AU5226498A

AU5226498A - N-(imidazolylbutyl) benzenesulphonamide derivatives, their preparation and the rapeutic application

Info

Publication number: AU5226498A
Application number: AU52264/98A
Authority: AU
Inventors: Jean-Michel Altenburger; Daniel Galtier; Gilbert Lassalle; Valerie Martin
Original assignee: Synthelabo SA
Current assignee: Synthelabo SA
Priority date: 1996-11-22
Filing date: 1997-11-19
Publication date: 1998-06-10
Also published as: IL129546A0; KR20000069063A; BG103414A; CN1238765A; BR9713291A; CA2270478A1; AR009627A1; FR2756285B1; TR199901143T2; JP2001504128A; EP0946517A1; ZA9710515B; FR2756285A1; NO992436D0; SK66799A3; CO4910158A1; HUP9904599A2; EE9900201A; WO1998022443A1; CZ178299A3

Description

1 N-(IMIDAZOLYLBUTYLE)BENZENESULPHONAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION The subject of the present invention is N (imidazolylbutyle) benzenesulphonamide derivatives, 5 their preparation and their application in therapeutics. Patent applications EP 718,307 and EP 565,396 describe 1-oxo-2-(phenylsulphonylamino)pentylpiperidine derivatives and 1-(2-(arylsulphonylamino)-1 10 oxoethyl)piperidine derivatives, respectively, these compounds having antithrombotic activity. Patent application EP 713,865 describes compounds which are useful as intermediates in the synthesis of compounds with antithrombotic activity. 15 The compounds of the invention correspond to the formula (I) 0 SO2NH A R RHN 2 (I) A4 N R1 N R1 H in which

R

1 and R' 1 each represent, -independently of one another, AMENDED SHEET 2 either a hydrogen atom or a halogen atom or a (Cl

C

4 )alkyl group,

R

2 represents either: a piperidin-1-yl group optionally substituted in the 4 position by one or more groups 5 chosen from hydroxyl, (C 1

-C

4 )alkyl, the latter being straight or branched, hydroxy(C 1

-C

4 )alkyl, (Cl

C

4 ) alkoxy (C 1

-C

4 ) alkyl, (C 1

-C

4 ) alkoxy, (C 1

-C

4 ) alkylthio, nitrile, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 10 (C 3 -C()cycloalkyl, -COOR' and -CONR'R" groups (R' being a (C 1

-C

4 )alkyl group and R" being a hydrogen atom or a

(C

1

-C

4 )alkyl group) or by a =CYZ group [Y and Z being chosen, independently of one another, from hydrogen and halogen atoms and (Cl-C 4 )alkyl (optionally substituted 15 by one or more halogen atoms), cyano and -COOR' groups, R' being defined as above] or by a 2 r group (r = 1 to 3) or by an =NOCH 3 group; or a spiro[(C 3 C 6 )cycloalkane-1,4'-piperidin]-1-yl group; or a 1,2,3,6 tetrahydropyridin-1-yl group optionally substituted in 20 the 4 position by a straight or branched (Cl-C 4 )alkyl group (optionally substituted by one or more halogen atoms) or a (C 3

-C

6 )cycloalkyl group; or a hexahydro-lH azepin-1-yl group optionally substituted in the 4 position by a trifluoromethyl or =CF 2 group; or a 25 heptahydroazocin-1-yl group; or an octahydro-1H-azonin AMENDED SHEET 3 (CH2 )M'B CL 1-yl group; or a group (a-B being a -CONR"

(CH

2 ) p group, m = 1 to 2 and p = 1 to 2); or a D IN- (CH2)r group (Q being a carbon or nitrogen atom, D a (C 1

-C

4 )alkyl or -CH 2

CF

3 group and r = 1 to 3); 5 R 3 represents either a straight or branched (Ci-C 5 ) alkyl group; or a -COR 5 group where R 5 is a (C 1

-C

4 ) alkyl, the latter being straight or branched, -(CH 2 )nOCH 3 ,

-CH

2

O(C

2

H

4 0),CH 3 , -(CH 2 )nCF 3 or -(CH 2 )nOH (n = 1 to 4) group; or a -S0 2

R

6 group; or a -CONHR 6 group; or an 10 -SO 2

N(R)

2 group where R 6 is a straight or branched

(C

1

-C

4 ) alkyl group,

R

4 represents either a hydrogen atom or a halogen atom and A represents either a phenyl group optionally 15 substituted by one or more substituents chosen from halogen atoms and straight or branched (C 1

-C

4 ) alkyl, straight or branched (C 1

-C

4 )alkoxy, trifluoromethyl, trifluoromethoxy, formyl, -CH 2 0Rio, -CH 2

OCOR

10 ,

-CH

2 OCONRioRaj, -COOR 1 0 , -CONRiOR 11 , nitro, -NRiOR 1 , -NHCOR 10 20 and -NH(CH 2 )qORio groups with Ri 0 and R 11 each being, independently of one another, a hydrogen atom or a AMENDED SHEET 4 straight or branched (Cl-C 4 )alkyl group and q being between 0 and 6; or a heterocycle chosen from the pyridinyl, thienyl, furyl, pyrimidyl and thiazolyl groups, it being possible for the said groups to be 5 substituted as above; or a cyclo(C.-C)alkyl group. According to the invention, the preferred compounds are the compounds of formula (I) in which

R

1 and R' 1 each represent, independently of one another, either a hydrogen atom or a halogen atom or a (Cl 10 C 4 )alkyl group,

R

2 represents either a piperidin-1-yl group optionally substituted in the 4 position by one or more groups chosen from (Ci-C 4 )alkyl, the latter being straight or branched, hydroxy(Ci-C 4 ) alkyl, (C 1

-C

4 ) alkoxy(C 1

-C

4 )alkyl, 15 (Ci-C 4 )alkoxy, (C 1

-C

4 )alkylthio, nitrile, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethoxy and (C 3 C 6 )cycloalkyl groups or by a =CYZ group (Y and Z being chosen, independently of one another, from hydrogen and halogen atoms and (Cl-C 4 )alkyl groups) or by an =NOCH 3 20 group; or a spiro[(C 3

-C

6 )cycloalkane-1,4'-piperidin]-l yl group; or a 1,2,3,6-tetrahydropyridin-1-yl group optionally substituted in the 4 position by a straight or branched (Cl-C 4 )alkyl group (optionally substituted by one or more halogen atoms); or a hexahydro-lH 25 azepin-1-yl group optionally substituted in the 4 position by a =CF 2 group; or an octahydro-lH-azonin-1-yl group; or a AMENDED SHEET 5 (CH 2 B group (a-B being a -CONR" group, m = 1 to

(CH

2 ) p D 2 and p = ito 2); or a N- group (Q being /(CH2) r a nitrogen or carbon atom, D a (C 1

-C

4 )alkyl or -CH 2

CF

3 group, and r = 1 to 3), 5 R 3 represents either a straight or branched (C,-C,)alkyl group; or a -COR 5 group where R, is a (Cl-C 4 ) alkyl, the latter being straight or branched, -CH 2 0(C 2

H

4 0) CH 3 ,

(CH

2 )nOH or (CH 2 )nOCH 3 group; or a -CONHR 6 group and A represents either a phenyl group optionally 10 substituted by one or more substituents chosen from halogen atoms and straight or branched, (C,-C 4 )alkyl, straight or branched (C 1

-C

4 )alkoxy, trifluoromethyl, trifluoromethoxy and -NR 1 ,R,, groups with R,, and R,, each being, independently of one another, a hydrogen atom or 15 a straight or branched (C,-C 4 )alkyl group; or a pyridinyl or thienyl group which can be substituted as above; or a cyclo(C,-C,)alkyl group. Among these compounds, the compounds of choice are those in which R. represents a (CI-C 4 )alkyl 20 group and R', a hydrogen atom, R 2 represents a piperidin-1-yl group substituted in the 4 position by a straight or branched (C 1

-C

4 )alkyl group or by a =CF 2 group, R 3 represents a -COR 5 group where R. is a straight or branched (C 1

-C

4 )alkyl group and A represents 25 a thienyl group optionally substituted as above or a cyclo (C,-C) alkyl group. The preferred configuration of the central amino acid part 0 S02HN

-

6 is [S] The compounds of the invention can exist in the form of racemates or of pure enantiomers or of a mixture of enantiomers. They can also exist in the form 5 of the free acid or the free base or of pharmaceutically acceptable addition salts. All these forms form part of the invention. In the following schemes, the -CPh 3 group represents the triphenylmethyl group. 0 According to the invention, the compounds of formula (Ia), in which R 3 represents a -COR, group where

R

5 is a straight or branched (Ci-C 4 )alkyl group or a

-(CH

2 )nCF 3 group (n = 1 to 4), can be synthesized according to Scheme 1. A compound of formula (II), in which R. 15 and R', each represent either a hydrogen atom or a (Cl

C

4 )alkyl group and R 2 is as defined above, is reacted with a compound of formula (III), in which A represents either a phenyl group optionally substituted as above or a heterocycle chosen from the pyridinyl, thienyl, 20 furyl, pyrimidyl and thiazolyl groups, it being possible for the said groups to be substituted as above, or a cyclo(C 5 -C,)alkyl group, and R 4 and R. are as defined above, in an aprotic solvent, such as dichloromethane, in the presence of a base, such as 25 triethylamine, and a compound of formula (IV) is obtained which is treated with an acetic acid:ethanol, acetic acid:water or acetic acid:tetrahydrofuran:water AMENDED SHEET 7 mixture at the reflux temperature. In an alternative form of the invention illustrated by Scheme 2, for the preparation of the compounds of formula (Ia) in which R 5 is a (Ci-C 4 )alkyl, 5 the latter being straight or branched, -(CH 2 )nOCH 3 ,

-CH

2

O(C

2

H

4 0) CH 3 , -(CH 2 )nCF 3 or -(CH 2 )nOH group (n = 1 to 4), a compound of formula (II) can be reacted with a compound of formula (V) in which A represents either a phenyl group substituted as above or a heterocycle 10 chosen from the pyridinyl, thienyl, furyl, pyrimidyl and thiazolyl groups, it being possible for the said groups to be substituted as above, or a cyclo(C 5 C 8 ) alkyl group, and R 4 and R 5 are as defined above, in an aprotic solvent, such as dichloromethane, in the 15 presence of a base, such as triethylamine, and a compound of formula (VI) is obtained which is treated with an acetic acid:ethanol, acetic acid:water or acetic acid:tetrahydrofuran:water mixture at the reflux temperature. 20 In an alternative form according to the invention, it is also possible to use the process illustrated in Scheme 3. A compound of formula (VII), in which R, and R' 1 each represent either a hydrogen atom or a (C 1

-C

4 ) alkyl group and R 2 , R 4 and R 5 are as 25 defined above, is reacted with a compound of formula (VIII) , in which R represents a (C 1

-C

4 ) alkyl group and A is as definedS AMENDED SHEET I 8 Scheme 0 HC1. H N R

R

1 N R' 1 CPh 3 R sOC so d A R 4 0 R s c so 2 NH (IV) A R N 1N CPh 3 0 so 2 NH RSH RIa) A N N X

H

9 Scheme 2 0 HC1. H N R N

R

1 NRll ICPh 3 so 2ci R y N(V) N (I Ni CPh 3 0 RSOCHN S0 NHR2 A R R

R

1 NRll

H

10 5 above, in a solvent, such as dimethylformamide, in the presence of a catalyst, such 10 as tetrakis(triphenylphosphine)-palladium(O), in order to form a compound of formula (IX) which is heated at the reflux temperature in acidic medium, for example in an acetic acid:water mixture. If it is desired to obtain a compound of 15 formula (Ia) in which R 4 is a hydrogen atom, then the corresponding compound of formula (Ia) in which R 4 is a halogen atom can be hydrogenolysed. When it is desired to obtain a compound of formula (Ia) in which Ri and/or R', represent a halogen atom, then the corresponding 20 compound of formula (Ia) in which R, and/or R' 1 represent a hydrogen atom is treated with a halogenating agent, such as, for example, N-bromo succinimide or N-chlorosuccinimide, in a solvent, such as dime thylformamide.

Scheme 3 0 s2 NH RSOCHNI&R 2 RNl ICPh 3 ASn(R) 3 IVIII) 0 RSOCHN s2NHR2 A R4N (IX) CPh 3 0 R 5 CHN so2NA 2 A R4N

H

12 Alternatively, in order to prepare the compounds of formula (Ib) in which R 3 represents either a -COR, group, or an -S0 2

R

6 group, or a -CONHR 6 group, or an -SO 2

N(R

6

)

2 group, where R. is a (C 1

-C

4 )alkyl, the 5 latter being straight or branched, -(CH 2 )nOCH 3 ,

-CH

2

O(C

2

H

4 0).CH 3 , -(CH 2 )nCF 3 or -(CH 2 )nOP group, P is a protecting group (n = 1 to 4) and R 6 is as defined above, the process illustrated in Scheme 4 is used. A compound of formula (II) is reacted with a compound of 10 formula (X), in which A and R 4 are as defined above, and a compound of formula (XI) is obtained which is reacted with an acid chloride of formula RCOCl or an alkyl isocyanate of formula RNCO or a sulphonyl chloride of formula R 6 S0 2 C1 or a sulphamoyl chloride of formula 15 (R 6

)

2 NS0 2 Cl and a compound of formula (XII) is obtained which is treated with an acetic acid:ethanol, acetic acid: water or acetic acid:tetrahydrofuran:water mixture at the reflux temperature. When it is desired to obtain a compound of 20 formula (Ib) in which R 1 and/or R' 1 represent a halogen atom, then the corresponding compound of formula (Ib) in which R. and/or R' 1 represent a hydrogen atom is treated with a halogenating agent, such as, for example, N-bromosuccinimide or N-chlorosuccinimide, in 25 a solvent, such as dimethylformamide. If it is desired to obtain a compound of formula (Ib) in which R 4 is a hydrogen atom, then the corresponding compound of formula (Ib) in which R 4 is a 13 Scheme 4 0 'I HC1.

H

2 N CR N 1i N 1,R' CPh 3 so 2ci

H

2 N

-

(X A4 0 02 R l N R 2 A R4N CKI) R Nl ICPh 3 0

R

3 HN S0N - R2 A4N N 1CPh 3 0 S0 2 NH R A R4N Ri NR'l

H

14 halogen atom is hydrogenolysed. In order to prepare the compounds of formula (Ic) in which R 12 corresponds to R 3 when R 3 represents a straight or branched (Cl-C,)alkyl group, the process 5 illustrated in Scheme 5 is used. A compound of formula (II) is reacted with a compound of formula (XIV) in which R.

2 represents a straight or branched (Ci-C,)alkyl group and A and R 4 are as defined above and a compound of formula (XV) is obtained which is treated with an 10 acetic acid:ethanol, acetic acid:water or acetic acid:tetrahydrofuran:water mixture at the reflux temperature. When it is desired to obtain a compound of formula (Ic) in which R, and/or R' 1 represent a halogen 15 atom, then the corresponding compound of formula (Ic) in which Ri and/or R' 1 represent a hydrogen atom is treated with a halogenating agent, such as, for example, N-bromosuccinimide or N-chlorosuccinimide, in a solvent, such as dimethylformamide. 20 If it is desired to obtain a compound of formula (Ic) in which R 4 is a hydrogen atom, then the corresponding compound of formula (Ic) in which R 4 is a halogen atom is hydrogenolysed. The starting compounds are commercially 25 available or are described in the literature or can be prepared according to methods which are described therein or which are known to a person skilled in the art.

15 Scheme 5 0 HC1.

H

2 N

R

2 N 1CPh 3 s02 Cl

R

12 HN xiv) A R 0 R 12 HN s2NHR2 A N (XV)

R

1 NR CPh 3 0 R1 2 HN so2N 2 (Ic) A R 4RN

R

1 N 1

H

16 Thus, the compounds of formula (II) are prepared according to a method analogous to that described in European Patent Application EP 0,643,047. Some compounds of formula (III) are described in 5 European Patent Application EP 0,718,307. The compounds of formula (VII) are prepared according to a method analogous to that described in European Patent Application EP 0,718,307. The compounds of formula (X) and (XIV) are described in 10 European Patent Application EP 0,713,865. 5-Ethyl-lH-imidazole is prepared according to the method described by Horne D.A., (1994), Heterocycles, 39, No. 1, 139. The preparation of 4-cyclopropylpyridine is described 15 by Eisch J.J., (1974), J. Org. Chem., 39, No. 21, 5110. 4-Difluoromethylenepiperidine is prepared according to a method analogous to that described by Schmidt W. et al., (1995), Liebigs Ann., 1319-1326. The preparation of N-cyclopentylformamide is described 20 by Bossio R. et al., (1993), Synthesis, 8, 783-785. The following Examples 1 to 11 illustrate the preparation of some compounds of formula (II); Examples 12 to 27 illustrate the preparation of some compounds of formula (I) according to the invention. 25 The microanalyses and the IR and NMR spectra confirm the structure of the compounds obtained. The numbers of the compounds exemplified refer to those in the table given later, which illustrates the 17 chemical structures and the physical properties of some compounds according to the invention. The ratios between brackets represent the (base:acid) ratio. 5 Example 1 (S)-5-Ethyl-a-[(4-ethylpiperidin-1-yl)carbonyll-1-(tri phenylmethyl)-1H-imidazole-4-butanamine hydrochloride (1:1) 1.1. 5-Ethyl-4-iodo-lH-imidazole 10 22.7 g (89 mmol) of iodine, in solution in 800 ml of chloroform, are added dropwise with stirring at 0*C over 3 hours to a solution of 8.6 g (89 mmol) of 5-ethyl-lH-imidazole in 600 ml of a 2N aqueous sodium hydroxide solution. Stirring is continued for 4 hours 15 at this temperature and then the chloroform is evaporated under reduced pressure. The aqueous phase is cooled to 0*C, neutralization is carried out using a 12N aqueous hydrochloric acid solution and extraction is carried out with 3 times 1 1 of ethyl acetate. The 20 organic phases are combined, washed with 100 ml of a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, elution being carried out with a 25 methanol:dichloromethane (1.5:98.5) mixture. 10.5 g of product are obtained in the form of a white powder. Yield = 53% 18 Melting point = 155*C 1.2. 5-Ethyl-4-iodo-1-[(4-methylphenyl)sulphonyl] 1H-imidazole 0.91 g (22.7 mmol) of 60% sodium hydride in 5 oil is added, portionwise, with stirring at 0*C under nitrogen to a solution of 4.8 g (21.6 mmol) of 5-ethyl 4 -iodo-lH-imidazole in 25 ml of anhydrous dimethyl formamide. Stirring is continued for 0.5 hour at 0*C and 4.35 g (22.7 mmol) of 4 -(methylphenyl)sulphonyl 10 chloride are added. Stirring is maintained for one hour at 0*C, the temperature of the mixture is allowed to return to room temperature, stirring is continued for one hour and then the reaction mixture is concentrated under reduced pressure. The residue is taken up in 15 400 ml of ethyl acetate and washing is carried out successively with 100 ml of a 0.5N aqueous hydrochloric acid solution, 100 ml of water and 100 ml of a saturated sodium chloride solution. Finally, the solution is dried over sodium sulphate and concentrated 20 under reduced pressure. 6.1 g of product are obtained in the form of a white solid after precipitation from an ethyl acetate:pentane mixture. Yield = 75% 25 Melting point = 95 0

C

19 1.3 Methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl] amino]-5-[5-ethyl-i-[(4-methylphenyl) sulphonyl]-lH-imidazol-4-yl]pent-4-ynoate 1.3.1. Methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl] 5 amino]pent-4-ynoate a) (S)-2-[[(1,1-Dimethylethoxy)carbonyl]amino]pent 4-ynoic acid 11.5 g (77 mmol) of (S)-2-aminopent-4-ynoic acid hydrochloride, 100 ml of dioxane, 50 ml of water 10 and 80 ml of 2N sodium hydroxide solution are introduced into a 250 ml round-bottomed flask under a nitrogen atmosphere. 17.9 g (82 mmol) of tert-butyl dicarbonate are added to the solution and stirring is carried out for 3 hours at room temperature. 200 ml of 15 ethyl acetate are added and acidification is carried out to pH 2 by addition of a 2N hydrochloric acid solution. The phases are separated and the aqueous phase is extracted with 50 ml of ethyl acetate. Drying is carried out over magnesium sulphate and evaporation 20 is carried out to dryness. 18.78 g of product are obtained in the form of a colourless oil which is used as is in the following stage. b) Methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl] 25 amino]pent-4-ynoate 13 g (154 mmol) of sodium hydrogencarbonate 20 are added, in a 250 ml round-bottomed flask under a nitrogen atmosphere, to a solution of 18.78 g (77 mmol) of (S)-2-[[(1,1-dimethylethoxy)carbonyl]aminopent 4-ynoic acid in 150 ml of dimethylformamide. 20 ml 5 (318 mmol) of methyl iodide are added and the mixture is stirred for 18 hours at room temperature. The mixture is poured into water and extraction is carried out with ethyl acetate. The organic phase is washed with water and then dried over magnesium sulphate. 10 Evaporation is carried out to dryness. 15.85 g of product are obtained in the form of a yellow oil which is used as is in the following stage. 1.3.2. Methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl] amino]-5-[5-ethyl-i-[(4-methylphenyl) 15 sulphonyl]-1H-imidazol-4-yl]pent-4-ynoate A mixture of 9.87 g (26.3 mmol) of 5-ethyl 4-iodo-l-[(4-methylphenyl)sulphonyl]-1H-imidazole, 8.94 g (39.4 mmol) of methyl (S)-2-[[(1,1-dimethyl ethoxy)carbonyl]amino]pent-4-ynoate, 0.25 g (1.3 mmol) 20 of copper iodide, 10.84 ml (105 mmol) of diethylamine and 0.92 g (1.3 mmol) of dichlorobis(triphenyl phosphine)palladium in 26 ml of dimethylformamide is heated for 8 hours at 50*C under argon. The reaction mixture is concentrated under reduced pressure and the 25 residue obtained in taken up in 300 ml of ethyl acetate and washed successively with 3 times 100 ml of water and 100 ml of a saturated sodium chloride solution. Finally, the solution is dried over sodium sulphate and 21 concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with an ethyl acetate:hexane (3:7) mixture. 5 11 g of product are obtained in the form of a viscous oil. Yield = 88% 1.4. Methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl] amino]-5-[5-ethyl-l-[(4-methylphenyl) 10 sulphonyl]-lH-imidazol-4-yl]pentanoate A mixture of 13.5 g (28.4 mmol) of methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-[5-ethyl 1-[(4-methylphenyl)sulphonyl]-lH-imidazol-4-yl]pent-4 ynoate in the presence of 1.8 g of 10% palladium-on 15 charcoal in 50 ml of methanol is hydrogenated for 10 hours at room temperature under a pressure of 0.35 MPa (50 psi). The reaction mixture is filtered through celite and the filtrate is concentrated under reduced pressure. The residue is purified by 20 chromatography on a column of silica gel, elution being carried out with a cyclohexane:ethyl acetate (7:3) mixture. 10.5 g of product are obtained in the form of a viscous oil. 25 Yield = 77% 22 1.5. Methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl] amino]-5-(5-ethyl-lH-imidazol-4-yl)pentanoate A mixture of 10.4 g (21.6 mmol) of methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-[5-ethyl 5 1-[(4-methylphenyl)sulphonyl]-lH-imidazol-4-yl] pentanoate and 8.79 g (65.2 mmol) of 1-hydroxybenzo triazole hydrate in 150 ml of methanol is stirred at room temperature for 4 hours. The reaction mixture is concentrated under reduced pressure and the residue is 10 taken up in 100 ml of ether and washed with 450 ml of a 0.7N aqueous hydrochloric acid solution. The phases are separated, the pH of the aqueous phase is adjusted to 8-9 with a sodium hydrogencarbonate solution and extraction is carried out with 2 times 500 ml of ethyl 15 acetate. The organic phases are combined, dried over sodium sulphate and concentrated under reduced pressure. 8.79 g of compound are obtained in the form of a viscous oil used as is in the following stage. 20 Yield = 88% 1.6. Methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl] amino]-5-[5-ethyl-l-(triphenylmethyl) 1H-imidazol-4-yl]pentanoate 2.9 ml (20.3 mmol) of triethylamine and 25 5.77 g (20.7 mmol) of triphenylmethyl chloride are successively added at 0*C to a solution of 5.95 g (18.3 mmol) of methyl (S)-2-[[(1,1-dimethylethoxy)- 23 carbonyl]amino]-5-(5-ethyl-lH-imidazol-4-yl)pentanoate in 70 ml of dichloromethane. The temperature of the mixture is allowed to return to room temperature, stirring is continued for 18 hours at this temperature 5 and then the reaction mixture is concentrated under reduced pressure. The residue is taken up in 300 ml of ethyl acetate and washed successively with 200 ml of a 0.1N aqueous hydrochloric acid solution, 200 ml of a saturated sodium hydrogencarbonate solution and 100 ml 10 of a saturated sodium chloride solution. The solution is dried over magnesium sulphate and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, elution being carried out with a dichloromethane:methanol (99:1) 15 mixture. 9.4 g of product are obtained in the form of a viscous oil. Yield = 90.6% 1.7. (S)-a-[[(1,1-Dimethylethoxy)carbonyl]amino] 20 5-ethyl-i-(triphenylmethyl)-1H-imidazole-4 pentanoic acid 0.83 g (19.8 mmol) of lithium hydroxide monohydrate is added with stirring at OC to 9.4 g (16.6 mmol) of methyl (S)-2-[[(1,1-dimethylethoxy) 25 carbonyl]amino]-5-[5-ethyl-1-(triphenylmethyl) 1H-imidazol-4-yl]pentanoate in a mixture of 48 ml of methanol and 16 ml of water. The temperature of the 24 mixture is allowed to return to room temperature and stirring is continued at this temperature for 24 hours. Evaporation is carried out under reduced pressure and the aqueous phase is acidified to pH 2 at O*C with a 1N 5 aqueous hydrochloric acid solution before extracting with 2 times 300 ml of dichloromethane. The organic phases are combined, washed with 100 ml of a saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue is 10 triturated in ether, filtered off and dried under reduced pressure. 8.87 g of product are obtained in the form of a white powder. Yield = 96.7% 15 Melting point = 141*C 1.8. 1,1-Dimethylethyl (S)-[1-[(4-ethylpiperidin 1-yl)carbonyl]-4-[5-ethyl-i-(triphenyl methyl)-lH-imidazol-4-yl]butyl]carbamate 1.8.1. 4-Ethylpiperidine hydrochloride 20 a) 1,1-Dimethylethyl 4-ethylpiperidine-1-carboxylate 20 g (190 mmol) of 4-ethenylpyridine are hydrogenated for 4 hours at 50*C, under an atmosphere of 0.42 MPa (60 psi), in the presence of 2 g of platinum(IV) oxide, the reaction mixture is filtered 25 through celite and the filtrate is concentrated under reduced pressure. The residue is taken up in 150 ml of water, the pH is adjusted to 8 with a saturated aqueous 25 sodium carbonate solution and 44 g (190 mmol) of bis(1,1-dimethylethyl) dicarbonate, in solution in 100 ml of tetrahydrofuran, are added dropwise. The temperature of the reaction mixture is allowed to 5 return to room temperature and stirring is maintained for 18 hours at this temperature. Evaporation is carried out under reduced pressure and the aqueous phase is extracted with 2 times 300 ml of ethyl acetate. The organic phases are combined and washed 10 with 100 ml of a saturated sodium chloride solution. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue thus obtained is purified by chromatography on a column of silica gel, elution being carried out with 15 a cyclohexane:ethyl acetate (9:1) mixture. 13.8 g of product are obtained in the form of an oil. Yield = 34% b) 4-Ethylpiperidine hydrochloride A solution of 13.8 g (64.8 mmol) of 20 1,1-dimethylethyl 4-ethylpiperidine-1-carboxylate in 200 ml of ether is treated with a stream of gaseous hydrochloric acid for 1 hour at 0*C. The temperature of the mixture is allowed to return to room temperature, stirring is continued at this temperature for 18 hours 25 and the mixture is concentrated under reduced pressure. The residue thus obtained is triturated in ether, filtered off and dried under reduced pressure.

26 6.62 g of product are obtained in the form of a white powder which is used as is in the following stage. Yield = 70% Melting point = 138*C 5 1.8.2. 1,1-Dimethylethyl (S)-[1-[(4-ethylpiperidin 1-yl)carbonyl]-4-[5-ethyl-i-(triphenyl methyl)-lH-imidazol-4-yl]butyl]carbamate 0.37 g (2.9 mmol) of diisopropylethylamine and 0.46 g (1.2 mmol) of [(benzotriazol-1 10 yl)oxy]tris(dimethylamino)phosphonium hexafluorophosphate are successively added at 0*C, under nitrogen and with stirring, to a mixture of 0.6 g (1.08 mmol) of (S)-a-[[(1,1-dimethylethoxy)carbonyl] amino]-5-ethyl-1-(triphenylmethyl)-lH-imidazole 15 4-pentanoic acid and 0.18 g (1.2 mmol) of 4-ethyl piperidine hydrochloride in 8 ml of dichloromethane. The temperature of the mixture is allowed to return to room temperature, stirring is continued at this temperature for 18 hours and the reaction mixture is 20 concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed successively with 80 ml of a 1N aqueous hydrochloric acid solution, 50 ml of a saturated sodium hydrogen carbonate solution and 50 ml of a saturated sodium 25 chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, 27 elution being carried out with a methanol:dichloro methane (2:98) mixture. 0.7 g of product is obtained in the form of a viscous oil. 5 Yield = 98% 1.9. (S)-5-Ethyl-a-[(4-ethylpiperidin 1-yl)carbonyl]-1-(triphenylmethyl) 1H-imidazole-4-butanamine hydrochloride (1:1) A solution of 0.7 g (1.07 mmol) of 10 1,1-dimethylethyl (S)-[1-[(4-ethylpiperidin-1-yl) carbonyl]-4-[5-ethyl-i-(triphenylmethyl)-lH-imidazol-4 yl]butyllcarbamate in 50 ml of benzene is treated with a stream of gaseous hydrochloric acid for 15 minutes at 0*C. The temperature of the mixture is allowed to 15 return to room temperature, stirring is continued at this temperature for 1.5 hours and the mixture is concentrated under reduced pressure. The residue thus obtained is triturated in ether, filtered off and dried under reduced pressure. 20 0.61 g of product is obtained in the form of a white powder which is used as is in the following stage. Yield = 97% Example 2 (8)-5-Methyl-a-[[4-(trifluoromethyl)-piperidin-l 25 yl]carbonyl]-1-(triphenylmethyl)-1H-imidazole-4 butanamine hydrochloride (1:1) 28 2.1. 1,1-Dimethylethyl (S)-[4-[5-methyl-i-(tri phenylmethyl)-lH-imidazol-4-yl]-1-[[4-(tri fluoromethyl)piperidin-1-yl]carbonyllbutyl] carbamate 5 2.2.1. (S)-a-[[(1,1-Dimethylethoxy)carbonyllamino] 5-methyl-i-(triphenylmethyl)-1H-imidazole 4-pentanoic acid It is prepared according to the method described in Example 1.7, from methyl 10 (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino] 5-[5-methyl-i-(triphenylmethyl)-lH-imidazol-4-yl] pentanoate. 2.2.2. 1,1-Dimethylethyl (S)-[4-[5-methyl-l-(tri phenylmethyl)-lH-imidazol-4-yl]-1-[[4-(tri 15 fluoromethyl)piperidin-1-yl]carbonyl]butyl] carbamate 0.834 g (2.2 mmol) of [(benzotriazol 1-yl)oxy]tris(dimethylamino)phosphonium hexafluoro phosphate is added portionwise at 0*C, under argon and 20 with stirring, to a mixture of 1.08 g (2 mmol) of (S)-a-[[(1,1-dimethylethoxy)carbonyl]amino]-5-methyl 1-(triphenylmethyl)-lH-imidazole-4-pentanoic acid, 0.306 g (2 mmol) of 4-(trifluoromethyl)piperidine and 1.04 ml (6 mmol) of diisopropylethylamine in 25 ml of 25 dichloromethane. The temperature of the mixture is allowed to return to room temperature, stirring is continued at this temperature for 18 hours and the reaction mixture is concentrated under reduced 29 pressure. The residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of a 1N aqueous hydrochloric acid solution, 50 ml of a saturated sodium hydrogencarbonate solution and 50 ml of a saturated 5 sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a methanol:dichloro methane (2:98) mixture. 10 1.2 g of product are obtained in the form of a viscous oil. Yield = 89% 2.2. (S)-5-Methyl-a-[[4-(trifluoromethyl) piperidin-1-ylcarbonyl]-1-(triphenylmethyl) 15 1H-imidazole-4-butanamine hydrochloride (1:1) A solution of 1.2 g (1.78 mmol) of 1,1-dimethylethyl (S)-[4-[5-methyl-l-(triphenyl methyl)-1H-imidazol-4-yl]-1-[[4-(trifluoromethyl) piperidin-1-yl]carbonyl]butyl]carbamate in 100 ml of 20 benzene is treated with a stream of gaseous hydrochloric acid for 20 minutes at 0*C. The reaction mixture is left stirring at this temperature for 1 hour and concentrated under reduced pressure. The residue thus obtained is triturated in ether, filtered off and 25 dried under reduced pressure. 1.05 g of product are obtained in the form of a white powder which is used as is in the following stage. Yield: 97% 30 Melting point = 78*C Example 3 (S)-a-[(4-Methoxypiperidin-1-yl)carbonyl]-5-methyl 1-(triphenylmethyl)-1H-imidazole-4-butanamine 5 hydrochloride (1:1) 3.1. 4-Methoxypiperidine hydrochloride 3.1.1. 1,1-Dimethylethyl 4-hydroxypiperidine 1-carboxylate 12 g (55 mmol) of bis(1,1-dimethylethyl) 10 dicarbonate, in solution of 50 ml of methanol, are added dropwise at room temperature to a solution of 5.06 g (50 mmol) of piperidin-4-ol in 50 ml of methanol. The reaction mixture is left stirring at this temperature for two hours and concentrated under 15 reduced pressure. The residue thus obtained is purified by chromatography on a column of silica gel, elution being carried out with a dichloromethane:methanol (95:5) mixture. 9.74 g of product are obtained in the form of an oil. 20 Yield = 97% 3.1.2. 1,1-Dimethylethyl 4-methoxypiperidine 1-carboxylate 1.59 g (39.8 mmol) of 60% sodium hydride in oil are added portionwise at O*C, under argon and with 25 stirring, to a mixture of 8 g (39.8 mmol) of 1,1-dimethylethyl 4-hydroxypiperidine-1-carboxylate and of 4.95 ml (79.5 mmol) of iodomethane in solution of 31 40 ml of dimethylformamide and stirring is continued at this temperature for 2 hours. The reaction mixture is poured into 100 ml of a saturated ammonium chloride solution and extracted with 2 times 200 ml of ethyl 5 acetate. The organic phases are combined, washed successively with 100 ml of water and 100 ml of a saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on 10 a column of silica gel, elution being carried out with an ethyl acetate:cyclohexane (2:8) mixture. 7.1 g of product are obtained in the form of an oil. Yield = 85% 3.1.3. 4-Methoxypiperidine hydrochloride 15 A solution of 7 g (32.5 mmol) of 1,1 dimethylethyl 4-methoxypiperidine-l-carboxylate in 100 ml of tetrahydrofuran is treated with a stream of gaseous hydrochloric acid for 30 minutes at O*C. The temperature of the mixture is allowed to return to room 20 temperature and stirring is continued for 18 hours at this temperature. The reaction mixture is concentrated under reduced pressure and the residue is triturated in ether, filtered off and dried under reduced pressure. 4.2 g of product are obtained in the form of a white 25 powder which is used as is in the following stage. Yield = 86% Melting point = 132 0 C 3.2. 1,1-Dimethylethyl (S)-El-[(4-methoxy- 32 piperidin-1-yl)carbonyl]-4-[5-methyl 1-(triphenylmethyl)-lH-imidazol-4-yl] butyl]carbamate 0.71 g (1.87 mmol) of [(benzotriazol-1-yl) 5 oxy]tris(dimethylamino)phosphonium hexafluorophosphate is added portionwise at 0*C, under nitrogen and with stirring, to a mixture of 0.918 g (1.7 mmol) of (S)-a-[[(1,1-dimethylethoxy)carbonyl]amino]-5-methyl 1-(triphenylmethyl)-1H-imidazole-4-pentanoic acid, 10 0.281 g (1.87 mmol) of 4-methoxypiperidine hydro chloride and 0.63 ml (3.57 mmol) of diisopropylethyl amine in 12 ml of dichloromethane. The temperature of the mixture is allowed to return to room temperature, stirring is continued at this temperature for 18 hours 15 and the reaction mixture is concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of a 0.5N aqueous hydrochloric acid solution, 50 ml of a saturated sodium hydrogencarbonate solution and 50 ml 20 of a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a methanol:dichloromethane (2:98) mixture. 25 1.05 g of product are obtained in the form of a viscous oil. Yield = 97% 3.3. (S)-a-[(4-Methoxypiperidin-1-yl)carbonyl]- 33 5-methyl-i-(triphenylmethyl)-lH-imidazole 4-butanamine hydrochloride (1:1) A solution of 1.05 g (1.65 mmol) of 1,1-dimethylethyl (S)-[1-[(4-methoxypiperidin-1-yl) 5 carbonyl]-4-[5-methyl-1-(triphenylmethyl)-lH-imidazol 4-yl]butyllcarbamate in 50 ml of benzene is treated with a stream of gaseous hydrochloric acid for 20 minutes at 0*C. The mixture is left stirring at this temperature for 30 minutes and concentrated under 10 reduced pressure. The residue thus obtained is triturated in ether, filtered off and dried under reduced pressure. 0.93 g of product is obtained in the form of a white powder which is used as is in the following stage. 15 Yield = 98% Melting point = 112*C Example 4 (S)-5-Methyl-a-[(4-methylenepiperidin-1-yl)-carbonyl] 1-(triphenylmethyl)-lH-imidazole-4-butanamine 20 hydrochloride (1:1) 4.1. 4-Methylenepiperidine hydrochloride 4.1.1. 1,1-Dimethylethyl 4-methylenepiperidine 1-carboxylate 17 ml of a 1.6M solution of n-butyllithium in 25 hexane are added at room temperature, under a nitrogen atmosphere, to a mixture of 9.81 g (27.5 mmol) of methyltriphenylphosphonium bromide in 60 ml of 34 anhydrous tetrahydrofuran. The mixture is left stirring for 4 hours at room temperature and a solution of 5 g (25 mmol) of 1,1-dimethylethyl 4-oxopiperidine 1-carboxylate in 20 ml of anhydrous tetrahydrofuran is 5 rapidly added. The reaction mixture is heated for 10 hours at the reflux temperature, poured into 400 ml of a saturated ammonium chloride solution and extracted with 2 times 300 ml of ether. The organic phases are combined, dried over sodium sulphate and concentrated 10 under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with an ethyl acetate:n-hexane (5:95) mixture. 2.8 g of product are obtained in the form of a glassy 15 oil. Yield = 57% 4.1.2. 4-Methylenepiperidine hydrochloride This compound is obtained, from 1,1-dimethyl ethyl 4-methylenepiperidine-1-carboxylate, according to 20 the method described in Example 3.1.3. 4.2. (S)-5-Methyl-a-[(4-methylenepiperidin-1-yl) carbonyl]-1-(triphenylmethyl)-lH-imidazole 4-butanamine hydrochloride (1:1) (S)-a-[[(1,1-Dimethylethoxy)carbonyl]amino] 25 5-methyl-i-(triphenylmethyl)-lH-imidazol-4-pentanoic [lacuna] is reacted with 4-methylenepiperidine hydro chloride according to the method described in Example 3.2. and 1,1-dimethylethyl (8)-[4-[5-methyl-i-(tri- 35 phenylmethyl)-lH-imidazol-4-yl]-1-[(4-methylene piperidin-1-yl)carbonyl]butyl]carbamate, an amorphous product, is obtained. Melting point = 85 0 C 5 This product is treated with a stream of gaseous hydrochloric acid according to the method described in Example 3.3. 0.74 g of product are obtained. Yield = 100% 10 Melting point = 148 0 C Example 5 (S)-a-[(4-Cyclopropylpiperidin-1-yl)-carbonyl]-5 methyl-l-(triphenylmethyl)-1H-imidazole-4-butanamine hydrochloride (1:1) 15 5.1. 4-Cyclopropylpiperidine hydrochloride 5.1.1. 4-Cyclopropylpiperidine 13 g (109 mmol) of 4-cyclopropylpyridine, in solution in 150 ml of acetic acid, are hydrogenated at 50*C in a Parr apparatus under a pressure of 0.35 MPa 20 (50 psi) in the presence of 0.7 g of platinum(IV) oxide. The reaction mixture is filtered through celite and the filtrate is concentrated under reduced pressure. 12.85 g of product are obtained, which product is used 25 as is in the following stage. Yield = 94% 5.1.2. 1,1-Dimethylethyl 4-cyclopropylpiperidine- 36 1-carboxylate 5 g (40 mmol) of 4-cyclopropylpiperidine are dissolved in 40 ml of dichloromethane, the mixture is cooled to 0*C and 6.98 g (32 mmol) of 5 bis(1,1-dimethylethyl) dicarbonate and 4.85 g (48 mmol) of triethylamine are added dropwise. The reaction mixture is concentrated and the residue is purified by chromatography on a column of silica gel, elution being carried out with a dichloromethane:methanol (99:1) 10 mixture. 4 g of product are obtained. Yield = 44% 5.1.3. 4-Cyclopropylpiperidine hydrochloride A stirred solution of 6.5 g (28.8 mmol) of 15 1,1-dimethylethyl 4-cyclopropylpiperidine-1-carboxylate in 100 ml of benzene is treated with a stream of gaseous hydrochloric acid for 30 minutes at 0*C. The temperature of the reaction mixture is allowed to return to room temperature, stirring is maintained for 20 4 hours at this temperature and the reaction mixture is concentrated under reduced pressure. The residue thus obtained is triturated in ether, filtered off and dried under reduced pressure. 4.1 g of product are obtained in the form of a white 25 powder which is used as is in the following stage. Yield = 88% Melting point = 186*C 5.2. 1,1-Dimethylethyl (S)-[1-[(4-cyclopropyl- 37 piperidin-1-yl)carbonyl]-4-[5-methyl-i-(tri phenylmethyl)-lH-imidazol-4-yl]butyl] carbamate A mixture of 6 g (11 mmol) of (S)-a 5 [[(1,1-dimethylethoxy)carbonylamino]-5-methyl-i-(tri phenylmethyl)-lH-imidazole-4-pentanoic acid, 1.79 g (11 mmol) of 4-cyclopropylpiperidine hydrochloride and 9.6 ml (55.5 mmol) of diisopropylethylamine in 100 ml of dichloromethane is stirred and 4.62 g (12.2 mmol) of 10 [(benzotriazol-1-yl)oxy]tris(dimethylamino)phosphonium hexafluorophosphate are added portionwise at 0*C, under argon and with stirring. The temperature of the mixture is allowed to return to room temperature, stirring is continued at this temperature for 4 hours and the 15 reaction mixture is concentrated under reduced pressure. The residue is taken up in 300 ml of ethyl acetate, washed successively with 100 ml of a 1N aqueous hydrochloric acid solution, 100 ml of a saturated sodium hydrogencarbonate solution and 100 ml 20 of a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a methanol:dichloromethane (1:99) mixture. 25 5 g of product are obtained. Yield = 70% 5.3. (S)-a-[(4-Cyclopropylpiperidin-1-yl) carbonyl]-5-methyl-1-(triphenylmethyl)- 38 1H-imidazole-4-butanamine hydrochloride (1:1) A stirred solution of 5.3 g (8 mmol) of 1,1-dimethylethyl (S)-[1-[(4-cyclopropylpiperidin 1-yl)carbonyl]-4-[5-methyl-l-(triphenylmethyl) 5 1H-imidazol-4-yl]butyl]carbamate in 200 ml of benzene is treated with a stream of gaseous hydrochloric acid for 30 minutes at 0*C. The temperature of the reaction mixture is allowed to return to room temperature, stirring is maintained for 3 hours and the reaction 10 mixture is concentrated under reduced pressure. The residue thus obtained is taken up in two times 280 ml of dichloromethane and dried under reduced pressure. 4.7 g of product are obtained in the form of a white powder which is used as is in the following stage. 15 Yield = 100% Melting point = 124*C Example 6 (S)-5-Methyl-a-[[4-(difluoromethylene)-piperidin-l yl]carbonyll-1-(triphenylmethyl)-lH-imidazole-4 20 butanamine hydrochloride (1:1) 6.1. 4-(Difluoromethylene)piperidine hydrochloride 6.1.1. 1,1-Dimethylethyl 4-(difluoromethylene) piperidine-1-carboxylate 45.6 ml (252 mmol) of hexamethylphosphor 25 amide, in solution in 30 ml of triglyme, are added dropwise at O*C under an argon atmosphere to 12 ml (120 mmol) of difluorobromomethane in solution in 39 180 ml of triglyme, which is kept stirring. The temperature of the reaction mixture is allowed to return to room temperature, stirring is maintained for 30 minutes at this temperature and the reaction mixture 5 is again cooled to 0*C. 11.94 g (60 mmol) of 1,1-dimethylethyl 4-oxopiperidine-l-carboxylate, in solution in 30 ml of triglyme, are then added, the temperature of the mixture is allowed to return to room temperature and the reaction mixture is stirred for 30 10 minutes at this temperature. The reaction mixture is heated for 2 hours at 80 0 C, cooled, poured into 1 litre of water and extracted with 3 times 400 ml of pentane. Washing is carried out with water, drying is carried out over sodium sulphate and evaporation is carried 15 out. The residue is purified by chromatography on a column of silica gel, elution being carried out with a cyclohexane:ethyl acetate (97:3) mixture. 8.5 g of product are obtained. Yield = 61% 20 6.1.2. 4-(Difluoromethylene)piperidine hydrochloride This compound is obtained in the form of a white powder, from 1,1-dimethylethyl 4-(difluoro methylene)piperidine-l-carboxylate, according to the method described in Example 3.1.3. 25 Yield = 100% Melting point = 196"C 6.2. (S)-5-Methyl-a-[[4-(difluoromethylene) piperidin-1-yl]carbonyl]-1-(triphenylmethyl)- 40 1H-imidazole-4-butanamine hydrochloride (1:1) (S)-a-[[(1,1-Dimethylethoxy)carbonyl]amino] 5-methyl-1-(triphenylmethyl)-lH-imidazol-4-pentanoic [lacuna] is reacted with 4-(difluoromethylene) 5 piperidine hydrochloride according to the method described in Example 3.2 and 1,1-dimethylethyl (S)-[4 [5-methyl-i-(triphenylmethyl)-1H-imidazol-4-yl]-1-[[4 (difluoromethylene)piperidin-1-yl)carbonyl]butyl] carbamate is obtained in the form of a glassy solid. 10 Yield = 75% Melting point = 86*C This product is treated with a stream of gaseous hydrochloric acid according to the method described in Example 3.3. 15 The product is obtained in the form of a white powder. Yield = 99% Melting point = 117*C Example 7 (S)-5-Methyl-a-[(4-(methylthio)piperidin-1-yl] 20 carbonyl]-1-(triphenylmethyl)-lH-imidazole-4-butanamine hydrochloride (1:1) 7.1. 4-(Methylthio)piperidine hydrochloride 7.1.1. 1,1-Dimethylethyl 4-[(methylsulphonyl)oxy] piperidine-1-carboxylate 25 5.6 ml (72 mmol) of methanesulphonyl chloride are added dropwise at 0*C under nitrogen to a solution of 13.9 g (69 mmol) of 1,1-dimethylethyl 4-hydroxy- 41 piperidine-l-carboxylate and of 5.6 ml (76 mmol) of triethylamine in 80 ml of dichloromethane. The reaction mixture is left stirring for 6 hours at this temperature and is concentrated under reduced pressure. 5 The residue is taken up in 200 ml of ethyl acetate and washed successively with 2 times 100 ml of a 1N aqueous hydrochloric acid solution, 100 ml of water and 100 ml of a saturated sodium chloride solution. The organic layer is dried over sodium sulphate and concentrated 10 under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with ethyl acetate. 16.2 g of product are obtained in the form of white crystals. 15 Yield = 95% Melting point = 93.9*C 7.1.2. 1,1-Dimethylethyl 4-(methylthio)piperidine 1-carboxylate A mixture of 2.47 g (10 mmol) of 20 1,1-dimethylethyl 4-[(methylsulphonyl)oxy]piperidine 1-carboxylate, 0.71 g (10.1 mmol) of sodium thio methoxide and 0.37 g (1 mmol) of tetrabutylammonium iodide in 10 ml of tetrahydrofuran is stirred for 72 hours at room temperature and then the mixture is 25 concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with an n-hexane:ethyl acetate (9:1) mixture.

42 1.5 g of product are obtained in the form of a viscous oil. Yield = 63% 7.1.3 4-(Methylthio)piperidine hydrochloride 5 This compound is obtained, from 1,1-dimethyl ethyl 4-(methylthio)piperidine-1-carboxylate, according to the method described in Example 3.1.3. Yield = 100% Melting point = 156.5*C 10 7.2. (8)-5-Methyl-a-[[4-(methylthio)piperidin 1-yl]carbonyl]-1-(triphenylmethyl) 1H-imidazole-4-butanamine hydrochloride (1:1) (S)-a-[[(1,1-Dimethylethoxy)carbonyl]amino] 5-methyl-l-(triphenylmethyl)-1H-imidazol-4-pentanoic 15 [lacuna] is reacted with 4-(methylthio)piperidine hydrochloride according to the method described in Example 3.2 and 1,1-dimethylethyl (S)-[4-[5-methyl 1-(triphenylmethyl)-1H-imidazol-4-yl]-1-[[4-(methyl thio)piperidin-1-ylcarbonyl]butyl]carbamate is 20 obtained in the form of an amorphous powder. Yield = 93% Melting point = 101.2*C This product is treated with a stream of gaseous hydrochloric acid according to the method described in 25 Example 3.3. The product is obtained in the form of an amorphous powder. Yield = 100% 43 Melting point = 127.7 0 C Example 8 (S)-5-Methyl-a-[(4-methyl-1,2,3,6-tetrahydro-pyridin-l yl)carbonyl]-1-(triphenylmethyl)-lH-imidazole-4 5 butanamine hydrochloride (1:1) 8.1. 4-Methyl-1,2,3,6-tetrahydropyridine hydrochloride 8.1.1. 1,1-Dimethylethyl 4-methyl 1,2,3,6-tetrahydropyridine-l-carboxylate 10 A solution of 18 ml (28.8 mmol) of methyllithium in ether is added at 0*C under nitrogen to a solution of 4.95 g (25 mmol) of 1,1-dimethylethyl 4-oxopiperidine-l-carboxylate in 30 ml of anhydrous tetrahydrofuran and stirring is continued for 2 hours 15 at this temperature. 3 ml (38 mmol) of methanesulphonyl chloride are then added dropwise, stirring is continued for 4 hours at 0*C and then the reaction mixture is concentrated under reduced pressure. The residue is taken up in 200 ml of ethyl acetate and washed 20 successively with 2 times 100 ml of a 0.1N aqueous hydrochloric acid solution, 100 ml of water and 100 ml of a saturated sodium chloride solution. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The residue is taken up in 25 100 ml of toluene and 15 ml of triethylamine, heated for 18 hours at the reflux temperature and concentrated under reduced pressure. The residue is purified by 44 chromatography on a column of silica gel, elution being carried out with an n-hexane:ether (95:5) mixture. 0.9 g of product is obtained in the form of a viscous oil. 5 Yield = 18% 8.1.2. 4-Methyl-1,2,3,6-tetrahydropyridine hydrochloride This compound is obtained, from 1,1-dimethylethyl 4-methyl-1,2,3,6-tetrahydropyridine 10 1-carboxylate, according to the method described in Example 3.1.3. Yield = 100% 8.2. (S)-5-Methyl-a-[(4-methyl-1,2,3,6-tetrahydro pyridin-1-yl)carbonyl]-1-(triphenylmethyl) 15 1H-imidazole-4-butanamine hydrochloride (1:1) (S)-a-[[(1,1-Dimethylethoxy)carbonyl]amino] 5-methyl-1-(triphenylmethyl)-lH-imidazol-4-pentanoic [lacuna] is reacted with 4-methyl-1,2,3,6-tetrahydro pyridine hydrochloride according to the method 20 described in Example 3.2 and 1,1-dimethylethyl (S)-[4-[5-methyl-i-(triphenylmethyl)-1H-imidazol-4-yl] 1-[(4-methyl-1,2,3,6-tetrahydropyridin-1-yl)carbonyl] butyl]carbamate is obtained in the form of an amorphous powder. 25 Yield = 90% Melting point = 90.7 0 C This product is treated with a stream of gaseous hydrochloric acid according to the method described in 45 Example 3.3. The product is obtained in the form of a white powder. Yield = 100% Melting point = 118*C 5 Example 9 1-[2-Amino-5-[5-methyl-l-(triphenylmethyl)-lH-imidazol 4-yl]-l-oxopentyl]-hexahydro-5H-1,4-diazepin-5-one hydrochloride 9.1. Hexahydro-5H-1,4-diazepin-5-one hydrochloride 10 9.1.1. 1-(Phenylmethyl)-hexahydro-5H-1,4-diazepin 5-one A solution of 9.86 g (87.18 mmol) of hydroxylamine-O-sulphonic acid in acetic acid is added over 10 minutes to a solution of 11 g (58.12 mmol) of 15 1-phenylmethylpiperidin-3-one in 60 ml of formic acid. The reaction mixture is heated for 4 hours at the reflux temperature. The mixture is allowed to cool and is poured into an ice:water mixture and then neutralized with a 5% aqueous sodium hydroxide 20 solution. Extraction is carried out with chloroform and the organic phase is recovered, dried and evaporated to dryness. The residue is purified by chromatography on a column of silica gel, elution being carried out with a dichloromethane:methanol (2:98) mixture. 25 6.94 g of product are obtained. Yield = 58.5% 9.1.2. Hexahydro-5H-1,4-diazepin-5-one hydrochloride 46 5.5 g (26.2 mmol) of 1-(phenylmethyl) hexahydro-1H-1,4-diazepin-5-one are dissolved in 100 ml of methanol, 0.7 g of 10% palladium-on-charcoal is added and the reaction mixture is heated for 3 hours at 5 45 0 C under a pressure of 0.29 MPa (42 psi). The reaction mixture is filtered, the solvents are evaporated and the residue is taken up in 30 ml of ethanol. Heating is carried out, the insoluble material is filtered off and rinsed with ether and the solvent 10 is evaporated. 2.44 g of product are obtained in the form of an off white powder which is used as is in the following stage. 9.2. 1-[2-Amino-5-[5-methyl-l-(triphenylmethyl) 15 1H-imidazol-4-yll-1-oxopentyl]-hexahydro 5H-1,4-diazepin-5-one hydrochloride 9.2.1. 1,1-Dimethylethyl (S)-[4-[5-methyl-1-(tri phenylmethyl)-lH-imidazol-4-yl]-1-[(5-oxo hexahydro-5H-1,4-diazepin-1-yl)carbonyl] 20 butyl]carbamate 2.15 g (4 mmol) of (S)-a-[[(1,1-dimethyl ethoxy)carbonyl]amino]-5-methyl-l-(triphenylmethyl)-1H imidazol-4-pentanoic acid, followed in succession by 2.8 ml (16 mmol) of N,N-diisopropylethylamine and by 25 1.5 g (4 mmol) of O-(benzotriazol-1-yl) N,N,N',N'-tetramethyluronium hexafluorophosphate, are added at OC to a solution of 0.6 g (4 mmol) of hexahydro-5H-1,4-diazepin-5-one hydrochloride in 40 ml 47 of dichloromethane. The temperature of the reaction mixture is allowed to return to room temperature, stirring is continued overnight at this temperature and the reaction mixture is concentrated under vacuum. The 5 residue is taken up in 200 ml of ethyl acetate and washed successively with 3 times 30 ml of a 1N aqueous hydrochloric acid solution, 2 times 20 ml of a saturated sodium hydrogencarbonate solution and then 20 ml of a saturated sodium chloride solution. The 10 organic layer is dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a dichloro methane:methanol (98:2 to 97:3) gradient. 15 1.87 g of product are obtained in the form of an off white foam. Yield = 74% 9.2.2. 1-[2-Amino-5-[5-methyl-l-(triphenylmethyl) 1H-imidazol-4-yl]-1-oxopentyl]-hexahydro 20 5H-1,4-diazepin-5-one hydrochloride A solution of 1.87 g (2.94 mmol) of 1,1-dimethylethyl (S)-[4-[5-methyl-l-(triphenyl methyl)-lH-imidazol-4-yl]-1-[(5-oxohexahydro 5H-1,4-diazepin-1-yl)carbonyl]butyl]carbamate in 200 ml 25 of toluene is treated with a stream of gaseous hydrochloric acid for 10 seconds at 0*C. The temperature of the mixture is allowed to return to room temperature and then the raaction mixture is 48 concentrated under reduced pressure. The residue is dissolved in a minimum volume of dichloromethane and 200 ml of ether are added. The mixture is triturated, filtered and dried. 5 1.64 g of product are obtained, which product is used as is in the following stage. Yield = 97% Example 10 (S) -a-Amino-N-cyclopentyl-N, 5-dimethyl 10 1- (triphenylmethyl) -lH-imidazole-4-pentanamide hydrochloride 10.1. N-Methylcyclopentanamine hydrochloride 10.1.1. N-Cyclopentylformamide A mixture of 10 g (117 mmol) of cyclopentan 15 amine and of 10.8 ml (140 mmol) of ethyl formate is heated for 4 hours at the reflux temperature and then the reaction mixture is concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with 20 an ethyl acetate:cyclohexane (1:9 to 6:4) gradient. 10 g of product are obtained in the form of an oil. Yield = 75% 10.1.2. 1, 1-Dimethylethyl cyclopentylmethylcarbamate 50 ml (50 mmol) of a 1M solution of lithium 25 aluminium hydride in tetrahydrofuran are added dropwise at 0*C under nitrogen to a solution of 4.37 g (38 mmol) of N-cyclopentylformamide in 20 ml of anhydrous 49 tetrahydrofuran. The temperature of the mixture is allowed to return to room temperature and the reaction mixture is heated at the reflux temperature for 8 hours. The reaction mixture is cooled to 0*C and 5 acidified to pH 2 with a 1N aqueous hydrochloric acid solution and the pH is adjusted to 8 with potassium carbonate. 8.6 g (40 mmol) of bis(1,1-dimethylethyl) dicarbonate, in solution in 40 ml of methanol, are then added dropwise. The temperature of the mixture is 10 allowed to return to room temperature and stirring is continued for 15 hours at this temperature. The reaction mixture is extracted with 2 times 300 ml of ether and the organic phases are combined. They are washed with 2 times 200 ml of a 1N aqueous hydrochloric 15 acid solution and then with 200 ml of a saturated sodium chloride solution. The combined organic phases are dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, 20 elution being carried out with a cyclohexane:ether (95:5) mixture. 2.91 g of product are obtained in the form of an oil. Yield = 38% 10.1.3. N-Methylcyclopentanamine hydrochloride 25 A solution of 2.9 g (14.5 mmol) of 1,1-dimethylethyl cyclopentylmethylcarbamate is treated with a stream of gaseous hydrochloric acid for 5 minutes at 0*C. The mixture is left stirring for 50 4 hours at this temperature and is then concentrated under reduced pressure. 1.96 g of product are obtained in the form of a white hygroscopic powder. 5 Yield = 100% Melting point = 123-126*C 10.2. (S)-a-Amino-N-cyclopentyl-N,5-dimethyl 1-(triphenylmethyl)-1H-imidazole 4-pentanamide hydrochloride 10 10.2.1. 1,1-Dimethylethyl (S)-[1-[(cyclopentylmethyl amino)carbonyll-4-[5-methyl-1-(triphenyl methyl)-1H-imidazol-4-yl]butyl]carbamate 0.68 g (5 mmol) of N-methylcyclopentanamine hydrochloride, 2.15 ml (12.3 mmol) of N,N-diisopropyl 15 ethylamine and 1.98 g (5.24 mmol) of O-(benzotriazol 1-yl) -N,N,N',N' -tetramethyluronium hexafluorophosphate are successively added, at 0*C under nitrogen, to a solution of 2.57 g (4.76 mmol) of (S)-a [[(1,1-dimethylethoxy)carbonyl]amino]-5-methyl-i-(tri 20 phenylmethyl)-1H-imidazol-4-pentanoic [lacuna] in 15 ml of dichloromethane. The temperature of the reaction mixture is allowed to return to room temperature, stirring is continued for 15 hours at this temperature and the reaction mixture is concentrated under vacuum. 25 The residue is taken up in 150 ml of ethyl acetate and washed successively with 100 ml of a 1N aqueous hydrochloric acid solution, 100 ml of a saturated sodium hydrogencarbonate solution and then 100 ml of a 51 saturated sodium chloride solution. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being 5 carried out with an ethyl acetate:cyclohexane (3:7 to 8:2) gradient. 2.26 g of product are obtained in the form of an amorphous solid. Yield = 77% 10 Melting point = 86-90*C 10.2.2. (8)-a-Amino-N-cyclopentyl-N,5-dimethyl 1-(triphenylmethyl)-lH-imidazole 4-pentanamide hydrochloride A solution of 2.2 g (3.5 mmol) of 15 1,1-dimethylethyl (S)-[1-[(cyclopentylmethylamino) carbonyl]-4-[5-methyl-i-(triphenylmethyl)-1H-imidazol 4-yl]butyllcarbamate is treated with a stream of gaseous hydrochloric acid for 5 minutes at 0*C. The mixture is left stirring for 5 hours at this 20 temperature and is then concentrated under reduced pressure. 2 g of product are obtained, which product is used as is in the following stage. Yield = 100% 25 Melting point = 138-142*C Example 11 (S)-a-Amino-N,5-dimethyl-N-pyrrolidin-1-yl- 52 1-(triphenylmethyl)-1H-imidazole-4-pentan-amide hydrochloride 11.1. N-Methylpyrrolidin-1-amine hydrochloride 11.1.1. 1,1-Dimethylethyl pyrrolidin-1-ylcarbamate 5 1.13 ml (8.15 mmol) of triethylamine are added dropwise to a solution of 1 g (8.15 mmol) of pyrrolidin-1-amine hydrochloride and of 1.62 g (7.4 mmol) of bis(1,1-dimethylethyl) dicarbonate in 8 ml of dichloromethane. The mixture is left stirring 10 for 15 hours and is concentrated under reduced pressure. The residue is taken up in 100 ml of ether and washed successively with 10 ml of water and 100 ml of a saturated aqueous sodium chloride solution. The organic layer is dried over sodium sulphate, filtered 15 through silica and concentrated under reduced pressure. 1 g of product is obtained. Yield = 67% Melting point = 108*C 11.1.2. 1,1-Dimethylethyl methylpyrrolidin-1-yl 20 carbamate 7.7 ml (7.7 mmol) of a 1M lithium bis (trimethylsilyl)amide solution in tetrahydrofuran are added dropwise at -78*C under nitrogen to a solution of 1.34 g (7 mmol) of 1,1-dimethylethyl pyrrolidin-1-yl 25 carbamate and of 1.75 ml (28 nmol) of methyl iodide in 3 ml of anhydrous tetrahydrofuran. The temperature of the mixture is allowed to return to room temperature and stirring is continued for 30 minutes at this 53 temperature. 150 ml of ether are added and washing is carried out successively with 100 ml of water and 100 ml of a saturated sodium chloride solution. The organic layer is dried over sodium sulphate, filtered 5 and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a cyclohexane:ethyl acetate (9:1) mixture. 0.75 g of product is obtained in the form of an oil. 10 Yield = 55% 11.1.3. N-Methylpyrrolidin-1-amine hydrochloride This product is prepared, from 0.75 g (3.7 mmol) of 1,1-dimethylethyl methylpyrrolidin-1-yl carbamate, according to the method described in 10.1.3. 15 0.5 g of product is obtained in the form of a viscous oil. Yield = 100% 11.2. (S)-a-Amino-N,5-dimethyl-N-pyrrolidin-1-yl 1-(triphenylmethyl)-lH-imidazole-4-pentan 20 amide hydrochloride 11.2.1. 1,1-Dimethylethyl (S)-[1-[(methylpyrrolidin 1-ylamino)carbonyl]-4-[5-methyl-l-(triphenyl methyl)-lH-imidazol-4-yl]butyl]carbamate The product is prepared according to the 25 procedure described in 10.2.1., from 1.8 g (3.3 mmol) of (S)-a-[[(1,1-dimethylethoxy)carbonyl]amino] 5-methyl-i-(triphenylmethyl)-1H-imidazol-4-pentanoic [lacuna] and from 0.48 g (3.5 mmol) of N- 54 methylpyrrolidin-l-amine hydrochloride. 1.8 g of product are obtained in the form of an amorphous solid. Yield = 88% 5 Melting point = 70-75 0 C 11.2.2. (S)-a-Amino-N,5-dimethyl-N-pyrrolidin-1-yl 1-(triphenylmethyl)-lH-imidazole-4-pentan amide hydrochloride The product is prepared according to the 10 procedure described in 10.2.2., from 1.8 g (2.8 mmol) of 1,1-dimethylethyl (8)-[l-[(methylpyrrolidin-1-yl amino)carbonyl]-4-[5-methyl-l-(triphenylmethyl) 1H-imidazol-4-yl]butyl]carbamate. 1.65 g of product are obtained in the form of an 15 amorphous solid. Yield = 100% Melting point = 130-135*C Example 12 (Compound No. 67) (8)-N-[3-[[[4-(5-Ethyl-lH-imidazol-4-yl)-1-[(4 20 ethylpiperidin-1-yl)carbonyl]butyl] amino]sulphonyl][1,1'-biphenyl]-2-yl]propan-amide hydrochloride (1:1) 12.1. (S)-N-[3-[[[l-[(4-Ethylpiperidin-1-yl) carbonyl]-4-[5-ethyl-l-(triphenylmethyl) 25 1H-imidazol-4-yl]butyl]amino] sulphonyl][1,1'-biphenyl]-2-yl]-N-(1-oxo propyl)propanamide 55 0.48 ml (3.4 mmol) of triethylamine is added dropwise at 0*C under nitrogen to a mixture of 0.435 g (1.25 mmol) of [bis(1-oxopropyl)amino] [1,1'-biphenyle]-3-sulphonyl chloride and of 0.61 g 5 (1.04 mmol) of (S)-5-ethyl-a-[(4-ethylpiperidin-1-yl) carbonyl]-1-(triphenylmethyl)-lH-imidazole-4-butan amine hydrochloride in 8 ml of dichloromethane. The mixture is left stirring for 4 hours and is concentrated under reduced pressure. The residue is 10 taken up in 100 ml of ethyl acetate, washed successively with 50 ml of a 1N aqueous hydrochloric acid solution, 50 ml of a saturated sodium hydrogen carbonate solution and 50 ml of a saturated sodium chloride solution, dried over magnesium sulphate and 15 concentrated under reduced pressure. 0.85 g of product is obtained in the form of a viscous oil which is used as is in the following stage. Yield = 95% 12.2. (S)-N-[3-[[[4-(5-Ethyl-1H-imidazol-4-yl) 20 1-[(4-ethylpiperidin-1-yl)carbonylibutyl] amino]sulphonyl][1,1'-biphenyl]-2-yl]propan amide hydrochloride (1:1) 0.85 g (0.95 mmol) of (S)-N-[3-[[[l [(4-ethylpiperidin-1-yl)carbonyl]-4-[5-ethyl-l-(tri 25 phenylmethyl)-lH-imidazol-4-yl]butyl]amino] sulphonyl][1,1'-biphenyl]-2-yl]-N-(1-oxopropyl) propanamide, in solution in a mixture of 30 ml of acetic acid and 10 ml of water, is heated for 16 hours 56 at the reflux temperature and the reaction mixture is concentrated under reduced pressure. The residue is taken up in 150 ml of ethyl acetate, washed successively with 50 ml of a saturated sodium hydrogen 5 carbonate solution and with 50 ml of a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a methanol:dichloro 10 methane (4:96) mixture. 0.44 g of product is obtained in the form of a base which is taken up in 10 ml of a 0.1N solution of hydrochloric acid in isopropanol and concentrated under reduced pressure. The residue is purified by 15 chromatography on an RP 18 column, elution being carried out with an acetonitrile:water (3:7) mixture. After lyophilization, 0.42 g of product is obtained in the form of a white powder. Yield = 69% 20 Melting point = 132 0 C [c]lD = +1120; (c = 0.2, methanol) Example 13 (Compound No. 40) (B)-N-[3-[[[4-(5-Methyl-lH-imidazol-4-yl)-1-[[4 (trifluoromethyl)piperidin-l-yl]carbonyl]butyll 25 amino]sulphonyl][1,1'-biphenyl]-2-yl]propanamide hydrochloride (1:1) 57 13.1. (S)-N-[3-[[[4-[5-Methyl-i-(triphenylmethyl) 1H-imidazol-4-yl]-1-[[4-(trifluoromethyl) piperidin-1-yl]carbonyl]butyllamino] sulphonyl][1,1'-biphenyl]-2-yl]-N-(1-oxo 5 propyl)propanamide 0.79 ml (5.7 mmol) of triethylamine is added dropwise at O*C under argon to a mixture of 0.65 g (1.72 mmol) of [bis(1-oxopropyl)amino] [1,1'-biphenyle]-3-sulphonyl chloride and of 1.05 g 10 (1.72 mmol) of (S)-5-methyl-a-[[4-trifluoromethyl) piperidin-1-yl]carbonyl]-1-(triphenylmethyl) 1H-imidazole-4-butanamine hydrochloride in 20 ml of dichloromethane. The temperature of the mixture is allowed to return to room temperature, stirring is 15 continued for 18 hours at this temperature and the reaction mixture is concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of a 1N aqueous hydrochloric acid solution, 50 ml of a saturated sodium 20 hydrogencarbonate solution and 50 ml of a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a 25 methanol:dichloromethane (2:98) mixture. 1.04 g of product are obtained in the form of a viscous oil. Yield = 70% 58 13.2. (S)-N-[3-[[[4-(5-Methyl-1H-imidazol-4-yl) 1-[[4-(trifluoromethyl)piperidin-l-yl] carbonyl]butyl]amino]sulphonyl] [1,1'-biphenyl]-2-yl]propanamide 5 hydrochloride (1:1) 1.02 g (1.1 mmol) of (S)-N-[3-[[[4-[5-methyl 1-(triphenylmethyl)-lH-imidazol-4-yl]-1-[[4-(trifluoro methyl)piperidin-1-yl]carbonyl]butyllamino]sulphonyl] [1,1'-biphenyl]-2-yl]-N-(1-oxopropyl)propanamide, in 10 solution in a mixture of 25 ml of acetic acid and 25 ml of water, are heated for 10 hours at the reflux temperature and the reaction mixture is concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed with 50 ml of a 15 saturated sodium hydrogencarbonate solution, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a methanol:dichloromethane (5:95) mixture. 0.42 g of 20 product is obtained in the form of a base which is taken up in 12 ml of a 0.1N solution of hydrochloric acid in isopropanol and concentrated under reduced pressure. The residue is purified by chromatography on an RP 18 column, elution being carried out with an 25 acetonitrile:water (3:7) mixture. After lyophilization, 0.33 g of product is obtained. Yield = 46% Melting point = 146-150 59 [a]* = +80* (c = 0.2, methanol) Example 14 (Compound No.34) (S)-N-[2-[[[1-[(4-Methoxypiperidin-1-yl)-carbonyl]-4 (5-methyl-lH-imidazol-4-yl)-butyl]amino]sulphonyl]-6 5 thien-2-ylphenyl]-propanamide hydrochloride (1:1) 14.1. (S)-1-[2-(3-Ethyl-1,1-dioxo-5-thien-2-yl 2H-1,2,4-benzothiadiazin-2-yl)-5-[5-methyl 1-(triphenylmethyl)-lH-imidazol-4-yl]-1-oxo pentyl]-4-methoxypiperidine 10 14.1.1. 2-[(l-Chloropropylidene)amino]-3-thien-2-yl benzenesulphonyl chloride 2.86 ml (33 mmol) of propionyl chloride are added dropwise at 0*C to a mixture of 3.8 g (15 mmol) of 2-amino-3-(thien-2-yl)benzenesulphonic acid and of 15 4 ml (49.5 mmol) of pyridine in 30 ml of dichloro methane. The reaction mixture is left stirring for 5 hours at this temperature and is then concentrated under reduced pressure. The residue is taken up in 40 ml of dichloromethane, 7.8 g (37.5 mmol) of 20 phosphorous pentachloride are added portionwise and the mixture is left stirring for 1 hour at 0*C and then for 2 hours at room temperature. 200 ml of ether are added to the reaction mixture, filtration is carried out and the filtrate is washed successively with 2 times 200 ml 25 of ice-cold water and 50 ml of a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue is 60 purified by chromatography on Florisil", elution being carried out rapidly with ether. 3.18 g of product are obtained after crystallization from pentane. 5 Yield = 61% Melting point = 74*C 14.1.2. (S)-l-[2-(3-Ethyl-1,1-dioxo-5-thien-2-yl 2H-1,2,4-benzothiadiazin-2-yl)-5-[5-methyl 1-(triphenylmethyl)-lH-imidazol-4-yl]-1-oxo 10 pentyl]-4-methoxypiperidine 0.55 ml (3.96 mmol) of triethylamine is added dropwise at 0*C to a mixture of 0.42 g (1.2 mmol) of 2 [(1-chloropropylidene)amino]-3-thien-2 ylbenzenesulphonyl chloride and of 0.69 g (1.2 mmol) of 15 (S)-a-[(4-methoxypiperidin-1-yl)carbonyl]-5-methyl 1-(triphenylmethyl)-lH-imidazole-4-butanamine hydrochloride in 15 ml of dichloromethane. The temperature of the mixture is allowed to return to room temperature, stirring is continued for 18 hours at this 20 temperature and the reaction mixture is concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of a 1N aqueous hydrochloric acid solution, 50 ml of a saturated sodium hydrogencarbonate solution and 50 ml 25 of a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. 1.07 g of product are obtained in the form of a viscous 61 oil which is used as is in the following stage. Yield = 100% 14.2. (S)-N-[2-[[[1-[(4-Methoxypiperidin-1-yl) carbonyl]-4-(5-methyl-lH-imidazol-4-yl) 5 butyl]amino]sulphonyl]-6-thien-2-ylphenyl] propanamide hydrochloride (1:1) 1.07 g (1.2 mmol) of (S)-l-[2-(3-ethyl 1,1-dioxo-5-thien-2-yl-2H-1,2,4-benzothiadiazin-2-yl) 5-[5-methyl-l-(triphenylmethyl)-1H-imidazol-4-yl] 10 1-oxopentyl]-4-methoxypiperidine, in solution in a mixture of 50 ml of acetic acid and 50 ml of water, are heated for 6 hours at the reflux temperature and the reaction mixture is concentrated under reduced pressure. The residue is taken up in 150 ml of ethyl 15 acetate, washed successively with 50 ml of a saturated sodium hydrogencarbonate solution and 50 ml of a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a column of 20 silica gel, elution being carried out with a methanol:dichloromethane (5:95) mixture. 0.43 g of product is obtained in the form of a base which is taken up in 12 ml of a 0.lN solution of hydrochloric acid in isopropanol and concentrated under 25 reduced pressure. The residue is purified by chromatography on an RP 18 column, elution being carried out with an acetonitrile:water (3:7) mixture. After lyophilization, 0.34 g of product is obtained in 62 the form of a white powder. Yield = 45% Melting point = 126*C []2* = +870 (c = 0.2, methanol)) 5 Example 15 (Compound No. 47) (S)-N-[2-[[[4-(5-Methyl-1H-imidazol-4-yl)-1-[(4 methylenepiperidin-1-yl)carbonyl] butyllamino]sulphonyll-6-thienyl-2-ylphenyl] propanamide hydrochloride (1:1) 10 This compound is prepared according to the method described in Example 14, from (8)-5-methyl a-[(4-methylenepiperidin-1-yl)carbonyl]-1-(triphenyl methyl)-lH-imidazole-4-butanamine hydrochloride and 2-[(1-chloropropylidene)amino]-3-thien-2-ylbenzene 15 sulphonyl chloride. Melting point = 115-120*C = +54* (c = 0.2, methanol) Example 16 (Compound No. 45) (8)-N-[2-[[[1-[( 4 -Cyclopropylpiperidin-1-yl)-carbonyl] 20 4-(5-methyl-lH-imidazol-4-yl)-butyl]amino]sulphonyl]-6 thienyl-2-ylphenyl]-propanamide hydrochloride (1:1) 16.1. (S)- 4 -Cyclopropyl--[2-(3-ethyl-1,1-dioxo 5-thien-2-yl-2H-1,2,4-benzothiadiazin-2-yl) 5-[5-methyl-i-(triphenylmethyl)-lH-imidazol 25 4-yl]-1-oxopentyl]piperidine 0.5 ml (3.63 mmol) of triethylamine is added 63 dropwise at 0*C to a mixture of 0.38 g (1.1 mmol) of 2-[(l-chloropropylidene)amino]- 3 -thien-2-ylbenzene sulphonyl chloride and of 0.64 g (1.1 mmol) of (S)-a-[( 4 -cyclopropylpiperidin-1-yl)carbonyl]-5-methyl 5 1-(triphenylmethyl)-lH-imidazole-4-butanamine hydrochloride in 20 ml of dichloromethane. The temperature of the mixture is allowed to return to room temperature, stirring is continued for 2 hours at this temperature and the reaction mixture is concentrated 10 under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of a 1N aqueous hydrochloric acid solution, 50 ml of a saturated sodium hydrogencarbonate solution and 50 ml of a saturated sodium chloride solution, dried over 15 sodium sulphate and concentrated under reduced pressure. 1.1 g of product are obtained in the form of a viscous oil which is used as is in the following stage. Yield = 100% 20 16.2. (S)-N-[2-[[[1-[( 4 -Cyclopropylpiperidin-1-yl) carbonyl]-4-(5-methyl-1H-imidazol-4-yl) butyl]amino]sulphonyl]-6-thienyl-2-ylphenyl] propanamide hydrochloride (1:1) 1.1 g (1.1 mmol) of (S)-4-cyclopropyl 25 1-[ 2

-(

3 -ethyl-1,1-dioxo-5-thien-2-yl-2H-1,2,4-benzo thiadiazin-2-yl)-5-[5-methyl-l-(triphenylmethyl) 1H-imidazol-4-yl]-1-oxopentyl]piperidine, in solution in a mixture of 25 ml of acetic acid and 25 ml of 64 water, are heated for 4 hours at the reflux temperature and the reaction mixture is concentrated under reduced pressure. The residue is taken up in 150 ml of ethyl acetate, washed successively with 50 ml of a saturated 5 sodium hydrogencarbonate solution and 50 ml of a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a 10 methanol:dichloromethane (2:98 to 8:92) mixture. 0.528 g of product is obtained in the form of the base. Yield = 80% 0.528 g of base is taken up in 10 ml of a 0.1N solution of hydrochloric acid in isopropanol and concentrated 15 under reduced pressure. The residue is purified by chromatography on an RP 18 column, elution being carried out with an acetonitrile:water (3:7) mixture. After lyophilization, 0.27 g of product is obtained in the form of a white powder. 20 Yield = 39% Melting point = 108-110 0 C [a]2" = +98* (c = 0.2, methanol) Example 17 (Compound No. 20) (8)-N-[3'-(Ethylamino)-3-[[[1-[(4-ethyl-piperidin-l 25 yl)carbonyl]-4-(5-methyl-lH-imidazol-4 yl)butyl]amino]sulphonyl]-[1,1'-biphenyl]-2 yllpropanamide hydrochloride (1:2) 65 17.1. (S)-l-[2-[7-Bromo-3-ethyl-5-(3-nitrophenyl) 1,1-dioxo-2H-1,2,4-benzothiadiazin-2-yl] 5-[5-methyl-i-(triphenylmethyl)-lH-imidazol 4-yl]-1-oxopentyl]-4-ethylpiperidine 5 17.1.1. 5-Bromo-2-[(l-chloropropylidene)amino] 3'-nitro[1,1'-biphenyl]-3-sulphonyl chloride a) Pyridine salt of 5-bromo-3'-nitro-2-[(l-oxo propyl)amino][1,1'-biphenyle]-3-sulphonic acid 1.62 ml (18.6 mmol) of propionyl chloride are 10 added dropwise at 0*C under a nitrogen atmosphere to a solution of 3.15 g (8.45 mmol) of 2-amino-5-bromo-3' nitro[1,1'-biphenyle]-3-sulphonic acid and 2.4 ml (29.6 mmol) of pyridine in 10 ml of dichloromethane. The temperature of the mixture is allowed to return to 15 room temperature and stirring is continued for 18 hours. The reaction mixture is concentrated under reduced pressure. The residue is used as is in the following stage. b) 5-Bromo-2-[(1-chloropropylidene)amino] 20 3'-nitro[1,1'-biphenyle]-3-sulphonyl chloride The residue obtained above is dissolved in 20 ml of dichloromethane and 4.6 g (21.2 mmol) of phosphorous pentachloride are added at 0*C under a nitrogen atmosphere. The temperature of the mixture is 25 allowed to return to room temperature and the mixture is kept stirring for 5 hours at this temperature. The reaction mixture is concentrated under reduced pressure and the residue is taken up in 150 ml of ether and 66 filtered through sintered glass. The filtrate is washed with 2 times 100 ml of water and then 100 ml of a saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced 5 pressure. 3 g of product are obtained in the form of a glassy oil which is used as is in the following stage. Yield = 77% 17.1.2. (S)-1-[2-[7-Bromo-3-ethyl-5-(3-nitrophenyl) 10 1,1-dioxo-2H-1,2,4-benzothiadiazin-2-yl] 5-[5-methyl-i-(triphenylmethyl)-lH-imidazol 4-yl]-1-oxopentyl]-4-ethylpiperidine 0.42 ml (3.5 mmol) of triethylamine is added dropwise at 0*C to a mixture of 0.53 g (1.15 mmol) of 15 5-bromo-2-[(l-chloropropylidene)amino] 3'-nitro[1,1'-biphenyle]-3-sulphonyl chloride and of 0.58 g (1.02 mmol) of (S)-a-[(4-ethylpiperidin-1-yl) carbonyl]-5-methyl-l-(triphenylmethyl)-lH-imidazole 4-butanamine hydrochloride in 5 ml of dichloromethane. 20 The temperature of the mixture is allowed to return to room temperature, stirring is continued for 18 hours at this temperature and the reaction mixture is concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed 25 successively with 50 ml of a 1N aqueous hydrochloric acid solution, 50 ml of a saturated sodium hydrogen carbonate solution and 50 ml of a saturated sodium chloride solution, dried over sodium sulphate and 67 concentrated under reduced pressure. 1 g of product is obtained in the form of a viscous oil which is used as is in the following stage. Yield = 100% 5 17.2. (S)-N-[5-Bromo-3-[[[1-[(4-ethylpiperidin 1-yl)carbonyl]-4-(5-methyl-lH-imidazol-4-yl) butyl]amino]sulphonyl] 3'-nitro[1,1'-biphenyl]- 2 -yl]propanamide 1 g (1 mmol) of (S)-l-[2-[7-bromo-3-ethyl 10 5-(3-nitrophenyl)-1,1-dioxo-2H-1,2,4-benzothiadiazin 2-yl]-5-[5-methyl-l-(triphenylmethyl)-1H-imidazol 4 -yl]-l-oxopentyl]-4-ethylpiperidine, in solution in a mixture of 30 ml of acetic acid and 20 ml of water, is heated for 8 hours at the reflux temperature and the 15 reaction mixture is concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed with 50 ml of a saturated sodium hydrogencarbonate solution, dried over sodium sulphate and concentrated under reduced pressure. The residue is 20 purified by chromatography on a column of silica gel, elution being carried out with a methanol:dichloro methane (5:95) mixture. 0.42 g of product is obtained in the form of a white solid. 25 Yield = 60% Melting point = 215*C 17.3. (8)-N-[3'-Amino-3-[[[l-[(4-ethylpiperidin 1-yl)carbonyl]-4-(5-methyl-lH-imidazol- 68 4-yl)butyl]amino]sulphonyl][1,1'-biphenyl] 2-yl]propanamide 0.4 g (0.56 mmol) of (S)-N-[5-bromo 3-[[[1-[(4-ethylpiperidin-1-yl)carbonyl]-4-(5-methyl 5 1H-imidazol-4-yl)butyl]amino]sulphonyl] 3'-nitro[1,1'-biphenyl]-2-yl]propanamide in 20 ml of ethanol is hydrogenated for 10 hours at room temperature at 0.35 MPa (50 psi) in the presence of 0.1 g of 10% palladium-on-charcoal. The reaction 10 mixture is filtered through celite and the filtrate is concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed with 50 ml of a saturated sodium hydrogencarbonate solution, dried over sodium sulphate and concentrated under reduced 15 pressure. 0.33 g of product is obtained in the form of a white solid. Yield = 100% Melting point = 160*C 20 17.4. (S)-N-[3'-(Ethylamino)-3-[[[1-[(4-ethyl piperidin-1-yl)carbonyl]-4-(5-methyl 1H-imidazol-4-yl)butyl]amino]sulphonyl] [1,1'-biphenyl]-2-yl]propanamide hydrochloride (1:2) 25 0.043 ml (0.78 mmol) of acetaldehyde and 70 mg of 10% palladium-on-charcoal are added to 0.33 g (0.56 mmol) of (S)-N-[3'-amino-3-[[[1-[(4-ethyl piperidin-1-yl)carbonyl]-4-(5-methyl-lH-imidazol-4-yl)- 69 butyl]amino]sulphonyl][1,1'-biphenyl]-2-yl]propanamide in 10 ml of ethanol and the mixture is stirred for 8 hours at room temperature under a pressure of 0.35 MPa (50 psi). The reaction mixture is filtered 5 through celite, 4 ml of a 0.1N solution of hydrochloric acid in isopropanol are added to the filtrate and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on an RP18 column, elution being carried out with an aceto 10 nitrile:water (3:7) mixture. After lyophilization, 0.2 g of product is obtained in the form of a white powder. Yield = 53% Melting point = 163*C 15 [o] 2 0 = +130* (c = 0.2, methanol) Example 18 (Compound No. 29) (S)-N-[3-[[El-[(4-Ethylpiperidin-1-yl)-carbonyl]-4-(5 methyl-lH-imidazol-4-yl)-butyl]amino]sulphonyl][1,1' biphenyl]-2-yl]-2-(2-methoxyethoxy)acetamide 20 hydrochloride (1:1) 18.1. (S)-2-Amino-N-[1-[(4-ethylpiperidin-1-yl) carbonyl]-4-[5-methyl-i-(triphenylmethyl) 1H-imidazol-4-yl]butyl][1,1'-biphenyl] 3-sulphonamide 25 0.365 ml (2.61 mmol) of triethylamine is added dropwise at 0*C under an argon atmosphere to a mixture of 0.5 g (0.87 mmol) of (S)-5-ethyl- 70 a-[(4-ethylpiperidin-1-yl)carbonyl]-1-(triphenyl methyl)-lH-imidazole-4-butanamine hydrochloride and of 0.281 g (1.05 mmol) of 2-amino[1,1'-biphenyle]-3 sulphonyl chloride in solution in 10 ml of 5 dichloromethane. The mixture is left stirring for 1 hour at this temperature and is then concentrated under reduced pressure. The residue is taken up in 50 ml of ethyl acetate, washed successively with 20 ml of a 1N hydrochloric acid solution, 20 ml of a 10 saturated sodium hydrogencarbonate solution and 20 ml of a saturated sodium chloride solution and then dried over magnesium sulphate. Finally, the organic phase is filtered and concentrated to dryness. The residue is purified by chromatography on a column of silica gel, 15 elution being carried out with a methanol:dichloro methane (1:99 then 3:97) mixture. 0.53 g of product is obtained in the form of a white solid. Yield = 79% 20 18.2. (S)-N-[3-[[El-[(4-Ethylpiperidin-1-yl) carbonyl]-4-(5-methyl-lH-imidazol-4-yl) butyl]aminolsulphonyl][1,1'-biphenyl]-2-yl] 2-(2-methoxyethoxy)acetamide hydrochloride (1:1) 25 2 g (13 mmol) of 2-(2-methoxyethoxy)acetyl chloride are added at room temperature under argon to 1 g (1.3 mmol) of (S)-2-amino-N-[l-[(4-ethylpiperidin 1-yl)carbonyl]-4-[5-methyl-1-(triphenylmethyl)- 71 1H-imidazol-4-yl]butyl][1,1'-biphenyl]-3-sulphonamide in solution in 10 ml of dimethylacetamide. The reaction mixture is left stirring at this temperature for 0.5 hour and is then cooled with an ice bath. 100 ml of 5 ethyl acetate and 100 ml of a 1N aqueous hydrochloric acid solution are added and the organic phase is recovered. It is washed successively with 50 ml of a saturated sodium hydrogencarbonate solution and 50 ml of a saturated sodium chloride solution and is then 10 concentrated under vacuum. The residue is taken up in an acetic acid:water:tetrahydrofuran (2:1:1) mixture, the mixture is heated for 3 hours at 80*C and is concentrated under vacuum. The residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml 15 of a 1N hydrochloric acid solution, 50 ml of a saturated sodium hydrogencarbonate solution and 50 ml of a saturated sodium chloride solution and is then dried over magnesium sulphate. Finally, the organic phase is filtered and concentrated under vacuum. The 20 residue is purified by chromatography on a column of silica gel, elution being carried out with a dichloromethane:methanol (98:2 then 90:10) mixture. 0.54 g of product is obtained in the form of the base. The hydrochloride is prepared in 10 ml of a 0.1N 25 solution of hydrochloric acid in isopropanol. After lyophilization, 0.57 g of product is obtained. Yield = 64.6% Melting point = 98*C 72 = +55.5* (c = 0.2, methanol) Example 19 (Compound No. 30) (S) -N- [2-Cyclopentyl-6- [ [El- [(4-ethyl-piperidin-l yl)carbonyl] -4- (5-methyl-lH-imidazol-4 5 yl) butyl] amino] sulphonyl] -phenyl] -N' -ethylurea hydrochloride (1:1) 19.1. (B) -2-amino-3-cyclopentyl-N- [1- [ (4-ethyl piperidin-1-yl) carbonyl] -4- [5-methyl-1- (tri phenylmethyl) -1H-imidazol-4-yl] butyl] benzene 10 sulphonamide 0.95 ml (6.75 mmol) of triethylamine is added dropwise at 0*C to a solution of 0.70 g (2.7 mmol) of 2-amino-3-cyclopentylbenzenesulphonyl chloride and of 1.54 g (2.7 mmol) of (S)-5-methyl-a-[(4-ethylpiperidin 15 1-yl) carbonyl] -1- (triphenylmethyl) -lH-imidazole 4-butanamine hydrochloride in 6 ml of dichloromethane. The reaction mixture is left stirring for 5 hours at this temperature and is then concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl 20 acetate, washed successively with 50 ml of a 1N hydrochloric acid solution, 50 ml of a saturated sodium hydrogencarbonate solution and 50 ml of a saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue is 25 purified by chromatography on a column of silica gel, elution being carried out with a dichloromethane:methanol (98:2) mixture.

73 1.8 g of product are obtained in the form of a viscous oil. Yield = 88% 19.2. (S)-N-[2-Cyclopentyl-6-[[[1-[(4-ethyl 5 piperidin-1-yl)carbonyl]-4-[5-methyl-i-(tri phenylmethyl)-lH-imidazol-4-yl]butyl]amino] sulphonyl]phenyl]-N'-ethylurea A solution of 0.75 g (1 mmol) of (S)-2-amino 3-cyclopentyl-N-[1-[(4-ethylpiperidin-1-yl)carbonyl] 10 4-[5-methyl-i-(triphenylmethyl)-1H-imidazol-4-yl] butyl]benzenesulphonamide and of 0.32 ml (4 mmol) of ethyl isocyanate in dimethylformamide is heated for 38 hours at 50*C and then the reaction mixture is concentrated under reduced pressure. The residue 15 obtained is purified by chromatography on a column of silica gel, elution being carried out with a methanol:dichloromethane (2:98) mixture. 0.53 g of product is obtained in the form of a white solid. 20 Yield = 65% Melting point = 115*C 19.3. (S)-N-[2-Cyclopentyl-6-[[[l-[(4-ethyl piperidin-1-yl)carbonyl]-4-(5-methyl 1H-imidazol-4-yl)butyl]amino]sulphonyl] 25 phenyl]-N'-ethylurea hydrochloride (1:1) A mixture of 0.53 g (0.64 mmol) of (B)-N-[2-cyclopentyl-6-[[[1-[(4-ethylpiperidin-1-yl) carbonyl]-4-[5-methyl-1-(triphenylmethyl)-lH-imidazol- 74 4-yl]butyl]amino]sulphonyl]phenyl]-N'-ethylurea and of 0.2 g of 10% palladium-on-charcoal in 8 ml of a 0.1N solution of hydrochloric acid in isopropanol is stirred for 40 hours at room temperature under a pressure of 5 0.35 MPa (50 psi). The mixture is filtered through celite and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified on an RP 18 column, elution being carried out with an acetonitrile:water (4:6) mixture. 10 After lyophilization, 0.30 g of product is obtained. Yield = 77% Melting point = 147*C [oi]" = +86* (c = 0.2, methanol) Example 20 (Compound No. 70) 15 (S)-N-[3-[[[4-(5-Chloro-1H-imidazol-4-yl)-l-[(4 ethylpiperidin-1-yl)carbonyl]butyl] amino]sulphonyl][1,1'-biphenyl]-2-yl]-propanamide hydrochloride (1:1) 20.1. (S)-N-[3-[[[1-[(4-Ethylpiperidin-1-yl) 20 carbonyl]-4-(lH-imidazol-4-yl)butyl]amino) sulphonyl][1,1'-biphenyl]-2-ylJpropanamide 20.1.1. 2-[(l-Chloropropylidene)-amino] [1,1'-biphenyle]-3-sulphonyl chloride It is prepared according to the method 25 described in Example 14.1.1., from 2-amino [1,1'-biphenyle]-3-sulphonic acid. The product is obtained in the form of a viscous oil 75 which is used as is in the following stage. 20.1.2. (S)-N-[3-[[1-[(4-Ethylpiperidin-1-yl carbonyl]-4-(lH-imidazol-4-yl)butyl]amino] sulphonyl][1,1'-biphenyl]-2-yl]propanamide 5 2.2 ml (15.84 mmol) of triethylamine are added dropwise at 0*C under nitrogen to a mixture of 1.8 g (5.3 mmol) of 2 -[(l-chloropropylidene)-amino [1,1'-biphenyle]-3-sulphonyl chloride and of 2.7 g (4.8 mmol) of (S)-a-[( 4 -ethylpiperidin-1-yl)carbonyl]-1 10 (triphenylmethyl)-lH-imidazole-4-butanamine hydrochloride in 30 ml of dichloromethane. The temperature of the mixture is allowed to return to room temperature, stirring is continued for 18 hours at this temperature and the reaction mixture is concentrated 15 under reduced pressure. The residue is taken up in 150 ml of ethyl acetate, washed successively with 100 ml of a 1N aqueous hydrochloric acid solution, 50 ml of a saturated sodium hydrogencarbonate solution and 50 ml of a saturated sodium chloride solution, 20 dried over sodium sulphate and concentrated under reduced pressure. The residue is taken up in a mixture of 60 ml of acetic acid and of 40 ml of water and the mixture is heated for 6 hours at the reflux temperature and the reaction 25 mixture is then concentrated under reduced pressure. The residue is taken up in 200 ml of ethyl acetate, washed successively with 50 ml of a saturated sodium hydrogencarbonate solution and 50 ml of a saturated 76 sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a methanol:dichloro 5 methane (5:95) mixture. 2.2 g of product are obtained in the form of a viscous oil. Yield = 81% 20.2. (S)-N-[3-[[[4-(5-Chloro-lH-imidazol-4-yl) 10 1-[(4-ethylpiperidin-1-yl)carbonyl]butyl] amino]sulphonyl][1,1'-biphenyl]-2-yl] propanamide hydrochloride (1:1) A solution of 0.56 g (1 mmol) of (S)-N-[3-{[[1-[(4-ethylpiperidin-1-yl]carbonyl] 15 4-(lH-imidazol-4-yl)butylamino] sulphonyl][1,1'-biphenyl]-2-yl]propanamide and of 0.116 g (1.1 mmol) of N-chlorosuccinimide in 2 ml of dimethylformamide is stirred for 5 hours at 0*C and the reaction mixture is then concentrated under reduced 20 pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a methanol:dichloromethane (2:98) mixture. 0.3 g of product is obtained in the form of the base. Yield = 50% 25 The base is taken up in 15 ml of a 0.1N solution of hydrochloric acid in isopropanol and concentration is carried out under reduced pressure. The residue thus obtained is purified on an RP 18 column, elution being 77 carried out with an acetonitrile:water (6:4) mixture. After lyophilization, 0.30 g of product is obtained. Yield = 94% Melting point = 100*C 5 [a]" = +102* (c = 0.2, methanol) Example 21 (Compound No. 23) (S)-N-[2-[[[1-[(4-Ethylpiperidin-1-yl)-carbonyl]-4-(5 methyl-1H-imidazol-4-yl)-butyl]amino]sulphonyl]-6 pyridin-2-ylphenyl]-propanamide hydrochloride (1:2) 10 21.1. (8)-N-[4-Bromo-2-[[[1-[(4-ethylpiperidin 1-yl)carbonyl]-4-[5-methyl-i-(triphenyl methyl)-lH-imidazol-4-ylbutyl]amino] sulphonyl]-6-iodophenyl]propanamide 2.24 g (4.4 mmol) of 2-[bis(1-oxopropyl) 15 amino]-5-bromo-3-iodobenzenesulphonyl chloride and then, dropwise, 1.84 ml (13.2 mmol) of triethylamine are successively added at O*C to a solution of 2.28 g (4 mmol) of (S)-5-methyl-a-[(4-ethylpiperidin-1-yl) carbonyl]-1-(triphenylmethyl)-lH-imidazole-4-butanamine 20 hydrochloride in 25 ml of dichloromethane. The mixture is left stirring for 6 hours at this temperature and is concentrated under reduced pressure. The residue is taken up in 200 ml of ethyl acetate, washed successively with 100 ml of a 1N aqueous hydrochloric 25 acid solution, 100 ml of a saturated sodium hydrogencarbonate solution and 100 ml of a saturated sodium chloride solution, dried over sodium sulphate 78 and concentrated under reduced pressure. The residue is taken up in 150 ml of tetrahydrofuran, a stream of gaseous ammonia is passed through the solution at 0*C for 2 hours and the mixture is concentrated under 5 reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a dichloromethane:methanol (98:2) mixture. 2.64 g of product are obtained in the form of a glassy 10 oil. Yield = 70% 21.2. (S)-N-[4-Bromo-2-[[[1-[(4-ethylpiperidin 1-yl)carbonyl]-4-[5-methyl-l-(triphenyl methyl)-lH-imidazol-4-yl)butyl]amino] 15 sulphonyl]-6-pyridin-2-ylphenyllpropanamide A mixture of 1.9 g (2 mmol) of (S)-N-[4-bromo-2-[[[1-[(4-ethylpiperidin-1-yl) carbonyl]-4-[5-methyl-l-(triphenylmethyl)-lH-imidazol 4-yl]butyllamino]sulphonyl]-6-iodophenyl]propanamide, 20 0.883 g (2.4 mmol) of 2 -(tributylstannyl)pyridine, 0.1 g (0.17 mmol) of bis(dibenzylideneacetone) palladium(0), 0.033 g (0.17 mmol) of copper iodide and 0.98 g (0.34 mmol) of triphenylarsine in 4 ml of dimethylformamide is heated at 80 0 C under argon for 25 5 hours. The reaction mixture is taken up in 150 ml of ethyl acetate and washed with two times 100 ml of a 10% aqueous ammonia solution and then with 50 ml of a saturated sodium chloride solution. The organic layer 79 is dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a dichloromethane:methanol (98:2) 5 mixture. 1.15 g of product are obtained in the form of a viscous oil. Yield = 64% 21.3. (S)-N-[4-Bromo-2-[[[1-[(4-ethylpiperidin 10 1-yl)carbonyl]-4-(5-methyl-lH-imidazol-4-yl) butyl]amino]sulphonyl]-6-pyridin-2-ylphenyl] propanamide 1.14 g (1.26 mmol) of (S)-N-[4-bromo 2-[[[1-[(4-ethylpiperidin-1-yl)carbonyl]-4-[5-methyl 15 1-(triphenylmethyl)-lH-imidazol-4-yl)butylamino] sulphonyl]-6-pyridin-2-ylphenyl]propanamide in a mixture of 30 ml of acetic acid and 15 ml of water are heated for 1 hour at the reflux temperature. The reaction mixture is concentrated under reduced pressure 20 and the residue is taken up in 150 ml of ethyl acetate. The organic layer is washed successively with 50 ml of a saturated sodium hydrogencarbonate solution and 50 ml of a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced 25 pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a methanol:dichloromethane (5:95) mixture.

80 0.66 g of product is obtained in the form of a glassy oil. Yield = 79.5% 21.4. (S)-N-[2-[[[1-[(4-Ethylpiperidin-1-yl) 5 carbonyl]-4-(5-methyl-1H-imidazol-4-yl) butyl]amino]sulphonyl]-6-pyridin-2-ylphenyl] propanamide hydrochloride (1:2) A mixture of 0.65 g (0.98 mmol) of (8)-N-[4-bromo-2-[[[1-[(4-ethylpiperidin-1-yl) 10 carbonyl]-4-(5-methyl-lH-imidazol-4-yl)butyl]amino] sulphonyl]-6-pyridin-2-ylphenyl]propanamide, 1.24 g (20 mmol) of ammonium formate and 0.065 g of palladium on-charcoal in 10 ml of methanol containing 0.2 ml of acetic acid is heated for 3 hours at the reflux 15 temperature and then the reaction mixture is concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of a saturated sodium hydrogen carbonate solution and 50 ml of a saturated sodium 20 chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a methanol:dichloro methane (5:95) mixture. 25 0.55 g of base is obtained in the form of a viscous oil. Yield = 96% The base is taken up in 25 ml of a 0.1N solution of 81 hydrochloric acid in isopropanol and concentrated under reduced pressure. The residue thus obtained is purified on an RP 18 column, elution being carried out with an acetonitrile:water (6:4) mixture. 5 0.44 g of product is obtained. Yield = 68% Melting point = 138-144*C [a]" = +121* (c = 0.2, methanol) Example 22 (Compound No. 22) 10 (S)-N-[2-[[[1-[(4-Ethylpiperidin-1-yl)-carbonyl]-4-(5 methyl-1H-imidazol-4-yl)-butyllamino]sulphonyl]-4 fluoro-6-thien-2-yl-phenyl]propanamide hydrochloride (1:1) 22.1. 2-[Bis(l-oxopropyl)amino]-5-fluoro-3-thien-2 15 ylbenzenesulphonyl chloride 22.1.1. N,N-Diethylethanamine salt of 2-[bis(1-oxo propyl)amino]-5-fluoro-3-thien-2-ylbenzene sulphonic acid A mixture of 10.92 g (40 mmol) of 2-amino-5 20 fluoro-3-thien-2-ylbenzenesulphonic acid and of 5.6 ml (40 mmol) of triethylamine in 77 ml (600 mmol) of propionic anhydride is heated for 24 hours at the reflux temperature and then the reaction mixture is concentrated under reduced pressure. The residue is 25 crystallized from an ethyl acetate:ether mixture. 16.9 [lacuna] of product are obtained. Yield = 90% 82 Melting point = 239 0 C 22.1.2. 2-[Bis(l-oxopropyl)amino]-5-fluoro-3-thien 2-ylbenzenesulphonyl chloride 14.22 g (68.2 mmol) of phosphorous 5 pentachloride are added at O*C under nitrogen to a solution of 1.60 g (34.1 mmol) of N,N-diethylethanamine salt of 2-[bis(1-oxopropyl)amino]-5-fluoro-3-thien 2-ylbenzenesulphonic acid in 60 ml of dichloromethane. The mixture is kept stirring for 5 hours at this 10 temperature, the temperature is allowed to rise to room temperature and stirring is continued for 1 hour at this temperature. 200 ml of ether are added, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in 15 800 ml of ether, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a Florisil' column, elution being carried out with an ether:pentane (1:9) then (1:1) mixture. 20 6.4 g of product are obtained in the form of a viscous oil. Yield = 55% 22.2. (S)-N-[2-[[[1-[(4-Ethylpiperidin-1-yl) carbonyl]-4-(5-methyl-lH-imidazol-4-yl) 25 butyl]amino]sulphonyl]-4-fluoro-6-thien-2-yl phenyl]propanamide hydrochloride (1:1) 6.16 g (18.1 mmol) of 2-[bis(1-oxopropyl) amino]-5-fluoro-3-thien-2-ylbenzenesulphonyl chloride 83 and then 5.5 mmol of triethylamine are added under nitrogen at 0*C to a solution of 9.83 g (17.2 mmol) of (S)-a-[(4-ethylpiperidin-1-yl)carbonyl]-5-methyl 1-(triphenylmethyl)-lH-imidazole-4-butanamine 5 hydrochloride in 60 ml of dichloromethane. The temperature of the reaction mixture is allowed to slowly return to room temperature, stirring is continued at this temperature for 15 hours and the reaction mixture is concentrated under reduced 10 pressure. The residue is taken up in 300 ml of ethyl acetate and washed successively with 300 ml of a 1N aqueous hydrochloric acid solution, 300 ml of a saturated sodium hydrogencarbonate solution and then 300 ml of a saturated sodium chloride solution. The 15 organic layer is dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue is heated for 12 hours in 225 ml of an acetic acid:water (2:1) mixture and concentrated under reduced pressure. The residue is taken up in 400 ml of 20 dichloromethane and washed successively with 200 ml of a saturated sodium hydrogencarbonate solution and then 200 ml of a saturated sodium chloride solution. The organic layer is dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue 25 thus obtained is purified by chromatography on a column of silica gel, elution being carried out with a dichloromethane:methanol (96:4) mixture. 7.7 g of product are obtained in the form of the base.

84 Yield = 74% Melting point = 145-150*C The hydrochloride is prepared by adding 45.1 ml of a 0.1N solution of hydrochloric acid in isopropanol to 5 2.5 g (4.5 mmol) of base. 2.7 g of product are obtained in the form of the hydrochloride. Melting point = 145*C [a][* = +1120 (c = 0.2, methanol) 10 Example 23 (Compound No. 53) (S)-N-[2-[[[1-[[4-(Difluoromethylene)-piperidin-1 yl]carbonyl]-4-(5-methyl-1H-imidazol-4-yl)butyl]amino] sulphonyl]-6-thien-2-ylphenylpropanamide hydrochloride (1:1) 15 This product is prepared according to the procedure described in Example 19, from 0.81 g (1.36 mmol) of (B)-5-methyl-a-[[4-(difluoromethylene) piperidin-1-yl]carbonyl]-1-(triphenylmethyl) 1H-imidazole-4-butanamine hydrochloride and from 0.47 g 20 (1.36 mmol) of 2-[(l-chloropropylidene)amino]-3-thien 2-ylbenzenesulphonyl chloride. 0.58 g of product is obtained in the form of a white powder. Yield = 67% 25 Melting point = 144-145*C [a]2D = +107.90 (c = 0.2, methanol) 85 Example 24 (Compound No. 25) (S)-N-[6-Cyclopentyl-2-[[[1-[(4-ethyl-piperidin-1 yl)carbonyl]-4-(5-methyl-lH-imidazol-4-yl)butyl] amino]sulphonyl]-phenyl]propanamide hydrochloride (1:1) 5 24.1. 3-Cyclopentyl-2-(diacetylamino)benzene sulphonyl chloride 24.1.1. N,N-Diethylethanamine salt of 3-cyclopentyl 2-(diacetylamino)benzenesulphonic acid 6.5 g (19 mmol) of N,N-diethylethanamine salt 10 of 2-amino-3-cyclopentylbenzenesulphonic acid, in solution in acetyl chloride, are heated for 48 hours at the reflux temperature and then the reaction mixture is concentrated under reduced pressure. 8.22 g of product are obtained, which product is used 15 as is in the following stage. Yield = 95% Melting point = 186*C 24.1.2. 3-Cyclopentyl-2-(diacetylamino)benzene sulphonyl chloride 20 This compound is prepared according to the procedure described in Example 22.1, from 8.2 g (18.1 mmol) of [lacuna] 3-cyclo-pentyl-2 (diacetylamino)benzenesulphonic acid. 3.81 g of product are obtained in the form of a viscous 25 oil which is used as is in the following stage. Yield = 57% 24.2. (S)-N-[6-Cyclopentyl-2-[[[l-[(4-ethyl piperidin-1-yl)carbonyl]-4-(5-methyl- 86 1H-imidazol-4-yl)butyl]amino]sulphonyl] phenyl]propanamide hydrochloride (1:1) This product is prepared according to the procedure described in Example 22.1, from 0.743 g 5 (2 mmol) of 3-cyclopentyl-2-(diacetylamino)benzene sulphonyl chloride and from 1.14 g (2 mmol) of (S)-a-[(4-ethylpiperidin-1-yl)carbonyl]-5-methyl 1-(triphenylmethyl)-lH-imidazole-4-butanamine [lacuna]. 0.73 g of product is obtained. 10 Yield = 60% Melting point = 124*C [a]"* = +890 (c = 0.2, methanol) Example 25 (Compound No. 64) (S)-N-[2-[[[4-(5-Methyl-1H-imidazol-4-yl)-1-[(5 15 oxohexahydro-lH-1,4-diazepin-1-yl)carbonylibutyl] amino]sulphonyl]-6-thien-2-yl-phenyl]propanamide hydrochloride (1:1) 25.1. 1-[2-[[(2-Amino-3-thien-2-ylphenyl) sulphonyl]amino]-5-[5-methyl-i-(triphenyl 20 methyl)-lH-imidazol-4-yl]-1-oxopentyl]-hexa hydro-5H-1,4-diazepin-5-one 0.618 g (2.26 mmol) of 2-amino-3-thien-2 ylbenzenesulphonyl chloride in 80 ml of dichloromethane is placed under argon and 1.29 mg (2.26 mmol) of 1-[2 25 amino-5-[5-methyl-1-(triphenylmethyl)-lH-imidazol-4 yl]-1-oxopentyl]-hexahydro-5H-1,4-diazepin-5-one hydrochloride are added. The mixture is cooled to 0*C 87 with an ice bath and 0.94 ml (6.74 mmol) of triethylamine is slowly added. The temperature of the reaction mixture is allowed to return to room temperature and stirring is continued overnight at this 5 temperature. 10 ml of a 0.5N aqueous hydrochloric acid solution are then added and the organic phase is washed with a 0.5N aqueous hydrochloric acid solution and then with a saturated sodium chloride solution and dried over magnesium sulphate. The residue is purified by 10 chromatography on a column of silica gel, elution being carried out with a dichloromethane:methanol (97.5:2.5) mixture. 1.33 g of product are obtained. Yield = 76% 15 25.2. (S)-N-[2-[[[4-[5-Methyl-1-(triphenylmethyl) 1H-imidazol-4-yll-1-[(5-oxohexahydro 1H-1,4-diazepin-1-yl)carbonyl]butylamino] sulphonyl]-6-thien-2-ylphenyl]propanamide 1.33 g (1.72 mmol) of 1-[2[[(2-amino-3-thien 20 2-ylphenyl)sulphonyl]amino]-5-[5-methyl-1-(tri phenylmethyl)-lH-imidazol-4-yl]-1-oxopentyl]-hexahydro 5H-1,4-diazepin-5-one are placed in 1.3 ml of dimethyl acetamide and 0.3 ml (3.44 mmol) of propionyl chloride is added. The mixture is left stirring for 2 hours and 25 then ethyl acetate is added. Evaporation is carried out to dryness and the residue is taken up in dichloromethane. The organic layer is washed with 2 times 20 ml of a 1N aqueous hydrochloric acid solution, 88 dried over magnesium sulphate and evaporated. 1.4 g of product are obtained, which product is used as is in the following stage. Yield = 100% 5 25.3. (S)-N-[2-[[[4-(5-Methyl-lH-imidazol-4-yl) 1-[ (5-oxohexahydro -lH-1,4-diazepin-1-yl) carbonylibutyl] amino] sulphonyl] -6-thien-2-yl phenyl]propanamide hydrochloride (1:1) 0.25 g (0.31 mmol) of (S)-N-[2-[[[4-[5 10 methyl-l- (triphenylmethyl) -lH-imidazol-4-yl] -1- [(5 oxohexa-hydro-1H-1, 4-diazepin-l yl) carbonyl] butyl] amino] -sulphonyl] -6-thien-2 ylphenyl]propanamide are placed in 4 ml of tetrahydrofuran, and 2 ml of acetic acid and 2 ml of 15 water are added. The mixture is heated overnight at 50*C, the mixture is evaporated to dryness and the residue is taken up in 100 ml of dichloromethane. The solution is washed with an aqueous sodium hydrogencarbonate solution and dried over magnesium 20 sulphate. It is filtered and the residue is purified by chromatography on a column of silica gel, elution being carried out with a dichloro-methane:methanol (90:10) mixture. The base is dissolved in a 0.1N solution of 25 hydrochloric acid in isopropanol and the product is purified by chromatography on an RP 18 silica column, elution being carried out with an acetonitrile/water mixture.

89 0.026 g of product is obtained in the form of the hydrochloride. Yield = 14% Melting point = 155*C 5 []"* = +80* (c = 0.2, methanol) Example 26 (Compound No. 65) (S)-N-Cyclopentyl-N,5-dimethyl-a-[[[2-[(1-oxopropyl) amino]- 3 -thien-2-yl-phenyllsulphonyl]amino]-lH imidazole-4-pentanamide hydrochloride (1:1) 10 26.1. (S)-a-[[(2-Amino-3-thien-2-ylphenyl) sulphonyl]amino]-N-cyclopentyl-N,5-dimethyl 1-(triphenylmethyl)-lH-imidazole-4-pentan amide 1 g (3.66 mmol) of 2 -amino-3-thien-2 15 ylbenzenesulphonyl chloride and then 1.12 ml (7.85 mmol) of triethylamine in 5 ml of dichloromethane are added successively at O*C under nitrogen to a solution of 1.95 g (3.5 mmol) of (S)-a-amino-N-cyclo pentyl-N,5-dimethyl-l-(triphenylmethyl)-lH-imidazole 20 4-pentanamide hydrochloride in 15 ml of dichloro methane. The temperature of the reaction mixture is allowed to return to room temperature and stirring is continued for 15 hours at this temperature. The reaction mixture is concentrated under reduced 25 pressure. The residue is taken up in 150 ml of ethyl acetate and washed successively with 50 ml of a 1N aqueous hydrochloric acid solution, 50 ml of a 90 saturated sodium hydrogencarbonate solution and then with 50 ml of a saturated sodium chloride solution. The organic layer is dried over sodium sulphate. The residue is purified by chromatography on a column of 5 silica gel, elution being carried out with a dichloro methane:methanol (97:3) mixture. 2.35 g of product are obtained in the form of an amorphous solid. Yield = 87% 10 Melting point = 102-107OC 26.2. (S) -N-Cyclopentyl-N,5-dimethyl a- [ [[2- [(l-oxopropyl) amino] -3-thien-2-yl phenyl] sulphonyl] amino] -lH-imidazole-4 pentanamide hydrochloride (1:1) 15 0.51 ml (5.9 mmol) of propionyl chloride is added dropwise at room temperature to a solution of 2.23 g (2.94 mmol) of (S)-a-[[(2-amino-3-thien-2-yl phenyl) sulphonyl] amino] -N-cyclopentyl-N, 5-dimethyl 1- (triphenylmethyl) -lH-imidazole -4-pentanamide in 20 1.5 ml of dimethylacetamide. The mixture is left stirring for 10 hours and then 150 ml of ethyl acetate are added. The organic layer is washed with 150 ml of water and then with 100 ml of a saturated sodium chloride solution. The organic layer is dried over 25 sodium sulphate, filtered and concentrated under reduced pressure. The residue is taken up in 60 ml of ethyl acetate and 30 ml of water and is then heated at the reflux temperature for 2 hours. 150 ml of 91 dichloromethane are then added and the organic layer is washed successively with 100 ml of a saturated sodium hydrogencarbonate solution and 100 ml of a saturated sodium chloride solution. The organic layer is dried 5 over sodium sulphate, filtered and concentrated under reduced pressure. The residue thus obtained is taken up in 40 ml of a 0.1N solution of hydrochloric acid in isopropanol and concentrated under reduced pressure. The residue is purified by chromatography on a column 10 of RP 18 silica gel, elution being carried out with an aceto-nitrile:water (2:8) mixture. 1.15 g of product are obtained. Yield = 64% Melting point = 140-145*C 15 [al'" = + 103* (c = 0.2, methanol) Example 27 (Compound No. 66) (S)-N,5-Dimethyl-ca-[[[2-[(l-oxopropyl)amino]-3-thien-2 ylphenyl]sulphonyl]amino]-N-pyrrolidin-1-yl-1H imidazole-4-pentanamide hydrochloride (1:1) 20 27.1. (S)-a-[[(2-Amino-3-thien-2-ylphenyl) sulphonyl]amino]-N,5-dimethyl-N-pyrrolidin 1-yl-1-(triphenylmethyl)-1H-imidazole 4-pentanamide This compound is prepared according to the 25 procedure described in 26.1, from 0.8 g (2.94 mmol) of 2-amino-3-thien-2-ylbenzenesulphonyl chloride and 1.56 g (2.8 mmol) of (S)-a-amino-N,5-dimethyl- 92 N-pyrrolidin-1-yl-1-(triphenylmethyl)-lH-imidazole 4-pentanamide hydrochloride. 1.84 g of product are obtained in the form of an amorphous solid. 5 Yield = 83% Melting point = 102-106 0 C 27.2. (S)-N,5-Dimethyl-a-[[[2-[(1-oxopropyl)amino] 3-thien-2-ylphenyl]sulphonyl]amino] N-pyrrolidin-1-yl-1H-imidazole-4-pentanamide 10 hydrochloride (1:1) This compound is prepared according to the procedure described in 26.2, from 1.8 g (2.37 mmol) of (S)-a-[[( 2 -amino-3-thien-2-ylphenyl)sulphonyl]amino] N,S-dimethyl-N-pyrrolidin-1-yl-1-(triphenylmethyl) 15 1H-imidazole-4-pentanamide. 1 g of product is obtained. Yield = 69% Melting point = 154-160*C [a]D 0 = +119* (c = 0.2, methanol) 20 Key to the table: in the "salt" column, "HCl" corresponds to a hydrochloride and the ratio between brackets is the (base:acid) ratio, in the " [a]2*" column, 25 c = 0.2, methanol, except for the compound 1 (c = 0.22, methanol), for the compound 6 (c = 0.265, 93 methanol), for the compound 12 (c = 0.25, methanol) and for the compounds 51, 54 and 56 (c = 0.4, methanol) 94 + + + H0% -4-4 -4--4 -4 -4)0 00 66 IIL O 0 95 LAn C0-LA 0 -. r-4 0 . . + + ++ 0- a -4 r4 4 4. I m uz Ln %0 Uc 1 r - 'I 96 o in 0N -o0% +. + + + + v o% C4 N~ CL 4 N Li

HE

97 %00 + + 0 -44 C4 o0 00 u U z I I I c; %D U U U 98 N Mn + + + + + + CL -44 'U UzU U U i L* Z-DI 4C z N N N N N 99 LM Ln + + +++ NA M No C4 N4 Nen 100 C 0% ++ + + c0 01 C 0n r *'5o .4 . (NN 144 -4.4 z6 U L, U U L -z m 1 101 Ln C oC- 0 0e -tcce .- + + + + + CD 0 LAn , - Ln4.-4 CL U)U 4~C4 UU ELI L)~ 6U U z M o". 1 102 In ol .o IC +4+ + + op N r. CD fn M uu zc In o 103 -e C + + + v NA cm LA LnL *- 0 v O ,N.-C 0 -4 1. Z'4 wM b-0 u u UU U0 u 0 N N w -- -inL 104 N w + + c .EU -4 i u4 0 Is.4 2 z 2 az a a 2 C~) 6 in22 z in Un Un 105 oo L ( M N4 cob--. to n- CI -nb ~~r u~~ cau6 I~ D I - , 1 M M U U UU U3U u Z- .n 106 co o4 CD C' - o -4 4 -4 C4 a, 0 L .. .................... T, Z.-w z2 I' 2

J

107 0 1 -C + ~~-1 C -' 0 * 5 0 ___ .4 (U Co ~ z U U C-) z U - -I U -4 2 108 The compounds of the invention have formed the subject of pharmacological studies which have demonstrated their antithrombotic properties and their advantage as substances possessing therapeutic 5 activity. 1. Determination of the inhibition constants (K.) with respect to thrombin The following are deposited in each well of a 96-well microplate: 25 gl of a solution of compound to 10 be tested (7 concentrations are studied), 50 Al of a solution of chromogenic substrate (2 concentrations are studied; S2238 Chromogenix) in solution in Tris buffer at pH 7.5 (50 mM Tris, 100 mM NaCl and 0.1% BSA) and finally 25 Al of a 300 U/ml thrombin solution. The 15 release of 4 -nitroaniline is monitored at 405 nm using a plate reader. The Ki is determined by the Dixon method. The compounds of the invention are inhibitors of thrombin and their K. is between 0.001 and 100 pM. 20 2. Clotting of rat plasma by human thrombin ex vivo Male CD rats weighing 150 to 200 g are treated with the compound to be tested or with the vehicle by the i.v., oral or subcutaneous route. The animals are then anaesthetized with Nembutal' (60 mg/kg; 25 0.1 ml/kg), the blood is withdrawn onto 3.8% trisodium citrate (1 vol/9 vol of blood) from the retro-orbital sinus and the plasma is prepared by centrifuging at 3600 g for 15 minutes at room temperature. 200 pl of 109 plasma are then incubated at 37 0 C with 200 Al of a solution of human thrombin, the final concentration of human thrombin being 0.75 NIH units/ml, and the clotting time is recorded. The anticoagulant effect is 5 expressed by the dose which increases the clotting time by 100%. They inhibit the clotting of rat plasma at doses of 0.01 to 5 mg/kg i.v. They are also active by the oral and subcutaneous routes. 10 The compounds of the invention can be used in all clinical indications related to thrombosis or in those where thrombotic complications could occur. To this end, they can be presented in any form appropriate for oral, parenteral or intravenous 15 administration, such as tablets, drag6es, capsules, including hard gelatin capsules, suspensions or solutions to be taken orally or to be injected, and the like, in combination with suitable excipients. All these forms contain doses which make possible an 20 administration of 1 to 1000 mg per day and per patient, in one or more doses.

Claims

1. Compounds of formula (I) 0 SO2NH 2R R 3 HN I (I) A R R1 N R' H in which Ri and R' 1 each represent, independently of one another, 5 either a hydrogen atom or a halogen atom or a (C.-C 4 )alkyl group, R 2 represents either: a piperidin-1-yl group optionally substituted in the 4 position by one or more groups chosen from hydroxyl, (C 1 -C 4 )alkyl, the latter being 10 straight or branched, hydroxy(Cl-C 4 )alkyl, (Ci C 4 ) alkoxy (Cl-C 4 ) alkyl, (Cl-C 4 ) alkoxy, (Cl-C 4 ) alkylthio, nitrile, monofluoromethyl, difluoromethyl, trifluoro methyl,

2-fluoroethoxy, 2 ,2,2-trifluoroethoxy, (C 3 C)cycloalkyl, -COOR' and -CONR'R " groups (R' being a 15 (C,-C 4 )alkyl group and R" being a hydrogen atom or a (C 1 -C 4 )alkyl group) or by a =CYZ group [Y and Z being chosen, independently of one another, from hydrogen and halogen atoms and (C,-C 4 )alkyl (optionally substituted by one or more halogen atoms), cyano and -COOR' groups, R being as defined above] or by a group (H2) r 4 an =NOCH 3 group; or a spiro[ (C 3 C6)cycloalkane-1,4'-piperidin]-l-yl group; or a 1,2,3,6 tetrahydropyridin-1-yl group optionally substituted in the 4 position by a straight or branched (C 1 -C 4 )alkyl 5 (optionally substituted by one or more halogen atoms) or a (C 3 -C 6 )cycloalkyl group; or a hexahydro-1H-azepin 1-yl group optionally substituted in the 4 position by a trifluoromethyl or =CF 2 group; or a heptahydroazocin 1-yl group; or an octahydro-lH-azonin-1-yl group; or a (CH2 .%B 10 N group (a-B being a -CONR" group, m = 1 to (CH 2)p 2 and p = 1 to 2); D or a N-- group (CH 2 ) (Q being a carbon or nitrogen atom, D a (C 1 -C 4 )alkyl or -CH 2 CF 3 group, and r = 1 to 3) ; 15 R 3 represents either a straight or branched (C 1 -C 5 )alkyl group; or a -COR 5 group where R 5 is a (C 1 -C 4 )alkyl, the AMENDED SHEET 112 latter being straight or branched, -(CH 2 )nOCH 3 , -CH 2 0(C 2 H 4 0)nCH 3 , -(CH 2 ) nCF 3 or -(CH 2 )nOH (n = 1 to 4) group; or an -S0 2 R 6 group; or a -CONHR 6 group; or an -SO 2 N(R 6 ) 2 group where R 6 is a straight or branched (Ci 5 C 4 )alkyl group, R 4 represents either a hydrogen atom or a halogen atom and A represents either a phenyl group optionally substituted by one or more substituents chosen from 10 halogen atoms and straight or branched (Cl-C 4 )alkyl, straight or branched (C 1 -C 4 )alkoxy, trifluoromethyl, trifluoromethoxy, formyl, -CH 2 0Rio, -CH20COR 10 , -CH 2 0CONRIOR 11 , -COORio, -CONRioRaj, nitro, -NRoRa 1 , -NHCOR 10 and -NH(CH 2 )gORo groups with R 10 and R,, each being, 15 independently of one another, a hydrogen atom or a straight or branched (Cl-C 4 )alkyl group and q being between 0 and 6; or a heterocycle chosen from the pyridinyl, thienyl, furyl, pyrimidyl and thiazolyl groups, it being possible for the said groups to be 20 substituted as above; or a cyclo(C 5 -CB)alkyl group, in the form of racemates or of enantiomers or of mixtures of enantiomers and in the form of the free acid or of the free base or of pharmaceutically acceptable addition salts. 25 2. Compounds according to Claim 1, characterized in that R 1 and R' 1 each represent, -independently of one another, AMENDED SHEET 113 either a hydrogen atom or a halogen atom or a (C 1 -C 4 ) alkyl group, R 2 represents either a piperidin-1-yl group optionally substituted in the 4 position by one or more groups 5 chosen from (C 1 -C 4 )alkyl, the latter being straight or branched, hydroxy (C-C 4 ) alkyl, (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, nitrile, difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethoxy and (C 3 -C 6 )cycloalkyl groups or by a =CYZ group (Y and Z 10 being chosen, independently of one another, from hydrogen and halogen atoms and (C 1 -C 4 )alkyl groups) or by an =NOCH 3 group; or a spiro[(C 3 -C 6 )cycloalkane-1,4' piperidin] -1-yl group; or a 1,2,3, 6-tetrahydropyridin 1-yl group optionally substituted in the 4 position by 15 a straight or branched (C 1 -C 4 )alkyl group (optionally substituted by one or more halogen atoms); or a hexahydro-lH-azepin-1-yl group optionally substituted in the 4 position by a =CF 2 group; or an octahydro-1H azonin-1-yl group; or a (CH2mB CL 20 group (a-B being a -CONR" group, m = 1 to (CH 2 ) P D 2 and p = 1 to 2); or a N-Q group (Q being AMENDED SHEET 114 a carbon or nitrogen atom, D a (C 1 -C 4 )alkyl or -CH 2 CF 3 group, and r = 1 to 3), R 3 represents either a straight or branched (Cl-C) alkyl group; or a -COR 5 group where R 5 is a (C 1 -C 4 ) alkyl, the 5 latter being straight or branched, -CH 2 O(C 2 H 4 0),CH 3 , (CH 2 )nOH or (CH 2 )nOCH 3 group; or a -CONHR 6 group and A represents either a phenyl group optionally substituted by one or more substituents chosen from halogen atoms and straight or branched (C,-C 4 )alkyl, 10 straight or branched (Cl-C 4 )alkoxy, trifluoromethyl, trifluoromethoxy and -NRiRjj groups with Rio and R 1 each being, independently of one another, a hydrogen atom or a straight or branched (Ci-C 4 )alkyl group; or a pyridinyl or thienyl group which can be substituted as 15 above; or a cyclo(C.-C,)alkyl group.

3. Compounds according to either one of Claims 1 and 2, characterized in that R 1 represents a (C 1 -C 4 )alkyl group and R' 1 a hydrogen atom, R 2 represents a piperidin-1-yl group substituted in the 4 position by 20 a straight or branched (Ci-C 4 )alkyl group or by a =CF 2 group, R 3 represents a -CORs group where R 5 is a straight or branched (C 1 -C 4 )alkyl group and A represents a thienyl group optionally substituted as above or a cyclo (C 5 -C,) alkyl group. 25

4. Compounds according to any one of Claims 1 to 3, characterized in that the preferred configuration of the central amino acid part AMENDED SHEET 0 SO 2 HN is [S] 5

5. Process for the preparation of the compounds of formula (Ia) (Ia) 100 10 A R RIN R' H according to Claim 1, in which R 1 , R' 1 , R 2 , R 4 and A are 15 as defined in Claim 1 and R. is a straight or branched (C,-C 4 )alkyl group or a -(CH 2 )nCF 3 group (n = 1 to 4), which process is characterized in that a compound of formula (II) 0 20 HC1, H 2 N 2 N Ri IN3.R' CPh 3 25 in which R 1 and R'i each represent either a hydrogen atom or a (C 1 -C 4 )alkyl group, is reacted with a compound AMENDED SHEET 116 of formula (III) ROC SOCi ROC .N(I) A R4 5 in which R 4 and A are as defined in Claim 1 and R 5 is a straight or branched (C 1 -C 4 )alkyl group or a -(CH 2 )nCF 3 group (n = 1 to 4), and a compound of formula (IV) 0 10 R 5 OC S0NR A R 4 N R1N CPh3 15 is obtained, which is treated in acidic medium to give the compound of formula (Ia), which is optionally halogenated, when R 1 and/or R', is a hydrogen atom, to give the compound of formula (Ia) in which R 1 and/or R', is a halogen atom. 20

6. Process for the preparation of the compounds of formula (Ia) AMENDED SHEET 117 0 R 3 OCHN SO 2 NH R 2 R2 (Ia) A R 4 N 5 RI N Rl H according to Claim 1, in which R 1 , R' 1 , R 2 , R 4 and A are as defined in Claim 1 and R 5 is a (CI-C 4 ) alkyl, the 10 latter being straight or branched, -(CH 2 )nOCH 3 , -CH 2 O(C 2 H 4 0)nCH 3 , -(CH 2 )nCF 3 or -(CH 2 )nOH group (n = 1 to 4), which process is characterized in that a compound of formula (II) as defined in Claim 5 is reacted with a compound of formula (V) 15 S02 Cl Rs N R 5 r N(V ) Cl N A R 4 in which A and R 4 are as defined in Claim 1 and R 5 is as 20 defined above, and a compound of formula (VI) AMENDED SHEET 118 R 4 A SO20 5 N N (VI) RR 10 is obtained, which is treated in acidic medium to give the compound of formula (Ia), which is optionally halogenated when R 1 and/or R' 1 is a hydrogen atom, to give the compound of formula (Ia) in which R 1 and/or R'i is a halogen atom. 15

7. Process for the preparation of the compounds of formula (Ia) 0 SO2NH 2 (Ia) 20 N 20A R- 4 O N RI N R' H according to Claim 1, in which R 1 , R' 1 , R 2 , R 4 , R_ and A 25 are as defined in Claim 1, characterized in that a compound of formula (VII) AMENDED SHEET 119 0 SO NO RsOCHN so2NH 2 (VI I) I 4 N 5 RI CPh 3 in which R 1 , R' 1 , R 2 , R 4 and R 5 are as defined in Claim 1, is reacted with a compound of formula (VIII) 10 ASn(R) 3 (VIII) in which R represents a (C 1 -C 4 ) alkyl group and A is as defined in Claim 1, in order to form a compound of formula (IX) 0 15 SO 2 NH RsOCHN 2 A R4 N (IX) R1 N R' CPh 3 20 which is heated to the reflux temperature in acidic medium, to give the compound of formula (Ia), which is optionally halogenated, when R 1 and/or R', is a hydrogen atom, to give the compound of formula (Ia) in which R 1 25 and/or R'I is a halogen atom.

8. Process for the preparation of the compounds of formula (Ib) AMENDED SHEET 120 0 SO2NH R 3 HN S02NH(Ib)R R N (Ib A R4 N 5 R. N R'I H in which R 1 , R' 1 , R 2 , R 4 and A are as defined in Claim 1 and R 3 represents either a -COR 5 group where R 5 is a (C 1 C 4 )alkyl, the latter being straight or branched, 10 -(CH 2 ) nOCH 3 , -CH 2 0(C 2 H 4 0),CH 3 , -(CH 2 )nCF 3 or -(CH 2 )nOP group (P is a protecting group) (n = 1 to 4) ; or an -S0 2 R 6 group; or an -CONHR 6 group; or an -SO 2 N(R 6 ) 2 group, where R 6 is a straight or branched (C 1 -C 4 )alkyl group, which process is characterized in that a compound of formula 15 (II) 0 HCl, H 2 N 2 (II) N 20 R R' CPh 3 in which R 1 and R' 1 each represent either a hydrogen atom or a (C 1 -C 4 ) alkyl group, is reacted with a compound 25 of formula (X) AMENDED SHEET 121 so 2c1 SO2 H 2 N I (X) A R 4 5 in which A and R 4 are as defined in Claim 1, and a compound of formula (XI) 0 SO 2NH 10 H 2 N R 2 10 H(XI) A R 4 N R R CPh3 15 is obtained, which is reacted with an acid chloride of formula R 5 COCl or an alkyl isocyanate of formula R 6 NCO or a sulphonyl chloride of formula R 6 SO 2 Cl or a sulphamoyl chloride of formula (R 6 ) 2 NSO 2 Cl, and a compound of formula (XII) 20 0 SO.NH R2 R HN 2 (XII) A R 4 N R1 N R'i 25 CPh 3 is obtained, which is treated in acidic medium to give AMENDED SHEET 122 the compound of formula (Ib), which is optionally halogenated, when R 1 and/or R', is a hydrogen atom, to give the compound of formula (Ib) in which R 1 and/or R' 1 is a halogen atom. 5

9. Medicament, characterized in that it contains a compound according to any one of Claims 1 to 4.

10. Pharmaceutical composition, characterized in that it contains a compound according 10 to any one of Claims 1 to 4 in combination with any pharmaceutically acceptable excipient. AMENDED SHEET