FR2749584A1 - New 2-amino-5-imidazolylpentanoyl-piperidine derivatives are thrombin inhibitors - Google Patents

Abstract

2-Amino-5-imidazolylpentanoyl-piperidine derivatives of formula (I) and their acid-addition salts are new. R1, R2 = H or 1-4C alkyl; R3 = 1-7C alkyl; R4 = H or halo; R5 = 1-4C alkyl; A = phenyl, pyrimidyl or thiazolyl (all optionally substituted by one or more CHO, CH2OR10, CH2OCOR10, CH2OCONR10R11, COOR10, CONR10R11, NO2, NR10R11, NHCOR10 and/or NH(CH2)nOR10); R10, R11 = H or 1-4C alkyl; and n = 0-6. Also claimed are intermediates of formula (XII). R7 = Cl; R8, R9 = COR3; or R8+R9 = =Cl(R3) (sic); or R7 = OH; R8 = H or COR3; and R9 = COR3.

Description

The present invention relates to 1-oxo-2 (1H-imidazol-4-yl) pentylpiperidine derivatives, their preparation and their therapeutic application.

dans laquelle
R1 représente soit un atome d'hydrogène, soit un groupe (C1-C4)alkyle,
R2 représente soit un atome d'hydrogène, soit un groupe
(C1-C4)alkyle droit ou ramifié,
R3 représente un groupe (C1-C7)alkyle droit ou ramifié,
R4 représente soit un atome d'hydrogène, soit un atome d'halogène,
R5 représente un groupe (Cl-C4)alkyle droit ou ramifié et
A représente un groupe phényle, pyrimidyle ou thiazolyle, les dits groupes pouvant etre substitués par un ou plusieurs substituants choisis parmi les groupes formyle, -CH2OR10, -CH2OCOR10, -CH2OCONR10R11, -COOR10, -CONR10R11, nitro, NR10R11, -NHCOR10, -NH(CH2)nOR10 avec Rlo et R11 étant chacun indépendamment l'un de l'autre un atome d'hydrogène ou un groupe (C1-C4)alkyle droit ou ramifié et n compris entre 0 et 6.The compounds of the invention correspond to formula (I)

in which
R1 represents either a hydrogen atom or a (C1-C4) alkyl group,
R2 represents either a hydrogen atom or a group
(C1-C4) straight or branched alkyl,
R3 represents a straight or branched (C1-C7) alkyl group,
R4 represents either a hydrogen atom or a halogen atom,
R5 represents a straight or branched (C1-C4) alkyl group and
A represents a phenyl, pyrimidyl or thiazolyl group, said groups possibly being substituted by one or more substituents chosen from the formyl groups, -CH2OR10, -CH2OCOR10, -CH2OCONR10R11, -COOR10, -CONR10R11, nitro, NR10R11, -NHCOR10, - NH (CH 2) nOR 10 with R 10 and R 11 each being independently of each other a hydrogen atom or a straight or branched (C 1 -C 4) alkyl group and n between 0 and 6.

The compounds of the invention have 3 asymmetric centers.

est [S]
Les composés peuvent exister sous forme de bases libres ou de sels d'addition à des acides pharmaceutiquement acceptables.The preferred configuration of the piperidinyl group is
[2R, 4R]
The preferred configuration of the central amino acid part

is S]
The compounds may exist as free bases or addition salts with pharmaceutically acceptable acids.

All these forms are part of the invention.

In the following schemes, the -CPh3 group represents the triphenylmethyl group.

According to the invention the compounds of formula (I) can be synthesized according to scheme 1.

A sulfonic acid of formula (II) in which A and R4 are as defined above is reacted with triethylamine to form a triethylamine salt which is reacted with an acid chloride of formula (IIIa) or with an anhydride of formula (IIIb) and a symmetrical imide is obtained in the form of a triethylamine salt of formula
(Va), salt which is treated with phosphorus pentachloride to obtain a compound of formula (VIa) on which is reacted the hydrochloride of the amine of formula (VII) wherein R1 and R5 are as defined above and R2 represents a straight or branched (C1-C4) alkyl group, in an aprotic solvent such as dichloromethane in the presence of a base such as triethylamine, then the imidazolyl nucleus is deprotected and one of the -COR3 residues is removed in an acidic mixture acetic acid: ethanol, acetic acid: water or acetic acid: tetrahydrofuran: water under reflux and a compound of formula (Ia) is obtained (in which R2 represents a (C1-C4) straight or branched alkyl group).

In the case where it is desired to obtain a compound of formula (I) in which R 2 represents a hydrogen atom, then a saponification of the corresponding compound of formula (Ia) (in which R2 represents a group) is carried out.
Diagram 1

 (C1-C4) straight or branched alkyl) under standard conditions known to those skilled in the art.

The method illustrated by Scheme 2 can also be used.

The compound of formula (IIb) in which R4 represents a halogen atom is treated with triethylamine and the salt thus obtained is reacted with an acid chloride of formula (IIIa) in which R3 is as defined above and a compound of formula (Vb) is obtained from which a compound of formula (VIb) is prepared by the action of phosphorus pentachloride in a solvent such as dichloromethane and then the compound (VIb) is reacted with the hydrochloride of the amine of formula (VII) in an aprotic solvent such as dichloromethane and then a residue -COR3 is removed by treatment with ammonia in an aprotic solvent and a compound of formula (VIII) is obtained which is reacted with a compound of formula (IX) (wherein A is as defined above and R is (C1-C4) alkyl) in a solvent such as dimethylformamide in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium (0) to form a composition of formula (Xa) which is heated at the temperature in acidic medium reflux, for example in an acetic acid: water mixture, and there is obtained a compound of formula (Ia) in which R4 represents a halogen atom.

If it is desired to obtain a compound of formula (Ia) in which R 4 is a hydrogen atom, then the corresponding compound of formula (Ia) (wherein R 4 is a halogen atom) is subjected to hydrogenolysis.

In the case where it is desired to obtain a compound of formula (I) in which R 2 represents a hydrogen atom, then a saponification of the corresponding compound of formula (Ia) (in which R 2 represents a (C 1 -C 4) group is carried out. ) straight or branched alkyl) under standard conditions known to those skilled in the art.

Figure 2

Figure 2 (continued)

In a variant, the compounds of formula (I) can also be prepared according to scheme 3.

A sulphonic acid of formula (II) is reacted with an acid chloride of formula (IIIa) in the presence of a base such as pyridine or triethylamine and an amide of formula (Vc) is obtained in the form of a basic salt which it is treated with phosphorus pentachloride to obtain a compound of formula (VIc) on which the hydrochloride of the amine of formula (VII) is reacted to prepare a compound of formula
(XI) that is treated with acetic acid to obtain a compound of formula (Ia) (wherein R2 represents a straight or branched (C1-C4) alkyl) group.

In the case where it is desired to obtain a compound of formula (I) in which R 2 represents a hydrogen atom, then a saponification of the corresponding compound of formula (Ia) (in which R2 represents a group) is carried out.
Figure 3

(C1-C4)alkyle droit ou ramifié) dans des conditions classiques connues de l'homme du métier.<tb><SEP> S03H
<tb><SEP> H2N
<tb><SEP> A <SEP> zip
<tb><SEP> 4
<tb><SEP> R3COCI / base <SEP> (villa)
<tb><SEP> SO3H. <SEP> base
<tb> R30C '<SEP> (Vc)
<tb><SEP> 4
<tb><SEP> l <SEP> PC15
<tb><SEP> I
<tb> Cl <SEP> SOzCI
<tb> R3 <SEP> AAR <SEP> (Vlc)
<tb><SEP> 4
<tb><SEP> HCI <SEP> H2N <SEP> 2 <SEP> (Vil)
<tb><SEP> / Rs
<tb><SEP> Rt
<tb><SEP> CPh3
<Tb>
Figure 3 (continued)

(C1-C4) straight or branched alkyl) under standard conditions known to those skilled in the art.

dans laquelle
A et R4 sont tels que définis précédemment et quand R7 représente un atome de chlore, R8 et Rg représentent chacun un groupe -COR3 (où R3 est tel que défini précédemment) ou forment ensemble un groupe =C1(R3) et quand R7 représente un groupe hydroxy, R8 représente un atome d'hydrogène ou un groupe -COR3 et Rg un groupe -COR3, R3 étant tel que défini précédemment, sont nouveaux et font également partie de l'invention.Intermediate compounds of formula (XII)

in which
A and R4 are as defined above and when R7 represents a chlorine atom, R8 and R8 each represent a -COR3 group (where R3 is as defined above) or together form a group = C1 (R3) and when R7 represents a hydroxy group, R8 represents a hydrogen atom or a group -COR3 and Rg a -COR3 group, R3 being as defined above, are new and are also part of the invention.

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

The compounds of formula (II) and their preparation are described in European Patent Application EP 954026076.

The compounds of formula (VII) are described in European Patent Application EP 0643047.

The following examples illustrate the preparation of certain compounds according to the invention.

The microanalyses and the IR and NMR spectra confirm the structure of the compounds obtained.

The numbers of the exemplified compounds refer to those of the table given below which illustrates the chemical structures and the physical properties of some compounds according to the invention.

The parenthesized relationships represent the ratio
(Acid: base).

Example 1 (Compound No. 5) [2R- [1 (S), 2a, 4B]] - 1- [2 - [[[3'-amino-2 - [(1-oxopropyl) amino] [1, hydrochloride Ethyl (biphenyl] -3-yl] sulfonyl] amino] -5- (5-methyl-1H-imidazol-4-yl) -1-oxopentyl] -4-ethylpiperidine-2-carboxylate (2: 1 1.1. pyridine salt of 5-bromo-3'-nitro-2 - [(1 oxopropyl) amino] [1,1'-biphenyl] -3-sulfonic acid
To a solution of 3.15 g (8.45 mmol) of 2-amino-5-bromo-3'-nitro [1,1'-biphenyl] -3-sulfonic acid and 2.4 ml
(29.6 mmol) of pyridine in 10 ml of dichloromethane is added dropwise at 0 ° C in a nitrogen atmosphere 1.62 ml (18.6 mmol) of propionyl chloride. The temperature of the mixture is allowed to warm to room temperature and stirring is continued for 18 hours. The reaction medium is concentrated under reduced pressure.

The residue is used as is in the next step.

1.2. 5-bromo-2 - [(1-chloropropylidene) amino] -3'-nitro [1,1'-biphenyl] -3-sulfonyl chloride
The residue obtained above is dissolved in 20 ml of dichloromethane and 4.6 g (21.2 mmol) of phosphorus pentachloride are added at 0 ° C. under a nitrogen atmosphere. The temperature of the mixture is allowed to return to ambient temperature and the mixture is kept stirring for 5 hours at this temperature. The reaction medium is concentrated under reduced pressure, the residue is taken up in 150 ml of ether and filtered on sinter. The filtrate is washed twice with 100 ml of water and then with 100 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure.

3 g of product are obtained which is used as it is in the next step.

Yield = 1.3. [2R- [1 (S), 2a, 4ss]] - 1- [2- [7-bromo-3-ethyl-5- (3-
nitrophenyl) -1,1-dioxo-2H-1,2,4-benzothiazin-2-yl] -5- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] -1-
ethyl oxopentyl] -4-ethylpiperidine-2-carboxylate
To a mixture of 1.02 g (2.2 mmol) of 5-bromo-2 - [(1-chloropropylidene) amino] -3'-nitro [1,1'-biphenyl] -3-sulfonyl chloride and 1 28 g (2 mmol) of hydrochloride
[2R- [1 (S), 2a, 4]] - 1- [2-amino-5- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] -1-oxopentyl] Ethyl 4-ethylpiperidine-2-carboxylate in 20 ml of dichloromethane is added dropwise at 0 ° C. under a nitrogen atmosphere 0.98 ml
(7 mmol) of triethylamine. The reaction mixture is left stirring for 3 hours at this temperature, then the stirring is continued for 3 hours at room temperature and evaporated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate and this solution is washed successively with twice 50 ml of a 0.5 N hydrochloric acid solution, twice with 50 ml of a saturated solution of sodium hydrogencarbonate. then with 50 ml of a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure.

1.8 g of product are obtained in the form of a viscous oil which is used as it is in the next step.

Yield = 90% 1.4. [2R- [1 (S), 2α, 4]] - 1- [2 - [[[5-bromo-3'-amino-2 - [(i-oxopropyl) amino] [1,1'-biphenyl] ] -3-yl] sulfonyl] amino] -5-
(5-methyl-1H-imidazol-4-yl) -1-oxopentyl] -4-éthylpipé
ridin-2-ethyl carboxylate
A solution of 1.8 g (1.8 mmol) of [2R- [1 (S), 2a, 4ss]] - [2- [7-bromo-3] was heated for 9 hours at reflux temperature. ethyl-5- (3-nitrophenyl) -1,1-dioxo-2H-1,2,4-benzothiazin-2-yl] -5- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-) yl] -1-oxopentyl] -4-ethylpiperidine-2-carboxylic acid ethyl ester in a mixture of 80 ml of acetic acid and 30 ml of water. The reaction medium is allowed to cool to room temperature and concentrated under reduced pressure.

The residue is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane mixture (5:95).

1.32 g of product are obtained.

Yield = 84 i
Melting point = 108-112 OC 1.5. [2R- [1 (S), 2a, 4ss]] - 1- [2 - [[[3'-amino-2 - [(1-oxopropyl)]
amino] [1,1'-biphenyl] -3-yl] sulfonyl] amino] -5- (5-methyl
1H-imidazol-4-yl) -1-oxopentyl] -4-ethylpiperidine-2
ethyl carboxylate
A mixture of 1.25 g (1.58 mmol) of [2R- [1 (S), 2a, 4B] -l- [is hydrogenated at 0.35 MPa (50 psi) for 10 hours at room temperature. 2 - [[[5-Bromo-3'-amino-2 - [(1-oxopropyl) amino] [1,1'-biphenyl] -3-yl] sulfonyl] amino] -5- (5-methyl-1H) ethyl (1-imidazol-4-yl) -1-oxopentyl] -4-ethylpiperidine-2-carboxylate and 0.2 g of palladium on charcoal in 20 ml of ethanol. The reaction medium is filtered through Celite, the filtrate is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel, eluting with a methanol: dichloromethane (7.5: 92.5) mixture.

0.78 g of product is isolated in base form.

Yield = 72% 1.6. [2R- [1 (S), 2a, 4ss]] - 1 [2 - [[[3'-amino-2- hydrochloride] hydrochloride
[(1-oxopropyl) amino] [1,1'-biphenyl] -3-yl] sulfonyl]
amino] -5- (5-methyl-lH-imidazol-4-yl) -1-oxopentyl] -4
Ethylpiperidine-2-carboxylic acid ethyl ester (2: 1)
0.1N 0.2 g (0.3 mmol) of [2R- [1 (S), 2a, 4ss]] - 1 - [2 - [[[3 are dissolved in 8 ml of 0.1N hydrochloric acid. -amino-2-
[(1-Oxopropyl) amino] [1,1'-biphenyl] -3-yl] sulfonyl] amino] -5
Ethyl (5-methyl-1H-imidazol-4-yl) -1-oxopentyl] -4-ethylpiperidine-2-carboxylate and concentrated under reduced pressure.

The residue obtained is purified by chromatography on a RP 18 type phase column, eluting with a mixture of acetonitrile: water (3: 7).

0.18 g of product is obtained.

Yield = 82%
Melting point = 175 ° C
[&alpha;] D20 = + 88 (c = 0.2; methanol)
Example 2 (compound 7) [2R- [1 (S), 2a, 4ss]] - 4-ethyl-1- [2 - [[[3'- (ethylamino) -2 - [(1-oxopropyl) hydrochloride) amino] [1,1'-biphenyl] -3-yl] sulfonyl] amino] -5- (5-methyl-1H-imidazol-4-yl) -1-oxopentyl] piperidine-2-carboxylic acid ethyl ester (2: 1)
0.18 g (0.27 mmol) of [2R- [1 (S), 2a, 4ss]] - 1- [2 - [[[3'-amino-2 - [(1-oxopropyl) amino] Ethyl [1,1'-biphenyl] -3-yl] sulfonyl] amino] -5- (5-methyl-1H-imidazol-4-yl) -1-oxopentyl] -4-ethylpiperidine-2-carboxylate 22 μl (0.4 mmol) of acetaldehyde, 30 mg of 10% palladium on charcoal and 10 ml of ethanol are added. The mixture was allowed to stir for 8 hours at 50 psi (0.35 MPa) and filtered through celite. The filtrate is concentrated under reduced pressure, the residue is taken up in 8 ml of a 0.1 N hydrochloric acid solution in isopropanol and concentrated under reduced pressure. The residue is purified by chromatography on a phase RP 18 type column, eluting with acetonitrile: water (3: 7).

0.15 g of product is obtained.

Yield = 60%
Melting point = 160 ° C [α] 20 = + 94 (c = 0.2, methanol)
Example 3 (Compound No. 6) [2R- [1 (S), 2a, 4ss]] - [2 - [[[2,3'-bis] hydrochloride hydrochloride
(acetylamino) [1,1'-biphenyl] -3-yl] sulfonyl] amino] -5- (5-methyl-1H-imidazol-4-yl) -1-oxopentyl] -4-ethylpiperidine-2-carboxylate ethyl (1: 1) 3.1. N, N-diethylethanamine salt of 2,3'-bis (diacetylamino) [1,1'-biphenyl] -3-sulfonic acid
A solution of 2.5 g (5.8 mmol) of N, N-diethylethanamine salt of 2,3'-diamino [1,1'-biphenyl] - N, N-diethylethanamine is heated for 18 hours at reflux temperature. 3-sulfonic acid in 60 ml of acetic anhydride. The reaction medium is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane mixture (5:95).

2.5 g of product are obtained in the form of a viscous oil which is used as it is in the next step.

Yield = 80 i 3.2. 2,3'-bis (diacetylamino) [1,1'-biphenyl] chloride -
3-sulfonyl chloride
To a solution of 1.7 g (3.1 mmol) of N, N-diethylethanamine salt of 2,3'-bis (diacetylamino) [1,1'-biphenyl] -3-sulfonic acid in 7 ml of dichloromethane, 0.73 g (3.5 mmol) of phosphorus pentachloride are added under nitrogen. The mixture is heated for 2 hours at the reflux temperature and then concentrated under reduced pressure. The residue thus obtained is purified by chromatography on a column of florisilw, eluting with ethyl acetate.

0.68 g of product is obtained in the form of a viscous oil which is used as such in the next step.

Yield = 3.3. [2R- [1 (S), 2a, 4ss]] - 1 - [2 - [[[2,3'-bis (diacetylamino)]
[1,1'-Biphenyl] -3-yl] sulfonyl] amino] -5- [5-methyl-1 (triphenylmethyl) -1H-imidazol-4-yl] -1-oxopentyl] -4-
Ethylpiperidine-2-ethyl carboxylate
To a mixture of 0.65 g (1.45 mmol) of 2,3'-bis (diacetylamino) [1,1'-biphenyl] -3-sulfonyl chloride and 0.95 g (1.45 mmol) of [2R- [1 (S), 2a, 413]] - 1- [2-amino-5- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] 1-oxopentyl] hydrochloride] Ethyl 4-ethylpiperidine-2-carboxylate in 3 ml of dichloromethane is added at 0 ° C. under nitrogen, 0.52 ml.
(3.6 mmol) triethylamine. The mixture is left stirring for 4 hours at this temperature and then concentrated under reduced pressure. The residue obtained is taken up in 100 ml of ethyl acetate and the solution is washed successively with twice 50 ml of a 0.5 N hydrochloric acid solution, twice with 50 ml of a saturated hydrogen carbonate solution. of sodium and 50 ml of a saturated solution of sodium chloride. Finally, it is dried over magnesium sulphate and then concentrated under reduced pressure.

1.2 g of product is obtained in the form of a viscous oil which is used as it is in the next step.

Yield = 80% 3.4. hydrochloride of [2R- [1 (S), 2a, 4ss]] - 1- [2 - [[[2,3'-bis
(acetylamino) [1,1'-biphenyl] -3-yl] sulfonyl] amino] -5- (5-methyl-1H-imidazol-4-yl) -1-oxopentyl] -4-ethylpiperidine
2-ethyl carboxylate (1: 1)
A solution of 1.2 g (1.16 mmol) of [2R- [1 (S), 2a, 4ss]] - 1- [2- [[[2,3 is refluxed for 8 hours at reflux temperature. bis (diacetylamino) [1,1'-biphenyl] -3-yl] sulfonyl] amino] -5- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl) -1 oxopentyl] - Ethyl 4-ethylpiperidine-2-carboxylate in 30 ml of acetic acid and 10 ml of water and then the reaction medium is concentrated under reduced pressure.

The residue is taken up in 20 ml of 0.1 N hydrochloric acid solution in isopropanol and concentrated under reduced pressure. The residue thus obtained is purified by RP-18 phase column chromatography, eluting with a water: acetonitrile (6: 4) mixture.

0.4 g of product is obtained in the form of a white powder.

Yield = 47%
Melting point = 136-140 ° C [α] 20 = + 100 (c = 0.2, methanol)
Example 4 (Compound No. 8) [2R- [1 (S), 2a, 45]] - 4-ethyl-1- [5- (5-methyl-1H-imidazol-4-yl) -1-oxo hydrochloride -2 - [[[2 - [(1-oxopropyl) amino] -3
Ethyl (pyrimidin-2-yl) phenyl] sulfonyl] amino] pentyl] piperidine-2-carboxylate (1: 1) 4.1. 2- [bis (1-oxopropyl) amino] -5-bromo-3-iodobenzenesulfonic acid N, N-diethylethanamine salt
A solution of 31.7 g (66 mmol) of N, N-diethylethanamine salt of 2-amino-5-bromo-3-iodobenzenesulfonic acid in 114 ml (1%) is heated for 16 hours at reflux temperature. 32 moles) of propionyl chloride. The reaction medium is concentrated under reduced pressure and the crude residue is crystallized in 100 ml of ethyl acetate.

32.5 g of product are obtained in the form of white crystals.

Yield = 84%
Melting point = 124-128 ° C 4.2 2- [bis (1-oxopropyl) amino] -5-bromo-3- chloride
iodobenzenesulfonyl
To a solution of 32.5 g (55 mmol) of
2- [bis (1-oxopropyl) amino] 5-bromo-3-iodobenzenesulfonic acid N, N-diethylethanamine in dichloromethane is added in small quantities, at 0 ° C. under nitrogen, 16.8 g.
(82.4 mmol) phosphorus pentachloride. The temperature of the reaction medium is allowed to return to room temperature and the mixture is heated for 4 hours at the reflux temperature. 200 ml of ether are added, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a florisilm column, eluting with an ether / hexane (2: 8) mixture. The product is recrystallized from an ether / pentane mixture.

12 g of product are obtained in the form of white crystals.

Yield = 43%
Melting point = 127-132 ° C 4.3. [2R- [1 (S), 2a, 4]] - 1- [2 - [[5-bromo-3-iodo-2 - [(1-
oXopropylEamino] phenyl] sulfonyl] amir.o] -5- [5-methyl-1-
(Triphenylmethyl) imidazol-4-yl] -1-oxopentyl] -4-
Ethylpiperidine-2-ethyl carboxylate
To a solution of 1.28 g (2 mmol) of
[2R- [1 (S), 2a, 4ss]] - 1- [2-amino-5- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] -1-oxopentyl] Ethyl 4-ethylpiperidine-2-carboxylate in 4 ml of dichloromethane is added successively to 0 OC under nitrogen, 1.02 g (2 mmol) of 2- [bis (1-oxopropyl) amino] -5 chloride -bromo-3-iodobenzenesulfonyl then dropwise 0.69 ml (5 mmol) of triethylamine. The reaction medium is left stirring for 6 hours at 0 ° C. and then 100 ml of ethyl acetate are added. Then washed successively with twice 50 ml of 0.5 N hydrochloric acid, 50 ml of a saturated solution of sodium hydrogencarbonate and 50 ml of a saturated solution of sodium chloride. Finally, it is dried over magnesium sulphate and concentrated under reduced pressure. 2.1 g of product is obtained in the form of a viscous oil which is taken up in 100 ml of tetrahydrofuran and treated at 0 ° C. with ammonia gas. The reaction medium is left stirring for 2 hours at this temperature and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel, eluting with a dichloromethane / methanol (98: 2) mixture.

1.4 g of product is obtained in the form of a viscous oil which is used as it is in the next step.

Yield = 70% 4.4. [2R- [1 (S), 2a, 4R] 1-1- [2 - [[[5-bromo-2 - [(1-oxopropyl) amino] -3- (pyrimidin-2-yl) phenyl] sulfonyl ] amino] -5- [5-
methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] -1
ethyl oxopentyl] -4-ethylpiperidine-2-carboxylate
A mixture of 0.24 g (0.65 mmol) of 2- (tributylstannyl) pyrimidine, 0.5 g, is heated for 7 hours under argon at 80 ° C.
(0.5 mmol) of [2R- [1 (S), 2a, 413]] - 1- [2 - [[[5-bromo-3-iodo-2-
[(1-Oxopropyl) amino] phenyl] sulfonyl] amino] -5- [5-methyl-1 (triphenylmethyl) -1H-imidazol-4-yl) -1-oxopentyl] -4-ethylpiperidine-2-carboxylate ethyl, 0.015 g (0.08 mmol) of copper iodide, 0.048 g (0.16 mmol) of triphenylarsine and 0.05 g (0.04 mmol) of palladium bis (dibenzylideneacetone) in 1.5 ml of dimethylformamide. The reaction medium is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of methanol / dichloromethane (3/97).

0.36 g of product is obtained in the form of a viscous oil which is used as it is in the next step.

Yield = 72 4.5. [2R- [1 (S), 2a, 4]] - 1 - [2 - [[[5-bromo-2 - [(1-oxopropyl)]
amino] -3- (pyrimidin-2-yl) phenyl] sulfonyl] amino] -5- [5
methyl-1H-imidazol-4-yl] -1-oxopentyl] -4-ethylpiperidine
2-ethyl carboxylate
0.78 g (0.8 mmol) of toluene are heated at 100 ° C. for 1.5 hours.
[2R- [1 (S), 2a, 4ss]] - 1- [2 - [[[5-bromo-2 - [(1-oxopropyl) amino] 3- (pyrimidin-2-yl) phenyl] sulfonyl] ethyl] -5- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] -1-oxopentyl] -4-ethylpiperidine-2-carboxylic acid ethyl ester in a mixture of 25 ml of acetic acid and 8 ml of water, and then the reaction medium is concentrated under reduced pressure. The residue is taken up in 50 ml of dichloromethane, the solution is neutralized with a stream of ammonia and concentrated under reduced pressure. The residue thus obtained is purified by chromatography on a column of silica gel, eluting with a methanol / dichloromethane (5/95) mixture.

0.38 g of product is isolated in the form of a viscous oil which is used as it is in the next step.

Yield = 65% 4.6. [2R- [1 (S), 2a, 413]] - 4-ethyl-1- [5- (S-) hydrochloride
methyl-1H-imidazol-4-yl) -1-oxo-2 - [[[2 - [(1-oxopropyl)
amino] -3- (pyrimidin-2-yl) phenyl] sulfonyl] amino] pentyl]
ethyl piperidine-2-carboxylate (1: 1)
A mixture of 0.38 g (0.52 mmol) of [2R- [1 (S), 2a, 413]] - [2-] was heated for 4 hours at reflux temperature.
[[[5-Bromo-2 - [(1-oxopropyl) amino] -3- (pyrimidin-2-yl) phenyl] sulfonyl] amino] -5- [5-methyl-1H-imidazol-4-yl] Ethyl 1-oxopentyl] -4-ethylpiperidine-2-carboxylate, 0.65 g (10.4 mmol) of ammonium formate and 0.038 g of 10% palladium on carbon in 8 ml of methanol and o, 2 ml of acetic acid. The mixture is diluted by the addition of 100 ml of dichloromethane, sintered and the filtrate concentrated under reduced pressure. The residue is taken up in 50 ml of dichloromethane, the solution obtained is neutralized with a stream of ammonia and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a methanol / dichloromethane (5/95) mixture.

The hydrochloride is prepared by adding 9 ml of a 0.1 N hydrochloric acid solution in isopropanol to 0.24 g (0.37 mmol) of base and then concentration under reduced pressure.

0.24 g of product is obtained in hydrochloride form.

Yield = 70%
Melting point = 105-110 OC
[] D20 = - 8 (c = 0.2, methanol) Table

<tb><SEP> Y
<tb><SEP> o <SEP><u
<tb><SEP> o <SEP> Ln <SEP> oo
<tb> No <SEP> R1 <SEP> R2 <SEP> K3 <SEP> R4 <SEP> R5 <SEP> A <SEP> Sel <SEP> F <SEP> (O <SEP> c) <SEP> [ ] D20 <SEP> (O)
<tb><SEP> COOH
<tb><SEP> o
<tb><SEP> i <SEP> -CH3 <SEP> -C2H5 <SEP> -C2H5 <SEP> -H <SEP> -c2H5 <SEP> (1: 1) <SEP> 150 <SEP> + <SEP > 50
<tb><SEP> CH2OH
<tb><SEP> chior.
<Tb>

<SEP> 2 <SEP> -CH3 <SEP> -C2H5 <SEP> -C2H5 <SEP> -H <SEP> -C2H5 <SEP> (1: 1) <SEP> 110-114 <SEP> + <SEP> 62
<tb><SEP> M <SEP> VN <SEP> Ú
<tb><SEP>
<tb><SEP> M <SEP> V <SEP> U
<tb><SEP> Z <SEP> H <SEP> CS
<Tb>

<tb><SEP> No <SEP> R1 <SEP> R2 <SE> R3 <SEP> R4 <SEP> R5 <SEP> A <SEP> Sel <SEP> F <SEP>(<SEP> C) <SEP > [] D20 <SEP> (O)
<tb><SEP> CO (CH3) 2
<tb><SEP> chior.
<Tb>

<SEP> 3 <SEP> -CH3 <SEP> -C2H5 <SEP> -C2H5 <SEP> -H <SEP> -C2H5 <SEP> (1: 1) <SEQ> 94-98 <SEP> + <SEP> 33
<tb><SEP> NO2
<tb> -
<tb> 4 <SEP> -H <SEP> -C2H5 <SEP> 93-9V <SEP> + <SEP> 68
<tb> -CH3 <SEP> -C2H5 <SEP> -C2H5 <SEP> (1: 1)
<tb><SEP> N112
<tb><SEP> chior.
<Tb>

<SEP> 5 <SEP> -CH3 <SEP> -C2H5 <SEP> -C2H5 <SEP> -H <SEP> -C2H5 <SEP> (2: 1>

<tb><SEP> rD <SEP> o <SEP> H <SEP> c9
<tb><SEP> o <SEP> kD <SEP> I
<tb><SEP> H <SEP> n <SEP> Ln
## EQU1 ## SEP> [] D20 <SEP><c>
<tb><SEP> NHC2H5
<tb><SEP> chlor.
<Tb>

<SEP> V <SEP> -CH3 <SEP> -C2H5 <SEP> -C2H5 <SEP> -H <SEP> -C2H5 <SEP> 160 <SEP> + <SEP> 94
<tb><SEP> 8 <SEP> -CH3 <SEP> -C2H5 <SEP> -C2H5 <SEP> -H <SEP> H <SEP> H
<tb> To <SEP> (1: 1)
<tb><SEP> 9 <SEP> -CH3 <SEP> -C2H5 <SEP> -C2H5 <SEP> -H <SEP> -C2H5 <SEP> o <SEP> chlor. <SEP> 115-120 <SEP> + <SEP> 41
<tb><SEP> 3: <SEP>Z><SEP> C <SEP> Zb
<tb><SEP> U) <SEP> UR <SEP> One
<tb><SEP> X <SEP> X <SEP> N <SEP> V
<tb><SEP>CE;<SEP> l <SEP> l
<tb><SEP> x <SEP> = o <SEP> U
<tb><SEP> X <SEP> = <SEP> = <SEP> Xn
<tb><SEP> l <SEP> l
<tb><SEP> Z
<tb> Table legend: in the column "Salt": "chlor." represents a hydrochloride; the parenthetical ratios represent the ratio (acid: base) and the absence of a reference corresponds to the product in basic form.

in the "[&alpha;]D20" column: c = 0.2; solvent = methanol
The compounds of the invention have been the subject of pharmacological studies which have demonstrated their antithrombotic properties and their interest as substances with therapeutic activity.

1. Determination of inhibition constants (Ki) with respect to thrombin
On a 96-well microplate, 25 μl of a solution of test compound (7 concentrations), 50 μl of a chromogenic substrate solution (2 concentrations, S2238 Chromogenix) are dissolved in each well. Tris buffer pH 7.5 (50mM Tris, 100mM NaCl and 0.1m BSA) and finally 25μl thrombin solution at 300 U / ml. The 4-nitroaniline release was monitored at 405 nm using a plate reader.

Ki is determined by the Dixon method.

The compounds of the invention are thrombin inhibitors and their K1 is between 0.001 and 100 WM.

2. Coagulation of rat plasma by human thrombin exvi vo
Male CD rats weighing 150 to 200 g are treated with the test compound or vehicle, iv, orally or subcutaneously. Then the animals are anesthetized with NembutalE (60 mg / kg, 0.1 ml / kg), the blood is taken from trisodium citrate at 3.8% (1 vol / 9 vol of blood) at the level of the retro-orbital sinus and the plasma is prepared by centrifugation at 3600 g for 15 minutes at room temperature. Then, at 37 ° C., 200 μl of plasma were incubated with 200 μl of a human thrombin solution, the final concentration of human thrombin being 0.75 NIH units / ml and the coagulation time was noted. The anticoagulant effect is expressed by the dose which increases the coagulation time by 100%.

They inhibit the coagulation of rat plasma at doses of 0.01 to 5 mg / kg i.v. They are also active by the oral and subcutaneous routes.

3. Rabbit platelet aggregation induced by human thrombin.

The blood is collected by cardiac puncture on trisodium citrate at 3.8 i (1 vol / 9 vol of blood). It is centrifuged at 250 g for 10 minutes. The platelet rich plasma (P3P) thus obtained is removed and the platelet count is carried out.

To P3P, 2 ng / ml of prostacyclin in solution was added in ice cold pH 9.0 tris buffer. It is centrifuged at 110 g for 10 minutes and decanted. Prostacyclin, in solution in 50 mM sodium hydroxide at pH 12, is added again so as to have a final concentration of 200 ng / ml. The P3P is again centrifuged at 800 g for 10 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
P3P. This suspension is centrifuged at 800 g for 10 minutes. It is repeated a second time and under the same conditions, the suspension of the pellet and centrifugation. 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 the aggregation of 50 (IC 50) is determined.

The compounds of the invention may be useful in all clinical indications related to thrombosis or in those where thrombotic complications could 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. All these forms are dosed to allow an administration of 1 to 1000 mg per day and per patient, in one or more doses.

Claims (9)

claims 1. Compounds of formula (I)

 in which R1 represents either a hydrogen atom or a group  (C1-C4) alkyl, R2 represents either a hydrogen atom or a group  (C1-C4) straight or branched alkyl, R3 represents a straight or branched (C1-C7) alkyl group, R4 represents either a hydrogen atom or a halogen atom, R5 represents a straight or branched (C1-C4) alkyl group and A represents a phenyl, pyrimidyl or thiazolyl group, the said groups possibly being substituted with one or more substituents chosen from the formyl groups, -CH 2 OR 10, -CH 2 OCOR 10, -CH 2 COONR 10 R 11, -COOR 10, -CONR 10 R 11, nitro, NR 1 O R 11, -NHCOR 1 O, NH (CH2) nOR1o with Rlo and R11 each being independently of each other a hydrogen atom or a straight or branched (C1-C4) alkyl group and n between 0 and 6, in the form of free bases or addition salts with pharmaceutically acceptable acids. 2. Compounds according to claim 1, characterized in that the preferred configuration of the piperidinyl group is [2R, 4R] 3. Compounds according to any one of claims 1 to 2 characterized in that the configuration of the central amino acid part

 is S]. 4. Process for the preparation of the compounds according to claim 1, characterized in that a compound of formula (II) is reacted

 wherein A and R4 are as defined in claim 1 with triethylamine to form a triethylamine salt which is reacted with an acid chloride of formula (IIIa)  R3COCl (IIIa) or with an anhydride of formula (IIIb)  (R3CO) 2C (IIIb) and a symmetrical imide of formula (Va) is obtained

 that is treated with phosphorus pentachloride to obtain a compound of formula (VI

 on which the hydrochloride of the amine of formula (VII) is reacted

 in which R 1 and R 5 are as defined in claim 1 and R 2 represents a straight or branched (C 1 -C 4) alkyl group and then treated in acidic medium and a compound of formula (Ia) (in which R 2 represents a group (C1-C4) straight or branched alkyl) which is saponified if it is desired to obtain a compound of formula (I) in which R2 represents a hydrogen atom. 5. Process for the preparation of the compounds according to claim 1, characterized in that a compound of formula (IIb) is reacted

 in which R4 represents a halogen atom with triethylamine and the salt thus obtained is reacted with an acid chloride of formula (IIIa)  R3COCl (IIIa) and a compound of formula (Vb) is obtained

 from which a compound of formula (VIb) is prepared

 by the action of phosphorus pentachloride and then the compound (VIb) is reacted with the hydrochloride of the amine of formula (VII) and then treated in a basic medium and a compound of formula (VIII) is obtained

 that is reacted with a compound of formula (IX)  ASn (R) 3 (IX) wherein A is as defined in claim 1 and R is (C1-C4) alkyl, to form a compound of formula (Xa)

 which is heated to the reflux temperature in an acidic medium, and a compound of formula (Ia) in which R 4 represents a halogen atom, which compound is subjected to hydrogenolysis if it is desired to obtain a hydrogenolysis, is obtained; compound of formula (Ia) in which R4 is a hydrogen atom, then which is saponified if it is desired to prepare a compound of formula (I) in which R2 represents a hydrogen atom. 6. Process for the preparation of the compounds according to claim 1, characterized in that a compound of formula (II) is reacted

 in which A and R q are as defined in claim 1 with an acid chloride of formula (IIIa) in the presence of a base and an amide of formula (Vc) is obtained

 that is treated with acetic acid to obtain a compound of formula (Ia) (wherein R2 represents a straight or branched (C1-C4) alkyl group) which is saponified if it is desired to prepare a compound of formula (I) wherein R2 represents a hydrogen atom.

 on which the hydrochloride of the amine of formula (VII) is reacted to prepare a compound of formula (XI)

<tb> as a basic salt which is treated with phosphorus pentachloride to obtain a compound of formula (VIc) <tb> <SEP> A <SEP> R4 <tb> R <SEP> OC <SEP> (Vc) <tb> <SEP> HN <SEP> 1 <SEP> (Vc) <tb> <SEP> SO3H. <SEP> base 7. Compounds of formula (XII)

 in which A and R4 are as defined in claim 1 and when R1 represents a chlorine atom, R8 and R8 each represent a -COR3 group (where R3 is as defined in claim 1) or together form a group = Cl (R3 ) and when R7 represents a hydroxy group, R8 represents a hydrogen atom or a -COR3 group and Rg a -COR3 group, R3 being as defined in claim 1, useful as synthesis intermediates of the compounds according to claim 1. 8. Medicinal product characterized in that it contains a compound according to any one of claims 1 to 3. 9. Pharmaceutical composition characterized in that it contains a compound according to any one of claims 1 to 3 in association with any pharmaceutically acceptable excipient.