CH623559A5 - Process for the preparation of new methylamine derivatives - Google Patents

Process for the preparation of new methylamine derivatives Download PDF

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Publication number
CH623559A5
CH623559A5 CH698080A CH698080A CH623559A5 CH 623559 A5 CH623559 A5 CH 623559A5 CH 698080 A CH698080 A CH 698080A CH 698080 A CH698080 A CH 698080A CH 623559 A5 CH623559 A5 CH 623559A5
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Switzerland
Prior art keywords
propyl
preparation
methyl
compounds
formula
Prior art date
Application number
CH698080A
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French (fr)
Inventor
Charles Pigerol
Pierre Eymard
Jean-Claude Vernieres
Madeleine Broll
Original Assignee
Labaz
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Publication date
Application filed by Labaz filed Critical Labaz
Publication of CH623559A5 publication Critical patent/CH623559A5/en

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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

623 559 623,559

Claims (4)

REVENDICATIONS 1. Procédé de préparation de nouveaux dérivés de méthylamine correspondant à la formule générale:1. Process for the preparation of new methylamine derivatives corresponding to the general formula: :-nhch ainsi que de leurs sels d'addition non toxiques, dans laquelle R représente n-propyle, isopropyle, isobutyle ou allyle, caractérisé en ce que l'on réduit, dans un milieu inerte et anhydre au moyen d'hydrure de lithium et d'aluminium, un isocyanate de formule générale::-nhch as well as their non-toxic addition salts, in which R represents n-propyl, isopropyl, isobutyl or allyl, characterized in that one reduces, in an inert and anhydrous medium by means of lithium hydride and aluminium, an isocyanate of the general formula: n-C_Hn-C_H R-C-N_C=0R-C-N_C=0 n-C Hn-CH 3 73 7 dans laquelle R a la même signification que précédemment, ce qui fournit le dérivé désiré de méthylamine que l'on peut, par la suite, faire réagir avec un acide organique ou inorganique pour obtenir un sel d'addition non toxique de ce dérivé.in which R has the same meaning as above, which provides the desired methylamine derivative which can subsequently be reacted with an organic or inorganic acid to obtain a non-toxic addition salt of this derivative. 2. Procédé selon la revendication 1, caractérisé en ce que le milieu inerte est l'éther éthylique.2. Method according to claim 1, characterized in that the inert medium is ethyl ether. 3. Procédé selon la revendication 1, caractérisé en ce que l'acide organique est l'acide fumarique et l'acide inorganique est l'acide chlorhydrique.3. Method according to claim 1, characterized in that the organic acid is fumaric acid and the inorganic acid is hydrochloric acid. 4. Procédé selon les revendications 1 à 3 pour la préparation de la N-méthyl di-n-propyl-1,1 n-butylamine et de ses sels d'addition non toxiques, caractérisé en ce que l'on réduit le di-n-propy 1-1,1-n-butylisocyanate.4. Process according to claims 1 to 3 for the preparation of N-methyl di-n-propyl-1,1 n-butylamine and its non-toxic addition salts, characterized in that the di- n-propy 1-1,1-n-butylisocyanate. n-CJyn-CJy R-C-NHCHR-C-NHCH (I)(I) 11 °3h711°3h7 dans laquelle R représente n-propyle, isopropyle, isobutyle ou allyle. L'invention se rapporte également à la préparation des sels d'addition non toxiques des composés de formule I ci-dessus, tels que les sels d'addition d'un acide inorganique, par exemple l'acide chlorhydrique, ou d'un acide organique dans lequel le radical carboxylique libre est attaché à un radical aliphatique saturé ou insaturé aromatique ou aralkyle pouvant éventuellement comprendre un second groupement carboxylique tel que, par exemple, l'acide fumarique.wherein R represents n-propyl, isopropyl, isobutyl or allyl. The invention also relates to the preparation of non-toxic addition salts of the compounds of formula I above, such as the addition salts of an inorganic acid, for example hydrochloric acid, or of an acid organic in which the free carboxylic radical is attached to a saturated or unsaturated aromatic or aralkyl aliphatic radical which may optionally comprise a second carboxylic group such as, for example, fumaric acid. Les composés de la présente invention peuvent présenter, suivant leur configuration chimique, ou ou plusieurs centres d'asymétrie et peuvent donc se trouver sous la forme de mélanges racé-miques ou d'isomères optiques individuels.The compounds of the present invention may have, depending on their chemical configuration, one or more asymmetry centers and may therefore be in the form of race mixtures or individual optical isomers. L'invention se rapporte à la fois aux mélanges racémiques et aux isomères optiques des composés faisant un des objets de la présente invention et notamment aux mélanges racémiques et aux isomères optiques des composés de formule I ci-dessus.The invention relates both to racemic mixtures and to optical isomers of the compounds forming one of the subjects of the present invention and in particular to racemic mixtures and to optical isomers of the compounds of formula I above. Comme il a été décrit dans la demande de brevet principal N° 6606/77, on a constaté que les dérivés N-substitués de méthyl-5 amine de formule I ci-dessus, ainsi que leurs sels d'addition non toxiques, sont doués de propriétés pharmacologiques susceptibles de les rendre efficaces, notamment dans le traitement de la maladie de Parkinson ainsi que pour la correction des troubles extrapyramidaux engendrés par les neuroleptiques. Suivant l'invention, io on a préparé les composés de formule I en réduisant, au moyen d'hydrure de lithium et d'aluminium, un isocyanate de formule générale:As described in main patent application No. 6606/77, it has been found that the N-substituted methyl-5-amine derivatives of formula I above, as well as their non-toxic addition salts, are endowed pharmacological properties likely to make them effective, in particular in the treatment of Parkinson's disease as well as for the correction of extrapyramidal disorders caused by neuroleptics. According to the invention, the compounds of formula I were prepared by reducing, using lithium aluminum hydride, an isocyanate of general formula: n-=3vn-=3v La présente invention se rapporte, d'une manière générale, à la préparation de nouveaux dérivés de méthylamine doués d'activités pharmacologiques ainsi qu'à la préparation de leurs sels d'addition non toxiques. Les composés pharmacologiquement actifs préparés selon l'invention peuvent être représentés par la formule générale:The present invention relates, in general, to the preparation of new methylamine derivatives endowed with pharmacological activities as well as to the preparation of their non-toxic addition salts. The pharmacologically active compounds prepared according to the invention can be represented by the general formula: r-c-n=c=0r-c-n=c=0 (II)(II) n"C3H7n"C3H7 20 dans laquelle R a la même signification que précédemment, ce qui fournit le dérivé désiré de méthylamine de formule I que l'on peut, par la suite, faire réagir avec un acide organique ou inorganique pour obtenir un sel d'addition non toxique de ce dérivé.wherein R has the same meaning as before, yielding the desired methylamine derivative of formula I which can subsequently be reacted with an organic or inorganic acid to obtain a non-toxic addition salt of this derivative. La réduction en question est effectuée dans un milieu inerte et 25 anhydre tel que, par exemple, l'éther éthylique.The reduction in question is carried out in an inert and anhydrous medium such as, for example, ethyl ether. Les composés de formule II sont tous des produits connus ayant été décrits, ainsi que leur procédé de préparation, dans le brevet suisse N° 605606.The compounds of formula II are all known products having been described, as well as their method of preparation, in Swiss patent No. 605606. La préparation des composés selon l'invention est illustrée par 30 l'exemple non limitatif suivant:The preparation of the compounds according to the invention is illustrated by the following non-limiting example: Exemple:Example: Préparation du chlorhydrate de N-méthyl di-n-propyl-1,1 n-butyl-Preparation of N-methyl di-n-propyl-1,1-n-butyl-hydrochloride amineamine 3535 A. N-Méthyl di-n-propyl-1,1 n-butylamineA. N-Methyl di-n-propyl-1,1 n-butylamine A une suspension de 1,9 g (0,05 mol) d'hydrure de lithium et d'aluminium dans 60 ml d'éther sulfurique anhydre, on ajoute une solution de 3,66 g (0,02 mol) de di-n-propyl-1,1 n-butylisocyanate, 40 préparé comme décrit dans le brevet suisse N° 605606, dans 20 ml d'éther sec. On réalise l'addition en 30 mn à la température ambiante, puis on porte le mélange réactionnel au reflux pendant 3 h. Après hydrolyse d'abord avec de l'éther saturé d'eau, puis avec de l'eau, on sépare la partie organique. On la sèche sur sulfate de 45 magnésium, on l'évaporé sous vide puis on distille sous pression réduite.To a suspension of 1.9 g (0.05 mol) of lithium aluminum hydride in 60 ml of anhydrous sulfuric ether, a solution of 3.66 g (0.02 mol) of di- n-propyl-1,1 n-butylisocyanate, prepared as described in Swiss Patent No. 605606, in 20 ml of dry ether. The addition is carried out in 30 min at room temperature, then the reaction mixture is brought to reflux for 3 h. After hydrolysis first with water-saturated ether and then with water, the organic part is separated. It is dried over magnesium sulphate, evaporated under vacuum and then distilled under reduced pressure. De cette manière, on obtient 3,2 g de N-méthyl di-n-propyl-1,1 n-butylamine sous la forme d'un liquide incolore.In this way, 3.2 g of N-methyl di-n-propyl-1,1 n-butylamine are obtained in the form of a colorless liquid. Rendement: 94%.Yield: 94%. so P.E.: 84°C sous 13 mm Hg.so P.E.: 84°C under 13 mm Hg. B. Chlorhydrate de la N-méthyl di-n-propyl-1,1 n-butylamineB. N-methyl di-n-propyl-1,1 n-butylamine hydrochloride Par barbotage d'un courant d'acide chlorhydrique gazeux et sec dans une solution éthérée de l'amine obtenue précédemment, on 55 précipite le chlorhydrate de N-méthyl di-n-propyl-1,1 n-butyl-amine sous forme de cristaux incolores.By bubbling a stream of gaseous and dry hydrochloric acid into an ethereal solution of the amine obtained above, the hydrochloride of N-methyl di-n-propyl-1,1-n-butyl-amine is precipitated in the form of colorless crystals. Rendement: 90%.Yield: 90%. P.F.: 133-134° C.M.P.: 133-134°C. De la même manière que celle décrite précédemment, mais au on départ des produits appropriés, on a préparé les composés suivants :In the same way as that described above, but starting from the appropriate products, the following compounds were prepared: ComposéCompound P.F.(C)P.F.(C) Chlorhydrate de N-méthyl n-propyl-1 Isopropyl-1N-methyl n-propyl-1 Isopropyl-1 hydrochloride 65 n-butylamine (Rendement: 80%)65 n-butylamine (Yield: 80%) Chlorhydrate de N-méthyl n-propyl-1 Isobutyl-1 n-butylamine 139N-methyl n-propyl-1-isobutyl-1-n-butylamine hydrochloride 139 144-145144-145 RR
CH698080A 1976-06-03 1980-09-17 Process for the preparation of new methylamine derivatives CH623559A5 (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

Publications (1)

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CH623559A5 true CH623559A5 (en) 1981-06-15

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ID=3842891

Family Applications (4)

Application Number Title Priority Date Filing Date
CH660677A CH624922A5 (en) 1976-06-03 1977-05-27 Process for the preparation of new methylamine derivatives
CH697880A CH624389A5 (en) 1976-06-03 1980-09-17 Process for the preparation of new methylamine derivatives
CH697980A CH623560A5 (en) 1976-06-03 1980-09-17 Process for the preparation of new methylamine derivatives
CH698080A CH623559A5 (en) 1976-06-03 1980-09-17 Process for the preparation of new methylamine derivatives

Family Applications Before (3)

Application Number Title Priority Date Filing Date
CH660677A CH624922A5 (en) 1976-06-03 1977-05-27 Process for the preparation of new methylamine derivatives
CH697880A CH624389A5 (en) 1976-06-03 1980-09-17 Process for the preparation of new methylamine derivatives
CH697980A CH623560A5 (en) 1976-06-03 1980-09-17 Process for the preparation of new methylamine derivatives

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)

* 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
DE3362734D1 (en) * 1982-01-18 1986-05-07 Exxon Research Engineering Co Secondary and tertiary amino alcohols
DE19827166A1 (en) 1998-06-18 1999-12-23 Merck Patent Gmbh Process for the catalytic disubstitution of carboxamides with at least one Grignard reagent
DE19827161A1 (en) 1998-06-18 1999-12-23 Merck Patent Gmbh Process for the catalytic, symmetrical disubstitution of carboxamides with Grignard reagents
JP2003524588A (en) * 1998-06-18 2003-08-19 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング Geminal substituted amine

Also Published As

Publication number Publication date
GB1565021A (en) 1980-04-16
HU175776B (en) 1980-10-28
IE45730B1 (en) 1982-11-17
DE2725245A1 (en) 1977-12-15
CH623560A5 (en) 1981-06-15
CA1076482A (en) 1980-04-29
CH624389A5 (en) 1981-07-31
BE842528R (en) 1976-12-03
GB1565023A (en) 1980-04-16
IT1114869B (en) 1986-01-27
DE2725245C2 (en) 1986-09-04
GB1565022A (en) 1980-04-16
CH624922A5 (en) 1981-08-31
OA05675A (en) 1981-05-31
IE45730L (en) 1977-12-03

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