WO1988002363A1 - Amino-2 ethanethiol derivatives, preparation and therapeutic application thereof - Google Patents

Abstract

The derivatives have the general formula (I) wherein R1? is an optionally mono or polyhalogenated aliphatic acyl group, a benzoyl or phenacetyl group which may carry on the phenyl residue one to three halogeno or alkyl substituents, an alcoxycarbonyl group, a phenoxy or benzyloxy-carbonyl group, an alkyl carbomoyl, phenylcarbamoyl or benzyl carbamoyl group, R2? is an optionally mono or polyhalogenated alkyl group, a phenyl or aralkyl group which may carry on the phenyl residue from one to three substituents selected amongst halogeno, hydroxy, mthoxy or benzyloxy, an indolyl, indolyl-methyl, cycloalkyl-alkyl or cycloalcenyl-alkyl group, R3? is a hydrogen atom or a methyl group and R4? is a hydrogen atom or a methyl group. Application to medicaments.

Description

 2-amino-ethanethiol derivatives, their preparation and their therapeutic use.

The present invention relates to new derivatives of 2-amino ethanethiol, to their methods of preparation and their therapeutic application.

The derivatives according to the present invention are inhibitors of aminopeptidases, such as aminopeptidase M, or a puromycin-sensitive membrane aminopeptidase, involved in the degradation of endogenous opioid peptides (C. Gros et al., Biochemistry, 1985, 24; 2179; Giros et al. Molec. Pharmacol. 1986, 21, 281).

Compounds capable of inhibiting aminopeptidases can prolong the effects of other neuropeptides and more particularly endogenous opioid peptides. These compounds are therefore capable of replacing morphine agents in all their effects (analgesia, hormonal, behavioral effects, etc.), without having the serious disadvantages, in particular in terms of the phenomena of addiction and dependence. 2-amino ethanethiol derivatives having such activity have now been found.

The derivatives according to the invention correspond to the general formula:

dans laquelle

in which

R ₁ represents a linear or branched C ₂ to C ₆ aliphatic acyl group, optionally mono or polyhalogenated, a benzoyl or phenacetyl group which can bear on the phenyl residue one to three halogen or C ₁ to C ₃ alkyl substituents, an alkoxy group (C ₁ to C ₆ ) linear or branched carbonyl except when R ₂ is an alkyl group, a pheroxy-or benzyloxy-carbonyl group, an alkyl group (C ₁ to C ₄ ) carbamoyl, phenylcarbamoyl or benzylcarbamoyl, R ₂ represents a linear or branched C ₂ to C ₁₀ alkyl group, optionally mono or polyhalogenated, a phenyl or aralkyl group (C ₁ -C ₄ ) which can bear on the phenyl residue one to three substituents chosen from halogeno, hydroxy, methoxy or benzyloxy, an indolyl, indolyl-methyl, cycloalkyl group (C ₃ to C ₆ ) -alkyl (C ₁ to C ₃ ) or cycloalkenyl

(C ₄ -C ₆ ) alkyl (C ₁ -C ₃ ),

R ₃ represents a hydrogen atom or a methyl group, and R ₄ represents a hydrogen atom or a methyl group.

Among the compounds of formula I, defined above, a preferred class of compounds comprises the derivatives in which R ₁ is an aliphatic acyl group (C ₂ to

C ₆ ) in particular acetyl, propionyl or butyryl, the acetyl group being preferred, optionally halogenated or a phenoxy-, isobutoxy- or tert-butoxycarbonyl group, or also a phenyl- or ethyl-carbamoyl group,

R ₂ is a linear or branched alkyl group

(C ₄ to C ₆ ), a benzyl or phenethyl group and

R ₃ and R ₄ have the meanings given above. As halogen, fluorine is particularly preferred.

The invention contemplates, as specific compounds, the following derivatives: Z

^NOT

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Les composés de formule I ont en général au moins un atome de carbone asymétrique. Ils peuvent donc exister sous forme de mélange racémique ou sous forme de stéréoisomère. Tous ces composés entrent dans le cadre de la présente invention. Les synthèses décrites ci-aprés peuvent utiliser le composé racémique ou l'un des énantiomères comme substance de départ. Quand on utilise dans le mode opératoire de synthèse la substance de départ racémique, on peut séparer les stéréoisomères obtenus dans le produit par des procédés classiques de chromatographie ou de cristallisation fractionnée. En général, le stéréoisomère correspondant a l'aminoacide naturel constitue la forme préférée. Les composés de formule I peuvent former des sels qui font également partie de cette invention. Les sels formés de manière classique comprennent les sels d'addition d'acide que l'on forme par réaction avec divers acides minéraux et organiques, par exemple, les halohydrates, le sulfate, le nitrate, le borate, le phosphate, l'oxalate, le tartrate, le maléate, le citrate, l'acétate, l'ascorbate, le succinate, le benzènesulfonate, le méthanesulfonate, la cyclohexane sulfonate et le toluènesulfonate. Les composés de la présente invention peuvent être préparés par les divers procédés définis ci-après.CC

The compounds of formula I generally have at least one asymmetric carbon atom. They can therefore exist in the form of a racemic mixture or in the form of a stereoisomer. All of these compounds are within the scope of the present invention. The syntheses described below can use the racemic compound or one of the enantiomers as starting material. When the racemic starting material is used in the synthesis procedure, the stereoisomers obtained in the product can be separated by conventional methods of chromatography or fractional crystallization. In general, the stereoisomer corresponding to the natural amino acid is the preferred form. The compounds of formula I can form salts which are also part of this invention. The conventionally formed salts include the acid addition salts which are formed by reaction with various mineral and organic acids, for example, halohydrates, sulfate, nitrate, borate, phosphate, oxalate , tartrate, maleate, citrate, acetate, ascorbate, succinate, benzenesulfonate, methanesulfonate, cyclohexane sulfonate and toluenesulfonate. The compounds of the present invention can be prepared by the various methods defined below.

The compounds of formula I can be prepared from known amino alcohols of the following formula:

dans laquelle R₂ et R₃ ont la même signification que dans la formule I. Les amino-alcools (II) peuvent le cas échéan t être préparés à partir d'amino-acides correspondants (connus), après estérification ou non, par réduction de la fonction carbonyle en fonction alcool au moyen de LiAlH₄, dans le tétrahydrofuranne (THF) anhydre.

in which R ₂ and R ₃ have the same meaning as in formula I. The amino alcohols (II) can, if necessary, be prepared from corresponding amino acids (known), after esterification or not, by reduction of the carbonyl function to alcohol function by means of LiAlH ₄ , in tetrahydrofuran ( THF) anhydrous.

The general reaction scheme is as follows: N-trifluoroacetyl-imidazole is reacted with an amino alcohol of formula 3

dans laquelle R₂ et R₃ ont la mème signification que dans la formule I, pour obtenir le dérivé trifluoroacétylé de formule*

in which R ₂ and R ₃ have the same meaning as in formula I, to obtain the trifluoroacetylated derivative of formula

uelle R₂ et R₃ ont la même signification que dans la formule I, on fait réagir sur ce dernier le chlorure de tosyle pour obtenir un composé protégé deformulein laq

uelle R ₂ and R ₃ have the same meaning as in formula I, is reacted on the latter tosyl chloride to obtain a protected compound of formula

dans laquelle R₂ eT R₃ ont la même signification que dans la formule I et TS représente le groupe tosyle, on fait réagir ce dernier avec l'acide thioacétique ou trifluorothioacétique en présence d'une base forte pour obtenir le dérivé thioacétylé de formule

in which R _{2 and} R ₃ have the same meaning as in formula I and TS represents the tosyl group, the latter is reacted with thioacetic or trifluorothioacetic acid in the presence of a strong base to obtain the thioacetylated derivative of formula

2 dans laquelle R₂ et R₃ ont la même signification que dans la formule I, et R'₁ représente un groupe acetyle ou trifluoroacétyle puis, soit on réalise la déprotection du groupe amino du composé V au moyen d'acide chlorhydrique gazeux pour obtenir les composés de formule I dans laquelle R₁ est un groupe acetyle ou trifluoroacétyle et R₄ est H.

2 in which R ₂ and R ₃ have the same meaning as in formula I, and R ' ₁ represents an acetyl or trifluoroacetyl group then, either deprotection of the amino group of compound V is carried out by means of gaseous hydrochloric acid to obtain the compounds of formula I in which R ₁ is an acetyl group or trifluoroacetyl and R ₄ is H.

- Either double deprotection of the amino and thio groups of compound V is carried out using gaseous hydrochloric acid to obtain an aminoethanethiol of formula

dans laquelle R₂ et R₃ ont la même signification que dans la formule I, et on fait réagir sur ce dernier un dérivé fonctionnel correspondant au radical R₁ pour obtenir un composé de formule I dans laquelle R₁ conserve sa signification sauf acetyle et trifluoroacétyle et R₄ est H, - puis le cas échéant on fait réagir les composés de formule I dans laquelle R₄ est H avec le formaldéhyde et on réduit la base de Schiff ainsi obtenue pour obtenir les composés de formule I dans laquelle R₄ est CH₃.

in which R ₂ and R ₃ have the same meaning as in formula I, and a functional derivative corresponding to the radical R ₁ is reacted on the latter to obtain a compound of formula I in which R ₁ retains its meaning except acetyl and trifluoroacetyl and R ₄ is H, - then optionally reacting the compounds of formula I in which R ₄ is H with formaldehyde and reducing the Schiff base thus obtained to obtain the compounds of formula I in which R ₄ is CH ₃ .

The first three steps of the previous diagram relate to the protection of the amino function, and the introduction and protection of the thio group. The conditions of these reactions have been studied at length in the literature. The fourth step concerning the deprotection of the thio and / or amino group of the compounds (V), can be carried out in a solution of gaseous hydrochloric acid in methyl alcohol at a temperature of approximately -20 to + 5ºC and under neutral gas such as argon. The compounds of formula I in which R ₁ is an acyl group other than acetyl or trifluoroacetyl, can be prepared from the corresponding acylthio-3-ethane-amino-tboc, by hydrolysis by gaseous HCl in dioxane between approximately -10º and 0ºC under argon.

The compounds of formula I in which R ₁ is a carbamoyl group can be prepared by reaction of the aminoethanethiols (VI) with the isocyanates corresponding to R ₁ , in a polar solvent such as dimethylformamide (DMF) at a temperature of approximately 0ºC. the compounds of formula I in which R ₄ =

CH ₃ can be prepared as follows. The compounds of formula I in which R ₄ = H are protected on the thiol by an acyl residue. They are formylated at room temperature with formaldehyde to give the corresponding Schiff base which is then reduced by a hydride such as LiAlH ₄ . The examples below are given by way of illustration of the processes for preparing the compounds according to the present invention.

Example 1. Acetyl-thio-2-benzyl-1 amino-1 ethane hydrochloride [S]

It is added slowly at 0º. with stirring, 43 g of trifluoroacelyl-imidazole and 90 g of tosyl chloride in 22 ml of pyridine to a solution of 36 g of L-amino-1-benzyl-1 ethanol in dry pyridine. After a night of contact, the product is extracted with methylene chloride, then evaporated and recrystallized from methanol. 69 g of a product with a melting point of 146 ° are obtained, which is trifluoroacetylamino-1 benzyl-1 ethanol tosylate. Make it ment of this step is 75%. To a solution cooled to 0º of 9 g of this compound, in 20 ml of DMF, is added 3.5 g of thioacetic acid mixed with 2.25 g of KOH in 2.3 ml of dry DMF. After a night of contact, the mixture is precipitated with 58 ml of demineralized water, the precipitate is filtered and recrystallized from methanol. There is thus obtained with a yield of 70% the trifluoroacetylamino-1 benzyl-1 acetylthio-2 ethane with melting point = 116 °. An anhydrous HCl solution in dioxane (4N) = 100 ml is then prepared. 5.60 g of the trifluoroacetylamino-1 derivative-1 benzyl-1 acetylthio-2 ethane derivative obtained above are added at -5 ° under argon.

The mixture is left to stir for 1 hour at room temperature. We're hunting dioxane. The pasty residue obtained is taken up in anhydrous ether. It is filtered, dried under vacuum and 4.50 g of product are obtained, which corresponds to 2-acetylthio-benzyl-1 amino-1 ethane hydrochloride. Fuse point = 1 92 - 1 94 º. Elementary analysis: I.R., R.M.N. and C.C. M. correct.

Example 2 Trifluoroacetylthio-2-benzyl-1 amino-1 ethane hydrochloride [S] The trifluoroacetyl-amino-1-benzyl-1 ethanol tosylate obtained during the preparation of the derivative of Example 1 is treated under the same conditions as previously (0º in DMF), but with 10 g of trifluorothioacetic acid (instead of thioacetic acid) in the presence of KOH.

We obtain the derivative trifluoroacetyl-amino-1 benzyl-1 trifluoroacétythio-2 éthane which is hydrolyzed as under the conditions of the previous example by a solution of HCl gas in dioxane at -5 º under argon. After 2 hours of contact at room temperature, the solvent is charged and taken up in the anhydrous stretch. It is filtered, dried under vacuum and the expected hydrochloride is obtained. Melting point = 198-200º.

Correct analysis and spectra. Pouvoin. rotary: levorotatory. Example 3. Phenylcarbamoyl-2-thio-2-benzyl-1 amino-1 ethane hydrochloride [S]. To a solution of gaseous hydrochloric acid in methyl alcohol (approximately 4N, ie 10 ml), cooled to 0 ° under a stream of argon, 5 g of the product obtained in Example 1, namely trifluoroacetylamino-1, are added 1-benzyl-2-acetylthio ethane. The mixture is quickly homogeneous. The temperature is allowed to rise to 20ºC, then it is brought to 45-50ºC for 3 h. The vacuum solvent is removed. After prolonged drying under vacuum, 2.90 g of product with melting point = 172-174 ° are obtained. which is L-phenyl-alanine-thiol hydrochloride [S] .CCM (CH ₂ Cl ₂ / CH ₃ OH / CH ₃ _COOH = 70/30/1).

Spectra 1.R., R.W.N. and correct elementary analysis.

Rotatory power: levorotatory. 5 g of this hydrochloride are dissolved in 75 ml of D.M.F. dry. Cool to 0º and pour dropwise 2.68 ml (2.95 g of phenyl-isocyanate.

It returns to ambient temperature and leaves to stir for 24 hours. The mixture becomes homogeneous fairly quickly. We evaporate the D.M.F. A viscous residue is obtained which becomes powder after stirring with ether. It is filtered, washed with ether and dried under vacuum. 7.6 g of white product are obtained.

Melting point = 212-214º.

IR.RMN spectra and correct elementary analyzes. EXAMPLE 4 Ethyl-carbamoyl-2-thio-2-benzyl-1 amino-1 ethane hydrochloride [S]

This product is prepared in the same way as Example 3, but the phenyl-isocyanate is replaced by the ethylisocyanate. A white crystallized product is obtained under the same conditions.

Melting point = 198-200º.

Example 5. Phenoxycarbonylthio-2 i so-butyl-1 amino-1 ethane hydrochloride [S]

This compound is prepared from L-leucine-thiol, the synthesis of which is as follows:

13.30 g of L-leucinol are added to one equivalent, (13.20 g) of benzyloxycarbonate and to 2 equivalents of tosyl chloride in 20 ml of pyridine (37.5 g) and maintained in contact with stirring for 2 h at ambient temperature. 32 g of benzyloxycarbamoyl-1 isobutyl-1 ethanol tosylate are obtained, the melting point of which is 92 ° C. To this derivative, 30 g of thioacetic acid are added with 25 g of KOH in 25 ml of D.M.F. dry and left in contact for 12 h at room temperature. It is precipitated with deiodinated water and filtered. Recrystallized from CH OH. 18 g of Z-amiπo-1 isobutyl-1 thioacetyl-2 ethane are obtained, the melting point of which is 56 ° C.

The hydrolysis of this compound by gaseous HCl in CH ₃ OH under a stream of argon at 0 ° is done under the same conditions as those described for obtaining L-phenylalanine-thiol hydrochloride.

Benzyloxycarbonyl chloride dissolved in aqueous sodium hydroxide is added to this derivative for 30 min at room temperature. The title compound is obtained with a yield of 712. Melting point = 1194ºC. EXAMPLE 6 Phenylcartamoylthio-2 isobutyl-1 amino-1 ethane hydrochloride [S]

This compound is prepared according to Example 3 from L-leucine-thiol hydrochloride, the preparation of which is described in Example 5.

Melting point = 218ºC.

Example 7. Isobutoxycarbonyl-thio-2 hydrochloride (2-phenyl ethyl) -1 amino-1 ethane [R, S].

This product is prepared from homophenylalanine-thiol [R, S] prepared analogously to phenyl-alanine-thiol. The homophenylalanine-thiol hydrochloride [R, S] is treated under the conditions described for obtaining Example 5, taking iso-butoxycarbamate (1 equivalent) as the protecting group for the thiol. A white crystallized product is obtained, the melting point of which is 75-77º.

EXAMPLE 8 Acetyl-thio-2-phenyl-1 amino-1 ethane hydrochloride [R, S]

This product is prepared under the conditions described for obtaining Example 1, from phenyl-glycine-thiol [R, S], itself obtained like the phenyl-alanine-thiol described above. Melting point = 186-187º.

Example 9. Acetyl-thio-2 p-fluorophenyl-methyl-1-amino-1 ethane hydrochloride [R, S] This product is prepared according to the conditions described for obtaining Example 1, starting from p- fluoro-phenyl-alanine-thiol, itself obtained as the phenyl-alanine-thiol described above. Melting point = 189-201º. Example 10. Phenylcarbamoyl-2-thio-isopropyl-1-amino-1 ethane hydrochloride [R, S]

This derivative is obtained according to Example 3 from L-valine-thiol hydrochloride, the preparation of which is as follows:

1 equivalent of L-valinol is stirred for 12 h at room temperature with 1 equivalent of trifluoroacetyl-imidazole and 2 equivalents of tosyl chloride in dry pyridine. Extraction is carried out with methylene chloride. Evaporated to dryness and recrystallized from methanol. The reaction product is treated with thioacetic acid and KOH in DMF for 12 hours and at room temperature, to give the trifluoroacetyl-1-amino-isopropyl-1 acetyl-2-thioethane. Hydrolysis by gaseous HCl in CH ₃ OH at 0 ° under argon is carried out under the same conditions as that of L-phenyl-alanine-thiol hydrochloride and results in the formation with an overall yield of 11% of L-hydrochloride valine-thiol. From the latter, the title compound is obtained in the same manner as Example 3.

Melting point = 136º. EXAMPLE 11 Ethyl-carbamoyl-thio-2 (methyl-1) -propyl-1 amino-1 ethane hydrochloride [R, S]

This product is synthesized according to the conditions described for obtaining the derivative of Example 4, from iso-leucine-thiol, itself obtained as the leucine-thiol described above. White crystallized product.

Melting point = 195º. EXAMPLE 12 Tert-butoxycarbonyl-2-thio-1-benzyl-1-amino-1 ethane hydrochloride [S]

This compound is obtained as the product of Example 5, replacing the benzyloxycarbonyl chloride with an equivalent of tert-butoxycarbonyl chloride.

Melting point = 68º.

Example 13. Acetyl-thio-2-ethyl-1-amino-1 ethane hydrochloride

Prepared as the derivative of Example 1, starting from homo-alanine-thiol. Melting point - 178º.

Example 14. Phenyl-carbamoyl-thio-2pxopyl-1 amino-1 ethane hydrochloride [S]

This compound is obtained in an identical manner to Example 3, starting from L-amino-1 propyl-1 thio-2 ethane hydrochloride, melting point = 145º.

The expected derivative is obtained with an overall yield of 12% and a melting point = 192º.

EXAMPLE 15 Trifluoroacetyl-thio-2-benzyl-1 methylamino-1 ethane hydrochloride [S]

The derivative of Example 2 is treated with ΗCHO to form a Schiff base, reduced by LiAlH ₄ at room temperature. Recrystallization from ether. White crystallized product.

Spectrum I.R., R.M.N. and correct analyzes. Melting point = 147-149º.

Example 16. Acetyl-thio-2-hexyl-1 amino-1 ethane hydrochloride [R, S]

Prepared according to Example 1, starting from 1-hexyl-1 amino-ethanethiol-2.

Melting point = 207-209º. Example 17. Phenyl-carbamoyl-thio-2-hexyl-1 amino-1 ethane hydrochloride [S]

Prepared identically to Example 3 from 1-hexyl-1 amino-1 ethanethiol-2. Melting point = 203º.

Example 18. Phenyl-carbamoyl-2-thio-butyl-1 amino-1 ethane hydrochloride [S]

Prepared identically to Example 3, starting from L-norleucine-thiol.

Melting point = 176º.

EXAMPLE 19 Trifluoroacetyl-thio-2-tert-butyl-1 amino-1-eithane hydrochloride [R, S] This product is obtained in an identical manner to the derivative of Example 2, from tert-butyl-glycinethiol / R, S / .

Melting point = 155º.

Example 20. Acetylthio-2 (2,2-dimethylpropyl) hydrochloride -1 amino-1 ethane [R, S]

Prepared according to Example 1, from tertbutyl-alanine-thiol.

White crystallized product. Melting point = 194ºC.

Example 21. Propionyl-2-thio-benzyl-1-amino-1 ethane hydrochloride [S]

It is prepared by the action of propionic acid chloride on phenyl-alanine-thiol hydrochloride, the synthesis of which is described during the preparation of Example 2. The propionic acid chloride is gradually added at 0 ° in DMF Agitation at room temperature for 12 hours. Evaporation. Vacuum drying. Recrystallization from ether.

Melting point = 172º.

Example 22. Benzoyl-2-thio-1-benzyl-1-amino-1 ethane hydrochloride [S]

Prepared in the same manner as the compound of Example 21, but with benzoyl chloride.

Melting point = 164º.

EXAMPLE 23 p-fluorobenzoylthio-2 isobutyl-1-amino-1 ethane hydrochloride [R, S]

It can be prepared under the conditions described for obtaining the derivative of Example 2 from the L-leucine-thiol hydrochloride described in the preparation of Example 5.

Example 24. Phenyl-acetyl-thio-2-p-fluoro-phenyl-methyl-1 amino-1 ethane hydrochloride [R, S] This product is prepared as described above by the action of phenyl acetic acid chloride on p-fluoxo-phenyl-alanine-thiol hydrochloride, the synthesis of which is described during the preparation of Example 2. Melting point = 166 °.

Example 25. 2,4,6-trimethylbenzoyl-thloy-2-benzyl-1 am ino-1 ethane hydrochloride [S]

It can be prepared according to Example 21, but with 2,4,4-trimethyl benzoic acid chloride.

Melting point = 181º. Example 26. Acetyl-thio-2 hydrochloride (3-indolyl methyl) -1 amino-1 ethane [R, S]

This product is prepared from tryptophan-thiol [R, S], according to Example 1.

Melting point = 208º.

Example 27. Acetyl-thio-2 hydrochloride (naphthyl-1-methyl) -1 amino-1 ethane [R, S]

This product is prepared from alphanaphthyl-alanine-thiol, according to Example 1.

Melting point, = 212º.

Example 28. Phenyl-carbamoyl-thio-2-cyclopentyl-methyl-1 amino-1 ethane [R, S] II hydrochloride can be prepared in an identical manner to Example 3, starting from β-cyclopentyl-DL-alaninethiol.

Melting point = 182º.

Example 29 Ethyl-carbamoyl-thio-2 hydrochloride

(cyclopenten-3-yl methyl) -1 amino-1 ethane [R.S]

This product is prepared in an identical manner to Examples 4 and 11, starting from (1-cyclopen- tenyl) - alanine-thiol.

Melting point = 184º.

Example 30. Phenyl-carbamoyl-2-thio-isobutyl-1-methyl-1-amino-1 ethane hydrochloride [R, S]

Prepared identically to Example 3, from methyl-leucine-thiol.

Melting point = 191º.

Example 31. Acetyl-thio-2 methyl-1 p-hydroxybenzyl-1 methyl-1 amino-1 ethane hydrochloride [R, S] Prepared as in Example 1, from methyl-tyrosine-thiol.

Melting point = 215º.

Example 32 Acetyl-thio-2 methyl-1 (indolyl-3-methyl) -1 amino-1 ethane hydrochloride [R, S]

Prepared: as above, from methyl-tryptophan-thiol.

Melting point = 220º.

Example 33. Phenyl-carbamoyl-2-thio-1-methyl-1-benzyl-1-amino-1 ethane hydrochloride [R, S]

Prepared identically to Example 3, from methyl-phenyl-alanine-thiol. Melting point = 187º.

Example 34. Acetyl-thio-2 p-methoxy-benzyl-1 amino-1 ethane hydrochloride [R, S]

Prepared as in Example 1, starting from p-methoxy-tyrosine-thiol.

Melting point = 137º.

Example 35. Phenyl-carbamoyl-thio-2 p-benzyloxy-benzyl-1 amino-1 ethane hydrochloride [R, S] Prepared identically to Example 3, starting from para-benzyloxy-phenyl-alanine-thiol . Melting point = 191 º.

The results of the biological and pharmacological studies reported below demonstrate the advantageous properties of the derivatives of the invention.

The present invention therefore also relates to a medicament having inhibitory properties. aminopeptidases, in particular analgesic, antidepressant, gastrointestinal antisecretory, characterized in that it contains, as active principle, a compound of formula I or an addition salt with an acid or a pharmaceutically acceptable base of this compound.

A - Biological study

1) Inhibition of the aminiopeptidasic activity of rat brain membranes.

The striatum membranes are prepared and the aminopeptidasic activity measured using the

(Met ⁵ ) enkephalin- ³ H (40 nM) as substrate, according to the protocol described by Gros et al. (Biochemistry, 1985, 2.4, 281).

The inhibitors are preincubated for 30 minutes with the membranes and the activity measured (in the presence of an enkephalinase inhibitor, Thiorphan, at 2 μM), after an incubation of 15 minutes at 37ºC.

Table 1 gives the values of the inhibitory concentrations 50% of the various compounds.

2) Protection des enkephalines endogènes libérées par dèpαlarisation de coupés de cerveau de rat.

2) Protection of the endogenous enkephalins released by depeplaration of sections of rat brain.

The globus pallidus sections are prepared, preincubated for 30 minutes in the presence of the compounds to be tested (and 2 μM of Thiorphan), depolarized by 50 mM of K ⁺ for 5 minutes and the recovery of (Met- ⁵ ) enkephaline released in the medium , evaluated according to the protocol described by Giros et al.

(Mol. Pharmacol., 1986, .29, 281). The results are collated below.

3) Inhibition of the metabolism of endogenous enkephalins in vivo.

The effect of the compounds was assessed by the evaluation of the level of the tripeptide Tyr-Gly-jGly, a caxactexistic metabolite of enkephalins, in the striatum of mice (Llorens-Cortes et al., Eur. J. Pharmacol., 1985 , 119.183).

The mice were sacrificed 45 minutes after administration of the compounds at a dose of 50 μmol / kg (i-v.).

The results are collated in Table 3 below. )

B - Pharmacological study

The pharmacological study of the products described above has made it possible to highlight an analgesic and anti-diarrheal effect and a potentiating action of the effects of an enkephalin Met-enkephalin.

The pharmacological tests carried out were as follows:

I - Acute toxicity

The determination of mortality in mice is observed following the single administration by intravenous route of increasing doses of the test compounds. The LD ₅₀ for all the compounds studied is greater than 100 mg / kg / iv.

II - Analgesic activity

(1) Hot plate test in mice Reflex of licking the paw and jumping with a mouse placed on a plate heated to 55ºC according to the method of J. Jacob et al. (Arch. Int. Pharmacodyn. 122. 287-300, 1959: 133. 296-300, 1961). a) Potentiation of the analgesic effect of Met-Enkephalin.

A subactive dose of Met-Enkephalin (1 ug) administered intracerebroventricularly is significantly potentiated - 200 to 400% - (p <0.05) by compounds 1, 3, 6, 7 and 17, at a dose of 10 mg / kg / - iv. We measure the increase in licking time compared to animals treated with Met-enkephaline alone. This effect is completely antagonized by the

Naloxone. b) Own analgesic effect of the derivatives.

It is measured by evaluating the increase (%) in the jump latency time of animals having received a dose of 10 mg / kg / sc. of products 1, 3, 12 and 18. The increase varies from 150 to 400%. It is significant (p. 0.01 to 0.05) and is antagonized by a prior injection of Naloxone (10 mg / kg / S.ent.). The effect is potentiated by the administration of an enkephalinase inhibitor such as acetorphan (1 mg / kg i.v.).

III - Antidiarrheal effect - Tes t rat with castor oil according to the method of Niemegeers and Janssen (Arz. Forshung, 1974, 24. 1622-1636).

Rats are significantly protected (p <0.05) against intestinal hypersecretion induced by castor oil (1 ml) after oral administration doses ranging from 5 to 15 mg / kg of products 1, 2, 3, 5 and 6. This effect is antagonized by Naloxone, injected before the dose of 10 mg / kg subcutaneously.

The results of the pharmacological tests described above make it possible to envisage the therapeutic application of the compounds of the invention, in particular as analgesics. gastrointestinal psychotropic and antisecretory agents.

The invention therefore also relates to pharmaceutical compositions containing a compound of formula I associated with a pharmaceutically acceptable vehicle or excipient. The drugs can be presented in particular in the form of tablets, injectable ampoules or suppositories, at doses varying from 10 to 500 mg per dose.

Claims

CLAIMS 1. Compounds corresponding to the general formula

in which R ₁ represents a linear or branched C ₂ to C ₆ aliphatic acyl group, optionally mono or polyhalogenated, a benzoyl or phenacetyl group which can bear on the phenyl residue one to three halogen or C ₁ to C ₃ alkyl substituents, an alkoxy group (C ₁ to C ₆ ) linear or branched carbonyl except when R ₂ is an alkyl group, a phenoxy- or benzyloxy-carbonyl group. a carbamoyl, phenylcarbamoyl or benzylcarbamoyl (C ₁ to C ₄ ) alkyl group, R ₂ represents a linear or branched C ₂ to C ₁₀ alkyl group, optionally mono or polyhalogenated, a phenyl or aralkyl group (C ₁ -C ₄ ) capable of carrying on the phenyl residue one to three selected sufastituants paxmi halogeno, hydroxy, methoxy or benzyloxy, an indolyl, indolyl-methyl, cycloalkyl (C ₃ to C ₆ ) -alkyl (C ₁ to C ₃ ) or cycloalkenyl (C ₄ to C ₆ ) alkyl (C ₁ to C) ₃ ), R ₃ represents a hydrogen atom or a methyl group, and R ₄ represents a hydrogen atom or a methyl group as well as their addition salts with pharmaceutically acceptable acids. 2. Compound according to claim 1, corresponding to formula I in which R ₁ is an aliphatic acyl group (C ₂ to C ₆ ) optionally halogen or a phenoxy-, isobutoxy- or tert-butoxy-carbonyl group, or also a phenyl- or ethyl-carbamoyl group, and R ₂ is a linear or branched C ₄ to C ₆ alkyl group, a benzyl or phenethyl group. 3. 2-Thio-acetyl-benzyl-1 amino-1 ethane or its hydrochloride. 4. Trifluoroacetylthio-2 benzyl-1 amino-1 ethane or its hydrochloride. 5. Phenylcarbamoyl-2-thio-benzyl-1 amino-1 ethane or its hydrochloride. 6. Ethyl-carbamoyl-thio-2 benzyl-1 amino-1 ethane or its hydrochloride. 7. Phenoxycarbonylthio-2 isobutyl-1 amino-1 ethane or its hydrochloride. 8. Phenylcarbamoylthio-2 isobutyl-1 amino-1 ethane or its hydrochloride. 9. Isobutoxycarbonylthio-2 (2-phenylethyl) -1 amino-1 ethane and its hydrochloride. 10. Process for the preparation of a compound according to claim 1, characterized in that the N-trifluoroacetyl-imidazole is reacted with an amino alcohol of formula

in which R ₂ and R ₃ have the same meaning as in formula I, to obtain the trifluoroacetylated derivative of formula

in which R ₂ and R ₃ have the same meaning as in formula I, the latter is reacted with the tosyl chloride to obtain a protected compound of formula

2 in which R _{2 and} R ₃ have the same meaning as in formula I and TS represents the tosyle group, the latter is reacted with thioacetic or trifluorothioacetic acid in the presence of a strong base to obtain the thioacetylated derivative of formula V k

in which R ₂ and R ₃ have the same meaning as in formula I, and R ′ ₁ represents an acetyl or trifluoroacetyl group then, either deprotection of the amino group of compound V is carried out by means of gaseous hydrochloric acid to obtain the compounds of formula I in which R ₁ is an acetyl or trifluoroacetyl group and R ₄ is H. - or the double deprotection of the amino and thio groups of compound V is carried out using gaseous hydrochloric acid to obtain an aminoethanethiol of formula

in which R ₂ and R ₃ have the same meaning as in formula I, and a functional derivative corresponding to the radical R ₁ is reacted thereon to obtain a compound of formula I in which R ₁ retains its meaning, except acetyl et- txifluoxoacetyl and R ₄ is H. then - Where appropriate, the compounds of formula I in which R ₄ is H are reacted with formaldehyde and the Schiff base thus obtained is reduced to obtain the compounds of formula I in which R ₄ is CH ₃ . 11. Pharmaceutical composition containing a compound according to any one of claims 1 to 9 as well as a pharmaceutically acceptable vehicle or excipient.