SI9800045A - Process for preparation of new derivatives of thieno (3,2-c) pyridine - Google Patents

Abstract

The invention refers to the preparation of new derivatives of tieno (3,2-c) pyridine with the general formula (I) where Y can be an OH hydroxyl group or an OR group, where R is a straight or branched lower alkyl radical, or Y represents NR1R2 when independently of each other R1 and R2 are hydrogen or a straight or branched lower alkyl group, or in the presence of a nitrogen atom to which they are bound R1 and R2 together form a heterocycle which can contain another hetero-atom such as oxygen or nitrogen which can be substituted by a lower alkyl radical or benzyl. X is hydrogen, halogen or a lower alkyl radical. The invention also refers to their addition salts with mineral or organic acids which are pharmacologically acceptable, Y representing an OR group or NR1R2 or with mineral bases when Y represents OH as well as both enantiomers or their mixture.

Description

PROCEDURE FOR THE PREPARATION OF NEW TIENO (3, 2 - c) PIRIDINE DERIVATIVES

The present invention relates to a process for the preparation of novel thieno (3, 2-c) pyridines for use in therapeutics. New derivatives prepared by the process also contemplated by the present invention have the following formula:

wherein Y is an OH group or OR; R is a straight or branched lower alkyl radical; or Y represents the group / ^R1

N _x

R 2 where R _x and R ₂ independently of one another are hydrogen or a lower straight or branched alkyl group, or R 1 and R ₂ together with the nitrogen atom to which they are attached form a heterocycle which may contain another heteroatom such as, for example of oxygen or nitrogen, which may be replaced by a lower alkyl radical or benzyl, and X represents hydrogen, halogen or a lower alkyl radical.

Compounds of the present invention containing asymmetric carbon exist in the form of two enantiomers. The invention also relates to the preparation of each enantiomer as well as a mixture thereof.

The present invention also encompasses the preparation of addition salts with mineral or organic acids that are pharmacologically acceptable when Y is an OR group or or with a mineral base when Y represents OH.

By the term lower alkyl radical is meant a saturated hydrocarbon chain Ci-C ₄

The process of preparing the compounds of formula I according to the present invention is based on the preparation of esters, wherein Y represents the OR as defined above by condensation of tetrahydro-4, 5, 6, 7 thieno (3, 2 - c) pyridine, s formula

(II) chlorophenyl acetate, of the formula

0.

.OR

C '/ C Cl H

(III)

X where R and X are as described above. The saponification of the esters yields acids of formula (I) wherein Y is a hydroxyl group of OH, for the preparation of amides, where Y is:

/ ^R1

R 2 where R 1 and R 2 are as described above or even some esters of formula (I); an acid of formula (I) (R = OH) reacts, if possible, with the amine hnC

R2 or with an alcohol R - OH.

α-halogenated esters of formula (III) are prepared by known methods (EL, Eliel, MT Fisk and T. Prosser, Organic Syntheses, Coli. Vol. IV, J. Wiley and Sons, Inc. New York, 1963, p.169 ).

Although it is entirely possible to obtain all esters of formula (I) by reactions between the compounds of formulas (II) and (III), it is particularly economically advantageous to prepare higher esters of formula (I) starting with an acid of formula ( I) and R-OH alcohol.

The condensation of tetrahydro-thieno-pyridine with an ester of formula (III) is carried out in the presence of an alkali metal carbonate, such as potassium carbonate, in an inert solvent such as dimethylformamide, tetrahydrofuran or dimethoxy-1,2 ethane, at a temperature between 60Π C and boiling point of solvent. The saponification of an ester of formula (I), wherein R is methyl or ethyl, is carried out using alkali metal hydroxide, as a conventional example of soda or potassium, in an aqueous alcoholic solvent in the temperature range between room temperature and the boiling point of the solvent.

The activation of an acid of formula (I) can be achieved by ethyl chloroformate in the presence of a slightly increased amount of triethylamine at a temperature between -5 D to ODC in an inert solvent such as chloroform, dimethoxy-1,2 ethane or tetrahydrofuran.

This produces a mixed anhydride of the formula:

—O — Et (IV) which treatment with a slightly increased amount of alcohol or amine at a temperature range of 10DC to room temperature gives us esters or amides of formula (I).

The acid of formula (I) can also be activated in other ways. For example, by preparing the amides of formula (I), which is achieved by condensing the acid (I) with the amines

HNs .RI 'R2 in the presence of a solution of dicyclohexycarbodiimide in dichloro 1,2 ethane.

Esters of formula (I) can also be obtained in a conventional manner by condensation of the acid and the corresponding ROH alcohol in the presence of hydrogen chloride gas or thionyl chloride.

The following examples do not limit the present invention, but are for illustration purposes only.

EXAMPLE 1 α - (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5) oxorophenyl-methyl acetate (R = - CH _3; X = 2-C1), derivative no. 1.

To a solution of 20 g (0.144 mol) of tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridine in 200 ml of dimethylformamide was added 31.47 g (0.144 mol) of chlorine-2, o-chloro phenylacetate methyl and 19.82 g (0.144 mol) of potassium carbonate and then heated at 90DC for 4 hours. The reagent was cooled to room temperature, the mineral salts filtered and the solvent evaporated. The resulting precipitate of water was then leached in ethyl ether. The ethereal extracts were washed with water, dried over sodium sulfate and, after evaporation, obtained a yellow oil which was purified by its hydrogen chloride:

White crystals; m.p. = 130-140DC (ethyl acetate, isopropanol), yield: 45%.

(Note: m.p. = melting point; melting point; Transl.)

EXAMPLE 2 methyl a - (tetrahydro-4,5,6,7 thieno (3, 2-c) pyridyl-5) phenylacetate (R = - CH _3; X = H), derivative no. 2.

This compound was prepared according to the procedure described in Example 1 by alkylation of tetrahydro-4,5,5,6,7 thieno (3,2-c) pyridine with methyl chloro-2-phenylacetate.

Hydrochloride; white crystals; m.p = 200DC (ethanol), yield: 50%.

EXAMPLE 3 methyl a - (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5) of fluoro phenylacetate (R = - CH ₃ : X = 2-F), derivative no. 3.

This compound was prepared according to the procedure described in Example 1 by alkylation of tetrahydro-4,5, 6, 7 thieno (3, 2-c) pyridine with methyl chloro-2 fluoro phenylacetate.

Hydrochloride; white crystals: m.p. (paste) = 100DC; yield: 76.5%

EXAMPLE 4 Ethyl a - (tetrahydro-4,5, 6, 7 thieno (3, 2-c) pyridyl-5) hindered phenylacetate (R = -CH ₂ - CH ₃ ; X = 2-CH ₃ ), derivative no. 4.

This compound was prepared according to the procedure described in Example 1 by alkylation of tetrahydro-4,5, 6, 7 thieno (3, 2-c) pyridine with ethyl chloro-2-o-methyl phenylacetate.

Hemisulfate; white crystals: m.p. = 188-190DC (isopropenol); yield: 54%.

EXAMPLE 5 a - (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5) o-chloro phenylacetic acid (R = H; X = 2-Cl), derivative no. 5.

A mixture of 157.9 g of a- (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5) o-chloro phenylacetate ethyl and 100 ml of a 30% caustic soda solution in 800 ml of ethanol was heated by two and half an hour at the time of weaning. After ethanol evaporation, the reaction mixture was acidified to glacial acetic acid and methylene chloride extract. The organic portion was washed with water, dried over sodium sulfate and evaporated. After recrystallization in water, it was isolated as monohydrate. White crystals: m.p. (paste) = 125DC (water), yield: 46%.

EXAMPLE 6 a - (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5) o-chloro phenylacetic acid (R = H; X = H), derivative no. 6.

This compound was prepared according to the procedure described in Example 9 by saponifying α- (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5) phenylacetate ethyl.

White crystals: mp.p - 210 - 215OC (ethanol, methanol);

yield: 74%.

EXAMPLE 7 n-propyl [alpha] - (tetrahydro-4,5, 6, 7 thieno (3, 2-c) pyridyl-5) o -chloro phenylacetine (R = -CH ₂ - CH ₂ -CH ₃ ; X = 2- C1), derivative no.

7.

Hydrogen chloride gas was left in a solution of 10 g (0.0306 mol) of a- (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5) monohydrate o-chloro phenylacetine (example 5) for 12 hours in 100 ml of n-propanol and heated to reflux temperature. The reaction medium is evaporated and the precipitate remains in water in the form of bicarbonate of soda and ethyl ether extract. The essential extracts were washed with water, dried over sodium sulfate and evaporated to give a yellow oil which was purified by its hemisulfate.

White crystals: m.p. = 145DC (gross); yield: 78%.

EXAMPLE 8 n-Butyl [alpha] - (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5) o -chloro phenylacetate (R = -CH ₂ - CH ₂ - CH ₂ - CH ₃ / X = 2-C1), derivative no. 8.

This compound was prepared according to the procedure described in Example 5 by esterification of the acid α- (tetrahydro-4,5, 6, 7 thieno (3, 2-c) pyridyl-5) monohydrate o-chloro phenylacetin (Example No. 5) with n-butanol. Purification by hemisulfate.

White crystals: m.p. = 155DC / Yield: 79.5%.

EXAMPLE 9 Isopropyl a - (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5) o -chloro phenylacetate

X = 2-C1, derivative no. 9.

In 1 g (0.0031 mol) of suspension of α- (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridini-5) monohydrate o-chloro phenylacetic acid (Example 5) in 20 ml of isopropanol, cooled at -10DC, 2 ml of thionyl chloride are added dropwise, then the reagent is heated to reflux for 6 hours. After evaporation, the precipitate remains in water, such as bicarbonate of soda and methylene chloride extract. The organic portion was washed with water, dried over sodium sulfate, followed by evaporation. We are left with a colorless resin, which is purified with the help of its hemisulfate.

White crystals: m.p. (paste) = 140-150DC; yield: 44%.

EXAMPLE 10 ethyl a - (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5) oxo-phenylacetate (R = CH ₂ -CH ₃ ; X = 2-C 1) derivative no. 10.

To a solution of 15 g (0.048 mol) of α- (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5) monohydrate o-chloro phenylacetic acid (Example 5) and 7.12 ml (0.051 mol) ) of triethylamine in 150 ml of chloroform, cooled to a temperature between -5 and 0DC, was added dropwise to 4.85 ml (0.051 mol) of ethyl chloroformate. After completion of the process, allow to warm to room temperature and stir for half an hour. The reagent was cooled to about 10DC and 30 ml of ethanol was added dropwise gradually. The mixture was stirred overnight at room temperature and then washed with water.

The organic portion, dried over sodium sulfate, is evaporated to leave a colorless oil which is purified by bromine hydrate.

White crystals: m.p. = 180DC; yield: 94%.

EXAMPLE 11

N, N-dimethyl [α- (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5)] o -chloro phenylacetamide.

x = 2-C1) derivative no. 11

To a solution of 30 g (0.092 mol) of the acid α- (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5) monohydrate o-chloro phenylacetin and 14.24 ml (0.102 mol) of triethylamine in 300 ml of chloroform, cooled to a temperature between -5 and 0 ° C, was added dropwise 9.72 ml (0.102 mol) of ethyl chloroformate. After completion of the process, allow to warm to room temperature and stir the reagent for half an hour. It was then cooled to about 10 ° C and gradually 4.57 ml (0.102 mol) of dimethylamine in 60 ml of chloroform was added dropwise. The mixture was stirred at room temperature overnight. Water was added, purified, the organic portion was dried over sodium sulfate and then evaporated to leave a colorless crystalline resin.

White crystals: m.p. = 95-100 ° C (isopropyl ether); yield: 49%.

EXAMPLE 12 [(chlorophenyl-2-phenyl) (tetrahydro-4,5,5,6-thieno (3,2-c) pyridyl-5) acetyl] -1-pyrrolidine.

X = 2-C1; derivative no. 12.

This compound was prepared according to the procedure described in Example 11 by condensation of α- (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl) monohydrate o-chloro phenylacetin with pyrrolidine.

White crystals: m.p. = 130 ° C (isopropyl ether); yield: 61.5%.

EXAMPLE 13 [(chloro-2 phenyl) (tetrahydro-4,5,5,6 thieno (3,2-c) pyridyl-5) acetyl] -1 morpholine.

R = —K 0

X = 2-C1; derivative no. 13.

To a solution of 10 g (0.031 mol) of the acid α- (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5) monohydrate o-chloro phenylacetin and 13.3 ml (0.064 mol) of dicyclohexylcarbodiimide in 100 ml of dichloro-1,2 ethane, 2.67 ml (0.031 mol) of morpholine were added. The mixture was stirred at room temperature overnight. The organic portion was evaporated to give 2N hydrochloric acid and ethyl ether. After filtration of the resulting dicyclohexylur, the filtrate is purified and the aqueous portion is changed to a base in reaction with 2N soda obtained from methylene chloride. The organic portion was washed with water, dried over sodium sulfate and evaporated. We are left with a yellow resin, which is purified using our own hydrochloric hemihydrate.

White crystals: m.p. = 215-225 ° C (isopropanol); yield: 71%.

EXAMPLE 14 [(Chlorophenyl-2-phenyl) (tetrahydro-4,5,5,6-thieno (3,2-c) pyridyl-5) acetyl] -1-piperidine.

X = 2-C1; derivative no. 14.

This compound was prepared according to the procedure described in Example 13 by condensing the acid α- (tetrahydro-4,5, 6, 7 thieno (3, 2-c) pyridyl-5) monohydrate o-chloro phenylacetin with piperidine. White crystals: m.p. = 138 ° C (isopropanol); yield: 51.5%.

The following compounds were prepared according to the procedure described in Example 11:

[a - (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5)] oxo phenylacetamide. (R = -NH 2; X = 2-C 1); derivative no. 15. White crystals: m.p. = 126 - 128 ° C (isopropyl ether of isopropanol); yield: 46%.

- benzyl-4 [(chlorophenyl-2-phenyl) (tetrahydro-4,5,5,6-thieno (3, 2-c) pyridyl-5) acetyl] -! piperazine.

X = 2-C1; derivative no. 16.

Oxalate: White crystals: m.p. = 178 ° C (ethanol); yield: 82.5%

- Ν, Ν-dimethyl [α- (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5)] o-fluoro phenylacetamide.

/ ^CH 3

R = —N _x ch ₃

X = 2-F; derivative no. 17.

Dust, slightly yellow in color; m.p. = 125 ° C (isopropyl ether of isopropanol); yield: 41%.

- N-methyl [α - (tetrahydro-4,5, 6, 7 thieno (3, 2-c) pyridyl 5)] -chloro phenylacetamide. (R = NH - CH ₃ ; X = 2-C 1);

derivative no. 18. White crystals: m.p. = 137 ° C (isopropanol); yield: 85.5%.

- N-butyl [α - (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl5)] o -chloro phenylacetamide; (R = NH - (CH ₂ ) 3- CH 3; X = 2-C 1); derivative no. 19. White crystals: mp = 110 ° C (isopropyl ether); yield: 85%.

- Ν, Ν-dimethyl [α - (tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridyl-5)] phenylacetamide.

_with ch ₃

R = —N.

ch ₃

X = H; derivative no. 20. White crystals: m.p. = 138 ° isopropyl ether); yield: 39%.

- N, N-dimethyl [α - (tetrahydro-4,5, 6, 7 thieno (3, 2-c) pyridyl-5)] o-methyl phenylacetamide.

/ CH ₃

R = —N.

ch ₃

X = 2- CH ₃ ; derivative no. 21. White crystals: mp = 119 ° C (hexane); yield: 15%.

The pharmacological and toxicological results listed below emphasize, in particular, the properties of the derivatives of formula (I), both from a toxicological and tolerant point of view, and from the point of view of their action, in particular in the prevention of plaque coupling and antithrombotic activities.

The derivatives of formula (I) may be formulated in the form of a drug having in particular the abovementioned inhibitory properties, the basic ingredient of which is a derivative of formula (I), or a mineral or organic acid addition salt thereof, which is pharmacologically acceptable when Y is a group OR or

RI

R2 or with a mineral base when Y represents OH.

TOXICOLOGICAL STUDY

The compounds of formula (I) have excellent tolerance and poor toxicity. In addition, tests for severe, chronic, subchronic and retardative toxicity performed on different animal species did not reveal any local or general reactions, disturbances or anomalies in biochemical, macro or microscopy studies performed during the study itself.

PHARMACOLOGICAL STUDY

1) Inhibitory action in tile aggregation

This experiment was performed on rats receiving the compound orally in a suspension of gum arabicum for three days orally, which was tested for 48, 24, and 2 hours. At 0 h, blood was drawn from the neck of the anesthetized animal according to the Renaud method, and the blood collected was used to measure aggregation.

a) Measure the tile aggregation according to ADP ml of citrated blood and pour it into a small jug standing on a magnetic stirrer equipped with a magnetized rod.

After a few seconds of shaking, 0.4 ml of a solution containing 0.66 pg of adenosine diphosphate (ADP) is added to the mug. After 90 seconds of shaking, two more samples of 0.5 ml of blood are taken:

- the first is mixed with 0,5 ml of some EDTA-formol solution,

- mix the other with 0.5 ml EDTA solution.

By adding EDTA-formol, we stabilize the blood so that it can be determined by bonding;

After a 10-minute rest of both mixtures followed by 5-minute low-speed centrifugation to separate red blood cells, the platelet-rich plasma (PRP) floating on the surface can be harvested, diluted and counted.

The intensity of aggregation is determined by the ratio:

number of tiles in EDTA-formol _ x 100 =% unreag. tile number of tiles in EDTA

The test sample is the more inhibitory to tile aggregation, as close as possible to the ratio of 100. Results expressing the average percentage of unaggregated tiles in groups of 5 rats are given in Table 1.

TABLE 1

Product Dose mg / kg Pot The result Control P.O. 16 + 4 Derivative no. 1 3 x 25 - 94 + 3 Control - 20 + 11 Derivative no. 1 3x5 - 82 ± 11 Control - 23 ± 15 Derivative no. 1 3x2,5 - 56 ± 17 Control - 8 + 0 Derivative no. 10 3 x 25 - 66 ± 2 Derivative no. 10 3 x 12.5 - 49 + 11 Control - 8 + 1 Derivative no. 10 3 x 10 - 24 ± 5 Control - 11 + 0 Derivative no. 9 3 x 60 - 65 ± 7 Control - 13 + 3 Derivative no. 4 3 x 100 - 89 ± 1 Control - 3 + 1 Derivative no. 4 3 x 100 - 89 + 4 Control - 4 + 0 Derivative no. 2 3 x 100 - 72 + 12 Control - 4 + 0 Derivative no. 12 3 x 100 - 27 ± 5 Control - 2 + 0 Derivative no. 17 3 x 100 - 11 + 3 Derivative no. 20 3 x 100 - 4 + 1 Control - 18 + 1 Derivative no. 6 3 x 100 - 22 ± 4

b) Measurement of collagen tile aggregation

1.5 ml of citrate-treated blood was supplemented with 0.10 ml of a solution containing 10 pg of collagen per milliliter of solution. The mixture was mixed and the tiles were counted continuously. The decrease in the number of free tiles, as a function of time, which we were constantly monitoring, allowed us to draw a curve whose slope tells us what the initial rate of aggregation is. results representing average values within each group of 5 rats (treated and controls) are summarized in Table 2.

TABLE 2

Product Dose mg / kg Pot The result Control P.O. 3.12 ± 0.47 Derivative no. 1 3 x 25 - 0.14 + 0.03 Control - 2.17 + 0.64 Derivative no. 1 3x5 - 0.19 ± 0.04 Control - 5,00 + 1.02 Derivative no. 1 3x2,5 - 0.60 + 0.20 Control - 3.92 + 0.63 Derivative no. 10 3 x 25 - 0.16 ± 0.07 Derivative no. 10 3 x 12.5 - 0.54 ± 0.12 Control - 2.00 ± 0.35 Derivative no. 7 3 x 100 - 0.66 ± 0.18 Derivative no. 8 3 x 100 - 0.86 + 0.18 Control - 2.25 + 0.32 Derivative no. 9 3 x 60 - 0.11 + 0.01 Control - 3.41 + 0.55 Derivative no. 4 3 x 100 - 0, 12 ± 0.02

Table 2 - continued

Control - 4.73 ± 0.55 Derivative no. 4 3 x 100 - 0.30 ± 0.02 Control - 5.00 ± 1.05 Derivative no. 2 3 x 100 0.51 ± 0.18 Control - 2.25 ± 0.32 Derivative no. 11 3 x 100 - 0.83 ± 0.02 Control - 2.77 ± 0.32 Derivative no. 14 3 x 100 - 1.89 + 0.13 Control - 3.99 ± 0.40 Derivative no. 17 3 x 100 - 2.22 ± 0.10 Control - 5.01 ± 0.79 Derivative no. 21 3 x 100 - 3.04 ± 0.22 Control - 11.35 ± 1.01 Derivative no. 18 3 x 100 - 10.82 ± 0.81

c) measurement of bleeding time

A study of the inhibitory action of platelet aggregation also revealed action on the compounds with respect to bleeding time. The procedure used is a variant of the process developed by L.Stella, M.B. Donati and G. de Gaetano, Thromb. Res., 1975,7,709-716.

The experiment was performed on a rat that initially received the test compound per os in a suspension containing 85 ml, kg, 41 hours and 17 hours containing 10 ml / kg of 5% aqueous gum arabicum solution. After pentobarbital anesthesia, the rat shortened its tail to 5 mm in length. The blood was carefully collected for 15 seconds, being careful not to touch the wound.

Hemostasis occurs in a minute.

The results shown in Table 3 represent the mean bleeding times, expressed in seconds, in each group of five rats. Times exceeding 1200 seconds (20 min) are ignored.

TABLE 3 Bleeding times

Product Dose mg / kg Pot The result Control P.O. 600 Derivative no. 10 3 x 200 > 1200 Derivative no. 2 3 x 200 - > 1200 Control - 420 derivative no. 1 3x25 - > 1200 Derivative no. 1 3x5 - 1080 Control - 435 Derivative no. 1 3 x 12.5 - > 1200 Control - 780 Derivative no. 3 3 x 200 - > 1200 Control - 600 Derivative no. 18 3 x 200 - > 1200 Control - 600 Derivative no. 12 3 x 200 - > 1200

2) Antithrombotic action

This activity was studied using the method of experimental thrombosis using silk thread.

The purpose of this study is to modify the experimental thrombosis method with the extracorporeal circulation method described by Teruhiko Umetsu and Kazuko Sanai (Thromb. Haemost., 30.1.1978). . The arteriovenous lateral conduit is formed by the central and two lateral catheters; a white natural silk thread is inserted into the central part and circulation is restored within 20 minutes. When this breaks, we carefully pull out the thread and immediately weigh it. The difference in weight between the previously weighed dry filament and the humid represents the weight of the platelets.

48, 24 and 2 hours prior to diversion of the circulation to the lateral line, the suspension of the test compound in 10 ml / kg of 5% gum arabic was orally administered, and only 5% gum arabicum solution was administered for control. Table 4 shows the platelet weights in mg.

TABLE 4

Antithrombotic function

Product Dose mg / kg Pot Weight platelets (mg) Derogations v percent Control P.O. 38.56 ± 2.42 Derivative no. 8 3 x 200 29, 99 ± 3.05 -22 Control - 42.65 ± 3.30 derivative no. 3 3 x 200 - 2.60 ± 0.24 -94 Control 36.24 ± 2.05 Derivative no. 1 3 x 35 - 6.56 ± 0.51 -82 Derivative no. 1 3 x 12.5 - 15.98 ± 1.81 -56 Control - 40.86 ± 2.02 Derivative no. 1 3x5 - 27.70 ± 2.82 -32 Control - 40.68 + 1.74 Derivative no. 2 3 x 200 - 8.42 ± 3.28 -79 Derivative No.10 3 x 200 - 5.89 ± 0.99 -86 Control - 35.75 ± 1.76 Derivative no. 11 3 x 200 - 21.39 ± 2.92 -40

The toxicological and pharmacological studies we presented highlighted the low toxicity of the compounds of Formula (I), as well as their excellent tolerance and their interesting inhibitory action on plaque aggregation and antithrombotic properties, making them of great importance in human and animal therapeutics.

It is used orally in the form of tablets, dragees, capsules, drops, granules or syrups. Rectal use with suppositories and parenteral injections is also possible.

Each unit contains from 0.005 g to 0.250 g of a new derivative, and daily amounts vary between 0.005 g and 1.00 g of the active substance depending on the patient's age and disease level.

Let's just list some pharmaceutical formulations as a non-binding example:

1) Tablets

Derivative No.l (0.050 g)

Binder: lactose, powdered sugar, rice starch, alginic acid, magnesium stearate.

2) Dragees

Derivative No.10 (0.100 g)

Binder: magnesium stearate, corn starch, gum arabicum, white sugar, glucose, white wax, carnauba wax, paraffin.

3) Capsules

Derivative No.17 (0.100 g)

Binder: magnesium stearate, corn starch, lactose

4) Solution for injection Derivative no. 4 (0.075 g) isotonic solvent - 3 ml

5) Candles

Derivative no. 21 (0.075 g) semi-synthetic triglycerides - 1 spark plug

Claims (12)

PATENT APPLICATIONS A process for the preparation of a compound of formula 0. s X (I) wherein Y represents OH or OR in which R is a lower alkyl group which may be straight or branched or Y represents a group: wherein R 1 and R ₂ independently of one another are hydrogen or a lower straight or branched alkyl group, or R _x and R ₂ together, in the presence of the nitrogen atom to which they are attached, form a heterocycle which may contain another heteroatom, such as for example oxygen or nitrogen, which may be substituted by a lower alkyl radical or benzyl; X is hydrogen, halogen or a lower alkyl radical; and their addition salts with mineral or organic acids which are pharmacologically acceptable and Y represents the group OR; Rl R2 or with mineral bases where Y represents OH, as well as both enantiomers or mixtures thereof, characterized in that esters of formula (I) in which Y represents an OR group are prepared by condensation of tetrahydro-4, 5, 6, 7 thieno (3, 2-c) pyridine of formula The NH (II) for -chlorophenylacetate of the formula wherein R and X are as defined above and, if desired, the acid of formula (I) wherein Y is OH can be obtained by saponification of these esters and, if possible, pre-activated, converted into an amide or an ester of formula (I) by treatment with an amine .Rl HN. R 2 where R 1 and R _{2 are} as defined above or with an alcohol ROH where R is as defined above. Process according to claim 1, characterized in that the condensation reaction between the thieno-pyridine of formula (II) and the ester of formula (III) is carried out in the presence of an alkali metal carbonate in an inert solvent at a temperature between 60DC and the boiling point of the solvent . Process according to claim 1, characterized in that the saponification of an ester of formula (I), wherein R is a methyl or ethyl group, is carried out with the help of an alkali metal hydroxide in a hydroalcoholic solvent, in the temperature range between room temperature and the boiling point of the solvent. . A process according to claim 1, characterized in that the acid of formula (I) is activated by ethyl chloroformate in the presence of triethylamine at a temperature between -5 and ODC in an inert solvent such as chloroform, dimethoxy 1-2 ethane, or tetrahydrofuran. Process according to claim 1, characterized in that the acid for the preparation of the amide of formula (I) is activated by dicyclohexylcarbodiimide. Process according to claim 1, characterized in that the acid for the preparation of esters of formula (I) is activated by a stream of hydrochloric gas or by thionyl chloride. 7. The process of claim 1, wherein the compound compound is methyl α- [tetrahydro-4,5,6,7 thieno (3,2-c) pyridyl-5] -chlorophenyl acetate. The process according to claim 1, characterized by the compound methyl α- [tetrahydro-4,5,6,7 phenylacetate. A process according to claim 1, characterized by the compound methyl α- [tetrahydro-4,5,6,6,7-fluoro phenylacetate. thieno (3,2-c) pyridyl-5] is prepared having thieno (3,2-c) pyridyl-5] A process according to claim 1, characterized in that the prepared compound is isopropyl α- [tetrahydro-4,5,6,7 thieno (3,2-c) pyridyl-5] -chloro phenylacetate. A process according to claim 1, characterized in that the prepared compound is ethyl α- [tetrahydro-4,5,6,7 thieno (3,2-c) pyridyl-5] o-chloro phenylacetate. A process according to claim 1, characterized in that the compound prepared is N, N-dimethyl α- [tetrahydro-4,5,6,7 thieno (3,2-c) pyridyl-5] o-chloro phenylacetamide.