GB1565023A - Methylamine derivatives and process for preparing the same - Google Patents

Methylamine derivatives and process for preparing the same Download PDF

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GB1565023A
GB1565023A GB46520/78A GB4652078A GB1565023A GB 1565023 A GB1565023 A GB 1565023A GB 46520/78 A GB46520/78 A GB 46520/78A GB 4652078 A GB4652078 A GB 4652078A GB 1565023 A GB1565023 A GB 1565023A
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propyl
acid addition
butylamine
pharmaceutically acceptable
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Labaz SA
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    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

PATENT SPECIFICATION
( 11) 1 565 023 ( 22) Filed 30 May 1977 ( 62) Divided out of No 1565021 ( 31) Convention Application No 167579 ( 32) Filed 3 Jun 1976 in ( 33) Belgium (BE) ( 44) Complete Specification Published 16 Apr 1980 ( 51) INT CL 3 C 07 C 87/24 91/06 119/08 C 07 D 295/02 ( 52) Index at Acceptance C 2 C 1290 1310 1562 202 20 Y 215 246 247 250 251 255 25 Y 286 29 X 29 Y 305 30 Y 322 323 328 32 Y 360 361 36 Y 456 45 Y 503 50 Y 619 620 623 633 730 733 771 772 776 802 80 Y AA LD ND NV ZM ( 72) Inventors: CHARLES PIGEROL PIERRE EYMARD JEAN-CLAUDE VERNIERES MADELEINE BROLL ( 19) 1 N 2 ' 4, & oy Cr.
MOO ( 54) METHYLAMINE DERIVATIVES AND PROCESS FOR PREPARING THE SAME ( 71) We, LABAZ, of 39 Avenue Pierre ler de Serbie, F-75008 Paris, France, a French body corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
The present invention relates to novel pharmacologically active derivatives of methylamine, to pharmaceutically acceptable acid addition salts thereof and to processes for preparing said derivatives.
The novel methylamine derivatives with which the invention is concerned are represented In by the general formula:
CH 3-CH 2-CH 2 RI CH 3-CH 2-CH 2-C-N CH 3-C 2-CH 2 R 2 CH 3-CH 2-CH 2 / R I wherein R, represents hydrogen, propargyl or 2-hydroxyethyl, R 2 represents propargyl, 2-hydroxyethyl or 3-hydroxy-n-propyl or R, and R 2, when they are taken together, represent methylene, emethylene, etethylene, ethylidene or -CH 2-CH 2-O-CH 2-CH 2 with the proviso that when R 2 represents 3-hydroxy-n-propyl then Ra represents hydrogen.
The invention also includes within its scope the pharmaceutically acceptable acid addition 20 salts of the compounds of formula I such as the acid addition salts obtained with an inorganic acid, for example, hydrochloric acid, or with an organic acid in which the free carboxyl is attached to a saturated or unsaturated aliphatic radical, or an aromatic or aralkyl radical which may optionally contain a second carboxyl group such as, for example, fumaric acid.
Depending on their chemical structure, the compounds of formula I possess one or more 25 isomeric centres and thus can be produced as optical isomers, or mixtures of these isomers.
The mixtures of these isomers can be resolved, if desired, at appropriate stages by methods known to those skilled in the art to obtain the respective individual isomers.
The compounds of general formula I above, can be prepared by different procedures in accordance with their chemical structure 30 Thus, the compounds of formula I wherein R, represents hydrogen or propargyl and R 2 represents propargyl, can be prepared by heating, in the presence of an alkaline agent, such as for example, sodium bicarbonate an amine of the general formula l 35 CCH 3-CH 2-CH 2 CH 3-CH 2-CH 2-C-NHR 3 II CH 3-CH 2-CH 2 ( 21) Application No 46520/78 m 1 z on Ls} IV l :Z 1,565,023 or an acid addition salt thereof, such as for example the hydrochloride, in which R 3 represents hydrogen or propargyl with an appropriate quantity of propargyl chloride or bromide or iodide, this reaction being undertaken either without any solvent, or in the presence of a solvent such as for example ethanol, to obtain the required compound of formula I which may then be reacted with an organic or inorganic acid to provide a pharmaceutically acceptable 5 acid addition salt of the said compound.
In accordance with known procedures and when it is desired to obtain N,Ndipropargyl1,1-di-n-propyl-n-butylamine, 1,1-di-n-propyl-n-butylamine is treated so that two molar equivalents of propargyl halide react with one molar equivalent of 1,1-din-propyl-n 10 butylamine.
It is well known that when N-propargyl-1,1-di-n-propyl-n-butylamine is desired, there will be obtained a mixture containing, in addition to the desired monosubstituted compound, a certain proportion of N,N-dipropargyl-1,1-di-n-propyl-n-butylamine, even when the molar equivalents indicated above are employed Such mixtures of mono and di-substituted derivatives can be separated out by known 15 techniques, for example by fractional distillation of the reaction mixture containing them or by fractional crystallization from their salts.
The N-wo-hydroxyalkyl derivatives of formula I i e N( 2-hydroxyethyl)-N,N-bis-( 2-hydroxyethyl) and N-( 3-hydroxy-n-propyl)-1, 1 20 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:
CH 3-CH 2-CH 2 CH 2-(CH 2)n-C 02 R 4 \% 25 CH 3-CH 2-CH 2-C-N III CH 3-CH 2-CH 2 R 5 wherein R 4 represents a straight or branched-chain alkyl radical having from 1 to 4 carbon atoms, N represents 0 or 1 and R 5 represents hydrogen or 2-hydroxyethyl with the proviso 30 that when R 5 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 an pharmaceutically acceptable acid addition salt of the said compound.
The compounds of formula I wherein R, and R 2, when they are taken together, represent an ethylene, trimethylene or -CH 2-CH 2-O-CH 2-CH 2 radical, can be obtained in a solvent or 35 in the absence of a solvent by reacting an appropriate cyclization agent with a methylamine derivative of the general formula:
CH 3-CH 2-CH 2 1 CH 2-(CH 2)m-CH 2 OH 40 CH 3-CH 2-CH 2-C-N IV CH 3-CH 2-CH 2 R 6 in which R 6 represents hydrogen or the radical CH 2-CH 2 OH and m represents 0 or 1 with the proviso that when R 6 represents CH 2-CH 2 OH, m represents 0, which provides the desired 45 compound of formula I which may then be reacted with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said compound.
When R 6 represents hydrogen, the compound of formula IV hereabove can also be used in the form of an addition salt such as for example the hydrochloride.
The cyclization operation which is involved in the aforesaid process can be effected: 50 a) in the absence of a solvent or in the presence of a solvent, such as for example benzene, by means of a suitable agent, such as for example chlorosulphonic acid, b) in a solvent such as for example acetonitrile or benzene, by means of a suitable agent such as for example triphenylphosphine bromide and in the presence of an organic base, such as for example triethylamine, 55 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 IV For example, chlorosulphonic acid or triphenylphosphine bromide can be used when in the compound of formula IV R 6 represents hydrogen Similarly, phosphoric anhyd 60 ride could be used, for example with a compound of formula IV wherein R 6 represents the radical CH 2-CH 2 OH and m represents O.
The compounds of formula I wherein R, and R 2, when they are taken together, represent a methylene or ethylidene radical can be obtained by condensing 1,1-di-npropyl-n-butylamine with formaldehyde or acetaldehyde respectively, the operation of condensation being carried 65 out either in the absence of a solvent or in the presence of a solvent, such as for example benzene, to provide the desired compound of formula I which may then be reacted, if desired, with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt.
A certain number of N-substituted methylamine derivatives of formula I can also be obtained in accordance with other methods than those already described herein 5 The different procedures set out hereunder for the preparation of some compounds of formula I are also included in the present invention, in addition to the general methods described above for the preparation of the whole of the methylamine derivatives covered by the invention.
For example, the compounds of formula I in which RI represents hydrogen and R 2 10 represents propanyl can be prepared starting with a compound of the general formula CH 3-CH 2-CH 2 CH 3-CH 2-CH 2-C-A V 15 CH 3-CH 2-CH 2 wherein A represents the group NH-CO-C-CH or N =CH-C-CH and reducing this compound:
a) in an appropriate anhydrous medium, such as for example ethyl or butyl ether, with 20 lithium aluminium hydride in the case where A represents NH-CO-C-CH b) in a solvent such as for example methanol, with sodium borohydride in the case where A represents N = CH-C-CH to provide the required compound of formula I which can then be treated, if desired, with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt of this 25 compound.
On the other hand, N-( 2-hydroxyethyl)-1,1-di-n-propyl-n-butylamine can be obtained by reacting ethylene oxide with 1,1-di-n-propyl-n-butylamine, in the presence of an appropriate catalyst, such as for example boron trifluoride used preferably in the form of an etherate, to to provide the desired compound of formula I which can then be treated with an organic or 30 inorganic acid to obtain a pharmaceutically acceptable acid addition salt of this compound.
The reaction in question will be effected by heating the reagents, preferably at a temperature between 171 and 200 C.
N,N-bis-( 2-hydroxyethyl)-1,1-di-n-propyl-n-butylamine can also be prepared by reacting under pressure a molar equivalent of 1,1-di-n-propyl-n-butylamine with two molar equival 35 ents of an ethylene oxide, this reaction being undertaken in the presence of a strong acid, such as for example hydrochloric acid, and in an inert medium, such as for example methanol, to provide the desired compound of formula I which can further be reacted with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt of the said compound 40 The reaction in question will be effected by heating the reagents, for example at a temperature between 40 and 80 C, preferably at 50 C and under pressure of 3 bars.
Likewise, N-( 3 (oxapentamethylene)-1, 1-di-n-propyl-n-butylamine can be prepared following other procedures than that mentioned hereabove.
Thus, this compound in question of formula I can also be obtained by heating 1,1-di-n 45 propyl n-butylamine or an acid addition salt thereof, for example the hydrochloride, with di-( 2-chloroethyl) oxide in the presence of an alkaline agent, such as for example sodium carbonate to provide the desired compound of formula I which can further be reacted with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt of this compound 50 Furthermore, N-( 3-oxapentanemethylene)-1, 1-di-n-propyl-n-butylamine can also be obtained by reacting, in an anhydrous ether, such as for example ethyl ether, 2N-morpholino-2-n-propyl-valeronitrile with n-propyl magnesium bromide and further hydrolyzing the complex so formed to provide the desired compound of formula I which can then be reacted with an organic or inorganic acid to obtain a pharmaceutically acceptable acid 55 addition salt of the said compound.
Amongst the compounds of formula II, that wherein R 3 represents hydrogen is a known product having been described together with its process of preparation in British Patent No.
1,467,739.
The other compound of formula II, namely that wherein R 3 represents propargyl is in fact a 60 compound of formula I for which two processes of preparation are described hereabove.
The compounds of formula II can be obtained by heating, in an appropriate medium, such as for example ethanol, and in the presence of an alkaline agent such as for example sodium bicarbonate, 1,1-di-n-propyl-n-butylamine or N-( 2-hydroxyethyl)-1, 1di-n-propyl-n-butylamine with an appropriate quantity of a halogenated compound of the 65 1,565,023 4 1,565,023 general formula Hal-CH 2-(CH 2)n-CO 2 R 5 in which R 5 has the same meaning as in formula III N represents O or 1 and Hal represents an atom of chlorine, bromine or iodine which gives the desired compound of formula III.
Furthermore, the compounds of formula III in which R 5 represents hydrogen and N 5 represents 1 can also be prepared by heating in an inert medium, such as for example methanol, 1,1,-di-n-propyl-n-butylammine with an acrylic acid ester of formula CH 2 =CHCO 2 R 5 wherein R 5 has the same meaning as in formula III to obtain the desired compound.
The compounds of formula IV are in fact compounds of formula I for which a process of preparation is described hereabove 10 The compounds of formula V wherein A represents N = CH-C-CH can be prepared by condensing 1,1-di-n-propyl-n-butylamine with propiolic anhydride while the other compound of formula V namely that in which A represents NH-CO-C-CH can be obtained either in the absence of a solvent or in a solvent, such as for example benzene and in the presence of an acid acceptor, such as for example pyridine or 2,6dimethyl-pyridine, by 15 reacting 1,1-di-n-propyl-n-butylamine with propiolic chloride or bromide or with propiolic anhydride.
With respect ot 2-N-morpholino-2-n-propyl-valeronitrile, this can be obtained by reacting potassium cyanide with a mixture of morpholine hydrochloride and di-npropylketone, the reaction being carried out in an appropriate medium such as for example methanol 20 It has been discovered that the methylamine derivatives of the invention possess valuable pharmacological properties which are likely to render them useful in human and veterinary therapy.
In particular, it has been found that the compounds of the invention present central noradrenergic and central dopaminergic properties These latter properties manifest them 25 selves by an inhibitory action on reserpine-induced and neurolepticinduced catatonia and catalepsy.
Furthermore, at doses which completely suppress neuroleptic induced catatonia and catalepsy, it was observed that the compounds of the invention do not influence the antiamphetamine effects of the neuroleptics in the rat and their antiapomorphine effects in the 30 dog Furthermore, the compounds of the invention have no emetic action in the dog at any doses and are not cholinolytic agents.
These pharmacological properties taken as a whole are likely to render the compounds of formula I useful in treating Parkinson's disease as well as for correcting extra-pyramidal disturbances provoked by neuroleptics 35 Amongst the N-substituted derivatives and N,N-di-substituted derivatives of the present invention that which has shown the most valuable properties for constituting an antiparkinsonian agent, is:
N,N-trimethylene-1, 1-di-n-propyl-n-butylamine this compound being used in the form of their free base or in the form of a pharmaceutically 40 acceptable acid addition salt such as, for example, the hydrochloride or the fumarate.
The central dopaminergic activity found in the compounds of the present invention is illustrated hereunder in comparison with amantadine These compounds were preferably studied in the form of a pharmaceutically acceptable acid addition salt They are the following 45: 45 N,N-trimethylene-1,1-di-n-propyl-n-butylamine (Compound 1) N-propargyl-1,1-di-n-propyl-n-butylamine (Compound 2) N,N-dipropargyl-1,1-di-n-propyl-n-butylamine (Compound 3) N.N-ethylene-1,1-di-n-propyl-n-butylamine (Compound 4) N-methylene-l,l-di-n-propyl-n-butylamine (Compound 5) 50 N-ethylidene-1,1-di-n-propyl-n-butylamine (Compound 6) N-( 2-hydroxyethyl) 1,1-di-n-propyl-n-butylamine (Compound 7) N,N-bis-( 2-hydroxyethyl)-1,1-di-n-propyl-n-butylamine (Compound 8) N-( 3-hydroxy-n-propyl)-1,1-di-n-propyl-n-butylamine (Compound 9) N,N-( 3-oxapentamethylene)-1,1-di-n-propyl-n-butylamine (Compound 10) 55 I Inhibition of reserpine-induced and neuroleptic-induced catatonia (dopaminergic properties) 1 Inhibition of reserpine-induced catatonia The test undertaken for this purpose is identical to that described in British Patent No 1,467,739 60 The results obtained with the compounds of the invention listed hereabove as well as with amantadine are given in Table I hereunder.
These results are expressed according to the same scoring system, from 0 to 4, as that set out in the above-cited British Patent.
A A 1,565,023 5 TABLE I
Dose administered in mg/kg 5.5 Inhibition of reserpineinduced catatonia Complementary trials have shown that at a dose as low as 3 mg/kg, the index of inhibition of reserpine-induced catatonia of Compound 1 is equal to 3.
2 Inhibition of neuroleptic-induced catatonia The test performed for this purpose is identical to that described in British Patent No 1,467,739.
The results obtained with Compounds listed above in comparison with amantadine are set out in the following Table II.
The scoring system was that used hereabove for Table I.
7 IABLE 11 Dose administered in mg/kg 5.5 6.5 Inhibition of neurolepticinduced catatonia 4 Compound Amantadine Compound 1,565,023 Amantadine 1,565,023 Complementary tests have shown that Compound 1 at a dose as low as 3 mg/kg have an index of inhibition of neuroleptic-induced catatonia equal to 2 while Compound 4 at the dose of 12 mg/kg has an index equal to 3.
II Acute toxicity The acute toxicity L Ds 50 was determined on mice by oral route using the same method as that described in British Patent No 1,467,739.
The following results were recorded with compounds of the invention in comparison with amantadine:
Compound LD 50 in mg/kg Amantidine > 150 > 150 > 150 > 150 250 1050 A comparison was made between the index LD 50 ED 20-30 of the compounds of the invention with the corresponding index of amantadine.
In this index, ED 20 -3 o represents the effective dose to obtain 20 to 30 % inhibition of the catatonia, this value being represented by the figure 1 in Tables I and II.
The following results were registered:
4 Compound Index -40 > 25 2 > 25 > 25 Amantidine 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 LD 50 was determined in comparison with amantadine.
ED 100 The following results were registered:
Compound 1 Amantadine 10 Index 10.8 1,565,023 These results again show that the compounds of the present invention offer a greater safety margin than amantadine.
It will be appreciated that for therapeutic use the compounds of the invention will normally be administered in the form of a pharmaceutical or veterinary composition in a dosage unit form appropriate to the required mode of administration, the composition comprising as 5 active ingredient a compound of the invention in association with a pharmaceutical carrier or excipient therefor For oral administration, the composition may take the form of, for example, a coated or uncoated tablet, a hard or soft-gelatin capsule, a suspension or a syrup.
The composition may alternatively take the form of a suppository for rectal administration, or of a solution or suspension for parenteral administration 10 When in dosage unit form the composition may contain from 5 to 50 mg, preferably from 5 to 20 mg of the active ingredient per dosage unit for oral administration, from 5 to 100 mg of the active ingredient per dosage unit for rectal administration, or from 1 to 20 mg of the active ingredient per dosage unit for parenteral administration.
The therapeutic compositions of the invention will be prepared by associating at least one 15 of the compounds of formula I or a pharmaceutically acceptable acid addition salt thereof with at least one appropriate carrier or excipient therefor Examples of suitable carriers or excipients are talc, magnesium stearate, milk sugar, saccharose, carboxymethylcellulose, starches, kaolin, levilite and cocoa butter.
Pharmaceutical and veterinary compositions containing as an essential ingredient a com 20 pound selected from inter alia the methylamine derivatives of formula I and the pharmaceutically acceptable acid addition salts thereof are claimed in our copending Application No.
22842/77 (Serial No 1565021).
The following Examples illustrate the preparation of the compounds of the invention EXAMPLE 1 25
Preparation of N-ethylidene-1, l-di-n-propyl-n-butylamino Into a 25-ml two-necked flask, were introduced 7 9 g ( 0 05 mol) of 1,1di-n-propyl-nbutylamine 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 roomtemperature The lower 30 phase was separated out from the organic phase which was distilled under vacuum in the presence of 1 g of ground potassium hydroxide and under nitrogen atmosphere.
In this manner, 7 8 g of N-ethylidene-1,1-di-n-propyl-n-butylamine were obtained in the form of a colourless liquid.
B P: 87 C under 13 mm Hg 35 Yield: 85 % EXAMPLE 2
Preparation of N-propargyl-l, -di-n-propyl-n-butylamine hydrochloride a) N-Propargyl-l, l-di-n-propyl-n-butylamine Over a period of 48 hours, a mixture constituted by 11 9 g ( 0 1 mol) of propargyl bromide, 40 g of sodium bicarbonate, 250 ml of ethanol and 19 7 g ( 0 1 mol) of 1,1di-n-propyl-nbutylamine was refluxed After the insoluble fraction was filtered out and the ethanol evaporated off, the mixture was treated by means of a diluted solution of sodium hydroxide.
The organic phase was extracted with ether and distilled using a spinning band column.
In this manner, 1 Og of N-propargyl 1,1 -di-n-propyl-n-butylamine were isolated in the form 45 of a pale yellow liquid.
B.P: 94-96 C under 5 mm Hg Yield: 51 % b) N-Propargyl,I-di-n-propyl-n-butylamine hydrochloride By bubbling dry and gaseous hydrochloric acid through an ethereal solution of the amine so 50 obtained, the desired hydrochloride was precipitated and was then filtered out and dried.
In this manner, N-propargyl-1,1-di-n-propyl-n-butylamine hydrochloride was obtained in the form of crystals.
M.P: 154-155 C Quantitative yield 55 EXAMPLE 3
Preparation of N,N-dipropargyl-l,l-di-n-propyl-n-butylamine hydrochloride.
a) N,N-Dipropargyl-l, l-di-n-propyl-n-butylamine By continuing the distillation operation commenced in the above Example 2 with a view to obtaining N-propargyl-1, 1-di-n-propyl-n-butylamine, the corresponding N, N-dipropargyl 60 derivative was isolated.
In this manner, 3 g of N,N-dipropargyl-1,1-di-n-propyl-n-butylamine were obtained in the form of a colourless liquid.
B.P: 120 C under 5 mm Hg Yield: 13 % 65 b) N,N-Dipropargyl-1,l-di-n-propyl-n-butylamine hydrochloride By bubbling dry gaseous hydrogen chloride through an ethereal solution of the amine thus obtained, the desired hydrochloride was precipitated.
In this manner, N,N-dipropargyl-1,1-di-n-propyl-n-butylamine hydrochloride was obtained in the form of colourless crystals 5 M.P: 177 C (decomposition) EXAMPLE 4
Preparation of N-( 2-hydroxyethyl)-1,1-di-n-propyl-n-butylamine hydrochloride a) Ethyl-2-( 1,1-di-n-propyl-n-butylamino)-ethanoate Into a 500-ml three necked flask fitted with a mechanical stirrer and a condenser, were 10 introduced 23 6 g ( 0 15 mol) of 1,1-di-n-propyl-n-butylamine, 16 8 g of sodium bicarbonate and 300 ml of ethanol To this mixture were then added 28 4 g ( 0 17) mol) of ethyl bromo-acetate and, while stirring the whole was refluxed for 20 hours After this operation, ml of ether were added and the precipitate which formed was separated out The solution was concentrated and the oil so obtained was distilled under reduced pressure 15 In this manner, 22 9 g of ethyl 2-( 1,1-di-n-propyl-n-butylamino)ethanoate were obtained.
B.P: 90-92 C under 0 3 mm Hg Yield: 63 % b) N-( 2-Hydroxyethyl)-l, 1-di-n-propyl-n-butylamine To a suspension of 7 6 g ( 0 2 mol) of lithium aluminium hydride in 15 ml of ether, were 20 added 22 8 g ( 0 094 mol) of ethyl 2-( 1,1-di-n-propyl-n-butylamino)ethanoate dissolved in 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-nbutylamine were obtained 25 Yield: 94 % c) N-( 2-Hydroxyethyl)-l,l-di-n-propyl-n-butylamine hydrochloride To a solution of 3 75 g ( 0 0187 mol) of the amine previously obtained in 150 ml of ethanol, were added 1 9 ml of concentrated hydrochloric acid After the solvent was eliminated under vacuum, the oil so obtained was taken up with 100 ml of isopropyl ether The desired 30 hydrochloride, which precipitated, was separated out and then recrystallized from 150 ml of ethyl acetate.
In this manner, 2 7 g of N-( 2-hydroxyethyl)-1,1-di-n-propyl-n-butylamine hydrochloride were obtained.
M P: 157 C 35 Yield: 60 % EXAMPLE 5
Preparation of N-( 3-oxapentamethylene)-1,1-di-n-propyl-n-butylamine hydrochloride or tri-n-propylmethylmorpholine hydrochloride a) N-( 3-Oxapentamethylene)-l 1-di-n-propyl-n-butylamine 40 Undervigorous stirring, a mixture of 39 g ( O 25 mol) of 1,1-di-propyl-nbutylamine,40 gof 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)-1,1-di-n-propyl-nbutylamine were collected in the form of colourless liquid.
B.P: 105-106 C (under 5 mm Hg) Yield: 44 % b) N-( 3-Oxapentamethylene)-l,l-di-n-propyl-n-butylamine hydrochloride 50 A solution of 3 g of N-( 3-oxapentamethylene)-1,1-di-n-propyl-nbutylamine, previously obtained, in 15 ml of isopropanol was treated with 1 5 ml of concentrated hydrochloric acid (d = 1 19) and the desired hydrochloride was precipitated by adding 25 ml of isopropyl ether.
In this manner, N-( 3-oxapentamethylene)-1,1-di-n-propyl-n-butylamine hydrochloride 55 was obtained in the form of brillant and colourless crystals which sublimated between 140 and 150 C.
Yield: 80 % EXAMPLE 6
Preparation of N,N-ethylene-l,1-di-n-propyl-n-butylamine 60 In a 250-ml three-necked flask containing 15 g ( 0 063 mol) of N-( 2hydroxyethyl)-1, 1di-n-propyl-n-butylamine hydrochloride, prepared as described hereabove, were slowly added, while stirring, 15 ml of freshly distilled chlorosulphonic acid During the operation of addition, a strong exothermic reaction was observed The mixture was further heated to 80 C and using a water pump, a partial vacuum was created in the flask Under these conditions, 65 1,565,023 9 1,565,023 9 heating was maintained at 80 C for one hour and then, at atmospheric pressure the mixture was heated at 140 C for 90 minutes The viscous mixture was stirred for 12 hours with 100 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 5 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-1,1-di-n-propyl-n-butylamine were isolated in the form of a colourless liquid.
B P: 103-104 C under 18 mm Hg 10 Yield: 76 % EXAMPLE 7
Preparation of N-( 3-hydroxy-n-propyl)-1, 1-di-n-propyl-n-butylamine hydrochloride a) Methyl 3-( 1,1-di-n-propyl-n-butylamino)-propanoate A solution of 28 4 g ( 0 33 mol) of methyl acrylate in 60 ml of methanol was heated under 15 reflux for 48 hours together with 47 1 g ( 0 3 mol) of 1,1-di-n-propyl-nbutylamine After the methanol was eliminated under vacuum, the liquid so obtained was distilled.
In this manner, 61 g of methyl 3-( 1,1-di-n-propyl-n-butylamino)propanoate were obtained.
B P: 97-98 C under 0 4 mm Hg 20 Yield: 82 %b) N-( 3-Hydroxy-n-propyl) 1,,-di-n-propyl-n-butylamine Into a 500-ml three-necked flask fitted with a mechanical stirrer, a condenser and a dropping-funnel were introduced 3 8 g ( 0 17 mol) of lithium aluminium hydride and 130 ml of dry ether To this mixture were slowly added 12 2 g( O 05 mol) of methyl 3 25 ( 1,1-di-n-propyl n-butylamino)-propanoate, prepared as previously described The reaction medium was heated under reflux for 12 hours and then hydrolyzed The precipitate which formed was washed with ether, the ether was evaporated off and the oil so obtained was distilled.
In this manner, 14 9 g of N-( 3-hydroxy-n-propyl)-1, 1-di-n-propyl-nbutylamine were 30 collected in the form of a colourless liquid.
B.P: 107-108 C under 0 4 mm Hg Yield: 85 % c) N-( 3-Hydroxy-n-propyl) l, 11-di-n-propyl-n-butylamine hydrochloride A solution of 10 2 gof the amine previously obtained in 150 ml of ethanol wastreated with 35 ml of concentrated hydrochloric acid The solution was concentrated to dryness and the oil so obtained was taken up with 100 ml of isopropyl ether The precipitate which formed was separated out and recrystallized from 120 ml of ethyl acetate.
In this manner, 11 25 g of N-( 3-hydroxy-n-propyl)-1,1-di-n propyl-nbutylamine hydrochloride were obtained 40 M.P: 121-122 C Yield: 90 % EXAMPLE 8
Preparation of N,N-trimothylene-l, l-di-n-propyl-n-butylamine hydrochloride a) N,N-Trimethylene-l,l-di-n-propyl-n-propyl-n-butylamine 45 Into a 500-ml three-necked flask, fitted with a mechanical stirrer, a dip thermometer, a dropping-funnel and a calcium chloride trap, were introduced 18 3 g( O 07 mol) of triphenylphosphine, 150 ml of acetonitrile and 50 ml of ethyl ether The mixture was cooled to O C and then 11 2 g ( 0 07 mol) of bromine were added, drop-by-drop and while stirring After this operation, a solution of 14 g ( 0 065 mol) of N 50 ( 3-hydroxy-n-propyl)-1,1-di-n-propyl-n-butylamine in 25 ml of acetonitrile was first added followed by 19 4 ml ( 0 14 mol) of anhydrous triethylamine while maintaining the reaction medium at a temperature of about O C The mixture was allowed to stand for 12 hours at room temperature and the precipitate which formed was separated out and washed with ether To the filtrate, 100 ml of water and 30 ml of concentrated hydrochloric acid were 55 added and the solvents were evaporated out under vacuum The precipitate was filtered off and washed first with 5 %-hydrochloric acid and then with water.
From the aqueous solution, made alkaline by adding sodium hydroxide, the organic fraction was continuously extracted for 48 hours with methylene chloride The solvent was eliminated and the residue was distilled under reduced pressure 60 In this manner, N,N-trimethylene-1,1-di-n-propyl-n-butylamine was obtained in the form of a colourless liquid.
B.P: 112-115 C under 14 mm Hg Yield: 57 % b) N,N-Trimethylene-l,l-di-n-propyl-n-butylamine hydrochloride 65 1,565,023 A solution of 6 9 g of the amine, previously obtained, in dry ether, was treated with ether saturated with gaseous hydrogen chloride to p H 3 to 4 The precipitate was separated out, washed with ether and dried.
In this manner, N,N-trimethylene-1,1-di-n-propyl-n-butylamine hydrochloride was obtained in the form of colourless crystals 5 M.P: 92-93 C Yield: 87 % EXAMPLE 9
Preparation of N-methylene-l, l-di-n-propyl-n-butylamine Into a 1-litre three-necked flask, equipped with a mechanical stirrer and a Dean Stark 10 apparatus fitted with a condenser, were introduced 300 ml of benzene, 120 ml of a 30 % 8 solution of formic aldehyde and 11 g ( 0 07 mol) of 1,1-di-n-propyl-nbutylamine The mixture was heated on an oil-bath to eliminate the water by azeotropic distillation, the benzene solution was evaporated to dryness and the oil so obtained was distilled.
In this manner, 11 g of N-methylene-1,1-di-n-propyl-n-butylamine were obtained in the 15 form of a colourless liquid.
B.P: 85 C under 13 mm Hg EXAMPLE 10
Preparation of N-( 2-hydroxyethyl)-1,1-di-n-propyl-n-butylamine hydrochloride In a 50-ml flask fitted with several inlet tubes, a mechanical stirrer, a condenser for reflux, a 20 thermometer and a dip tube for allowing the entry of nitrogen or ethylene oxide, was introduced 0 2 ml of boron trifluoride in the form of etherate and 10 g of 1,1-di-n-propyl-nbutylamine The apparatus was cleared with nitrogen and the reaction medium was heated, while stirring, to 160 C by means of an oil-bath After that, ethylene oxide was continuously bubbled through the reaction medium for 4 hours, care being taken to maintain the reaction 25 temperature at 180 -200 C The flask was cleared with nitrogen before cooling and the reaction mixture was acidified with 20 ml of 36 %-hydrochloric acid After cooling to O C, the mixture was maintained at this temperature for 2 hours and then suctionfiltered and dried to constant weight.
In this manner, 5 g of N-( 2-hydroxyethyl)-1,1-di-n-propyl-n-butylamine hydrochloride 30 were obtained.
M.P: 175 C EXAMPLE 11
Preparation of N,N-bis-( 2-hydroxyethy O-l, l-di-n-propyl-n-butylamine hydrochloride I 5 In an enamelled bomb-apparatus fitted with a dip-thermometer, a manometer, an adjusted 35 safety valve, were introduced at low temperature, 48 6 g ( 60 ml) of methanol, 74 8 g ( 84 ml) ( 0.85 mol) of liquid ethylene oxide, 2 5 g of 36 %-hydrochloric acid and 25 g ( 0 159 mol) of 1.1 l-di-n-propyl-n-butylamine The bomb-apparatus was closed, cleared with nitrogen and immersed in a water-bath thermostated at 50 + 2 C (pressure about 2 8 bars) The reaction was maintained for 40 hours and then the pressure was lowered to atmospheric pressure The 40 apparatus was cleared with nitrogen and the reaction medium was concentrated in a rotary evaporator to constant weight ( 45 g) The oil so obtained was taken up with 300 ml of ethyl ether and the ethereal solution was washed with 50 ml of a 4 %-aqueous solution of sodium hydroxide and then with water The organic fraction was dried over anhydrous sodium sulphate and then evaporated to dryness to obtain 39 g of an oil which crystallized at about 45 C This solid was recrystallized by dissolving in 160 ml of heptane under reflux, suctionfiltered after 2 hours at -5 C and dried to constant weight.
In this manner, 34 g of N,N-bis-( 2-hydroxyethyl)-1,1-di-n-propyl-nbutylamine hydrochloride were obtained.
M P: 64 C 50 Yield: 87 % EXAMPLE 12
Preparation of N-( 3-Oxapentamethylene)-l,l-di-n-propyl-n-butylamine hydrochloride a) N-2-Morpholino-2-n-propyl-valeronitrile A solution of 43 5 g ( 0 5 mol) of morpholine in 200 ml of methanol was treated with 40 ml 55 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 nours at room-temperature and then heated to 50 C for 12 hours The precipitate which formed was filtered out, the methanol was 60 evaporated off under vacuum and the oil so obtained was taken up with 100 ml of distilled water The organic phase was extracted with ether, the ether was evaporated off and the residue was distilled under reduced pressure.
In this manner, N-2-morpholino-2-n-propyl-valeronitrile was obtained in the form of a colourless liquid 65 Yield: 17 %B.P: 137-140 C (under 3 5 mm Hg) b) N-( 3-Oxapentamethylene)-1, 1-di-n-propyl-n-butylamine To a solution of propyl magnesium bromide, prepared from 1 1 g of magnesium turnings, from 5 6 g of propyl bromide and from 60 ml of dry ethyl ether, were added at room 5 temperature and while stirring, 8 4 g ( 0 04 mol) of 2-N-morpholino-2-npropyl-valero-nitrile previously obtained, in 30 ml of anhydrous ether.
The reaction mixture was refluxed for 2 hours and then, while cold, 30 ml of distilled water were added The ether was separated out, dried over magnesium sulphate and evaporated off 10 under vacuum The resulting residue was distilled under reduced pressure.
In this manner, N-( 3)oxapentamethylene)-1,1-di-n-propyl-n-butylamine was obtained.
Yield: 65 % B.P: 96-97 C (under 4 mm Hg) c) N-( 3-Oxapentamethylene)-l, 1-di-n-propyl-n-butylamine hydrochloride A solution of 4 5 g of N-( 3-oxapentamethylene)-1,1-di-n-propyl-nbutylamine in 23 ml of 15 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 150 C 20 EXAMPLE 13
Preparation of N-( 3-oxapentamethylene)-1,1-di-n-propyl-n-butylamine hydrochloride a) N-( 3-Oxapentamethylene)-l, -di-n-propyl-n-butylamine A solution of 5 g (about 0 02 mol) of N,N-bis-( 2-hydroxyethyl)-1, 1di-n-propyl-n-butylamine, prepared as previously described, in 50 ml of benzene was heated 25 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 30 B.P: 256 C (under 750 mm Hg) b) N-( 3-Oxapentamethylene)-l, -di-n-propyl-n-butylamine hydrochloride A solution of 4 g of N-( 3-oxapentamethylene)-1,1-di-n-propyl-nbutylamine in 20 ml of isopropanol was treated with 2 ml of concentrated hydrochloric acid (d = 1 19) and then 33 ml of isopropyl ether were added 35 In this manner, N-( 3-oxapentamethylene)-1,1-di-n-propyl-n-butylamine hydrochloride was obtained which sublimated between 140 and 150 C.

Claims (38)

WHAT WE CLAIM IS:-
1 Methylamine derivatives corresponding to the general formula: 40 CH 13-Cl-12-CH 2 RI CH 3-CH 2-CH 2-C-N CH 3-CH 2-CH 2 R 2 45 and the pharmaceutically acceptable acid addition salts thereof wherein R, represents hydrogen, propargyl or 2-hydroxyethyl, R 2 represents propargyl, 2hydroxyethyl or 3-hydroxy-n-propyl or R, and R 2, when they are together, represent methylene, ethylene, trimethylene, ethylidene or -CH 2-CH 2-O-CH 2-CH 2 with the proviso that when R 2 repres O ents 3-hydroxy-n-propyl then R, represents hydrogen.
2 N-Propargyl-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof.
3 N,N-Dipropargyl-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof.
4 N-Ethylidene 1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid 55 addition salts thereof.
N-Methylene-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof.
6 N,N-Ethylene-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof 60
7 N-( 2-Hydroxyethyl)-1,1-di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof.
8 N-( 3-Hydroxy-n-propyl) 1,1 -di-n-propyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof.
9 N,N-( 3-Oxapentamethylene)-1,1-di-n-propyl-n-butylamine and the pharmaceutically 65 1,565,023 1 1 1,565,023 acceptable acid addition salts thereof.
Methylamine derivatives according to Claims 1 to 9 wherein the pharmaceutically acceptable acid addition salt is the hydrochloride or the fumarate.
11 Process for preparing methylamine derivatives according to Claim 1 wherein R, represents hydrogen or propargyl and R 2 represents propargyl, whereby an amine of the general formula:
CH 3-CH 2-CH 2 CH 3-CH 2-CH 2-C-NHR 3 CH 3-CH 2-CH 2 C 113-CH 2-CH 2 or an acid addition salt thereof, in which R 3 represents hydrogen or propargyl, is heated in the presence of an alkaline agent, with an appropriate quantity of propargyl chloride or bromide or iodide, this reaction being undertaken either without any solvent or in the presence of a solvent, to obtain the required methylamine derivative which may then be reacted with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said derivative.
12 Process according to Claim 11 wherein the alkaline agent is sodium bicarbonate.
13 Process according to Claim 11 wherein the solvent is ethanol.
14 Process according to Claim 11 wherein the acid addition salt of the starting compound is the hydrochloride.
Process for preparing methylamine derivatives according to Claim 1 wherein R, represents hydrogen or 2-hydroxyethyl and R 2 represents 2-hydroxyethyl or 3hydroxy-n-propyl with the proviso that when R 2 represents 3-hydroxy-npropyl, R, represents hydrogen whereby an ester of the general formula:
CH 3-CH 2-CH 2 CH 2-(CH 2)n-C 02 R 4 CH 13-CH 2-CH 12-C-N CH 3-CH 2-CH 2 wherein R 4 represents a straight or branched-chain alkyl radical having from 1 to 4 carbon atoms, N represents O or 1 and R 5 represents hydrogen or 2-hydroxyethyl with the proviso that when R 5 represents 2-hydroxyethyl, N represents 0, is treated, by means of an appropriate reducing agent and in an inert and anhydrous medium, to obtain the required methylamine derivative which may then be reacted with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said derivative.
16 Process according to Claim 15 wherein the reducing agent is lithium aluminium hydride.
17 Process according to Claim 15 wherein the inert medium is ethyl ether.
18 Process for preparing methylamine derivatives according to Claim 1 wherein R and R 2, taken together, represent an ethylene, trimethylene or-CH 2-CH 2-OCH 2-CH 2 radical, whereby an appropriate cyclization agent is reacted, in a solvent or in the absence of a solvent, with a compound of the general formula:
CH 3-CH 2-CH 2 CH 2-(CH 2)m-CH 2 OH C 113-CH 2-CH 2-C-N CH 3-CI-H 2-CH 2 R 6 in which R 6 represents hydrogen or the radical CH 2-CH 2 OH and m represents O or 1, with the proviso that when R 6 represents CH 2-CH 2 OH, m represents 0, with an acid addition salt of this compound wherein R 6 represents hydrogen, which provides the required methylamine derivative which may then be reacted with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt of the said derivative.
19 Process according to Claim 18 wherein the solvent is benzene or acetonitrile.
Process according to Claim 18 wherein the cyclization agent is chlorosulphonic acid, triphenylphosphine dibromide or phosphoric anhydride.
21 Process according to Claim 18 wherein the acid addition salt of the starting compound is the hydrochloride.
22 Process for preparing methylamine derivatives according to Claim 1 wherein R, and R 2, taken together, represent methylene or ethylene whereby 1,1-di-npropyl-n-butylamine is condensed with formaldehyde or acetaldehyde respectively, the operation of condensation being carried out either in the absence of a solvent or in the presence of a solvent, to obtain 1,565,023 the required methylamine derivative which may then be reacted, if desired, with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said derivative.
23 Process according to Claim 22 wherein the solvent is benzene.
24 Process for preparing methylamine derivatives according to Claim 1 wherein R, 5 represents hydrogen and R 2 represents propargyl, whereby a compound of the general formula: CH 3-CH 2-CH 2 CH 13-CH 2-CH 2-C-A 10 CH 3-CH 2-CH 2-C-A CH 3-CH 2-CH 2 wherein A represents the group NH-CO-C CH or N=CH-C-CH is reduced:
a) in an appropriate anhydrous medium with lithium aluminium hydride in the case where 15 A represents NH-CO-C-CH b) in a solvent with sodium borohydride in the case where A represents N=CH-C CH to obtain the required methylamine derivative which may then be treated, if desired, with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said derivative.
25 Process according to Claim 24 wherein the appropriate medium is ethyl ether 20
26 Process according to Claim 24 wherein the solvent is methanol.
27 Process for preparing the methylamine derivative according to Claim 1 wherein R, represents hydrogen and R 2 represents 2-hydroxyethyl, whereby ethylene oxide is reacted, in the presence of an appropriate catalyst, with 1,1-di-n propyl-nbutylamine to obtain the required methylamine derivative which may then be treated with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said derivative.
28 Process according to Claim 27 wherein the catalyst is boron trifluoride.
29 Process according to Claim 27 wherein boron trifluoride is in the form of an etherate.
Process according to Claim 27 wherein the reaction is carried out at a temperature
30 between 170 C and 200 c.
31 Process for preparing the methylamine derivative according to Claim 1 wherein R 1 and R 2, which are identical, each represent 2-hydroxyethyl, whereby a molar equivalent of 1,1-di-n-propyl-n-butylamine is heated under pressure with two molar equivalents of ethylene oxide, this reaction being carried out in the presence of a strong acid and in an inert 3 medium, to obtain the required compound of formula I which may then be treated with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said derivative.
32 Process according to Claim 31 wherein the reaction is carried out at a temperature between 40 and 80 C.
33 Process according to Claim 31 wherein the pressure is 3 bars 40
34 Process according to Claim 31 wherein the strong acid is hydrochloric acid.
Process according to Claim 31 wherein the inert medium is methanol.
36 Process for preparing the methylamine derivative according to Claim 1 wherein R, and R 2, taken together, represent -CH 2-CH 2-O-CH 2-CH 2 whereby 1,1-din-propyl-n 45 butylamine or an acid addition salt thereof is heated with di-( 2chloroethyl) oxide in the 45 presence of an alkaline agent, to obtain the required methylamine derivative which may be treated with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said derivative.
37 Process for preparing the methylamine derivative according to Claim 1 wherein R O and R 2, taken together, represent -CH 2-CH 2-O-CH 2-CH 2 whereby 2-Nmorpholino-2-n 50 propyl-valeronitrile is reacted, in an anhydrous ether, with n-propyl magnesium bromide and the complex so formed is hydrolized to obtain the required methylamine derivative which may then be treated with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt of the said derivative.
38 Process for preparing a methylamine derivative or a salt thereof according to Claim 1 55 substantially as described in any one of the foregoing Examples 1 to 13.
14 1,565,023 14 Agents for the Applicants HASELTINE LAKE & CO Chartered Patent Agents Hazlitt House 28, Southampton Buildings 5 Chancery Lane London WC 2 A 1 AT also Temple Gate House Temple Gate 10 Bristol B 51 6 PT -and9 Park Square Leeds L 51 2 LH Yorks Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited Croydon Surrey, 1980.
Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A IAY,from which copies may be obtained.
GB46520/78A 1976-06-03 1977-05-30 Methylamine derivatives and process for preparing the same Expired GB1565023A (en)

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