GB1565022A - Methylamine derivatives and provesses for preparing the same - Google Patents

Methylamine derivatives and provesses for preparing the same Download PDF

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Publication number
GB1565022A
GB1565022A GB18083/78A GB1808378A GB1565022A GB 1565022 A GB1565022 A GB 1565022A GB 18083/78 A GB18083/78 A GB 18083/78A GB 1808378 A GB1808378 A GB 1808378A GB 1565022 A GB1565022 A GB 1565022A
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acid addition
pharmaceutically acceptable
acceptable acid
propyl
methyl
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Labaz SA
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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)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (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) 1 565 022
> ( 21) Application No 18083/78 ( 22) Filed 30 May 1977 ( 19), O ( 62) Divided out of No 1565021 ( 31) Convention Application No 167579 ( 32) Filed 3 Jun 1976 in O ' ( 33) Belgium (BE) 0 ( 44) Complete Specification Published 16 Apr 1980 ( 51) INT CL 3 C 07 C 87/127 87/24 ( 52) Index at Acceptance C 2 C 200 20 Y 286 288 29 X 29 Y 30 Y 322 32 Y 452 455 456 45 Y 618 619 620 772 802 80 Y AA NC ND ( 54) METHYLAMINE DERIVATIVES AND PROCESSES 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 tby the following statement:-
The present invention relates to novel pharmacologically active derivatives of 5 methylamine, to pharmaceutically acceptable acid addition salts thereof and to processes for preparing said derivatives.
The novel methylamine derivatives with which the invention is concerned are represented by the general formula: 10 CH 3-CH 2-CH 2 R-C-NHCH 3 I CH 3-CH 2-CH 2 / 15 wherein R represents n-propyl, isopropyl, isobutyl or allyl.
The invention also includes within its scope the pharmaceutically acceptable acid addition salts of the compounds of formula I such as the acid addition salts obtained with an inorganic r acid, for example, hydrochloric acid, or which an organic acid in which the free carboxyl is attached to a saturated or unsaturated aliphatic radical, or an aromatic or aralkyl radical 20 which may optionally contain a second carboxyl group such as, for example, fumaric acid.
Depending on their chemical structure, the compounds of formula I possess one or more isomeric centres and thus can be produced as optical isomers, or mixtures of these isomers.
The mixtures of these isomers can be resolved, if desired, at appropriate stages by methods known to those skilled in the art to obtain the respective individual isomers 25 The compounds of formula I can be prepared by heating, in the presence of an alkaline agent, such as for example, sodium bicarbonate, an amine of the general formula:
CH 3-CH 2 -CCH 2 \ 30 R-C-NH 2 II CH 3-CH 2-CH 2 or an acid addition salt thereof, such as for example the hydrochloride, in which R has the 35 same meaning as given above with methyl 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 acid addition salt of the said compound 40 It is well known that when the compounds of formula I, which are monosubstituted on the nitrogen atom, will be so prepared there will be obtained a mixture containing, in addition to the desired monosubstituted compound, a certain proportion of the corresponding disubstituted compound.
Such mixtures of mono and di-substituted derivatives can be separated out by known 4 f I 1,565,022 techniques, for example by fractional distillation of the reaction mixture containing them or by fractional crystallization from their salts.
The N-substituted methylamine derivatives of formula I can also be obtained in accordance with other methods than that already described herein.
The different procedures set out hereunder for the preparation of the compounds of formula I are also included in the present invention, in addition to the method described above.
For example, the compounds of formula I can also be prepared by reducing, with lithium aluminium hydride, an isocyanate of the general formula: 10 CH 3-CH 2-CH 2 R-C-N=C=O III CH 3-CH 2-CH 2 15 wherein R has the same meaning as in formula I to provide the required methylamine derivative of formula I, which can further be treated with an organic or inorganic acid to give a pharmaceutically acceptable acid addition salt.
The reduction in question can be effected in an inert and anhydrous medium such as for 20 example ethyl ether.
Likewise, the compounds of forumla I can be prepared starting with a compound of the general formula:
CH 3-CH 2-CH 2 25 R-C-A IV CH 3-CH 2-CH 2 wherein R has the meaning given in formula I and A represents the group NH-CH or N = CH 2 30 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 O NH-CH.
b) in a solvent such as for example methanol, with sodium borohydride in the case where A represents N = CH 2, to provide the required compound of formula I which can then be treated, if desired, with an organic or inorganic acid to obtain a pharmaceutically acceptable acid addition salt of this compound.
The compounds of formulae II and III are known products having been described together 4 with their process of preparation in British Patent No 1,467,739.
The compounds of formula IV wherein A represents N CH 2 can be obtained by condensing an amine of formula II with formaldehyde, the operation of condensation being carried out either in the absence of solvent or in the presence of a solvent, such as for example 4 benzene.
Besides, the compounds of formula IV wherein A represents O 11 NH-Cr can be prepared either in the presence of an acid acceptor, such as for example pyridine or 50 2,6-dimethylpyridine, by reacting an amine of formula II with formic anhydride.
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 5 noradreneryic and central dopaminergic properties These latter properties manifest themselves by an inhibitory action on reserpine-induced and neurolepticinduced catonia and catalepsy.
Furthermore, at doses which completely suppress neuroleptic induced catatonia and catalepsy, it was observed that the compounds of the invention do not influence the anti 60 amphetamine effects of the neuroleptics in the rat and their antiapomorphine effects in the dog Furthermore, the compounds of the invention have no emetic action in the dog at any doses and are not cholinolytic agents.
These pharmacological properties taken as a whole are likely to render the compounds of formula I useful in treating Parkinson's desease as well as for correcting extra-pyramidal 65 3 1,565,022 3 disturbances provoked by neuroleptics.
The N-substituted derivative of the present invention which has shown the most valuable properties for constituting an antiparkinsonian agent, is:
N-methyl-1, 1-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, 5 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: 10 N-methyl-i, 1-di-n-propyl -n-butylamine (Compound 1) N-methyl-1 -n-propyl- 11-isopropyl -n-butylamine (Compund 2) N-methyl-1 -n-propyl-1-isobutyl -n-butylamine (Compound 3) N-methyl-1 -n-propyl-l-allyl -n-butylamine (Compound 4) I Inhibition of reserpine-induced and neuroleptic-induced catatonia 15 (dopaminergic properties) 1 Inhibition of reserpine-induced catatonia The test undertaken for this purpose is identical to that described in British Patent No.
1,467,739.
The results obtained with the compounds of the invention listed hereabove as well as with 20 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.
TABLEI 25
Compound Dose administered Inhibition of reserpinein mg/kg induced catatonia 1 6 4 30 2 6 4 3 6 5 3 4 5 2 35 Amantadine 100 4 2 Inhibition of neuroleptic-induced catatonia The test performed for this purpose is identical to that described in British Patent No.
1,467,739 40 The results obtained with the compounds listed above in comparison with amantadine are set out in the following Table II.
The scoring system was that used hereabove for Table I.
TABLE II 45
Compound Dose administered Inhibition of neurolepticin mg/kg induced catatonia 1 6 3 À 50 50 2 6 3 3 6 5 4 4 5 2 55 Amantadine 100 4 II Acute toxicity The acute toxicity LD 50 was determined on mice by oral route using the same method as 60 that described in British Patent No 1,467,739.
The following results were recorded with compounds of the invention in comparison with amantadine:
1,565,022 Compound LD 50 in mg/kg 1 100 2 > 150 5 4 170 Amantadine 1050 10 10 A comparison was made between the index LDS A comparison was made between the index of the compounds of the invention with the 15 corresponding index of amantadine.
In this index, ED 100 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 in comparison with amantadine:
Compound Index 20 1 16 5 2 > 25 25 Amantadine 10 These results 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 30 be adminstered in the form of a pharmaceutical or veterinary composition in dosage unit form appropriate to the required mode of administration, the composition comprising as active ingredient a compound of the invention in association with a pharmaceutical carrier or excipient therefor For oral administration, the composition may take the form of, for example, a coated or uncoated tablet, a hard or soft-gelatin capsule, a suspension or a syrup 35 The composition may alternatively take the form of a suppository for rectal administration, or of a solution of suspension for parenteral administration.
When in dosage unit form the composition may contain from 5 to 50 mg, preferably from 5 to 20 mg of the active ingredient per dosage unit for oral administration, from 5 to 100 mg of the active ingredient per dosage unit for rectal administration, or from 1 to 20 mg of the active ingredient per dosage unit for parenteral administration.
The therapeutic compositions of the invention will be prepared by associating at least one of the compounds of formula I or a pharmaceutically acceptable acid addition salt thereof with at least one appropriate carrier or excipient therefore Examples of suitable carriers or excipients are talc, magnesium stearate, milk sugar, saccharose, carboxymethylcellulose, 5 starches, kaolin, levilite and cocoa butter.
Pharmaceutical and veterinary compositions containing as an essential ingredient a compound selected from inter alia the methylamine derivatives of formula I and the pharmaceutically acceptable acid addition salts thereof are claimed in our copending Application No.
22842/77 (Serial No 156501) 50 The following Examples illustrate the preparation of the compounds of the invention together with a suitable therapeutic composition:
EXAMPLE 1
Preparation of N-methyl-I, 1-di-n-propyl-n butylamine hydrochloride 55 a) N-Methyl-I, 1-di-n-propyl-n butylamine To a suspension of 1 9 g ( 0 05 mol) of lithium aluminium hydride in 60 ml of anhydrous sulphuric ether was added a solution of 3 66 g ( 0 02 mol) of 1,1-di-npropyl-n butylisocyanate in 20 ml of dry ether.
The operation of addition was carried out over a period of 30 minuts at room-temperature 60 after which the reaction medium was heated under reflex for 3 hours After hydrolysis, first with ether saturated with water and then with water, the organic fraction was separated out.
The organic phase was dried over magnesium sulphate and distilled under reduced pressure.
In this manner, 3 2 g of N-methyl 1,1 -di-n-propyl-n butylamine were obtained in the form of a colourless liquid 65 A_ A 1,565,022 5 B.P: 84 C under 13 mm Hg Yield: 94 % b) N-Methyl-l, 1-di-n-propyl-n butylamine hydrochloride By bubbling dry gaseous hydrogen chloride through the ethereal solution of the amine previously obtained, N-methyl-l, 1-di-n-propyl-n butylamine hydrochloride was precipi 5 tated in the form of colourless crystals.
M.P: 133-134 C Yield: 90 % By following the same procedure as that described hereabove but using the appropriate starting-products, the compound hereunder was prepared: 10 Compound Melting point C N-Methyl-1 -n-propyle-1 isopropyl-nbutylamine hydrochloride 144-145 (Yield: 80 %o) EXAMPLE 2 i 5 EXAMPLE 2 15 Preparation of N-methyl-i, 1-di-n-propyl-3 buten-l-ylamine fumarate First 1,1-di-n-propyl-3 buten-l-ylisocyanate was prepared by reacting bromine and 2,2di-n-propyl-4 buten-l-ylamide in the presence of sodium hydroxide The desired product was obtained in the form of a colourless liquid boiling at 79-82 C under 5 mm Hg The 20 2,2-di-n-propyl 4-buten-1-ylamide so obtained was then reduced by means of lithium aluminium hydride to provide without purification, N-methyl-i, 1-di-npropyl-3 buten-lylamine in a yield of 89 %.
To a solution of 2 32 g ( 0 02 mol) of fumaric acid in 400 ml of acetone, were added under stirring 3 38 g ( O 02 mol) of the amine, prepared hereabove, dissolved in 30 ml of acetone 25 Stirring was maintained for one hour after which the colourless crystals which precipitated were separated out They were washed with acetone and dried.
In this manner, 5 2 g of N-methyl-l, l-di-n-propyl -3-buten-l-ylamine fumarate were obtained.
M P: 149 C 30 Yield: 91 % EXAMPLE 3
Preparation of N-methyl-l-n propyle-l-isobutyl-n burylamine hydrochloride a) N-Methyl-l-n-propyl-1-isobutyl-n-burylamine 35 In a one-litre three-necked flask, equipped with a condenser of the Dean Stark type, were placed 30 g ( 0 175 mol) of l-n-propyl-l isobutyl-n-butylamine, 150 ml of 30 %formol and 400 ml of benzene The mixture was refluxed for 5 hours so as to eliminate by azeotropic distillation about 100 ml of water After evaporating the benzene under vacuum, the oil so obtained was taken up in 250 ml of methanol and, at a temperature of 10 C, 13 3 g ( 0 35 mol) 40 of sodium borohydride were added by small fractions The temperature of the mixture was maintained at 10 C during the operation of addition of the hydride and stirring was maintained for 30 minutes at this temperature The reaction medium was refluxed for one hour and the methanol was then evaporated off under vacuum To the product so obtained, 200 ml of distilled water and 100 ml of a concentrated solution of sodium hydroxide were added The 45 organic fraction was extracted with ether and dried over magnesium sulphate The ether was evaporated out under vacuum and the residual liquid was distilled using a column.
In this manner, 11 g of N-methyl-i-n propyle-1-isobutyl-n butylamine were obtained in the form of a colourless liquid.
B P: 86 C under 12 mm Hg 50 Yield: 34 % b) N-Methyl-l-n-propyl -1 -isobutyl-n-butylamine hydrochloride In 150 ml of absolute ethanol, 10 4 g of the amine previously obtained were dissolved and the resulting solution was treated by means of 5 6 ml of concentrated hydrochloric acid and evaporated to dryness 55 The oil so obtained was taken up in 50 ml of hexane and the desired hydrochloride crystallized when cold It was separated out and recrystallized in isopropyl ether In this manner, 7 5 g of N-methyl-l-n propyl-l-isobutyl n-butylamine hydrochloride were obtained.
Yield: 61 % 60 M.P: 139 C By following the same procedure as that described hereabove but using the appropriate starting-products, the compound hereunder was prepared:
6 1,565,022 Compound MP C N-Methyl-1, 1-di-n-propyl-nbutylamine hydrochloride 133-134 5 S EXAMPLE 4
A hard-gelatin capsule containing the following ingredients was prepared in accordance with known pharmaceutical techniques:
Ingredients mg 10 N-methyl-1, 1-di-n-propyl-n-butylamine hydrochloride 15 Milk sugar 50 15

Claims (16)

WHAT WE CLAIM IS:-
1 Methylamine derivatives corresponding to the general formula: 20 CH 3-CH 2-CH 2 R-C-NHCH 3 CH 3-CH 2-CH 2 25 and the pharmaceutically acceptable acid addition salts thereof wherein R represents n-propyl, isopropy, isobutyl or allyl.
2 N-Methyl-i, 1-di-n-propyl n-butylamine and the pharmaceutically acceptable acid 30 addition salts thereof.
3 N-Methyl-1-n-propyl -1-isopropyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof.
4 N-Methyl-1-n-propyl 1-isobutyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof.
5 N-Methyl-1-n-propyl -1-allyl-n-butylamine and the pharmaceutically acceptable acid addition salts thereof.
6 Methylamine derivatives according to Claims 1 to 5 wherein the pharmaceutically acceptable acid addition salt is the hydrochloride or the fumarate.
7 Process for preparing methylamine derivatives according to Claim 1, whereby an amine of the general formula:
CH 3-CHI 2-CH 12 R-C-NH 2 4 CH 3-CH 2-CH 2 or an acid addition salt thereof, in which R has the same meaning as in Claim 1 is heated, in the presence of an alkaline agent with methyl chloride or bromide, this reaction being undertaken either without any solvent or in the presence of a solvent, to obtain the required 50 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.
8 Process according to Claim 7 wherein the alkaline agent is sodium bicarbonate.
9 Process according to Claim 7 wherein the solvent is ethanol.
Process according to claim 7 wherein the acid addition salt of the starting compound 55 is the hydrochloride.
11 Process for preparing methylamine derivatives according to Claim 1 whereby an isocyanate of the general formula:
CH 13-CH-12-CH 2 60 R-C-N=C=O CH 3 CH 2-CI 12 65 c 7 1,565,022 7 wherein R has the same meansing as in Claim 1, is reduced with lithium aluminium hydride in an anhydrous and inert solvent to obtain the required methylamine derivative which may then be reacted, if desired, with an organic or inorganic acid to provide a pharmaceutically acceptable acid addition salt of the said erivative.
12 Process according to Claim 11 wherein the inert medium is ethyl ether 5
13 Process for preparing methylamine derivatives according to Claim 1, whereby a compound of the general formula:
CH 3-CH 2-CH 2 10 R- C-A CH 3-C It 2-C 2 CI II wherein R has the same meaning as in Claim 1 and A represents the group NH-CH 15 or N = CH 2 is reduced:
a) in an appropriate anhydrous medium with lithium aluminium hydride in the case where A represents 1 1 20 II 20 NH-CH b) in a solvent with sodium borohydride in the case where A represents N = CH 2, 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 deriva 25 tive.
14 Process according to Claim 13 wherein the appropriate medium is ethyl ether.
Process according to Claim 13 wherein the solvent is methanol.
16 Process for preparing a methylamine derivative or a salt thereof according to Claim 1 substantially as described in any one of the foregoing Examples 1 to 3 30 HASELTINE, LAKE & CO.
Chartered Patent Agents, Hazlitt House, 28, Southampton Buildings, Chancery Lane, London, WC 2 A 1 AT 35 -alsoTemple Gate House, Temple Gate, 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 l A Yfrom which copies may be obtained.
GB18083/78A 1976-06-03 1977-05-30 Methylamine derivatives and provesses for preparing the same Expired GB1565022A (en)

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

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GB18083/78A Expired GB1565022A (en) 1976-06-03 1977-05-30 Methylamine derivatives and provesses for preparing the same
GB22842/77A Expired GB1565021A (en) 1976-06-03 1977-05-30 Pharmaceutical compositions containing alkylamine deratives
GB46520/78A Expired GB1565023A (en) 1976-06-03 1977-05-30 Methylamine derivatives and process for preparing the same

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GB22842/77A Expired GB1565021A (en) 1976-06-03 1977-05-30 Pharmaceutical compositions containing alkylamine deratives
GB46520/78A Expired GB1565023A (en) 1976-06-03 1977-05-30 Methylamine derivatives and process for preparing the same

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BE (1) BE842528R (en)
CA (1) CA1076482A (en)
CH (4) CH624922A5 (en)
DE (1) DE2725245C2 (en)
GB (3) GB1565022A (en)
HU (1) HU175776B (en)
IE (1) IE45730B1 (en)
IT (1) IT1114869B (en)
OA (1) OA05675A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR61148B (en) * 1976-06-03 1978-09-27 Labaz Preparation process of active methylamine derivatives
EP0084943B2 (en) * 1982-01-18 1989-08-02 Exxon Research And Engineering Company Secondary and tertiary amino alcohols
DE19827161A1 (en) * 1998-06-18 1999-12-23 Merck Patent Gmbh Process for the catalytic, symmetrical disubstitution of carboxamides with Grignard reagents
WO1999065864A2 (en) * 1998-06-18 1999-12-23 Merck Patent Gmbh Geminally substituted amines
DE19827166A1 (en) * 1998-06-18 1999-12-23 Merck Patent Gmbh Process for the catalytic disubstitution of carboxamides with at least one Grignard reagent

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Publication number Publication date
CH624389A5 (en) 1981-07-31
GB1565021A (en) 1980-04-16
IE45730L (en) 1977-12-03
IT1114869B (en) 1986-01-27
HU175776B (en) 1980-10-28
GB1565023A (en) 1980-04-16
CH624922A5 (en) 1981-08-31
CA1076482A (en) 1980-04-29
OA05675A (en) 1981-05-31
DE2725245A1 (en) 1977-12-15
CH623559A5 (en) 1981-06-15
CH623560A5 (en) 1981-06-15
IE45730B1 (en) 1982-11-17
DE2725245C2 (en) 1986-09-04
BE842528R (en) 1976-12-03

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