FR2479218A2 - 1-Heterocyclyl:oxy-3,5-di:halobenzene derivs. - useful as local anaesthetics - Google Patents

1-Heterocyclyl:oxy-3,5-di:halobenzene derivs. - useful as local anaesthetics Download PDF

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FR2479218A2
FR2479218A2 FR8007352A FR8007352A FR2479218A2 FR 2479218 A2 FR2479218 A2 FR 2479218A2 FR 8007352 A FR8007352 A FR 8007352A FR 8007352 A FR8007352 A FR 8007352A FR 2479218 A2 FR2479218 A2 FR 2479218A2
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sep
compounds according
compounds
formula
general formula
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FR2479218B2 (en
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Michel Thominet
Jacqueline Franceschini
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ILE DE FRANCE ETUDES SCIENTIFIQU
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ILE DE FRANCE ETUDES SCIENTIFIQU
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Priority to FR8007352A priority Critical patent/FR2479218A2/en
Priority to US06/162,796 priority patent/US4379161A/en
Priority to BG8048341A priority patent/BG35039A3/en
Priority to AT80400999T priority patent/ATE10739T1/en
Priority to BG8362115A priority patent/BG35746A3/en
Priority to YU1710/80A priority patent/YU42344B/en
Priority to AT83105420T priority patent/ATE17119T1/en
Priority to DE8383105420T priority patent/DE3071314D1/en
Priority to CS804693A priority patent/CS216933B2/en
Priority to SU802938255A priority patent/SU1085507A3/en
Priority to EP83105420A priority patent/EP0094102B1/en
Priority to OA57149A priority patent/OA06561A/en
Priority to EP80400999A priority patent/EP0024960B1/en
Priority to DE8080400999T priority patent/DE3069789D1/en
Priority to IL60472A priority patent/IL60472A/en
Priority to AU60028/80A priority patent/AU536482B2/en
Priority to BE1/9873A priority patent/BE884124A/en
Priority to PT71482A priority patent/PT71482A/en
Priority to RO101590A priority patent/RO81532B/en
Priority to NZ194230A priority patent/NZ194230A/en
Priority to RO110029A priority patent/RO85323B/en
Priority to HU80801658A priority patent/HU181147B/en
Priority to HU822217A priority patent/HU186539B/en
Priority to AR281635A priority patent/AR224012A1/en
Priority to DK289580A priority patent/DK157538C/en
Priority to MX8011334U priority patent/MX7642E/en
Priority to IE1392/80A priority patent/IE50060B1/en
Priority to CH5684/84A priority patent/CH655100A5/en
Priority to IT49163/80A priority patent/IT1188985B/en
Priority to ZW152/80A priority patent/ZW15280A1/en
Priority to ES493111A priority patent/ES8103049A1/en
Priority to PL1980225473A priority patent/PL127393B1/en
Priority to MA19091A priority patent/MA18893A1/en
Priority to IE1653/85A priority patent/IE50061B1/en
Priority to NO802027A priority patent/NO156086C/en
Priority to MX80100439U priority patent/MX6366E/en
Priority to LU82584A priority patent/LU82584A1/en
Priority to GR62381A priority patent/GR69638B/el
Priority to FI802156A priority patent/FI74274C/en
Priority to CH5169/80A priority patent/CH648827A5/en
Priority to IN779/CAL/80A priority patent/IN153037B/en
Priority to JO19801077A priority patent/JO1077B1/en
Priority to JP9321680A priority patent/JPS5639065A/en
Priority to DD80234984A priority patent/DD201141A5/en
Priority to PH24248A priority patent/PH16449A/en
Priority to DD222455A priority patent/DD153206A5/en
Priority to JP13751280A priority patent/JPS5649351A/en
Publication of FR2479218A2 publication Critical patent/FR2479218A2/en
Priority to CA000417963A priority patent/CA1163273A/en
Priority to YU2801/82A priority patent/YU42824B/en
Priority to US06/456,523 priority patent/US4594428A/en
Priority to IL68854A priority patent/IL68854A0/en
Application granted granted Critical
Publication of FR2479218B2 publication Critical patent/FR2479218B2/fr
Priority to IN1246/CAL/83A priority patent/IN158706B/en
Priority to AU25260/84A priority patent/AU563009B2/en
Priority to NO861988A priority patent/NO861988L/en
Priority to FI872955A priority patent/FI872955A/en
Priority to HK556/89A priority patent/HK55689A/en
Priority to HK558/89A priority patent/HK55889A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/08—Oxygen atoms

Abstract

Intermediates of formula (VI) in which Y is OH or Cl and R is 1-cyclohexenylmethyl are new.

Description

On a décrit dans la demande de brevet principal (demande de brevet nO 79 17610 du 6 Juillet 1979) de nouvelles phénoxyamines hétérocycliques substituées possédant d'intéressantes propriétés pharmacologiques, notamment comme anesthésiques locaux.The main patent application (patent application No. 79 17610 of July 6, 1979) describes new substituted heterocyclic phenoxyamines having valuable pharmacological properties, especially as local anesthetics.

Or, la demanderesse a constaté, et c'est ce qui fait l'objet du présent certificat d'addition que des phénoxyamines hétérocycliques de structure voisine étaient douées des mêmes propriétés pharmacologiques.However, the Applicant has found, and this is the subject of this certificate of addition that heterocyclic phenoxyamines of similar structure were endowed with the same pharmacological properties.

Les phénoxyamines hétérocycliques de la présente invention sont définies par la formule générale

Figure img00010001

dans laquelle
m = O ou 2
n = O ou 2 avec la condition que m + n = 2
A représente un groupe alcoxy inférieur ou alcényloxy inférieur
X représente un halogène
R représente un groupe cycloalkyl-alkyle
L'invention s'étend aussi aux formes optiquement actives des composés de formule générale I ainsi qu'a leurs sels d'addition avec les acides pharmaceutiquement acceptables, leurs sels d'ammonium quaternaire, leurs
N-oxydes.The heterocyclic phenoxyamines of the present invention are defined by the general formula
Figure img00010001

in which
m = 0 or 2
n = 0 or 2 with the condition that m + n = 2
A represents a lower alkoxy or lower alkenyloxy group
X represents a halogen
R represents a cycloalkyl-alkyl group
The invention also extends to the optically active forms of the compounds of general formula I and their addition salts with pharmaceutically acceptable acids, their quaternary ammonium salts, their
N-oxides.

Par suite de l'existence dans ces composés d'un carbone asymétrique ceux-ci peuvent se présenter sous forme racémique ou sous forme optiquement active après dédoublement.As a result of the existence in these compounds of an asymmetric carbon, these can be in racemic form or in optically active form after resolution.

Les produits de l'invention manifestent des propriétés pharmacologiques intéressantes sur le système nerveux central notamment comme anesthésiques locaux. The products of the invention exhibit interesting pharmacological properties on the central nervous system, particularly as local anesthetics.

L'invention s'étend donc à l'application comme mTdicament des composés de formule générale I.The invention therefore extends to the application as a drug of compounds of general formula I.

L'invention comprend encore les compositions pharmaceutiques renfermant comme principe actif au moins un des composés de formule générale I associé a un excipient inerte pharmaceutique.The invention also comprises pharmaceutical compositions containing as active ingredient at least one of the compounds of general formula I associated with a pharmaceutical inert excipient.

L'invention concerne également un procédé d'obtention des composés de formule générale I caractérisé en ce que l'on condense un phénol répondant à la formule générale Il

Figure img00020001

dans laquelle A et X sont définis comme ci-dessus, avec un composé de formule générale III :
Figure img00020002
The invention also relates to a process for obtaining compounds of general formula I, characterized in that a phenol corresponding to general formula II is condensed.
Figure img00020001

in which A and X are defined as above, with a compound of general formula III:
Figure img00020002

Dans laquelle R a les significations déjà données et Y est un reste anionique susceptible d'être éliminé, le reste Y sera par exemple un atome d'halogène, en particulier le chlore, le brome ou l'iode, pour obtenir un composé de formule générale I

Figure img00020003

dans laquelle la définition de m, n, A, X et R demeure inchangé. In which R has the meanings already given and Y is an anionic residue which can be eliminated, the remainder Y will be, for example, a halogen atom, in particular chlorine, bromine or iodine, to obtain a compound of formula general I
Figure img00020003

wherein the definition of m, n, A, X and R remains unchanged.

Ces composés peuvent être salifiés. Ils peuvent être dédoublés par réaction avec un acide optiquement actif en leurs isomères optiques actifs pharmacologiquement.These compounds can be salified. They can be resolved by reaction with an optically active acid in their pharmacologically active optical isomers.

Les phénols de formule Il sont mis en jeu sous forme de phénolates de métaux alcalins particulièrement de phénolate de sodium que l'on obtient par exemple par réaction des phénols avec les alcoolats de métaux alcalins.The phenols of the formula II are used in the form of alkali metal phenolates, particularly sodium phenolate, which is obtained, for example, by the reaction of the phenols with the alkali metal alcoholates.

On effectue la réaction des composés de formule II avec les composés de formule III dans un solvant organique inerte comme par exemple le toluène, le xylène... On opère à la température de reflux. du mélange réactionnel.The compounds of the formula II are reacted with the compounds of the formula III in an inert organic solvent such as, for example, toluene or xylene. The reaction is carried out at reflux temperature. of the reaction mixture.

On obtient des composés qui sont ensuite séparés, isolés et purifiés selon les méthodes habituelles, par exemple, extraction, formation de sels, recristallisation, chromatographie, etc....Compounds are obtained which are then separated, isolated and purified according to the usual methods, for example, extraction, salt formation, recrystallization, chromatography, etc.

La salification des composés de formule générale I est effectuée de préférence par addition d'un acide minéral comme par exemple l'acide chlorhydrique, l'acide bromhydrique, l'acide phosphorique ou d'un acide organique comme par exemple l'acide fumarique, l'acide citrique, l'acide oxalique.Salification of the compounds of general formula I is preferably carried out by adding a mineral acid such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or an organic acid such as fumaric acid, citric acid, oxalic acid.

Les composés de formule générale I peuvent également réagir par exemple, avec des halogénures ou des sulfates d'alkyle pour donner des sels d'ammonium quaternaires.The compounds of the general formula I can also react for example with alkyl halides or sulphates to give quaternary ammonium salts.

Les composés de formule I peuvent etre oxydés d'une manière connue soi par exemple au moyen d'eau oxygénée et de bioxyde de manganèse pour donner les N-oxydes correspondants.The compounds of formula I can be oxidized in a known manner, for example by means of hydrogen peroxide and manganese dioxide, to give the corresponding N-oxides.

Le dédoublement des composés de formule générale I est effectué avec un acide optiquement actif.The resolution of the compounds of the general formula I is carried out with an optically active acid.

Les composés de départ de formule II dans laquelle X représente le chlore peuvent être préparés à partir de phénols par acétylation, chloration, désacétylation puis purification. The starting compounds of formula II wherein X is chlorine can be prepared from phenols by acetylation, chlorination, deacetylation and purification.

Les composés de départ de formule II dans laquelle X représente le brome
peuvent être préparés à partir de l'o.nitrophénol par bromuration,
alkylation de la fonction phénol, réduction du groupe nitro, diazotation
et décomposition.The starting compounds of formula II in which X represents bromine
can be prepared from o.nitrophenol by bromination,
alkylation of the phenol function, reduction of the nitro group, diazotation
and decomposition.

Les composés de départ de formule III peuvent être préparés selon la
4ème méthode décrite par YAO-HUA-WU et J.R. CORRIGAN - J. ORG. CHEM.The starting compounds of formula III can be prepared according to the
4th method described by YAO-HUA-WU and JR CORRIGAN - J. ORG. CHEM.

(1961) p. 1531. (1961) p. 1531.

Afin d'illustrer les caractéristiques techniques de la présente invention, un exemple de réalisation va être décrit étant bien entendu que celui-ci n'est pas limitatif quant à son mode de mise en oeuvre et aux applications que l'on peut en faire. L'invention s'étend en particulier à tous les composés formule analogue à celle des composés des exemples et présentant les mêmes propriétés pharmacologiques.In order to illustrate the technical features of the present invention, an exemplary embodiment will be described being understood that it is not limiting as to its mode of implementation and the applications that can be made. The invention extends in particular to all compounds analogous to that of the compounds of the examples and having the same pharmacological properties.

Exemple 1 1-cyclopropylméthyl-4-[2-méthoxy-3,5-dichlorophénoxy]hexaméthylène imine 1-cyclopropylméthyl-2-[2-méthoxy-3,5-dichlorophénoxyéthyl] pyrrolidine
En suivant la technique de l'Exemple 1 du brevet principal on obtient par réaction de 174 g de 3,5-dichloro galacol (0,90 mole) et 186 g de 1-cyclopropylméthyl-2- [2-chloroéthyl] pyrrolidine (0,90 mole + 10 g) 329 g de produit (théorie 310 g) qui est' d'après l'analyse C.C.M. un mélange de deux isomères : 1 cyclopropylméthyl-4-[2-méthoxy-3,5-dichlorophénoxy]hexaméthylène imine et 1-cyclopropylméthyl-2-[2-méthoxy-3,5-dichlorophénoxyéthyl]pyrrolidine.Example 1 1-cyclopropylmethyl-4- [2-methoxy-3,5-dichlorophenoxy] hexamethyleneimine 1-cyclopropylmethyl-2- [2-methoxy-3,5-dichlorophenoxyethyl] pyrrolidine
Following the procedure of Example 1 of the main patent, 174 g of 3,5-dichloro galacol (0.90 mole) and 186 g of 1-cyclopropylmethyl-2- [2-chloroethyl] pyrrolidine (174 g) are obtained by reaction. 90 mole + 10 g) 329 g of product (theory 310 g) which is, according to TLC analysis, a mixture of two isomers: 1 cyclopropylmethyl-4- [2-methoxy-3,5-dichlorophenoxy] hexamethylene imine and 1-cyclopropylmethyl-2- [2-methoxy-3,5-dichlorophenoxyethyl] pyrrolidine.

On dissout 328,5 g de base dans 500 ml d'éthanol et ajoute à la solution obtenue 173 g d'acide citrique (0,9 mole) dissous dans 1000 ml d'éthanol.328.5 g of base are dissolved in 500 ml of ethanol and 173 g of citric acid (0.9 mol) dissolved in 1000 ml of ethanol are added to the solution obtained.

Le citrate cristallise lentement. Il est essoré, lavé avec 300 mi d'éthanol et séché à 400C. On obtient 389 g de citrate fondant à 60-650C qui d'après l'analyse C.C.M. est un mélange plus riche en dérivé hexaméthylèneimino qu'en dérivé pyrrolidino. Citrate crystallizes slowly. It is drained, washed with 300 ml of ethanol and dried at 400C. 389 g of citrate, m.p. 60-650C, which according to C.C.M. is a mixture richer in hexamethyleneimino derivative than in pyrrolidino derivative.

Ce citrate est recristallisé avec filtration sur noir successivement dans 780 nil d'acdtonitrile, 510 ml puis 645 ml de méthyléthylcétone. On obtient 189 g de 1-cyclopropylméthyl-4-[2-méthoxy-3,5-dichlorophénoxy] hexaméthylène imine fondant à 71-730C et ne présentant plus qu'une tache en C.C.M. Les jus alcooliques de cristallisation du citrate sont concentrés jusqu'à un volume de 280 ml. On dilue avec un litre d'eau et alcalinise la solution par addition d'ammoniaque à 20 %. L'huile qui décante est extraite au chlorure de méthylène. La phase organique est séchée sur carbonate de potassium puis le chlorure de méthylène est distillé en terminant sous vide jusqu'à poids constant. Poids obtenu = 76 g.This citrate is recrystallized with black filtration successively in 780 ml of actonitrile, 510 ml and then 645 ml of methyl ethyl ketone. 189 g of 1-cyclopropylmethyl-4- [2-methoxy-3,5-dichlorophenoxy] hexamethyleneimine are obtained, melting at 71-7 ° C. and having only one spot of C.C.M. The citric alcoholic juices are concentrated to a volume of 280 ml. It is diluted with one liter of water and the solution is alkalized by addition of 20% ammonia. The decanting oil is extracted with methylene chloride. The organic phase is dried over potassium carbonate and the methylene chloride is distilled by ending under vacuum until constant weight. Weight obtained = 76 g.

69 g de base (0,2 mole) sont dissous dans 275 ml d'éthanol absolu. On ajoute 23 g d'acide fumarique (0,2 mole) et chauffe jusqu'à dissolution.69 g of base (0.2 mole) are dissolved in 275 ml of absolute ethanol. 23 g of fumaric acid (0.2 mol) are added and heated until dissolution takes place.

On refroidit. Le fumarate qui cristallise est essoré, lavé avec 60 ml d'éthanol et séché en étuve. Poids obtenu = 65 g.We cool. The fumarate which crystallizes is drained, washed with 60 ml of ethanol and dried in an oven. Weight obtained = 65 g.

Ce produit est un mélange contenant en majorité du dérivé pyrrolidino.This product is a mixture containing mainly pyrrolidino derivative.

Il est recristallisé avec filtration avec du noir dans 130 ml d'éthanol à 950
On obtient 45 g de fumarate de 1-cyclopropylméthyl-2- [2-méthoxy-3,5- dichloro phénoxyéthyl] pyrrolidine fondant à 162-1630C. L'analyse C.C.M.It is recrystallized with filtration with black in 130 ml of 950 ethanol.
45 g of 1-cyclopropylmethyl-2- [2-methoxy-3,5-dichlorophenoxyethyl] pyrrolidine fumarate, m.p. 162-16 ° C., are obtained. CCM analysis

ne permet pas de déceler de dérivé hexaméthylène imino.does not detect hexamethylene imino derivative.

Les produits selon l'invention sont utilisés sous forme de solution injectable, de collyre, de lotion dont la préparation est connue en soi.The products according to the invention are used in the form of injectable solution, eyedrops, lotion whose preparation is known per se.

Les composés de l'invention peuvent être utilisés en injection locale sous forme d'ampoules dosées à 1Q mg/5 ml. On peut également appliquer les composés de l'invention localement sous forme de badigeonnages
Les composés de l'invention exercent d'intéressantes propriétés pharmacologiques sur le système nerveux central notamment comme anesthésiques locaux. La toxicité des composés de l'invention a été déterminée chez la souris par voie parentérale (intraveineuse, intrapéritonéale, souscutanée) et par voie orale. Les doses léthales 50 sont rassemblées à titre d'exemple dans le tableau I. The compounds of the invention may be used in local injection in the form of ampoules dosed at 1 mg / 5 ml. The compounds of the invention may also be applied locally in the form of whitewashes
The compounds of the invention have interesting pharmacological properties on the central nervous system, particularly as local anesthetics. The toxicity of the compounds of the invention was determined in the mouse parenterally (intravenously, intraperitoneally, subcutaneously) and orally. The lethal doses 50 are collected by way of example in Table I.

Les composés de l'invention sont, dans le tableau I et dans les suivants, numérotés comme ci-après :

Figure img00060001
The compounds of the invention are, in Table I and in the following, numbered as follows:
Figure img00060001

<tb> <SEP> COMPOSES <SEP> MUMEROS
<tb> Fumarate <SEP> de <SEP> 1-cyclopropylméthyl
<tb> 2-[2-méthoxy <SEP> 3,5-dichlorophénoxy- <SEP> Composé <SEP> 1
<tb> éthyl) <SEP> pyrrolidine
<tb> Citrate <SEP> de <SEP> 1-cyclopropylméthyl
<tb> 4-[2-méthoxy-3,5-dichlorophénoxy) <SEP> Composé <SEP> 2
<tb> hexaméthylène <SEP> imine
<tb>
TABLEAU I - TOXICITE
DL 50 - SOURIS - MG/KG (BASE)

Figure img00060002
<tb><SEP> COMPOUNDS <SEP> MUMEROS
<tb> Fumarate <SEP> of <SEP> 1-cyclopropylmethyl
<tb> 2- [2-methoxy <SEP> 3,5-dichlorophenoxy- <SEP> Compound <SEP> 1
<tb> ethyl) <SEP> pyrrolidine
<tb> Citrate <SEP> of <SEP> 1-cyclopropylmethyl
<tb> 4- [2-methoxy-3,5-dichlorophenoxy) <SEP> Compound <SEP> 2
<tb> hexamethylene <SEP> imine
<Tb>
TABLE I - TOXICITY
LD 50 - MOUSE - MG / KG (BASE)
Figure img00060002

<tb> COMPOSES <SEP> Iv <SEP> Ip <SEP> SC <SEP> PO
<tb> <SEP> 1 <SEP> 22,9-26,9 <SEP> 142-136 <SEP> 479-512 <SEP> 293-303
<tb> <SEP> 2 <SEP> 18,5-19,1 <SEP> 122-116 <SEP> 411-404 <SEP> 270-254
<tb>
Les propriétés anesthésiques locales des composés de l'invention ont été mises en évidence d'après les différents tests décrits dans le brevet principal. Les index d'activité qui sont définis par
CE 50 de l'anesthésique de référence
Le rapport =
CE 50 de produit à étudier sont mentionnés dans le tableau ci-dessous :

Figure img00070001
<tb> COMPOUNDS <SEP> IV <SEP> Ip <SEP> SC <SEP> PO
<tb><SEP> 1 <SEP> 22.9-26.9 <SEP> 142-136 <SEP> 479-512 <SEP> 293-303
<tb><SEP> 2 <SEP> 18.5-19.1 <SEP> 122-116 <SEP> 411-404 <SEP> 270-254
<Tb>
The local anesthetic properties of the compounds of the invention have been demonstrated from the various tests described in the main patent. Activity indexes that are defined by
CE 50 of the reference anesthetic
The report =
EC 50 of product to be studied are mentioned in the table below:
Figure img00070001

<tb> <SEP> Anesthésie <SEP> de <SEP> Anesthésie <SEP> de <SEP> Anesthésie
<tb> <SEP> surface <SEP> chez <SEP> conduction <SEP> chez <SEP> infiltration
<tb> <SEP> le <SEP> lapin <SEP> le <SEP> rat <SEP> chez <SEP> le <SEP> cobaye
<tb> Index <SEP> d'activité <SEP> 5,68 <SEP> 1,75 <SEP> 2,55
<tb> composé <SEP> 1
<tb>
L'intérêt suscité par les expérimentations pratiquées chez les animaux de laboratoire s'est vu très largement justifié lors des essais en clinique humaine des composés de l'invention. <tb><SEP> Anesthesia <SEP> of <SEP> Anesthesia <SEP> of <SEP> Anesthesia
<tb><SEP> surface <SEP> in <SEP> conduction <SEP> at <SEP> infiltration
<tb><SEP> the <SEP> rabbit <SEP><SEP> rat <SEP> at <SEP> the <SEP> guinea pig
<tb> Index <SEP> of activity <SEP> 5.68 <SEP> 1.75 <SEP> 2.55
<tb> compound <SEP> 1
<Tb>
The interest aroused by the experiments carried out in laboratory animals has been very widely justified in human clinical trials of the compounds of the invention.

Claims (6)

REVENDICATIONS 1 - Nouvelles phénoxyamines hétérocycliques substituées de formule générale 11 - Novel substituted heterocyclic phenoxyamines of general formula 1
Figure img00080001
Figure img00080001
 dans laquelle m = O ou 2 where m = 0 or 2 n = O ou 2 à la condition que m + n = 2 n = 0 or 2 provided that m + n = 2 A représente un groupe alcoxy inférieur ou alcényloxy A represents a lower alkoxy or alkenyloxy group inférieur inferior X représente un halogène X represents a halogen R représente un groupe cycloalkyl-alkyle 2 - Nouveaux composés selon la revendication 1 caractérisés en ce qu'ils sont sous forme de sels d'addition avec un acide minéral ou organique, de sels d'ammonium quaternaire ou de N-oxydes. R represents a cycloalkyl-alkyl group 2 - New compounds according to claim 1 characterized in that they are in the form of addition salts with an inorganic or organic acid, quaternary ammonium salts or N-oxides. 3 - Un composé selon l'une des revendications 1 ou 2 caractérisé en ce qu'il est sous forme d'un isomère optiquement actif.3 - A compound according to one of claims 1 or 2 characterized in that it is in the form of an optically active isomer. 4 - Composés selon l'une quelconque des revendications 1, 2 ou 3 pour lesquels n = O, m = 2, m + n = 2.4 - Compounds according to any one of claims 1, 2 or 3 for which n = 0, m = 2, m + n = 2. 5 - Suivant l'une des revendications 1, 2, 3 ou 4, le fumarate de 1cyclopropylméthyl 2- [2-méthoxy 3,5-dichlorophénoxyéthyl] pyrrolidine.5 - According to one of claims 1, 2, 3 or 4, 1cyclopropylmethyl fumarate 2- [2-methoxy 3,5-dichlorophenoxyethyl] pyrrolidine. 6 - A titre de médicaments nouveaux, à activité anesthésique locale, les composés selon l'une quelconque des revendications 1 à 5. 6 - As new drugs, local anesthetic activity, the compounds according to any one of claims 1 to 5. 7 - Compositions pharmaceutiques caractérisées en ce qu'elles contiennent comme principe actif, l'un des composés selon l'une quelconque des revendications 1 à 5 joint à des excipients pharmaceutiquement acceptables 8 - Prc@édé de préparation des composés selon l'une quelconque des revondications 1 à 5 qui consiste a traiter un phénol 3,5-dihalogéne de formule II7 - Pharmaceutical compositions characterized in that they contain as active ingredient, one of the compounds according to any one of claims 1 to 5 joined to pharmaceutically acceptable excipients 8 - Prc @ edé preparation of compounds according to any one revonditions 1 to 5 which consists in treating a phenol 3,5-dihalogen of formula II
Figure img00090001
Figure img00090001
 dans laquelle A et X sont définis comme dans la revendication 1, sous forme de phenolata alcalin avec une amine de formule III : in which A and X are defined as in claim 1, in the form of an alkaline phenolate with an amine of formula III:
Figure img00090002
Figure img00090002
 dans laquelle Y est un reste anionique susceptible d'être éliminé et R est défini comme dans la revendication 1.  in which Y is an anionic residue that can be removed and R is defined as in claim 1.
FR8007352A 1979-06-07 1980-04-01 1-Heterocyclyl:oxy-3,5-di:halobenzene derivs. - useful as local anaesthetics Granted FR2479218A2 (en)

Priority Applications (57)

Application Number Priority Date Filing Date Title
FR8007352A FR2479218A2 (en) 1980-04-01 1980-04-01 1-Heterocyclyl:oxy-3,5-di:halobenzene derivs. - useful as local anaesthetics
US06/162,796 US4379161A (en) 1979-06-07 1980-06-25 Novel substituted heterocyclic phenoxyamines, the method of preparation thereof and the use thereof as local anaesthetics
BG8048341A BG35039A3 (en) 1979-07-06 1980-07-01 Method for preparing substituted heterocyclic rhenoxyamines
AT80400999T ATE10739T1 (en) 1979-07-06 1980-07-01 SUBSTITUTED HETEROCYCLIC PHENOXYAMINE, PROCESS FOR THEIR PRODUCTION AND USE AS AGENTS FOR LOCAL ANESTHESIA.
BG8362115A BG35746A3 (en) 1979-07-06 1980-07-01 Method for preparing 1- cyclohexenylmethylpyrolidines
YU1710/80A YU42344B (en) 1979-07-06 1980-07-01 Process for obtaining new substituted heterocyclic phenoxyamines
AT83105420T ATE17119T1 (en) 1979-07-06 1980-07-01 1-(1-CYCLOHEXENYLMETHYL)PYRROLIDINE DERIVATIVES AND PROCESS FOR THEIR PREPARATION.
DE8383105420T DE3071314D1 (en) 1979-07-06 1980-07-01 1-(1-cyclohexanyl-methyl) pyrrolidine derivatives, and process for their preparation
CS804693A CS216933B2 (en) 1979-07-06 1980-07-01 Method of making the heterocyclic phenoxyemines
SU802938255A SU1085507A3 (en) 1979-07-06 1980-07-01 Process for preparing derivatives of heterocyclic phenoxyamines
EP83105420A EP0094102B1 (en) 1979-07-06 1980-07-01 1-(1-cyclohexanyl-methyl) pyrrolidine derivatives, and process for their preparation
OA57149A OA06561A (en) 1979-07-06 1980-07-01 New heterocyclic substituted phenoxyamines, their method of preparation and their application as local anesthetics.
EP80400999A EP0024960B1 (en) 1979-07-06 1980-07-01 Substituted heterocyclic phenoxy amines, their preparation method and their use as local anaesthetics
DE8080400999T DE3069789D1 (en) 1979-07-06 1980-07-01 Substituted heterocyclic phenoxy amines, their preparation method and their use as local anaesthetics
IL60472A IL60472A (en) 1979-07-06 1980-07-02 Substituted heterocyclic phenoxyamines,their preparation and pharmaceutical compositions containing them
AU60028/80A AU536482B2 (en) 1979-07-06 1980-07-02 Pyrrolidine and hexamethyleneimine derivatives
BE1/9873A BE884124A (en) 1979-07-06 1980-07-02 NOVEL SUBSTITUTED HETEROCYCLIC PHENOXYAMINES, THEIR PREPARATION METHOD AND THEIR APPLICATION AS LOCAL ANESTHETICS
PT71482A PT71482A (en) 1979-07-06 1980-07-02 PROCESS FOR PREPARING NOVEL SUBSTITUTED HETEROCYCLIC PHENOXYAMINES USED AS NEW MEDICAMENTS WITH LOCAL ANESTHESIC ACTIVITY OF OPTICALLY ACTIVE FORMS AND THUS AS INTERMEDIATE PRODUCTS FOR THE SAME COMPOUNDS
RO101590A RO81532B (en) 1979-07-06 1980-07-03 Process for preparing heterocyclic phenoxyamines
NZ194230A NZ194230A (en) 1979-07-06 1980-07-03 Phenoxy-(alkyl)-heterocyclic compounds intermediates pharmaceutical compositions
RO110029A RO85323B (en) 1979-07-06 1980-07-03 Process for the preparation of heterocyclic phenoxyamines
HU80801658A HU181147B (en) 1979-07-06 1980-07-03 Process for preparing substituted heterocyclin phenoxamines
HU822217A HU186539B (en) 1979-07-06 1980-07-03 Process for producing 1-bracket-1-cyclohexenyl-methyl-bracket closed-2-bracket-2-chloroethyl-bracket closed-pyrrolidine
AR281635A AR224012A1 (en) 1979-07-06 1980-07-03 A PROCEDURE FOR THE PREPARATION OF NEW SUBSTITUTED HETERO CYCLIC PHENOXYAMINS
DK289580A DK157538C (en) 1979-07-06 1980-07-04 METHOD OF ANALOGY FOR THE PREPARATION OF HETEROCYCLIC PHENOXYAMINES AND 1-CYCLOHEXENYLMETHYL-PYRROLIDINES FOR USING THE INTERMEDIATE PROCEDURE
MX8011334U MX7642E (en) 1979-07-06 1980-07-04 PROCEDURE FOR PREPARING 1-CYCLE-HEXENYLMENTIL-2-CHLOROETIL PIRROLIDINA
IE1392/80A IE50060B1 (en) 1979-07-06 1980-07-04 Substituted heterocyclic phenoxyamines,method of preparation thereof and the use thereof as local anaesthetics
CH5684/84A CH655100A5 (en) 1979-07-06 1980-07-04 1-CYCLOHEXENYL-2-(HYDROXY- OR CHLORO-)ETHYL-PYRROLIDINE AND METHOD FOR THE PREPARATION.
IT49163/80A IT1188985B (en) 1979-07-06 1980-07-04 HETEROCYCLIC PHENOSMIA REPLACED PROCEDURE TO PREPARE THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
ZW152/80A ZW15280A1 (en) 1979-07-06 1980-07-04 Novel substituted heterocyclic phenoxyamines the method of preparation thereof and the use thereof as local anaestheetics
ES493111A ES8103049A1 (en) 1979-07-06 1980-07-04 Substituted heterocyclic phenoxy amines, their preparation method and their use as local anaesthetics.
PL1980225473A PL127393B1 (en) 1979-07-06 1980-07-04 Method of obtaining new substituted heterocyclic phenoxyamines
MA19091A MA18893A1 (en) 1979-07-06 1980-07-04 NOVEL SUBSTITUTED HETEROCYCLIC PHENOXYAMINS, THEIR PREPARATION METHOD AND THEIR APPLICATION AS LOCAL ANESTHETICS
IE1653/85A IE50061B1 (en) 1979-07-06 1980-07-04 1-(1-cyclohexenylmethyl)pyrrolidine derivatives and process for their preparation
NO802027A NO156086C (en) 1979-07-06 1980-07-04 ANALOGY PROCEDURE FOR THE PREPARATION OF SUBSTITUTED HETEROCYCLIC PHENOXYAMINES.
MX80100439U MX6366E (en) 1979-07-06 1980-07-04 PROCEDURE FOR THE PREPARATION OF SUBSTITUTED HETERO CYCLICAL PHENOXYAMINS
LU82584A LU82584A1 (en) 1979-07-06 1980-07-04 NOVEL SUBSTITUTED HETEROCYCLIC PHENOXYAMINS, THEIR PREPARATION METHOD AND THEIR APPLICATION AS LOCAL ANESTHETICS
GR62381A GR69638B (en) 1979-07-06 1980-07-04
FI802156A FI74274C (en) 1979-07-06 1980-07-04 FOERFARANDE FOER FRAMSTAELLNING AV NYA, SAOSOM LOKALANESTETIKA ANVAENDBARA SUBSTITUERADE HETEROCYKLISKA FENOXIAMINER.
CH5169/80A CH648827A5 (en) 1979-07-06 1980-07-04 SUBSTITUTED HETEROCYCLIC PHENOXYAMINES, THEIR PREPARATION AND MEDICAMENTS CONSISTING OF OR COMPRISING SUCH COMPOUNDS.
IN779/CAL/80A IN153037B (en) 1979-07-06 1980-07-05
JO19801077A JO1077B1 (en) 1979-07-06 1980-07-05 Novel Substituted Heterocyclic Phenoxyamines, The Method of Preparation Thereof and The use Thereof As Local Anaesthetics.
JP9321680A JPS5639065A (en) 1979-07-06 1980-07-07 Novel phenoxy heterocyclic amine* its manufacture and local narcotic as active component thereof
DD80234984A DD201141A5 (en) 1979-07-06 1980-07-07 METHOD FOR PRODUCING NEW SUBSTITUTED HETEROCYCLIC PHENOXYAMINES
PH24248A PH16449A (en) 1979-07-06 1980-07-07 Novel substituted heterocyclic phenoxyamines and their use thereof as local anaesthetic
DD222455A DD153206A5 (en) 1979-07-06 1980-07-07 METHOD FOR PRODUCING NEW SUBSTITUTED HETEROCYCLIC PHENOXYAMINES
JP13751280A JPS5649351A (en) 1979-07-06 1980-09-30 Heterocyclic amine and its manufacture
CA000417963A CA1163273A (en) 1979-07-06 1982-12-16 Substituted heterocyclic phenoxyamines, preparation process and application as topical anesthetics
YU2801/82A YU42824B (en) 1979-07-06 1982-12-17 Process for obtaining new substituted pyrolidines
US06/456,523 US4594428A (en) 1979-07-06 1983-01-07 Novel substituted heterocyclic amines and methods of preparation thereof
IL68854A IL68854A0 (en) 1979-07-06 1983-06-01 Substituted 1-cyclohexenylmethyl 2-ethyl pyrrolidines and their preparation
IN1246/CAL/83A IN158706B (en) 1979-07-06 1983-10-10
AU25260/84A AU563009B2 (en) 1979-07-06 1984-03-02 1-(cyclohexenylmethylene)-pyrrolidine derivatives
NO861988A NO861988L (en) 1979-07-06 1986-05-20 INTERMEDIATES FOR THE PREPARATION OF NEW SUBSTITUTED HETEROCYCLIC PHENOXYAMINES AND PROCEDURES FOR THE PREPARATION OF THEREOF.
FI872955A FI872955A (en) 1979-07-06 1987-07-03 1-CYKLOHEXENYLMETYLETYL-PYRROLIDINDERIVAT.
HK556/89A HK55689A (en) 1979-07-06 1989-07-13 Substituted heterocyclic phenoxy amines,their preparation method and their use as local anaesthetics
HK558/89A HK55889A (en) 1979-07-06 1989-07-13 1-(1-cyclohexanyl-methyl)pyrrolidine derivatives,and process for their preparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR8007352A FR2479218A2 (en) 1980-04-01 1980-04-01 1-Heterocyclyl:oxy-3,5-di:halobenzene derivs. - useful as local anaesthetics

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FR2479218B2 FR2479218B2 (en) 1983-07-08

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1096441A (en) * 1964-01-15 1967-12-29 Bristol Myers Co Ethers of benzyl phenols and a process for the preparation thereof
DE2026688A1 (en) * 1969-06-12 1970-12-17 Pfizer Corp., Colon (Panama) Orthosubstituted phenoxyamines with antihistaminic effects
EP0002672A2 (en) * 1977-12-02 1979-07-11 Byk Gulden Lomberg Chemische Fabrik GmbH Substituted pyrrolidines, process for their preparation and medicaments containing them
EP0004288A2 (en) * 1978-03-18 1979-10-03 MERCK PATENT GmbH Phenoxyalkyl amines, pharmaceutical compositions containing them, and process for their preparation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1096441A (en) * 1964-01-15 1967-12-29 Bristol Myers Co Ethers of benzyl phenols and a process for the preparation thereof
DE2026688A1 (en) * 1969-06-12 1970-12-17 Pfizer Corp., Colon (Panama) Orthosubstituted phenoxyamines with antihistaminic effects
EP0002672A2 (en) * 1977-12-02 1979-07-11 Byk Gulden Lomberg Chemische Fabrik GmbH Substituted pyrrolidines, process for their preparation and medicaments containing them
EP0004288A2 (en) * 1978-03-18 1979-10-03 MERCK PATENT GmbH Phenoxyalkyl amines, pharmaceutical compositions containing them, and process for their preparation

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