WO1993022279A1

WO1993022279A1 - Diamine derivatives having selective affinity for sigma receptors

Info

Publication number: WO1993022279A1
Application number: PCT/CH1993/000106
Authority: WO
Inventors: Jean-Philippe Rocher
Original assignee: Battelle Memorial Institute
Priority date: 1992-04-28
Filing date: 1993-04-22
Publication date: 1993-11-11
Also published as: CA2112490A1; AU3886693A; JPH06509586A; EP0605667A1; ZA932761B

Abstract

Diamine derivatives of formula (I), wherein n = 0-8; R1 is hydrogen or a C1-3 alkyl residue; each of R2, R3, R4, R5 and R6 is hydrogen, a C1-6 alkyl residue, branched C4-12 alkyl or alkenyl; R2 and R3 together may form a C3-8 ring optionally including a heteroatom and optionally partially or wholly unsatured; R5 and R6 taken together may form a C2-8 ring; X is a single bond, -CH2-, -C (=O)-, -S (O)-, or -S (O)2-; Y is an alkyl residue, cycloalkyl, cycloalkylalkyl, adamantyl, optionally substituted phenyl or an aromatic heterocyclic ring; Ar is an optionally substituted phenyl radical, naphtyl or an aromatic heterocyclic ring. Said derivatives are psychotropic agents particularly suitable for treating psychotic disorders, convulsion, dyskinesia, brain distress (ischaemia, hypoxia) and anxiety, and further have anti-inflammatory properties.

Description

DIAMINE DERIVATIVES HAVING SELECTIVE AFFINITY FOR SIGMA RECEPTORS

The present invention relates mainly to the field of neurology and relates to new derivatives of 1,2-ethylene diamine structure substituted α and their acharically acceptable salts thereof. These compounds are ligands with high af¬ finity for sigma receptors and they have a very high selectivity for these receptors. They are useful for the treatment of psychotic disorders, convulsions, dyskinesias and brain suffering consecutive to episodes of hypoxia, anoxia or ischemia associated with cerebral, cardiac or perinatal attacks. . They also have anxiolytic properties and can be used for this purpose.

On the other hand, these compounds are indicated in inflammatory conditions and more particularly those which involve cell-mediated immune reactions.

State of the art

Conventional neuroleptics have a mechanism of action based in part on a strong blockade of dopamine D2 receptors. This phenomenon is however the cause of their major side effects. The discovery of atypical potential neuroleptics with few side effects like rimcazole, remoxipride, BMY 14802 opens new perspectives in the treatment of these pathologies. The latter compounds have a low affinity for D2 dopaminergic receptors, but a fairly strong affinity for sigma receptors [H. Prϋcher, R. Gottschlich, A. Haase, M. Stohrer and C. Seyfried, Bioorganic & Médicinal Chemistry Letters, 1992, 2, 165-170].

Sigma receptors are therefore currently the subject of intense research, not only in the field of psychotropic substances [JM Walker, WD Bowen, FO Walker, RR Matsumoto, B. De Costa and KC Rice, Pharmacological Reviews, 1990, 42, 355-402], but also in the discovery of new neuroprotectants [MJ Pontecorvo, EW Karbon, S. Goode, DB Cissold, SA Borosky, RJ Patch and JW Ferkany, Brain Research Bul¬ letin, 1991, 26, 461-465].

Most sigma ligands carry amino functions, some have an "ethylene-diamino" motif totally included in a cycle such as the piperazine ring (rimcazole,

BMY 14802

BMY 14802, opipramol) or partially included in a ring, which is the case for 2-methylene-amino-pyrrolidine derivatives such as remoxipride.

Remoxipride

International application WO 91/12247 describes pyrrolidinylcyclohexylamiπes having a high affinity on the receptors. sigma as well as psychotropic properties. A recent publication [BR De Costa, L. Radesca, L. Di Paolo and WD Bowen, J. Med. Chem. , 1992, 35, 38-47] describes pyrrolidinylethylamines as being powerful ligands of the sigma receptor, but a micromolar affinity for the dopamine receptor D2 is however observed.

The document US 5039706 describes a derivative of the phenylethylene-diamine type belonging to a family of molecules exhibiting anti-inflammatory properties by inhibition of phospholipase A2 (humoral immunity); this document does not suggest any psychotropic effect for these compounds. European documents EP 0 402 646 and EP 0 407 217 present very broad claim formulas but no compound described relates to formula I; it does not indicate any interest in neuropharmacology for these products.

European document EP 0290377 describes a class of benzamide derivatives having anti-arrhythmic activities only.

The present invention is based on the discovery of a new class of compounds of 1,2-ethylene diamine structure substituted at α by a benzyl radical. Structurally, these molecules show that, compared to other sigma ligands of the pyrrolidinyl type, the aromatic radical Ar surprisingly provides absolute selectivity with respect to dopaminergic receptors. In addition, the amino function in α, even unsubstituted, confers a strong activity in vitro and in vivo.

Due to their molecular specificity, these molecules have the pharmacological properties generally observed for the other sigma ligands. The compounds described in this patent tagonize the convulsions induced by N-methyl-D-aspartate (NMDA) and have a remarkable effect in hypoxia, as well as in several antipsychotic tests at doses hitherto never reached for this class. ligands. Anti-amnesic effects [B. Earley, M. Burke, BE Léonard, C. Gouret and JL Junien, Brain Research, 1991, 546, 282-286; L. Tristsmans, G. Clincke and B. Peelmans, Drug Develop. Res., 1990, 20, 473-482], anxiolytics (WO 90/14067) and on digestive motility [JL Junien, M. Gue, X. Pascaud, J. Fioramonti and L. Bueno, Gastroenterology, 1990, 99, 684-689] have been described for sigma compounds, which gives obvious interest to the compounds of the invention in these pharmacological and therapeutic fields.

Sigma receptors have been characterized on the surface of lymphocytes and effects on lymphocyte proliferation have been observed [D.J.J. Carr, B.R. De Costa, L. Radesca and J.E. Blalock, Journal of Neuroimmunology, 1991, 35, 153-166] with sigma ligands; European document EP 0 386 997 describes immunosuppressive and anti-inflammatory activities for sigma ligands. The molecules of the present invention are therefore potential anti-inflammatory drugs, more particularly applicable in pathological conditions which are consequential to the use of cellular immunity, for example in chronic inflammatory conditions such as in arthritis and arthritis. inflammatory skin conditions such as eczema.

Description of the invention

The compounds of the invention correspond to the following formula:

(I) in which:

n = is a selected number from 0 to 8;

R 1 represents a hydrogen, an alkyl, branched alkyl, cycloalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl residue; 2, R3, R4, Rs and Rβ independently represent a hydrogen gene, an alkyl, branched alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkoxylyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl, carboxyalkyl , alkanoyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl;

R2 and R3 taken together can form a cycle corresponding to the formula:

- (CH ₂ ) mA- (CH ₂ ) m-

where A represents a single bond, an oxygen atom or a nitrogen atom substituted by a hydrogen radical, an alkyl radical, branched alkyl, cycloalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl;

m is a selected number from 1 to 3;

R2 and R3 taken together can form an unsaturated hydrocarbon ring from C ₄ to Cs;

Rs and Rβ taken together can form a cycle (2 to 8 C);

X represents a single bond, -CH2-, -C (= 0) -, -S (O) -, -S (0) 2 -;

Y is an alkyl, cycloalkyl, hydroxyalkyl, haalkyl, cycloalkylalkyl, adamantyl, alkoxyalkyl, aralkyl, aryl, alkenyl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkylsulfinyl, alkylsulfonyl, arylsulfonylsulfonyl residue aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, aryla ino, heteroarylamino, aralkyla- ino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio; each of the preceding groups Y can additionally carry one or more selected substituents among the hydrogen, hydroxy, alkyl, branched alkyl, cycloalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkylalkyl, adamantyl, alkoxyalkyl, haloalkoxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkylamino, aminoalkyl radicals , carboxyalken and alkynyl;

Ar is a radical selected from the following radicals: aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio, heteroalkyl; each of the preceding groups Ar can additionally carry one or more substituents selected from the radicals hydrogen, hydroxy, alkyl, branched alkyl, cycloalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl¬ alkyl, adamantyl, alkoxyalkyl, haloalkoxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, cyano, amino, nitro, monoalkylamino, dialkylamino, carboxy¬ alkenyl and alkynyl;

The invention also extends to all pharmaceutically acceptable salts.

It is understood that the present invention includes the racemic compounds corresponding to formula I and also the optically active enantiomers, especially those which have the absolute configuration in R 1 which has been fixed by a natural amino acid (L) precursor of synthesis.

The treatment of neurological disorders, in particular psychotic disorders, dyskinesias, convulsions, episodes of hypoxia, anoxia or ischemia associated with cerebral attacks as well as the prevention of disorders of neurotoxic origin as well as those consecutive to neurodegenerative disorders, can be achieved by the administration of therapeutic doses of compound of formula I.

A preferred family of compounds always corresponds to molecules of formula I for which: n = is a selected number from 0 to 8;

R 1 represents a hydrogen, an alkyl residue from C1 to C3, branched alkyl, al kenyl, cycloal kyle, aral kyle, aryl, al ké¬ nyl al kyle, al kynylal kyl e;

R2, R3, R4, R5 and Rβ independently represent a hydrogen, a C1 to C6 alkyl radical, branched alkyl, alkenyl cycloalkyl, hydroxyalkyl cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl;

R2 and R3 taken together can form a cycle corresponding to the formula:

- (CH ₂ ) mA- (CH ₂ ) m-

where A represents a single bond, an oxygen atom or a nitrogen atom substituted by a hydrogen residue, an alkyl residue of C1 to C3;

m = 2;

R2 and R3 taken together can form an unsaturated hydrocarbon-based cycle from C ₄ to C 5.

X represents a single bond, -CH2-, -C (= 0) -;

Y is an alkyl, cycloalkyl, cycloalkylalkyl, ada¬ mantyl, aralkyl, aryl, alkenyl, alkenylalkyl, heteroaryl, aryloxy, heteroarylox, aralkoxy, heteroaralkoxy radical, each of the preceding groups Y can additionally carry one or more substituents selected from the groups hydrogen, hydroxy, alkyl, branched alkyl, cycloalkyl, adamantyl, halo, haloalkyl, aralkyl, aryl, carboxyalkyl, alkanoyl, cyano, amino, monoalkylamino, dialkylamino, carboxyalkenyl and alkynyl radicals;

Ar is a radical selected from the following radicals: aryl, heteroaryl, aryloxy, heteroaryloxy, aral¬ coxy, heteroaralcoxy, each of the preceding Ar groups may additionally carry one or more substituents selected from the radicals hydrogen, hydroxy, alkyl, branched alkyl, cycloalkyl, adamantyle, halo, haloalkyle, aralkyle, aryle, carboxyalkyle, alkanoyl, cyano, amino, monoalkylamino, dial- kylamino, carboxyalkenyl and alkynyl;

The following compounds are of particular interest:

(S) - (+) - N- (2-amino-3-phenylpropyl) -N- (5-phenyl) -valeramide;

(R, S) -N- (2-amino-3-phenylpropyl) -N-methyl-N- (5-phenyl) -valeramide;

(S) - (-) - N- (2-dimethylamino-3-phenylpropyl) -N-methyl-N- (5-phenyl) -valeramide;

(S) - (+) - N- (2-dimethylamino-3-phenylpropyl) -N-methyl-N- (5-pheπyl) -pentanamiπe;

(S) - (-) - N- (2-amino-3-phenylpropyl) -N-methyl-N- (3,4-dichlorophenyl) -acetamide;

(S) - (-) - N- (2-amino-3-pheπylpropyl) -N-methyl-N- (1-adamantyl) - acetamide;

(S) - (+) - N- (2-amino-3-phenylpropyl) -N-methyl-N- (5-phenyl) -penanam ne;

(R) - (-) - N- (2-amino-3-phenylpropyl) -N-methyl-N- (5-phenyl) -penanamine;

(S) - (+) - N- (2-methylamino-3-phenylpropyl) -N-methyl-N- (5-phenyl) -pentanamine;

(S) - (+) - N- [2- ⁽ 4-morpholino) -3-phenylpropyl] -N-methyl-N- (5-pheny1) -pentanamine;

(S ⁾ - (+) - N- [2- (1-pyrrolo ⁾ -3-phenylpropyl] -N-methyl-N- (5-phenyl) -pentanamine;

⁽ S ⁾ - ⁽ + ⁾ -N- [2- ⁽ 1-pyrrolidino ⁾ -3-phenylpropyl] -N-methyl-N- (5-phenyl) -pentanamine; (S) - (+) - N- [2- (1-butyrami do) -3-phenyl propyl] -N-methyl-N- (5-phenyl) -pentanamine;

(S) - (+) - N- [2- (1-butanamino) -3-phenylpropyl] -N-methyl-N- (5-phenyl) -pentanamine.

Detailed description of the invention

In the compounds of formula I, the term "alkyl", used alone or joined with other terms such as "hydroxyalkyl", extends to linear or branched hydrocarbon chains which can comprise up to 10 atoms such as ethyl, ethyl groups , n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl. The term cycloalkyl corresponds to cyclic radicals of 3 to 10 carbon atoms such as cyclopropyl and cyclohexyl. The term cycloalkylalkyle corresponds to cyclic radicals of 4 to 20 atoms which can be branched like the methylcyclopropyl radical or else polycyclic like the adamantyl radical.

The term "haloalkyl" describes hydrocarbon chains where one or more carbon atoms of the alkyl chain are substituted by one or more halogen atoms, in particular bromine, chlorine or fluorine. This term also includes the terms monohaloalkyle and polyhaloalkyle where in this case an alkyl chain can be substituted by a combination of the various halogen atoms mentioned, for example it can be a trifluoromethyl group.

The term "hydroxyalkyl" corresponds to linear or branched alkyl groups from Ci to Cio where one of the atoms can be substituted by a hydroxyl group.

The term "alkenyl" and the term "alkenylalkyl" include linear or branched residues having 2 to 10 carbon atoms and containing at least one carbon-carbon double bond such as the allyl group while the group "alkinyl" and "al - kinylalkyl "must itself contain at least one carbon-carbon triple bond, for example the propargyl radical.

The term "alkoxyalkyl" designates linear or branched chains containing an oxygen atom and an alkyl portion which may have up to 10 carbon atoms, such as for example the methoxy group. These latter radicals can themselves be substituted by halogen atoms to lead to the "haloalkoxyalkyl" groups.

The term "aryl" applies to all aromatic hydrocarbon systems of Cs to Cio mono or polycyclic such as phenyl, naphthyl. The term "heteroaryl" includes aromatic systems containing one or more heteroatoms independently selected from oxygen, nitrogen or sulfur; they may be mono or polycyclic systems having 5 to 10 atoms such as the pyrrolyl, imidazolyl, thiazolyl, furanyl, pyridinyl, indolyl, benzothiophenyl, quinolinyl groups.

The compounds of the invention correspond to formula I, they can be isolated in the form of a free base or else in the form of addition salts with pharmaceutically acceptable acids as medicaments; by way of nonlimiting examples, they may be mineral acids such as hydrochloric acid, hydrous acid, sulfuric acid, niric acid, or organic acids such as fumaric acid, maleic acid, oxalic acid, aryl or alkyl sulfonic acids. These compounds can be partially solvated, for example hydrated.

The invention extends not only to racemic compounds, but also to optically active forms of the compounds and their salts. The chiral compounds can be prepared from chiral precursors such as natural amino acids, or else by conventional methods of fractional crystallization by reaction of the racemic form with an optically active acid such as levorotatory tartaric acid or dextro- gyre.

Synthesis processes

The compounds of the invention correspond to formula I, they can be isolated in the form of a free base or else in the form of addition salts with pharmaceutically acceptable acids as medicaments. The invention extends not only to racemic compounds, but also to optically active forms.

The compounds having the formula I can be prepared in a known manner. Two synthetic routes are illustrated in the examples below.

According to scheme 1, the condensation of a carboxylic acid derivative of formula II is carried out on an ethylene diamine substituted at α and corresponding to formula III.

Diagram 1

The substituents carried by the starting products correspond to those specified in the general formula of the present invention except the fact that the ethylene-diamino III half cannot be diacylated. Consequently, R2 and / or R3 may represent a protective group for the primary amino function. mayor or secondary such as shown for example in "Protective Group in Organic Synthesis" TW Greene, ι édi¬ tion ^era (Wiley) 218-287. The preferred protecting group is a t-Butyl carbamate (BOC). A deprotection step is therefore added after the acylation reaction when at least one of the R∑ and R3 is H.

The starting compounds of ethylene-diamino structure corresponding to formula III generally come from α-amino-α-arylalkyl-carboxamides which are derivatives of aci¬ of natural amines or obtained by synthesis according to conventional methods. When the precursor amino acids are chiral, the synthesis leads to optically active compounds.

The acylation reaction according to scheme 1 is carried out in a conventional manner using the compound of formula II in the form of acid chloride (Q = Cl) in the presence of a tertiary amine, or else directly from the acid form. according to usual activation methods such as methods using the formation of a mixed anhydride or an imidazole derivative. A preferred method is that using a carbodimimide, such as dicyclohexylcarbodiimide in the presence of 1-hydroxybenzotriazole, which is an agent which limits the racemization phenomena.

The carboxamido compound (la) can also be reduced by conventional reduction agents: lithium aluminum hydride (LiAlH-i), alane (AIH3), borane ethyl sulfide, etc. It thus leads to derivatives of structure I where X = -CH2 -. In the case where (la) has a protective group, an additional deprotection step is carried out before or after the reduction.

Diagram 2 represents the condensation of a derivative of natural or synthetic amino acid, on an amino part. This reaction is carried out according to the methods mentioned above, however, preference will be given to methods using a carbodimimide and combining a reagent to minimize the risks of racemization. Diagram 2

The derivative of formula VI leads to the type I compounds claimed after a reduction step, carried out according to the methods described above. A deprotection step can possibly be carried out before or after the reduction of the carboxamido function.

When R2 and / or R3 represent a hydrogen atom, the compound VI may be alkylated, for example according to conventional methods using alkyl halides in the presence of a base, by methods of reductive amination using sant an aldehyde and sodium cyanoborohydride, or to lead to an unsaturated heterocycle of pyrrole type according to the process described by M. Artico, F. Corelli, S. Massa and G. Stefancich, Synthesis, 1983, 931.

When R2 and / or R3 represent a hydrogen atom and R4 an alkyl residue, the compound I thus substituted can itself serve as a substrate for conventional acylation or alkylation reactions depending on the final product of desired structure I .

The following procedures illustrate, without limitation, the preparation of the diamines of the invention as well as intermediate derivatives. The products are either obtained in a satis¬ ing state of purity, or purified by the appropriate techniques which are indicated in the examples such as recrystallization and column chromatography. In the latter case, the technique known as "Flash" chromatography on a silica support is favorably used ("SDS" brand, chromagel 60 ACC silica gel product, particle size 230 to 400 mesh).

The purity, identity and physicochemical characteristics of the prepared products are reported and determined by:

- their melting point determined by the capillary tube method

- thin layer chromatography (TLC) of silica ("MERCK" brand ref. 60 F 254).

The chromatograms are observed in ultraviolet light with a wavelength of 254 nm and / or after revelation by spraying of common reagents. The observed Rf are indicated as well as the migration conditions.

- elementary analysis

- mass spectrometry using the electronic impact technique (El).

- the measurement of the rotary power ([α] D) under conditions (concentration, solvent, temperature) indicated in a conventional manner.

Example 1

Fu arate of (S) - (+) - N- (2-amino-3-phenylpropyl) -N- (5-phenyl) - val eramide.

a) (S) -N- (tert-Butyloxycarbonyl) -phenylalaninamide.

In a ball, we introduce 7 g (42.6 mM) of (S) -phenylalaninamide and 1.8 g (45 mM) of sodium hydroxide in 4 ml of water and 8 ml of tert-butanol are added. Then, 10.92 g (50 mM) of di-tert-butyl-dicarbonate are added with stirring in small portions. A slight exotherm occurs and at the end of the addition, 4 ml of tert-butanol are added. After 1 hour of reaction, the reaction medium is taken up in ethyl acetate and this organic phase is washed with water, then with a 20% potassium carbonate solution in water. The organic phase is then dried over sodium sulphate, then evaporated to dryness. The crude product obtained is washed with water and hexane. 9.6 g (85.3%) of white powder are obtained. F = 147-149 ^* C.

b) (S) -N- (2tert-Butyloxycarbonylamino-3-phenylpropyl) - amine.

3.23 g (85 mM) of lithium aluminum hydride and 100 ml of dry THF are introduced into a 500 ml three-necked flask kept under nitrogen and fitted with a magnetic stirrer. In main¬ holding the temperature at 60 ^° C, poured 9g (34 mM) of amide obtained as above and dissolved in 200 ml of THF. The reaction is stopped after 1 hour 30 minutes. A "bonding" of the aluminum salts is carried out by adding 3.3 ml of water to the cooling medium, then 3.3 ml of 1N sodium hydroxide and then 7 ml of water. The organic phase is decanted, dried over Na ₂ S04, then evaporated. The oily residue (7.5 g) is used as for the rest of the synthesis.

c) 5-Phenylvaleric acid chloride.

8.0 g (45 mM) of 5-phenylvaleric acid, 80 ml of toluene and 0.1 ml of dimethylformamide are introduced into a flask. The mixture is heated to 80 ° C. and 4.3 ml (49 mM) of thionyl chloride are added dropwise with stirring, then the mixture is heated until the evolution of gas ceases. It is evaporated to dryness, thus obtaining 8 , 8 g of 5-phenylvaleric acid chloride which is used as it is for the following synthesis. d) (S) -N- (2tert-Butyloxycarbonylamino-3-phenylpropyl) - N- (5-phenyl) -valeramτde.

5.1 g (20.4 mM) of (S) -N- (2tert-Butyloxycarbonylamino-3-phenylpropyl) -amine obtained in 1 (b) are taken up in 100 ml of dry THF and placed in a flask. 2.2 g (22 mM) of triethylamine are added and the flask is placed in an ice bath. Then poured dropwise 4.32 g (22 mM) of acid chloride 1 (c) diluted in 50 ml of THF. After the end of the addition, the mixture is left to stir overnight, then the reaction medium is discarded in water and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium bicarbonate, then dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on a silica column (eluent: mixture of 40% ethyl acetate and 60% hexane). After evaporation of the fractions containing the product of Rf 0.3 in TLC with the same eluent, 3.6 g (43%) of (S) -N- (2tert-Butyloxycarbony1amino-3-pheny1propy1) -N- are recovered (5 - phenyl) -valeramide. F = 132-134 ^* C.

e) (S) - (+) - N- (2-amino-3-phenylpropyl) -N- (5-phenyl) - Yalera ide.

25 ml of dry dichloromethane are introduced into a 250 ml flask containing 3.5 g (8.5 mM) of the compound prepared above. The medium is kept under stirring in an ice bath. Then poured slowly, 10 ml of trifluoroacetic acid. After 2 hours, the medium is evaporated to dryness, then the residue is taken up in 150 ml of ether. After washing the ethereal phase with water, then with a 20% potassium carbonate solution, the organic phase is decanted, dried over Na∑S04 and evaporated to dryness. After recrystallization of the residue from ethyl acetate, 1.84 g (69.9%) of (S) - (+) - N- (2-amino-3-pheπylpropyl) -N- (5) are obtained. -phenyl) -valeramide. F = 64-66 ^* C, pasty.

TLC: 0.4 - 0.5 (dichloromethane 90% - ethanol 10%) [a] ²⁴ D = + 8.0 ^* (C = 2%, methanol)

Elemental analysis: calculated for C20H26N2O + 2/3 H2O: C: 74.53, H: 8.29, N: 8.69. Found: C: 74.59, H: 8.20, N: 8.63.

m / z (El) 310 (M ⁺ ).

f) (S) - (+) - N- (2-amino-3-phenylpropyl) -N- (5-phenyl) -valeramide fumarate.

17.0 g (54.8 mM) of product 1 (e) are taken up in 400 ml of ether and 50 ml of methanol, then 6.38 g (55 mM) of acid are added to an ice bath fumaric in solution in methanol. After hot washing in isopropanol of the precipitate obtained, 13.2 g (56.5%) of fumarate of (S) - (+) - N- (2-amino-3-phenylpropyl) -N- are recovered ( Pure 5-phenyl) -valeramide. F = 111-113 ^* C.

[α] ^ZB D = + 5.9 ^* (C = 1.2%, methanol)

Elemental analysis: calculated for C24H30N2O5: C: 67.59, H: 7.09, N: 6.57. Found: C: 67.63, H 7.07, N: 6.71.

Example 2

(R, S) -N- (2-amino-3-phenylpropyl) -N-methyl-N- (5-phenyl) valeramide fumarate.

a) (R, S) -N- (tert-Butyloxycarbonyl) -N'-methylphenylalanimide.

A solution containing 15.9 g (60 mM) of (R, S) -N- (tert- Butyloxycarbonyl) -phenylalanine, 6.06 g (60 mM) of triethylamine in 240 ml of dry THF is stirred in an ice bath to 4 ^° C. drop was added dropwise 7.8 ml (60 mM) of isobutyl chloroformate, then after 15 min, poured 9.0 ml (100 mM) of a solution of methylamine in 33% in Vethanol. Two hours after the end of the addition, the mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium bicarbonate solution, then dried and evaporated under reduced pressure. The solid residue obtained is then washed with water and with hexane, then the product is then dried to yield 12.75 g (76.4%) of the expected derivative. F = 150-152 'C.

b) (R, S) -N- (2tert-Butyloxycarbonylamino-3-phenylpropyl) - N-methylamine.

Analogously to Example 1 (b), it is synthesized from 12 g (43 mM) of previous amide. 9.3 g (81.9%) of a colorless oil are obtained, which is used as described below.

c) (R, S) -N- (2tert-But 1oxycarbony1amino-3-pheny1propy1) - N-methy1-N- (5-phen 1) -γaléramide.

Similarly to Example 1 (d), from 9.3 g (35 mM) of amine 2 (b) and from 6.9 g (35 mM) of 5-phenylvaleric acid chloride. Is isolated after chromatography on a silica column (eluent: 40% ethyl acetate - 60% hexane), 3.7 g (25%) of the expected product in the form of an oil.

d) (R, S) -N- (2-amino-3-phenylpropyl) -N-methyl- N- (5-phenyl) valeramide fumarate.

Analogously to Example 1 (e), starting from 1.5 g (3.5 mM) of product 2 (c), the oily product obtained is taken up in 100 ml of ether and 406 mg is added ( 3.5 M) fumaric acid in solution in methanol. After recrystallization in isopropanol, 1.18 g (76.6%) of fumarate of (R, S) -N- (2-amino-3-phenylpropyl) -N-methyl-N- (5- phenyl) -valeramide. F = 125-127 ^* C TLC (base): 0.5 - 0.6 (dichl oromethane 92% - methanol 8%)

Elemental analysis: calculated for C25H32N2O5: C: 68.16, H: 7.32, N: 6.36. Found: C: 67.91, H: 7.39, N: 6.39.

m / z (El) 324 (M ⁺ ).

Example 3

(S) - (-) - N- (2-dimethylamino-3-phenylpropyl) -N- methyl-N- (5-phenyl) -valeramide hydrochloride.

a) (S) -N'-methyl-phenylalaninamide trifluoroacetate.

26.8 g (96.4 M) of (S) -N- (tert-Butyloxycarbonyl) -N'-methyl-phenylalaninamide prepared as in 2 (a) from (S) -N- (tert-Butyloxycarbonyl) -phenylalanine are placed in a flask containing 80 ml of dry dichloromethane, then, in an ice bath, 60 ml of trifluoroacetic acid are gradually poured in and allowed to stir overnight. The reaction mixture is then evaporated to dryness, taken up in a mixture of 50% hexane and 50% ether. The salt is collected by filtration and dried. 23.7 g (84.2%) of (S) -N'-methyl-phenylalaninamide trifluoroacetate are obtained. F t = 139-141 ^* C.

b) (S) -N- (dimethylamino) -N'-methyl-phenylalaninamide.

To a solution containing 18.4 g (63 mM) of salt 3 (a) in 200 ml of methanol, is added with stirring, at room temperature, 63 ml (735 mM) of formaldehyde at 35 X. The mixture is brought to gentle reflux for 1 hour and then, after returning to 20 ^° C, was slowly added in small portions 8.4 g (222 mM) of sodium borohydride. After 1 hour of stirring, the medium is evaporated to dryness, the residue is then taken up in 30 ml of 1N sodium hydroxide and extracted with dichloromethane. The organic phase is washed with a saturated aqueous solution of sodium bicar¬ bonate, then dried and concentrated in vacuo. Oil obtained is chromatographed on a silica column (eluent: 50% ethyl acetate - 50% dichloromethane). 7.0 g (53.9%) of oil are obtained, corresponding to the product of Rf = 0.4 in the eluent mixture of dichloromethane 90% - methanol 10%. It is used as is for the rest.

The product has been characterized in the form of hydrochloride, from 618 mg (3 mM), 560 mg (76.6%) of (S) -N- (dimethylamino) -N'-methyl-phenylalaninamide chlorhy¬ . F = 140-142 ^* C.

c) (S) -N- (2-dimethylamino-3-phenylpropyl) -N-methylamine.

Similarly to Example 1 (b), starting from 6.4 g (31 mM) of the preceding product, 6.0 g of crude product used for the next step are isolated.

d) (S) - (-) - N- (2-dimethylamino-3-phenylpropyl) -N-methyl-N- (5-phenyl) -valeramide hydrochloride.

Analogously to Example 1 (d), from 4.0 g (20.8 mM) of amine 3 (c) and 3.9 g (20 mM) of acid chloride 1 (c ), is isolated after chromatography on a silica column (eluent: 70% ethyl acetate - 30% dichloromethane) 3.2 g (45.4%) of the expected product of Rf = 0.2 in this eluent mixture. The hydrochloride is produced in ether, from 1.4 g of product, after recrystallization from a dichloromethane mixture 70 ml - ether 30 ml, 1.4 g of (S) - (-) - N- hydrochloride are obtained ( 2-dimethylamino-3-phenylpropyl) -N- methyl-N- (5-phenyl) -valeramide. F = 86-88 ^* C, pasty, hygroscopic.

TLC (base): 0.6 - 0.7 (dichloromethane 95% - methanol 5%) [α] ¹⁹ D = - 19.4 ^* (C = 0.62%, ethanol)

Elemental analysis: calculated for C23H33CIN2O + 1/6 H2O +1/4 HC1: C: 68.80, H: 8.33, N: 6.90, Cl: 11.20. Found: C: 68.80, H: 8.55, N: 6.90, Cl: 11.22. m / z (El) 352 (M ⁺ )

Example 4

(S) - (+) - N-hydrochloride - N- (2-dimethylamino-3-phenylpropyl) - N-methyl1-N- (5-pheny1) -pentanamine.

a) (S) -N, N-dimethyl-phenylalanine hydrochloride.

The N-dimethylation of methyl ester of (S) -phenyl-alanine is carried out according to the method described in 3 (b), starting from 21.55 g (100 M) of methyl ester of (S) -pheny- lananine, 16.7 g (80.6%) of (S) -N- (dimethylamino) -phenylalanine methyl ester are obtained. The saponification is carried out on 14.5 g (70 M) of ester, in 150 ml of 6N HCl at reflux. After evaporation to dryness of HCl, the residue is taken up in 150 ml of absolute ethanol and 60 ml of propylene oxide and brought to reflux. 4.4 g (27%) of precipitate is isolated by filtration, washed with ether, identified as (S) -N, N-dimethylphenylalanine hydrochloride. F = 213-215 ^* C.

b) N-methyl-N- (5-phenyl) -valeramide.

A 500 ml three-necked flask fitted with a magnetic stirrer and containing 51.7 ml (420 mM) of 33% methylamine in ethanol and 100 ml of THF is kept in an ice bath. 27 g (140 mM) of 5-phenylvaleric acid chloride 1 (c) diluted in 250 ml of dry THF are gradually added. After the end of the addition, the mixture is left to return to ambient temperature and stirred for 12 hours. The medium is then thrown into water and extracted with ethyl acetate. The organic phase is washed several times with water and with a 20% aqueous potassium carbonate solution. The organic phase is dried over sodium sulphate, then evaporated to dryness to give 25.7 g (96%) of orange oil used as such for the following. c) N-methy 1 -phenyl -5-penty 1 friend ne.

According to the method described in 1 (b), starting from 24.0 g (125 mM) of amide 4 (b), we arrive at 21.7 g (98) of N-mé¬ thy 1 -phenyl -5 -penty lamin which is an oil.

d) (S) -N, N- (dimethyl) -N'-methyl-N '- (5-phenylpentyl) -phenylalaninamide.

4.8 g (20.9 mM) of (S) -N, N-dimethyl-1-phenylalanine hydrochloride 4 (a) are placed in a 100 ml three-necked flask fitted with a magnetic stirrer and kept under nitrogen and at 4 ^* C. 54 ml of anhydrous chloroform, 3 ml (20.9 mM) of triethylamine, 3.7 g (20.9 M) of amine 4 (c) and 3.2 g (17.4 M) are added. ) of 85% 1-hydroxy-benzotriazole. After 10 n of stirring, 4.8 g (23.3 mM) of dicyclohexylcarbodiimide are added. The medium is stirred for 24 hours, allowing it to gradually rise to ambient temperature, then filtered to remove the dicyclohexylurea formed during the reaction. The solvent is evaporated, the residue is taken up in ethyl acetate and after several washes with a saturated aqueous solution of NaHCO 3, the organic phase is dried over sodium sulfate and concentrated in vacuo. After chromatography on a silica column (eluent: 95% dichl oromethane - 5% methanol, 4.7 g (61.1%) of the expected product are obtained in the form of an oil, Rf: 0.5 in the eluent used for the purification .

e) (S) - (+) - N- (2-dimethylamino-3-phenylpropyl) -N-methyl-N- (5-phenyl) -pentanamine hydrochloride.

A 1 M alane (A1H3) solution is prepared by adding dropwise 0.5 equivalents of sulfuric acid at room temperature to a 1 M solution of lithium aluminum hydride maintained under stirring and at 20 ' vs. 60 ml of this freshly prepared solution are introduced into a 250 ml three-necked flask kept under a nitrogen atmosphere. A solution of 4.2 g (11.9 mM) of a- mide 4 (d) in 20 ml of anhydrous THF. 30 minutes after the end of the addition, the reaction mixture is poured into a 4 ° C solution of 100 ml of 1N sodium hydroxide, then extracted with dichloromethane. The organic phase is dried over magnesium sulphate, then evaporated to yield 3.9 g (97%) of oily product.

From 1.2 g of base product, the di-hydrochloride is made in ether, 720 mg (48%) of (S) - (+) - N- (2-dimethylamino-3-) di-hydrochloride are obtained. phenylpropyl) -N-methyl-N- (5-phenyl) -pentanamine. F = 43-45 "C (pasty), contains 1.4% water.

TLC (base): 0.5-0.6 (dichloromethane 85% - methanol 15%) [α] ¹⁹ D = + 26.7 ^* (C = 0.6%, ethanol)

Elemental analysis: calculated for C23H3βCl2N2 + 1/3 H2O: C: 66.10, H: 8.79, N: 6.70, Cl: 17.00. Found: C: 66.10, H: 8.95, N: 6.70, Cl: 17.06.

m / z (EI) 338 (M ⁺ ).

Example 5

(S) - (-) - N- (2-amino-3-phenylpropyl) -N-methyl-N- (3,4-dichlorophenyl) -acetamide hydrochloride.

a) (S) -N- (2tert-Buty1oxycarbony1amino-3-pheny1propy1) -N-methy1-N- (3,4-dich1orophény1) -acetamide.

Analogously to Example 4 (d), from 3.7 g (18 mM) of 3,4-dichlorophenylacetic acid and from 3.2 g (12.1 mM) of (S) -N- ( 2tert-Butyloxycarbonylamino-3-phenylpropyl -) - N-methylamine, prepared according to 2 (b) from the optically active precursor, isolated after chromatography on a silica column (eluent: 30% ethyl acetate - 70% hexane ) 3.0 g (55%) of expected product (Rf = 0.3). F = 83-85 ^* C. b) (S) - (-) - N- (2-amino-3-phenylpropyl) -N- methyl-N- (3,4-dichloropheny1) -acetamide hydrochloride

2.9 g (6.4 M) of (S) -N- (2tert-Butyloxycarbonylamino-3-phenyl-propy1) -N-methy1-N- (3,4-dich1orophény1) -acetamide are treated according to the process described in 1 (e) to yield 2.3 g of colorless oil. This product is taken up in 150 ml of ether and treated with a solution of hydrochloric acid in ether to give, after recrystallization from an ethanol-ether mixture (70 X-30 X), 1.4 g (56.4 %) of (S) - (-) - N- (2-amino-3-phenylpropyl) -N-methyl-N- (3,4-dichloro-phenyl) -acetamide hydrochloride. F = 130-132 ^* C.

TLC (base): 0.2 - 0.3 (dichloromethane 95% - methanol 5%) [α] ²⁴ D = - 11.0 "(C = 2%, methanol)

Elemental analysis: calculated for CιβH2iCl3N2θ: C: 55.76, H: 5.46, N: 7.22, Cl: 27.43. Found: C: 55.72, H: 5.50, N: 7.22, Cl: 27.19.

m / z (El) 351 (M ⁺ ).

Example 6

(S) - (-) - N- (2-amino-3-phenylpropyl) -N-methyl-N- (1-adamanty1) -acetamide hydrochloride.

a) (S) -N- (2tert-Butyloxycarbonylamino-3-phenylpropyl) -N-methyl-N- (1-adamanty1) -acetamide.

Analogously to Example 4 (d), starting from 3.49 g (18 M) of 1-adamanty! Acetic acid and 3.2 g (12.1 mM) of (S) -N- (2tert-Butyloxycarbony1amino-3-phen 1propy1) -N-methyl1- amine, recovered after chromatography on silica (eluent: ethyl acetate 30% - hexane 70%) 3.2 g (60.6%) of the expected product (Rf = 0.3). F = 97-99 ^* C. d) (S) - (-) - N- (2-amino-3-phenylpropyl) -N- methyl-N- (1-adamantyl) -acetamide hydrochloride.

According to the process described in 1 (e), starting from 2.1 g (4.7 mM) of the preceding product, 1.7 g of oily compound are obtained from which the hydrochloride is made. After recrystallization from an isopropanol-ether mixture (60-40), 700 mg (39.5%) of (S) - (-) - N- (2-amino-3-phenylpropyl) -N-methyl hydrochloride are isolated. -N- (1-adamanty1) -acetamide.

TLC (base): 0.2 - 0.3 (95% dichloromethane - 5% methanol)

F = 169-171 ^* C.

[α] ¹⁹ D = - 27.5 ^* (C = 0.4%, ethanol)

Elemental analysis: calculated for C22H33CIN2O: C: 70.10, H: 8.82, N: 7.43, Cl: 9.40. Found: C: 70.02, H: 8.90, N: 7.47, Cl: 9.54.

m / z (El) 340 (M ⁺ ).

Example 7

(S) - (+) - N- (2-amino-3-phenylpropyl) -N-methyl-N - (5-phenyl) -pentanamine di-oxalate.

a) (S) -N- (tert-Butyloxycarbonyl) -N'-methyl-N '- [5- (phenyl) -penty 1] -phenyl al ani nami de.

Analogously to Example 4 (d), starting from 26.5 g (100 mM) of (S) -N- (tert-Butyloxycarbonyl) -phenylalanine and 19.5 g (110 mM) of amine 4 ( c), 41.4 g (97.6%) of product in the form of a colorless oil are obtained after chromatography on silica (eluent: 10% ethyl acetate - 90X hexane).

b) (S) -N'-methyl-N '- [5- (phenyl) -pentyl] -phenylalanina- mid of.

21.2 g (50 M) of the preceding product are treated according to the process described in 1 (e) to lead to 14.3 g (88.2%) of (S) -N'-methy1-N '- [5 - (pheny1) -penty1] -phenylalaninamide.

c) (S) - (+) - N- (2-amino-3-phenylpropyl) -N- methyl-N- (5-phenyl) -pentanamine di-oxalate.

The reduction of 5.0 g (15.4 mM) of amide 7 (b) is carried out as described in Example 4 (e) and makes it possible to obtain 3.7 g (77.5%) of amine in the form of an oil "

The oily product obtained is taken up in 200 ml of ether and 2.16 g (24 mM) of oxalic acid in solution in ethanol are added. After hot washing in ethanol, 4.8 g (82.3%) of (S) - (+) - N- (2-amino-3-phenylpropyl) -N- di-oxalate are isolated. methyl-N- (5-phenyl) -pentanamine in the form of a white crystallized product. F = 172-174 ^* C.

TLC (base): 0.5 - 0.6 (dichloromethane 85% - methanol 15%) [α] ^2β D = + 26.9 ^* (C = 0.26%, methanol)

Elemental analysis: calculated for C25H34N2O8: C: 61.21, H: 6.99, N: 5.71. Found: C: 61.03, H: 6.91, N: 5.71.

m / z (El) 219 (M ⁺ - 91).

Example 8

(R) - (-) - N- (2-amino-3-phenylpropyl) -N-methyl- -N- (5-phenyl) -pentanamine di-oxalate.

a) (R) -N ^* -methyl-N '- [5- (phenyl) -pentyl] -phenylalanina mide.

According to the methods described in Examples 7 (a) and 7 (b), from 4.8 g (18 mM) of (R) -N- (tert-Butyloxycarbonyl) - phenylalanine, 4.8 g (82.3%) of (R) -N'-methyl-N'- are obtained [5- (phenyl) -pentyl] -phenylalaninamide in the form of a colorless oil.

b) (R) - (-) - N- (2-amino-3-phenylpropyl) -N- methyl-N- (5-phenyl) -pentanamine di-oxalate.

Similarly to the example (b), the reduction of 4.7 g (14.5 mM) of amide 8 (a) leads to 4.2 g (93.4%) of the expected product in the form of an oil. The di-oxalate is produced as described in 7 (c) from 4.1 g (13.2 mM) of base, 5.1 g (78.7%) of (R) - (-) - Pure N- (2-amino-3-pheny1propyl) -N-methyl-N- (5-phenyl) -pentanamine are isolated. F = 173-174 "C.

TLC (base): 0.5 - 0.6 (dichloromethane 85% - methanol 15%) [α] ^2β D = - 24.7 ^* (C = 0.24, methanol)

Elemental analysis: calculated for C25H34N2OB: C: 61.21, H: 6.99, N: 5.71. Found: C: 61.12, H: 6.93, N: 5.74.

m / z (El) 219 (M ⁺ - 91).

Example 9

(S) - (+) - N- (2-methylamino-3-phenylpropyl) -N-methy1-N- (5-pheny1) -pentanamine di-oxalate.

a) (S) -N- (tert-Butyloxycarbonyl) -N-methyl-N'-methyl-N'— [5- (phenyl) -pentyl] -phenylalaninamide.

Analogously to Example 4 (d), from 2 g (7.17 M) of (S ⁾ -N- (tert-Butyloxycarbonyl) -N-methyl-phenylalanine and 1.4 g (7 , 9 mM) of amine 4 (c), after chromatography on silica is obtained (eluent: ethyl acetate 10% - hexane 90%) 2.8 g (89.1%) of product in the form of a colorless oil. b) (S) -N-methyl-N'-methyl-N '- [5- (phenyl) -pentyl] -phenylalanamide.

2.8 g (6.4 mM) of the preceding product are treated according to the process described in 1 (e) to result in 1.75 g (80.9%) of (S) -N-methyl-N'-methyl -N '- [5- (phenyl) -pentyl] -phenylalaninamide

c) (S) - (+) - N- (2-methylamino-3-phenylpropyl) - N-methyl-N- (5-phenyl) -pentanamine di-oxalate.

The reduction of 1.75 g (5.2 mM) of amide 8 (b) is carried out as described in Example 4 (e) and makes it possible to obtain 1.6 g (77.5%) of oil colorless.

This oily product is taken up in 100 ml of ether and 936 mg (10.4 mM) of oxalic acid in solution in ethanol are added. The precipitate obtained is recrystallized from ethanol. 1.7 g (82.3% of (S) - (+) - N- (2-methylamino-3-phenylpropyl) -N-methyl-N- (5-phenyl) -pentanamine are obtained. form of a white crystallized product.

F = 85-87 ^* C, pasty.

TLC (base): 0.3-0.4 (dichl oromethane 90% - methanol 10%)

[α] ²⁶ D = + Î8.8 ^* (C = 1.54%, methanol)

Elementary analysis: calculated for C2βH3βN2θa + 1/3 H2O: C: 61.11, H: 7.18, N: 5.48. Found: C: 61.22, H: 7.32, N: 5.53.

m / z (El) 233 (M ⁺ - 91).

Example 10

(S) - (+) - N- [2- (4-morphol ino) -3-pheπylpropyl] -N- methyl-N- (5-phenyl) -pentanamine di-oxalate. a) (S) -N-methy1-N- (5-pheny1) -penty1-2- (4-morpho1ino) -3- phenylpropionamide.

4.84 g (15 mM) of (S) - N'-methyl-N '- [5- (phenyl) -pentyl] -phenylalaninamide 7 (b), 60 ml of dimethylformamide are introduced into a 250 ml flask dry, 8.18 g (60 M) of potassium carbonate, 4.5 g (30 M) of sodium iodide and 2.14 g (15 mM) of 2,2'-dichloro-diethylether. This mixture was stirred at 50 ^° C for 3 heures.Après cooling, the product was extracted with ethyl acetate, the organic phase is washed with water and with a sodium bicarbonate solution satura¬ tion, then it is dried over sodium sulfate and concentrated to dryness. The residue obtained is chromatographed on a silica column (eluent: mixture of 20% ethyl acetate and 80% dichloromethane). After evaporation of the fractions containing the product of Rf 0.2 in TLC with the same eluent, 3.75 g (63.4%) of a white solid are recovered. F = 72-74 ^* C.

b) Di-oxalate of (S) - (+) - N- [2- (4-morpholino) -3-phenylpropyl] -N-methyl-N- (5-phenyl) -pentanamine

As described for Example 4 (e), the reduction of 3.7 g (9.3 mM) of amide 10 (a) leads to 3.4 g (96%) of base product in the form of an oil colorless.

The di-oxalate is prepared from 2.7 g (7.1 mM) of this oil and 1.26 g (14 mM) of oxalic acid. The product obtained is recrystallized from an ethanol-ether mixture (10-90). 2 g (50%) of a hygroscopic white powder of (S) - (+) - N- [2- (4-morpholino) -3-phenylpropyl] -N- methyl-N- ( 5-phenyl) -pentanam ne. F = 82-84 "C.

TLC (base): 0.4 - 0.5 (dichloromethane 90% - methanol 10%) [α] ^Z6 D = + 26.9 ^* (C = 1.3%, methanol)

Elemental analysis: calculated for C29H4θN2θs + 0.8 H2O: C: 66.94, H: 8.18, N: 5.78. Found: C: 66.93, H: 8.19, N: 5.72. m / z (El) 289 (M ⁺ - 91)

Example 11

(S) - (-) - N- [2- (1-pyrrolo) -3-phenylpropyl] -N-methyl- -N- (5-phenyl) -pentanamine oxalate.

^'A) (S) -N-methyl-N- (5-phenyl) pentyl-2- (1-pyrrolo) -3-phe- nylpropîonamide.

1.6 g (4.9 mM) of (S) - N'-methyl-N '- [5- (phenyl) -pentyl] -phenylalanaminide 7 (b), 20 ml are introduced into a 250 ml flask of dimethylformamide, 5 mM hydrochloric acid and 660 mg (5 mM) of 2,5-dimethoxy-tetrahydrof uranne. This mixture was stirred at 80 ^° C for 15 minutes. After cooling, the product is extracted with ethyl acetate, this organic phase is washed with water and with a saturated sodium bicarbonate solution, then it is dried over sodium sulfate and concentrated to dryness. The residue obtained is chromatographed on a silica column (eluent: mixture of 20% ether and 80% hexane). After evaporation of the fractions containing the product of Rf 0.2 in TLC with the same eluent, 1.15 g (61.5%) of a colorless oil are recovered.

b) Oxalate of (S) - (-) - N- [2- (1-pyrrolo) -3-phenylpropyl] -N- methyl-N- (5-phenyl) -pentanamine.

As described for Example 4 (e), the reduction of 1.1 g (2.9 mM) of amide 11 (a) leads to 1 g (95%) of base product in the form of a colorless oil.

The oxalate prepared from this oil is recrystallized from an isopropanol-ether mixture (10-90). 370 mg (28%) of (S) - (-) - N- [2- (1-pyrrolo) -3-phenylpropyl] - N-methyl-N- (5-pheπyl) -pentanamine are obtained. F = 129-131 ^* C.

TLC (base): 0.7 - 0.8 (d chloromethane 90% - methanol 10%) [α] ^2β D = - 34.6 ^* (C = 1.04%, methanol)

Elemental analysis: calculated for C27H34N2O4: C: 72.0, H: 7.55, N: 6.22. Found: C: 71.91, H: 7.55, N: 6.24.

m / z (El) 360 (M ⁺ ).

Example 12

(S) - (+) - N- [2- (1-pyrrolidino) -3-phenylpropyl] -N- methy1-N- (5-pheny1) -pentanamine di-oxalate.

a) (S) -N- (1-pyrrolidinyl) -phenylalanine.

48 ml of a 1.5 M solution of 1,4-butyric di-aldehyde are introduced into a 250 ml three-necked flask (prepared according to the method described in the publication by GF Costello, R. James, JSShaw, AM Slater and NCJ Stutchbury, J.Med.Chem., 1991, 34, 181-189) to a stirred mixture at 0 ^° C and consisting of 12.9 g (60 mM) ester hydrochloride méthy¬ L lic -phenylalanine in 90 ml of ethanol and 6 ml of glacial acetic acid. Then 7.2 g (114.6 M) of sodium cyanoborohydride are added in small portions. The pH of the solution is maintained at 5 by addition of acetic acid, then after stirring overnight at room temperature, the solution is cooled and the mixture is extracted with 2 times 100 ml of dichloromethane after having added sufficient potassium hydroxide. as a tablet to make it basic. The organic phase is washed with saturated sodium bicarbonate solution, then dried over sodium sulfate. After evaporation to dryness, 6.6 g of colorless oil are obtained. This oily residue is taken up in 60 ml of 6N hydrochloric acid and brought to reflux for 2 hours. After evaporation to dryness, the product is taken up in 70 ml of ethanol and 30 ml of propylene glycol and then brought to reflux. A white precipitate is formed which is isolated by filtration and washed with ethanol. Or 1.9 g (13.6%) of white powder. F = 224-226 ^* C. b) (S) -N-methyl-N- (5-phenyl) -pentyl-2- (1-pyrrolidino) -3- phenylpropionamide.

From 1.9 g (8.15 mM) of acid 12 (a) previously prepared and 1.45 g (8.2 mM) of amine 4 (c) according to the method described for 'example 4 (d) is obtained after chromatography on silica (eluent: 50% ethyl acetate - 50% dichloromethane) 1.76 g (57.1%) of the expected product in the form of a white solid of Rf 0 , 2 in the previous eluent mixture. F = 47-49 ^* C.

c) (S) - (+) - N- [2- (1-pyrrolidino) -3-phenylpropyl] -N-methyl-N- (5-phenyl) -pentanamine di-oxalate.

The reduction of 1.7 g (4.5 mM) of amide 12 (b) is carried out according to the procedure described for example 4 (e) and allows to obtain 1.5 g (91.6 %) colorless oil which is (S) - (+) - N- [2- (1-pyrrolidino) -3-phenylpropyl] -N-methyl-N- (5-phenyl) -pentanamine in base form. The di-oxalate is prepared using 800 mg of this oil, 1.1 g (78.3%) of very hygroscopic white powder are obtained. F = 54-56 ^* C, pasty.

TLC (base): 0.3 (dichloromethane 90% - methanol 10%) [α] ²⁶ D = + 23.2 '(C = 1.08%, methanol)

Elemental analysis: calculated for C29H40N2O8: C: 63.95, H: 7.40, N: 5.14. Found: C: 64.02, H: 7.42, N: 5.18.

m / z (El) 273 (M ⁺ -91).

Example 13

Oxal ate of (S) - (-) -N- [2- (1-butyramido) -3-phenyl propyl] -N- methy 1 -N- (5-pheny 1) -pentanami ne.

2.5 g of a 100 ml sorted ball, equipped with a magnetic stirrer and placed in an ice bath (8mM) of amine 7 (c) in base form, 25 ml of dry tetrahydrofuran and 890 mg (8.8 mM) of triethylamine. Poured onto this mixture, stirred, 933 mg (8.8 mM) of butyric acid chloride diluted in 10 ml of tetrahydrofuran. After 1 hour, the reaction mixture is poured into 100 ml of ice water and the product is extracted with 2 times 100 ml of ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution, then dried over sodium sulfate and evaporated to dryness. This oily residue is taken up in 200 ml of anhydrous ether and, after addition of 810 mg (9 mM) of oxalic acid in solution in ether, the salt is recovered in the form of a white precipitate. After recrystallization from ethanol, 2.5 g (66.4 mM) of (S) - (-) - N- [2- (1-butyramido) -3-phenylpropyl] -N-methyl oxalate are isolated. -N- (5-phenyl) -pentan- amine. F = 167-169 ^* C.

TLC (base): 0.5 - 0.6 (dichloromethane 90% - methanol 1056) [α] ^2β D = - 10.2 ^* (C = 1.47%, ethanol)

Elemental analysis: calculated for C27H3BN2O5 + 0.4 H ₂ 0: C: 68.13, H: 8.18, N: 5.87. Found :, C: 67.92, H: 8.14, N: 5.87.

m / z (El) 380 (M ⁺ ).

Example 14

(S) - (+) - N- [2- (1-butanamino) -3-phenylpropyl] -N- methyl-N- (5-phenyl) -pentanamine di-oxalate.

According to the procedure described for Example 4 (e), the reduction of 2.0 g (5.26 M) of Tamide described in Example 13 used in its base form leads to 1.85 g (96 %) colorless oil. The di-oxalate is prepared according to the usual operating protocol, starting from the preceding oily residue, 1.85 g (67.7%) of di-oxalate from (S) - (+) - N- [2] are isolated - (1-buta- namino) -3-phenylpropyl] -N-methyl-N- (5-phenyl) -pentanamine under form of a very hygroscopic white powder.

TLC (base): 0.5 - 0.6 (dichl oromethane 90% - methanol 10%) [α] ^2B D = + 19.0 ^* (C = 1.84%, methanol)

Elemental analysis: calculated for C29H42N2O8 + 1/3 H2O: C: 63.14, H: 7.85, N: 5.04. Found: C: 63.15, H: 7.75, N: 5.08.

m / z (El) 176 (M ⁺ - 190)

Table I represents the most remarkable compounds corresponding to formula I. The preparation of these representative compounds has been described in detail in the examples above.

TABLE I

Biological evaluation

In vitro results:

The binding of the compounds of the invention to the sigma sites is measured according to the technique described by BL Largent, AL Gundlach, and SH Snyder [Proc. Natl. Acad. USA., 1984, 81, 4983]. The membrane preparations are made from rat brains (Sprague-Dawley, 150-170 g). Brains were weighed and homogenized with a Polytron in 25 volumes of Tris-HCl buffer pH 7.7 at + 4 ^° C. The homogenate is then centrifuged at 45 000 g during 10 min and the supernatant removed. The centrifugation pellet is rinsed twice with Tris-HCl buffer pH 7.7 at +4 ^* C and then taken up in 80 volumes of Tris-HCl buffer pH 8.0 at +25 ^* C, The membrane fractions (0.4 ml) are then incubated in the presence of increasing concentrations of the reference drug (peπtazocine 10 ~ ¹⁰ to 10 " ⁵ M) or of the products to be tested (10 ^{~ 10} to 10 ^{" 5} M) and the ra¬ dioactive ligand ( [ ³ H] -Propyl-3- (3-hydroxyphenyl) piperidine ([ ³ H] - PPP), 3 nM, 90-120 Ci / mmol, New England Nuclear, Dupont de Nemours) for 120 min at room temperature. The test ends by filtration through a Whatman GF / B filter under suction using a Brandel apparatus. The filters are rinsed 3 times with Tris-HCl buffer pH 7.7 at + 4 ^° C. Non-specific binding is determined in the presence of 10 microM pentazo- film.

The filters are distributed in counting bottles. The ³ H radioactivity was counted by scintillation in liquid medium using the scintillating medium Formula 989 (New England Nuclear, Dupont de Nemours) and a scintillation counter LS 6000 TA (Beckman).

The inhibition curves are analyzed using the Ligand program [GA Me Pherson,, Computer Programs in Biomedicine, 1983, 17, 107] and an IC 50 and a K are calculated. TABLE II

* i = inactive (displacement <30% at 10 OOO nM)

The binding of the compounds to the dopaminergic D ₂ receptor is measured according to the method described by M. Terai, K. Hidaka, and Y. Nakamura. [Eur. J. Pharmacol. , 1989, 173, 177]. Of striata of rats were weighed and homogenized with a Polytron in nine volumes of buffer 50 mM Tris, 5 mM EDTA, 8 mM _MgCl2, pH 7.15 to 4 ^* C. The homogenate is then centrifuged at 18 000 g for 20 min and the supernatant is removed. The centrifugation pellet is taken up in 200 volumes of incubation buffer (Tris 50 mM, EDTA 1 mM, MgCl∑ 5 mM, CaCl2 1.5 mM, NaCl 120 M, 5 M KC1, 0.1% ascorbate and 10 μM pargyline, pH 7.15 at +25 "C.) The membrane fractions (0.4 ml) are then in¬ cubed in the presence of increasing concentrations of the reference drug. (sulpiride 10 ^{~ 10} to 10 ^"5 M) or test products (10 ^-10 to 10 ^{" 5} M) and the radioactive ligand ([ ³ H] -YM-091512, 0.1 nM, 70-87 Cî / mmol, New England Nuclear, Dupont de Nemours). The samples are incubated for 60 min at room temperature. The test is terminated by filtration through a What an GF / B filter under suction with the aid of an ap ¬ Brandel same. the filters are rinsed 4 times the incubation buffer at 4 ^° C. the nonspecific binding was determined in the presence of 3 .mu.M sulpiride. the counting the radioac¬ tivity and analysis of results are performed as described above.

The results presented in Table II show that the compounds described have a high affinity and a high selectivity for sigma receptors.

"In-vîvo" results:

Antagonism of convulsions and mortality induced by N-methyl1-D-aspartic acid (NMDA)

The time to onset of convulsions (clonic and to¬ nics) and the survival time after the injection of NMDA (175 g / kg, ip) are measured in male Swiss mice (20 -25 g) according to the method described. by JD Leander, RR Lawson, PL Ornstein and DM Zimmerman [Brain Research, 1988, 448, 115-120]. The products to be tested are injected ip 30 minutes before the start of the test. -

39

TABLE III

* significant result for p <0.05

The results of this study are presented in the ta ble _¬ III. An anticonvulsant effect and a protective effect with respect to the toxicity induced by NMDA are observed for several compounds administered at a dose of 1 mg / kg. Normobaric hypoxia

The survival time (time of appearance of the 1st respiratory gasp) is measured in male Swiss mice (20 -25 g) exposed to an oxygen-poor atmosphere (96- * "N2, 4% O2) according to the technique described by JC Lamar, H. Poignet, M. Beaughard and G. Dureng, [Drug Development Research, 1988, 14, 297-304]. The test products and the reference drug (vincamine 20 mg / kg) are injected i.p. 30 min before the start of the test.

The results described in Table IV are representative of the effect of the compounds of the invention.

TABLE IV

* significant result for p <0.05 Antagonism of group toxicity induced by amphetamine

Male Swiss mice (20-25 g) are treated with dexamphetamine sulfate (8 mg / kg, ip) and then placed in 25 x 19.5 x 13.5 cm cages (10 mice per cage) [ MRA Chance, J. Pharmacol. , 1946, 87, 289-296]. Dead animals are counted 1, 2, 3, 4, 5 and 24 hours later. The products to be tested are injected i.p. 30 minutes before Tamphetamine. At a dose of 30 mg / kg, the compounds described in Examples 1 and 2 protect 90% of the animals.

Antagonism of amphetamine-induced stereotypies

Male Swiss mice (20-25 g) are treated with dexamphetamine sulfate (8 mg / kg, i.p.) and placed in individual cages. The intensity of stereotypies is determined every 10 min for 2 hours according to the following scale [P. Simon P. and R. Chermat, J. Pharmacol., 1972, 3, 235]: 0 = absence of stereotypy and abnormal movement, 1 = rare stereotypical movements or almost continuous sniffing, the head of the animal being directed upwards , 2 = intense sniffing or jerky and rapid movements of the head, sometimes interrupted by short phases of chewing, 3 = intense and continuous stereotypical movements (chewing, licking, head movements), often accompanied by repeated movements of the forelegs against a wall of the cage. The products to be tested are administered i.p. 30 mins before amphetamine. A significant decrease in stereotyped movements is observed with the molecules corresponding to Examples 2, 5 and 6 at a dose of 1 mg / kg.

Antagonism of behavioral response and hypothermia induced by Tapomorphine

Male Swiss mice (20-25 g) are treated with Tapomorphine (1 mg / kg, sc). The behavioral response (climbing behavior and stereotypes) and hypothermia induced by Tapomorphine are determined respectively 20 and 30 min after its administration according to the protocol defined by AJ Puech, R. Chermat, M. Poncelet, L. Doaré and P. Simon [Psychopharmacol. , 1981, 75, 84]. The presence or absence of the climbing behavior is noted. The intensity of the stereotypies is determined 20 minutes later according to the following scale: 0 = absence of stereotypy and / or abnormal movement, 1 = rare stereotyped movements or intermittent sniffles, 2 = jerky and rapid movements of the head , sniffing, licking, 3 = intense licking and chewing phase. The products of the invention and the reference drug (haloperidol 0.5 mg / kg) are injected ip 30 minutes before Tapomorphine. The rectal temperature is measured.

Statistical analysis of the results (ANOVA and Dunnett tests) is carried out using Statview software (Brain-Power) for all of the tests described above.

TABLE V

* significant result for p <0.05 The results presented in Table V above show that the compounds described have a pharmacological profile fairly close to that of Thaloperidol which is a conventional antipsychotic drug.

Therapeutic use

For the therapeutic use of the compounds of formula I as neuroprotectors, anxiolytics and for the treatment of psychotic disorders, dyskinesias, convulsions, memory disorders and inflammations, the doses administered to patients are between 0.1 and 10,000 mg per day. For a normal adult weighing 70 kg, these doses are between 0.001 to 100 mg / kg of body weight per day. The therapeutic doses can vary according to the clinical condition of the patient and are established by the person skilled in the art. Administration can be by enteral, parenteral, topical or ocular route.

Pharmaceutical compositions

This invention also includes all of the pharmaceutical compositions containing the compounds of formula I in combination with all of the pharmaceutically acceptable adjuvants and ingredients.

By enteral route, the drugs can be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions. The preparation of oral forms may combine one or more of the following products: lactose, sucrose, starch, cellulose esters, talc, stearic acid, magnesium stearate, magnesium oxide, calcium or magnesium salts of phosphoric acid or of sulfuric acid, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohols nyl ic.

By the parenteral route, the compositions can be in the form of aqueous or nonaqueous sterile solutions or suspensions for infusion or for injection, these solutions or these suspensions can be prepared extemporaneously from sterile powders or granules which may contain one or more of the adjuvants mentioned above as well as an aqueous or non-aqueous vehicle.

Topically, the pharmaceutical compositions based on the compounds according to the invention are in the form of ointments, tincture, cream, ointments, powders, suspensions, solutions, lotions, gels. The topical compositions preferably contain from 0.001 to about 5% by weight of compound (s) of formula (I). By eye, these are mainly eye drops or ointments.

The compositions according to the invention may also contain flavor-improving agents, preserving agents, stabilizing agents, moisture regulating agents, pH regulating agents, agents modifying osmotic pressure, agents, antioxidants.

By way of example, the formulation of tablets and ointments prepared according to the usual methods known to those skilled in the art is presented:

- 0.2 g tablets:

Active substance of Example 5 5 to 50 mg

Bicalcium phosphate 20 mg

Lactose 30 mg

Talc 10 mg

Magnesium stearate 5 mg

Starch in sufficient quantity for 200 mg In this example, the compound of example 5 can be replaced by the same amount of compounds of examples 1 to 15.

- ointment:

Active substance of Example 2 1 to 5 mg stearyl alcohol 3 g

Lanolin 5 g

Vaseline 15 g

Distilled water sufficient for 100 g

In this example, the compound of Example 2 can be replaced by the same amount of compound of Examples 1 to 15.

Claims

1. Diameter compounds corresponding to the following general formula:

Ar

in which:

n is a selected number from 0 to 8;

R 1 represents a hydrogen, an alkyl, branched alkyl, cycloalkyl, hydroxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl residue;

R2, R3, R4, Rs and Rβ independently represent a hydrogen, an alkyl, branched alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, residue. alkoxyalkyl, haloalkox¬ yalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl, car¬ boxyalkyl, alkanoyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl;

R2 and R3 taken together can form a cycle corresponding to the formula:

- (CH ₂ ) mA- (CH ₂ ) m-

where A represents a single bond, an oxygen atom or a nitrogen atom substituted by a hydrogen residue, an alkyl residue ,. branched alkyl, cycloalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl; m is a selected number from 1 to 3;

R2 and R3 taken together can form an unsaturated hydro¬ carbon cycle from C4 to Cs;

Rs and Rβ taken together can form a cycle (2 to 8 C); X represents a single bond, -CH2-, -C (= 0) -, -S (O) -, -S (0) 2 -;

Y is an alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, adamantyl, alkoxyalkyl, aralkyl, aryl, alkenyl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkylsulf inyl, alkylsulfonyl, arylsulfonyl, aryloxyaryloxyalkyl, arylsulfonyl residue , heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio; each of the preceding groups Y can additionally carry one or more substituents selected from the radicals hydrogen, hydroxy, alkyl, branched alkyl, cycloalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkylalkyl, adamantyl, alkoxyalkyl, haloalkoxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, cyano, α ino, monoalkylamino, dialkylamino, carboxyalkenyl and alkynyl;

Ar is a radical selected from the following radicals: aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, .arylthio, heteroarylthio, aralkylthio, heteroaralkyl; each of the preceding groups Ar may also carry one or more substituents selected from the radicals hydrogen, hydroxy, alkyl, branched alkyl, cycloalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkylalkyl, adamantyl, alkoxyalkyl, haloalkoxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, cyano, amino, nitro, monoalkylamino, dialkylamino, carboxyalkenyl and alkynyl; as well as all their pharmaceutically acceptable salts with mineral and organic acids.

2. Compounds according to Claim 1, characterized in that:

n is a selected number from 0 to 8;

R 1 represents a hydrogen, a C1 to C3 alkyl, branched alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alken nylalkyl, alkynylalkyl;

R2, R3, R4, Rs and Rβ independently represent a hydrogen gene, a C1 to Ce alkyl radical, branched alkyl, alkenyl cycloalkyl, hydroxyalkyl cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenylalkyl;

R2 and R3 taken together can form a cycle corresponding to the formula:

- (CH ₂ ) mA- (CH ₂ ) m-

where A represents a single bond, an oxygen atom or a nitrogen atom substituted by a hydrogen residue, an alkyl residue from C1 to C3;

m = 2;

R2 and R3 taken together can form an unsaturated hydrocarbon cycle from C4 to Cs;

X represents a single bond, -CH2-, -C (= 0) -;

Y is an alkyl, cycloalkyl, cycloalkylalkyl, ad¬ amantyl, aralkyl, aryl, alkenyl, residue. alkenylalkyl, heteroar¬ yl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, each of the preceding groups Y can additionally carry one or more substituents selected from the radicals hydrogen, hy¬ droxy, alkyl, branched alkyl, cycloalkyl, adamantyl, halo, haloalkyl, aralkyl, aryl, carboxyalkyl, alkanoyl, cyano, amino, monoalkylamino, dialkylamino, carboxyalkenyl and alky¬ nyl;

Ar is a radical selected from the following radicals: aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, each of the preceding groups Ar can additionally carry one or more substituents selected from the radicals hydrogen, hydroxy, alkyl, branched alkyl, cycloalkyl, adamantyl, halo, haloalkyl, aralkyl, aryl, carboxyalkyl, alkanoyl, cyano, amino, monoalkylamino, dialkylamino, carboxyalkenyl and alkynyl, as well as their pharmaceutically acceptable salts with mineral and organic acids;

3. Compounds according to Claim 1 or Claim 2, comprising the racemic compounds corresponding to formula I as well as their optically active enantiomers, including those having the absolute configuration in R 1 as fixed by a natural amino acid (L) precursor of synthesis.

4. Compounds according to one of the preceding claims and chosen from:

(S) - (+) - N- (2-amino-3-phenylpropyl) -N- (5-phenyl) -valeramide;

(R, S) -N- (2-friend no-3-phen 1 propy 1) -N-methyl 1 -N- (5-pheny 1) -val eradide;

(S) - (-) -N- (2-d i methy 1 am i no-3-pheny l p ropy l) -N-methy l - -N- (5-pheny1) -val erami of;

(S) - (+) - N- (2-dimethylamino-3-phenylpropyl) -N-methyl- -N- (5-pheny1) -pentanamine;

(S) - (-) - N- (2-amino-3-pheny1prop 1) -N-methyl1-N- (3,4-dichloro¬ pheny1) -acetamide;

(S) - (-) - N- (2-amino-3-phenylpropyl) -N-methyl-N- (1-adamantyl) - -acetamide;

(S) - (+) - N- (2-amino-3-phenylpropyl) -N-methyl-N- (5-phenyl) -penanamine;

(R) - (-) - N- (2-amino-3-phenylpropyl) -N-methyl-N- (5-phenyl) -penanamine;

(S) - (+) - N- (2-methylamino-3-phenylprop 1) -N-methyl-N- (5-phenyl)

-pentanamine;

(S) - (+) - N- [2- (4-morpholino) -3-pheny1propy1] -N-methyl-N- (5- phenyl) -pentanamine;

(S) - (+) - N- [2- (1-pyrrolo) -3-phenylpropyl] -N-methyl-N- (5-ρhenyl) -pentanamine;

(S) - (+) - N- [2- (1-pyrrolidino) -3-phenylpropyl] -N-methyl-N- (5-phenyl) -pentanamine;

(S) - (+) - N- [2- (1-butyramido) -3-phenylpropyl] -N-methyl-N- (5-phenyl) -pentanamine;

5. Compounds according to one of the preceding claims in the form of pharmaceutically acceptable salts.

6. Compounds according to one of the preceding claims which are in the form of a racemic mixture or else in the form of R or S enantiomers.

7. Pharmaceutical compositions comprising a therapeutically active amount sufficient for the compounds defined by claims 1 to 6 in association with adjuvant substances.

8. Use of the compounds defined by claims 1 to 6 as medicaments.

9. Use of the compounds defined by claim 8 in the treatment of psychotic disorders, dyski¬ néiesies, in convulsions and cerebral sufferings in particular those consecutive to episodes of hypoxia, anoxia or ischemia.

10. Use of the compound compounds defined by Claims 1 to 6 as an anxiolytic drug.

11. The use of the compounds defined by claims 1 to 6 as an anti-inflammatory medicament, particularly in arthritis and in skin inflammations.