FR2537132A1 - New sulphur-containing 2-amino-1-phenyl-1-ethanol derivatives, their therapeutic use and process for preparing them - Google Patents

Abstract

The present invention relates to: i. the sulphur-containing 2-alkylamino-1-phenyl-1-ethanol derivatives of general formula (where R is i-C3H7 or t-C4H9 and X is S, SO or SO2); and, ii. their addition salts, as new industrial products. These new products are useful in therapy.

Description

NOVEL 2-AMINO-1-PHENYL-I-ETHANOL SULFUR DERIVATIVES, USE
THERAPEUTIC METHOD AND PREPARATION METHOD.

 The present invention relates, as industrial products, to novel sulfur derivatives of 2-amino-1-phenyl-1-ethanol. It also relates to the use in therapy and the method of preparation of these products.

 It has been found that the compounds of formula I below and their addition salts are of therapeutic interest, especially as ss-blocking agents useful in the treatment of disorders of the cardiovascular system. These compounds also have interesting properties on the central nervous system (CNS).

According to the invention, a new sulfur derivative of 2-amino-1-phenylethanol is recommended, characterized in that it is chosen from the group consisting of
(i) sulfur derivatives of 2-alkylamino-1-phenyl-1-ethanol
responding to the general formula

(where R is i-C3H7 or t-C4H9 and X is S, SO or SO2), and
(ii) their addition salts.

By addition salts is meant here the addition salts
of acids obtained by reaction of a free base of formula I with
a mineral or organic acid, and ammonium salts.

Among the acids that can be used for salifying the bases of formula I, mention may be made especially of hydrochloric acid and hydrobromic acid,
acetic, propionic, oxalic, fumaric, maleic, succinic,
benzoic, cinnamic, mandelic, citric, malic, tartaric,
aspartic, p-toluenesulfonic and methanesulfonic. From
compounds which make it possible to obtain ammonium salts, mention may be made
including ICH3 and C1CH3. The acid addition salts are the
preferred salts.

Table I shows a number of
derivatives according to the invention in no way limiting.

TABLE I

<tb><SEP> PRODUCT <SEP> NODE <SEP> CODE <SEP> X <SEP> R
<tb> EX.I <SEP> (a) <SEP> CRL <SEP> 40850 <SEP> S <SEP> i-C3H7
<tb> Ex.2 <SEP> (a) <SEP> CRL <SEQ> 41026 <SEP><SEP> S <SEP> t-C4Hg
<tb> Ex.3 <SEP> (a) <SEP> CRL <SEP> 41029 <SE> SO <SEP> i-C3H7
<tb> Ex.4 <SEP> (a) <SEP> t <SEP> N / A <SEP><SEP> t-C4H9 <SEP>
<tb> Ex.5 <SEP> (a) <SEP> CRL <SEP> 40851 <SE> SO2 <SEP> i-C3H7
<tb> Ex.6 <SEP> (a) <SEP> - <SEP><SEP> SO2 <SEP> t-C4H9
<tb> Note
<tb><SEP> (a) <SEP> = <SEP> hydrochloride
<Tb>
The compounds of formula I can be prepared according to a method known per se by application of conventional reaction mechanisms. The process which is advocated herein consists in: 10) reacting a sulfur α-bromoacetophenone of formula

(où X et R sont définis comme ci-dessus), puis 2 ) à réduire 1 > 1' -alkylamino-acetophénone soufrée IV ainsi obtenue au moyen de NaBH ,en quantités stoechiométriques, dans un alcool en
4 C1-C2 , en présence de NaOH, à une température comprise entre -5 et +200C pendant au moins une heure.(where X is defined as above with an amine of formula
NH 2 R (III) (where R is defined as above), at least 2 moles of III
for 1 mole of II in an inert solvent, in particular chosen from
methanol, ethanol and ethyl acetate at a
less than or equal to 300C, to obtain an alpha-alkylamino-aceto
sulfur phenone of formula

(where X and R are as defined above), and then 2) to reduce the thus obtained 1>1'-alkylamino-acetophenone IV by means of NaBH, in stoichiometric amounts, in an alcohol.
C1-C2, in the presence of NaOH, at a temperature between -5 and + 200C for at least one hour.

 Of course, it is also possible to obtain the "sulfinyl" (X = SO) and "sulphonyl" (X = SO 2) derivatives from the corresponding "thio" derivative (X = S), by oxidation using H 2 O 2.

This method is interesting from the point of view of the reaction yields for obtaining the products of Examples 3 and 4 from the products of Examples 1 and 2 respectively.

qui donne de bons rendements en ce qui concerne l'obtention des dérivés "sulfonyle".The compounds according to the invention can also be obtained according to the mechanism

which gives good yields in terms of obtaining "sulfonyl" derivatives.

 According to the invention, it is recommended a therapeutic composition which is characterized in that it contains, in association with a physiologically acceptable excipiert, at least one compound of formula I in which one of its non-toxic salts, as an ingredient active. In such a composition, the active ingredient will, of course, occur at a pharmaceutically effective dose.

 Other advantages and characteristics of the invention will be better understood on reading the following nonlimiting examples of preparation, but given by way of illustration, on the one hand, and of pharmacodynamic tests, on the other hand share.

PREPARATION I
Obtaining I- (4-methylthiophenyl) L 2 -isopropylamino-1-ethanol hydrochloride).

(example 1, code N: CRL 40850)
a) P-methylthioacetophenone.

Within a solution maintained at 00C of 43.4 g
(0.350 mole) of thioanisole and 30.2 g (0.385 mole) of chloride
of acetyl in 400 ml of CS2, 53.7 g (0.402 mol) of aluminum chloride are added in portions over a period of 20 minutes. The reaction mixture is stirred for 1 hour at room temperature (15-200 ° C.).
then 1.5 hours between 30 and 400C and thrown on a mixture of
750 g of ice-and 300 ml of 4N hydrochloric acid.

The organic phase is decanted, washed with water, dried
on dry sodium sulphate, and the solvent is evaporated to give
57 g of a light gray powder. After purification
by recrystallization from petroleum ether-cyclohexane (3: 1) v / v 50.2 g (yield = 86.4%) of p-methylthioacetophenone
presenting in the form of a white powder. Finst. (K3fler) = 820C.

 b) go-Bromo-pmethylthioacetophenone.

In a solution maintained at 5 ° C. of 10 g (0.0602 mol) of p-methylthioacetophenone in 75 ml of diethyl ether.
and 40 ml of tetrahydrofuran, in the presence of a
aluminum chloride and under nitrogen atmosphere, poured in 1.25 h
9.7 g (0.0602 moles) of bromine. It is then stirred under a bubbler
nitrogen for 0.75 h at room temperature (15-20 C) and
brings to dryness under reduced pressure. The residue thus obtained is
purified by recrystallization from anhydrous ethanol to give
10.6 g (72% yield) of O-bromo-p-methylthioacetophenone is
presenting in the form of a pale yellow powder.

 Finst. (Köfler) = 65 C.

 c) α-isopropylamino-β-methylthioacetophenone hydrochloride.

In a solution of 4.72 g (0.080 mole) of isopropyl
amine in 25 ml of ethyl acetate is poured in 35 minutes, without
exceed 300C, a solution of 10 g (0.040 mol) of dR-bromo-p-methylthioacetophenone in 50 ml of ethyl acetate. It is then stirred for 0.5 h at room temperature, the insoluble material is removed by filtration, the filtrate is washed with water and dried over dry sodium sulphate. After acidification of the organic phase with hydrochloric ethanol, 7.85 g (yield = 75.5%) of alpha-isopropylamino-p-methylthioacetophenone hydrochloride in the form of a pale yellow powder are isolated. Ends. (Kofler) 2300C (with decomposition).

 d) CRL 40850.

 In a suspension maintained at -50 ° C. of 10 g (0.0385 mol of isopropylamino-p-methyl thioacetophenone hydrochloride and 1.55 g (0.0385 mol) of sodium hydroxide in pellets in 75 ml of methanol. 1.46 g (0.0385 mol) of NaBH 4 are added in portions over 0.5 hours, the mixture is stirred for 1 hour at room temperature, the reaction medium is acidified with dilute hydrochloric acid and the reaction medium is acidified. The residue thus obtained is taken up with water and the solution obtained liberates, after alkalinization with diluted sodium hydroxide, 8.5 g of] - (4-methylthiophenyl) -2-isopropylamino ethanol under the shape of a white powder Finst. (Köfler) = 950C.

 The free base is dissolved in diethyl ether and tetrahydrofuran; the solution thus obtained is treated with carbon black (black CXA) then acidified with hydrochloric ethanol.

The precipitate obtained is purified by recrystallization from acetonitrile to give 8 g (yield of stage d) = 79.5%; overall yield = 37.34%) of CRL 40850 in the form of a white powder soluble in water. F. ins t. (Kofler) = 1210C.

PREPARATION II
Obtaining 1- (4-methylthiophenyl) -2-tert-butylamino-1-ethanol hydrochloride.

(example 2, code N: CRL 41026)
a) α-tert-butylamino-β-methylthioacetophenone hydrochloride.

 In a solution of 20 g (0.081 mol) of α-Bromo-β-methylthioacetophenone in 125 ml of ethyl acetate, a solution of 11.9 g (0.163 mol) of tert-butylamine in 25 ml of ethyl acetate. The precipitate is filtered off and the filtrate is washed with water. The organic phase is dried over dry sodium sulphate and then treated with hydrochloric ethanol to give 16.8 g (yield = 75%) of α-tert-butylamino-β-methylthioacetophenone hydrochloride in the form of a white powder, isolated by filtration.

F. t. (Kofler) = 2600C (approximately).

 inst.

(b) CRL 41026
In a solution maintained at 0 ° C. of 10 g (0.036 mol) of α-tert-butylamino-β-methylthioacetophenone hydrochloride in 100 ml of methanol, 3.6 ml of 10N NaOH are then run in, followed by 1.4 g (0.036 moles) of NaBH4 were collected over 10 minutes.

The mixture is stirred for 2 hours at room temperature (15-20 ° C.), acidified with 4N hydrochloric acid and the methanol is evaporated off under reduced pressure. The residue is taken up in water and the resulting solution is alkalinized with 4N sodium hydroxide; the precipitate formed is extracted with ethyl acetate. The organic phase is dried over dry sodium sulphate and treated with hydrochloric methanol to give 7.15 g (Yield: 72%) of CRL 41026 in the form of a white powder soluble in water. water. Finst. (Köfler) = 243 C.

PREPARATION III
Obtaining 1- (4-methylsulfinylphenyl) -2 isoEroEylamino-1-ethanol hydrochloride.

(Example 3, Code No .: CRL 41029).

 A mixture of 5.3 g (0.0202 mol) of 1- (4-methylthiophenyl) -2-isopropyl-amino-1-ethanol hydrochloride (CRL 40850), of 2, is stirred for 3 hours at 15 ° to 200 ° C. 3 ml (0.0230 mol) of H 2 O 2 at 110 volumes and 40 ml of acetic acid. It is brought to dryness under reduced pressure and the residue thus obtained is taken up with ethyl acetate. After stirring and filtration, 5.5 g (yield = 98%) of CRL 41029 is obtained in the form of a white powder soluble in water. Finst (Köfler) = 1520C.

PREPARATION IV
Obtaining 1- (4-methylsulfonylphenyl) -2-isopropylamino-1-ethanol hydrochloride.

(Example 5 - Code No. CRL 4Q851)
a) &alpha; -Bromo-p-methylsulfonylacetophenone.

Within a mixture maintained at 250C of 21 g (0.106 mol) of p-methylsulfonylacetophenone (F = 1280C) and AlCl3 in 250 ml of tetrahydrofuran, is run under a nitrogen atmosphere in 2 hours.
17 g (0.106 mol) of bromine. The stirring of nitrogen is then continued for 1 hour, and the reaction medium is brought to dryness under reduced pressure. The evaporation residue is purified by recrystallization with treatment with carbon black (CXA black) in anhydrous ethanol to give 18 g (yield = 61.3%) of α-bromo-p-methylsulphonylacetophenone under the form of a white Finst powder. (Köfler) = 127 C.

 b) 2-Bromo-1- (4-methylsulfonylphenyl) -1-ethanol.

 Within a suspension maintained between -5 ° C. and 0 ° C. of 16.8 g (0.0606 mol) of α-Bromo-β-methylsulphonylacetophenone in 100 ml of methanol, the fractions are introduced in 0.75 hours. 4 g (0.0606 mol) of NaBH4. The mixture is stirred for 1 h at 0 ° C., acidified with acetic acid and the methanol is eliminated under reduced pressure.

The evaporation residue is taken up in water and the precipitate isolated by filtration to give 14.6 g (yield = 86.35%) of 2-bromo-1- (4-methylsulfonylphenyl) -1-ethanol. presenting in the form of a white powder. F. (Köfler) = 1400C.

c) Cru 40851
Stirring is carried out for 1 hour at room temperature (15 ° C. to 200 ° C.) and then for 2 hours under reflux, a mixture of 13.3 g (0.0476 mol) of 2-bromo-1- (4-methylsulfonylphenyl) -1-ethanol and 11.2 g (0.1904 moles) of isopropylamine in 75 ml of anhydrous ethanol. The reaction medium is brought to dryness under reduced pressure, taken up in ethyl acetate and the precipitate is removed by filtration. The filtrate is brought to dryness, the evaporation residue thus obtained is dissolved in anhydrous ethanol and treated with hydrochloric ethanol. The resulting suspension is heated to reflux, treated with carbon black (CXA black) and allowed to crystallize in the cold. The isolated precipitate is further purified by recrystallization from acetonitrile to give 7.6 g (yield = 54.4%). %) of CRL 40851 in the form of a white powder soluble in water. F.inst. (Köfler) = 165 C then 185 C.

 The tests which have been undertaken with the products according to the invention are summarized below.

I - TESTS RELATING TO CRL 40850
A - TOXICITY AND ACTION ON THE CNS
In these tests, CRL 40850 (product of Example 1), in solution in distilled water, was administered intraperitoneally in a volume of 20 ml / kg in the male mouse and 5 ml / kg in the male rat.

1) Toxicity
In the male mouse, the LD-O (maximum non-lethal dose) by IP is greater than 64 mg / kg, and the LD-50 I, P. is of the order of 115 mg / kg.

20) CNS Action
In the mouse, CRL 40850 was found to cause sedation and a decrease in respiratory rate for 1 hour at 32 mg / kg IP on the one hand, and hypothermia (-1.3 C) for 0, 5 pm, on the other hand.

 In rats it is observed that CRL 40850 induces at the dose of 16 mg / kg I.P. a fleeting decrease (0.5 h) of the reactivity to the touch and a mydriasis of a duration of 1 h.

Furthermore, besides sedation and hypothermia, CRL 40850 causes hypomotility in animals and worsens the hypothermic effect of apomorphine, reserpine and, above all, oxotremorine. Finally,
CRL 40850 moderately potentiates stereotypies due to amphetamine.

B - ACTION ON THE CARDIOVASCULAR SYSTEM 1 ") In the anesthetized dog
Two dogs anesthetized with nembutal receive CRL 40850 intraduodenally at successive doses of 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 2.5 mg / kg, 5 mg / kg and 10 mg / kg.

Blood pressure, heart rate, femoral arterial flow, vertebral arterial flow, rectal temperature are measured. The coloration of the skin and the coloration of the bile collected by catheterization of the bile duct are observed after ligation of the cystic.

 It is found that CRL 40850 is devoid of any femoral and vertebral vasodilator action; on the contrary, it significantly decreases the flow rates of the femoral and vertebral arteries. Proportional bradycardia appears from 1 mg / kg; at 10 mg / kg, this effect lasts more than one hour.

Diastolic blood pressure and mean arterial pressure are not altered, but systolic blood pressure and differential blood pressure are decreasing.

 It is also noted that the effects of isoprenaline are decreased after the cumulative dose of 19.1 mg / kg CRL 40850.

Thus vis-à-vis I g / kg of isoprenaline, blood pressure rose from 60 mmHg (approximately 8 x 103 pascals), before administration of CRL 40850, to 100 mmHg (or about 1.33 x 104 pascals) , after administration of said CRL 40850, and the heart rate goes from 245 beats / minute before administration of CRL 40850 to 135 beats / minute, after administration of said CRL 40850.

20) In the normotensive rat anesthesia
Normotensive rats are anesthetized with pentobarbital (75 mg / kg IP) and atropineous (1 mg / kg IP). Their carotid arterial pressure, their heart rate, are measured by integration of the arterial pressure. A jugular vein is catheterized for injections. If necessary, anesthesia is maintained by subcutaneous injection of pentobarbital.

a) Determination of the -blocking dose
Three rats received CRL 40850 intravenously at successive doses of 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg and 30 mg / kg. The dose which blocks the tachycardia induced by 0.03 / g / kg of isoprenaline is determined (the dose necessary to obtain a 30-50 beats / minute increase in heart rate),
that is 3 mg / kg IV of CRL 40850.

b) Duration of the actionv-bloguante
5 rats received 3 mg / kg CRL 40850 intravenously. It is observed that - the diastolic blood pressure is not modified and is close
90 mmHg (ie approximately 1.2 x 104 pascals), and - the heart rate changes, in 5 minutes, from 340 to 304 beats
per minute (a variation of -11%) then progressively
to regain its initial value at 90 minutes.

In these 5 rats, the administration of isoprenaline (0.03 μg / kg) raises the blood pressure from 90 mmlig (approximately 1.2 x 104 pascals) to 64 mmllg (approximately 8.53 x 103 pascals). ) and heart rate from 340 to 386 beats / minute; the administration of CRL 40850 after isoprenaline leads to a change in blood pressure of + 10 mmllg
(ie about 1.33 x 103 pascals) - that is, a variation of -61% over controls - for 1 h, and + 16 ngHg (or about 2.13 x 103 pascals) - c that is, a variation of -38% compared to the controls - at 1.5 h and 2 h, on the one hand, and an inhibition of tachycardia for 5 minutes, the tachycardia returning to 50% of its value at time 15 minutes, on the one hand, and 86% of its value at time 2 hours, on the other hand.

 In 5 rats treated with saline in place of CRL 40850, arterial pressure remained constant and isoprenaline-induced hypotension decreased by 40% in the course of the study. I-induced tachycardia isoprenaline remaining constant during the 2 hours of observation.

In conclusion, CRL 40850 presents in the normotensive anesthetized rat an effect / 9 30) Isolated guinea pig atrium
Two guinea pig isolated right atria were used to determine the CRL 40850 pA2 against the chronotropic effect of isoprenaline; after 15 minutes of contact, the average of the pA2 is 6.61 (for propanolol, product
p-reference blocker, the average of pA2 is 8.19).

 On these atria, the inotropic and chronotropic action of CRL 40850 is evaluated. It is observed that at low concentrations, CRL 40850 is stimulating and becomes ino and chrono at the highest concentration.

40) Cclusion of tests on the cardiovascular system
At a dose of 3 mg! Kg IV in the anesthetized rat, CRL 40850 - is not hypotensive, - is bradycardic: the immediate bradycardic effect can be
considered valid (variation of the heart rate of
- he %) ; however, the duration of this effect can not
be, given the bradycardia due to the maintenance of
anesthesia, - decreases the hypotensive action of isoprenaline, - decreases the tachycardic action of isoprenaline and even
hangs for 5 minutes; half of the tachycardic effect
is restored at 15 minutes, and 86% at 120 minutes.

 CRL 40850 is bradycardic and decreases isoprenaline tachycardia by more than 50% for 15 minutes at a dose of 3 mg / kg. It is a competitive antagonist of the positive chronotropic effect of isoprenaline in the isolated right guinea pig atrium and has a stimulating effect at low concentrations. In addition, the CRL 40850 has an effect / not insignificant.

II - TESTS RELATING TO CRL 41026
-A - TOXICITY AND ACTION ON THE CNS
In these tests CRL 41026 (product of Example 2), in solution in distilled water (at pH 5), was administered IP in a volume of 20 ml / kg in male mice and ml / kg in male rat I "> Toxicity
In the male mouse the LD-O is greater than 64 mg / kg IP and the LD-50 is of the order of 140 mg / kg IP

20) CNS Action
CRL 41026 causes hypothermia at high dose (32 mg / kg) and worsens apomorphine, oxotremorine and reserpine-induced hypothermia (32 and 8 mg / kg). It decreases intergroup aggression in mice.

 Paradoxically, at a high dose, CRL 41026 opposes the hypnogenic action of barbital and decreases the immobility of "despair". Moreover, it leads to a clear potentiation of amphetamine stereotypies.

B - ACTION ON THE CARDIOVASCULAR SYSTEM
CRL 41026 has been studied in normotensive anesthetized rats, genetically hypertensive awake rats, and isolated guinea pig atria. Only 19) in normotensive anesthetized rats, CRL 41026 at dose
10 mg / kg IV

- is moderately hypertensive (+ 14%)
- is bradycardic (variation of the frequency
-22% heart rate at 5 and 10 minutes)
- decreases the hypotensive action of isoprenaline,
but this effect must be considered in relation to the
spontaneous decrease observed in the controls,
- decreases the tachycardic action of isoprenaline
and even blocks it at time 5 minutes
half tachycardic effect of isoprenaline
is restored at time 10 minutes, and 75% at the time
30 minutes 20) in the genetically hypertensive awake rat, CRL 41026
at the dose of 20 mg / kg per os is moderately hypotensive and
clearly bradycardic; and 30) on the isolated guinea pig atrium, CRL 41026 shows competitive isoprenaline antagonist (effect ss) with pA2
average of 6.52.

III - TESTS RELATING TO CRL 41029
The toxicity and CNS action with CRL 41029 (product of Example 3) was summarized below. In these tests, the product to be studied, in solution in distilled water (pH 5), was administered intraperitoneally in a volume of 20 ml / kg in the male mouse and 5 ml / kg in the male rat.

1e) Toxicity
LD-O in mice is greater than 512 mg / kg
IP and LD-50 is in the range of 1000 mg / kg IP 20) CNS action
At doses of 8 to 16 mg / kg, CRL 41029 causes hypothermia (and worsens the hypothermic effect of apomorphine, reserpine or oxotremorine), on the one hand, and decreases motor activity spontaneous mouse, on the other hand
In addition, the CRL 41029 causes a significant decrease in the duration of immobility test "desperate behavioral" and this paradox remains, for the moment, unexplained. Finally,
CRL 41029 strongly potentiates amphetamine stereotypies.

IV - TESTS RELATING TO CRL 40851
A - TOXICITY AND ACTION ON THE CNS
In these tests CRL 40851 (product of Example 5), in solution in distilled water, was administered by IP

in a volume of 20 ml / kg in the male mouse and 5 ml / kg in the male rat.

10) Toxicity
In the male mouse, DL-O is greater than
512 mg / kg IF and DI.-5Q is of the order of 1000 mg / kg IP

2 ") CNS Action
CRL 40851 has sedative and hypothermic effects
and aggravates the hypothermia induced by apomorphine,
reserpine and oxotremorine. In addition, it leads to a potentialisa
net of amphetamine stereotypies.

B - ACTION ON THE CARDIOVASCULAR SYSTEM
1) In the dog anesthesia
Two dogs anesthetized with nembutal receive the
CRL 40851 intraduodenally, at successive doses of 0.1 mg / kg,
0.5 mg / kg, 1 mg / kg, 2.5 mg / kg, 5 mg / kg and 10 mg / kg. We measure the
blood pressure, heart rate, arterial flow
femoral, vertebral arterial flow, rectal temperature. We
observe the coloring of the skin and the coloring of the bile
collected by catheterization of the common bile duct after ligation
cystic.

We can see that CRL 40851 has no action
femoral and vertebral vasodilator and hypotensive action
only a dose-dependent bradycardia effect is observed
from the dose of 2.5 mg / kg.

It is also observed that the effects of isopre
studied after the cumulative dose of] 9.1 mg / kg CRL 40851
are decreased on diastolic blood pressure and frequency
heart. Thus the dose of 3 / rcg / kg IV of administered isoprenaline
after CRL 40851, decreases diastolic blood pressure at
80 mmHg (about 1.06 x] 04 pascals) instead of 54 mmHg (approximately
7.20 x 103 Pascals), on the one hand, and raises the heart rate
at 182 beats / minute instead of 230 beats / minute.

20) In the genetically hypertensive awake rat
Six genetically hypertensive patients with implanted femoral arterial catheters receive CRL 40851 at a dose of 20 mg / kg and then 40 mg / kg orally.

At the doses administered, it is observed that the
CRL 40851 is devoid of activity on arterial pressure and heart rate spontaneously hypertensive rat awake.

Clinically, good results have been obtained in humans by applying the following dosages - for CRL 40850 (product of Example 1): 1 capsule containing
10 mg of active ingredient, three times daily; for CRL 41029 (product of Example 3): 2 capsules containing
each 30 mg of active ingredient, 1 to 3 taken per
day; and - for CRL 40851 (product of Example 5): 1 to 2 capsules
each containing 25 mg of active ingredient, 1 to 3 times
per day.

Claims (9)

A novel sulfur derivative of 2-amino-1-phenyl-1-ethanol characterized in that it is selected from the group consisting of  (i> sulfur derivatives of 2-alkylamino-1-phenyl-1  ethanol corresponding to the general formula

 (ii) their addition salts.  (where R is i-C3H7 or t-C4Hg and X is S, SO or SO2); and, 2. 1- (4-Methylthiophenyl) -2-isopropylamino-1-ethanol and its addition salts. 3. 1- (4-Methylthiophenyl) -2-tert-butylamino-1-ethanol and its addition salts. 4. 1- (4-Methylsulfinylphenyl) -2-isopropylamino-1-ethanol and its addition salts. 5. 1- (4-Methylsulphinylphenyl) -2-tert-butylamino-1-ethanol and its addition salts. 6. 1- (4-Methylsulfonylphenyl) -2-isopropylamino-1-ethanol and its addition salts. 7. 1- (4-Methylsulfonylphenyl) -2-tert-butylamino-1-ethanol and its addition salts. 8. Therapeutic composition characterized in that it contains, in combination with a physiologically acceptable excipient, at least one sulfur derivative of 2-alkylamino-1-phenyl-1-ethanol of formula I according to claim 1 or one of its non-toxic addition salts. 9. Process for the preparation of a sulfur derivative of 2-alkylamino-1-phenyl-1-ethanol of formula I according to claim 1, said process being characterized in that successively  1 ") a sulfur-containing o (-bromoacetophenone of formula

 (where X is defined as above with an amine of formula  NH 2 R (III) (where R is defined as above), in a proportion of at least 2 moles of III to 1 mole of II, in an inert solvent especially chosen from methanol, ethanol and acetate of ethyl, at a temperature of less than or equal to 300C, to obtain a sulfurized alkyl-amino-acetophenone of formula

 1 h.  temperature between - 5 and + 200C for at least  in a C1-C2 alcohol, in the presence of NaOH at a  obtained by means of NaBH4 in stoichiometric quantities,  (where X and R are defined as above), then 20) the sulfur-containing o (-alkylamino-acetophenone IV as well as