CA1078869A

CA1078869A - Process for the preparation of novel benzylamines

Info

Publication number: CA1078869A
Application number: CA332,309A
Authority: CA
Inventors: Charles Malen; Pierre Roger; Michel Laubie; Jean-Claude Poignant
Original assignee: Science Union et Cie
Current assignee: Science Union et Cie
Priority date: 1974-06-20
Filing date: 1979-07-20
Publication date: 1980-06-03

Abstract

PRECIS DE LA DIVULGATION

L'invention se rapporte à l'obtention de trifluoro-methylbenzylamines substituées à l'azote, répondant à la formule générale I:

(I) dans laquelle X est de l'hydrogène, un atome d'halogène ou un radical trifluorométhyle et les substituants R1, R2, R3 et R4 sont soit de l'hydrogène soit un substituant hydrocarboné linéaire ou cyclique, sous forme racémique ou optiquement active ainsi que des sels de ces composés avec un acide minéral ou organique qui consiste à cycliser par chauffage une .beta.-halo-éthylurée de formule générale:

Les composes de formule générale I et leurs sels manifestent des propriétés pharmacologiques intéressantes. En particulier ils possèdent des propriétés anti-hypertensives très marquées. Par contre ils ne manifestent de propriétés neurodépressives qu'à des doses très élevées, bien supérieures à celles utilisées pour l'effet anti-hypertensif. Les composés de formule générale I ainsi que leurs sels trouvent un emploi en thérapeutique humaine ou animale, notamment comme agent anti-hypertensif. PRECISION OF DISCLOSURE

The invention relates to the production of trifluoro-nitrogen-substituted methylbenzylamines, meeting the general formula I:

(I) in which X is hydrogen, an atom halogen or a trifluoromethyl radical and the substituents R1, R2, R3 and R4 are either of hydrogen either a linear hydrocarbon substituent or cyclic, in racemic or optically active form as well as salts of these compounds with a mineral or organic acid which consists in cyclizing by heating a .beta.-halo-ethylurea of general formula:

The compounds of general formula I and their salts show interesting pharmacological properties. In particular they have anti-hypertensive properties very marked. By cons they do not show properties only at very high doses, much higher to those used for the anti-hypertensive effect. Compounds of general formula I and their salts find use in human or animal therapy, in particular as an agent anti-hypertensive.

Description

7l38~i9 La presente invention concerne des nouveaux inter-mediaires utiles pour la preparation de nouvelles benzylamines substituees à l'azote. Elle concerne plus particulièrement des benzylamines N-substituees dont le noyau aromatique porte un substituant trifluoromethyle en position meta.
Les intermediaires de la presente invention corres-pondent à la formule gênerale II:
X

~ C - NH ~ 6 - NH - ICH - ICH - Hal dans laquelle X, Rl, R2, R3, R4, 0 et Hal seront definis ci-après.
Le procede d'obtention des compos~s de formule generale I:
X

F3C I ~ ~ (I) dans laquelle X represente de l'hydrogène, un atome d'halogène ou un radical trifluoromêthyle;
Rl represente un radical alcoyle inferieur ou un radical cycloalcoyle inferieur;
R2 represente de l'hydrogène ou un radical alcoyle inferieur;
R3 et R4, distinctement ou simultanement represen-tent de l'hydrogène ou un radical alcoyle inferieur ou forment ensemble une chaîne alcoylène ayant de 3 à 6 atomes de carbone ainsi que des sels des composes de formule generale I avec un acide mineral ou organique, de preference un acide therapeutiquement compatible, _ 1 i~7-138t~9 consiste à cycliser par chauffage du compose de l'invention de formule generale II:
X

R
~ C - NH - I - NH - fH - CH - Hal (II) dans laquelle la definition des substituants X, Rl, 2, R3 et R4 demeure inchangee et Hal represente un atome d'halog~ne pour obtenir un compose de formule generale I:
X

~ I - NH ~/ ~

que l'on peut, si desire, salifier par addition d'un acide mineral ou organique ou d~doubler en ses isomères optiques par combinaison avec un reactif optiquement actif.
Le procede d'obtention des composes de formule generale II de la presente invention consiste en ce qu'on condense une m. trifluoromethylbenzylamine de formule generale III:

~ C - NH2 (III) dans laquelle X, Rl et R2 sont definis comme precedemment avec un isocyanate d'~-halogenoalcoyle de formule generale IV:
X - CH - CH - N = C = B 7l38 ~ i9 The present invention relates to new inter-useful media for the preparation of new benzylamines substituted for nitrogen. It relates more particularly N-substituted benzylamines with an aromatic nucleus a trifluoromethyl substituent in the meta position.
The intermediaries of the present invention correspond to lay in general formula II:
X

~ C - NH ~ 6 - NH - ICH - ICH - Hal in which X, Rl, R2, R3, R4, 0 and Hal will be defined below.
The process for obtaining the compounds of formula general I:
X

F3C I ~ ~ (I) in which X represents hydrogen, an atom halogen or a trifluoromethyl radical;
Rl represents a lower alkyl radical or a lower cycloalkyl radical;
R2 represents hydrogen or an alkyl radical inferior;
R3 and R4, distinctly or simultaneously represented try hydrogen or a lower alkyl radical or form together an alkylene chain having 3 to 6 carbon atoms as well as salts of the compounds of general formula I with a mineral or organic acid, preferably an acid therapeutically compatible, _ 1 i ~ 7-138t ~ 9 consists of cycling by heating the compound of the invention of general formula II:
X

R
~ C - NH - I - NH - fH - CH - Hal (II) in which the definition of the substituents X, Rl, 2, R3 and R4 remains unchanged and Hal represents a halogen atom to obtain a compound of general formula I:
X

~ I - NH ~ / ~

that one can, if desired, salify by adding a mineral or organic acid or to double its isomers optics by combination with an optically active reagent.
The process for obtaining the compounds of formula General II of the present invention consists in that condenses a m. trifluoromethylbenzylamine of general formula III:

~ C - NH2 (III) where X, Rl and R2 are defined as previously with an isocyanate of ~ -halogenoalkyl of formula General IV:
X - CH - CH - N = C = B

- 2 -3L6~7~8~9 dans laquelle X est un atome d'halogène R3 et R4 sont definis comme precedemment et B est un atome d'oxygène pour produire une uree de formule generale II.
Les composes de formule generale II peuvent egale-ment être obtenus par un procede qui consiste en ce que l'on condense une m. trifluoromethylbenzylamine de formule genêrale III avec un haloformiate d'aryle de formule genêrale V:
O ( V ) dans laquelle Ar est un radical phenyle ou un radical phenyle substitue par un ou plusieurs radicaux caractere electrophile, pour obtenir un carbamate de formule generale VI:
X

~ f - NH ~ 6 - OAr (VI) dans laquelle X, Rl, R2 et Ar sont definis comme precedemment que l'on condense avec un aminoalcanol de formule generale VII:
2HN - CH - fH - OH (VII) dans laquelle R3 et R4 sont definis comme precedemment pour obtenir une ~-hydroxy alcoyluree de formule generale VIII:

~0'7~ 36~

~ C - NH - CO - NH - CH - ICH - OH (VIII) et soumet celle-ci à l'action d'un agent d'haloge-nation pour former un compose de formule generale II.
Les composes de formule generale I peuvent etre obtenus par les modes d'execution suivants:
- la cyclisation du compose de formule generale II
est effectuee par chauffage de preference en milieu aqueux, en presence ou en l'absence d'un agent basique capable de fixer la molecule d'hydracide formee lors de la reaction de cycli-sation.
- l'agent basique peut être un agent min~ral comme par exemple un carbonate de metal alcalin ou alcalino-terreux, un bicarbonate alcalin, un hydroxyde de metal alcalin, un oxyde de metal alcalino-terreux, de magnesium ou d'aluminium, un carbonate ou un phosphate de magnesium, un sel basique d'aluminium.
- l'agent basique peut être un agent organique comme par exemple une dialcoylamine, une trialcoylamine~ la dimethylaniline, une base pyridique.
2~ - la cyclisation s'effectue par chauffage a une temperature comprise entre 50 et 120C, selon la nature du solvant et de la nature de la molecule à deshydrogener. La cyclisation s'effectue de preference aux environs de 100.
- l'halogenoformate d'aryle de formule generale V
est de preference un chlorure ou un bromure.
- le radical aryle est de preference un radical phenyle, dinitrophenyle, nitrophenyle, ou chloro nitrophenyle.
- la condensation de l'halogenoformate d'aryle avec ~(~7~869 la m. trifluoromethyl benzylamine de formule genêrale III est effectuee en pr~sence d'un agent basique comme une trialcoyl-amine, une dialcoylaniline, la pyridine, la collidine, la 4-dimethylaminopyridine ou le dimethylformamide.
- l'agent d'halogenation est par exemple le chlorure de thionyle, le pentachlorure ou le pentabromure de phosphore, l'oxychlorure de phosphore, la N-bromoacetamide.
- le dedoublement des composes de formule generale I
est effectuee de preference par salification avec un acide optiquement actif comme par exemple l'acide d-tartrique, l'acide NN dimethyl tartramique, l'acide abietique, l'acide d- ou l-chrysanthemique, l'acide d-glucose l-phosphorique, l'acide l-menthoxy acetique ou l'acide d-dibenzoyl tartrique.
Le dedoublement peut être egalement effectue sur une matiere première comme par exemple une m. trifluorom~thyl-benzylamine de formule generale III ou une ~-hydroxy alcoyl-uree de formule generale VIII.
L' on peut aussi obtenir des formes optiquement actives des composes de formule generale I. L'atome de carbone benzylique est substitue par au moins trois radicaux differents et de ce fait asymetrique. Une telle molecule peut être dedoublee en ses antipodes optiques.
En outre lorsque le cycle oxazolique est substitue par une ou plusleurs cha~nes carbonees lineaires ou cycliques, les nouveaux centres de symetrie peuvent donner naissance à
des composes dedoubles. Les isomères optiques qui en resul-tent font egalement partie de l'invention.
L'on peut aussi employer un procede de preparation de la DL N- ~-cyclopropyl) (3-trifluoromethylphenyl~ methy 2-aminooxazoline qui consiste en ce que l'on condense la DL
(3-trifluoromethylphenyl) cyclopropylmethylamine avec l'iso-~3788~;9 cyanate de ~-chloroethyle pour former la N-(~-chloroethyl) N'-~rcyclopropyl) (3-trifluoromethylphenyl) methy ~ uree que l'on cyclise par chauffage en milieu aqueux pour obtenir l'oxazoline desiree.
L'on peut aussi employer un procede de preparation du 2-(a-cyclopropyl) 2-(3'-trifluoromethylphenyl) 2-(oxazoli-nyl-2' amino) ethane racemique ou optiquement actif qui consiste en ce que l'on condense la 2-(3'-trifluoromethyl-phênyl) 2-(~-cyclopropyl) ethylamine racemique ou optiquement active avec l'isocyanate de ~-chloroethyle pour obtenir la ~-chloroethyl uree correspondante que l'on cyclise par chauffage en 2-(~-cyclopropyl) 2-(3'-trifluoromethylphenyl) 2-(oxazoli-nyl-2' amino) ethane~
Les isomères optiques de la N- ~ ~-cyclopropyl~ ~3-trifluoromethylphenyl) methy ~ 2-aminooxazoline peuvent être obtenus par un procede qui consiste en ce que l'on dedouble en ses isomères optiques la dl (3-trifluoromethylphenyl~ cyclo-propylmethylamine par salification à l'aide de l'acide d-tartrique, opère la synthèse au depart d'un isomère dedouble et obtient finalement l'oxazoline levogyre ou dextrogyre dedoublee~
Les composes de formule generale I:
X

F3~ ~ ¦ - NH ~/ ~

ainsi que leurs sels d'addition avec un acide mineral ou organique et leurs isomeres optiques peuvent aussi être obtenus~

~L07886~

L'invention comprend ~ titre de composes nouveaux, utiles notamment pour l'obtention des composes de formule generale I, les composes de formule generale II:

~ f - NH - ICl - NH - fH - fH - Hal ( I I ) dans laquelle les substituants X, Rl, R2, R3 et R4 sont definis comme precedemment et Hal est un atome d'halogene, sous forme racemique ou dedoublee.
- les composes de formule generale VIII:
X

~ f - NH - CO - NH - fH - fH - OH (VIII) dans laquelle la definition des substituants X, Rl, R2, R3 et R4 demeure inchangee, sous forme racemique ou dedoublee.
- les benzylamines de formule generale III:
X R

- NH (III) dans laquelle la definition des substituants X, Rl et R2 demeure celle fixee anterieurement, sous forme racemique ou dedoublee.

- les carbamates de formule gênerale VI:

1~7886~

F3C I ~ NH - C - OAr (VI) dans laquelle la definition des substituants X, Rl, R2 et Ar demeure inchangee, sous forme racemique ou dedoublee.
Les composes de formule generale I et leurs sels manifestent des proprietes pharmacologiques interessantes. En particulier ils possedent des proprietes anti-hypertensives tres marquees. Par contre ils ne manifestent de proprietes neurodepressives qu'à des doses très elevees, bien superieures à celles utilisees pour l'effet anti-hypertensif.
Les composes de formule generale I ainsi que leurs sels trouvent un emploi en th~rapeutique humaine ou animale, notamment comme agent hypertensif.
Ils se differencient des composes de structure analogue comme ceux decrits dans le brevet americain 3,626,067 par l'extrême reduction des proprietes neurodepressives. Le risque d'apparition de phenomenes de somnolence, de sedation ou de relâchement musculaire se trouve ainsi considerablement - reduit.
En vue de l'usage therapeutique, les composes de formule generale I sont employes sous forme de compositions pharmaceutiques, adaptees a l'administration par voie parente-rale, buccale, perlinguale, ou rectale, en association avec un excipient inerte, non-toxique, pharmaceutiquement acceptable.
Les composes pharmaceutiques se presentent sous forme de comprimes nus ou enrobes, de dragees, de solutions ou suspension buvables ou injectables, de gelules, de supposi-toires, de comprimes sublinguaux, de gels d'emulsions, de sirops ou de gouttes.

i(378869 La posologie utile Yarie selon l'~ge du patient9 la gravite de l'indication therapeutique et la voie d'adminis-tration.
Elle peut s'echelonner entre 0.5 mg et 2~ mg par prise et entre 0.5 mg et 80 mg par jour. La posologie pr~f~r~e s'~chelonne entre 2 mg et 20 mg par prise renouvelee de 1 a 4 fois par jour chez l'homme.
A titre de composes actuellement preferes, on pourra citer plus particulierement: -- la dl 2- ~ 3-trifluorom~thylph~nyl~-cyclopropyl-- methy ~ aminooxazoline - la d 2- ~ 3-trifluoromethylphenyl)-cyclopropyl-mthy ~ aminooxazoline - la dl 2- ~ 3-trifluoromethyl 4-fluorophenyl)-cyclopropylmethy ~ aminooxazoline - la dl 2- ~ 3,5-ditrifluoromethylph~nyl)a-cyclo-propylmethy ~ aminooxazoline - la dl 2- ~ 3-trif1uoromethylphenyl) 2-~oxazolinyl-2') amin ~ ethane - la dl 2-(-cyclopropyl) 2-(oxazolinyl-2') amino-2-(3-trifluoromethylphenyl) ethane et ses isomères optiques.
Les ben~ylamines de formule generale III, utilis~es comme matieres premi~res, sont obtenues d'une maniere g~n~rale au depart d'un l-halog~no 3-trifluoromethylbenzène de formule generale:
X

- ~ Hal que l'on fait reaglr avec un metal ou un m~tallolde en presence de chlorure de cadmlum puls avec halogenure d'ac~de ~L~)7~8~9 de formule Rl COCl pour former une c~tone de formule gênerale:

Ç~ lC ~ R 1 puis soumet celle-ci ~ une reduct;on. alcoylante ou non, pour former le d~rive hydroxyle de formule g~nerale:

I OH
~ C - R

F3~
que l'on transforme en amine correspondante selon les m~thodes connues par exemple par formation d'un lsocyanate, transformation en carbamate puis reduct;on.
Lorsque R2 est de l'hydrogène les composes de formule genérale III peuvent également être obtenus par formation d'une oxime au depart d'une cétone de formule génerale:
X

~ CO--R

puis réduction de l'oxime de formule génerale:

~C--R 1 NOH

au moyen d'un metal alcalln dans un alcanol ou d'un hydrure mixte de metal alcalin.
Le metal ou le metallo~de utllise pour le premier stade de la pr~paration de la matière premiere peut être du :IL0788~

magnesium, du zinc, du cadmium, clu mercure, du cuiYre ou de l'etain.
Le substituant X peut ~tre en n'importe quelle position du cycle benzenique a l'exclusion des positions 1 et - 2 -3L6 ~ 7 ~ 8 ~ 9 in which X is a halogen atom R3 and R4 are defined as above and B is an oxygen atom to produce a urea of general formula II.
Compounds of general formula II can also-ment be obtained by a process which consists in that one condenses a m. trifluoromethylbenzylamine of general formula III with an aryl haloformate of general formula V:
O (V) in which Ar is a phenyl radical or a phenyl radical substituted by one or more radicals electrophilic character, to obtain a carbamate of general formula VI:
X

~ f - NH ~ 6 - OAr (VI) where X, Rl, R2 and Ar are defined as previously which is condensed with an aminoalkanol of formula General VII:
2HN - CH - fH - OH (VII) in which R3 and R4 are defined as previously to obtain a ~ -hydroxy alkylated formula General VIII:

~ 0'7 ~ 36 ~

~ C - NH - CO - NH - CH - ICH - OH (VIII) and subjects it to the action of a halogen nation to form a compound of general formula II.
The compounds of general formula I can be obtained by the following execution modes:
- cyclization of the compound of general formula II
is carried out by heating preferably in an aqueous medium, in presence or absence of a basic agent capable of fixing the hydracid molecule formed during the cyclic reaction station.
- the basic agent can be a minimal agent such as for example an alkali or alkaline earth metal carbonate, alkaline bicarbonate, alkali metal hydroxide, alkaline earth metal, magnesium or aluminum oxide, a carbonate or a magnesium phosphate, a basic salt aluminum.
the basic agent can be an organic agent such as for example a dialkoylamine, a trialcoylamine ~ la dimethylaniline, a pyridic base.
2 ~ - the cyclization is carried out by heating a temperature between 50 and 120C, depending on the nature of the solvent and the nature of the molecule to be dehydrogenated. The cyclization preferably takes place around 100.
- aryl haloformate of general formula V
is preferably a chloride or a bromide.
- the aryl radical is preferably a radical phenyle, dinitrophenyle, nitrophenyle, or chloro nitrophenyle.
- the condensation of aryl halogenoformate with ~ (~ 7 ~ 869 the m. trifluoromethyl benzylamine of the general formula III is performed in the presence of a basic agent such as a trialcoyl-amine, dialkoylaniline, pyridine, collidine, 4-dimethylaminopyridine or dimethylformamide.
the halogenating agent is, for example, chloride thionyl, pentachloride or phosphorus pentabromide, phosphorus oxychloride, N-bromoacetamide.
- the splitting of the compounds of general formula I
is preferably carried out by salification with an acid optically active, for example d-tartaric acid, NN dimethyl tartramic acid, abietic acid, acid d- or l-chrysanthemique, d-glucose l-phosphoric acid, l-menthoxy acetic acid or d-dibenzoyl tartaric acid.
Duplication can also be performed on a raw material such as for example a m. trifluorom ~ thyl-benzylamine of general formula III or a ~ -hydroxy alkyl-General formula VIII.
One can also obtain forms optically active compounds of general formula I. The atom of benzyl carbon is substituted by at least three radicals different and therefore asymmetrical. Such a molecule can to be split into its optical antipodes.
Also when the oxazolic cycle is substituted by one or more linear or cyclic carbon chains, new centers of symmetry can give birth to double compounds. The resulting optical isomers tent are also part of the invention.
You can also use a preparation process DL N- ~ -cyclopropyl) (3-trifluoromethylphenyl ~ methy 2-aminooxazoline which consists of condensing the DL
(3-trifluoromethylphenyl) cyclopropylmethylamine with iso-~ 3788 ~; 9 ~ -chloroethyl cyanate to form N- (~ -chloroethyl) N'- ~ rcyclopropyl) (3-trifluoromethylphenyl) methy ~ uree que cyclized by heating in an aqueous medium to obtain the desired oxazoline.
You can also use a preparation process 2- (a-cyclopropyl) 2- (3'-trifluoromethylphenyl) 2- (oxazoli-2-amino-nyl) racemic or optically active ethane which consists of condensing the 2- (3'-trifluoromethyl-phenyl) 2- (~ -cyclopropyl) ethylamine racemically or optically active with ~ -chloroethyl isocyanate to obtain ~ -corresponding chloroethyl uree which is cycled by heating in 2- (~ -cyclopropyl) 2- (3'-trifluoromethylphenyl) 2- (oxazoli-nyl-2 'amino) ethane ~
The optical isomers of N- ~ ~ -cyclopropyl ~ ~ 3-trifluoromethylphenyl) methy ~ 2-aminooxazoline can be obtained by a process which consists in splitting its optical isomers dl (3-trifluoromethylphenyl ~ cyclo-propylmethylamine by salification using d- acid tartaric, operates the synthesis from a double isomer and finally obtains the levogyre or dextrogyre oxazoline split ~
The compounds of general formula I:
X

F3 ~ ~ ¦ - NH ~ / ~

as well as their addition salts with an acid mineral or organic and their optical isomers can also to be obtained ~

~ L07886 ~

The invention comprises ~ as new compounds, useful in particular for obtaining the compounds of formula general I, the compounds of general formula II:

~ f - NH - ICl - NH - fH - fH - Hal (II) in which the substituents X, R1, R2, R3 and R4 are defined as above and Hal is a halogen atom, in racemic form or split.
- the compounds of general formula VIII:
X

~ f - NH - CO - NH - fH - fH - OH (VIII) in which the definition of the substituents X, R1, R2, R3 and R4 remains unchanged, in racemic form or split.
- the benzylamines of general formula III:
XR

- NH (III) in which the definition of the substituents X, Rl and R2 remains the one previously fixed, in racemic form or split.

- the carbamates of general formula VI:

1 ~ 7886 ~

F3C I ~ NH - C - OAr (VI) in which the definition of the substituents X, R1, R2 and Ar remain unchanged, in racemic or split form.
The compounds of general formula I and their salts show interesting pharmacological properties. In particular they have anti-hypertensive properties very marked. By cons they do not show properties neurodepressive only at very high doses, much higher to those used for the anti-hypertensive effect.
The compounds of general formula I and their salts find use in human or animal therapy, especially as a hypertensive agent.
They are different from the structural compounds analogous like those described in the American patent 3,626,067 by the extreme reduction of neurodepressive properties. The risk of drowsiness, sedation or muscle sagging is thus found to be considerably - reduced.
For therapeutic use, the compounds of general formula I are used in the form of compositions pharmaceutical, suitable for parenteral administration-oral, buccal, perlingual, or rectal, in combination with a inert, non-toxic, pharmaceutically acceptable excipient.
Pharmaceutical compounds come in in the form of naked or coated tablets, dragees, solutions or oral or injectable suspension, capsules, roofs, sublingual tablets, emulsion gels, syrups or drops.

i (378869 The useful dose Yarie according to the age of the patient severity of the therapeutic indication and route of administration tration.
It can range between 0.5 mg and 2 ~ mg per taken and between 0.5 mg and 80 mg per day. The preferred dosage ranges from 2 mg to 20 mg per renewed dose from 1 to 4 times a day in humans.
As currently preferred compounds, to quote more particularly: -- la dl 2- ~ 3-trifluorom ~ thylph ~ nyl ~ -cyclopropyl-- methy ~ aminooxazoline - d 2- ~ 3-trifluoromethylphenyl) -cyclopropyl-mthy ~ aminooxazoline - dl 2- ~ 3-trifluoromethyl 4-fluorophenyl) -cyclopropylmethy ~ aminooxazoline - dl 2- ~ 3,5-ditrifluoromethylph ~ nyl) a-cyclo-propylmethy ~ aminooxazoline - dl 2- ~ 3-trif1uoromethylphenyl) 2- ~ oxazolinyl-2 ') amin ~ ethane - dl 2 - (- cyclopropyl) 2- (oxazolinyl-2 ') amino-2- (3-trifluoromethylphenyl) ethane and its optical isomers.
The ben ~ ylamines of general formula III, used as raw materials, are obtained in a general way at the start of an l-halog ~ no 3-trifluoromethylbenzene of formula general:
X

- ~ Hal that we do adjust with a metal or a metal in the presence of cadmlum puls chloride with ac halide of ~ L ~) 7 ~ 8 ~ 9 of formula Rl COCl to form a c ~ tone of general formula:

Ç ~ lC ~ R 1 then submit it ~ a reduct; on. alkylating or no, to form the hydroxylated bank of general formula:

I OH
~ C - R

F3 ~
which we transform into a corresponding amine according to known methods, for example by forming a lsocyanate, transformation into carbamate then reduct; on.
When R2 is hydrogen the compounds of formula general III can also be obtained by forming a oxime at the start of a ketone of general formula:
X

~ CO - R

then reduction of the general formula oxime:

~ C - R 1 NOH

by means of a metal alkalln in an alkanol or a mixed alkali metal hydride.
Metal or metallo ~ from utllise for the first stage of the preparation of the raw material can be : IL0788 ~

magnesium, zinc, cadmium, mercury, copper or tin.
The substituent X can be in any position of the benzenic cycle excluding positions 1 and

3 par rapport a la chaSne benzylique.
Dans les dêfinitions fournies ci-dessus le terme alcoyle inferieur designe un radical hydrocarbone ayant de 1 à
6 atomes de carbone comme un méthyle, un ethyle, un isopropyle ou un n-hexyle.
Le terme cycloalcoyle inferieur designe un radical cyclique sature ayant de 3 a 6 atomes de carbone ~ventuellement substitue par un ou plusieurs alcoyles inferieur comme un 1,1-dimethylcyclopropyle, un 3,3,5-trimethylcyclohexane ou un cyclopentyle.
Les exemples suivants illustrent llinYention. Ils ne là limitent en aucune facon.
EXEMPLE I
DL N- ~ -cyclopropyl) (3-trifluoromethylphenyl) methy ~ 2-aminooxazoline stade a) ~-cyclopropyl (3-trifluoromethylphenyl) cetone On prepare le derive magnesien du l-(trifluoromethyl3 3-bromobenzène en solution dans l'ether a partir de 22~ 9 de l-(trifluoromethyl) 3-bromobenzène de manière a realiser une concentration de l'ordre de 3 M. On convertit le magnesien en derive cadmie par addition de 0.53 mol de chlorure de cadmium a 0. Le melange est ensuite port~ au reflux du solvant pendant 60 minutes.
L'ether est distille et remplace au fur et ~ mesure par un Yolume double de benzène. On ajoute alors 105 9 de chlorure de l'acide cyclopropane carboxylique goutte ~ goutte ~L~7~8~9 en maintenant la temperature du milieu reactionnel en dessous de 30. Après achèvement de l'addition, on poursuit l'agita-tion pendant une heure puis detruit l'excès de reactif par addition menagee d'acide chlorhydrique. Après dilution ~
l'eau, on separe la phase benz~nique qu'on lave à l'eau, s~che et distille sous vide. On recueille par distillation frac-tionnee 90 9 d'a-cyclopropyl (3-trifluoromethylphenyl) cetone soit un rendement de 42X.
Eb = 115-118 nD25 _ 1,4811 Le spectre IR montre une bande carbonyle.
stade b) a-cyclopropyl (3-trifluoromethylphenyl) cetoxime On traite 75 9 8 d'~-cyclopropyl (3-trifluoromethyl-phenyl) cetone par 78 9 de chlorhydrate d'hydroxylamine dans 280 ml d'un melange a parties ~gales de pyridine et d'ethanol au reflux pendant 16 heures.
On obtient ainsi 62 9 d'oxime sous forme d'un melange d'isomeres syn et an~i. Le produit apr~s recristallisation du pentane fond à 60-61.
Le spectre infra-rouge montre une bande hydroxyle 3250 cm 1 et l'absence de bande carbonyle.
stade c) DL--cyclopropyl 3-trifluoromethylbenzylamine On dissout 61 9 d'a-cyclopropyl (3-trifluoromethyl-phenyl) cetoxime dans 450 ml d'êther. On ajoute 20 9 d'hydrure de lithium et d'aluminium et on porte au reflux pendant 3 heures. Après elimination de l'exces de reactif et du solvant~
on obtient 41 9 8 d'amine soit un rendement de 65X.

- ~2 -~(~7~3869 Ebl3 _ 106-1~0 n23 - 1,4775 Le produit est puri~ie par transformation en chlorhydrate F superieur a 260 (sublimation) stade d) chloroethyl) 3- ~-cyclopropyl) (3-trifluoromethylbenzyl On dissout 4 9 3 d'a-cyclopropyl m. trifluoromethyl-benzylamine dans 8 ml de tetrahydrofuran. On ajoute 2 9 1 d'isocyanate de ~-chloro~thyle dissouts dans 4 ml de tetra-hydrofuran à une temperature ne depassant pas 0. On laisse reposer 4 heures puis distille le solvant sous vide. On recueille ainsi 6.2 g d'uree soit un rendement de 97%. Apr~s recristallisation d'un melange de cyclohexane et de benzene on obtient la l (~-chloroethyl) 3- ~a-cyclopropyl) (3-trifluoro-methylbenzyl ~ uree pure fondant ~ 91-95.
Le spectre infra-rouge montre une bande -NH- a 3300 cm~
stade e) DL N- ~-cyclopropyl (3-trifluoromethylphenyl) methy ~ 2-amino-oxazoline On met en suspension dans 60 ml d'eau 14 9 de 1~
chloroethyl) 3- ~a-cyclopropyl) (3-trifluoromethylbenzyl ~ uree et on porte au reflux pendant 30 minutes. Le produit se dissout progressivement. Après refroidissement on alcalinise la solution claire par addition progressive de 4 ml d'ammo-niaque. On epuise la phase aqueuse par l'ether ~ trois reprises, on separe les solutions etherees que l'on s~che et distille à sec sous vide. Le residu sec est repris par l'ether isopropyl;que. On obtient ainsi 7 9 de produit pur fondant 84-86 (rendement 60~).

1al78869 Le spectre IR montre une liaison C=N a 1685 cm 1 EXEMPLE_ dl 2-(-cyclopropyl) 2-(3'-trifluoromethylph~nyl) 2-(oxazolinyl-2' amino) ethane stade a) m~thyl -cyclopropyl (3-tri~luorom~thylphenyl) carbinol On dissout 107 9 d'-cyclopropyl (3-trifluorom~thyl-phenyl3 cetone obtenue au stade a) de l'exemple I,dans 1000 ml d'ether et on ajoute sous atmosphere inerte 600 ml d'une solu-10 tion dans l'ether de methyl lithium 1, 65 M ~ une temperatureinferieure à -10. Apres addition on laisse le m~lange r~ac-tionnel revenir ~ la temperature ordinaire pendant une nuit.
On verse ensuite le melange sur un melange de glace et d'acide chlorhydrique N. La phase aqueuse est epuisee a l'ether. Les solutions organiques sont reunies puis lavees avec une solution de chlorure de sodium jusqu'a ce que les eaux de lavage soient . neutres. On seche ensuite sur sulfate de sodium, filtre et evapore à sec.
On recueille ainsi 106.5 g de methyl a-cyclopropyl 20 (3-trifluoromethylphenyl) carbinol soit un rendement de 93%.
Ebl7 _ 123-125 nD = 1,4765 Analyse C12H13F30 ~ 230,22 C ~1 Calcule 62,61 5,70 Trouve 62,89 5,74 stade b) 2-(3'-trifluoromethylphenyl) 2-(cL-cyclopropyl) ~thylamine A une solution de 46 9 de methyl (c~-cyclopropyl) 30 (3-trifluoromethylphenyl) carbinol dans 100 ml de t~trahydro-furan on a~oute 8 9 d'hydrure de sodium et on porte le m~lange ~0788~

au reflux pendant 10 heures. On introduit alors sous agitation cette solution dans une solution refroidie de 47 g de bromure de cyanogene dans 50 ml de tetrahydrofuran. On maint;ent sous agitation pendant 2 heures ~ temperature ordinaire puis filtre le bromure de sodium forme et evapore ~ sec le filtrat. Le residu sec est repris dans 100 ml de m~thanol et porte au reflux pendant 12 heures. ~a solution de carbamate ainsi o`btenue est evaporee ~ sec. Le résidu est alors additionne de 10~ ml d'acide chlorhydrique concentrê et chauffe ~ 60 pendant 8 heures. Apres avoir alcalinise le melange par addition de . potasse, on epuise la solution aqueuse a plusieurs reprises de l'~ther. On reunit les phases eth~r~es qu'on lave à l'eau, seche, filtre et evapore a sec. On reprend par une solution saturee de gaz chlorhydrique dans l'ether. Le chlorhydrate de 2-(3'-trifluoro~ethylphenyl) 2-(a-cyclopropyl) ethylamin~
precipite. On le separe par filtration et le sèche. Après recrist~llisation de l'acetonitrile il fond ~ 180-lg5.
Analyse~12H14F3N, ClH = 266,70 i C H N Cl~
Calcule54,24 5,69 5,28 13,35 Trouve54,09 5,63 5,39 13,39 stade c) ~ chloroet~yl) 3- ~ -cyclopropyl) methyl (3'-trifluoro-methylphenyl~/ uree En op~rant selon le mode operatoire de l'exemple I
stade d) on obtient l'uree avec un rendement quantitatif. Le produit est utilise tel quel int~gralement pour l'~tape suivante.
stade d) 3~ dl 2-(a-cyclopropyl) 2-(3'-trifluoromethylphenyl) 2-(oxazo-linyl-2' amino) ethane En op~rant selon le mode operatoire de l'exemple I

~788~;9 stade e) on obtient avec un rendement de 75% la dl 2~ cyclo-propyl) 2-(3'-trifluoromethylphenyl) 2-(oxazolinyl-2' amino) ethane. Le produit pur fond à 1l2-119.
Analyse C15Hl7F3N2 - 298~30 C H N%
Calcule 60,39 5,75 9,39 Trouve 60,27 6,05 9,35 EXEMPLE III
N- ~ a-cyclopropyl) (3'-trifluoromethylphenyl) m~thy 2-aminooxazoline levogyre.
La synthese est effectuee au depart de la (3-tri-fluoromethyl)-cyclopropyl methylamine dextrogyre selon le mode operatoire de l'exemple I.
La (3-trifluoromethyl)~-cyclopropyl methylamine est dedoublee par l'acide d-tartrique en contrôlant en chromato-graphie en phase vapeur la purete de l'isomere optique separ~, au moyen du reactif de Mosher.
On obt;ent ainsi les isomeres suivants:
- (3-trifluoromethylphenyl)-cyclopropyl methylamine dextrogyre = ~ 35.6 ~c = l~ ethanol) - + l30.4 - N- ~ ~-cyclopropyl) (3-trifluoromethylphenyl) methy~
2-aminooxazoline levogyre F = 59-68 -22 _ _ 2l (c = l% ethanol) = - 86.4 (c = l~ ~thanol) :107B869 EXEMPLE IY
N- ~ -cyclopropyl) (3-trifluoromethylphenyl) methy 2-aminooxazoline dextrogyre selon le m~me mode operatolre qu'~ l'exemple III on obtient ~ -cyclopropyl (3-trifluoromethylphenyl) methyl-amine levogyre - - 35.8 (c _ l~ ethanol) _ - 129.5 (c = 1% ethanol) - l'(a-cyclopropyl) (3-trifluoromethylphenyl) m~thyl 2-aminooxazoline dextroqyre F = 59-65 - ~ 21.5 (c - i~ ethanol) r~ = ~ 89 (c ~ lX ethanol) EXEMPLE V
dl ~-(3'-trifluoromethylphenyl) 2-(oxazolinyl-2) amin ~ ethane En operant selon le mode operatoire de l'exemple I
au depart du 2-(3'-trifluorom~thylphenyl) 2-amino ethane on obtient la dl 2-(3'-trifluoromethylphenyt) 2-(oxazolinyl-2 amino ethane fondant a 89-94 apres recristall;sation de l'~ther isopropylique. Le produit est soluble dans l'ac1de chlorhydrique normal. Après ~vaporation a sec du solvan~ on recueille le chlorhydrate de dl ~ -(3'-trifluoromethylph~nyl) 2-~oxazolinyl-2) amin ~ ethane.

~07~3~369 Analyse de la base: C12H13F3N2~2 =258~23 ~ N%
Calcule 55,80 5"30 10,82 Trouve 55,69 5"23 10,78 EXEMPLE VI
dl N~ -cyclopropyl) (3'-trifluoromêthyl 4'-fluoro-phenyl) methy~7 2-aminooxazoline.
En operant selon le mode operatoire de l'exemple I
au depart du l-iodo 3-trifluoromethyl 4-fluorobenz~ne obtenu au d~part de l'o-chloro trifluoromethylbenzene on obtient successivement:
- la (3-trifluoromethyl 4-fluorophenyl)a-cyclopropyl c~tone Ebo 6 = 104-107 n25 - 1,4805 - la (3-trifluoromethyl 4-fluorophenyl)-cyclopropyl cetoxime fondant en dessous de 50 (rendement 91X~
- la dl ~3-trifluoromethyl 4-fluorophenyl) (a-cyclo-propyl) methylamine isolee sous forme de chlorhydrate fondant au dessus de 250 (decomp.) - la dl 1-~T3'-trifluorome~hyl 4'-fluorophenyl) (a-cyclopropyl) methy~7 3-(~-chloro~thyl) uree fondant a 108-111 - la dl N-¢c~-cyclopropyl) (3-trifluoromethyl 4-fluorophenyl) methy~7 2-aminooxazoline fondant ~ 81-87 apres recristallisation du pentane.
Analyse C14H14F4N20 30 C H NX
Calcule 55,63 4,67 9,27 Trouve 55,83 4,77 9,32 Le compose est soluble dans l'acide chlorhydr~que donnant naissance au chlorhydrate.

1~ 7~9 EXEMPLE VII
dl N- ~3,5-ditrifluorom~thylphenyl) (a-cyclopropyl m~thyl ~ 2-aminooxazoline.
En operant selon le mode operatoire de l'exemple I
au d~part du l-iodo 3,5-(ditrifluorom~thyl) benzène obtenu selon le proc~de d~crit dans le J. of Am. Chem. Soc. 75 (1953) 4967-4969 on obtient successivement:
- la (3,5-ditrifluoromethyl)~-cyclopropyl cetone Ebl = 79-81 n22 _ 1,444 - la (3,5-ditrifluoromethylphenyl)a-cyclopropyl f- cetoxime Ebo 7 = 82-85 - la dl (3,5-ditrifluorom~thylph~nyl) ~a-cyclopropy1) m~thylamine Ebl2 = 98-102 - son chlorhydrate fond au dessus de 250 - la N-~-chloroethyl) N'- ~ a-cyclopropyl~ (3,5-ditrifluoromethylphenyl) m~thy ~ uree fondant ~ 128-132 - la dl ~ 3,5-ditrifluoromethylphenyl) (a-cyclo-propyl) methy ~ 2-aminooxazoline ~ondant a 133-13B apr~s recristallisation de l'ether de petrole.
Analyse C15H14F6N20 = 352~27 C H N%
Calcule 51,14 4,01 7,95 Trouve 51,54 4,3 7,95 Le compose est soluble dans l'acide chlorhydr~que normal.
EXEMPLE YIII
EtudP pharmacolog~que des composes de formule generale I:
- determination de la toxicite aigue La dose lethale moyenne a ete determinée sur des lots de souris Rockland pesant 20-22 9 par inject~on ~ntr~-1~7886g peritoneale de doses ~roissante~ des produits a essayer. La dose lethale moyenne est determinee graphiquement apras avoir denombre les morts apres 8 jours d'observation. Les resultats suivants ont ~te obtenus:
- compose de l'exemple I DL~o env. lOO mg/kg - compose de l'exemple II DL50 env. 40 m9/kg - compos~ de 7'exemple III DL50 ~ mg/kg - compose de l'exemple IV DL50 ~ mg/kg - compose de l'exemple Y DL50 entre 50 et lOO mg/kg - compos~ de l'exemple YI DL50 entre 50 et lOO mg/kg - compos~ de l'exemple YII DL50 entre lOO et 200 mg/kg - recherche d'une activite neurodepressive Chez la souris la premi~re dose attestant d'une action sur le systeme nerveux central est dejà subtoxique et se situe au voisinage de 25 mg/kg par voie intraperiton~ale.
On constate une legere baisse de la motricite et une perte du tonus musculaire. Une dose de 50 mg/kg n'aggrave pas le tableau de sedation.
Les produits de l'invention ont ete compares avec un analogue structurel non trifluoromethyle. Celui-ci possède une DL50 de 30 mg/kg. La premiere dose neurosedative chez la souris est de l mg/kg par voie intraperitoneale et de 500 y/kg IP chez le rat.
Au contraire le compos~ de l'exemple II a pour effet aussi bien che~ la souris que chez le rat d'augmenter la motricite, le tonus muscualire et l'excitabilite. Il ne paraft donc pas y avoir à ces doses d'effet neurod~presseur.
- determination de l'effet anti-hypertensif L'activite anti-hypertens1ve a éte mise en evidence pour les compos~s de l'invention sur le chien rendu hypertens~
par nephroscl~rose.

~:378~9 Le produit injecte par voie ~ntraveineuse ~ des doses comprises entre 0.05 et O.S mg/kg provoque une baisse de la pression arterielle superieure à 10 mm Hg et d'une duree superieure à 1 heure. En outre on constate une diminution de la frequence cardiaque de 10 a 20X selon les doses injectees.
La presente demande est une demande divisionnaire No.
Serie 229,350 depos~e le 13 juin 1975. 3 compared to the benzyl chain.
In the definitions provided above the term lower alkyl denotes a hydrocarbon radical having from 1 to 6 carbon atoms such as methyl, ethyl, isopropyl or an n-hexyl.
The term lower cycloalkyl designates a radical saturated cyclic having 3 to 6 carbon atoms ~ possibly substituted by one or more lower alkyls such as 1,1-dimethylcyclopropyle, a 3,3,5-trimethylcyclohexane or a cyclopentyle.
The following examples illustrate llinYention. They don't limit it in any way.
EXAMPLE I
DL N- ~ -cyclopropyl) (3-trifluoromethylphenyl) methy ~ 2-aminooxazoline stage a) ~ -cyclopropyl (3-trifluoromethylphenyl) ketone We prepare the magnesium derivative of l- (trifluoromethyl3 3-bromobenzene in solution in ether from 22 ~ 9 l- (trifluoromethyl) 3-bromobenzene so as to achieve concentration of the order of 3 M. We convert the magnesian into cadmium derivative by adding 0.53 mol of cadmium chloride at 0. The mixture is then brought to reflux of the solvent for 60 minutes.
The ether is distilled and replaces as and when with a double Yolume of benzene. We then add 105 9 of cyclopropane carboxylic acid chloride drop ~ drop ~ L ~ 7 ~ 8 ~ 9 keeping the temperature of the reaction medium below of 30. After completion of the addition, the agitation is continued.
tion for one hour and then destroys the excess reagent by household addition of hydrochloric acid. After dilution ~
water, we separate the benz ~ nique phase which we wash with water, s ~ che and distilled under vacuum. Frac-tionnee 90 9 of a-cyclopropyl (3-trifluoromethylphenyl) ketone or a yield of 42X.
Eb = 115-118 nD25 _ 1.4811 The IR spectrum shows a carbonyl band.
stage b) a-cyclopropyl (3-trifluoromethylphenyl) cetoxime 75 9 8 of ~ -cyclopropyl (3-trifluoromethyl-phenyl) ketone per 78 9 of hydroxylamine hydrochloride in 280 ml of a mixture of equal parts of pyridine and ethanol at reflux for 16 hours.
62 9 of oxime are thus obtained in the form of a mixture of syn isomer and an ~ i. The product after recrystallization of the pentane melts at 60-61.
The infrared spectrum shows a hydroxyl band 3250 cm 1 and the absence of carbonyl band.
stage c) DL - cyclopropyl 3-trifluoromethylbenzylamine 61 9 of a-cyclopropyl (3-trifluoromethyl-phenyl) cetoxime in 450 ml of ether. 20% of hydride are added of lithium and aluminum and the mixture is brought to reflux for 3 hours. After removal of excess reagent and solvent ~
41 9 8 of amine are obtained, ie a yield of 65X.

- ~ 2 -~ (~ 7 ~ 3869 Ebl3 _ 106-1 ~ 0 n23 - 1.4775 The product is puri ~ ie by transformation into hydrochloride F greater than 260 (sublimation) stage d) chloroethyl) 3- ~ -cyclopropyl) (3-trifluoromethylbenzyl 4 9 3 of α-cyclopropyl m are dissolved. trifluoromethyl-benzylamine in 8 ml of tetrahydrofuran. We add 2 9 1 of isocyanate of ~ -chloro ~ thyle dissolved in 4 ml of tetra-hydrofuran at a temperature not exceeding 0. We leave stand 4 hours then distill the solvent in vacuo. We thus collects 6.2 g of urea, ie a yield of 97%. After recrystallization of a mixture of cyclohexane and benzene on obtains l (~ -chloroethyl) 3- ~ a-cyclopropyl) (3-trifluoro-methylbenzyl ~ pure urea fondant ~ 91-95.
The infrared spectrum shows a band -NH- a 3300 cm ~
stage e) DL N- ~ -cyclopropyl (3-trifluoromethylphenyl) methy ~ 2-amino-oxazoline Is suspended in 60 ml of water 14 9 of 1 ~
chloroethyl) 3- ~ a-cyclopropyl) (3-trifluoromethylbenzyl ~ uree and the mixture is brought to reflux for 30 minutes. The product is gradually dissolves. After cooling, alkalinize the clear solution by progressive addition of 4 ml of ammonia niac. The aqueous phase is exhausted with ether ~ three times, we separate the ethereal solutions that we dry and dry distilled under vacuum. The dry residue is taken up by ether isopropyl; as. 7 9 of pure fondant product are thus obtained 84-86 (yield 60 ~).

1al78869 The IR spectrum shows a bond C = N at 1685 cm 1 EXAMPLE_ dl 2 - (- cyclopropyl) 2- (3'-trifluoromethylph ~ nyl) 2-(oxazolinyl-2 'amino) ethane stage a) m ~ thyl -cyclopropyl (3-tri ~ luorom ~ thylphenyl) carbinol 107 9 of cyclopropyl (3-trifluorom ~ thyl-) are dissolved phenyl3 ketone obtained in stage a) of Example I, in 1000 ml of ether and 600 ml of a solution are added under an inert atmosphere 10 tion in methyl lithium ether 1, 65 M ~ a temperatureinferieure to -10. After addition, the mixture is left to react.
return to room temperature overnight.
Then pour the mixture over a mixture of ice and acid hydrochloric N. The aqueous phase is exhausted with ether. The organic solutions are combined and then washed with a solution sodium chloride until the wash water is . neutral. It is then dried over sodium sulfate, filtered and evaporates to dryness.
106.5 g of methyl a-cyclopropyl are thus collected.
20 (3-trifluoromethylphenyl) carbinol, ie a yield of 93%.
Ebl7 _ 123-125 nD = 1.4765 Analysis C12H13F30 ~ 230.22 C ~ 1 Calculate 62.61 5.70 Find 62.89 5.74 stage b) 2- (3'-trifluoromethylphenyl) 2- (cL-cyclopropyl) ~ thylamine To a 46 9 solution of methyl (c ~ -cyclopropyl) 30 (3-trifluoromethylphenyl) carbinol in 100 ml of t ~ trahydro-furan we have ~ 8 8 sodium hydride and we wear the mixture ~ 0788 ~

at reflux for 10 hours. Then introduced with stirring this solution in a cooled solution of 47 g of bromide of cyanogen in 50 ml of tetrahydrofuran. We now keep under stirring for 2 hours at room temperature then filter sodium bromide forms and evaporates the filtrate to dryness. The dry residue is taken up in 100 ml of m ~ thanol and brought to reflux for 12 hours. ~ a carbamate solution as well where obtained is evaporated ~ dry. The residue is then added with 10 ~ ml concentrated hydrochloric acid and heats ~ 60 for 8 hours. After basifying the mixture by adding . potash, the aqueous solution is exhausted several times from the ~ ther. We combine the phases eth ~ r ~ es which we wash with water, dries, filters and evaporates to dryness. We resume with a solution saturated with hydrochloric gas in ether. Hydrochloride 2- (3'-trifluoro ~ ethylphenyl) 2- (a-cyclopropyl) ethylamin ~
precipitate. It is separated by filtration and dried. After recrystallization of acetonitrile it melts ~ 180-lg5.
Analysis ~ 12H14F3N, ClH = 266.70 i CHN Cl ~
Calculate 54.24 5.69 5.28 13.35 Found 54.09 5.63 5.39 13.39 stage c) ~ chloroet ~ yl) 3- ~ -cyclopropyl) methyl (3'-trifluoro-methylphenyl ~ / uree By operating according to the operating mode of Example I
stage d) the urea is obtained with a quantitative yield. The product is used as is integrally for the stage next.
stage d) 3 ~ dl 2- (a-cyclopropyl) 2- (3'-trifluoromethylphenyl) 2- (oxazo-linyl-2 'amino) ethane By operating according to the operating mode of Example I

~ 788 ~; 9 stage e) the dl 2 ~ cyclo- is obtained with a yield of 75%
propyl) 2- (3'-trifluoromethylphenyl) 2- (oxazolinyl-2 'amino) ethane. The pure product melts at 11-2119.
Analysis C15Hl7F3N2 - 298 ~ 30 CHN%
Calculate 60.39 5.75 9.39 Find 60.27 6.05 9.35 EXAMPLE III
N- ~ a-cyclopropyl) (3'-trifluoromethylphenyl) m ~ thy Levogyre 2-aminooxazoline.
The synthesis is carried out at the start of the (3-tri-fluoromethyl) -cyclopropyl methylamine dextrorotatory according to the mode example I.
(3-Trifluoromethyl) ~ -cyclopropyl methylamine is split by d-tartaric acid by checking in chromato-written in vapor phase the purity of the separated optical isomer ~, using Mosher's reagent.
The following isomers are thus obtained:
- (3-trifluoromethylphenyl) -cyclopropyl methylamine dextrorotary = ~ 35.6 ~ c = l ethanol) - + l30.4 - N- ~ ~ -cyclopropyl) (3-trifluoromethylphenyl) methy ~
Levogyre 2-aminooxazoline F = 59-68 -22 _ _ 2l (c = 1% ethanol) = - 86.4 (c = l ~ ~ thanol) : 107B869 EXAMPLE IY
N- ~ -cyclopropyl) (3-trifluoromethylphenyl) methy 2-aminooxazoline dextrorotatory according to the same operating mode as in example III
obtains ~ -cyclopropyl (3-trifluoromethylphenyl) methyl-amine levogyre - - 35.8 (c _ l ethanol) _ - 129.5 (c = 1% ethanol) - (a-cyclopropyl) (3-trifluoromethylphenyl) m ~ thyl 2-aminooxazoline dextroqyre F = 59-65 - ~ 21.5 (c - i ~ ethanol) r ~ = ~ 89 (c ~ lX ethanol) EXAMPLE V
dl ~ - (3'-trifluoromethylphenyl) 2- (oxazolinyl-2) amin ~ ethane By operating according to the operating mode of example I
from 2- (3'-trifluorom ~ thylphenyl) 2-amino ethane on obtains dl 2- (3'-trifluoromethylphenyt) 2- (oxazolinyl-2 amino ethane melting at 89-94 after recrystallization;
isopropyl ~ ther. The product is soluble in acid normal hydrochloric. After ~ dry vaporization of solvan ~ on collects dl ~ - (3'-trifluoromethylph ~ nyl) hydrochloride 2- ~ oxazolinyl-2) amin ~ ethane.

~ 07 ~ 3 ~ 369 Analysis of the base: C12H13F3N2 ~ 2 = 258 ~ 23 ~ N%
Calculates 55.80 5 "30 10.82 Find 55.69 5 "23 10.78 EXAMPLE VI
dl N ~ -cyclopropyl) (3'-trifluoromethyl 4'-fluoro-phenyl) methy ~ 7 2-aminooxazoline.
By operating according to the operating mode of example I
from l-iodo 3-trifluoromethyl 4-fluorobenz ~ not obtained starting from o-chloro trifluoromethylbenzene we obtain successively:
- (3-trifluoromethyl 4-fluorophenyl) a-cyclopropyl c ~ tone Ebo 6 = 104-107 n25 - 1,4805 - (3-trifluoromethyl 4-fluorophenyl) -cyclopropyl cetoxime melting below 50 (yield 91X ~
- dl ~ 3-trifluoromethyl 4-fluorophenyl) (a-cyclo-propyl) methylamine isolated as melting hydrochloride above 250 (decomp.) - dl 1- ~ T3'-trifluorome ~ hyl 4'-fluorophenyl) (a-cyclopropyl) methy ~ 7 3- (~ -chloro ~ thyl) uree fondant at 108-111 - dl N- ¢ c ~ -cyclopropyl) (3-trifluoromethyl 4-fluorophenyl) methy ~ 7 2-aminooxazoline fondant ~ 81-87 after recrystallization of pentane.
Analysis C14H14F4N20 30 CH NX
Calculates 55.67 4.67 9.27 Found 55.83 4.77 9.32 The compound is soluble in hydrochloric acid ~ than giving rise to the hydrochloride.

1 ~ 7 ~ 9 EXAMPLE VII
dl N- ~ 3,5-ditrifluorom ~ thylphenyl) (a-cyclopropyl m ~ thyl ~ 2-aminooxazoline.
By operating according to the operating mode of example I
from l-iodo 3,5- (ditrifluorom ~ thyl) benzene obtained according to the method described in the J. of Am. Chem. Soc. 75 (1953) 4967-4969 we obtain successively:
- (3,5-ditrifluoromethyl) ~ -cyclopropyl cetone Ebl = 79-81 n22 _ 1.444 - (3,5-ditrifluoromethylphenyl) a-cyclopropyl f- cetoxime Ebo 7 = 82-85 - dl (3,5-ditrifluorom ~ thylph ~ nyl) ~ a-cyclopropy1) m ~ thylamine Ebl2 = 98-102 - its hydrochloride melts above from 250 - N- ~ -chloroethyl) N'- ~ a-cyclopropyl ~ (3,5-ditrifluoromethylphenyl) m ~ thy ~ uree fondant ~ 128-132 - dl ~ 3,5-ditrifluoromethylphenyl) (a-cyclo-propyl) methy ~ 2-aminooxazoline ~ undulating at 133-13B apr ~ s recrystallization of petroleum ether.
Analysis C15H14F6N20 = 352 ~ 27 CHN%
Calculate 51.14 4.01 7.95 Find 51.54 4.3 7.95 The compound is soluble in hydrochloric acid ~ than normal.
EXAMPLE YIII
Pharmacology study as compounds of formula general I:
- determination of acute toxicity The average lethal dose was determined on batches of Rockland mice weighing 20-22 9 per injection ~ on ~ ntr ~ -1 ~ 7886g peritoneal doses ~ increasing ~ of the products to be tested. The average lethal dose is determined graphically after count the dead after 8 days of observation. The results have obtained:
- consists of example I DL ~ o approx. 100 mg / kg - consists of example II LD50 approx. 40 m9 / kg - compound ~ of Example III LD50 ~ mg / kg - consists of example IV LD50 ~ mg / kg - consists of example Y LD50 between 50 and 100 mg / kg - composed of example YI LD50 between 50 and 100 mg / kg - compound ~ of example YII LD50 between 100 and 200 mg / kg - search for neurodepressive activity In mice the first dose attesting to a action on the central nervous system is already subtoxic and is in the vicinity of 25 mg / kg intraperitoneally.
There is a slight drop in motor skills and a loss of Muscle tone. A dose of 50 mg / kg does not worsen the sedation chart.
The products of the invention were compared with a non-trifluoromethyl structural analogue. This one has an LD50 of 30 mg / kg. The first neurosedative dose in mouse is l mg / kg intraperitoneally and 500 y / kg PI in rats.
On the contrary, the compound of Example II has the effect both in the mouse and in the rat to increase the motor skills, muscle tone and excitability. It does not appear therefore not have at these doses of neurod ~ pressure effect.
- determination of the anti-hypertensive effect Anti-hypertensive activity has been highlighted for the compos ~ s of the invention on the hypertensive dog ~
by nephroscl ~ rose.

~: 378 ~ 9 The product injects ~ intravenously ~ doses between 0.05 and OS mg / kg causes a drop in blood pressure greater than 10 mm Hg and lasting greater than 1 hour. In addition, there is a decrease in heart rate from 10 to 20X depending on the doses injected.
This application is a divisional application No.
Series 229,350 filed June 13, 1975.

Claims

The embodiments of the invention about which an exclusive right of property or privilege is claimed, are defined as follows:

1. Process for the preparation of a compound of general formula:

in which X represents hydrogen or a halogen atom or a trifluoromethyl radical;
R1 represents a lower alkyl radical or a lower cycloalkyl radical;
R2 represents hydrogen or an alkyl radical inferior;
R3 and R4, distinctly or simultaneously represented try hydrogen or lower alkyl or form together an alkylene chain having 3 to 6 atoms of carbon; and R5 represents a halogen atom or a hydroxy;
characterized in that:
A) when R5 is a halogen: a m is condensed. sorting-fluoromethylbenzylamine of general formula III:

(III) with an omega.-haloalkyl isocyanate of general formula IV:

(IV) or B) when R5 is a hydroxyl: a carbamate is condensed of general formula VI:

(VI) in which Ar is a phenyl radical or a radical substituted phenyl, with an aminoalkanol of formula general VII:

.

2. Process for the preparation of a compound of general formula:

in which X represents hydrogen or a halogen atom or a trifluoromethyl radical;
R1 represents a lower alkyl radical or a lower cycloalkyl radical;
R2 represents hydrogen or an alkyl radical inferior;
R3 and R4, distinctly or simultaneously represented try hydrogen or lower alkyl or form together an alkylene chain having 3 to 6 atoms of carbon; and R5 represents a halogen atom, characterized in that a m. trifluoromethyl-benzylamine of general formula III:

(III) with an omega.-haloalkyl isocyanate of general formula IV:
(IV)

3. Process for the preparation of a compound of general formula:

in which X represents hydrogen or a halogen atom or a trifluoromethyl radical;
R1 represents a lower alkyl radical or a lower cycloalkyl radical;
R2 represents hydrogen or an alkyl radical inferior;
R3 and R4, distinctly or simultaneously represented try hydrogen or lower alkyl or form together an alkylene chain having 3 to 6 atoms of carbon, and R5 represents hydroxy, characterized in that a carbamate of the formula is condensed general VI:

(VI) in which Ar is a phenyl radical or a substituted phenyl radical, with an aminoalkanol of the formula general VII:
(VII)

4. The compounds of the general formula:

in which X represents hydrogen or a halogen atom or a trifluoromethyl radical;
R1 represents a lower alkyl radical or a lower cycloalkyl radical;
R2 represents hydrogen or an alkyl radical inferior;
R3 and R4, distinctly or simultaneously represented try hydrogen or lower alkyl or form together an alkylene chain having 3 to 6 atoms of carbon; and R5 represents a halogen atom or a hydroxy, when prepared by the process of claim 1 or by an equivalent chemical process.

5. The compounds of the general formula:

in which X represents hydrogen or a halogen atom or a trifluoromethyl radical;
R1 represents a lower alkyl radical or a lower cycloalkyl radical;
R2 represents hydrogen or an alkyl radical inferior;
R3 and R4, distinctly or simultaneously represented try hydrogen or lower alkyl or form together an alkylene chain having 3 to 6 atoms of carbon; and R5 represents a halogen atom, when prepared by the process of claim 2 or by an equivalent chemical process.

6. The compounds of the general formula:

in which X represents hydrogen or a halogen atom or a trifluoromethyl radical;
R1 represents a lower alkyl radical or a lower cycloalkyl radical;
R2 represents hydrogen or an alkyl radical inferior;

R3 and R4, distinctly or simultaneously represented try hydrogen or lower alkyl or form together an alkylene chain having 3 to 6 atoms of carbon; and R5 represents hydroxy, when prepared by the process of claim 3 or by an equivalent chemical process.