FR2626879A1 - 1-(Aminophenyl)-2-(N-2-hydroxyethylamino)propanone derivatives, process of preparation and use in therapeutics - Google Patents

Abstract

The present invention relates to, as new industrial products, compounds chosen from: a) 1-(4-Aminophenyl)-2-(N-2-hydroxyethylamino)propanones corresponding to the formula: in which A and B, which can be identical or different, each represent H, F, Cl or Br, and R is H or CH3CO; and, b) their addition salts. These compounds are useful as antidepressants of the CNS.

Description

dans laquelle
X est NH2 on CH3CONH,
Y est un atome d'hydrogène ou d'halogène,
Z est un atome d'hydrogène ou d'halogène,
R1 est un groupe alkyle en C1-C4 ou un groupe cyclalkyle en C3-C6,
R2 est l'atome d'hydrogène ou un groupe alkyle en C1-C4,
R1 et R2, considérés ensemble, peuvent former
avec l'atome d'azote auquel ils sont liés un
groupe N-hétérocyclique de 5 à 7 scm-ets,
pouvant comporter un second hétéroatome choisi
parmi N,O et S et pouvant être substitué, ledit
groupe hétérocyclique NR1R2 étant choisi parmi
l'ensemble comprenant les groupes pyrrolidino,
moupholino, thiomorpholino, pipéridino, hexaméthylène
imino, pipérazino, 4-méthylpipérazino, 4-(2-hydroxy
éthyl)-pipérazino, 4-phénylpipérazino, 4-(p-chloro
phényl)-pipérazino; et leurs sels d'addition, en tant qu'agents antidépresseurs du système nerveux central (z). On sait également que, parmi les composés de formule Io ci-dessus, quelques produits seulement présentent en outre des propriétés cardiovasculaires et/ou immunologiques bénéfiques Voir à cet effet le brevet
EP-B-O 174 242 relatif aux composés aminés (X=NH2) et le brevet EP
B-O 138 714 relatif aux composés acétylaminés (X=CH3CONH).1- (AMINOPHKNYL) -2- (N-2-HYDROXYETHYLAMINO) -PROPANONE DERIVATIVES,
PROCESS FOR THE PREPARATION AND USE IN THERAPEUTICS
FIELD OF THE INVENTION
The present invention relates, as new industrial products, to 1- (aminophenyl) -2- (N-2-hydroxyethylamino) -propanone derivatives. It also relates to the process for preparing these products and their use in therapy.
PRIOR ART
It has been known that derivatives of 1- (aminophenyl) -2-aminopropanone of the formula have already been advocated in the past.

in which
X is NH2 on CH3CONH,
Y is a hydrogen or halogen atom,
Z is a hydrogen or halogen atom,
R1 is a C1-C4 alkyl group or a C3-C6 cyclalkyl group,
R2 is a hydrogen atom or a C1-C4 alkyl group,
R1 and R2, considered together, can form
with the nitrogen atom to which they are linked a
N-heterocyclic group of 5 to 7 scm-ss,
may include a second selected heteroatom
from N, O and S and being substitutable, said
heterocyclic group NR1R2 being chosen from
the group comprising pyrrolidino groups,
moupholino, thiomorpholino, piperidino, hexamethylene
imino, piperazino, 4-methylpiperazino, 4- (2-hydroxy)
ethyl) -piperazino, 4-phenylpiperazino, 4- (p-chloro)
phenyl) piperazino; and their addition salts as antidepressant agents of the central nervous system (z). It is also known that among the compounds of formula Io above, only a few products have, in addition, beneficial cardiovascular and / or immunological properties.
EP-BO 174 242 relating to amino compounds (X = NH 2) and the EP patent
BO 138 714 relating to acetylamino compounds (X = CH3CONH).

PURPOSE AND OBJECT OF THE INVENTION
According to the invention, new derivatives belonging to the family of 1- (aminophenyl) -2-aminopropanone derivatives are recommended, but which are structurally different from the compounds of formula Io described in EP-BO 174 242 and EP-BO 138 714 cited above, by the nature of the NR1R2 residue, namely here a 2-hydroxyethylamino residue.

 It is also recommended according to the invention a process for the preparation of these new compounds, which have particularly advantageous neuropsychopharmacological properties with regard to their properties of antidepressant agents of the central nervous system (CNS).

dans laquelle
A et B, qui peuvent être identiques ou différents, représente chacun H, F,Cl ou Br, et
R est H ou CH3CO; et,
b) leurs sels d'addition,
L'invention concerne donc des composés aminophényle (R = H) et les composés acétylaminophényle (R = CH3CO) susceptibles de comporter sur le noyau phényle un ou deux atomes d'balogène tels que le fluor, le chlore et le brome, l'atome de chlore êtant ici l'atome d'halogène préféré.The novel compounds according to the invention are characterized in that they are selected from the group comprising 1
(a) 1- (4-aminophenyl) -2- (N-2-hydroxyethylamino) propanones having the formula:

in which
A and B, which may be the same or different, each represents H, F, Cl or Br, and
R is H or CH3CO; and,
(b) their addition salts,
The invention therefore relates to aminophenyl compounds (R = H) and acetylaminophenyl compounds (R = CH3CO) which may contain on the phenyl ring one or two hydrophobic atoms such as fluorine, chlorine and bromine, the atom chlorine being here the preferred halogen atom.

In the present state of the art, aminophenyl compounds (R = H 2) are preferred to acetylaminophenyl compounds (R = CH 3 CO), in view of the intensity of their beneficial antidepressant effects.
Of particular interest according to the invention are 1- (4-amino-3,5-dichlorophenyl) -2- (N-2-hydroxyethylamino) -propanone and its addition salts, on the one hand, and especially the 1- (4-aminophenyl) -2- (N-2-hydroxyethylamino) propanone and its addition salts, on the other hand,
By addition salts is meant here acid addition salts obtained by reacting a free base of formula I with an inorganic or organic acid, on the one hand, and ammonium sals, on the other hand, Among the acids that can be used for salifying the free bases of formula I, mention may be made especially of the hydric, hydrobromic, acetic, formic, propionic, oxalic, fumaric, maleic, succinic, benzoic, cinnamic, mandelic, citric, malic and tartaric acids. aspartic, glutamic, methanesulfonic, p-toluenesulfonic. Among the compounds making it possible to obtain ammonium salts, mention may especially be made of
ICH3 and CICH3. In general, the acid addition salts, such as in particular the hydrochlorides, are preferred to the ammonium salts.

A certain number of compounds according to the invention have been recorded in no way limiting in Table I below.

TABLE I
CO-CH (CH3) -NH-CH2CH2OH

<tb><SEP> xample <SEP> No <SEP> of <SEP> Code <SEP> R <SEP> A <SEP> B
<tb><SEP> Ex <SEP> 1 <SEP> (a) <SEP> CRL <SEP> 41 <SEP> 426 <SEP> H <SEP> H <SEP> H
<tb><SEP> Ex <SEP> 2 <SEP> (a) <SEP> CRL <SEP> 41 <SEP> 427 <SEP> H <SEP> 3-C1 <SEP> 5-Cl <SEP>
<tb><SEP> Ex <SEP> 3 <SEP> (a) <SEP> - <SEP> CH3CO <SEP> H <SEP> H
<tb> Ex <SEP> 4 <SEP> (a) <SEP> - <SEP> CH3CO <SEP> 3-Cl <SEP> 5-Cl
<tb><SEP> Ex <SEP> 5 <SEP> (b) <SEP> - <SEP> H <SEP> 3-Cl <SEP> H
<tb><SEP> And <SEP> 6 <SEP> (c) <SEP> - <SEP> H <SEP> 3-C1 <SEP> H
<Tb>
Notes
(a): monohydrochloride
(b): dihydrochloride
(c): monomethanesulfonate
The compounds of formula I can be prepared according to a method known per se by application of reaction mechanisms
They can in particular be synthesized according to the operating methods described in EP-BO 174 242 and EP-BO 138 714 cited above.

où A et B sont définis comme indiqué ci-dessus, avec la 2hydroxyéthylamine de formule
HO-CH2CH2-NH2 (III) suivant un rapport moliare III/II supérieur ou égal à 4,5/1, à une température de 70 C à 100 c, pendant au moins 1 h, pour obtenir un composé de formule I où R =H; et,
2 ) si nécessaire, à soumettre ledit composé de formule I où
R = H, à une réaction d'acétylation, pour obtenir le composé de formule I où R = CH3CO.The method that is recommended here is:
1) reacting a 1- (4-aminophenyl) -2-chloropropanone of formula

where A and B are defined as indicated above, with the 2hydroxyethylamine of formula
HO-CH 2 CH 2 -NH 2 (III) in a molar ratio III / II greater than or equal to 4.5 / 1, at a temperature of 70 ° C. to 100 ° C., for at least 1 h, to obtain a compound of formula I in which R = H; and,
2) if necessary, to subject said compound of formula I where
R = H, to an acetylation reaction, to obtain the compound of formula I wherein R = CH3CO.

 Advantageously stage 1) will be carried out in suspension in water, at a temperature of 80-90 C, for one hour.

duration of 1.5-2 h, with a molar ratio III / II of about 5/1.

 In Step 2) at room temperature (15-20 C) 1 mole of compound of formula I wherein R is H with at least 3 moles of acetyl chloride in acetic acid for 8-12 h are treated.

 The compounds according to the invention have beneficial therapeutic properties. They all act as antidepressant means of the CNS, and generally have psychostimulating and / or awakening effects.

 According to the invention, a therapeutic composition which is characterized in that it contains, in association with a physiologically acceptable excipient, at least one derivative chosen from the compounds of formula 1 and their nontoxic addition salts.

Of course, in such a composition the active ingredient, namely the compound of formula I or one of its non-toxic salts, 3nterviant in pharmaceutically effective amount
According to the invention, it is therefore recommended to use a substance chosen from the group comprising: (i) the 1- (4-aminophenyl) -2- (N-2-hydroxyethylamino) propanone compounds of formula I above, and (ii) their non-toxic addition salts, for obtaining an antidepressant drug of the
CNS intended for use in human therapy with respect to depressions and depressive states.

 The best mode of implementation of the invention is to use 1- (4-aminophenyl) -2- (N-2-hydroxyethylamino) propanone and its non-toxic addition salts, in particular the monohydrochloride, as antidepressant means of the CNS.

 Other advantages and characteristics of the invention will be better understood on reading the following examples of preparation and results of pharmacological tests, all of these elements being in no way limiting but given by way of illustration. .

(Example 1 ; No de Code : CRL 41 426).PREPARATION I
Obtaining 1- (4-aminophenyl) -2- (N-2hydroxyethylamino) propanone monohydrochloride

(Example 1, Code No .: CRL 41 426).

 a) 1- (4-Acetamidophenyl) -2-chloropropanone.

 Within a mixture of 69.2 g (0.50 mol) of acetanilide and 255 g (1.50 mol) of aluminum chloride in 525 and carbon disulphide, it is poured in 1.5 hours. 118 g (0.93 mole) of 2-chloropropionyl chloride and refluxed for 1 hour the resulting reaction medium, decanted, removed the supernatant, and hydrolyzed the residue with a mixture of 1900 nil water iced and 385 ml of 4N HCl.

 The precipitate formed is isolated by filtration and then taken up in benzene which is azeotropically distilled using a Dean-Stark apparatus. After treatment of the resulting hot solution with CXA black and cooling, 102.4 g of expected product are isolated in the form of a slightly beige powder.

 Finst. (Kofler) = 120 C.

 Yield = 90.82%.

 b) 1- (4-Aminophenyl) -2-chloropropanone.

 Refluxed for 1.5 hours a mixture of 102 g (0.45 mole) of 1- (4-acetamidophenyl) -2-chloropropanone obtained as indicated above and 400 ml of 6N HCl acid. The resulting hot solution is treated with CXA black and neutralized with ammonia.

The precipitate formed is isolated by filtration and then taken up in benzene which is azeotropically distilled by means of a Dean.
Stark. After treatment with CXA black of the resulting hot solution, 65 g of expected product are allowed to crystallize and isolate in the form of a beige powder.

 Finst. (Kofler) = 100-102C.

 Yield = 78.7%.

 (c) CRL 41,426.

 A suspension of 30 g (0.163 mol) of 1- (4-aminophenyl) -2-chloropropanone obtained as indicated above and 500 g (0.817 mol) of ethamolamine of 50 ml are heated for 2 hours at 80 ° C. of water. The reaction medium is diluted with water, the precipitate formed is isolated by filtration and purified by crystallization from ethanol to give 16.7 g of 1- (4-aminophenyl) -2- (N-2). hydroxyethylamino) propanone (free base of CRL 41,426) as a slightly yellow powder.

 Finst. (Kofler) = 140 C.

 After treatment of the free base thus obtained, in anhydrous ethanol with hydrochloric ethanol, 18.1 g of expected CRL 41 426 are obtained in the form of a slightly beige powder, which is soluble in water. water at 200 g / l.

Finst. (Koffer) = about 180 C (with decomposition)
Yield (stage c) = 39.5%.

(Exemple 2 , No de Code : CRL 41 427)
a) 1-(4-Amino-3,5-dichlorophényl)-2-chloropropanone.Overall yield (stages ac) = 28.2%
PREPARATION II
Obtaining 1- (4-amino-3,5-dichlorophenyl) -2 (N-2-hydroxyethylamino) propanone monohydrochloride

(Example 2, Code No .: CRL 41 427)
a) 1- (4-Amino-3,5-dichlorophenyl) -2-chloropropanone.

Within a suspension maintained at about 70 ° C. of 33 g (0.18 mole) of 1- (4-aminophenyl) -2-chloro-propanone, obtained as indicated in Preparation Ib above, in 180 ml of OCl 4, 72 g (0.54 mole) of N-chlorosuccinimide were added in portions over 1 hour.
The reaction medium is diluted with 200 ml of chloroform, the insoluble material formed is removed by filtration and the filtrate is brought to dryness by evaporation under reduced pressure. the evaporation residue is taken up in diethyl ether, then the insoluble material is again removed as well as the solvent. The brown mass obtained is purified by crystallization in isopropanol to give 30.8 g of the expected product, in the form of a white powder
Finst. (Kofler) = 110-112 C.

Yield = 67.8%
(b) CRL 41,427.

 A suspension of 25.25 g (0.10 mol) of 1- (4-amino-3,5-dichlorophenyl) -2-chloropropanone and 30.5 g is heated to 80 ° -90 ° C. for 1.5 hours. (0.50 mole) 2-ethanolamine in 30 ml of water. The reaction medium is diluted with water and the insoluble material is extracted with ethyl acetate to give 30.7 g of 1- (4-amino-3,5-dichlorophenyl) after drying and evaporation of the solvent. 2- (N-2-hydroxyethylamino) -propanone (free base of CRL 41,427), as a tan-orange oil.

 This oil is treated in acetone with hydrochloric ethanol to pH 4. After isolation of the precipitate by filtration and then purification by hot washing in anhydrous ethanol, 10.5 g of the expected CRL 41 427 are obtained. the form of a slightly beige color powder which is soluble in water at 200 g / l.

Finst. (Kofler) = about 40 C (with decomposition)
Yield (stage b) = 33.5%.

 Total yield (stages Ia, Ib, IIa and IIb) = 16.2%.

 The results of the tests which have been performed with the compounds according to the invention are summarized below.

A. TESTS RELATING TO CRL 41 426 (PRODUCT OF EXAMPLE 1)
During the study of neuropsychopharmacological properties, CRL 41,426 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. .

 The pH of the injected aqueous solution varies depending on the concentration of CRL 41 426 as shown in Table II below.

TABLE II

<tb> Concentration <SEP> pH <SEP> of <SEP> la
<tb> of <SEP> CRL <SEP> 41 <SEP> 426 <SEP> aqueous <SEP> solution
<tb> in <SEP> the <SEP> Administration Solution <SEP>
<tb> aqueous <SEP> administration
<tb><SEP> 50 <SEP> g / l <SEP> 1.5
<tb><SEP> 25 <SEP> g / l <SEP> 2.0
<tb> 3.2 <SEP> g / l <SEP> 2.5
<tb> 0.8 <SEP> g / l <SEP> 3.0
<tb> 0.4 <SEP> g / l <SEP> 4.0
<tb> 0.2 <SEP> g / l <SEP> 4.5
<tb> 0.05 <SEP> g / l <SEP> 5.0
<tb><SEP> 0.013 <SEP> g / l <SEP> 5.5
<Tb>
I. TOXICITY
In the male mouse, the DL-O (maximum non-lethal IP dose of CRL 41,426 is greater than 256 mg / kg, and the LD-100 (minimum lethal dose for all treated animals) is less than 512 mg / kg. kg (at this dose, the death of the mice occurs approximately within 15 minutes after administration of CRL 41,426)
II.COMPORIEME
Batches of three animals were observed before, then 0.25 h, 0.50 h, 1 h, 2 h, 3 h and 24 h after administration of CRL 41 426.

We aknowledge
1) in the mouse
at doses of 2 and 8 mg / kg:
- a behavior and reactivities substantially compared
those of the control group;
at the dose of 32 mg / kg
- an excitation of short duration is manifested 1 h after
administration of the CRL 41 426
at the dose of 64 mg / kg
- an excitation, and
- stereotypes
at the dose of 128 mg / kg:
- a fleeting decrease (0.25 h) of the respiratory rate,
- an excitation for a duration of 3 hours accompanied
of stereotypes
- an increase in reactivity to touch is maintained
festant between 30 and 60 minutes after
The administration of CRL 41 426.

20) In the rat
at the dose of 1 mg / kg:
- a behavior, reactivities, a variation of the
Rectal temperature and pupillary diameter significantly
SL comparable to those in the control group;
at the dose of 4 mg / kg:
an excitation 1 h after the administration of CRL 41 426,
- a mydriasis for 3 hours which is maximum 20 to 30 minutes
after the administration of CRL 41,426;
at the dose of 16 mg / kg:
- an excitation during 2 hours accompanied by movements
stereotyped from the first to the second hours following
the administration of CRL 41 426,
- a mydriasis for 3 hours which is maximum 30 minutes
after the administration of CRL 41,426; and
at the dose of 64 mg / kg:
- an excitation during 3 hours accompanied by movements
stereotyped,
an increase in responsiveness to touch, and
a mydriasis for 3 h.

INTERACTION WITH APOMORPHINE
1) In the mouse
Lots of 6 mice receive the product to be tested by
PI 0.5 h before subcutaneous injection of 1 or 16 mg / kg of apomorphine. It is observed that at the dose of 8 mg / kg and especially at doses of 32 mg / kg to 128 mg / kg, CRL 41 426 antagonizes hypothermia induced by apomorphine.

 Moreover, CRL 41 426 does not significantly modify verticalization behaviors and stereotyped movements.

2) In the rat
The test product is administered to batches of 6 rats 0.5 h before the subcutaneous injection of 0.5 mg / kg of apomorphine.

It is observed that at a dose of 16 mg / kg, CRL 41,426 potentiates the apomorphine-induced stereotypies in the rat. This potentiation is very important at the dose of 64 mg / kg.

IV. INTERACTION WITH AMPHETAMINE
Amphetamine (2 mg / kg) is injected intraperitoneally into the batches of 6 rats 30 minutes after administration of the test product. It is noted that at the dose of 16 mg / kg and especially at the dose of 64 mg / kg, the CRL 41 426 potentiates the amphetamiuic stereotypies. For the highest dose used (64 mg / kg), the
CRL 41 426 potentiates in intensity and duration said stereotypies due to amphetamine.

V. INTERACTION WITH RESTRPINE
Four hours after the intraperitoneal injection of 2.5 mg / kg of reserpine, lots of 6 mice receive the product to be tested.

 It is found that at doses of 8 and 32 mg / kg, CRL 41 426 antagonizes reserpine hypothermia. The antagonism is very clear at the dose of 128 mg / kg of CRL 41,426. On the other hand it is observed that the reserpinic ptosis is not modified by CRL 41,426.

VI. INTERACTION WITH OXOTREMORINE
the product to be studied is administered to batches of 6 mice 0.5 h before the intraperitoneal injection of 0.5 mg / kg of oxotremorine.

1) Action on the temperature
At the dose of 8 mg / kg, and especially at doses of 32 d 128 mg / kg, the CRL 41 426 opposes 9 the hypothermic action of oxotremorine.

20) Action on tremors
At the dose of 32 mg / kg and especially at the dose of 128 mg / kg, the
CRL 41 426 reduces tremor caused by oxotremorine.

3) Actions on peripheral cholinergic symptoms
It is found that CRL 41 426 does not modify the signs of peripheral cholinergic stimulation due to oxotremorine.

VII. ACTION ON THE TEST OF THE FOUR PLATES, THE TRAC
The test is performed on batches of 10 mice, 30 minutes after the administration of the product to be studied.

 It is found that CRL 41 426 does not result in a net increase in the number of passes allowed, does not cause major motor disability and does not modify the convulsive and lethal effects of electroshock.

VIII. ACTION ON SPONTANEOUS MOTILITY
0.5 h after receiving the product to be studied, the mice (12 per dose, 24 controls) are placed in an actimeter where their motility is recorded for 30 minutes.

 It is found that at doses of 32 to 128 mg / kg, CRL 41 426 induces a significant increase in spontaneous motility in mice.

IX. ACTION ON
After having stayed for 3 weeks in each of the halves of a cage separated by an opaque partition, groups of 3 mice receive the product to be studied. Half an hour later, the two groups of the same cage are gathered by removing the partition and we note the number of fights that occur in 10 minutes.

 At doses of 8 and 32 mg / kg, CRL 41 426 increases the number of fights in mice.

X. ACTION VIX-A-VIS OF SOME DISTURBED BEHAVIORS BY MISCELLANEOUS
AGENTS
1) Motility reduced by habituation to the enclosure
It is found that at doses of 32 and 128 mg / kg, the CRL 41 426 causes a net recovery of motor activity in the sieves accustomed to its enclosure.

2) Motility reduced by hypoxic aggression
Half an hour after receiving the test product, the mice (10 per dose, 20 tes) are subjected to an acute hypobaric anoxia depression of 600 mmHg (ie approximately 8 x 104 Pa) in 90 seconds: relaxation of 45 seconds, then they are placed in an actimeter where their motility is recorded for 10 minutes.

 It is observed that, at doses of 32 to 128 mg / kg, CRL 41 426 causes an improvement in motor recovery in mice whose motility was depressed following a brief stay in a reduced pressure chamber.

3) Asphyxial anoxia
Lots of 10 mice received the test product half an hour before intraperitoneal administration of 32 mg / kg gallamine triiodetylate (reference curative agent).

 Or find that CRL 41 426 does not substantially change the onset of seizures and the onset of asphyxiated anoxia caused by a curative agent.

XI. INTERACTION WITH THE BARBITAL
Half an hour after administration of the product to be studied, batches of 10 mice receive an intraperitoneal injection of barbital (220 mg / kg).

 It is found that at the dose of 8 mgtkg, and especially at doses of 32 and 128 mg / kg, the CRL 41 426 results in a significant decrease in the barbiturate sleep juror. Antagonism is virtually complete at doses of 32 to 128 mg / kg.

XII. ACTION ON "DESPAIR
Half an hour after receiving the product to be tested, batches of 6 mice are placed in a beaker filled with water to a height of 6 cm. We note the total duration of imobility between the 2nd and 6th minutes after immersion.

 It is observed that, as of the dose of 0.5 mg / kg, the CRL 41 426 decreases the duration of immobility of the mouse placed in forced immersion. The effect is particularly clear from the dose of 8 mg / kg.

 mid.

 Lots of 6 rats receive an IP injection of CRL 41 426 or amphetamine, and are immediately placed in small bales (20 x 10 x 10 cm) where their stereotyped behavior is rated from 0 to 3 until extinction. of the effect.

 At a dose of 16 mg / kg, CRL 41,426 causes net stereotypies whose intensity is almost comparable to that obtained with 1 mg / kg of amphetamine.

 At a dose of 32 mg / kg CRL 41,426 induces net stereotypies comparable in intensity to 2 mg / kg amphetamine.

 At a dose of 64 mg / kg CRL 41,425 causes net stereotypies that are greater in intensity than 2 mg / kg of amphetamine.

XIV. CONCLDSIONS
As a result of all the neuropsychopharmacological tests as reported above, CRL 41 426 has effects
- antidepressants, objectified by the antagonism of hypothermia induced by apomorphine, reserpine and oxotremorine, and, by reducing the duration of so-called "desperation"immobility; and,
- stimulants and / or arousals, which are manifested in the rat by the presence of stereotypies, the potentiation of stereotypies caused by amphetamine and apomorphine, on the one hand, and in the mouse by an excitation, the antagonism of the barbiturate sleep, the increase in motor recovery after hyposia and the resumption of motor activity in mice accustomed to its presence, on the other hand.

 In general, the stimulating and / or awakening effects of CRL 41 426 appear at slightly higher doses than those where the antidepressant effects of said 41 426 begin to occur.

B. TESTS RELATING TO CRL 41 427 (PRODUCT OF EXAMPLE 2)
The neuropsychopharmacological study of CRL 41 427 was carried out according to the operating modalates described above for the
CRL 41,426, the CRL 41,427 being administered IP in solution in distilled water (pH 5.5) in a volume of 20 ml / kg in the male mouse and 5 ml / kg in the male rat.

I. TOXICITY
CRL 41,427 is more toxic than CRL 41,426: its LD-O is greater than 128 mg / kg and its LD-100 is less than 256 mg / kg, in male mice by IP

We aknowledge :
1) in the mouse
at doses of 1 mg / kg, 4 mg / kg and 16 mg / kg:
- a behavior and reactivities that are reasonably comparable
those of the control group;
at the dose of 64 mg / kg:
- an excitement,
- an increase in the reaction of fear, reactivity
to touch, and, muscle tone,
- an exophthalmia,
a piloerection for 2 hours,
salivation for 1 h;
at the dose of 128 mg / kg:
- convuisions,
- an exophthalmia,
- salivation.

- excitement and stereotyped movements manifesting themselves
1 h after administration of CRL 41 427
2) in rats
at doses of 0.5 mg / kg and 2 mg / kg
- a behavior, reactivities, a variation of the
Rectal temperature and pupillary diameter significantly
comparable to those in the control group
at a dose of 8 mg / kg
a mydriasis for 1 hour; and,
at the dose of 32 ing / kg:
- a mydriasis for 3 hours, the intensity of which is maximal
1 h after administration of CRL 41 427.

III. INTERACTION WITH APOMORPHTNE
1) In the mouse
At doses of 16 and 64 mg / kg, CRL 41 427 is opposed to
hypothermia induced by apomorphine. At a dose of 64 mg / kg, the
CRL 41 427 decreases the verticalization behavior but does not change the stereotypies.

2) In the rat
CRL 41,427 does not alter the apomorphine-induced stereotypies in the rat.

IV. INTERACTION WITH AMPHETAMINE
It is found that CRL 41 427 hardly modifies amphetamine stereotypies.

V. INTERACTION WITH THE RESERPINE
It is observed that at doses of 16 and 64 mg / kg, CRL 41 427 opposes reserpine hypothermia and decreases the intensity of ptosis.

VI. INTERACTION WITH OXOTREMORINE
It is found that at doses of R mg / kg, and especially 16 mg / kg, CRL 41 427 is opposed to the hypothermic action of oxotremorine.

 It is also noted that at the dose of 64 mg / kg, CRL 41 427 decreases slightly the tremor due to oxotremorine.

 Finally, it is observed that CflL 41 427 does not modify the signs of peripheral chloinergic stimulation due to oxotremorine.

VII. ACTION ON THE TESTING OF THE FOUR PLATES, TRACTION AND
ELECTRIC SHOCK
At a dose of 64 mg / kg, CRL 41 427 increases the number of passages punished and clearly opposes convulsive effects without altering the lethal effects of electroshock. At doses used, CRL 41 427 does not cause major motor disability.

VIII. ACTION ON SPONTANEOUS MUTILITY
CRL 41 427 hardly modifies the spontaneous motility of the soybean.

IX. ACTION ON AGGRESSIVE INTERGROUP
At a dose of 16 mg / kg and especially 64 mg / kg, CRL 41 427 reduces the number of fights in mice.

X. ACTION WITH RESPECT TO QUEIQUES INCLUDES @@ ENTS PE @@ TURHES BY MISCELLANEOUS
AGENLS
1) Motility reduced by habituation to the enclosure
It is found that the CRL 41 427 does not cause a resumption of motor activity in the mouse accustomed to its enclosure.

2) Motility reduced by hypoxic aggression
It is observed that at doses of 16 and 64 mg / kg, CRL 41 427 causes a marked improvement in motor recovery in mice whose motility has been depressed following a stay in a reduced pressure chamber.

3) Asphyxial anoxia
It is observed that the CRL 41 427 hardly modifies the time of onset of convulsions and death following an asphyxial anoxia caused by a curarizing agent.

XI. INTERACTION WITH BAREBITAI.

 It is found that at doses of 16 and 64 mg / kg, CRL 41 427 causes a decrease in the duration of barbiturate sleep.

XII. ACTION ON "BEHAVIORAL DISASTER"
It is noted that at the dose of 64 mg / kg, CRL 41 427 decreases the duration of the immobility of the mouse placed in forced immersion.

XIII. CONCLUSIONS
The neuropsychopharmacological study of CRL 41 427 shows:
- a predictive effect of an anti-depressive activity
- antagonism of hypothermia induced by
apomorphine, reserpine or oxotremorine,
- decrease in immobility time in the
mouse placed in forced immersion (perhaps
partially related to the stimulating component) s
- stimulating effects of frustration in mice
- excitation for 2 hours,
- improvement of motor recovery
after hypobaric hypoxia,
- decrease in the duration of barbiturate sleep,
- increase in the number of punished passages
the four-plate test, and
- peripheral alpha-adrenergic stimulation
- in the mouse: exophthalmia, piloerection,
hypersalivation, antagonism of ptosis reserpine,
antagonism of the tremor induced by the oxo,
morine;
- in the rat: mydriasis.

 CRL 41 427 therefore behaves, with regard to all these tests, as a substance endowed mainly with antidepressant effects, associated with a frustrating stimulant component.

 Clinically, CRL 41 426 has been shown to be a good antidepressant in human therapy at a daily dose of 300 to 450 mg per os (two to three doses of 150 mg each daily).

Claims (8)

 A compound belonging to the family of 1- (aminophenyl) -2-aminopropanone derivatives, characterized in that it is selected from the group consisting of: a) 1- (4-aminophenyl) -2- (N-) 2-hydroxyethylamino) propanones repudiating the formula:

 in which A and B, which may be the same or different, each represents H, F, Cl or Br, and R is H or CH3CO; and,  b) their addition salts.  2. 1- (4-Amino-3,5-dichlorophenyl) -2- (N-2-hydroxyethylamino) propanone and its addition salts.  3. 1- (4-Aminophenyl) -2- (N-2-hydroxyethylamino) propanone and its addition salts.  4. Therapeutic composition, characterized in that it contains, in combination with a physiologically acceptable excipient, at least one compound selected from the compounds of formula I according to claim 1 and their nontoxic addition salts.  5. Therapeutic use, catactérisée in that one uses a substance selected from the set comprising; (i) the compounds 1- (4-aminophenyl) -2- (N-2-hydroxyethylamino) propanones of formula I above, and (ii) their non-toxic addition salts, for obtaining a antidepressant drug CNS intended for use in human therapy for depressions and depressive states,  6. Therapeutic use according to claim 5, characterized in that 1- (4-aminophenyl) -2- (N-2-hydroxyethylamino) -propanone and its nontoxic addition salts are used.  A process for the preparation of a compound of formula I according to claim 1, said process being characterized in that it consists  1) reacting a 1- (4-aminophenyl) -2-chloropropanone of formula

 where A and B are defined as indicated above, with the 2hydroxyethylamine of formula HO-CH 2 CH 2 -NH 2 (III) in a III / II molar ratio greater than or equal to 4.5 / 1, at a temperature of 70 ° C. to 100 ° C., for at least 1 h, to obtain a compound of formula I in which R = H; and,  2) if necessary, to subject said compound of formula I where R = H, to an acetylation reaction, to obtain the compound of formula I wherein R = CH3CO.  8. Process according to claim 7, characterized in that, in stage 1) the reaction of II with III is carried out in suspension in water, at a temperature of 80-90 C, for a period of 1.5- 2 h, with a molar ratio III / II of about 5/1.