SK66799A3 - N-(imidazolylbutyl) benzenesulphonamide derivatives, their preparation and therapeutic application - Google Patents

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

N- (imidazolylbutyl) benzenesulfonamide derivatives, process for their preparation and their use for medical purposes

Technical field

The present invention relates to N- (imidazolylbutyl) benzenesulfonamide derivatives, processes for their preparation and their use for medical purposes.

BACKGROUND OF THE INVENTION

Patent applications EP 718,307 and EP 565,396 disclose 1-oxo-2- (phenylsulfonylamino) pentylpiperidine and 1- [2- (arylsulfonylamino) -1-oxoethyl] piperidine derivatives having antithrombotic activity. Patent application EP 713,865 describes compounds which are useful in the synthesis of compounds with antithrombotic activity.

SUMMARY OF THE INVENTION

The compounds of the present invention have the general formula I

where

R ¹ and R ¹ 'are, independently of one another, either a hydrogen atom or a halogen atom or an alkyl group having 1 to 4 carbon atoms;

R ² is either 1-piperidyl optionally substituted at the 4-position with one or more substituents selected from the group consisting of hydroxyl, straight or branched (C 1 -C 4) alkyl, (C 1 -C 4) hydroxyalkyl, (C 1 -C 4) alkoxyalkyl (1-4C) alkoxy and (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylthio, nitrile, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethoxy, , 2,2-trifluoroethoxy, C 3 -C 6 cycloalkyl, -COOR 'and -CONR'R''(R' is C 1-4 alkyl and R '' is hydrogen or alkyl containing 1 to 4 carbon atoms), or = CYZ [Y and Z are independently selected from the group consisting of a hydrogen atom, a halogen atom and a (C 1 -C 4) alkyl group (optionally substituted by one or more halogen atoms), a cyano group and a -COOR ', R' group is as previously defined], or (CH ₂ ) _r ( r is 1 to 3), or = NOCH 3; or a spiro [cycloalkane-1,4'-piperidin] -1-yl group having from 3 to 6 carbon atoms in the cycloalkane moiety; or a 1,2,3,6-tetrahydropyridin-1-yl group optionally substituted in the 4-position by a straight or branched alkyl group having 1 to 4 carbon atoms (optionally substituted by one or more halogen atoms) or a cycloalkyl group having 3 to 6 carbon atoms; or hexahydro-1H-azepin-1-yl optionally substituted in the 4-position with trifluoromethyl or = CF ₂ ; or a heptahydroazocin-1-yl group; or an octahydro-1H-azonin-1-yl group; or a group

(a-B is -CONR '', m is 1-2 and p is 1-2); or group /

(Q is C or N, D is C 1 -C 4 alkyl or -CH 2 CF 3 and r is 1 to 3);

R ³ is either a straight or branched alkyl group having 1 to 5 carbon atoms; or -COR ⁵ wherein R ⁵ is a C 1-4 alkyl group that is straight or branched, - (CH 2) n OCH 3, -CH 2 O (C 2 H 4 O) n CH 3, - (CH 2) n CF 3, or -? CH2) nOH (n = 1 to 4); or -SO ² R ⁶ ; or -CONHR ⁶ ; or -SO ₂ N (R ⁶ ) ₂ , wherein R ⁶ is a straight or branched alkyl group having 1 to 4 carbon atoms;

R 4 is either a hydrogen atom or a halogen atom; and

A is either phenyl optionally substituted by one or more substituents selected from the group consisting of halogen and straight or branched (C 1 -C 4) alkyl, straight or branched (C 1 -C 4) alkoxy, trifluoromethyl, trifluoromethoxy, formyl , -CH ₂ OR ^10, -CH2OCOR group ^10, group -CH2OCONR ¹⁰ R ^11, -COOR ^10, -CONR ¹⁰ R ^11, nitro, -NR ¹⁰ R ^11, -NHCOR ¹⁰ and -NH ( CH ₂ ) _q OR ¹⁰ , wherein the groups R ¹⁰ and R ¹¹ are independently hydrogen or a straight or branched alkyl group having 1 to 4 carbon atoms and q is 0 to 6; or a heterocycle selected from the group consisting of pyridinyl, thienyl, furyl, pyrimidinyl and thiazolyl; said groups may be substituted as previously mentioned; or a cycloalkyl group containing 5 to 8 carbon atoms.

According to the present invention, compounds of formula I are preferred wherein:

R ¹ and R ¹ 'are independently hydrogen or halogen or C 1 -C 4 alkyl;

R ² is either a piperidin-1-yl group optionally substituted at the 4-position with one or more substituents selected from the group consisting of C 1 -C 4 alkyl, which may be straight or branched, C 1 -C 4 hydroxyalkyl, (C 1 -C 4) alkoxyalkyl and (C 1 -C 4) alkyl moiety, (C 1 -C 4) alkoxy, nitrile-containing alkylthio, difluoromethyl, 2,2,2-trifluoroethoxy (C 4 -C 4), C 3 -C 6 trifluoromethyl and cycloalkyl, or = CYZ (Y and Z are independently selected from the group consisting of hydrogen, halogen and C 1 -C 4 alkyl), or = NOCH 3, Or spiro [cycloalkane

A -1,4'-piperidin] -1-yl group having from 3 to 6 carbon atoms in the cycloalkane moiety; or 1,2,3,6-tetrahydropyridine-1

an alkyl group optionally substituted in the 4-position by a straight or branched (C 1 -C 4) alkyl group (optionally substituted by one or more halogen atoms); or a hexahydro-1H-azepin-1-yl group optionally substituted at the 4-position with = CF ₂ ; or an octahydro-1H-azonin-1-yl group; or a group (CH _{2) m} -B

J '(CH 2) 4 (a-B is -CONR 1', m is 1-2 and p is 1-2); or group

D

(Q is C or N, D is C 1 -C 4 alkyl or -CH 2 CF 3 and r is 1 to 3);

R ³ is either a straight or branched alkyl group having 1 to 5 carbon atoms; or -COR ⁵ , wherein R ⁵ is C 1-4 alkyl, which is straight or branched, -CH ₂ O (C ₂ H ₄ O) _n CH 3, - (CH ₂ ) _n OH, or (CH 2) _n OCH ₃ ; or -CONHR ⁶ ; and

A is either phenyl optionally substituted with one or more substituents selected from the group consisting of halogen and straight or branched (C 1 -C 4) alkyl, straight or branched (C 1 -C 4) alkoxy, trifluoromethyl, trifluoromethoxy and - NR ¹⁰ R ^n, wherein R ¹⁰ and R ¹¹ are independently H or straight or branched- alkyl group having 1 to 4 carbon atoms; or a pyridinyl or thienyl group which may be substituted as defined above; or a cycloalkyl group containing 5 to 8 carbon atoms.

Among these compounds, those compounds wherein R ¹ is C 1 -C 4 alkyl and R ¹ 'is hydrogen, R ² is piperidin-1-yl substituted in the 4-position with a straight or branched C 1 -C 4 alkyl group are preferred. or R = CF 2, R ³ is -COR ⁵ wherein R ⁵ is a straight or branched alkyl group having 1 to 4 carbon atoms and A is a thienyl group optionally substituted as defined above or a cycloalkyl group having 5 to 8 carbon atoms; carbon atoms.

The preferred configuration of the central amino acid portion

O is (S).

The compounds of the present invention may exist in the form of racemates or pure enantiomers or mixtures of enantiomers. They may also exist in the form of the free acid or free base or in the form of pharmaceutically acceptable addition salts. All these forms are part of the present invention.

In the following schemes, -CPh ₃ is triphenylmethyl.

According to the present invention, compounds of formula Ia wherein R ³ is -COR ⁵ , wherein R ⁵ is a straight or branched alkyl group having 1 to 4 carbon atoms or - (CH ₂ ) _n CF ₃ (n = 1 to 4) may be prepared according to Scheme 1. A compound of formula II wherein R ¹ and R ¹ 'are either hydrogen or C 1 -C 4 alkyl and R ² is as defined above, reacts with a compound of formula III wherein A is either a phenyl group optionally substituted as defined above, or a heterocycle selected from the group consisting of pyridinyl, thienyl, furyl, pyrimidinyl, and thiazolyl, wherein said groups may be optionally substituted as defined above, or cycloalkyl a group containing 5 to 8 carbon atoms, and R ⁴ and R ⁵ have already been defined, in an aprotic solvent such as dichloromethane in the presence of a base such as triethyl amine to prepare a compound of formula IV which is reacted with acetic acid / ethanol, acetic acid water or acetic acid / tetrahydrofuran / water at boiling point.

Ί

Scheme 1

(II)

(III)

(Ia)

In an alternative embodiment of the present invention illustrated in Scheme 2 for the preparation of compounds of formula Ia, wherein R ⁵ is a C 1-4 alkyl group which may be straight or branched, - (CH ₂ ) _n OCH 3, -CH ₂ O (C ₂ H ₄ O) _n CH 3, - (CH ₂ ) _n CF 3, or - (CH ₂ ) _n OH (n = 1 to 4), a compound of formula II may be reacted with a compound of formula V wherein A is either a phenyl group as defined above or a heterocycle selected from the group consisting of pyridinyl, thienyl, furyl, pyrimidinyl and thiazolyl, which groups may be substituted as defined above, or a cycloalkyl group containing 5 to 8 carbon atoms, and R ⁴ and R ⁵ are as defined above in an aprotic solvent, such as dichloromethane, in the presence of a base such as triethylamine to give the compound eobecná of formula VI which is reacted with a mixture of acetic acid / ethanol, acetic acid / water or acetic acid / tetrahydrofuran / water at reflux.

Scheme 2

(II)

(IN)

(VI)

(Ia)

Alternatively, according to the present invention, the method illustrated in Scheme 3 may also be used. A compound of formula VII wherein R ¹ and R ¹ 'are either hydrogen or C 1 -C 4 alkyl and R ² , R ⁴ and R ⁵ as defined above, reacts with a compound of formula VIII wherein R is a C 1 -C 4 alkyl group and A is as defined above in a solvent such as dimethylformamide in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium to form a compound IX, which is heated to boiling point in an acidic medium such as acetic acid / water.

If a compound of formula Ia in which R @ ⁴ is hydrogen is to be prepared, the corresponding compound of formula Ia in which R @ ⁴ is halogen may be subjected to hydrogenolysis.

If a compound of the formula Ia in which R ^{@ 1} and / or R ^{@ 1} 'is a halogen atom is to be prepared, then the corresponding compound of the formula Ia in which R ^{@ 1} and / or R ^{@ 1} ' is a hydrogen atom is reacted with a halogenating agent such as N-bromosuccinimide or N-chlorosuccinimide, in a solvent such as dimethylformamide.

Scheme 3

(VII)

ASn (R) 3

ABOUT

CPh ₃ (IX)

(Ia)

Alternatively, for the preparation of compounds of formula Ib, wherein R ³ is either -COR ⁵ , or -SO ² R ⁶ or -CONHR ⁶ or -SO ² N (R ⁶ ) 2, wherein R ⁵ is C 1-4 alkyl carbon, which may be straight or branched, - (CH 2) _n OCH ₃ , -CH ₂ O (C ₂ H ₄ O) _n CH ₃ , ^- (CH ₂ ) _n CF ₃ , or - (CH 2) nOP, wherein P is a protecting group, n is 1 to 4, and R ⁶ is as previously defined, using the method illustrated in Scheme 4. A compound of formula II is reacted with a compound of formula X wherein A and R are as defined above to give a compound of formula XI, which is reacted with an acid chloride ^R5 COC1 or alkyl isocyanate of formula R ⁶ NCO or sulfonyl chloride of formula R ⁶ SO2C1 or a sulfamoyl chloride of formula (R ⁶⁾ ₂ NSO ₂ C 1, to obtain the compound of formula XII which is reacted with a mixture of acid / ethanol, acetic acid / water or acetic acid / tetrahydrofuran / water at boiling point.

If a compound of the formula Ib wherein R ¹ and / or R ¹ 'is a halogen atom is to be prepared, then the corresponding compound of the formula Ib wherein R ¹ and / or R ¹ ' is a hydrogen atom is reacted with a halogenating agent such as N-bromosuccinimide or N-chlorosuccinimide, in a solvent such as dimethylformamide.

If a compound of formula Ib wherein R ⁴ is a hydrogen atom is to be prepared, then the corresponding compound of formula Ic wherein R ⁴ is a halogen atom is subjected to hydrogenolysis.

Scheme 4

(II)

(X) (XI) (XII) (Ib)

A process for preparing compounds of formula Ic wherein R ¹² is R ³ when R ³ is a straight or branched (C 1 -C 5) alkyl group is illustrated in Scheme 5. The compound of formula II is reacted with a compound of formula XIV wherein R ¹² is straight or branched (C 1 -C 5) alkyl group and A and R ⁴ have already been defined to give a compound of formula (XV) which is reacted with acetic acid / ethanol, acetic acid / water or acetic acid / tetrahydrofuran / water at temperature reflux.

If a compound of formula Ic wherein R ¹ and / or R ¹ 'is a halogen atom is to be prepared, then the corresponding compound of formula Ic wherein R ¹ and / or R ¹ ' is a hydrogen atom is reacted with a halogenating agent such as e.g. N-bromosuccinimide or N-chlorosuccinimide, in a solvent such as dimethylformamide.

If a compound of formula Ic wherein R ⁴ is hydrogen is to be prepared, then the corresponding compound of formula Ic wherein R ⁴ is halogen is subjected to hydrogenolysis.

The starting materials are commercially available or described in the literature or can be prepared according to the methods described in the invention or known to those skilled in the art.

Scheme 5

(X) (X) (XV)

(Ic)

The compounds of formula (II) are thus prepared in an analogous manner to that described in the European patent application EP

0,643,047.

Some compounds of formula (II) are described in European Patent Application EP 0,718,307.

Compounds of formula (VII) are prepared analogously to that described in European patent application EP 0,718,307.

Compounds of formula X and XIV are described in European patent application EP 0,713,865.

5-Ethyl-1H-imidazole was prepared according to the method described by Horne D. A., Heterocycles, 39 (1), 139 (1994).

The preparation of 4-cyclopropylpyridine is described in Eisch J. J., J. Org. Chem. 39 (21), 5110 (1974).

4-Difluoromethylene-piperidine 'was prepared in an analogous manner to that described in Schmidt W. et al., Liebigs Ann. Chem. 1995, 1319-1326.

The preparation of N-cyclopentylformamide is described in Bossio R. et al., Synthesis 1993 (8), 783-785.

The following Examples 1 to 11 illustrate the preparation of some compounds of Formula II; Examples 12 to 27 illustrate the preparation of some compounds of Formula I of the present invention.

Elemental analyzes and IR and NMR spectra are consistent with the structure of the compounds obtained. The numbers of the compounds given in the examples correspond to those given in the table after the examples which illustrate the chemical structures and physical properties of some of the compounds according to the invention.

The ratios in brackets correspond to ratios (base: acid).

DETAILED DESCRIPTION OF THE INVENTION

Example 1

(S) -5-Ethyl-α - [(4-ethylpiperidin-1-yl) carbonyl] -1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride (1: 1)

1.1 5-Ethyl-4-iodo-1H-imidazole

A solution of 22.7 g (89 mmol) of iodine in 800 ml of chloroform was added dropwise to the solution over 3 hours at 0 ° C.

8.6 g (89 mmol) of 5-ethyl-1H-imidazole in 600 ml of 2N aqueous sodium hydroxide solution. Stirring was continued at this temperature for 4 hours and then the chloroform was evaporated under reduced pressure. The aqueous layer was then cooled to 0 ° C, neutralized using 12 N aqueous hydrochloric acid, and extracted three times with 1 L of ethyl acetate. The organic layers are combined,

I was washed with 100 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel, eluting with methanol: dichloromethane (1.5: 98.5). 10.5 g of product are obtained in the form of a white powder.

Yield 53%. Mp 155 ° C.

1.2 5-Ethyl-4-iodo-1 - [(4-methylphenyl) sulfonyl] -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 the solution.

4.8 g (21.6 mmol) of 5-ethyl-4-iodo-1H-imidazole in 25 ml of anhydrous dimethylformamide. Stirring at 0 ° C was continued for 0.5 h and 4.35 g (22.7 mmol) of 4- (methylphenyl) sulfonyl chloride was added. The mixture was stirred for 1 hour at 0 ° C, then allowed to warm to room temperature, stirring was continued for 1 hour, and then the reaction mixture was evaporated under reduced pressure. The residue is taken up in 400 ml of ethyl acetate and washed successively with 100 ml of a 0.5N aqueous hydrochloric acid solution, 100 ml of water and 100 ml of a saturated aqueous sodium chloride solution. Finally, the solution is dried over sodium sulphate and evaporated under reduced pressure. After precipitation from ethyl acetate: pentane, 6.1 g of product are obtained in the form of a white solid. Yield 75%. Melting point 95 ° C.

1.3 Methyl (S) -2 - {[(1,1-dimethylethoxy) carbonyl] amino} -5- {5-ethyl-

1 - [(4-methylphenyl) sulfonyl] -lH-imidazol-4-yl} pent-4-ynoate

1.3.1 Methyl (S) -2 - {[(1,1-dimethylethoxy) carbonyl] amino} pent-4-ynoate

(a) (S) -2 - {[(1,1-dimethylethoxy) carbonyl] amino} pent-4-ynoic acid

11.5 g (77 mmol) of (S) -2-aminopent-4-ynoic acid hydrochloride, 100 ml of dioxane, 50 ml of water and 80 ml of 2N sodium hydroxide solution are placed in a 250 ml round bottom flask under nitrogen. To the solution was added 17.9 g (82 mmol) of tert-butyl dicarbonate, and the reaction mixture was stirred for 3 hours at room temperature. Ethyl acetate (200 ml) was added and the solution was acidified to pH 2 with 2N hydrochloric acid. The layers were separated and the aqueous layer was extracted with ethyl acetate (50 ml). The solution was dried over magnesium sulfate and evaporated to dryness. 18.78 g of product are obtained in the form of a colorless oil, which is used as is in the following stage.

b) Methyl (S) -2 - {[(1,1-dimethylethoxy) carbonyl] amino} pent-4-ynoate (154 mmol) sodium bicarbonate was added to a solution of 18.78 g (77 mmol) of acid under nitrogen. (S) -2 - {[(1,1-dimethylethoxy) carbonyl] amino} pent-4-yne in 150 ml dimethylformamide in a 250 ml round bottom flask. Methyl iodide (20 mL, 318 mmol) was added and the mixture was stirred at room temperature for 18 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated to dryness. 15.85 g of product are obtained in the form of a yellow oil which is used as is in the following stage.

1.3.2 Methyl (S) -2 - {[(1,1-dimethylethoxy) carbonyl] amino} -5- {5-ethyl-1 - [(4-methylphenyl) sulfonyl] -1H-imidazol-4-yl} pent-4-ynoate

A mixture of 9.87 g (26.3 mmol) of 5-ethyl-4-iodo-1 - [(4-methylphenyl) sulfonyl] -1H-imidazole, 8.94 g (39.4 mmol) of methyl (S) -2 - {[(1,1-dimethylethoxy) carbonyl] amino} pent-4-ynoate, 0.25 g of copper (I) iodide,

10.84 ml (105 mmol) of diethylamine and 0.92 g (1.3 mmol) of dichlorobis (triphenylphosphine) palladium in 26 ml of dimethylformamide were heated at 50 ° C under argon for 8 hours. The reaction mixture is evaporated under reduced pressure, the residue is taken up in 300 ml of ethyl acetate and washed successively with 100 ml of water and 100 ml of saturated sodium chloride solution. Finally, the solution is dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate: hexane (3: 7). 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) sulfonyl] -lH-imidazol-4-yl} pentanoate

A mixture of 13.5 g (28.4 mmol) of methyl (S) -2 - {[(1,1-dimethylethoxy) carbonyl] amino} -5- {5-ethyl-1 - [(4-methylphenyl) sulfonyl] 1 H-imidazol-4-yl} pent-4-ynoate in the presence of 1.8 g of 10% palladium on activated carbon in 50 ml of methanol is hydrogenated for 10 hours at room temperature and 50 psi of hydrogen. The reaction mixture was filtered through diatomaceous earth and evaporated under reduced pressure. The residue was purified by silica gel chromatography eluting with cyclohexane: ethyl acetate (7: 3). 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) sulfonyl] 1 H -imidazo-4-ylpentanoate and 8.79 g (65.2 mmol) of 1-hydroxybenzotriazole hydrate in 150 ml of methanol are stirred for 4 hours at room temperature. The reaction mixture is evaporated under reduced pressure, the residue is taken up in 100 ml of ether and washed with 450 ml of a 0.7N aqueous hydrochloric acid solution. Separate the layers, adjust the pH of the aqueous layer to 8-9 with sodium bicarbonate solution and extract twice with 500 mL ethyl acetate. The organic layers were combined and evaporated under reduced pressure. 8.79 g of product are obtained in the form of a viscous oil, which product is used as is in the following stage. Yield 88%.

1.6 Methyl (S) -2 - {[(1,1-dimethylethoxy) carbonyl] amino} -5- [5-ethyl-

1- (triphenylmethyl) -lH-imidazol-4-yl] pentanoate

2.9 ml (20.3 mmol) of triethylamine and 5.77 g (20.7 mmol) of triphenylmethyl chloride are gradually added to the solution at 0 ° C.

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 reaction mixture was allowed to warm to room temperature and stirred at this temperature for 18 hours and then evaporated 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 bicarbonate solution and 100 ml of a saturated sodium chloride solution. This solution is dried over magnesium sulphate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel, eluting with dichloromethane: methanol (99: 1). 9.4 g of product are obtained in the form of a viscous oil. Yield 90.6%.

(S) -α - ([(1,1-dimethylethoxy) carbonyl] amino} -5-ethyl-

1- (triphenylmethyl) -lH-imidazole-4-pentanoic acid

0.83 g (19.8 mmol) of lithium hydroxide monohydrate was added to 9.4 g (16.6 mmol) of methyl (S) -2 - {[(1,1-dimethylethoxy) carbonyl] with stirring at 0 ° C. amino] -5- [5-ethyl-1H-imidazol-4-yl] pentanoate in a mixture of 48 mL of methanol and 16 mL of water. The reaction mixture was allowed to warm to room temperature and stirring was continued at this temperature for 24 hours. The reaction mixture was evaporated under reduced pressure and the aqueous layer was acidified to pH 2 with 1N aqueous hydrochloric acid solution and then extracted twice with 300 ml of dichloromethane. The organic layers were combined, washed with 100 mL of saturated sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was triturated with 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-l- (triphenylmethyl) -lH-imidazol-4-yl] butyl} carbamate

1.8.1. 4-Ethylpiperidine hydrochloride

(a) 4-Ethenylpyridine 1,1-dimethylethyl 4-ethylpiperidine-1-carboxylate g (190 mmol) is hydrogenated for 4 hours at 50 ° C and 60 psi of hydrogen in the presence of 2 g platinum oxide; the reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure. The residue is taken up in 150 ml of water, the pH is adjusted with saturated aqueous solution

I solution to 8 and a solution of 44 g of bis (1,1-dimethylethyl) dicarbonate in 100 ml of tetrahydrofuran is added dropwise. The reaction mixture was allowed to warm to room temperature and stirring was continued at this temperature for 18 hours. The reaction mixture was evaporated under reduced pressure and the aqueous layer was extracted twice with 300 mL of ethyl acetate. The organic layers were combined and washed with 100 mL of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel, eluting with cyclohexane: ethyl acetate (9: 1). 13.8 g of product are obtained in the form of an oil. Yield 34%.

b) 4-Ethylpiperidine hydrochloride

A solution of 13.8 g (64.8 mmol) of 1,1-dimethylethyl 4-ethylpiperidine-1-carboxylate in 200 mL of ether was treated with a stream of hydrochloric acid at 0 ° C for 1 hour. The reaction mixture was allowed to warm to room temperature, stirring was continued at this temperature for 18 hours, and the mixture was evaporated under reduced pressure. The residue is triturated with 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%. Mp 138 ° C.

1,8.2 1,1-Dimethylethyl (S) - {1 - [(4-ethylpiperidin-1-yl) carbonyl] -4- [5-ethyl-1- (triphenylmethyl) -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 hexafluorophosate were gradually stirred at 0 ° C under nitrogen atmosphere with stirring add 0.6 g (1.08 mmol) of (S) -α - {[(1,1-dimethylethoxy) carbonyl] amino} -5-ethyl-1- (triphenylmethyl) -1H-imidazole-4- pentane and 0.18 g (1.2 mmol) of 4-ethylpiperidine hydrochloride in 8 mL of dichloromethane. The reaction mixture was allowed to warm to room temperature, stirring was continued at this temperature for 18 hours, and the reaction mixture was evaporated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed successively with 80 ml of 1N hydrochloric acid, 50 ml of saturated sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with methanol: dichloromethane (2: 98). 0.7 g of product is obtained in the form of a viscous oil. Yield 98%.

(S) -5-Ethyl-α - [(4-ethylpiperidin-1-yl) carbonyl] -1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride (1: 1)

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 at 0 ° C for 15 minutes. The reaction mixture was allowed to warm to room temperature, then stirred at this temperature for 1.5 hours and evaporated under reduced pressure. The residue thus obtained was triturated with 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 in the next step without further purification. Yield 97%.

Example 2

(S) -5-Methyl-α - {[4- (trifluoromethyl) piperidin-1-yl] carbonyl} -1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride (1: 1)

2.1 1,1-Dimethylethyl (S) (4- [5-methyl-1- (triphenylmethyl) -1H-lipidazol-4-yl] -1 - {[4- (trifluoromethyl) piperidin-1-yl] carbonyl} butyl) carbamate

(S) -α - {[(1,1-dimethylethoxy) carbonyl] amino} -5-methyl-1- (triphenylmethyl) -1H-imidazole-4-pentanoic acid

The compound was prepared according to the method described in the example

1.7 from methyl (S) -2 - {[(1,1-dimethylethoxy) carbonyl] amino} -5- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] pentanoate.

2.1.2 1,1-Dimethylethyl (S) (4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl) -1 - ([4- (trifluoromethyl) piperidin-1-yl] carbonyl] butyl ) carbamate

0.834 g (2.2 mmol) of [(benzotriazol-1-yl) oxy] tris (dimethylamino) phosphonium hexafluorophosphate was added in portions to a mixture of 1.08 g (2 mmol) of acid (S) at 0 ° C under argon with stirring. 1-A - {[(1,1-dimethylethoxy) carbonyl] amino] -5-methyl-1- (trifluoromethyl) -1H-imidazole-4-pentanoic acid, 0.306 g (2 mmol) of 4- (trifluoromethyl) piperidine and 1.04 ml (6 mmol) of diisopropylethylamine in 25 ml of dichloromethane. The reaction mixture was allowed to warm to room temperature, stirring was continued at this temperature for 18 hours, and the reaction mixture was evaporated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of 1N aqueous hydrochloric acid solution, 50 ml of saturated sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with methanol: dichloromethane (2: 98). 1.2 g of product are obtained in the form of a viscous oil. Yield 89%.

(S) -5-Methyl-α - {[4- (trifluoromethyl) piperidin-1-yl] carbonyl} -1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride (1: D)

A solution of 1.2 g (1.78 mmol) of 1,1-dimethylethyl (S) (4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl) -1 - {[4- (trifluoromethyl) (piperidin-1-yl) carbonyl} butyl) carbamate in 100 ml benzene at 0 ° C was treated with a stream of gaseous hydrochloric acid for 20 minutes. The reaction mixture was allowed to stir at this temperature for 1 hour and evaporated under reduced pressure. The residue thus obtained was triturated with ether, filtered off and dried under reduced pressure. 1.05 g of product is obtained in the form of a white powder which is used in the next step. Yield 97%. Mp 78 ° C.

Example 3

(S) -? - [(4-Methoxy-piperidin-1-yl) -carbonyl] -5-methyl-1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride (1: 1)

3.1. 4-Methoxypiperidine hydrochloride

3.1.1 1,1-Dimethylethyl 4-hydroxypiperidine-1-carboxylate

A solution of 12 g (55 mmol) of bis (1,1-dimethylethyl) dicarbonate in 50 ml of methanol is added dropwise at room temperature to a solution of 5.06 g (50 mmol) of piperidin-4-ol in 50 ml of methanol. The reaction mixture was allowed to stir at this temperature for 2 hours and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol (95: 5). 9.74 g of product are obtained in the form of an oil. Yield 97%.

3.1.2 1,1-Dimethylethyl 4-methoxy-piperidine-1-carboxylate

1.59 g (39.8 mmol) of 60% sodium hydride in oil are added portionwise at 0 ° C under argon and with stirring to a solution of 8 g (39.8 mmol) of 1,1-dimethylethyl 4-hydroxypiperidine-1. -carboxylate and 4.95 ml (79.5 mmol) of methyl iodide in 40 ml of dimethylformamide and stirring at this temperature was continued for 2 hours. The reaction mixture was poured into 100 mL of saturated ammonium chloride solution and extracted twice with 200 mL of ethyl acetate. The organic layers were combined, washed successively with 100 mL of water and 100 mL of saturated sodium chloride solution, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate: cyclohexane (2: 8). 7.1 g of product are obtained in the form of an oil. Yield 85%.

3.1.3. 4-Methoxy-piperidine hydrochloride

A solution of 7 g (32.5 mmol) of 1,1-dimethylethyl 4-methoxy-piperidine-1-carboxylate in 100 ml of tetrahydrofuran at 0 ° C was treated with a stream of gaseous hydrochloric acid for 30 minutes. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue was triturated with 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 in the next step without further purification. Yield 86%. M.p. 132 ° C.

3.2 1,1-Dimethylethyl (S) - {1 - [(4-methoxypiperidin-1-yl) carbonyl] -4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] butyl} carbamate

0.71 g (1.87 mmol) of [(benzotriazol-1-yl) oxy] tris (dimethylamino) phosphonium hexafluorophosphate was added in portions to the mixture of 0.918 g (1.7 mmol) of acid at 0 ° C under nitrogen and stirred in portions. (S) -α - {[(1,1-dimethylethoxy) carbonyl] amino) -5-methyl-1- (triphenylmethyl) -1H-imidazole-4-pentanoic acid, 0.281 g (1.87 mmol) of 4-methoxypiperidine hydrochloride and 0.63 mL (3.57 mmol) of diisopropylethylamine in 12 mL of dichloromethane. The reaction mixture was allowed to warm to room temperature, stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate and washed successively with 50 ml of a 0.5N aqueous hydrochloric acid solution, 50 ml of a saturated aqueous sodium bicarbonate solution and 50 ml of a saturated aqueous sodium chloride solution and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with methanol: dichloromethane (2: 98). 1.05 g of product is obtained in the form of a viscous oil. Yield 97%.

(S) -? - [(4-Methoxy-piperidin-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 benzene at 0 ° C for 20 minutes was treated with a stream of hydrogen chloride gas. The reaction mixture was allowed to stir at this temperature for 30 minutes and evaporated under reduced pressure. The residue is triturated with 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 in the next step without further purification. Yield 98%. Melting point

112 [deg.] C.

Example 4

(S) -5-Methyl-α - [(4-methylenepiperidin-1-yl) carbonyl] -1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride (1: 1)

4.1. 4-Methylene-piperidine hydrochloride

4.1.1 1,1-Dimethylethyl 4-methylenepiperidine-1-carboxylate ml of a 1,6 M solution of n-butyllithium in hexane at room temperature under nitrogen is added to a mixture of 9,81 g (27,5 mmol) of methyltriphenylphosphonium bromide in 60 ml of anhydrous tetrahydrofuran . The mixture was stirred at room temperature for 4 hours and then a solution of 5 g (25 mmol) of 1,1-dimethylethyl 4-oxopiperidine-1-carboxylate in 20 ml of anhydrous tetrahydrofuran was added rapidly. The reaction mixture is heated at reflux for 10 hours, poured into 400 ml of saturated ammonium chloride solution and extracted twice with 300 ml of ether. The organic layers were combined, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate: n-hexane (5:95). 2.8 g of product are obtained in the form of a glassy oil. Yield 57%.

Are you

4.1.2. 4-methylenepiperidine hydrochloride.

This compound was prepared from 1,1-dimethylethyl 4-methylene-piperidine-1-carboxylate according to the method described in Example 3.1.3.

4.2 (S) -5-Methyl-α - [(4-methylenepiperidin-1-yl) carbonyl] -1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride (1: 1)

(S) -? - {[(1,1-Dimethylethoxy) carbonyl] amino} -5-methyl-1- (triphenylmethyl) -1H-imidazole-4-pentanoic acid was reacted with 4-methylenepiperidine hydrochloride according to the method described in Example 3.2 to give 1,1-dimethylethyl (S) {4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] -1 - [(4-methylenepiperidin-1-yl) carbonyl] butyl } amorphous carbamate. Mp 85 ° C.

This product is reacted with a stream of hydrogen chloride gas according to the method described in Example 3.3. 0.74 g of product is obtained. Yield 100%. Mp 148 ° C.

Example 5

(S) -? - [(4-Cyclopropylpiperidin-1-yl) carbonyl] -5-methyl-1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride (1: 1)

5.1. 4-Cyclopropylpieridine hydrochloride

5.1.1 4-Cyclopropylpiperidine

A solution of 4-cyclopropylpyridine (13 g, 109 mmol) in acetic acid (150 mL) was hydrogenated at 50 ° C in a Parr vessel under 50 psi of hydrogen in the presence of 0.7 g platinum oxide. The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure. 12.85 g of product are obtained, which product is used as is in the following stage.

Yield 94%.

5.1.2 Dissolve 4-cyclopropylpieridine 1,1-dimethylethyl 4-cyclopropylpiperidine-1-carboxylate g (40 mmol) in 40 ml of dichloromethane, cool to 0 ° C and add dropwise.

6.98 g (32 mmol) of bis (1,1-dimethylethyl) dicarbonate and 4.85 g (48 mmol) of triethylamine. The reaction mixture was evaporated and the residue was purified by silica gel chromatography eluting with dichloromethane: methanol (99: 1). 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 100 ml of benzene at 0 ° C was treated with a stream of gaseous hydrochloric acid for 30 minutes. The reaction mixture was allowed to warm to room temperature, stirring was continued at this temperature for 4 hours and the reaction mixture was evaporated under reduced pressure. The residue thus obtained was triturated with 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 in the next step without further purification. Yield 88%. Melting point 186 ° C.

5.2 1,1-Dimethylethyl (S) -1 - {[(4-cyclopropylpiperidin-1-yl) carbonyl] -4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] butyl } carbamate

To a stirred mixture of (S) -? - {[(1,1-dimethylethoxy) carbonyl] amino} -5g (11 mmol) -5-methyl-1- (triphenylmethyl) -1H-imidazole-4-pentanoic acid, 79 g (11 mmol) of 4-cyclopropylpiperidine hydrochloride and 9.6 ml (55.5 mmol) of diisopropylethylamine in 100 ml of dichloromethane are added portionwise at 0 ° C and under argon [4.62 g (12.2 mmol) [( benzotriazol-l-yl) oxy] tris (dimethylamino) phosphonium hexafluorophosphate. The mixture was allowed to warm to room temperature, stirred at room temperature for 4 hours and then evaporated in vacuo. The residue is taken up in 300 ml of ethyl acetate, washed successively with 100 ml of 1N aqueous sodium hydrogen carbonate solution and 100 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel, eluting with methanol: dichloromethane (1:99). 5 g of product are obtained. Yield 70%.

5.3 (S) -? - [(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 benzene at 0 ° C was treated with a stream of hydrogen chloride gas for 30 minutes. The reaction mixture was allowed to warm to room temperature, stirred for 3 hours and then evaporated under reduced pressure. The residue thus obtained is taken up in 280 ml of dichloromethane and dried under reduced pressure. 4.7 g of product are obtained in the form of a white powder which is used as is in the following stage. Yield 100%. Melting point 124 ° C.

Example 6

(S) -5-Methyl-α - {[4- (difluoromethylene) piperidin-1-yl] carbonyl} -1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride (1: 1)

6.1. 4- (Difluoromethylene) piperidine hydrochloride

6.1.1 1,1-Dimethylethyl 4- (difluoromethylene) piperidine-1-carboxylate

A solution of 45.6 mL (252 mmol) of hexamethylphosphoramide in 30 mL of triglyme was added dropwise at 0 ° C under argon to a stirred solution of 12 mL (120 mmol) of difluorobromomethane in 180 mL of triglyme. The reaction mixture was allowed to warm to room temperature, stirring was continued at this temperature for 30 minutes, and the reaction mixture was recooled to 0 ° C. A solution of 11.94 g (60 mmol) of 1,1-dimethylethyl 4-oxopiperidine-1-carboxylate in 30 ml of triglyme is then added, the reaction mixture is allowed to warm to room temperature and stirred at this temperature for 30 minutes. The reaction mixture was then heated at 80 ° C for 2 hours, cooled, poured into 1 L of water and extracted three times with 400 mL of pentane. It is washed with water, dried over sodium sulphate and evaporated. The residue was purified by silica gel chromatography eluting with cyclohexane: ethyl acetate (97: 3). 8.5 g of product are obtained. Yield 61%.

6.1.2. 4- (Difluoromethylene) piperidine hydrochloride

This compound is obtained as a white powder from

1,1-dimethylethyl 4- (difluoromethylene) piperidine-1-carboxylate according to the method described in Example 3.1.3. Yield 100%. Melting point 196 ° C.

6.2. (S) -5-Methyl-α - {[4- (difluoromethylene) piperidine-1-] hydrochloride

-yl] -carbonyl} -1- (triphenylmethyl) -1H-imidazole-4-butanamine d: D

(S) -α - {[(1,1-dimethylethoxy) carbonyl] amino) -5-methyl-1- (triphenylmethyl) -1H-imidazole-4-pentanoic acid is reacted with 4- (difluoromethylene) piperidine hydrochloride according to the method described in Example 3.2 to give 1,1-dimethylethyl (S) - (4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl) -1- {[4- (difluoromethylene) piperidine- 1-yl] carbonyl} butyl) carbamate as a glassy solid. Yield 75%. Melting point 86 ° C. This product is reacted with a stream of hydrogen chloride gas according to the method described in the example

3.3 Obtained as a white powder. Yield 99%. Melting point 117 ° C.

Example 7

(S) -5-Methyl-α - {[4- (methylthio) piperidin-1-yl] carbonyl} -1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride (1: 1)

7.1. 4- (Methylthio) piperidine hydrochloride

7.1.1 1,1-Dimethylethyl 4 - [(methylsulfonyl) oxy] piperidine-1-carboxylate

5.6 ml (72 mmol) of methanesulfonyl chloride are added dropwise at 0 ° C under nitrogen to a solution of 13.9 g (69 mmol) of 1,1-dimethylethyl 4-hydroxypiperidine-1-carboxylate and 5.6 ml (76 mmol) of triethylamine. in 80 ml of dichloromethane. The reaction mixture was stirred at this temperature for 6 hours and evaporated under reduced pressure. The residue is taken up in 200 ml of ethyl acetate and washed successively with 100 ml of 1N aqueous hydrochloric acid solution, 100 ml of water and 100 ml of saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting 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- (trimethylethyl 4 - [(methylsulfonyl) oxy] piperidine-1-carboxylate, 0.71 g (10.1 mmol) of sodium thiomethoxide and 0.37 g (1 mmol). of tetrabutylammonium iodide in 10 ml of tetrahydrofuran is stirred at room temperature for 72 hours and then the mixture is evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with n-hexane: ethyl acetate (9: 1). 1.5 g of product are obtained in the form of a viscous oil. Yield 63%.

7.1.3. 4- (Methylthio) piperidine hydrochloride

This compound was prepared from 1,1-dimethylethyl 4- (methylthio) -piperidine-1-carboxylate according to the method described in Example

3.1.3. Yield 100%. 156.5 ° C.

7.2 (S) -5-Methyl-α - {[4- (methylthio) piperidin-1-yl] -

-carbonyl} -1- (triphenylmethyl) -1H-imidazole-4-butanamine (1: D

(S) -α - {[(1,1-dimethylethoxy) carbonyl] amino} -5-methyl-1- (triphenylmethyl) -1H-imidazole-4-pentanoic acid reacts with 4- (methylthio) piperidine hydrochloride according to the procedure described in the example

3.2 to give 1,1-dimethylethyl (S) - (4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl) -1 - {[4- (methylthio) piperidin-1- yl] carbonyl} butyl) carbamate as an amorphous powder. Yield 93%. Mp 101.2 ° C. This product is reacted with a stream of hydrogen chloride gas according to the method described in Example 3.3. The product is obtained as an amorphous powder. Yield 100%. 127.7 ° C.

Example 8

(S) -5-Methyl-α - [(4-methyl-1,2,3,6-tetrahydropyridin-1-yl) carbonyl] -1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride d: D

8.1. 4-Methyl-1,2,3,6-tetrahydropyridine hydrochloride

8.1.1 1,1-Dimethylethyl 4-methyl-1,2,3,6-tetrahydropyridine-1-carboxylate

A solution of 18 ml (28.8 mmol) of methyl lithium in ether at 0 ° C under nitrogen was added to a solution of 4.95 g (25 mmol) of 1,1-dimethylethyl 4-oxopiperidine-1-carboxylate in 30 ml of anhydrous tetrahydrofuran and stirred at this temperature continue for 2 hours. Then 3 ml (38 mmol) of methanesulfonyl chloride are added dropwise, stirring at 0 ° C is continued for 4 hours and then the reaction mixture is evaporated under reduced pressure. The residue is taken up in 200 ml of ethyl acetate and washed successively twice with 100 ml of a 0.1N aqueous hydrochloric acid solution, 100 ml of water and 100 ml of saturated sodium chloride solution. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue is taken up in 100 ml of toluene and 15 ml of triethylamine, heated at reflux for 18 hours and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with n-hexane: ether (95: 5). 0.9 g of product is obtained in the form of a viscous oil. Yield 18%.

8.1.2. 4-Methyl-1,2,3,6-tetrahydropyridine hydrochloride

This compound was prepared from 1,1-dimethylethyl 4-methyl-1,2,3,6-tetrahydropyridine-1-carboxylate according to the procedure described in Example 3.1.3. Yield 100%.

8.2 (S) -5-Methyl-α - [(4-methyl-1,2,3,6-tetrahydropyridin-1-yl) carbonyl] -1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride (1) : 1)

(S) -α - {[(1,1-dimethylethoxy) carbonyl] amino} -5-methyl-1- (triphenylmethyl) -1H-imidazole-4-pentanoic acid reacts with 4-methyl-1,2,3-hydrochloride 6-tetrahydropyridine according to the method described in Example 3.2 to give 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 as an amorphous powder. Yield 90%. Melting point 90.7 ° C. This product is reacted with hydrogen chloride gas as described in Example 3.3. Obtained as a white powder. Yield 100%. Melting point 118 ° C.

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

9.1.1 1- (Phenylmethyl) hexahydro-5H-1,4-diazepin-5-one

A solution of 9.86 g (87.18 mmol) of hydroxylamine-O-sulfonic acid was added to a solution of 11 g (58.12 mmol) of 1-phenylmethylpiperidin-3-one in 60 ml of formic acid over 10 minutes. The reaction mixture is heated at reflux for 4 hours. The reaction mixture was allowed to cool, poured into ice / water and neutralized with 5% aqueous sodium hydroxide solution. The mixture was extracted with chloroform, the organic layer was separated, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol (2: 98). 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 carbon are added and the reaction mixture Heat at 45 ° C for 3 hours at 42 psi of hydrogen. The reaction mixture is filtered through diatomaceous earth, the solvent is evaporated and the residue is taken up in 30 ml of ethanol. The mixture was heated, the insoluble material was filtered off, washed with ether and the solvent was evaporated. It will be obtained

2.44 g of the product in the form of a white powder, which was used in the next step without further purification.

9.2. 1- {2-Amino-5- [5-methyl-1- (triphenylmethyl) -1H-

-imidazol-4-yl] -1-oxopentyl) hexahydro-5H-1,4-diazepin-5-one

9.2.1 1,1-Dimethylethyl (S) - {4- [Symethyl-1- (triphenylmethyl) -1H-imidazol-4-yl] -1 - [(5-oxohexahydro-5H-1,4-diazepine-1)] (yl) carbonyl] butyl) carbamate

2.15 g (4 mmol) of (S) -? - {[(1,1-dimethylethoxy) carbonyl] amino) -5-methyl-1- (triphenylmethyl) -1H-imidazole-4-pentanoic acid, then 2, 8 ml (16 mmol) of N, N-diisopropylethylamine and 1.5 g (4 mmol) of O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate are added to 0 ° C at 0 ° C. solution of 0.6 g (4 mmol) of hexahydro-5H-1,4-diazepin-5-one hydrochloride in 40 ml of dichloromethane. The reaction mixture was allowed to warm to room temperature, stirring was continued overnight and the mixture was evaporated in vacuo. The residue is taken up in 200 ml of ethyl acetate and washed successively three times with 30 ml of 1N aqueous hydrochloric acid solution, twice with 20 ml of saturated sodium hydrogen carbonate solution and then with 20 ml of saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of dichloromethane: methanol (98: 2 to: 3). 1.87 g of product are obtained in the form of a 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

A solution of 1.87 g (2.94 mmol) of 1,1-dimethylethyl (S) - {4- [5-methyl-1- (triphenylmethyl) -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 hydrogen chloride gas at 0 ° C for 10 seconds. The reaction mixture was allowed to warm to room temperature and then evaporated in vacuo. The residue was dissolved in a minimum volume of dichloromethane and 200 mL of ether was added. The mixture was 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, t,

(S) -α-Amino-N-cyclopentyl-N, 5-dimethyl-1- (triphenylmethyl) -1H-imidazole-4-pentanamide hydrochloride

10.1. N-methylcyclopentanamine hydrochloride

10.1.1 N-Cyclopentylformamide

A mixture of 10 g (117 mmol) of cyclopentanamine and 10.8 ml (140 mmol) of ethyl formate was heated to reflux for 4 hours and then the reaction mixture was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of ethyl acetate: cyclohexane (1: 9 to 6: 4). 10 g of product are obtained in the form of an oil. Yield 75%.

10.1.2 1,1-Dimethylethyl cyclopentylmethylcarbamate ml (50 mmol) of a 1 M solution of lithium aluminum hydride in tetrahydrofuran is added dropwise to the solution at 0 ° C under nitrogen.

4.37 g (38 mmol) of N-cyclopentylformamide in 20 ml of anhydrous tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and then heated to reflux for 8 hours. The reaction mixture is cooled to 0 ° C, acidified to pH 2 with 1N aqueous hydrochloric acid solution and then adjusted to pH 8 with potassium carbonate. Then a solution of 8.6 g (40 mmol) of bis (1,1-) is added dropwise. dimethylethyl) dicarbonate in 40 ml of methanol. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 15 hours. The reaction mixture was extracted twice with 300 mL of ether and the organic layers were combined. They are washed twice with 200 ml of 1N hydrochloric acid solution and then with 200 ml of saturated sodium chloride solution. The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with cyclohexane: ether (95: 5). 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 was treated with hydrogen chloride gas at 0 ° C for 5 minutes. The mixture was allowed to stir at this temperature for 4 hours and then evaporated under reduced pressure. 1.96 g of product are obtained in the form of a white hygroscopic powder. Yield 100%. mp 123-126 ° C.

10.2 (S) -α-Amino-N-cyclopentyl-N, 5-dimethyl- (triphenylmethyl) -1H-imidazole-4-pentanamide hydrochloride

10.2.1 1,1-Dimethylethyl (S) - {1 - [(cyclopenylmethylmethylamino) carbonyl] -4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] butyl} carbamate

0.68 g (5 mmol) of N-methylcyclopentanamine hydrochloride,

2.15 ml (12.3 mmol) of N, N-diisopropylethylamine and 1.98 g (5.24 mmol) of O- (benzotriazol-1-yl) -1, Ν, am ', Ν'-tetramethyluronium hexafluorophosphate were added at room temperature. (S) -α - {[(1,1-dimethylethoxy) carbonyl] amino} -5-methyl-1- (triphenylmethyl) - is added gradually to a solution of 0 ° C under nitrogen. 1H-imidazole-4-pentanoic acid in 15 ml of dichloromethane. The reaction mixture was allowed to warm to room temperature, stirred at room temperature for 15 hours and then evaporated in vacuo. The residue is taken up in 150 ml of ethyl acetate and washed successively with 100 ml of 1N aqueous hydrochloric acid solution, 100 ml of saturated aqueous sodium hydrogen carbonate solution and then 100 ml of saturated sodium chloride solution. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of ethyl acetate: cyclohexane (3: 7 to 8: 2). 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) -α-Amino-N-cyclopentyl-N, 5-dimethyl-1-

- (triphenylmethyl) -lH-imidazole-4-pentanamide

A solution of 2.2 g (3.5 mmol) of 1,1-dimethylethyl (S) - {1 - [(cyclopentylmethylamino) carbonyl] -4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] The butyl carbamate is reacted with a stream of hydrogen chloride gas at 0 ° C for 5 minutes. The reaction mixture was allowed to stir at this temperature for ’5 hours and then evaporated under reduced pressure. 2 g of product are obtained, which product is used as is in the following stage. Yield 100%. Mp 138-142 ° C.

Example 11

(S) -α-Amino-N, 5-dimethyl-N-pyrrolidin-1-yl-1- (triphenylmethyl) -1H-imidazole-4-pentanamide hydrochloride

11.1 N-Methylpyrrolidin-1-amine hydrochloride

11.1.1 1,1-Dimethylethyl pyrrolidin-1-ylcarbamate

1.13 ml (8.15 mmol) of triethylamine was added dropwise to a solution of 1 g (8.15 mmol) of pyrrolidin-1-amine hydrochloride and 1.62 g (7.4 mmol) of bis (1,1-dimethylethyl) carbonate in 8 ml of dichloromethane. The reaction mixture was allowed to stir for 15 hours and then evaporated 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 saturated aqueous sodium chloride solution.

The organic layer was dried over sodium sulfate, filtered through Celite and evaporated under reduced pressure. 1 g of product is obtained. Yield 67%. Melting point 108 ° C.

11.1.2 1,1-Dimethylethyl methylpyrrolidin-1-ylcarbamate

7.7 ml (7.7 mmol) of a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran was added dropwise to a solution of 1.34 g (7 mmol) of 1,1-dimethylethyl pyrrolidin-1-ylcarbamate under nitrogen at -78 ° C and 1.75 mL (28 mmol) of methyl iodide in 3 mL of anhydrous tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 30 minutes. Ether (150 ml) was added and the solution was washed successively with water (100 ml) and brine (100 ml). The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography eluting with cyclohexane: ethyl acetate (9: 1). 0.75 g of product is obtained in the form of an oil. Yield 55%.

11.1.3. N-Methylpyrrolidin-1-amine hydrochloride

This product was prepared from 0.75 g (3.7 mmol) of 1,1-dimethylethyl methylpyrrolidin-1-ylcarbamate according to the procedure described in Example 10.1.3. 0.5 g of product is obtained in the form of a viscous oil. Yield 100%.

(S) -α-Amino-N, 5-dimethyl-N-pyrrolidin-1-yl-1-

- (triphenylmethyl) -lH-imidazole-4-pentanamide

11.2.1 1,1-Dimethylethyl (S) - {1 - [(methylpyrrolidin-1-ylamino) carbonyl] -4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] butyl} carbamate

The product was prepared according to the procedure described in the example

10.2.1 from 1.8 g (3.3 mmol) of (S) -α - {[(1,1-dimethylethoxy) carbonyl] amino} -5-methyl-1- (triphenylmethyl) -1H-imidazole- 4-pentanoate 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%. M.p. 70-75 ° C.

(S) -α-Amino-N, 5-dimethyl-N-pyrrolidin-1-yl-1-

- (triphenylmethyl) -1H-imidazole-4-pentanamide

The product was prepared according to the procedure described in the example

10.2.2 from 1,8 g (2,8 mmol) 1,1-dimethylethyl (S) - {1 - [(methylpyrrolidin-1-ylamino) 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 100%. Melting point

130-135 ° C.

Example 12 (Compound No. 67)

(S) -N- (3 - [({4- (5-ethyl-1H-imidazol-4-yl) -1 - [(4-ethylpiperidin-1-yl) carbonyl] butyl} amino) sulfonyl] hydrochloride [ 1,1'-Biphenyl] -2-yl} propanamide (1: 1)

12.1 (S) N- {3 - [({1 - [(4-Ethylpiperidin-1-yl) carbonyl] -4- [5-ethyl-1- (triphenylmethyl) -1H-imidazol-4-yl] butyl} amino) sulfonyl] - [1,1'-biphenyl] -2-yl} -N- (1-oxopropyl) propanamide

0.48 ml (3.4 mmol) of triethylamine was added dropwise to 0.435 g (1.25 mmol) of 2-bis [(1-oxopropyl) amino] [1,1'-biphenyl] -3- under nitrogen at 0 ° C. sulfonyl chloride and 0.61 g (1.04 mmol) of (S) -5-ethyl-α - [(4-ethylpiperidin-1-yl) carbonyl] -1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride in 8 ml of dichloromethane. The mixture was allowed to stir for 4 hours and evaporated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of 1N aqueous hydrochloric acid solution, 50 ml of saturated sodium hydrogen carbonate solution and 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated 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) -1-] -

- [(4-ethylpiperidin-1-yl) carbonyl] butyl} amino) sulfonyl] [1,1'-biphenyl] -2-yl} propanamide (1: 1)

0.85 g (0.95 mmol) of (S) N- {3 - [({1 - [(4-ethylpiperidin-1-yl) carbonyl] -4- [5-ethyl-1- (triphenylmethyl) - 1H-imidazol-4-yl] butyl} amino) sulfonyl] [1,1'-biphenyl] -2-yl) -N- (1-oxopropyl) propanamide dissolved in a mixture of 30 ml of acetic acid and 10 ml of water is heated to boiling for 16 hours and the reaction mixture is evaporated under reduced pressure. The residue is taken up in 150 ml of ethyl acetate, washed successively with 50 ml of saturated sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography on silica gel, eluting with methanol: dichloromethane (4: 96). 0.44 g of product is obtained in the form of a base, which is taken up in 10 ml of a 0.1N solution of hydrochloric acid in isopropanol and evaporated under reduced pressure. The residue was purified by RP 18 column chromatography eluting with acetonitrile: water (3: 7). After freeze-drying, 0.42 g of product is obtained in the form of a white powder. Yield 69%. M.p. 132 ° C. [.alpha.] _D @ ²⁰ = + 112 DEG (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} hydrochloride sulfonyl) [1,1'-biphenyl] -2-yl} propanamide (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] sulfonyl} [1,1'-biphenyl] -2-yl) -N- (1-oxopropyl) propanamide

0.79 ml (5.7 mmol) of triethylamine was added dropwise under argon at 0 ° C to 0.65 g (1.72 mmol) of 2-bis [(1-oxopropyl) amino] - [1,1'-biphenyl] ] -3-sulfonyl chloride and 1.05 g (1.72 mmol) of (S) -5-methyl-α - {[4- (trifluoromethyl) piperidin-1-yl] carbonyl} -1- (triphenylmethyl) -1H -imidazole-4-butanamine in 20 ml of dichloromethane. The reaction mixture was allowed to warm to room temperature, stirring was continued at this temperature for 18 hours, and the reaction mixture was evaporated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of 1N aqueous hydrochloric acid solution, 50 ml of saturated sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with methanol: dichloromethane (2: 98). 1.04 g of product is obtained in the form of a viscous oil. Yield 70%.

13.2. (S) -N- {3 - ({[4- (5-Methyl-1H-imidazol-4-yl) -1-] -

- {[4- (trifluoromethyl) piperidin-1-yl] carbonyl} butyl] amino} sulfonyl) [1,1'-biphenyl] -2-yl} propanamide (1: 1)

1.02 g (1.1 mmol) of (S) -N- (3 - {[(4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl)] - 1 - {[4- (trifluoromethyl) piperidin-1-yl] carbonyl) butyl) amino] sulfonyl] [1,1'-biphenyl] -2-yl) -N- (1-oxopropyl) propanamide dissolved in a mixture of 25 ml acetic acid and 25 ml water The mixture is heated at reflux for 10 hours and then the reaction mixture is evaporated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed with 50 ml of saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with methanol: dichloromethane (5:95). 0.42 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 evaporated under reduced pressure. The residue was purified by RP 18 column chromatography eluting with acetonitrile: water (3: 7). After freeze-drying, 0.33 g of product is obtained. Yield 46%. Mp 146-150 ° C. [.alpha.] _D @ ²⁰ = + 80 DEG (c = 0.2, methanol).

Example 14 (Compound No. 34)

(S) -N- {2 - [({1 - [(4-Methoxypiperidin-1-yl) carbonyl] -4- (5-methyl-1H-imidazol-4-yl) butyl] amino) sulfonyl] - (6-Thien-2-yl) phenyl] propanamide (1: 1)

14.1 (S) -1- {2- (3-Ethyl-1,1-dioxo-5-thien-2-yl-2H-1,2,4-benzothiadiazin-2-yl) -5- [5-methyl -l- (triphenylmethyl) -lH-imidazol-4-

yl] -1-oxo-pentyl} -4-methoxy-piperidin

14.1.1 2-1 - [(Chloropropylpropyl) amino] -3-thien-2-ylbenzenesulfonyl chloride

2.86 ml (33 mmol) of propionyl chloride is added dropwise at 0 ° C to a mixture of 3.8 g (15 mmol) of 2-amino-3- (thien-2-yl) -benzenesulfonic acid and 4 ml of pyridine in 30 ml of dichloromethane. . The reaction mixture was stirred at this temperature for 5 hours and then evaporated under reduced pressure. The residue is then taken up in 40 ml of dichloromethane, 7.8 g (37.5 mmol) of phosphorus pentachloride are added in portions and the mixture is stirred for 1 hour at 0 ° C and then for 2 hours at room temperature. Ether (200 ml) was added, the reaction mixture was filtered, and the filtrate was washed successively with ice-cold water (2 x 200 ml) and brine (50 ml), dried over sodium sulfate and evaporated in vacuo. The residue is purified by column chromatography on Florsil®, eluting with ether. After recrystallization from pentane, 3.18 g of product is obtained. Yield 61%. Mp 74 ° C.

14.1.2 (S) -1- {2- (3-Ethyl-1,1-dioxo-5-thien-2-yl-2H-1,2,4-benzothiadiazin-2-yl) -5- [5] methyl-l- (triphenylmethyl) -lH-imidazol-4-yl] -1-oxo-pentyl} -4-methoxy-piperidine

0.55 ml (3.96 mmol) of triethylamine is added to a mixture of 0.42 g (1.2 mmol) of 2-1 - [(chloropropylpropyl) amino] -3- (thien-2-yl) at 0 ° C. benzenesulfonyl chloride and 0.69 g (1.2 mmol) of (S) -α - [(4-methoxypiperidin-1-yl) carbonyl] -5-methyl-1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride in 15 ml of dichloromethane. The reaction mixture was allowed to warm to room temperature, stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of 1N hydrochloric acid solution, 50 ml of saturated sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. 1.07 g of product is obtained in the form of a viscous oil, which is used as is in the following stage. Yield 100%.

14.2. (S) -N- {2 - [({1 - [(4-Methoxypiperidin-1-yl) carbonyl] -4- (5-methyl-1H-imidazol-4-yl) butyl] amino) sulfonyl] hydrochloride - (6-Thien-2-yl) phenyl} propanamide (1: 1)

1.07 g (1.2 mmol) of (S) -1- {2- (3-ethyl-1,1-dioxo-5-thien-2-yl-2H-1,2,4-benzothiadiazine-2- yl) -5- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] -1-oxopentyl} -4-methoxy-piperidine dissolved in a mixture of 50 ml of acetic acid and 50 ml of water is heated to boiling for 6 hours and then the reaction mixture is evaporated in vacuo. The residue is taken up in 150 ml of ethyl acetate, washed successively with 50 ml of saturated sodium hydrogen carbonate solution and 50 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with methanol: dichloromethane (5:95). 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 evaporated under reduced pressure. The residue was purified by RP 18 column chromatography eluting with acetonitrile: water (3: 7). After freeze-drying, 0.34 g of product is obtained in the form of a white powder. Yield 45%. Melting point 126 ° C. [.alpha.] _D @ ²⁰ = + 87 DEG (c = 0.2, methanol).

Example 15 (Compound No. 47)

(S) -N- (2 - {[(4- (5-Methyl-1H-imidazol-4-yl) -1 - [(4-methylenepiperidin-1-yl) carbonyl] butyl) amino] sulfonyl} - 6- (thien-2-yl) phenyl) propanamide

This compound was prepared according to the procedure described in Example 14 from (S) -5-methyl-α - [(4-methylenepiperidin-1-yl) carbonyl] -1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride and

2 - [(1-chloropropyl) amino] -3- (thien-2-yl) benzenesulfonyl chloride. Melting point 115-120 ° C. [.alpha.] _D @ ²⁰ = + 54 DEG (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) sulfonyl] - 6-Thien-2-yl-phenyl-propanamide (1: 1)

16.1 (S) -4-Cyclopropyl-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) piperidine

0.5 ml (3.63 mmol) of triethylamine is added dropwise at 0 [deg.] C. to a mixture of 0.38 g (1.1 mmol) of 2-1 - [(chloropropyl) amino] -3-thien-2-ylbenzenesulfonyl chloride and 0. 64 g (1.1 mmol) of (S) -? - [(4-cyclopropylpiperidin-1-yl) carbonyl] -5-methyl-1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride in 20 mL of dichloromethane . The reaction mixture was allowed to warm to room temperature, stirring was continued at this temperature for 2 hours and the reaction mixture was evaporated in vacuo. The residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of 1N hydrochloric acid solution, 50 ml of saturated sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. 1.1 g of product are obtained in the form of a viscous oil, which product is used as is in the following stage. Yield 100%.

(S) -N- {2 - [({1 - [(4-Cyclopropylpiperidin-1-yl) carbonyl] -4- (5-methyl-1H-imidazol-4-yl) butyl} amino) sulfonyl] 6-thien-2-ylphenyl) propanamide (1: 1)

1.1 g (1.1 mmol) of (S) -4-cyclopropyl-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 dissolved in a mixture of 25 ml of acetic acid and 25 ml of water is heated to boiling for 4 hours and the reaction mixture is evaporated under reduced pressure. The residue is taken up in 150 ml of ethyl acetate, washed successively with 50 ml of saturated sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of methanol: dichloromethane (2: 98 to 8: 92). 0.528 g of product is obtained in base form. Yield 80%. 0.528 g of the base is taken up in 10 ml of a 0.1N solution of hydrogen chloride in isopropanol and evaporated under reduced pressure. The residue was purified by RP 18 column chromatography eluting with acetonitrile: water (3: 7). After freeze-drying, 0.27 g of product is obtained in the form of a white powder. Yield 39%. Melting point 108-110 ° C. [.alpha.] _D @ ²⁰ = + 98 DEG (c = 0.2, methanol).

Example 17 (Compound No. 20)

(S) -N- {3 '- (ethylamino) -3 - [({1 - [(4-ethylpiperidin-1-yl) carbonyl] -4- (5-methyl-1H-imidazol-4-yl) hydrochloride) butyl} amino) sulfonyl] - [1,1'-biphenyl] -2-yl} propanamide (1: 2)

17.1 (S) -1- {2- [7-Bromo-3-ethyl-5- (3-nitrophenyl) -1,1-dioxo-2H-1,2,4-benzothiadiazin-2-yl] -5- [5-methyl-l- (triphenylmethyl) -lH-imidazol-4-yl] 1-oxo-pentyl} -4-ethylpiperidine

17.1.1 5-Bromo-2 - [(1-chloropropyl-amino) amino] -3'-nitro [1,1'-biphenyl] -3-sulfonyl chloride

a) Pyridinic salt of 5-bromo-3'-nitro-2 - [(1-oxopropyl) amino] [1,1'-biphenyl] -3-sulfonic acid

1.62 ml (18.6 mmol) of propionyl chloride was added dropwise at 0 ° C under nitrogen to a solution of 3.15 g (8.45 mmol) of 2-amino-5-bromo-3'-nitro [1,1 '] -biphenyl] -3-sulfonic acid and 2.4 mL (29.6 mmol) of pyridine in 10 mL of dichloromethane. The reaction mixture was allowed to warm to room temperature, stirred at room temperature for 18 hours and evaporated under reduced pressure. The residue was used in the next step.

b) 5-Bromo-2 - [(1-chloropropyl-amino) amino] -3'-nitro [1,1'-biphenyl] -3-sulfonyl chloride

The residue obtained above was dissolved in 20 ml of dichloromethane and 4.6 g (21.2 mmol) of phosphorus pentachloride was added at 0 ° C under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 5 hours. The reaction mixture is evaporated under reduced pressure and the residue is taken up in 150 ml of ether and filtered through a frit. The filtrate is washed twice with 100 ml of water and then with 100 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated 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 77%.

17.1.2 (S) -1- {2- [7-Bromo-3-ethyl-5- (3-nitrophenyl) -1,1-dioxo-2H-

-1,2,4-benzothiadiazin-2-yl] -5- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl-1H-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-chloropropyl-amino) amino] -3'-nitro [ 1,1'-biphenyl] -3-sulfonyl chloride and 0.64 g (1.1 mmol) of (S) -? - [(4-ethylpiperidin-1-yl) carbonyl] -5-methyl-1- (triphenylmethyl) hydrochloride 1H-imidazole-4-butanamine in 5 ml of dichloromethane. The reaction mixture was allowed to warm to room temperature, stirred at this temperature for 18 hours, and evaporated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of 1N hydrochloric acid solution, 50 ml of saturated sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated 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) amino) sulfonyl] -3'-nitro- [1,1'-biphenyl] -2-yl} propanamide g (1 mmol) (S) -1- {2- [7-Bromo-3-ethyl-5- (3-nitrophenyl) -1,1-dioxo-2H-1,2,4-benzothiadiazin-2-yl] -5- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl-] 1-oxopentyl} -4-ethylpiperidine dissolved in a mixture of 30 ml of acetic acid and 20 ml of water is heated to boiling for 8 hours and then the reaction mixture is evaporated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed with 50 ml of saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica gel, methanol: dichloromethane (5:95). in the form of a white solid. The yield was purified by column eluting with a mixture to give 0.42 g of the product in 60%. Mp 215 ° C.

17.3. (S) -N- {3'-Amino-3 - [({1 - [(4-ethylpiperidin-1-yl) carbonyl] -

-4- (5-methyl-1H-imidazol-4-yl) butylamino) sulfonyl] [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} amino) sulfonyl] -3'-nitro [1,1'-biphenyl] -2-yl} propanamide in 20 ml of ethanol is hydrogenated for 10 hours at room temperature and hydrogen pressure (50 psi) in the presence of 0.1 g of 10% palladium on charcoal. The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate and washed with 50 ml of saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated under reduced pressure. 0.33 g of product is obtained in the form of a white solid. Yield 100%. mp 160 ° C.

17.4. (S) -N- {3 '- (ethylamino) -3 - [({1 - [(4-ethylpiperidin-1-yl) carbonyl] -4- (5-methyl-1H-imidazol-4-yl) hydrochloride) butyl} amino) sulfonyl] - [1,1'-biphenyl] -2-yl} propanamide (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-ethylpiperidin-1-yl) carbonyl] -4- (5-methyl-1H-imidazol-4-yl) butyl amino) sulfonyl] [1,1'-biphenyl] -2-yl} propanamide in 10 ml of ethanol, and the mixture is stirred for 8 hours at room temperature and 50 psi of hydrogen. The reaction mixture is filtered through diatomaceous earth, 4 ml of a 0.1N solution of hydrochloric acid in isopropanol are added to the filtrate and the filtrate is evaporated under reduced pressure. The residue was purified by RP 18 column chromatography eluting with acetonitrile: water (3: 7). After freeze-drying, 0.2 g of product is obtained in the form of a white powder. Yield 53%. Mp 163 ° C. [.alpha.] _D @ ²⁰ = + + 130 DEG (c = 0.2, methanol).

Example 18 (Compound No. 29)

(S) -N- {3 - [({1 - [(4-ethylpiperidin-1-yl) carbonyl] -4- (5-methyl-1H-imidazol-4-yl) butyl) amino) sulfonyl] [ 1,1'-Biphenyl] -2-yl} -2- (2-methoxyethoxy) acetamide (1: 1)

18.1 (S) -2-Amino-N- {1 - [(4-ethylpiperidin-1-yl) carbonyl] -4 - [(5-

-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] butyl} [1,1'-biphenyl] -3-sulfonamide

0.365 ml (2.61 mmol) of triethylamine was added dropwise under argon at 0 ° C to a mixture of 0.5 g (0.87 mmol) of (S) -5-ethyl-α- [(4-ethylpiperidine-1-) - hydrochloride. yl) carbonyl] -1- (triphenylmethyl) -1H-imidazole-4-butanamine and 0.281 g (1.05 mmol) of 2-amino [1,1'-biphenyl] -3-sulfonyl chloride in 10 mL of dichloromethane. The reaction mixture was allowed to stir at this temperature for 1 hour and then evaporated under reduced pressure. The residue is taken up in 50 ml of ethyl acetate, washed successively with 20 ml of 1N hydrochloric acid solution, 20 ml of saturated sodium bicarbonate solution and 20 ml of saturated sodium chloride solution and dried over magnesium sulfate. Finally, the organic layer is filtered and evaporated to dryness. The residue was purified by silica gel column chromatography eluting with a gradient of methanol: dichloromethane (1:99 to 3: 97). 0.53 g of product is obtained in the form of a white solid. Yield 79%.

(S) -N- {3 - [({1 - [(4-Ethyl-piperidin-1-yl) -carbonyl] -4- (5-methyl-1H-imidazol-4-yl) -butyl] -amino] -sulfonyl] -hydrochloride [1,1'-Biphenyl] -2-yl} -2- (2-methoxyethoxy) acetamide (1: 1) g (13 mmol) of 2- (2-methoxyethoxy) acetyl chloride was added to 1 g at room temperature under argon. (1.3 mmol) of (S) -2-amino-

I

-N- {1 - [(4-ethylpiperidin-1-yl) carbonyl] -4 - [(5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] butyl] [1,1'-biphenyl] The reaction mixture was stirred at this temperature for 0.5 hour and then cooled in an ice bath, 100 ml of ethyl acetate and 100 ml of 1N aqueous hydrochloric acid solution were added and the organic layer was separated. 50 ml of saturated sodium bicarbonate solution and 50 ml of saturated aqueous sodium chloride solution are then evaporated in vacuo, the residue is taken up in acetic acid: water: tetrahydrofuran (2: 1: 1) and heated to 80 ° C. for 3 h and evaporated in vacuo. the residue is taken up in 100 ml ethyl acetate, washed successively with 50 ml iN hydrochloric acid. 50 ml of saturated sodium _'(hydrogen carbonate solution and 50 ml of saturated sodium chloride solution and then dried over MgSO Finally, organic The residue was purified by silica gel column chromatography eluting with a gradient of dichloromethane: methanol (98: 2 to 90: 10). 0.54 g of product is obtained in base form. The hydrochloride is prepared in 10 ml of a 0.1N solution of hydrogen chloride in isopropanol. After freeze-drying, 0.57 g of product is obtained. Yield 64.6%. Melting point 98 ° C. [α] _D ²⁰ = + 55.5 ° (c = 0.2, methanol).

Example 19 (Compound No. 30)

(S) -N- {2-Cyclopentyl-6 - [({1 - [(4-ethylpiperidin-1-yl) carbonyl] -4- (5-methyl-1H-imidazol-4-yl) butyl] amino) sulfonyl] phenyl] -N'-ethylurea (1: 1)

19.1 (S) -2-Amino-3-cyclopentyl-N- {1 - [(4-ethylpiperidin-1-yl) carbonyl] -4- [5-methyl-1- (triphenylmethyl) -1H-imidiazole-4- yl] butylbenzenesulfonamide

0.95 ml (6.75 mmol) of triethylamine is added dropwise at 0 ° C to 0.70 g (2.7 mmol) of 2-amino-3-cyclopentylbenzenesulfonyl chloride and 1.54 g (2.7 mmol) of hydrochloride (S). 5-Methyl-α - [(4-ethylpiperidin-1-yl) carbonyl] -1- (triphenylmethyl) -1H-imidazole-4-butanamine in 6 mL of dichloromethane. The reaction mixture was stirred at this temperature for 5 hours and then evaporated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of 1N hydrochloric acid solution, 50 ml of saturated sodium hydrogen carbonate solution and 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol (98: 2). 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-ethylpiperidin-1-yl) carbonyl] -4- (5-methyl-1H-imidazol-4-yl) butyl] amino (sulfonyl) phenyl} -N'-ethylurea

A solution of 0.75 g (1 mmol) of (S) -2-amino-3-cyclopentyl-N- {1 - [(4-ethylpiperidin-1-yl) carbonyl] -4- [5-methyl-1- (triphenylmethyl) 1 H -imidazol-4-yl] butyl} benzenesulfonamide and 0.32 ml (4 mmol) of ethyl isocyanate in dimethylformamide are heated at 50 ° C for 38 hours and then the reaction mixture is evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with methanol: dichloromethane (2: 98). 0.53 g of product is obtained in the form of a white solid. Yield 65%. Melting point 115 ° C.

19.3. (S) -N- {2-Cyclopentyl-6 - [({1 - [(4-ethylpiperidin-1-yl) carbonyl] -4- (5-methyl-1H-imidazol-4-yl) butyl} amino hydrochloride ) sulfonyl] phenyl} -N'-ethylurea (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-1H) -imidazol-4-yl) butyl} amino) sulfonyl] phenyl} -N'-ethylurea and 0.2 g of 10% palladium on charcoal in 8 ml of a 0.1N solution of hydrochloric acid in isopropanol are stirred at room temperature and hydrogen pressure 50 psi for 40 hours. The mixture was filtered through diatomaceous earth and the filtrate was evaporated under reduced pressure. The residue was purified by RP 18 column chromatography eluting with acetonitrile: water (4: 6). After freeze-drying, 0.30 g of product is obtained. Yield 77%. Melting point 147 ° C. [.alpha.] D @ ²⁰ = + 86 DEG (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) sulfonyl] [ 1,1'-Biphenyl] -2-ylpropanamide (1: 1)

20.1 (S) -N- {3 - [({1 - [(4-Ethylpiperidin-1-yl) carbonyl] -4- (1H-imidazol-4-yl) butyl] amino) sulfonyl] [1,1'-biphenyl] -2-yl} propanamide

20.1.1 2 - [(1-Chloropropylpropylidene) amino] [1,1-biphenyl] -3-sulfonyl chloride

2.2 ml (15.84 mmol) of triethylamine are added dropwise at 0 ° C under nitrogen to a mixture of 1.8 g (5.3 mmol) of 2 - [(1-chloropropyl) amino] [1,1'-biphenyl] - 3-sulfonyl chloride and 2.7 g (4.8 mmol) of (S) -? - [(4-ethylpiperidin-1-yl) carbonyl] -1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride in 30 mL dichloromethane. The reaction mixture was allowed to warm to room temperature, stirring was continued at this temperature for 18 hours, and the reaction mixture was evaporated under reduced pressure. The residue is taken up in 150 ml of ethyl acetate, washed successively with 100 ml of 1N aqueous hydrochloric acid solution, 50 ml of saturated sodium bicarbonate solution and 50 ml of saturated sodium chloride solution and evaporated under reduced pressure. The residue is taken up in a mixture of 60 ml of acetic acid and 40 ml of water, heated at reflux for 6 hours and then evaporated under reduced pressure. The residue is taken up in 200 ml of ethyl acetate, washed successively with 50 ml of saturated sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with methanol: dichloromethane (5:95). 2.2 g of product are obtained in the form of a viscous oil. The yield is 81%.

20.2. (S) - {N-3 - [({4- (5-Chloro-1H-imidazol-4-yl) -1-] -

- [(4-ethylpiperidin-1-yl) carbonyl] butyl} amino) sulfonyl] -

- [1,1'-biphenyl] -2-yl} propanamide (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) sulfonyl ] [1,1'-Biphenyl] -2-yl] propanamide and 0.116 g (1.1 mmol) of N-chlorosuccinimide in 2 ml of dimethylformamide were stirred at 0 ° C for 5 hours and then the reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with methanol: dichloromethane (2: 98). 0.3 g of product is obtained in base form. Yield 50%. The base is taken up in 15 ml of a 0.1N solution of hydrogen chloride in isopropanol and evaporated under reduced pressure. The residue was purified by RP 18 column chromatography eluting with acetonitrile: water (6: 4). After freeze-drying, 0.30 g of product is obtained. Yield 94%. Mp 100 ° C. [.alpha.] _D @ ²⁰ = + 102 DEG (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) sulfonyl] - 6-Pyridin-2-ylphenyl] propanamide (1: 2)

21.1 (S) -N- {4-Bromo-2 - [({1 - [(4-ethylpiperidin-1-yl) carbonyl] -4-

- [5-Methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] butyl} amino) sulfonyl] -6-iodophenyl} propanamide

2.24 g (4.4 mmol) of 2- [bis (1-oxopropyl) amino] -5-bromo-3-iodobenzenesulfonyl chloride and then dropwise 1.84 ml (13.2 mmol) of triethylamine at 0 ° C to a solution of (S) -5-methyl-α - [(4-ethylpiperidin-1-yl) carbonyl] -1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride in 2.28 g (4 mmol) in 25 ml of dichloromethane. The mixture was stirred at this temperature for. 6 hours and then evaporated under reduced pressure. The residue is taken up in 200 ml of ethyl acetate, washed successively with 100 ml of 1N aqueous hydrochloric acid solution, 100 ml of saturated aqueous sodium hydrogencarbonate solution and 100 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The residue is taken up in 150 ml of tetrahydrofuran, a stream of ammonia gas is bubbled through at 0 ° C for 2 hours, and the mixture is evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane: methanol (98: 2). 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-l '

- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] butyl} amino) sulfonyl] -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] butylamino) sulfonyl] -6-iodophenyl] propanamide, 0.883 g (2.4 mmol) of 2- (tributylstannyl) pyridine, 0.1 g (0.17 mmol) of bis (dibenzylideneacetone) palladium, 0.033 g (0.17 mmol) of copper (I) iodide and 0.98 g of triphenylarzine in 4 ml of dimethylformamide were heated at 80 ° C for 5 hours under argon. The reaction mixture is taken up in 150 ml of ethyl acetate and washed twice with 100 ml of 10% aqueous ammonia solution and then with 50 ml of saturated sodium chloride solution. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol (98: 2). 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) sulfonyl] -6-pyridin-2-ylphenyl] propanamide

1.14 g (1.26 mmol) of (S) -N- {4-bromo-2 - [({1 - [(4-ethylpiperidin-1-yl) carbonyl] -4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] butylamino) sulfonyl] -6-pyridin-2-ylphenyl] propanamide in a mixture of ml of acetic acid and 15 ml of water is heated to boiling for 1 hour. The reaction mixture is taken up in 150 ml and evaporated under reduced pressure and ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution (50 ml) and a saturated aqueous sodium chloride solution (50 ml), dried over sodium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel, methanol: dichloromethane (5:95).

Purification by column eluting with a mixture gave 0.66 g of the product as a glassy oil. Yield 79.5%.

(S) -N- {2 - [({1 - [(4-ethylpiperidin-1-yl) carbonyl] -4- (5-methyl-1H-imidazol-4-yl) butyl] amino) sulfonyl] -6.4. -pyridin-2-ylphenyl] propanamide (1: 2)

A mixture of 0.65 g (0.98 mmol) of (S) -N- {4-bromo-2 - [({1 - [(4-ethylpiperidin-1-yl) carbonyl] -4- [5-methyl-1H] -imidazol-4-yl] butyl} amino) sulfonyl] -6-pyridin-2-ylphenyl] propanamide, 124 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 are heated to boiling for 3 hours and then the reaction mixture is evaporated in vacuo. The residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with methanol: dichloromethane (5:95). It will be obtained

0.55 g of base in the form of a viscous oil. Yield 96%. The base is taken up in 25 ml of a 0.1N solution of hydrogen chloride in isopropanol and evaporated under reduced pressure. The residue was purified by RP 18 column chromatography eluting with acetonitrile: water (6: 4). 0.44 g of product is obtained. yield

%. Mp 138-144 ° C. [α] _D ²⁰ = + 121 ° (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) sulfonyl] - 4-Fluoro-6-thien-2-yl-phenyl} -propanamide (1: 1)

22.1 2- [Bis (1-oxopropyl) amino] -5-fluoro-3-thien-2-ylbenzenesulfonyl chloride

22.1.1 2- [Bis (1-oxopropyl) amino] -5-fluoro-3-thien-2-ylbenzenesulfonic acid N, N-diethylethanamine salt

A mixture of 10.92 g (40 mmol) of 2-amino-5-fluoro-3-thien-2-ylbenzenesulfonic acid and 5.6 ml (40 mmol) of triethylamine in 77 ml (600 mmol) of propionic anhydride is heated to boiling point. The reaction mixture was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate: ether. 16.9 g of product are obtained. Yield 90%. Mp 239 ° C.

22.1.2 2- [Bis (1-oxopropyl) amino] -5-fluoro-3-thien-2-ylbenzenesulfonyl chloride

14.22 g (68.2 mmol) of phosphorus pentachloride are added to a solution of 1.60 g (34.1 mmol) of 2- [bis (1-oxopropyl) amino] N, N-diethylethanamine salt at 0 ° C under nitrogen. 5-Fluoro-3-thien-2-yl-benzenesulfonic acid in 60 mL of dichloromethane. The reaction mixture was stirred at this temperature for 5 hours, then allowed to warm to room temperature and stirred at this temperature for 1 hour. Ether (200 ml) was added, the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue is taken up in 800 ml of ether, filtered and evaporated under reduced pressure. The residue was purified by Florsil® column chromatography eluting with an ether: pentane gradient (1: 9 to 1: 1). It will be obtained

6.4 g of product as a viscous oil. Yield 55%.

(S) -N- {2 - [({1 - [(4-ethylpiperidin-1-yl) carbonyl] -4- (5-methyl-1H-imidazol-4-yl) butyl] amino) sulfonyl] (22.2) 4-Fluoro-6-thien-2-yl-phenyl] -propanamide (1: 1)

6.16 g (18.1 mmol) of 2- [bis (1-oxopropyl) amino] -5-fluoro-3-thien-2-ylbenzenesulfonyl chloride and then 5.5 mmol of triethylamine are added to nitrogen at 0 ° C under nitrogen. of a solution of (S) -α - [(4-ethylpiperidin-1-yl) carbonyl] -5-methyl-1- (triphenylmethyl) -1H-imidazole-4-butanamine hydrochloride (9.83 g, 17.2 mmol) in 60 mL ml of dichloromethane. The reaction mixture was allowed to warm slowly to room temperature, stirred at this temperature for 15 hours and then evaporated under reduced pressure. The residue is taken up in 300 ml of ethyl acetate and washed successively with 300 ml of 1N hydrochloric acid solution, 300 ml of saturated sodium hydrogen carbonate solution and then with 300 ml of saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was heated for 12 hours in 225 L of acetic acid: water (2: 1) and evaporated under reduced pressure. The residue is taken up in 400 ml of dichloromethane and

It is washed successively with 200 ml of saturated sodium bicarbonate solution and then with 200 ml of saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol (96: 4). 7.7 g of product are obtained in base form. Yield 74%. Mp 145-150 ° C.

The hydrochloride is prepared by adding 45.1 ml of a 0.1N solution of hydrogen chloride in isopropanol to 2.5 g (4.5 mmol) of base. It will be obtained

2.7 g of the product as the hydrochloride salt. [.alpha.] _D @ ²⁰ = + 112 DEG (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 hydrochloride sulfonyl) -6-thien-2-ylphenyl] propanamide (1: 1)

This product was prepared according to the procedure described in Example 19 from 0.81 g (1.36 mmol) of (S) -5-methyl-α - {[4- (difluoromethylene) piperidin-1-yl] carbonyl} -1- (triphenylmethyl) -1H-imidazole-4-butanamine and 2 - [(1-chloropropyl) amino] -3-thien-2-ylbenzenesulfonyl chloride. 0.58 g of product is obtained in the form of a white powder. Yield 67%. Mp 144-145 ° C. [α] D ²⁰ - + 107.9 ° (c = 0.2, methanol).

Example 24 (Compound No. 25)

(S) -N- {6-Cyclopentyl-2 - ([{1 - [(4-ethylpiperidin-1-yl) carbonyl] -4- (5-methyl-1H-imidazol-4-yl) butyl} amino hydrochloride Sulfonyl) phenyl] propanamide (1: 1)

24.1 3-Cyclopentyl-2- (diacetylamino) benzenesulfonyl chloride

24.1.1 Acid Ν, Ν-Diethylethanamine salt

3-cyclopentyl-2- (diacetylamino) benzenesulphonic acid

6.5 g (19 mmol) of 2-amino-3-cyclopentylbenzenesulfonic acid Ν, Ν-diethylethanamine salt dissolved in acetyl chloride was heated at reflux for 48 hours and then evaporated under reduced pressure. 8.22 g of product are obtained, which product is used as is in the following stage. Yield 95%. Melting point 186 ° C.

24.1.2 3-Cyclopentyl-2- (diacetylamino) benzenesulfonyl chloride

This compound was prepared according to the procedure described in Example 22.1 from 8.2 g (18.1 mmol) of the N, N-diethylethanamine salt of 3-cyclopentyl-2- (diacetylamino) benzenesulfonic acid. It will be obtained

3.81 g of the product as a viscous oil, which was used in the next step without further purification. Yield 57%.

(S) -N- {6-Cyclopentyl-2 - ([{1 - [(4-ethylpiperidin-1-yl) carbonyl] -4- (5-methyl-1H-imidazol-4-yl) butyl] hydrochloride amino] sulfonyl) phenyl] propanamide (1: 1)

This product was prepared according to the procedure described in Example 22.2 from 0.743 g (2 mmol) of 3-cyclopentyl-2- (diacetylamino) -benzenesulfonyl chloride and 1.14 g (2 mmol) of (S) -α - [(4-ethylpiperidine-) hydrochloride. yl) carbonyl] -5-methyl-l- (triphenylmethyl) -1 H -imidazol-4-butanamine. 0.73 g of product is obtained. Yield 60%. Melting point 124 ° C. [.alpha.] _D @ ²⁰ = + 89 DEG (c = 0.2, methanol).

Example 25 (Compound No. 64)

(S) -N- {2 - [({4- (5-Methyl-1H-imidazol-4-yl) -1- [5-oxohexahydro-1H-1,4-diazepin-1-yl) carbonyl] hydrochloride] butyl] amino) sulfonyl] -6-thien-2-ylphenyl} propanamide (1: 1)

25.1 1- (2 - {[(2-Amino-3-thien-2-ylphenyl) sulfonyl] amino} -5- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] -1- oxopentyl) hexahydro-5H-1,4-diazepin-5-one

To 0.618 g (2.26 mmol) of 2-amino-3-thien-2-ylbenzenesulfonyl chloride in 80 ml of dichloromethane under argon was added 1.29 g.

1- (2-Amino-5- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] -1-oxopentyl} hexahydro-5H-1,4-diazepine hydrochloride (2.26 mmol) 5-one. The mixture was cooled to 0 ° C in an ice bath and triethylamine (0.94 mL, 6.74 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. 10 ml of a 0.5N aqueous hydrochloric acid solution are added and the organic layer is washed with 0.5 hydrochloric acid solution and then with a saturated sodium chloride solution and dried over magnesium sulfate. The residue was purified by silica gel chromatography eluting with dichloromethane: methanol (97.5: 2.5). 1.33 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-diazepine- yl) carbonyl] butyl} amino) sulfonyl] -6-thien-2-yl-phenyl} propanamide

1.33 g (1.72 mmol) of 1- (2 - {[(2-amino-3-thien-2-ylphenyl) sulfonyl] amino} -5- [5-methyl-1- (triphenylmethyl) -1H- imidazol-4-yl] -1-oxo-pentyl) hexahydro-5H-1,4-diazepin-5-one was dissolved in 1.3 ml of dimethylacetamide and 0.3 ml (3.44 mol) of propionyl chloride was added. The mixture was stirred for 2 hours and then ethyl acetate was added. The reaction mixture was evaporated to dryness and taken up in dichloromethane. The organic layer was washed twice with 20 ml of 1N aqueous hydrochloric acid solution, dried over magnesium sulfate and evaporated. 1.4 g of product are obtained, which product is used as is in the following stage. Yield 100%.

(S) -N- {2 - [({4- (5-methyl-1H-imidazol-4-yl) -1- [5-

-oxohexahydro-1H-1,4-diazepin-1-yl) carbonyl] butyl} amino) sulfonyl] -6-thien-2-ylphenyl} propanamide (1: 1)

0.25 g (0.31 mmol) of (S) -N- {2 - [({4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] -1- [5-oxohexahydro] -1H-1,4-diazepin-1-yl) carbonyl] butyl) amino) sulfonyl] -6-thien-2-ylphenyl) propanamide was dissolved in 4 mL of tetrahydrofuran and 2 mL of acetic acid and 2 mL of water were added. The mixture is heated at 50 ° C overnight, evaporated to dryness and the residue is taken up in 100 ml of dichloromethane. The solution was washed with aqueous sodium bicarbonate solution and dried over magnesium sulfate. Filter and purify the residue by column chromatography on silica gel, eluting with dichloromethane: methanol (90: 10). The base was dissolved in a 0.1N solution of hydrochloric acid in isopropanol and the product was purified by RP18 column chromatography eluting with acetonitrile: water. 0.026 g of product is obtained in the form of the hydrochloride. Yield 14%. Mp 155 ° C. [.alpha.] _D @ ²⁰ = + 80 DEG (c = 0.2, methanol).

Example 26 (Compound No. 65)

(S) -N-Cyclopentyl-N, 5-dimethyl-α - [({2 - [(1-oxopropyl) amino] -3-thien-2-ylphenyl) sulfonyl) amino] -1H-imidazole-4- pentane amide (1: 1)

26.1 (S) - {x - {[(2-Amino-3-thien-2-ylphenyl) sulfonyl] amino} -N-cyclopentyl-N, 5-dimethyl-1- (triphenylmethyl) -1H-imidazole-4- pentanamide g (3.66 mmol) of 2-amino-3-thien-2-ylbenzenesulfonyl chloride and then 1.12 ml (7.85 mmol) of triethylamine in 5 ml of dichloromethane are gradually added to a solution of 1.95 g at 0 ° C. (3.5 mmol) of (S) -α-amino-N-cyclopentyl-N, 5-dimethyl- (1-triphenylmethyl) -1H-imidazole-4-pentanamide hydrochloride in 15 mL of dichloromethane. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 15 hours. The reaction mixture was evaporated 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, 50 ml of a saturated aqueous sodium hydrogen carbonate solution and then 50 ml of a saturated sodium chloride solution. The organic layer was dried over sodium sulfate. The residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol (97: 3). 2.35 g of product are obtained in the form of an amorphous solid. Yield 87%. Mp 102-107 ° C.

26.2 (S) -N-Cyclopentyl-N, 5-dimethyl-α - [({2 - [(1-oxopropyl) amino] -3-thien-2-ylphenyl} sulfonyl) amino] -1H-imidazole-4 hydrochloride -Pentanamide (1: 1)

0.51 ml (5.9 mmol) of propionyl chloride is added dropwise at room temperature to a solution of 2.23 g (2.84 mmol) of (S) -α - {[(2-amino-3-thien-2-ylphenyl) sulfonyl] amino] -N-cyclopentyl-N, 5-dimethyl-1- (triphenylmethyl) -1H-imidazole-4-pentanamide in 1.5 ml dimethylacetamide. The mixture was stirred for 10 hours and then 150 mL of ethyl acetate was added. The organic layer was washed with 150 mL of water and then with 100 mL of saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is taken up in 60 ml of ethyl acetate and 30 ml of water and heated at reflux for 2 hours. 150 ml of dichloromethane are added and then the organic layer is washed successively with 100 ml of saturated sodium bicarbonate solution and

100 ml of saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is taken up in 40 ml of a 0.1N solution of hydrochloric acid in isopropanol and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with acetonitrile: water (2: 8). 1.15 g of product is obtained. Yield 64%. Mp 140-145 ° C. [.alpha.] _D @ ²⁰ = + 103 DEG (c = 0.2, methanol).

Example 27 (Compound No. 66)

(S) -N, 5-Dimethyl-α - [({2 - [(1-oxopropyl) amino] -3-thien-2-ylphenyl} sulfonyl) amino] -N-pyrrolidin-1-yl-1H- imidazole-4-pentane amide (1: 1)

27.1 (S) -α - {[(2-Amino-3-thien-2-ylphenyl) sulfonyl] amino) -N,5-dimethyl-N-pyrrolidin-1-yl-1- (triphenylmethyl) -1H-imidazole -4-pentanamide * t ·

I

This compound was prepared according to the procedure in Example 26.1, from 0.8 g (2.94 mmol) of 2-amino-3-thien-2-ylbenzenesulfonyl chloride and 1.56 g (2.8 mmol) of (S) -a- hydrochloride. amino-N, 5-dimethyl-N-pyrrolidin-1-yl-1- (triphenylmethyl) -1H-imidazole-4-pentanamide. 1.84 g of product are obtained in the form of an amorphous solid. Yield 83%. mp 102-106 ° C.

27.2 (S) -N, 5-Dimethyl-α - [({2 - [(1-oxopropyl) amino] -3-thien-2-ylphenyl} sulfonyl) amino] -N-pyrrolidin-1-yl-1H -imidazole-4-pentanamide (1: 1)

This compound was prepared according to the procedure in Example 26.2, from 1.8 g (2.37 mmol) of (S) -α - {[(2-amino-3-thien-2-ylphenyl) sulfonyl] amino] -N, 5 -dimethyl-N-pyrrolidin-1-yl-1- (triphenylmethyl) -1H-imidazole-4-pentanamide. 1 g of product is obtained. Yield 69%. Mp 154-160 ° C. [.alpha.] _D @ ²⁰ = + 119 DEG (c = 0.2, methanol).

Table key:

- in the column 'salt' means' HCl hydrochloride and the ratio in brackets is the ratio (base: acid)

- in column "[a] d ²⁰ , c = 0,2, methanol except for data for compound 1 (c = 0,22, methanol), for compound 6 (c = 0,265, methanol), for compound 12 (c = 0 , 25, methanol) and for compounds 51, 54 and 56 (c = 0.4, methanol).

table

ABOUT M Q f '´ f — Ί C ä - + 76 + 109 T. t. C 118-122 160-164 salt HC1 (1: 1) HC1 (1: 1) b b In those The 1 X 1 n tí m X U o CM N X u about CM X u o u 1 m X o CM X U o u 1 (N t 0 1 o 1 rd tí x 1 x 1 they m X U 1 m X u 1 Ό rh CXI

Ο CM ο f — 1 r — I 0 ä - + 91 m + to r- + 135 + 114.3 + 105, 5 + 68 - about 0 • H CM CM t-I r * XT c-1 rH VO VO 1 CM VD CO m rH XT T "H o m i — 1 Sol i — 1 t-1 o ·· X r- < i — 1 rH O ·· X i — 1 H rH ABOUT X «—1 i-1 rH U ·· x i-i i- | pH U ·· X tH r-1 rH u ·· X 1-1 b about b b b V a; x 1 x 1 x 1 X 1 X 1 x 1 m CC d x o CM x o o u 1 d x u o CM CM x u about CM x u o u 1 d x u CM x u CM x u 1 d x u o u 1 D x u N x u o u 1 x o CM X o CM x u o u 1 CM CC o 1 o 1 à 5 1 à 6 1 à 6 1 à 5 1 \ 1H-Cd x 1 x 1 x 1 x 1 x 1 x 1 they m x o 1 d x o 1 d X u d x o 1 d X u 1 d x u 1 > the m m VO r- 00

Ο CM Q - · r— »0 ϋ - + 105 + 113 + 105 + 99 + 118 - c 0 • H CM n rd o m rd <iF t — 1 CO CM rd <x> m-1 r — 1 O ω i-1 t — 1 o ·· X rd i — 1 rd ABOUT ·· X rd i — 1 rd U ·· X rd rd rd o ·· X rd r-d rd 1 ABOUT · rd u. £ CD X 1 x 1 x 1 x 1 x 1 (Ό CC m X U «Μ X u o u <n X U CM X u o u 1 m X U CM X u o u 1 m X u CM X u o u 1 m X O CM X o o o CM CC £ č 1 à 6 1 £ ó ' 1 £ 6 1 £ ó 1 \ CC x 1 x 1 x 1 x 1 x 1 ac m X U 1 m X u 1 m X u 1 r> X o m X O 1 XJ <Λ o rd rd rd CN rH n rd

Ο CM Q ch 21 16 o m 0 f1 R-1 i-1 ε5 + + + + • 4J at 0 OJ OJ CD about tn OJ M ¹ • t-1 tH R-1 t-1 E < H R-1 rh r — 1 <- < r-1 r-1 • H i — 1 0 at • · about ·· u ·· about ·· cn x X rH X 1-1 X 1-1 % »« <· à \ \ r ~ -υ \ F \ _ < > à \ -T / "K about WHAT _r ~ \ in ~ J •about ABOUT Cr J about- dd x 1 x 1 x 1 x 1 <n ro m n x x x x about at at at CM CM CM CM <1 * x X x x from at at at about about about about about about 1 about 1 about 1 about 1 □ I ' à à 3¼ r ° r ° r ° CM 1 1 1 X C J 1 0 1 about 1 about 1 * x x x x c £ 1 1 ¹ 1 m n m m • H x x x x X about 1 at about 1 at 1 • sr m Φ r- > the <-i rh i- <

Ο CM Q · —ι r — i O and - + 66 + 107 + 130 + 114 + 112 - about 0 • H kO OJ r — 4 kO Csl r-H m <x> r-1 00 OJ rH m> sr i— < salt and · “1 T— <o ·· X r-l r-H rH o ·· X iH »—1 OJ U ·· X 1-1 r ^- 1 r1 ¹ u ·· X 1-1 t — l I — 1 o ·· X i-l D? b - ** x z > 9, I b b OI X 1 x X 1 x 1 UJ 1 m they m X U Ol X u o 1 m X o M x u o o 1 m X o CM x u o o 1 cn x o <N x u o u n X U CM X u o u 1 CM CC f ó 1 à 6 1 à 6 1 ŕ ó ' 1 à 5 1 \ here x x 1 x 1 x 1 x rH tú <*> x u 1 <n X U 1 n X U 1 <n X U 1 m X U 1 Ό 00 rH ΟΊ t — 1 o Axis rH CN OJ OJ

Ο Μ Q * - ' r-0 0 ä - l_ — i + 121 + 135 o> 00 + + 85 + 95 + 101 - ο ο Η sr sr rH 1 00 CO i — 1 ω rH OJ rH m sr rH OJ tn rH ID o t — 1 Sol r-4 OJ U ·· X rH ι — 1 OJ CD ·· X rH rH <—t u ·· X rH f — 1 rH u ·· X rH rH rH cj. X rH i — i r — 1 ABOUT ·· X rH b b b b b they x 1 X 1 x 1 En 1 x 1 X 1 Μ tí m X u CM X u o u 1 n X u CM X U o 1 M x u CM x u o u 1 <n X U CM X u o 1 CM r> X u x u o o 1 m X u o CM X o o o 1 (. Th à from 1 à 6 1 £ 6 1 à 0 1 £ ó 1 £ 1 \ rd tí x 1 x 1 x x 1 x 1 x rd tí cn X U 1 r> X U 1 r> X U 1 n X U 1 m X U 1 <n X o 1 > About my sr OJ in OJ <D OJ swarm 00 OJ

Ο CM α · - · r — ι 0 a + 55.5 + 86 + 96 + 98 ST 00 + + 87 T. t. C CO ΟΪ r ~ Tc-1 About CM rd 1 rd rd o m tH 1 00 C-1 o CO r-1 1 \ o Ol i — 1 <x> CX1hH Sol i — 1 rd o · X τ — 1 r — 1 rH O ·· X c-1 f-d rd u ·· X c-1 rd rd u · □ C rd rd rd u ·· X I-H rd rd u ·· X c-1 b δ b δ δ IN X 1 x X 1 x X 1 x 1 m tí m X U O CM CM x u ABOUT CM X u o u 1 n X o CM X o x z o o 1 <n X o CM x u o o 1 <n X ω CM X u o u 1 m X U CM X o O σ »X o N x u o o 1 CM tí ŕ ó ' 1 ŕ ó 1 f ^ŕ s 1 I o o 1 f o 1 o é 1 o o o 1 \ »-4 cm x 1 x 1 x x 1 x 1 x rh al m X U 1 M x u 1 m X U 1 m X O en X O 1 n X O 1 "about σ> CX1 o CO rd CO OJ oo CO CO TT m

Ο CM Q ä ¹ L · .J ABOUT + 149 + 99 + 103 + 71 06 + o ao + CX) ID WHAT about • r ~ 'ζΓ and 4> at about rh t-1 rh sr rh | 1 1 m 1 • ⁰ rh WHAT rh xo Eh <D sr rh i-1 rh t-1 Γ-1 α-d rH 1—1! —1 f - 1 rH f - 1 rH i-1 rH r-1 rH about about ·· u ·· u ·· about ·· u ·· about ·· ω x <-1 X H X «-Ι X i-l X rH X rH b "b b b b V tx x 1 x x 1 x 1 x 1 X 1 m n what <n what x x x x <n XC x at about υ at about CM CM CM CM at CM what x X X X x tZ at at about at about about about about about about at about at 1 at 1 at 1 at 1 1 about 1 f o II co U. CO IX / ω I o I Y Y about 1 o i CM 1 A A A A Article about 1 about 1 0 1 0 1 0 1 0 1 x x x x x x OI 1 ¹ 1 1 1 1 m what M <n m WHAT x x X x x x (X at about 1 at 1 at 1 at 1 about 1 m <0 WHAT σι about Ό m m m m WHAT

ο £ r "-i 0 + 105 + 108 + 101.5 + 122 + 98 T. t. ABOUT 0 121 140 148 133 108-110 Sol HC1 (1: 1) HC1 (1: 1) HC1 (1: 1) HC1 (1: 1) HC1 (1: 1) » • C b ŕ O u. b CH, b In those x 1 x 1 x 1 x 1 x 1 m tí m X o CM X u o u 1 m X U CM X u o 1 m  x u CM X o o o 1 m X U CM X u o 1 m X U CM X u o u 1 CO U. Μ about \ / • CM tí <o A x s X 0 1 1 C J 1 0 1 1 x • H x x 1 x 1 x 1 x 1 x 1 m X u 1 <n X o 1 <n X U 1 <n X u 1 m X o > J rh 42 43 45

Ο CM Q · - · f — i O ä + 84 XT m + + 71 + 127 + 128 + 101 T. t. C m kO r-1 1 CH ID t-1 o CM t — 1 1 LD · 1 rH mo ¹ r-1 CO σ> xr XT c — 1 1 σι n r-1 xr m c-1 1 CXI LD rH Sol r-1 f — i O ·· X r-i z-x rH rH u ·· X rH H rH U ·· SP t — i rH rH U ·· X rH f - 1 rH X · RH rH rH ABOUT ·· X rH b ^w \ ^ b b b b- • e · X x 1 x 1 x 1 x 1 x 1 x 1 m X CO x o CM x o o u 1 x o CM x o o o 1 m X O CM X u o u 1 n X U CM x u o o 1 <n X O CM X u o 1 m X O O o 1 CM Pi m - LL T o o 0 1 f * o ó 1 o 1 WHAT T ó 1 6 1 3 1 \ rH x x 1 x 1 x 1 x 1 x 1 x 1 «Η X m X U 1 CO x o 1 <n X O 1 m X o 1 n X u 1 m X U 1 XJ kD XT r- WHAT Gk XT o m rH m

Ο (N ο · - 1 — ι Ο ä. - + 87.5 + 116 + 93 + 84 + 53 τ. t. C LD * ςτ i — 1 m i — 1 O M ¹ r ^- i m τ — I 1 o <-1 o <T1 1 sr 00 Soi i — 1 rH U ·· X i-H r — 1 t — 1 ABOUT ·· x «- < rH τ — 1 ABOUT ·· f1 <—1 rH O ·· X τ-1 rH τ — 1 u ·· X <H b b b b b and; X 1 x 1 x 1 x 1 x 1 ΓΊ tí m X O CM X u o 1 m X U CM X u o 1 n X U CM X u o u 1 m X u CM X u o u 1 m X U CM X u o 1 CM tí M x ϋ 1 of '°. 1 0 1 x o ó 1 lll O Ô 1 Ό % rH cz x 1 x 1 x 1 x 1 x 1 rM Λ m X O 1 m X u 1 <n X O 1 m X u 1 m X u 1 No. Γ ~ m 00 m ai m about rH VO

Ο CM Q · —i r — i O ä · - ' + 73 + 49 o CO + + 103 + 119 T. t. C CO cn rH 1 sr m r-1 CM rd 1 00 rd i — l m m rH m • sr rH 1 O rh o in rH 1 m i — 1 Sol — — 1 rd U ·· rc r-1 i— <rH U ·· X «-i r-1 ri U ·· X ¾ ¹ - H rH U · X i-l i — 1 rd C ··: C rd km * "b b b Al, x 1 x 1 x 1 X 1 x m Ä m, X o CM x u o u r> X U CM X u o 1 m X U CM X o o u 1 m X u CM x u o u 1 Cl X O CM X u o 1 CM CC u. 'd 0 / about 0 \ Q _f zo / Q _f / ^z - ° % rH x x 1 x 1 x 1 x 1 x 1 rH ad m X o 1 n X U 1 m X O 1 m X u m X U 1 > About (N VO n vo sr VO m vo VO VO

Ο CN Q · - ' f—> 0 ä “ 1 → + 112 CO 00 + + 78 + 102 + 39 - u 0 • Eh OJ m i-1 about CX1 i-l OJ M ¹ rd o o r — 1 m o rd salt r-1 i — 1 U X r — 1 r-1 t — 1 U ·· X rH rd rd U ·· S rd rd rd o ·· X rH > ”D rd u ·· X rH b b b b b and; x 1 x 1 x 1 X 1 X 1 1 r) IX m X U CM X u o u 1 <n ’X O CM X U o ω 1 m X U CM X u o 1 ’M X O CM X u o u 1 c *> x u CM X u o 1 CN Cu ŕ č 1 F 6 1 à 6 1 à b 1 ŕ ó 1 x • -4 x x 1 x 1 m X o 1 x 1 r — 10 O 1 ^ 4 x n X U CM X o 1 n X U CM X u 1 r »X u 1 Ή O 1 rd u 1 KJ R <D 00 l £> σ> KD o r- rd r-

The compounds of the present invention have been subjected to pharmacological testing which has demonstrated their antithrombotic properties and their utility as substances having therapeutic activity.

1. Determination of inhibition constant (KJ with respect to thrombin)

Each well of a 96-well microtiter plate was placed with 25 μΐ of test compound solution (seven concentrations tested), 50 μΐ of chromogenic substrate solution (two concentrations tested; S2238 Chromogenix) dissolved in Trs buffer at pH 7.5 (50 mM Tris) , 100 mM sodium chloride and 0.1% BSA) and finally 25 μΐ 300 U / ml thrombin solution. The release of 4-nitroaniline at 405 nm was monitored using a plate reader. Ki was determined by the Dioxon method. The compounds of the present invention are thrombin inhibitors and have a K i of between 0.001 and 100 µΜ.

I

2. Rat plasma clotting of human thrombin tested ex vivo

Male CD rats weighing 150 compound or vehicle up to 200 g are administered

i.v., taken orally or subcutaneously by the route.

with blood blood) from

The animals

Trisodium citrate is anesthetized with nembutal (1 volumes by centrifugation at 3 (60 mg / kg), volume is adjusted by retro-orbital fold and plasma

600 g for 15 minutes at room temperature.

200 μΐ of plasma is incubated at 37 ° C with 200 μΐ of human thrombin solution (the final concentration of human thrombin is

0.75 NIH units / ml) and the clotting time is recorded. The anticoagulant effect is a dose that reduces the clotting time by 100%. The compounds inhibit rat plasma clotting at doses of 0.01 to 5 mg / kg i.v. They are also active when administered orally and subcutaneously.

The compounds of the present invention may be used in all clinical indications associated with thrombosis or in indications where thrombotic complications may occur.

Thus, the compounds may be present in all forms suitable for oral, parenteral or intravenous administration, such as tablets, dragees, capsules, including hard gelatin capsules, suspensions or solutions for oral or injectable administration and the like, in combination with suitable excipients. All of these forms contain dosages which allow the administration of 1 to 1000 mg per day per patient in one or more doses.

Claims (10)

PATENT CLAIMS Compounds of general formula I wherein R ¹ and R ¹ 'are, independently of one another, either a hydrogen atom or a halogen atom or an alkyl group having 1 to 4 carbon atoms; R ² is either a piperidin-1-yl group in point 4. branched hydroxyalkyl alkoxyalkyl carbon atoms containing an alkoxy group containing 1 optionally substituted in one or more substituents selected from the group consisting of a hydroxyl alkyl group containing a group containing a moiety containing a moiety and an alkyl group having from 1 to 4 atoms group, straight or ca 1 to 4 carbon alkyl, 1 to 4 carbon alkyl, alkoxy part 1 to 4 1 to 4 carbon alkyl, 4 carbon atoms, carbon atoms, nitrile alkylthio, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, cycloalkyl having 3 to 6 carbon atoms, -COOR 'and -CONR' R '' (R 'is C 1-4 alkyl and R''is hydrogen or C 1-4 alkyl), or = CYZ [Y and Z are independently selected from the group consisting of is hydrogen, halogen, and C1-C4alkyl (optionally substituted with one or more halogen), cyano and -COOR ', R' is as defined herein], or (r is 1-3), or = NOCH ₃ ; or a spiro [cycloalkane-1,4'-piperidin] -1-yl group having from 3 to 6 carbon atoms in the cycloalkane moiety; or a 1,2,3,6-tetrahydropyridin-1-yl group optionally substituted in the 4-position by a straight or branched alkyl group having 1 to 4 carbon atoms (optionally substituted by one or more halogen atoms) or a cycloalkyl group having 3 to 6 carbon atoms; or hexahydro-1H-azepin-1-yl optionally substituted in the 4-position with trifluoromethyl or = CF ₂ ; or a heptahydroazocin-1-yl group; or an octahydro-1H-azonin-1-yl group; or a group (aB is -CONR '', m is 1-2 and p is 1-2); or a group (Q is a carbon atom or a nitrogen atom, D is a C 1 -C 4 alkyl group or a -CH ₂ CF 3 group is 1 to 3); R ³ is either a straight or branched alkyl group having 1 to 5 carbon atoms; or -COR ⁵ wherein R ⁵ is C 1-4 alkyl which is straight or branched, - (CH 2) n OCH 3, -CH 2 O (C 2 H 4 O) n CH 3, - (CH 2) n CF 3, or - ( CH2) nOH (n = 1 to 4); or -SO ² R ⁶ ; or -CONHR ⁶ ; or -SO ₂ N (R ⁶ ) ₂ , wherein R ⁶ is a straight or branched alkyl group having 1 to 4 carbon atoms; R 4 is either a hydrogen atom or a halogen atom; and A is either phenyl optionally substituted with one or more substituents selected from the group consisting of halogen and straight or branched (C 1 -C 4) alkyl, straight or branched (C 1 -C 4) alkoxy, trifluoromethyl, trifluoromethoxy, formyl , -CH ₂ OR ^10, -CH2OCOR group ^10, group -CH2OCONR ¹⁰ R ^11, -COOR ^10, -CONR ¹⁰ R ^11, nitro, -NR ¹⁰ R ^n, -NHCOR ¹⁰ and -NH ( CH ₂ ) _q OR ¹⁰ , wherein R ¹⁰ and R ¹¹ are independently hydrogen or a straight or branched alkyl group having 1 to 4 carbon atoms and q is 0 to 6; or a heterocycle selected from the group consisting of pyridinyl, thienyl, furyl, pyrimidyl and thiazolyl; said groups may be substituted as previously mentioned; or a cycloalkyl group containing 5 to 8 carbon atoms; in the form of racemates or enantiomers or mixtures of enantiomers and in the form of the free acid or free base or in the form of pharmaceutically acceptable addition salts. The compound of claim 1, wherein R ¹ and R ¹ 'are, independently of one another, either a hydrogen atom or a halogen atom or an alkyl group having 1 to 4 carbon atoms; R ² is either a piperidin-1-yl group optionally substituted at the 4-position with one or more substituents selected from the group consisting of C 1 -C 4 alkyl, which may be straight or branched, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxyalkyl and C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, nitrile, difluoromethyl, trifluoromethyl, 2,2,2 -trifluoroethoxy and cycloalkyl of 3 to 6 carbon atoms, or = CYZ (Y and Z are independently selected from the group consisting of hydrogen, halogen and (C1-C4) alkyl), or = NOCH ₃ ; or a spiro [cycloalkane-1,4'-piperidin] -1-yl group having from 3 to 6 carbon atoms in the cycloalkane moiety; or a 1,2,3,6-tetrahydropyridin-1-yl group optionally substituted in the 4-position by a straight or branched alkyl group having 1 to 4 carbon atoms (optionally substituted by one or more halogen atoms); or a hexahydro-1H-azepin-1-yl group optionally substituted at the 4-position with = CF ₂ ; or an octahydro-1H-azonin-1-yl group; or (CH ₂ ) _m -B (CH ₂ ) 2 - (aB is -CONR 1 ', m is 1 to 2 and p is 1 to 2); or a group (Q is a carbon atom or a nitrogen atom, D is a C 1 -C 4 alkyl group or a -CH ₂ CF ₃ ar group is 1 to 3); R ³ is either a straight or branched alkyl group having 1 to 5 carbon atoms; or -COR ⁵ , wherein R ⁵ is C 1-4 alkyl, which is straight or branched, -CH ₂ O (C ₂ H ₄ O) _n CH ₃ , - (CH ₂ ) _n OH, or ( CH ₂ ) _n OCH ₃ ; or -CONHR ⁶ ; and A is either phenyl optionally substituted with one or more substituents selected from the group consisting of halogen and straight or branched (C 1 -C 4) alkyl, straight or branched (C 1 -C 4) alkoxy, trifluoromethyl, trifluoromethoxy and - NR ¹⁰ R ^1X , wherein R ¹⁰ and R ¹¹ are independently hydrogen or straight or branched (C 1 -C 4) alkyl; or a pyridinyl or thienyl group which may be substituted as defined above; or a cycloalkyl group containing 5 to 8 carbon atoms. Compounds according to any one of claims 1 and 2, wherein R ¹ is C 1 -C 4 alkyl and R ¹ 'is hydrogen, R ² is piperidin-1-yl substituted in the 4-position with straight or branched C 1 -C 4 alkyl or = CF ₂ , R ³ is -COR ⁵ wherein R ⁵ is a straight or branched alkyl group having 1 to 4 carbon atoms and A is a thienyl group optionally substituted as defined above or a cycloalkyl group having 5 to 8 carbon atoms. 4.. Compounds according to any one of claims 1 to 3, wherein the preferred configuration of the central amino acid portion is (S). 5th A process for preparing a compound of formula Ia (Ia) according to claim 1, wherein R ¹ , R ¹ ', R ² , R ⁴ and A are as defined in claim 1. 1 and R ⁵ is a straight or branched alkyl group having 1 to 4 carbon atoms or - (CH ₂ ) _n CF ₃ (n is 1 to 4), characterized in that the compound of formula II (II) wherein R ¹ and R ¹ 'are either hydrogen or alkyl 1-4 carbon atoms, reacts with a compound of formula III R5OC | SObCI I R 5 OC ^ ^{N x} t A. (III) wherein R ⁴ and A are as defined in claim 1 and R ⁵ is a straight or branched alkyl group containing 1 to 4 carbon atoms or - (CH 2) _n CF 3 (n is 1 to 4) to give a compound of formula IV (IV) which is reacted in an acidic medium to give a compound of formula Ia which is optionally halogenated when R ¹ and / or R ¹ 'is a hydrogen atom to give a compound of formula Ia wherein R ¹ and / or R ¹ ' is halogen atom. 6th A process for the preparation of a compound of formula (Ia) wherein R ¹ , direct or carbon, - (CH ₂ ) n CF _3, or wherein: 5 is reacted with a compound of formula V (Ia) as defined in claim 1 and R ^{5 is a} branched alkyl group containing 1 to - (CH ₂ ) _n OCH ₃ , -CH ₂ O (C ₂ H ₄ O) CH ₃ or - {CH ₂ ) _n OH (n is 1 to 4), characterized by the compound of formula (II) defined according to 4 atoms of claim (V) wherein A h and R ⁴ are as defined in claim 1 and R ⁵ is as previously defined to give a compound of formula (VI) which is reacted in an acidic medium to form a compound of formula (Ia) optionally halogenated when R ¹ and / or R ¹ 'is a hydrogen atom to give a compound of formula (Ia) wherein R 1 ¹ and / or R ¹ 'is a halogen atom. 7th A process for the preparation of compounds of formula Ia according to claim 1, wherein R ¹ , R ¹ ', R ² , claim 1, characterized by formula VII R ⁴ , R ⁵ and A are as defined in that compound (VII) wherein R ¹ , R ¹ ', R ² , R ⁴ and R ⁵ are as defined in claim 1, is reacted with a compound of formula VIII ASn (R) ₃ (VIII) wherein R is an alkyl group having 1 to 4 carbon atoms and A is as defined in claim 1 to form a compound of formula IX (IX) which is heated to boiling point in an acid medium to form a compound of general formula of formula Ia, which is optionally halogenated when R ¹ and / or R ¹ 'is a hydrogen atom, to give a compound of formula Ia wherein R ¹ and / or R ¹ ' is a halogen atom. A process for the preparation of compounds of the general formula Ib (Ib) wherein R ¹ , R ¹ ', R ² , R ⁴ and A are as defined in claim 1 and R ³ is either -COR ⁵ wherein R ⁵ is a straight or branched (C 1 -C 4) alkyl group, - (CH ₂ ) _n OCH 3, -CH ₂ O (C ₂ H ₄ O) _n CH ₃ , - (CH 2) _n CF _3, or - (CH ₂ ) _n OP, where P is a protecting group (n is 1 to 4) or -SO ₂ R ⁶ or a group -CONHR ⁶ or -SO ₂ N (R ⁶ ) ₂ , wherein R ⁶ is a straight or branched alkyl group having 1 to 4 carbon atoms, characterized in that the compound of formula II (II) wherein R ¹ 1 to 4 CPhj and R are either hydrogen, carbon, reacts with or an alkyl group containing a compound of formula X (X) of claim 1 to give a compound according to wherein A and R ⁴ are as defined in (XI) which reacts with or an alkylisocyanate chloride of general acid of formula R ⁵ COCl of formula R ⁶ NCO or sulfonyl of formula R ⁶ SO ² Cl or sulfamoyl chloride (R ⁶ ) 2NSO 2 Cl to give a compound of formula XII (XII) which is reacted in an acidic medium to give a compound of formula Ib, which optionally halogenated when R ¹ and / or R ¹ 'is a hydrogen atom to give a compound of formula Ib wherein R ¹ and / or R ¹ ' is a halogen atom. 9th A process for the preparation of compounds of formula Ic (Ic) according to claim 1, wherein R ¹ , R ¹ ', R ² , R ⁴ and A are as defined in claim 1, and wherein R ¹² is a straight or branched alkyl group | The compound of formula II as defined in claim 5 reacts with a compound of formula XIV (XIV) wherein R ¹² is a straight or branched alkyl group having 1 to 5 carbon atoms and A and R ⁴ are as defined in claim 1 to give a compound of formula XV (XV) which is reacted in an acidic medium to give a compound of formula Ic which is optionally halogenated when R ¹ and / or R ¹ 'is a hydrogen atom a compound of formula (Ic) wherein R ¹ and / or R ¹ 'is halogen. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 in combination with any pharmaceutically acceptable excipient.