CA2270478A1

CA2270478A1 - N-(imidazolylbutyl) benzenesulphonamide derivatives, their preparation and therapeutic application

Info

Publication number: CA2270478A1
Application number: CA002270478A
Authority: CA
Inventors: Daniel Galtier; Gilbert Lassalle; Jean-Michel Altenburger; Valerie Martin
Original assignee: Individual
Current assignee: Synthelabo SA
Priority date: 1996-11-22
Filing date: 1997-11-19
Publication date: 1998-05-28
Also published as: BR9713291A; EE9900201A; AU5226498A; SK66799A3; HUP9904599A2; IL129546A0; NO992436D0; CN1238765A; CZ178299A3; WO1998022443A1; ZA9710515B; CO4910158A1; FR2756285A1; BG103414A; NO992436L; FR2756285B1; JP2001504128A; AR009627A1; EP0946517A1; KR20000069063A

Abstract

The invention concerns compounds of formula (I) in which R1 and R'1 represent hydrogen, halogen or (C1-C4) alkyl, R2 represents a piperidin-1-yl group, 1, 2, 3, 6-tetrahydropyridin-1-yl optionally substituted, hexahydro-1H-azepin-1-yl, heptahydroazocin-1-yl, octahydro-1H-azonin-1-yl, (a) (A-B = -CONR", m = 1 to 2 and p = 1 to 2), (b) (Q = carbon or nitrogen, D = (C1-C4) alkyl or -CH2CF3, and r = 1 to 3, R3 represents (C1-C5) alkyl, -COR5 [R5 being (C1-C4) alkyl, -(CH2)nOCH3, -CH2O(C2H4O)nCH3, -(CH2)nCF3, -(CH2)nOH (n = 1 to 4)], -SO2R6, -CONHR6, -SO2N(R6)2 (R6 being (C1-C4) alkyl), R4 represents hydrogen or halogen and A represents phenyl or heterocycle optionally substituted or cyclo (C5-C8) alkyl. The invention is applicable in therapeutics.

Description

1 ' TI~EIR PREPARATION AND THEIR THERAPEUTIC APPL~IC~rTION
The present invention relates to N-(imidazolylbutyl)benzenesulphonamide derivatives, to their preparation and to their therapeutic application.
Patent applications EP 718,307 and EP S65,396 describe 1-oxo-2-(phenylsulphonylamino)pentylpiperidine derivatives and 1-(2-(arylsulphonylamino)-1-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.
The compounds of the invention correspond to formula (I) S 0=NFi R3~ /
(I) A R
~W1 R i x in which R1 and R'1 represent, independently of each other, either a hydrogen atom or a halogen atom or a (C1-A.
C,) alkyl group, Rz represents either a 1-piperidyl group optionally substituted in position 4 with one or more groups chosen from hydroxyl, straight or branched (C1-C,) alkyl, hydroxy (Cl-C,) alkyl, (C,-C,) alkoxy (Cl-C,) alkyl, C,) alkoxy, (Cl-C,) alkylthio, nitrile, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, (C3-C6)cycloalkyl, -COOR' and -CONR'R~
(R' being a~

a (C1-C,)alkyl group and R" being a hydrogen atom or a (C1-C,) alkyl group) or by a =CYZ group [Y and Z being chosen. independently of oae another, from hydrogen and halogen atoms and (Ci-C,)alkyl (optionally substituted by one or more halogen atoms) cyano and -COOR' groups, R1 being defined as above or by a group (r = 1 to 3 ) or by an aNOCH~ group; or a spiro [ (C,-C~)cyclo-alkane-1,4'-piperidinl-1-yl group; or a 1.a,3.6-tetra-hydropyridin-1-yl group optionally substituted is the 4 position by a straight or branched (C,-C,)alkyl group (optionally substituted by one or more halogen atoms) or a (C3-C,) cycloalkyl group; or a hexahydro-lE-azepin-1-yl group optionally substituted in the 4 position by a trifluoromethyl or =CPS group; or a heptahydroazocin-1-yl group; or an octahydro-lA-azonia-1-yl group: or a (~)' H ~ 0.
group ~ N ~ (a-B being a group -CONR", rn = 1 to .(~)a a and p = 1 to Z) ; or a DN- ~ group (Q being (CH ) i r a carbon or nitrogen atom. D a (C,-C,) alkyl or -CH~CF, 2 0 group and r = 1 t0 3 ) ;
R~ represents either a straight or branched (Cl-Cs) alkyl group; or a -CORs group where RS is a (Cl-C,) alkyl, the latter being straight or breached, - (C8=) sOCH~, -CH=O (CzH,O),CH~. - (CH=) ,CF3 Or - (CH=) o0H (a = 1 t0 4 ) group; or an -SO~R~ group; or a -CONHR, group; or an -SO,N (R6) s group where R6 is a straight or branched (C1-C,) alkyl group, R, 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 halogen atoms and straight or branched (C1-C,)alkyl, straight or branched (C1-C,)alkoxy, trifluoromethyl, trifluoromethoxy, formyl, -CHsORlo, -CHZOCORlo, -CHzOCONRloRll, -COORlo, -CONRloRll, nitro. -NRloRil, -NHCORio and -NH (CHs) QORlo groups with Rlo and Rll each being, independently of one another, a hydrogen atom or a straight or branched (C1-C~)alkyl group and q 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 substituted as above; or a cyclo (CS-Ce) alkyl group.
According to the invention, the preferred compounds are the compounds of formula (I) in which Rl and R'1 each represent, independently of one another, either a hydrogen atom or a halogen atom or a (C1 Cs) alkyl group, Rs represents either a piperidin-1-yl group optionally substituted in the 4 position by one or more groups chosen from (Cl-C4)alkyl, the latter being straight or branched, hydroxy (C~-C,) alkyl, (C1-C,) alkoxy (C1-C,) alkyl, (CI-C,) alkoxy, (Cl-C,) alkylthio, nitrile, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethoxy and (C,-C6)cyclo-alkyl groups or by a =CYZ group (Y and Z being chosen, independently of one another, from hydrogen and halogen atoms and (Ci-C,) alkyl groups) or by an =NOCH, group; or a spiro[(Cl-C~)cycloalkane-1,4~-piperidial-1-yl group;
or a 1.Z.3.6-tetrahydropyridin-1-yl group optionally substituted in the ~ position by a straight or branched (C1-C,)alkyl group (optionally substituted by one or more halogen atoms): or a hexahydro-iX-azepin-1-yl group optionally substituted in the 4 position by a =CF=
group; or as octahydro-1X-azonia-1-yl group; or a (C'H.,): B jai group N' ~ (a-B being a group -CONR", m - 1 to 2 (~) a D
and p = 1 to 2): or a N - ~ group (Q being a ( CH ) Z
nitrogen or carbon atom, D a (Cl-C,) alkyl or -C&~CFs group, and r = 1 to 3).
R, represents either a straight or branched (C,-CS)alkyl group: or a -CORS group where Rs is a (C1-C,) alkyl, the latter being straight or branched, -CH,O(C=H,O),CH,, - (C8~)nOH or - (C8=)nOCH, group; or a -CONBR, group and A represents either a phenyl group optionally substituted by one or more substitueats chosen from halogen atoms and straight or branched (C1-C,)alkyl, straight or breached (C1-C,)alkoxy, trifluoroaethyl, trifluoromethoxy and -NR1oR11 groups with Rla and Ri, each being, independently of one another, a hydrogen atom or a straight or branched (C1-C,) alkyl group; or a pyridinyl or thienyl group which can be substituted as above; or a cyclo (Cs-Ce) alkyl group.
Among these compounds, the compounds of choice are those in which R1 represents a (C1-C,) alkyl 5 group and R~l a hydrogen atom, Rz represents a piperidin-1-yl group substituted in the 4 position by a straight or branched (C1-C,,)alkyl group or by a =CFs group, R, represents a -CORS group where RS is a straight or branched (Cl-C,,)alkyl group and A represents a thienyl group optionally substituted as above or a cyclo (CS-Ce) alkyl group.
The preferred configuration of the central amino acid part so2x~~
is tS] .
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 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 -CPh3 group represents the triphenylmethyl group.
According to the invention, the compounds of formula (Ia), in which R~ represents a -CORS group where Rs is a straight or branched (Ci-C,) alkyl group or a - (CH,)nCF, group (n = 1 to 4) , can be synthesized according to Schema 1. A compouad~ of formula (II), in which R1 and R'i each represent either a hydrogen atom or a (C1-C,) alkyl group and R= is as def iaed 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, furyl, pyrimidyl and thiazolyl groups, ft being possible for the said groups to be substituted as above, or a cyclo (CS-C,) alkyl group, and R, and RS are as defined above, in an aprotic l0 solvent such as dichloromethane in the presence of a base such as 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 mixture at the reflux , temperature.

Scheme 1 O
HC1. H2N
Rz (II) Ri N R , i i CPh3 i RSOC~N i I (III) A Ra O
RsOC1 S02NH
Rz RsOC ~ N
I (IV) /
Ri N R y i CPh3 O

R~
RSOCHN
i I (Ia) R' N
Ri N R ~ i H

In an alternative form of the invention illustrated by Scheme 2, for the preparation of the compounds of formula (Ia) in which RS is a (C1-C~) alkyl, the latter being straight or branched, -(CH~)nOCH,, -CHaO ( CzH~O ) aCH3 , - ( CH, ) aCF3 Or - ( CHI ) nOH group (n = 1 t0 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 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(CS-C8)alkyl group, and R, and RS are as defined above, in an aprotic solvent, such as dichloromethane, in the 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.

Scheme 2 HC1. HzN
RZ
(II) N
, Ai N R i i CPh3 SO~C1 Rs N / (V) C1 w A R~
R
s i A ~ S02 O
N~N A (VI) '~' s Rs f , Rl N R i I CPh~
O
SOiNH
Ri RSOCHN
(Ia) A R~ /
Ri N A, i H

In an alternative form of the invention, it is also possible to use the process illustrated in Scheme 3. A
compound of formula (VII), in which Rl and R'1 each represent either a hydrogen atom or a (C1-C~)alkyl group 5 and Rz, R, and R5 are as defined above, is reacted with a compound of formula (VIII), in which R represents a (C1-C~)alkyl group and A is as defined above, in a solvent, such as dimethylformamide, in the presence of a catalyst, such as tetrakis(triphenylphosphine)-10 palladium(0), 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 formula (Ia) in which R, is a hydrogen atom, then the corresponding compound of formula (Ia) in which R, is a halogen atom can be hydrogenolysed. When it is desired to obtain a compound of formula (Ia) in which R1 and/or R'1 represent a halogen atom, then the corresponding compound of formula (Ia) in which R1 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 di.methylformamide.

Scheme 3 SOiNH
RSOCHN Rz Ra N ('JII) Ri N R ~ i CPh3 ASn(R)~ :VIII) O
SOzNH
RSOCHN R~
A Ra N iIX) /
Ri N Ry CPh3 O
SOzNH
RSOCHN RZ
i :a) A~ Ra N
Ri N Ry H

Alternatively, in order to prepare the compounds of formula (Ib) in which R3 represents either a -CORS group, or an -SO=R6 group, or a -CONHR6 group, or an -SO1N (R6) s group, where RS is a (C1-C,) alkyl, the latter being straight or branched, -(CHz)nOCH3, -CHsO (C,H,,O) nCH3, - (CH=) aCF3 or - (CH,) aOP group, P is a protecting group (n = 1 to 4) and R6 is as defined above, the process illustrated in Scheme 4 is used. A
compound of formula (II) is reacted with a compound of formula (X), in which A and R,, are as defined above, and a compound of formula (XI) is obtained which is reacted with an acid chloride of formula RSCOC1 or an alkyl isocyanate of formula R6NC0 or a sulphonyl chloride of formula R6SO,C1 or a sulphamoyl chloride of formula (R6) 2NSOzCI 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 formula (Ib) in which R1 and/or R'1 represent a halogen atom, then the corresponding compound of formula (Ib) in which Rl and/or R', 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.
If it is desired to obtain a compound of formula (Ib) in which R, is a hydrogen atom, then the corresponding compound of formula (Ib) in which R, is a Scheme 4 HC1. HEN
R:
(II) R~~R' N
CPh~
SOiCl H=N / IX1 A ~ R, O
SO~NH
R=
HzN
A ~ R~ N (!( I ) Ri N R,i CPh~
O
SO~NH
R HN
(XII) A R~
R~ N Ry CPh~

SO~NH
R=
R~HN
(:bi A R, N
/

H

halogen atom is hydrogenolysed.
In order to prepare the compounds of formula (Ic) in which Rl~ corresponds to R, when R3 represents a straight or branched (Cl-C5)alkyl group, the process illustrated in Scheme 5 is used. A compound of formula (II) is reacted with a compound of formula (XIV) in which Rls represents a straight or branched (C1-CS) alkyl group and A and R, are as defined above and a compound of formula (XV) 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 formula (Ic) in which Rl and/or R'1 represent a halogen atom, then the corresponding compound of formula (Ic) in which R1 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.
If it is desired to obtain a compound of formula (Ic) in which R~ is a hydrogen atom, then the corresponding compound of formula (Ic) in which R, is a halogen atom is hydrogenolysed.
The starting compounds are commercially 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.

Scheme 5 O
HC1. HzN
Rz (I.) N
Ri N R ~ i C Phi SOzCl Rl~~ i XIVI
A R, O
SOZNH
Rz R:ZHN
A R, N (xv>
Ri N Ry CPh~
O
SOzNH
Rz R1~~ ~ ( Ic) A ~~ Rv N
Ri N R y H

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 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 European Patent Application EP Q,713,865.
5-Ethyl-1X-imidazole is prepared according to the method described by Horne D.A., (l994), Heterocycles, 39, No. 1, 139.
The preparation of 4-cyclopropylpyridine is described by Eisch J.J., (l974), J. Org. Chem., 39, No. 21, 5l10.
4-Difluoromethylenepiperidine is prepared according to a method analogous to that described by Schmidt W. et al., (1995), Liebigs Ann., l319-1326.
The preparation of N-cyclopentylformamide is described 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 2? illustrate the preparation of some compounds of formula (I) according to the invention.
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 chemical structures and the physical properties of some compounds according to the invention.
The ratios between brackets represent the (base: acid) ratio.
Example 1 (S)-5-Ethyl-a-[(4-ethylpiperidin-1-yl)carbonyl]-1-(tri-phenylmethyl)-1H-imidazole-4-butanamine hydrochloride (1:1) 1.1. 5-Ethyl-4-iodo-1H-imidazole 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-1H-imidazole in 600 ml of a 2N aqueous sodium hydroxide solution. Stirring is continued for 4 hours 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 organic phases are combined, washed with l00 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 methanol:dichloromethane (1.5:98.5) mixture. 10.5 g of product are obtained in the form of a white powder.
Yield = 53%

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 oil is added, portionwise, with stirring at 0~C under nitrogen to a solution of 4.8 g (21.6 a~ol) of 5-ethyl-4-iodo-1H-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 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 400 ml of ethyl acetate and washing is carried out successively with 100 ml of a 0.5N aqueous hydrochloric acid solution, l00 ml of water and 100 ml of a saturated sodium chloride solution. Finally, the solution is dried over sodium sulphate and concentrated 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%
Melting point = 95~C

1.3 Methyl (S)-2-[[(l,l-dimethylethoxy)carbonyl]-amino]-5-[5-ethyl-1-[(4-methylphenyl)-sulphonyl]-1H-imidazol-4-yl]pent-4-ynoate 1.3.1. Methyl (S)-2-[[(1,1-dimethylethoxy)carbonyll-amino]pent-4-ynoate a) (S)-2-[[(1,1-Dimethylethoxy)carbonyl]amino]pent-4-ynoic acid 11.5 g (77 m~aol) of (S)-2-aminopent-4-ynoic acid hydrochloride, 100 ml of dioxane, 50 ml of water 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 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 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-[[(l.l-dimethylethoxy)carbonyl]-amino]pent-4-ynoate 13 g (154 mmol) of sodium hydrogencarbonate 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] amino] pent-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. l5.85 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-[[(l,l-dimethylethoxy)carbonyl]-amino]-5-[5-ethyl-1-[(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-1-[(4-methylphenyl)sulphonyl]-1H-imidazole, 8.94 g (39.4 mmol) of methyl (S)-2-[[(l,l-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 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 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.
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-1- [ (4-methylphenyl) -sulphonyl]-1H-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]-1X-imidazol-4-yl]pent-4-ynoate in the presence of 1.8 g of 10% palladium-on-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 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.
Yield = 77%

1.5. Methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl]-amino]-5-(5-ethyl-1H-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-1-[(4-methylphenyl)sulphonyl]-1H-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 taken up in l00 ml of ether and Washed with 450 m1 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 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.
Yield = 88%
1.6. Methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl]-amino]-5-[5-ethyl-1-(triphenylmethyl)-1H-imidazol-4-yl]pentanoate 2.9 ml (20.3 mmol) of triethylamine and 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)-carbonyl]amino]-5-(5-ethyl-1H-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 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 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) 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] -5-ethyl-1-(triphenylmethyl)-1H-imidazole-4-pentanoic acid 0.83 g (19.8 mmol) of lithium hydroxide monohydrate is added with stirring at 0~C to 9.4 g (16.6 mmol) of methyl (S)-2-[[(l,l-dimethylethoxy)-carbonyl]amino]-5-[5-ethyl-1-(triphenylmethyl)-1H-imidazol-4-yl]pentanoate in a mixture of 48 m1 of methanol and 16 ml of water. The temperature of the 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 0~C with a 1N
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 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%
Melting point = 141~C
1.8. 1,1-Dimethylethyl (S)-[1-[(4-ethylpiperidin-1-yl)carbonyl]-4-[5-ethyl-1-(triphenyl-methyl)-1H-imidazol-4-yl]butyl]carbamate 1.8.1. 4-Ethylpiperidine hydrochloride 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 through celite and the filtrate is concentrated under reduced pressure. The residue is taken up in l50 ml of water, the pFI is adjusted to 8 with a saturated aqueous 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 m1 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 l3.8 g (64.8 mmol) of 20 1,1-dimethylethyl 4-ethylpiperidiae-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.

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
l.8.2. l,l-Dimethylethyl (S)-[1-[(4-ethylpiperidin-1-yl)carbonyl]-4-[5-ethyl-1-(triphenyl-methyl)-1H-imidazol-4-yl]butyl]carbamate 0.37 g (2.9 mmol) of diisopropylethylamine and 0.46 g (1.2 mmol) of [(benzotriazol-1-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)-1H-imidazole-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 concentrated under reduced pressure. The residue is taken up in l00 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 chloride solution, 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 methanol:dichloro-methane f2:98) mixture.
0.7 g of product is obtained in the form of a viscous oil.
Yield = 98%
1.9. (S)-5-Ethyl-a-[(4-ethylpiperidin-1-yl)carbonyl]-1-(triphenylmethyl)-1H-imidazole-4-butanamine hydrochloride (l: l) A solution of 0.7 g (1.07 mmol) of 1, 1-dimethylethyl (S) - [1- [ (4-ethylpiperidin-1-yl) -carbonyl]-4-[5-ethyl-1-(triphenylmethyl)-1H-imidazol-4-yl]butyl]carbamate 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 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.
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 (S)-5-Methyl-a-[[4-(trifluoromethyl)-piperidin-1-yl]carbonyl]-1-(triphenylmethyl)-1H-imidazole-4-butanamine hydrochloride (1:1) 2a 2.1. 1.1-Dimethylethyl (S)-[4-[5-methyl-1-(tri-phenylmethyl)-1H-imidazol-4-yl]-1-[[4-(tri-fluoromethyl)piperidin-1-yl]carbonyl]butyl]-carbamate 2.2.1. (S)-a-[[(l,l-Dimethylethoxy)carbonyl]amino]-5-methyl-1-(triphenylmethyl)-1H-imidazole-4-pentanoic acid It is prepared according to the method described in Example 1.7, from methyl (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-pentanoate.
2.2.2. 1,1-Dimethylethyl (S)-[4-[5-methyl-1-(tri-phenylmethyl)-1H-imidazol-4-yl]-1-[[4-(tri-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 with stirring, to a mixture of 1.08 g (2 mmol) of (S)-a-[[(1,1-dimethylethoxy)carbonyl]amino]-5-methyl-1-(triphenylmethyl)-1H-imidazole-4-pentanoic acid, 0.306 g (2 mmol) of 4-(trifluoromethyl)piperidine and 1.04 ml (6 a~aaol) of diisopropylethylamine in 25 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 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 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-methane (2:98) mixture.
1.2 g of product are obtained in the form of a viscous oil.
Yield = 89%
2.2. (S)-S-Methyl-a-[[4-(trifluoromethyl)-piperidin-1-yllcarbonyl]-1-(triphenylmethyl)-1H-imidazole-4-butanamine hydrochloride (1:1) A solution of 1.2 g (1.78 mmol) of 1,1-dimethylethyl (S)-[4-[5-methyl-1-(triphenyl-methyl)-1H-imidazol-4-yl]-1-[[4-(trifluoromethyl)-piperidin-1-yl]carbonyl]butyl]carbamate in 100 ml of 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 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%

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.l.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 amnol) of piperidin-4-of 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.l.2. 1,1-Dimethylethyl 4-methoxypiperidine-1-carboxylate l.59 g (39.8 mmol) of 60% sodium hydride in oil are added portionwise at 0~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 40 ml of dimethylformamide and stirring is continued at this temperature for 2 hours. The reaction mixture is poured into l00 ml of a saturated ammonium chloride solution and extracted with 2 times 200 ml of ethyl acetate. The organic phases are combined, washed successively with l00 ml of water and l00 ml of a saturated sodium chloride solution, 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 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 A solution of 7 g (32.5 mmol) of l,l-dimethylethyl 4-methoxypiperidine-1-carboxylate in 100 ml of tetrahydrofuran is treated with a stream of gaseous hydrochloric acid for 30 minutes at 0~C. The temperature of the mixture is allowed to return to room 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 powder which is used as is in the following stage.
Yield = 86%
Melting point = l32~C
3 . 2 . 1,1-Dimethylethyl (S) - [1- [ (4-methoxy-piperidin-1-yl)carbonyl]-4-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-butyl]carbamate 0.71 g (1.87 mmol) of [(benzotriazol-I-yl)-oxy]tris(dimethylamino)phosphonium hexafluorophosphate is added portionwise at 0~C, under nitrogen and with stirring, to a mixture of 0.9l8 g (1.7 mmol) of (S)-a-[[(1,1-dimethylethoxy)carbonyl]amino]-5-methyl-1-(triphenylmethyl)-1H-imidazole-4-pentanoic acid, 0.28l 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 and the reaction mixture is concentrated under reduced pressure. The residue is taken up in 100 mI 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 m1 of a saturated sodium chloride solution, dried over sodium sulphate and concentrated wader 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.
1.05 g of product are obtained in the form of a viscous oil.
Yield = 97'k 3.3. (S)-a-[(4-Methoxypiperidin-1-yl)carbonyl]-5-methyl-1-(triphenylmethyl)-1H-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) -carbonyl]-4-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]butyl]carbamate 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 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.
Yield = 98%
Melting point = 112~C
Example 4 (S)-5-Methyl-a-((4-methylenepiperidin-1-yl)-carbonyl]-1-(triphenylmethyl)-1H-imidazole-4-butanamine 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 a-butyllithium in 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 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 ie rapidly added. The reaction mixture is heated for 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 I5 oil.
Yield = 57$
4.1.2. 4-Methylenepiperidine hydrochloride This compound is obtained, from 1,1-dimethyl-ethyl 4-methylenepiperidine-1-carboxylate, according to the method described in Example 3.1.3.
4.2. (S)-5-Methyl-a-[(4-methylenepiperidin-1-yl)-carbonyl]-1-(triphenylmethyl)-1H-imidazole-4-butanamine hydrochloride (1:1) (S)-a-[[(1,1-Dimethylethoxy)carbonyl]amino]-5-methyl-1-(triphenylmethyl)-1H-imidazole-4-pentanoic acid is reacted with 4-methylenepiperidine hydro-chloride according to the method described in Example 3.2. and 1,1-dimethylethyl (S)-[4-[5-methyl-1-(tri-phenylmethyl)-1H-imidazol-4-yl]-1-[(4-methylene-piperidin-1-yl)carbonyl]butyl]carbamate, an amorphous product, is obtained.
Melting point = 85~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~C
Examvle 5 (S) -cx- [ (4-Cyclopropylpiperidin-1-yl) -carbonyl] -5-methyl-1-(triphenylmethyl)-1H-imidazole-4-butanamine hydrochloride (l: l) 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 uader 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.
l2.85 g of product are obtained, which product is used 25 as is in the following stage.
Yield = 94%
5.l.2. 1,1-Dimethylethyl 4-cyclopropylpiperidine-1-carboxylate 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) Bicarbonate and 4.85 g (48 amnol) 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) 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 1,1-dimethylethyl 4-cyclopropylpiperidine-1-carboxylate in l00 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 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 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-piperidin-1-yl)carbonyl]-4-[5-methyl-1-(tri-phenylmethyl)-1X-imidazol-4-yl]butyl]-carbamate A mixture of 6 g (11 mmol) of (S)-a-[[(l,l-dimethylethoxy)carbonyl]amino]-5-methyl-1-(tri-phenylmethyl)-1X-imidazole-4-pentanoic acid, l.79 g (11 mmol) of 4-cyclopropylpiperidine hydrochloride and 9.6 ml (55.5 mmol) of diisopropylethylamine in l00 ml of dichloromethane is stirred and 4.62 g (12.2 mmol) of [(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 reaction mixture is concentrated under reduced pressure. The residue is taken up in 300 ml of ethyl acetate, washed successively with l00 ml of a 1N
aqueous hydrochloric acid solution, l00 ml of a saturated sodium hydrogencarbonate solution and 100 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:dichloromethane (1:99) mixture.
5 g of product are obtained.
Yield = 70$
5.3. (S)-a-[(4-Cyclopropylpiperidin-1-yl)-carbonyl]-5-methyl-1-(triphenylmethyl)-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-1-(triphenylmethyl)-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 mixture is concentrated under reduced pressure. The residue thus obtained is taken up in two times 280 m1 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.
Yield = 100%
Melting point = 124~C
Example 6 (S)-5-Methyl-a-[[4-(difluoromethylene)-piperidin-1-yl]carbonyl]-1-(triphenylmethyl)-1H-imidazole-4-butanamine hydrochloride (l: l) 6.1. 4-(Difluoromethylene)piperidine hydrochloride 6.1.l. 1,1-Dimethylethyl 4-(difluoromethylene)-piperidine-1-carboxylate 45.6 ml (252 mmol) of hexamethylphosphor-amide, in solution in 30 ml of triglyme, are added dropwise at 0~C under an argon atmosphere to 12 ml (120 mmol) of difluorobromomethane in solution in 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 is again cooled to 0~C. 1l.94 g (60 mmol) of 1,1-dimethylethyl 4-oxopiperidine-1-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 minutes at this temperature. The reaction mixture is heated for 2 hours at 80~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 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%
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-1-carboxylate, according to the method described in Example 3.l.3.
Yield = 100%
Melting point = 196~C
6.2. (S)-5-Methyl-a-[[4-(difluoromethylene)-piperidin-1-yl]carbonyl]-1-(triphenylmethyl)-1H-imidazole-4-butanamine hydrochloride (l: l) (S)-a-[[(1,1-Dimethylethoxy)carbonyl]amino]-5-methyl-1-(triphenylmethyl)-1H-imidazole-4-pentanoic acid is reacted with 4-(difluoromethylene)piperidine 5 hydrochloride according to the method described in Example 3.2 and l,l-dimethylethyl (S)-[4-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-[[4-(difluoro-methylene)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-20 1-yl]carbonyl]-1-(triphenylmethyl)-1H-imidazole-4-butanamine hydrochloride (1:1) 7.1. 4-(Methylthio)piperidine hydrochloride 7.1.l. 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-piperidine-1-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.
The residue is taken up in 200 ml of ethyl acetate and washed successively with 2 times l00 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 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.
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 1,1-dimethylethyl 4-[(methylsulphonyl)oxy]piperidine-1-carboxylate, 0.7l 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 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.

1.5 g of product are obtained in the form of a viscous oil.
Yield = 63%
7.l.3 4-(Methylthio)piperidine hydrochloride This compound is obtained, from l,l-dimethyl-ethyl 4-(methylthio)piperidine-1-carboxylate, according to the method described in Example 3.l.3.
Yield = 100%
Melting point = 156.5~C
7.2. (S)-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-1-(triphenylmethyl)-1H-imidazole-4-pentanoic acid 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-thin)piperidin-1-yl]carbonyl]butyl]carbamate is obtained in the form of an amorphous powder.
Yield = 93%
Melting point = l01.2~C
This product is treated with a stream of gaseous hydrochloric acid according to the method described in Example 3.3.
The product is obtained in the form of an amorphous powder.
Yield = 100%

Melting point = 127.7~C
Example 8 (S)-5-Methyl-a-[(4-methyl-1,2,3,6-tetrahydro-pyridin-1-yl)carbonyl]-1-(triphenylmethyl)-1H-imidazole-4-butanamine hydrochloride (1:1) 8.1. 4-Methyl-1,2,3,6-tetrahydropyridine hydrochloride 8.l.1. 1,1-Dimethylethyl 4-methyl-1,2,3,6-tetrahydropyridine-1-carboxylate 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-1-carboxylate in 30 ml of anhydrous tetrahydrofuran and stirring is continued for 2 hours 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 successively with 2 times 100 ml of a O.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 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 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.
Yield = 18%
8.l.2. 4-Methyl-1,2,3,6-tetrahydropyridine hydrochloride This compound is obtained, from 1,1-dimethylethyl 4-methyl-l,2,3,6-tetrahydropyridine-1-carboxylate, according to the method described in Example 3.1.3.
Yield = 100%
8.2. (S)-5-Methyl-a-[(4-methyl-l,2,3,6-tetrahydro-pyridin-1-yl)carbonyl]-1-(triphenylmethyl)-1H-imidazole-4-butanamine hydrochloride (1:1) (S)-a-[[(l,l-Dimethylethoxy)carbonyl]amino]-5-methyl-1-(triphenylmethyl)-1H-imidazole-4-pentanoic acid is reacted with 4-methyl-1,2,3,6-tetrahydro-pyridine 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-1,2,3,6-tetrahydropyridin-1-yl)carbonyl]-butyl]carbamate is obtained in the form of an amorphous powder.
Yield = 90%
Melting point = 90.7~C
This product is treated with a stream of gaseous hydrochloric acid according to the method described in Example 3.3.
The product is obtained in the form of a white powder.
Yield = 100%
Melting point = 1l8~C
5 Example 9 1-(2-Amino-5-(5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl)-1-oxopentyl]-hexahydro-5H-1,4-diazepin-5-one hydrochloride 9.1. Hexahydro-5H-1,4-diazepin-5-one hydrochloride 10 9.l.1. 1-(Phenylmethyl)-hexahydro-5H-1,4-diazepin-5-one A solution of 9.86 g (87.18 amnol) of hydroxylamine-O-sulphonic acid in acetic acid is added over 10 minutes to a solution of 11 g (58.12 Col) 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 5.5 g (26.2 mmol) of 1-(phenylmethyl)-hexahydro-5H-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 45~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. Heatiag is carried out, the insoluble material is filtered off and rinsed with ether and the solvent 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-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-oxopentyl]-hexahydro-5H-1,4-diazepin-5-one hydrochloride 9.2.1. 1,1-Dimethylethyl (S)-[4-[5-methyl-1-(tri-phenylmethyl)-1H-imidazol-4-yl]-1-[(5-oxo-hexahydro-5H-1,4-diazepin-1-yl)carbonyl]-butyl]carbamate 2 .15 g (4 m~mol) of (S) -a- [ [ (1, 1-dimethyl-ethoxy)carbonyl]amino]-5-methyl-1-(triphenylmethyl)-1H-imidazole-4-pentanoic acid, followed in succession by 2.8 ml (16 mmol) of N,N-diisopropylethylamine and by 1. 5 g (4 mmol) of O- (benzotriazol-1-yl) -N,N,N',N'-tetramethyluronium hexafluorophosphate, are added at 0~C to a solution of 0.6 g (4 Col) of hexahydro-5H-1,4-diazepin-5-one hydrochloride in 40 ml 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 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 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.
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-1-(triphenylmethyl)-1H-imidazol--4-yl]-1-oxopentyl]-hexahydro-5H-1,4-diazepin-5-one hydrochloride A solution of 1.87 g (2.94 armol) of l, 1-dimethylethyl (S) - [4- [5-methyl-1- (triphenyl-methyl)-1H-imidazol-4-yl]-1-[(5-oxohexahydro-5H-1,4-diazepin-1-yl)carbonyl]butyl]carbamate in 200 ml 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 reaction mixture is 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.
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-1-(triphenylmethyl)-1H-imidazole-4-pentanamide hydrochloride 10.l. N-Methylcyclopentanamine hydrochloride 10.1.1. N-Cyclopentylformamide A mixture of 10 g (117 mmol) of cyclopentan-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 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. l,l-Dimethylethyl cyclopentylmethylcarbamate 50 ml (50 mmol) of a 1M solution of lithium aluminium hydride in tetrahydrofuran are added dropwise at 0~C under nitrogen to a solution of 4.37 g (38 a~ol) of N-cyclopentylformamide in 20 ml of anhydrous 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 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(l,l-dimethylethyl) dicarbonate, in solution in 40 ml of methanol, are then added dropwise. The temperature of the mixture is 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 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, 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 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 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 = l23-l26~C
10.2. (S)-a-Amino-N-cyclopentyl-N,5-dimethyl-1-(triphenylmethyl)-1H-imidazole-4-pentanamide hydrochloride 10 10.2.l. 1,1-Dimethylethyl (S)-[1-[(cyclopentylmethyl-amino)carbonyl]-4-[5-methyl-1-(triphenyl-methyl)-1X-imidazol-4-yl]butyl]carbamate 0.68 g (5 mmol) of N-methylcyclopentanamine hydrochloride, 2.l5 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-[[(l,l-dimethylethoxy)carbonyl]amino]-5-methyl-1-(tri-20 phenylmethyl)-1H-imidazole-4-pentanoic acid 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 l50 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 l00 ml of a 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 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~
Melting point = 86-90~C
10.2.2. (S)-a-Amino-N-cyclopentyl-N,5-dimethyl-1-(triphenylmethyl)-1X-imidazole-4-pentanamide hydrochloride A solution of 2.2 g (3.5 mmol) of l,l-dimethylethyl (S)-[1-[(cyclopentylmethylamino)-carbonyl]-4-[5-methyl-1-(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 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 Melting point = l38-142~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 1l.1.1. 1,1-Dimethylethyl pyrrolidin-1-ylcarbamate 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 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 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-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-carbamate and of 1.75 ml (28 mmol) 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 temperature. 150 ml of ether are added and washing is carried out successively with l00 mI of water and 100 ml of a saturated sodium chloride solution. The organic layer is dried over sodium sulphate. filtered 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.
Yield = 55%
11.l.3. N-Methylpyrrolidin-1-amine hydrochloride This product is prepared, from 0.75 g (3.7 mmol) of l,l-dimethylethyl methylpyrrolidin-1-yl-carbamate, according to the method described in 10.l.3.
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)-1X-imidazole-4-pentan-amide hydrochloride l1.2.1. 1,1-Dimethylethyl (S)-[1-[(methylpyrrolidin-1-ylamino)carbonyl]-4-[5-methyl-1-(triphenyl-methyl)-1H-imidazol-4-yl]butyl]carbamate The product is prepared according to the procedure described in 10.2.l., from 1.8 g (3.3 mmol) of (S)-a-[[(1.1-dimethylethoxy)carbonyl]amino]-5-methyl-1-(triphenylmethyl)-1X-imidazole-4-pentanoic acid and from 0.48 g (3.5 mmol) of N-methylpyrrolidin-1-amine hydrochloride.
1.8 g of product are obtained in the form of an amorphous solid.
Yield = 88%
Melting point = 70-75~C
l1.2.2. (S)-a-Amino-N,5-dimethyl-N-pyrrolidin-1-yl-1-(triphenylmethyl)-1H-imidazole-4-pentan-amide hydrochloride The product is prepared according to the procedure described in 10.2.2., from 1.8 g (2.8 manol) of 1,1-dimethylethyl (S)-[1-[(methylpyrrolidin-1-yl-amino)carbonyl]-4-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]butyl]carbamate.
1.65 g of product are obtained in the form of an amorphous solid.
Yield = l00%
Melting point = 130-135~C
Example 12 (Compound No. 67) (S) -N- [3- [ [ [4- (5-Ethyl-1H-imidazol-4-yl) -1- [ (4-ZO ethylpiperidin-1-yl)carbonyl]butyl]-amino] sulphonyl] [1,1' -biphenyl] -2-yl] propan-amide hydrochloride (1:1) 12 .1. (S) -N- [3- [ [ [1- [ (4-Ethylpiperidin-1-yl) -carbonyl]-4-[5-ethyl-1-(triphenylmethyl)-1X-imidazol-4-yl]butyl]amino]-sulphonyl][1,1'-biphenyl]-2-yl]-N-(1-oxo-propyl)propanamide 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 amnol) of 2- [bis (1-oxopropyl) amino] -[1,1'-biphenyl]-3-sulphonyl chloride and of 0.61 g 5 (1.04 Col) of (S) -5-ethyl-a- [ (4-ethylpiperidin-1-yl) -carbonyl]-1-(triphenylmethyl)-1H-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)carbonyl]butyl]-amino] sulphonyl] [1,1' -biphenyl] -2-yl]propan-amide hydrochloride (1:1) 0.85 g (0.95 mmol) of (S) -N- [3- [ [ [1-[(4-ethylpiperidin-1-yl)carbonyl]-4-[5-ethyl-1-(tri-25 phenylmethyl)-1H-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 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-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-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 O.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 acetonitrile:water (3:7) mixture.
After lyophilization, 0.42 g of product is obtained in the form of a white powder.
Yield = 69%
Melting point = 132~C
[a]D = +l12~: (c = 0.2, methanol) Example 13 (Compound No. 40) (S) -N- [3- ( [ [4- (5-Methyl-1H-imidazol-4-yl) -1- [ [4 (trifluoromethyl)piperidin-1-yl]carbonyl]butyl]
amino] sulphonyl] [1,1' -biphenyl] -2-yl] propanamide hydrochloride (1:1) 13.1. (S)-N-[3-[[[4-[5-Methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-[[4-(trifluoromethyl)-piperidin-1-yl]carbonyl]butyl]amino]-sulphonyl][l,l'-biphenyl]-2-yl]-N-(1-oxo-propyl)propanamide 0.79 ml (5.7 mmol) of triethylamine is added dropwise at 0~C under argon to a mixture of 0.65 g (1.72 mmol) of 2-[bis(1-oxopropyl)amino]-[1,1'-biphenyl]-3-sulphonyl chloride and of l.05 g (1.72 amnol) 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 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 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 methanol:dichloromethane (2:98) mixture.
1.04 g of product are obtained in the form of a viscous Oll.
Yield = 70%

13.2. (S)-N-[3-[[[4-(5-Methyl-1H-imidazol-4-yl)-1-[[4-(trifluoromethyl)piperidin-1-yl]-carbonyl] butyl] amino] sulphonyl] -[1,1'-biphenyl]-2-yl]propanamide S hydrochloride (I:1) 1.02 g (l.l amtol) of (S) -N- [3- [ [ [4- [5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-[[4-(trifluoro-methyl) piperidin-1-yl] carbonyl] butyl] amino] sulphonyl] -[1,1'-biphenyl]-2-yl]-N-(1-oxopropyl)propanamide, in ZO solution in a mixture of 25 ml of acetic acid and 25 ml of water, are heated for 10 hours at the reflex 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 O.1N solution of hydrochloric acid in isopropanol and concentrated under reduced pressure. The residue is purified by chromatography on an RP Z8 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 = 146-1S0~C

[a] p~ _ +80~ (c = 0.2, methanol) Example 14 (Compound No.34) (S) -N- [2- [ [ [1- [ (4-Methoxypiperidin-1-yl) -carbonyl] -4 (5-methyl-1X-imidazol-4-yl)-butyl]amino]sulphonyl]-6 thien-2-ylphenyl]-propanamide hydrochloride (1:1) l4.1. (S)-1-[2-(3-Ethyl-1,1-dioxo-5-thien-2-yl-2H-1,2.4-benzothiadiazin-2-yl)-5-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-oxo-pentyl]-4-methoxypiperidine 14.1.1. 2-[(1-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 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 phosphorous pentachloride are added portioawise 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 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 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.l.2. (S)-1-[2-(3-Ethyl-1.1-dioxo-5-thien-2-yl-2H-1,2,4-benzothiadiazin-2-yl)-5-[5-methyl-1-(triphenylmethyl)-1H-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)amigo]-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)-1H-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 l00 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.
l.07 g of product are obtained in the form of a viscous oil which is used as is in the following stage.
Yield = 100%
l4.2 . (S) -N- [2- [ [ [1- [ (4-Methoxypiperidin-1-yl) -carbonyl]-4-(5-methyl-1H-imidazol-4-yl)-butyl ] amino] sulphonyl ] - 6 - thi en- 2 -ylphenyl ] -propanamide hydrochloride (l: l) 1.07 g (1.2 mmol) of (S) -1- [2- (3-ethyl-1,1-dioxo-5-thien-2-yl-2H-1,2,4-benzothiadiazin-2-yl)-5-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-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 i.s concentrated under reduced pressure. The residue is taken up in 150 ml of ethyl 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 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 0.1N 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 acetonitrile:water (3:7) mixture.
After lyophilization, 0.34 g of product is obtained in the form of a white powder.
Yield = 45%
Melting point = 126~C
[a]D = +87~ (c = 0.2, methanol) Exarnnple 15 (Compound No. 47) (S)-N-[2-[[I4-(5-Methyl-1H-imidazol-4-yl)-1-[(4-methylenepiperidin-1-yl)carbonyl]-butyl]amino]sulphonyl]-6-thien-2-ylphenyl]-propanamide hydrochloride (1:1) This compound is prepared according to the method described in Example 14, from (S)-5-methyl-a-[(4-methylenepiperidin-1-yl)carbonyl]-1-(triphenyl-methyl)-1H-imidazole-4-butanamine hydrochloride and 2-[(1-chloropropylidene)amino]-3-thien-2-ylbenzene-sulphonyl chloride.
Melting point = 1l5-l20~C
[a] D~ _ +54 ~ (c = 0 .2, methanol) Example 16 (Compound No. 45) (S) -N- [2- [ [ [1- [ (4-Cyclopropylpiperidin-1-yl) -carbonyl]
4-(5-methyl-1H-imidazol-4-yl)-butyl]amino]sulphonyl]-6 thien-2-ylphenyl]-propanamide hydrochloride (l: l) 16.1. (S)-4-Cyclopropyl-1-I2-(3-ethyl-l,l-dioxo-5-thien-2-yl-2H-l,2,4-benzothiadiazin-2-yl)-5-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-oxopentyl]piperidine 0.5 ml (3.63 mmol) of triethylamine is added dropwise at 0~C to a mixture of 0.38 g (1.1 mmol) of 2-[(1-chloropropylidene)amino]-3-thien-2-ylbenzene-sulphonyl chloride and of 0.64 g (1.1 a~ol) of (S)-a-[(4-cyclopropylpiperidin-1-yl)carbonyl]-5-methyl-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 continued for 2 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 hydrogencarbonate solution and 50 ml of a saturated sodium chloride solution, dried over 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 = l00%
l6.2 . (S) -N- [2- [ [ [1- [ (4-Cyclopropylpiperidin-1-yl) -carbonyl]-4-(5-methyl-1H-imidazol-4-yl)-butyl] amino] sulphonyl] -6-thien-2-ylphenyl] -propanamide hydrochloride (1:1) 1.1 g (l.l mmol) of (S)-4-cyclopropyl-1-[2-(3-ethyl-1,1-dioxo-5-thien-2-yl-2H-1,2,4-benzo-thiadiazin-2-yl)-5-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-oxopentyl]piperidine, in solution in a mixture of 25 ml of acetic acid and 25 m1 of 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 l50 ml of ethyl 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 silica gel, elution being carried out with a 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 m1 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 acetonitrile:water (3:7) mixture.
After lyophilization, 0.27 g of product is obtained in the form of a white powder.
Yield = 39%
Melting point = l08-l10~C
[a]D - +98~ (c = 0.2, methanol) Example 17 (Compound No. 20) (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) 17 .1. (S) -1- [2- [7-Bromo-3-ethyl-5- (3-nitrophenyl) -l,l-dioxo-2H-l,2,4-benzothiadiazin-2-yl]-5-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-oxopentyl]-4-ethylpiperidine 5 17.l.1. 5-Bromo-2-[(1-chloropropylidene)amino]-3'-vitro[1,1'-biphenyl]-3-sulphonyl chloride a) Pyridine salt of 5-bromo-3'-vitro-2-[(1-oxo-propyl)amino][1,1'-biphenyl]-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'-vitro[l,l'-biphenyl]-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'-vitro[l, l'-biphenyl]-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 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 pressure.
3 g of product are obtained in the form of a glassy oil which is used as is in the following stage.
Yield = ??%
1? .1.2. (S) -1- (2- (?-Bromo-3-ethyl-5- (3-nitrophenyl) -1,1-dioxo-2H-1,2,4-benzothiadiazin-2-yl]-5-(5-methyl-1-(triphenylmethyl)-1X-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 5-bromo-2-((1-chloropropylidene)amino]-3'-vitro(1,1'-biphenyl]-3-sulphonyl chloride and of 0 . 58 g (I.02 mmol) of (S) -a- ( (4-ethylpiperidin-1-yl) -carbonyl]-5-methyl-1-(triphenylmethyl)-1H-imidazole-4-butanamine hydrochloride in 5 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 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 hydrogen-carbonate solution and 50 ml of a saturated sodium chloride solution, dried over sodium sulphate and 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%
17.2. (S)-N-[5-Bromo-3-[[[1-[(4-ethylpiperidin-1-yl)carbonyl]-4-(5-methyl-1H-imidazol-4-yl)-butyl]smino]sulphonyl]-3'-nitro(1,1'-biphenyl]-2-yllpropanamide 1 g (1 mmol) of (S) -1- [2- [7-bromo-3-ethyl-5-(3-nitrophenyl)-l,l-dioxo-2H-1,2,4-benzothiadiazin-2-yl]-5-E5-methyl-1-(triphenylmethyl)-1X-imidazol-4-yl]-1-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 reaction mixture is concentrated under reduced pressure. The residue is taken up in l00 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 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.
Yield = 60%
Melting point = 2l5~C
17.3. (S)-N-[3'-Amino-3-[[[1-[(4-ethylpiperidin-1-yl)carbonyl]-4-(5-methyl-1H-imidazol-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-1H-imidazol-4-yl)butyl]aminolsulphonyl]-3' -nitro [l, l' -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 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 pressure.
0.33 g of product is obtained in the form of a white solid.
Yield = 100%
Melting point = 160~C
17.4. (S)-N-[3'-(Sthylamino)-3-[[[1-[(4-ethyl-piperidin-1-yl)carbonyl]-4-(5-methyl-1H-imidazol-4-yl) butyl] amino] sulghonyl] -[1,1'-biphenyl]-2-yl]propanamide hydrochloride (1:2) 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-1H-imidazol-4-yl)-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 through celite, 4 ml of a O.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-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
[a]D = +l30~ (c = 0.2, methanol) Exaa~le 18 (Compound No. 29) (S) -N- [3- [ [ [1- [ (4-Ethylpiperidin-1-yl) -carbonyl] -4- (5-methyl-1H-imidazol-4-yl)-butyl]amino]sulphonyl)[1,1'-biphenyl]-2-yl]-2-(2-methoxyethoxy)acetamide hydrochloride (l: l) l8.1. (S) -2-Amino-N- [1- [ (4-ethylpiperidin-1-yl) -carbonyl]-4-(5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]butyl][1,1'-biphenyl]-3-sulphonamide 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-a-[(4-ethylpiperidin-1-yl)carbonyl]-1-(triphenyl-methyl)-1H-imidazole-4-butanamine hydrochloride and of 0.281 g (1.05 mmol) of 2-amino[1,1'-biphenyl]-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 hydrogenearbonate 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-[[[1-[(4-Ethylpiperidin-1-yl)-carbonyl]-4-(5-methyl-1H-imidazol-4-yl)-butyl] amino] sulphonyl] [l, l' -biphenyl] -2-yl] -2-(2-methoxyethoxy)acetamide hydrochloride (1:1) 25 2 g (13 amnol) of 2- (2-methoxyethoxy) acetyl chloride are added at room temperature under argon to 1 g (1.3 mmol) of (S)-2-amino-N-[1-[(4-ethylpiperidin-1-yl)carbonyl]-4-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]butyl][l,l'-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. l00 ml of ethyl acetate and l00 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 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 l00 ml of ethyl acetate, washed successively with 50 ml of a 1N hydrochloric acid solution, 50 m1 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 residue is purified by chromatography on a column of silica gel, elution being carried out with a dichloromethane:methanol (98:2 then 90:l0) mixture.
0.54 g of product is obtained in the form of the base.
The hydrochloride is prepared in 10 ml of a O.1N
solution of hydrochloric acid in isopropanol.
After lyophilization, 0.57 g of product is obtained.
Yield = 64.6%
Melting point = 98~C

[a]D - +55.5~ (c = 0.2, methanol) Example 19 (Compound No. 30) (S)-N-[2-Cyclopentyl-6-[[[1-[(4-ethyl-piperidin-1-yl)carbonyl]-4-(5-methyl-1H-imidazol-4-yl) butyl] amino] sulphonyl] -phenyl] -N' -ethylurea hydrochloride (l: l) 19.1. (S)-2-amino-3-cyclopentyl-N-[1-[(4-ethyl-piperidin-1-yl)carbonyl]-4-[5-methyl-1-(tri-phenylmethyl)-1H-imidazol-4-yl]butyl]benzene-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-1-yl)carbonyl]-1-(triphenylmethyl)-1H-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 l00 ml of ethyl 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 purified by chromatography on a column of silica gel, elution being carried out with a dichloromethane:methanol (98:2) mixture.

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-piperidin-1-yl)carbonyl]-4-[5-methyl-1-(tri-phenylmethyl)-1H-imidazol-4-yl]butyl]amino]-sulphonyl]phenyl]-N'-ethylurea A solution of 0.7S g (1 mmol) of (S)-2-amino-3-cyclopentyl-N-[1-[(4-ethylpiperidin-1-yl)carbonyl]-4-[5-methyl-1-(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 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.
Yield = 65%
Melting point = 1l5~C
19 . 3 . (S) -N- [2-Cyclopeatyl-6- [ [ [1- [ (4-ethyl-piperidin-1-yl)carbonyl]-4-(5-methyl-1H-imidazol-4-yl) butyl] amino] sulphonyl] -phenyl]-N'-ethylurea hydrochloride (1:1) A mixture of 0.53 g (0.64 mmol) of (S)-N-[2-cyclopentyl-6-[[[1-[(4-ethylpiperidin-1-yl)-carbonyl]-4-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yi]butyl]aminolsulphonyl]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 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.
After lyophilization, 0.30 g of product is obtained.
Yield = 77%
Melting point = 147~C
[a]D~ _ +86~ (c = 0.2, methanol) Example 20 (Compound No. 70) (S)-N-[3-[[[4-(5-Chloro-1H-imidazol-4-yl)-1-[(4-ethylpiperidin-1-yl)carbonyl]butyl]-amino] sulphonyl] [1,1' -biphenyl] -2-yl] -propanamide hydrochloride (l:l) 20.1. (S) -N- [3- [ [ [1- [ (4-Ethylpiperidin-1-yl) -carbonyl] -4- (1H-imidazol-4-yl)butyl] amino] -sulphonyl ] [ l , l' -bipheayl ] - 2 -yl ] propanamide 20.1.1. 2-[(1-Chloropropylideae)-amino][1,I'-biphenyl]-3-sulphonyl chloride It is prepared according to the method described in Example 14.1.1., from 2-amino-[1,1'-biphenyl]-3-sulphonic acid.
The product is obtained in the form of a viscous oil which is used as is in the following stage.
20.l.2. (S)-N-I3-[[[1-[(4-Ethylpiperidin-1-yl)-carbonyl] -4- (1H-imidazol-4-yl) butyl] amino] -sulphonyl][1.1'-biphenyl]-2-yllpropanamide 5 2.2 ml (Z5.84 mmol) of triethylamine are added dropwise at 0~C under nitrogen to a mixture of 1.8 g (5.3 mmol) of 2-[(1-chloropropylidene)-amino][1,1'-biphenyl]-3-sulphonyl chloride and of 2.7 g (4.8 mmol) of (S)-a-[(4-ethylpiperidin-1-yl)carbonyl]-10 1-(triphenylmethyl)-1H-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, 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 takes up is 200 ml of ethyl acetate, washed successively with 50 ml of a saturated sodium hydrogencarbonate solution and SO 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-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-1H-imidazol-4-yl)-1-[(4-ethylpiperidin-1-yl)carbonyl]butyl]-amino] sulphonyl] [l, l' -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] -4-(1H-imidazol-4-yl)butyl]amino]-sulphonyl] [1,1' -biphenyl] -2-yl] propanamide and of 0.l16 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 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%
The base is taken up in 15 ml of a 0.1N solution of hydrochloric acid is isopropanol and concentration is carried out 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.
After lyophilization, 0.30 g of product is obtained.
Yield = 94%
Melting point = l00~C
(a]p~ _ +l02~ (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) 21.l. (S) -N- I4-Bromo-2- [ ( [1- [ (4-ethylpiperidin-1-yl)carbonyl]-4-[5-methyl-1-(triphenyl-methyl)-1H-imidazol-4-yl]butyl]amino]-sulphonyl]-6-iodophenyl]propanamide 2.24 g (4.4 mmol) of 2-[bis(1-oxopropyl)-amino]-5-bromo-3-iodobenzenesulphonyl chloride and then, dropwise, 1.84 ml (13.2 mmol) of triethylamine are successively added at 0~C to a solution of 2.28 g (4 mmol) of (S)-5-methyl-a-[(4-ethylpiperidin-1-yl)-carbonyl]-1-(triphenylmethyl)-1H-imidazole-4-butanamine 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 acid solution, 100 ml of a saturated sodium hydrogencarbonate solution and 100 ml of a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue is taken up in l50 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 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 oil.
Yield = 70%
21.2. (S)-N-[4-Bromo-2-[[[1-[(4-ethylpiperidin-1-yl)carbonyl]-4-[5-methyl-1-(triphenyl-methyl)-1H-imidazol-4-yl)butyl]amino]-sulphonyl]-6-pyridin-2-ylphenyl]propanamide A mixture of 1.9 g (2 mmol) of (S)-N-[4-bromo-2-[[[1-[(4-ethylpiperidin-1-yl)-carbonyl]-4-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl] butyl] amino] sulphonyl] -6-iodophenyl] propanamide, 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 a~ol) of triphenylarsine in 4 ml of dimethylformamide is heated at 80~C under argon for 5 hours. The reaction mixture is taken up in l50 ml of ethyl acetate and washed with two times 100 m1 of a 10%
aqueous ammonia solution and then with 50 ml of a 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 carried out with a dichloromethane:methanol (98:2) 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 1-yl)carbonyl]-4-(5-methyl-1H-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-yI)carbonyl]-4-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl)butyl]amino]-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 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 m1 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 (5:95) mixture.

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 (S) -N- [4-bromo-2- [ [ [1- [ (4-ethylpiperidin-1-yl) -10 carbonyl]-4-(5-methyl-1H-imidazol-4-yl)butyl]amino]-sulphonyl]-6-pyridin-2-ylphenyl]propanamide, l.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 reflex 15 temperature and then the reaction mixture is concentrated under reduced pressure. The residue is taken up in l00 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 O.1N solution of hydrochloric acid in isopropanol and concentrated uader reduced pressure. The residue thus obtained is purified on an RP 18 column, elution being carried out with an acetonitrile:water (6:4) mixture.
0.44 g of product is obtained.
Yield = 68%
Melting point = 138-l44~C
[a]D~ _ +l21~ (c = 0.2, methanol) Example 22 (Compound No. 22) (S) -N- [2- [ [ [1- [ (4-Ethylpiperidin-1-yl) -carbonyl) -4- (5-methyl-1H-imidazol-4-yl)-butyl]amino]sulphonyl]-4-fluoro-6-thien-2-yI-phenyl]propanamide hydrochloride (1:1) 22.1. 2-[Bis(1-oxopropyl)amino]-5-fluoro-3-thien-2-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-fluoro-3-thien-2-ylbenzenesulphonic acid aad of 5.6 ml (40 mmol) of triethylamine in 77 ml (600 mmol) of propionic anhydride is heated for 24 hours at the reflex temperature and then the reaction mixture is concentrated under reduced pressure. The residue is crystallized from an ethyl acetate: ether mixture.
16.9 g of product are obtained.
Yield = 90%

Melting point = 239~C
22.1.2. 2-[His(1-oxopropyl)amino]-5-fluoro-3-thien-2-ylbenzenesulphonyl chloride 14.22 g (68.2 mmol) of phosphorous pentachloride are added at 0~C under nitrogen to a solution of 1.60 g (34.1 amnol) of N,N-diethylethanamine salt of 2-Ibis(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 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 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 l:l) mixture.
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-1H-imidazol-4-yl)-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 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)-1H-imidazole-4-butanamine 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 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 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 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 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.

Yield = 74%
Melting point = 145-150~C
The hydrochloride is prepared by adding 45.l ml of a 0.1N solution of hydrochloric acid is isopropanol to 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] D~ - +112 ~ (c = 0 .2, methanol) 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-ylphenyl]propanamide hydrochloride (1:1) This product is prepared according to the procedure described is Example 19, from 0.8l g (1.36 mmol) of (S)-5-methyl-a-[[4-(difluoromethylene)-piperidin-1-yl]carbonyl]-1-(triphenylmethyl)-1H-imidazole-4-butanamine hydrochloride and from 0.47 g (1.36 mmol) of 2-[(1-chloropropylidene)amino]-3-thien-2-ylbenzenesulphonyl chloride.
0.58 g of product is obtained in the form of a white powder.
Yield = 67%
Melting point = 144-l45~C
[a]D~ - +l07.9~ (c = 0.2, methanol) Example 24 (Compound No. 25) (S)-N-[6-Cyclopentyl-2-[[[1-[(4-ethyl-piperidin-1-yl)carbonyl]-4-(5-methyl-1H-imidazol-4-yl)butyl]-amino]sulphonyl]-phenyl]propanamide hydrochloride (l: l) 5 24.l. 3-Cyclopentyl-2-(diacetylamino)benzene-sulphonyl chloride 24.l.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 reflex 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 = l86~C
24.1.2. 3-Cyclopentyl-2-(diacetylamino)benzene-sulphonyl chloride 20 This compound is prepared according to the procedure described in Example 22.l, from 8.2 g (18.1 mmol) of N,N-diethylethanamine salt of 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- [ [ [1- [ (4-ethyl-piperidin-1-yl)carbonyl]-4-(5-methyl-1X-imidazol-4-yl)butyl]amino]sulphonyl]-phenyllpropanamide hydrochloride (l: l) This product is prepared according to the procedure described in Example 22.2, from 0.743 g (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)-1H-imidazole-4-butanamine hydrochloride.
0.73 g of product is obtained.
Yield = 60%
Melting point = 124~C
[a]D~ _ +89~ (c = 0.2, methanol) Exan~le 25 (Compound No. 64) (S) -N- [2- [ [ [4- (5-Methyl-1H-imidazol-4-yl) -1- [ (5-oxohexahydro-1H-1,4-diazepin-1-yl)carbonyl]butyl]-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-1-(triphenyl-methyl)-1X-imidazol-4-yl]-1-oxopentyll-hexa-hydro-5X-1,4-diazepin-5-one 0.6l8 g (2.26 mmol) of 2-amino-3-thien-2-ylbenzenesulphonyl chloride in 80 ml of dichloromethane is placed wader argon and 1.29 mg (2.26 mmol) of 1-[2-amino-5-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-oxopentyl]-hexahydro-5H-1,4-diazepin-5-one hydrochloride are added. The mixture is cooled to 0~C
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 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 chromatography on a column of silica gel, elution being carried out with a dichloromethane:methanol (97.5:2.5) mixture.
l.33 g of product are obtained.
Yield = 76%
25.2. (S)-N-[2-[[[4-[5-Methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-[(5-oxohexahydro-1H-1,4-diazepin-1-yl)carbonyl]butyl]amino]-sulphoayl]-6-thien-2-ylphenyl]propanamide 1.33 g (1.72 a:mol) of 1- [2- [ [ (2-amino-3-thien-2-ylphenyl)sulphoayl]amino]-5-[5-methyl-1-(tri-phenylmethyl)-1H-imidazol-4-yl]-1-oxopeatyl]-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 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, dried over magnesium sulphate and evaporated.
1.4 g of product are obtained, which product is used as is in the following stage.
Yield = l00%
25.3. (S)-N-[2-[[[4-(5-Methyl-1H-imidazol-4-yl)-1-I(5-oxohexahydro-1H-1,4-diazepin-1-yl)-carbonyl]butyl]amino]sulphonyl]-6-thien-2-yl-phenyl]propanamide hydrochloride (l: l) 0.25 g (0.31 mmol) of (S) -N- [2- [ [ I4- [5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-[(5-oxohexa-hydro-1H-1,4-diazepin-1-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 water are added. The mixture is heated overnight at 50~C, 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 magaesium sulphate. It is filtered aad 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 O.1N solution of hydrochloric acid in isopropanol and the product is purified by chromatography on an RP 18 silica column, x elution being carried out with an acetonitrile/water mixture.
0.026 g of product are obtained in the form of the hydrochloride is obtained.
Yield = 14~
Melting point = 155~C
[a]D~ - 80~ (c = 0.1, methanol) Example 26 (Compound No. 65) (S)-N-Cyclopentyl-N,5-dimethyl-a-[[L2-[(1-oxopropyl)-amino]-3-thien-2-yl-phenyl]sulphonyl]amino]-1H-imidazole-4-pentanamide hydrochloride (l: l) 26.1. (S)-a-[[(2-Amino-3-thien-2-ylphenyl)-sulphonyl]amino]-N-cyclopentyl-N,5-dimethyl-1-(triphenylmethyl)-1H-imidazole-4-pentan-amide 1 g (3.66 mmol) of 2-amino-3-thien-2-ylbenzenesulphonyl chloride and then l.12 ml (7.85 amnol) of triethylamine in 5 ml of dichloromethane are added successively at 0~C under nitrogen to a solution of l.95 g (3.5 mmol) of (S)-a-amino-N-cyclo-pentyl-N,5-dimethyl-1-(triphenylmethyl)-1H-imidazole-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 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, with 50 ml of a saturated sodium hydrogencarbonate solution and then with 50 ml of a saturated sodium chloride solution. The organic layer is dried over sodium sulphate. The 5 residue is purified by chromatography on a column of 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.
10 Yield = 87%
Melting point = 102-107~C
26.2. (S)-N-Cyclopentyl-N,5-dimethyl-a-[[[2-[(1-oxopropyl)amino]-3-thien-2-yl-phenyl]sulphonyl]amino]-1H-imidazole-4-15 pentanamide hydrochloride (l: l) 0.5l 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-20 1-(triphenylmethyl)-1H-imidazole-4-pentanamide in 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 l50 ml of water and then with 100 ml of a saturated sodium 25 chloride solution. The organic layer is dried over 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 reflex temperature for 2 hours. l50 ml of dichloromethane are then added and the organic layer is washed successively with l00 ml of a saturated sodium hydrogencarbonate solution and 100 ml of a saturated sodium chloride solution. The organic layer is dried 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 of silica gel, elution being carried out with an aceto-nitrile:water (2:8) mixture.
1.l5 g of product are obtained.
Yield = 64%
Melting point = 140-l45~C
[a] D~ - + 103 ~ (c = 0 .2, methanol) Example 27 (Compound No. 66) (S) -N, 5-Dimethyl-a- [ [ [2- [ (1-oxopropyl) amino] -3-thien-2-ylphenyl]sulphonyl]amino]-N-pyrrolidin-1-yl-1X-imidazole-4-pentanamide hydrochloride (l: l) 27.1. (S)-a-[I(2-Amino-3-thien-2-ylphenyl)-sulphonyl]amino]-N,5-dimethyl-N-pyrrolidin-1-yl-1-(tripheaylmethyl)-1H-imidazole-4-pentanamide This compound is prepared according to the procedure described in 26.l, from 0.8 g (2.94 u~mol) of 2-amino-3-thien-2-ylbenzenesulphonyl chloride and 1.56 g (2.8 mmol) of (S)-a-amino-N,5-dimethyl-N-pyrrolidin-1-yl-1-(triphenylmethyl)-1H-imidazole-4-pentanamide hydrochloride.
1.84 g of product are obtained in the form of an amorphous solid.
Yield = 83%
Melting point = 102-106~C
27 .2 . (S) -N, 5-Dimethyl-a- [ [ [2- [ (1-oxopropyl) amino]
3-thien-2-ylpheayl]sulphonyl]amino]
N-pyrrolidin-1-yl-1H-imidazole-4-pentanamide hydrochloride (l: l) 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,5-dimethyl-N-pyrrolidin-1-yl-1-(triphenylmethyl)-1F1-imidazole-4-pentanamide.
1 g of product is obtained.
Yield = 69%
Melting point = l54-160~C
[a]D~ - +1l9~ (c = 0.2, methanol) Key to the table:
is the "salt" Column, "HC1" corresponds to a hydrochloride and the ratio between brackets is the (base: acid) ratio, is the " [a] w~" column, c = 0.2, methanol, except for the compound 1 (c =

0.22, methanol), for the compound 6 (c = 0.265, methanol), for the compound 12 (c = 0.25, methanol) and for the compounds 51, 54 and 56 (c =
0.4, methanol) S'6L ; L'4ii ('(JH) ., ' H_ EH'OE(tHJIOtH~- EH'--~N- H_ t~' b t6 ~ TT( (LJH) ~ H ~HJLHJOJ- ~HJ ~N-- H- ~HJ~ E
60T ~ b9i-09I ~iJH? ( H_ EHJtHJOJ- tFiJ-~N- H_ E~_ Z
';' 9L + ZZL-8ii (jJH? ( H' EHJOt(tHJIOtHJOJ- ~N - H- tHJ_ i o _ o, 01 a ~ ~ ~ ~U~OfI ;~B$ H EM t8 t~l t ~ ~t t~l 'ON
0L ~ ~UI~~BW
r -~._.

r H
N

(Tl / NH~2!
HN~OS

ajqes Melting (a~
po No R R Ry Ry R~ A Saltpoint ~

. ~ ( C~

HCl 5 -CN, -H '-'N~~ -CHzCH~CH3 -H ~ ~ (1:1)62-66 + 135 CH, ~ HCl 114.3 0 H H '-N\ ' \ -COCHy -H
i1:1)13A

f, y --C

CH, ~ HCl - N\~ -COCHZCHy -H ~ (1 144 1) + 105.5 -H ~ ' :

CH, 8 -CH3 -H - N'~ -COCHZCHZOH -H \ ( HC1 l50 i1:1)+ 68 cH, _H - N -COCHZCH~ -H \ ~ (iCl)132 + 10S

CH, F

10 -CH3 -H "-N\ / \ -COCHzCH3 -H ~ '' (iCi) 130 + 113 CH, F

'H~ 'xa~ ~
H_ 'HJ' St (i'T) H- EHJ~HJOJ- ~N -TZT + Z6T ZJH ~ ~ ~
i 'Ha 'H~
(W H- 'HJtHaOJ- H' cHJ- 6T
T) -N

+ ZET TJH ~
tb av (I cH~ 'HJtHJOJ- 'x~ (,I._ ~ ~..~ H' 'HJ- ET
T~ H-N ett + 9Et IJH I

o, ~ 3 'H~ ZT
00 ~ 'HJZHJOJ- _ H-'Ha_ ( N .-) H

0 66 a 8ZT IJN ' 1 r N

c U H_ t~_ Lt (I't1 ~ 'HJLHJOJ- H~
H- ~~~N _ + ~6'C TJH ~ f Sot /

to ~ , it ~a 'o (aof d ' ~
'b ,wod ups of ip~ ~ ~ ~ _ 6un18W

'H~
vT) H- 'HJrHJOJ. H_ 'HJ- 6T
~ f1 y U (T ~
iJH S

'x~ ~ H_ EHJ- et (T ~ H- 'HJtHJOJ- ~~--~H' tl 99 4 9ZT t~H ~ ~/

N

d' O

IT'T) \ H- EHJiHJO~- N
H- 'HJ- LT

OET + ObT t~H I
/

o ~HJ _ r _ N

o 'HJ 'H~
d T'TI 'HJtHJOJ- ~'~ ~
H- 'HJ- 9T
H- H

9TT + 9ZT I \
i~H

LH t,~ tb 'ON

I'o) ~a f~

iulod~IeB
f 1') ~

o sulilBW

(t;T' 'Ha ~

H- EHOtHaoa- \~N - H- EW 5z ' se i dzT ~

i~

H

EHa ~z't) ~ H- ~HJtHJOJ- \~M._. H_ ~~_ bL

SET t 9bT
TJH ~ N

~H~
~ H_ E~_ Z

~ ~ H- EHJiHaOJ- ~N--~

~
t'H
TZT + bbT-AEt N _N.

~H~
{T~T) ~ ~ (~-~HJiHJOJ- ~~N - H- EHJ- ZZ

Ztt + Sbt ZJH

tHJ t TZ
tW I) J ~ H- tHJtHJOJ ~~N - H- HJ-bTt 8Zt ' ZJH

o v _ ~Ha t ~ H- EHJtHJOJ- ~~N - H_ Ha' OZ
' 0I + E9t jJH i c HN~J H , ~Jo~ ~ y ~2!

i,21tM 'oN
a ~u~od Heg d z ~ p i BuisiaW

~

laNinn 7A
__ ~ A Salt Na.A' R

'- N -COCHyCH; ~ (HC1) 145 + 85 ~~ -F

26 -CH; -H

H
C 3 y HCl N
- N\~~ COCHtCH3l; I l32 95 H (1:1) o CHI
F

r N~ -COCH~OCH3 I Q 1;1)106 + 10l ~~ -H

2g -CH -H \

CH

N
~ N )yOCH3 -H ~ (lCl) 98 + SS.S ' ~~ O(CH
-COCH

-CH; -N Z

Z

CH
a 30 -CH; -H - N~ -CONHCHzCH; -H ~ tlC1?147 + 86 ~~

CH

CH3 / HCl H N -COCHZCH3 -H ~ (1a1)114-120+ 96 ~
-~

31 -CH; - ' ~ H
C

Melting No.R~ R'1 Rt R H p I
~ ' a ~

Salt Point (C) S
32 -CH -H '- N -COCHZCH1 -H ' ~ ( icy) OH +

33 CH3 -H 'N COCH~CH) -H 'S~

(lel) N
N
J
O

34 -CH -H -N O~ -COCH~CH3 -H ~S ~
h~
CHI (r (lCl) +
8'T
o i HC1 35 -CH -H - N S~ -COCHZCH3 -H ~ ' CHI (1:1) +

N

S
36 -CH3 -H -N_, J-C-t3 -COCH~CH3 -H ~ ~ (lCl)168-1~2~ 99 F S
3~ -CH1 -H -" H~~F -COCHZCH3 H 1 ! ' (1~1)194-146t 103 Melting ~Q
~

p Salt R point ( ) No. Rl R'i RZ ~
(C) F
H ~ N -COCH2CH; -H
(1C11 ~~ 194-14B

F n N

N

~ -COCH; -H I 154 39 -CH; -H IN~CF~ ' + aaa ~ 90 (1:1i H' o D ~o HCl -H ~ -COCHyCH; -H I
(1:1) ' 0 -CH -N~CF~ '~

+

;

HCl 41 -CH; -H -!3 ~ CF; -COCHZCH3 -H ' I
+

(1:1) 42 -CH; -H ---N'~ -COCHZCH; -H ' I
(1:1i 140 + 108 CH

i Melting R~ A Salt t ( o ) R 'on NO. R1 R' R~ ~ C

1 ) ~ // -COCHyCH~ ~ 4 (lCl) 148 101.5 - N\ -H +

,~ F n / N
N

44 -CH3 -H -f1\~-~ -COCHZCH3 ~ (1:1) 133 + 122 -H

CHI a N

_ - -COCHzCH3 ~ ~ l1:1) 108-l10+ 98 -H

-CH -H - N ~ -COCHZCH3 -H ~ ~ (1:1) 159-163+ 84 ~'~

~ HCl 47 -CH -H -N -COCHyCH3 -H ~ ~ (1:1) 115-120+ 54 J'-CH

3 _ .

I

l03 m (~ ..
o rv o... ~ ~ ~ ~
.- o _ t a + +
p P N
a ra d ~ ~ N
r1 _ ~, a .. a ..
v~ ~ ~-~ x ~' _ '~ x ~
x U
i cn rs N \ / O
a x x s x x x z x a x r z n U x U U
U
O ~-' ~ ' U
U G V
n x w w w w w x U
V
x x~ x x zJ
x x x x x a , x x x .. x V U V V
N
Z a~ C ~n ~n ~n a n 0... I~ N m m ~ ni d O N m ri t t t 1 f C ~ ~ r ~ N
r ~ a r ? 1f1 V' O ~ m r~t rl p Q t~1 ,H -w rl ri ~-1 .~ .m-i .a e-i n-1 n-1 .i ri ~-1 H x:.. s.~ x.. x', s'. x::
E
x s m m x x r r r r r x x V Z x x x n = n n a n a n ~ ~ x x x U p U
.J ~ r r r w w m w w w x c1. a I I I I ~~o I I i ~J
5e x x x x x v r r r n n n n .z a a a U
r r r d r1 a~ m to e~ ao Z 1I7 N M I!1 1f1 1I1 ~ r~) v r, r, a~ o s 01 m 1f~ ~ P CD
t ~ t t t _. N _. _... m P
m _ a~ o e~ rv o -~ a .a c U Q, ~ , ~. ~~ o P P ~ ,-I
v ao e~~ .r -a .r .a r.y .1 r.~ H ., .~ .~ r~1 'r . a '~
v i :: i :: s :: s :: s ::
x..
a m c~ cn t~ t~
x x x x x x ~ ~ ~ ~
U U U U V V
eV n ~ v x n U
V ~ V U V V
U U ~'' O
y zJ Z ~z z z / ~z~/
i x x s x x s ' ~ ' ' a a 0 0~ o ., n ", z u, ~o ~o ~o ~o ~o Melting~ (y ~ po R4 p Saltpoint ( a ) No. R2 ; (~C) R'1 CH -H ~ ( 1 190-145+ 103 -COCH 1( 65-CH; -H I ; ' _ CHI y o S

-COCH~CH3 -H ' il;l)154-i60~ 119 \ / 0 CH -H / I iCi 132 + 112 LOCH ~ ' 67-CH=CH;-H
3 ( ; ) -H

I
C N

_ S HCi - CH -H 120 + 88 ~~ -COCH

68-CHZCH;-H N ; ~ l (1:11 Z

CHI

- CH -H 142 + 78 \~ -COCH

69-CH; -CH3N ; 1 ~ (1;1) Z

-N -COCHZCH; -H / I (lCl 70-C1 -H \~ 100 + 102 y ) i l07 l08 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 S activity.
1. Determination of the inhibition constants (Ri with respect to thrombin The following are deposited in each well of a 96-well microplate: 25 ~.l of a solution of compound to be tested (7 concentrations are studied), 50 ~C1 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% HSA) and finally 25 ~.1 of a 300 U/ml thrombin solution. The release of 4-nitroaniline is monitored at 405 nm using a plate reader.
The Ri is determined by the Dixon method.
The compounds of the invention are inhibitors of thrombin and their Ri is between 0.001 and l00 ACM.
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;
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 ~,1 of l09 plasma are then incubated at 37~C with 200 ~l of a solution of human thrombin, the final concentration of human thrombin being 0.75 NIH uaits/ml, and the clotting time is recorded. The anticoagulant effect is expressed by the dose which increases the clotting time by 100%.
They inhibit the clotting of rat plasma at doses of 0.0l to 5 mg/kg i.v. They are also active by the oral and subcutaneous routes.
The compounds of the invention can be used in a11 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 administration, such as tablets. dragees, 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 administration of 1 to 1000 mg per day and per patient.
in one or more doses.

Claims

110

1. Compounds of formula (I) in which R1 and R'1 each represent, independently of one another, either a hydrogen atom or a halogen atom or a (C1-C4) alkyl group, R2 represents either: a piperidin-1-yl group optionally substituted in the 4 position by one or more groups chosen from hydroxyl, (C1-C4) alkyl, the latter being straight or branched, hydroxy (C1-C4) alkyl, (C1-C4) alkoxy (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkylthio, nitrile, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, (C3-C6) cycloalkyl, -COOR' and -CONR'R" groups (R' being a (C1-C4)alkyl group and R" being a hydrogen atom or a (C1-C4) alkyl group) or by a =CYZ group [Y and Z being chosen, independently of one another, from hydrogen and halogen atoms and (C1-C4)alkyl (optionally substituted by one or more halogen atoms), cyano and -COOR' groups, R1 being as defined above] or by a group (r = 1 to 3) or by an =NOCH, groups or a spiro [(C3-C6) cycloalkane-1,4'-piperidin)-1-yl group; or a 1,2,3,6-tetra-hydropyridin-1-yl group optionally substituted in the 4 position by a straight or branched (C1-C4)alkyl group (optionally substituted by one or more halogen atoms) or a (C3-C6) cycloalkyl group; or a hexahydro-1H-azepia-1-yl group optionally substituted in the 4 position by a trifluoromethyl or =CF2 group; or a heptahydroazocin-1-yl group; or an octahydro-1H-azonia- 1-yl groups or a group (a-B being a group -CONR"
m = 1 to 2 and p = 1 to 2 ) or a group (Q being a carbon or nitrogen atom, D a (C1-C4) alkyl or -CH2CF3 group and r =
1 to 3):

R3 represents either a straight or branched (C1-C5)alkyl group; or a -COR5 group where R5 is a (C1-C4) alkyl, the latter being straight or branched, - (CH2) nOCH3, -CH2O (C2H4O)nCH3, - (CH2)nCF3 or - (CH2) nOH (n = 1 to 4) group; or an -SO2R6 group; or a -CONHR6 group; or an -SO2N(R6)2 group where R6 is a straight or branched (C1-C4) alkyl group, R4 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 halogen atoms and straight or branched (C1-C4)alkyl, straight or branched (C1-C4)alkoxy, trifluoromethyl, trifluoromethoxy, formyl, -CH2OR10, -CH2OCOR10, -CH2OCONR10R11, -COOR10, -CONR10R11, nitro, -NR10R11, -NHCOR10 and -NH (CH2)qOR10 groups with R10 and R11 each being, independently of one another, a hydrogen atom or a straight or branched (C1-C4)alkyl group and q 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 substituted as above; or a cyclo (C5-C8) 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.

2. Compounds according to Claim 1, characterized in that R1 and R'1 each represent, independently of one another, either a hydrogen atom or a halogen atom or a (C1-C4) alkyl group.
R2 represents either a piperidin-1-yl group optionally substituted in the 4 position by one or more groups chosen from (C1-C4) alkyl, the latter being straight or branched, hydroxy(C1-C4) alkyl, (C1-C4) alkoxy (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkylthio, nitrile, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethoxy and (C3-C6)cycloalkyl groups or by a =CYZ group (Y and Z being chosen, independently of one another, from hydrogen and halogen atoms and (C1-C4) alkyl groups) or by an =NOCH3 group; or a spiro[(C3-C6)cycloalkane-1,4'-piperidin]-1-yl group;
or a 1,2,3,6-tetrahydropyridin-1-yl group optionally substituted in the 4 position by a straight or branched (C1-C4)alkyl group (optionally substituted by one or more halogen atoms); or a hexahydro-1H-azepin-1-yl group optionally substituted is the 4 position by a =CF2 group; or as octahydro-1H-azoain-1-yl group: or a group (a-B being a group -CONR", m = 1 to 2 and p = 1 to 2): or a group (Q being a carbon or nitrogen atom, D a (C1-C4) alkyl or -CH2CF3 group, and r = 1 to 3), R3 represents either a straight or branched (C1-C5)alkyl group; or a -COR5 group where R5 is a (C1-C4) alkyl, the latter being straight or branched, -CH2O(C2H4O)nCH3, - (CH2) nOH or - (CH2) nOCH3 group; or a - CONHR6 group and A represents either a phenyl group optionally substituted by one or more substituents chosen from halogen atoms and straight or branched (C1-C4)alkyl, straight or branched (C1-C4)alkoxy, trifluoromethyl, trifluoromethoxy and -NR10R11 groups with R10 and R11 each being, independently of one another, a hydrogen atom or a straight or branched (C1-C4)alkyl group; or a pyridinyl or thienyl group which can be substituted as above; or a cyclo (C5-C8) alkyl group.

3. Compounds according to either one of Claims 1 and 2, characterized in that R1 represents a (C1-C4) alkyl group and R'1 a hydrogen atom, R2 represents a piperidin-1-yl group substituted in the 4 position by a straight or branched (C1-C4)alkyl group or by a =CF2 group, R3 represents a -COR5 group where R5 is a straight or branched (C1-C4)alkyl group and A represents a thienyl group optionally substituted as above or a cyclo (C5-C8) alkyl group.

4. Compounds according to any one of Claims 1 to 3, characterized in that the preferred configuration of the central amino acid part is [S].

5. Process for the preparation of the compounds of formula (Ia) according to Claim 1, in which R1, R'1, R2, R4 and A are as defined in Claim 1 and R5 is a straight or branched (C1-C4) alkyl group or a - (CH2)nCF3 group (n = 1 to 4), which process is characterized in that a compound of formula (II) in which R1 and R'1 each represent either a hydrogen atom or a (C1-C4)alkyl group, is reacted with a compound of formula (III) in which R4 and A are as defined in Claim 1 and R5 is a straight or branched (C1-C4)alkyl group or a -(CH2)nCF3 group (n = 1 to 4), and a compound of formula (IV) is obtained, which is treated in acidic medium to give the compound of formula (Ia), which is optionally halogenated, when R1 and/or R'1 is a hydrogen atom, to give the compound of formula (Ia) in which R1 and/or R'1 is a halogen atom.

6. Process for preparing the compounds of formula (Ia) according to Claim 1, in which R1, R'1, R2, R4 and A are as defined in Claim 1 and R5 is a straight or branched (C1-C4) alkyl, - (CH2) nOCH3, -CH2O (C2H4O)nCH3, - (CH2) nCF3 or -(CH2)nOH group (n equals 1 to 4), this process being characterized in that a compound of formula (II) as defined in Claim 5 is reacted with a compound of formula (V) in which A and R4 are as defined in Claim 1 and R5 is as defined above, and a compound of formula (VI) is obtained, which is treated in acidic medium to give the compound of formula (Ia), which is optionally halogenated when R1 and/or R'1 is a hydrogen atom, to give the compound of formula (Ia) in which R1 and/or R'1 is a halogen atom.

7. Process for preparing the compounds of formula (Ia) according to Claim 1, in which R1, R'1, R2, R4, R5 and A
are as defined in Claim 1, characterized in that a compound of formula (VII) in which R1, R'1, R2, R4 and R5 are as defined in Claim 1, is reacted with a compound of formula (VIII) ASn(R)3 (VIII) in which R represents a (C1-C4)alkyl group and A is as defined in Claim 1, to form a compound of formula (IX) which is heated to the reflux temperature in acidic medium, to give the compound of formula (Ia), which is optionally halogenated, when R1 and/or R'1 is a hydrogen atom, to give the compound of formula (Ia) in which R1 and/or R'1 is a halogen atom.

8. Process for preparing the compounds of formula (Ib) in which R1, R'1, R2, R4 and A are as defined in Claim 1 and R3 represents either a group -COR5 in which R5 is a straight or branched (C1-C4) alkyl, - (CH2) nOCH3, -CH2O (C2H4O) nCH3, -(CH2) nCF3 or - (CH2) nOP (protecting group P) (n equals 1 to 4) group, or a group -SO2R6, or a group -CONHR6, or a group -SO2N (R6)2, in which R6 is a straight or branched (C1-C4)alkyl group, this process being characterized in that a compound of formula (II) in which R1 and R'1 each represent either a hydrogen atom or a (C1-C4)alkyl group, is reacted with a compound of formula (X) in which A and R4 are as defined in Claim 1, and a compound of formula (XI) is obtained, which is reacted with an acid chloride of formula R5COCl or an alkyl isocyanate of formula R6NCO
or a sulphonyl chloride of formula R6SO2Cl or a sulphamoyl chloride of formula (R6)2NSO2Cl, and a compound of formula (XII) is obtained, which is treated in acidic medium to give the compound of formula (Ib), which is optionally halogenated, when R1 and/or R'1 is a hydrogen atom, to give the compound of formula (Ib) in which R1 and/or R'1 is a halogen atom.

9. Medicinal product, 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 to any one of Claims 1 to 4 in combination with any pharmaceutically acceptable excipient.