FR2626880A1 - N-Substituted derivatives of 2-amino-1-phenylpropanone, process of preparation and use in therapeutics - Google Patents

Abstract

The present invention relates to, as new industrial products, 1-(4-hydroxyphenyl)-2-(3,3,5-trimethylhexahydroazepino)propanone, 1-(3,5-dichloro-4-hydroxyphenyl)-2-isopropylaminopropanone and 2-hexamethyleneamino-1-phenyl-2-methylpropanone, on the one hand, and their addition salts, on the other hand. These new products are useful in therapeutics.

Description

2-AMINO-1-PHENYLPROPANONE N-SURSTTTUE DERIVATIVES, PROCESS FOR
PREPARATION AND USE IN THERAPEUTICS
FIELD OF THE INVENTION
The present invention relates as products
new industrial compounds belonging to the family of
N-substituted derivatives of 2-amino-1-phenylpropanone of formil I ci
after. It also relates to the process for preparing these products and their use in therapy.

dans laquelle
X est NH2 ou 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
cycloalkyle 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 b 7 sommets,
pouvant comporterun 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,
morpholino, thiomorpholino, pipéridino,
hexaméthylèneimino, pipérazino, 4-méthyl
pipérazino, 4-(2-hydroxyéthyl)-pipérazino,
4-phénylpipérazino, 4-(p-chlorophényl)-pipérazino ; et leurs sels d'addition, en tant qu'agents antidépresseurs. du système nerveux central (SNC). 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).PRIOR ART
We know that in the past we have already recommended derivatives of
1- (Aminophenyl) -2-aminoproanone of formula

in which
X is NH2 or CH3CONH,
Y is a hydrogen or halogen atom,
Z is a hydrogen or halogen atom,
R1 is a C1-C4 alkyl group or a group
C3-C6 cycloalkyl,
R2 is the hydrogen atom or an alkyl group
in C1-C4,
R1 and R2, considered together, can form
with the nitrogen atom to which they are linked a
N-heterocyclic group of 5 to 7 vertices,
which may comprise a second heteroatom selected
from N, O and S and being substitutable, said
heterocyclic group NR1R2 being chosen from
the group comprising pyrrolidino groups,
morpholino, thiomorpholino, piperidino,
hexamethyleneimino, piperazino, 4-methyl
piperazino, 4- (2-hydroxyethyl) piperazino,
4-phenylpiperazino, 4- (p-chlorophenyl) piperazino; and their addition salts as antidepressant agents. central nervous system (CNS). It is also known that among the compounds of formula Io above, only a few products also have beneficial cardiovascular and / or immunological properties. See for this purpose the patent EP-BO 174 242 relating to the amine compounds (X = NH2) and the patent EP-BO 138 714 relating to acetylamino compounds (X = CH3CONH).

 It is known that a compound of formula 1 below has already been described in the past. This is 1- (4-hydroxyphenyl) -2-hexamethyleneiminopropanone described as laboratory curiosity in J. Med. Chem., 13, 480-488, (1970).

PURPOSE AND OBJECT OF THE INVENTION
According to the invention, compounds belonging to the family of N-substituted derivatives of 2-amino-1-phenylpropanone are therefore proposed which are (i) new Car structurally different from the products of the aforementioned prior art, and (ii) useful in therapeutically with respect to their neuropsychopharmacological and / or immunological properties, while their analogs of formula I the close pines are either inactive or too toxic.

The novel compounds according to the invention, which belong to the family of N-substituted 2-amino-1-phenylpropanone derivatives of formula
Ar-CO-CR (CH3) -B (I)
in which
Ar is phenyl, hydroxyphenyl, acetyloxy
phenyl, halohydroxyphenyl, haloacetyloxy
phenyl,
R is H or CH3.

et ses sels d'addition, (b) la 1-(3,5-dichloro-4-hydroxyphényl)-2-isopropylaminopropanone de formule

et ses sels d'addition, et (c) la 2-hexaméthylèneimino-1-phényl-2-méthylpropanone de formule

et ses sels d'addition.B is a secondary or tertiary amino residue and the
where appropriate heterocyclic,
are characterized in that they are selected from the set
consisting of :
(a) 1- (4-hydroxyphenyl) -2- (3,3,5-trimethylhexahydroazepino)
formula propanone

and its addition salts, (b) 1- (3,5-dichloro-4-hydroxyphenyl) -2-isopropylaminopropanone of the formula

and its addition salts, and (c) 2-hexamethyleneimino-1-phenyl-2-methylpropanone of the formula

and its addition salts.

According to another aspect of the invention, a process for the preparation of these novel compounds is recommended.
According to yet another aspect of the invention, a therapeutic composition containing at least one of said compounds as active ingredient is recommended.
DETAILED DESCRIPTION OF THE INVENTION
The invention thus relates to 1- (4-hydroxyphenyl) -2- (3,3,5-trimethylhexahydroazepino) -propanone, 1- (3,5-dichloro-4-hydroxyphenyl) -2-isopropylaminopropanone and 2-hexamethyleneimino-1- phenyl2-methylpropanone, on the one hand, and their addition salts, on the other hand.

By addition salts is meant here acid addition salts obtained by reaction of a free base of form II, III or IV with a mineral or organic acid, on the one hand, and the salts of ammonium, on the other hand. Among the acids which can be used for salifying the free base of formula 11, yarn or IV, mention may in particular be made of hydrochloric, hydrobromic, acetic, formic, propionic, oxalic, fumaric, maleic, succinic, benzoic, cinnamic, mandelic, citric, malic acids. , tartaric, aspartic, glutamic, methanesulfonic, p-toluenesulfonic,
Among the compounds making it possible to obtain ammonium salts, mention may in particular be made of ICH9 and CICH. 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.

 For convenience, the compounds according to the invention ("Ex" compounds) with their closest structural analogues ("CP" compounds) were combined in Table I to compare (i) Ex 1 (CRL 41 521) with CP. -1, CP-2, and CP-3; (ii) Ex 2 (CRL 41,446) with CP-4 and CP-5; and (iii) Ex 3 (CRL 41,428) with CP-6.

In agreement with the standard nomenclature, the group Ac mentioned in said table t represents the acetyl group TABLE 1
Ar-A-CR (CH3) -B

Product <SEP> No <SEP> of <SEP> Code <SEP> Ar <SEP> A <SEP> R <SEP> B <SEP><SEP> Point of <SEP> Merge
<tb> Ex <SEP> 1 <SEP> (a) <SEP> CRL <SEP> 41 <SEP> 521 <SEP>#<SEP> CO <SEP> H <SEP>#<SEP> 250 C <SEP> (b)
<tb> CP-1 <SEP> (a, d) <SEP> CRL <SEP> 41 <SEP> 431 <SEP>#<SEP> CO <SEP> H <SEP>#<SEP> 230-240C
<tb> CP-2 <SEP> (a) <SEP> CRL <SEP> 41 <SEP> 435 <SEP>#<SEP> CO <SEP> H <SEP>#<SEP> 200 C
<tb> CP-3 <SEP> (a) <SEP> CRL <SEP> 41 <SEP> 437 <SEP>#<SEP> CO <SEP> H <SEP>#<SEP> 200 C
<tb> TABLE I (continued)

Product <SEP> No <SEP> of <SEP> Code <SEP> Ar <SEP> A <SEP> R <SEP> B <SEP><SEP> Point of <SEP> Merge
<tb> Ex <SEP> 2 <SEP> (a) <SEP> CRL <SEP> 41 <SEP> 448 <SEP>#<SEP> CO <SEP> H <SEP> -NHCH (CH3) 2 <SEP> 150-180C <SEP> (c)
<tb> CP-4 <SEP> (a) <SEP> - <SEP>#<SEP> CO <SEP> H <SEP> -NHCH (CH3) 2 <SEP>
CP-5 <SEP> (a) <SEP> - <SEP>#<SEP> CO <SEP> H <SEP> -NHCH (CH3) 2 <SEP>
Ex <SEP> 3 <SEP> (a) <SEP> CRL <SEP> 41 <SEP> 428 <SEP>#<SEP> CO <SEP> H <SEP>#<SEP> 165 C
<tb> CP-6 <SEP> (a) <SEP> CRL <SEP> 41 <SEP> 429 <SEP>#<SEP> CHOH <SEP> CH3 <SEP>#<SEP> 260 C
<tb> TABLE I (end)
Notes (a): hydrochloride; (b): with decomposition; (c): pasty fusion; (d): described in J. Med. Chem., 13, 480-488, (1970).

 The results of the comparative tests given below demonstrate that there is no structure-activity relationship among the compounds belonging to the family of N-substituted derivatives of 2-amino-1-phenylpropanone of formula I ci -above.

In particular the beneficial antidepressant effects of the CNS, sedatives or immunostimulants depend on the nature of the aryl group
Ar (and more particularly the possible substituents it contains), on the one hand, and the nature of the amino group B, on the other hand. In practice it is impossible to predict in advance which serout the useful properties of a product of formula I. It is necessary to undertake tests to determine precisely whether or not a product of formula I will be therapeutically useful. In fact, when we compare Ex 1 with CP-1, CP-2 and CP-3, it is found that the hexamethyleneimino group of CP-1, CP-2 and CP-3 is clearly not suitable, and that to impart immuno-stimulatory properties said hexamethyleneimino group It should be polysubstituted like Ex 1. On the other hand, the unsubstituted hexamethyleneimino group of Ex 3 is suitable for conferring antidepressant effects, whereas in contrast its counterpart CP-6 which comprises an unsubstituted hexamethyleneimino group is not suitable for the purpose of the invention in that it is too toxic.

 The compounds of formula II, III and IV according to the invention, as well as their addition salts can be prepared according to a method known per se, by application of conventional reaction mechanisms.

The process which is here advocated is to react a 2-halo-1-phenylpropanone of formula
Ar-CO-CR (CH3) -Hal (V) where Ar and R are defined as indicated above, and Hal represents a halogen atom, preferably Cl and Br, with an amine of formula
HB (VI) where B is defined as indicated above, the reaction V + VI being carried out in a molar ratio, VI / V greater than or equal to 2/1, at a temperature between 50 C and the temperature reflux of the reaction medium, for at least 1 h.

 particularly advantageously this reaction is carried out at a temperature of 80-90 C for a period of 1.5 to 2 hours with a molar ratio VI / V of about 3.5 / 1.

 the compounds according to the invention have beneficial therapeutic properties. They all act on the CNS. They all have antidepressant effects more or less intense.

In addition to these antidepressant effects, some of them may be particularly useful as sedating agents or as immunological agents.
In short, the product of Example 1 is recommended as an immunostimulatory substance, the product of Example 2 as a sedative substance, and the product of Example 3 as an antidepressant means of the CNS.

 According to the invention, a therapeutic composition which is characterized in that it contains, in association with a physiologically acceptable excipient, at least one compound chosen from 1- (4-hydroxyphenyl) -2- (3,3 , 5-trimethylhexahydroazepino) -propanone, 1- (3,5-dichloro-4-hydroxyphenyl) -2-isopropylaminopropanone, 2-hexamethyleneimino-1-phenyl-2-methylpropanone and their non-toxic addition salts.

 Of course, in such a composition the active ingredient, namely the compound of formula II, III or IV above or one of its non-toxic salts, occurs in a pharmaceutically effective amount.

 According to the invention, it is recommended to use a substance chosen from the group comprising (i) 2-hexamethyleneimino-1-phenyl-2-methylpropanone and (ii) its non-toxic addition salts, in order to obtain a CNS antidepressant drug for use in human therapeutics for depressions and depressive states.

 According to the invention, the use of a substance chosen from the group comprising (i) 1- (3,5-dichloro-4-hydroxyphenyl) -2-isopropylaminopropanone and (ii) its non-toxic addition salts is also recommended. , to obtain a sedative drug for use in human therapy in the case of sedation is necessary.

 Finally, the use of a substance selected from the group consisting of (i) 1- (4-hydroxyphenyl) -2- (3,3,5-trimethylhexahydroazepino) propanone and (ii) its non-toxic addition salts, for obtaining a drug.

immunostimulant for use in human therapy in the case where immunostimulation is required.

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

PREPARATION I
Obtaining 1- (4-hydroxyphenyl) -2- (3,3,5-trimethylhexahydroazepino) propanone hydrochloride (Example 1, Code No. CRL 41,521).

 a) 2-bromo-1- (4-hydroxyphenyl) propanone.

 In a solution of 30 g (0.20 mole) of 4-hydroxypropiophenone in 150 ml of dioxane and 100 ml of diethyl ether, is poured between 40 and 45 C in 1.5 hours 34.7 g (0.23 mol) ) of bromine. It is stirred for 1 hour under a nitrogen atmosphere and is brought to dryness under reduced pressure. The evaporation residue is taken up in water and after stirring, the precipitate is isolated by filtration. The precipitate is purified by crystallization in benzene. 35.2 g of the expected product are obtained in the form of a slightly gray powder.

 Finst. (Kofler) = 100 C.

 Yield = 76.85%.

 (b) CRL 41,521.

 In a refluxing solution of 40.6 g (0.29 mol) of 3,3,5-trimethylhexahydroazepine in 100 ml of toluene, 30 g (0.13 mol) of 2 -bromo-1- (4hydroxyphenyl) -propanone and then refluxing for 0.5 h. The reaction medium is diluted with ethyl acetate and washed with water. After drying over dry sodium sulphate and evaporation of the solvent, the evaporation residue is purified by washing in diisopropyl ether to obtain 13.5 g of 1- (4-hydroxyphenyl) -2- (3,3,5-trimethylhexahydroazepine). -propanone in the form of a yellow powder.

Finst. (Kofler) = 160 C
This free base thus obtained is heat treated in acetone with hydrochloric ethanol. The precipitate formed is purified by recrystallization from ethanol-water (80:20) viv. 5.5 g of the expected CRL 41 521 is obtained which is in the form of a white powder soluble in hot water.

 Approximately 250 ° C (with decomposition).

Performance of the stadium b. 13 X
Overall yield (stages a + b): 10 X
PREPARATION II
Proceeding as indicated in Preparation I, replacing 3,3,5-trimethylhexahydroazepine with hexamethyleneimine gives the comparative product CP-1 (CRL 41,431).

 F = 230-240C.

PREPARATION III
By proceeding as indicated in Preparation I, but replacing 3,3,5-trimethylhexahydroazepine with hexamethyleneimine, on the one hand, and 4-hydroxypropiophenone with 4-acetyloxypropiophenone, on the other hand, obtained the comparative product CP-2 (CRL 41,435).

 F = 200 C.

PREPARATION IV
Proceeding couine indicated in Preparation I, but replacing 3,3,5-trimethylhexahydroazepine with hexamethyleneimine on the one hand, and 4-hydroxypropiophenone with 4-acetyloxy2,6-dichloropropiophenone, on the other hand, obtained the comparative product CP-3 (CRL 41,437).

 F = 220 C.

PREPARATION V
Obtaining 1- (3,5-dichloro-4-hydroxyphenyl) -2-isopropylaminopropanone hydrochloride (Example 2, Code No. CRL 41,446).

a) 2-chloro-1- (3,5-dichloro-4-hydroxyphenyl) propanone
In a suspension of 13.35 g (D, 10 moles) of aluminum chloride in 25 ml of carbon sulide, a solution of 25.35 g (0.10 mole) of O, o'-dichlorophenyl 2-chloropropionate in 25 ml of carbon disulfide. The mixture is refluxed for 15 minutes and the solvent is distilled off. The evaporation residue is heated for 45 minutes between 130 and 140 ° C. and then cooled. The resulting resinous reaction medium is hydrolysed by means of 35 ml of 6 N hydrochloric acid and 60 g of ice. The precipitate formed is extracted with ethyl acetate and then purified by recrystallization of benzene to give 16.1 g of expected product that comes in the form of a brown powder.

 Finst. (Kofler) = 126 C.

 Yield = 63.5%.

 (b) CRL 41,446.

A solution of 17 g (0.067 mol) of 2-chloro-1- (3,5-dichloro-4-hydroxyphenyl) -propanone, prepared as indicated above, is heated at 60 ° C. for 1 hour (according to the rearrangement of
FRIES) and 57.3 ml (0.670 mole) of isopropylamine in 50 ml of water. The reaction medium is brought to dryness by evaporation, the evaporation residue is taken up in water and the precipitate is isolated by filtration. The filter cake thus obtained is dissolved in acetone and the solution obtained after filtration in the presence of dry sodium sulphate is treated with hydrochloric ethanol.

 The precipitate obtained is purified by crystallization from anhydrous acetonitrile-ethanol (50:15) v / v. After drying for 1 hour at 100 ° C. under 5 mmHg (ie approximately 666.5 Pa), 8.1 g of CRL 41 446 is obtained in the form of a slightly yellow powder, insoluble in water but soluble in sodium hydroxide.

 M.p. 150-160 ° C (pasty fusion).

 Yield: 34.8%.

PREPARATIONS VI AND VII
By proceeding according to the operating procedures indicated in Preparation V but replacing 2-chloro-1- (3,5-dichloro-4-hydroxyphenyl) -propanone by 2-chloro-1- (4-hydroxyphenyl) propanone and, prespectively 2-chloro-1- (3-chloro-4-hydroxyphenyl) -propanone gives the comparison products CP-4 and CP-5 respectively.

PREPARATION VIII
Obtaining 2-hexamethyleneimino-1-phenyl-2-methylpropanone hydrochloride (Example 3, Code No. CRL 41,428).

a) 1-ethoxy-2-methyl-1-phenyl-1,2-epoxypropane
In a refluxing solution of 11.5 g (0.50 g) of sodium in 500 ml of anhydrous ethanol is poured in 0.25 h 113.5 g (0.50 mol) of 2-bromine. 1-phenyl-2-méthylpropanone. The reaction medium is poured into 1500 ml of ice water, extracted with benzene and the benzene phase is dried over anhydrous sodium sulphate.

 Evaporation of the solvent gives 93.5 g of a slightly yellow oil. This oil is ground under reduced pressure to give 86.2 g of expected product in the form of a colorless oil.

 = 78-79 C.

Yield = 89.8%
(4 mm Hg correspond to about 533.2 Pa).

 (b) CRL 41,428.

 In a Parr apparatus, a mixture of 80 g (0.416 mol) of 1-ethoxy-2-methyl-1-phenyl-1,2-epoxypropane obtained as above and heated to 200 ° C. for 20 hours is heated at 20 ° C. for 20 hours. 450 ml (4,160 moles) of hexamethyleneimine. The reaction medium is then taken up in methanol and evaporated to dryness under reduced pressure. The evaporation residue is poured onto dilute, ice-cold hydrochloric acid and washed with diethyl ether. The aqueous phase, after alkalinization with sodium hydroxide, is extracted with diethyl ether to give a brown-orange oil.

This oil is treated in ethyl acetate with hydrochloric ethaaol. A precipitate is formed which is purified by two successive crystallizations with a CXA treatment of the black mixture of ethyl acetate / ethanol (5: 1). v / v then ethyl acetate / acetonitrile (5: 3) v / v. 28.9 g of the expected CRL 41 428 are obtained in the form of a water-soluble beige powder which is soluble in water at 200 g / l.

 F = 165 C.

 Yield = 24.7%.

 The results of the tests which have been undertaken with the products according to the invention and their structural analogues as mentioned in Table I above are summarized below.

A. IMHINOLOGICAL STUDY
The immunological study was carried out according to several protocols to assess, by comparative tests, the possible immunomodulatory properties of CRL 41 521 and its analogs CP-1, CP-2 and CP-3.

 In particular, the so-called lysis plaque forming test described by A.J. CUNNINGHAM et al. ("Further improvements in the technical plate for detecting single antibody-forming cells"), Immunology 14, pp. 599-601, (1968), on the one hand, and the so-called test of the intensity of delayed hypersensitivity to red blood cells. sheep described by TE MILLER et al.

("Immunopotentiation with BCG II modulstion of the response to sheep blood cells"), Journal of the National Cancer Institute 51 (No. 5), pages 1669-1676, (1973), on the other hand.

1) The Lysis Range Cell (or PFC IgM) test explores humoral immunity. Four days after immunization with a dependent T antigen (here sheep red blood cells), we count the spleen cells expressing a direct IgM antibody response. The mice used for this purpose are conventional OF1 female mice, examples of specific pathogenic organisms, weighing 20 to 30 g, and distributed in a control batch of 14 animals and batches of 7 animals each per dose and per product. study administered orally on the same day as the antigen.An activity index I is calculated for each dose of product according to the relation:
average lysis by spleen treated mice
average lysis by spleen of control mice
This test is performed at least twice for each dose
(1; 10; and 100 mg / kg) product 1 test, and a study
Statistic is undertaken using the Student's t-test after analysis of variance on the number of lyses per spleen.

It is observed that the activity index increases at all doses for the CRL 41 521 and reaches the value I = 1.85 b the dose of 100 mg / kg PO, whereas CP-1, CP-2 and CP- 3 do not modify said
activity index.

2) The test of the intensity of delayed hypersensitivity to
red blood cells of sheep is a technique of exploration of
cellular immunity. The compound to be studied is administered either by
if it is insoluble, either (as is the case here) by
subcutaneous in the pad of the paw, when soluble
in water, the administration of said compound intervening three days
before immunization (by subcutaneous administration of sheep red blood cells in the footpad) of mice
conventional OF1 females distributed in a control group of 10 animals and batches of 5 animals each per dose and per product
to study.

This test is performed at least twice for each dose
(1 2 10, and 100 mg / kg) of product to be tested and a study
statistic is undertaken as indicated above.

The thickness of the foot pad is measured to determine the percentage increase in the thickness of the footpad.
foot pad. An activity index is then calculated according to the relationship
= E / Eo
E = average of the percentage increase of the thickness of the
plantar pad of the treated mice; and,
Eo = average of the percentage increase of the thickness of the
footpad of the control mice.

It can be seen that the CRL 41 521, unlike the products of
CP-1, CP-2 and CP-3, is the only one that gives a positive reaction in the so-called delayed hypersensitivity test.
red blood cells of sheep. More precisely, the following CRL 41 521. The invention gives a positive response to all the doses used to reach the IHSR value of 1.72 at a dose of 100 mg / kg SC.

All these results, including those recorded in the table
II below, demonstrate that CRL 41 521 (i) is an immunomodulatory product unlike the other three, and (ii) acts more specifically as an immunostimulatory substance.

TABLE II
IMMONOLOCIC STUDY, COMPARATIVE TRIALS

<tb><SEP> Product <SEP> No <SEP> of <SEP> Code <SEP> Dose <SEP> (a) <SEP> I (b) <SEP> IHSR <SEP> (c)
<tb><SEP> Ex1 <SEP> CRL <SEP> 41 <SEP> 521 <SEP> 100 <SEP> 1.85 * <SEP> 1.72 *
<tb><SEP> CP-1 <SEP> CRL <SEP> 41 <SEP> 431 <SEP> 100 <SEP> 1.01 <SEP> 0.99
<tb> CP-2 <SEP> CRL <SEP> 41 <SEP> 435 <SEP> 100 <SEP> 0.98 <SEP> 1.01
<tb><SEP> CP-3 <SEP> CRL <SEP> 41 <SEP> 437 <SEP> 100 <SEP> 1.01 <SEP> 1.01
<tb><SEP> witnesses <SEP> - <SEP> - <SEP> 1.00 <SEP> 1.00
<Tb>
Notes (a) dose expressed in mg / kg, the method of administration being
the oral route for the measurement of activity index I,
and the subcutaneous route for that of the index of acti
IHSR.

(b) Activity index following the so-called cell test
forming lysis ranges:
average lysis by spleen treated mice I--
average spleen lyses of the control mice (c) activity index following the hypersensitivity test
delayed to red blood cells of sheep,
* statistically significant compared to controls.

B. NEUROPSYCHOPHARMACOLOGICAL STUDY OF CRL 41 446
A neuropsychopharmacological study was undertaken to compare CRL 41 446 with its closest structural analogues. In this study the products to be tested were administered intraperitoneally in solution in distilled water or in suspension in an aqueous gum arabic solution in a volume of ZO ml / kg in the male mouse and 5 ml / kg in the male rat.

In this study, CRL 41 446 was used in solution in distilled water at a concentration of 3.2 g / l or less and suspended in an aqueous solution of gum arabic at a higher concentration. , 2 g / l,
The pH of the aqueous solution containing the CRL 41 446 to be injected varies depending on the concentration of CRL 41 446, as shown in Table III below.

TABLE III

<tb><SEP> Concentration <SEP> pH <SEP> of <SEP> the <SEP> solution
<tb><SEP> of the <SEP> CRL <SEP> 41 <SEP> 446 <SEP> Aqueous <SEP> Administration
<tb> in <SEP> the <SEP> solution
<tb><SEP> Aqueous <SEP> Administration
<tb><SEP> 3.2 <SEP> g / l <SEP> 3.5
<tb><SEP> 1.6 <SEP> g / l <SEP> 4.0
<tb><SEP> 0.4 <SEP> g / l <SEP> 4.5
<tb><SEP><0.05<SEP> g / l <SEP> 5.0
<Tb>
I. TOXICTTE
In the male mouse, the LD-O (maximum non-lethal dose) by IP is greater than 512 mg / kg and the DL-30 (lethal dose for 30% of treated animals) is of the order of 1024 mg / kg. kg (at this dose the death of mice occurs two hours after administration of CRL 41 446.

II. GLOBAL BEHAVIOR AND REACTIVITIES
Lots of three animals are observed before,
0.50 h, 1 h, 2 h, 3 h and 24 h after CRL administration
It is found in the mouse
at doses of 4 and 16 mg / kg;
- behavior and responsiveness substantially
comparable to those of the control group;
at the dose of 64 mg / kg:
- moderate hypothermia for 2 hours, the maximum of
intensity (-2 C) occurring 0.5 h after
the administration of CRL 41 446;
at the dose of 256 mg / kg:
- a sedation with a decrease in the respi
for an hour,
- a decrease in reactivity to touch is mani
0.5 to 2 hours after administration of CRL 41
446
- a very important hypothermia for a duration of
three hours, the maximum intensity (- 6.1 C) is
0.5 h after the administration of CRL 41 446;
at the dose of 512 mg / kg ::
- sedation,
- a decrease in the respiratory rate,
- abdominal cramps.

III. INTERACTION WITH APOMORPHINE
Lots of 6 mice receive the product to be tested by
PI 0.5 h before subcutaneous injection of 1 or 16 mg / kg
apomorphine. It is observed that at the highest dose used (256
mg / kg), CRL 41 446 aggravates hypothermia induced by
apomorphine. It should be noted in this connection that, at
64 mg / kg and especially 256 mg / kg, the hypothermic effect of CRL
41 446 occurs before the apomorphine injection. We aknowledge
Moreover, CRL 41 446 hardly modifies the
verticalizing behaviors and stereotypies due to
apomorphine.

IV. INTERACTION WITH THE RESERPINE
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 the highest dose used (256 mg / kg), CRL 41 446 aggravates reserpine hypothermia. It is also observed that the maximum peak ostepsis is not modified by CRL 41 446.

V. INIERACTION WITH THE
the product to be studied is administered to groups of six mice 0.5 h before the intraperitoneal injection of 0.5 mg / kg of oxotremorine.

1) Action on the temperature
At the highest dose (256 mg / kg), CRL 41 446 was very mildly and briefly opposed to oxotremorine-induced hypothermia. It should be noted that the hypothermic effect of CRt 41 446 occurs prior to injection of oxotremorine.

2) Action on tremors
At the highest dose (256 mg / kg), CRL 41 446 appears to potentiate the intensity of oxotremorine-induced tremor.

3) Action on peripheral cholinergic symptoms
It is observed that CRL 41 446 does not substantially modify the signs of peripheral cholinergic stimulation due to oxotremorine.

VI. ACTION ON THE TEST OF THE FOUR
The test is performed on batches of 10 mice, 30 minutes after the administration of the product to be studied. It is found that, b the highest dose used (256 mg / kg), the CRL 41 446 decreases the number of passages punished, does not cause major motor incapacity, does not oppose the convulsive effects, but only moderately lethal effects of electroshock.

VII. ACTION ON THE SPONTANEOUS MOTILT
0.5 h after receiving the product to be studied, the mice (6 per dose, 12 controls) are placed in an actimeter where their motility is recorded for 0.5 h. It is found that, at the highest dose used (256 mg / kg), CRL 41 446 greatly reduces the spontaneous motor activity of the mouse.

VIII. NOTILTTE REDUTTE BY HABTTUATION AT THE
After 18 hours of stay in the actimeters, the mice (6 per dose, 12 controls) receive the product to be tested. They are immediately placed in their respective chambers and, 30 minutes later, their motility is recorded for 0.5 h,
It is found that CRL 41 446 does not result in recovery of motor activity in mice accustomed to its use.

INTERACTION WITH THE BARRITAL
Half an hour after administration of the product to be studied, lots of 10 mice receive an intraperitoneal injection of barhital (220 mg / kg).

It is observed that at the highest dose used (256 mg / kg) the
CRL 41 446 significantly reduces the amount of barbiturate sleep.

X. ACTION ON "BEHAVIORAL DISEASE"
Half an hour after receiving the product to be tested, lots of 6 mice are placed in a beaker filled with water to a height of 6 cm. We note the total duration of immobility between the 2nd and 6th minautes following immersion.

It is found that at the highest dose used (256 mg / kg), the
CRL 41 446 significantly reduces the duration of immobility of the mouse placed in forced immersion.

XI. CONCLUSIONS
As a result of all the tests summarized above, the
CRL 41 446 has effects in its neuropsychopharmacological profile:
sedatives qt are objectified by sweating with
decreased tactile reactivity in mice,
a very significant decrease in motor activity
in the mouse and the number of passages punished
to the four-plate test, and, a very im very hypothermia
with aggravation of hypothermia induced by
apomorphine or reserpine in mice;
- very moderate high dose antidepressants who get married
both by a weak and fleeting antagonism of hypothermia
induced by oxotremorine in mice.

Paradoxically, the CRL 41 446 decreases, high dose, the
-barbiturate sleep duration and so-called
"despair".

The neuropsychopharmacological study of comparsison products
CP-4 and CP-5 company following the same modus operandi
described above shows that these two products can not be
used in therapy, indeed (i) CP-4 is too toxic, and
(ii) at the highest dose used, CP-4 and CP-5 exert
exophthalmia in the rat and dyspnea in the
mouse and in the rat.

In addition, the immunological study undertaken according to
protocols described above shows that CRL 41 446 is lacking
significant immunomodulatory action.

C. NEUROPSYCHOPHARMACOLOGICAL STUDY OF CRL 41 428
The neuropsychopharmacological study of CRL 41 428 was carried out
according to the modus operandi described above for the CRL
41 446. In this study, CRL 41,428 was administered intraperitoneally in solution in distilled water in a volume
of 20 ml / kg in the male mouse and 5 ml / kg in the mixed rat. The
pH of the aqueous solution of CRL 41 428 to be administered varies in
according to the concentration of CRL 41 428 as indicated in the
table IC below.

TABLE IV

<tb> Concentration <SEP> pH <SEP> of <SEP> the <SEP> solution
<tb><SEP> of <SEP> CRL <SEP> 41 <SEP> 428 <SEP> Aqueous <SEP> Administration
<tb> in <SEP> the <SEP> solution
<tb> aqueous <SEP> administration
<tb> 50 <SEP> g / l <SEP> 3.0
<tb> 25 <SEP> g / l <SEP> 4,5
<tb> 0.8 <SEP> g / l <SEP> 5.0
<tb> 0.4 <SEP> g / l <SEP> 5.5
<Tb>
I. TOXICTTE
DL-O (non-lethal maize dose) of CRL 41,428
PI in male mice is greater than 128 mg / kg, DL-60 (lethal dose for 60% of treated animals) is around 256 mg / kg, and the DL-100 minimum lethal dose for all the treated animals is less than 512 mg / kg (at this dose the death of the animals occurs within 24 hours after the administration of CRL 41 428).

II. GLOBAL BEHAVIOR AND REACTIVITIES
According to the operating modalities described above,
1) in the mouse
at doses of 1 mg / kg, 4 mg / kg and 64 mg / kg:
-a behavior and reactivities substantially
those of the control group; and,
at the dose of 128 mg / kg:
- a decrease in the respiratory rate;
2e) in rats
at doses of 0.5 mg / kg and 2 mg / kg:
- a behavior, reactivities, a variation of the
Rectal temperature and sensory pupillary diameter
comparable to those in the control group;
at the dose of 8 mg / kg:
- a mydriasis lasting 2 hours, the intensity of which
occurs 5 hours after the administration of the
CRL 41,428, and,.

at the dose of 32 mg / kg:
- a mydriasis lasting 3 hours, the intensity of which
maximum is 1 hour after administration of the
CRL 41,428.

III. INIERACTION WITH APOMORPHINE
It is observed that at a dose of 16 mg / kg and especially at a dose of 64 mg / kg, CRL 41 428 opposes apomorphine-induced hypothermia in mice and does not modify the verticalization behaviors and stereotypies due to apomorphine in mice and rats.

IV. INTERACTION WITH AMPHETAMINE
Amphetamine (2 mg / kg) is injected intraperitoneally to batches of 6 rats 30 minutes after administration of the product to be tested. It is found that CRL 41 428 does not change the stereotypies induced by amphetamine.

V. INTERACTION OF THE
It is found that, at a dose of 16 mg / kg and especially at a dose of 64 mg / kg, CRL 41 428 is clearly opposed to reserpine hypothermia. Furthermore, CRL 41 428 does not modify the reserpine-induced ptsis.

VI. INTERACTION WITH OXOTREMORINE
It is found that CRL 41 428, at the highest dose used (64 mg / kg), antagonizes oxotremorine-induced hypothermia.

It is also observed that CRL 41 428 does not modify tremor of oxotremorine and does not modify the signs of peripheral cholinergic stimulation caused by oxotremorine.

VII. ACTION ON THE TEST OF THE FOUR PLATES, TRACTION AND
ELECTRIC SHOCK
It is observed that CRL 41 428 does not modify the number of passages punished. It does not cause major motor disability but is moderately opposed, at the highest dose used (64 mg / kg), the convulsive effects of electroshock without changing the lethal effects of electroshock.

VIII. ACTION SOR LA
It is observed that CRL 41 428 does not change clearly the spontaneous motor activity of the mouse.

IX. ACTION OUT AGGRESSIVITY
After having spent three weeks in each of the halves of a cage separated by an opaque partition, groups of 3 mice receive the product to be studied. A half hour later, the two groups of a small cage are joined by removal of the partition and we note the number of fights that occur in 10 minutes.

 It is found that at a dose of 16 mg / kg and especially at a dose of 64 mg / kg, CRL 41 428 reduces the number of fights in mice.

X. ACTION WITH RESPECT TO SOME DISTURBED BEHAVIORS BY MISCELLANEOUS
AGENTS
1) Motility reduced by habituation to the enclosure
By proceeding as indicated above, we find that the CRL
41 428 does not result in a recovery of motor activity in
mouse accustomed to its enclosure.

2) Motility reduced by hyporic aggression
Half an hour after receiving the product to be tested,
mice (20 per dose, 40 controls) are subject to anoxia
hypobaric acute depression of 600 mmHg (ie approximately 8 x 104Pa) in
90 seconds; then relax for 45 seconds * then they are placed
in actimeter where their motility is recorded for 10 minutes.

It is found that at the highest dose used (64 mg / kg), the
CRL 41,428 results in a clear improvement in recovery
motility in mice whose motility was depressed as a result
a brief stay in an enclosure with reduced pressure.

3) Asphyxial anoxia
Lots of 10 mice receive the test product half a
hour before intraperitoneal administration of 32 mg / kg of
gallamine triiodoethylate (reference curative agent). We
notes that CRL 41 428 hardly modifies the deadline
onset of convulsions and death following anoxia caused by a curarizing agent.

XI. INTERACTION WITH THE BARBITAL
It is observed that at the dose of 16 mg / kg and especially at the dose of
64 kg / mg, CRL 41 428 reduces the duration of barbiturate sleep.

XII. ACTION ON "BEHAVIORAL DISASTER"
It is found that at the dose of 4 mg / kg, the CRL 41 428 decreases
the so-called "despair" duration of immobility of the mouse placed in
forced immersion. The decrease in this duration is very clear at the
dose of 64 mg / kg.

XIII. CONCLUSIONS
The results of the tests summarized above highlight
that the CRL 41 428 presents in its profile neuropsychopharmacolo
effects
- antidepressants that are objectified by
- the antagonism of the hypothermia induced by the reservoir
pine, oxotremorine and apomorphine,
- the decrease in the so-called
"despair"; and,
- very moderate stimulants objectified by
- the increase in motility after hypo-
xique,
- the decrease in the duration of barbiturate sleep.

In general, the stimulating effects of CRL 41 428 are moderate as indicated above, on the one hand, and fleeting on the other hand. CRL 41 428 behaves according to the present neuropsychopharmacological study me an antidepressant agent of
having a frustrating stimulating component.

Comparative Product Study CP-6 Similar to CRL 41,428
shows that said comparative product is toxic (its DL-100 in the
male mice by the IP route is of the order of 90 mg / kg) and
has no effect on predicting a therapeutic indication.
against the CNS as an antidepressant, sedative
stimulating.

Claims (10)

 1. Compound belonging to the family of N derivatives  where appropriate heterocyclic, said compound being characterized in that it is selected from the group conatited by: (a) 1- (4-hydroxyphenyl) -2- (3,3,5-trimethylhexahydroazepino) propanone and its salts thereof addition, (b) 1- (3,5-dichloro-4-hydroxyphenyl) -2-isopropylaminopropanone and its addition salts, and (c) 2-hexamethyleneimino-1-phenyl-2-methylpropanone and its salts addition.  B is a secondary or tertiary amino residue and the  R is H or CH3,  phenyl,  phenyl, halohydroxyphenyl, haloacetyloxy  Ar is phenyl, hydroxyphenyl, acetyloxy  in which  Ar-CO-CR (CH3) -B (I) substituted 2-amino-1-phenylpropanone of the formula  2. 1- (4-Hydroxyphenyl) -2- (3,3,5-trimethylhexahydroazepino) propanone and its addition salts.  3. 1- (3,5-Dichloro-4-hydroxyphenyl) -2-isopropylaminopropanone and its addition salts.  4. 2-Hexamethyleneimino-1-phenyl-2-methylpropanone and its addition salts.  5. Process for the preparation of a compound according to claim 1, characterized in that it consists in reacting a 2halo-1-phenylpropanone of formula  Ar-CO-CR (CH3) -Hal (V) where Ar and R are defined as indicated above, and Hal represents a halogen atom, preferably Cl and Br, with an amine of formula  HB (VI) where B is defined as indicated above, the reaction V + VI being carried out in a molar ratio, VI / V higher, or equal 2/1, ê a temperature between 500C and the temperature reflux of the reaction medium, for at least 1 h.  6. Process according to claim 5, characterized in that the reaction of 2-halo-1-phenylpropanone of formula V with the amine of formula VI is carried out at a temperature of 8090 ° C. for a period of 1, 5 to 2 hours with an IV / V molar ratio of about 3.5 / 1.  7. Therapeutic composition, characterized in that it contains, in combination with a physiologically acceptable excipient, at least one compound selected from 1- (4-hydroxyphenyl) -2- (3,3,5-trimethylhexahydroazepino) - propanone, 1- (3,5-dichloro-4-hydroxyphenyl) -2-isopropylaminopropanone, 2-hexamethyleneimino-1-phenyl-2-methylpropanone and their non-toxic addition salts.  8, therapeutic use, characterized in that B is a substance selected from the group consisting of (i) 2-hexamethyleneimino-1-phenyl-2-methylpropanone and tii) its non-toxic addition salts, to obtain a CNS antidepressant drug for human therapeutic use against depressions and depressive states.  9. Therapeutic use, characterized in that one uses a substance selected from the group consisting of (i) 1- (3,5-dichloro-4-hydroxyphenyl) -2-isopropylaminopropanone and (ii) its salts non-toxic additives, for obtaining a sedative drug for use in human therapy in the case where sedation is necessary.  10. Therapeutic use, characterized in that a substance selected from the group consisting of (i) 1- (4-hydroxyphenyl) -2- (3,3,5-trimethylhexahydroazepino) -propanone and ( il) its non-toxic addition salts, for obtaining an immunostimulant drug for use in human therapy in the case where immunostimulation is required.