FR2568249A1 - 1-Amino-3-aryloxy-2-propanols, processes of preparation and medicaments which contain them - Google Patents

Abstract

1-Amino-3-aryloxy-2-propanols represented by the formula in which R is the isopropyl or tert-butyl group. Application of these compounds as active principle of cardiovascular medicaments.

Description

 the present invention relates to 1-amino-3-aryloxy pro panols-2 processes for their preparation and their application in the therapeutic field.

dans laquelle R est le radical isopropyle ou tertiobutyle et X le radical méthyle ou éthyle. Le dérivé pour lequel a=CE3 et connu sous la désignation Métoprolol constitue un étalon reconnu comme principe actif dans le traitement de certaines maladies cardiovasculaires. Dans le brevet allemand 2.649.605 on trouve la descrip- tion de. produits répondant à la formule I pour lesquels X est un groupe oycloalcoylméthyle. enfin la demande de brevet PCT. WO 82.00.According to German Patent 2,106,209, compounds of formula

in which R is the isopropyl or tert-butyl radical and X is the methyl or ethyl radical. The derivative for which a = CE3 and known under the name Metoprolol constitutes a standard recognized as an active ingredient in the treatment of certain cardiovascular diseases. In German Patent 2,649,605 there is the description of. products corresponding to formula I for which X is an oycloalkylmethyl group. finally the PCT patent application. WO 82.00.

141, mentions compounds of formula I for which the constituent
X represents the methyl or cyclopropylmethyl radical and R represents the (4-methoxyphenoxy) ethylamino group.

dans laquelle R est le groupe isopropyle ou tertiobutyle.Compounds represented by the formula have been found

wherein R is isopropyl or tert-butyl.

 The presence of the trifluoromethyl group gives these products remarkable beta-blocking properties. In fact, the products of the invention possess a high intensity of action, a strong cardioselectivity and a very long duration of action.

 The pharmaceutically acceptable salts form an integral part of the invention. Particularly preferred salts are salts obtained from mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid or from organic acids such as maleic acid, fumaric acid, acid tartaric, citric acid, oxalic acid, methanesulfonic acid, acetic acid.

 Compounds having an asymmetric carbon can therefore exist as pairs of optical isomers. Each optical isomer and their mixture are part of the invention. The optical isomers can be obtained in the usual manner. For example, the racemic can be treated with an optically active acid and the mixture of the diastereomers obtained by fractional recrystallization can be separated off and the active bases can be liberated from their salts. One can also operate from aptically active starting materials.

The compounds of the invention are obtained according to the scheme

<tb> reaction <SEP> below <SEP>: <SEP>
<tb><SEP> CF3-sH2-O-CH-CH2 <SEP> OH <SEP> + <SEP> OR <SEP> + <SEP> Cl-E2-U-CH2
<tb><SEP> (III) <SEP> 0
<tb><SEP> OC2C \ REtH2
<tb><SEP> r <SEP> CS3-CH2-o-CH2 <SEP> C <SEP> 2 <SEP> \\ SEP> 9
<tb><SEP> (IV)
<tb><SEP> CF3-CH2O-E2CH2 <SEP><<SEP> OH <SEP> O-CR2-CR-CR2-NR-R
<tb><SEP> OR
<tb><SEP> (11)
<Tb>
R being the isopropyl or tert-butyl radical.

 the phenol III is treated with epichlorohydrin in an alkaline medium to give the epoxide IV which is then opened with isopropylamine or tert-butylamine to yield the derivatives of formula II. This opening is done in the presence of an excess of amine, either without solvent or in a solvent such as methanol, ethanol or isopropane.

par le trifluoro-2,2,2 éthanol en présence d'un métal alcalin comme le sodium ou le potassium ou en présence d'une base telle qu'un hydroxyde alcalin préférentiellement la potasse ou la soude. La réaction peut se faire soit en présence d'un solvant inerte comme le benzène, le toluène, le dioxanne-1,4, soit dans un grand excès de trifluoro-2,2,2 éthanol qui peut être facilement récupéré en fin le réaction.The phenol of formula III is an intermediate product forming part of the invention. It can be obtained by one of the following methods; a) treatment of (4-bromoethyl) phenol of formula V

by 2,2,2-trifluoroethanol in the presence of an alkali metal such as sodium or potassium or in the presence of a base such as an alkali hydroxide preferentially potash or sodium hydroxide. The reaction can be carried out either in the presence of an inert solvent such as benzene, toluene, 1,4-dioxane or in a large excess of 2,2,2-trifluoroethanol which can be easily recovered at the end of the reaction. .

par hydrogénation en présence d'un catalyseur comme le palladium déposé sur charbon. On opère de préférence dans un alcool de bas poids moléculaire, à température ambiante.b) Debenzylation of a compound of formula VI

by hydrogenation in the presence of a catalyst such as palladium deposited on charcoal. It is preferably carried out in a low molecular weight alcohol at room temperature.

par le trifluoro-2,2,2 éthanol.The compound of formula VI can be obtained in two different ways: i) Treatment of a derivative of formula VII

by 2,2,2-trifluoroethanol.

In formula VII, Z represents a group easily displaceable with an alkoxide and is preferably a halogen atom or a tosyl or mesyl group. The reaction is carried out in the presence of an alkali metal to generate the 2,2,2-trifluoroethylate ion. Very good results have been obtained when Z is the tosyl group, operating in the presence of sodium in an excess of 2,2,2-trifluoroethanol.

par un dérivé de formule IX CF3-OH2-Z (IX), Z ayant la signification donnée précédemment.ss) Treatment of 2- (4-benzyloxyphenyl) ethanol of formula VIII

by a derivative of formula IX CF 3 -OH 2 -Z (IX), Z having the meaning given above.

The reaction is preferably carried out in the presence of an alkali metal hydride such as sodium or potassium in N, N-dimethylformamide.

 The compounds of the invention represented by the general formula II possess very interesting properties.

The blocking effect of ss sympathetic receptors was investigated in the anesthetized or vigilant dog by studying the protection afforded by the products of the invention with respect to the voltage or chronotropic effects of isoprenaline. Isoprenaline is a stimulant of sympathetic receptors whose effects are exerted to the same degree on the 1 (essentially cardiac) and the 2 (mainly vascular and bronchial) receptors. The products of the invention have been compared with propranoyl-1-propylamino-1 (naphthylo-2-yl) -3-propanol-22 hydrochloride, which interchangeably blocks both types of receptors, as well as metoprolol 1-disopropylamino (methoxy) tartrate. 2-ethyl-4-phenoxyg-3-propanol] which is a selective blocking agent for adrenergic receptors.

Anesthetized Dog Trial: Bastard dogs are anesthetized with 30 mg / kg / IV sodium pentobarbital, placed under artificial respiration and bivagotomized. Carotid arterial pressure is measured by a pressure sensor designated under the brand name "Statham
P 23 ID "and the average heart rate using a" Gilson "brand cardiotachometer from the pressure signal Both parameters are recorded on a" Gilson "brand polygraph Intravenous injections are performed in a saphenous vein The products to be tested are injected at cumulative doses The protection conferred by the treatment was determined by the calculation of the ED 50 (doses reducing by 50% the tachycardia or hypotension to isoprenaline).

Test on the vigilant dog: This method excluding the influence of anesthesia and using the oral route of administration makes it possible to place oneself in conditions very close to those encountered in human use. Bastard dogs, weighing between 7 and 12 kg, are held in loose contention on a hammock. The average heart rate is measured and recorded with a Gilson cardiotachometer triggered by E. C. G. taken in 12. A catheter introduced into a saphenous vein allows repeated I.V. injections. Each dog receives 0.3 g / kg / I.V.

isoprenaline every 30 minutes. The products of the trial are administered as a single oral dose of 2 mg / kg immediately after the second injection of isoprenaline.

Regular injections of isoprenaline are then performed for 30 minutes in 30 minutes until the inhibition of tachycardia has fallen below 50%.

In Table I are recorded the results obtained in each of the tests described above for the products of the invention and for the selected standards.

TABLE I

<tb><SEP> inhibition <SEP> of <SEP><SEP> effects of <SEP> isoprenaline <SEP> *
<tb><SEP> PRODUCT <SEP> Dog <SEP> anesthetized, <SEP> lane <SEP> IV <SEP> Dog <SEP> vigil <SEP> lane
<tb><SEP> Of <SEP> 50 ** <SEP> (nanomoles / kg) <SEP> oral, <SEP> duration <SEP> of ac
<tb><SEP> Effect <SEP> time- <SEP> Effect <SEP> ten- <SEP>#<SEP><SEP> error <SEP> standard
<tb><SEP> trope <SEP>
<SEQUENCEID>SEP> II, R = isopropyl <SEP> 27 <SEP> [22-32] <SEP> No <SEP> of activity <SEP> 16.7 <SEP>#<SEP> 0.9
<tb><SEP> (hydrochloride)
<tb> II, R = tert-butyl <SEP> 19 <SEP> [16-24] <SEP> No <SEP> of activity <SEP> 12.5 <SEP>#<SEP><SEP> 1
<tb><SEP> (maleate)
<tb> Propranolol <SEP> 78 <SEP> [51-118] <SEP> 95 <SEP> 5.3 <SEP>#<SEP><SEP> 0.4
<tb> (hydrochloride)
<tb> Metoprolol <SEP> 66 <SEP> [46-94] <SEP> No <SEP> of activity <SEP> 4.6 <SEP>#<SEP><SEP> 0.5
<tb> (tartrate)
<tb> number of animals used for each test: 4.

* figures in parentheses are the 95% confidence limits
compounds of the invention are low in toxicity. Acute intravenous toxicity was evaluated in female Swiss mice (10 animals per day) and mortality was observed over a period of 15 days following administration of the compounds.Lethal doses 50 (LD 50) were calculated according to tiller and Tainter Proc, Soc., Biol., 1944, 57, 261). The results are given in Table II, below.

TABLE II

<SEP> Product <SEP> LD <SEP> 50 <SEP> IV <SEP> mouse <SEP> (mg / kg)
<tb><SEP>#<SEP> standard <SEP> error
<tb><SEP> II, <SEP> R <SEP> = <SEP> isopropyl <SEP> (hydrochloride) <SEP> 72 <SEP>#<SEP> 3
<tb><SEP> II, <SEP> R <SEP> = <SEP> tertiobutyl <SEP> (maleate) <SEP> 61 <SEP>#<SEP><SEP> 3
<tb> Propranolol <SEP> 31 <SEP>#<SEP><SEP> 2,5
<tb><SEP> Metoprolol <SEP> 70 <SEP>#<SEP> 2,5
<Tb>
The compounds of the invention are active ingredients of medicaments useful in the treatment or prevention of arterial hypertension, cardiac arrhythmia or angina pectoris.These medicaments may be administered orally in the form of tablets. , coated tablets or capsules, or intravenously as an injectable solution. The active ingredient is associated with various pharmaceutically compatible excipients. Daily dosages can vary from 10 to 100 mg of active principle taken orally and from 1 to 5 mg of active principle taken intravenously. Some pharmaceutical formulations are given below by way of nonlimiting examples.

- composition of a 100 mg tablet, possibly coated
. active ingredient ......................... 10 mg
. lactose 50 mg
. wheat starch ............................ 27 mg
. gelatin ................................ 2 mg
alginic acid 5 mg
. talc .................................... 5 mg
. magnesium stearate 1 mg - composition of an ampoule of injectable solution
. active ingredient ........................... 2 mg
. sorbitol ................................. 80 mg
. water for injection qs 2 ml
The following examples illustrate the invention in a nonlimiting manner. In nuclear magnetic resonance (NMR) data the following abbreviations were used: s for singlet, d for doublet, t for triplet, q for quadruplet and m for multiplet.

Example 1: 1-Isopropylamino-1- [[(trifluoro-2,2,2 ethoxy) -2 ethyl] -4-phenoxy] -3-propanol: C16H24F3NO3.

a) 1,2-Epoxy-1,2 - [[(trifluoro-2,2,2 ethoxy) ethyl] -4-phenoxy] propane
A mixture of 390 g (1.77 moles) of 2- (2-trifluoro-2-oxoethoxyethyl) -4-ethylphenol, 736.7 g (5.33 moles) of potassium carbonate and 6 l of butanone- 2 is refluxed for 1 hour. 1312 g (14.2 mol) of epichlorohydrin are then slowly added and the reflux is continued for 11 hours. After cooling, the reaction medium is filtered. The filtrate is concentrated to dryness under reduced pressure. The residue obtained is taken up in ether, washed with 2 l of 2N sodium hydroxide and then with water until neutral. The organic phase is dried over sodium sulphate and concentrated to dryness. 475 g (yield 97%) of 1,2-epoxy-1,2 - [[(trifluoro-2,2,2 ethoxy) -2 ethyl] phenoxy] are obtained -3 propane used in the next step without further purification.

NMR (CDCl3): # = 2.5-4.5 (11H, complex solid); 6.7-7.3 (4H, m) b) 1-Isopropylamino-1- [[(trifluoro-2,2,2-ethoxy) -2-ethyl] phenoxy] -3-propanol. A solution of 314.4 g (5.3 moles) of isopropylamine in 1520 cm3 of ethanol is added dropwise to a solution of 489 g (1.78 mole) of 1,3-epoxy [[(trifluoro -2,2,2 ethoxy) -2 ethyl] -4 phenoxy] -3 propane in 216u cm3 of ethanol. The mixture is stirred for 30 minutes at room temperature and then 3h30 at reflux. After cooling, it is concentrated under reduced pressure. The residue is dissolved in ethen
The solution is washed with water, dried over sodium sulphate and then evaporated to dryness. The residue is taken up in toluene and the solution obtained again evaporated to dryness under reduced pressure. The residual solid is triturated in pentane and filtered and dried. 515.9 g (yield 87%) of 1-isopropylamino-1- [[(trifluoro-2,2,2-ethoxy) -2-ethyl] -phenoxy] -3-propanol-2 melting at 61-63 ° C., a sample is obtained. Analytical is obtained by recrystallization from hexane. Mp 65-67 ° C.

Centesimal analysis: C% H% F% N% calculated 57.30 7.21 16.99 4.18 found 57.28 7.47 17.11 4.10
IR (KBr): # (OH) = 3400 cm -1
NMR (CDCl 3): δ = 1.1 (6H, d); 2.5-3.2 (5H, complex solid); 3.3 (2H, peak exchangeable with D2O) 3.5-4.4 (7H, complex solid); 6,7
Example 2: 1-Isopropylamino-1- [[(trifluoro-2,2,2 ethoxy) -2 ethyl] -4-phenol-2-propanol hydrochloride: C16H25ClF3NO3.

310 cc (3.1 moles) of hydrochloric acid (10 g) are added to a solution of 515 g (1.54 moles) of 1-isopropylamino [[(trifluoro-2,2,2 ethoxy) -2 ethyl] - 4-phenoxy-3-propanol crude obtained in Example 1.

The solution obtained is evaporated to dryness under reduced pressure. The solid residue is purified by recrystallization from acetone-diisopropyl ether in the presence of Norit. 442.5 g of hydrochloride (Yield 77%) are obtained. F = 105-106C.

Centesimal analysis: C% H% Cl% F% N% calculated 51.68 6.78 9.54 15.33 3.37 found 51.85 6.81 9.60 15.31 3.79
Example 3: 1-Isopropylamino [[(3-trifluoro-2,2,2-ethoxy) ethyl] -4-phenoxy] -3-propanol, mlaeate: C20H28F3NO7.

A solution of 2 g (0.017 mol) of maleic acid in 50 cm 3 of ethanol is added to a solution of 5.7 g (0.017 mol) of 1-isopropylamino [[(2,2,2-trifluoroethoxy)]. 2-ethyl-4-phenoxy] -3-propanol crude prepared according to Example 1. The solution obtained is concentrated to dryness under reduced pressure. Recrystallization of the residue from ethyl acetate gives 4.7 g (yield 61%) of the desired maleate. Mp 66-67 ° C.

Centesimal analysis: C% H% F% N% calculated 53.21 6.25 12.63 3.10 found 52.94 6.03 12.53 3.24
Example 4: Tertiobutylamino-1- [[(trifluoro-2,2,2 ethoxy) -2 ethyl] -4-phenoxy-2-propanol. maleate: C17H26F3NO3.

A solution of 7.9 g (0.108 mole) of tert-butylamine in 30 cm3 of ethanol is added dropwise to a solution of 10 g (0.036 mole) of 1,2-epoxy-ethanol [[(trifluoro-2) 2,2-ethoxy) -2-ethyl-phenoxy] -3 propane, obtained according to Example 1, in 45 cm3 of ethanol. The mixture is stirred for 3 h at room temperature and then heated for 4 hours. After cooling, it is evaporated to dryness under reduced pressure. The residue is dissolved in 40 cm3 of ethanol. A solution of 4.1 g (0.035 mol) of maleic acid in 20 cm3 of ethanol is added and evaporated to dryness.

Recrystallization of the residual solid from ethyl acetate-ether gave 11.2 g (Hdt 67%) of 1-tert-butylamino [2- (2-trifluoroethoxy) ethoxy] ethyl maleate. phenoxy] -3-propanol. M = 114117C.

Centesimal analysis:
C% H% F% N% calculated 54G19 6.50 12.24 3.01 found 54.46 0.40 12.49 3.01
NMR (CDCl3): # = 1.4 (9H, s); 2.8 (2H, t); 2.8-4.7 (9H, complex mass); 6.2 (2H, s); 6.7-7.3 (4H, m); 8.6 (4H, peak exchangeable by 1) 20).

Example 5 Benzyloxy-1 [[(trifluoro-2,2,2 ethoxy) -2 ethyl] -4 benzzene
C17H17F3O2.

a) Benzyloxy-1 - [(4-methyl-benenesulfonyl) -2-ethyl] benzene. To a solution cooled to 0 ° C. of 25 g (0.11 mol) of (4-benzyloxyphenyl) ethanol [prepared according to J. Van Lijke and H. D. Moed, Rec. Trav. Chim.

Netherlands, 1973, 92, 1281] in 500 cm3 of pyridine, 41.7 g (0.22 moles) of 4-methyl benzenesulfonyl chloride are added in small portions. The mixture is stirred 6E30 to 0OC, left 48 hours at this temperature and then thrown into 2 1 of water. The white solid which separates is filtered, washed with water and dried under vacuum. After recrystallization from ethanol, 38.3 g (yield 91%) of benzyloxy-1- [4- (4-methylbenzenesulphonyl) ethyl] benzene are obtained. M.p. 90.5 - 92 C.

Centesis analysis: C% H% S% C22H22O4S calculation 69.08 5.80 8.39 found 69.08 5.71 8.33
NMR (CDCl3): # = 2.4 (3H, s); 2.9 (2H, t); 4.2 (2H, t); 5.0 (2H, s); 6.8-7.8- (13H, complex mass).

b) Benzyloxy-1- [2- (2,2,2-trifluoro-ethoxy) ethyl] -4-benzene e 21 g (0.055 mole) of 1-benzyloxy-1- (4-methylbenzenesulphonyl) ethyl are added in portions. Benzene to a solution of 1.3 g (0.055 at) sodium in 125 cm3 of 2,2,2-trifluoroethanol. The reaction mixture is refluxed for 2h30. After cooling, 7Ucm3 of water are added and the mixture is extracted several times with ether. The ethereal extracts are washed with brine and dried over sodium sulphate. The ether is evaporated and the residue is treated under reflux with 50 cm3 of hexane. Insoluble material is removed by filtration. After concentrating the filtrate under reduced pressure; the residue obtained is purified by distillation. 14 g (yield 82%) of 1-benzyloxy-[9,2-trifluoro-2,2,2-ethoxy] -2-ethyl] benzene Eb0.25 = 126 ° C. The product solidifies at room temperature.

 = = 36-40 C.

NMR (CDCl3): # = 2.9 (2H, t); 3.6 (2H, t); 3.8 (2H, q); 5.1 (2H, s); 6.8-7.6 (9H, complex mass).

Example 6 Benzyloxy-1 - [(trifluoro-2,2,2-ethoxy) -2-ethyl] benzene.

3.5 g (0.012 mol) of benzyloxy-1- (2-bromoethyl) benzene [prepared according to J. Van Dijk and H. D. Moed, Rec. Trav.

Chim. Netherlands 1973, 92, 1281] to a solution of 0.28 g (0.012 at.g) of sodium in 28 cm3 of 2,2,2-trifluoroethanol. The reaction mixture is refluxed for 5 hours. After cooling, 30 cm3 of water are added and the mixture is extracted several times with ether. The ethereal extracts are washed with brine and dried over sodium sulphate. Evaporation of the ether gives a residue which is purified by chromatography on a silica column (eluent: hexane) and then vacuum distillation. 1.45 g (yield 39) of 1-benzylozy-1 [9,2-trifluoro-2,2,2-ethoxy] -2-ethylbenzene identical to that obtained in Example 5 are obtained.

Example 7: Benzyloxy-1- [2- (trifluoro-2,2,2-ethoxy) -2-ethyl] benzene.

A solution of 22.8 g (0.1 mol) of 2- (4-benzyloxyphenyl) ethanol in 120 cm3 of anhydrous N, N-dimethylformamide is added dropwise to a suspension of 4.6 g (0.105 mol). of 55% sodium hydride in 100 cm3 of anhydrous N, N-dimethylformamide. While maintaining the temperature at 30 ° C., a solution of 26.7 g (0.105 mole) of 2,2,2-trifluoroethyl paratoluenesulphonate in 40 cm3 of N, N-dimethylformamide was added to this mixture. The reaction medium is heated for 8 hours at 60 ° C. After cooling, it is thrown on ice and extracted several times with ether. The combined ether extracts are washed with brine until neutral and dried over sodium sulfate. After evaporation of the ether, the residue is purified by chromatography on a silica column (eluent: hexane). 6.5 g (yield 21%) of benzyloxy-1- (2,2,2-trifluoroethoxy) -2 are obtained. ethyl] -4 benzene identical to that obtained in Example 5.

Example 8 Benzyloxy-1 - [(2,2,2-trifluoroethoxy) -2-ethyl] benzene.

Operating as in Example 7 from 5.7 g (0.025 mol) of (4-benzyloxy-phenyl) ethanol, 1.2 g (0.027 mol) of sodium hydride and 16.1 g. (0.077 mole) of 2-iodo-1,1,1-trifluoroethane in N, N-dimethylformamide gives 1.1 g (yield 14%) of benzylosy-1 (2,2,2-trifluoroethoxy) - 2 ethyl] -4 benzene identical to that obtained in Example 5.

Example 9: [(2- (2,2,2-Trifluoroethoxy) -2-ethyl] -4-phenol: C10H11F3O2.

294.9 g (1.47 mol) 4-bromo-ethyl-4-phenol [prepared according to K. Torsell and K. ahlberg, Acta Chem. Scand.

1967, 21, 53] to a solution of 170.6 g (7.4 moles) of sodium in 3350 cm3 of 2,2,2-trifluoroethanol. The resulting mixture is refluxed for 5 hours. After cooling, the 2,2,2-trifluoroethanol is recovered in part by distillation under reduced pressure. The residue is taken up in 2.5 l of water, acidified with sulfuric acid and extracted several times with ether. ether extracts are collected, washed with brine and dried over sodium sulphate. After evaporation of the ether the residue is distilled. 154.9 g (yield 48%) of 2- [(trifluoro-2,2,2-ethoxy) ethyl] -4-phenol are obtained. Eb1 = 88900C.

Centesimal analysis: C% H% F% calculated 54.54 5.04 25.89 found 54.17 5.20 26.18
IR: # (OH) = 3400 cm-1 NMR (CDCl3): = 2.8 (2H, t); 3.8 (2H, t); 3.8 (2H, q); 5.4 (1H, peak exchangeable with CF3COOD); 6.6-7.3 (4H, m).

Example 10: 1- (2,2,2-Trifluoroethoxy) -2-ethyl-phenol.

A mixture of 560 g (5.6 moles) of 2,2,2-trifluoroethanol and 112 g (2 moles) of potassium hydroxide is heated for 1 hour at 70 ° C. 40 g (0.2 mole) are added in small portions. ) (4-bromo-ethyl) phenol and continues the heating for 1 h at 70 C and then 1 h at reflux. The reaction medium is treated as in Example 9. 27.6 g (yield 63%) of [(trifluoro-2,2,2-ethoxy) -2-ethyl] -4-phenol identical to the product obtained in Example 9 are obtained. .

Example 11: [(2- (2,2,2-Trifluoroethoxy) ethyl] -4-phenol.

A solution of 480 g (2.39 mol) of 4- (bromo-ethyl) phenol and 840 cm -1 of 1,4-dioxane is added dropwise to a mixture heated to 75 ° C. of 1217 g (12.2 g). moles) of 2,2,2-trifluoroethanol, 668g (11.9 moles) of potassium hydroxide and 360 cm3 of 1,4-dioxane. The heating is continued for 2 h at 75 ° C. The reaction medium is treated as in Example 9. 305.9 g (yield 58%) of [(trifluoro-2,2,2 ethoxy) -2 ethyl] are obtained. 4 phenol identical to the product obtained in Example 9.

Example 12: [2- [2- (2,2,4-Trifluoroethoxy) ethyl] -4-phenol
A mixture of 102 g (1.02 mol) of 2,2,2-trifluoroethanol, 56 g (1 mol) of potassium hydroxide and 30 cm3 of toluene is refluxed for 1 hour. A solution of 40 g (0.2 mole) of (4-bromo-ethyl) phenol in 90 cm3 of hot toluene is added dropwise and the reflux is continued for 2 hours. After treatment of the reaction medium as in Example 9, 22.6 g (yield 52) of [(trifluoro-2,2,2-ethoxy) -2-ethyl-4-phenol identical to the product obtained in Example 9 are obtained.

Example 13: [(Trifluoro-2,2,2-ethoxy) -2-ethyl-4-phenol.

A solution of 14.7 g (0.047 mol) of 1-benzyloxy-2- (2,2,2-trifluoroethoxy) -4-ethylbenzene in 350 cm 3 of methanol is hydrogenated under 5 atmospheres in the presence of 4 g of palladium on carbon. at 10% for 3h30. After filtration of the catalyst, the reaction medium is concentrated to dryness under reduced pressure and the residue obtained distilled under vacuum. 9.1 g (yield 88%) of 1- (trifluoro-2,2,2-ethoxy) -2-ethyl-phenol identical to the product obtained in Example 9 are obtained.

Claims (11)

1. Amino-1 arylozy-3-propanols-2 characterized by the formula:

 wherein R is isopropyl or tert-butyl, their optical isomers and pharmaceutically acceptable salts thereof.  2. Salts of 1-amino-3-aryloxy-2-propanols according to claim 1, obtained from mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid or organic acids such as maleic acid , fumaric acid, tartaric acid, citric acid, oxalic acid, methanesulfonic acid, acetic acid.  3. Process for the preparation of the compounds according to claim 1, characterized in that the phenol of formula

 by epichlorohydrin to give the intermediate epoxide of formula:

 which is then opened with isopropylamine or tert-butylamine.  4. Intermediate trifluoro (1,2,2-ethoxy) -2-ethyl-phenol-phenol in the preparation of the compounds of claim 1, according to the process of claim 3.  5. Process for the preparation of the compound according to claim 4, characterized in that (2- (bromo-ethyl) phenol is treated with 2,2,2-trifluoroethanol in the presence of an alkali metal or a alkaline hydroxide.  6. Process for the preparation of the compound according to Claim 4, characterized in that the compound is debenzylated.

 by catalytic hydrogenation.  7. Benzyloxy-1- (2,2,2-trifluoroethoxy) -2,4-ethylbenzene, an intermediate product in the preparation of the compound of Claim 4, according to Claim 6.  8. Process for the preparation of the compound according to claim 7, characterized in that a product of formula

 wherein Z represents a group easily displaceable with an alkoxide and is preferably a halogen atom or a tosyl or mesyl group, by 2,2,2-trifluoroethanol.  9. Process for the preparation of the compound according to claim 7, characterized in that the product of formula

 by a derivative of formula CF3-CH2-Z, in which Z represents a halogen atom or a tosyl or mesyl group.  10. Medicament containing as active ingredient a 1-amino-3-aryloxy-2-propanol characterized by the formula

 in which R is the isopropyl or tert-butyl group or its pharmaceutically acceptable salts, obtained from mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid or organic acids such as maleic acid, fumaric acid, tartaric acid, citric acid, oxalic acid, methanesulfonic acid, acetic acid.  11. The medicament according to claim 10, in the form of tablets, coated tablets, capsules or injectable solution.