FR2783521A1 - New thrombin-inhibiting N-arylsulfonyl arginine derivatives useful as antithrombotic agents - Google Patents

Abstract

N-Arylsulfonyl arginine derivatives (I) are new. N-Arylsulfonyl arginine derivatives of formula (I) and their enantiomers and salts are new. R = H or 1-4C alkyl; R1 = H, 1-4C alkyl, 1-4C alkoxycarbonyl, 1-4C alkenyloxycarbonyl, phenyl(1-4C)alkoxycarbonyl, 1-4C alkanoyl, phenyl(1-4C)alkanoyl, phenyl(1-4C)alkyl(1-4C)alkanoyl or (1-4C)alkanoyloxy(1-4C)alkoxycarbonyl; R'1 = (1-4C)alkanoyloxy(1-4C)alkoxycarbonyl; R2 = piperidino (optionally 4-substituted by OH, 1-4C alkyl, 1-4C hydroxyalkyl, 1-4C alkoxy, (1-4C)alkoxy(1-4C)alkyl, CN, 1-4C alkylthio, CH2F, CHF2, CF2, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 3-6C cycloalkyl, COOR', CONR'R'', =CY'T, 3-5C cycloalkylidene or =NOMe), spiro((3-6C)cycloalkane-1,4'-piperidin)-1-yl; 1,2,3,6-tetrahydro-1-pyridyl (optionally substituted in the 4 position by 1-4C alkyl, 1-4C perfluoroalkyl or 3-6C cycloalkyl and/or in the 3 position by halo, 1-4C alkyl, 1-4C perfluoroalkyl, (CH2)nOH or (CH2)nCOOR'), hexahydro-1H-azepin-1-yl; heptahydroazocin-1-yl, octahydro-1H-azonin-1-yl or a group of formula (i) or (ii) R' = 1-4C alkyl; R'' = H or 1-4C alkyl; Y', T = H, halo, CN, COOR' or optionally halogenated 1-4C alkyl; n = 1-6; A'-B' = CO-NR''; m, p = 1-2; Q = C or N; D = 1-4C alkyl or CH2CF3; r = 1-3; R3 = H, 1-5C alkyl, COR5, SO2R6, CONHR6 or SO2N(R6)2; R5 = 1-4C alkyl, (CH2)xOMe, CH2O(C2H4O)xMe, (CH2)xCF3 or (CH2)xOH; x = 1-4; R6 = 1-4C alkyl; R4 = H or halo; A = halo; phenyl (optionally substituted by halogen, 1-4C alkyl, 1-4C alkoxy, CF3, OCF3, CHO, CH2OR10, CH2OCOR10, CH2OCONR10R11, COOR10, CONR10R11, NO2, NR10R11, NHCOR10, NH(CH2)qOR10 and/or SOyR10); pyridyl, thienyl, furyl, pyrimidinyl or thiazolyl (all optionally substituted as above) or 5-8C cycloalkyl; y = 0-2; q = 0-6. An Independent claim is also included for a process for preparing (I).

Description

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The present invention relates to N- (arginyl) benzenesulphonamide derivatives, their preparation and their therapeutic application.

dans laquelle R représente soit un atome d'hydrogène, soit un groupe (Ci- C4) alkyle, R1 représente soit un atome d'hydrogène, soit un groupe

(C,-C4) alkyle, soit un groupe (C1-C4) alcoxycarbonyle, soit un groupe (C2-C4)alcényloxycarbonyle, soit un groupe phényl (C1-C4) alcoxycarbonyle, soit un groupe (C1-Cq) alcanoyle, soit un groupe phényl(C1-C4)alcanoyle soit un groupe phényl (C-C4) alkyle (C1-C4) alcanoyle, soit un groupe (C-C4)alkyl carbonyloxy (Cl-C,) alkyloxycarbonyle,

RI, représente un groupe (Cl-C4) alkylcarbonyloxy(C1-C4) alkyloxy carbonyle, R2 représente soit un groupe pipéridin-1-yle éventuellement substitué en position 4 par un ou plusieurs groupes choisis parmi les groupes hydroxy, (C1-C4)alkyle,

hydroxy(C-C4) alkyle, (C-C4)alcoxy droit ou ramifié, (Cl -C4) alcoxy (Cl-C4) alkyle, cyano, (C,-C4) alkylthio, monofluorométhyle, difluorométhyle, trifluorométhyle, 2fluoroéthoxy, 2,2,2-trifluoroéthoxy, (C3-C6)cycloalkyle, -COOR' et-CONR'R" [R' étant un groupe (C1-C4)alkyle et R" étant un atome d'hydrogène ou un groupe (C1-C4)alkyle] ou par The compounds of the invention correspond to formula (I)

wherein R represents either a hydrogen atom or a (C 1 -C 4) alkyl group, R 1 represents either a hydrogen atom or a group

(C 1 -C 4) alkyl, either a (C 1 -C 4) alkoxycarbonyl group, a (C 2 -C 4) alkenyloxycarbonyl group, a phenyl (C 1 -C 4) alkoxycarbonyl group, a (C 1 -C 4) alkanoyl group, or a phenyl (C1-C4) alkanoyl group is a phenyl (C1-C4) alkyl (C1-C4) alkanoyl group, or a (C1-C4) alkylcarbonyloxy (C1-C4) alkyloxycarbonyl group,

R1 represents a (C1-C4) alkylcarbonyloxy (C1-C4) alkyloxycarbonyl group, R2 represents either a piperidin-1-yl group optionally substituted in the 4-position by one or more groups selected from hydroxy groups, (C1-C4) alkyl,

hydroxy (C1-C4) alkyl, (C1-C4) straight or branched alkoxy, (C1-C4) alkoxy (C1-C4) alkyl, cyano, (C1-C4) alkylthio, monofluoromethyl, difluoromethyl, trifluoromethyl, 2fluoroethoxy, 2 , 2,2-trifluoroethoxy, (C3-C6) cycloalkyl, -COOR 'and-CONR'R "[R' being a (C1-C4) alkyl group and R" being a hydrogen atom or a group (C1- C4) alkyl] or by

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groupe , (r = 1 à 3), ou par un groupe =NOCH,, (CH 2) m

soit un groupe spiro [ (C3-C6) cycloalkane-1, 4' -pipéridin] -1- yle, soit un groupe 1,2,3,6-tétrahydropyridin-1-yle éventuellement substitué en position 4 par un groupe (C1-C4)alkyle, perfluoro (C1-C4) alkyle ou (C3-C6) cycloalkyle et/ou en position 3 par un atome d'halogène, un groupe (C1-C4) alkyle, perfluoro(C1-C4) alkyle, (CH2)nOH ou (CH2)nCOOR' (n = 1 à 6), soit un groupe hexahydro-lH-azépin-1-yle, soit un groupe heptahydroazocin-1-yle, soit un groupe octahydro- 1H-azonin-1-

( CH2 ) m' B yle, soit un groupe \1 (A'-B étant un groupe -CONR", (CH2) m = 1 à 2 et p = 1 à 2) , soit un groupe N#Q (CH 2)r (Q étant un atome de carbone ou d'azote, D un groupe (C1-C4)alkyle ou -CH2CF3, et r = 1 à 3), R3 représente soit un atome d'hydrogène, soit un groupe (C1-C5)alkyle droit ou ramifié, soit un groupe -CORS où R5 est

un groupe (CI-C4) alkyle, -(CH2)nOCH3, -CH2O (C2H4O) nCH3i - (CH2) nCF3, - -(CH2)nOH (n égal 1 à 4 ) , soit un groupe -SO2R6, soit un groupe -CONHR6, soit un groupe -SO2N(R6)2où R6 est un groupe (C1-C4)alkyle, R4 représente soit un atome d'hydrogène, soit un atome d'halogène et A représente soit un atome d'halogène, soit un groupe phényle éventuellement substitué par un ou plusieurs substituants choisis parmi les atomes d'halogène et les groupes

(CI-C4) alkyle, (C1-Cq) alcoxy droit ou ramifié, a group = CYT [Y and T being chosen independently of one another from the hydrogen and halogen atoms and the cyano groups, -COOR ', R' being as defined above, and (C1 -C4) alkyl optionally substituted by one or more halogen atoms] or by a

group, (r = 1 to 3), or by a group = NOCH ,, (CH 2) m

either a spiro [(C3-C6) cycloalkane-1,4'-piperidin] -1-yl group, or a 1,2,3,6-tetrahydropyridin-1-yl group optionally substituted in the 4-position by a group (C1 -C4) alkyl, perfluoro (C1-C4) alkyl or (C3-C6) cycloalkyl and / or in position 3 by a halogen atom, a (C1-C4) alkyl group, perfluoro (C1-C4) alkyl, ( CH2) nOH or (CH2) nCOOR '(n = 1 to 6), being a hexahydro-1H-azepin-1-yl group, a heptahydroazocin-1-yl group or an octahydro-1H-azonin-1 group

(CH2) m 'B yle, that is a group 1 (A'-B being a group -CONR ", (CH2) m = 1 to 2 and p = 1 to 2), or a group N # Q (CH 2 where Q is a carbon or nitrogen atom, a (C1-C4) alkyl group or -CH2CF3, and r = 1 to 3), R3 represents either a hydrogen atom or a group (C1- C5) straight or branched alkyl, a -COR group where R5 is

a (C1-C4) alkyl group, - (CH2) nOCH3, -CH2O (C2H4O) nCH3i - (CH2) nCF3, - - (CH2) nOH (n is 1 to 4), a -SO2R6 group, or a group -CONHR6, a -SO2N (R6) 2 group where R6 is a (C1-C4) alkyl group, R4 represents either a hydrogen atom or a halogen atom and A represents either a halogen atom or a halogen atom; phenyl group optionally substituted by one or more substituents selected from halogen atoms and groups

(C1-C4) alkyl, (C1-Cq) straight or branched alkoxy,

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-CH20COR,O, -CH20CONRIOR,,, -COOR10' -CONR10RU, nitro, NR10Rllf NHCOR10, -NH(CH2)qOR10 et RloS (O-) avec Rio et Rll étant chacun indépendamment l'un de l'autre un atome d'hydrogène ou un groupe (C1-C4) alkyle, m étant compris entre 0 et 2 et q compris entre 0 et 6, soit un hétérocycle choisi parmi les groupes pyridinyle, thiényle, furyle, pyrimidyle et thiazolyle les dits groupes pouvant être substitués comme ci-dessus, soit un groupe cyclo(C5-C8)alkyle. trifluoromethyl, trifluoromethoxy, formyl, -CH2OR10,

-CH 2 OCOR, O, -CH 2 CONOROR 1, -COOR 10 -CONR 10 R 8, nitro, NR 10 R 11 NHCOR 10, -NH (CH 2) qOR 10 and R 10 S (O-) with R 10 and R 11 being each independently of each other an atom of hydrogen or a group (C1-C4) alkyl, m being between 0 and 2 and q between 0 and 6, a heterocycle selected from pyridinyl, thienyl, furyl, pyrimidyl and thiazolyl groups said groups may be substituted as above, a cyclo (C 5 -C 8) alkyl group.

(C1-C4)alkylcarbonyloxy(Cl-C4)alkyloxycarbonyle, R'1représente un groupe (C1-C4) alkylcarbonyloxy (C1-C4) alkyloxycarbonyle, R2 représente soit un groupe pipéridin-1-yle éventuellement substitué en position 4 par un ou plusieurs groupes choisis parmi les groupes hydroxy, (C1-C4)alkyle,

hydroxy(C1-C4)alkyle, (C1-C,)alcoxy droit ou ramifié, (Cl-C4) alcoxy (C1-C4) alkyle, cyano, (C1-C4) alkylthio, monofluorométhyle, difluorométhyle, trifluorométhyle, 2fluoroéthoxy, 2,2,2-trifluoroéthoxy, (C3-C6)cycloalkyle, -COOR' et -CONR'R" [R' étant un groupe (C1-C4)alkyle et R" étant un atome d'hydrogène ou un groupe (C1-C4)alkyle] ou par un groupe =CYT [Y et T étant choisis indépendamment l'un de l'autre parmi les atomes d'hydrogène et d'halogène et les groupes cyano, -COOR', R' étant tel que défini ci-dessus et (C1-C4)alkyle éventuellement substitué par un ou plusieurs atomes d'halogène] ou par un

groupe 1 (r = 1 à 3), ou par un groupe =NOCH3, (CH2) m R3 représente un groupe -COR5 ou R5 est un groupe

(C1-C4) alkyle, - (CHZ) nOCH3, -CH20 (CZH40) nCH3, - (CH2)nCF31 - (CH2) "OH (n égal 1 à 4), Among these compounds, the preferred compounds according to the invention are the compounds of formula (I) in which R represents a hydrogen atom, R1 represents either a hydrogen atom or a group

(C1-C4) alkylcarbonyloxy (C1-C4) alkyloxycarbonyl, R1 is (C1-C4) alkylcarbonyloxy (C1-C4) alkyloxycarbonyl, R2 is either piperidin-1-yl optionally substituted at the 4-position by one or more groups selected from hydroxy, (C1-C4) alkyl,

hydroxy (C1-C4) alkyl, (C1-C4) straight or branched alkoxy, (C1-C4) alkoxy (C1-C4) alkyl, cyano, (C1-C4) alkylthio, monofluoromethyl, difluoromethyl, trifluoromethyl, 2fluoroethoxy, 2 , 2,2-trifluoroethoxy, (C3-C6) cycloalkyl, -COOR 'and -CONR'R "[R' being a (C1-C4) alkyl group and R" being a hydrogen atom or a group (C1- C4) alkyl] or by a group = CYT [Y and T being chosen independently of each other from among hydrogen and halogen atoms and cyano groups, -COOR ', R' being as defined herein above and (C1-C4) alkyl optionally substituted by one or more halogen atoms] or by a

group 1 (r = 1 to 3), or by a group = NOCH3, (CH2) m R3 represents a group -COR5 or R5 is a group

(C1-C4) alkyl, - (CH2) nOCH3, -CH2O (CZH40) nCH3, - (CH2) nCF31 - (CH2) n (n is 1 to 4),

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- CH20R10' - -CH20COR,o, -CH20CONR,OR,,, COOR10 - CONR10Rll1 nitro, NR10Rll' -NHCOR,O, -NH (CH2) qORlo et RloS (O-) avec R10 et RX1 étant chacun indépendamment l'un de l'autre un atome d'hydrogène ou un groupe (C1-C4)alkyle, m étant compris entre 0 et 2 et q compris entre 0 et 6, soit un hétérocycle choisi parmi les groupes pyridinyle, thiényle, furyle, pyrimidyle et thiazolyle les dits groupes pouvant être substitués comme ci-dessus, soit un groupe cyclo(C5-C8)alkyle. R, represents a hydrogen atom and A represents either a phenyl group optionally substituted by one or more substituents chosen from halogen atoms and (C1-C4) alkyl groups, (C1-C4) straight or branched alkoxy, trifluoromethyl , trifluoromethoxy, formyl,

- CH20R10 '- -CH20COR, o, -CH20CONR, OR ,,, COOR10 - CONR10R111 nitro, NR10R11' -NHCOR, O, -NH (CH2) qORlo and RloS (O-) with R10 and RX1 each independently being one on the other a hydrogen atom or a (C1-C4) alkyl group, m being between 0 and 2 and q between 0 and 6, a heterocycle chosen from pyridinyl, thienyl, furyl, pyrimidyl and thiazolyl groups; said groups may be substituted as above, or a cyclo (C 5 -C 8) alkyl group.

est [SI . The preferred configuration of the central amino acid part

is so .

The compounds of the invention may exist as pure racemates or enantiomers or enantiomeric mixtures. They may also exist in the form of free bases or pharmaceutically acceptable addition salts.

All these forms are part of the invention.

In the following schemes, P, P1 and P2 represent protective groups such as for example phenylmethoxycarbonyl, 1,1-dimethylethoxycarbonyl, fluorenylmethoxycarbonyl, prop-2-enyloxycarbonyl.

According to the invention, the compounds of formula (I) are prepared according to scheme 1.

Selective deprotection is carried out of a compound of formula (II) in which P1, P2 and R2 are as defined above according to the method described in the application for

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Diagram 1

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Figure 1 (Continued)

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 French patent FR 9703392 (in Scheme 3) and a compound of formula (III) is obtained.

Then, the compound of formula (III) is reacted with a compound of formula (IV) in which A, R4 and R5 are groups as defined above, in the presence of a base such as triethylamine, in a solvent. aprotic such as dichloromethane, to obtain a compound of formula (VIa) which is treated with ammonia gas, in an aprotic solvent such as tetrahydrofuran to obtain a compound of formula (VII).

or a compound of formula (III) is reacted with a compound of formula (V) in which A and R4 are groups as defined above, in the presence of a base such as triethylamine, in an aprotic solvent such as dichloromethane to obtain a compound of formula (VIb) which is reacted with a compound of formula R5COCl in which R5 is as defined above, in an aprotic solvent such as N, N-dimethylacetamide to obtain a compound of formula (VII ), then the N5 amine function of the compound of formula (VII) is deprotected to obtain a compound of formula (VIII).

Then, the compound of formula (VIII) is reacted with a reagent of formula (A) in which P and R 1 are as defined above, in an aprotic solvent such as tetrahydrofuran, dimethylformamide or dichloromethane, followed by deprotection in an acidic medium, and a compound of formula (I) is obtained, with R1 = a hydrogen atom.

 or the compound of formula (VIII) is reacted with a reagent of formula (B1) or (B2) in which R1 and R'1 are as defined above, in an aprotic solvent such as tetrahydrofuran, dimethylformamide or dichloromethane and a compound of formula (I) is obtained.

 According to the invention, intermediates (A) (B1) and (B2) are prepared according to Schemes 2,3 and 4.

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Schéma 3

Figure 2

Figure 3

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 Preparation of Reagent (A) (Scheme 2) Preparation of Reagent (A) is described in patent application WO 9733576.

 a compound of formula (XII) in which R 1 is as defined above is reacted with a compound of formula (XIII) in which P is defined as above, in the presence of a base such as sodium hydride, in an aprotic solvent such as tetrahydrofuran and the reagent (A) is obtained.

Preparation of Reagent (B1) (Scheme 3) The preparation of reagent (B1) is described in patent application WO 9733576.

A compound of formula (IX) in which R'1 is as defined above is reacted with a compound of formula (X), in the presence of a base such as diisopropylethylamine, in an aprotic solvent such as dimethylformamide, and a compound of formula (XI) which is reacted with a compound of formula (XII) in which R 1 is as defined above, in the presence of a base such as sodium hydride, in an aprotic solvent such as tetrahydrofuran, to obtain the reagent (B1).

Preparation of the Reagent (B2) (Scheme 4) The preparation of the reagent (B2) is carried out in analogy to the synthesis described in Biorganic and Medecinal Chemistry Letters, Vol. 4, No. 16, pp. 1985 to 1990.1994.

A compound of formula (XIII) in which R'1 is as defined above is reacted and Pa is a group such as -Cl or 4-nitrophenoxy with S-methylisothiourea hemisulfate, in the presence of a base such as sodium hydrogencarbonate. sodium, in a two-phase system such as the water / dichloromethane system and a compound of formula (XIV) is obtained which is reacted with a compound of formula (XV) in which R 1 is as defined above and Pa a chlorine atom to obtain a compound of formula (XVI) which is reacted with sulfuryl chloride in an aprotic solvent such as dichloromethane to obtain the reagent (B2).

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All the above-mentioned (C1-C4) alkyl groups are straight or branched.

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.

Thus the compounds of formula (IV) are described in French patent application FR 9506954, the compounds of formula (V) in European patent applications EP 0713865 and EP 0718307 and the compounds of formula (II) in patent FR 9703392 .

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 ratio (x: y) represents the ratio (acid: base).

(difluorométhylène)pipéridin-1-yl] carbonyl] -4-[[[2-[(l- oxopropyl)amino]-3-thién-2-ylphényl]sulfonyl]amino] butyl]amino]iminométhyl]amino]carbonyl]oxy]-2,2- diméthyléthyle. Example 1 (Compound No. 1) 2-Methylpropanoate Hydrochloride of (S) -2 - [[[[[[4 - [[4-

(difluoromethyl) piperidin-1-yl] carbonyl] -4 - [[[2 - [(1-oxopropyl) amino] -3-thien-2-ylphenyl] sulfonyl] amino] butyl] amino] iminomethyl] amino] carbonyl] oxy] -2,2-dimethylethyl.

 1. 2-hydroxy-2-methylpropylate 2-methylpropanoate.

A mixture of 25 g (0.34 moles) of isobutylene oxide, 297 g

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 (2.7 moles) of sodium isobutyrate and 59.8 g (0.68 moles) of isobutyric acid in 680 ml of dimethylformamide is heated at 80 ° C. for 3 days. The cooled medium is poured into 2 l of water and extracted 3 times with 1 l of ether. The ethereal phases are combined and washed with 1 liter of water, 1 liter of saturated sodium hydrogen carbonate solution and 500 ml of saturated sodium chloride solution and are then dried over sodium sulfate. After filtration and evaporation under reduced pressure, 48 g of 2-hydroxy-2-methylpropyl 2-methylpropanoate are obtained in the form of an oil and used as such in the next step.

Yield (%) = 88
2,2-Dimethyl-2 - [[(4-nitrophenoxy) carbonyl] oxy] ethyl 2,2-methylpropanoate.

To a solution of 16 g (0.1 mol) of 2-hydroxy-2-methylpropyl 2-methylpropanoate in 110 ml of dichloromethane was added 23 ml (0.88 mol) of pyridine. After cooling to 0 ° C., a solution of 16 g (0.08 mol) of paranitrophenol chloroformate in 110 ml of dichloromethane is added. Stirred at 0 C for 1 h, then at room temperature for 18 hours. The medium is evaporated under reduced pressure and the residue taken up in pentane (3 × 300 ml) and filtered. The filtrate is evaporated under reduced pressure. The residue is purified on a silica column, eluting with dichloromethane. 11 g of 2,2-dimethyl-2 - [[(4-nitro phenoxy) carbonyl] oxy] ethyl 2-methylpropanoate are isolated as an oil.

éthoxy)carbonyl]imino](1H-pyrazol-1-yl) méthyl]amino] carbonyl]oxy]-2,2-diméthyl éthyle. Yield (%) = 34
1. 3. 2-Methylpropanoate of 2 - [[[[[[(1,1-dimethyl)

ethoxy) carbonyl] imino] (1H-pyrazol-1-yl) methyl] amino] carbonyl] oxy] -2,2-dimethylethyl.

To a suspension of 0.5 g (12.5 mmol) of sodium hydride, 60% dispersed in oil, in 8 ml of anhydrous tetrahydrofuran, is added, at 0 C under an inert atmosphere,

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solution de 1,05 g (5 mmoles) d'[imino(1H-pyrazol-1- yl)méthyl]carbamate de 1,1-diméthyl éthyle dans 4 ml de tétrahydrofurane anhydre. Après 10 min d'agitation à 0 C, on ajoute une solution de 2,10 g (6. 5 mmoles) de 2méthylpropanoate de 2,2-diméthyl-2-[[(4nitrophénoxy)carbonyl]oxy]éthyle dans 4 ml de tétrahydrofurane anhydre à 0 C. On agite pendant 1 h à 0 C, puis pendant 18 heures à température ambiante.

solution of 1.05 g (5 mmol) of 1,1-dimethylethyl [imino (1H-pyrazol-1-yl) methyl] carbamate in 4 ml of anhydrous tetrahydrofuran. After stirring for 10 min at 0 ° C., a solution of 2.10 g (6.5 mmol) of 2,2-dimethyl-2 - [[(4-nitrophenoxy) carbonyl] oxy] ethyl 2-methylpropanoate in 4 ml of anhydrous tetrahydrofuran at 0 ° C. It is stirred for 1 h at 0 ° C. and then for 18 hours at room temperature.

The reaction medium is poured into 50 ml of ethyl acetate and 50 ml of a saturated aqueous solution of ammonium chloride. The aqueous phase is washed with 50 ml of ethyl acetate, the ethyl acetate phases are combined and are washed with a saturated solution of sodium hydrogencarbonate, then with a saturated solution of sodium chloride and are dried. on sodium sulphate. After filtration and evaporation under reduced pressure, the residue is purified on a silica column, eluting with hexane: ethyl acetate (5: 1).

diméthyléthoxy)carbonyl]imino] (lH-pyrazol-1-yl)méthyl] amino]carbonyl]oxy]-2,2-diméthyléthyle sous forme d'huile et utilisé tel quel à l'étape finale. Rdt (%) = 40

1.4. [1- [ [4- (difluorométhylène) pipéridin-1-yl] carbonyl]-4-[[(1,1-diméthyléthoxy)carbonyl] amino]butyl]carbamate de 9H-fluorèn-9-yl méthyle. 0.8 g of 2-methylpropanoate of 2 - [[[[[[(1,1-

dimethylethoxy) carbonyl] imino] (1H-pyrazol-1-yl) methyl] amino] carbonyl] oxy] -2,2-dimethylethyl as an oil and used as such in the final step. Yield (%) = 40

1.4. 9H-Fluoren-9-ylmethyl [1- [[4- (difluoromethyl) piperidin-1-yl] carbonyl] -4 - [[(1,1-dimethylethoxy) carbonyl] amino] butyl] carbamate.

12 g d'hexafluorophoshate de O-(benzotriazol-I-yl)- N,N,N',N'tétraméthyluronium (31. 5 mmoles). To a solution of 13. 62 g (30 mmol) of 5 - [[(1,1-dimethylethoxy) carbonyl] amino] -2 - [[(9H-fluoren-9-ylmethoxy) carbonyl] amino] pentanoic acid in 60 ml of dichloromethane are added, at 0 ° C. under nitrogen, 5.021 g (30 mmol) of 4- (difluoromethylene) piperidine hydrochloride, 13. 35 ml (75 mmol) of diisopropylethylamine, and finally

12 g of O- (benzotriazol-1-yl) -N, N, N ', N'tetramethyluronium hexafluorophoshate (31.5 mmol).

The ice bath is removed and stirred for 16 hours at room temperature. The reaction medium is evaporated under

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 reduced pressure, and the residue taken up in 200 ml of ethyl acetate, washed with 100 ml of a 1N solution of hydrochloric acid, then with 100 ml of a saturated solution of sodium bicarbonate, and finally, with 50 ml of ml of a saturated solution of sodium chloride.

After drying over sodium sulphate, the solvent is evaporated off under reduced pressure and 17 g of [1 - [[4- (difluoromethylene) piperidin-1-yl] carbonyl] -4 - [[are obtained in the form of a white powder. 9H-Fluoren-9-yl methyl (1,1-dimethylethoxy) carbonyl] amino] butyl] carbamate.

Yield (%) = 100 F (C) = 110 C
1.5. 1,1-Dimethylethyl [4-amino-5- [4- (difluoromethylene) piperidin-1-yl] -5-oxopentyl] carbamate.

méthylène)pipéridin-1-yl]carbonyl]-4-[[(1,1-diméthyl éthoxy)carbonyl]amino]butyl]carbamate de 9H-fluorèn-9ylméthyle dans 150 ml de dichlorométhane, on ajoute à 0 C, 11.86 ml de pipéridine (120 mmoles). On retire le bain de glace et on agite 1 heure à température ambiante. Le milieu est évaporé sous pression réduite et le résidu chromatographié sur silice par un gradient dichlorométhane : méthanol de 0 à 10% en méthanol. On obtient, sous forme de solide blanc, 8 g de [4-amino-5-[4- (difluorométhylène)pipéridin-1-yl]-5-oxopentyl] carbamate de 1,1-diméthyléthyle. To a solution of 17 g (30 mmol) of [1 - [[4- (difluoro)

9.7-Fluoro-9-methylmethyl (methylene) piperidin-1-yl] carbonyl] -4 - [[(1,1-dimethylethoxy) carbonyl] amino] butyl] carbamate in 150 ml of dichloromethane is added at 0 ° C., 11.86 ml. piperidine (120 mmol). The ice bath is removed and stirred for 1 hour at room temperature. The medium is evaporated off under reduced pressure and the residue is chromatographed on silica using a 0 to 10% dichloromethane: methanol gradient in methanol. 8 g of [4-amino-5- [4- (difluoromethylene) piperidin-1-yl] -5-oxopentyl] carbamate of 1,1-dimethylethyl are obtained in the form of a white solid.

amino]-4-[[4-(difluorométhylène)pipéridin-1-yl] carbonyl]butyl]carbamate de 1,1-diméthyléthyle. Yield (%) = 76 F (C) = 71
1. 6. [4 - [[(2-amino-3-thien-2-ylphenyl) sulfonyl]

amino] -4 - [[4- (difluoromethylene) piperidin-1-yl] carbonyl] butyl] carbamate 1,1-dimethylethyl.

méthylène)pipéridin-1-yl]-5-oxopentyl]carbamate de 1,1- diméthyléthyle (4. 4 mmoles) dans 20ml de dichlorométhane, To a solution of 1. 53 g of [4-amino-5- [4- (difluoro)

1,1-dimethylethyl methylene) piperidin-1-yl] -5-oxopentyl] carbamate (4.4 mmol) in 20 ml of dichloromethane,

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 0.195 g (4 mmol) of 2-amino-3-thien-2-ylbenzenesulfonyl chloride and 0.92 ml of triethylamine (6.6 mmol) were successively added at 0.degree. The ice bath is removed and stirred at room temperature for 18 hours. The medium is evaporated off under reduced pressure and the residue taken up in 100 ml of ethyl acetate and washed with 50 ml of a 1N hydrochloric acid solution, 50 ml of saturated sodium bicarbonate solution and dried over sulphate. sodium. After filtration and evaporation under reduced pressure, 2.25 g of [4 - [[(2-amino-3-thien-2-ylphenyl) sulfonyl] amino] -4 - [[4- (difluoro-methylene) piperidine] are obtained. 1,1-Dimethylethyl] -carbonyl] butyl] carbamate.

Yield (%) = 96 F (C) = 78
1. 7. N- [2 - [[[4-amino-1 - [[4- (difluoro methylene) -1,2,3,6-tetrahydropyridin-1-yl] carbonyl] butyl] amino hydrochloride] sulfonyl] -6-thien-2-ylphenyl] propanamide To a solution of 1. 2 g of [4 - [[(2-amino-3-thien-2-ylphenyl) sulfonyl] amino] -4 - [[4- (2 dmethylethyl) (difluoromethylene) piperidin-1-yl] carbonyl] butyl] carbamate (2. 05 mmol) in 2 ml of dimethylacetamide is added dropwise, at room temperature and under argon, 0.4 ml of sodium chloride. propionyl (4.5 mmol). After 2 hours at room temperature, the medium is taken up by
100 ml of ethyl acetate, washed with 100 ml of saturated sodium bicarbonate solution and then with 50 ml of saturated sodium chloride solution, then dried over sodium sulfate. It is filtered and evaporated under reduced pressure and the residue is chromatographed on silica using a gradient of dichloromethane: methanol from 0 to 15% in methanol.

The isolated product is taken up in 50 ml of ethyl acetate
0 C and saturated with gaseous hydrochloric acid. It is allowed to return to ambient temperature with stirring and, after
30 minutes, the medium is evaporated under reduced pressure, and 1. 23 g of N- [2 - [[[4-amino-1 - [[4-) hydrochloride are obtained.

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 (1,2,3,6-difluoromethylene) tetrahydropyridin-1-yl] carbonyl] butyl] amino] sulfonyl] -6-thien-2-yl] phenyl] propanamide.

[[[[[[4-[[4-(difluo-rométhylène)pipéridin-1-yl] carbonyl]-4-[[[2-[(l-oxopropyl)amino]-3-thién- 2 -ylphényl ] sul f onyl ] amino] butyl ] amino] imino méthyl]amino]carbonyl]oxy]-2,2-diméthyléthyle. Yield (%) = 95 F (C) = 148
1. 8. (S) -2-methylpropanoate hydrochloride

[[[[[[4 - [[4- (difluoro-romethylene) piperidin-1-yl] carbonyl] -4 - [[[2 - [(1-oxopropyl) amino] -3-thien-2-yl] phenyl] sulfonyl] amino] butyl] amino] imino methyl] amino] carbonyl] oxy] -2,2-dimethylethyl.

imino](lH'-pyrazol-l-yl)méthyl]amino]carbonyl]oxy]-2,2- diméthyléthyle dans 10 ml de tétrahydrofurane anhydre, on ajoute, à 0 C et sous azote, une solution de 0,6 g (1,05 mmoles) de chlorhydrate de N-[2-[[[4-amino-l-[[4- (difluorométhylène)-1,2,3,6-tétra hydropyridin-1-yl] carbonyl]butyl]amino]sulfonyl]-6-thién-2-ylphényl] propanamide dans 5 ml de tétrahydrofurane sous agitation, puis goutte à goutte, 0,68 ml de N,N-diisopropyléthylamine (3,85 mmoles). On laisse l'agitation se poursuivre pendant 18 heures à température ambiante. Le mélange réactionnel est évaporé, puis est repris par 100 ml d'acétate d'éthyle et lavé par 50 ml d'acide chlorhydrique 1 N, puis par 50 ml d'une solution saturée d'hydrogénocarbonate de sodium et par 50 ml d'une solution saturée de chlorure de sodium. Après séchage sur sulfate de sodium et évaporation sous pression réduite, le résidu est purifié par chromatographie sur colonne de gel de silice en éluant par un mélange de dichlorométhane : méthanol (97 : 3). On obtient 1,1 g de produit qui est repris dans 10 ml de dichlorométhane à 0 C et additionné de 10 ml d'acide trifluoroacétique. Après 2 h d'agitation à température ambiante, le milieu est évaporé sous pression réduite et le résidu obtenu est repris par 100 ml d'acétate d'éthyle et est lavé par 50 ml d'une solution saturée d'hydrogénocarbonate de sodium et 50 ml d'une solution saturée de chlorure de sodium. On sèche sur sulfate To a solution of 0.435 g (1.1 mmol) of 2 - [[[[[[(1,1-dimethylethoxy) carbonyl] 2-methyl propanoate]

imino] (1H-pyrazol-1-yl) methyl] amino] carbonyl] oxy] -2,2-dimethylethyl in 10 ml of anhydrous tetrahydrofuran, a solution of 0.6 g is added at 0 ° C. under nitrogen. (1.05 mmol) N- [2 - [[[4-amino-1 - [[4- (difluoromethylene) -1,2,3,6-tetrahydropyridin-1-yl] carbonyl] butyl] hydrochloride] amino] sulfonyl] -6-thien-2-ylphenyl] propanamide in 5 ml of tetrahydrofuran with stirring, then dropwise, 0.68 ml of N, N-diisopropylethylamine (3.85 mmol). Stirring is allowed to continue for 18 hours at room temperature. The reaction mixture is evaporated and then taken up in 100 ml of ethyl acetate and washed with 50 ml of 1 N hydrochloric acid, then with 50 ml of a saturated solution of sodium hydrogencarbonate and with 50 ml of a saturated solution of sodium chloride. After drying over sodium sulphate and evaporation under reduced pressure, the residue is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane: methanol (97: 3). 1.1 g of product is obtained, which is taken up in 10 ml of dichloromethane at 0 ° C. and treated with 10 ml of trifluoroacetic acid. After stirring for 2 h at room temperature, the medium is evaporated off under reduced pressure and the residue obtained is taken up in 100 ml of ethyl acetate and is washed with 50 ml of a saturated solution of sodium hydrogencarbonate and 50 ml of ethyl acetate. ml of a saturated solution of sodium chloride. We dry on sulphate

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 of sodium, and then concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel in a mixture of dichloromethane: methanol (95: 5). The isolated product is taken up in 10 ml of a 0.1 N solution of hydrogen chloride in isopropanol and is evaporated under reduced pressure. The residue is purified by RP 18 column chromatography eluting with a gradient of acetonitrile: water from 0 to 50% acetonitrile.

(S)-2-[[[[[[4-[[4-(difluorométhylène)pipéridin-l- yl]carbonyl]-4-[[[2-[(1-oxopropyl)amino]-3-thién-2- ylphényl]sulfonyl]amino]butyl]amino]imino méthyl] amino] carbonyl]oxy]-2,2-diméthyléthyle. 0.6 g of 2-methyl propanoate hydrochloride are obtained.

(S) -2 - [[[[[[4 - [[4- (difluoromethylene) piperidin-1-yl] carbonyl] -4 - [[[2 - [(1-oxopropyl) amino] -3-thieno 2-ylphenyl] sulfonyl] amino] butyl] amino] imino methyl] amino] carbonyl] oxy] -2,2-dimethylethyl.

Yield (%) = 76 F (C) = 135 [[alpha]] D20 () = + 90 (c = 0.2, methanol).

rométhylène)pipéridin-1-yl]carbonyl]-4-([[2-[(1oxopropyl)amino]-3-thién-2-ylphényl]sulfonyl]amino] butyl]amino][[[l,l-diméthyl-2-(2-méthyl-l-oxo-propoxy) éthoxy] carbonyl] amino] méthylène] amino] carbonyl] oxy] -2, 2- diméthyléthyle. Example 2 (Compound No. 2) 2-Methylpropanoate of (S) -2 - [[[[[[4 - [[4- (difluoride)

romethylene) piperidin-1-yl] carbonyl] -4 - ([[2 - [(1oxopropyl) amino] -3-thien-2-ylphenyl] sulfonyl] amino] butyl] amino] [[1,1-dimethyl] 2- (2-methyl-1-oxo-propoxy) ethoxy] carbonyl] amino] methylene] amino] carbonyl] oxy] -2,2-dimethylethyl.

 2,2-Dimethyl-2 - [[[imino (1H-pyrazol-1-yl) methyl] amino] carbonyl] oxy] ethyl 2,2-methylpropanoate.

To a solution of 2.10 g (6.5 mmol) of 2,2-dimethyl-2 - [[(4-nitrophenoxy) carbonyl] oxy] ethyl 2-methyl propanoate, as obtained in Example 1 2 described above, in 10 ml of dimethylformamide, at 0 ° C. and under nitrogen, 2.89 ml (16.25 mmol) of N, N-diisopropylethylamine are added, followed by 0.952 g (6.5 mmol) of H-pyrazole-1-carboximidamide. It is stirred for 15 min at 0 ° C. and then 18 hours at room temperature.

The reaction medium is then poured into a mixture of 100 ml of ethyl acetate: water (1: 1). The aqueous phase is extracted with 50 ml of ethyl acetate. The phases

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propanoate de 2,2-diméthyl-2-[[[[imino(1H-pyrazol-1- yl)méthyl]amino]carbonyl]oxy] éthyle sous forme d'huile. The organic compounds are combined and washed with 50 ml of water, 50 ml of saturated sodium hydrogencarbonate solution, 50 ml of saturated sodium chloride solution and dried over sodium sulfate. After filtration and evaporation under reduced pressure followed by purification on a silica column, eluting with a mixture of hexane: ethyl acetate (4: 1), 1.8 g of 2-methyl are obtained.

2,2-dimethyl-2 - [[[imino (1H-pyrazol-1-yl) methyl] amino] carbonyl] oxy] ethyl propanoate as an oil.

oxy] carbonyl ] imino] ( 1H-pyrazol -1-yl ) méthyl ] amino] carbonyl]oxy]éthyle. Yield (%) = 94
2.2-Dimethyl-2 - [[[[[[[[1,1-dimethyl-2 - [(2-methyl-1-oxo-propoxy)] ethyl] 2,2-methylpropanoate

oxy] carbonyl] imino] (1H-pyrazol-1-yl) methyl] amino] carbonyl] oxy] ethyl.

diméthyl-2-((2-méthyl-1-oxo-propoxy)]éthyl] oxy] carbonyl] imino] (1H-pyrazol-1-yl) méthyl] amino] carbonyl]oxy]éthyle. To a solution of 1.2 g (4 mmol) of 2,2-dimethyl-2 - [[[imino (1H-pyrazol-1-yl) methyl] amino] carbonyl] oxy] ethyl 2-methyl propanoate in 10 ml anhydrous tetrahydrofuran is added at 0 ° C and under nitrogen, 48 g of sodium hydride (60%, 12 mmol) in small amounts. After 10 minutes at 0 ° C., a solution of 1.8 g of 2,2-dimethyl-2 - [[(4-nitrophenoxy) carbonyl] oxy] ethyl 2-methylpropanoate (5. 6 mmol) in 2 ml of tetrahydrofuran is added. . It is stirred for 16 hours at room temperature and then for 4 hours at 60 ° C. The reaction medium is cooled and is filtered under nitrogen. The filtrate is diluted with 200 ml of ethyl ether, washed with 60 ml of a saturated aqueous ammonium chloride solution, with 100 ml of saturated sodium hydrogencarbonate solution, dried over sodium sulphate and filtered. is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel in a cyclohexane: ethyl acetate gradient from 0% to 50% ethyl acetate. 0.9 g of 2,2-dimethyl-2 - [[[[[[[[1,1-dimethyl-2-methylpropanoate are obtained as an oil).

dimethyl-2 - ((2-methyl-1-oxo-propoxy) -ethyl] oxy] carbonyl] imino] (1H-pyrazol-1-yl) methyl] amino] carbonyl] oxy] ethyl.

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rométhylène)pipéridin-1-yl) carbonyl] -4- [ ( [2- [1oxopropyl)amino]-3-thién-2-ylphényl]sulfonyl]amino] butyl]amino][[[1,1-diméthyl-2-(2-méthyl-1-oxo-propoxy) éthoxy]carbonyl]amino]méthylène]amino]carbonyl]oxy]-2,2- diméthyléthyle. Yield (%) = 47
2. 3-Methylpropanoate of (S) -2 - [[[[[[4 - [[4- (difluoride)

romethylene) piperidin-1-yl) carbonyl] -4 - [([2- [1oxopropyl) amino] -3-thien-2-ylphenyl] sulfonyl] amino] butyl] amino] [[1,1-dimethyl-2 - (2-Methyl-1-oxo-propoxy) ethoxy] carbonyl] amino] methylene] amino] carbonyl] oxy] -2,2-dimethylethyl.

de 2,2-diméthyl-2-[[[[[[[[1,l-diméthyl-2-[(2-méthyl-1oxopropoxy)éthyl]oxy]carbonyl]imino] (lH-pyrazol-1- yl) méthyl] amino] carbonyl] oxy] éthyle dans 7 ml de tétrahydrofurane anhydre, on ajoute 0,969 g (1,7 mmoles) de chlorhydrate de N-[2-[[[4-amino-l-[[4-(difluorométhylène)- 1,2,3,6-tétra hydropyridin-1-yl]

carbonyl ) butyl ] amino] sul f onyl ] - 6 - thién-2 -ylphényl propanamide. dans 14 ml de tétrahydrofurane anhydre, et goutte à goutte, à 0 C et sous azote, 0,836 ml de N,Ndiisopropyléthyl amine (4,7 mmoles). On laisse revenir à température ambiante pendant 3 heures puis le milieu est évaporé sous pression réduite. Le résidu obtenu est repris dans 100 ml d'acétate d'éthyle et est lavé par 50 ml d'acide chlorhydrique 1 N, puis par 50 ml d'une solution saturée d'hydrogénocarbonate de sodium, 50 ml d'une solution saturée de chlorure de sodium, séché sur sulfate de sodium, filtré, puis évaporé sous pression réduite. Le résidu est purifié par chromatographie sur colonne de gel de silice dans un gradient cyclohexane : acétate d'éthyle de 20 à 50 % en acétate d'éthyle. On isole 1,1 g de 2-méthyl propanoate de (S)-2-[[[[[[4-[[4-(difluo-rométhylène) pipéridin-1-

yl] carbonyl] -4- [ [ [2- [1-oxopropyl) amino] -3-thién-2ylphényl] sulfonyl] amino] butyl] amino] [ [[[l,l-diméthyl-2-(2- méthyl-l-oxo-propoxy)éthoxy]carbonyl] amino]méthylène]amino]carbonyl]oxy]-2,2-diméthyléthyle. To a solution of 0.9 g (1.88 mmol) of 2-methyl propanoate

2,2-dimethyl-2 - [[[[[[[1,1-dimethyl-2 - [(2-methyl-1-oxopropoxy) ethyl] oxy] carbonyl] imino] (1H-pyrazol-1-yl) methyl] amino] carbonyl] oxy] ethyl in 7 ml of anhydrous tetrahydrofuran, 0.969 g (1.7 mmol) of N- [2 - [[[4-amino-1 - [[4- (difluoromethylene) hydrochloride) 1,2,3,6-tetrahydropyridin-1-yl

carbonyl) butyl] amino] sulphonyl] -6-thien-2-ylphenylpropanamide. in 14 ml of anhydrous tetrahydrofuran, and dropwise, at 0 ° C. and under nitrogen, 0.836 ml of N, Ndiisopropylethylamine (4.7 mmol). Allowed to warm to room temperature for 3 hours then the medium is evaporated under reduced pressure. The residue obtained is taken up in 100 ml of ethyl acetate and is washed with 50 ml of 1N hydrochloric acid, then with 50 ml of a saturated solution of sodium hydrogencarbonate, 50 ml of a saturated solution of sodium chloride, dried over sodium sulphate, filtered and then evaporated under reduced pressure. The residue is purified by chromatography on a silica gel column in a cyclohexane: ethyl acetate gradient of 20 to 50% ethyl acetate. 1.1 g of (S) -2 - [[[[[[4 - [[4- (difluoromethyl) piperidin-1-2-methylpropanoate are isolated

yl] carbonyl] -4 - [[[2- [1-oxopropyl) amino] -3-thien-2-yl] phenyl] sulfonyl] amino] butyl] amino] [[[1,1-dimethyl-2- (2-methyl) 1-oxo-propoxy) ethoxy] carbonyl] amino] methylene] amino] carbonyl] oxy] -2,2-dimethylethyl.

F (C) = 65 [[alpha]] D20 () = +79 (c = 0.2;

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Acétate d'[[[[[[[(acétyloxy)méthoxy]carbonyl]amino][[4-[[[2- [(1-oxopropyl)amino]-3-thién-2-ylphényl]sulfonyl]amino]-4- [[4-(trifluorométhyl)-1,2,3,6-tétrahydropyridin-1-yl] carbonyl] butyl] amino] méthylène] amino] carbonyl] oxy] méthyle . Example 3 (Compound No. 5)

[[[[[[[(Acetyloxy) methoxy] carbonyl] amino] [[4 - [[[2 - [(1-oxopropyl) amino] -3-thien-2-ylphenyl] sulfonyl] amino acetate] - 4- [4- (trifluoromethyl) -1,2,3,6-tetrahydropyridin-1-yl] carbonyl] butyl] amino] methylene] amino] carbonyl] oxy] methyl.

 3. 1. Acetate of [[[[[[[(acetyloxy) methoxy] carbonyl] amino] (methylthio) methylene] amino] carbonyl] oxy] methyl.

To a solution of 1.458 g (10.5 mmol) of imino (methylthio) methanamine semisulfate in 60 ml of saturated aqueous sodium hydrogencarbonate solution, a solution of 3.19 g (21 mmol) of sodium acetate is added at room temperature. [(chlorocarbonyl) oxy] methyl [prepared from Folkmann M .; Lund F.J .; 1990, 1553] in 30 ml of dichloromethane. The mixture is stirred vigorously for 22 hours and the dichloromethane is decanted. The aqueous phase is extracted with 10 ml of dichloromethane, the organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is chromatographed on silica in a cyclohexane: ethyl acetate gradient from 0 to 100% ethyl acetate. 1.5 g of [[[[[[[[(acetyloxy) methoxy] carbonyl] amino] (methylthio) methylene] amino] carbonyl] oxy] methyl acetate is isolated in the form of a white powder.

chlorométhylène]aminoJcarbonyl]oxy]méthyle. Yield (%) = 40 F (C) = 81
3. 2. Acetate of [[[[[[[(acetyloxy) methoxy] carbonyl] amino]

chloromethylene] aminoJcarbonyl] oxy] methyl.

To a solution of 0.385 g (1. 2 mmol) of [[[[[[[(acetyloxy) methoxy] carbonyl] amino] (methylthio) methyl] amino] carbonyl] oxy] methyl acetate in 6 ml of dichloromethane, 0.29 ml of sulfuryl chloride (3. 6 mmol) is added at room temperature. After 3 hours at room temperature, the reaction medium is concentrated under reduced pressure. 0.3 g of [[[[[[[[(acetyloxy) methoxy] carbonyl] amino] chloromethylene] amino] carbonyl] oxy] methyl acetate, as used, is obtained as an oil.

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 in the next step.

Yield (%) = 100
3.3. 9H-Fluoren [4- [[(1,1-dimethylethoxy) carbonyl] amino] -1- [[4- (trifluoromethyl) -1,2,3,6-tetrahydropyridin-1-yl] carbonyl] butyl] carbamate -Methyl.

diméthyléthoxy) carbonyl] amino) -1- [ [4- (trifluorométhyl) - 1,2,3,6-tétrahydropyridin-1-yl]carbonyl]butyl] carbamate de 9H-fluorén-9-ylméthyle. To a solution of 7.3 g of 5 - [[(1,1-dimethylethoxy) carbonyl] amino] -2 - [[(9H-fluoren-9-ylmethoxy) carbonyl] amino] pentanoic acid (16 mmol) in 30 ml of dichloromethane are added at 0 ° C. under nitrogen successively, 3 g (16 mmol) of 4- (trifluoromethyl) -1,2,3,6-tetrahydropyridine hydrochloride, 7. 2 ml (41.6 mmol) of diisopropylethylamine, and 6.8 g of 0- (benzotriazol-1-yl) -N, N, N ', N'tetramethyluronium hexafluorophoshate (17.6 mmol). After stirring for 16 hours at ambient temperature, the reaction medium is evaporated off under reduced pressure and the residue is taken up in 200 ml of ethyl acetate and washed with 100 ml of a 1N solution of hydrochloric acid and then with 100 ml of a saturated solution of sodium bicarbonate, and 50 ml of a saturated solution of sodium chloride. After drying over sodium sulphate and concentration under reduced pressure, 9.4 g of [4 - [[(1,1-

9H-Fluoren-9-ylmethyl dimethylethoxy) carbonyl] amino) -1- [[4- (trifluoromethyl) -1,2,3,6-tetrahydropyridin-1-yl] carbonyl] butyl] carbamate.

tétrahydropyridin-1-yl]pentyl]carbamate de 1,1- diméthyléthyle. F (C) = 126
3. 4. [4-amino-5-oxo-5- [4- (trifluoromethyl) -1,2,3,6-

1,1-dimethylethyl tetrahydropyridin-1-yl] pentyl] carbamate.

1,2,3,6-tétrahydropyridin-1-yl]carbonyl]butyl]carbamate de 9H-fluorén-9-ylméthyle dans 40 ml de dichlorométhane, on ajoute à 0 C, 6. 22 ml de pipéridine (62. 9 mmoles). Après To a solution of 9.25 g (15. 7 mmol) of [4 - [[(1,1-dimethylethoxy) carbonyl] amino] -1 - [[4- (trifluoromethyl)] -

9H-Fluoren-9-ylmethyl 1,2,3,6-tetrahydropyridin-1-yl] carbonyl] butyl] carbamate in 40 ml of dichloromethane is added at 0 ° C. 6.2 ml of piperidine (62.9 mmol) ). After

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 stirring for 1 hour at room temperature, the medium is evaporated under reduced pressure and the residue is purified on a silica column by a gradient of dichloromethane: methanol from 0 to 10% methanol. 5 g of [4-amino-5-oxo-5- [4- (trifluoro-methyl) -1,2,3,6-tetrahydropyridin-1-yl] pentyl] carbamate are obtained in the form of a white solid. , 1diméthyléthyle.

Yield (%) = 87 F (C) = 96
3. 5. N- [2 - [[[4-amino-1 - [[4- (trifluoromethyl) -1,2,3,6-tetrahydropyridin-1-yl] carbonyl] butyl] amino] sulfonyl hydrochloride] 6-thien-2-ylphenyl] propanamide.

(trifluorométhyl)-1,2,3,6-tétrahydropyridin-1-yl] pentyl]carbamate de 1,1-diméthyléthyle (4. 5 mmoles) dans 20 ml de dichlorométhane, on ajoute à 0 C successivement 1.73 g (4. 5 mmoles) de chlorure de 2-[bis(loxopropyl)amino]-3-thién-2-ylbenzènsulfonyle et 0. 81 ml de triéthylamine (5. 82 mmoles) goutte à goutte. Après agitation pendant 3 heures à température ambiante, le milieu est évaporé sous pression réduite et le résidu est repris par 100 ml d'acétate d'éthyle et lavé par 50 ml d'une solution d'acide chlorhydrique 1N, 50 ml d'une solution saturée de bicarbonate de sodium, 50 ml d'une solution saturée de chlorure de sodium et séché sur sulfate de sodium. Après filtration et évaporation sous pression réduite, le résidu est purifié sur une colonne de silice en éluant par un mélange dichlorométhane : méthanol (99 : 1). Le produit obtenu est repris dans 100 ml de tétrahydrofurane et traité 2 minutes à 0 C par un courant d'ammoniac gazeux. Après agitation à température ambiante pendant 3 heures et évaporation sous pression réduite, le résidu est purifié sur une colonne de silice par un mélange de dichlorométhane : méthanol (98 : 2), puis repris dans 50 ml d'acétate d'éthyle à 0 C, et traité 1 min 30s par un courant d'acide chlorhydrique gazeux. Après agitation pendant 3 heures et To a solution of 1. 64 g of [4-amino-5-oxo-5- [4-

1,1-Dimethylethyl (trifluoromethyl) -1,2,3,6-tetrahydropyridin-1-yl] pentyl] carbamate (4. 5 mmol) in 20 ml of dichloromethane, 1.73 g (4 g) are added in succession. 5 mmol) of 2- [bis (loxopropyl) amino] -3-thien-2-ylbenzenesulfonyl chloride and 0.81 ml of triethylamine (5. 82 mmol) dropwise. After stirring for 3 hours at room temperature, the medium is evaporated off under reduced pressure and the residue is taken up in 100 ml of ethyl acetate and washed with 50 ml of 1N hydrochloric acid solution, 50 ml of saturated sodium bicarbonate solution, 50 ml of a saturated solution of sodium chloride and dried over sodium sulfate. After filtration and evaporation under reduced pressure, the residue is purified on a silica column, eluting with a dichloromethane: methanol (99: 1) mixture. The product obtained is taken up in 100 ml of tetrahydrofuran and treated for 2 minutes at 0 ° C. with a stream of ammonia gas. After stirring at ambient temperature for 3 hours and evaporation under reduced pressure, the residue is purified on a silica column with a mixture of dichloromethane: methanol (98: 2) and then taken up in 50 ml of ethyl acetate at 0 ° C. and treated for 1 min 30s with a gaseous hydrochloric acid stream. After stirring for 3 hours and

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1,2,3,6-tétra hydropyridin-1-ylJcarbonyl]butyl]amino] sulfonyl]-6-thién-2-ylphényl]propanamide. After evaporation under reduced pressure, 75 g of N- [2 - [[[4-amino-1 - [[4- (trifluoromethyl)] hydrochloride are isolated.

1,2,3,6-tetrahydropyridin-1-yl] carbonyl] butyl] amino] sulfonyl] -6-thien-2-ylphenyl] propanamide.

[ [4- [ [ [2- [ (1-oxopropyl) amino] -3-thién-2-ylphényl] sulfonyl]amino]-4-[[4-(trifluorométhyl)-l,2,3,6tétrahydropyridin-1-yl]carbonyl]butyl]amino] méthylène] amino] carbonyl] oxy] méthyle . Yield (%) = 66 F (C) = 135
3. 6. [[[[[[[(acetyloxy) methoxy] carbonyl] amino acetate]

[[4- [[[2- [(1-Oxopropyl) amino] -3-thien-2-ylphenyl] sulfonyl] amino] -4 - [[4- (trifluoromethyl) -1,2,3,6-tetrahydropyridin] -yl] carbonyl] butyl] amino] methylene] amino] carbonyl] oxy] methyl.

N- [2- [ [ [4-amino-1- [ [4- (trifluorométhyl) -1, 2, 3, 6-tétrahydro pyridin-1-yl]carbonyl]butyl]amino]sulfonyl]-6-thién-2ylphényl]propanamide et de 0. 5 ml (3. 6 mmoles) de triéthylamine dans 10 ml de dichlorométhane à 0 C, on ajoute goutte à goutte une solution de 0. 37 g (1. 2 mmoles) d'acétate d'[[[[[[[(acétyloxy)méthoxy] carbonyl]amino](méthylthio)méthylène]amino]carbonyl]oxy]méth yle dans 5ml de dichlorométhane. On laisse revenir à température ambiante. Après 2 h d'agitation à température ambiante, le milieu est évaporé sous pression réduite. Le résidu est repris par 20ml d'acétate d'éthyle, lavé par 10 ml d'une solution d'acide chlorhydrique 1N, 10 ml d'une solution saturée de bicarbonate de sodium, 5 ml d'une solution saturée de chlorure de sodium, séché sur sulfate de sodium, filtré et évaporé sous pression réduite. Le résidu est purifié sur une colonne de silice en éluant par un gradient dichlorométhane : méthanol de 0 à 5% en méthanol.

To a solution of 0.64 g (1. 13 mmol) of chlorohydrate

N- [2 - [[[4-Amino-1- [[4- (trifluoromethyl) -1,2,3,6-tetrahydro-pyridin-1-yl] carbonyl] butyl] amino] sulfonyl] -6-thienoacetate; 2-methylphenylpropanamide and 0.5 ml (3. 6 mmol) of triethylamine in 10 ml of dichloromethane at 0 ° C., a solution of 0.37 g (1.2 mmol) of acetate of [C] is added dropwise. [[[[[[(acetyloxy) methoxy] carbonyl] amino] (methylthio) methylene] amino] carbonyl] oxy] methyl] in 5 ml of dichloromethane. It is allowed to return to room temperature. After stirring for 2 h at room temperature, the medium is evaporated under reduced pressure. The residue is taken up in 20 ml of ethyl acetate, washed with 10 ml of a 1N hydrochloric acid solution, 10 ml of saturated sodium bicarbonate solution, 5 ml of a saturated solution of sodium chloride. dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified on a silica column, eluting with a 0 to 5% dichloromethane: methanol gradient in methanol.

0.34 g of [([[[[[(acetyloxy) methoxy] carbonyl) amino] [[4 - [[[2 - [(1-oxopropyl) amino] -3-thien-2-yl] phenyl] sulfonyl acetate is obtained ] amino] -4 - [[4- (trifluoromethyl) -1,2,3,6-tetrahydropyridin-1-yl] carbonyl] butyl] amino] methylene] amino] carbonyl] oxy] methyl.

Yield (%) = 35 F (C) = 95 [[alpha]] D20 () = +83 (c = 0.2;

<Desc / Clms Page number 23>

Board

<tb> Point
<Tb>

Sel de 20 N RI R' A rapport fusion (0) (x y) fusion ( )

Salt 20N RI R 'A fusion ratio (0) (xy) fusion ()

<tb> O <SEP> CH <SEP> CH
<tb>#<SEP>#<SEP>#<SEP>#<SEP> F <SEP>. <SE> S.
<Tb>

1 H -H) lo + O, -CX-COCH, CH, -H HCl 135 + 90 - 1C (1: i) 135 CHI CHI cw, Cl, -COCH2CH, p N, IIN ') lo -1 ::. 0, -NJ = <F -COCH.CH, U - 6 5 + 7 9 3 -H Cm, 00, N -NJ = <F COCH, CH3 - -HU - 8 6 + 9 7

<tb> O <SEP> O
<Tb>

<Desc / Clms Page number 24>

<tb> Point
<tb> N <SEP> R ', <SEP> Sel <SEP> of <SEP> [and] <SEP> 20 <SEP>
## EQU1 ##
<tb> merge
<tb> (C)
<Tb>

4 -H -C02CH20COCH] -CO2CH20COCH3 -NJ=<F -COCH2CH3 -H U - 86 +95 5 - H -C02CH20COCH) C02CH,OCOCH3 - N. ,- f, -COCH2CH] -H U - 95 +83 o (H, 0 C".

## STR2 ## wherein 0 C ".

6H-NMR, -N, CH, -N, -COCH 2 CH-H 102-106 + 78 CH. CH. (H, C ".

7 -H) 100%, 100%, -N, -COCH 2 CH 3 -H u-68-72 + 95O 8 -H-CO, CH, OCOCH, -CO 2 CH 2 OCOCH, -NJ =:: -COCH 2 CH, - ## STR2 ## CM | -H) loA ,, "" / 'rf' <' ) looc .. -Np -COCH2CH3 -H Cy - 90 +56 (II

<Desc / Clms Page number 25>

<tb> Point
<tb> Salt <SEP> of <SEP> [ci <SEP> 20 <SEP>
## EQU1 ##
<tb> (x: y) <SEP> merge <SEP> ()
<tb> (C)
<tb> O <SEP> CH <SEP> O <SEP> CH <SEP> CH1
<tb>#<SEP>#<SEP>#<SEP>#
<Tb>

il -H Vï" Vy#' "0 -COCH,CH, -H - 118 +91

it -H Vï "Vy # '" 0 -COCH, CH, -H - 118 +91

<Desc / Clms Page number 26>

 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) were examined in each well, 50 μl of a solution of chromogenic substrate (2 concentrations of S2238 Chromogenix) in solution in Tris buffer pH 7.5 (50 mM Tris, 100 mM NaCl and 0.1% BSA) and finally 25 μl of a solution of thrombin at 300 U / ml. The nitroaniline release was monitored at 405 nm using a plate reader.

K1 is determined by the Dixon method.

The compounds of the invention inhibit thrombin and their K1 is greater than 300nM.

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

 The anticoagulant effect is expressed as a percentage increase in thrombin time on the plasma samples taken 30 and 90 minutes after administration of 20 mg / kg p. o.

 The compounds of the invention are evaluated in a model of

<Desc / Clms Page number 27>

 Membrane permeability on a Caco-2 cell line derived from a human adenocarcinoma. This cell line is a model of choice for the study of xenobiotic absorption [P. Artusson, Therapeutics Drug Carrier System (1991), 8 (4), pp305-330]. The passage of the compounds of the invention is expressed as a function of the dose having crossed the cell barrier for 2 hours.

The values are between 0 and 50%.

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 (6)

 hydroxy (C1-C4) alkyl, (C1-C4) straight or branched alkoxy, (C1-C4) alkoxy (C1-C4) alkyl, cyano, (C1-C4) alkylthio, monofluoromethyl, difluoromethyl, trifluoromethyl, 2fluoroethoxy, 2,2,2-trifluoroethoxy, (C3-C6) cycloalkyl, -COOR 'and -CONR'R "[R' being a (C1-C4) alkyl group and R" being a hydrogen atom or a group (C1 -C4) alkyl] or by a group = CYT [Y and T being chosen independently of one another from the hydrogen and halogen atoms and the cyano groups, -COOR ', R' being as defined above, and (C1-C4) alkyl optionally substituted by one or more halogen atoms] or by a

 (Cx-C4) alkyl, either a (C1-C4) alkoxycarbonyl group, a (C2-C4) alkenyloxycarbonyl group, a phenyl (C1-C4) alkoxycarbonyl group, or a (C1-C4) alkanoyl group, either a phenyl (C 1 -C 4) alkanoyl group, a phenyl (C 1 -C 4) alkyl (C 1 -C 4) alkanoyl group, or a (C 1 -C 4) alkylcarbonyloxy (C 1 -C 4) alkyloxycarbonyl group, R 'represents a group (C1-C4) alkylcarbonyloxy (C1-C4) alkyloxycarbonyl, R2 represents either a piperidin-1-yl group optionally substituted in the 4-position by one or more groups chosen from hydroxy groups, (C1-C4) alkyl,

 wherein R represents either a hydrogen atom or a (C 1 -C 4) alkyl group, R 1 represents either a hydrogen atom or a group

 1. Compounds of formula (I) <Desc / Clms Page number 29>  -CH 2 OCOR 10, -CH 2 CONROR-COOR 10, -CONRORU 'nitro, NR 1 R 11 NHCOR 4, -NH (CH 2), ORI, and R 10 S (O) R 1 with R 1 and R 11 each independently of one another an atom of hydrogen or a group (C1-C4) alkyl, m being between 0 and 2 and q between 0 and 6, a heterocycle chosen from

 a group (C1-C4) alkyl, - (CH2) nOCH3, -CH2O (CH40) nCH3, - (CH2) nCF3, - - (CH2) nOH (n is 1 to 4), a -SO2R6 group, or a -CONHR6 group, that is a group -SO2N (R6) 2 where R6 is a (C1-C4) alkyl group, R4 represents either a hydrogen atom or a halogen atom and A represents a halogen atom, is a phenyl group optionally substituted with one or more substituents chosen from halogen atoms and (C1-C4) alkyl, (C1-C4) straight or branched alkoxy, trifluoromethyl, trifluoromethoxy, formyl, -CH2OR10,

 (C-C4) alkyl or -CH, CF3, and r = 1 to 3), R3 represents either a hydrogen atom, a straight or branched (C1-C5) alkyl group, or a -COR group where R5 is

 (CH2) m "B yle, ie a group NA (A'-B being a group -CONR", (CH2) m and p 2), or a group D / 'Nq (CH2) (Q being a carbon atom or nitrogen, D group

 (C1-C4) alkyl, perfluoro (C1-C4) alkyl or (C3-C6) cycloalkyl and / or in position 3 by a halogen atom, a (C1-C4) alkyl group, perfluoro (C1-C4) alkyl (CH2) nOH or (CH2), COOR '(n = 1-6), either a hexahydro-1H-azepin-1-yl group, a heptahydroazocin-1-yl group, or an octahydro-1H-azonine group -1-

 either a spiro [(C3-C6) cycloalkane-1,4'-piperidin] -1-yl group, or a 1,2,3,6-tetrahydropyridin-1-yl group optionally substituted in the 4-position by a group

 group = <'J (r = 1 to 3), or by a group = NOCH3, () m

<Desc / Clms Page number 30>  above, either a cyclo (C 5 -C 8) alkyl group, in the form of pure racemates or enantiomers or a mixture of enantiomers, in the form of free bases or pharmaceutically acceptable addition salts.

 pyridinyl, thienyl, furyl, pyrimidyl and thiazolyl groups, which groups may be substituted as 2. Compounds according to claim 1, characterized in that R represents a hydrogen atom, R1 represents either a hydrogen atom or a group

 (C1-C4) alkylcarbonyloxy (C1-C4) alkyloxycarbonyl, R 'represents a (C1-C4) alkylcarbonyloxy (C1-C4) alkyloxycarbonyl group, R2 represents either a piperidin-1-yl group optionally substituted in the 4-position by one or several groups selected from hydroxy groups, (C1-C4) alkyl,

 hydroxy (C1-C4) alkyl, (C1-C4) alkoxy straight or branched, (C1-C4) alkoxy (C1-C4) alkyl, cyano, (C1-C4) alkylthio, monofluoromethyl, difluoromethyl, trifluoromethyl, 2fluoroethoxy, 2, 2,2-trifluoroethoxy, (C3-C6) cycloalkyl, -COOR 'and -CONR'R "[R' being a (C1-C4) alkyl group and R" being a hydrogen atom or a group (C1-C4) ) or by a group = CYT [Y and T being chosen independently of each other from among the hydrogen and halogen atoms and the cyano groups, -COOR ', R' being as defined hereinabove. and (C1-C4) alkyl optionally substituted by one or more halogen atoms] or by a

 group = <J (r = 1 to 3), or by a group = NOCH3, (CH 2) 111 R3 represents a group -CORS where R5 is a group

 (C1-C4) alkyl, - - (CH1), OCH2 -CH2O (C2H4O) nCH3, (CH2) nCF3, - (CH2) nOH (n is 1 to 4), R, represents a hydrogen atom and A represents either a phenyl group optionally substituted by one or more substituents selected from halogen atoms and (C1-C4) alkyl, (C1-C4) straight alkoxy groups; <Desc / Clms Page number 31>  -CH 2 ORIO, -CH 2 OCOR 10, -CH 2 CONROR1, -COOR, O, -CONRIOR1, nitro, NR1oR11. -NHCOR10 / -NH (CH 2) qORlo and R ,, S (O-), with Rlo and R11 being each independently of one another a hydrogen atom or a (C1-C4) alkyl group, m being between 0 and 2 and q between 0 and 6, a heterocycle selected from pyridinyl, thienyl, furyl, pyrimidyl and thiazolyl groups said groups may be substituted as above, or a cyclo (C 5 -C 8) alkyl group in the form of pure racemates or enantiomers or of enantiomeric mixtures, in the form of free bases or of pharmaceutically acceptable addition salts.

 or branched, trifluoromethyl, trifluoromethoxy, formyl, 3. Compounds according to any one of claims 1 to 3, characterized in that the preferred configuration of the central amino acid part

 0 02NHYR2 is [SI. 4. Process for preparing the compounds of formula (I)

 Wherein R, R 1, R 1, R 2, R 3, R 4, A are as defined in claim 1, characterized in that a reaction is carried out in which R 1, R 1, R 1, R 2, R 3, R 4 and R 4 are as defined in claim 1. compound of formula (VIII) <Desc / Clms Page number 32>  wherein R1 and R'1 are as defined in claim 1.

 in which R 1 and R are as defined in claim 1, or with a reagent of formula (B2)

 wherein P represents a protecting group such as for example phenylmethoxycarbonyl, 1,1-dimethylethoxycarbonyl, fluorenylmethoxycarbonyl, prop-2-enyloxycarbonyl and R'1 is as defined in claim 1, to obtain a compound of formula (I) with R1 = a hydrogen atom, or with a reagent of formula (B1)

 wherein R2, R3, R4 and A are as defined in claim 1, or with a reagent of formula (A)

<Desc / Clms Page number 33>  5. Medicament characterized in that it contains a compound according to any one of claims 1 to 3. 6. 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.