Pain relief compounds

Abstract

The present invention relates to the use of compounds for the treatment or prevention of pain in mammals, in particularly in human beings, and also to a process for preparing these compounds.

Claims

1. A compound of formula (A1): ##STR00056## wherein: R represents: ##STR00057## Q represents CN; X represents O, or NH; T represents: a hydrogen atom; a phenyl group; a group ##STR00058## a cyclohexyl group; Q.sup.2 represents O, or NH; or a pharmaceutically acceptable salt of said compound.

2. The compound according to claim 1, wherein: Q represents CN; Q.sup.2 represents O, or NH X represents O or NH T represents: a hydrogen atom; a phenyl group; a group ##STR00059##

3. The compound according to claim 1, wherein: Q.sup.2 represents O; X represents O; T represents H.

4. The compound according to claim 1 of formula (1b): ##STR00060## wherein Q.sup.2, Q, X and T are as defined in claim 1.

5. A method for treatment of pain comprising administering to a patient, a composition comprising a compound according to claim 1.

6. A method for treatment of pain comprising administering to a patient, a composition comprising a compound according to claim 2.

7. A method for treatment of pain comprising administering to a patient, a composition comprising a compound according to claim 1.

8. A method for treatment of pain comprising administering to a patient, a composition comprising a compound according to claim 3.

Description

EXAMPLE 1

(E)-2-cyano-3-(3,4-dihydroxyphenyl) 3-phenylprop-2-ynyl acrylate

(1) ##STR00029##

(2) Under argon, iodobenzene (8.9 mmol) was solubilized in a mixture of 1,2-dimehoxythane (10 mL) and water (10 mL). Next, were successively added potassium carbonate (21.7 mmol), copper iodide (0.36 mmol), triphenylphosphine (0.72 mmol) and 10% palladium on carbon (0.02 mmol Pd) and then left with stirring for 20 mins at room temperature. Propargylic alcohol was then added and the reaction mixture was brought to 80 C. for 18 h. After cooling, the reaction mixture was filtered on Celite and the filter evaporated in vacuum. Next, the residue was dissolved in 20 mL of ethyl acetate and 20 mL of water and the aqueous phase was extracted with ethyl acetate (320 mL), dried with magnesium sulfate, filtered and evaporated in vacuum. The crude product is purified on silica (10% cyclohexane ethyl acetate) and the alcohol is isolated (99%) in the form of a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.59-7.24 (m, 5H), 4.52 (s, 2H), 2.12 (se, 1H).

(3) Under argon, cyanoacetic acid (1.0 mmol) and the alcohol (0.8 mmol) were solubilized in 4 mL anhydrous dichloromethane and N,N-dicyclohexylcarbodiimide (1.0 mmol) and N,N-dimethylaminopyridine (cat.) were successfully added at 0 C. After total consumption of the acid (CLC), the formed white precipitate was filtered and the filtrate evaporated in vacuum. The residue was purified on silica, (SiO.sub.2, 20% ethyl acetatecyclohexane) and the ester was obtained as a colorless oil (52%). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.64-7.28 (m, 5H), 5.06 (s, 2H), 3.57 (s, 2H).

(4) Under argon, 3,4-dihydroxybenzaldehyde (0.45 mmol) and piperidine (cat.) were added on the 3-phenylprop-2-ynyl 2-cyanoacetate (0.45 mmol) solubilized in 4 mL of anhydrous dichloromethane. Next, at room temperature the reaction mixture was stirred until total consumption of the 3-phenylprop-2-ynyl 2-cyanoacetate (TLC). After adding an aqueous solution saturated with magnesium chloride, the organic phase was extracted with ethyl acetate (38 mL), dried with magnesium sulfate and filtered. After evaporation in vacuum of the solvent, the residue was purified on silica (SiO.sub.2, 30% ethyl acetatecyclohexane) and the (E-2-cyano-3-(3,4-dihydroxyphenyl) 3-phenylprop-2-ynyl acrylate ester was obtained in the form of a pale yellow solid (40%). .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.17 (s, 1H), 7.69-7.27 (m, 8H), 5.14 (s, 2H). HR-ESI-MS calculated for C.sub.19H.sub.13NO.sub.4 (M+Na.sup.+)=342.0732; found 342.0742.

EXAMPLE 2

(E)-2-cyano-3-(furan-3-yl) acrylic acid

(5) ##STR00030##

(6) Under argon, the cyanoacetic acid (7.05 mmol) was dissolved in anhydrous dichloromethane (10 mL); t-butanol (7.76 mmol), N,N-dicyclohexylcarbodiimide (7.05 mmol) were added at room temperature. After one hour, the precipitate was filtered in vacuum and the filtrate evaporated in vacuum. The residue was purified on silica (SiO.sub.2, 10% ethyl acetatecyclohexane) and a t-butyl ester was obtained in the form of a colorless oil (61%). .sup.1H NMR (400 MHz, CDCl.sub.3): : 3.39 (s, 2H), 1.51 (s, 9H).

(7) Under argon, the 3-furaldehyde (2.34 mmol) and the piperidine (cat.) were added on the butyl ester (2.12 mmol) solubilized in 15 mL of anhydrous dichloromethane. Mixed at room temperature, the reaction mixture was stirred until total consumption of the ester (TLC). After adding an aqueous solution saturated with ammonium chloride, the aqueous phase was extracted with ethyl acetate (38 mL), dried with magnesium sulfate and filtered. After evaporation in vacuum of the solvent, the residue was purified on silica (eluent: cyclohexane and ethyl acetate) and the alkene was obtained as a yellow powder (45%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.03 (s, 1H), 8.02-7.23 (m, 3H), 1.56 (se, 9H).

(8) Under argon, the alkene (0.29 mmol) was solubilized in (1 mL). After 1 h 30 mins of stirring at room temperature, the trifluoroacetic acid was evaporated in vacuum. The residue was triturated with ether and the ether was then evaporated in vacuum. The experiment was repeated 3 times and (E)-2-cyano-3-(furan-3-yl) acrylic acid as a pale yellow powder (90%) was obtained. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.28 (s, 1H), 8.26 (s .sup.1H, 1H), 7.73 (m, 1H), 7.27 (d, J=1.9 Hz, 1H). HR-ESI-MS calculated for C.sub.8H.sub.5NO.sub.3 (M+Na.sup.+)=186.0167; found 186.0170.

EXAMPLE 3

6.7-dihydroxy-1H-indole-2-carboxylic acid

(9) ##STR00031##

(10) DL-DOPA (5 mmol) was solubilized in water (500 mL). After 5 mins of stirring at room temperature, a solution of potassium ferricyanide (20 mmol) in 60 mL of water was added. Next, a 1 M soda aqueous solution was added until pH=13. After 20 mins of stirring under argon, the reaction mixture was acidified with a 6 M hydrochloric acid aqueous solution until pH=2 and the aqueous phase was extracted with ethyl acetate (3100 mL). The collected organic phases were dried and filtered in vacuum and a pale brown solid was obtained and washed with a saline solution containing 1 mmol of Na.sub.2S.sub.2O.sub.5 and then with a saline solution (2100 mL). The organic phase was dried with magnesium sulfate, filtered and evaporated in vacuum. The residue was purified on silica (SiO.sub.2, 90% ethyl acetate methanol) and 6,7-dihydroxy-1H-indole-2-carboxylic acid was obtained as a pale brown powder. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 6.95 (s, 1H); 6.93 (s, 1H); 6.82 (s, 1H).

EXAMPLE 4

(E)-2-carboxy-3-(3,4-dihydroxyphenyl)prop-2-en-1-ammonium chloride

(11) ##STR00032##

(12) Triethylphosphonoacetate (44.62 mmol) was added to a methanol solution (108 mL) containing paraformaldehyde (89.24 mmol) and piperidine (4.46 mmol). After 24 hours of refluxing, the solvent was evaporated in vacuum and the primary alcohol was obtained. The residue was solubilized in toluene (60 ml), treated with para-toluenesulfonic acid monohydrate (4.46 mmol) and the reaction mixture was refluxed in a Dean-Stark setup. After 16 h, the mixture was concentrated in vacuum and distilled under reduced pressure in order to obtain vinyl phosphonate as a pale yellow oil (92%). .sup.1H NMR (400 MHz, CDCl.sub.3): 6.82 (dd, J=2 Hz and J.sub.H-P=41.9 Hz, 1H), 6.62 (dd, J=2 Hz and J.sub.H-P=20.9 Hz, 1H), 4.18 (m, 6H), 1.36 (m, 3H), 1.33 (m, 6H).

(13) A solution of t-butoxycarbonylamine (5.08 mmol) in anhydrous tetrahydrofurane (7 ml) was added, with stirring, dropwise, to a suspension of sodium hydride (50% in the oil, 9.30 mmol) in anhydrous tetrahydrofurane (15 mL) under argon at 0 C. The reaction mixture was stirred for 30 mins at 0 C. and a solution of ethyl 2-diethoxyphosphoryl acrylate (4.23 mmol) in anhydrous tetrahydrofurane (7 mL) was added. The reaction was stirred for 1 h at room temperature. Water (20 mL) was then added to the reaction mixture. The latter was acidified to pH 5 with a 1 M hydrochloric acid aqueous solution. The aqueous phase was extracted with ethyl acetate (330 mL), dried with magnesium sulfate and evaporated in vacuum. Finally, the residue was purified by column chromatography (70% ethyl acetate/cyclohexane) in order to obtain the ethyl 3-t-butoxycarbonylamino-2-diethoxyphosphoryl-3-propionate as a colorless oil (62%). .sup.1H NMR (400 MHz, CDCl.sub.3): 5.10 (se, 1H), 4.15 (m 6H), 3.60 (m, 2H), 3.26 (td, J=23.0, 7.0 Hz, 1H), 1.40 (se, 9H), 1.33 (m, 6H), 1.25 (t, J=7.0 Hz, 3H).

(14) Under argon, a solution of ethyl 3-t-butoxycarbonylamino-2-diethoxyphosphoryl-3-propionate (6.56 mmol) in anhydrous tetrahydrofurane (11 mL) was added dropwise on sodium hydride (50% in a mineral oil, 9.2 mmol) suspended in anhydrous tetrahydrofurane (11 mL) at 0 C.

(15) The reaction mixture was stirred for 30 mins at 0 C. and then 3,4-bis(methoxymethoxy)benzaldehyde (5.05 mmol) was solubilized in anhydrous tetrahydrofurane (11 mL) which is added dropwise. After full consumption of the aldehyde (TLC), the reaction was stopped with water. The aqueous phase was extracted with ethyl acetate (320 mL), dried with magnesium sulfate and filtered. After evaporation in vacuum of the solvent, the residue was purified on silica by column chromatography (20% ethyl acetate cyclohexane) and the alkene (E) was obtained as a colorless oil (60%). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.69 (s, 1H), 7.15-7.33 (m, 3H), 5.25 and 5.28 (2s, 4H), 5.8 (se, 1H), 4.26 (q, J=7.0 Hz, 2H), 4.20 (d, J=7.0 Hz, 2H), 3.50 (s, 6H), 1.42 (se, 9H), 1.30 (t, J=7.0 Hz).

(16) The alkene E (0.642 mmol) was solubilized in methanol (2.5 mL) and then a 1M aqueous solution of lithium hydroxide (1.92 mmol) was added. After full consumption of the ester (TLC), the solvent was evaporated in vacuum. The aqueous phase was treated with a 1 M hydrochloric acid aqueous solution down to pH =2. Next, the aqueous phase was extracted with ethyl acetate (310 mL), dried with magnesium sulfate and filtered. After evaporation of the solvent in vacuum, the desired acid (91%) is obtained. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.69 (s, 1H), 7.15-7.33 (m, 3H), 5.25 and 5.28 (2s, 4H), 5.8 (se, 1H), 4.20 (d, J=7.0 Hz, 2H), 3.50 (s, 6H), 1.42 (se, 9H).

(17) To a solution of (E)-3-(3,4-bis(methoxymethoxy)phenyl)-2-((t-butoxy-carbonyl-amino)-methyl) acrylic acid (0.25 mmol) in methanol (50 mL) was added a 10% hydrochloric acid aqueous solution (10 mL). The reaction mixture was stirred for 2 days at room temperature. Next, the solvent was evaporated in vacuum and the residue was dissolved in 2 mL of dichloromethane and then methanol was added, causing precipitation of the compound. The precipitate was filtered under reduced pressure and (E)-2-carboxy-3-(3,4-dihydroxyphenyl)prop-2-en-1-ammonium chloride was obtained as a white powder (40%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 13.00 (s, 1H), 9.71 (se, 1H), 9.28 (se, 1H), 8.13 (se, 3H), 7.73 (s, 1H), 6.99 (d, J=1.7 Hz, 1H), 6.87 (d, J=1.7 Hz, 1H), 6.86 (dd, J=8.0, 1.7 Hz, 1H), 3.84 (se, 2H). HR-ESI-MS calculated for C.sub.10H.sub.12NO.sub.4(M+H.sup.+)=210.0766; found 210.0776.

EXAMPLE 5

(Z)-2-fluoro-3-phenylacrylic acid

(18) ##STR00033##

(19) To a freshly distilled solution of diisopropylamine (19.3 mmol) in anhydrous tetrahydrofurane (8 mL) was added 1.6 M n-butyl lithium (18.8 mmol) at 30 C. The solution was stirred for 30 mins at 30 C. It was then transferred into a solution consisting of ethyl 2-fluoroacetate (4.7 mmol) and of trimethylsilyl chloride (28.3 mmol) in 45 mL of anhydrous tetrahydrofurane, at 78 C. The reaction mixture was stirred and then left to return to 0 C. over a period of 4 h. The reaction mixture was treated with a saturated sodium carbonate solution (100 mL) at 0 C. The aqueous phase was extracted with ether (350 mL). The organic phase was dried on magnesium sulfate, filtered and then concentrated (20 mL). It was washed with a tartaric solution (50 mL) and stirred for 12 h at room temperature. The aqueous phase was extracted twice with ether (220 mL). The organic phases are collected and dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (SiO.sub.2, 10% diethyl ether/pentane) in order to lead to ethyl 2-fluoro-2-(trimethylsilyl)acetate as a colorless oil (800 mg, 95%). EI-MS (70 eV) mz: 178. .sup.1H NMR (400 MHz, CDCl.sub.3): 4.95 (d, J=48.1 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H), 0.18 (s, 9H).

(20) To a freshly distilled solution of diisopropylamine (2.57 mmol) in anhydrous tetrahydrofurane (13 mL) was added a 1.6 M solution de n-BuLi (2.57 mmol) 30 C.). La solution was stirred for 30 mins at 30 C. and then cooled to 78 C. Ethyl 2-fluoro-2-(trimethylsilyl)acetate (2.25 mmol), dissolved in anhydrous tetrahydrofurane (2 mL) was added to the formed LDA solution and the stirred for 40 mins at 78 C. followed by the addition of a solution of benzaldehyde (2.31 mmol) in anhydrous tetrahydrofurane (2 mL). The solution was brought to 78 C. until total disappearance of ethyl 2-fluoro-2-(trimethylsilyl)acetate (tracked by GC-MS). The reaction mixture was treated with a saturated solution of ammonium chloride (30 mL) at 0 C. The aqueous phase was extracted with ethyl acetate (320 mL). The collected organic phases are dried with magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% ethyl acetatecyclohexane) so as to lead to ethyl (Z)2-fluoro-3-phenylacrylate as a colorless oil (216.7 mg, 50%). EI-MS (70 eV): mz=194. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.65-7.31 (m 5H), 6.92 (d, J=35.2 Hz, 1H), 4.36 (q, J=7 Hz, 2H), 1.40 (t, J=7 Hz, 3H).

(21) The ester (1.12 mmol) was solubilized in methanol and a 1.5 M soda aqueous solution (2.23 mmol) is then added. After a full consumption of the ester (TLC), the solvent was evaporated in vacuum. The aqueous phase was treated with a 1M hydrochloric acid solution down to pH=2. Next, the aqueous phase was extracted with ethyl acetate (310 mL), tried with magnesium sulfate and filtered. After evaporation of the solvent in vacuum, the (Z)-2-fluoro-3-phenylacrylic acid was obtained as a white solid (91%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.75 (se, 1H), 7.67-7.38 (m, 5H), 7.07 (d, J=34.6 Hz, 1H). HR-ESI-MS calculated for C.sub.9H.sub.6O.sub.2F (MH.sup.+)=165.0352; found 165.0341

EXAMPLE 6

(E)-2-cyano-3-(1H-indol-2-yl)acrylic acid

(22) ##STR00034##

(23) Sulfuric acid (248 L) was added to a solution of indole-2-carboxylic acid (2.48 mmol) in absolute ethanol (8 mL). The reaction mixture was refluxed for 15 h, and sulfuric acid (248 L) was added. The reaction mixture was heated for a further 3 h. After cooling to room temperature, the solvent was evaporated under reduced pressure, the residue was dissolved in 10 mL of DCM, and the resulting solution was washed with a saturated sodium carbonate aqueous solution (320 mL), water (10 mL) and brine (10 mL). The organic phase is dried with magnesium sulfate, filtered, evaporated under reduced pressure in order to obtain a white powder (365.8 mg, 77%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.93 (s, 1H), 7.70 and 7.43 (2d, J=8.1 Hz, 2H), 7.36-7.24 (m, 2H), 7.16 (t, J=7.3 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H). A solution of ethyl 1H-indole-2-carboxylate (2.65 mmol) in anhydrous tetrahydrofurane (10 mL) was added dropwise to a cooled solution (0 C.), a lithium aluminium hydride (3.98 mmol) suspension in anhydrous tetrahydrofurane (10 mL) and the mixture was stirred for 2 h. The reaction was stopped by dropwise addition of (5 mL) and washed with water (20 mL). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, 40% ethyl acetate cyclohexane) in order to obtain a white powder (386.7 mg, 99%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.38 (se, 1H), 7.61 and 7.37 (2d, J=8.0 Hz, 2H), 7.21 and 7.13 (m, 2H), 6.43 (t, J=7.3 Hz, 1H), 4.84 (se, 2H), 1.93 (se, 1H).

(24) (1H-indol-2-yl) methanol (2.63 mmol) was dissolved in anhydrous tetrahydrofurane (40 mL) and treated with manganese oxide (30.24 mmol). After stirring for 18 h at room temperature, the reaction mixture was filtered and the filtrate concentrated under reduced pressure in order to obtain a brown powder (302 mg, 79%). .sup.1H NMR (400 MHz, CDCl.sub.3): 9.86 (s, 1H), 9.30 (se, 1H), 7.76 and 7.48 (2d, J=8.1 Hz, 2H), 7.40-7.19 (m, 2H), 7.29 (s, 1H).

(25) Under argon, cyanoacetic acid (7.05 mmol) was dissolved in anhydrous dichloromethane (10 mL); t-butanol (7.76 mmol) and N,N-dicyclohexylcarbodiimide (7.05 mmol) are added at room temperature. After 1 h, the precipitate formed was filered and the filtrate evaporated in vacuum. The residue was purified on silica (SiO.sub.2, 10% ethyl acetate cyclohexane) and the t-butyl ester is obtained as a colorless oil (61%). .sup.1H NMR (400 MHz, CDCl.sub.3): : 3.39 (s, 2H), 1.51 (s, 9H).

(26) Under argon, indole-2-carbaldehyde (1.91 mmol) and piperidine (cat.) are added on t-butyl 2-cyanoacetate (1.91 mmol) solubilized in 4 mL of anhydrous dichloromethane. Next, at room temperature, the reaction mixture was stirred until t-butyl 2-cyanoacetate was fully consumed (TLC). After adding a saturated ammonium chloride solution, the aqueous phase was extracted with ethyl acetate (38 mL), dried with magnesium sulfate and filtered. After evaporation in vacuum of the solvent, the residue was purified on silica (SiO.sub.2, 30% ethyl acetate/cyclohexane) and the ester is obtained as a yellow solid (69%). .sup.1H NMR (400 MHz, CDCl.sub.3): 9.50 (se, 1H), 8.09 (s, 1H), 7.67 and 7.46 (2d, J=8.1 Hz, 2H), 7.42-7.17 (m, 3H,), 1.59 (se, 9H).

(27) Under argon, the t-butyl ester (0.74 mmol) was solubilized in trifluoroacetic acid (3 mL). After 1 h 30 mins of stirring at room temperature, trifluoroacetic acid was evaporated in vacuum. The residue was triturated with ether followed by evaporation of the latter. The experiment was repeated 3 times and (E)-2-cyano-3-(1 H-indol-2-yl)acrylic acid was obtained as a pale yellow solid (78%). .sup.1H NMR (400 MHz, MeOD-d.sub.4): 11.17 (se, 1H), 8.27 (s, 1H), 7.68 and 7.46 (2d, J=8.2 Hz, 2H), 7.65 (s, 1H), 7.32 and 7.12 (2t, J=7.5 Hz, 2H). HR-ESI-MS calculated for C.sub.12H.sub.8N.sub.2O.sub.2 (MH.sup.+)=211.0508; found 211.0514.

EXAMPLE 7

(E)-tert-butyl 3-(4-(bis(benzyloxy)phosphoryloxy)phenyl)-2-cyanoacrylate

(28) ##STR00035##

(29) Under argon, N-chlorosuccinimide (1.05 mmol) was dissolved in anhydrous toluene (5 mL), and then benzyl phosphite (0.95 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature, and then filtered in order to remove the precipitate. The thereby obtained filtrate was concentrated under reduced pressure in order to obtain dibenzylphosphorochloridate as a colorless oil (95%).

(30) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.35 (bs, 10H), 5.25 (m, 4H).

(31) Under argon, cyanoacetic acid (7.16 mmol) and t-butanol (6.51 mmol) are dissolved in anhydrous dichloromethane (30 mL) and cooled to 0 C. DCC (7.16 mmol) and DMAP (cat.) are added to the solution. The medium is stirred for 4 hours at 0 C. and 1 h at room temperature. The reaction mixture is filtered, then concentrated under reduced pressure. The thereby obtained is purified by column chromatography (SiO.sub.2, 20% EtOAccyclohexane) in order to obtain the t-butyl ester as a colorless oil (86%).

(32) .sup.1H NMR (400 MHz, CDCl.sub.3): 4.23 (q, J=6.5 Hz, 2H, H-3), 3.44 (s, 2H, H-2), 1.28 (t, J=6.5 Hz, 3H, H-4).

(33) Under argon, 4-hydroxybenzaldehyde (0.53 mmol) and piperidine (cat.) were added to the t-butyl ester (0.53 mmol) solubilized in anhydrous dichloromethane. Next, the reaction mixture was stirred, at room temperature, until the ester is totally consumed (TLC). After adding a saturated ammonium chloride aqueous solution, the organic phase was extracted with ethyl acetate (38 mL), dried with magnesium sulfate and filtered. After evaporation in vacuum of the solvent, the residue was purified on silica (eluent: cyclohexane and ethyl acetate) in order to obtain the compound (E)-tert-butyl 2-cyano-3-(4-hydroxyphenyl)acrylate as a brown powder (71%).

(34) .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.13 (s, 1H, H-3), 7.96 (m, 2H, H-2 and H-6), 6.93 (m, 2H, H-3 and H-5), 1.58 (s, 9H, 3CH.sub.3).

(35) Under argon, to a solution of (E)-tert-butyl 2-cyano-3-(4-hydroxyphenyk)acrylate (0.41 mmol) in acetonitrile (2 mL), were successively added at room temperature, dibenzyl chlorophosphonate (0.61 mmol) and then potassium carbonate (1.64 mmol). The reaction mixture was stirred for 5 days, and then treated by adding an aqueous solution. The aqueous phase was extracted with ethyl acetate (38 mL), dried with magnesium sulfate and filtered. After evaporation in vacuum of the solvent, the residue was purified on silica (SiO.sub.2, EtOAccyclohexane) and the compound is obtained as a colorless oil (20%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.09 (s, 1H), 7.90 (d, J=8.8 Hz, 2H), 7.38-7.29 (m, 10H), 7.21 (d, J=8.3 Hz, 2H,), 5.13 (d, J.sub.P,H=10.5 Hz, 4H), 1.59 (s, 9H).

EXAMPLE 8

Evaluation of the Activation of TREK-1 Channels bt the Compounds According to the Invention

(36) Xenope ovocytes without their follicle cells are injected with 50 ng of cRNA coding for the TREK-1 channel.

(37) 18-24 h after injection, the TREK-1 currents are recorded with the double electrode technique. In a perfusion chamber of 0.3 mL, the ovocyte is impaled with two standard microelectrodes (resistance 1-2.5 M) filled with a 3M KCl solution and maintained at an imposed voltage by means of a Dagan TEV 200 amplifier in a ND96 standard solution (96 mM NaCl, 2 mM KCl, 1.8 mM CaCl.sub.2, 2 mM MgCl.sub.2, 5 mM HEPES, pH 7.4 with NaOH) for 3 mins. And then a solution of the compound (20 nM) is perfused for 15 minutes, followed by rinsing with ND96 for 6 minutes. Stimulation of the preparation, data acquisition and analyses are carried out by using the software package pClamp. The results are shown in Table 1.

(38) TABLE-US-00001 TABLE 1 R (in Compound vitro) 2.87 1.31 2.2 1.43 0 2.44 1.44 1.12 1.14 1.20 1.22
The results show that the compounds according to the invention have the property of activating the TREK-1 channels.

EXAMPLE 9

Evaluation of the Analgesic Effect of the Compounds According to the Invention

(39) The animals (mice weighing 15-20 g) are pretreated with the compound (10 mg/kg) or the carrier (control) 15 mins before injecting acetic acid (0.6% solution, 10 mL/kg) into the peritoneal cavity of the animal where it activates the nociceptors directly and/or causes an inflammation of the viscera (subdiaphragmatic organs) and subcutaneous (muscle wall) inflammation of the tissues. The number of induced abdominal cramps, determined for 15 mins after injection of acetic acid is used as a pain parameter. Pain inhibition (an analgesic effect) is determined by comparing the number of induced cramps in the presence and in the absence of the molecules.

(40) The results are shown in Table 2.

(41) TABLE-US-00002 TABLE 2 Inhibi- tion of pain in % Compound (in vivo) 50 51 22 31 0 26 34 45 55 43 27

(42) The results show that the compounds according to the invention have significant pain inhibition properties.