CA1076482A - 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
- Publication number
- CA1076482A CA1076482A CA279,749A CA279749A CA1076482A CA 1076482 A CA1076482 A CA 1076482A CA 279749 A CA279749 A CA 279749A CA 1076482 A CA1076482 A CA 1076482A
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutical
- propyl
- active ingredient
- butylamine
- veterinary composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Abstract
ABSTRACT OF THE DISCLOSURE:
A pharmaceutical or veterinary composition for use in the treatment of Parkinson's disease and the correction of extra-pyramidal disturbances provoked by neuroleptics. This composition comprises, as essential active ingredient, at least one compound represented by the general formula :
or a pharmaceutically acceptable acid addition salt thereof, wherein R1 and R3, which are the same or different , each represent a branched-or straight- chain alkyl radical having 3 or 4 carbon atoms, R4 represents hydrogen or a branched-or straight- chain alkyl, alkenyl or alkynyl radical having from 1 to 5 carbon atoms and R5 represents a branched- or straight- chain alkyl, alkenyl or alkynyl radical having from 1 to 5 carbon atoms, with the proviso that:
- when R4 represents hydrogen, R5 is other than methyl or propargyl - when R4 represents propargyl, R5 is other than propargyl.
This compound is in association with a pharmaceutical carrier or excipient therefor.
A pharmaceutical or veterinary composition for use in the treatment of Parkinson's disease and the correction of extra-pyramidal disturbances provoked by neuroleptics. This composition comprises, as essential active ingredient, at least one compound represented by the general formula :
or a pharmaceutically acceptable acid addition salt thereof, wherein R1 and R3, which are the same or different , each represent a branched-or straight- chain alkyl radical having 3 or 4 carbon atoms, R4 represents hydrogen or a branched-or straight- chain alkyl, alkenyl or alkynyl radical having from 1 to 5 carbon atoms and R5 represents a branched- or straight- chain alkyl, alkenyl or alkynyl radical having from 1 to 5 carbon atoms, with the proviso that:
- when R4 represents hydrogen, R5 is other than methyl or propargyl - when R4 represents propargyl, R5 is other than propargyl.
This compound is in association with a pharmaceutical carrier or excipient therefor.
Description
1C)7~41~'~
This invention relates to pharmaceutical or veterinary compositions containing methylamine derivatives useful in the treatment of Parkinson's disease and Eor the correction of extra-pyramidal disturbances provoked by neuroleptics.
Thus in accordance with the invention there is provided a pharmaceutical or veterinary composition comprising as an essential active ingredient, at least one methylamine derivative represented by the general formula :
CH3-C~l2-c~-2 \ , / 4 R3 R5 .-wherein Rl and R3, which are the same or different, each .
represent a branched- or straight-chain alkyl radical having 3 ~:
or 4 carbon atoms, R4 represents hydrogen or a branched- .
or straight- chain alkyl, alkenyl or alkynyl radical having from 1 to 5 carbon atoms and R5 represents a branched- or .. ~ .
straight- chain alkyl, alkenyl or alkynyl radical having from :
1 to S carbon atoms with the proviso that : :
- when R4 represents hydrogen, R5 is other than methyl or propargyl ~ .
- when R4 represents p.~opargyl, R5 is other than propargyl, in association with a pharmaceutical carrier or excipient therefor.
The present invention also includes within its scope .
a pharmaceutical or ve-terinary composition comprising, as I essential active ingredient, a pharmaceutically acceptable acid addition salt o~ at least one compound of the above formula I
such as an acid addition salt obtained with an inorganic acid, for example, hydrochloric acid, or with an inorganic acid in which the free carboxyl group is attached to a saturated or unsaturated aliphatic radical, or an aromatic or aralkyl radical, which may optionally contain a second carboxyl group as, for ~, J
,,,,,,,; ~
~, :~ , . .
1C~764~2 example fumaric acid, in association with a pharmaceutical carrier or excipient therefor.
Daily dosage will preferably be between 10 and 60 mg of active ingredient for a human beiny weighing 60 kg.
A preferred class of compounds of formula I can be represented by the fo]lowing general formula :
n C3H7 \ / R'~
n~ C-N R~5 Ia n-C3H7 wherein R'4 represents hydrogen or methyl and R'5 represents methyl, ethyl, n-propyl, isopropyl or allyl with the proviso that when R'4 represents hydrogen, R'5 is other than me-thyl and pharmaceutically acceptable acid addition salts thereof.
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 pharmaceutical or veterinary composition of the invention will normally be administered in the form of a dosage unit form appropriate to the required mode of administration, the composition comprising as active ingredient a compound of the invention in association with a pharmaceutical carrier or excipient therefor. For oral administration, the composition may take the form of, for example, a coated or uncoated tablet, a hard- or soft-gelatin capsule, a susuension 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~nit form the composition may contain
This invention relates to pharmaceutical or veterinary compositions containing methylamine derivatives useful in the treatment of Parkinson's disease and Eor the correction of extra-pyramidal disturbances provoked by neuroleptics.
Thus in accordance with the invention there is provided a pharmaceutical or veterinary composition comprising as an essential active ingredient, at least one methylamine derivative represented by the general formula :
CH3-C~l2-c~-2 \ , / 4 R3 R5 .-wherein Rl and R3, which are the same or different, each .
represent a branched- or straight-chain alkyl radical having 3 ~:
or 4 carbon atoms, R4 represents hydrogen or a branched- .
or straight- chain alkyl, alkenyl or alkynyl radical having from 1 to 5 carbon atoms and R5 represents a branched- or .. ~ .
straight- chain alkyl, alkenyl or alkynyl radical having from :
1 to S carbon atoms with the proviso that : :
- when R4 represents hydrogen, R5 is other than methyl or propargyl ~ .
- when R4 represents p.~opargyl, R5 is other than propargyl, in association with a pharmaceutical carrier or excipient therefor.
The present invention also includes within its scope .
a pharmaceutical or ve-terinary composition comprising, as I essential active ingredient, a pharmaceutically acceptable acid addition salt o~ at least one compound of the above formula I
such as an acid addition salt obtained with an inorganic acid, for example, hydrochloric acid, or with an inorganic acid in which the free carboxyl group is attached to a saturated or unsaturated aliphatic radical, or an aromatic or aralkyl radical, which may optionally contain a second carboxyl group as, for ~, J
,,,,,,,; ~
~, :~ , . .
1C~764~2 example fumaric acid, in association with a pharmaceutical carrier or excipient therefor.
Daily dosage will preferably be between 10 and 60 mg of active ingredient for a human beiny weighing 60 kg.
A preferred class of compounds of formula I can be represented by the fo]lowing general formula :
n C3H7 \ / R'~
n~ C-N R~5 Ia n-C3H7 wherein R'4 represents hydrogen or methyl and R'5 represents methyl, ethyl, n-propyl, isopropyl or allyl with the proviso that when R'4 represents hydrogen, R'5 is other than me-thyl and pharmaceutically acceptable acid addition salts thereof.
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 pharmaceutical or veterinary composition of the invention will normally be administered in the form of a dosage unit form appropriate to the required mode of administration, the composition comprising as active ingredient a compound of the invention in association with a pharmaceutical carrier or excipient therefor. For oral administration, the composition may take the form of, for example, a coated or uncoated tablet, a hard- or soft-gelatin capsule, a susuension 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~nit form the composition may contain
2 -.
. .
.
6~182 Erom 5 to 50 mg, preerably from 5 to 20 mg of the active ingredient per dosage unit Eor 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 oE 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, kaokin, levilite and cocoa butter.
The compounds of formula I are believed to be known being either covered by general formulae of previous references or specifically cited in such references.
- In this connection Canadian Patent N 522,710 and U.S. Patent N 3,067,101 can be cited. -The compounds of formula I above can be prepared by heating, in the presence of an alkaline agent, such as for example, sodium bicarbonate, an amine of the yeneral formula:
CH3-CH2 CH2 ~
Rl~ C-NHR7 II
Ri' or an acid addition salt thereof, such as for example, the hydrochloride, in which Rl and R3 have the same meaning as in formula I and R7 represents hydrogen or a branched or straight-chain alkyl, alkenyl or alkynyl radical having from 1 to 5 carbon atoms, with an appropriate quantity of an halide of the genéral formula :
wherein R8 represents a branched- or straight-chain alkyl, .... .
..... ~.
', . , .~, .
, 1 ~76~8Z
alkenyl or alkynyl radical having from 1 to 5 carbon atoms and X
represents chlorine, bromine or iodine, this reaction being undertaken either without any solvent or in the presence of a solvent, such as for example ethanol, to obtain the required compound of formula I.
In accordance with known chemical proceclures and when it is desired to obtain a compound of formula I having two identical substituents on the nitrogen atom, the appropriate compound of formula II i.e. a compound of formula II wherein Rl and R3 have the desired meaning and R7 represents hydrogen, is treated so that two molar equivalents of the halide of formula III react with one molar equivalent of the compound of formula II.
Likewise, when it is desired to obtain a compound of formula I having a hydrogen atom on the nitrogen atom, the appro-priate compound of formula II i.e. a compound of formula II
wherein Rl and R3 have the desired meaning and R7 represents hydro -hydrogen is treated so that one molar equivalent oE 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 monosubstituted 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 I 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 mixtures of mono- and di-substituted derivatives can be separated out by known techniques, for example by ,.. . . . .
. . .
.
~076~82 fractional distillation of the reaction mixture containing them or by fractional crystallization from their salts.
A certain number of N-substituted methylamine deriva-tives of formule I can also be obtained in accordance with other methods than those already described herein.
For instance, the compound of formula I in which .
Rl, R3 and R5 have the meaning cited therein ancl R4 represents ~.
hydrogen can be prepared starting with a compound of the general formula :
CH3-CH2 CH2 ~
/ C-A IX
wherein Rl and R3 have the meaning given in formula I and A
represents the group NH-CO-R14 or N=CH-R14 in which R14 :
represents a branched- or straight- chain alkyl, alkenyl or alkynyl radical having from 1 to 4 carbon atoms and reducing this compound:
a) in an appropriate anhydrous medium, such as for example ~ ~:
ethyl or butyl ether,. with lithium aluminium hydride in the case where A represents NH-CO-R14 b) in a solvent such as for example methanol, with sodium borohydride in the case where A represents N-CH~R14 to provide the required compound of formula I .
- The compounds of formula I wherein Rl and R3 have the meaning cited therein, R4 represents methyl and R5 represents I a straight- or branched - chain alkyl radical having from 1 to 5carbon atoms can also be obtained by heating a methylamine . .
derivative of the general formula :
CH3~CH2-CH2 \
30 Rl.-_ C NHR15 X
or an acid addition salt thereof, for example the hydrochloride, ' 10764~3~
wherein Rl and R3 have the same meaning as in formula I and R15 represents a straight- or branched- chain alkyl radical having from 1 to 5 carbon atoms, in the presence of Eormic aldehyde and formic acid to give the desired compound of Eormula I.
The compounds of formula I prepared in accordance with any one of the above cited processes can be reacted r with an organic or inorganic acid so as to provide a pharmaceu-tically acceptable acid addition salt thereof.
Amongst the compounds oE formula II, those wherein R
represents hydrogen are known products having been described together with their process of preparation in Canadian Patent N 1,056,730.
The other compounds of formula II as well as the compounds of formula V are compounds which can be prepared by methods described above.
The compounds of formula IX in which A represents the group NH-CO-R14 can be prepared either in the absence of a solvent or in a solvent, such as for example benzene, and in the presence of an acid acceptor, such as for example pyridine or 2,6-dimethyl-pyridine, by reacting a methylamine derivative of formula II in which R7 represents hydrogen with a halide or an anhydride of the general formula:
O
Il XV
R14-C-Rlg ~. ~
in which R14 has the same meaning as in formula IX and Rlg I represents an atom of chlorine, bromine or a radical O-CO-R14 wherein R14has the same meaning as in formula IV, to provide the required compound.
The other compounds of formula IX, namely those wherein A represents N-CH-R14 can be obtained by condensing a methylamine derivative of formula II in which R5 represents hydrogen with an aldehyde or a ketone of the general formula:
~ 6 -'~ ', ' ': ., ' 10764~32 ll XVI
17 Rl~
in which Rl7 represents hydrogen or an alkyl, alkenyl or alkynyl radical having Erom 1 to 3 carbon atoms and R18 represents an alkyl having from 1 to 3 carbon atoms, the operation of condensation being carried out either in the absence of a solvent or in the presence of a solvent such as for example benzene, to provide the desired compound.
As mentioned above, it has been discovered that the methylamine derivatives oE 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 cholinolytic agents.
These pharmacological properties taken as a wholè
I are likely to render the compounds of formula I useful in treating Parkinson's disease as well as for correcting extra-pyramidal disturbances provoked by neuroleptics.
Compounds which are tri-substituted on the methyl-amine moiety but not substitu~ted on the nitrogen atom are alreadyknown as possessing central noradrenergic and central dopaminergic properties which are likely to be used in the treatment of ...
- ' ' ' ,, '' :'', ' . ' , ' . , 1C~76482 Parkinson's dise~se ancl Eor the correction oE extra-pyramidal disturbanees provoked by neuroleptics. -Such compounds have been described in Canadian Patent NO 1,056,730.
However, pharmaeological tests have shown that the methylamine derivatives of the invention have a weak tremor-indueing action. This tremor-indueing aetion was even found to be less potent than that of l,l-di-n-propyl-n-butylamine described in the above-cited Canadian Patent.
It is desirable that the tremor-induciny action in question be as weak as possible since tremors are the first sign of a motor stimulation whieh ean be eonsidered as an undesirable side-effect.
Sueh a motor stimulation frequently provokes mental and physieal fatigue.
In persons suffering from depression a phase of intensi-fied mental depression ean therefore occur which must, of course, be avoided.
A motor stimulation is also contra-indicated in epileptic patients sinee it can give rise to seizures.
Furthermore, the eompounds of the invention are also more advantageous than amantadine i.e. l-amino-adamantane, a product which is widely used in the treatment of Parkinson's disease.
Although the pharmaeologieal spectrum of the compounds I of *he invention is very similar to that of amantadine, pharma-eologieal trials performed with the compounds of the invention , ~ ., have revealed marked differenees in eomparison with amantadine.
For example, when eomparing the doses of the eompounds of the invention and of amantadine whieh have a eertain degree of aetivity, it has been observed that the aetive dose in question is always proportionally farther from the toxie dose in the L .i.,` - ~3 - ' . ,. . ~ . . .
~' . ' , : ' .
'', - 1()7~482 ~
case of the compounds of the invention than in the case of amantadine. ~n other words, the saEety margin offered by the compounds oE the invention is superior to that of amantadine.
The search for new antiparkinsonian agents is of primary importance since the treatment is of long duration and the alternating use of different products is necessary.
From this point of view, the compounds of the invention will constitute valuab]e additions to the;available antiparkinsonian agents, since at present there is no ideal agent for the treatment of this disease as explained hereabove.
The N,N-di-substituted derivative of the present invention which has shown the most valuable properties for constituting an antiparkinsonian agent, is:
N,N-dimethyl-l,l-di-n-propyl-n-butylamine this compound being used in the form of its free base or in the form of a pharmaceutically acceptable acid addition salt such as, for example, the hydrochloride or the fumarate.
The central dopaninergic activity found in the compounds of the present invention is illustrated hereunder in the case of some compounds of the invention in comparison with amantadine.
These compounds were preferably studied in the Eorm of a pharma-ceutically acceptable acid addition salt. They are the following:
N,N-dimethyl-l,l-di-n-propyl-n-butylamine (Compound 1) N-ethyl-l,l-di-n-propyl-n-butylamine (Compound 2) N-isopropyl-l,l-di-n-propyl-n-butylamine (Compound 3) I N-allyl-l,l-di-n-propyl-n-butylamine (Compound 4) -N,N-dimethyl-l-n-propyl-l-isobutyl-n-butylamine (Compound 5) N-methyl-N-ethyl-l,l-di-n-propyl-n-butylamine (Compound 6) I. Inhibition of reserPine-induced and neuroleptic-induced catatonia (dopaminergic properties) ~1 . 9 1~)7648Z
1. Inhibltlon of reser~ine-induced catatonla' The test undertaken for this purpose is identical -to that described in Canadian Patent No 1,056,730.
The results obtained with the compounds of the .
invention listed hereabove as well as with amantadine are given in Table I hereunder. ~ :
These results are expressed according to the same .
scoring system, from 0 to 4, as that set out in the above-cited Canadian'Patent.
TABLE I
' , Dose Inhibition of Compound administered reserpine in mg/kg induced catatonia 2 6 2 .-
. .
.
6~182 Erom 5 to 50 mg, preerably from 5 to 20 mg of the active ingredient per dosage unit Eor 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 oE 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, kaokin, levilite and cocoa butter.
The compounds of formula I are believed to be known being either covered by general formulae of previous references or specifically cited in such references.
- In this connection Canadian Patent N 522,710 and U.S. Patent N 3,067,101 can be cited. -The compounds of formula I above can be prepared by heating, in the presence of an alkaline agent, such as for example, sodium bicarbonate, an amine of the yeneral formula:
CH3-CH2 CH2 ~
Rl~ C-NHR7 II
Ri' or an acid addition salt thereof, such as for example, the hydrochloride, in which Rl and R3 have the same meaning as in formula I and R7 represents hydrogen or a branched or straight-chain alkyl, alkenyl or alkynyl radical having from 1 to 5 carbon atoms, with an appropriate quantity of an halide of the genéral formula :
wherein R8 represents a branched- or straight-chain alkyl, .... .
..... ~.
', . , .~, .
, 1 ~76~8Z
alkenyl or alkynyl radical having from 1 to 5 carbon atoms and X
represents chlorine, bromine or iodine, this reaction being undertaken either without any solvent or in the presence of a solvent, such as for example ethanol, to obtain the required compound of formula I.
In accordance with known chemical proceclures and when it is desired to obtain a compound of formula I having two identical substituents on the nitrogen atom, the appropriate compound of formula II i.e. a compound of formula II wherein Rl and R3 have the desired meaning and R7 represents hydrogen, is treated so that two molar equivalents of the halide of formula III react with one molar equivalent of the compound of formula II.
Likewise, when it is desired to obtain a compound of formula I having a hydrogen atom on the nitrogen atom, the appro-priate compound of formula II i.e. a compound of formula II
wherein Rl and R3 have the desired meaning and R7 represents hydro -hydrogen is treated so that one molar equivalent oE 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 monosubstituted 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 I 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 mixtures of mono- and di-substituted derivatives can be separated out by known techniques, for example by ,.. . . . .
. . .
.
~076~82 fractional distillation of the reaction mixture containing them or by fractional crystallization from their salts.
A certain number of N-substituted methylamine deriva-tives of formule I can also be obtained in accordance with other methods than those already described herein.
For instance, the compound of formula I in which .
Rl, R3 and R5 have the meaning cited therein ancl R4 represents ~.
hydrogen can be prepared starting with a compound of the general formula :
CH3-CH2 CH2 ~
/ C-A IX
wherein Rl and R3 have the meaning given in formula I and A
represents the group NH-CO-R14 or N=CH-R14 in which R14 :
represents a branched- or straight- chain alkyl, alkenyl or alkynyl radical having from 1 to 4 carbon atoms and reducing this compound:
a) in an appropriate anhydrous medium, such as for example ~ ~:
ethyl or butyl ether,. with lithium aluminium hydride in the case where A represents NH-CO-R14 b) in a solvent such as for example methanol, with sodium borohydride in the case where A represents N-CH~R14 to provide the required compound of formula I .
- The compounds of formula I wherein Rl and R3 have the meaning cited therein, R4 represents methyl and R5 represents I a straight- or branched - chain alkyl radical having from 1 to 5carbon atoms can also be obtained by heating a methylamine . .
derivative of the general formula :
CH3~CH2-CH2 \
30 Rl.-_ C NHR15 X
or an acid addition salt thereof, for example the hydrochloride, ' 10764~3~
wherein Rl and R3 have the same meaning as in formula I and R15 represents a straight- or branched- chain alkyl radical having from 1 to 5 carbon atoms, in the presence of Eormic aldehyde and formic acid to give the desired compound of Eormula I.
The compounds of formula I prepared in accordance with any one of the above cited processes can be reacted r with an organic or inorganic acid so as to provide a pharmaceu-tically acceptable acid addition salt thereof.
Amongst the compounds oE formula II, those wherein R
represents hydrogen are known products having been described together with their process of preparation in Canadian Patent N 1,056,730.
The other compounds of formula II as well as the compounds of formula V are compounds which can be prepared by methods described above.
The compounds of formula IX in which A represents the group NH-CO-R14 can be prepared either in the absence of a solvent or in a solvent, such as for example benzene, and in the presence of an acid acceptor, such as for example pyridine or 2,6-dimethyl-pyridine, by reacting a methylamine derivative of formula II in which R7 represents hydrogen with a halide or an anhydride of the general formula:
O
Il XV
R14-C-Rlg ~. ~
in which R14 has the same meaning as in formula IX and Rlg I represents an atom of chlorine, bromine or a radical O-CO-R14 wherein R14has the same meaning as in formula IV, to provide the required compound.
The other compounds of formula IX, namely those wherein A represents N-CH-R14 can be obtained by condensing a methylamine derivative of formula II in which R5 represents hydrogen with an aldehyde or a ketone of the general formula:
~ 6 -'~ ', ' ': ., ' 10764~32 ll XVI
17 Rl~
in which Rl7 represents hydrogen or an alkyl, alkenyl or alkynyl radical having Erom 1 to 3 carbon atoms and R18 represents an alkyl having from 1 to 3 carbon atoms, the operation of condensation being carried out either in the absence of a solvent or in the presence of a solvent such as for example benzene, to provide the desired compound.
As mentioned above, it has been discovered that the methylamine derivatives oE 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 cholinolytic agents.
These pharmacological properties taken as a wholè
I are likely to render the compounds of formula I useful in treating Parkinson's disease as well as for correcting extra-pyramidal disturbances provoked by neuroleptics.
Compounds which are tri-substituted on the methyl-amine moiety but not substitu~ted on the nitrogen atom are alreadyknown as possessing central noradrenergic and central dopaminergic properties which are likely to be used in the treatment of ...
- ' ' ' ,, '' :'', ' . ' , ' . , 1C~76482 Parkinson's dise~se ancl Eor the correction oE extra-pyramidal disturbanees provoked by neuroleptics. -Such compounds have been described in Canadian Patent NO 1,056,730.
However, pharmaeological tests have shown that the methylamine derivatives of the invention have a weak tremor-indueing action. This tremor-indueing aetion was even found to be less potent than that of l,l-di-n-propyl-n-butylamine described in the above-cited Canadian Patent.
It is desirable that the tremor-induciny action in question be as weak as possible since tremors are the first sign of a motor stimulation whieh ean be eonsidered as an undesirable side-effect.
Sueh a motor stimulation frequently provokes mental and physieal fatigue.
In persons suffering from depression a phase of intensi-fied mental depression ean therefore occur which must, of course, be avoided.
A motor stimulation is also contra-indicated in epileptic patients sinee it can give rise to seizures.
Furthermore, the eompounds of the invention are also more advantageous than amantadine i.e. l-amino-adamantane, a product which is widely used in the treatment of Parkinson's disease.
Although the pharmaeologieal spectrum of the compounds I of *he invention is very similar to that of amantadine, pharma-eologieal trials performed with the compounds of the invention , ~ ., have revealed marked differenees in eomparison with amantadine.
For example, when eomparing the doses of the eompounds of the invention and of amantadine whieh have a eertain degree of aetivity, it has been observed that the aetive dose in question is always proportionally farther from the toxie dose in the L .i.,` - ~3 - ' . ,. . ~ . . .
~' . ' , : ' .
'', - 1()7~482 ~
case of the compounds of the invention than in the case of amantadine. ~n other words, the saEety margin offered by the compounds oE the invention is superior to that of amantadine.
The search for new antiparkinsonian agents is of primary importance since the treatment is of long duration and the alternating use of different products is necessary.
From this point of view, the compounds of the invention will constitute valuab]e additions to the;available antiparkinsonian agents, since at present there is no ideal agent for the treatment of this disease as explained hereabove.
The N,N-di-substituted derivative of the present invention which has shown the most valuable properties for constituting an antiparkinsonian agent, is:
N,N-dimethyl-l,l-di-n-propyl-n-butylamine this compound being used in the form of its free base or in the form of a pharmaceutically acceptable acid addition salt such as, for example, the hydrochloride or the fumarate.
The central dopaninergic activity found in the compounds of the present invention is illustrated hereunder in the case of some compounds of the invention in comparison with amantadine.
These compounds were preferably studied in the Eorm of a pharma-ceutically acceptable acid addition salt. They are the following:
N,N-dimethyl-l,l-di-n-propyl-n-butylamine (Compound 1) N-ethyl-l,l-di-n-propyl-n-butylamine (Compound 2) N-isopropyl-l,l-di-n-propyl-n-butylamine (Compound 3) I N-allyl-l,l-di-n-propyl-n-butylamine (Compound 4) -N,N-dimethyl-l-n-propyl-l-isobutyl-n-butylamine (Compound 5) N-methyl-N-ethyl-l,l-di-n-propyl-n-butylamine (Compound 6) I. Inhibition of reserPine-induced and neuroleptic-induced catatonia (dopaminergic properties) ~1 . 9 1~)7648Z
1. Inhibltlon of reser~ine-induced catatonla' The test undertaken for this purpose is identical -to that described in Canadian Patent No 1,056,730.
The results obtained with the compounds of the .
invention listed hereabove as well as with amantadine are given in Table I hereunder. ~ :
These results are expressed according to the same .
scoring system, from 0 to 4, as that set out in the above-cited Canadian'Patent.
TABLE I
' , Dose Inhibition of Compound administered reserpine in mg/kg induced catatonia 2 6 2 .-
3 6.5 2 , ' ::
4 6 2 6.5 3 6 6.5 2 ~, Amantadine 100 4 ., ~''~'' ~ .',.; ~: ~
Complementary trials have shown that at a dose of : 13 mg/kg, Compound 3 causes inhibition of reserpine~
I . induced catatonia equal to 4.
2. Inhibition oE neurole~tic-induced catatonia ____ _______________ _ __ _ The test performed for this purpose is identical to ' :' . 30 that described,in Ca'nadian Patent No 1,056,730. ~' The results obtained with compounds listed above in comparison with amantadine are set out in the following ,! ~, Table II together with the results obtained with the compound hereunder :
N-n-propyl-l,l-di-n-propyl-n-butylamine (Compound 7) The scoring system was that used hereabove for Table I.
TABLE II
, Dose Inhibit~on of Compound administered neuroleptic-induced . in my/kg catatonia ~, l 6 4 3 6.5 4 6.5 2 `~
: 6 6.5 2 7 6.5 2 ~:~ Amantadine lO0 4 .
~.
Complementary tests have shown that Compounds l and 3 at a dose as low as 3 mg/kg have an index of inhibi-tion of neuroleptic-induced catatonia equal to 2.
II. Acute toxicitY
The acute toxicity LD50 was determined on mice by I oral route using the same method as that described in Canadian Patent No 1,056,730.
- . The following results were recorded with compounds of the invention in comparison with amantadine:
. .
10~648Z
Compound LD50 in mg/kg ' ~ ' 2 100 ~- -110 .
6 > 120 Amantadine 1050 A comparison was made between the index 1,D50 EDioo of the compounds of the invention with the correspond-ing index of amantadine.
In this index, EDloo represents the effective dose to obtain 100% inhibition of the catatonia, this value being represented by the figure 4 in Tables I and II.
The following results were registered~
. Compound Index ~-: 2 16.5 21.6 : Amantadine 10 :~
These results again show that the compounds oE the present invention offer a greater safety margin than amantadlne.
: It will be appreciated that for therapeutic use the ~ :
compounds of the invention will normally be administered in the ~:~
form of a pharmaceutical or veterinary composition in a dosage unit form appropriate to the required mode of administration, :~
the composition comprising as active ingredient a compound of the invention in association with a pharmaceutical carrier or excipient therefor. For oral administration, the composition may take the form of, for example, a coated or uncoated tablet, a hard- or soEt-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 .1,"~, .
~ - 12 - . -.
,, . . ~ ~
, 1~76~L8Z
parenteral administration When in dosage uni~ ~orm the composition may contain from 5 to S0 mg, preferably from 5 to 20 mg of the active ingredient per dosage unit Eor 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 inven~ion 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, kaokin, levilite and cocoa butter.
The following Examples illustrate the preparation of the compounds of the invention together with a suitable therapeutic composition:
Preparation of N-ethyl-l,l-di-n-propyl-n-butylamine hydrochloride a) N-Ethyl-l~l-di-n-Pro~yl-n-butylamlne Ir;to a 500-ml three-necked flask, fitted with a mechanical stirrer and a condenser, were introduced 17.6 g (0.096 mol) of N-ethylidene-l,l-di-n-propyl-n-butylamine, and 150 ml of methanol. To this solution when cooledj 7.6 g (0.2 mol) of sodium borohydride were added slowly and while stirring.
After this operation, the mixture was maintained at a temperature of 5C for 30 minutes and then progressively heated under reflux. Thirty minutes later, the methanol was evaporated ofE under vacuum and 200 ml of water were added to the residue so obtained followed by 100 ml oE a solution of sodium hydroxide (d = I.38). The organic fraction was extracted with ether and the solu-tion was distilled under reduced pressure.
~1 13 -, . . ., .i ,~
1~7t;48Z
In this manner, 11.8 g of N-ethyl-l,l-cli-n-propyl-n-butylamine were collected in the form oE a colourless liquid.
s.P. : 80-~1 C under 11 to 12 mm ~Ig Yield : 69~
b) N-Ethyl~ di-n-~ro~yl-n-butxlamine hydrochloride _____ ___ _______ __ _______ ________ ___________ By bubbling dry gaseous hydrogen chloride through an ethereal solution of the amine previously prepared, N-ethyl-l,l-di-n-propyl-n-butylamine hydrochloride precipitated.
M.P. : l90-191C
Quantitative yield.
Preparation oE N-ethyl-l,l-di-n-propyl-n-butylamine hydrochloride a) N_Ac_tyl-l,l-di-n_pro~yl-n-butylamlne ~ -To a solution of 7.85 g (0.05 mol) of l,l-di-n-propyl-n-butylamine in 5.3 g of pyridine, 3.9 g of acetyl chloride were slowly added. The mixture was heated to 80C for 3 hours and then poured into 60 ml of iced water. The precipi- ~
tated so obtained was separated out, washed with water ~ ~ ;
and dried.
In this manner, 7 g of N-acetyl-l,l-di-n-propyl-n-butylamine were obtained after recrystallization Érom heptane.
M.P. : 91C.
Yield : 70%.
b) N-Etbyl-l~l-dl-n-~ro~yl-n-butylamine hydrochlorlde I To a suspension of 1.9 g of lithium aluminium hydride in 80 ml of butyl ether, were added, while stirring, 4 g (0.02 mol) of the N-acetylated derivative previousl~ obtained, dissolved in 20 ml of butyl ether. The mixture was progressi-vely heated under reflux which was maintained for 5 hours.
After hydrolysis by adding ice, the ethereal Eraction was separated out and washed twice with 70 ml of a 10~-hydro-r ~? 14 -} ~, .. .
1076~8Z
chloric acid solution. From the aqueous fraction, the hydrochloride of the desired amine was extracted with methylene chloride and the solution evaporated under vacuum.
In this mannerr 3 g of N-ethyl-l,l-di-n-butylamine hydrochloride were obtainecl in the form of colourless crystals.
M.P. : 190-191C
Yield : 67'~
EXAMPL~ 3 PreParation of N-n-propyl-l,l-di-n-propyl-n-butylamine hydro-chloride a) N-Propionyl-l,l-di-n-propyl-n-butylamine To a solution of 7.85 g (0.05 mol) of l,l-di-n-propyl-n-butylamine and 5.3 g of 2,6-dimethyl-pyridine in 100 ml of dry benzene were added, drop-by-drop and at room-temperature, ~ -
Complementary trials have shown that at a dose of : 13 mg/kg, Compound 3 causes inhibition of reserpine~
I . induced catatonia equal to 4.
2. Inhibition oE neurole~tic-induced catatonia ____ _______________ _ __ _ The test performed for this purpose is identical to ' :' . 30 that described,in Ca'nadian Patent No 1,056,730. ~' The results obtained with compounds listed above in comparison with amantadine are set out in the following ,! ~, Table II together with the results obtained with the compound hereunder :
N-n-propyl-l,l-di-n-propyl-n-butylamine (Compound 7) The scoring system was that used hereabove for Table I.
TABLE II
, Dose Inhibit~on of Compound administered neuroleptic-induced . in my/kg catatonia ~, l 6 4 3 6.5 4 6.5 2 `~
: 6 6.5 2 7 6.5 2 ~:~ Amantadine lO0 4 .
~.
Complementary tests have shown that Compounds l and 3 at a dose as low as 3 mg/kg have an index of inhibi-tion of neuroleptic-induced catatonia equal to 2.
II. Acute toxicitY
The acute toxicity LD50 was determined on mice by I oral route using the same method as that described in Canadian Patent No 1,056,730.
- . The following results were recorded with compounds of the invention in comparison with amantadine:
. .
10~648Z
Compound LD50 in mg/kg ' ~ ' 2 100 ~- -110 .
6 > 120 Amantadine 1050 A comparison was made between the index 1,D50 EDioo of the compounds of the invention with the correspond-ing index of amantadine.
In this index, EDloo represents the effective dose to obtain 100% inhibition of the catatonia, this value being represented by the figure 4 in Tables I and II.
The following results were registered~
. Compound Index ~-: 2 16.5 21.6 : Amantadine 10 :~
These results again show that the compounds oE the present invention offer a greater safety margin than amantadlne.
: It will be appreciated that for therapeutic use the ~ :
compounds of the invention will normally be administered in the ~:~
form of a pharmaceutical or veterinary composition in a dosage unit form appropriate to the required mode of administration, :~
the composition comprising as active ingredient a compound of the invention in association with a pharmaceutical carrier or excipient therefor. For oral administration, the composition may take the form of, for example, a coated or uncoated tablet, a hard- or soEt-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 .1,"~, .
~ - 12 - . -.
,, . . ~ ~
, 1~76~L8Z
parenteral administration When in dosage uni~ ~orm the composition may contain from 5 to S0 mg, preferably from 5 to 20 mg of the active ingredient per dosage unit Eor 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 inven~ion 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, kaokin, levilite and cocoa butter.
The following Examples illustrate the preparation of the compounds of the invention together with a suitable therapeutic composition:
Preparation of N-ethyl-l,l-di-n-propyl-n-butylamine hydrochloride a) N-Ethyl-l~l-di-n-Pro~yl-n-butylamlne Ir;to a 500-ml three-necked flask, fitted with a mechanical stirrer and a condenser, were introduced 17.6 g (0.096 mol) of N-ethylidene-l,l-di-n-propyl-n-butylamine, and 150 ml of methanol. To this solution when cooledj 7.6 g (0.2 mol) of sodium borohydride were added slowly and while stirring.
After this operation, the mixture was maintained at a temperature of 5C for 30 minutes and then progressively heated under reflux. Thirty minutes later, the methanol was evaporated ofE under vacuum and 200 ml of water were added to the residue so obtained followed by 100 ml oE a solution of sodium hydroxide (d = I.38). The organic fraction was extracted with ether and the solu-tion was distilled under reduced pressure.
~1 13 -, . . ., .i ,~
1~7t;48Z
In this manner, 11.8 g of N-ethyl-l,l-cli-n-propyl-n-butylamine were collected in the form oE a colourless liquid.
s.P. : 80-~1 C under 11 to 12 mm ~Ig Yield : 69~
b) N-Ethyl~ di-n-~ro~yl-n-butxlamine hydrochloride _____ ___ _______ __ _______ ________ ___________ By bubbling dry gaseous hydrogen chloride through an ethereal solution of the amine previously prepared, N-ethyl-l,l-di-n-propyl-n-butylamine hydrochloride precipitated.
M.P. : l90-191C
Quantitative yield.
Preparation oE N-ethyl-l,l-di-n-propyl-n-butylamine hydrochloride a) N_Ac_tyl-l,l-di-n_pro~yl-n-butylamlne ~ -To a solution of 7.85 g (0.05 mol) of l,l-di-n-propyl-n-butylamine in 5.3 g of pyridine, 3.9 g of acetyl chloride were slowly added. The mixture was heated to 80C for 3 hours and then poured into 60 ml of iced water. The precipi- ~
tated so obtained was separated out, washed with water ~ ~ ;
and dried.
In this manner, 7 g of N-acetyl-l,l-di-n-propyl-n-butylamine were obtained after recrystallization Érom heptane.
M.P. : 91C.
Yield : 70%.
b) N-Etbyl-l~l-dl-n-~ro~yl-n-butylamine hydrochlorlde I To a suspension of 1.9 g of lithium aluminium hydride in 80 ml of butyl ether, were added, while stirring, 4 g (0.02 mol) of the N-acetylated derivative previousl~ obtained, dissolved in 20 ml of butyl ether. The mixture was progressi-vely heated under reflux which was maintained for 5 hours.
After hydrolysis by adding ice, the ethereal Eraction was separated out and washed twice with 70 ml of a 10~-hydro-r ~? 14 -} ~, .. .
1076~8Z
chloric acid solution. From the aqueous fraction, the hydrochloride of the desired amine was extracted with methylene chloride and the solution evaporated under vacuum.
In this mannerr 3 g of N-ethyl-l,l-di-n-butylamine hydrochloride were obtainecl in the form of colourless crystals.
M.P. : 190-191C
Yield : 67'~
EXAMPL~ 3 PreParation of N-n-propyl-l,l-di-n-propyl-n-butylamine hydro-chloride a) N-Propionyl-l,l-di-n-propyl-n-butylamine To a solution of 7.85 g (0.05 mol) of l,l-di-n-propyl-n-butylamine and 5.3 g of 2,6-dimethyl-pyridine in 100 ml of dry benzene were added, drop-by-drop and at room-temperature, ~ -
5 g of propionyl chloride. The mixture was heated to 90C
for 5 hours and then poured into water. The benzene fraction was separated out and washed first with a diluted solution of sodium hydroxide and then with diluted hydrochloric acid.
The organic phase was dried over magnesium sulphate and evaporated under vacuum. -.
In this manner, 7 g of N-propionyl-l,l-di-n-propyl-n-butylamine were obtained after recrystallization from acetone.
This product was in the form of colourless crystals.
M.P. : 96C
i Yield : 66% ~ ;
b) N~n~PrOeyl-lLl-d~ roeyl-n-butylamille hydrochlorid_ To a suspension of 0.760 g (0.02 mol) of lithium aluminium hydride in 50 ml of anhydrous ethyl ether, were added 2,13 g (0.01 mol) of N-propionyl-l,l-di-n-propyl-n-butylamine, prepared as described hereabove. The mixture was heated . - under reflux for 3 hours and then hydrolysed by adding ice.
.....
' , ~ .. ': ~' , ~,,' , ; ' '' ' .
1076~8Z
The ethereal Eraction was separated out, washed twice with a 10%-hydrochloric acid solution and dried over magnesium sulphate. The desired hydrochloride was then precipitated by adding gaseous hydrogen chloride.
- In this manner, 1.5 g of N-n-propyl-l,l-di-n-propyl-n-butylamine hydrochloride were obtained after recrystalliza-tion from acetonitrile. This product was in the form o colourless crystals.
M.P. : 223C
Yield : 65~
..
Preparation of N-isopropYl-l,l-di-n-propyl-n-but~lamine hydro-chloride -~
~ -a) N-Iso~ro~yl-l,l-di-n-ero~yl-n-butylamine _ _ _ _ _ _ _ _ _ ,_ _ _ ~ :
Into a ~lask, fitted with a condenser, were introduced 15.7 g (0.1 mol) of l,l-di-n-propyl-n-butylamine, 20.4 g (0.12 ;
mol) of isopropyl iodide and lO.l g (0.12 mol~ of sodium - .
bicarbonate.
While stirring, the mixture was heated by means of an oil-bath maintained at 140C for 72 hours. The precipitate so obtained was filtered out and washed twice with ether.
after evaporation of the solvent, the oil so obtained was distilled using a spinning band column.
In this manner, 7.8 g of N-isopropyl-1,1-di-n-propyl-n-butylamine were obtained in the form of a colourless I liquid~
B.P. : 85C under 9 mm Hg Yield : 40~
b) N-Iso~ro~yl-l,l-di-n-~ropyl-n-butylamine hydrochloride _____ __ ___________ __ ___ ___ ________ ___________ In 100 ml of ethanol were dissolved 6 g Oe the amine previously prepared and the solution so obtained was treated with 3 ml of concentrated hydrochlorlc acid. The solution , ~ 1 16 - ~
.... . . .
. " , , , ~ .
-: , : ' ~07648Z
was evaporated to dryness and the desired hydrochloride was precipitated by adding lO0 ml of iso~eopyl ether. The - hydrochloride in question was then purified by sublimation under 1 mm Hg at a temperature of 210C.
In this manner, 4.8 g of N-isopropyl-l r l-n-propyl-n-butylamine hydrochloride were obtained in the form of cilourless crystals.
M.P. : 197 C (sublimation) Yield : 68%
Preparation of N-allyl-l,l-di-n-propvl-n-butylamine hydrochloride a) N-Allyl-lLl-di-n-~ro~yl-n-butylamine _ _ _ _ _ _ _ _ :
A mixture constituted by 12.1 g of allyl bromide, 25 9 of sodium bicarbonate, 250 ml of ethanol and 19.35 g (O.l mol) of l,l-di-n-propyl-n-butylamine hydrochloride was refluxed for 48 hours. After separation of the insoluble fraction, the ethanol was evaporated out under vacuum and ~he oil so obtained was treàted with 50 ml of a 10%-sodium hydroxide solution and 200 ml of ether. The organic phase was separated out and distilled under reduced pressure.
In this manner, 9 g of N-allyl-l,l di-n-p~opyl-n-butylamine were obtained in the form of a slightly coloured liquid.
B.P. : 1l6C under 20 mm Hg Yield : 89%
I b) N-Allyl-l l-di-n-~roeyl-n-butylamine hydrochloride _____ ___~_______ __ _____~_ ________ ___________ By bubbling dry gaseous hydrogen chloride through all ethereal solution of the amine so prepared, the desired hydrochloride was precipitated and then filtered out and dried.
In this manner, N-allyl-l,l-di-n-propyl-n-butylamine hydrochloride was obtained in the form of colourless crystals.
.
I~ 1 - 17 -,i,",, I
., . - .
, .
~(1 764~3Z
M.P. : 19~-195C
Quantitative yield.
~ XAMPLE 6 Preparation of N,N-dimethyl-l,l-di-n-propyl-n-butYlamine hydro-chloride a~ NLN-Dimethyl-lLl-di-n-prop~l-n-butylamine ________ ___ _______ __ _______ ______ Over a period of 6 hours, 40 ml of a 30~-solution of formic aldehyde and 15.7 g (O.Ol mol) of l,l-di-n-propyl-n-butylamine, were heated under reflux. After this operation, `
40 ml of pure formic acid were added and heating was maintain-ed for 7 hours. A-fter the solution was concentrated, the oil so obtained was treated with a diluted and ixed solution ~;~
of sodium hydroxide. The organic fraction was extracted with ether, dried over magnesium sulphate, concentrated under vacuum and distilled under reduced pressure.
In this manner, 16 g of N,N-dimethyl-l,l-di-n-propyl-n-butylamine were collected in the form of a col~urless liquid.
B.P. : 96-97 C under 15 mm Hg Yield : 86%
b) NLN-Dimethyl-lLl-di-n-~ro~yl-n-butylamine hydrochloride By bubbling gaseous dry hydrogen chloride through an ethereal solution of the amine previously obtained, the desired hydrochloride was precipitated.
In this manner, N,N-dimethyl-l,l-di-n-propyl-n-butyl-amine hydrochloride was obtained in the form of colourless I crystals.
M.P. : 228-229C (with sublimation) Quantitative yield.
Preparation of N,N-dimethyl-l-n-propYl-l-is~butyl-n-butyl mine hydrochloride a) NLN-Dimethyl-l-n-proPyl-l-lsobutyl-n-butylamine , - 18 -' ~ :' , ' ` ,,,, :
" , ,, :,.,, , , ~ .
10769L~3Z
In a two~necked flask, Eitted with a mechanical stirrer and a condenser, was heated under reflux for 5 hours a mixture of 10 ml of a 30%-aqueous solution of Eormic aldehyde, 10 ml of formic acid and 10.7 g (0.62 mol) of l-n-propyl-l-isobutyl-n-butylamine. After that, 10 ml of fuming hydrochloric acid (d= 1.19) were added to the cold solution which was then concentrated under partial vacuum.
The residual oil so obtained was then treated with 100 ml of distilled water and 30 ml of a sodium hydroxide solution (d = 1.38). The amine so obtained was extracted with ether and the organic fraction was distilled under reduced pressure.
- In this manner, 7.25 g of N,N-dimethyl-l-n-propyl-l- ~ `
isobutyl-n-butylamine was isolated in the form of a colourless liquid.
B.P. : 106-107C under 17 mm Hg Yield : 57%
b) N,N-Dimethyl-l-n-~ropyl-l-lsobutyl-n-butylamine hydrochloride By adding concentrated hydrochloric acid to an ethanolic solution of the amine previously obtained, the desired hydrochloride was precipitated, crystallized in isopropyl ether and then recrystallized from methylethylketone.
In this manner, N,N-dimethyl-l-n-propyl-l-isobutyl-n-butylamine hydrochloride was obtained in the form of colourless crystals.
M.P. : 186-187C
I Yield : 60%
Preparation of N-ethyl~N-methyl-l,l-di-n-propYl-n-butylamine hydrochloride a) N-Ethyl-N-methyl-l l-di-n-eropyl-n-butylamine _____ ________ ___~_______ __ _______ ______ Over a period of 5 hours, a mixture of 11.3 y (0.061 mol) of N-ethyl-l,l-di-n-propyl-n-butylamine, 10 ml of a .. . .
.
.. .. ..
.
.
.
. . .
.
~()7~48;2 :
30~-aqueous solution of formic aldehyde and 9.4 ml of ~ormic acid was reEluxed. To the reaction medium was added lO ml of concentrated and iced hydrochloric acid and the solution was then concentrated under vacuum. The oil so obtained was taken up with lO0 ml of water and 30 ml of a concentrated sodium hydroxide solution. The organic fraction was extracted with ether and distilled under reduced pressure using a spinning band column.
In this manner, lO g of N-ethyl-N-methyl-l,l-n-propyl~n-butylamine were isolated in the form of a colour-less liquid.
B.P. : 92C under ll mm Hg Yield : 83% ~ -b) N-Ethyl-N-meth~l-l,l-di-n-~ro~yl-n-butylamine hydrochloride _ _ _ _ _ _ _ _ _ :
To a solution of 7 g (0.035 mol) of the amine in lO0 ml of ethanol, were added 5 ml of concentrated hydrochloric acid.
The solution was concentrated to dryness and the oil so obtained was kaken up with 50 ml o~ isopropyl ether. The -precipitate was separated out and dried under vacuum at 50C in the presence of phosphorlc anhydride and potassium hydroxide. The dry product so obtained was then recrystalli-zed from lO0 ml of methylethylketone.
In this manner, 5 g of N-ethyl-N-methyl-l,l-di-n-propyl-n-butylamine hydrochloride were obtained in the form of colourless crystals which subl1mated at about 200C.
I Yield : 61 ~X~MPL~
A hard-gelatin capsule containing the following ingredients was prepared in accordance with known pharmaceutical techniques:
j~ J
.. .A. . .
.
. .
.. . . . . .
.
. .
.. . . . .
i~71~4~
Inqredients mq N,N-Dimethyl-l,l-di-n-propyl-n-butylamine hydrochloride 15 Milk sugar 50 ., ~"
, .. . . . . .
: ~ , . . . .
:~ ,, ,, ' . . . .
for 5 hours and then poured into water. The benzene fraction was separated out and washed first with a diluted solution of sodium hydroxide and then with diluted hydrochloric acid.
The organic phase was dried over magnesium sulphate and evaporated under vacuum. -.
In this manner, 7 g of N-propionyl-l,l-di-n-propyl-n-butylamine were obtained after recrystallization from acetone.
This product was in the form of colourless crystals.
M.P. : 96C
i Yield : 66% ~ ;
b) N~n~PrOeyl-lLl-d~ roeyl-n-butylamille hydrochlorid_ To a suspension of 0.760 g (0.02 mol) of lithium aluminium hydride in 50 ml of anhydrous ethyl ether, were added 2,13 g (0.01 mol) of N-propionyl-l,l-di-n-propyl-n-butylamine, prepared as described hereabove. The mixture was heated . - under reflux for 3 hours and then hydrolysed by adding ice.
.....
' , ~ .. ': ~' , ~,,' , ; ' '' ' .
1076~8Z
The ethereal Eraction was separated out, washed twice with a 10%-hydrochloric acid solution and dried over magnesium sulphate. The desired hydrochloride was then precipitated by adding gaseous hydrogen chloride.
- In this manner, 1.5 g of N-n-propyl-l,l-di-n-propyl-n-butylamine hydrochloride were obtained after recrystalliza-tion from acetonitrile. This product was in the form o colourless crystals.
M.P. : 223C
Yield : 65~
..
Preparation of N-isopropYl-l,l-di-n-propyl-n-but~lamine hydro-chloride -~
~ -a) N-Iso~ro~yl-l,l-di-n-ero~yl-n-butylamine _ _ _ _ _ _ _ _ _ ,_ _ _ ~ :
Into a ~lask, fitted with a condenser, were introduced 15.7 g (0.1 mol) of l,l-di-n-propyl-n-butylamine, 20.4 g (0.12 ;
mol) of isopropyl iodide and lO.l g (0.12 mol~ of sodium - .
bicarbonate.
While stirring, the mixture was heated by means of an oil-bath maintained at 140C for 72 hours. The precipitate so obtained was filtered out and washed twice with ether.
after evaporation of the solvent, the oil so obtained was distilled using a spinning band column.
In this manner, 7.8 g of N-isopropyl-1,1-di-n-propyl-n-butylamine were obtained in the form of a colourless I liquid~
B.P. : 85C under 9 mm Hg Yield : 40~
b) N-Iso~ro~yl-l,l-di-n-~ropyl-n-butylamine hydrochloride _____ __ ___________ __ ___ ___ ________ ___________ In 100 ml of ethanol were dissolved 6 g Oe the amine previously prepared and the solution so obtained was treated with 3 ml of concentrated hydrochlorlc acid. The solution , ~ 1 16 - ~
.... . . .
. " , , , ~ .
-: , : ' ~07648Z
was evaporated to dryness and the desired hydrochloride was precipitated by adding lO0 ml of iso~eopyl ether. The - hydrochloride in question was then purified by sublimation under 1 mm Hg at a temperature of 210C.
In this manner, 4.8 g of N-isopropyl-l r l-n-propyl-n-butylamine hydrochloride were obtained in the form of cilourless crystals.
M.P. : 197 C (sublimation) Yield : 68%
Preparation of N-allyl-l,l-di-n-propvl-n-butylamine hydrochloride a) N-Allyl-lLl-di-n-~ro~yl-n-butylamine _ _ _ _ _ _ _ _ :
A mixture constituted by 12.1 g of allyl bromide, 25 9 of sodium bicarbonate, 250 ml of ethanol and 19.35 g (O.l mol) of l,l-di-n-propyl-n-butylamine hydrochloride was refluxed for 48 hours. After separation of the insoluble fraction, the ethanol was evaporated out under vacuum and ~he oil so obtained was treàted with 50 ml of a 10%-sodium hydroxide solution and 200 ml of ether. The organic phase was separated out and distilled under reduced pressure.
In this manner, 9 g of N-allyl-l,l di-n-p~opyl-n-butylamine were obtained in the form of a slightly coloured liquid.
B.P. : 1l6C under 20 mm Hg Yield : 89%
I b) N-Allyl-l l-di-n-~roeyl-n-butylamine hydrochloride _____ ___~_______ __ _____~_ ________ ___________ By bubbling dry gaseous hydrogen chloride through all ethereal solution of the amine so prepared, the desired hydrochloride was precipitated and then filtered out and dried.
In this manner, N-allyl-l,l-di-n-propyl-n-butylamine hydrochloride was obtained in the form of colourless crystals.
.
I~ 1 - 17 -,i,",, I
., . - .
, .
~(1 764~3Z
M.P. : 19~-195C
Quantitative yield.
~ XAMPLE 6 Preparation of N,N-dimethyl-l,l-di-n-propyl-n-butYlamine hydro-chloride a~ NLN-Dimethyl-lLl-di-n-prop~l-n-butylamine ________ ___ _______ __ _______ ______ Over a period of 6 hours, 40 ml of a 30~-solution of formic aldehyde and 15.7 g (O.Ol mol) of l,l-di-n-propyl-n-butylamine, were heated under reflux. After this operation, `
40 ml of pure formic acid were added and heating was maintain-ed for 7 hours. A-fter the solution was concentrated, the oil so obtained was treated with a diluted and ixed solution ~;~
of sodium hydroxide. The organic fraction was extracted with ether, dried over magnesium sulphate, concentrated under vacuum and distilled under reduced pressure.
In this manner, 16 g of N,N-dimethyl-l,l-di-n-propyl-n-butylamine were collected in the form of a col~urless liquid.
B.P. : 96-97 C under 15 mm Hg Yield : 86%
b) NLN-Dimethyl-lLl-di-n-~ro~yl-n-butylamine hydrochloride By bubbling gaseous dry hydrogen chloride through an ethereal solution of the amine previously obtained, the desired hydrochloride was precipitated.
In this manner, N,N-dimethyl-l,l-di-n-propyl-n-butyl-amine hydrochloride was obtained in the form of colourless I crystals.
M.P. : 228-229C (with sublimation) Quantitative yield.
Preparation of N,N-dimethyl-l-n-propYl-l-is~butyl-n-butyl mine hydrochloride a) NLN-Dimethyl-l-n-proPyl-l-lsobutyl-n-butylamine , - 18 -' ~ :' , ' ` ,,,, :
" , ,, :,.,, , , ~ .
10769L~3Z
In a two~necked flask, Eitted with a mechanical stirrer and a condenser, was heated under reflux for 5 hours a mixture of 10 ml of a 30%-aqueous solution of Eormic aldehyde, 10 ml of formic acid and 10.7 g (0.62 mol) of l-n-propyl-l-isobutyl-n-butylamine. After that, 10 ml of fuming hydrochloric acid (d= 1.19) were added to the cold solution which was then concentrated under partial vacuum.
The residual oil so obtained was then treated with 100 ml of distilled water and 30 ml of a sodium hydroxide solution (d = 1.38). The amine so obtained was extracted with ether and the organic fraction was distilled under reduced pressure.
- In this manner, 7.25 g of N,N-dimethyl-l-n-propyl-l- ~ `
isobutyl-n-butylamine was isolated in the form of a colourless liquid.
B.P. : 106-107C under 17 mm Hg Yield : 57%
b) N,N-Dimethyl-l-n-~ropyl-l-lsobutyl-n-butylamine hydrochloride By adding concentrated hydrochloric acid to an ethanolic solution of the amine previously obtained, the desired hydrochloride was precipitated, crystallized in isopropyl ether and then recrystallized from methylethylketone.
In this manner, N,N-dimethyl-l-n-propyl-l-isobutyl-n-butylamine hydrochloride was obtained in the form of colourless crystals.
M.P. : 186-187C
I Yield : 60%
Preparation of N-ethyl~N-methyl-l,l-di-n-propYl-n-butylamine hydrochloride a) N-Ethyl-N-methyl-l l-di-n-eropyl-n-butylamine _____ ________ ___~_______ __ _______ ______ Over a period of 5 hours, a mixture of 11.3 y (0.061 mol) of N-ethyl-l,l-di-n-propyl-n-butylamine, 10 ml of a .. . .
.
.. .. ..
.
.
.
. . .
.
~()7~48;2 :
30~-aqueous solution of formic aldehyde and 9.4 ml of ~ormic acid was reEluxed. To the reaction medium was added lO ml of concentrated and iced hydrochloric acid and the solution was then concentrated under vacuum. The oil so obtained was taken up with lO0 ml of water and 30 ml of a concentrated sodium hydroxide solution. The organic fraction was extracted with ether and distilled under reduced pressure using a spinning band column.
In this manner, lO g of N-ethyl-N-methyl-l,l-n-propyl~n-butylamine were isolated in the form of a colour-less liquid.
B.P. : 92C under ll mm Hg Yield : 83% ~ -b) N-Ethyl-N-meth~l-l,l-di-n-~ro~yl-n-butylamine hydrochloride _ _ _ _ _ _ _ _ _ :
To a solution of 7 g (0.035 mol) of the amine in lO0 ml of ethanol, were added 5 ml of concentrated hydrochloric acid.
The solution was concentrated to dryness and the oil so obtained was kaken up with 50 ml o~ isopropyl ether. The -precipitate was separated out and dried under vacuum at 50C in the presence of phosphorlc anhydride and potassium hydroxide. The dry product so obtained was then recrystalli-zed from lO0 ml of methylethylketone.
In this manner, 5 g of N-ethyl-N-methyl-l,l-di-n-propyl-n-butylamine hydrochloride were obtained in the form of colourless crystals which subl1mated at about 200C.
I Yield : 61 ~X~MPL~
A hard-gelatin capsule containing the following ingredients was prepared in accordance with known pharmaceutical techniques:
j~ J
.. .A. . .
.
. .
.. . . . . .
.
. .
.. . . . .
i~71~4~
Inqredients mq N,N-Dimethyl-l,l-di-n-propyl-n-butylamine hydrochloride 15 Milk sugar 50 ., ~"
, .. . . . . .
: ~ , . . . .
:~ ,, ,, ' . . . .
Claims (12)
1. A pharmaceutical or veterinary composition for use in the treatment of Parkinson's disease and the correction of extra-pyramidal disturbances provoked by neuroleptics comprising as an essential active ingredient at least one compound represented by the general formula :
or a pharmaceutically acceptable acid addition salt thereof, wherein R1 and R3, which are the same or different, each represent a branched-or straight- chain alkyl radical having 3 or 4 carbon atoms, R4 represents hydrogen or a branched-or straight- chain alkyl, alkenyl or alkynyl radical having from 1 to 5 carbon atoms and R5 represents a branched- or straight- chain alkyl, alkenyl or alkynyl radical having from 1 to 5 carbon atoms with the proviso that:
- when R4 represents hydrogen, R5 is other than methyl or propargyl - when R4 represents propargyl, R5 is other than propargyl, in association with a pharmaceutical carrier or excipient therefor.
or a pharmaceutically acceptable acid addition salt thereof, wherein R1 and R3, which are the same or different, each represent a branched-or straight- chain alkyl radical having 3 or 4 carbon atoms, R4 represents hydrogen or a branched-or straight- chain alkyl, alkenyl or alkynyl radical having from 1 to 5 carbon atoms and R5 represents a branched- or straight- chain alkyl, alkenyl or alkynyl radical having from 1 to 5 carbon atoms with the proviso that:
- when R4 represents hydrogen, R5 is other than methyl or propargyl - when R4 represents propargyl, R5 is other than propargyl, in association with a pharmaceutical carrier or excipient therefor.
2. A pharmaceutical or veterinary composition for use in the treatment of Parkinson's disease and the correction of extra-pyramidal disturbances provoked by neuroleptics comprising as an essential active ingredient at least one compound represented by the general formula :
or a pharmaceutically acceptable acid addition salt thereof, wherein R'4 represents hydrogen or methyl and R'5 represents methyl, ethyl, n-propyl, isopropyl or allyl with the proviso that when R'4 represents hydrogen, R'5 is other than methyl, in association with a pharmaceutical carrier or excipient therefor.
or a pharmaceutically acceptable acid addition salt thereof, wherein R'4 represents hydrogen or methyl and R'5 represents methyl, ethyl, n-propyl, isopropyl or allyl with the proviso that when R'4 represents hydrogen, R'5 is other than methyl, in association with a pharmaceutical carrier or excipient therefor.
3. A pharmaceutical or veterinary composition according to claim 1 or 2, wherein the pharmaceutically acceptable acid addition salt is the hydrochloride or the fumarate.
4. A pharmaceutical or veterinary composition accord-ing to claim 1 or 2, wherein said carrier is selected from the group consisting of talc, magnesium stearate, milk sugar, saccharose, carboxymethylcellulose, starches, kaokin, levilite and cocoa butter.
5. A pharmaceutical or veterinary composition accord-ing to claim 1 or 2, wherein the composition is in a dosage unit form for oral administration and contains from 5 to 50 mg of said active ingredient per dosage unit form.
6. A pharmaceutical or veterinary composition according to claim 1 or 2, wherein the composition is in a dosage unit form suitable for rectal administration and contains from 5 to 100 mg of said active ingredient per dosage unit.
7. A pharmaceutical or veterinary composition according to claim 1 or 2, wherein the composition is in a dosage unit form suitable for parenteral administration and contains from 1 to 20 mg of said active ingredient per dosage unit.
8. A pharmaceutical or veterinary composition according to claim 1 or 2, wherein said active ingredient comprises N,N-dimethyl-1,1-di-n-propyl-n-butylamine or a pharmaceutically acceptable acid addition salt thereof.
9. A pharmaceutical or veterinary composition according to claim 1 or 2, wherein said active ingredient comprises N-ethyl-1,1-di-n-propyl-n-butylamine or a pharmaceu-tically acceptable acid addition salt thereof.
10. A pharmaceutical or veterinary composition according to claim 1 or 2, wherein said active ingredient comprises N-allyl-1,1-di-n-propyl-n-butylamine or a pharmaceu-tically acceptable acid addition thereof.
11. A pharmaceutical or veterinary composition accord-ing to claim 1 or 2, wherein said active ingredient comprises N-methyl-N-ethyl-1,1-di-n-propyl-n-butylamine or a pharmaceutical-ly acceptable acid addition salt thereof.
12. A pharmaceutical or veterinary composition according to claim 1 or 2, wherein said active ingredient comprises N,N-trimethylene-1,1-di-n-propyl-n-butylamine or a pharmaceutically acceptable acid addition salt thereof.
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 (1)
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1076482A true CA1076482A (en) | 1980-04-29 |
Family
ID=3842891
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA279,749A Expired 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 |
Country Status (9)
| Country | Link |
|---|---|
| BE (1) | BE842528R (en) |
| CA (1) | CA1076482A (en) |
| CH (4) | CH624922A5 (en) |
| DE (1) | DE2725245C2 (en) |
| GB (3) | GB1565023A (en) |
| HU (1) | HU175776B (en) |
| IE (1) | IE45730B1 (en) |
| IT (1) | IT1114869B (en) |
| OA (1) | OA05675A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GR61148B (en) * | 1976-06-03 | 1978-09-27 | Labaz | Preparation process of active methylamine derivatives |
| DE84943T1 (en) * | 1982-01-18 | 1983-11-10 | Exxon Research and Engineering Co., 07932 Florham Park, N.J. | SECOND AND TERTIARY AMINO ALCOHOLS. |
| WO1999065318A2 (en) * | 1998-06-18 | 1999-12-23 | Merck Patent Gmbh | Geminally substituted amines |
| DE19827161A1 (en) * | 1998-06-18 | 1999-12-23 | Merck Patent Gmbh | Process for the catalytic, symmetrical disubstitution of carboxamides with Grignard reagents |
| DE19827166A1 (en) | 1998-06-18 | 1999-12-23 | Merck Patent Gmbh | Process for the catalytic disubstitution of carboxamides with at least one Grignard reagent |
-
1976
- 1976-06-03 BE BE167579A patent/BE842528R/en not_active IP Right Cessation
-
1977
- 1977-05-27 CH CH660677A patent/CH624922A5/en not_active IP Right Cessation
- 1977-05-30 GB GB46520/78A patent/GB1565023A/en not_active Expired
- 1977-05-30 GB GB22842/77A patent/GB1565021A/en not_active Expired
- 1977-05-30 GB GB18083/78A patent/GB1565022A/en not_active Expired
- 1977-05-31 IT IT24186/77A patent/IT1114869B/en active
- 1977-06-01 IE IE1131/77A patent/IE45730B1/en unknown
- 1977-06-02 HU HU77LA917A patent/HU175776B/en unknown
- 1977-06-02 CA CA279,749A patent/CA1076482A/en not_active Expired
- 1977-06-03 DE DE2725245A patent/DE2725245C2/en not_active Expired
- 1977-06-03 OA OA56184A patent/OA05675A/en unknown
-
1980
- 1980-09-17 CH CH698080A patent/CH623559A5/en not_active IP Right Cessation
- 1980-09-17 CH CH697980A patent/CH623560A5/en not_active IP Right Cessation
- 1980-09-17 CH CH697880A patent/CH624389A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| BE842528R (en) | 1976-12-03 |
| HU175776B (en) | 1980-10-28 |
| DE2725245C2 (en) | 1986-09-04 |
| OA05675A (en) | 1981-05-31 |
| CH623560A5 (en) | 1981-06-15 |
| CH624922A5 (en) | 1981-08-31 |
| GB1565021A (en) | 1980-04-16 |
| DE2725245A1 (en) | 1977-12-15 |
| GB1565022A (en) | 1980-04-16 |
| IT1114869B (en) | 1986-01-27 |
| CH623559A5 (en) | 1981-06-15 |
| IE45730B1 (en) | 1982-11-17 |
| IE45730L (en) | 1977-12-03 |
| CH624389A5 (en) | 1981-07-31 |
| GB1565023A (en) | 1980-04-16 |
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