FR2718444A1 - Tetra:hydro:quinolin-8-yl sulphonyl:amino:imidazolyl oxo:pentyl:piperidine(s) - Google Patents

Abstract

Imidazolyl oxopentyl piperidine derivs. of formula (I), their salts and mixtures of diastereoisomers, are new. In (I), R is 1H-imidazol-4(5)-yl, 4,5-dihydro-1H-imidazol-4(5)yl, 1H-pyrazol-4-yl, isoxazol-5-yl, oxazol-4-yl, oxazol-5-yl, 4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl, 1H-triazol-4(5)-yl 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, or 1,3,4-oxadiazol-2-yl, opt. substd. by OH and/or ZH; Z is O, S or NH; R1 and R2 are H or methyl.

Description

The present invention relates to derivatives of (3-methyl)

  1,2,3,4-tetrahydroquinolin-8-yl) sulfonyl, their

  preparation and their application in therapeutics.

  The compounds of the invention correspond to the formula (I) O R SO2HNIN]> tk HN H

H3C N

  Wherein R is either 1H-imidazol-4 (5) -yl or 4,5-dihydro-1H-imidazol-4 (5) -yl or 1Hpyrazol-4-yl, either an 1H-pyrazol-5-yl group, an isoxazol-4-yl group, an isoxazol-5-yl group, an oxazol-4-yl group, an oxazol-5-yl group, or a

  4,5-dihydrooxazol-4-yl group, a 4,5-dihydro-

  oxazol-5-yl, a 1H-triazol-4 (5) -yl group, or a

  1,2,4-oxadiazol-3-yl group, a 1,2,4-oxadiazole group;

  -yl, a 1,3,4-oxadiazol-2-yl group, optionally substituted with a hydroxyl group and / or with a ZH 0 Z group, is chosen from oxygen, sulfur and imino and Rl groups; and R2 are each independently of one another,

  either a hydrogen atom or a methyl group.

  The compounds of the invention have 4 asymmetric centers.

  and may exist in the form of a mixture of diastere-

  réoisomères. The preferred configuration of the piperidinyl group is

  [2R, 4R], the preferential configuration of asymmetric carbon

  of the central amino part is [S].

  The compounds according to the invention may exist in the form of

  free bases or addition salts with pharmaceutical

acceptable.

  According to the invention, the compounds can be synthesized

of formula (I) according to scheme 1.

Figure 1 R3 HN {

H3C N

(M R2 l

C (C6H5) 3

R1 3

S02HWN A

HN

3C N

(IV) 2 I

C (c6H5> 3 o R

SO 2HW- '

HN

H3C N

() R NH

  A compound of formula (II) in which R3 is either equal to R as described above or is a 3-ethoxy-1,310-oxypropyl group is reacted with the compound of formula (III) in a solvent such as dichloromethane in the presence of a base such as N, Ndiisopropylethylamine (Hunig base) and a coupling agent such as 1H-benzotriazol-lyloxy [tris (dimethylamino)] phosphonium hexafluorophosphate;

  1H-benzotriazol-1-yloxy hexafluorophosphate (tripyrrolidine)

  din-1-yl)) phosphonium, or hexafluorophosphate of N - [(1H-

  benzotriazol-1-yloxy) (dimethylamino) methylene] -N-méthylmé-

  thanaminium, at a temperature between 0 C and 20 OC, to obtain a compound of formula (IV) which is deprotected

preferably in acidic medium.

  When it is desired to prepare the compounds of formula (I) in which R represents a 3-hydroxyisoxazol-5-yl group, it is possible to treat the compounds of formula (I) in which R represents a 3-ethoxy-1,3-dioxopropyl group. with hydroxylamine hydrochloride in basic medium, according to a method similar to that described by N. Jacobsen et al.,

Can. J. Chem., (1984), 62, 1940.

  In the same way, when one wants to prepare the compounds of

  formula (I) wherein R represents a 5-hydroxy group

  1H-pyrazol-3-yl, the compounds of formula (I) in which R represents a 3-ethoxy-1,3-dioxopropyl group by a protic solvent are treated by a method analogous to that described by S.R.F. Kagaruki et al. , Bull. Chem. Soc. Jpn.,

(1981), 54, 3221.

  Compounds analogous to the compounds of formula (I) are

  described in European Patent Application No. 0565396.

  The starting compounds are commercially available or described in the literature or may be prepared according to methods described therein or which are known from

the skilled person.

  Thus, the compounds of formula (II) are prepared from

  (2R-trans) -4-methyl-1- (1,1-dimethylethyl) ester

  thylpiperidine-1,2-dicarboxylic acid, the preparation of which is

  described in European Patent Application No. 0565396.

  Preparation of (S) -a - [[(3-methyl-1,2,3,4-tetrahydroquinolin-8-yl) sulfonyl] amino] -1- (triphenylmethyl) -1H-i-midazole acid 4-pentanoic acid of formula (III) is described in European Patent Application No. 0565396. The preparation of (2R-trans) -1 - [(1,1-dimethylethoxy) carbohydrate

  Ethyl 4-methyl-3-oxopiperidine-2-propanoate is analogous to that described by D. W. Brooks, Angew. Chem., Int., Ed. Engl., (1979), 18, 72.10 The following examples illustrate in detail the preparation of some compounds according to the invention. Elemental microanalyses and IR and NMR spectra confirm the structure of the compounds obtained. The compound numbers indicated in parentheses in the titles of the examples refer to those in the table given below. This table illustrates the chemical structures and

  physical properties of some compounds according to the invention.

  The ratio in parenthesis indicates the molar ratio

  from: base when it is different from 1.

EXAMPLE 1 (compound no. 1)

  [2R- [1 (S), 2a, 4B]] - 2- (3-hydroxyisoxazol) hydrochloride

  yl) -l- [5- (lH-imidazol-4-yl) -2 - [[(3-methyl-l, 2,3,4-tetrahydro-

  quinolin-8-yl) sulfonyl] amino] -1-oxopentyl] -4-méthylpipéri-

dine

  1.1. [2R- [1 (S), 2a, 4B]] - 1- [5- (1H-imidazole) hydrochloride;

  4-yl) -2 - [[(3-methyl-1,2,3,4-tetrahydroquinolin-8-yl)

  sulfonyl] amino] -1-oxopentyl] -4-methyl-B-oxopiperidine-2-

ethyl propanoate

  1.1.1. [2R- [1 (S), 2a, 4B]] - 1- [2 - [[(3-methyl-1,2,3,4-tetrahydro)

  droquinoléin-8-yl) sulfonyl] amino] -l-oxo-5- [1- (triphenyl

  nylméthyl) imidazol-4-yl] pentyl] -4-methyl-B-oxopi-

ethyl peridine-2-propanoate

  1.1.1.1. (2R-trans) -l - [(1,1-dimethylethoxy) carbonyl] -4-me-

  ethyl-B-oxopiperidine-2-propanoate

  To a solution of 486 mg (2 mmol) of 1- (1,1-dimethyl)

  ethyl acetate) of (2R-trans) -4-methylpiperidine-1,2-dicarboxylic acid in 4 ml of tetrahydrofuran, 360 mg (2.2 mmol) of N, N'-carbonyldiimidazole are added and the mixture is shaken. The reaction medium is then stirred for 6 hours at room temperature. C. 570 mg (2.2 mmol) of magnesium salt of ethyl malonate are then added and the mixture is left stirring for 16 hours at 20 ° C.. 25 ml of ether and washed successively with 10 ml of a solution of hydrochloric acid and then with 10 ml of a saturated solution of sodium chloride. The organic phase is collected, dried over magnesium sulphate, filtered, concentrated and the residue is purified by chromatography on a gel column.

  silica eluting with a mixture of ethyl acetate and

xane (10:90).

  520 mg of product is obtained in the form of a colorless oil.

  [α] D = + 81.6 (c = 1, chloroform)

  1.1.1.2. [2R- [1 (S), 2a, 48]] - 1- [2 - [[(3-methyl-1,2,3,4-tetrasulfonyl)

  hydroquinolin-8-yl) sulfonyl] amino] -l-oxo-5- [1- (tri-

  phenylmethyl) imidazol-4-yl] pentyl] -4-methyl-B-

  ethyl oxopiperidine-2-propanoate

  520 mg (1.6 mmol) of (2R-trans) -1 - [(1,1-dimethyl)

  ethoxy) carbonyl] -4-methyl-3-oxopiperidine-2-propanoate in 2 ml of ether, the mixture is cooled to 0.degree. C. and 2 ml of a 4N solution of hydrochloric acid are added to the mixture. dioxane. The reaction medium is left stirring for 1 hour at 0 ° C., the temperature of the mixture is allowed to rise to ambient temperature, stirring is continued.

  for 4 hours at 20 ° C. and then the mixture is concentrated to dryness.

  845 mg (1.3 mmol) of the (S) -a - [[(3-methyl)

  thyl-1,2,3,4-tetrahydroquinolin-8-yl) sulfonyl] amino] -1-

  (triphenylmethyl) -1H-imidazole-4-pentanoic acid and 5 ml of dichloromethane. The solution is cooled to 0.degree. C., 730 ml (4.2 mmol) of N, Ndiisopropylethylamine and then 572 mg (1.3 mmol) of [(benzotriazol-1-yl) oxy] tris (dimethylamino) hexafluorophosphate are added. phosphonium and let the mixture

  with stirring for 1 hour at 0 C. The temperature is

  erase the reaction medium back to the temperature

  room temperature and stirring is continued for 5 hours at 20 ° C.

  Then the reaction medium is diluted with 50 ml of ethyl acetate and washed successively with 20 ml of a 0.5N solution of hydrochloric acid, 10 ml of water, 20 ml of a saturated solution of sodium hydrogencarbonate and 10 ml of saturated sodium chloride solution. The organic phase is collected and dried over sodium sulfate.

  sodium and filtered. The residue is purified by chroma-

  ongraphy on silica gel column eluting with a

  ethanol mixture: dichloromethane (2:98).

  780 mg of product is obtained which is used as such in

the next step.

  1.1.2. [2R- [1 (S), 2a, 4B]] - 1- [5- (1H-imidazole) hydrochloride

  4-yl) -2 - [[(3-methyl-l, 2,3,4-tetrahydroquinolin-8-yl)

  sulfonyl] amino] -1-oxopentyl] -4-methyl-B-oxopipéridine-

2-ethyl propanoate

  780 mg (0.93 mmol) of [2R- [1 (S), 2a, 4B]] - [2-

  [[(3-methyl-1,2,3,4-tetrahydroquinolin-8-yl) sulfonyl] amino] -

  1-oxo-5- [1- (triphenylmethyl) imidazol-4-yl] pentyl] -4-me-

  ethyl-B-oxopiperidine-2-propanoate in 5 ml of dichloromethane, the solution is cooled to 0 ° C. and anisole and 2.5 ml of trifluoroacetic acid are added. We shake

  the mixture at a temperature of between 0 and 20 C

  After 5 hours, it is hydrolysed at 0 ° C. with 20 ml of a solution.

  saturated sodium hydrogencarbonate solution and neutralize it

  read with solid sodium bicarbonate. We separate

  , the aqueous phase is extracted with twice 25 ml of dichloromethane

  romethane and the organic phases are combined. Then they are dried over sodium sulfate, filtered and concentrated. An oily residue is obtained which is purified by chromatography on a column of silica gel, eluting with a

  ethanol mixture: dichloromethane (5:95).

  390 mg of base are obtained in the form of a colorless foam.

  The hydrochloride is prepared by solubilizing 390 mg (0.590 mmol).

  1) of product by sonication in an equivalent of a 0.1 N solution of hydrochloric acid and then lyophilizing the solution.

  415 mg of hydrochloride are obtained in the form of a solid

  colored. [α] 2 = + 76 ° (c = 0.5, methanol) Melting point = 91 ° C

  1.2. [2R- [1 (S), 2a, 4B]] - 2- (3-hydroxyisoxa) hydrochloride

  zol-5-yl) -1- [5- (1H-imidazol-4-yl) -2 - [[(3-methyl-1,2,3,4-

  tetrahydroquinolin-8-yl) sulfonyl] amino] -1-oxopentyl] -

  4-methylpiperidine To a solution of 280 mg (0.5 mmol) of [2R- [1 (S), 2a, 4B]] -

  1- [5- (1H-imidazol-4-yl) -2 - [[(3-methyl-1,2,3,4-tetrahydro-

  quinolin-8-yl) sulfonyl] amino] -1-oxopentyl] -4-methyl-B-oxopi-

  ethyl peridine-2-propanoate in 1 ml of methanol is added simultaneously 0.5 ml of a 1N sodium hydroxide solution and mg (0.5 mmol) of hydroxylamine hydrochloride in solution in 0.5 ml of 1N sodium hydroxide solution. The reaction medium is then stirred for 1 hour at 20 ° C., then it is thrown into

  a mixture containing 5 ml of a hydrochloric acid solution

  concentrated and 5 g of ice and stirred for 16 hours at 20 ° C., concentrated to dryness, the residue is taken up in 5 ml of water and purified by chromatography on a column of silica gel, eluting with a mixture of 0.2 N hydrochloric acid and acetonitrile (0 to 100% acetonitrile gradient in minutes). Finally we collect the fractions containing

  the product is evaporated to dryness and the residue is taken up

  if obtained with 5 ml of water and freeze-dried.

100 mg of product is obtained.

  [a] = + 94 o (c = 0.36, chloroform) Melting point = 130-135 C Example 2 (compound 2)

  [2R- [1 (S), 2a, 4B]] - 2- (5-hydroxy-1H-pyrazol) hydrochloride;

  3-yl) -1- [5- (lH-imidazol-4-yl) -2 - [[(3-methyl-1,2,3,4-tetrahydroisoquinoline

  droquinoléin-8-yl) sulfonyl] amino] -1-oxopentyl] -4-méthylpipé-

  ridine is brought to the reflux temperature for 16 hours, under

  nitrogen, a solution containing 250 mg (0.44 mmol)

  le) of [2R- [1 (S), 2a, 48]] - 1- [5- (1H-imidazol-4-yl) -2 - [[(3-

  methyl-1,2,3,4-tetrahydroquinolin-8-yl) sulfonyl] amino] -l-

  oxopentyl] -4-methyl-3-oxopiperidine-2-propanoate and

  mg (0.50 mmol) of hydrazine hydrate in 3 ml of ethanol.

  The medium is evaporated to dryness, the residue is taken up in 5 ml of a 0.1 N aqueous solution of hydrochloric acid and purified by chromatography on a LOBARS LichroprepO RP 18 column, eluting with a mixture of 0 hydrochloric acid, 02 N and acetonitrile (0 to 100% acetonitrile gradient in minutes). Finally, the fractions containing the product are collected, evaporated to dryness and the residue is taken up.

  thus obtained with 5 ml of water and freeze-dried.

180 mg of product is obtained.

  [a] D = - 1 (c = 0.4, methanol) Melting point = 135-140 ° C. Example 3 (Compound No. 3)

  [2R- [1 (S), 2a, 4B]] - 2- (3-amino-1,2,4-hydrochloride) hydrochloride

  oxadiazol-5-yl) -1- [5- (1H-imidazol-4-yl) -2 - [[(3-methyl-

  1,2,3,4-tetrahydroquinolin-8-yl) sulfonyl] amino] -1-oxo-

pentyl] -4-methylpiperidine

  3.1. (2R-trans) -2- (3-amino-1,2,4-oxadiazol-5-yl) -4-me-

  1,1-dimethylethylthylpiperidine-1,-carboxylate

  323 mg (10 mmol) of sodium are solubilized in 10 ml of ethanol.

  850 mg of molecular sieve (4 A) and 1.05 g (4 mmol) of hydroxyguanidine hemisulfate are added. The reaction medium is left stirring for 30 minutes at room temperature, 542 mg (2 mmol) of

  (2R-trans) -l - [(1,1-dimethylethoxy) carbonyl] -4-methyl-piperidyl

  ethyl dine-2-carboxylate and the mixture is brought to the reflux temperature for 3 hours. Then it is filtered and concentrated to dryness. The residue is taken up in 50 ml of a dichloromethane: water (1: 1) mixture, the organic phase is recovered, dried over magnesium sulphate and concentrated to dryness. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of

methanol: dichloromethane (5:95).

  308 mg of product is obtained in the form of an incoating oil.

  lore that we use as is in the next step.

  3.2. [2R- [1 (S), 2a, 4B]] - 2- (3-amino-1,2,4-hydrochloride) hydrochloride

  oxadiazol-5-yl) -1- [5- (1H-imidazol-4-yl) -2 - [[(3-methyl-

  1,2,3,4-tetrahydroquinolin-8-yl) sulfonyl] amino] -1-oxo-

  pentyl] -4-methylpiperidine (S) -a - [[(3-methyl-1,2,3,4-tetrahydro)

  quinolin-8-yl) sulfonyl] amino] -1- (triphenylmethyl) -1H-imidazolyl

  zole-4-pentanoic acid with (2R-trans) -2- (3-amino-1,2,4-oxa-

  1,1-diazol-5-yl) -4-methylpiperidine-1-carboxylate

  thylethyl, according to the method described in step 1.1.1.2, then the compound obtained is deprotected and the

  hydrochloride according to the method described in step 1.1.2.

  150 mg of product is obtained in the form of a colorless solid.

  [a] 2 = 165 O (c = 0.2, methanol) Melting point = 165 C Example 4 (Compound No. 4)

  [2R- [1 (S), 2a, 4B]] - 2- (5-mercapto-1,3,4-oxohydrochloride) hydrochloride

  diazol-2-yl) -1- [5- (1H-imidazol-4-yl) -2 - [[(3-methyl-1,2,3,4-

  tetrahydroquinolin-8-yl) sulfonyl] amino] -1-oxopentyl] -4-me-

thylpipéridine

  4.1. (2R-trans) -2- (5-mercapto-1,3,4-oxadiazol-2-yl) -4-methyl-

  1,1-dimethylethyl piperidine-1-carboxylate

  4.1.1. (2R-trans) -1 - [(1,1-dimethylethoxy) carbonyl] -4-methyl-

  piperidine-2-carboxyhydrazide is heated at reflux temperature for 18 hours, a

  solution containing 2.71 g (10 mmol) of (2R-trans) -1- [(1,1-

  ethyl dimethylethoxycarbonyl] -4-methylpiperidine-2-carboxylate and 1 g (20 mmol) of hydrazine hydrate in 10 ml of methanol. The medium is concentrated to dryness and the residue is purified by chromatography on a silica gel column.

  eluting with dichloromethane: methanol (96: 4).

  2.23 g of product are obtained in the form of a colorless oil.

  4.1.2. (2R-trans) -2- (5-mercapto-l, 3,4-oxadiazol

  2-yl) -4-methyl-piperidine-1-carboxylic acid 1,1-dimethylethyl ester

  To a solution of 1.12 g (4.33 mmol) of (2R-trans) -1- [(1,1-

  dimethylethoxy) carbonyl] -4-methyl-piperidine-2-carboxyhydra-

  0.77 g (10 mmol) of carbon disulfide and 0.26 g (4.6 mmol) of potassium hydroxide pellets are added at 0.degree. The mixture is heated at reflux temperature for 7 hours and then concentrated to dryness. The residue is taken up in a 1: 1 mixture of ether and a 1N solution of hydrochloric acid, the organic phase is collected, dried over

  magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue obtained is purified by column chromatography on silica gel, eluting with a dichloromethane: methanol (95: 5) mixture.

  0.93 g of product is obtained in the form of a colorless oil.

  4.2. [2R- [1 (S), 2a, 4B]] - 2- (5-mercapto-1,3,4) -hydrochloride hydrochloride.

  oxadiazol-2-yl) -l- [5- (1H-imidazol-4-yl) -2 - [[(3-methyl-

  1,2,3,4-tetrahydroquinolin-8-yl) sulfonyl] amino] -1-oxo-

pentyl] -4-methylpiperidine, (2: 1)

  (S) -a - [[(3-methyl-1,2,3,4-tetrahydro) acid is reacted

  quinolin-8-yl) sulfonyl] amino] -1- (triphenylmethyl) -LH-imidazolyl

  zole-4-pentanoic with (2R-trans) -2- (5-mercapto-1,3,4-

  1,1-dimethylethyl oxadiazol-2-yl) -4-methyl-piperidine-1-carboxylate, according to the method described in step 1.1.1.2, then the compound obtained is deprotected and the

  hydrochloride according to the method described in step 1.1.2.

  300 mg of product are obtained in the form of a colorless solid [a] 2 = + 130 ° C. (c = 0.25, methanol). Melting point = 167 ° -172 ° C.

Board

o R s02HW-IN / HN%

H3C N

NH No R Ri R2 [a] 2 (0) F (C) Salt

Y N + 94

  1H -H 130-135 HClNH-H0.N (c = 0.36, chloroform)

RN-N -1

2H -H 135-140HCl

0OH (c = 0.4, methanol)

O-N + 165

3HH 165C1H

NH2 (C = 0.2, methanol)

N-N +130

  The compounds of the invention were tested against the

  thrombin and trypsin in vitro in the following tests.

  1. Precipitation of human fibrinogen by bovine thrombin. The test compound or its vehicle (10 μl) is incubated for 2 minutes at 37 ° C. in a fibrinogen solution.

  human (200 μl, 2 mg / ml in saline).

  Next, 200 μl of bovine thrombin dissolved in distilled water is added. The final concentration of thrombin is 0.5 NIH units / ml. The formation time, expressed in seconds, of a visible fibrin network is shaken and noted. Inhibition of fibrinoformation is quantified by calculating the concentration of compound which increases the precipitation time by 100% (CAlm). The results are expressed in CAlm, mean s.e.m. at least three experiments. 2. Precipitation of human fibrinogen by thrombin

human.

  The test compound or its vehicle (10 μl) is incubated for 2 minutes at 37 ° C. in a fibrinogen solution.

  human (200 μl, 2 mg / ml in saline).

  Then, 200 μl of human thrombin dissolved in distilled water is added. The final concentration of thrombin is 2 NIH units / ml. The formation time, expressed in seconds, of a visible fibrin network is shaken and noted. Inhibition of fibrinoformation is quantified by calculating the concentration of compound which increases the precipitation time by 100% (CAlm). The results are expressed in CAlm, mean s.e.m. at least three experiences.

  3. Coagulation of rat plasma with bovine thrombin.

  Male CD rats, weighing 150 to 200 g, were anesthetized with nembutal (60 mg / kg, 0.1 ml / kg). The blood is taken from trisodium citrate at 3.8% (1 vol / 9 vol of blood) from the retro-orbital sinus. The plasma is prepared by centrifugation at 3600 g for 15 minutes at room temperature. The test compound or its carrier (10 1) is incubated with M1 plasma at 37 ° C for 2 minutes before addition.

  200 M1 of a solution of bovine thrombin. The concentration

  Final thrombin treatment is 0.75 NIH units / ml. Note the coagulation time, expressed in seconds. Inhibition of thrombin is quantified by the calculation of

  the concentration which increases the coagulation time by 100% (CA 1o) -

  4. Rabbit platelet aggregation induced by

human thrombin.

  The blood is collected by cardiac puncture on trisodium citrate at 3.8% (1 vol / 9 vol of blood). It is centrifuged at 250 g for 10 minutes. The platelet-rich plasma (PRP) thus obtained is removed and the platelet count is carried out. At PRP, 2 ng / ml of prostacyclin in solution was added in ice cold pH 9.0 tris buffer. It is centrifuged at 110 g for minutes and decanted. Prostacyclin, in solution in mM sodium hydroxide at pH 12, is added again so as to have a final concentration of ng / ml. The PRP is again centrifuged at 800 g for minutes. The platelet-poor plasma is removed and the pellet is suspended in a tyroid volume containing 200 ng / ml prostacyclin, a volume equal to the initial volume of

  PRP. This suspension is centrifuged at 800 g for 10 minutes.

  utes. We start again a second time and in the same

  conditions, the suspension of the pellet and the centrifugation

  gation. The final pellet is resuspended in prostacyclin-free tyrode solution and allowed to stand for 2 hours to allow complete elimination of the prostacyclin. Aggregation of these platelets with human thrombin is induced at the final concentration of 0.3 NIH units / ml. The optical density variations are recorded by means of a 4-channel aggregometer. The test compound or its carrier is added to the platelet suspension (maximum added volume of 3 μl), 2 minutes before the addition of thrombin. The concentration which inhibits aggregation by 50% (CId) is determined. The results are expressed as IC.sub.2, average half of at least three experiments 5. Activity with respect to bovine trypsin The test compound or its vehicle (50 Al) is incubated for 5 minutes at room temperature. 50 μl of bovine trypsin dissolved in Tris-HCl buffer, pH 8.0 The final trypsin concentration was 229 units / ml The reaction was started by the addition of the N-benzoyl-L substrate. -Arginine-4 nitro-aniline (50 Ml, final concentration 50 M) Incubate for 20 minutes at room temperature

  and the optical density of the 4-nitro-

  liberated aniline at 405 nm. The concentration of 4-nitroaniline is calculated from a calibration curve after subtracting the optical density of the "blanks" (100 μl of buffer + 50 μl of substrate). The concentration which inhibits enzymatic activity by 50% (CI ") is determined.

  results are expressed in CI ", mean s.e.m ..

  In parallel, the compounds of the invention have been tested with

  with respect to the coagulation of ex-vivo rat plasma.

  The animals are treated with the test compound or with its vehicle, intravenously, subcutaneously or orally, before taking the blood. We measure time

thrombin as described in 3.

  The compounds of the invention are thrombin inhibitors with CAI 0 and CI w between 10-9 and 104 M. They do not exhibit or exhibit little inhibitory activity towards bovine trypsin. shows

their specificity.

  They inhibit coagulation of rat plasma at doses less than or equal to 1 mg / kg i.v. and are also active

  subcutaneously and orally.

  The compounds of the invention may be useful in all clinical indications related to thrombosis or in those

  o thrombotic complications may occur.

  For this purpose they may be presented in any form suitable for oral, parenteral or intravenous administration, such as tablets, dragees, capsules, capsules, suspensions or oral or injectable solutions, etc. in combination with suitable excipients, and dosed to allow administration of 1 to 1000 mg per

  day and per patient, in one or more doses.

Claims (7)

claims   1. Compounds of formula (I) optionally in the form of a mixture of diastereoisomers, R SO2HNN) t. HN H3C N   Wherein R is either 1H-imidazol-4 (5) -yl or 4,5-dihydro-1H-imidazol-4 (5) -yl, or 1H-pyrazol-4-yl, either 1H-pyrazol-5-yl, isoxazol-4-yl, isoxazol-5-yl or oxazol-4-yl, or oxazol-5-yl group, one   4,5-dihydrooxazol-4-yl group, a 4,5-dihydro-   oxazol-5-yl, either 1H-triazol-4 (5) -yl or a   1,2,4-oxadiazol-3-yl group, a 1,2,4-oxadiazole group;   -yl, or a 1,3,4-oxadiazol-2-yl group, optionally substituted with a hydroxyl group and / or with a group ZH o Z is chosen from oxygen, sulfur and imino and RI groups; and R2 each independently represent a hydrogen atom or a methyl group, as well as their pharmaceutically acid addition salts. acceptable.   2. Compounds according to claim 1, characterized in that the preferred configuration of the piperidinyl group is   [2R, 4R] and the preferential configuration of asymmetric carbon   of the central amino part is [S].   3. Process for the preparation of the compounds according to claim 1, characterized in that a compound of formula (II) is reacted HNA ... (II)   in which R3 is equal to R as defined in the   Claim 1, or represents a 3-ethoxy-1,3-group   dioxopropyl, with a compound of formula (III) S02HN-.H ! Oz V OH HN o - (III) N H3CJ X H (II R2 C (C6H5) 3   wherein R2 is as defined in claim 1, in an aprotic solvent, in the presence of a base and a coupling agent, and there is obtained a compound of formula (IV) o R3 SO2HN J 1 (IV) H3C N C (C6H5) 3   that is deprotected preferably in an acidic medium.   4. Process for the preparation of compounds according to claim   1, for which R represents a 3-hydroxyisoxazole   characterized in that the compounds are treated   of formula (I) in which R represents a 3-ethoxy-   1,3-dioxopropyl with hydroxylamine hydrochloride in basic medium.   5. Process for preparing compounds according to claim   1, for which R represents a 5-hydroxy-1H-pyrazole   3-yl, characterized in that the compounds of the formula (I) in which R represents a 3-ethoxy group are treated.   1,3-dioxopropyl with a protic solvent.   6. Medicinal product characterized in that it contains a compound   according to any one of claims 1 and 2.   7. Pharmaceutical composition characterized in that   contains a compound according to any one of the claims   1 and 2 in combination with any suitable excipient.