FR2589468A1 - New 2-substituted 2-(acylamino)ethanethiol derivatives, process for their preparation, their application as medicaments and the pharmaceutical compositions which contain them - Google Patents

Abstract

New compounds of formula in which R1 is hydrogen or (R'1 is 1-5 alkyl), or aryl optionally substituted by OH, (1-5) alkyl or alkoxy, NO2 or halogen, R2 is a pyridyl radical optionally substituted with a 1-5 alkyl, or a phenyl substituted with one or more 1-5 alkyl or alkoxy, halogen, OH or NO2 or R2 is a cycloalkyl radical containing 3 to 12 carbon atoms, X is H or 1-5 alkyl or alkoxy, OH, halogen or CF3, provided that when X and R1 = H, R2 does not represent a phenyl, in their racemic or optically active forms and their addition salts with acids. The invention also relates to a process for the preparation of the compounds of formula I, their application as medicaments and the compositions which contain them.

Description

 The present invention relates to new derivatives of 2-substituted 2-acylamino ethane thiol, their preparation process, the new intermediates obtained, their application as medicaments and the pharmaceutical compositions containing them.

dans laquelle R1 représente un atome d'hydrogène ou un radical

The subject of the invention is the compounds of formula (I)

in which R1 represents a hydrogen atom or a radical

R'1 being an alkyl radical containing 1 to 5 carbon atoms or an aryl radical optionally substituted by a hydroxy radical, an alkyl radical containing 1 5 carbon atoms, an alkoxy radical containing 1 5 carbon atoms, the radical nitro or a halogeneg R2 atom represents a pyridinyl radical possibly substituted by an alkyl radical containing from 1 to 5.

carbon atoms or R2 represents a phenyl radical optionally substituted by one or more radicals chosen from the group consisting of alkyl radicals containing from 1 to 5 carbon atoms, alkoxy radicals containing from 1 to 5 carbon atoms, the atoms d halogenes, the hydroxyl radical, the nitro radical or a ~ cycloaicoyl radical containing 3 to 12 carbon atoms and X represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, an alkoxy radical containing 1 to 5 carbon atoms, a hydroxyl radical, a halogen atom or a trifluoromethyl radical, provided that when X and Rq represent a hydrogen atom,
R2 does not represent a phenyl radical, said products of formula (I) being in their racemic or optically active forms, as well as their addition salts with acids.

R1 est de préférence un radical méthyle ou éthyle.When R1 represents a radical

R1 is preferably a methyl or ethyl radical.

 When R1 is an aryl radical, it is preferably a phenyl radical.

 When R1 is a substituted aryl radical, it is preferably an aryl radical substituted by a radical chosen from the group formed by hydroxy radicals, methyl or ethyl radicals, methoxy or ethoxy radicals, the nitro radical or a chlorine atom.

 When R2 represents a substituted phenyl radical, it is preferably a phenyl radical substituted by one or more radicals chosen from the group formed by methyl or ethyl, methoxy or ethoxy radicals, a chlorine atom, a hydroxyl radical, a nitro radical.

 When R2 represents a pyridinyl radical, it is a 4-pyri di nyl e 3-pyri di nyl e or 2-pyri di nyl e radical.

 When R2 represents a pyridinyl radical substituted by an alkyl radical, it is preferably a substitution with a methyl or ethyl radical.

 When R2 is a cycloalkyl radical, it is preferably a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl radical.

 X is preferably a hydrogen atom or a methyl or ethyl radical, methoxy or ethoxy, a hydroxyl radical, a chlorine atom, a trifluormethyl radical.

 The addition salts with organic naked mineral acids can be, for example, the salts formed with hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, acetic, formic, propionic, benzolic, maleic, fumaric, succinic, tartaric, citric acids. , oxalic, glyoxylic, aspartic, alkane sulfonic such as methane and ethane sulfonic acids, arylsulfonic, such as benzene and paratoluene sulfonic and arylcarboxylic acids.

 The invention relates in particular to the compounds of formula (I) for which R1 is a hydrogen atom in their racemic or optically active forms, as well as their addition salts with acids and for which R1 is an acetyl radical in their forms racemic or optically active as well as their addition salts with acids.

 A more particular subject of the invention is the compounds of formula (I) for which R2 is a pyridinyl radical or a cyclohexyl radical or a phenyl radical substituted by one or more chlorine atoms or by one or more methoxy radicals in their racemic forms, or optically active, as well as their addition salts with acids and very particularly - N - / (1-mercaptomethyl)) O-phenylethyl / 4-pyridine carboxamide.

- N - / (1-mercaptomethyl) 2-phenylethyll cyclohexane carboxamide in their racemic and optically active forms as well as their addition salts with acids.

éventuellement sous forme de chlorhydrate, que laon condense avec un produit de formule IV, sous forme racémique ou optiquement active

dans laquelle X a la signification précédente pour obtenir un produit de formule V, sous forme racémique ou optiquement active

que l'on soumet à l'action d'un thioacide de formule VI :

pour obtenir un produit de formule (I) dans laquelle

et dans laquelle X et R2 ont les significations précédentes, que l'on saponifie, si désiré, pour obtenir un produit de formule (I) dans laquelle R1 est un atome d'hydrogène, produits de formule (I) que l'on peut, le cas échéant, dédoubler par des méthodes usuelles et que l'on soumet, si désiré, à l'action d'un acide pour en former le sel.The invention also relates to a process for preparing the products of formula (I), characterized in that a product of formula II is subjected
R2-CN II in which R2 has the preceding meaning, to the action of an alkali metal alcoholate of formula R'OA, R 'being an alkyl radical of 1 to 4 carbon atoms and A an alkali metal or gaseous hydrochloric acid in the presence of an alcohol of formula R'OH, to obtain a product of formula III

optionally in the form of hydrochloride, which is condensed with a product of formula IV, in racemic or optically active form

in which X has the above meaning for obtaining a product of formula V, in racemic or optically active form

which are subjected to the action of a thioacid of formula VI:

to obtain a product of formula (I) in which

and in which X and R2 have the above meanings, which is saponified, if desired, to obtain a product of formula (I) in which R1 is a hydrogen atom, products of formula (I) which can be , if necessary, split by usual methods and subject, if desired, to the action of an acid to form the salt.

 The process described above essentially relates to the preparation of the products of formula (I) from the products of formula III.

 Under the preferred conditions for carrying out the process which is the subject of the invention - The formation of the imino-ether of formula III is carried out pro $ erence in the presence of a sodium methylate in methanol or by the action of gaseous hydrochloric acid in the presence of ether and methanol.

- The condensation between the product of formula III and the product of formula IV is carried out in the presence of a chlorinated solvent, in particular chloroform or of usual solvents such as tetrahydrofuran, dimethylformamide, ether.

 This condensation takes place in the presence of a base such as triethyl amine when the product of formula IV is in the form of the hydrochloride.

- The reaction between the product of formula V and the thioacid of formula VI is preferably carried out in a solvent such as tetrahydrofuran or an ether.

- The saponification of the products of formula (I) in which -
R1 = R'1-C- is carried out by usual means, in particular by using
o an alkali metal hydroxide such as sodium hydroxide in an alcoholic medium.

 The compounds of formula (T} as defined above and the product of formula {I} for which R1 and X represent a hydrogen atom and R2 is a phenyl radical as well as their addition salts with acids and the bases have interesting pharmacological properties, they have, in particular, very interesting inhibitory properties for enkephalinase and are endowed with very good analgesic activity.

Enkephalinase is a dipeptidylcarboxypeptidase which specifically hydrolyzes methionine and enkephalin leucine between the 3rd and 4th amino acid, thus releasing a tripeptide Tyr-Gly-Gly (Swerts,
JP, Perdrisot, R., Patey, G., De La Baume, S., and Schwartz, JC,
Europ. J. Pharmacol., 1979, 57, 279).

 Enkephalinase thus directly participates in the physiological degradation of enkephalins, endogenous natural ligands of opiate receptors. The compounds of the invention, which retard the degradation of enkephalins, therefore stimulate the body's defense reactions against pain.

dans laquelle R1 représente un atome d'hydrogène ou un radical

These properties justify their application in therapy and the subject of the invention is also, as medicaments, the compounds of formula (I)

in which R1 represents a hydrogen atom or a radical

R'1 being an alkyl radical containing from 1 to 5 carbon atoms or an aryl radical optionally substituted by a hydroxy radical, an alkyl radical containing from 1 to 5 carbon atoms, an alkoxy radical containing from 1 to 5 carbon atoms, the nitro radical or a halogen atom, R2 represents a pyridinyl radical optionally substituted by an alkyl radical containing from 1 to 5 carbon atoms or R2 represents a phenyl radical optionally substituted by one or more radicals chosen from the group consisting of radicals alkyls containing from 1 to 5 carbon atoms, the alkoxy radicals containing from 1 to 5 carbon atoms, the halogen atoms, the hydroxyl radical, the nitro radical, or R2 represents a cycloalkyl radical containing from 3 to 12 carbon atoms , X represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms, an alkoxy radical containing from 1 to 5 carbon atoms, a hydroxyl radical, a halogen atom or a trifluoromethyl radical, in their racemic or optically active forms as well as their addition salts with pharmaceutically acceptable acids.

 The subject of the present invention is very particularly, as medicaments: - N-t (1-mercaptomethyl) 2-phenylethyl / 4-pyridine carboxamide.

- N - / (1-mercaptomethyl) 2-phenylethyl / cyclohexane carboxamide in their racemic and optically active forms as well as their addition salts with pharmaceutically acceptable acids and - N - / (l-mercaptomethyl) 2-phenylethyl / benzamide, in racemic or optically active forms, as well as its addition salts with pharmaceutically acceptable acids.

 The medicaments which are the subject of the invention can be used in the treatment of muscle, joint or nerve pain, rheumatic affections, dental pain, zonas and migraines, as well as in the treatment of inflammatory diseases, in particular arthritis , lumbago, and also as complementary treatment in infectious and febrile states.

 The invention extends to pharmaceutical compositions containing, as active principle, the medicaments defined above.

 These pharmaceutical compositions can be administered by the oral, rectal, parenteral or local route by topical application to the skin and mucous membranes.

 These compositions can be solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, capsules, granules, suppositories, injections, ointments, creams, gels and aerosol preparations; they are prepared according to the usual methods. The active principle can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

 The dosage varies in particular depending on the route of administration, the condition treated and the subject concerned.

 For example, in adults, it can vary between 20 mg and 2 g of active ingredient, per day, orally.

 The compounds of formula (V) are new chemicals; the invention therefore relates to these products as new industrial products, in particular as intermediate products necessary for the implementation of the process of the invention.

The examples given below illustrate the invention without, however, limiting it.
Example 1: Ethane thioate of 2mphenyl methyl 2v / (4 pyridRrylcarbony1) amino / ethyl.

Stage A: methyl 4-pyridine carboximidate.

 0.575 g of sodium is added at 20 ° C., while maintaining this temperature, in small fractions in 220 cm 3 of methanol, then, when the gas evolution has ceased, 26 g of 4-pyridine carbonitrile, in 30 minutes.

 The mixture is left for 4 days at room temperature, 1.46 cm 3 of acetic acid diluted in 15 cm 3 of methanol are added, concentrated to dryness under reduced pressure.

The residue is taken up in 200 cm3 of methylene chloride, filtered, eliminates the organic phase and 32.3 g of expected product is obtained.
F 550C.

Stage B: 4- / 4,5-dihydro 4- (phenylmethyl) 2-isoxazolyl / pyridine.

 5.55 g of ls -amino benzene propanol are added at 0 ° C. in a chloroform-methylene chloride mixture in 5 g of product obtained in stage A dissolved in a chloroform-methylene chloride mixture (mixture consisting of 150 crB of methylene chloride and 160 cm3 of chloroform).

 The mixture is refluxed at 800C for 5 days, cooled, poured the mixture into 300 cm3 of water, washed the organic phase with water, dried, concentrated to dryness under reduced pressure and obtained 8.1 g of the expected product.

Stage C: Ethane thioate of 2-phenylmethyl 2 - / (4-pyridinyl carbonyl) amino / ethyl.

 4.5 cm3 of thioacetic acid are added to 7.5 g of product obtained in Stage B dissolved in 50 cm3 of tetrahydrofuran, brought to reflux for 16 hours, again added 2.25 cm3 of thioacetic acid and brought to 16 hours at reflux, add 600 cm3 of methylene chloride. The solution obtained is washed with a saturated aqueous solution of sodium bicarbonate, the organic phases are combined, dried, concentrated to dryness under reduced pressure and obtained 11.7 g of crude product. Chromatography on silica 5.7 g of this eluting product: methylene chloride w ethyl acetate 65-35) and 4 g of expected product is obtained (F = 1400C).

Example 2: N - / (1-mercaptomethyl) 2-phenylethyl / 4-pyridine carboxamide.

 59 ml of 0.1 N sodium hydroxide in 1.86 g of product obtained in Example 1, dissolved in 200 cm3 of methanol, are added at -20 ° C. over 30 minutes. The temperature is allowed to return to at 15 cm 3 of N hydrochloric acid, and the methanol is eliminated under reduced pressure. To the residue is added 100 cm3 of a saturated aqueous solution of sodium bicarbonate extracted with ether, dried, the filtrate is removed under reduced pressure, and 1.59 g of crude product is obtained which is purified by chromatography on silica ( eluent: methylene chloride-ethyl acetate 6/4) and obtains 1.41 g of expected product F = 107 C).

Example 3: N - / (1-mercaptomethyl) 2-phenylethyl / 4-pyridine carboxamide hydrochloride.

 0.1 g of product of Example 1 is dissolved in a mixture of 70% ether and 30% methylene chloride. The temperature of the mixture is brought to -10 ° C., and a stoichiometric amount of hydrochloric acid in ether is added, the hydrochloride precipitates. The solvents are removed under reduced pressure and the residue is dried under reduced pressure.

0.143 g of expected product is obtained (F = 130 C).

Example 4: Ethanethloate of 2 - / (cyclohexyl carbonyl) amino / 2 (phenymethyl) ethyl.

Stage A: methyl cyclohexane hydrochloride carboximidate.

 13.4 g of gaseous hydrochloric acid are introduced over 1 hour at 0 ° C. into a mixture containing 10 g of cyclohexane carbonitrile, 3.84 g of methanol and 70 cmS of ether.

 It is left for 24 hours at 0 ° C., the precipitate obtained is filtered, washed with ether, and dried under reduced pressure.

 7.7 g of expected product are obtained.

Stage B: 4- / 4,5-dihydro 4- (phenylmethyl) 2-isoxazolyl / cyclohexane
3.91 cin3 of triethylamine diluted in a chloroform-methylene chloride mixture in 5 g of product obtained in Example A diluted in a chloroform-methylene chloride mixture is added over 10 minutes at 0 ° C., then 4 is added. 25 g of ss-akino benzene propanol diluted in a total chloroform-methylene chloride mixture; 175 cm3 of methylene chloride and 175 cm3 of chloroform).

It is brought to reflux for three days at 80 ° C., the solvents are removed under reduced pressure and the residue is taken up with 500 cm3 of ether
The precipitated triethylamine hydrochloride is drained and washed several times with ether. The ethereal phases are combined, washed with water, dried, concentrated to dryness under reduced pressure. 5.1 g of the expected product are obtained in the form of an oil.

Stage C: 2 - / (cyclohexylcarbonyl) iiiinol 2 (phenylnethyl) ethyl ethanethioate.

 1.49 cm3 of thioacetic acid dissolved in 6 cm3 of tetrahydrofuran is added in 5.1 g of product obtained in stage B dissolved in 10 cm3 of tetrahydrofuran.

 Homogenized, left for 4 days at room temperature.

 A solid is recovered which is suspended in isopropyl ether.

 Chromatography on silica (eluent: chloroform - Ether 99/1) and 3.93 g of expected product is obtained.

Example 5: N - / (1-mercaptomethyl) 2-phenylethyl / cyclohexane carboxamide.

 45 cm 3 of 0.3 N sodium hydroxide in 3.93 g of product of Example 4 dissolved in 200 cm 3 of methanol are added at 10 ° C.

 The temperature rises to 0 C in 1 hour, 13.5 cm3 of N hydrochloric acid are added and the methanol is removed under reduced pressure. The precipitate formed is filtered in the residual reaction medium, washed with water and dried under reduced pressure. 3.15 g of crude product are obtained.

 The filtrate is extracted with methylene chloride. The organic phases are dried, concentrated to dryness under reduced pressure and 0.21 g of crude product is obtained.

 The 3.36 g of crude product thus obtained is chromatographed on silica (eluent: methylene chloride) and 2.88 g of expected product is obtained (F = 125 C).

Example 6:
Tablets corresponding to the formula were prepared: - Compound of Example 3 ........................... 50 mg - Excipient qs for one tablet finished at 0 350 mg (detail of excipient: lactose, starch, magnesium stearate, talc).

Biological study 1 /. Determination of the activity of enkephalinase and determination of the effect of the inhibitors.

The activity of enkephalinase is determined from a renal membrane fraction of rats. The kidneys are removed on ice and homogenized in HEPES 0.05M ph7.5 buffer containing magnesium chloride (50 times the volume). After a first centrifugation at 1500 g, the particulate fraction is obtained after centrifugation at 15000 g for 20 minutes. The pellet is then washed and suspended in a buffer
HEPES and stored at -20oC. An aliquot of this membrane preparation is placed in the presence of octyl ss O glucopyranoside (50 mM in final concentration) for 15 minutes at 4 C. After centralization at 100,000 g for one hour, the supernatant is removed and frozen in aliquots a - 20 C. The protein concentration is determined by the blue method
Comassie.

 After a principle of 15 minutes at 25 ° C., an aliquot of proteins is incubated for 15 minutes at 25 ° C. in the presence of 20 nanomoles of tritiated leucine-enkephalin (on the first amino acid) previously purified, 1 mM of puromycin and product to be tested in TRIS buffer. The hydrolysis reaction is stopped by adding 0.2N hydrochloric acid and the incubation undergoes deproteinization by heat (15 minutes at 95 ° C.). Under these conditions, the kinetics of the reaction are linear.

 The tritiated metabolites obtained by hydrolysis are separated from the enkephalin by chromatography on a porapak Q column: they are eluted in TRIS buffer while the enkephalin is retained on the column and then collected in the ethanolic phase.

 The activity of the various products is expressed in inhibitory concentrations 50%.

IC50 results
Product of Example 3 8 x 10-9 M
Product of Example 5 8 x 10-8 M N - / (1-mercaptomethyl) 2 phenylethyl / benzamide, 4 x 10-8 M 2 /. Test for stretching caused by acetic acid in rats.

 This test is inspired by that described by Koster et alXl) and carried out in the rat.

 The intraperitoneal injection of acetic acid causes repeated movements of stretching and twisting in the rat which can be considered as manifestations of diffuse abdominal pain, since they are attenuated by analgesics.

 Acetic acid is injected at a dose of 100 mg / kg, ie 1 cm 3 of an aqueous solution at 1; per 100 g of body weight, to male rats with an average weight of 110 g.

 The product to be studied is administered per os 30 minutes before the injection of acetic acid to groups of ten animals, each test comprising a control group which receives the vehicle. Five minutes after the injection of the irritant, the stretches and twists are counted for each animal for a period of fifteen minutes.

 The analgesic effect of each dose of the product studied is expressed as a percentage of protection relative to the average number of movements observed in the controls who received acetic acid alone. The DA50, or dose needed to reduce the number of stretches by 50%, is calculated using the method of least squares.

 The DA50 for the product of Example 3 as well as for N-I (1-mercaptomethyl) 2-phenylethylî benzamide is 20 mg / kg.

(1) Koster, R., Anderson, M. and De Beer, E.J. Acetic acid for analgesic screening Fed. Prou. 1959, 18, 412.

Claims (7)

1 /. The compounds of formula (I)

 in which R1 represents a hydrogen atom or a radical

 being an alkyl radical containing from 1 to 5 carbon atoms or an aryl radical optionally substituted by a hydroxy radical, an alkyl radical containing from 1 to 5 carbon atoms, an alkoxy radical containing from 1 to 5 carbon atoms, the nitro radical or a halogen atom, R2 represents a pyridinyl radical optionally substituted by an alkyl radical containing from 1 to 5 carbon atoms or R2 represents a phenyl radical optionally substituted by one or more radicals chosen from the group consisting of alkyl radicals containing 1 to 5 carbon atoms, the alkoxy radicals reforming from 1 to 5 carbon atoms, the halogen atoms, the hydroxyl radical, the nitro radical or a cycloalkyl radical containing 3 to 12 carbon atoms and X represents an atom d hydrogen or an alkyl radical containing from 1 to 5 carbon atoms, an alkoxy radical containing from 1 to 5 carbon atoms, a hydroxyl radical, a halogen atom or a t rifluoromethyl, provided that when X and R1 represent a hydrogen atom, R2 does not represent a phenyl radical, said products of formula (I) being in their racemic or optically active forms, as well as their addition salts with acids.  2 compounds of formula (I) as defined in claim 1 for which R1 is a hydrogen atom in their racemic or optically active forms, as well as their addition salts with acids 3 /. The compounds of formula (I) as defined in claim 1, for which R1 is an acetyl radical in their racemic or optically active forms, as well as their addition salts with acids. 4 /. The compounds of formula I) as defined in any one of claims 1 to 3, for which R2 is a pyridinyl radical or a cyclohexyl radical or a phenyl radical substituted by one or more chlorine atoms or by one or more methoxy radicals in their racemic or optically active forms, as well as their addition salts with acids.  5f. The compounds of formula (I) according to claim 1, the names of which follow  - N - / (1-mercaptomethyl) 2-phenylethyl / 4-pyridine carboxamide.  - N - / (1-mercaptomethyl) 2-phenylethyl / cyclohexane carboxamide  in their racemic and optically active forms as well as their  addition salts with acids 6 /. Process for the preparation of products of formula (I), characterized in that a product of formula II is subjected  R2-CN II in which R2 has the preceding meaning, to the action of an alkali metal alcoholate of formula R'OA, R 'being an alkyl radical of 1 to 4 carbon atoms and A an alkali metal -or d hydrochloric acid gas in the presence of an alcohol of formula R'GH, to obtain a product of formula III

 optionally in the form of the hydrochloride, which is condensed with a product of formula IY, in the acemic or optically active form

 in which X has the above meaning for obtaining a product of formula V, in racemic or optically active form:

 which is subjected to the action of a thioacid of formula VI:

 to obtain a product of formula (I) in which

 and in which X and R2 have the above meanings, which are saponified, if desired, to obtain a product of formula (I) in which R1 is a hydrogen atom, products of formula (I) which can be , if necessary, split by usual methods and 1 subject, if desired, to the action of an acid to form the salt. 7 /. As medicaments, the compounds of formula (I)

 in which R1 represents a hydrogen atom or a radical

R'1 being an alkyl radical containing from 1 to 5 carbon atoms or an aryl radical optionally substituted by a hydroxy radical, an alkyl radical containing from 1 to 5 carbon atoms, an alkoxy radical containing from 1 to 5 carbon atoms , the nitro radical on a halogen atom, R2 represents a pyridinyl radical optionally substituted by an alkyl radical containing from 1 to 5 carbon atoms or R2 represents a phenyl radical optionally substituted by one or more radicals chosen from the group consisting of alkyl radicals containing from 1 to 5 carbon atoms, the alkoxy radicals containing from 1 to 5 carbon atoms the halogen atoms, the hydroxyl radical, the nitro radical, or R2 represents a cycloalkyl radical containing from 3 to 12 carbon atoms , X represents a hydrogen atom or an alkyl radical containing from 1 to carbon atoms, an alkoxy radical containing from 1 to 5 carbon atoms, a hydroxyl radical1 a halogen atom or u n trifluoromethyl radical, in their racemic or optically active forms as well as their addition salts with pharmaceutically acceptable acids. 8 /. As medicaments, the products as defined in claim 5, in their racemic or optically active forms as well as their addition salts with pharmaceutically acceptable acids. 9 /. P as medicaments - N - / (1-mercaptomethyl) 2-phenylethyl / / benzamide, in racenic or optically active forms, as well as its addition salts with pharmaceutically acceptable acids. 10 /. Pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined in claims 7 to 9. 11 /. As intermediate products necessary for carrying out the process of claim 6, the products of formula Y.