FR2464953A1 - Alpha-2-thienyl-thio phenyl-acetamide derivs. - hypocholesterolaemics, antiinflammatories and analgesics prepd. by condensing amine with appropriate phenyl acetic acid chloride - Google Patents

Abstract

N,N-R1,R2-alpha-(2-thienylthio)-R3, R4-substd-phenylacetamide derivs. of formula (I) and their salts are new. R1, R2 are each H, 1-6C alkyl, 1-6C alkenyl, 1-6C alkynyl, aralkyl (in which the aromatic ring is opt. mono- or poly-substd. by halo, alkyl, alkoxy, hydroxy, nitro or trifluoromethyl), heteroarylalkyl or dialkylaminoalkyl or R1 and R2 together with the N atom form a 5-7 membered heterocyclic group, opt. having a further heteroatom, such as O, S orN, this N atom opt. substd. by 1-6C alkyl, aralkyl or aryl in which the aromatic ring is opt. mono-or poly-substd. by halo, alkyl, alkoxy, hydroxy, nitro or trifluoromethyl); R3 and R4 are each H, halo, 1-6C alkyl, 1-6C alkoxy, hydroxy, nitro or trifluoromethyl. Intermediates are novel cpds. (I) are hypocholesterolemic, antiinflammatory and analgesic, which may be administered orally, parenterally or rctally in unit doses of 0.025-0.500g.

Description

 The present invention relates to novel i- (thienyl-2-thio) phenylacetamides, to their process of preparation and to their application in human and veterinary medicine.

dans laquelle R1 et R2 représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène; un groupe alcoyle en à à C6, alcényle en C1 à C6 > alcynyle en C à C un groupe alcoyle dans lequel le noyau aromatique est éventuellement mono- ou polysubstitué par un atome d'halogéne, un groupe alcoyle, alcoxy, hydroxy, nitro, trifluorométhyle; un groupe hétéroarylalcoyle; un groupe dialcoylaminoalcoyle; ou les deux radicaux R1 et R2 forment avec l'atome d'azote sur lequel ils sont fixés un hétérocycle de 5 à 7 charnons pouvant éventuellement comporter un autre hétéroatome tel que l'oxygène, le soufre ou l'azote, ce dernier hétéroatome pouvant éventuellement être substitué par un groupe alcoyle en C1-C6, aralcoyle ou aroyle dans lesquels le noyau aromatique peut être mono- ou polysubstitué par un atome d'halogène, un groupe alcoyle alc ox y , hydroxy, nitro ou trifluorométhyle; R3 et R représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou d'halogène; un groupe alcoyle en C1 à C6, alcoxy en C1 à C6; ou un groupe hydroxy, nitro ou trifluorométhyle.The new compounds of the invention correspond to the following general formula

wherein R1 and R2 each independently represent a hydrogen atom; a C 1 -C 6 alkyl, C 1 -C 6 alkenyl or C 1 -C 6 alkynyl group; an alkyl group in which the aromatic ring is optionally mono- or polysubstituted with a halogen atom, an alkyl, alkoxy, hydroxy, nitro group; trifluoromethyl; a heteroarylalkyl group; a dialkylaminoalkyl group; or the two radicals R1 and R2 form, with the nitrogen atom to which they are attached, a 5- to 7-membered heterocycle which may optionally comprise another heteroatom such as oxygen, sulfur or nitrogen, the latter heteroatom being able to optionally being substituted with a C1-C6 alkyl, aralkyl or aroyl group in which the aromatic ring may be mono- or polysubstituted with a halogen atom, an alkyl group, alkoxy, hydroxy, nitro or trifluoromethyl; R3 and R are each independently of one another a hydrogen or halogen atom; C1-C6 alkyl, C1-C6 alkoxy; or a hydroxy, nitro or trifluoromethyl group.

 By way of nonlimiting example, the radicals R 1 and R 2 may be a heteroarylalkyl group such as pyridylmethyl; they can also form with the nitrogen atom to which they are attached a heterocycle such as pyrrolidino, piperidino, morpholino or piperazino.

 These compounds have an asymmetric carbon atom and can therefore exist as two enantiomers.

The invention relates to each stereoisomer, as well as their mixture.

 The invention also relates to the pharmaceutically acceptable inorganic or organic salts of the salt-forming compounds.

The subject of the invention is also a process for the preparation of the compounds of formula I, characterized in that an acid chloride of formula II in which R 3 and R 4 have the abovementioned meanings are condensed with an amine III of formula HNR Wherein R1 and R2 have the above meanings.

The reaction is carried out at ambient temperature, in an inert solvent such as chloroform, methylene chloride, benzene or toluene, in the presence of an excess of the amine HNR1R2 intended to fix the hydrochloric acid. released.

The acid chlorides II are obtained from conventional dewax by treatment of the corresponding acids of formula IV with thionyl chloride or, preferably, phosphorus pentachloride according to the reaction scheme.

 The reaction is carried out at room temperature in an inert solvent such as benzene or toluene. The use of one equivalent of phosphorus pentachloride makes it possible to carry out the two reactions (IV) e (II) -i (I) in the same container.

The acids (IV) are original and they were prepared in three stages from thiophene according to the reaction scheme

In practice, the first two steps are carried out in the same container: the salt (V) is prepared according to the method of E. JONES and JI SHULMAN, Organic Syntheses, Vol. 50
J. Wiley and Sons, inc. New York, 1970, p. 104.

 The condensation of the salt of formula (V), at room temperature, with an equivalent of α -chloro phenylacetate of formula (VI) wherein R3 and R4 have the abovementioned meanings and R is a lower alkyl group such as methyl or ethyl , leads to the esters of formula (VII) whose saponification, at room temperature, with an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, in a hydroalcoholic solvent, provides the acids (IV).

The 6 -halogenated (VI) esters are prepared according to known techniques described in the literature, for example:
EL ELIEL, MT FISK and T. PROSSER, Organic Syntheses, coll.

flight. IV, J. Wiley and Sons, Inc. New York, 1963, p. 169.

 The preparations described below illustrate the process for the preparation of the derivatives of formula (IV).

1 - Acido <- (thienyl-2-thio) nhenylacetate (IV) R3 = R = H
a) - ethyl (thienyl-2thio) phenylacetate
To a solution of 100.8 g (1.2 mol) of thiophene in a hexagonal solution of 16% butyl lithium in hexane is added dropwise at -80 ° C. (1.2 mole) 300 cm3 of anhydrous tetrahydrofuran. The solution obtained is stirred at -400C for one hour and brought to -550C before adding in portions 42 g (1.1 eq.) Of sulfur. After stirring at -500 ° C. for one hour, 238 g (1.2 moles) of ethyl 2-chlorophenylacetate are added dropwise, the reaction medium is allowed to return to ambient temperature, poured onto a mixture of water. and ice, and extracted with ethyl acetate.

The dried and evaporated extracts are chromatographed on a silica column (eluent: toluene). An orange oil (yield: 66%) is obtained which can be used directly for the following operation. An analytical sample is obtained by vacuum distillation (Eb0.1 = 1280C).

b) Saponification
A solution of 220 g (0.8 mole) of ethyl i- (thienyl-2-thio) phenylacetate and 56 g (0.8 mol) of potassium hydroxide in 300 cm 3 of ethanol is stirred at ambient temperature for 4 hours. . After evaporation of the ethanol, the residue is acidified with 6N hydrochloric acid and then extracted with ether. The ethereal extracts are dried over sodium sulphate, evaporated and chromatographed on silica (eluent: toluene, ethyl acetate). An oil is obtained which crystallizes: orange crystals, mp = 880 ° C (petroleum ether), yield: 57%.

2 - 2-Alpha-2-thienylthio-D-tolylacetic acid (IV)
R3 = p-CH3, R = H.

a) - (thienyl-2-thio) p-tolyl ethyl acetate
This compound is prepared according to the procedure described in 1 - a) above by condensation of mercapto-2-thiophene with ethyl 2-chloro-p-tolylacetate.

 Orange oil, Ego 1 = 1450C (yield: 43%).

b) 2- (2-thienylthio) p-tolylacetic acid
This compound is prepared according to the procedure described in 1 - b) above by saponification of ethyl α- (thienyl-2-thio) p-tolylacetate.

 Yellow crystals, mp 122-1240 ° C (yield: 63%).

3 - p-Chloro-o (2-thienylthio) phenylacetic acid (IV)
R3 = p-Cl, R4 = H.

a) p-chloro &ethyl; -2-thienyl-2-thio) phenylacetate
This compound is prepared according to the procedure described in 1 - a) above by condensation of 2-mercapto thiophene and 2-chloro-p-chlorophenyl ethyl acetate.

 Light oil, Eb0.1 = 155 ° C (yield: 64).

(b) p-Chloro-α- (2-thienylthio) phenylacetic acid
This compound is prepared according to the procedure described in 1 - b) above by saponification of ethyl p-chloro o (- (thienyl) thio) phenylacetate.

 Beige crystals, mp 90-920 ° C (yield: 72).

4-O-chloro-alpha- (2-thienylthio) phenylacetic acid (IV)
R3 = o-Cl, R4 = H.

a) o-chloro &alpha;- (thienyl-2-thio) phenylacetate ethyl
This compound is prepared according to the procedure described in 1 - a) above by condensation of 2-mercapto-thiophene and 2-chloro-2-chlorophenylacetate.

 Amber oil, Eb0 1 = 1700C (yield: 42%).

b) o-Chloro & alpha- (2-thienylthio) phenylacetic acid
This compound is prepared according to the procedure described in 1 - b) above by saponification of ethyl 2-chloro (- (thien-2-thio) phenylacetate.

 Clear oil, (yield: 74%).

The following nonlimiting examples illustrate the invention
EXAMPLE 1
N, N-dimethyl-alpha- (2-thienylthio) phenylacetamide (I): R 1 = R 2 = Me, R 3 = R 4 = H (derivative 1)
10.4 g (0.05 mol) of phosphorus pentachloride are added portionwise at room temperature to a solution of 11.5 g (0.045 mol) of 2-alpha-thienyl-2-thio) phenylacetic acid in 150 g. cm3 of benzene. The resulting solution is stirred at room temperature for 24 hours. 150 cm3 of a 30% solution of dimethylamine in benzene are added dropwise. After stirring at ambient temperature for 15 minutes, the reaction medium is taken up in water and extracted with benzene. The benzene extracts are dried over sodium sulphate and evaporated under vacuum. After concretion of the oil obtained and recrystallization from isopropyl ether, white crystals are obtained, mp = 760 ° C. (yield: 58%).

EXAMPLE 2 N, N-dimethyl p-chloro-alpha-thienyl-2-thio) phenylacetamide (I): R 1 = R 2 = Me, R 3 = H, R 4 = p-Cl (derivative 2)
This compound is prepared according to the procedure described in Example 1 by condensation of dimethylamine with p-chloro-alpha (2-thienylthio) phenylacetic acid chloride.

White crystals, mp = 900C (isopropyl ether, isopropyl alcohol). (yield: 68.5%).

EXAMPLE 3
N, N-dimethyl-chloro-thienyl-2-thio phenylacetamide (I): R12 = Me, R3 = H, R4 = o-Cl (derivative 3)
This compound is prepared according to the procedure described in Example 1 by condensation of dimethylamine with o-chloro-alpha (2-thienylthio) phenylacetic acid chloride.

White crystals: F = 950C (isopropyl ether), (yield: 91%).

EXAMPLE 4
N-methyl-alpha- (2-thienylthio) p-tolylacetamide (I): R1 = H, R2 = Me, R3 = H, R4 = p-CH3 (derivative No. 4)
This compound is prepared according to the procedure described in Example 1 by condensation of methylamine with 1-alpha-thienyl-2-thio-p-tolylacetic acid chloride.

White crystals, mp = 1300C (benzene), (yield: 34%).

EXAMPLE 5 N-Isopropyl-alpha (2-thienyl-2-thio) phenylacetamide (I): R 1 = H, R 2 = iPr, R 3 = R 4 H (derivative 5)
8.3 g (0.036 mol) of phosphorus pentachloride are added portionwise at room temperature to a solution of 9 g (0.036 mol) of 2-alpha-thienyl-2-thio) phenylacetic acid in 150 cm 3 of benzene. . The resulting solution is stirred at room temperature for 24 hours. A solution of 10.6 g (0.18 mol) of isopropylamine in 20 cm3 of benzene is added dropwise. After stirring at room temperature for 15 minutes, the reaction medium is taken up in water and decanted. The benzene extracts are dried over sodium sulphate and evaporated under vacuum. A colorless oil is obtained which crystallizes.

White crystals, mp = 113 ° C (isopropanol), (yield: 47%)
EXAMPLE 6
N- (dimethylaminoethyl) - (thienyl-2-thio) phenylacetamide (I): R1 = H, R2- (CH2) 2-N (CH3) 2, R3-R4-H (derivative No. 6)
This compound is prepared according to the procedure described in Example 5 by condensation of dimethylaminoethylamine with O (- (thienyl-2-thio) phenylacetic acid chloride;
Beige crystals, mp = 860C (cyclohexane), (yield: 39%).

EXAMPLE 7
N- (3-pyridylmethyl) alpha- (2-thienylthio) phenylacetamide (I): R1 = H

R3 = R4 = H (derivative No. 7)
This compound is prepared according to the procedure described in Example 5 by condensation of 3-aminomethylpyridine on the chloride of alpha-2-thienylthio phenylacetic acid.

Beige crystals, mp = 1250C (isopropanol), (yield: 41).

EXAMPLE 8
N-benzyl-alpha- (2-thienylthio) p-tolylacetamide (I): R1 = H, R2 = C6H5-CH2, R3 = H, R4 = p-CH3 (derivative No. 8)
This compound is prepared according to the procedure described in Example 5 by condensation of benzylamine with O (- (thienyl-2-thio) p-tolylacetic acid chloride.

White crystals, mp = 1440C (toluene) (yield: 38%).

EXAMPLE 9
N-propargyl-alpha (2-thienylthio) p-tolylacetamide (I): R1 = H R2 = HC = C-CH2, R3-H, R4 = p-CH3 (derivative No. 9)
This compound is prepared according to the procedure described in Example 5 by condensation of propargylamine on the chloride of - (thienyl-2-thio) p-tolylacetic acid.

White crystals, mp = 126 ° C (cyclohexane-benzene) (yield: 34.5%).

EXAMPLE 10
N-Isopropyl o-chloro-2-thienylthio phenylacetamide (I): R 1 = H, R 2 = (CH 3) 2 -CH, R 3 = H, R 4 = o-Cl (derivative No. 10)
This compound is prepared according to the procedure described in Example 5 by condensation of isopropylamine with o-chloro-alpha- (2-thienylthio) phenylacetic acid chloride.

White crystals, F: 1200C (isopropyl ether-isopropyl alcohol) (yield: 19%).

EXAMPLE 11
N- (dimethylaminoethyl) o-chloro-alpha- (thienyl-2-thio) phenylacetamide (I): R1 = H, R2 = (CH3) 2NCH2CH2, R3 = H, R4 = o-Cl (derivative No. 11)
This compound is prepared according to the procedure described in Example 5 by condensation of dimethylaminoethylamine with o-chloro-(2-thienylthio) phenylacetic acid chloride.

Oxalate: white crystals, mp = 1350C (isopropyl alcohol) (yield: 58).

EXAMPLE 12 [phenyl (2-thienylthio) acetyl] -1-pyrrolidine (I)

R3 = R4 = H (derivative No. 12)
This compound is prepared according to the procedure described in Example 5 by condensation of pyrrolidine with o (- (thienyl-2-thio) phenylacetic acid chloride.

Beige crystals, mp = 1080 ° C (isopropyl ether) (yield: 72%).

R3=R4=H (dérivé n 13)
Ce composé est préparé selon le mode opératoire décrit dans l'exemple 5 par condensation de la pipéridine sur le chlorure de l'acide &alpha;-(thiényl-2 thio) phénylacétique.EXAMPLE 13 Phenyl (thienyl-2-thio) acetyl-1-piperidine (I)

R3 = R4 = H (derivative No. 13)
This compound is prepared according to the procedure described in Example 5 by condensation of the piperidine on the chloride of alpha-2-thienylthio phenylacetic acid.

White crystals, mp = 760C (petroleum ether - isopropyl ether), (yield: 50%).

EXAMPLE 14 [phenyl (2-thienylthio) acetyl] -1 morpholine (I):

R3 = R4 = H (derivative No. 14)
This compound is prepared according to the procedure described in Example 5 by condensation of the morpholine on the chloride of the acid alpha- (thienyl-2-thio) phenylacetic acid.

White crystals, mp = 960C (ethanol-isopropyl ether) (yield: 62).

EXAMPLE 15 Dienyl (thien-2-thio) acetyl-7-p-chlorophenyl-4-di-diazazine
(I):

R3 = R4 = H (derivative No. 15)
This compound is prepared according to the procedure described in Example 5 by condensation of 1-p-chlorophenylpiperazine on the chloride of the acid - (thienyl-2 thio) phenylacetic acid.

White crystals, mp = 114 ° C (isopropyl alcohol), yield: 35%.

R3-H , R4=p-Cl (dérivé n 16)
Ce composé est préparé selon le mode opératoire décrit dans l'exemple 5 par condensation de la pyrrolidine sur le chlorure de l'acide p-chloro &alpha;-(thiényl-2 thio) phénylacétique.EXAMPLE 16 [p-Chlorophenyl (2-thienylthio) acetyl] -1-pyrrolidine (i)

R3-H, R4 = p-Cl (derivative No. 16)
This compound is prepared according to the procedure described in Example 5 by condensation of pyrrolidine with p-chloro-alpha- (2-thienylthio) phenylacetic acid chloride.

White crystals, F: 840C (isopropyl ether) (yield: 48%).

R3=H , R4=o-Cl (dérivé n 17)
Ce composé est préparé selon le mode opératoire décrit dans l'exemple 5 par condensation de la pyrrolidine sur le chlorure de l'acide i-(thiényl-2 thio) o-chlorophénylacétique. EXAMPLE 17/0-Chiorophenyl (2-thienylthio) acetyl-1-pyrrolidine (I):

R3 = H, R4 = o-Cl (derivative No. 17)
This compound is prepared according to the procedure described in Example 5 by condensation of pyrrolidine with i-(thienyl-2-thio) o -chlorophenylacetic acid chloride.

White crystals, mp = 720C (isopropyl ether) (yield: 88%).

EXAMPLE 18 [2-phenylthienyl-2-thio) acetyl-4-methylpiperazine (i)

R3 = R4 = H (derivative No. 18)
This compound is prepared according to the procedure described in Example 5 by condensation of 1-methyl-piperazine on i-6-ihenoylthio) phenylacetic acid chloride.

Fumarate: white crystals, mp = 170 ° C (ethanol) (yield 37.5).

 The results of the toxicological and pharmacological tests which are reported below highlight the interesting activities of the derivatives of formula I, especially hypocholesterolemic, anti-inflammatory and analgesic.

 The subject of the invention is therefore a medicinal product having, in particular, hypocholesterolemic, anti-inflammatory and analgesic actions, characterized in that it contains as active principle a compound of formula I or an addition salt with a pharmaceutically acceptable acid or still another isomer of this derivative.

TOXICOLOGICAL STUDY
It has demonstrated the low toxicity and good tolerance of the derivatives of the invention.

 As an indication, the LD50 / 24 hours / kg of body weight, determined by the Miller and Teinter method by the intravenous route, in mice, is 51 mg for derivative 11 and 32 mg for derivative 9.

 For the oral route and for all derivatives, the LD50 is greater than 250 mg.

 This experiment has shown that the derivatives of the invention have provoked, in the experimental animals, throughout the clay toxicity tests, chronic or delayed, no local or general reaction, no disturbance in the biological controls regularly performed , no abnormality in macroscopic or microscopic examinations in sacrificed and autopsied animals at the end of the experiment. In addition, monitoring of the third generation progeny showed that the derivatives of the invention lacked teratogenic action.

PHARMACOLOGICAL STUDY
1) Hypocholesterolemic action
This experiment demonstrated the clear hypocholesterolemic and normolipemic action of the compounds of the invention. It was carried out according to two methods.

a) Propyl-Thiouracil Test (RANNEY & Co., PHARMACOL EXPER THERAP, 1963, 142, 132-136)
Propyl-thiouracil administered to adult rats has the property of rendering them hypercholesterolemic: the plasma cholesterol level increases under these conditions by approximately 15%. The experiment is carried out on different batches of rats, the control group receiving only propyl-thiouracil and the other treated batches additionally receiving the drug of the invention at the oral dose of 10 mg / kg.

 On the 11th day of the experiment, the blood samples are taken and the free cholesterol and the total cholesterol are measured. It is found that in treated animals, cholesterol levels are significantly lower compared to control animals.

The results obtained for certain derivatives are reported in the following table.

<tb><SEP> cholesterol <SEP> free <SEP> cholesterol <SEP> total
<tb><SEP> g / 1 <SEP> g / 1
<tb><SEP> control <SEP> 0.25 <SEP> 0.84
<tb><SEP> derivative <SEP> N <SEP> 1 <SEP> 0.15 <SEP> 0.60
<tb><SEP> derivative <SEP> N <SEP> 2 <SEP> 0.14 <SEP> 0.56
<tb><SEP> derivative <SEP> N <SEP> 3 <SEP> 0.18 <SEP> 0.58
<tb><SEP> derivative <SEP> N <SEP> 4 <SEP> 0.16 <SEP> 0.58
<tb><SEP> derivative <SEP> N <SEP> 5 <SEP> 0.18 <SEP> 0.57
<tb><SEP> derivative <SEP> N <SEP> 6 <SEP> 0.18 <SEP> 0.58
<tb><SEP> derivative <SEP> N <SEP> 7 <SEP> 0.15 <SEP> 0.55
<tb><SEP> derivative <SEP> N <SEP> 8 <SEP> 0.14 <SEP> 0.56
<tb><SEP> derivative <SEP> N <SEP> 9 <SEP> 0.17 <SEP> 0.53
<tb> derivative <SEP> N <SEP> 10 <SEP> 0.15 <SEP> 0.60
<tb><SEP> derivative <SEP> N <SEP> 11 <SEP> 0.13 <SEP> 0.58
<tb><SEP> derivative <SEP> N <SEP> 12 <SEP> 0.18 <SEP> 0.55
<tb><SEP> derivative <SEP> N <SEP> 13 <SEP> 0.16 <SEP> 0.52
<tb><SEP> derivative <SEP> N <SEP> 14 <SEP> 0.15 <SEP> 0.58
<tb><SEP> derivative <SEP> N <SEP> 15 <SEP> 0.18 <SEP> 0.55
<tb><SEP> derivative <SEP> N <SEP> 16 <SEP> 0.14 <SEP> 0.54
<tb><SEP> derivative <SEP> N <SEP> 17 <SEP> 0.16 <SEP> 0.57
<tb><SEP> derivative <SEP> N <SEP> 18 <SEP> 0.14 <SEP> 0.54
<Tb>

These results are confirmed by the following experimentation
b) This study was carried out on the rabbit subjected to a hypercholesterolemic diet. Rabbits are divided into lots of 40 animals. While Lot A, as a control, does not receive any treatment, the other batches (B, C, D, ...) are administered daily, orally, at a dose of 10 mg / kg. test.

On the first day of the experiment, then every 15 days for 75 days, all the animals are subjected to biological examinations during which the different elements reflecting dyslipemia are measured.
Total cholesterol (T)
Esterified cholesterol (E)
Free Cholesterol (L)
Esterification report (E / T)
Kunkel-phenol test (K1)
Kunkel-phenol X test (K2)
Dextran Burstein Test (B)
Serum lipids (LS) (i): KUNKEL et al. (Gastroenterol., 1948, 11, 4, 499-507) (x): CASTAIGNE A (Toulouse Méd., 1957, g, 805-823).

 At the end of the test all the animals are sacrificed and autopsied: a macroscopic examination of the livers and aortas is then carried out and the importance of fatty infiltration of the liver and from 0 to 4 are noted from 0 to 3. atherosclerotic lesions. The most significant results, which are summarized in the tables below, represent the average values established within each lot.

ler lour

<tb><SEP> Lots <SEP> T <SEP> E <SEP> L <SEP> E / T <SEP> K1 <SEP> K2 <SEP> B <SEP> LS
<tb><SEP> A
<tb> control <SEP> 0.56 <SEP> 0.27 <SEP> 0.29 <SEP> 0.48 <SEP> 8.00 <SEP> 12.5 <SEP> 10.8 <SEP> 2 2
<tb><SEP> B <SEP>
<tb> Derivative <SEP> 2 <SEP>, 54 <SEP> 0.27 <SEP> 0.27 <SEP> 0.50 <SEP> 8.3 <SEP> 12.9 <SEP> 11.00 <SEP> 2.1
<tb><SEP> C
<tb> Derivative <SEP> 16 <SEP> 0.58 <SEP> 0.28 <SEP> 0.30 <SEP> 0.48 <SEP> 8.1 <SEP> 13.2 <SEP> 11.4 <SEP> 1.98
<tb> 30th day

<tb><SEP> Lots <SEP> T <SEP> E <SEP> L <SEP> E / T <SEP> kl <SEP> K2 <SEP> B <SEP> LS
<tb><SEP> A
<tb> control <SEP> 2.35 <SEP> 1.48 <SEP> 0.87 <SEP> 0.62 <SEP> 21.8 <SEP> 31.8 <SEP> 26.8 <SEP> 3 95
<tb><SEP> B
<tb> Derivative <SEP> 2 <SEP> 1.38 <SEP> 0.90 <SEP> 0.48 <SEP> 0.65 <SEP> 18.8 <SEP> 26.1 <SEP> 20.9 <SEP> 2.82
<tb><SEP> C
<tb> Derivative <SEP> 16 <SEP> 1.45 <SEP> 0.92 <SEP> 0.53 <SEP> 0.63 <SEP> 18.5 <SEP> 25.5 <SEP> 21.2 <SEP> 2.87
<tb> 75th day

<tb><SEP> Lots <SEP> T <SEP> E <SEP> L <SEP> E / T <SEP> kl <SEP> K2 <SEP> B <SEP> LS
<tb><SEP> A
<tb> control <SEP> 3.70 <SEP> 2.30 <SEP> 1.40 <SEP> 0.62 <SEP> 44.00 <SE> 66.8 <SE> 52.1 <SEP> 5 ,30
<tb><SEP> B
<tb> derivative <SEP> 2 <SEP> 2.93 <SEP> 1.75 <SEP> 1.18 <SEP> 0.59 <SEP> 32.5 <SEP> 41.5 <SEP> 35.2 <SEP> 3.95 <SEP>
<tb><SEP> C
<tb> Derivative <SEP> 16 <SEP> 2.90 <SEP> 1.78 <SEP> 1.12 <SEP> 0.61 <SEP> 33.2 <SEP> 40.9 <SEP> 36.00 <SEP> 4.18
<Tb>

<SEP> Lots <SEP> Infiltrations <SEP> Lesions <SEP> atheromatous
<tb><SEP> fat <SEP> of the <SEP> liver <SEP> aortic
<tb> A <SEP> - <SEP> control <SEP> 2.8 <SEP> 3.6
<tb> B <SEP> - <SEP> derivative <SEP> 2 <SEP> 0.9 <SEP> 1,3
<tb> C <SEP> = <SEP> derivative <SEP> 16 <SEP> 1,1 <SEP> 1,3
<Tb>
2) Anti-inflammatory action
This action has been studied by two methods
a - Method of localized edema caused by carrageenan
A 1 μg solution of carrageenan (0.1 ml) is injected into the metatarsal flexors of the right hind paw of the rat at time 0. The animals of the treated batch are additionally orally administered with 10 mg / kg of the test compound. respectively one hour before, at the same time as the injection of the phlogogenic agent then one hour and two and a half hours later.The measurements which are made using the Roch micrometer at time 0, one hour, two hours , three hours and five hours after the administration of carrageenan, allow to determine, as a function of time, the percentage of anti-inflammatory activity compared to the control group.

The results, as regards, for example, the most significant derivatives are reported in the following table

<tb><SEP> Percentage <SEP> of anti-inflammatory activity <SEP>
<tb><SEP> after <SEP> 1 <SEP> h <SEP> after <SEP> 2 <SEP> h <SEP> after <SEP> 3 <SEP> h <SEP> after <SEP> 5 <SEP> h
<tb> Derived <SEP> n <SEP> 1 <SEP> 36 <SEP> 49 <SEP> 53 <SEP> 56
<tb> Derivative <SEP> n <SEP> 10 <SEP> 33 <SEP> 47 <SEP> 52 <SEP> 53
<tb> Derivative <SEP> n <SEP> 13 <SEP> 38 <SEP> 52 <SEP> 53 <SEP> 54
<Tb>
b - Method of generalized edema with ovalbumin
A simultaneous intraperitoneal injection of 1 ml of ovalbumin and 0.5 ml of a 1% aqueous solution of Evans blue is carried out on the rat. On the other hand, 50 mg of the treated animals are administered per os. of the test compound one hour before and at the same time as ovalbumin injection. The intensity of the phenomenon thus caused is noted by a number ranging from 1 to 5 following the progression of the inflammatory syndrome. The mean edematous intensity and the percentage decrease in edematous reaction compared with the control are thus determined.

The results for the same derivatives are shown in the following table

<tb><SEP> Percentage <SEP> of <SEP> decrease <SEP> of <SEP><SEP> reaction
<tb><SEP> oedematous
<tb><SEP> 2nd <SEP> hour <SEP> 3rd <SEP> hour
<tb> Derived <SEP> n <SEP> 1 <SEP> 46 <SEP> 55
<tb> Derived <SEP> n <SEP> 10 <SEP> 45 <SEP> 52
<tb> Derived <SEP> n <SEP> 13 <SEP> 50 <SEP> 58
<Tb>
3) Analgesic action
This action was demonstrated by the Koster test method, Anderson & Beer (Fed., Proceed, 18, 1959, 412, 1. 626).

 Intraperitoneal injection of a dilute solution of acetic acid causes in the mouse characteristic and repeated extension movements under the effect of pain.

 The administration of a dose of 50 mg / kg of the test compound, per os, thirty minutes before the injection of acetic acid reduces the number of these movements within thirty minutes. The average number of stretches and the percentage of analgesic obtained are thus determined, corresponding to the percentage of decrease in the number of stretches relative to the controls.

 The most significant results show that the mean analgesic percentage obtained is 58% for derivative # 3, 65% for derivative # 6, 64% for derivative # 10, 70% for derivative # 15 and 68 ss for derivative 18.

 The toxicological and pharmacological studies which have just been reported show that the compounds of the invention are endowed with good tolerance and that they possess significant hypocholesterolemic, anti-inflammatory and analgesic activity.

 The medicament of the invention may be presented for administration by the oral route in the form of tablets, sugar-coated tablets, capsules, drops or syrup. It may also be presented for rectal administration, in the form of suppositories and for parenteral administration as injectable solution.

 Each unit dose advantageously contains from 0.025 g to 0.500 g of active principle, the doses administered daily may vary from 0.025 g to 2.00 g of active principle.

 Some pharmaceutical formulations of the drug of the invention will be given hereinafter as a non-limiting example.

1 - Sugared tablets
Derivative n 9: 0.100 g
Excipient: microcrystalline cellulose, apple starch
soil, microcolloidal silica, stearic acid
arique, rice starch, shellac, gum
arabic, titanium oxide, sucrose, wax
white.

2 - Tablets
Derivative n 3: 0.150 150 g
Excipient: Lactose, wheat starch, talc, algi acid
potato starch, stearate of
magnesium.

3 - Capsules
Derivative No. 1: 0.100 g
Excipient: Sucrose, corn starch, talc, gum
that, stearic acid.

4 - suppositories
Derivative No. 17: 0.075 075 g
Excipient: semi synthetic triglycerides.

5 - Injectable solution
Derivative nO 10: 0, i25 g
Excipient: Isotonic solution. qsp 3 ml.

 Thanks to its important properties hypocholesterol lemic, anti-inflammatory and analgesic, the drug of the invention can be used with advantage in human and veterinary medicine.

 By its action cholesterol-lowering, it normalizes the blood levels of cholesterol and lipids by regulating their metabolism. It is indicated for the treatment of isolated lipid disturbances and clinical manifestations of atherosclerotic disease.

 By its actions anti-inflammatory and analgesic, it is indicated in the treatment of the inflammatory and painful phenomena, whatever their etiology.

Claims (9)

 1. (2-thienylthio) phenylacetamide derivatives having the following general formula:

 wherein R 1 and R 2 each independently represent a hydrogen atom, a lower alkyl group, C1 to C6, C1 to C6 alkenyl, C1 to C6 alkynyl; an aralkyl group in which the aromatic ring is optionally mono- or polysubstituted with a halogen atom, an alkyl, alkoxy, hydroxy, nitro, trifluoromethyl group; a heteroarylalkyl group; a dialkylaminoalkyl group; or the two radicals R 1 and R 2 form, with the nitrogen atom to which they are attached, a 5- to 7-membered heterocyl which may optionally comprise another heteroatom such as oxygen, sulfur or nitrogen, the latter heteroatom being able to optionally be substituted by a C1-C6 alkyl, alkyl or aroyl group in which the aromatic ring can be mono- or polysubstituted with a halogen atom, an alkyl, alkoxy, hydroxy, nitro or trifluoromethyl group; R3 and R4; each independently of one another represents a hydrogen or halogen atom; C1-C6 alkyl-C1-C6 alkoxy; or a hydroxy, nitro or trifluoromethyl group and their pharmaceutically acceptable salts.  2. Derivatives according to claim 1, corresponding to the general formula I, wherein R1 and R2 each represent, independently of one another, a hydrogen atom; C1-C6 alkyl, C1-C6 alkynyl; a benzyl group optionally mono- or polysubstituted on the aromatic ring by a halogen atom, an alkyl, alkoxy, hydroxy, nitro, trifluoromethyl group; a pyridylmethyl group; a dialkylaminoalkyl group; or the two radicals R1 and R2 form, with the nitrogen atom to which they are attached, a pyrrolidino, piperidino, morpholino or piperazino group, optionally substituted by a C1-C4 alkyl or phenyl group; R3 and R are each independently of one another a hydrogen, halogen or an alkyl group.  3. Process for the preparation of t - (thienyl-2-thio) phenylacetamide derivatives according to claim 1, characterized in that an acid chloride of following formula is condensed.

 in which R3 and R4 are as defined in claim 1, with an amine III of formula  HNR1R2 wherein R1 and R2 are as defined in claim 1, in an inert solvent and in the presence of an excess of amine (III).  4. Method according to claim 3, characterized in that the solvent is selected from chloroform, methylene chloride, benzene or toluene.  5. Process according to claim 3 or 4, characterized in that the acid chloride of formula (II) is prepared by the action of a chlorinating agent on the corresponding acid of formula IV

 6. Process according to claim 5, characterized in that the acid of formula IV - a) is prepared by reacting a salt of formula V below.

 with an i-chlorophenylacetate of formula VI below

 in which R1 and R2 are as previously defined and R is a lower alkyl group, and b) saponification of the resulting product with an alkali metal hydroxide.  7. Medicament in particular having a hypocholesterolemic, anti-inflammatory and analgesic activity, characterized in that it contains as active ingredient a compound according to claim 1.  8. Medicament according to claim 3, characterized in that the active ingredient is associated with a suitable vehicle by oral, parenteral or rectal administration.  9. Medicament according to claim 7 or 8, characterized in that it is presented in unit dose form each containing from 0.025 to 0.500 g of active principle.