask, fitted with a mechanical stirrer, a dip thermometer, a dropping-funnel and a clacium 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 colled to 0C and then 11.2 g (0.07 mol) of bromine were added, drop-by-drop and while stirring. After this operation, a solution of 1~ 9 (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 b~ 19.4 ml (0.14 mol) of anh~drous triethylamine while maintaining the reaction medium at a temperature of about 0C. 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 b~ adding sodium hydroxide~ the organic fraction was continuously extracted for 48 hours with methylene chloride. The solvent , :
iLi~)78~37 was eliminated and the residue ~as 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. : 1 ~ 115C under 14 mm Hg Yield : 57~
b) N~N-Trimethylene-l,l-dl-n-~ropyl-n-butylamlne hydrochlorlde 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-trimethylene-l,l-di-n-propyl-n-butylamine hydrochloride was obtained in the form of colourless crystals.
M.P. : 92-93C ..
Yield : 87~
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-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-l,l-di-n-propyl-n-butylamine were obtained in the form of a colourless liquid.
B.P. : 85C ~nder 13 mm Hg Preparation of N-(2-hydroxyethyl~-1,1-di-n-~ro~yl-n-butylamine hydrochloride In a 50-ml flask fitted with several inlet tube~, a mechanical stirrer, a condenser for reflux, a thermometer and a dip tube for allowing the entry of nitrogen or ethylene oxide, was introduced 002 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 ana the reaction medium was heated, while stirring, to 160C 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 180-200C. The flask was cleared with nitrogen before cooling and the reaction mixture was acidified with 20 ml of 36%-hydrochloric acid. After cooling to 0C, 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-t2-hydroxyethyl)-1,1-di-n-propyl-n-butylamine hydrochloride were obtained.
M.P. : 175C
~XAMPLE 15 - Preparation of N,N-bis-(2-hydroxvethyl)-1~-di-n-propyl-n-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.~ g (84 ml) (0.85 moI) 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 bomb-apparatus was closed, cleared with nitrogen and immersed in a water-bath thermostated at 50 + 2C (pressure about 2.8 bars). The reaction was maintained for 4~ hours and then the pressure was lowered to atmosphereic pressure. The apparatus was cleared with nitrogen and the reaction medium was concentrate~
in a rotary evaporator to constant weight (45 g). The oil so obtained was taken up with 300 mi of ethyl ether and the ~ . .
~)7~3837 ethereal solution was washed with 50 ml of a 4%-aqueous solu-tion of sodium hydroxide and then with water. The oLganic fraction was dried over anhydrous sodium sulphate and then evaporated to dryness to obtain 39 g of an oil which crystallized at about 50C. This solid was recrystallized by dissolving in 160 ml o~ heptane under reflux, suction-filtered after 2 hours at -5C and dried to constant weight.
In this manner, 34 g of N,N-bis-(2-hydroxyethyl)-l,l-di-n-propyl-n-butylamine hydrochloride were obtained.
M.P. : 64C
Yield : 87%
Preparation of_N-(3-Oxapentamethylene)-l,l-di-n-propyl-n-butYlamine hydrochloride a) N-N-2-Morpholino-2-n-pro~yl-valeronitr1le A solution of 43.5 g (0.5 mol) of morpholine in 200 ml o~ 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 50C for 12 hours. ~he precipita~e which formed was filtered out, the methanol was evaporated off under vacuum and the'oil so obtained was taken up wi~h 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. : 137-140C (under 3.5 mm Hg).
b) N-~3-Oxapentamethylene)-lLl-dl-n-~ro~yl-n-butylamin_ To a solution o~ 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 than, 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-oxapentamethylene)~ di-n-propyl-n-butylamine was obtained.
Yield : 65~
B.P. : 96-97C (under 4 mm Hg) c) N-l3-Oxapentamethylene)-l~l-di-n-E~roI2yl-n-butylaml-ne hydrochlorlde A solution of 4.5 g of N-(3-oxapentamethylene)-l,l-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 hydrochloride was obtained.
Sublimation : between 140 and 150C
Preparation of N-(3-oxapentamethylene~-1,1-di-n-propyl-n-butylamine hydrochloride a) N-l3-Oxa~entamethylenel-lLl-di-n-pro~yl-n-butylamine A solution of 5 9 (about 0.02 mol) of N,N-bis-(2-.
.
~' ' ' , ' ~ILO'~1337 hydroxyethyl)~ 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.
10 B.P. : 256C (under 750 mm Hg) b) N-(3-Oxa~entamethylene)-l,l-di-n-~ro~yl-n-butylamlne hydrochlorlde A solution o 4 g of N-(3-oxapentamethylene)-1,1-di-n-propyl-n-butylamine in 20 ml of isopropanol was treated with 2 ml o concentrated hydrochloric acid (d = 1.19) and then 33 ml of isopropyl ether were added.
In this manner, N-(3-oxapentamethylene)-1,1-di-n-propyl-n-butylamine hydrochloride was obtained which sublimated between 140 and 150C.
A hard-gelatin capsule containing the following ingredients was prepared in accordance with known pharmaceutical techniques :
Ingredients mg N-methyl-l,l-di-n-propyl-n-butylamine hydrochloride 15 milk sugar 50 :, - . . . ..
CH3-CH2-CH2 Rlo wherein Rg represents a straight- or branched-chain alkyl radical having Erom 1 to 4 carbon atoms, n represents 0 and 1 and Rlo represents hydrogen or 2-hydroxyethyl with the proviso that when Rlo 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 pharma-ceutically acceptable acid addition salt of the said compound.
The compounds of formula I wherein R2 has the meaning cited thereinl R4 represents hydrogen and R5 represents methyl can also be obtained by heating a n-butylamine derivative of the general formula :
CH3-CH2 CH2\
R7C-NHR15 X , .
CH3-C~2 CH2 or an acid addition salt thereofl for example the hydrochloride, :
wherein R2 has the same meaning as in formula I and Rl~ represents ~ .7n ~ ~ ~d~
hydrogen, in the presence of formic aldehyde and~-~a~L~_~xk5 to give the desired compound of formula I which can then be reacted with an organic or inorganic acid to provide a pharma-ceutically acceptable acid addition salt of this compound.
The compounds of formula I wherein R2 represents n-propyl and R4 and R5, when they are taken together, represent an ethylene, trimethylene of -CH2-CH2-0-CH2-CH2- radical, can be obtained in a solvent or in the absence of a solvent by reacting an appropriate cyclization agent with a n-butylamine ~
derivative of the general formula : :
CH3-CH2-CH2 \ / cH2-(CH2)m-CH20H
CH3-CH2-CH2/C-N~
CH3-CH2-CH2 Rll : , - , ., :' ' ' ~' .
in which Rll represents hydrogen or the radical CH2-CH20H
and m represents 0 or 1 with the proviso that when Rll represents CH2-CH20H, 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 pharmaceuticall~ acceptable acid addition salt of the said compound.
When Rll 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 chlorosulphonic acid, b) in a solvent such as for example acetonitrile or benzene, by means OL 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 cylization 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~Rg represents hydrogen.
Similarly, phosphoric anhydride could be used, for example with a compound of formula V wherein R11 represents the radical CH2-CH20H and m represents ~.
The compounds of formula I wherein R2 represents n-propyl and R4 and R5, when they are taken together, represent ~)7~337 a methylene or ethylidene radical can be obtained by condensing l,l-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 prcvide the desired compound of formula I which may then be reacted, if desired, with an organic or inorganic acid to provide a phar~aceutically acceptable acid addition salt.
A certain number of N-substituted n-butylamine deriva-tives 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 n-butylamine derivatives covered by the invention.
For example, the compounds of formula I wherein R2 has the meaning cited therein, R4 represents hydrogen and R5 represents methyl, can also be prepared by reducing, with lithium aluminium hydride, an isocyanate of the general formula :
CH3--CH2 CH2 \
R2~ --C-N=C=OVIII
wherein R2 has the same meaning as in formula I to provide the required methylamine derivative oE formula I, which can further be treated with an organic or inorganic acid to give a pharma-ceutically acceptable acid addition salt~
The reduction in question can be effected in an inert and anhydrous medium such as for example ethyl ether.
Like wise, the compounds of formula I in which R2 has the meaning cited therein, R4 represents hydrogen and R5 represents methyl as well as N-propargyl-l,l-di-n-propyl-n-~78~3~7 butylamine can be prepared starting with a compound of the general formula :
CH3-CEI2-CH2\
wherein R2 has the meaning given in formula I and A represents the group NH-C0-R14 or N=CH-R14 in which R14 represents hydrogen or ethynyl and reducing this compound:
a) in an appropriate anhydrous medium, such as Eor example ethyl or butyl ether, with lithium aluminium hydride in the case where A represents NH-CO-R14 ~
b) in a solvent such as for example methanol, with sodium borohydride in the case where A represents 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~-1,1-di-n-propyl-n-bu~ylamine can be obtained by reacting ethylene oxide with l,l-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 inosganic acid to obtain a pharmaceutically acceptable acid addition salt of this compound.
The reaction in question will be effected by heating the reayents , preferably at a temperature between 171 and ~ : -200C.
N,N-bis-(2-hydroxyethyl)-1,1-di-n-butylamine can also be prepared by reacting under pressure a molar equivalent of :~
l,l-di-n-propyl-n-butylamine with two molar equivalents of ~)7~37 an ethylene oxide, this reaction being undertaken in the presenee of a strong acid, such as for example hydroehloric 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 aeid to obtain a pharma-ceuticall~ acceptable acid addition salt o the said compound.
The reaction in question will be effected by heating the reagents, for example at a temperature between 40 and 80C, preferably at 50C and under pressure of 3 bars.
1~ ~ikewise, N-~3-oxapentamethylene)-1,1-di-n-propyl-n-butylamine can be prepared fQllowing other procedures than that mentioned hereabove.
Thus, this eompound in question of formula I can also be obtained by heating l,l-di-n-propyl-n-butylamine or an acid addition salt thereof, for example the hydroehloride, with di-(2-ehloroethyl) oxide in the presence o an alkaline agent, sueh as for example sodium carbonate, to provide the desired compound of formula I which can further be reacted with an ~ organic or inorganie aeid ~ obtain a pharmaceutically accept-able aeid addition salt of this eompound.
Furthermore, N-(3-oxapentanemethylene)-1,1-di-n-propyl-n-butylamine ean also be obtained by reaeting, in an anhydrous ether, sueh as for example ethyl ether, 2-N-morpholino-2-n-propyl-valeronitrile with n-propyl magnesium bromide and further hydrolyzing the eomplex so formed to provide the desired compound of formula I which ean then be reaeted with an organie or inorganie aeid to obtain a pharmaceutically acceptable aeid addition salt of the said eompound.
Amongst the eompounds of formula II, those wherein R4 represents hydrogen are known produets having been deseribed together with their process of preparation in Canadian Patent N 1,056,730. -.
.. . , ".
.
~Im~7 The other compound of formula II, namely that wherein R4 represents propargyl is in fact a compound of formula I
for which several processes of preparation are described here-above.
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, l,l-di~n-propyl-n-butylamine or N-(2-hydroxyethyl)-l,l-di-n-propyl-n-butylamine with an appropriate quantity of a halogenated compound of the general formula :
Hal-cH2-(cH2)n-co2R9 XIV
in which R5 has the same meaning as in formula IV n represents 0 or 1 and Hal represents an atom of chlorine, bromine or iodine which gives the desired compound of formula IV.
Furthermore, the compounds of formula IV in which Rlo represents hydrogen and n represents 1 can also be prepared by heating in an inert medium, such as for example methanol, l,l-di-n-propyl-n-but~lamine with an acrylic acid ester of formula CH2=CH-C02Rg wherein Rg has the same meaning as in formula IV to obtain the desired compound.
The compounds of formula V are in fact co~pounds of formula I for which a process of preparation is described hereabove while the compounds of formula VIII are also known products having been described together with their prQCeSs of preparation in Canadian Patent N 1,056,730.
The compound of formula IX wherein A represents N=CH2 is in fact a compound of formula I for which a process of preparation is described hereabove. The other compound of formula IX wherein A represents N=CH-R14 can be prepared in accordance with the same procedure.
The compounds of formula IX wherein A represents NH-C0-R14 can be prepared either in the absence of a solvent , _ g _ . .
~'7~ill5137 or in a solven~, such as for example benzene and in the presence of an acid acceptor, such as Eor example pyridine or 2,6 dimethyl-pyridine, by reacting l,l-di-n-propyl-n-butylamine with a halide or an anhydride of the general formula:
R14-C0-Rlg in which R14 has the same meaning as in formula IX and Rlg represents an atom of chlorine, bromine or the radical 0-C0-R14 wherein R14 has the same meaning as in formula IX, to provide the required compound.
With respect to 2-N-morpholino-2-n-propyl-valeronitrile, this can be obtained b~ 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 n-butylamine deriva-tives 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 neurolepticinduced 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 chlolinolytic 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 .
- - .
g~ 78~3~7 :
disturbances provoked by neuroleptics.
Compounds which are tri-substituted on the butyl-amine moiety but not substituted on the nitrogen atom are already known as possessing central noradrenergic and central dopaminergic properties which are likely to be used in the treatment of Parkinson's disease and for the correction of extra-pyramidaldisturbancesprovoked by neuroleptics.
Such compounds have been described in Canadian Patent ~o 1,506,730. -Likewise, it has been found that compounds which are di-substituted on the butylamine moiety but having no substitution on the nitrogen atom, such as l-n-propyl-n-butyl-amine, also possess the required qualities to be used as anti-parkinsonian agents.
However, the di-substituted and tri-substituted derivatives of butylamine which are not substituted on the nitrogen atom in question exert, ~ various degrees, an inhibitory action on the monoamine oxidase.
In clinical use, this inhibitory action can manifest - itself by undesirable side-effects such as tachycardia, paroxystic hypotension and hypertension.
However, it has been discovered, very surprisingly, that at the same concentrations the compounds of the invention exert an inhibitory action on the monoamine oxidase which is much weaker than the inhibitory action presented by the di-and tri-substituted derivatives of methylamine cited hereabove, this inhibitory action being even nil in some cases.
This entirely unexpected advantage presented by the N-substituted derivatives of butylamine of the inven-tion ;~
- in comparison with the di- and tri-substituted derivatives of methylamine which are not substituted on the nitrogen atom is likely to render the compounds of the invention more advantageous ~ID781~37 than the derivatives which are unsubstituted on the nitrogen atom.
The compounds of the invention are also more advantage-ous than amantadine i.e. l-amino-adamantane, a product ~hich is widely used in the treatment of Parkinson's disease.
Although the pharmacological spectrum of the compounds of the invention is very similar to that o amantadine, pharmacological tr`ials performed with the compounds of the invention have revealed marked diferences in comparison with ;
amantadine. For example, when comparing the doses of the compounds of the invention and of amantadine which have a certain degree of activity, it has been observed that the active dose in question is always proportionally farther from the toxic dose in the case of the compounds of the invention than in the case of amantadine. In other words, the safety margin offered by the compounds of the invention is superior to that o amantadine.
The search for new antiparkinsonian agents is of primary importance since the treatment is of long duration and the alternating use of diferent products is necessary.
From this point o view, the compounds o the invention will constitute valuable additions to the available antiparkinsonian agents, since at present there is no ideal agent or the treatment of this disease as explained hereabove.
The N-substituted derivatives and N,N-substituted derivatives of the present invention which have shown the most valuable properties for constituting antiparkinsonian agents, are : -N-methyl-l,l-di-n-propyl-n-butylamine N,N-trimethylene-l,l-di-n-propyl-n-butylamine these compounds being used in the form of their free base or in these compounds being used in the form of their free - . : .
~ .
~V78837 base or in the form o~ a pharmaceutically acceptable acid a addition salt such as, for example, the hydrochloride or the ~umarate.
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 amantadien. These compounds were preEerably studied in the form o~ a pharmaceutically acceptable acid addition salt.
They are the following:
N-methyl~l,l-di-n-propyl-n-butylamine (Compound 1) N,N-trimethylene-l,l-di-n-propyl-n-butylamine(compound 2) N-methyl-l-n-propyl-l-isopropyl-n-butylamine (Compound 3) ~-N-methyl-l-n-propyl-l-isobutyl-n-butylamine (Compound 4) N-methyl-l-n-propyl-l-allyl-n-butylamine (Com~ound S) N-propargyl-l,l-di-n-propyl-n-butylamine ~Compound 6) N,N-dipropargyl-l,l-di-n-propyl-n-butylamine (Compound 7) N,N-ethylene-l,l-di-n-propyl-n-propyl-n-butylamine (Compound 8) N-methylene-l,l-di-n-propyl-n-butylamine (Compound 9) N-ethylidene-l,l-di-n-propyl-n-butylamine (Compound 10) N-(2-hydroxyethyl)-ljl-di-n-propyl-n-butylamine (Compound 11) N,N-bis-(2-hydroxyethyl)-1,1-di-n-propyl-n-butylamine (Compound 12) N-(3-hydroxy-n-propyl)-1,1-di-n-propyl-n-butylamine (Compound 13) N,N-(3-oxapentamethylene)-1,1-di-n-propyl-n-butylamine (Compound 14 I. Inhibition of reserpine-induced and neuroleptic-induced catatonia (dopaminergic properties) 1. Inhlbitlon of_reser~ine-lnduced catatonia The test undertaken for this purpose is identical to that described in Canadian Patent No 1,506,730 The results obtained with the compounds of the invention listed hereabove as well as with amantadine .
. : , ~ ~' 3l~7~3~37 are given in Table I hereunder.
These results are expressed according to the same scoring system, from 0 to 4, as that set out in the above-cited Canad1an Patent.
TABLE I
_ ~
Dose adminis- Inhibition of reserpine ~ ~ ;
" ' ~ ' ~' . ' ~" .
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 2 is equal`to 3.
2. Inhibition of neurole~tic-induced catatonia __________ ___ ______ _______________ ____ The test performed for this purpose is identical to . that described in Canadian Patent No 1,506,~30.
The results obtained with compounds listed above in ' comparison with amantadine are set out in the following .- 14 - . :
, , , , ,., , ~, .. , . . . , . . :
~71~337 Table II.
The scoring system was that used hereabove for Table.I.
TABLE I I
_ .
C d Dose adminis- Inhibition of neurolep-.
ompoun tered in mg/kg tic-induced catatonia 6 ; 3 ~- -10 ~L~i - I ~
.... ~ :
~
, Complementary tests have shown that Compounds 2 at a dose as low as 3 mg/kg have an index of inhibition of neuroleptic-induced catatonia equal to 2 while Compound 8 at the dose o 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 Canadian Patent No 1,056,730.
The following ~esults were recorded with compounds of the invention in comparison with amantadine:
. - 15 -.
: .
8~33'7 Compound LD50 in mg/kg 3 > 150 6 > 150 7 > 150 8 > 150 9 > 150 1~ 250 Amantadine 1050 A comparison was made between the index LD50 of the compounds of the invention with the corres-ponding index of amantadine.
In this index~ ED20-3o represents the effective dose to obtain 20 to 30% inhibition of the catatonla, this value being represented by the figure 1 in Tables I and II.
The following results ~ere registered:
Compound Index 6 `> 25 8 ~ 25 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 was determined in comparisOn with amantadine. D
The following results were registered:
Compound Index 1 16.5 2 10.8 3 > 25 10Amantadine 10 These results again show that the compounds of the present invention ofEer 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 (pH = 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 mol.
c) 0.1 ml of the suspension of mitochondrias previously prepared namely 12.5 mg of proteine.
Three minutes after this operation, the reaction was .
, )7~337 initiated by adding 0.2 ml of a 0.05 molar solution of serotonine-creatine 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 reerence.
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 10 compounds unde:r 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 o~ two methyl-amine.derivatives unsubstituted on the nitrogen atom, these two derivatives being studied under the same conditions:
TABLE
Ml of l-n-propyl-n- l,l-di-n-propyl- n-methyl-l,l-di-n-h-b t butylamine n-butylamine propyl-n-butylamine . ln 1 1 or hydrochloride hydrochloride hydrochloride . .
_ .
: 0.01 22 1.5 3 .02 25 6 1.5 0.04 35.5 11.5 .
. 0.06 44 11.5 0 0.08 48 14.5 0 .
0.1.0 54 14.5 3 i These results show that the inhibitory action on the mono-amine 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 hydro-- chloride.
.
, ' , .
~7~837 It Will be appreciated that ~or therapeutic use the compounds of the invention will normally be administered in the form of a pharmaceutical or veterinary composition in a dosage unit form appropriate to the required mode of administra-tion, the composition comprising as active ingredient a compound of the invention in association with a pharmaceutical carrier or excipient therefor. For oral administrationr 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 Erom 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.
The following Examples illustrate the preparation - of the compounds of the invention together with a suitable therea thereapeutic composition :
Preparation of N-methyl-l,l-di-n-propyl-n-butylamine hydro-- chloride a) N-Methyl-l~l-dl-n-propyl-n-butylamine ~)7~337 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 9 (0.02 mol) of l,l-di-n-propyl-n-butylisocyanate in 20 ml of dry ether.
The operation of addition was carried out over a period of 30 minutes at room-tempera-ture aEter which the reaction medium was heated under reflux for 3 hours. After hydrolysic 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 9 of N-methyl-l,l-di-n-propyl-n-butylamine were obtained in the form of a colourless liquid.
B.P. : 84C under 13 mm Hg.
Yield : 94~
b) N-Methyl-l,l-dl-n-~ro~yl-n-butylamine_hydrochlorlde 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. : 133-134C
Yield : 90~
By following the same procedure as that described hereabove but using the appropriate starting-products, the compound hereunder was prepared:
~ Melting point C
N-Methyl-l-n-propyl-l-isopropyl-n-butylamine hydrochloride 144-145 (Yield : 80~) Preparation of N-methyl-l,l-di-n-propyl-3-buten-1-ylamine fumarate .,:, . ~
: ................... . - . . : ~ .
71 3~3~
First 1,1-di-n-propyl-3-buten-1-ylisocyanate was prepared by reacting bromine and 2,2-di n-propyl-4-buten-1-ylamide in the presence of sodium hydroxide. The desired product was obtained in the form of a colourless liquid boiling at 79-82C
under 5 mm Hg. The 2,2-di-n-propyl-4-buten-1-~Ylamide so obtained was then reduced by means of lithium aluminium hydride to provide without purification, N-methyl-l,l-di-n-propyl-3-buten-l-ylamine in a yield of 89%.
To a solution of 2.32 g (0.02 mol) of fumaric acid in 400 ml of acetone, were added under stirring 3.38 g (0.02 mol) of the amine, prepared hereabove, dissolved in 30 ml of acetone.
Stirring was maintained for one hour after which the colourless crystals which precipitated were separated out.
They 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. : 149C
Yield : 91%
- Preparation of N-methyl-l-n-propyl-l-isobutyl-n-butYlamine hydrochloride a) N-Me_hyl-l-n-ero~yl-l-i_obutyl-n-butylamine ~n a one-litre three-necked flask, equipped with a condenser of the Dean Stark type, were placed 30 g (0.175 mol) of l-n-propyl-l-isobutyl-n-butylamine, 150 ml of 30%
formol and 400 ml of benzene. The mixture was refluxed for 5 hours so as to eliminate by azeotropic distillation about 100 ml of water. After evaporating the benzene under vacuum, the oil so obtained was taken up in 250 ml of methanol and, at a temperature of 10C, 13.3 g (0.35 mol) of sodium borohydride were added by small fractions. The ~ .
~7~337 temperature of the mixture was maintained at 10C 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, 200ml of distilled water and 100 ml of a concentrated solution of sodium hydroxide were addedO The organic ~raction 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-meth~l-l-n-propyl-l-isobutyl-n-butylamine were obtained in the form of a colourless liquid.
B.P. : 86C under 12 mm Hg Yield : 3~
b) N-Methyl-l-n-~roeyl-l-lsobutyl-n-butylamine hydrochloride In 150 ml of absolute ethanol, 10O4 g of the amine previously obtained were dissolved and the resulting solution was treated by means 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 llydrochloride crystallized when cold.
It was separated out and recrystallized ïn isopropyl ether~
In this manner, 7.5 g of N-methyl-l-n-propyl-l-isobutyl-n-butylamine hydrochloride were obtained.
Yield : 61%
M.P. : 139C
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 ~ 22 -~)7~7 Preparation of N-ethylidene-l,l-di-n-propyl-n-but~lamine Into a 25-ml two-necked 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 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-l,l-di-n--propyl-n-butylamine were obtained in the form of a colourless liquid.
B.P. : 78C under 13 mm Hg Yield : 85%
Preparation of N-methyl-l,l-di-n-propyl-n-butylamine hydro-chloride a) N-formyl-l,l-di-n-pro~yl-n-butylamine To a solution of 7.85 g (0.05 mol) of l,l-di-n-propyl-n-butylamine in 5.3 g of pyridine, 3.3 g of formyl chloride were slowly added. The mixture was heated to 80C 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, formyl-l,l-di-n-propyl-n-butylamine were obtained after recrystallization from heptane.
b) N-Methyl-l,l-di-n-~ro~yl-n-but~lamine hydrochloride _____ ___ _______ __ _______ ________ ___________ to a suspension of 1.9 g of lithium aluminium hydride 30in 80 ml of butyl ether, were added, while stirring, 3.7 g ~0.02 mol) of the N-formylated derivative previously obtained, dissolved in 20 ml-of butyl ether. The mixture was - 23 - ;~
. , ~
progressively heated under reElux 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~-hydrochloric 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, N-methyl-l,l-di-n-propyl-n-butylamine hydrochloride were obtained in the form of colourless crystals.
M.P. : 133~134C
Preparation of N-propargyl-l,l-di-n-propy~ -butylamine hydrochloride a) N-Pro~ar~yl-l~l-di-n-~ro~yl-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 ~0 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 9 of N-propargyl-l,l-di-n-propyl-n-butylamine were isolated in the form of a pale yellow liquid.
B.P. : 94-96C under 5 mm Hg Yield : 51%
b) N-Propargyl-lLl-di-n-propyl-n-butylamine hydrochloride _____ __ ___ _______ __ _______ ________ ___________ By bubbling dry and gaseous hydrochloric acid - through an ethereal solution of the amine so obtained, the .. ~ - .. . , -f~
~1~7~}~37 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. : 154 155C
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~ di-n-propyl-n-butylamine hydrochloride 133-134 Preparation of N,N-dipropar~y~ l-di-n-pr~pyl-n-butylamine hydrochloride a) NLN-Dl~ropar~yl-lLl-dl-n-2ro~yl-n-butylamine By continuing the distillation operation commenced in the above Example 6 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 9 of N,N-dipropargyl-l,l-di-n-propyl-n-butylamine were obtained in the form o~ a colourless liquid.
B.P. : 120C under 5 mm Hg Yield : 13%
b) NLN-Di~ropar~yl-l,l-dl-n-~ro~yl-n-butylam_ne 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. : 177C (decomposition) .. ., ' . .
`~
EXAMPL,E 8 Preparation o~ N-~2-hydroxyethyl)-1,1-di-n~propyl-n-butylamlne hydrochloride -a) Ethyl 2-(lLl-di-n-~ro~yl-n-butylamlnol-ethanoate Into a S00 ml 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 (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 Qut. The solution was concentrated and the oil so obtained was distilled undeL reduced pressure.
In this manner, 22.9 g of ethyl 2-(1,1-di-n-propyl-n-butylamine)-ethanoate were obtained.
B.P. : 90-92C under 0.3 mm Hg Yield : 63%
b) N-(2-Hydroxyethyl)-l,l-di-n-ero~yl-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 (0.094 mol~ of ethyl 2-(1,1-di-n-propyl-n-butylamino)-etha-noate dissolved in 5Q 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-hydroxyethyl)-1,1-di-n-propyl-n-butylamine were obtained.
Yield : 94%
c) N-(_-Hydroxyethyl~-lLl-di-n-~ro~yl-n-butylamine hydrochloride 30 - - 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 hvdrochloric acid. After the solven~ 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 o ethyl acetate.
In this manner, 2.7 g of N~ hydroxyethyl)-l,l-di-n-propyl-n-butylamine hydrochloride were obtained.
M.P. : 157C
Yield : 60 Preparation of N-(3-oxa~enta~eth~lene)-1,1-di-n-propyl-n-butylamine a) N-~3_0xa~entamethylenel-lLl-dl-n-pro~yl-n-butylamine Under vigorous stirring, a mixture of 39 g (0.25 mol) of l,l-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 sulphate evaporated under vacuum and distilled under reduced pressure.
In this manner, 25 g of N-(3-oxapentamethylene)~l,l-di-n-propyl-n-butylamine were collected in the form of colourless liquid.
B.P. : 105-106C (under 5 mm Hg) Yield : 44%
b) N-l3-OxapentamethyleneL-l l-di-n-eropyl-n-butylamine hydro-, __ _____ ________ __ _ __L____------ ---- -------------- ------chloride ________ 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 hydro-chloric acid (d = 1.19) and the desired hydrochloride was precipitated by adding 25 ml of isopropyl ether.
In this manner, N-(3-oxapentamethylene)-1,1-di-n-.
3~
propyl~n-butylamine hydrochloride was obtained in the form of brillant and colourless crystals which sublimated between 140 and 150C.
Yield : 80%
Preparation of N,N-ethylene-l,l-di-n-propyl-n butylamine In a 250~ml three~necked flask containing 15 g ~0.063 mol~ of N-(2-hydroxyethyl)-1,1-di-n propyl-n-butyl~
amine 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 80C and using a water pump, a partial vacuum was created in the flask. Under these conditions, heating was maintained at 80C for one hour and then, at atmospheric pressure the mixture wàs heated at 140C for 90 minutes. The viscous mixture was stirred for 12 hours with 100 ml of distilled water and then poured into a flask containing 300 ml of water and 100 ml of a sodium hydroxide solution. The mixture was then 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,l-di-n-propyl-n-butylamine were isolated in the form of a colourless liquid.
B.P. : 103 104C under 18 mm Hg Yield : 76~
_~earation of N-~3-hydroxy-n-propyl~-1,1-di-n~r~y~-n-butylamine hydrochloride '' . ' . . . ' ., '. ' ' : : :' : ', a) Methyl 3-~lLl-dl-n-ero~yl-n-butylaminol-~ro~anoate A solution of 28 . 4 g (O . 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-n-butyl-amine. After the methanol was eliminated under vacuum, the liquid so obtained was distilled.
In this manner, 61 9 of methyl 3-[1,1-di-n-propyl-n-butylamino)-propanoate were obtained.
B.P. : 97-98C under 0.4 mm Hg Yield : 82~
b) N-13-Hydroxy-n-~ro~yl~-lLl-di-n-~ro~yl-n-butylamlne Into a 500-ml three-necked flask itted with a me mechanical stirrer, a condenser and a dropping-~unnel 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-butyl-amino)-propanoatel 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 oE~ and the oil so obtained was distilled.
In this manner, 14.9 9 of N-(3-hydroxy-n-propyl)-l,l-di-n-propyl-n-butylamine were collected in the form of a colourless liquid.
B.P. : 107-108C under 0.4 mm Mg Yield : 85%
c) N-~3-Hydroxy-n-ero~ylL-l,l_dl_n_~ro~yl-n-butylamine hydroc_loride 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 concen-trated to dryness and the oil so obtained was taken up 83~
with 100 ml o~ 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-n-propyl)-l,l-di-n-propyl-n-butylamine hydrochloride were ~btained.
M.P. : 121-12~C
Yield : 90%
Preparation of N,N-trimethylene-l,l-di-n-propyl-n-butylamine hydrochloride a) N~N-Trimethylene-lLl-dl-n-~ro~l-n-butylamlne Into a 500-ml three-necked flask, fitted with a mechanical stirrer, a dip thermometer, a dropping-funnel and a clacium 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 colled to 0C and then 11.2 g (0.07 mol) of bromine were added, drop-by-drop and while stirring. After this operation, a solution of 1~ 9 (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 b~ 19.4 ml (0.14 mol) of anh~drous triethylamine while maintaining the reaction medium at a temperature of about 0C. 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 b~ adding sodium hydroxide~ the organic fraction was continuously extracted for 48 hours with methylene chloride. The solvent , :
iLi~)78~37 was eliminated and the residue ~as 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. : 1 ~ 115C under 14 mm Hg Yield : 57~
b) N~N-Trimethylene-l,l-dl-n-~ropyl-n-butylamlne hydrochlorlde 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-trimethylene-l,l-di-n-propyl-n-butylamine hydrochloride was obtained in the form of colourless crystals.
M.P. : 92-93C ..
Yield : 87~
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-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-l,l-di-n-propyl-n-butylamine were obtained in the form of a colourless liquid.
B.P. : 85C ~nder 13 mm Hg Preparation of N-(2-hydroxyethyl~-1,1-di-n-~ro~yl-n-butylamine hydrochloride In a 50-ml flask fitted with several inlet tube~, a mechanical stirrer, a condenser for reflux, a thermometer and a dip tube for allowing the entry of nitrogen or ethylene oxide, was introduced 002 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 ana the reaction medium was heated, while stirring, to 160C 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 180-200C. The flask was cleared with nitrogen before cooling and the reaction mixture was acidified with 20 ml of 36%-hydrochloric acid. After cooling to 0C, 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-t2-hydroxyethyl)-1,1-di-n-propyl-n-butylamine hydrochloride were obtained.
M.P. : 175C
~XAMPLE 15 - Preparation of N,N-bis-(2-hydroxvethyl)-1~-di-n-propyl-n-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.~ g (84 ml) (0.85 moI) 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 bomb-apparatus was closed, cleared with nitrogen and immersed in a water-bath thermostated at 50 + 2C (pressure about 2.8 bars). The reaction was maintained for 4~ hours and then the pressure was lowered to atmosphereic pressure. The apparatus was cleared with nitrogen and the reaction medium was concentrate~
in a rotary evaporator to constant weight (45 g). The oil so obtained was taken up with 300 mi of ethyl ether and the ~ . .
~)7~3837 ethereal solution was washed with 50 ml of a 4%-aqueous solu-tion of sodium hydroxide and then with water. The oLganic fraction was dried over anhydrous sodium sulphate and then evaporated to dryness to obtain 39 g of an oil which crystallized at about 50C. This solid was recrystallized by dissolving in 160 ml o~ heptane under reflux, suction-filtered after 2 hours at -5C and dried to constant weight.
In this manner, 34 g of N,N-bis-(2-hydroxyethyl)-l,l-di-n-propyl-n-butylamine hydrochloride were obtained.
M.P. : 64C
Yield : 87%
Preparation of_N-(3-Oxapentamethylene)-l,l-di-n-propyl-n-butYlamine hydrochloride a) N-N-2-Morpholino-2-n-pro~yl-valeronitr1le A solution of 43.5 g (0.5 mol) of morpholine in 200 ml o~ 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 50C for 12 hours. ~he precipita~e which formed was filtered out, the methanol was evaporated off under vacuum and the'oil so obtained was taken up wi~h 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. : 137-140C (under 3.5 mm Hg).
b) N-~3-Oxapentamethylene)-lLl-dl-n-~ro~yl-n-butylamin_ To a solution o~ 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 than, 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-oxapentamethylene)~ di-n-propyl-n-butylamine was obtained.
Yield : 65~
B.P. : 96-97C (under 4 mm Hg) c) N-l3-Oxapentamethylene)-l~l-di-n-E~roI2yl-n-butylaml-ne hydrochlorlde A solution of 4.5 g of N-(3-oxapentamethylene)-l,l-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 hydrochloride was obtained.
Sublimation : between 140 and 150C
Preparation of N-(3-oxapentamethylene~-1,1-di-n-propyl-n-butylamine hydrochloride a) N-l3-Oxa~entamethylenel-lLl-di-n-pro~yl-n-butylamine A solution of 5 9 (about 0.02 mol) of N,N-bis-(2-.
.
~' ' ' , ' ~ILO'~1337 hydroxyethyl)~ 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.
10 B.P. : 256C (under 750 mm Hg) b) N-(3-Oxa~entamethylene)-l,l-di-n-~ro~yl-n-butylamlne hydrochlorlde A solution o 4 g of N-(3-oxapentamethylene)-1,1-di-n-propyl-n-butylamine in 20 ml of isopropanol was treated with 2 ml o concentrated hydrochloric acid (d = 1.19) and then 33 ml of isopropyl ether were added.
In this manner, N-(3-oxapentamethylene)-1,1-di-n-propyl-n-butylamine hydrochloride was obtained which sublimated between 140 and 150C.
A hard-gelatin capsule containing the following ingredients was prepared in accordance with known pharmaceutical techniques :
Ingredients mg N-methyl-l,l-di-n-propyl-n-butylamine hydrochloride 15 milk sugar 50 :, - . . . ..
Claims (47)
1. Process for the preparation of n-butylamine derivatives having the general formula :
(I) and the pharmaceutically acceptable acid addition salts thereof wherein R4 represents hydrogen, propargyl or 2-hydroxyethyl, R5 represents methyl, propargyl, 2-hydroxyethyl, 3-hydroxy-n-propyl or R4 and R5, when they are taken together, represent methylene, ethylene, trimethylene, ethylidene or -CH2-CH2-0-CH2-CH2- and R2 is such that:
- when R4 represents hydrogen and R5 represents methyl, R2 represents n-propyl, isopropyl, isobutyl or allyl - when R4 represents hydrogen and R5 represents propargyl, 2-hydroxyethyl or 3-hydroxy-n-propyl or when R4 and R5 are identical and each represent propargyl or 2-hydroxyethyl or when R4 and R5 are taken together and represent methylene, ethylene, trimethylene, ethylidene or -CH2-CH2-0-CH2-CH2-, then R2 represents n-propyl, which process comprises:
a) either heating an amine of the general formula:
II
R2 / C-NHR7 II :~
or an acid addition salt thereof, in which R2 represents n-propyl, isopropyl, isobutyl or allyl when R7 represents hydrogen or wherein R2 represents n-propyl when R7 represents propargyl, in the presence of an alkaline agent, with an appropriate quantity of a halide of the general formula:
wherein R8 represents methyl or propargyl and X represents a chlorine, bromine or iodine atom, this reaction being undertaken either without any solvent or in the presence of a solvent, to obtain the required n-butylamine derivative in which R2 represents n-propyl, isopropyl, isobutyl or allyl when R4 represents hydrogen and R5 represents methyl or wherein R2 represents n-propyl when R4 represents hydrogen or propargyl and R5 represents propargyl, b) or treating an ester of the general formula :
IV
wherein R9 represents a straight-or branched- chain alkyl radical having from 1 to 4 carbon atoms, n represents O or 1 and R10 represents hydrogen or 2-hydroxyethyl with the proviso that when R10 represents 2-hydroxyethyl, n represents 0, by means of an appropriate reducing agent and in an inert and anhydrous medium and hydrolysing the reduced product, to obtain the required n-butylamine derivative, wherein R2 represents n-propyl, R4 represents hydrogen or 2-hydroxyethyl and R5 represents 2-hydroxyethyl or 3 hydroxy-n-propyl with the proviso that when R5 represents 3-hydroxy-n-propyl, R4 represents hydrogen c) or reacting an appropriate cyclization agent, in a solvent or in the absence of a solvent, with a compound of the general formula :
V
in which R11 represents hydrogen or the radical CH2-CH20H
and m represents O or 1, with the proviso that when R11 represents CH2-CH20H, m represents 0, or with an acid addition salt of this compound wherein R11 represents hydrogen, which provides the required n-butylamine derivative wherein R2 represents n-propyl and R4 and R5, taken together, represent an ethylene, trimethylene or -CH2-CH2-0-CH2-CH2 radical, d) or condensing 1,1-di-n-propyl-n-butylamine, with formaldehyde or acetaldehyde respectively, the operation or condensation being carried out either in the absence of a solvent or in the presence of a solvent, to obtain the required n-butylamine derivative wherein R2 represents n-propyl and R4 and R5 taken together, represent methylene or ethylene, e) or reducing an isocyanate of the general formula:
VIII
wherein R2 has the same meaning as above, is reduced with lithium aluminium hydride in an anhydrous inert solvent to obtain the required n-butylamine derivative wherein R2 has the meaning given therein, R4 represents hydrogen and R5 represents methyl, f) or reducing a compound of the general formula :
IX
wherein R2 has the same meaning as above and A represents the group NH-CO-R14 or N=CH-R14 in which R14 represents hydrogen or ethynyl is reduced:
- in an appropriate anhydrous medium with lithium aluminium hydride in the case where A represents NH-CO-R14, - in a solvent with sodium borohydride in the case where A
represents N=CH-R14, to obtain the required n-butylamine derivative wherein R2 has the meaning given therein, R4 represents hydrogen and R5 represents methyl or propargyl with the proviso that when R4 represents propargyl R2 represents n-propyl g) or reacting ethylene oxide in the presence of an appropriate catalyst, with 1,1-di-n-propyl-n-butylamine to obtain the required n-butylamine derivative in which R2 represents n-propyl, R4 represents hydrogen and R5 represents 2-hydroxyethyl, h) or heating a molar equivalent of 1,1-di-n-propyl-n-butyl-amine under pressure with two molar equivalents of ethylene oxide, this reaction being carrled out in the presence of a strong acid and in an inert medium, to obtain the required derivative of n-butylamine wherein R2 represents n-propyl and R4 and R5, which are identical, each represent 2-hydroxyethyl, i) or heating 1,1-di-n-propyl-n-butylamine or an acid addition salt thereof with di-(2-chloroethyl)oxide in the presence of an alkaline agent, to obtain the required n-butylamine derivative wherein R2 represents n-propyl and R4 and R5, taken together, represent -CH2-CH2-0-CH2-CH2-, j) or reacting in an anhydrous ether 2-N-morpholino-2-n-propyl-valeronitrile with n-propyl magnesium bromide and hydrolyzing the complex so formed to obtain the required n-butylamine derivative in which R2 represents n-propyl and R4 and R5 taken together, represent -CH2-CH2-0-CH2-CH2-, k) or heating on amine of the general formula :
X
or an acid addition salt thereof, wherein R2 has the same meaning as above and R15 represents hydrogen, in the presence of formic aldehyde and sodium borohydride to obtain the corresponding n-butylamine;
- the n-butylamine derivative so obtained being reacted, if desired with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt thereof.
(I) and the pharmaceutically acceptable acid addition salts thereof wherein R4 represents hydrogen, propargyl or 2-hydroxyethyl, R5 represents methyl, propargyl, 2-hydroxyethyl, 3-hydroxy-n-propyl or R4 and R5, when they are taken together, represent methylene, ethylene, trimethylene, ethylidene or -CH2-CH2-0-CH2-CH2- and R2 is such that:
- when R4 represents hydrogen and R5 represents methyl, R2 represents n-propyl, isopropyl, isobutyl or allyl - when R4 represents hydrogen and R5 represents propargyl, 2-hydroxyethyl or 3-hydroxy-n-propyl or when R4 and R5 are identical and each represent propargyl or 2-hydroxyethyl or when R4 and R5 are taken together and represent methylene, ethylene, trimethylene, ethylidene or -CH2-CH2-0-CH2-CH2-, then R2 represents n-propyl, which process comprises:
a) either heating an amine of the general formula:
II
R2 / C-NHR7 II :~
or an acid addition salt thereof, in which R2 represents n-propyl, isopropyl, isobutyl or allyl when R7 represents hydrogen or wherein R2 represents n-propyl when R7 represents propargyl, in the presence of an alkaline agent, with an appropriate quantity of a halide of the general formula:
wherein R8 represents methyl or propargyl and X represents a chlorine, bromine or iodine atom, this reaction being undertaken either without any solvent or in the presence of a solvent, to obtain the required n-butylamine derivative in which R2 represents n-propyl, isopropyl, isobutyl or allyl when R4 represents hydrogen and R5 represents methyl or wherein R2 represents n-propyl when R4 represents hydrogen or propargyl and R5 represents propargyl, b) or treating an ester of the general formula :
IV
wherein R9 represents a straight-or branched- chain alkyl radical having from 1 to 4 carbon atoms, n represents O or 1 and R10 represents hydrogen or 2-hydroxyethyl with the proviso that when R10 represents 2-hydroxyethyl, n represents 0, by means of an appropriate reducing agent and in an inert and anhydrous medium and hydrolysing the reduced product, to obtain the required n-butylamine derivative, wherein R2 represents n-propyl, R4 represents hydrogen or 2-hydroxyethyl and R5 represents 2-hydroxyethyl or 3 hydroxy-n-propyl with the proviso that when R5 represents 3-hydroxy-n-propyl, R4 represents hydrogen c) or reacting an appropriate cyclization agent, in a solvent or in the absence of a solvent, with a compound of the general formula :
V
in which R11 represents hydrogen or the radical CH2-CH20H
and m represents O or 1, with the proviso that when R11 represents CH2-CH20H, m represents 0, or with an acid addition salt of this compound wherein R11 represents hydrogen, which provides the required n-butylamine derivative wherein R2 represents n-propyl and R4 and R5, taken together, represent an ethylene, trimethylene or -CH2-CH2-0-CH2-CH2 radical, d) or condensing 1,1-di-n-propyl-n-butylamine, with formaldehyde or acetaldehyde respectively, the operation or condensation being carried out either in the absence of a solvent or in the presence of a solvent, to obtain the required n-butylamine derivative wherein R2 represents n-propyl and R4 and R5 taken together, represent methylene or ethylene, e) or reducing an isocyanate of the general formula:
VIII
wherein R2 has the same meaning as above, is reduced with lithium aluminium hydride in an anhydrous inert solvent to obtain the required n-butylamine derivative wherein R2 has the meaning given therein, R4 represents hydrogen and R5 represents methyl, f) or reducing a compound of the general formula :
IX
wherein R2 has the same meaning as above and A represents the group NH-CO-R14 or N=CH-R14 in which R14 represents hydrogen or ethynyl is reduced:
- in an appropriate anhydrous medium with lithium aluminium hydride in the case where A represents NH-CO-R14, - in a solvent with sodium borohydride in the case where A
represents N=CH-R14, to obtain the required n-butylamine derivative wherein R2 has the meaning given therein, R4 represents hydrogen and R5 represents methyl or propargyl with the proviso that when R4 represents propargyl R2 represents n-propyl g) or reacting ethylene oxide in the presence of an appropriate catalyst, with 1,1-di-n-propyl-n-butylamine to obtain the required n-butylamine derivative in which R2 represents n-propyl, R4 represents hydrogen and R5 represents 2-hydroxyethyl, h) or heating a molar equivalent of 1,1-di-n-propyl-n-butyl-amine under pressure with two molar equivalents of ethylene oxide, this reaction being carrled out in the presence of a strong acid and in an inert medium, to obtain the required derivative of n-butylamine wherein R2 represents n-propyl and R4 and R5, which are identical, each represent 2-hydroxyethyl, i) or heating 1,1-di-n-propyl-n-butylamine or an acid addition salt thereof with di-(2-chloroethyl)oxide in the presence of an alkaline agent, to obtain the required n-butylamine derivative wherein R2 represents n-propyl and R4 and R5, taken together, represent -CH2-CH2-0-CH2-CH2-, j) or reacting in an anhydrous ether 2-N-morpholino-2-n-propyl-valeronitrile with n-propyl magnesium bromide and hydrolyzing the complex so formed to obtain the required n-butylamine derivative in which R2 represents n-propyl and R4 and R5 taken together, represent -CH2-CH2-0-CH2-CH2-, k) or heating on amine of the general formula :
X
or an acid addition salt thereof, wherein R2 has the same meaning as above and R15 represents hydrogen, in the presence of formic aldehyde and sodium borohydride to obtain the corresponding n-butylamine;
- the n-butylamine derivative so obtained being reacted, if desired with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt thereof.
2. Process according to Claim 1a) wherein the alkaline agent is sodium bicarbonate.
3. Process according to Claim 1a) wherein the solvent is ethanol.
4. Process according to Claim 1a) wherein the acid addition salt of the starting compound is the hydrochloride.
5. Process according to Claim 1b) wherein the reducing agent is lithium aluminium hydride.
6. Process according to Claim 1b) wherein the inert medium is ethyl ether.
7. Process according to Claim 1c) wherein the solvent is benzene or acetonitrile.
8. Process according to Claim 1c) wherein the cyclization agent is chlorosulphonic acid, triphenylphosphine dibromide or phosphoric anhydride.
9. Process according to Claim 1c) wherein the acid addition salt of the starting compound is the hydrochloride.
10. Process according to Claim 1d) wherein the solvent is benzene.
11. Process according to Claim 1e) wherein the inert medium is ethyl ether.
12. Process according to Claim 1f) wherein the appropriate medium is ethyl ether.
13. Process according to Claim 1f) wherein the solvent is methanol.
14. Process according to Claim 1g) wherein the catalyst is boron trifluoride.
15. Process according to Claim 1g) wherein boron trifluoride is in the form of an etherate.
16. Process according to Claim 1g) wherein the reaction is carried out at a temperature between 170°C and 200°C.
17. Process according to Claim 1h) wherein the reaction is carried out at a temperature between 40° and 80°C.
18. Process according to Claim 1h) wherein the pressure is 3 bars.
19. Process according to Claim 1h) wherein the strong acid is hydrochloric acid.
20. Process according to Claim 1h) wherein the inert medium is methanol.
21. n-Butylamine derivatives having the general formula :
I
and the pharmaceutically acceptable acid addition salts thereof wherein R4 represents hydrogen, propargyl or 2-hydroxyethyl, R5 represents methyl, propargyl, 2-hydroxyethyl, 3-hydroxy-n-propyl or R4 and R5, when they are taken together, represent methylene, ethylene, trimethylene, ethylidene or -CH2-CH2-0-CH2-CH2- and R2 is such that:
- when R4 represents hydrogen and R5 represents methyl, R2 represents n-propyl, isopropyl, isobutyl or allyl - when R4 represents hydrogen and R5 represents propargyl, 2-hydroxyethyl or 3-hydroxy-n-propyl or when R4 and R5 are identical and each represent propargyl or 2-hydroxyethyl or when R4 and R5 are taken together and represent methylene, ethylene, trimethylene, ethylidene or -CH2-CH2-0-CH2-CH2-, then R2 represents n-propyl, whenever obtained by a process according to claim 1 or its obvious chemical equivalents.
I
and the pharmaceutically acceptable acid addition salts thereof wherein R4 represents hydrogen, propargyl or 2-hydroxyethyl, R5 represents methyl, propargyl, 2-hydroxyethyl, 3-hydroxy-n-propyl or R4 and R5, when they are taken together, represent methylene, ethylene, trimethylene, ethylidene or -CH2-CH2-0-CH2-CH2- and R2 is such that:
- when R4 represents hydrogen and R5 represents methyl, R2 represents n-propyl, isopropyl, isobutyl or allyl - when R4 represents hydrogen and R5 represents propargyl, 2-hydroxyethyl or 3-hydroxy-n-propyl or when R4 and R5 are identical and each represent propargyl or 2-hydroxyethyl or when R4 and R5 are taken together and represent methylene, ethylene, trimethylene, ethylidene or -CH2-CH2-0-CH2-CH2-, then R2 represents n-propyl, whenever obtained by a process according to claim 1 or its obvious chemical equivalents.
22. Process according to Claim 1 for the preparation of N-methyl-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof, comprising either reducing 1,1-di-n-propyl-n-butylisocyanate with lithium aluminium hydride in an anhydrous inert solven or heating 1,1-di-n-propyl-n-butylamine in the presence of formol and sodium borohydride or in the presence of an alkaline agent and methyl bromide, and reacting the so-obtained n-butylamine with an acid to form the salt.
23. N-Methyl-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof whenever obtained by a process according to Claim 22 or its obvious chemical equivalents.
24. Process according to Claim 1c) for the preparation of N,N-trimethylene-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof, comprising reacting an appropriate cyclization agent with an acid addition salt of N-(3-hydroxy-n-propyl)-1,1-di-n-propyl-n-butylamine and reacting the so obtained n-butylamine with an acid to form the salt.
25. N,N-Trimethylene-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof whenever obtained by a process according to Claim 24 or its obvious chemical equivalents.
26. Process according to Claim 1e) for the preparation of N-methyl-1-n-propyl-1-isopropyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof, comprising reducing 1-n-propyl-1-isopropyl-n-butylisocyanate with lithium aluminium hydride in an anhydrous inert solvent and reacting the so-obtained n-butylamine with an acid to form the salt.
27. N-Methyl-1-n-pr,opyl-1-isopropyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof whenever obtained by a process according to Claim 26 or its obvious chemical equivalents.
28. Process according to Claim 1k) for the preparation of N-methyl-1-n-propyl-1-isobutyl-n-butylamine and the pharmaceu-tically acceptable acid addition salts thereof, comprising heating 1-n-propyl-1-isobutyl-n-butylamine in the presence of formol and sodium borohydride and reacting the so-obtained n-butylamine with an acid to form the salt.
29. N-Methyl-1-n-propyl-1-isobutyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof whenever obtained by a process according to Claim 28 or its obvious chemical equivalents.
30. Process according to Claim 1a) for the preparation of N-propargyl-1,1-di-n-propyl-n-butylamine and the pharmaceu-tically acceptable acid addition salts thereof, comprising heating 1,1-di-n-propyl-n-butylamine with an adequate quantity of propargyl bromide in the presence of an alkaline agent and reacting the so-obtained n-butylamine with an acid to form the salt.
31. N-Propargyl-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof whenever obtained by a process according to Claim 30 or its obvious chemical equivalents.
32. Process according to Claim 1a) for the preparation of N,N-dipropargyl-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof, comprising heating 1,1-di-n-propyl-n-butylamine with an adequate quantity of propargyl bromide in the presence of an alkaline agent and reacting the so-obtained n-butylamine with an acid to form the salt.
33. N,N-Diproparyyl-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof whenever obtained by a process according to claim 32 or its obvious chemical equivalents.
34. Process according to Claim 1d) for the preparation of N-ethylidene-1,1-di-n-propyl-n-butylamine and the pharmaceu-tically acceptable acid addition salts thereof, comprising condensing 1,1-di-n-propyl-n-butylamine with acetaldehyde and reacting the so-obtained n-butylamine with an acid to form the salt.
35. N-Ethylidene-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof whenever obtained by a process according to Claim 34 or its obvious chemical equivalents.
36. Process according to Claim 1d) for the preparation of N-methylene-1,1-di-n-propyl-n-butylamine and the pharmaceuti-cally acceptable acid addition salts thereof, comprising condensing 1,1-di-n-propyl-n-butylamine with formaldehyde and reacting the so-obtained n-butylamine with an acid to form the salt.
37. N-Methylene-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof whenever obtained by a process aecording to Claim 36 or its obvious chemical equivalents.
38. Process according to Claim 1c) for the preparation of N,N-ethylene-1,1-di-n-propyl-n-butylamine and the pharmaceu-tically acceptable acid addition salts thereof, comprising reacting an appropriate cyclization agent with N-(2-hydroxyethyl)-1,1-di-n-propyl-n-butylamine hydrochloride and reacting the so-obtained salt with a base to form the corresponding n-butylamine that can be further acidified with an acid to form the salt.
39. N,N-ethylene-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof whenever obtained by a process according to claim 38 or its obvious chemica1 equivalents.
40. Process according to Claim 1b) for the preparation of N-(2-hydroxyethyl)-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof, comprising treating ethyl 2-(1,1-di-n-propyl-n-butylamine) -ethanoate with lithium aluminium hydride in an inert and anhydrous medium, hydrolyzing the treated product and reacting the so-obtained n-butylamine with an acid to form the salt.
41. N-(2-Hydroxyethyl)-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof whenever obtained by a process according to Claim 40 or its obvious chemical equivalents.
42. Process according to Claim 1b) for the preparation of N-(3-hydroxy-n-propyl)-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof, comprising treating methyl 3-(1,1-di-n-propyl-n-butylamino) -propanoate with lithium aluminium hydride in an inert and anhydrous medium, hydrolyzing the treated product and reacting the so-obtained n-butylamine with an acid to form the salt.
43. N-(3-Hydroxy-n-propyl)-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof whenever obtained by a process according to Claim 42 or its obvious chemical equivalents.
44. Process according to Claim 1j) for the preparation of N,N-(3-oxapentamethylene)-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts, comprising reacting in an anhydrous ether, 2-N-morpholino-2-n-propyl-valeronitrile with n-propyl magnesium bromide, hydrolyzing the complex so-formed and reacting the so-obtained n-butylamine with an acid to form the salt.
45. N,N?3-Oxapentamethylene)-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof whenever obtained by a process according to claim 44 or its obvious chemical equivalents.
46. Process according to Claim 1 for the preparation of the hydrochloride and fumarate salts of the n-butylamine derivatives of the general formula I, wherein the obtained derivative of the general formule I is reacted with hydrochloric or fumaric acid.
47. Hydrochloride or fumarate salt of the n-butyl derivatives of the general formula I, whenever obtained by a process according to Claim 46 or its obvious chemical equivalents.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA338,050A CA1078837A (en) | 1976-06-03 | 1979-10-19 | Active derivatives of methylamine, therapeutic compositions containing the same and processes for preparing the said derivatives and compositions |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BE167579A BE842528R (en) | 1976-06-03 | 1976-06-03 | METHYLAMINE ACTIVE DERIVATIVES, THERAPEUTIC COMPOSITIONS CONTAINING THEM AND THE PROCESSES FOR THE PREPARATION OF THESE DERIVATIVES AND COMPOSITIONS |
| CA279,749A CA1076482A (en) | 1976-06-03 | 1977-06-02 | Active derivatives of methylamine, therapeutic compositions containing the same and processes for preparing the said derivatives and compositions |
| CA338,050A CA1078837A (en) | 1976-06-03 | 1979-10-19 | Active derivatives of methylamine, therapeutic compositions containing the same and processes for preparing the said derivatives and compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1078837A true CA1078837A (en) | 1980-06-03 |
Family
ID=27158598
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA338,050A Expired CA1078837A (en) | 1976-06-03 | 1979-10-19 | Active derivatives of methylamine, therapeutic compositions containing the same and processes for preparing the said derivatives and compositions |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1078837A (en) |
-
1979
- 1979-10-19 CA CA338,050A patent/CA1078837A/en not_active Expired
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