FR2518093A2 - 3-1,2,5,6-Tetra:hydro-1-substd.-3-pyridyl phenol derivs. - dopaminergic agonists and/or antagonists and antiemetics, used to treat Parkinson's disease, psychic disorders etc. - Google Patents

Abstract

3-(1,2,5,6-tetrahydro-1 -R1-3-pyridyl)-phenol derivs. of formula (I') which are covered in claim 1 of the parent patent, (FR2496099 - Derwent 82-52660E/26 DE3149703) and their acid addn. salts, are new (where R1 is phenethyl, ethyl, cyclopropylmethyl, 2-hydroxy-2-phenethyl or allyl). Intermediates (II') and their acid addn. salts are also new. Depending on the nature of R1, (I') have dopaminergic agonist and/or antagonist activity, and some cpds. have antiemetic activity. (I') are used to treat syndromes of extrapyramidal origin, such as Parkinson's disease and post-encephalitic parkinsonism syndromes, psychic disorders, behavioural disorders and vomitting and nausea due to any cause. (I') may be administered orally or parenterally e.g. in doses of 5-200 mg per day. Activity tests are described.

Description

 In its French patent application filed December 15, 1980 under the number 80-26540, the Applicant has described and claimed new derivatives of hydroxyphenyl tetrahydropyridine and their salts, their process and preparation intermediates, the application as medicaments said derivatives and the compositions containing them.

dans laquelle X représente un atome d'hydrogène ou un radical acyle renfermant de 2 à. 7 atomes de carbone, Y représente un atome d'hydrogène ou un groupement - OX dans lequel X est défini comme ci-dessus et R représente un atone d'hydrogene, un radical alcoyle renfermant de 1 à 5 atomes de carbone, cycloalcoylalcoyle renfermant de 4 à 7 atomes de carbone, alcényle au alcynyle renfermant de 3 à 5 atomes de carbone, ou eraîccyle renfermant de 7 à 12 atomes de carbone, étant entendu cue lorscue R représente un atome d'hydrogène, X représente un atome d'hydrogène.The main patent has described more particularly new derivatives of hydroxyphenyl tetrahydropyridine, and their addition salts with mineral or organic acids, characterized in that they correspond to the general formula (I)

wherein X represents a hydrogen atom or an acyl radical containing from 2 to 7 carbon atoms, Y represents a hydrogen atom or a group -OX in which X is defined as above and R represents a hydrogen atone, an alkyl radical containing from 1 to 5 carbon atoms, cycloalkylalkyl containing 4 to 7 carbon atoms, alkynyl alkenyl having 3 to 5 carbon atoms, or ethylene containing 7 to 12 carbon atoms, it being understood that when R is a hydrogen atom, X is a hydrogen atom.

dans laquelle Y'représente un atome d'hydrogène ou un radical méthoxy et R a la signification déjà indiquée, pour obtenir un dérivé de

dans laquelle YA représente un atome d'hydrogène ou un radical hydroxy, et que - soit l'on isole et salifie si désiré ledit dérivé de formule - soit l'on soumet ledit dérivé de formule (IA) sous forme salifiée à une acylation pour obtenir un produit de formule

dans laquelle X' représente un radical acyle renfermant de 2 à 6 atomes de carbone, YB représente un atome d'hydrogène ou un radical OX dans lequel X' est défini comme ci-dessus et
R a la signification déJà indiquée, que l'on isole et salifie si désiré.The main patent also claimed a process for the preparation of the hydroxyphenyl tetrahydropyridine derivatives corresponding to formula (I) above, as well as their salts, said process being characterized in that a derivative of the formula ( II)

in which Y 'represents a hydrogen atom or a methoxy radical and R has the meaning already indicated, to obtain a derivative of

in which YA represents a hydrogen atom or a hydroxyl radical, and that - either one isolates and salifies if desired said derivative of formula - either one subjects said derivative of formula (IA) in salified form to an acylation for get a formula product

in which X 'represents an acyl radical containing from 2 to 6 carbon atoms, YB represents a hydrogen atom or an OX radical in which X' is defined as above and
R has the meaning already indicated, which is isolated and salified if desired.

 The main patent has further claimed the drug application of the derivatives of general formula (I) above, and their pharmaceutically acceptable salts, as well as pharmaceutical compositions containing, as active ingredient, one or more derivatives of general formula (I) and / or their pharmaceutically acceptable salts.

 The purpose of this application for a certificate of addition is to illustrate by new examples the invention described in the main patent.

dans laquelle R1 représente un radical phé-nyléthyl, éthyl, cyclopropylméthyl, 2-hydroxy 2-phényléthyl ou allyl, ainsi que leurs sels d'addition avec les acides minéraux ou organiques.It relates more particularly to derivatives of hydroxyphenyl tetrahydropyridine corresponding to the formula (I) of claim 1 of the main patent, of formula (I ')

in which R 1 represents a phenylethyl, ethyl, cyclopropylmethyl, 2-hydroxy-2-phenylethyl or allyl radical, as well as their addition salts with mineral or organic acids.

 These derivatives can be prepared by the method described in the main patent application, and above mentioned.

 Examples of such a preparation are given below in the experimental part.

 The addition salts with inorganic or organic acids may be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, formic, propionic, benzoic, malonic, maleic, fumaric, succinic acids. tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulfonic, such as methane or ethanesulphonic, arylsulphonic acids, such as benzene or paratoluenesulphonic and arylcarboxylic acids.

 Among the preferred derivatives of the invention, the products described in the examples are more particularly retained.

 As indicated in the main patent application, the addition salts of the derivatives of formula (I ') can be prepared according to conventional methods, for example by reacting, in substantially stoichiometric proportions, an inorganic or organic acid with said derivative of formula (I '). The salts can be prepared without isolating the corresponding bases.

 The derivatives, subject of the present application of the certificate of addition, as well as those of the main patent application, have very interesting pharmacological properties which may differ according to the nature of the substituents; they are endowed in particular with agonist properties and / or dopaminergic antagonists, as well as, for some of them, antiemetic properties. Thus, for example, the product of Example 2 hereinafter has properties both dopamine agonist and antagonist, and that the product of Example 3 below has predominantly dopaminergic antagonist properties.

 These properties are illustrated further in the experimental section.

 These properties make use of the hydroxyphenyl tetrahydropyridine derivatives, as well as their salts, as drugs.

 The present application thus also relates to the application, as medicaments, hydro phenyl tetrahydropyridine derivatives, as defined by formula (I) and their addition salts with pharmaceutically acceptable acids.

 Among the medicaments, obået of the invention, it retains preferably the drugs characterized in that they consist of the new derivatives of hydroxyphenyl tetrahydropyridine described in the examples.

 The drugs of the invention find their use, according to their pharmacological activity, for example, in the treatment of syndromes of extrapyramidal origin, such as in the treatment of Parkinson's disease and in the treatment of Fost-encenhalitic Parkinson syndromes, in the treatment of mental disorders, disorders of the compounding, character disorders as cue in the treatment of vomiting and nausea of all origins.

 The usual dose, variable according to the derivative used, the treated suet and the affection in question may be, for example, from 5 mg to 200 mg per day, the oral route in humans of the derivative of Example 3.

 The invention also relates to pharmaceutical compositions which contain at least one aforementioned derivative or one of its addition salts with pharmaceutically acceptable acids, as active principle.

 As pharmaceuticals, the derivatives of formula (I) and their pharmaceutically acceptable acid addition salts may be incorporated into pharmaceutical compositions for the intended or parenteral route.

 These pharmaceutical compositions can be, for example, solid or liquid and be in the pharmaceutical forms commonly used in human medicine, such as, for example, tablets, simple or coated, capsules, granules, suppositories, injectable preparations; they are prepared according to the usual methods.

The active principle (s) can be incorporated into the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, acylated or unbranched vehicles. , fats of animal or vegetable origin, caraffinic derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.

dans laquelle R1 représente un radical phényléthyl, éthyl, cyclopropylmétnyl, 2-hydroxy 2-phényléthyl ou allyl, ainsi que leurs sels d'addition avec les acides minéraux ou organiques.Finally, the subject of the invention is the novel industrial products which are particularly useful for the preparation of the derivatives corresponding to formula (I '), namely the products of formula (II')

in which R 1 represents a phenylethyl, ethyl, cyclopropylmethanyl, 2-hydroxy-2-phenylethyl or allyl radical, as well as their addition salts with mineral or organic acids.

 Exemplary embodiments of the invention will now be given.

Example 1: 3- [1-Phenethyl-1,2,5,6-tetrahydropyridin-3-yl) phenol fumarate
A mixture of 6 c of 3- (3-methoxyphenyl) -1-phenethyl-1,2,5,6-tetrahydropyridine and 12 g of pyridinium hydrochloride is heated at 2 ° C. with stirring for 2 hours. It is cooled, diluted with water, added ammonia and extracted with methylene chloride. The organic phase is washed with water; Dry and evaporate the solvent. The residue is chromatographed on silica eluting with a chloroform-acetone mixture (8-2) to give 4.9 g of the expected product. F = 155 C.

 3.5 g of the product obtained above are dissolved in hot water in 50 cm 3 of isopropanol and then 1.5 g of fumaric acid are added in 15 cm 3 of isopropanol. It is cooled, drained, washed with isopropanol and dried and 3.4 g of expected salt are obtained. F = 210 C.

Analysis: C 23 H 25 NO 5 = 395.458
Calculated CX 69.85% 6.34 Mx 3.54
Found 69.9 6.5 3.5
The starting 3- (3-methoxyphenyl) 1-phenethyl-1,2,5,6-tetrahydropyridine was prepared as follows.

 Refluxed for 16 hours a mixture of 5 g of 3- (3-methoxyphenyl 1,2,5,6-tetrahydropyridine hydrochloride, 100 cm3 of acetone, 7 g of sodium carbonate and 3.5 cm3 of bromide. The mixture is filtered and evaporated to dryness and the residue is chromatographed on silica, eluting with a cyclohexane-ethyl acetate mixture (7-3) to give 6.2 g of the expected product.

EXAMPLE 2 Neutral Oxalate of 3- (1-ethyl-1,2,5,6-tetrahydropyridin-3-yl) phenol
A mixture of 5.2 g of 3- (3-methoxyphenyl) -1-ethyl-1,2,5,6-tetrahydropyridine and 10.4 g of pyridinium hydrochloride, cooled, diluted to 0.degree. water, add ammonia, and extract with methylene chloride. The extract is washed with water, dried, evaporated to dryness and the residue is chromatographed on silica eluting with a cyclohexane-chloroform-triethylamine mixture (6-3-1). 3.95 g of expected product are obtained.

 3.85 g of the product obtained above is dissolved in 40 cm3 of isopropanol and then 2.4 g of oxalic acid are added. Cooled, filtered, washed with isopropanol, dried and gives 3.57 c of expected product. Mp = 2400C.

Analysis: (C14H18NO3) 2 = 496.608
Calculated C 67.72 H 7.31 Nt 5.64
Found 67.4 7.3 5.6
The starting 3- (3-methoxyphenyl) 1-ethyl-1,2,5,6-tetrahydropyridine was prepared as follows.

 7 g of 3- (3-methoxyphenyl) -1,2,5,6-tetrahydropyridine hydrochloride are suspended in 70 cm 3 of dimethylformamide and then 9.8 g of sodium carbonate and 2.6 cm 3 of sodium iodide are added. 'ethyl. Stirring is maintained for 16 hours and then diluted with water, extracted with ethyl acetate, washed with water, dried and evaporated to dryness. The residue is chromatographed on silica eluting with cyclohexane-chloroform-triethylamine (8-1-1). 5.3 g of expected product are obtained.

Example 3: Neutral lamina of 3- (1-cyclopropylmethyl 1,2,5,6-tetrahydropyridin-3-yl) phenol.

 The procedure is analogous to that described in Example 2, starting from 13.35 g of 1- (cyclopropylmethyl) 3- (3-methoxyphenyl) 1,2,5,6-tetrahydropyridine and 27 g of pyridinium hydrochloride. . 10.2 g of expected product are obtained and then, starting from 4.5 g of this product, 5.04 g of expected fumarate. F = 210 C.

Analysis: C34H42N2O6 = 574.732
Calculated C 71.06 H% 7.37 Ni 4.8?
Found 71.3 7.4 4.9
The starting 1- (cyclopropylmethyl) 3- (3-methoxyphenyl) 1,2,5,6-tetrahydropyridine was prepared as follows.

 A mixture of 10 g of 3- (3-methoxyphenyl) -1,2,5,6-tetrahydropyridine hydrochloride, 100 cm 3 of dimethylformamide, 14 g of sodium carbonate and 4.4 cm 3 of sodium carbonate is heated at 75 ° C. for 24 hours. chloromethyl cyclopropane. It is cooled, diluted with water and extracted with ethyl acetate, the extract is washed with water and dried, the solvent is evaporated off and the residue is chromatographed on silica, eluting with a cyclohexane-chloroform-triethylamine mixture ( 8-1-1). 9.25 g of expected product are obtained.

 Example 4: Neutral Fumarate of α 3- (3-hydroxyphenyl) 1,2,5,6-tetrahydropyridin-1-ylmethyl / benzene methanol.

 A mixture of 5 g of - - (3-methoxyphenyl) -1,2,5,6-tetrahydropyridin-1-yl / methyl / benzene methanol is refluxed for 3 hours. 200 cm3 of dimethylformamide and 4.3 g of thiomethylate are added. lithium. Cooled, poured into ice water, extracted with ethyl acetate, the extract washed with water, dried and concentrated to dryness.

The residue is chromatographed on silica eluting with chloroform-methanol (95-5). 5 g of the base of the expected product are obtained.

 5.4 g of product obtained as above is dissolved in 100 cm3 of isopropanol and 2.12 g of fumaric acid are added.

It is cooled, wrung out, washed with iospropnaol and dried. After recrystallization from ethanol, 4.33 g of expected product are obtained. M = 1730C.

Analvse: (C21H23NO4) 2 = 706.844
Calculated C 71.37 H% 6.56 N% 3.96
Found 71, i 6, 8 4.0
The starting α, β- (3-methoxyphenyl) 1,2,5,6-tetrahydropyridin-1-yl / methyl / benzene methanol was prepared as follows
Step A: α-Phenyl-2- [3- (3-methoxyphenyl) -1,2,5,6-tetrahydropyridin-1-yl] ethanone.

 A mixture of 10 g of 3- (3-methoxyphenyl) 1,2,5,6-tetrahydropyridine hydrochloride, 200 cm3 of acetone, 14 g of sodium carbonate and 9.3 g of sodium hydroxide is refluxed for 3 hours. phenacyl bromide. The mixture is filtered and the solvent evaporated. 14 g of expected product are obtained.

Step B: o -phenyl 3- (3-methoxyphenyl) 1,2,5,6-tetrahydropyridine ethanol.

 The 14 g of product obtained in Stage A are dissolved in 135 cm 3 of methanol and then cooled to 0 ° C. and 2.72 g of sodium hydroboride are added. Stirred at 0 C for 2 hours and then poured into 500 cm3 of ice water. Extracted with ethyl acetate, washed with water, dried and evaporated to dryness. The residue is chromatographed on silica eluting with a benzene-ethyl acetate mixture (7-3) to obtain 13.44 g of the expected product. Exernoles Fumarateneutre of 3- (1-allyl) 1,2,5,6-tetrahydropyridin-3 - yl) phenol.

 The procedure is analogous to that described in Example 4, starting from 4.9 g of 1-allyl 3- (3-methoxyphenyl) 1,2,5,6-tetrahydropyridine and 4 g of thiomethylate. of lithium. After chromatography of the crude product on silica, eluting with the cyclohexane-chloroform-triethylamine mixture (6-3-1), and after treatment with fumaric acid in isopropanol, 5.73 g of the expected product. F = 168 C.

 The starting 1-allyl 3- (3-methoxyphenyl) 1,2,5,6-tetrahydropyridine was prepared as follows.

 A mixture of 7 g of 3- (3-methoxyphenyl) -1,2,5,6-tetrahydropyridine hydrochloride, 100 cm3 of dimethylformamide, 9.8 g of sodium carbonate and 3% was stirred for 6 hours. 5 g of allyl bromide. The mixture is filtered, evaporated to dryness and chromatographed on silica eluting with benzene-ethyl acetate (7-3). 5.9 g of expected product are obtained.

3- (3-Methoxyphenyl) 1,2,5,6-tetrahydropyridine hydrochloride can be prepared as follows
Step A: 3- (3-Methoxyphenyl) 1-phenylmethylpiperidin-3-ol hydrochloride.

 9 g of magnesium are activated by sublimation of iodine, refoidit, 20 cm3 of ethyl ether and 2 cm3 of tetrahydrofuran are added, then 2 cc of n-m-bromoanisole under an inert atmosphere, initiates the reaction, is added dropwise in 2 hours 50 cm3 this m-bromoanisole dissolved in 200 cm3 of ethyl ether and 20 cm3 of tetrahydrofuran, heated for another hour under reflux, left to stand for 16 hours, cooled 120 cm 2 this solution obtained, added drop by drop at +5, + 10 ° C. under an inert atmosphere, 20 g of N-benzyl 3-piperidone dissolved in 100 cm 3 of tetrahydrofuran, stirred for 3 hours, cooled in an ice bath, added dropwise to +15, + 20 C., 200 cm3 of saturated aqueous ammonium chloride solution, drained, decanted, extracted with aqueous ethyl acetate, the organic phase extracted with 2N hydrochloric acid, alkalized by addition of scouring liquor, extracted with ethyl acetate, washed with water, dried, distilled to dryness under reduced and gets 30 g of product. This product is dissolved in ethyl acetate, a solution of gaseous hydrochloric acid in ethyl acetate is added until the pH is acidic, the hydrochloride is crystallized and the oil is filtered off.

F = 210 C.

Step B: 1- (phenylmethyl) 3- (3-methoxyphenyl) 1,2,5,6-tetrahydropyridine.

 3.25 g of 1- (phenylmethyl) 3- (3-methoxyphenyl) piperidin-3ol hydrochloride in 65 cm 3 of xylene are heated to 140 ° C. with stirring, 2 g of phosphoric anhydride are added, the mixture is stirred for 2 hours at 140 ° C. Cool, carefully add ice, dilute with water, with ethyl acetate, alkalize by addition of triethylamine, stir until completely dissolved, filter, decant, acetate extract. ethyl, washed with water saturated with sodium chloride, dried, distilled to dryness under reduced pressure, purified by chromatography on silica eluting with a cyclohexane ethyl acetate (9-1), and obtained 1.97 g of the product expected.

Stage C: Ethyl 3- (3-methoxyphenyl) 1,2,5,6-tetrahydro-1-pyridine carboxylate.

 11.4 g of the product obtained in Step 9 dissolved in 25 μl of benzene are heated under reflux for 3 hours, with stirring, with 5.9 cm 3 of ethyl chloroformate, distilled to dryness under reduced pressure, and the residue is removed. excess of ethyl chloroformate by entrainment with benzene and obtains the desired product.

Stage D: 3- (3-methoxyphenyl) 1,2,5,6-tetrahydropyridine hydrochloride.

 11 g of the product obtained in the preceding stage, dissolved in 110 cm 3 of n-butanol with 11 g of potassium hydroxide, are heated at 120 ° C. for 6 hours, cooled, diluted with water, extracted with ethyl acetate, washed with the water saturated with sodium chloride, dried, distilled to dryness under reduced pressure, purified by chromatography on silica / Eluent, chloroform-acetonetriethylamine (6-3-1) /, the residue of the fractions distilled with methylene chloride, filtered, distil to dryness under reduced pressure and obtain 8 g of product.

7.7 g of this latter are dissolved in ethyl acetate (30 cc), hydrochloric ethyl acetate is added to acidic pH, crystallization is initiated, ice is poured for two hours, filtered, washed with acetate of ethyl, dried under reduced pressure, recrlstallise in isopropanol and 6.5 g of the expected product. F = 2020C Example 6
Tablets having the formula - 3- (1-cyclopropylmethyl 1,2,5,6-tetrahydropyridin-3-yl) phenol fumarate were prepared. ...................... 100 mg - Excipient qs for one tablet ends at ................ 150 mg .

(Detail of excipient: lactose, starch, talc, magnesium stearate).

 PHARMACOLOGICAL STUDY 1.- Antagonism with apomorphine stereotypies.

 The tests are carried out on batches of 5 rats according to a protocol inspired by JANSSEN et al. (Arzneim-Forsch 1965, 15, 104-117, 1967, 17, 41-854). Each animal is individually placed in a Plexiglas box (20 x 10 x 10 cm, NICOLET), the bottom of which is covered with a thin layer of wood curl.

 A dose of 1.5 mg of apomorphine hydrochloride is injected intravenously half an hour after intraperitoneal administration of the test compound.

The animals are observed for one minute, 15 minutes after the injection of apomorphine. The stereotyped movements of the oral sphere are evaluated according to BAISSIER and SIMON (Therapy, 1970, 25, 933-949): no characteristic reaction (0), some sniffling, licking and curing (1), intense sniffing and continuous licking (2 ), continuous cures (3)
The intensity of the stereotypies is expressed as a score between 0 and 15 corresponding to the sum of the values obtained on the Srats of a lot, 15 minutes after the injection of apomorphine.

 It is found that 3- (1-propyl-1,2,5,6-tetrahydropyridin-3-yl) phenol hydrochloride antagonizes stereotypies with apomorphine from the dose of 10 mg / kg.

2. - Rotational behavior after unilateral lesion of the nigrostriatal tract by 6-hydroxydopamine.

Technical:
The lesion is performed in male rats of approximately 220 g by unilateral injection into the nigrostriatal dopaminergic beam of 8 μg of 6-hydroxydopamine in 2 μ solution (Ungerstedt, Acta Physiol, Scand 1971, 82 Suppl 367, 6993).

 In such animals, direct dopaminergic agonists, such as apomorphine, administered systemically, lead to rotational behavior in the contralateral direction on the injured side.

 The test products are administered intraperitoneally at least 5 weeks after the lesion. The animals are placed in an automated rotometer which allows counting the number of rotations made by each animal in both directions.

 To evaluate the dopaminergic agonist activity, the test products are administered, and the contralateral rotations thus provoked are observed.

In order to evaluate the dopaminergic antagonist activity, the products to be tested are then administered, followed by apomorphine, and the number of rotations caused is observed to decrease.
by apomorphine.

It can be seen that
4- (1-propyl-1,2,5,6-tetrahydropyridin-3-yl) hydrobromide
1,2-benzene diol causes contralateral rotations at the
dose of 10 mg / kg;
3- (1-propyl-1,2,5,6-tetrahydropyridin-3-yl) hydrochloride
phenol and the product of Example 3 antagonize rotations
induced by apomorphine at the dose of 10 mg / kg and 20 mg / kg respectively; the product of Example 2 has both dopaminergic agonist and antagonist properties at the dose of 20 mg / kg.

3. - Antiemetic activity
Antagonism to apomorphine-induced vomiting is studied in dogs (CHEN and ENSOR J. Pharmac.

exp. Therap. 1959, 93, 245-250).

 The number of vomiting caused by a subcutaneous injection of 0.1 mg / kg of apomorphine hydrochloride is determined on each animal 8 days before the test.

 The test compound, placed in aqueous solution, is administered subcutaneously at variable doses, half an hour before apomorphine hydrochloride.

 4- (1-propyl-1,2,5,6-tetrahydropyridin-3-yl) hydrobromide. 1,2-benzene diol and 3- (1-propyl-1,2,5,6-tetrahydropyridin-3-yl) phenol hydrochloride antagonize apomorphine-induced vomiting.

4. - Study of acute toxicity.

 The lethal LDg doses of the various compounds tested after oral administration were evaluated in mice.

 DLC is the maximum dose causing no mortality after 8 days.

The results obtained are as follows

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<tb><SEP> Hydrobromide <SEP> of <SEP> 4- (1,2,5,6-tetrahydropyridine) <SEP> 300
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<tb><SEP> dropyridin-3-yl) 1,2-benzene <SEP> diol <SEP>> 1000
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<tb><SEP> 3-yl) <SEP> phenol
<sep>SEP> Hydrochloride <SEP> from <SEP> 3- (1-propyl <SEP>1,2,5,6-tetrayr->SEP> 200
<tb><SEP> dropyridin-3-yl) <SEP> phenol <SEP> 200
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<tb> 2 <SEP>#<SEP><SEP> 400
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Claims (10)

 wherein R 1 represents penenylethyl, ethyl, cyclopropylmethyl, 2-hydroxy-2-phenylethyl or allyl, as well as their addition salts with mineral or organic acids.

 1. The products of formula (I), as defined in claim 1 of the main patent application, of formula (I ') 2. 3- (1-Phenylethyl 1,2,5,6-tetrahydropyridin-3-yl) phenol fumarate. 3. Neutral oxalate of 3- (1-ethyl 1,2,5,6-tetrahydropyridin-3-yl) phenol. 4. Neutral fumarate of 3- (1-cyclopropylmethyl 1,2,5,6-tetrahydropyridin-3-yl) phenol. 5. Neutral fumarate of α- [3- (3-hydroxyphenyl) 1,2,5,6-tetrahydropyridin-1-yl] methyl] benzene methanol. 6. Neutral fumarate of 3- (1-allyl 1,2,5,6-tetrahydropyridin-3-yl) phenol. 7.- Medicaments, characterized in that they consist of the new derivatives of hydroxyphenyl tetrahydropyridine as defined by the general formula (I) of claim 1, and by their addition salts with pharmaceutically acceptable acids . 8.- Medicaments, characterized in that they consist of the new derivatives of hydroxyphenyl tetrahydropyridine as defined in one of claims 2 to 6. 9.- Pharmaceutical compositions, characterized in that they contain, as active ingredient, at least one drug as defined in one of claims 7 or 8. 10. As new industrial products necessary for the preparation of the derivatives corresponding to the formula (I ') of claim 1, the products of formula (II')

 in which R 1 represents a phenylethyl, ethyl, cyclopropylmethyl, 2-hydroxy-2-phenylethyl or allyl radical, as well as their addition salts with mineral or organic acids.