WO2000058346A1

WO2000058346A1 - N-sulfonyl-dipeptide derivatives, production and use thereof in therapy

Info

Publication number: WO2000058346A1
Application number: PCT/FR2000/000696
Authority: WO
Inventors: Chantal Alcouffe; Patrice Bellevergue; Geneviève DELLAC; Christopher Latham; Valérie Martin; Christine Masson; Gary Mccort
Original assignee: Sanofi-Synthelabo
Priority date: 1999-03-30
Filing date: 2000-03-21
Publication date: 2000-10-05
Also published as: FR2791683A1; AU3301700A

Abstract

The present invention relates to compounds of general formula (I) wherein R1 represents a (C1-C7) alkyl group which can be substituted or a cycloalkyl or cycloalkylalkyl group or a (CH2)n-X-R3 group, R2 represents a (C1-C7) alkyl group which can be substituted or a cycloalkyl or cycloalkylalkyl group or a phenyl, benzyl or 2-phenylethyl group which can be substituted on the phenyl group or a carbocyclic or heterocyclic group, Y is represented by the two tautomeric forms of formula (II) wherein R4 represents a hydrogen atom or a methyl group and Q represents an R5-SO2- group wherein R5 represents a (C1-C8)alkyl group or a cycloalkylalkyl group or a benzyl group which can be substituted. The invention also relates to methods for the production and use thereof in therapy.

Description

N-SULFONYL-DIPEPTIDES DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION

The subject of the present invention is W-sulfonyl-dipeptide derivatives, their preparation and their therapeutic use.

The compounds of the invention correspond to the general formula (I)

in which,

R] _ represents either a (C- ^ C ^) alkyl group which may be substituted by a hydroxy group or a trifluoromethyl group, or a cycloalkyl group or a cycloalkylalkyl group, or a group - (CH ₂ ) _n -XR ₃ where R ₃ represents a (C ₁ -C ₃ ) alkyl group, n is equal to al, 2 or 3 and X represents a sulfur or oxygen atom,

R ₂ represents either a (C;, - C ₇ ) alkyl group which may be substituted by an amino group, a -COOH group, a hydroxyl group or a trifluoromethyl group, or a cycloalkyl group or a cycloalkylalkyl group, or a phenyl group, benzyl or 2-phenylethyl, which may be substituted on the phenyl group by one of the following substituents: a halogen atom, a trifluoromethyl group, an amino group or a (C ₁ -C ₄ ) alkoxy group, or a carbocyclic group or a heterocyclic group, Y is represented by the two tautomeric forms of formula (II)

or

A represents either a hydrogen atom or an NH ₂ group or an OH group, or a (C _x -C ₄ ) alkyl group, or a group

alkoxycarbonyl,

R ₄ represents either a hydrogen atom or a methyl group,

and Q represents a group R ₅ -S0 ₂ - where R ₅ represents either a (C 1 -C 6) alkyl group, or a cycloalkylalkyl group, or a benzyl group, which can be substituted on the phenyl group by a methoxy group, or a group B- (CH ₂ ) _p -S0 ₂ -, where B can be a group -COOH or -CF ₃ and p can vary from 1 to 3.

In the context of the present invention, the terms below have the following meanings: an alkyl group is a saturated, linear or branched hydrocarbon chain,

a cycloalkyl group is a cyclic saturated hydrocarbon chain comprising 3 to 7 carbon atoms,

- a cycloalkylalkyl group is a linked cycloalkyl group an alkyl group, the latter group comprising 1 to 3 carbon atoms,

a carbocyclic group is a hydrocarbon chain comprising two rings, aromatic or not, chosen from naphthyl, 2-naphthylmethyl, 2-indanyl, 1-benzocyclobutanylmethyl groups,

a heterocyclic group is a hydrocarbon chain comprising one or two rings, comprising 1 or two heteroatoms of oxygen, sulfur or nitrogen, these rings being aromatic or not, chosen from the group

2,3-dihydro-1,4-benzodioxyn-2-ylmethyl, indol-2 or 3-ylmethyl, benzofuran-2 or 3-ylmethyl, benzothiophen-2 or 3-ylmethyl, benzisoxasol-3-ylmethyl, indazol-3- ylmethyl, thiazol-4 or 5-ylmethyl, oxazol-4 or 5-ylmethyl, 2,3 or 4-pyridylmethyl, pyrimidin-2, 4 or 5-ylmethyl, 2-pyridazinylmethyl, 1 or 3-isoquinolinylmethyl, 3,4 or 5-isothiazolylmethyl, 4-imidazolylmethyl and all their isomeric forms.

The compounds of general formula (I) may contain one or more asymmetric carbons. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and their mixtures, including racemic mixtures are part of the invention.

In the context of the present invention, the halogen atoms are preferably chlorine and fluorine.

The compounds of general formula (I) can be in the form of free bases or of addition salts with pharmaceutically acceptable acids, which also form part of the invention.

The preferred compounds according to the invention are such that the carbon which carries R _τ is of absolute configuration (S), and the carbon which carries R ₂ is of absolute configuration (R). These preferred compounds can be prepared according to the diagrams which will follow, starting from starting compounds chirals.

The compounds of formula (I) can be readily synthesized using many synthetic approaches habitually employed by the skilled person (Fridkin and Patchornik, Ann Rev. Biochem, 43, 419-443 _(1974)...; Kent, Ann. Rev. Biochem., 57, 957-990 (1988); Bodansky, "The practice of peptide synthesis", Springer-Verlag, Berlin (1984); Jones, "Amino a cid and peptide syn thesis", Oxford University Press, Oxford (1997)).

The peptide couplings used to prepare the compounds of the invention typically employ the IV method ((3-dimethylaminopropyl) -IV-ethylcarbodiimide (N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide) / 1-hydroxybenzotriazole or [ O- (7-azabenzotriazol-1-yl) - 1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU). Other methods of forming the amide bonds include the use of an acid chloride, azide, mixed anhydride or activated ester. The functional groups of the amino acid derivatives used can, for example, be blocked by orthogonal protective groups in order to prevent side reactions during coupling. Examples of such protective groups and their use are described for example in Greene, "Protecting Groups in

Organic Synthesis ", 2nd edition, iley-Interscience (1991), in Jones" Amino acid and Peptide Synthesis ", Oxford University Press (1997) and in" The Peptides ", Gross and Meienhofer, vol 3, Académie Press (1981). Typically, the syntheses are carried out in the liquid phase but the solid phase synthesis of the Merrifield type can also be used. According to the invention, the compounds of formula (I) can be prepared by methods illustrated by schemes 1, 2 and 3.

Diagram 1

age

(I)

; ιχ)

According to scheme 1, a sulfonyl chloride of formula Q-Cl, in which Q is as defined above, is reacted with an amino acid of formula (III), in which R ₂ is as defined above and the carboxylic acid function is protected by a protective group GP _X , where QL? _X represents, for example, a methyl, ethyl, tert-butyl or benzyl group, in the presence of an organic base such as triethylamine or Λ7-methylmorpholine, in an aprotic solvent such as dichloromethane or dimethylformamide, at a temperature between 0 and 60 ° C. . The compound of formula (IV) obtained is deprotected, for example by lithium hydroxide, in a tetrahydrofuran / water mixture, in the case of a methyl or ethyl ester, or by anhydrous trifluoroacetic or hydrochloric acid in dichloromethane in the case of a tert-butyl ester, at a temperature between 0 and 25 ° C, to obtain the carboxylic acid of formula (V). The derivative of formula (V) is condensed with an amino acid of formula (VI), in which R _λ is as defined above, in the presence of a peptide coupling agent such as iV '- (3-dimethylaminopropyl ) -N-ethylcarbodiimide (N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide) / 1-hydroxybenzotriazole or [O- (7-azobenzotriazol-l-yl) - 1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU ), in the presence of an organic base such as

N, N-diisopropyl-ΛJ-ethylamine, N-methylmorpholine or triethylamine, in an aprotic solvent such as dichloromethane or dimethylformamide or a mixture of the two, at a temperature between 0 and 25 ° C. The dipeptide compound of formula (VII) thus obtained is deprotected under the conditions described above for GP _} and the carboxylic acid of formula (VIII) is then condensed with a compound of formula (II), in which R ₄ is as defined above and Z represents a protective group such as a benzyloxycarbonyl group, in the presence of a coupling agent such as those described for the preparation of the compounds of formula (VII). The compound of formula (IX) thus obtained is then hydrogenolysed in the presence of palladium on carbon and hydrochloric acid in a polar solvent such as methanol or ethanol to obtain a compound of formula (I), which can be purify, for example by reverse phase HPLC, eluting, for example with a gradient of 0 to 100% acetonitrile in aqueous hydrochloric acid N / 1000 or 0.1 to 1% trifluoroacetic acid.

According to the invention, the compounds of formula (I) can also be synthesized according to scheme 2.

Diagram 2

(seen: (XII:

An amino acid of formula (X) is condensed, in which the amino function is protected by an orthogonal protective group GP ₂ , where GP ₂ represents, for example, a tert-butyloxycarbonyl group, with an amino acid of formula (VI) whose the carboxylic acid function is protected by an orthogonal protective group GP _X , where GPi represents, for example, a methyl or ethyl group, in the presence of a coupling agent such as N '- (3-dimethylaminopropyl) -N- ethylcarbodiimide, HATU or the like, and an organic base such as N, ΛJ-diisopropyl-N-ethylamine,

or triethylamine, in an aprotic solvent such as dichloromethane or dimethylformamide or in a mixture of the two, at a temperature between 0 and 25 ° C. A doubly protected dipeptide derivative of formula (XI) is obtained. The amino function of the derivative (XI) is deprotected, for example, when GP ₂ represents a tert-butyloxycarbonyl group, using trifluoroacetic or anhydrous hydrochloric acid in a solvent such as dichloromethane or ethyl acetate and at a temperature between 0 and 25 ° C, to provide a compound of formula (XII). This compound of formula (XII) is treated with a sulfonyl chloride of formula Q-Cl in the presence of an organic base in an aprotic solvent, at a temperature between 0 and 50 ° C, to obtain a sulfonamide of formula (VII ), which is treated as described in Scheme 1 to obtain a compound of formula (I).

Diagram 3

(XVII): ιχ) According to the invention, the compounds of formula (I) can also be synthesized according to scheme 3. An amino acid of formula (X) is reacted, in which the amino function is protected by an orthogonal protective group GP ₂ , where GP ₂ represents for example a tert-butyloxycarbonyl group, with a compound of formula (II), as defined for scheme 1 in the presence of a coupling agent as described above and of an organic base in an aprotic solvent such as dichloromethane or dimethylformamide or a mixture of the two at a temperature between 0 and 25 ° C. The compound of formula (XIII) thus obtained is deprotected at its N-terminal end by treatment with anhydrous trifluoroacetic or hydrochloric acid, when GP ₂ represents a tert-butyloxycarbonyl group, to provide a compound of structure (XIV). The compound of structure (XIV) is condensed with an amino acid derivative of formula (XV) suitably protected, in the presence of a coupling agent under the conditions described above. A compound of structure (XVI) is formed from which the N-terminal end is unprotected under the conditions described for the compounds of formula (XVII). The compound of formula (XVII) thus obtained is reacted with a sulfonyl chloride of formula Q-Cl in the presence of an organic base to obtain a sulfonamide of structure (IX). Finally, the compounds of structure (IX) are transformed into compounds of formula (I), by hydrogenolysis as already described above.

According to the invention, the compounds of formula (I) where A is an OH group or (C _x -C ₆ ) alkoxycarbonyl, can be prepared according to the following scheme: Diagram 4

According to the scheme, a compound of formula (IX) is reacted with ydroxylamine hydrochloride in an alcohol, preferably ethanol, at ordinary temperature, in the presence of an organic base such as triethylamine. A compound of formula (I) is obtained in which A is an OH group. When a compound of formula (I) is reacted where A represents a hydrogen atom with a chloroformate of

(C ^ Cg) alkyl in a solvent such as dichloromethane or tetrahydrofuran in the presence of an organic base such as 1, 1, 3, 3-tetramethylguanidine, diisopropylethylamine or triethylamine at a temperature between 0 and 30 ° C, we obtain a compound of formula

(I) where A represents a (C ^ Cg) alkoxycarbonyl group.

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

[[4- (aminomethyl) phenyl] iminomethyl] phenylmethyl carbamate is prepared according to a modification of patent EP 672658. The examples which follow illustrate the invention without limiting it. Microanalyses and NMR, mass and IR spectra confirm the structure of the compounds obtained. The numbers indicated in parenthesis in the titles of the examples correspond to those in the 1st column of the table given below.

Example 1: (compound N ° 8)

(AR) -N- [(1S) -1- [[[[4- (aminoiminomethyl) phenylmethyl] amino] carbonyl] pentyl] hydrochloride-pentyl] -α- [[(phenylmethyl) sulfonyl] amino] -lH-indole -3-propanamide.

1.1. (oι- R) -α- [[(phenylmethyl) sulfonyl] amino] -liï-indole-3-methyl propanoate.

To a mixture of 1.09 g (5.0 mmol) of the (R) -tryptophan methyl ester and 1.30 ml (11.80 mmol) of N-methylmorpholine in 20 ml of dichloromethane at 5 ° C, a solution of 1.15 g (6.03 mmol) of toluene sulfonyl chloride in 10 ml of dichloromethane is added dropwise. The reaction medium is then stirred at room temperature for 15 hours and then evaporated to dryness. The residue is taken up in 200 ml of ethyl acetate and the solution is washed successively with 1M aqueous citric acid (2 x 50 ml), saturated aqueous sodium bicarbonate (2 x 50 ml) then saturated aqueous sodium chloride. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure. 1.78 g of the product are obtained in the form of an oil. Efficiency: 96%

1.2. (Α-JR) -α- [[(phenylmethyl) sulfonyl] amino] -1H- indole-3-propanoic acid.

To 1.78 g (4.78 mmol) of (aR) -α- [[(phenylmethyl) sulfonyl] amino] -lH-indole-3-methyl propanoate dissolved in 14 ml of tetrahydrofuran, a solution of 0 is added. , 30 g (7.09 mmol) of lithium hydroxide monohydrate in 7 ml of water. The reaction mixture is stirred at room temperature for 3 hours, then the organic solvent is evaporated. The aqueous solution is acidified to pH 2 with IN hydrochloric acid and the product is extracted with ethyl acetate (2 x 75 ml). The organic phases are dried over sodium sulfate, filtered and then the solvent is evaporated off under reduced pressure.

1.68 g of an orange-yellow oil are obtained. Yield: 98%

1.3. (2S) -2- [[(2i?) - 3- (lif-Indol-3-yl) -l-oxo-2-

[[(phenylmethyl) sulfonyl] amino] propyl] amino] methyl hexanoate.

To a stirred mixture of 0.500 g (1.40 mmol) of (aR) - α- [[(phenylmethyl) sulfonyl] amino] -lH-indole-3-propanoic acid and 0.266 g (1.46 mmol) of hydrochloride of ethyl (S) -2-aminohexanoate in 20 ml of dichloromethane at 20 ° C., 0.207 g (1.53 mmol) of 1-hydroxybenzotriazole, 0.73 ml (4.2 mmol) of N, N are added -diisopropyl-N-ethylamine and 0.294 g (1.53 mmol of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide and stirring is continued at this temperature for 16 hours. The reaction medium is concentrated and the solvent is evaporated off under reduced pressure The residue is taken up in 200 ml of ethyl acetate The solution is washed successively with 1M aqueous citric acid (2 x 50 ml), with saturated aqueous sodium bicarbonate (2 x 50 ml) and then with saturated aqueous sodium chloride The organic phase is dried over sodium sulphate, filtered and the solvent is evaporated off under reduced pressure The crude product is purified by chromatoflash on silica gel, eluting with a methanol / dichloromethane mixture (2:98).

0.567 g of product is obtained in the form of a foam. Yield: 83%.

1.4. (2 S) -2- [[(2R) -3- (1H-indol-3-yl) -1-oxo-2- [[(phenylmethyl) sulfonyl] amino] propyl] amino] hexanoic acid. A mixture of 0.567 g (1.17 mmol) of (2 S) -2- [[(2R) -3- (lff- indol-3-yl) -l-oxo-2 is stirred at room temperature for two hours. - [[(phenylmethyl) sulfonyl] amino] propyl] amino] methyl hexanoate and 0.105 g (2.5 mmol) of lithium hydroxide monohydrate in 10 ml of a tetrahydrofuran / water solution (2: 1). The organic solvent is evaporated and the aqueous solution is acidified to pH2 with IN hydrochloric acid. The precipitate is drained and rinsed with water and then dried under vacuum. 0.460 g of a white powder is obtained. Yield: 84%. Melting point: 193 ° C

1.5. [[4- [[[(2S) -2- [[(2i?) - 3- (1H-Indol-3-yl) -l-oxo-2- [[(phenylmethyl) sulfonyl] amino] propyl] amino ] -1- oxohexyl] amino] methyl] phenyl] iminomethyl] phenylmethyl carbamate.

To a mixture of 0.450 g (0.95 mol) of (2S) -2- [[(2R) - 3- (li-Indol-3-yl) -l-oxo-2- [[(phenylmethyl) acid sulfonyl] amino] propyl] amino] hexanoic acid and 0.356 g (1.0 mmol) of phenylmethyl [[4- (aminomethyl) phenyl] iminomethyl] dihydrochloride in 15 ml of dimethylformamide at room temperature, 0.150 g ( 1.11 mmol) of 1-hydroxybenzotriazole, 0.53 ml (3.04 mmol) of

N, Λ7-diisopropyl-Λ7-ethylamine then 0.21 g (1.09 mmol) of N '- (3-dimethylaminopropyl) -ΛJ-ethylcarbodiimide. Stirring is continued at this temperature overnight then the reaction medium is concentrated. The residue is taken up in 150 ml of dichloromethane and the solution is washed successively with 1M aqueous citric acid (2 × 25 ml), with sodium bicarbonate in saturated aqueous solution, then with sodium chloride in saturated aqueous solution. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure.

0.500 g of an off-white solid is obtained. Melting point: 212-214 ° C Yield: 71% 1.6. (AR) -N- [(1S) -1- [[[[4-

(aminoiminomethyl) phenyl] methyl] amino] carbonyl] pentyl] -α- [[(phenylmethyl) sulfonyl] amino] -lH-indole- 3-propanamide.

Hydrogenate at 40 psi for 3 hours 0.50 g (0.68 mmol) of [[4- [[[(2 S) -2- [[(2R) -3- (liî-Indol-3-yl) -l-oxo-2- [[(phenylmethyl) sulfonyl] amino] propyl] amino] -1-oxohexyl] amino] methyl] phenyl] iminomethyl] phenylmethyl carbamate in 80 ml of methanol in the presence of 0.38 g of palladium on 10% charcoal. The reaction medium is then filtered on sandpaper and the filtrate is concentrated under reduced pressure. The crude product is purified by reverse phase HPLC C-18, eluting with a gradient of acetonitrile from 20 to 80% in 150 minutes, in aqueous hydrochloric acid N / 1000. After lyophilization of the fractions containing the product, 0.150 g of the expected compound is obtained. Melting point: 125 ° C [] _D = + 10 ° (c = 0.2; methanol) HPLC: retention time: 16.3 min C18 (20% to 50% acetonitrile in 20 minutes in water at 0.1% trifluoroacetic acid) Yield: 35%

Example 2: (compound N ° 2)

(2R) -N- [(1 S) -1- [[[[4- (aminoiminomethyl) phenyl] methyl] amino] carbonyl] -3- (methylthio) propyl] hydrochloride -

3, 3-dimethyl-2- [[(phenylmethyl) sulfonyl] amino] butanamide

2.1. (2R) -3,3-dimethyl-2- [[(phenylmethyl) sulfonyl] amino] butylate of 1,1-dimethylethyl.

To a solution cooled to 0 ° C of 2.00 g (10.07 mmol) of (R) -2-amino-3, tert-butyl 3-dimethylbutyrate and 3.0 ml (27.29 mmol) of ÎV -methylmorpholine in 40 ml of dichloromethane, a solution of 2.60 g (13.64 mmol) of -toluene sulfonyl chloride in 10 ml of dichloromethane is added dropwise. Stirred at room temperature for 17 hours then dilute the medium reaction in 200 ml of dichloromethane. The solution is washed successively with a 1M aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution, then a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure. The crude product is purified by chromatoflash on silica gel, eluting with a methanol / dichlorometane mixture (2:98). 2.04 g of a thick colorless oil are obtained. Yield: 56%

2.2. (2R) -3,3-dimethyl-2- [[(phenylmethyl) sulfonyl] amino] butanoic acid.

15.0 ml of trifluoroacetic acid is added dropwise to a cooled 0 ° C solution of 2.04 g (5.99 mmol) of (2R) -3,3-dimethyl-2- [[(phenylmethyl) 1, 1-dimethylethyl sulfonyl] amino] butanoate in 40 ml of dichloromethane. The reaction medium is stirred at room temperature for 6 hours and then concentrated under reduced pressure. The residue obtained is taken up in 250 ml of diethyl ether and the solution is washed with a saturated aqueous solution of sodium bicarbonate (3 x 75 ml). The aqueous phases are acidified to pH 1-2 with 6N hydrochloric acid and extracted several times with ether. The organic phases are dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure. 1.45 g of product are obtained in the form of a colorless oil. Efficiency: 85%

2.3. (2S) -2- [[(2Λ) -3,3-dimethyl-1-oxo-2- [[(phenylmethyl) sulfonyl] amino] butyl] amino] -4- (methylthio) butanoate.

To a mixture of 1.10 g (3.85 mmol) of (2J?) - 3,3-dimethyl-2- [[(phenylmethyl) sulfonyl] amino] butanoic acid and 0.81 g (4.06 mmoles) of hydrochloride of () -methionine methyl ester, methyl ester in 20 ml of dichloromethane cooled to 5 ° C., 0.57 g (4.22) is added mmol) of 1-hydroxybenzotriazole, 2.00 ml (11.48 mmol) of N, N-diisopropyl-N-ethylamine, then 0.82 g (4.43 mmol of N '- (3-dimethylaminopropyl) -N- ethylcarbodiimide then stirred at room temperature for 16 hours, the reaction mixture is concentrated under reduced pressure and the residue is taken up in 200 ml of ethyl acetate. The solution is washed successively with a 1M aqueous solution of citric acid (3 x 50 ml), a saturated aqueous solution of sodium bicarbonate (3 x 50 ml) and finally a saturated aqueous solution of sodium chloride (50 ml). The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated under pressure. The crude product is purified by chromatoflash on silica gel, eluting with a methanol / dichloromethane mixture (2:98) to give 1.36 g of product in the form of white foam.

2.4. (2 S) -2- [[(2R) -3,3-dimethyl-l-oxo- acid

2 [[(phenylmethyl) sulfonyl] amino] butyl] amino] -4- (methylthio) butanoic.

A solution of 1.34 g (3.09 mmol) of (2 S) -2 - [[(2R) -3, 3-dimethyl-l-oxo-2- [[(phenylmethyl)) is cooled to 0 ° C. sulfonyl] amino] butyl] amino] -4- (methylthio) butanoate in 16 ml of a tetrahydrofuran / water mixture (3: 1). 0.50 g (11.92 mmol) of lithium hydroxide monohydrate is added and the reaction medium is then stirred at room temperature for 4 hours. The tetrahydrofuran is evaporated under reduced pressure and the aqueous solution is acidified to pH 1 with 1Ν aqueous hydrochloric acid. Extraction is carried out twice with ethyl acetate and the organic phases are combined, then washed with a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure.

1.40 g of a white solid are obtained. Melting point: 100-102 ° C Yield: 100% 2. 5. [[4 - [[[(2 S) -2 - [[(2β) -3, 3-dimethyl- l-oxo-2 -

[[(phenylmethyl) sulfonyl] amino] butyl] amino] -4- (methylthio) -1-oxobutyl] amino] methyl] phenyl] iminomethyl] phenylmethyl carbamate.

To a mixture of 0.80 g (1.70 mmol) of (2S) -2- [[(2R) -3,3-dimethyl-1-oxo-2- [[(phenylmethyl) sulfonyl]] acid is added amino] butyl] amino] -4- (methylthio) butanoic and 0.636 g (1.79 mmol) of [[4- (aminomethyl) phenyl] iminomethyl] phenylmethyl carbamate hydrochloride in 10 ml of dichloromethane and 2 ml of dimethylformamide, cooled to 5 ° C, 0.253 g (1.87 mmol) of 1-hydroxybenzotriazole, 1.20 ml (6.89 mmol) of N, N-diisopropyl-N-ethylamine then 0.36 g (1.88 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide. The temperature is allowed to rise to room temperature and the mixture is stirred at this temperature for 15 hours. The reaction medium is concentrated under reduced pressure and then the residue is taken up in 150 ml of ethyl acetate. The solution is then washed successively with an aqueous solution of citric acid 1 (3 x 50 ml), a saturated aqueous solution of sodium bicarbonate (3 x 50 ml), then a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure. The crude product is purified by chromatoflash on silica gel, eluting with a methanol / dichloromethane mixture (3:97). 0.567 g of product is obtained. Yield: 46%

2.6. (2R) -N- [(1S) -1- [[[[4-

(aminoiminomethyl) phenyl] methyl] amino] carbonyl] -3- (methylthio) propyl] -3, 3-dimethyl-2- [[(phenylmethyl) sulfonyl] amino] butanamide.

1.0 g (1.46) mmol of [[4- [[[(2 S) -2- [[(2R) -3, 3-dimethyl-1-oxo-2- [[(phenylmethyl) sulfonyl]] amino] butyl] amino] -4- (methylthio) -1-oxobutyl] amino] methyl] phenyl] iminomethyl] phenylmethyl carbamate in 40 ml of methanol is hydrogenated for 6 hours at a pressure of 50 psi in the presence of 0.50 g of 10% palladium on carbon and 3 ml of IN hydrochloric acid. The catalyst is then filtered on sandpaper and the filtrate is evaporated under reduced pressure. The crude product is purified by reverse phase HPLC C-18, eluting with a gradient of acetonitrile from 0 to 100% in 180 minutes, in aqueous hydrochloric acid N / 1000. After lyophilization of the fractions containing the product, 0.505 g of white lyophilisate is obtained. Melting point: 150 ° C (decomposition) [αJ _D = + 10.0 ° (c = 0.3; methanol)

HPLC: retention time: 18.4 min C18 (2% to 98% acetonitrile in 35 minutes in water at 0.02% trifluoroacetic acid) Yield: 58%

Example 3: (compound N ° 23)

(AR) -N- [(1S) -1- [[[[4- (aminoiminomethyl) phenyl] methyl] amino] carbonyl] pentyl] hydrochloride-pentyl] -α- [[(phenylmethyl) sulfonyl] amino] thiazole-4 -propanamide.

3.1. (2S) -2- [[(2R) -2- [[(1, 1-dimethylethoxy) carbonyl] amino] -1-oxo-3-thiazol-4-ylpropyl] amino] methyl hexanoate.

To a stirred mixture and cooled to 0 ° C. of 2.50 g (9.18 mmol) of the methyl ester of N-tert-butyloxycarbonyl- (D) -4-thiazol-β-yl-alanine and of 1, 75 g (9.64 mmol) of (L) -norleucine hydrochloride in 30 ml of dichloromethane, 1.37 g (10.10 mmol) of 1-hydroxybenzotriazole are added, 2.00 g (10.10 mmol) of Λ7 '- (3-dimethylaminopropyl) -N-ethylcarbodiimide, then 5.70 ml (33.01 mmol) of N, N-diisopropyl-N-ethylamine, drop by drop. The temperature is allowed to rise to ambient temperature and the mixture is stirred at this temperature for 16 hours. The reaction medium is diluted in 100 ml of dichloromethane and the solution is washed successively with a 1M citric acid solution, a saturated aqueous solution of sodium bicarbonate, then a saturated aqueous solution. in sodium chloride. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure.

3.54 g of a thick colorless syrup are obtained. Yield: 100%

3.2. (2 S) -2- [[(2R) -2-amino-1-oxo-3-thiazol-4-ylpropyl] amino] methyl hexanoate hydrochloride.

A stream of hydrochloric acid gas is bubbled for 5 minutes in a solution cooled to 0 ° C of 3.50 g (9.08 mmol) of (2 S) -2- [[(2R) -2- [[ (1, 1-dimethylethoxy) carbonyl] amino] -1-oxo-3-thiazol-4-ylpropyl] amino] methyl hexanoate in 100 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 8 hours, concentrated under reduced pressure. The solid obtained is triturated in diethyl ether, then drained and dried under vacuum. 2.64 g of a white powder are obtained. Melting point: 158 ° C (decomposition) Yield: 87%

3.3. (2S) -2- [[(2) -1-Oxo-2- [[(phenylmethyl) sulfonyl] amino] -3-thiazol-4-ylpropyl] amino] methyl hexanoate.

To a suspension cooled to 5 ° C of 1.50 g (4.47 mmol) of (2 S) -2- [[(2R) -2-amino-1-oxo-3-thiazol-4-ylpropyl hydrochloride ] amino] methyl hexanoate and 0.894 g (4.69 mmol) of α-toluene sulfonyl chloride in 10 ml of dichloromethane, a solution of 1.18 g (11.64 mmol) of N- is added dropwise methylmorphonin in 5 ml of dichloromethane. The reaction medium is stirred at room temperature for 15 hours and then diluted in 100 ml of dichloromethane. The solution is washed with water and then with a saturated aqueous sodium bicarbonate solution, then again with water. The organic phase is dried over sodium sulfate, filtered and then the solvent is evaporated off under reduced pressure. 1.24 g of a thick colorless oil are obtained. Yield: 63%.

3.4. (2 S) -2- [[(2R) -1-oxo-2- [[(phenylmethyl) sulfonyl] amino] -3-thiazol-4-ylpropyl] amino] hexanoic acid.

A 1.22 g (2.70 mmol of (25) -2- [[(2R) -1-oxo-2- [[(phenylmethyl) sulfonyl] amino] -3-thiazol-4-ylpropyl] amino] hexanoate of methyl in solution in 10 ml of tetrahydrofuran at ordinary temperature, a solution of 0.29 g (6.91 mmol) of lithium hydroxide monohydrate in 2 ml of water is added. The solution is stirred at this temperature for 4 hours then the solvent is evaporated off under reduced pressure, the aqueous solution is diluted in 3 ml of water, then acidified to pH 2 with 6N hydrochloric acid, the product is extracted with ethyl acetate and the organic phases are dried over sodium sulphate, filtered and then the solvent is evaporated in vacuo to give 1.11 g of an amorphous solid, yield: 94%.

3.5. [[4- [[[(2S) -2- [[(2.R) -l-oxo-2-

[[(phenylmethyl) sulfonyl] amino] -3-thiazol-4-ylpropyl] amino] -1-oxohexyl] amino] methyl] phenyl] iminomethyl] phenylmethyl carbamate.

0.55 g (1.54 mmol) (2S) -2- [[(2R) -1-oxo-2- [[(phenylmethyl) sulfonyl] amino] acid] stirred suspension cooled to 5 ° C -3-thiazol-4-ylpropyl] amino] hexanoic acid and 0.550 g (1.54 mmol) of [[4- (aminomethyl) phenyl] iminomethyl] dihydrochloride phenylmethyl carbamate in 10 ml of dichloromethane, 0.199 g is added ( 1.47 mmol) of 1-hydroxytriazole and 0.292 g (1.48 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide. A solution of 0.61 g (4.69 mmol) of N, W-diisopropyl-N-ethylamine in 10 ml of dichloromethane is then added dropwise. The reaction medium is stirred at room temperature for 15 hours and then the solvent under reduced pressure. The residue is taken up in 150 ml of ethyl acetate and the solution is washed successively with a 1M aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, then a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure.

0.51 g of an amorphous solid is obtained which is used as it is in the next step. Yield: 54%

3.6. (A-R) -N- [(1S) -1- [[[[4-

(aminoiminomethyl) phenyl] methyl] amino] carbonyl] pentyl] -α- [[(phenylmethyl) sulfonyl] amino] thiazole-4-propanamide.

Hydrogenate for 4 hours at a pressure of 40 psi 0.50 g (0.709 mmol) of [[4- [[[(2S) -2- [[(2R) -1-oxo-2- [[(phenylmethyl) sulfonyl] amino] -3-thiazol-4-ylpropyl] amino] -1-oxohexyl] amino] methyl] phenyl] iminomethyl] phenylmethyl carbamate in 30 ml of methanol in the presence of 0.10 g of "black" palladium and 10 ml of 0.1N hydrochloric acid in isopropanol. The catalyst is drained on sandpaper and the filtrate is concentrated under reduced pressure. The crude product is purified by reverse phase MPLC C18, eluting with a mixture of methanol / aqueous hydrochloric acid N / 1000 (3: 7). 0.38 g of a white solid is obtained. Melting point: 164 ° C [] _D : + 14 ° (c = 0.45, methanol)

HPLC: retention time: 15.1 min C18 (2% to 98% acetonitrile in 35 minutes in water at 0.02% trifluoroacetic acid)

Yield: 43%

Example 4: (compound No. 1)

(AR) -N- [(1S) -1- [[[[4- (aminoiminomethyl) phenyl] methyl] amino] carbonyl] -3- (methylthio) propyl] hydrochloride -α- [(butylsuifonyl) amino] -2, 3-dihydro-1H-indene-1-acetamide. 4.1. (25) -2- [[(2 -) - 2- (2,3-Dihydro-1H-inden-1-yl) -2- [[(1,1- dimethylethoxy) carbonyl] amino] acetyl] amino] -4- methyl (methylthio) butanoate.

To a mixture cooled to 5 ° C of 1.0 g (3.43 mmol) of

N-tert-butyloxycarbonyl- (2-indanyl) - (D) -glycine and 0.72 g (3.61 mmol) of methyl ester of () -methionine in 10 ml of dichloromethane, 0.51 g is added (3.78 mmol) of 1-hydroxybenzotriazole, 1.8 ml (10.33 mmol) of N, N-diisopropyl-N-ethylamine, then 0.724 g (3.78 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide. The reaction medium is stirred at room temperature for 13 hours and then diluted in 200 ml of ethyl acetate. The solution is washed successively with a 1M aqueous citric acid solution (3 x 50 ml), a saturated aqueous sodium bicarbonate solution (3 x 50 ml), then a saturated aqueous sodium chloride solution (50 ml) . The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure. 1.36 g of a white solid are obtained. Melting point: 120 ° C Yield: 90%

4.2. (2S) -2- [[(2R) -2-amino-2- (2,3-dihydro-1H-inden-1-yl) acetyl] amino] -4- (methylthio) butanoate hydrochloride.

A stream of gaseous hydrochloric acid is bubbled for 5 minutes in a solution cooled to 5 ° C. of 1.36 g (3.11 mmol) of (2 S) -2- [[(2R) -2- (2 , 3-dihydro-1H-inden-1-yl) -2- [[((1, 1-dimethylethoxy) carbonyl] amino] acetyl] amino] -4- (methylthio) butanoate dissolved in 100 ml of dichloromethane. The reaction medium is stirred at room temperature for 5 hours and then the solvent is evaporated off under reduced pressure.

1.16 g of product are obtained in the form of a thick syrup. Yield: 100%.

4.3. (25) -2- [[(2R) -2- {(butylsulfonyl) amino] -2- (2, 3- methyl dihydro-1H-inden-1-yl) acetyl] amino] -4- (methylthio) butanoate.

0.85 g (5.43 mmol) of n-butyl sulfonyl chloride dissolved in 3 ml of dichloromethane is added dropwise to a solution cooled to 0 ° C. of 1.16 g (3.11 mmol) of hydrochloride (25) -2- [[(2R) -2-amino-2- (2,3-dihydro-1H-inden-1-yl) acetyl] amino] -4- (methylthio) butanoate in 6 ml dichloromethane, followed by a solution of 1.10 g (10.89 mmol) of

N-methylmorpholine in 6 ml of dichloromethane. The reaction medium is stirred at room temperature for 18 hours and then diluted in 150 ml of dichloromethane. The solution is washed successively with an aqueous solution of citric acid IM, a saturated aqueous solution of sodium bicarbonate, then a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure. The crude product is purified by chromatoflash on silica gel, eluting with a methanol / dichloromethane mixture (2:98).

1.02 g of product are obtained in the form of a white solid. Melting point: 140 ° C Yield: 72%

4.4. (2 S) acid -2- [[(2J) -2- [(butylsulfonyl) amino] -2- (2, 3- dihydro-1E-inden-1-yl) acetyl] amino] -4- (methylthio) butanoic.

To a stirred solution at 20 ° C of 1.02 g (2.23 mmol of

(2S) -2- [[(2R) -2- [(butylsulfonyl) amino] -2- (2,3-dihydro-1H- inden-1-yl) acetyl] amino] -4- (methylthio) butanoate methyl in 9 ml of tetrahydrofuran and 3 ml of water, 0.34 g (8.10 mmol) of lithium hydroxide monohydrate is added and stirring is continued for 4 hours. The tetrahydrofuran is evaporated under reduced pressure and the aqueous solution is diluted in 10 ml of water. Acidified to pH 1-2 by addition of IN hydrochloric acid and extracted several times with ethyl acetate. We dry the phases organic on sodium sulphate, filters them and evaporates the solvent under reduced pressure.

0.98 g of product is obtained in the form of a colorless oil. Yield: 100%.

4.5. [[4- [[[(25) -2- [[(2J?) - 2- [(Butylsulfonyl) amino] -2- (2,3-dihydro-1H-inden-1-yl) acetyl] amino] -4- (methylthio) -1- oxobutyl] amino] methyl] phenyl] iminomethyl] phenylmethyl carbamate.

To a suspension cooled to 0 ° C. of 0.98 g (2.21 mmol) of (25) -2- [[(2R) -2- [(butylsulfonyl) amino] acid] -2- (2,3- phenylmethyl dihydrochloride, phenylmethyl carbamate dihydro-1H-inden-1-yl) acetyl] amino] -4- (methylthio) butanoic, 0.83 g (2.34 mmol) 0.300 g (2.44 mmol) of

1-hydroxybenzotriazole and 0.47 g (2.44 mmol) of N '- (3-dimethylaminopropyl) -AJ-ethylcarbodiimide in 13 ml of dichloromethane and 4 ml of dimethylformamide, 1.50 ml are added dropwise (8, 61 mmol) of N, N-diisopropyl-N-ethylamine. The reaction medium is stirred for 15 hours and then concentrated under reduced pressure. The residue is taken up in 200 ml of ethyl acetate and the solution is washed successively with an aqueous solution of 1M citric acid, a saturated aqueous solution of sodium bicarbonate and finally a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure.

The crude product is purified by chromatoflash on silica gel, eluting with a methanol / dichloromethane mixture (2:98). 1.20 g of a white solid are obtained. Melting point: 163 ° C Yield: 77%

4.6. (A-R) -N- [(15) -1- [[[[4-

(aminoiminomethyl) phenyl] methyl] amino] carbonyl] -3- (methylthio) propyl] -α- [(butylsulfonyl) amino] -2, 3-dihydro-1H-indene-1-acetamide.

In a Parr apparatus, 50 psi of hydrogen is subjected for 12 hours to 1.20 g (1.70 mmol) of [[4- [[[(25) -2- [[(21? ) -2- [(butylsulfonyl) amino] -2- (2,3- dihydro-1H-inden-1-yl) acetyl] amino] -4- (methylthio) -1- oxobutyl] amino] methyl] phenyl] iminomethyl ] phenylmethyl carbamate in 70 ml of methanol in the presence of 0.50 g of 10% palladium on carbon and 3.4 ml of IN hydrochloric acid. The catalyst is filtered and the filtrate is concentrated under reduced pressure. The crude product is purified by reverse phase C18 HPLC, eluting with an acetonitrile gradient from 0 to 100% in 180 minutes in an aqueous solution of hydrochloric acid N / 1000. 0.257 g of a white solid is obtained. Melting point: 150 - 155 ° C [α] _D : - 5.4 ° (c = 0.13; methanol) HPLC: retention time = 20.0 min C18 (2 to 98% acetonitrile in 35 min in water at 0.02% trifluoroacetic acid) Yield: 20%

Example 5: (Compound No. 27) (-R) -N- [(1R) -2 - [[[4- (aminoimino methyl) phenyl] methyl] amino] -1 hydrochloride] -1- [(ethylthio) methyl] -2- oxoethyl] -α- [[(phenylmethyl) sulfonyl] amino] benzenebutanamide.

5.1. [[4- [[[(2R) -2- [[(1,1-dimethylethoxy) carbonyl] amino] - 2- [(ethylthio) methyl] acetyl] amino] methyl] phenyl] iminomethyl] phenylmethyl carbamate.

To a stirred mixture at 0 ° C of 1.0 g (4.01 mmol) of (L) -N-tert-butyloxycarbonyl S-ethylcysteine and 1.50 g (4.21 mmol) of [[4] dihydrochloride - (aminomethyl) phenyl] iminomethyl] phenylmethyl carbamate in 12 ml of a dichloromethane / dimethylfornamide mixture (2: 1), 0.60 g is added (4.44 mmol) of 1-hydroxybenzotriazole, 2.80 ml (16.07 mmol) of N, N-diisopropyl-N-ethylamine, then 0.85 g (4.43 mmol) of N ^r - (3- dimethylaminopropyl) -N- ethylcarbodiimide. The reaction medium is stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue is taken up in 200 ml of diethyl ether and the solution is washed successively with an aqueous solution of citric acid at IM (3 x 50 ml), water (50 ml), a saturated aqueous solution of sodium bicarbonate , and finally a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure.

1.43 g of product are obtained in the form of a white powder.

Melting point: 100-101 ° C Yield: 69%

5.2. Phenylmethyl carbamate [[4- [[[(21?) -2-amino-3- (ethylthio) -1- oxopropyl] amino] methyl] phenyl] iminomethyl] hydrochloride.

A stream of gaseous hydrochloric acid is bubbled for 5 minutes in a solution cooled to 0 ° C of 1.43 g (2.77 mmol) of [[4- [[[(2R) -2- [[(1 , 1- dimethylethoxy) carbonyl] amino] -2- [(ethylthio) methyl] acetyl] amino] methyl] phenyl] iminomethyl] phenylmethyl carbamate in 100 ml of dichloromethane. The reaction medium is stirred at 20 ° C for 4 hours and then concentrated under reduced pressure.

1.01 g of a white powder are obtained. Melting point: 149 ° C Yield: 80%

5.3. (a-R) -a- [[(Phenylmethyl) sulfonyl] amino] methyl benzene butanoate.

To a suspension cooled to 0 ° C of 3.0 g (13.06 mmol) of methyl ester hydrochloride (D) -homophenylalanine in 50 ml of dichloromethane, a solution of 3.74 g (19.62 mmol) of α-toluene sulfonyl chloride in 30 ml of dichloromethane is added dropwise, followed by dropwise addition 4.23 g (41.79 mmol) drop of N-methylmorpholine. The reaction medium is stirred at 20 ° C. for 17 hours and then washed with a solution of IN hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, then a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure. The crude product is purified by chromatoflash on silica gel, eluting with a methanol / dichloromethane mixture (3:97). 2.73 g of product are obtained in the form of an off-white meringue.

Yield: 60%

5.4. (A-R) -a- [[(phenylmethyl) sulfonyl] amino] benzene butanoic acid.

To a stirred solution at room temperature of 0.732 g (2.10 mmol) of (aR) -a- [[(phenylmethyl) sulfonyl] amino] methyl benzene butanoate in 8 ml of tetrahydrofuran and 3 ml of water, the following is added 0.31 g (7.40 mmol) of lithium hydroxide monohydrate which is stirred at this temperature for 4 hours. The tetrahydrofuran is evaporated under reduced pressure and the aqueous solution is diluted in 15 ml of water. The solution is acidified to pH 1 by addition of IN hydrochloric acid. Extraction is carried out several times with ethyl acetate and the combined organic phases are washed with a saturated aqueous solution of sodium chloride, which is then dried over sodium sulfate. It is filtered and then the solvent is evaporated off under reduced pressure. 0.671 g of product is obtained in the form of a white solid. Melting point: 130 ° C Yield: 95%.

5.5. [[4- [[[(25) -3- (Ethylthio) -2- [[(21?) -L-oxo-4-phenyl-2- [[(phenylmethyl) sulfonyl] amino] butyl] amino] - 1- oxopropyl] amino] methyl] phenyl] iminomethyl] phenylmethyl carbamate.

To a mixture cooled to 5 ° C. of 0.658 g (1.97 mmol) of (aR) -a- [[(phenylmethyl) sulfonyl] amino] benzene butanoic acid and of 0.934 g (2.07 mmol) of dihydrochloride [[4- [[t (21?) -2-amino-3- (ethylthio) -1-oxopropyl] amino] methyl] phenyl] iminomethyl] phenylmethyl carbamate in 10 ml of dichloromethane, 0.293 g (2, 17 mmol) of 1-hydroxybenzotriazole, 0.764 g (5.91 mmol) of

N, JV-diisopropyl-N-ethylamine, then 0.416 g (2.17 mmol) of N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide. The reaction medium is stirred at 20 ° C for 16 hours and then diluted in 200 ml of ethyl acetate. The solution is washed successively with an aqueous solution of IM citric acid (3 x 100 ml), water (100 ml), a saturated aqueous solution of sodium bicarbonate (3 x 100 ml) and then a saturated aqueous solution in sodium chloride. The organic phase is dried, dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure. The crude product is purified by chromatoflash on silica gel, eluting with a methanol / dichloromethane mixture (3:97). 0.82 g of product is obtained in the form of a white meringue. Yield: 60%

5.6. (Α-1?) -N- [(11?) -2- [[[4-

(aminoiminomethyl) phenyl] methyl] amino] -1- [(ethylthio) methyl] -2-oxoethyl] - - [[(phenylmethyl) sulfonyl] amino] benzenebutanamide.

A solution of 0.818 g (1.17 mmol) of [[4- [[[((2S) -3- (ethylthio) -2- [[(21?) -L-oxo-4-phenyl-2- [[ (phenylmethyl) sulfonyl] amino] butyl] amino] -1-oxopropyl] amino] methyl] phenyl] iminomethyl] phenylmethyl carbamate in 40 ml of methanol is hydrogenated in a Parr apparatus at a pressure of 50 psi for 4 hours, in presence of 0.30 g of 10% palladium on charcoal and 1.2 ml of IN hydrochloric acid. The catalyst is filtered and the filtrate under reduced pressure. The product is purified by HPLC on reverse phase C-18, eluting with a gradient from 0 to 100% acetonitrile in 180 minutes in N / 1000 hydrochloric acid. 0.250 g of product is obtained in the form of a white solid. Melting point: 125 ° C [α] _D : - 5.77 ° (c = 0.225; methanol) HPLC: retention time = 20.7 min C18 (2 to 98% acetonitrile in 35 min in water at 0.02% trifluoroacetic acid) Yield: 35%

Example 6: (compound N ° 5)

(-1?) -N- [(1S) -1- [[[[4- (aminoiminomethyl) phenyl] methyl] amino] carbonyl] pentyl] hydrochloride-pentyl] -α- [[(phenylmethyl) sulfonyl] amino] aphthalene -3-propanamide.

6.1. (25) -2- [[(21?) -2- [[(1, 1-Dimethylethoxy) carbonyl] amino] -3-naphthalen-2-yl-1-oxopropyl] amino] methyl hexanoate.

To a mixture cooled to 0 ° C of 2.0 g (6.34 mmol) of (D) -Al-tert-butyloxycarbonyl-3- (2-naphthyl) alanine, 1.20 g (6.60 mmol) of (L) -norleucine methyl ester hydrochloride, 0.943 g (6.98 mmol) of

1-hydroxybenzotriazole and 3.30 ml (18.94 mmol) of Al, N-diisopropyl-Λl-ethylamine, 1.34 g (6.99 mmol) of N '- (3-dimethylaminopropyl) -ΛJ-ethylcarbodiimide are added then stirred at room temperature for 12 hours. The reaction medium is diluted in 300 ml of diethyl ether and the solution is washed successively with an aqueous solution of IM citric acid (3 x 100 ml), water (100 ml), a saturated aqueous solution of sodium bicarbonate (3 x 100 ml), and finally a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and then the solvent is evaporated off under reduced pressure. The crude product is purified by chromatoflash on silica gel, eluting with a methanol / dichloromethane mixture (2:98). 2.74 g of product are obtained in the form of a meringue. Yield: 98%

6.2. Methyl (25) -2- [[((21?) -2-amino-3-naphthalen-2-yl-1-oxopropyl] amino] hydrochloride hexanoate.

A stream of gaseous hydrochloric acid is bubbled for 5 minutes in a solution cooled to 0 ° C. of 2.80 g (6.42 mmol) of (2S) -2- [[(21?) -2- [[ (1, 1-dimethylethoxy) carbonyl] amino] -3-naphthalen-2-yl-1-oxopropyl] amino] methyl hexanoate in 200 ml of dichloromethane then stirring is continued at 20 ° C for 4 hours. The reaction medium is concentrated under reduced pressure. 2.40 g of an amorphous solid are obtained. Yield: 100%

6.3. (25) -2- [[(21?) - 3-naphthalen-2-yl-l-oxo-2-

[[(phenylmethyl) sulfonyl] amino] propyl] amino] methyl hexanoate.

To a mixture of 2.40 g (6.33 mmol) of hydrochloride of (25) -2- [[21?) -2-amino-3-naphthalen-2-yl-1-oxopropyl] amino] hexanoate methyl and 3.53 ml (25.34 mmol) of triethylamine in 100 ml of dichloromethane cooled to 0 ° C., 2.20 g (11.54 mmol) of α-toluene sulfonyl chloride are added and then the mixture is stirred at room temperature for 19 hours. The solution is washed with a hydrochloric acid solution IN, then a saturated aqueous solution of sodium bicarbonate, and finally a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure. The crude product is purified by chromatoflash on silica gel, eluting with a methanol / dichloromethane mixture (1:99).

1.60 g of product are obtained in the form of a meringue. Yield: 51%

6.4. Acid (25) -2- [[(21?) -3-naphthalen-2-yl-l-oxo-2- t [(phenylmethyl) sulfonyl] amino] propyl] amino] hexanoic.

To a stirred solution at room temperature of 1.60 g (3.22 mmol) of (2 S) -2- [[((21?) -3-naphthalen-2-yl-1-oxo-2- [[( phenylmethyl) sulfonyl] amino] propyl] amino] methyl hexanoate in 12 ml of tetrahydrofuran and 4 ml of water, 0.48 g (11.44 mmol) of lithium hydroxide monohydrate is added. The reaction medium is stirred at 20 ° C for 4 hours, then the tetrahydrofuran is evaporated under reduced pressure. The aqueous solution is diluted in 10 ml of water and then acidified to pH 2 by addition of 3N hydrochloric acid. Extraction is carried out several times with ethyl acetate and then the organic phases are dried over sodium sulfate, filtered and the solvent is evaporated off under reduced pressure.

1.50 g of a white solid are obtained. Melting point: 129 ° C Yield: 97%.

6.5. [[4- [[[(25) -2- [[(21?) -3-naphthalen-2-yl-l-oxo-2- [[(phenylmethyl) sulfonyl] amino] propyl] amino] -1- oxohexyl] amino] methyl] phenyl] iminomethyl] phenylmethyl carbamate.

0.26 g (1.36 mmol) of

N '- (3-dimethylaminopropyl) -Λl-ethylcarbodiimide to a mixture of 0.60 g (1.24 mmol) (2S) -2- [[(21?) -3-naphthalen- 2-yl-) acid l-oxo-2- [[(phenylmethyl) sulfonyl] amino] propyl] amino] hexanoic, 0.42 g (1.31 mmol) phenylmethyl [[4-aminomethyl) phenyl] iminomethyl dihydrochloride, 0.185 g (1.37 mmol) of 1-hydroxybenzotriazole and 0.65 ml (3.73 mmol) of N, N-diisopropyl-M-ethylamine in 6 ml of a dichloromethane / dimethylformamide mixture (1: 1) cooled on a bath ice cream. The reaction medium is concentrated under reduced pressure and the crude product is purified by chromatoflash on silica gel, eluting with a methanol / dichloromethane mixture (3:97). 0.79 g of product is obtained in the form of a foam. white. Efficiency: 85%

6.6. (Α-1?) -N- [(1S) -1- [[[[4- (aminoimino methyl) phenyl] methyl] amino] carbonyl] pentyl] hydrochloride -α- [[(phenylmethyl) sulfonyl] amino ] naphthalene-3-propanamide.

Hydrogenated for 5 hours at room temperature at a pressure of 40 psi 0.790 g (1.06 mmol) of [[4- [[[(2S) -2- [[(21?) -3-naphthalen-2-yl -l-oxo-2- [[(phenylmethyl) sulfonyl] amino] propyl] amino] -1-oxohexyl] amino] methyl] phenyl] iminomethyl] phenylmethyl carbamate in 30 ml of methanol in the presence of 0.20 g of palladium on 10% charcoal and 1 ml of IN hydrochloric acid. The catalyst is filtered and the filtrate is evaporated to dryness. The crude product is purified by HPLC on reverse phase C-18, eluting with a gradient of 0 to 100% acetonitrile in 180 minutes in N / 1000 aqueous hydrochloric acid. 0.505 g of a white solid is obtained. Melting point: 135-140 ° C [] _D : + 5.0 ° (c = 0.2; methanol) HPLC: retention time = 8.7 min C18 (40% acetonitrile in water at 0.1% trifluoroacetic acid) Yield: 74%

Example 7: (compound n ° 51)

(2S) -N- [[4- [Amino (hydroxyimino) methyl] phenyl] methyl] -2- [[(21?) -4-methyl-1-oxo-2- [[(phenylmethyl) sulfonyl] amino] pentyl] amino] hexanamide

To a solution of 0.56 g (8.06 mmol) of hydroxylammonium chloride and 3.00 ml (21.52 mmol) of triethylamine in 30 ml of absolute ethanol at room temperature, 0.900 g (1, 36 mmol) of [imino [4- [[[(2S) -2- [[(21?) -4-methyl-l-oxo-2- [[(phenylmethyl) sulfonyl] amino]] pentyl] amino hydrochloride ] -1-oxohexyl] amino] methyl] phenylmethyl] phenylmethyl carbamate, then the mixture is stirred at room temperature for 96 hours. The reaction medium is evaporated to dryness and the crude product is purified by chromatoflash on silica gel, eluting with a methanol / dichloromethane mixture (2:98).

0.340 g of a white solid is obtained. Melting point: 198 ° C [α] _D : + 15.8 ° (c = 0.12; methanol) Yield: 52%

Example 8 [compound No. 52)

[Imino [4- [[[(2S) -2- [[(21?) -4-methyl-l-oxo-2- [[(phenylmethyl) sulfonyl] amino] pentyl] amino] -1-oxohexyl] amino ] methyl] phenyl] methyl] methyl carbamate

To a mixture cooled to 0 ° C of 0.438 g (0.77 mmol) of (25) -N- [[4- (aminoiminomethyl) phenyl] methyl] hydrochloride -2- [[(21?) -4-methyl -l-oxo-2- [[(phenylmethyl) sulfonyl] amino] pentyl] amino] hexanamide (compound No. 48, prepared as in the examples above) in 20 ml of dichloromethane 0.39 ml is added (3, 10 mmol) of

1, 1, 3, 3-tetramethylguanidine, followed by 0.077 ml (1.00 mmol) of methyl chloroformate and then stirred at room temperature for 4 hours. The reaction medium is then evaporated to dryness and the crude product is purified by chromatoflash on sillice gel, eluting with a methanol / dichloromethane mixture (2:98).

0.314 g of white powder is obtained. Melting point: 208 ° C

[α] _D : + 16.5 ° (c = 0.2; methanol)

Yield: 70% Board

In the picture

- [] _D denotes the rotary power.

All the compounds in the table are optically pure, of configuration (S) on the carbon bearing R _± and (R) on the carbon bearing R ₂ .

- "dec" means that the compound decomposes at its melting point.

- "tBu" represents the tert-butyl group (or 1, 1-dimethylethyl). - "nBu" represents the linear butyl group.

- "nPr" represents the linear propyl group.

All of these compounds are in the form of the hydrochloride, except the compounds marked with * which are dihydrochlorides or compounds marked "base" which are not salified.

The compounds of the invention have been the subject of pharmacological studies which have demonstrated their interest as active substances in therapy.

The compounds of the invention were subjected in particular to a test for inhibition of the coagulation factor VlI / VIIa (factor VlI / VIIa).

Ki VII test

Principle of the Ki Factor Vlla test

The purpose of this test is to measure the amidolytic activity of the Factor VIIa / Tissue Factor complex on a chromogenic substrate in the presence of variable concentrations of the inhibitor tested. A compound is said to be a competitive inhibitor if it increases the Km of Factor VIIa for its substrate, that is to say that it decreases the affinity of Factor VIIa for its substrate.

This amidolytic activity of Factor VIIa (FVIIa), tested at a concentration, is measured kinetically (calculation of the speed) by determining the cleavage of the substrate (two concentrations tested) over time using a microplate reader which determines the release of para-nitroaniline by measuring the absorbance at 405 nm. The compound is tested at 7 concentrations.

The determination of Ki is made according to the Dixon method in which 1 / speed is plotted as a function of the concentration of the compound and for each concentration of substrate (SI and S2). The point of intersection of the linear regression lines projected on the x-axis determines the concentration of inhibitor corresponding to -Ki.

Protocol The Factor VIIa used is recombinant human (produced in CHO cells). The Tissue Factor (FT) is recombinant human (produced in E. Coli) and corresponds to the soluble extracellular part (amino acids 1 to 219). The FVIIa / Tissue Factor complexes are previously formed by incubating Factor VIIa and Tissue Factor in a molar concentration ratio of 1/5 in the presence of calcium chloride at 5 mM and used at the final concentration of 3.75 nM of FVIIa in the presence of 18.75 nM FT.

A TBSA buffer is used: 50 mM Tris pH7.5, 100 mM sodium chloride, 0.1% BSA; an FVIIa / FT complex at 3.75 nM / 18.75 nM in TBSA buffer + 5 mM calcium chloride; a chromogenic substrate CBS-3447 (HD-CHG-But-Arg-pNA) at 0.66 and 2.64 mM. The compounds are dissolved in 1 mM to be tested.

The reagents are placed in the wells in the following order (without incubation; final concentrations): compound (at 7 concentrations + one control) then substrate (Sl = 0.66 mM and S2 = 2.64 mM) then FVIIa / complex FT (3.75 nM / 18.75 nM), the respective volumes of the wells being 25 μl, 50 μl and 25 μl.

The Ki of the compounds of the invention are preferably less than 1 μM.

The compounds of the invention have also been the subject of a study of their antithrombotic activity.

In vivo antithrombotic test

Principle of the test

The formation of an FT-dependent thrombus in rats or guinea pigs is obtained by placing an arteriovenous shunt into which is inserted a cotton thread impregnated with thromboplastin (Tissue Factor: FT).

Protocol We anesthetize the Rat, (Sprague Dawley), or the Guinea Pig

(Hartley), of an average weight of 300-350 g with sodium pentobarbital (60 mg / kg ip). A femoral vein (Rat) or the right jugular vein (Guinea pig) is cannulated for intravenous injections while the left jugular vein and the right carotid artery are cannulated using a catheter filled with physiological solution at 0 , 9% for the constitution of the shunt. Five minutes after the intravenous administration of several doses of compound (treated groups) or of its solvent (control group), the shunt is assembled by connecting the two catheters using a flexible plastic tube of 3 mm internal diameter and 6 cm long containing a cotton thread impregnated with thromboplastin. The blood circulation is restored for 5 min (Rat) or 10 min (Guinea pig). The shunt is then removed and the cotton thread associated with the thrombus is removed and immediately weighed.

Expression of results

The means (± ESM) of the thrombi weights in the different groups are determined. The percentages of reduction of the thrombus weight for each group treated, compared to the control group, are calculated in order to determine an DA ₅₀ , dose of compound inhibiting by 50% the weight of thrombus in the control animals. The DA ₅₀ of the compounds of the invention are preferably less than 5 mg / kg.

The results of these biological tests have shown that the compounds of the invention exhibit factor VII / factor VIIa inhibiting properties.

As such, they can be used in the treatment and prevention of various forms of pathology involving factor Vil / factor Vlla and the coagulation cascade. They can therefore be used in the treatment of venous, arterial or coronary thrombosis, disseminated intravascular coagulation, restenosis after angioplasty, oncological hypercoagulability, atral fibrillation, pulmonary embolism, edema, inflammation or pulmonary fibrosis, septic shock, post-cardiac bypass treatment, prevention of aggravated reocclusion following thrombosis or prophylaxis for unstable angina.

To this end, these compounds of the invention, in combination with suitable excipients, can be presented in any form suitable for oral, parenteral or intravenous administration, such as tablets, capsules, dragees, capsules, suspensions, oral solutions or solutions. injectable and dosed to allow administration of 0.1 mg to 1 g per day, in one or more doses. They can also be presented in any form suitable for transdermal and ocular administration.

Claims

claims

1. Compound of general formula (I!

in which, R _λ represents either a group

) alkyl which may be substituted by a hydroxy group or a trifluoromethyl group, either a cycloalkyl group or a cycloalkylalkyl group, or a group: CH 2 / n -XR ₃ where R ₃ represents a group

(C ₁ -C ₃ ) alkyl, n is equal to 1, 2 or 3 and X represents a sulfur or oxygen atom,

R ₂ represents either a (C ^ C- alkyl group which may be substituted by an amino group, a -COOH group, a hydroxyl group or a trifluoromethyl group, or a cycloalkyl group or a cycloalkylalkyl group, or a phenyl, benzyl or 2 -phenylethyl, which may be substituted on the phenyl group by one of the following substituents: a halogen atom, a trifluoromethyl group, an amino group or a group (C ^ C alkoxy, either a carbocyclic group or a heterocyclic group,

Y is represented by the two tautomeric forms of formula

(l ⁾

or

A represents either a hydrogen atom or an NH ₂ group _/ or an OH group, or a (C ₁ -C ₄ ) alkyl group, or a (C ₁ -C 6) alkoxycarbonyl group,

R ₄ represents either a hydrogen atom or a methyl group,

and Q represents a group R ₅ -S0 ₂ - where R ₅ represents either a group (C ^ C alkyl, or a cycloalkylalkyl group, or a benzyl group, which can be substituted on the phenyl group by a methoxy group or a group B- (CH ₂ ) _p -S0 ₂ -, where B can be a group -COOH or -CF ₃ and p can vary from 1 to 3, their enantiomers, diastereoisomers and their mixtures, as well as their salts.

2. Compound according to claim 1, characterized in that the carbon which carries R _x is of absolute configuration (S), and the carbon which carries R ₂ is of absolute configuration (R).

3. Process for the preparation of a compound of formula (I) according to claim 1 or 2, characterized in that a compound of formula (VIII) is reacted

in which R _1r R ₂ , and Q are as defined in claim 1, with a compound of formula (II)

wherein R ₄ is as defined in claim 1 and Z is a protective group, to obtain a compound of formula (IX)

wherein R _1f R ₂ , Q and R ₄ are as defined in claim 1 and Z is as defined in formula (II), which is reacted with hydroxylamine hydrochloride in the presence of a base organic to obtain a compound of formula (I) in which A is an OH group or else that is subsequently hydrogenolysed to obtain a compound of formula (I) in which A is an H group, which is optionally made react with a (C ^ Cg) alkyl chloroformate in the presence of an organic base to obtain a compound of formula (I) in which A represents a (Ci-Cg) alkoxycarbonyl group.

4. Process for the preparation of a compound of formula (I) according to claim 1 or 2, characterized in that a compound of formula (XIV) is reacted

in which R _λ and R ₄ are as defined in claim 1 and Z is a protective group with a compound of formula (XV)

wherein R ₂ is as defined in claim 1 and GP ₂ is an orthogonal protective group to obtain a compound of formula (XVI)

in which R _lr R ₂ and R ₄ are as defined in claim 1 and Z and GP ₂ are as defined respectively in formulas (XIV) and (XV), which are deprotected and then reacted with sulfonyl chloride of formula Q-Cl, in which Q is as defined in claim 1, to obtain a compound of formula (IX) as defined in claim 3, which is finally deprotected by hydrogenolysis.

5. Medicament, characterized in that it contains a compound according to claim 1 or 2.

6. Pharmaceutical composition characterized in that it contains a compound according to claim 1 or 2 in combination with any pharmaceutically acceptable excipient.