Metalloprotease inhibitors, methods for producing same, and therapeutics uses thereof

Abstract

The invention relates to new -vinyl carbonylated compounds corresponding to general formula (I), wherein R.sub.1, R.sub.2,R.sub.3, R.sub.4, R.sub.5 and Y are as defined in claim 1, their isomers, their diastereoisomers and acid addition salts or a pharmaceutically acceptable base. The invention also relates to a method for producing said compounds (I). It further relates to the use of said compound (I) as selective metalloprotease inhibitors, especially matrix metalloproteases 12 (MMP-12) and/or 9 (MMP-9). The compounds (I) are particularly useful for the prevention and/or treatment of chronic obstructive pulmonary disease (COPD), particularly emphysema induced by cigarette smoke. ##STR00001##

Claims

1. An -vinyl carbonyl compound characterized in that it has formula (I): ##STR00029## in which R.sub.1 represents an acyl radical of formula COR.sub.8, in which R.sub.8 represents OH, NHR.sub.10 or NR.sub.10R.sub.11, with R.sub.10 and R.sub.11, which may be identical or different, representing, independently of one another, hydrogen, alkyl, alkenyl, alkynyl, OH, phenyl (C.sub.6H.sub.5), methoxyphenyl (C.sub.6H.sub.4OCH.sub.3), phenyloxyphenyl (C.sub.6H.sub.4OC.sub.6H.sub.5), biphenyl (C.sub.12H.sub.9), benzyl (CH.sub.2C.sub.6H.sub.5), cyclohexyl (C.sub.6H.sub.11), cyclopentyl (C.sub.5H.sub.9), R.sub.2 or R.sub.3, which may be identical or different, represent, independently of one another: an alkyl, alkenyl, alkynyl radical, a (CH.sub.2).sub.nR.sub.12 radical, in which n represents an integer ranging from 1 to 6, with R.sub.12 representing OH, phenyl, biphenyl, benzyl, cyclohexyl, cyclopentyl, COOH, COOR.sub.9, SR.sub.9, S.sup.(cation), with R.sub.9 representing hydrogen, alkyl, alkenyl, alkynyl, a (CH.sub.2).sub.nN(R.sub.9).sub.2 or (CH.sub.2).sub.nN(COOR.sub.9).sub.2 radical in which n represents an integer ranging from 1 to 6, a cycloalkyl radical, an aryl radical, or R.sub.1 and R.sub.2 together form a cycloalkyl or aryl radical, Y represents a nitrogen or oxygen atom, R.sub.4 represents a hydrogen atom, an alkyl, alkenyl, alkynyl or aryl radical, a doublet of electrons, a (CH.sub.2).sub.n-R.sub.12 radical with n and R.sub.12 as previously defined, R.sub.5 represents: an XR.sub.6R.sub.7 radical with X representing an oxygen, nitrogen or sulfur atom, R.sub.6 and R.sub.7, which may be identical or different, representing, independently of one another, a hydrogen atom, an alkyl radical, a doublet of electrons, an SO.sub.2R.sub.13 radical with R.sub.13 representing an alkyl, alkenyl, alkynyl, aryl radical as previously defined, a (CH.sub.2).sub.nR.sub.12 radical as previously defined, a halogen, an alkyl, alkenyl, akynyl radical, isomers thereof, diastereoisomers thereof and addition salts thereof with a pharmaceutically acceptable acid or base.

2. The compound as claimed in claim 1, characterized in that, in formula (I): Y represents a nitrogen atom and R.sub.4 represents a hydrogen atom, R.sub.5 represents an XR.sub.6R.sub.7 radical in which X represents an oxygen atom, R.sub.6 represents a hydrogen and R.sub.7 represents a doublet of electrons, R.sub.1 represents an acyl radical of formula COR.sub.8, in which R.sub.8 represents OH or NHR.sub.10 with R.sub.10 as defined in claim 1.

3. The compound as claimed in claim 1, characterized in that, in formula (I), R.sub.2 represents a (CH.sub.2).sub.nR.sub.12 radical, a (CH.sub.2).sub.nN(R.sub.9).sub.2 radical or an aryl radical as defined in claim 1.

4. The compound as claimed in claim 1, characterized in that, in formula (I), R.sub.3 represents an alkyl radical or an aryl radical as defined in claim 1.

5. The compound of formula (I) as claimed in claim 1, characterized in that it is selected from the group consisting of: (S)-N-((S)-1-(cyclohexylamino)- 1-oxo- 3-phenylpropan- 2- yl)- 2-(R)- 1-hydroxyethyl)but-3-enamide, (S)-2-((S)-biphenyl-4-yl(hydroxyl)methyl)-N-((S)-1-(cyclohexylamino)-1-oxo-3-phenylpropan-2-yl)but-3-enamide, (S)-N-((S)-1-(cyclohexylamino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-hydroxy-(5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazol-3-yl)methyl)but-3-enamide, (S)-2-((S)-2-((S)-hydroxy-5(4-methoxybenzyloxy)-1-phenyl-1H-pyrazol-3-yl)methyl)but-3-enamido)-3-phenylpropanoic acid, (S)-2-((S)-hydroxy-(5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazol-3-yl)methyl-N-((S)-1-(hydroxyamino)-1-oxo-3-phenylpropan-2-yl)but-3-enamide, (S)-2-((S)-2-((S)-hydroxy-(5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazol-3-yl)methyl)but-3-enamido)succinic acid, (S)-2-((2S,3R)-3-hydroxy-2-vinylheptanamido)-4-(methylthio)butanoic acid, (S)-2-((R)-1-hydroxyethyl)-N-((S)-1-oxo-1-(4-phenoxyphenylamino)-3-phenylpropan-2-yl)but-3-enamide, (S)-3-((S)-2-((R)-1-hydroxyethyl)but-3-enamido)-4-oxo-4-(4-phenoxyphenylamino)butanoic acid, (S)-2-((R)-1-hydroxyethyl)-N-((R)-3-mercapto-1-oxo-1-(4-phenoxyphenylamino)propan-2-yl)but-3-enamide, (S)-N-((R)-1-(cyclohexylamino)-3-mercapto-1-oxopropan-2-yl)-2-((R)-1-hydroxyethyl)but-3-enamide, and mixtures thereof.

6. The compound as claimed in claim 1, characterized in that, in formula (I): Y represents an oxygen atom and R.sub.4 represents a doublet of electrons, R.sub.5 represents an XR.sub.6R.sub.7 radical in which X represents an oxygen atom, R.sub.6 represents a hydrogen and R.sub.7 represents a doublet of electrons.

7. The compound as claimed in claim 6, characterized in that, in formula (I), R.sub.1 and R.sub.2 together form a cycloalkyl or aryl radical.

8. The compound of formula (I) as claimed in claim 1, which is (S)-((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)-2-((R)-1-hydroxyethyl)but-3-enoate.

9. A process for producing the compounds of formula (I) as claimed in claim 1, characterized in that it comprises the following steps: reacting a compound of formula (II): ##STR00030## in which R.sub.1, R.sub.2 and R.sub.4 are as defined in formula (I), with a compound of formula (II): ##STR00031## so as to produce the compounds of formula (III), ##STR00032## in which R.sub.1, R.sub.2 and R.sub.4 are as previously defined, Y representing a nitrogen atom, reacting the compound (III) obtained in the previous step, under neutral conditions, with a compound of formula (III): ##STR00033## so as to produce the compounds of formula (IV): ##STR00034## in which R.sub.1, R.sub.2, R.sub.4 and Y are as previously defined, reacting the compound of formula (IV) obtained in the previous step, under basic conditions, with a compound of formula (IV): R.sub.3CHO (IV) in which R.sub.3 is as defined in formula (I) so as to produce the compounds of formula (I): ##STR00035## in which R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined in formula (I), Y represents a nitrogen.

10. A process for producing a compound of formula (I) as claimed in claim 1, characterized in that it comprises the following steps: reacting a compound of formula (V): ##STR00036## in which R.sub.1 and R.sub.2 are as defined in formula (I), with a compound of formula (II): ##STR00037## so as to produce the compounds of formula (VI): ##STR00038## in which R.sub.1 and R.sub.2 are as previously defined, reacting the compound (VI) obtained in the previous step, under neutral conditions, with a compound of formula (III): ##STR00039## so as to produce the compounds of formula (VII): ##STR00040## in which R.sub.1 and R.sub.2 are as previously defined, reacting the compound of formula (VII) obtained in the previous step, under basic conditions, with a compound of formula (IV):
R.sub.3CHO (IV) in which R.sub.3 is as defined in formula (I), so as to produce the compounds of formula (I): ##STR00041## in which R.sub.1, R.sub.2 and R.sub.3 are as defined in formula (I).

11. A method for treating or reducing the symptoms of chronic obstructive pulmonary disease (COPD) comprising administering to a subject in need thereof a compound of formula (I) as claimed in claim 1.

12. A composition comprising at least one compound of formula (I) as claimed in claim 1 and optionally at least one pharmaceutically acceptable excipient.

13. The method of claim 11, wherein said COPD comprises emphysema caused by cigarette smoke.

14. A method for treating or reducing the symptoms of chronic obstructive pulmonary disease (COPD) comprising administering to a subject in need thereof a compound of formula (I) as claimed in claim 5.

15. A method for treating or reducing the symptoms of chronic obstructive pulmonary disease (COPD) comprising administering to a subject in need thereof a compound of formula (I) as defined in claim 8.

16. The compound of formula (I) as claimed in claim 1, wherein : the cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 2-isopropyl-5-methylcyclohexyl, and the aryl is selected from the group consisting of phenyl (C6H5), methoxyphenyl (C6H4OCH3), phenyloxyphenyl (C6H4OC6H5), benzyl (C6H5CH2), phenethyl (C6H5CH2CH2), tolyl (C6H4CH3), xylyl (C6H3(CH3)2), benzylidene (C6H5CH), benzoyl (C6H5CO), biphenyl (or diphenyl) (C12H9), naphthyl (C10H7), pyrazole or 5-(4-methoxybenzyloxy)-1-phenylpyrazole.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIGS. 1 and 2 illustrate the synthesis scheme for the compounds of formula (I) of the invention. More particularly, FIG. 1 illustrates the synthesis scheme for the compounds of formula (I) in which Y represents a nitrogen atom, and FIG. 2 illustrates the synthesis scheme for the compounds of formula (I) in which Y represents an oxygen atom and R.sub.4 a doublet of electrons.

(2) FIG. 3 illustrates, respectively, the interactions of compound 1 of the invention with the MMP-12 inhibitor (figure on the left) and with the MMP-9 inhibitor (figure on the right).

(3) FIG. 4 illustrates, respectively, the interactions of compound 3 of the invention with the MMP-12 inhibitor (figure on the left) and with the MMP-9 inhibitor (figure on the right).

(4) FIG. 5 illustrates, respectively, the interactions of compound 2 of the invention with the MMP-12 inhibitor (figure on the left) and with the MMP-9 inhibitor (figure on the right).

(5) FIG. 6 relates to specific examples of compounds of the invention corresponding to formula (I).

EXAMPLE 1

Processes for Producing 7 Compounds Corresponding to General Formula (I) in which Y Represents a Nitrogen Atom

(6) The 7 compounds synthesized in this example are hereinafter denoted 1 to 7. They correspond to formula (I) in which: Y represents a nitrogen and R.sub.4 represents a hydrogen atom, R.sub.5 represents an XR.sub.6R.sub.7 radical in which X represents an oxygen atom, R.sub.6 represents a hydrogen atom and R.sub.7 represents a doublet of electrons.

Preparation of Compound 1

(S)N((S)-1-(cyclohexylamino)-1-oxo-3-phenylpropan-2-yl)-2-((R)-1-hydroxyethyl)but-3-enamide

(7) ##STR00016##

(8) Compound 1 corresponds to formula (I) in which:

(9) R.sub.1=acyl radical COR.sub.8 with R.sub.8NHR.sub.10 with R.sub.10 representing a cyclohexyl,

(10) R.sub.2=(CH.sub.2).sub.nR.sub.12, with n=1 and R.sub.12=phenyl,

(11) R.sub.3=alkyl radical, namely a methyl (CH.sub.3).

Stage A

Preparation of (S)N-(1-cyclohexylamino)-1-oxo-3-phenylpropan-2-yl)acryl-amide

(12) 6 mmol (millimol) of triethylamine and then 6 mmol of acryloyl chloride are added, at 0 C., under an inert atmosphere, to a solution of 5 mmol of H-Phe-cyclohexylamide in 20 ml of THF (tetrahydrofuran). After stirring for 1 hour at ambient temperature, the reaction mixture is hydrolyzed with an ammonium chloride solution, and then the mixture is extracted with ethyl acetate (3 times) and with dichloromethane (twice). The organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (dichloromethane/methanol: 99/1) makes it possible to isolate the expected product in solid form.

Stage B

Preparation of (S,E)-N-(1-cyclohexylamino)-1-oxo-3-phenylpropan-2-yl)-4-(trimethylsilyl)but-2-enamide

(13) 6 mmol of allyltrimethylsilane and 0.1 mmol of the catalyst 1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)-ruthenium are added to a solution of 2 mmol of the compound obtained in stage A in 15 ml of dichloromethane. After stirring for 24 hours at ambient temperature, the solution is evaporated under vacuum, and silica gel chromatography (dichloromethane/methanol: 99/1) makes it possible to isolate the expected product in solid form.

Stage C

Preparation of (S)N((S)-1-(cyclohexylamino)-1-oxo-3-phenylpropan-2-yl)-2-((R)-1-hydroxyethyl)but-3-enamide (1)

(14) 1.1 mmol of acetaldehyde and then 1.1 mmol of tetrabutylammonium fluoride are added successively, at 78 C., to a solution of 1 mmol of the compound obtained in stage B in 15 ml of THF or of acetone. After stirring for 15 minutes at this same temperature, the reaction mixture is hydrolyzed with a saturated ammonium chloride solution, and then extracted with ethyl acetate (3 times). The organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (dichloromethane/methanol: 99/1) makes it possible to isolate the expected product 1 in solid form. HRMS calculated: 381.2154 [(M+Na.sup.+), C.sub.21H.sub.30N.sub.2O.sub.3Na]. found: 381.2155, .sup.1H NMR (CDCl.sub.3, 300 MHz) : 7.27-7.14 (m, 5H), 6.73 (d, J=9 Hz, 1H, NH), 5.94-5.74 (m, 1H), 5.71 (d, J=6 Hz, 1H, NH), 5.27 (d, J=14.9 Hz, 1H), 5.18 (d, J=9.8 Hz, 1H), 4.53 (m, 1H), 4.09 (m, 1H), 3.60 (m, 1H), 3.09-2.76 (m, 2H+1H), 1.75-0.88 (m, 10H), 1.08 (d, J=6.7 Hz, 3H).

Preparation of Compound 2

(S)-2-((S)-biphenyl-4-yl(hydroxy)methyl)-N((S)-1-(cyclohexylamino)-1-oxo-3-phenylpropan-2-yl)but-3-enamide

(15) ##STR00017##

(16) Compound 2 corresponds to formula (I) in which:

(17) R.sub.1 and R.sub.2 have the same meaning as for compound 1,

(18) R.sub.3=aryl radical, namely a biphenyl.

(19) Stages A and B: similar to stages A and B for compound 1.

Stage C

Preparation of (S)-2-((S)-biphenyl-4-yl(hydroxyl)methyl)-N((S)-1-(cyclohexylamino)-1-oxo-3-phenylpropan-2-yl)but-3-enamide (2)

(20) 0.5 mmol of 4-biphenylaldehyde and then 0.55 ml of tetrabutylammonium fluoride are added successively, at 78 C., to a solution of 0.5 mmol of the compound obtained in stage B in 15 ml of THF or acetone. After stirring for 15 minutes at this same temperature, the reaction mixture is hydrolyzed with a saturated ammonium chloride solution, and then extracted with ethyl acetate (3 times). The organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (dichloromethane/methanol: 99/1) makes it possible to isolate the expected product 2 in solid form. HRMS calculated: 497.2804 [(M+.sup.+), C.sub.32H.sub.37N.sub.2O.sub.3]. found: 497.2801. .sup.1H NMR (DMSO, 300 MHz) : 8.31 (d, J=9 Hz, 1H, NH) 7.70-7.14 (m, 5H+9H), 5.81 (d, J=6 Hz, 1H, NH), 5.60-5.45 (m, 1H), 4.80-4.65 (m, 2H+1H), 4.53 (m, 1H), 3.53 (m, 1H), 3.34-3.10 (m, 2H), 2.78 (m, 1H), 1.74-1.04 (m, 10H).

Preparation of Compound 3

(S)N((S)-1-(cyclohexylamino)-1-oxo-3-phenylpropan-2-yl)-2-4S)-hydroxy-(5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazol-3-yl)methyl)but-3-enamide

(21) ##STR00018##

(22) Compound 3 corresponds to formula (I) in which:

(23) R.sub.1 and R.sub.2 have the same meaning as for compound 1,

(24) R.sub.3=aryl radical, namely 5-(4-methoxybenzyloxy)-1-phenylpyrazole.

(25) Stages A and B: similar to stages A and B for compound 1.

Stage C

Preparation of (S)N((S)-1-(cyclohexylamino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-hydroxy(5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazol-3-yl)methyl)but-3-enamide (3)

(26) 0.5 mmol of 5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazole-3-carbaldehyde and then 0.55 ml of tetrabutylammonium fluoride are added successively, at 78 C., to a solution of 0.5 mmol of the compound obtained in stage B in 15 ml of THF or acetone. After stirring for 15 minutes at this same temperature, the reaction mixture is hydrolyzed with a saturated ammonium chloride solution, and then extracted with ethyl acetate (3 times). The organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (dichloromethane/methanol: 99/1) makes it possible to isolate the expected product 3 in solid form. HRMS calculated: 623.3233 [(M+H.sup.+), C.sub.37H.sub.43N.sub.4O.sub.5]. found: 623.3220. .sup.1H NMR (CDCl.sub.3, 300 MHz) : 7.66-6.88 (1 m, 14H), 6.13 (d, J=9 Hz, 1H, NH), 5.94 (m, 1H), 5.75 (s, 1H), 5.24 (m, 2H), 5.02 (s, 2H), 4.92 (d, 1H, NH), 4.69-4.57 (m, 2H), 3.81 (s, 3H), 3.77 (m, 1H), 3.49 (m, 1H), 3.13-2.96 (m, 2H+1H), 1.71-0.88 (m, 10H).

Preparation of Compound 4

(S)-2-((S)-2-((S)-hydroxy-(5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazol-3-yl)methyl)but-3-enamido)-3-phenylpropanoic acid

(27) ##STR00019##

(28) Compound 4 corresponds to formula (I) in which:

(29) R.sub.1=acyl radical COR.sub.8 with R.sub.8OH,

(30) R.sub.2 has the same meaning as for compound 1,

(31) R.sub.3 has the same meaning as for compound 3.

Stage A

Preparation of (S)-methyl-2-acrylamido-3-phenylpropanoate

(32) 44 mmol of triethylamine and then 20 mmol of acryloyl chloride are added, at 0 C., under an inert atmosphere, to a solution of 20 mmol of H-Phe-alanine methyl ester hydrochloride in 40 ml of THF. After stirring for 1 hour at ambient temperature, the reaction mixture is hydrolyzed, and then extracted with ethyl acetate (3 times) and with dichloromethane (twice). The organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (cyclohexane/EtOAc: 7/3) makes it possible to isolate the expected product in the form of a white solid.

Stage B

Preparation of (S,E)-methyl 3-phenyl-2-(4-(trimethylsilyl)but-2-enamido)-propanoate

(33) 36 mmol of allyltrimethylsilane and 0.2 mmol of the catalyst 1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)-ruthenium are added to a solution of 12 mmol of the compound obtained in stage A in 20 ml of dichloromethane. After stirring for 76 hours at ambient temperature, the solution is evaporated under vacuum, and silica gel chromatography (cyclohexane/EtOAc: 7/3) makes it possible to isolate the expected product in the form of a cream solid.

Stage C

Preparation of (S)-methyl 2-((S)-2-((S)-hydroxy-(5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazol-3-yl)methyl)but-3-enamido)-3-phenylpropanoate

(34) 1 mmol of 5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazole-3-carbaldehyde and then 1.1 ml of tetrabutylammonium fluoride are added successively, at 78 C., to a solution of 1 mmol of the compound obtained in stage B in 15 ml of THF or acetone. After stirring for 15 minutes at this same temperature, the reaction mixture is hydrolyzed with a saturated ammonium chloride solution, and then extracted with ethyl acetate (3 times). The organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (cyclohexane/EtOAc: 7/3) makes it possible to isolate the expected product in solid form.

Stage D

(S)-2-((S)-2-((S)-hydroxy-(5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazol-3-yl)methyl)but-3-enamido)-3-phenylpropanoic acid (4)

(35) 2.4 mmol of LiOH are added to 0.8 mmol of the compound obtained in stage C in a 3/1: THF/H.sub.2O mixture. After stirring for 3 hours at 25 C., the solvents are evaporated off and the residual aqueous phase is diluted with water, acidified to pH=2 by adding a 5% hydrochloric acid solution, and then extracted with ethyl acetate. The combined organic phases are washed, dried, filtered, and then evaporated under reduced pressure. Silica gel chromatography (dichloromethane/methanol: 92/8) makes it possible to isolate the expected product 4 in solid form. HRMS calculated: 540.2135 [(MH.sup.+), C.sub.31H.sub.30N.sub.3O.sub.6]. found: 540.2141. .sup.1H NMR (CDCl.sub.3, 300 MHz) : 7.57-6.87 (1 m, 14H+NH), 6.04 (m, 1H), 5.80 (s, 1H), 5.31-4.97 (m, 2H+NH), 5.02 (s, 2H, OCH2), 4.77 (m, 2H), 3.81 (s, 3H), 3.45-2.94 (m, 2H+1H+OH).

Preparation of Compound 5

(S)-2-((S)-hydroxy-(5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazol-3-yl)methyl)-N((S)-1-(hydroxyamino)-1-oxo-3-phenylpropan-2-yl)but-3-enamide

(36) ##STR00020##

(37) Compound 5 corresponds to formula (I) in which:

(38) R.sub.1=acyl radical COR.sub.8 with R.sub.8NHR.sub.10 and R.sub.10OH,

(39) R.sub.2 has the same meaning as for compound 1,

(40) R.sub.3 has the same meaning as for compound 3.

(41) Stages A, B, C, D: similar to stages A, B, C and D for compound 4.

Stage E

Preparation of (S)N((S)-1-(tert-butyldimethylsilyloxyamino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-hydroxy-(5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazol-3-yl)methyl)but-3-enamide

(42) 0.6 mmol of the compound obtained in stage D, 0.6 mmol of 1-hydroxybenzo-triazole, 3 mmol of N-methylmorpholine and 1.2 mmol of 0-silyltertbutyldimethylhydroxylamine hydrochloride are dissolved in 9 ml of dichloromethane. 0.78 mmol of N-[(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride is then added to this solution and the reaction is stirred at ambient temperature for 12 hours. The reaction mixture is then diluted by adding water, and then extracted with dichloromethane. The combined organic phases are washed with a saturated NaCl solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (dichloromethane/methanol: 99/1) makes it possible to isolate the product in the form of a syrup.

Stage F

Preparation of (S)-2-((S)-hydroxy-(5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazol-3-yl)methyl)-N((S)-1-hydroxyamino)-1-oxo-3-phenylpropan-2-yl)but-3-enamide (5)

(43) A solution containing 0.31 mmol of the compound obtained in stage E in 2 ml of THF and 2 ml of TBAF (2 mmol) is stirred for 1 hour at ambient temperature. The reaction mixture is then diluted by adding water, and then extracted with ethyl acetate. The combined organic phases are washed with a saturated NaCl solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (dichloromethane/methanol: 99/1) makes it possible to isolate the product 5 in solid form. HRMS calculated: 555.2244 [(MH.sup.+), C.sub.31H.sub.31N.sub.4O.sub.6]. found: 555.2247. .sup.1H NMR (CDCl.sub.3, 300 MHz) : 10.04 (bs, 1H, NHOH), 7.59-6.64 (1 m, 14H+NH), 5.79-5.59 (m, 1H+1H pyrazole), 5.10-4.76 (1 m, 2H+NH), 4.90 (s, 2H, OCH2), 4.59 (m, 2H), 3.70 (s, 3H), 3.41-2.90 (m, 2H+1H+OH).

Preparation of Compound 6

(S)-2-((S)-2-((S)-hydroxy-(5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazol-3-yl)methyl)but-3-enamido)succinic acid

(44) ##STR00021##

(45) Compound 6 corresponds to formula (I) in which:

(46) R.sub.1 has the same meaning as for compound 4,

(47) R.sub.2=(CH.sub.2).sub.nR.sub.12, with n=1 and R.sub.12COOH,

(48) R.sub.3 has the same meaning as for compound 3.

Stage A

Preparation of (S)-dimethyl 2-acrylamidosuccinate

(49) 22 mmol of triethylamine and then 10 mmol of acryloyl chloride are added, at 0 C., under an inert atmosphere, to a solution of 10 mmol of H-aspartic dimethyl ester hydrochloride in 20 ml of THF. After stirring for 1 hour at ambient temperature, the reaction mixture is hydrolyzed, and then extracted with ethyl acetate (3 times) and with dichloromethane (twice). The organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (cyclohexane/EtOAc: 7/3) makes it possible to isolate the expected product.

Stage B

Preparation of (S,E)-dimethyl 2-(4-(trimethylsilyl)but-2-enamido)succinate

(50) 7.5 mmol of allyltrimethylsilane and 0.1 mmol of the catalyst 1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)-ruthenium are added to a solution of 2.5 mmol of the compound obtained in stage A in 15 ml of dichloromethane. After stirring for 36 hours at ambient temperature, the solution is evaporated under vacuum. Silica gel chromatography (cyclohexane/EtOAc: 7/3) makes it possible to isolate the expected product.

Stage C

Preparation of (S)-dimethyl 2-((S)-2-((S)-hydroxy-(5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazol-3-yl)methyl)but-3-enamido)succinate

(51) 1 mmol of 5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazole-3-carbaldehyde and then 1.1 ml of tetrabutylammonium fluoride are added successively, at 78 C., to a solution of 1 mmol of the compound obtained in stage B in 5 ml of THF or acetone. After stirring for 15 minutes at this temperature, the reaction mixture is hydrolyzed with a saturated ammonium chloride solution, and then extracted with ethyl acetate (3 times). The organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (dichloromethane/methanol: 99/1) makes it possible to isolate the expected product in solid form.

Stage D

Preparation of (S)-2-((S)-2-((S)-hydroxy-(5-(4-methoxybenzyloxy)-1-phenyl-1H-pyrazol-3-yl)methyl)but-3-enamido)succinic acid (6)

(52) 2 mmol of LiOH are added to 0.5 mmol of the compound obtained in stage C in a 3/1: THF/H.sub.2O mixture. After stirring for 3 hours at 25 C., the solvents are evaporated off, and the residual aqueous phase is diluted with water, acidified to pH=2 by adding a 5% hydrochloric acid solution, and then extracted with ethyl acetate. The combined organic phases are washed, dried, filtered, and then evaporated under reduced pressure. Silica gel chromatography (dichloromethane/methanol: 92/8) makes it possible to isolate the expected product 6 in solid form. HRMS calculated: 508.1720 [(MH.sup.+), C.sub.26H.sub.26N.sub.3O.sub.8]. found: 508.1717. .sup.1H NMR (DMSO, 300 MHz) : 7.61-6.95 (1 m, 14H+NH), 5.95 (m, 1H), 5.75 (m, 1H pyrazole), 5.29-5.0 (1 m, 2H+NH), 5.12 (s, 2H OCH2), 4.92 (m, 1H), 4.69 (m, 1H), 3.74 (s, 3H), 3.35-2.90 (m, 2H+1H).

Preparation of Compound 7

(S)-2-((2S,3R)-3-hydroxy-2-vinylheptanamido)-4-(methylthio)butanoic acid

(53) ##STR00022##

(54) Compound 7 corresponds to formula (I) in which:

(55) R.sub.1 has the same meaning as for compound 4,

(56) R.sub.2=(CH.sub.2).sub.nR.sub.12, with n=2 and R.sub.12SR.sub.9 with R.sub.9=alkyl, namely methyl,

(57) R.sub.3=alkyl radical, namely butyl.

Stage A

Preparation of (S)-methyl 2-acrylamido-4-(methylthio)butanoate

(58) 22 mmol of triethylamine and then 10 mmol of acryloyl chloride are added, at 0 C., under an inert atmosphere, to a solution of 10 mmol of H-methionine methyl ester hydrochloride in 20 ml of THF. After stirring for 1 hour at ambient temperature, the reaction mixture is hydrolyzed and then extracted with ethyl acetate (3 times) and with dichloromethane (twice). The organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (cyclohexane/EtOAc: 7/3) makes it possible to isolate the expected product in the form of a white solid.

Stage B

Preparation of (S,E)-methyl 4-(methylthio)-2-(4-(trimethylsilyl)but-2-enamido)butanoate

(59) 9 mmol of allyltrimethylsilane and 0.09 mmol of the catalyst 1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)-ruthenium are added to a solution of 3 mmol of the compound obtained in stage A in 15 ml of dichloromethane. After stirring for 36 hours at ambient temperature, the solution is evaporated under vacuum. Silica gel chromatography (cyclohexane/EtOAc: 7/3) makes it possible to isolate the expected product.

Stage C

Preparation of (S)-methyl-2-((2S,3R)-3-hydroxy-2-vinylheptanamido)-4-(methylthio)butanoate

(60) 1.1 mmol of pentanal and then 1.1 ml of tetrabutylammonium fluoride are added successively, at 78 C., to a solution of 1 mmol of the compound obtained in stage B in 5 ml of THF or acetone. After stirring for 15 minutes at this same temperature, the reaction mixture is hydrolyzed with a saturated ammonium chloride solution, and then extracted with ethyl acetate (3 times). The organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (dichloromethane/methanol: 99/1) makes it possible to isolate the expected product in solid form.

Stage D

Preparation of (S)-2-((2S,3R)-3-hydroxy-2-vinylheptanamido)-4-(methylthio)-butanoic acid (7)

(61) 1 mmol of LiOH is added to 0.5 mmol of the compound obtained in stage C in a 3/1: THF/H.sub.2O mixture. After stirring for 3 hours at 25 C., the solvents are evaporated off, and the residual aqueous phase is diluted with water, acidified to pH=2 by adding a 5% hydrochloric acid solution, and then extracted with ethyl acetate. The combined organic phases are washed, dried, filtered, and then evaporated under reduced pressure. Silica gel chromatography (dichloromethane/methanol: 92/8) makes it possible to isolate the expected product 7 in solid form. HRMS calculated: 302.1426 [(MH.sup.+), C.sub.14H.sub.24NO.sub.4S]. found: 302.1419. .sup.1H NMR (CDCl.sub.3, 300 MHz) : 6.84 (d, J=9 Hz, 1H, NH), 6.25 (bs, OH), 5.92 (m, 1H), 5.32 (d, J=10.9 Hz, 1H), 5.24 (d, J=14.7 Hz, 1H), 4.62 (m, 1H), 4.05 (m, 1H), 2.96 (m, 1H), 2.48 (m, 2H), 2.51-1.75 (m, 2H), 2.04 (s, 3H), 1.49-1.10 (m, 6H), 0.82 (t, J=6.7 Hz, 3H).

EXAMPLE 2

Process for Preparing a Compound 8 Corresponding to General Formula (I) in which Y Represents an Oxygen Atom and R4 a Doublet of Electrons

Preparation of (S)-((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)-2-((R)-1-hydroxyethyl)but-3-enoate (8)

(62) ##STR00023##

(63) Compound 8 corresponds to formula (I) in which: Y represents oxygen and R.sub.4 a doublet of electrons, R.sub.1 and R.sub.2 together form a cycloalkyl radical substituted with 2 alkyls, namely 2-isopropyl-5-methylcyclohexyl, R.sub.3 represents an alkyl radical, namely methyl, R.sub.5 represents an XR.sub.6R.sub.7 radical in which X represents an oxygen atom, R.sub.6 represents a hydrogen and R.sub.7 represents a doublet of electrons.

Stage A

Preparation of (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl acrylate

(64) 22 mmol of diisopropylmethylamine and then 10 mmol of acryloyl chloride are added, at 78 C., under an inert atmosphere, to a solution of 10 mmol of (1R,2S,5R)-()-menthol in 20 ml of CH.sub.2Cl.sub.2 (dichloromethane). After stirring for 1 hour at ambient temperature, the reaction mixture is hydrolyzed, and then extracted with ethyl acetate (3 times) and with dichloromethane (twice). The organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (cyclohexane/EtOAc: 9/1) makes it possible to isolate the expected product in the form of a white solid.

Stage B

Preparation of (E)-((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)-4-(trimethyl-silyl)but-2-enoate

(65) 6 mmol of allyltrimethylsilane and 0.08 mmol of the catalyst 1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)-ruthenium are added to a solution of 2 mmol of the compound obtained in stage A in 15 ml of dichloromethane. After stirring for 24 hours at ambient temperature, the solution is evaporated under vacuum. Silica gel chromatography (cyclohexane/EtOAc: 9.5/0.5) makes it possible to isolate the expected product.

Stage C

Preparation of (S)-((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)-2-((R)-1-hydroxyethyl)but-3-enoate (8)

(66) 1.1 mmol of acetaldehyde and then 1.1 ml of tetrabutylammonium fluoride are added successively, at 78 C., to a solution of 1 mmol of the compound obtained in stage B in 5 ml of THF or acetone. After stirring for 15 minutes at this same temperature, the reaction mixture is hydrolyzed with a saturated ammonium chloride solution, and then extracted with ethyl acetate (3 times). The organic phases are dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (cyclohexane/ethyl acetate: 8/2) makes it possible to isolate the expected product 8. .sup.1H NMR (CDCl.sub.3, 300 MHz) : 5.87 (m, 1H, CH), 5.17 (m, 2H), 5.24 (d, J=14.7 Hz, 1H), 4.64 (m, 1H), 4.01 (m, 1H), 3.28 (m, 1H OH), 2.94 (m, 1H), 1.95-0.63 (unresolved peak, 20H).

EXAMPLE 3

Tests for Enzymatic Inhibition of Metalloproteases MMP-9 and MMP-12

(67) The inhibition selectivity of the synthesized compounds 1 to 7 was tested with respect to MMP-9 and MMP-12.

(68) The duality between the hydrophobic part (S.sub.1 pocket) and the hydrophilic part (zinc atom) of an MMP inhibitor plays an important role with regard to the degree of inhibition and consequently can also play a determining role in the inhibition selectivity with respect to a single MMP.

(69) The inventors in particular studied the interactions between the hydrophobic part which occupies the S.sub.1 pocket of the MPP inhibitor with the compounds of the invention. More particularly, the various possible orientations and the various possibilities of introduction of the hydrophobic group, in particular for the R.sub.1 group of the compounds of the invention, were studied.

(70) Protocols of the Tests for Enzymatic Inhibition of MMP-9 and MMP-12

(71) The enzymatic tests for screening compounds 1 to 7 were carried out in solution on two purified human enzymes: the gelatinase MMP-9 (Anaspec, USA) and the metalloelastase MMP-12 (Anaspec, USA).

(72) The activity is revealed by means of a colorimetric method suitable for a 96-well plate format.

(73) The principle is based on the cleavage, by the MMP-9 or MMP-12 enzyme, of a chromogenic substrate: the thiopeptide (Ac-Pro-Leu-Gly-[2-mercapto-4-methylpentanoyl]-Leu-Gly-OC.sub.2H.sub.5) (Enzo Life Sciences, USA).

(74) The hydrolysis of this thiopeptide produces a sulfhydryl group which reacts with Ellman's reagent: 5,5-dithiobis(2-nitrobenzoic acid) (DTNB) to form 2-nitro-5-thiobenzoic acid (TNB), which is detected by its absorbance at 412 nm

(75) The tests are carried out in the buffer 50 mM Hepes, 10 mM CaCl.sub.2, 0.5% Brij35, 1 mM DTNB, pH 7.0 containing the purified MMP-9 and MMP-12 enzymes diluted to the final concentration of 0.8 g/ml.

(76) After preincubation of the enzymes (1 h at ambient temperature in the dark) with or without the products tested (minimum of four doses serially diluted one-in-ten), the cleavage reactions are initiated by adding 150 M (final concentration) of substrate in a total final volume of 100 l (96-well plate format).

(77) The plates containing the reactions are read in a microplate reader (Multiskan Ascent, ThermoElectron, France) in order to continuously measure the absorbance and to record values every 3 mM for 3 h. Each condition is carried out in triplicate.

(78) The concentration which inhibits 50% of the reaction (IC.sub.50) is determined from curves representing the absorbance (optical density) of the final reaction product (TNB) as a function of the doses tested. Each experiment is carried out at least twice.

(79) Results

(80) During this test, compounds 1 to 7 of the invention exhibited IC.sub.50 values of between 5 and 330 M and K, (inhibition constant) values of between 2.5 and 160 M for the MMP-9 and MMP-12 enzymes (see table 1 below).

(81) TABLE-US-00001 TABLE 1 IC50 MMP9 K.sub.i MMP9 IC50 MMP12 Inhibitor (M) (M) (M) K.sub.i MMP12 (M) 1 18.10 8.95 19.54 9.95 2 125.9 62.23 19.98 10.17 3 5 2.47 7.23 3.68 4 259.3 128.17 20.18 10.27 5 19.79 9.78 22.31 11.36 6 13.09 6.47 6.30 3.21 7 330.4 163.32 78.33 39.87
Analysis of the Results and Conclusion

(82) According to biological tests results table 1, the 7 compounds tested can be divided up into two categories, namely, on the one hand, compounds 1, 3 and 5, and, on the other hand, compounds 2, 4, 6 and 7.

(83) The first category (compounds 1, 3, and 5) corresponds to the compounds which have similar inhibition values on the two MMPs tested.

(84) Compounds 1 and 3 have binding modes which are very original and different with respect to MMP-12 and MMP-9. Compound 5, for its part, has the same binding mode with respect to the two MMPs.

(85) More particularly, compound 1 is very advantageous by virtue of its low number of atoms and its good biological activity. It has an identical K, with respect to the two enzymes MMP-12 and MMP-9, but its binding mode is very different with these two enzymes.

(86) Compound 1 behaves with respect to MMP-9 like a pseudopeptide inhibitor with the formation of two hydrogen bonds with the backbones of the residues of the groove of the protein substrate. The benzyl part of compound 1 (namely the substituent R.sub.2) interacts with the hydrophobic pocket S.sub.1 of MMP-9 and the carbonyl of the hydroxy acid part of compound 1 chelates the zinc atom of MMP-9 (see FIG. 3, right).

(87) When it interacts with MMP-12, the cyclohexylcarboxamide part (namely the substituent R.sub.1) of compound 1 is in the S.sub.1 pocket of MMP-12 and the hydroxy acid part interacts with the groove of the protein substrate by forming two hydrogen bonds. The interaction with the zinc atom takes place by means of the benzyl radical (substituent R.sub.2) of compound 1 by forming -cation interactions (see FIG. 3, left). This interaction is entirely original in the inhibition of matrix metalloproteinases.

(88) Compound 3 also has the same K, value with respect to the two enzymes. However, two binding modes are demonstrated with respect to MMP-12 and MMP-9.

(89) With the structure of MMP-9, the formation of a zinc-chelating pincer is noted between the carbonyl and the hydroxyl function of the central part of compound 3. The pyrazole part (substituent R.sub.3) of compound 3 interacts with the S.sub.1 pocket by means of its phenyl radical (FIG. 4, right).

(90) With MMP-12, the pyrazole part of compound 3 interacts with the S.sub.1 pocket via its p-methoxybenzyloxy radical and forms once again a -cation interaction with its phenyl radical and the zinc atom (FIG. 4, left).

(91) Compound 3 is itself also very advantageous by virtue of its particular binding mode wherein the pyrazole part interacts with the S.sub.1 pocket and forms once again a -cation interaction with the zinc atom. The chirality of the amino acid part does not appear to be important for the activity.

(92) The second category of compounds (compounds 2, 4, 6 and 7) exhibits different inhibition values on the two MMPs, with an increasing factor of 2 to 13 times in favor of MMP-12. Compound 2 is found to be particularly advantageous.

(93) This is because a difference in K.sub.i by a factor of 6 is demonstrated with compound 2. However, this compound exhibits the same binding mode characterized by an interaction with the S.sub.1 pocket by means of its biphenyl part (substituent R.sub.3). The benzyl part of compound 2 mimics the protein substrate in its groove by forming three hydrogen bonds for MMP-12 and only one hydrogen bond with MMP-9. It can be noted that the hydroxyl function of compound 2 chelates the zinc atom of MMP-12 (FIG. 5, left), whereas no interaction is observed with the zinc atom in the case of MMP-9 (FIG. 5, left), thereby certainly explaining this selectivity.

(94) Compound 2 is therefore particularly promising and exhibits good selectivity with respect to MMP-12.

CONCLUSION

(95) The compounds of the invention distinguish themselves for their biological activities (selectivity with respect to MMP-12 and/or MMP-9) and their binding modes. Indeed, they generate binding modes which are very original and selective according to the MMP targeted (-cation interaction). The binding modes of the compounds of the invention with the MMP matrix metalloproteases are very different than those of the prior art compounds known to be MMP inhibitors, for instance Marimastat, which itself always binds with the zinc part of MMPs by means of its hydroxamic acid part, which is not the case with the compounds of the invention.

(96) The compounds of the invention made it possible to define the duality between the hydrophobic (S.sub.1 pocket) and hydrophilic (zinc atom) binding mode of the MMP inhibitor.

(97) Advantageously, the compounds of the invention are selective inhibitors of metalloproteases, and in particular of matrix metalloproteases 12 (MMP-12) and 9 (MMP-9), and even more particularly of MMP-12.

(98) The compounds of the invention also prove to be advantageous because of their particularly advantageous production process: low number of steps (3-4) for synthesizing said compounds, modulability of the process at each step of the synthesis (diversity of structures for better inhibition selectivity).

EXAMPLE 4

Study of the Docking Score of Compounds Corresponding to Formula (I)

(99) Various compounds corresponding to formula (I) below:

(100) ##STR00024##

(101) in which the substituent R.sub.1 is represented by the CONHR.sub.10 radial, Y is represented by nitrogen, R.sub.4 is represented by hydrogen and R.sub.5 is represented by the hydroxyl OH,

(102) were tested in a study of the docking score, by varying the substituents R.sub.10, R.sub.2 and R.sub.3 in the manner represented in table 2 below.

(103) These compounds were denoted by the numbers 1 and 9 to 36.

(104) The measurement of the docking score makes it possible to give a provisional value for the inhibition. The higher the value of the docking score in absolute value, the better the inhibition.

(105) The values of certain pharmacokinetic parameters were also measured. These parameters, which are important for obtaining activity in vivo, can be predicted by virtue of the QuickProp module of the Schrodinger suite.

(106) The QplogPo/w parameter corresponds to the water/octanol partition coefficient commonly referred to as Log P. The optimal values of this parameter (Lipinzky's rule) are between 3 and 5 (<3 for nonpolar compounds targeting the central nervous system).

(107) The QplogHERG parameter corresponds to the log of the IC.sub.50 of the compound studied with respect to very important potassium-ion cardiac channels. Thus, if this value is less than 5, the compound can induce cardiac toxicity.

(108) TABLE-US-00002 TABLE 2 Compo (I) R.sub.3 R.sub.2 R.sub.10 docking score QPlogPo/w QPlogHERG 9 Me CH.sub.2CO.sub.2H C.sub.6H.sub.4OC.sub.6H.sub.5 15.316476 3.513 3.345 10 CH.sub.2C.sub.6H.sub.5 CH.sub.2CO.sub.2H C.sub.6H.sub.4OC.sub.6H.sub.5 6.992449 3.154 3.061 1 Me CH.sub.2C.sub.6H.sub.5 C.sub.6H.sub.11 7.427621 3.416 2.801 11 CH.sub.2C.sub.6H.sub.5 CH.sub.2C.sub.6H.sub.5 C.sub.6H.sub.11 7.450145 3.393 2.988 12 Me CH.sub.2C.sub.6H.sub.5 n-C.sub.7H.sub.15 7.243734 3.984 2.873 13 Me CH.sub.2C.sub.6H.sub.5 n-C.sub.5H.sub.11 7.164123 3.525 3.328 14 Me CH.sub.2C.sub.6H.sub.5 C.sub.6H.sub.4OMe 8.57941 3.928 5.064 15 Me CH.sub.2C.sub.6H.sub.5 C.sub.6H.sub.4OC.sub.6H.sub.5 8.981474 5.29 6.054 16 Me CH.sub.2C.sub.6H.sub.5 C.sub.6H.sub.4C.sub.6H.sub.5 8.944325 5.581 6.061 17 Me CH.sub.2SH C.sub.6H.sub.11 10.492747 2.802 2.085 18 CH.sub.2C.sub.6H.sub.5 CH.sub.2SH C.sub.6H.sub.11 7.181084 2.666 1.734 19 Me CH.sub.2S.sup. C.sub.6H.sub.4OC.sub.6H.sub.5 12.917503 4.746 5.205 20 Me CH.sub.2SH C.sub.6H.sub.4OC.sub.6H.sub.5 9.85305 4.395 4.794 21 CH.sub.2C.sub.6H.sub.5 CH.sub.2S.sup. C.sub.6H.sub.4OC.sub.6H.sub.5 13.196498 6.539 6.657 22 CH.sub.2C.sub.6H.sub.5 CH.sub.2SH C.sub.6H.sub.4OC.sub.6H.sub.5 10.695544 6.405 6.531 23 Me CH.sub.2CO.sub.2H C.sub.6H.sub.4OC.sub.6H.sub.5 13.871861 3.486 3.306 24 Me CH.sub.2C.sub.6H.sub.5 C.sub.6H.sub.11 7.568168 3.524 3.086 25 Me CH.sub.2SH C.sub.6H.sub.11 11.109145 2.665 1.847 26 CH.sub.2C.sub.6H.sub.5 CH.sub.2SH C.sub.6H.sub.11 6.530526 2.605 1.555 27 Me CH.sub.2S.sup. C.sub.6H.sub.4OC.sub.6H.sub.5 12.82189 4.623 5.075 28 Me CH.sub.2SH C.sub.6H.sub.4OC.sub.6H.sub.5 9.953112 4.623 5.237 29 CH.sub.2C.sub.6H.sub.5 CH.sub.2S.sup. C.sub.6H.sub.4OC.sub.6H.sub.5 12.957148 6.031 5.598 30 CH.sub.2C.sub.6H.sub.5 CH.sub.2SH C.sub.6H.sub.4OC.sub.6H.sub.5 9.821999 6.433 6.576 31 Me C.sub.4H.sub.8NH.sub.2 C.sub.6H.sub.11 6.505873 1.3 2.821 32 Me C.sub.6H.sub.5 C.sub.6H.sub.11 7.825161 3.214 2.591 33 Me CH.sub.2C.sub.6H.sub.4OH C.sub.6H.sub.11 7.855433 2.626 2.563 34 Me C.sub.4H.sub.8NH.sub.2 C.sub.6H.sub.11 7.034941 1.115 2.688 35 Me C.sub.6H.sub.5 C.sub.6H.sub.11 7.160804 3.03 2.64 36 Me CH.sub.2C.sub.6H.sub.4OH C.sub.6H.sub.11 7.909279 2.793 2.837

(109) By way of indication, the chirality of the amino acid part is D for compounds 24 to 33 described above.

(110) Compounds 9, 15, 17 and 20, represented respectively by the chemical formulae and names below, have in particular advantageous docking score values: (S)-3-((S)-2-((R)-1-hydroxyethyl)but-3-enamido)-4-oxo-4-(4-phenoxy-phenylamino)butanoic acid

(111) ##STR00025## (S)-2-((R)-1-hydroxyethyl)-N((S)-1-oxo-1-(4-phenoxyphenylamino)-3-phenylpropan-2-yl)but-3-enamide

(112) ##STR00026## (S)N((R)-1-(cyclohexylamino)-3-mercapto-1-oxopropan-2-yl)-2-((R)-1-hydroxyethyl)but-3-enamide

(113) ##STR00027## (S)-2-((R)-1-hydroxyethyl)-N((R)-3-mercapto-1-oxo-1-(4-phenoxyphenyl-amino)propan-2-yl)but-3-enamide

(114) ##STR00028##

(115) However, other compounds of table 2 also have advantageous docking score values.

(116) The pharmacokinetic parameters important for in vivo activity were modeled by virtue of the QuickProp module of the Schrodinger suite. The parameters of some of the compounds of the invention tested are in agreement with a future evaluation in vivo; an oral absorption greater than 90% with an optimal intestine-blood passive transport and a very weak interaction with the Herg potassium channels responsible for cardiac toxicity, torsade de pointes, QT interval prolongation, etc.

LITERATURE REFERENCES

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