EP0000299B1 - Novel derivatives of substituted 2-benzoyl-4-chloro-glycinanilides, their preparation and their use as medicines. - Google Patents

Novel derivatives of substituted 2-benzoyl-4-chloro-glycinanilides, their preparation and their use as medicines. Download PDF

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Publication number
EP0000299B1
EP0000299B1 EP78400009A EP78400009A EP0000299B1 EP 0000299 B1 EP0000299 B1 EP 0000299B1 EP 78400009 A EP78400009 A EP 78400009A EP 78400009 A EP78400009 A EP 78400009A EP 0000299 B1 EP0000299 B1 EP 0000299B1
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Prior art keywords
chloro
benzoyl
general formula
methyl
compound
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German (de)
French (fr)
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EP0000299A1 (en
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Gilbert Mouzin
Henri Cousse
Antoine Stenger
Sylvano Casadio
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Pierre Fabre SA
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Pierre Fabre SA
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the present invention carried out at the PIERRE FABRE Research Center relates to new derivatives of substituted 2-benzoyl-4-chloro-glycinanilides, their preparation process and their application as medicaments.
  • the present invention however relates to derivatives which differ from those of the aforementioned prior art by a substitution on the first nitrogen atom in the glycynanilide series, corresponding to the formula:
  • Alkyl groups denote straight or branched chain alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.pentyl, hexyl, isohexyl, heptyle, etc.
  • the alkoxy substituents can for example be chosen from methoxy, ethoxy, propoxy, isopropoxy, etc. groups.
  • the aralkyl groups can be chosen from benzyl, phenethyl, phenylpropyl, etc.
  • the alkenyl groups can be chosen from allyl, butenyl, pentadienyl groups, etc.
  • the alkynyl groups can be chosen from ethynyl, propargyl, etc.
  • saturated or unsaturated heterocycles are chosen for example from pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrinidinyl, pyridazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, etc.
  • the present invention also applies to the salts of the compounds of formula 1 obtained with therapeutically acceptable acids.
  • therapeutically or physiologically acceptable addition salts mention may be made of the salts of mineral acids, such as hydrochloric, phosphoric and sulfuric acids, and the salts of organic acids, such as succinic acids. , tartaric, etc.
  • the present invention finally relates to the application of the compounds of general formula I as medicaments with activity on the central nervous system and in particular as anxiolytic, sedative, anticonvulsant, hypnotic agents or as muscle relaxant.
  • the crystals are recovered by filtration, then these crystals are dissolved in two liters of ethyl acetate, the aqueous phase formed is decanted, the organic phase is dried over sodium sulfate and discolored by addition of animal black. After filtration, the organic phase is evaporated. A crude crystallized residue is recovered which is triturated in petroleum ether. The coloration partly disappears and 330 g of pale yellow crystals are obtained after filtration and drying. Yield 95%.
  • the mixture is stirred at ambient temperature for 6 hours and left to stand overnight, then the mixture is brought to 50 ° C. for 2 hours and to 70 ° C. for 3 hours.
  • the free base is poured into 6 liters of ice water, released and crystallized.
  • the crystals are recovered by filtration. These crystals are dissolved in 1.5 liters of ethyl acetate, the aqueous phase is decanted and the organic phase is dried over sodium sulfate. After filtration and concentration, 124.5 g of yellow crystals are recovered. 85% yield.
  • 2-methyl-5-chloro-benzophenone can also be prepared by direct methylation of 2-amino-5-chloro-benzophenone according to the following procedure:
  • the organic phase is dried over sodium sulfate.
  • the mixture After addition of the brominated derivative, the mixture is heated for 6 hours at 45 ° C., then left to stand overnight and evaporated to dryness under reduced pressure. The residue is taken up in a bicarbonate solution and extracted with ethyl acetate. Washed with water, dried over sodium sulfate and discolored in animal black. After filtration, evaporated to dryness. The residual oil is treated with an ethanolic solution saturated with hydrochloric acid.
  • Solubility soluble in water at 1%.
  • Solubility soluble in water at 1%.
  • the compounds of the present invention endowed with remarkable activity on the central nervous system, are therefore capable of being administered to humans or to animals: orally or by injection, in the form of a base. free or one of its therapeutically acceptable salts.
  • the compounds of the present invention have been subjected to toxicity controls.
  • the toxicity of certain compounds determined by the lethal dose 50 is reported in the following table. It was tested on batches of 10 mice by oral, intraperitoneal and intravenous route in certain cases, and calculated according to the method of MILLER and TAINTER (Proc. Soc. Exper. Biol. Méd., 1944, 57,261) .
  • mice have tonic convulsions whose outcome is fatal.
  • the compound is administered orally 60 minutes before the injection of pentamethylenetetrazole.
  • the animals are observed for 2 hours after administration of pentamethylenetetrazole. In certain specific cases the tests have been confirmed intraperitoneally.
  • the results are expressed by the effective dose of DE 50 (Goodman and Col. ⁇ J. Pharmacol. 108, 1953).
  • mice This test is carried out on male Swiss strain mice.
  • the mouse is placed on a wooden rod with a diameter of 3 cm, rotating at the rate of 5 revolutions / minute. Mice are chosen which can remain on the rod for at least 3 minutes during successive tests and they are grouped together in groups of 10 for the test of each dose. If the mouse falls from the stem in less than 2 minutes, the compound tested is considered to be effective.
  • the results are expressed by the effective dose DE 50 according to NW DUNHAN and TS MIVA-J. bitter. pharm. Ass., 1957, 46, 208.
  • the compounds of the invention and more particularly the compounds of Examples 2, 10, 11, 14, 19 and 20 can be used therapeutically in the treatment of anxiety and neuroses.
  • These compounds and their therapeutically compatible acid addition salts can be used as medicaments, for example in the form of pharmaceutical preparations suitable for enteral or parenteral administration, with for example water, lactose, gelatin, starches , magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, petroleum jelly, etc.
  • preparations can be in solid form, for example tablets, dragees, capsules, etc. or in liquid form, for example solutions, suspensions or emulsions.
  • compositions in a form suitable for injection are preferred. These preparations can be subjected to conventional pharmaceutical operations such as sterilization and / or can contain adjuvants, for example preservatives, wetting or emulsification stabilizers, buffer compounds, etc.
  • the dosages, to which the active compounds and their therapeutically compatible acid addition salts can be administered can vary in large proportions depending on the condition of the patient.
  • a daily dosage of about 0.01 mg to 1 mg per kg of body weight is preferred, however.
  • compositions according to the invention can be used in internal medicine, for example in the treatment of organic pathological conditions, such as high blood pressure and coronary artery, accompanied and aggravated by an anxious state; in psychosomatic medicine, for example for the treatment of asthma, peptic ulcers, colopathies and other functional digestive disorders; as well as in psychiatry, for example for the treatment of anxious states of agitation in psychotic subjects.
  • organic pathological conditions such as high blood pressure and coronary artery
  • psychosomatic medicine for example for the treatment of asthma, peptic ulcers, colopathies and other functional digestive disorders
  • psychiatry for example for the treatment of anxious states of agitation in psychotic subjects.

Description

La présente invention réalisée au Centre de Recherches PIERRE FABRE concerne de nouveaux dérivés de benzoyl-2 chloro-4 glycinanilides substitués, leur procédé de préparation et leur application en tant que médicaments.The present invention carried out at the PIERRE FABRE Research Center relates to new derivatives of substituted 2-benzoyl-4-chloro-glycinanilides, their preparation process and their application as medicaments.

Dans la technique antérieure la plus proche, par exemple illustrée par le Brevet Spécial de Médicament français n° 1397 M, on a déjà proposé, à titre de médicaments doués de propriétés anti- convulsives et tranquillisantes, des dérivés de 2-amino-acétamidobenzophénones.In the closest prior art, for example illustrated by the French Special Medicines Patent No. 1397 M, derivatives of 2-amino-acetamidobenzophenones have already been proposed as medicaments with anti-convulsive and tranquilizing properties.

Il s'est avéré cependant que de tels composés à structure ouverte présentent une très grande instabilité et ont spontanément tendance à se cycliser pour donner naissance à des composés à structure benzodiazépinique fermée.However, it has been found that such open structure compounds exhibit very great instability and spontaneously tend to cyclize to give rise to compounds with closed benzodiazepine structure.

Les travaux de Von H. Oelschlàger & Coll. (Arzneimittel Forsch. 1973, pages 802 et suivantes) ont ensuite révélé que les benzophénones à structure ouverte étaient inactives et que la présence d'un cycle diazépinique était la condition sine qua non pour obtenir une activité.The work of Von H. Oelschlàger & Coll. (Arzneimittel Forsch. 1973, pages 802 et seq.) Then revealed that the open structure benzophenones were inactive and that the presence of a diazepine cycle was the sine qua non condition for obtaining activity.

La présente invention se rapporte en revanche à des dérivés se distinguant, de ceux de la technique antérieure précitée, par une substitution sur le premier atome d'azote en série glycynanilidique, répondant à la formule:

Figure imgb0001
The present invention however relates to derivatives which differ from those of the aforementioned prior art by a substitution on the first nitrogen atom in the glycynanilide series, corresponding to the formula:
Figure imgb0001

Or, il a été démontré que cette substitution en série glycynanilidique influençait la distance N-N, laquelle apparaît comme étant un paramètre déterminant pour l'activité de ce type de composés.However, it has been shown that this substitution in glycynanilide series influences the distance N-N, which appears to be a determining parameter for the activity of this type of compound.

Il convient de noter que cette constatation est tout à fait surprenante, compte tenu du fait que dans le cas de composés benzodiazépiniques il n'existe qu'une faible différence d'activité entre le diazépam et le diméthlydiazépam, alors qu'en série glycynanilidique la différence d'activité s'est révélée très importante.It should be noted that this finding is quite surprising, given the fact that in the case of benzodiazepine compounds there is only a slight difference in activity between diazepam and dimethlydiazepam, while in glycynanilide series the difference in activity turned out to be very significant.

Les nouveaux dérivés de la présente invention repondent à la formule qénérale I

Figure imgb0002
dans laquelle

  • R représente un groupe alcoyle linéaire ou ramifié, de préférence un groupe alcoyle inférieur;
  • R, et R2 peuvent être identiques ou différents et sont choisis parmi l'hydrogène, les groupes alcoyle, alcényle, alcynyle, hydroxyalcoyle, alcoxyalcoyle, aralcoyle, ces divers groupes pouvant être linéaires ou ramifiés, et parmi les groupes cycloalcoyle ayant de 3 à 6 chaînons et étant éventuellement substitués sur le carbone en α par un radical alcynyle;
  • les groupes Ri et R2 pouvant en outre former avec l'atome d'azote auquel ils sont reliés un hétérocycle azoté à 5 ou 6 chaînons, saturé ou non, et comprenant éventuellement un second hétéroatome choise parmi l'oxygène et l'azote, ledit hétérocycle étant éventuellement substitué, de préférence sur le second atome d'azote, par un radical alcoyle inférieur;
  • ainsi que leurs sels obtenus avec des acides minéraux ou organiques thérapeutiquement acceptables.
The new derivatives of the present invention correspond to the general formula I
Figure imgb0002
 in which
  • R represents a linear or branched alkyl group, preferably a lower alkyl group;
  • R, and R 2 may be the same or different and are chosen from hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, aralkyl groups, these various groups possibly being linear or branched, and from cycloalkyl groups having from 3 to 6 links and being optionally substituted on carbon at α by an alkynyl radical;
  • the groups R i and R 2 can also form with the nitrogen atom to which they are linked a nitrogen heterocycle with 5 or 6 members, saturated or not, and optionally comprising a second heteroatom chosen from oxygen and nitrogen , said heterocycle being optionally substituted, preferably on the second nitrogen atom, by a lower alkyl radical;
  • as well as their salts obtained with therapeutically acceptable mineral or organic acids.

On donnera ci-après une explication illustrative de quelques significations données à propos des radicaux R, R, et R2. Les groupes alcoyle désignent des groupes alcoyle à chaîne linéaire ou ramifiée, tels que méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, sec.butyle, tert.-butyle, pentyle, isopentyle, néopentyle, tert.pentyle, hexyle, isohexyle, heptyle, etc. Les substituants alcoxy peuvent par exemple être choisis parmi les groupes méthoxy, éthoxy, propoxy, isopropoxy, etc. Les groupes aralcoyle peuvent être choisis parmi les groupes benzyle, phénéthyle, phénylpropyle, etc. Les groupes alcényle peuvent être choisis parmi les groupes allyle, butényle, pentadiényle, etc. Les groupes alcynyle peuvent être choisis parmi les groupes éthynyle, propargyle, etc. Enfin, les hétérocycles saturés ou non sont choisis par exemple parmi les groupes pyrrolyle, imidazolyle, pyrazolyle, isoxazolyle, pyridyle, pyrazinyle, pyrinidinyle, pyridazinyle, pyrrolidinyle, imidazolidinyle, pyrazolidinyle, pipéridyle, pipérazinyle, morpholinyle, etc.An illustrative explanation will be given below of a few meanings given with respect to the radicals R, R, and R 2 . Alkyl groups denote straight or branched chain alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.pentyl, hexyl, isohexyl, heptyle, etc. The alkoxy substituents can for example be chosen from methoxy, ethoxy, propoxy, isopropoxy, etc. groups. The aralkyl groups can be chosen from benzyl, phenethyl, phenylpropyl, etc. The alkenyl groups can be chosen from allyl, butenyl, pentadienyl groups, etc. The alkynyl groups can be chosen from ethynyl, propargyl, etc. Finally, saturated or unsaturated heterocycles are chosen for example from pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrinidinyl, pyridazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, etc.

La présente invention s'applique également aux sels des composés de formule 1 obtenus avec des acides thérapeutiquement acceptables. A titre d'exemples non limitatifs de sels d'addition thérapeutiquement ou physiologiquement acceptables, on peut citer les sels d'acides minéraux, tels que les acides chlorhydrique, phosphorique et sulfurique, et les sels d'acides organiques, tels que les acides succinique, tartrique, etc.The present invention also applies to the salts of the compounds of formula 1 obtained with therapeutically acceptable acids. By way of nonlimiting examples of therapeutically or physiologically acceptable addition salts, mention may be made of the salts of mineral acids, such as hydrochloric, phosphoric and sulfuric acids, and the salts of organic acids, such as succinic acids. , tartaric, etc.

La présente invention concerne également un procédé de préparation des composés de formule I, consistant à faire réagir un composé de formule générale II

Figure imgb0003
dans laquelle:

  • R a la signification donnée à propos de la formule générale I et X représente un atome d'halogène, avec une amine de formule générale III
    Figure imgb0004
    dans laquelle:
  • R1 et R2 ont la signification donnée à propos de la formule générale I.
The present invention also relates to a process for preparing the compounds of formula I, comprising reacting a compound of general formula II
Figure imgb0003
 in which:
  • R has the meaning given with respect to the general formula I and X represents a halogen atom, with an amine of general formula III
    Figure imgb0004
     in which:
  • R 1 and R 2 have the meaning given with respect to the general formula I.

Les produits de départ de formule générale Il peuvent être préparés selon l'un des schémas réactionnels suivants:The starting materials of general formula II can be prepared according to one of the following reaction schemes:

a) Procédé au tosylatea) Tosylate process

Figure imgb0005
Figure imgb0005
Figure imgb0006
Figure imgb0006

  • X et R ayant les définitions données précédemment.X and R having the definitions given above.
  • b) Procédé au sulfate d'alcoyleb) Alkyl sulfate process
Figure imgb0007
Figure imgb0007

La présente invention concerne enfin l'application des composés de formule générale I en tant que médicaments doués d'une activité sur le système nerveux central et en particulier en tant qu'agents anxiolytiques, sédatifs, anticonvulsifs, hypnotiques ou comme agent de relaxation musculaire.The present invention finally relates to the application of the compounds of general formula I as medicaments with activity on the central nervous system and in particular as anxiolytic, sedative, anticonvulsant, hypnotic agents or as muscle relaxant.

La présente invention sera décrite ci-après plus en détails à propos des exemples non limitatifs suivants:The present invention will be described below in more detail with regard to the following nonlimiting examples:

Exemple 1Example 1 Chlorohydrate de N-isopropyl, N' méthyl (benzoyl-2 chloro-4) glycynanilideN-isopropyl hydrochloride, N 'methyl (2-benzoyl-4-chloro) glycynanilide a) Préparation de la tosylamido-2 chloro-5 benzophénonea) Preparation of 2-tosylamido-5 chloro-benzophenone

A une solution de 208,5 g (0,9 mole) d'amino-2 chloro-5 benzophénone dans 500 cm3 de pyridine, on ajoute 190,6 g de chlorure de tosyle de façon que la température du milieu réactionnel ne dépasse pas 48°C. Après cette addition on maintient l'agitation pendant 15 minutes, puis on porte à 100°C pendant 1 heure.To a solution of 208.5 g (0.9 mole) of 2-amino-5-chloro-benzophenone in 500 cm 3 of pyridine, 190.6 g of tosyl chloride are added so that the temperature of the reaction medium does not exceed step 48 ° C. After this addition, stirring is continued for 15 minutes, then the mixture is brought to 100 ° C. for 1 hour.

On obtient ainsi une solutin homogène de couleur brune. On laisse revenir à température ambiante, puis on hydrolyse le milieu réactionnel en le versant dans 4 litres d'acide chlorhydrique 3 N en présence de glace. On obtient alors une huile épaisse qui cristallise.A homogeneous brown-colored solutin is thus obtained. The mixture is allowed to return to ambient temperature, then the reaction medium is hydrolyzed by pouring it into 4 liters of 3N hydrochloric acid in the presence of ice. A thick oil is then obtained which crystallizes.

Les cristaux sont récupérés par filtration, puis on dissout ces cristaux dans deux litres d'acétate d'éthyle, on décante la phase aqueuse formée, sèche la phase organique sur sulfate de sodium et on décolore par addition de noir animal. Après filtration, on évapore la phase organique. On récupère un résidu brut cristallisé que l'on triture dans l'ether de pétrole. La coloration disparaît en partie et l'on obtient après filtration et séchage 330 g de cristaux jaune-pâle. Rendement 95%.The crystals are recovered by filtration, then these crystals are dissolved in two liters of ethyl acetate, the aqueous phase formed is decanted, the organic phase is dried over sodium sulfate and discolored by addition of animal black. After filtration, the organic phase is evaporated. A crude crystallized residue is recovered which is triturated in petroleum ether. The coloration partly disappears and 330 g of pale yellow crystals are obtained after filtration and drying. Yield 95%.

Point de fusion: 123,5°CMelting point: 123.5 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: acétate d'éthyle-éther de pétrole 10/90
  • -révélation: UV et iode
  • -Rf: 0,26
Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: ethyl acetate-petroleum ether 10/90
  • -revelation: UV and iodine
  • -Rf: 0.26

b) Préparation de la N-méthyl tosylamido-2 chloro-5-benzophénoneb) Preparation of N-methyl tosylamido-2 chloro-5-benzophenone

On dissout 308,7 g (0,8 mole) de tosylamido-2 chloro-5 benzophénone dans deux litres de toluène, puis on additionne, en maintenant le milieu réactionnel à 20°C, une solution de 18,5 g (0,805 atome/g) de sodium dans 300 cm3 de méthanol.308.7 g (0.8 mole) of 2-tosylamido-5 chloro-benzophenone is dissolved in two liters of toluene, then an 18.5 g solution (0.805 atom) is added, while maintaining the reaction medium at 20 ° C. / g) sodium in 300 cm 3 of methanol.

On maintient l'agitation 15 minutes puis on additionne goutte à goutte 201,8 g de sulfate de méthyle.Stirring is continued for 15 minutes and then 201.8 g of methyl sulfate are added dropwise.

On agite à température ambiante pendant 6 heures et on laisse une nuit au repos, puis on porte à 50°C pendant 2 heures et à 70°C pendant 3 heures.The mixture is stirred at ambient temperature for 6 hours and left to stand overnight, then the mixture is brought to 50 ° C. for 2 hours and to 70 ° C. for 3 hours.

On ajoute un litre de soude 3 N et on agite pendant 1/2 heure. On décante, lave 3 fois à l'eau jusqu'à pH neutre, puis on sèche sur sulfate de sodium et on décolore au noir animal.One liter of 3N sodium hydroxide is added and the mixture is stirred for 1/2 hour. Decanted, washed 3 times with water until neutral pH, then dried over sodium sulfate and discolored in animal black.

On filtre, évapore jusqu'à siccité, l'huile épaisse obtenue étant dissoute dans l'éthanol. On obtient, en glaçant, des cristaux que l'on recristallise dans l'éthanol.Filtered, evaporated to dryness, the thick oil obtained being dissolved in ethanol. Crystallized crystals are obtained which are recrystallized from ethanol.

On récupère après filtration et séchage 279,5 g de cristaux blancs. Rendement 87%.After filtration and drying, 279.5 g of white crystals are recovered. Yield 87%.

Point de fusion: 105°CMelting point: 105 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: acétate d'éthyle-éther de pétrole 10/90
  • -révélation: UV et iode
  • -Rf: 0,24
Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: ethyl acetate-petroleum ether 10/90
  • -revelation: UV and iodine
  • -Rf: 0.24

c) Préparation de la méthyl-amino-2 chloro-5 benzophénonec) Preparation of 2-methyl-5-chloro-benzophenone

Dans 600 g de glace, on ajoute lentement 1400 cm3 d'acide sulfurique à 96%. On porte à 110°C puis on additionne'240 g (0,6 mole) de N-méthyl tosylamido-2 chloro-5 benzophénone, maintient 20 minutes à cette température et on laisse revenir à température ambiante.In 600 g of ice, slowly adding 1400 cm 3 of 96% sulfuric acid. Was raised to 110 ° C followed by addition of '240 g (0.6 mol) of N-methyl tosylamido-2-chloro-5-nitrobenzophenone, maintained 20 minutes at this temperature and allowed to return to ambient temperature.

On jette dans 6 litres d'eau glacée, la base libre, relargue et cristallise. On récupère les cristaux par filtration. On dissout ces cristaux dans 1,5 litre d'acétate d'éthyle, décante la phase aqueuse et sèche la phase organique sur sulfate de sodium. Après filtration et concentration on récupère 124,5 g de cristaux jaunes. Rendement 85%.The free base is poured into 6 liters of ice water, released and crystallized. The crystals are recovered by filtration. These crystals are dissolved in 1.5 liters of ethyl acetate, the aqueous phase is decanted and the organic phase is dried over sodium sulfate. After filtration and concentration, 124.5 g of yellow crystals are recovered. 85% yield.

Point de fusion: 94°CMelting point: 94 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: acétate d'éthyle-éther de pétrole 10/90
  • -révélation: UV et iode
  • -Rf: 0,55
Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: ethyl acetate-petroleum ether 10/90
  • -revelation: UV and iodine
  • -Rf: 0.55

Remarque:Note:

Le méthyl amino-2 chloro-5 benzophénone peut être également préparée par méthylation directe de l'amino-2 chloro-5 benzophénone selon le mode opératoire suivant:2-methyl-5-chloro-benzophenone can also be prepared by direct methylation of 2-amino-5-chloro-benzophenone according to the following procedure:

A une suspension de 100 g d'amino-2 chloro-5 benzophénone dans 500 cm3 d'acide acétique, on ajoute 42 cm3 de sulfate de méthyle et on porte deux heures au reflux.To a suspension of 100 g of 2-amino-5-chloro-benzophenone in 500 cm 3 of acetic acid, 42 cm 3 of methyl sulfate are added and the mixture is brought to reflux for two hours.

On hydrolyse par deux litres d'eau et extrait au chloroforme.It is hydrolyzed with two liters of water and extracted with chloroform.

On sèche la phase organique sur sulfate de sodium.The organic phase is dried over sodium sulfate.

Après évaporation de la phase organique, on récupère une huile qui cristallise lentement. Par recristallisation dans le méthanol on obtient 70,8 g de cristaux jaunes. Rendement: 86%.After evaporation of the organic phase, an oil is recovered which slowly crystallizes. By recrystallization from methanol, 70.8 g of yellow crystals are obtained. Yield: 86%.

Point de fusion: 93,5°C.Melting point: 93.5 ° C.

d) Préparation du N-méthyl (benzoyl-2 chloro-4) phényl bromacétamided) Preparation of N-methyl (2-benzoyl-4-chloro) phenyl bromacetamide

On glace à 0°C une solution de méthylamino-2 chloro-5 benzophenone dans un mélange de 200 cm3 de benzène et 100 cm3 d'éther et on ajoute goutte à goutte en 25 minutes 5,8 cm3 de chlorure de bromacétyle en solution dans 40 cm3 d'éther. On laisse une nuit sous agitation à température ambiante puis on évapore jusqu'à siccité. Le résidu huileux trituré dans l'éther de pétrole cristallise rapidement. On filtre, lave à l'éther de pétrole, puis dissout dans l'acétate d'éthyle et on décolore au noir animal. Après filtration et concentration, précipitation par l'éther de pétrole et filtration, on récupère 19,3 g de produit. Rendement: 82%.A solution of 2-methylamino-5-chloro-benzophenone in a mixture of 200 cm 3 of benzene and 100 cm 3 of ether is ice-cold at 0 ° C. and 5.8 cm 3 of bromacetyl chloride are added dropwise over 25 minutes dissolved in 40 cm 3 of ether. The mixture is left stirring overnight at room temperature and then evaporated to dryness. The oily residue triturated in petroleum ether crystallizes quickly. Filtered, washed with petroleum ether, then dissolved in ethyl acetate and discolored in animal black. After filtration and concentration, precipitation with petroleum ether and filtration, 19.3 g of product are recovered. Yield: 82%.

Point de fusion: 90°CMelting point: 90 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: acétate d'éthyle-éther de pétrole 25/75
  • -révélation: UV et iode
  • -Rf: 0,43
Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: ethyl acetate-petroleum ether 25/75
  • -revelation: UV and iodine
  • -Rf: 0.43

e) Préparation du chlorhydrate de N-isopropy, N' méthyl (benzoyl-2 chloro-4) glycynanilidee) Preparation of N-isopropy hydrochloride, N 'methyl (2-benzoyl-4-chloro) glycynanilide

A une solution de 34 cm3 d'isopropylamine dans 200 cm3 d'acétone, on ajoute par spatulées 16,98 g de N-méthyl (benzoyl-2 chloro-4) phényl bromacétamide. La dissolution est immédiate et assez exothermique.To a solution of 34 cm 3 of isopropylamine in 200 cm 3 of acetone, 16.98 g of N-methyl (2-benzoyl-4-chloro) phenyl bromacetamide are added by spatulas. The dissolution is immediate and quite exothermic.

Après addition du dérivé bromé, on chauffe 6 heures à 45°C puis on laisse une nuit au repos et on évapore jusqu'à siccité sous pression réduite. On reprend le résidu par une solution bicarbonatée et extrait à l'acétate d'éthyle. On lave à l'eau, sèche sur sulfate de sodium et décolore au noir animal. Après filtration, on évapore à sec. L'huile résiduelle est traitée par une solution éthanolique saturée d'acide chlorhydrique.After addition of the brominated derivative, the mixture is heated for 6 hours at 45 ° C., then left to stand overnight and evaporated to dryness under reduced pressure. The residue is taken up in a bicarbonate solution and extracted with ethyl acetate. Washed with water, dried over sodium sulfate and discolored in animal black. After filtration, evaporated to dryness. The residual oil is treated with an ethanolic solution saturated with hydrochloric acid.

On ajoute de l'éther éthylique pour faciliter la cristallisation, on filtre et on sèche. On récuptère 13,18 g de produit de formule:

Figure imgb0008

  • Formule brute: C19H22Cl2N2O2
  • Masse moléculaire: 381,29
  • Cristaux blancs
  • Point de fusion: 239°C
Ethyl ether is added to facilitate crystallization, filtered and dried. 13.18 g of product of formula:
Figure imgb0008
  • Gross formula: C 19 H 22 Cl 2 N 2 O 2
  • Molecular mass: 381.29
  • White crystals
  • Melting point: 239 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: butanol-acide acétique-eau 6/2/2
  • -révélation: UV et iode
  • -Rf: 0,53
Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: butanol-acetic acid-water 6/2/2
  • -revelation: UV and iodine
  • -Rf: 0.53

Solubilité: soluble dans l'eau à 1%.Solubility: soluble in water at 1%.

Exemple 2Example 2

Chlorhydrate de N-méthyl N'-diméthyl-1-1 propargyl (benzoy/-2 chloro-4) glycynanilideN-methyl N'-dimethyl-1-1 propargyl (benzoy / -2 chloro-4) glycynanilide hydrochloride

D'une manière analogue à celle de l'exemple 1, mais en utilisant la diméthyl-1-1 propargylamine, on obtient le produit de formule:

Figure imgb0009

  • Formule brute: C21H22Cl2N2O2
  • Masse moléculaire: 405,33
  • Cristaux blancs
  • Point de fusion: 185°-186°C
In a manner analogous to that of Example 1, but using 1-dimethyl-propargylamine, the product of formula is obtained:
Figure imgb0009
  • Gross formula: C 21 H 22 Cl 2 N 2 O 2
  • Molecular mass: 405.33
  • White crystals
  • Melting point: 185 ° -186 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: acétate d'éthyle-éther de pétrole 50/50
  • -révélation: UV et iode
  • -Rf: 0,37
Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: ethyl acetate-petroleum ether 50/50
  • -revelation: UV and iodine
  • -Rf: 0.37

Solubilité: soluble dans l'eau à 1%.Solubility: soluble in water at 1%.

Exemple 3Example 3 Chlorhydrate de N-N' diméthyl (benzoyl-2 chloro-4) glycynanilideN-N 'dimethyl hydrochloride (2-benzoyl-4-chloro) glycynanilide

D'une manière analogue à celle de l'exemple 1, mais en utilisant la méthylamine on obtient le produit de formule:

Figure imgb0010

  • Formule brute: C17H18Cl2N2O2
  • Masse moléculaire: 353,25
  • Cristaux blancs
  • Point de fusion: 180°C
In a manner analogous to that of Example 1, but using methylamine, the product of formula:
Figure imgb0010
  • Gross formula: C 17 H 18 Cl 2 N 2 O 2
  • Molecular mass: 353.25
  • White crystals
  • Melting point: 180 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: butanol-acide acétique-eau 6/2/2
  • -révélation: UV et iode
  • -Rf: 0,37
Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: butanol-acetic acid-water 6/2/2
  • -revelation: UV and iodine
  • -Rf: 0.37

Solubilité: soluble dans l'eau à 15%Solubility: soluble in water at 15%

Exemple 4Example 4 N,N'-N' triméthyl (benzoyl-2 chloro-4)-glycynanilideN, N'-N 'trimethyl (2-benzoyl-4-chloro) -glycynanilide

D'une manière analogue à celle de l'exemple 1, mais en utilisant la diméthyl amine, on obtient le produit de formule:

Figure imgb0011

  • Formule brute: C18H19Cl N2O2
  • Masse moléculaire: 330,8
  • Cristaux blancs
  • Point de fusion: 95,5°C
In a manner analogous to that of Example 1, but using dimethylamine, the product of formula is obtained:
Figure imgb0011
  • Gross formula: C 18 H 19 Cl N 2 O 2
  • Molecular mass: 330.8
  • White crystals
  • Melting point: 95.5 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • ―solvant: butanol―acide acétique―eau 6/2/2
  • ―révélation: UV et iode
  • -Rf: 0,34
Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • ―Solvent: butanol ― acetic acid ― water 6/2/2
  • ―Revelation: UV and iodine
  • -Rf: 0.34

Spectre Infra-rouge: νc-H aromatique à 3060 cm-1;
νc=o à 1660 cm-1; νc=c à 1590 cm-1.
Solubilités: Insoluble dans l'eau. Soluble à 20% dans l'éthanol à 95°GL et dans le diméthyl formamide.Infrared spectrum: ν cH aromatic at 3060 cm -1 ;
νc = o at 1660 cm -1 ; ν c = c at 1590 cm -1 .
Solubilities: Insoluble in water. Soluble at 20% in ethanol at 95 ° GL and in dimethyl formamide.

Exemple 5Example 5 Chlorhydrate de N-méthyl N'(méthoxy-2' éthyl) (benzoyl-2 chloro-4) glycynanilideN-methyl hydrochloride N '(2-methoxy-ethyl) (2-benzoyl-4-chloro) glycynanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant la méthoxy-2 éthylamine, on obtient le produit de formule:

Figure imgb0012

  • Formule brute: C19H22Cl2N2O3
  • Masse moléculaire: 397,29
  • Cristaux blancs
  • Point de fusion: 160°C
In a manner analogous to that described in Example 1, but using 2-methoxyethylamine, the product of formula is obtained:
Figure imgb0012
  • Gross formula: C 19 H 22 Cl 2 N 2 O 3
  • Molecular mass: 397.29
  • White crystals
  • Melting point: 160 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • ―solvant: butanol―acid acétique―eau 6/2/2
  • -révélation: UV et iode
  • -Rf: 0,52
Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • Olsolvent: butanol ― acetic acid ― water 6/2/2
  • -revelation: UV and iodine
  • -Rf: 0.52

Spectre Infra-rouge: νc=o à 1665 cm-1 et νc=c à 1595 cm-1
Solubilité: soluble dans l'eau à 50%Infrared spectrum: ν c = o at 1665 cm -1 and ν c = c at 1595 cm -1
Solubility: 50% water soluble

Exemple 6Example 6 Chlorhydrate de N-méthyl N' benzyl (benzoyl-2 chloro-4) glycynanilideN-methyl hydrochloride N 'benzyl (2-benzoyl-4-chloro) glycynanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant la benzylamine, on obtient le produit de formule:

Figure imgb0013

  • Formule brute: C23H22Cl2N2O2
  • Masse moléculaire: 429,35
  • Cristaux beiges
  • Point de fusion: 150°C
In a manner analogous to that described in Example 1, but using benzylamine, the product of formula is obtained:
Figure imgb0013
  • Gross formula: C 23 H 22 Cl 2 N 2 O 2
  • Molecular mass: 429.35
  • Beige crystals
  • Melting point: 150 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: acétate d'éthyle
  • -révélation: UV et iode
  • -Rf: 0,23
Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: ethyl acetate
  • -revelation: UV and iodine
  • -Rf: 0.23

Spectre Infra-rouge: νc=o à 1662 et 1676 cm-1
Solubilité: soluble dans l'eau à 2,5%.Infrared spectrum: ν c = o at 1662 and 1676 cm -1
Solubility: soluble in water at 2.5%.

Exemple 7Example 7 Chlorhydrate de N-méthyl N' allyl (benzoyl-2 chloro-4) glycynanilideN-methyl hydrochloride N 'allyl (2-benzoyl-4-chloro) glycynanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant l'allylamine, on obtient le produit de formule:

Figure imgb0014

  • Formule brute: C19H20Cl2N2O2
  • Masse moléculaire: 379,29
  • Cristaux blancs
  • Point de fusion: 190°C
In a manner analogous to that described in Example 1, but using allylamine, the product of formula is obtained:
Figure imgb0014
  • Gross formula: C 19 H 20 Cl 2 N 2 O 2
  • Molecular mass: 379.29
  • White crystals
  • Melting point: 190 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: butanol―acide acétique―eau 6/2/2
  • -révélation: UV et iode
  • -Rf: 0,56

Spectre infra-rouge: νc=o à 1663 cm-1 et νc=c à 1598 cm-1
Solubilité: soluble dans l'eau à 3%.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: butanol ― acetic acid ― water 6/2/2
  • -revelation: UV and iodine
  • -Rf: 0.56

Infrared spectrum: ν c = o at 1663 cm -1 and ν c = c at 1598 cm -1
Solubility: soluble in water at 3%.

Exemple 8Example 8 Chlorhydrate de N-méthyl N' (diéthyl-l'-l' propargyl) (benzoyl-2 chloro-4) glycynanilideN-methyl N 'hydrochloride (diethyl-l-propargyl) (2-benzoyl-4-chloro) glycynanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant la diéthyl-1-1 pro- parqylamine, on obtient le produit de formule:

Figure imgb0015

  • Formule brute: C23H26Cl2N2O2
  • Masse moléculaire: 433,35
  • Cristaux blancs
  • Point du fusion: 191 °C
In a manner analogous to that described in Example 1, but using 1-1-diethyl-propylamine, the product of formula is obtained:
Figure imgb0015
  • Gross formula: C 23 H 26 Cl 2 N 2 O 2
  • Molecular mass: 433.35
  • White crystals
  • Melting point: 191 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: acétate d'éthyle
  • -révélation: UV et iode
  • -Rf: 0,73

Spectre infra-rouge: ν≡C-H à 3165 cm-1; νc≡c à 2105 cm-1; νc=o (amide à 1690 cm-1 et νc=o (cétone) à 1675 cm-1.
Solubilités: Insoluble dans l'eau. Soluble à 1% dans l'éthanol à 95° GL et dans le diméthyl formamide.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: ethyl acetate
  • -revelation: UV and iodine
  • -Rf: 0.73

Infrared spectrum: ν ≡CH at 3165 cm -1 ; ν c≡c at 2105 cm -1 ; ν c = o (amide at 1690 cm -1 and ν c = o (ketone) at 1675 cm -1 .
Solubilities: Insoluble in water. Soluble at 1% in ethanol at 95 ° GL and in dimethyl formamide.

Exemple 9Example 9 Chlorhydrate de N-méthylN'(éthynyl-1' cyclohexyl) (benzoyl-2 chloro-4) glycynanilideN-methylN 'hydrochloride (1-ethynyl-cyclohexyl) (2-benzoyl-4-chloro) glycynanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant l'éthynyl-1 cyclohexylamine, on obtient le produit de formule

Figure imgb0016

  • Formule brute: C24H25Cl2N2O2
  • Masse moléculaire: 445,38
  • Cristaux blancs
  • Point de fusion: 193°C
In a manner analogous to that described in Example 1, but using 1-ethynyl cyclohexylamine, the product of formula is obtained
Figure imgb0016
  • Gross formula: C 24 H 25 Cl 2 N 2 O 2
  • Molecular mass: 445.38
  • White crystals
  • Melting point: 193 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: acétate d'éthyle-éther de pétrole 30/70
  • -révélation: UV et iode

Rf: 0,31
Spectre infra-rouge: νc-H à 3180 cm-1; νc≡c à 2110 cm-1; νc=o à 1675 cm-1.
Solubilités: Insoluble dans l'eau. Soluble à 3% dans l'éthanol à 95° GL et à 2% dans le diméthyl formamide.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: ethyl acetate-petroleum ether 30/70
  • -revelation: UV and iodine

Rf: 0.31
Infrared spectrum: ν cH at 3180 cm -1 ; ν c≡c at 2110 cm -1 ; ν c = o at 1675 cm -1 .
Solubilities: Insoluble in water. Soluble at 3% in ethanol at 95 ° GL and at 2% in dimethyl formamide.

Exemple 10Example 10 Chlorhydrate de N-méthyl N' cyclopropyl (benzoyl-2 chloro-4) glycynanilideN-methyl hydrochloride N 'cyclopropyl (2-benzoyl-4-chloro) glycynanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant la cyclopropylamine, on obtient le produit de formule:

Figure imgb0017

  • Formule brute: C19H20Cl2N2O2
  • Masse moléculaire: 379,26
  • Cristaux blancs
  • Point de fusion: 209°C
In a manner analogous to that described in Example 1, but using cyclopropylamine, the product of formula is obtained:
Figure imgb0017
  • Gross formula: C 19 H 20 Cl 2 N 2 O 2
  • Molecular mass: 379.26
  • White crystals
  • Melting point: 209 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: acétate d'éthyle
  • -révélation: UV et iode
  • -Rf: 0,27

Spectre infra-rouge: νc=o amide à 1670 cm-1; νc=o cétone à 1655 cm-1
Solubilité: soluble dans l'eau à 1,3%.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: ethyl acetate
  • -revelation: UV and iodine
  • -Rf: 0.27

Infrared spectrum: ν c = o amide at 1670 cm -1 ; ν c = o ketone at 1655 cm -1
Solubility: water soluble at 1.3%.

Exemple 11Example 11 Chlorhydrate de N-méthyl N' cyclohexyl (benzoyl-2 chloro-4) glycynanilideN-methyl hydrochloride N 'cyclohexyl (2-benzoyl-4-chloro) glycynanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant la cyclohexylamine, on obtient le produit de formule:

Figure imgb0018

  • Formule brute: C22H26Cl2N2O2
  • Masse moléculaire: 421,34
  • Cristaux blancs
  • Point de fusion: 224°C
In a manner analogous to that described in Example 1, but using cyclohexylamine, the product of formula is obtained:
Figure imgb0018
  • Gross formula: C 22 H 26 Cl 2 N 2 O 2
  • Molecular mass: 421.34
  • White crystals
  • Melting point: 224 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • ―solvant: butanol―acide acétique―eau 6/2/2
  • -révélation: UV et iode
  • -Rf: 0,61

Spectre infra-rouge: νc=o à 1660 cm-1 et νc=c à 1588 cm-1
Solubilités: Insoluble dans l'eau. Soluble à 3% dans l'éthanol à 95° GL et à 1% dans le diméthyl formamide.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • ―Solvent: butanol ― acetic acid ― water 6/2/2
  • -revelation: UV and iodine
  • -Rf: 0.61

Infrared spectrum: ν c = o at 1660 cm -1 and ν c = c at 1588 cm -1
Solubilities: Insoluble in water. Soluble at 3% in ethanol at 95 ° GL and at 1% in dimethyl formamide.

Exemple 12Example 12 N-méthyl N'(diméthyl-1'-1' hydroxy-2' éthyl) (benzoyl-2 chloro-4) glycynanilideN-methyl N '(dimethyl-1'-1' hydroxy-2 'ethyl) (2-benzoyl-4-chloro) glycynanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant 1'amino-2 méthyl-2 propanol, on obtient le produit de formule:

Figure imgb0019

  • Formule brute: C20H23Cl N2O3
  • Masse moléculaire: 374,86
  • Cristaux jaune-citron
  • Point de fusion: 95°C
In a manner analogous to that described in Example 1, but using 2-amino-2-methylpropanol, the product of formula is obtained:
Figure imgb0019
  • Gross formula: C 20 H 23 Cl N 2 O 3
  • Molecular mass: 374.86
  • Lemon-yellow crystals
  • Melting point: 95 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: acétate d'éthyle
  • -révélation: UV et iode
  • -Rf: 0,19

Spectre infra-rouge: ν-OH à 3440 cm-1; νc=o à 1655 cm-1 et νc=c à 1598 cm-1.
Solubilités: Insoluble dans l'eau. Soluble à 10% dans l'éthanol à 95° GL et à 25% dans le diméthylformamide.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: ethyl acetate
  • -revelation: UV and iodine
  • -Rf: 0.19

Infrared spectrum: ν -OH at 3440 cm -1 ; ν c = o at 1655 cm -1 and ν c = c at 1598 cm -1 .
Solubilities: Insoluble in water. Soluble at 10% in ethanol at 95 ° GL and at 25% in dimethylformamide.

Exemple 13Example 13 Chlorhydrate de N-methyl N'(éthyl-1' hydroxyméthyl-1' hydroxy-2' éthyl) (benzoyl-2 chloro-4) glycynanilideN-methyl N 'hydrochloride (1-ethyl-1-hydroxymethyl-2-hydroxy-2' ethyl) (2-benzoyl-4-chloro) glycynanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant l'amino-2 éthyl-2 propane diol-1,3, on obtient le produit de formule:

Figure imgb0020

  • Formule brute: C21H26Cl2N2O4
  • Masse moléculaire: 441,36
  • Cristaux jaune-clair
  • Point de fusion: 191°C
In a manner analogous to that described in Example 1, but using 2-amino-2-ethyl propane-1,3-diol, the product of formula is obtained:
Figure imgb0020
  • Gross formula: C 21 H 26 Cl 2 N 2 O 4
  • Molecular mass: 441.36
  • Light yellow crystals
  • Melting point: 191 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: butanol-acide acétique-eau 6/2/2
  • -révélation: UV et iode
  • -Rf: 0,47

Spectre infra-rouge: ν-OH à 3320 cm-1; νc=o à 1660 cm-1 et νc=c à 1596 cm-1.
Solubilité: soluble dans l'eau à 50%.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: butanol-acetic acid-water 6/2/2
  • -revelation: UV and iodine
  • -Rf: 0.47

Infrared spectrum: ν -OH at 3320 cm -1 ; ν c = o at 1660 cm -1 and ν c = c at 1596 cm -1 .
Solubility: water soluble at 50%.

Exemple 14Example 14 N-N' diméthyl-N' (hydroxy-2' éthyl) (benzoyl-2 chloro-4) glycynanilideN-N 'dimethyl-N' (2-hydroxy-ethyl) (2-benzoyl-4-chloro) glycynanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant la N-méthyl éthanolamine, on obtient le produit de formule:

Figure imgb0021

  • Formule brute: C19H21Cl N2O3
  • Masse moléculaire: 360,83
  • Cristaux blancs
  • Point de fusion: 109°C
In a manner analogous to that described in Example 1, but using N-methyl ethanolamine, the product of formula is obtained:
Figure imgb0021
  • Gross formula: C 19 H 21 Cl N 2 O 3
  • Molecular mass: 360.83
  • White crystals
  • Melting point: 109 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • ―solvant: butanol―acide acétique―eau 6/2/2
  • ―révélation: UV et iode
  • -Rf: 0,47

Spectre infra-rouge: ν-OH à 3190 cm-1; νc=o à1668 cm-1 et νc=c à 1592 cm-1.
Solubilités: Insoluble dans l'eau. Soluble à 20% dans l'ethanol à 95° GL et dans le diméthylformamide.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • ―Solvent: butanol ― acetic acid ― water 6/2/2
  • ―Revelation: UV and iodine
  • -Rf: 0.47

Infrared spectrum: ν -OH at 3190 cm -1 ; ν c = o at 1668 cm -1 and ν c = c at 1592 cm -1 .
Solubilities: Insoluble in water. Soluble at 20% in ethanol at 95 ° GL and in dimethylformamide.

Exemple 15Example 15 N-méthyl N' éthyl N' (hydroxy-2' éthyl) (benzoyl-2 chloro-4) glycynanilideN-methyl N 'ethyl N' (2-hydroxy-ethyl) (2-benzoyl-4-chloro) glycynanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant l'éthyl amino-2 éthanol, on obtient le produit de formule:

Figure imgb0022

  • Formule brute: C20H23Cl N2O3
  • Masse moléculaire: 374,86
  • Cristaux blancs
  • Point de fusion: 79°C
In a manner analogous to that described in Example 1, but using 2-aminoethyl ethanol, the product of formula is obtained:
Figure imgb0022
  • Gross formula: C 20 H 23 Cl N 2 O 3
  • Molecular mass: 374.86
  • White crystals
  • Melting point: 79 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • ―solvant: butanol―acide acétique―eau 6/2/2
  • -révélation UV et iode
  • -Rf: 0,35

Spectre infra-rouge: νc=o à 1668 cm-1; νc=c à 1592 cm-1.
Solubilités: Insoluble dans l'eau. Soluble à 10% dans l'éthanol à 95° GL et à 30% dans le diméthyl formamide.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • ―Solvent: butanol ― acetic acid ― water 6/2/2
  • - UV and iodine revelation
  • -Rf: 0.35

Infrared spectrum: ν c = o at 1668 cm -1 ; ν c = c at 1592 cm -1 .
Solubilities: Insoluble in water. Soluble at 10% in ethanol at 95 ° GL and at 30% in dimethyl formamide.

Exemple 16Example 16 Chlorhydrate de N-méthyl N'-N' bis (hydroxy-2' éthyl) (benzoyl-2 chloro-4) glycynanilideN-methyl N'-N 'bis (2-hydroxy-ethyl) hydrochloride (2-benzoyl-4-chloro) glycynanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant la diéthanolamine, on obtient le produit de formule:

Figure imgb0023

  • Formule brute: C20H24Cl2N2O4
  • Masse moléculaire: 427,33
  • Cristaux blancs
  • Point de fusion: 174°C
In a manner analogous to that described in Example 1, but using diethanolamine, the product of formula is obtained:
Figure imgb0023
  • Gross formula: C 20 H 24 Cl 2 N 2 O 4
  • Molecular mass: 427.33
  • White crystals
  • Melting point: 174 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: butanol-acide acétique-eau 6/2/2
  • -rélévation: UV et iode
  • -Rf: 0,35 5

Spectre infra-rouge: νc=o à 1669 cm-1 et νc=c à 1596 cm-1.
Solubilité: soluble dans l'eau à 5%.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: butanol-acetic acid-water 6/2/2
  • - elevation: UV and iodine
  • -Rf: 0.35 5

Infrared spectrum: ν c = o at 1669 cm -1 and ν c = c at 1596 cm -1 .
Solubility: soluble in water at 5%.

Exemple 17Example 17 Chlorhydrate de N-méthylpipéridino-2 (benzoyl-2' chloro-4') acétanilideN-methylpiperidino-2 hydrochloride (2-benzoyl-4 'chloro-4') acetanilide

Comme dans l'exemple 1, mais en utilisant la pipéridine, on obtient le produit de formule

Figure imgb0024

  • Formule brute: C21H24Cl2N2O2
  • Masse moléculaire: 407,34
  • Cristaux blancs
  • Point de fusion: 140°C
As in Example 1, but using piperidine, the product of formula is obtained
Figure imgb0024
  • Gross formula: C 21 H 24 Cl 2 N 2 O 2
  • Molecular mass: 407.34
  • White crystals
  • Melting point: 140 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • ―solvant: butanol-acide acétique―eau 6/2/2
  • -révélation: UV et iode
  • -Rf: 0,55

Spectre infra-rouge: νc=o (amide) à 1680 cm-1; νc=o (cétone) à 1667
cm-1; et νc=c à 1592 cm-1.
Solubilité: soluble dans l'eau à 50%.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • Ol solvent: butanol-acetic acid ― water 6/2/2
  • -revelation: UV and iodine
  • -Rf: 0.55

Infrared spectrum: ν c = o (amide) at 1680 cm -1 ; ν c = o (ketone) at 1667
cm -1 ; and ν c = c at 1592 cm -1 .
Solubility: water soluble at 50%.

Exemple 18Example 18 Chlorhydrate de N-méthyl morpholino-2 (benzoyl-2' chloro-4') acétanilideN-methyl morpholino-2 (benzoyl-2 'chloro-4') hydrochloride acetanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant la morpholine, on obtient le produit de formule:

Figure imgb0025

  • Formule brute: C20H22Cl2N2O3
  • Masse moléculaire: 409,3
  • Cristaux blancs
  • Point de fusion: 172°C
In a manner analogous to that described in Example 1, but using morpholine, the product of formula is obtained:
Figure imgb0025
  • Gross formula: C 20 H 22 Cl 2 N 2 O 3
  • Molecular mass: 409.3
  • White crystals
  • Melting point: 172 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • ―solvant: butanal―acide acétique―eau 6/2/2
  • -révélation: UV et iode
  • -Rf: 0,61

Spectre infra-rouge: νc=o à 1663 cm-1 et νc=c à 1595 cm-1
Solubilité: soluble dans l'eau à 10%.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • ― Solvent: butanal ― acetic acid ― water 6/2/2
  • -revelation: UV and iodine
  • -Rf: 0.61

Infrared spectrum: ν c = o at 1663 cm -1 and ν c = c at 1595 cm -1
Solubility: soluble in water at 10%.

Exemple 19Example 19 Chlorhydrate de N-méthyl N' (méthyl-2' ally/) (benzoyl-2 chloro-4) glycynanilideN-methyl hydrochloride N '(methyl-2' ally /) (2-benzoyl-chloro-4) glycynanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant la méthyl-2 allylamine, on obtient le produit de formule:

Figure imgb0026

  • Formule brute: C20H22Cl2N2O2
  • Masse moléculaire: 393,32
  • Cristaux blancs
  • Point de fusion: 166°C
In a manner analogous to that described in Example 1, but using 2-methyl allylamine, the product of formula is obtained:
Figure imgb0026
  • Gross formula: C 20 H 22 Cl 2 N 2 O 2
  • Molecular mass: 393.32
  • White crystals
  • Melting point: 166 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: butanol-acide acétique-eau 6/2/2
  • -révélation: UV et iode
  • -Rf: 0,54

Solubilité: soluble dans l'eau à 5%.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: butanol-acetic acid-water 6/2/2
  • -revelation: UV and iodine
  • -Rf: 0.54

Solubility: soluble in water at 5%.

Exemple 20Example 20 Chlorhydrate de N-N' diméthyl N' cyclohexyl (benzoyl-2 chloro-4) glycynanilideN-N 'dimethyl N' cyclohexyl hydrochloride (2-benzoyl-4-chloro) glycynanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant la N-méthyl cyclohexylamine, on obtient le produit de formule:

Figure imgb0027

  • Formule brute: C23H28Cl2N2O2
  • Masse moléculaire: 435,4
  • Cristaux blancs
  • Point de fusion: 141°C
In a manner analogous to that described in Example 1, but using N-methyl cyclohexylamine, the product of formula is obtained:
Figure imgb0027
  • Gross formula: C 23 H 28 Cl 2 N 2 O 2
  • Molecular mass: 435.4
  • White crystals
  • Melting point: 141 ° C

Chromatographie sur plaque:

  • ―support: gel de silice 60 F 254 Merck
  • -solvant: butanol-acide acétique-eau 6/2/2
  • -révélation: UV et iode
    Rf: 0,43

Solubilité: Soluble dans l'eau à 2%.Plate chromatography:
  • ―Support: silica gel 60 F 254 Merck
  • -solvent: butanol-acetic acid-water 6/2/2
  • -revelation: UV and iodine
    Rf: 0.43

Solubility: Soluble in water at 2%.

Exemple 21Example 21 Chlorhydrate de N-méthyl N' isopropyl N' cyclohexyl (benzoyl-2 chloro-4) glycynanilideN-methyl hydrochloride N 'isopropyl N' cyclohexyl (2-benzoyl-4-chloro) glycynanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant la N-isopropyl cyclohexylamine, on obtient le produit de formule:

Figure imgb0028

  • Formule brute: C25H32Cl2N2O2
  • Masse moléculaire: 463,45
  • Cristaux jaunes
  • Point de fusion: 145°C
In a manner analogous to that described in Example 1, but using N-isopropyl cyclohexylamine, the product of formula is obtained:
Figure imgb0028
  • Gross formula: C 25 H 32 Cl 2 N 2 O 2
  • Molecular mass: 463.45
  • Yellow crystals
  • Melting point: 145 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: butanol-acide acétique-eau 6/2/2
  • -révélation: UV et iode
    Rf: 0,51

Solubilité: soluble dans l'eau à 5%.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: butanol-acetic acid-water 6/2/2
  • -revelation: UV and iodine
    Rf: 0.51

Solubility: soluble in water at 5%.

Exemple 22Example 22 N-méthyl méthyl-4' pipérazino-2 (benzoyl-2 chloro-4) acétanilideN-methyl methyl-4 'piperazino-2 (2-benzoyl-chloro-4) acetanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant la N-méthyl pipérazine, on obtient le produit de formule:

Figure imgb0029

  • Formule brute: C21H24Cl N3O2
  • Masse moléculaire: 385,89
  • Cristaux blancs
  • Point de fusion: 146°C
In a manner analogous to that described in Example 1, but using N-methyl piperazine, the product of formula is obtained:
Figure imgb0029
  • Gross formula: C 21 H 24 Cl N 3 O 2
  • Molecular mass: 385.89
  • White crystals
  • Melting point: 146 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvant: butanol-acide acétique-eau 6/2/2
  • -révélation: UV et iode
  • -Rf: 0,20

Solubilités: Insoluble dans l'eau. Soluble à 5% dans l'éthanol à 95° GL et dans le diméthyl formamide.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: butanol-acetic acid-water 6/2/2
  • -revelation: UV and iodine
  • -Rf: 0.20

Solubilities: Insoluble in water. Soluble at 5% in ethanol at 95 ° GL and in dimethyl formamide.

Exemple 23Example 23 N-méthyl imidazolyl-2 (benzoyl-2 chloro-4) acétanilideN-methyl imidazolyl-2 (2-benzoyl-chloro-4) acetanilide

D'une manière analogue à celle décrite dans l'exemple 1, mais en utilisant l'imidazol, on obtient le nroduit de formule:

Figure imgb0030

  • Formule brute: C19H16Cl N3O2
  • Masse moléculaire: 353,81
  • Cristaux blancs
  • Point de fusion: 143°C
In a manner analogous to that described in Example 1, but using imidazol, the noduct of formula is obtained:
Figure imgb0030
  • Gross formula: C 19 H 16 Cl N 3 O 2
  • Molecular mass: 353.81
  • White crystals
  • Melting point: 143 ° C

Chromatographie sur plaque:

  • -support: gel de silice 60 F 254 Merck
  • -solvent: butanol-acide acétique-eau 6/2/2
  • -révélation: UV et iode
  • -Rf: 0,39

Solubilités: Insoluble dans l'eau. Soluble à 10% dans l'éthanol à 95° GL et à 20% dans le diméthylformamide.Plate chromatography:
  • -support: silica gel 60 F 254 Merck
  • -solvent: butanol-acetic acid-water 6/2/2
  • -revelation: UV and iodine
  • -Rf: 0.39

Solubilities: Insoluble in water. Soluble at 10% in ethanol at 95 ° GL and at 20% in dimethylformamide.

Les composés de la présente invention, doués d'une remarquable activité sur le système nerveux central, sont donc susceptibles d'être administrés à l'homme ou a l'animal: par voie orale ou par injection, sous la forme d'une base libre ou bien de l'un de ses sels thérapeutiquement acceptables.The compounds of the present invention, endowed with remarkable activity on the central nervous system, are therefore capable of being administered to humans or to animals: orally or by injection, in the form of a base. free or one of its therapeutically acceptable salts.

A titre de simple illustration on indiquera ci-après quelques résultats des divers essais toxicologiques et pharmacologiques effectués sur les composés de l'invention.By way of simple illustration, some results of the various toxicological and pharmacological tests carried out on the compounds of the invention will be indicated below.

a) Etude de toxicitéa) Toxicity study

Les composés de la présente invention ont été soumis à des contrôles de toxicité. La toxicité de certains composés déterminée par la dose létale 50 est rapportée dans le tableau suivant. Elle a été recherchée sur des lots de 10 souris par voie orale, intra-péritonéale et intra-veineuse dans certains cas, et calculée selon la méthode de MILLER et TAINTER (Proc. Soc. expér. Biol. Méd., 1944, 57,261).

Figure imgb0031
The compounds of the present invention have been subjected to toxicity controls. The toxicity of certain compounds determined by the lethal dose 50 is reported in the following table. It was tested on batches of 10 mice by oral, intraperitoneal and intravenous route in certain cases, and calculated according to the method of MILLER and TAINTER (Proc. Soc. Exper. Biol. Méd., 1944, 57,261) .
Figure imgb0031

b) Propriétés pharmacologiquesb) Pharmacological properties Activité antagoniste au pentaméthylènetétrazolePentamethylenetetrazole antagonist activity

On réalise cet essai sur un groupe de 10 souris mâles de souche Swiss. Dans un délai de 15 minutes après l'injection sous-cutanée de 125 mg/kg de pentaméthylènetétrazole, les souris ont des convulsions toniques dont l'issue est fatale.This test is carried out on a group of 10 male mice of Swiss strain. Within 15 minutes after the subcutaneous injection of 125 mg / kg of pentamethylenetetrazole, the mice have tonic convulsions whose outcome is fatal.

Pour l'essai, on administre le composé par voie orale 60 minutes avant l'injection de pentaméthylènetétrazole. Les animaux sont observés pendant 2 heures après administration du pentaméthylènetétrazole. Dans certains cas particuliers les assais ont été confirmés par voie intra-péritonéale. Les résultats sont exprimés par la dose efficace DE50 (Goodman et Col.―J. Pharmacol. 108, 1953).

Figure imgb0032
For the test, the compound is administered orally 60 minutes before the injection of pentamethylenetetrazole. The animals are observed for 2 hours after administration of pentamethylenetetrazole. In certain specific cases the tests have been confirmed intraperitoneally. The results are expressed by the effective dose of DE 50 (Goodman and Col. ―J. Pharmacol. 108, 1953).
Figure imgb0032

Activité dans l'essai sur tige tournante (Rota Rod)Activity in the Rota Rod test

On réalise cet essai sur des souris mâles de souche Swiss. On place la souris sur une tige de bois d'un diamètre de 3 cm, tournant à raison de 5 tours/minute. On choisit les souris qui peuvent rester sur la tige pendant au moins 3 minutes au cours d'essais successifs et on les rassamble par groupe de 10 pour l'essai de chaque dose. Si la souris tombe de la tige en moins de 2 minutes, on considère que le composé essayé est efficace. On exprime les résultats par la dose efficace DE50 selon N. W. DUNHAN et T.S. MIVA-J. amer. pharm. Ass., 1957, 46, 208.

Figure imgb0033
This test is carried out on male Swiss strain mice. The mouse is placed on a wooden rod with a diameter of 3 cm, rotating at the rate of 5 revolutions / minute. Mice are chosen which can remain on the rod for at least 3 minutes during successive tests and they are grouped together in groups of 10 for the test of each dose. If the mouse falls from the stem in less than 2 minutes, the compound tested is considered to be effective. The results are expressed by the effective dose DE 50 according to NW DUNHAN and TS MIVA-J. bitter. pharm. Ass., 1957, 46, 208.
Figure imgb0033

Compte tenu de leurs propriétés pharmacologiques, les composés de l'invention, et plus particulièrement les composés des exemples 2, 10, 11, 14, 19 et 20 peuvent être utilisés en thérapeutique dans le traitement de l'anxiété et des névroses.Given their pharmacological properties, the compounds of the invention, and more particularly the compounds of Examples 2, 10, 11, 14, 19 and 20 can be used therapeutically in the treatment of anxiety and neuroses.

Ces composés et leurs sels d'addition d'acides thérapeutiquement compatibles peuvent être utilisés comme médicaments, par exemple sous forme de préparations pharmaceutiques adaptées à l'administration entérale ou parentérale, avec par exemple l'eau, le lactose, la gélatine, les amidons, le stéarate de magnésium, le talc, les huiles végétales, les gommes, les polyalcoylèneglycols, la vaseline, etc.These compounds and their therapeutically compatible acid addition salts can be used as medicaments, for example in the form of pharmaceutical preparations suitable for enteral or parenteral administration, with for example water, lactose, gelatin, starches , magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, petroleum jelly, etc.

Ces préparations peuvent se présenter sous forme solide, par exemple de comprimés, dragées, capsules, etc. ou sous forme liquide, par exemple de solutions, suspensions ou émulsions.These preparations can be in solid form, for example tablets, dragees, capsules, etc. or in liquid form, for example solutions, suspensions or emulsions.

Les préparations pharmaceutiques sous une forme appropriée à l'injection sont préférées. Ces préparations peuvent être soumises à des opérations pharmaceutiques classiques telles que stérilisation et/ou peuvent contenir des adjuvants par exemple des agents conservateurs, stabilisants de mouiliage ou d'émulsification, des composés-tampons, etc.Pharmaceutical preparations in a form suitable for injection are preferred. These preparations can be subjected to conventional pharmaceutical operations such as sterilization and / or can contain adjuvants, for example preservatives, wetting or emulsification stabilizers, buffer compounds, etc.

Les dosages, auxquels les composés actifs et leurs sels d'addition d'acide thérapeutiquement compatibles peuvent être administrés, peuvent varier dans des proportions importantes selon l'état du patient. Un dosage quotidien d'environ 0,01 mg à 1 mg par kg de poids corporel est toutefois préféré.The dosages, to which the active compounds and their therapeutically compatible acid addition salts can be administered, can vary in large proportions depending on the condition of the patient. A daily dosage of about 0.01 mg to 1 mg per kg of body weight is preferred, however.

Les compositions pharmaceutiques selon l'invention peuvent être utilisées en médecine interne, par exemple dans le traitement d'états pathologiques organiques, tels que l'hypertension artérielle et les coronarites, accompagnés et aggravés par un état anxieux; en médecine psychosomatique, par exemple pour le traitement de l'asthme, des ulcères gastrodudodénaux, des colopathies et d'autres affections digestives fonctionnelles; ainsi qu'en psychiatrie, par exemple pour le traitement d'états d'agitation anxieux chez les sujets psychotiques.The pharmaceutical compositions according to the invention can be used in internal medicine, for example in the treatment of organic pathological conditions, such as high blood pressure and coronary artery, accompanied and aggravated by an anxious state; in psychosomatic medicine, for example for the treatment of asthma, peptic ulcers, colopathies and other functional digestive disorders; as well as in psychiatry, for example for the treatment of anxious states of agitation in psychotic subjects.

Bien entendu, la présente invention ne se trouve pas limitée aux exemples particuliers mentionnés à simple titre illustratif, mais il est parfaitement possible, sans pour autant sortir du cadre de l'invention, d'en imaginer un certain nombre de variantes et de modifications.Of course, the present invention is not limited to the specific examples mentioned for illustrative purposes only, but it is perfectly possible, without departing from the scope of the invention, to imagine a number of variants and modifications.

Claims (27)

1. New 2-benzoyl-4-chloroglycyanilide derivatives correspondinq to general formula I below
Figure imgb0042
in which
R represents a linear or branched alkyl group, preferably a lower alkyl group;
R, and R2 may be the same or different and are selected from hydrogen, alkyl, alkenyl, alkynyl, hydroxy alkyl, alkoxy alkyl and aralkyl groups, these various groups optionally being linear or branched, and from 3- to 6-membered cycloalkyl groups optionally substituted on the a-carbon atom by an alkynyl radical;
in addition, the groups R, and R2 may form with the nitrogen atom to which they are attached an optionally saturated 5-membered or 6-membered nitrogen heterocycle optionally containing a second heteroatom selected from oxygen and nitrogen, said heterocycle optionally being substituted, preferably on the second nitrogen atom, by a lower alkyl radical; and their salts obtained with therapeutically acceptable mineral or organic acids.
2. Compounds of general formula I as claimed in Claim 1, characterised in that R represents the methyl radical.
3. A compound of general formula I as claimed in Claim 2, characterised in that it is the hydrochloride of N - methyl - N' - dimethyl - 1,1 - propargyl - (2 - benzoyl - 4 - chloro) - glycynanilide.
4. A compound of general formula I as claimed in Claim 2, characterised in that it is the hydrochloride of N - methyl - N' - (2' - methoxy - ethyl) - (2 - benzoyl - 4 - chloro) - glycynanilide.
5. A compound of general formula I as claimed in Claim 2, characterised in that it is the hydrochloride of N - methyl - N' - allyl - (2 - benzoyl - 4 - chloro) - glycynanilide.
6. A compound of general formula I as claimed in Claim 2, characterised in that it is the hydrochloride of N - methyl - N' - (1',1' - diethyl - propargyl) - (2 - benzoyl - 4 - chloro) - glycynanilide.
7. A compound of general formula I as claimed in Claim 2, characterised in that it is the hydrochloride of N - methyl - N' - (1' - ethynyl - cyclohexyl) - (2 - benzoyl - 4 chloro) - glycynanilide.
8. A compound of general formula I as claimed in Claim 2, characterised in that it is the hydrochloride of N - methyl - N' - cyclopropyl - (2 - benzoyl - 4 - chloro) - glycynanilide.
9. A compound of general formula I as claimed in Claim 2, characterised in that it is the hydrochloride of N - methyl - N' - cyclohexyl - (2 - benzoyl - 4 - chloro) - glycynanilide.
10. A compound of general formula I as claimed in Claim 2, characterised in that it is N,N' - dimethyl - N' - (2' - hydroxyethyl) - (2 - benzoyl - 4 - chloro) - glycynanilide.
11. A compound of general formula I as claimed in Claim 2, characterised in that it is N - methyl - N' - ethyl - N' - (2' - hydroxyethyl) - (2 - benzoyl - 4 - chloro) - glycynanilide.
12. A'compound of general formula I as claimed in Claim 2, characterised in that it is the hydrochloride of N - methyl - N' - bis - (2' - hydroxyethyl) - (2 - benzoyl - 4 - chloro) - glycynanilide.
13. A compound of general formula I as claimed in Claim 2, characterised in that it is the hydrochloride of N - methyl - 2 - piperidino - (2' - benzoyl - 4' - chloro) - acetanilide.
14. A compound of general formula as claimed in Claim 2, characterised in that it is the hydrochloride of N - methyl - 2 - morpholino - (2' - benzoyl- 4' - chloro) - acetanilide.
15. A compound of general formula I as claimed in Claim 2, characterised in that it is the hydrochloride of N - methyl - N' - (2' - methyl - allyl) - (2 - benzoyl - 4 - chloro) - glycynanilide.
16. A compound of general formula I as claimed in Claim 2, characterised in that it is the hydrochloride of N,N' - dimethyl - N' - cyclohexyl - (2 - benzoyl - 4 - chloro) - glycynanilide.
17. A compound of general formula I as claimed in Claim 2, characterised in that it is the hydrochloride of N - methyl - N' - isopropyl - N' - cyclohexyl) - (2 - benzoyl - 4 - chloro) - glycynanilide.
18. A compound of general formula I as claimed in Claim 2, characterised in that it is N - methyl - 4' - methyl - 2 - piperazino - (2' - benzoyl - 4' - chloro) - acetanilide.
19. A compound of general formula I as claimed in Claim 2, characterised in that it is N - methyl - 2 - imidazolyl - (2' - benzoyl - 4' - chloro) - acetanilide.
20. A process for preparing the compounds of general formula I claimed in any of Claims 1 to 19, characterised in that it comprises reacting a haloacetamide corresponding to general formula II below
Figure imgb0043
in which
R is as defined in Claim 1 and
X represents a halogen atom,

with an amine corresponding to formula III below
Figure imgb0044
in which
R, and R2 are as defined in Claim 1.
21. A process as claimed in Claim 20, characterised in that the halo-acetamide of formula II is obtained by reacting a halo-acetyl halide corresponding to formula IV below
Figure imgb0045
with an N-substituted derivative of 2 - amino - 5 - chlorobenzophenone corresponding to formula V below
Figure imgb0046
in which
R and X are as defined in Claim 20.
22. A process as claimed in Claim 21, characterised in that the N-substituted derivative of 2 - amino - 5 - chlorobenzophenone of formula V is obtained by the hydrolysis of an N-substituted compound of 2 - tosylamido - 5 - chlorobenzophenone corresponding to formula VI below
Figure imgb0047
in which R is as defined in Claim 20.
23. A process as claimed in Claim 22, characterised in that the N-substituted compound of 2 - tosylamido - 5 - chlorobenzophenone corresponding to formula VI is obtained by reacting a halide corresponding to formula VII below
Figure imgb0048
in which R and X are as defined in Claim 20, with 2 - tosylamido - 5 - chlorobenzophenone.
24. A process as claimed in Claim 23, characterised in that the 2 - tosylamido - 5 - chlorobenzophenone is obtained by reacting a tosyl halide with 2 - amino - 5 - chlorobenzophenone.
25. A process as claimed in Claim 21, characterised in that the N-substituted derivative of 2 - amino - 5 - chlorobenzophenone corresponding to formula V is obtained by reacting a sulphate corresponding to formula VIII below
Figure imgb0049
in which R is as defined in Claim 20, with 2 - amino - 5 - chlorobenzophenone in the presence of acetic acid.
26. As new medicaments, the compounds corresponding to general formula I claimed in any of Claims 1 to 19 and their acid addition salts with physiologically acceptable acids.
27. Pharmaceutical compositions, characterised in that they contain as active substance at least one compound of general formula I as claimed in any of Claims 1 to 19 or one of its acid addition salts with physiologically acceptable acids.
EP78400009A 1977-06-16 1978-06-01 Novel derivatives of substituted 2-benzoyl-4-chloro-glycinanilides, their preparation and their use as medicines. Expired EP0000299B1 (en)

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FR7718511 1977-06-16
FR7718511A FR2403330A1 (en) 1977-06-16 1977-06-16 NEW DERIVATIVES OF BENZOYL-2-CHLORO-4-GLYCINANILIDES SUBSTITUTES, THEIR METHOD OF PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS

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EP0000299A1 EP0000299A1 (en) 1979-01-10
EP0000299B1 true EP0000299B1 (en) 1980-11-12

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US (1) US4372975A (en)
EP (1) EP0000299B1 (en)
JP (1) JPS5436238A (en)
CA (1) CA1124256A (en)
DE (1) DE2860270D1 (en)
ES (1) ES470861A1 (en)
FR (1) FR2403330A1 (en)
IT (1) IT1156820B (en)
ZA (1) ZA783410B (en)

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FR2436776A1 (en) * 1978-09-25 1980-04-18 Fabre Sa Pierre NOVEL ORTHO CHLORO BENZOYL-2 CHLORO-4 GLYCYLANILIDE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS
FR2449677B1 (en) * 1979-02-26 1986-03-28 Fabre Sa Pierre NOVEL SUBSTITUTED BENZOYL-2 GLYCYLANILIDES DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS ANXIOLYTIC DRUGS
FR2459793A1 (en) * 1979-06-25 1981-01-16 Fabre Sa Pierre NOVEL BENZOYL-2 NITRO-4 ANILIDE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS
FR2492818B1 (en) * 1980-10-28 1988-03-04 Fabre Sa Pierre ORTHO HALOGENO BENZOYL-2 HALOGENO-4 SUBSTITUTED GLYCYLANILIDES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS
FR2552083B1 (en) * 1983-09-15 1986-05-09 Cerm Cent Europ Rech Mauvernay (ALKYNYLOXY-3 HYDROXY-2-PROPYL) -4 PIPERAZINYL-1 N-PHENYL ACETAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
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US6900228B1 (en) 1998-03-10 2005-05-31 Research Triangle Institute Opiate compounds, methods of making and methods of use
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US7227035B2 (en) * 2002-11-18 2007-06-05 Chemocentryx Bis-aryl sulfonamides
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ES470861A1 (en) 1979-02-01
FR2403330B1 (en) 1982-11-05
CA1124256A (en) 1982-05-25
DE2860270D1 (en) 1981-02-05
US4372975A (en) 1983-02-08
ZA783410B (en) 1979-06-27
IT1156820B (en) 1987-02-04
FR2403330A1 (en) 1979-04-13
IT7849859A0 (en) 1978-06-14
EP0000299A1 (en) 1979-01-10
JPS5436238A (en) 1979-03-16

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