FR2593813A1 - Derivatives of N- alpha -arylsulphonylaminoacyl-p-amidinophenylalanine amides, process for their preparation, their application as medicaments and the compositions which contain them - Google Patents

Abstract

Compounds of formula: in which: - R1 represents a lower alkyl, hydroxymethyl, hydroxyalkyl or benzyl group, a phenyl group or a 4-hydroxyphenyl group. - R2 and R3, which are identical or different, each represent a lower alkyl, lower alkenyl or lower alkynyl radical or form, together with the nitrogen to which they are attached, a morpholino, thiomorpholino, pyrrolidino, piperazino, 4-(lower alkyl)piperazino or 4-(lower hydroxyalkyl)piperazino group or a piperidino group which is unsubstituted or substituted by a lower alkyl, benzyl, hydroxyl, lower hydroxyalkyl, amino or lower aminoalkyl group. - Ar represents an optionally substituted phenyl, alpha-naphthyl or beta-naphthyl group, or else a heteroaryl group chosen from optionally substituted pyridyl, quinolyl or isoquinolyl, as well as their stereoisomers and their salts with pharmaceutically acceptable inorganic or organic acids. The invention also relates to a process for the preparation of the products of formula I, to their application as medicaments and to the compositions which contain them.

Description

The present invention relates to novel Not-arylsulfonylaminoacyl p-amidino-phenylalaninamide derivatives, to their process of preparation and to their use as selective thrombin inhibiting and antithrombotic agents.

dans laquelle - Rl réprésente l'hydrogène, un groupe alcoyle inférieur, hydroxyméthyle, hydroxyalcoyle, benzyle, un groupe phényle ou un groupe hydroxy-4 phényle.The compounds of the invention correspond to the general formula (I):

wherein R 1 is hydrogen, lower alkyl, hydroxymethyl, hydroxyalkyl, benzyl, phenyl or 4-hydroxyphenyl.

R 2 and R 3, which may be identical or different, each represents a lower alkyl, lower alkenyl or lower alkynyl radical, or together with the nitrogen to which they are attached form a morpholino, thiomorpholino, pyrrolidino, piperazino, (lower alkyl) -4 piperazino group; (lower hydroxyalkyl) -4 piperazino or piperidino group unsubstituted or substituted by lower alkyl, benzoyl, hydroxy, lower hydroxyalkyl, amino, lower aminoalkyl.

Ar represents an optionally substituted phenyl, alpha-naphthyl or beta-naphthyl group, or a heteroaryl group chosen from pyridyl, quinolinyl and isoquinolinyl, which are optionally substituted.

The carrier carbon of group R1 may have the configuration R or S or RS.

All compounds having said configurations are included in the present invention.

The compounds of formula (I) above, comprising one or more asymmetric centers may exist in the form of several isomers (diastereoisomers, enantiomers). The invention also relates to each stereoisomer and their mixtures.The invention also comprises addition salts of the compounds of formula (I) with pharmaceutically acceptable inorganic or organic acids.

The terms "lower alkyl", "lower alkenyl", and lower alkynyl "as used herein refer to branched or linear aliphatic hydrocarbon radicals containing up to six carbon atoms, such as methyl, ethyl, isopropyl, isobutyl and the like. , tert-butyl, n-hexyl, allyl, propargyl, crotyl, 2-methylcrotyl, 2-methylallyl, butyryl-2.

Synthetic thrombin inhibitors having an amidinophenylalanine group have been described in the literature.

G. WAGNER and his collaborators (DD-Patent 142804 (16.07.80)) have described the compounds of general formula (A)

The insertion of an amino acid glycine residue between the sulphonyl group and the N-OC nitrogen of p-amidinophenylalanine has led to compounds of general formula (B) whose in vitro activity is potentiated compared with those of formula General (A) (G. WAGNER and DD Coll.
Patent 155954 (03.02.81)).

among these, the compound of formula (B) where n = 1, Ar = -naphthyl,
NR1R2 = piperidino, hereinafter referred to as Compound (C) exhibits the best inhibitory activity of thrombin in vitro (J. STURZEBECHER et al., Thrombosis Research 1983, 29, 635) and ex vivo (J. HAUPTMANN and A. Thrombosis Research 1985 , 39, 771).

The products of formula (A) and (B) above are prepared according to the processes described in patents DDR 142804 and DDR 1559549 the amides are prepared from the corresponding free acids by activation and reaction with the corresponding amine. These processes involve reaction conditions which induce racemisations at the asymmetric center. In addition, they do not make it possible to obtain compounds bearing the substituent R 1, I, the Applicant has found that the compounds of formula (I) below. above can be obtained by a method which allows, by the use of coupling methods and protective groups, judiciously chosen, to respect the centers of asymmetry in their original configuration and which does not induce racemization.

à partir de la fonction acide du synthon p-cyanophénylalanine , avant la partie arylJulfonylaminoacyle. This result is obtained, unlike the processes described by Go et al., By first constructing the amide-C0 N portion.

from the acid function of the synthon p-cyanophenylalanine, before the arylJulfonylaminoacyl part.

dans laquelle R 2 et R3 ont les memes significations que dans la formule (I) un acide de formule

sous sa forme activée (IV)

dans laquelle Ar et R1 ont les mêmes significations que dans la formule (I) et R représente un bon groupement nucléofuge, tel que chloro, alcoxycarbonyloxy ou hétéroaryle pour obtenir le composé de formule (V)

dans laquelle Ar, R1, R2 et R3 ont les mêmes significations que dans la formule (I), qu'on traite avec un excès d'une solution saturée de gaz chlorhydrique dans un alcool de formule X-OH dans laquelle X représente un radical alcoyle inférieur, pour obtenir le composé de formule (VI) sous forme de chlorhydrate

dans lequel Ar, R1, R2, R3 et X ont les mêmes significations précitées.The subject of the invention is also a process for the preparation of the compounds of formula (I), characterized in that the 4-cyano phenylalaninamide of formula (II) is reacted

in which R 2 and R 3 have the same meanings as in formula (I) an acid of formula

in its activated form (IV)

in which Ar and R 1 have the same meanings as in formula (I) and R represents a good nucleofugal group, such as chloro, alkoxycarbonyloxy or heteroaryl to obtain the compound of formula (V)

in which Ar, R1, R2 and R3 have the same meanings as in formula (I), treated with an excess of a saturated solution of hydrochloric gas in an alcohol of formula X-OH in which X represents a radical lower alkyl, to obtain the compound of formula (VI) in hydrochloride form

wherein Ar, R 1, R 2, R 3 and X have the same abovementioned meanings.

The imido ester of formula (VI) is then treated with an excess of a solution of ammonia gas in an alcohol lower than the boiling temperature of the reaction mixture to obtain the compound of formula (I) desired.

This compound is isolated in salt form, the free base can be obtained by conventional methods and optionally converted into another pharmaceutically acceptable salt such as, for example, in addition to the hydrochloride, hydrobromide, sulfate, methanesulphonate, acetate, naphthalenesulfonate-2, maleate, fumarate / citrate, or gluconate.

The preparation of the novel compound of formula (II) which is described in an application filed jointly by the applicant is carried out starting from the 4-cyano phenylalanine of formula:

a été préparé selon le schéma réactionnel ci-après:

Formula acid

was prepared according to the reaction scheme below:

The introduction of an asymmetric center in the aminoester (VII, A = lower alkyl) whose initial configuration "R" or "S" must be preserved up to the acid (III), requires the use of methods no racemizing
the sulphonylation of the amino ester (VII) is carried out in two-phase medium, preferably the water-dichloromethane, water-chloroform, water-carbon tetrachloride mixture, in the presence of a base, preferably an alkaline carbonate such as potassium carbonate, sodium carbonate, at temperatures between 100C and 250C.

 the saponification of the ester (VIII) is carried out in a hydroalcoholic medium such as water-methanol or water-ethanol, in the presence of an equivalent of alkaline hydroxide, preferably sodium hydroxide, at temperatures between 100C and 250C. Neutralization of the reaction medium by the addition of one equivalent of a 1N aqueous solution of mineral acid, preferably hydrochloric acid, leads to the acid (III). This saponification can also be carried out in a hydro-organic medium, such as water-dioxane under the same conditions.

For the conversion of the acid of formula (III) into an activated form of formula (IV), two cases are to be considered: a) Case in which the carrier carbon of group R1 has the "RS" configuration
(racemic): (non-stereospecific synthesis)
It is possible to use either the activation of the acid function by
example by
- Transformation of the acid function to acyl halide (IV: R = C1) according to the reaction scheme

 (III) (IV: R = Cl) the halogenating agent may be thionyl chloride or phosphorus pentachioride in the presence of phosphorus oxychloride, at the reflux temperature of the halogenating agent.

selon le schéma réactionnel :

- transformation of the acid function into mixed carbon dioxide

according to the reaction scheme:

où Y1 est un radical alcoyle inférieur ramifié ou non, an présence d'une amine tertiaire comme base. Le chîcroformate d'alcoyle préférentiellement utilisé est le chloroformate d'éthyle (Y1 = C2H5) ou dtisobutyle (Y1 = CH2-CH(CH3)2),
L'amine tertiaire préférentielle est la triéthylamine. Cette condensation s'opère de préférence à des températures comprises entre -50C et + lO0C, dans un solvant inerte tel que le dichlorométhane, le chloroforme ou le tétrachlorure de carbone.The reaction uses an alkyl chioroformate

where Y1 is a branched or unsubstituted lower alkyl radical, in the presence of a tertiary amine as a base. The alkyl chromoformate preferentially used is ethyl chloroformate (Y1 = C2H5) or isobutyl (Y1 = CH2-CH (CH3) 2),
The preferred tertiary amine is triethylamine. This condensation preferably takes place at temperatures between -50 ° C. and + 100 ° C., in an inert solvent such as dichloromethane, chloroform or carbon tetrachloride.

The obtained bodies of formula (IV) are reacted with the compounds of formula (II) in an inert solvent in the presence of an acid acceptor such as a tertiary amine.

(b) Where the R7 group carrier carbon has an "R" configuration or
"S" (R or SA enantiomers (stereospecific synthesis) In this case, it is necessary to use methods which do not induce racemization.

Transformation of the acid function of compounds of formula (III) into activated esters gives compounds of general formula (IV: R = O-z) according to the reaction scheme

en présence de N,N-dicyclohexylcarbodiimide (DCC) selon le mode opératoire décrit par E.C. JORGENSEN et ad .(J. Am. Chem. Soc. 1971, 93, 6318)
Hexafluorophosphate de benzotriazolyl-1 oxytris (dim6thylamino) phosphonium (BOP) (Y2 = [(CH3)2N]3 P-O PF8# ;

selon le mode opératoire décrit par B. CASTRO et Coll.Synthesis 1976, 751.(III) (1V: R = OZ)
The Y2-Z coupling reagents, which do not induce racemization and which are preferably used but not limiting, are as follows:
1-Hydroxybenzotriazole (HOBT) (Y2 = OH;

in the presence of N, N-dicyclohexylcarbodiimide (DCC) according to the procedure described by EC JORGENSEN et al (J. Chem Chem Soc 1971, 93, 6318)
Benzotriazolyl-1-oxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) (Y2 = [(CH3) 2N] 3 PO PF8 #;

according to the procedure described by B. CASTRO and Coll.Synthesis 1976, 751.

selon le mode opératoire décrit par
D.H. RICH et al . J. Am. Chem. Soc. 1985, 107, 4342'. N, N-bis (oxo-2-oxazolidin-3-yl) phosphorodiamidic chloride (Y2 = Cl)

according to the procedure described by
DH RICH et al. J. Am. Chem. Soc. 1985, 107, 4342 '.

The activation and coupling reaction is carried out in the presence of tertiary amines, preferably triethylamine, in an inert solvent such as dichloromethane, dimethylformamide or acetonitrile, at temperatures of between 150 ° C. and 40 ° C.

The imidoester (VI) is formed in an alcoholic medium such as methanol or ethanol, at a temperature of between -10 ° C. and + 100 ° C., preferably at 0 ° C. for a period of 16 h to 24 h.

 The amidine of formula (I) is obtained by treating the compound (VI) previously obtained without further purification, in an alcoholic solution of ammonia gas at a normality of 3 N to 15 N, at room temperature and then heating the mixture is refluxed for 1 to 3 hours.

The following nonlimiting examples are given by way of illustration of the present invention.

EXAMPLE 1 [N, α-Bétanaphthylsulphonyl- (R) -phenylalanyl) p-cyanophenylamino] -1 piperidine (V: Ar = p -naphthyl; R1 = CH2-CsH5; NR2R3 = piperidino)
To a suspension of 12.5 g (0.0425 mol) of (p-cyanophenylalanyl) -1 piperidine hydrochloride in 200 ml of dichloromethane, 15.1 g (0.0425 mol) of Nci- (betanaphthylsulfonyl) are added successively. ) (R) -phenylalanine, 4.3 g (0.0425 mole) of triethylamine, 6.5 g (0.0425 mole) of 1-hydroxybenzotriazole (HOBT). The reaction medium is cooled between 0 ° C. and 5 ° C. and 8.8 g (0.0425 mol) of N, N-dicyclohexylcarbodiimide (DCC) dissolved in 50 ml of dichloromethane are added dropwise. The reaction medium is left behind. with good stirring, at room temperature, for 17 h. The dicyclohexylurea precipitate is filtered off and the organic filtrate is washed with a saturated aqueous solution of sodium bicarbonate. The organic phase, dried over anhydrous sodium sulphate is evaporated to dryness. Evaporation of the solvent leaves a residue which is triturated with ethyl acetate. The white crystals are filtered and washed with diisopropyl ether.

White crystals, yield: 64%, mp = 1730C (ethyl acetate).

Examples 2 to 6 use the same procedure as that described in Example 1. They lead to the nitriles of formula (V) and result from the coupling of the synthons of general formula (II) with the acids of general formula (III), previously activated by conversion of the acid function to the activated ester (IV) function using the DCC / HOBT non-racemising coupling reagent. They are grouped in the table below.

(V: Ar = B-naphthyl)

<tb> Example
<tb> Example <SEP> R1 <SEP> (Configuration <SEP> NR2R3 <SEP> I <SEP> Yield <SEP> FOC
<tb><SEP> of <SEP> amino acid) <SEP> 2 <SEP> 3
<tb><SEP> 2 <SEP> CH3 <SEP> (R) <SEP> N <SE> O <SEP> 1600
<tb><SEP> I
<tb><SEP> 3 <SEP> C6H5 <SEP> (R) <SEP> 38 <SEP> X <SEP> 1940
<tb><SEP> 4 <SEP> CH20H <SEP> 75 <SEP> 75 <SEP> X <SEP> 970
<tb><SEP> 5 <SEP> CH3 <SEP> (R) <SEP> 9 <SEP> CH3 <SEP> 73 <SEP>% <SEP> 1600
<tb><SEP> 6 <SEP> CH3 <SEP> (S) <SEP> - <SEP> 9 <SEP> CH3 <SEP> 72 <SEP>% <SEP> 1500
<Tb>
EXAMPLE 7 [N- (N- (N-) -betanaphthylsulfonyl- (S) -alanyl) p -cyanophenylalanyl] -7-piperidine (V: Ar = p-naphthyl; R1 = CH3; NR2R3 = piperidino)
To a solution of 7.5 g (0.027 mol) of NdL- (betanaphthylsulfonyl) - (S) -alanine (III: R1 = CH3, Ar = p-naphthyl sulphonyl) of S configuration in 300 ml of acetonitrile is added successively. 11.9 g (0.027 mol) of benzotriazolyl-1-oxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), 6.9 g (0.027 mol) of (p-cyanophenylalanyl) -1 piperidine, (II: NR2R3 = piperidino) 2 75 g (0.027 mol) of triethylamine. The reaction medium is left under an inert atmosphere with good stirring at room temperature for 20 hours. The reaction medium is diluted with ethyl acetate and washed successively with a saturated aqueous sodium chloride solution, a 2N hydrochloric acid solution, water, a saturated aqueous solution of sodium bicarbonate and then sodium hydroxide solution. the water. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a silica column (elution: ethyl tolueneacetate 1: 1). White crystals are recovered and dried.

White crystals, yield: 45 4; F = 1550C.

EXAMPLE 8 [N- (N- (N-) -betanaphthylsulfonyl- (RS) -phenylglycyl) p -cyanophenylalanyl] -1-piperidine: (V: N-aryl-naphthyl; R1 = C6H5; NR2R3 = piperidino)
3.4 g (0.01 mol) of N, α-betanaphthylsulphonylphenylglycine are refluxed under an inert atmosphere for one hour (III: R 1 = C 6 H 5).
Ar = s-naphthyl) racemic (RS) in 30 ml of thionyl chloride. The reaction medium is evaporated to dryness and the oily residue is dissolved in 50 ml of dichloromethane. The acid chloride solution (IV: R1 = C6.5!
Ar = ss-naphthyl; R = Cl) in dichloromethane is added dropwise, under an inert atmosphere, to a solution of 1.3 g (0.005 mol) of (p-cyanophenylalanyl) -1 piperidine (II: NR 2 R 3 = piperidino) and 0 , 6 g (0.005 mol) of triethylamine in 20 ml of dichloromethane, which has been previously cooled between OB and + 50C. The reaction medium is left at room temperature for 20 hours. The insoluble salts are filtered and the filtrate is evaporated to dryness.

The residue is taken up in 1N hydrochloric acid and the resulting acidic aqueous phase is extracted with dichloromethene. The organic extracts are dried over anhydrous sodium sulphate and evaporated to dryness. The residue obtained after evaporation is purified by chromatography on a silica column (elution: toluene-ethyl acetate 1: 1). White crystals are obtained.

White crystals, yield: 80% 3 F = 1900C
EXAMPLE 9 [N- (N-) -N- [alpha] -betanaphthylsulfonyl- (RS) -valyl) p -cyanophenylalanyl] -1-piperidine (V: Ar = p-naphthyl; R1 = CH (CH3) 2; NR1R2 = piperidino)
To a suspension of 7 g (0.023 mol) of racemic N-betanaphthylsulfonyivaline (III: R1 = CH (CH3) 2; Ar = ss-naphthyl) racemic (RS) in 100 ml of dichloromethane, maintained between 0 and +5 C 2.6 g (0.023 mol) of triethylamine are added, 3.4 g (0.025 mol) of isobutyl chloroformate are then added dropwise and the mixture is left for one hour at this temperature. 6.2 g is then added ( 0.024 mole) of (p-cyanophenylalanyl) -1 piperidine (II: NR 2 R 3 = piperidino) dissolved in 50 ml of dichloromethane and the reaction medium is left at room temperature for 20 hours. It is evaporated to dryness and the residue is taken up in water. The aqueous phase is extracted with dichloromethane,
The organic extracts are dried over anhydrous sodium sulphate and evaporated to dryness. The oily residue is purified by chromatography on a silica column (elution: toluene-ethyl acetate 1: 1).

White crystals, yield: 78%; F = 178C
EXAMPLE 10 [N- (N-) -N- [alpha] -betanaphthylsulfonyl- (R) -phenylglycyl) P = amino @ inopenylalenyl] -1 piperidine: ## STR5 ## @ deed N 1
a) Formation of the imid @@ ester
Saturated at 0.degree. C., inert with 100 ml of methanol with hydrochloric gas, and added alone (0.03 mole) of [N &alpha; - (N-) -betanaphthylsulfon @] - R @ phenylg @ y @, @@ @@@] - 1 piperidine (example @ and one abar @ nne to @@@ pendan @ 2 @ @@ evaporated dry, without heating the methanol and obtaining an imido-ester hydrochloride salt of the general formula (VII = @ -s-naphthyl;
R1 = C6H5; NR2R3 = piperidino), which is used without further purity in the subsequent step.

b) Formation of amidine
Saturated at temperatures between 0 ° and -5 ° C., under an inert atmosphere, 100 ml of methanol with ammonia @ ga @ eu @ and added to this ammoniacal methanol solution, the blue resin, obtained in the example 10a, after dissolution in 29 ml of methanol. The reaction mixture is heated to reflux for 3 hours.

The mixture is evaporated to dryness and the residue is taken up in excess of 1N excess acid. The acidic aqueous phase is not extracted
The organic phase is dried over anhydrous sodium sulfate and evaporated to dryness. The semipyristene residue is taken up afterwards by water. The crystals insoluble in the water were stored and dried and treated with ethyl acetate, brought to reflux for 10 minutes.

The crystals insoluble in boiling ethyl acetate are filtered and dried.

white crystals, hydrochloride, hydrate, yield: 84%, mp = 188 ° C
Examples 11 to 16 use the same operating procedures as those described in Example 10. They lead to N &alpha; - arylsulfonylamincacyl p-amidino phenylalaninamides of general formula (I) and result from the conversion of nitriles of general formula (V) via imido-esters of general formula (VI) .They are grouped in the table ---- below.

<tb> Derived '<SEP> Ar <SEP> R1 <SEP> NR <SEP> R <SEP> x <SEP> Yield <SEP> FOC
<tb> example <SEP> (configuratlon
<tb><SEP> -e <SEP> -Iaminoacicae)
<tb><SEP> li <SEP> 2 <SEP> C <SEP> C?! 2-C6?! 5 (R) <SEP> C <SEP> 1 <SEP> 83 <SEP>% <SEP> 1780
<tb><SEP> 11 <SEP> 2 <SEP> v3
<tb><SEP> 12 <SEP> 3 <SEP> CH3 (R) <SEP> O <SEP> 1.5 <SEP> 53 <SEP>% <SEP> 170
<tb><SEP> 13 <SEP> 4 <SEP> O <SEP> CH3 (S) <SEP> 1 <SEP> 1 <SEP> 54 <SEP>% <SEP> 1760
<tb><SEP> 14 <SEP> 5 <SEP>><SEP> CH3 (R) <SEP> O <SEP> CF3 <SEP> 2 <SEP> 69 <SEP>% <SEP> 1770
<tb> 15 <SEP> 6 <SEP> (Mi <SEP> CH3 (S) <SEP> N <SEP> 2 <SEP> 64 <SEP>% <SEP> 1760
<tb><SEP> 16 <SEP> 7 <SEP><SEP> CH2OH (S) <SEP><SEP> 1 <SEP> 51 <SEP>% <SEP> 1620
<Tb>

The results of the toxicological and pharmacological studies which are reported below, have demonstrated the interesting properties of the compounds of the invention.

The latter are endowed with a very good thrombin inhibitory activity and also possess remarkable in vivo antithrombotic properties which are not manifested by the compounds of the formulas (A) and (B) and the compound (C).

Compared with heparin, they have a much longer duration of action without inducing an increase in bleeding time.

The invention therefore also relates to a medicament having, in particular, antithrombotic properties, characterized in that it contains, as active ingredient, a compound of formula (I) or an addition salt with a mineral acid or therapeutically acceptable organism.

Toxicological study
The compounds of the invention benefit from good tolerance and low toxicity.

Trials conducted on different animal species on acute, subobronic, and chronic toxicities, did not reveal any local or general reaction, disturbance or abnormality in the biochemical, macroscopic and microscopic examinations carried out throughout the tests.

Pharmacological study
In this study, the compounds of the invention were compared to heparin and [N- (N-alpha-betanaphthylsulfonylglycyl) p-amidinophenylalanyl] -piperidine, a closely related compound described as a potent thrombin inhibitor. (J. HAUPTMANN et al., Thromb., Res., 39, 771-775, 1983) and which will be named derivative C.

10) Thrombin time
The coagulation time of citrated plasma in the presence of thrombin is measured ex vivo in the rat, according to the technique of BIGGS RM (human blood coagulation, Haemostasis and Thrombosis, Oxford, Blackwell Scientific
Publications, 1972).

The samples are taken one hour after subcutaneous administration of the test compound, by puncture at the abdominal aorta. The blood is collected on 3.8% sodium citrate (1 volume for 9 volumes of blood). The plasma is obtained by centrifugation at 2600 g for 10 minutes. To 0.2 nm of the plasma, 0.2 ml of a solution of thrombin (20 U / ml) is added.

The coagulation time is recorded.

The results are summarized in the table below and are expressed in seconds.

<tb> Product <SEP> Dose <SEP> Path <SEP> Result <SEP>%
<tb><SEP> mg / kg <SEP>(SEP><SEP> buffers) <SEP> lengthening <SEP> p
<tb> witness <SEP> sc <SEP> 6 <SEP>#<SEP> 0
<tb><SEP> heparin <SEP> 10 <SEP> sc <SEP> 20 <SEP>#<SEP> 4 <SEP><SEP> 230 <SEP> 0.001
<tb> witness <SEP> sc <SEP> 7 <SEP>#<SEP> 0
<tb> derivative <SEP> C <SEP> 10 <SEP> sc <SEP> 9 <SEP>#<SEP> 0 <SEP> 29 <SEP> 0.001
<tb> witness <SEP> sc <SEP> 5.9 <SEP>#<SEP> 0
<tb> derivative <SEP> N <SEP> 7 <SEP> 10 <SEP> sc <SEP> 48.6 <SEP>#<SEP> 10.8 <SE> 78 <SEP> 0.001
<tb> control <SEP> sc <SEP> 8.2 <SEP>#<SEP><SEP> 0.2
<tb> derivative <SEP> N <SEP> 4 <SEP> 10 <SEP> sc <SEP> 49.9 <SEP>#<SEP> 6.2 <SEP> 508 <SEP> 0.001
<tb> control <SEP> sc <SEP> 7.7 <SEP>#<SEP><SEP> 0.1
<tb> derivative <SEP> N <SEP> 6 <SEP> 10 <SEP> sc <SEP> 12.7 <SEP> 3 <SEP> 0.3 <SEP> 65 <SEP> 0.001
<Tb>

) Thrombosis @eineuse with tendril
The tests were carried out according to an adaptation of the method of
T. KUMADA et al. ; (Thromb Res., 18, 189-203, 1980) A metal spiral (dentist paste floss cut) is inserted into the anesthetized rat's inferior eine cava. An hour earlier, the animals were subcutaneously injected, the test compound, five hours later,
The spiral is removed with the thrombus it retains, then dried by repeated padding on filter paper and weighed. The spiral is then freed from the thrombus, dried and weighed again. The difference in weight gives the weight of the thrombus,
The results are summarized in the table below:

<tb><SEP> Product <SEP> Dose <SEP> Weight <SEP> of <SEP> thrombus <SEP> Variation <SEP> p
<tb> mg / kg <SEP> to <SEP> mg
<tb><SEP> control <SEP> 4.47 <SEP>#<SEP> 0.51
<tb><SEP> Heparin <SEP> 5 <SEP> 2.91 <SEP>#<SEP><SEP> 0.53 <SEP> - <SEP> 35 <SEP>% <SEP> 0.05
<tb> heparin <SEP> 10 <SEP> @, 62 <SEP><SEP>#<SEP><SEP> 0.34 <SEP> - <SEP> 64 <SEP>% <SEP> 0.001
<tb><SEP> Heparin <SEP> 20 <SEP> 0.26 <SEP>#<SEP><SEP> 0.04 <SEP> - <SEP> 94 <SEP>% <SEP> 0.001
<tb><SEP> witness <SEP> 4,77 <SEP>#<SEP> @, 47
<tb><SEP> derivative <SEP> C <SEP> 20 <SEP> 3.99 <SEP>#<SEP> 0.45 <SEP> - <SEP> 16 <SEP>% <SEP><SEP> ns
<tb><SEP> derivative <SEP> C <SEP> 50 <SEP> 3.63 <SEP>#<SEP><SEP> 0.37 <SEP> - <SEP> 24 <SEP>% <SEP> ns
<tb> derivative <SEP> C <SEP> 100 <SEP> 3.08 <SEP>#<SEP><SEP> 0.28 <SEP> - <SEP> 35 <SEP>% <SEP> 0.01
<tb><SEP> control <SEP> 3.81 <SEP>#<SEP> 0.38
<tb><SEP> derivative <SEP> N <SEP> 4 <SEP> 5 <SEP> 2.67 <SEP>#<SEP> 0.22 <SEP> - <SEP> 20 <SEP>% <SEP> 0.05
<tb> derivative <SEP> N <SEP> 4 <SEP> 10 <SEP> 2.48 <SEP>#<SEP> 0.35 <SEP> - <SEP> 33 <SEP>% <SEP> 0.05
<tb><SEP> derivative <SEP> N <SEP> 4 <SEP> 10 <SEP> 1.92 <SEP>#<SEP> 0.14 <SEP> - <SEP> 60 <SEP>% <SEP> 0,001
<tb><SEP> control <SEP> 3.72 <SEP>#<SEP><SEP> 0.33
<tb><SEP> derivative <SEP> N <SEP> 4 <SEP> 50 <SEP> 2.62 <SEP>#<SEP> 0.26 <SEP> - <SEP> 30 <SEP>% <SEP> 0.05
<tb><SEP> control <SEP> 3.72 <SEP>#<SEP> 0.33
<tb><SEP> derivative <SEP> N <SEP> 7 <SEP> 10 <SEP> 2.42 <SEP>#<SEP> 0.26 <SEP> - <SEP> 35 <SEP>% <SEP> 0.01
<Tb>

30) bleeding time
This study was carried out according to an adaptation of the technique of
L. STELLA et al. (Thromb Res, 1975, 7, 709-716).

After anesthesia of the rat with pentobarbital, the tail is cut 5 mm from the end and the blood from the wound carefully buffered every 15 seconds, using a filter paper until haemostasis. This is reached when no stain appears for one minute. The products to be tested are administered subcutaneously one hour before the section of the tail.

The results are gathered in the table below:

<tb><SEP> Product <SEP> Dose <SEP> Time <SEP> in <SEP> Extremes <SEP> p
<tb><SEP> mg / Kg <SEP> seconds
<tb> witness <SEP> 360 <SEP> 330-480
<tb> heparin <SEP> 5 <SEP> 465 <SEP> 330-540 <SEP> ns
<tb> Heparin <SEP> 10 <SEP> 3600 <SEP> 525 <SEP>#<SEP> 3600 <SEP> 0.01
<tb> heparin <SEP> 20 <SEP> 3600 <SEP> 690 <SEP>#<SEP> 3600 <SEP> 0.01
<tb> control <SEP> 540 <SEP> 405-675
<tb> derived <SEP> C <SEP> 10 <SEP> 375 <SEP> 360-510 <SEP> ns
<tb> derivative <SEP> C <SEP> 20 <SEP> 750 <SEP> 420-960 <SEP> ns
<tb> derivative <SEP> C <SEP> 50 <SEP> 600 <SEP> 435-615 <SEP> ns
<tb> control <SEP> 405 <SEP> 390-510
<tb> derivative <SEP> N <SEP> 4 <SEP> 10 <SEP> 440 <SEP> 400-520 <SEP> ns
<tb> derivative <SEP> N <SEP> 4 <SEP> 20 <SEP> 450 <SEP> 420-530 <SEP> ns
<tb> derivative <SEP> N <SEP> 4 <SEP> 50 <SEP> 480 <SEP> 420-3500 <SEP> ns
<tb> control <SEP> 540 <SEP> 400-680
<tb> derivative <SEP> N <SEP> 6 <SEP> 10 <SEP> 380 <SEP> 340-480 <SEP> ns
<tb> derivative <SEP> N <SEP> 6 <SEP> 20 <SEP> 550 <SEP> 420-700 <SEP> ns
<tb> derivative <SEP> N <SEP> 6 <SEP> 50 <SEP> 600 <SEP> 430-605 <SEP> ns
<tb> control <SEP> 525 <SEP> 450-610
<tb> derivative <SEP> N <SEP> 7 <SEP> 10 <SEP> 605 <SEP> 530-760 <SEP> ns
<tb> derivative <SEP> N <SEP> 7 <SEP> 20 <SEP> 585 <SEP> 495-860 <SEP> ns
<tb> derivative <SEP> N <SEP> 7 <SEP> 50 <SEP> 540 <SEQ> 460-650 <SEP> ns
<Tb>

Bleeding time: This study clearly showed the hemorrhagic risk induced by heparin which considerably prolongs the bleeding time.

Being without any action on the bleeding time, the derivatives of the invention have a margin of safety much higher than that of heparin.

The drug of the invention may be presented for oral administration in the form of tablets, coated tablets, capsules, drops, syrup or granules.

It may also be presented for rectal administration in the form of suppositories and for parenteral administration as an injectable solution.

Each unit dose advantageously contains from 0.005 g to 0.500 g of active principle depending on the age of the patient and the severity of the condition treated.

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

1) tablets
derivative NO 4
excipient 0.050 g lactose, corn starch, talc, colloidal silica, magnesium stearate.

2) sugar-coated tablets
derivative NO 6
excipient 0.025 g sugar, corn starch, polyvinyl pyrrolidone, silicic acid, magnesium stearate, talc, orange-yellow.

3) capsules
derivative NO 3
excipient 0.100 g talc, wheat starch, magnesium stearate.

4) suppositories
derivative NO 5
excipient 0.050 g semi-synthetic glycerides.

5) injectable solution
derivative NO 11
excipient 0.025 g isotonic solvent qs 5 ml
For EDS anticoagulant and antithrombotic properties, devoid of side effects due to haemorrhagic risk, the drug of the invention is usefully administered in the prevention and treatment of thromboembolic disease.

Claims (11)

REVENDICArL'IrONS 1 - Compounds of formula

 in which R 1 is lower alkyl, hydroxymethyl, hydroxyalkyl, benzyl, phenyl or 4-hydroxyphenyl. R 2 and R 3, which are identical or different, each represents a lower alkyl, lower alkenyl or lower alkynyl radical, or together with the nitrogen to which they are attached form a morpholino, thiomorpholino, pyrrolidino, piperazino, (lower alkyl) -4 piperazino group; (lower hydroxyalkyl) -4 piperazino, or an unsubstituted or lower alkyl-substituted piperidino group, benzyl, hydroxy, lower hydroxyalkyl, amino, lower aminoalkyl. Ar represents an optionally substituted phenyl, alpha-naphthyl or beta-naphthyl group or a heteroaryl group chosen from pyridyl, quinolinyl and isoquinolinyl, optionally substituted, and their addition salts with pharmaceutically acceptable mineral or organic acids, as well as the isomers or their melanget; - 2 - Process for the preparation of compounds according to claim I characterized in that it is reacted on cyano-4 phenylalaninamido of formula (II)

  in which R2 and R3 have the same sinifications as in formula (I), an acid of formula

 in its activated form (III)

 in which Ar and R 1 have the same meanings as in formula (I) and R represents a good nucleofugal group, such as chloro, alkoxycarbonyloxy or heteroaryl to obtain the compound of formula (V)

 in which Ar, R1, R2 and R3 have the same meanings as in formula (I), treated with an excess of a saturated solution of hydrochloric gas in an alcohol of formula X-OH in which X represents a radical lower alkyl to obtain the imido ester of formula (VI) in hydrochloride form:

  wherein Ar, R 1, R 2, R 3 and X have the same abovementioned meanings, which is then treated with an excess of an ammonia gas solution in an alcohol lower than the boiling temperature of the reaction mixture to obtain the compound of formula (I) sought. 3 - Process according to claim 2 characterized in that the activation of the acid of formula (III) is carried out by the action of a halogenating agent or an alkyl chloroformate. 4 - Process according to claim 2 characterized in that the activation of the acid of formula (III) is carried out by action of coupling reagents not inducing racemization, such as hydroxy-1 benzotriazole in the presence of N N, N-dicyclohexylcarbodiimide, benzotriazolyl-1-oxytris (dimethylamino) phosphonium hexafluorophosphate or N, N bis (oxo-2-oxazolidin-3-yl) phosphorodiamidic chloride. 5 - method according to one of claims 2 to 4, characterized in that the preparation of the imido-ester of formula (VI) is carried out in an alcoholic medium at a temperature between -10C and + 100C for a period of time from 4 pm to midnight, in the presence of a strong acid. 6 - Process according to one of claims 2 to 5, characterized in that the formation of the amidine of formula (I) is carried out in an alcoholic medium by the action of ammonia gas. 7-F N- (N-alpha-betanaphthylsulfonyl- (S) -alanyl) p-amidinophenylalanyl] -1 piperidine and its pharmaceutically acceptable salts. N- (N -betanaphthylsulfonyl- (S) -alanyl) p-amidinophenylalanyl] -1-methyl-4-piperidine and pharmaceutically acceptable salts thereof.  9 - [N- (N-) -N- [alpha] -betanaphthylsulfonyl- (S) -seryl) p-amidinophenylalanyl] -1 piperidine and pharmaceutically acceptable salts thereof. 10 - Drug characterized in that it contains, as active ingredient, a derivative of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.  11 - Medicament according to claim 10, characterized in that it contains, as active principle, [N- (N-) -N- [alpha] -betanaphthylsulfonyl- (S) -alanyl) p-amidinophenylalanyl] -1-piperidine and its pharmaceutically acceptable salts. . 12 - Medicament according to claim 10 characterized in that it contains as active principle, [N-alpha] - (N &alpha; betanaphthylsulfonyl- (S) -alanyl) p-amidinophenylalanyli-1-methyl-4-piperidine and its salts pharmaceutically acceptable. 13 - Drug according to claim 10 characterized in that it contains, as active principle, the t-N- (N-alpha-betanaphthylsulfonyl- (s) -seryl) p-amidinophenylalanyl] -1 piperidine and its salts pharmaceutically acceptable. 14 - Drug according to one of claims 10, 11, 12 or 13 characterized in that each unit dose contains from 0.005 g to 0.500 g of active ingredient.