Indian Patents. 249627:ARYLOXYALKYLCARBAMATE COMPOUNDS, PREPARATION METHOD THEREOF AND COMPOSITION COMPRSING THEM

Title of Invention	ARYLOXYALKYLCARBAMATE COMPOUNDS, PREPARATION METHOD THEREOF AND COMPOSITION COMPRSING THEM
Abstract	The invention discloses a compound conforming to the formula (I) wherein X, Y, R1, R2, R3. R4, m, n and p are as defined in the specification. The invention is also for a process for preparation of said compound and pharmaceutical composition comprising it.

Full Text	The invention relates to aryloxyalkyl- carbamate derivatives, to their preparation and to their application in therapy. The compounds of the invention conform to the general formula (I): in which m represents 0, 1, 2 or 3; n represents 0, 1, 2 or 3; X represents an oxygen or sulphur atom or an SO or SO2 group; — R1 and R2 represent independently of one another a hydrogen atom or a C1-3 alkyl group, or R1 and R2 together form a group -(CH2)P-, where p represents an integer ranging from 1 to 5 such that n + p is an integer ranging from 2 to 5; R3 represents a hydrogen or fluorine atom or a hydroxyl or methyl group; R4 represents a group of general formula CHR5CONHR6 in which R5 represents a hydrogen atom or a C1-6 alkyl group and R6 represents a hydrogen atom or a C1-6 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl-C1-6 alkylene group; Y represents a group Y1 selected from in particular a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, naphthyl, guinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl and benzothiadiazolyl; the group Y1 being optionally substituted by one or more substituents Y2, which are identical to or different from one another, or by a group Y3 ; Y2 represents a halogen atom or a cyano, nitro, C1-8 alkyl, C1-8 alkoxy, C1-8 thioalkyl, C1-8 fluoroalkyl, C1-8 fluoroalkoxy, C1-8 fluorothioalkyl, C3-7 cycloalkyl, C3-7 cycloalkyloxy, C3-7 cycloalkyl-C1-8 alkylene, C3-7 cycloalkyl-C1-8 alkyloxy, hydroxyl, NR7R8, NHCOR7, NHSO2R7, COR7, CO2R7, CONR7R8, SO2R7, SO2NR7R8, -O- (C1-3 alkylene)-O-, phenyloxy, phenylthio, phenyl-C1-C8 alkylene, phenyl-Ci-C8 alkyloxy or phenyl-Ci-C8 alkylthio group; Y3 represents a group selected from in particular a phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; it being possible for the group or groups Y3 to be substituted by one or more groups Y2 which are identical to or different from one another; R7 and R8 represent independently of one another a hydrogen atom or a Ci-6 alkyl group, or with the nitrogen atom carrying them form an azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine or piperazine ring optionally substituted by a C1-3 alkyl or benzyl group. Among the compounds of general formula (I) a first group of compounds is that for which: Y represents a group Yi selected from in particular a phenyl, pyridinyl, pyrimidinyl, thiazolyl, naphthyl, quinolinyl, isoquinolinyl and benzoxazolyl; the group Yi being optionally substituted by one or more substituents, more particularly by one or two substituents, Y2, which are identical to or different from one another, or by a group Y3; Y2 represents a halogen atom, more particularly a chlorine, a fluorine or a bromine, a cyano, Ci.8 alkyl, more particularly a methyl, isopropyl, butyl, tert-butyl or tetramethylbutyl, Ci_8 alkoxy, more particularly a methoxy, ethoxy or propoxy, Ci-8 fluoroalkyl, more particularly a trifluoromethyl, Ci-8 fluoroalkoxy, more particularly a trifluoromethoxy, phenyloxy or phenyl-Ci-C8 alkylene group, more particularly a phenyl(1,1-dimethylmethylene); Y3 represents a phenyl group; it being possible for Y3 to be substituted by one or more groups, more particularly by one or two groups, Y2 which are identical to or different from one another. Among the compounds of the first group as defined above a second group of compounds is that for which: ^ Y represents a group Yx selected from in particular a phenyl or a naphthyl; the group Y3. being optionally substituted by one or more substituents, more particularly by one or two substituents, Y2, which are identical to or different from one another, or by a group Y3; Y2 represents a halogen atom, more particularly a chlorine, a fluorine or a bromine, a cyano, Ci_8 alkyl, more particularly a methyl, isopropyl, butyl, tert-butyl or tetramethylbutyl, Ci.8 alkoxy, more particularly a methoxy, ethoxy or propoxy, Ci-8 fluoroalkyl, more particularly a trifluoromethyl, Ca-s fluoroalkoxy, more particularly a trifluoromethoxy, phenyloxy or phenyl-Ci-C8 alkylene group, more particularly a phenyl(1,1-dimethylmethylene); Y3 represents a phenyl group; it being possible for Y3 to be substituted by one or more groups, more particularly by one or two groups, Y2 which are identical to or different from one another. Among the compounds of general formula (I) a third group of compounds is that for which: m represents 0, 1, 2 or 3; and/or n represents 0, 1,-2 or 3; and/or Ri and R2 represent independently of one another a hydrogen atom or a Ci_3 alkyl group, or Ri and R2 together form a group -(CH2)P-, where p represents an integer ranging from 1 to 5 such that n + p is an integer ranging from 2 to 5; with the proviso that, when Ri and R2 represent independently of one another a hydrogen atom or a Ci_3 alkyl group, m + n > 1. Among the compounds of the third group as defined above, a fourth group of compounds is that for which: m represents 0, 1, 2 or 3; and/or n represents 0, 1, 2 or 3; and/or Ri and R2 together form a group -(CH2)P-, where p represents an integer ranging from 1 to 4 such that n + p is equal to 4.— Among the compounds of general formula (I), a fifth group of compounds is that for which X represents an oxygen atom. Among the compounds of general formula (I), a sixth group of compounds is that for which R3 represents a hydrogen atom. A seventh group is formed of the compounds for which simultaneously Rlf R2, R3, R4, R5, R6, R7, Rs/ X, Y, Yi, Y2/ Y3/ n and m are as defined in the subgroups of compounds above. The compounds of general formula (I) may include one or more asymmetric carbons. They may exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including the racemic mixtures, form part of the invention. The compounds of formula (I) may exist in the form of bases or of addition salts with acids. Such-———-- - addition salts form part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, although the salts of other acids which are of use, for example, for purifying or isolating compounds of formula (I) likewise form part of the invention. The compounds of general formula (I) may be in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates likewise form part of the invention. In the context of the invention the terms are understood as follows: Ct-z/ where t and z may take the values from 1 to 8, is a carbon chain which may have from t to z carbon atoms; for example, Ci_3 is a carbon chain which may have from 1 to 3 carbon atoms; alkyl is a saturated, linear or branched aliphatic group; for example, a C3.-3 alkyl group represents a linear or branched carbon chain of 1 to 3 carbon atoms, more particularly a methyl, ethyl, propyl or 1-methylethyl; alkylene is a saturated, linear or branched divalent alkyl group; for example, a C1-3 alkylene group represents a linear or branched, divalent carbon chain of 1 to 3 carbon atoms, more particularly a methylene, ethylene, 1-methylethylene, propylene or 1,1-dimethyl- methylene; cycloalkyl is a cyclic alkyl group; for example, a C3.5 cycloalkyl group represents a cyclic carbon group of 3 to 5 carbon atoms, more particularly a cyclopropyl, cyclobutyl or cyclopentyl; alkenylene is a divalent unsaturated aliphatic group containing 2 carbons, more particularly an ethylene; alkoxy is an -O-alkyl group having a saturated, linear or branched aliphatic chain; thioalkyl is an -S-alkyl group having a saturated linear or branched aliphatic chain; fluoroalkyl is an alkyl group in which one or more hydrogen atoms have been substituted by a fluorine atom; fluoroalkoxy is an alkoxy group in which one or more hydrogen atoms have been substituted by a fluorine atom; fluorothioalkyl is a thioalkyl group in which one or more hydrogen atoms have been substituted by a fluorine atom; and a halogen atom is a fluorine, a chlorine, a bromine or an iodine. The compounds of the invention may be prepared according to different methods, which are illustrated by the schemes which follow. Thus one method of preparation (Scheme 1) consists in reacting an amine of general formula (II), in which Y, X, Ri, R2, R3, m and n are as defined in the general formula (I.) , with a carbonate of general formula (III), in which Z represents a hydrogen atom or a nitro group, R5 is as defined in the general formula (I) and R represents a methyl or ethyl group, in a solvent such as toluene or dichloroethane, at a temperature of between 0 and 80°C . The resultant carbamate esters of general formula (IV) are subsequently converted into compounds of general formula (I) by aminolysis, by means of an amine of general formula R6NH2 where R6 is as defined in the general formula (I). The aminolysis reaction may be carried out in a solvent such as methanol or ethanol, or a mixture of solvents such as methanol and tetrahydrofuran. Another method (Scheme 2) of obtaining the compounds of general formula (I) in which R2 represents more particularly a hydrogen atom consists in reacting a derivative of general formula (Ila) in which W represents a hydroxyl, mesylate or tosylate group or a chlorine, bromine or iodine atom, and in which Y, X, Ri, R3, m and n are as defined in the general formula (I), with an oxazolidine dione of general structure (V), in which R5 is as defined in the general formula (I), to give the oxazolidine dione derivative of general structure (VI). In the case where W represents a hydroxyl group the reaction may be conducted according to the conditions of Mitsunobu (Synthesis, 1981, 1-28) ; for example, by the action of diethyl or diisopropyl azodicarboxylate in the presence of triphenylphosphine. In the case where W represents a chlorine, bromine or iodine atom or a mesylate or tosylate group the reaction may be conducted in the presence of a base such as 1,1,3,3-tetramethylguanidine, sodium hydride or sodium tert-butoxide in a solvent such as tetrahydrofuran, acetonitrile or dimethylformamide at a temperature of between 0°C and the reflux temperature of the solvent. The resultant oxazolidine dione derivative of general formula (VI) is subsequently converted into a compound of general formula (I) by aminolysis, by means of an amine of general formula R6NH2 where R6 is as defined in the general formula (I) . Another variant (Scheme 3), for obtaining the compounds of general formula (I) in which X represents more particularly an oxygen atom, consists in reacting an alcohol derivative of general formula (Vila), (Vllb) or (VIIc) with a phenol derivative of general structure YOH, in which the Y is as defined in the general formula (I), for example in accordance with the Mitsunobu reaction conditions (Synthesis, 1981, 1-28) or modified conditions (Tetrahedron Letters 1993, 34, 1639-1642), the carbamate ester (IVa) and oxazolidine dione (Via) derivatives being subsequently converted into compounds of general formula (I) by aminolysis reaction by means of an amine of general structure R6NH2 where R6 is as defined in the general formula (I). In the general formulae (Vila), (Vllb) and (VIIc) , the groups Ri, R2, R3, R5, R6, m, n and R are as defined above. Scheme 3 Another variant (Scheme 4) for obtaining the compounds of general formula (I) in which Y represents more particularly a group Yx-Y3 of aryl-aryl, aryl- heteroaryl, heteroaryl-aryl or heteroaryl-heteroaryl type, consists in reacting an aryl halide derivative of general structure (VIII), in which U is a bromine or iodine atom and Yi, X, Ri, R2/ R3, R5, R6, n and m are as defined in the general formula (I), with an arylboronic or heteroarylboronic acid derivative of formula Y3B(OH)2, where Y3 is as defined in the general formula (I), in accordance with the Suzuki reation conditions (Chem. Rev. 1995, 9_5, 2457-2483) or with an aryl- or heteroaryl-tri-alkylstannane derivative of formula Y3Sn(R')3/ where Y3 is as defined in the general formula (I) and R' is a Ci_4 alkyl, in accordance with the ^— Stille reaction conditions (Angew. Chem. Int. Ed. 1986, 25, 504-524). The compounds of general formulae (II) , (Ha) , (III), (V), (Vila), (Vllb) , (VIIc) and (VIII) and the phenol derivatives of general structure YOH, when the method by which they are prepared is not described, are available commercially or are described in the literature, or else may be prepared according to methods which are described therein or which are known to the person skilled in the art. The amines of general formula R6NH2 are available commercially. The examples which follow illustrate the preparation of some compounds of the invention. These examples are not limitative, and merely illustrate the invention. The microanalyses, the IR and NMR spectra and/or the LC-MS (Liquid Chromatography coupled to Mass Spectroscopy) confirm the structures and purities of the compounds obtained. m.p. (°C) represents the melting point in degrees Celsius. The numbers indicated in parentheses in the titles of the examples correspond to those from the 1st column of the table thereafter. The IUPAC (International Union of Pure and Applied Chemistry) nomenclature has been used for naming the compounds in the following examples. For example, for the biphenyl group, the following numbering has been respected: Example 1 (Compound 1) 2-(methylamino)-2-oxoethyl {2-[(4-chlorophenyl)- oxy]ethyl}carbamate 1.1 ethyl [(phenyloxycarbonyl)oxy]acetate A solution of 25 g (240 mmol) of ethyl glycolate and of 55 ml (315 mmol) of diisopropylethylamine in 500 ml of toluene is admixed slowly at ambient temperature with 32 ml (256 mmol) of phenyl chloroformate. Stirring is continued at ambient temperature for 2 hours. The salt formed is separated off and the filtrate is concentrated under reduced pressure. This gives 53.7 g of oily product, used as it is in the following step. 1.2. ethyl {[({2-[(4-chlorophenyl)oxy]ethyl}- amino)carbonyl]oxy}acetate A solution of 0.6 g (3.5 mmol) of [(4-chloro- phenyl) oxy] ethylamine (Chim. Ther. 1973, £, 259-270) and 1.3 g (5.8 mmol) of ethyl [(phenyloxy- carbonyl)oxy]acetate, prepared in Step 1.1., in 3 0 ml of toluene is heated at 60°C overnight. It is evaporated to dryness and the product is purified by chromatography on silica gel, eluting with a 30/70 mixture of ethyl acetate and cyclohexane. This gives 0.7 g of oily product, containing -10% of cyclized oxazolidine dione product, used as it is in the following step. 1.3. 2-(methylamino)-2-oxoethyl {2-[(4- chlorophenyl)oxy]ethyl}carbamate 3.5 ml (7 mmol) of a 2M solution of' methylamine in tetrahydrofuran are added to a solution of 0.7 g (2.3 mmol) of ethyl {[({2-[(4-chlorophenyl)- oxy]ethyl}amino)carbonyl]oxy}acetate, prepared in Step 1.2., in 5 ml of methanol. The mixture is left to react at ambient temperature overnight. It is evaporated to dryness and the residual solid is washed v_„ with hexane and then with diisopropyl ether, to give 0.59 g of product in powder form. Melting point (°C): 147-149 LC-MS: M+H = 287 XH NMR (DMSO) 5(ppm): 7.75 (m, 1H), 7.40 (m, 1H), 7.25 (d, 2H) , 6.95 (d, 2H), 4.35 (s, 2H), 3.95 (t, 2H), 3.35 (m, 2H), 2.60 (d, 3H). Example 2 (compound 11) 2 - amino-2 -oxoethyl (2-[(4-cyanophenyl)oxy]ethyl)- carbamate 2.1 3-(2-hydroxyethyl)-1,3-oxazolidine- 2,4-dione A solution of 3 ml (39.6 mmol) of methyl glycolate in 25 ml of tetrahydrofuran is added dropwise over 2 hours to a solution of 49 ml (95 mmol) of phosgene, 1.9M in toluene, which is diluted in 50 ml of tetrahydrofuran and cooled using an ice bath. The mixture is subsequently stirred at ambient temperature for 16 hours and evaporated to dryness. Coevaporation is carried out 4 times with 3 0 ml of dichloromethane. The residue is taken up with 4 0 ml of acetonitrile and added dropwise over 1 hour to a solution of 3.4 ml (59.4 mmol) of ethanolamine and 30 ml (178 mmol) of diisopropylethylamine in a 50/10 mixture of acetonitrile and dichloromethane, cooled using an ice bath. The mixture is subsequently stirred at ambient temperature for 16 hours. It is filtered over celite and evaporated to dryness and the product is purified by chromatography on silica gel, eluting with a 70/3 0 then 80/20 mixture of ethyl acetate and n-hexane, to give 4.9 g of product in white solid form. 2.2. 2-amino-2-oxoethyl (2-[(4-cyanopheny1)- oxy]ethyl)carbamate 0.61 ml (1.35 mmol) of a 2.2M solution of diethyl azodicarboxylate in toluene is added dropwise to a solution of 0.13 g (0.88 mmol) of 3-(2- hydroxyethyl)-1,3-oxazolidine-2,4-dione, prepared in Step 2.1., 0.35 g (1.35 mmol) of triphenylphosphine and 0.10 g (0.89 mmol) of 4-hydroxybenzonitrile in 2 ml of benzene, cooled using an ice bath. The reaction mixture is subsequently stirred at ambient temperature for 16 hours. It is evaporated to dryness and the product is purified by chromatography on silica gel, eluting with a 99/1 then 98/2 mixture of dichloromethane and ethyl acetate. The product is taken up in 1.5 ml of a 7M solution of ammonia (10.5 mmol) in methanol. This solution is stirred for one hour. The precipitate is filtered off and washed with ethyl acetate, to give 0.035 g of white solid. ' Melting point (°C): 204-206 LC-MS: M+H = 264 XH NMR (DMSO) 8(ppm): 7.55 (d, 2H), 7.05 (m, 1H), 6.90- 6.80 (m+d, 4H), 4.35 (s, 2H), 4.05 (t, 2H), 3.45 (m, 2H) Example 3 (compound 58) 2-amino-2-oxoethyl [4-(1-naphthalenyloxy]butyl]- carbamate 3.1. 3-[4-(1-naphthalenyloxy]butyl]-1,3- oxazolidine-2,4-dione A solution of 3.1 g (11.1 mmol) of l-[(4- bromobutyl)oxy]naphthalene (Eur. J. Med. Chem. 1997, 32, 175-179) and 1.35 g (13.3 mmol) of 1,3-oxazolidine- 2,4-dione (J. Med. Chem. 1991, 34, 1542-1543) in 30 ml of tetrahydrofuran is admixed dropwise with a solution of 2.55 g (22.2 mmol) of 1,1,3,3-tetramethylguanidine in 15 ml of tetrahydrofuran. The mixture is heated at reflux for 8 hours. 0.28 g (2.7 mmol) of 1,3-oxazolidine-2,4-dione and 0.32 g (2.7 mmol) of 1,1,3,3-tetramethylguanidine are added and the mixture is heated at reflux for 4 more hours. The reaction mixture is cooled using an ice bath, and 100 ml of ethyl acetate and then 50 ml of 1M aqueous hydrochloric acid are added. The system is decanted and the aqueous phase is extracted with 2 x 80 ml of ethyl acetate. The organic phases are subsequently washed with 80 ml of water and then with 80 ml of saturated aqueous sodium chloride solution. They are dried over sodium sulphate and then evaporated to dryness. The product is purified by chromatography on silica gel, eluting with an 80/20 mixture of cyclohexane and ethyl acetate, to give 2.0 g of product, which is used as it is in the following step. 3.2. 2-amino-2-oxoethyl [4-(1-naphthalenyl- oxy)butyl]carbamate 1.50 g (5.0 mmol) of 3-[4-(1-naphthalenyl- oxy) butyl] -1, 3-oxazolidine-2 , 4-dione, prepared in Step 3.1., are dissolved in a mixture of 10 ml of tetrahydrofuran and 2 8 ml of a 7N solution of ammonia (200 mmol) in methanol. The solution is left to react overnight at ambient temperature and then evaporated to dryness. The product is purified by chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol. It is recrystallized from ethyl acetate and then washed with diethyl ether, to give 0.73 g of product in white solid form. Melting point (°C): 80-82 LC-MS: M+H =317 XH NMR (CDC13) (J(ppm) : 8.25 (dd, 1H) , 7.80 (dd, 1H) , 7.55-7.30 (m, 4H), 6.80 (d, 1H), 6.00 (m, 1H), 5.65 (m, 1H), 5.05 (m, 1H), 4.65 (s, 2H), 4.20 (t, 2H), 3.35 (m, 2H), 2.00 (m, 2H), 1.90 (m, 2H) Example 4 (compound 85) 2-(methylamino)-2-oxoethyl 4-[(4'-fluoro-4-biphenyl)- oxy]-1-piperidinecarboxylate 4.1. 1,1-dimethylethyl 4-[(4-bromophenyl)- oxy]-1-piperidinecarboxylate A solution of 2.01 g (10 mmol) of 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate in 20 ml of dimethylformamide is admixed with 7 g (40 mmol) of l-bromo-4-fluorobenzene and 2.5 g (50 mmol) of sodium hydride at 50% in mineral oil. The mixture is stirred at 100°C for 3 hours and then evaporated to dryness. The residue is taken up in 50 ml of ice-water and extracted with dichloromethane. The organic extracts are evaporated to dryness, to give 3.5 g of an oily product, which is used as it is in the following step. 4.2. 4-[(4-bromophenyl)oxy]piperidine A solution of 3.5 g (9.83 mmol) of 1,1- dimethylethyl 4-[(4-bromophenyl)oxy]-1-piperidine- carboxylate, prepared in Step 4.1., in 2 0 ml of dichloromethane is admixed with 10 ml of trifluoroacetic acid and the solution is stirred at ambient temperature for 1 hour. It is evaporated to dryness and then the residue is taken up in 3 0 ml of toluene, which is evaporated again to dryness. The residue is subsequently washed with pentane and then taken up in a mixture of 60 ml of dichloromethane and 20 ml of 4N aqueous ammonia solution. It is stirred vigorously for 15 minutes and then the organic phase is decanted, dried over sodium sulphate and evaporated to dryness, to give 2.7 g of product in oil form, which is used as it is in the following step. 4.2. 2- (ethyloxy) -2-oxoethyl 4- [ (4-bromo- _^-' " phenyl)oxy]-1-piperidinecarboxylate 2.7 g (7.58 mmol) of 4-[ (4-bromophenyl) - ^s^' oxy]piperidine, prepared in Step 4.2., and 1.70 g (7.6 mmol) of ethyl {[(phenyloxy)carbonyl]oxy}acetate, prepared in accordance with Example 1.1, are mixed in 40 ml of toluene and the solution is heated at 50°C for 20 hours. After cooling, it is evaporated to dryness and the product is purified by chromatography on silica gel, eluting with a 40/60 mixture of ethyl acetate and cyclohexane. The eluate is subsequently triturated in diisopropyl ether, to give 2.9 g of product in powder form. —....- Melting point (°C): 87-88 4.3. 2-(methylamino)-2-oxoethyl 4-[(4-bromophenyl)oxy]-1-piperidinecarboxylate 2.9 g (7.5 mmol) of 2-(ethyloxy)-2-oxoethyl 4-[(4-bromophenyl)oxy]-1-piperidinecarboxylate, prepared in Step 4.3., in solution in 10 ml of a 33% ethanolic solution of methylamine are stirred at ambient temperature for 20 hours. Following evaporation, the product is purified by chromatography on silica gel, eluting with ethyl acetate, to give ^ . 0.8 g of product in gum form, which is used as it is in the following step. 4.5. 2-(methylamino)-2-oxoethyl ^^ 4- [ (4'-fluoro-4-biphenyl)oxy]-1-piperidinecarboxylate 0.1 g (0.27 mmol) of 2-(methylamino)- 2-oxoethyl 4-[(4-bromophenyl)oxy]-1-piperidine- .^" carboxylate, prepared in Step 4.4., 0.01 g of tetrakis(triphenylphosphine)palladium(0) and 0.057 g (0.4 mmol) of 4-fluorophenylboronic acid are placed in a glass tube with stopper. 4 ml of toluene, 2 ml of a 2N aqueous solution of sodium carbonate and 0.5 ml of ethanol are added. The mixture is heated at 8 0°C with stirring for 2 hours. After it has cooled, 1 ml of water and 2 ml of toluene are added. The organic phase is withdrawn and the product is purified by chromatography on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol. The product is redissolved in 1 ml of ethanol and then reprecipitated by adding 2 ml of water, to give 0.031 g of product in powder form. Melting point (°C) : 117-119 v— "' LC-MS: M+H 3 87 XH NMR (CDC13) 5(ppm): 7.70 (dd, 2H) , 7.65 (d, 2H) , 7.30 (dd, 2H) , 7.20 (d, 2H) , 6.25 (broad s, 1H) , 4.80 (s + m, 3H) , 4.00-3.70 (m, 4H) , 3.05 (d, 3H), 2.25-2.00 (m, 4H) Example 5 (compound 12 0) 2-(methylamino)-2-oxoethyl 4-{[(4-bromophenyl)oxy] - methyl}-l-piperidinecarboxylate 5.1. 1,1-dimethylethyl 4-{[(4-bromophenyl)- oxy]methyl}-1-piperidinecarboxylate The procedure described in Example 4.1. is repeated. Starting from 2.5 g (11.6 mmol) of 1,1-dimethylethyl 4-(hydroxymethyl)-1-piperidine- carboxylate and 8.13 g (4 6.4 mmol) of 1-bromo- 4-fluorobenzene gives 5.75 g of crude product in oil form. 5.2. 4-{ [ (4-bromophenyl)oxy]methyl}piperidine The procedure described in Example 4.2 is repeated. Starting from 5.75 g of 1,1-dimethylethyl 4-{ [ (4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate, prepared in Step 5.1, gives 3 g of product in oil form. 5.3. 2-(ethyloxy)-2-oxoethyl 4-{[(4- bromophenyl)oxy]methyl}-1-piperidinecarboxylate The procedure described in Example 4.3. is repeated. Starting from 1.6 g (5.9 mmol) of 4-{[(4- bromophenyl)oxy]methyl}piperidine, prepared in Step 5.2., and from 1.32 g (5.9 mmol) of ethyl {t(phenyloxy)carbonyl]oxy}acetate, prepared in accordance with Example 1.1., gives the product in oil form. 5.4. 2-(methylamino)-2-oxoethyl 4-{[(4- bromophenyl)oxy]methyl}-1-piperidinecarboxylate The procedure described in Example 4.4. is repeated. Starting from 2-(ethyloxy)-2-oxoethyl 4-{[(4- bromophenyl)oxy]methyl}-1-piperidinecarboxylate, prepared in Step 5.3, gives 1.1 g of product in powder form. Melting point (°C): 163-165 LC-MS: M+H = 386 XH NMR (CDC13) 8(ppm): 7.35 (d, 2H) , 6.75 (d, 2H) , 6.05 (broad s, 1H), 4.70-4.50 (m, 2H), 4.30-4.10 (m, 2H) , 3.80 (d, 2H), 3.00-2.75 (m, 2H), 2.85 (d, 3H), 2.10-1.80 (m, 3H), 1.45-1.20 (m, 2H) Example 6 (compound 154) 2-(methylamino)-2-oxoethyl 4-{[(4'-(trifluoromethyl)- 4-biphenyl)oxy]methyl}-1-piperidinecarboxylate The procedure described in Example 4.5. is repeated. Starting from 0.1 g (0,26 mmol) of 2-(methylamino)-2- oxoethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidine- carboxylate, prepared in accordance with Example 5, and from 0.074 g (0.389 mmol) of 4-trifluoromethylphenyl- boronic acid gives 0.049 g of product in powder form. Melting point (°C): 197-199 LC-MS: M+H =451 XH NMR (DMSO) 8(ppm) : 7.85-7.65 (m, 7H) , 7.05 (d, 2H) , 4.35 (s, 2H) , 4.05 (broad d, 2H), 3.90 (d, 2H), 2.85 (m, 2H), 2.60 (d, 3H), 2.00 (m, 1H), 1.80 (broad d, 2H), 1.35-1.10 (m, 2H). Example 7 (compound 137) 2-amino-2-oxoethyl 4-[(l-naphthalenyloxy)methyl]- 1-piperidinecarboxylate 7.1. 1,1-dimethylethyl 4-[(1-naphthalenyl- oxy)methyl]-1-piperidinecarboxylate A solution of 5.0 g (23.2 mmol) of 1,1- dimethylethyl 4-(hydroxymethyl)-1-piperidine- carboxylate, 4.3 g (2 9.8 mmol) of 1-naphthalenol and 7.82 g (29.8 mmol) of triphenylphosphine in 12 0 ml of tetrahydrofuran, cooled under nitrogen by means of an ice bath, is admixed dropwise with a solution of 6.03 g (29.8 mmol) of diisopropyl azodicarboxylate. The reaction mixture is allowed to return to ambient temperature and stirring is continued overnight. 2 ml of methanol are added and then the mixture is evaporated to dryness. The residue is taken up in 2 00 ml of dichloromethane and washed in succession with a 10% aqueous potassium hydrogen sulphate solution, water and a 1M aqueous solution of sodium hydroxide. The system is dried over sodium sulphate and evaporated to dryness. The product is purified by chromatography on silica gel, eluting with an 80/20 then 70/30 and 50/50 mixture of cyclohexane and dichloromethane, to give 7.96 g of product in oil form, which solidifies. Melting point (°C): 97-100 7.2. 4- [ (1-naphthalenyloxy)methyl]piperidine A solution of 7.96 g (29.1 mmol) of 1,1-dimethylethyl 4-[(1-naphthalenyloxy)methyl]- 1-piperidinecarboxylate, prepared in Step 7.1., in 120 ml of methanol and 2 8 ml of 35% aqueous hydrochloric acid is heated at 60°C for 6 hours. It is cooled to ambient temperature and evaporated to dryness, and then coevaporation is carried out twice with ethanol. The solid residue is washed with diethyl ether and then dried under vacuum in the presence of phosphorus pentoxide, to give 3.1 g of white solid. The solid is taken up in 80 ml of water and a 3 0% aqueous sodium hydroxide solution is added until a basic pH is obtained, after which the system is extracted twice with 150 ml of diethyl ether. The extracts are dried over sodium sulphate and concentrated to dryness, to give 2.75 g of oily product, which is used as it is in the following step. 7.3. 2-(ethyloxy)-2-oxoethyl 4-[(l- naphthalenyloxy)methyl]-1-piperidinecarboxylate A solution of 2.75 g (11.4 mmol) of 4-[ (1- naphthalenyloxy)methyl]piperidine, prepared in Step 7.2., and 2.56 g (11.4 mmol) of ethyl [(phenyloxy- carbonyl)oxy]acetate, prepared in accordance with Example 1.1, in 80 ml of toluene is heated at 50°C overnight. It is evaporated to dryness and the residue is taken up in a mixture of water, dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The organic phase is decanted, dried over sodium sulphate and evaporated to dryness. The product is purified by chromatography on silica gel, eluting with a 50/50 mixture of cyclohexane and dichloromethane and then with dichloromethane and with a 95/5 mixture of dichloromethane and ethyl acetate. This gives 2.05 g of product in oil form, which is used as it is in the following step. 7.4. 2-amino-2-oxoethyl 4-[(1-naphthalenyl- oxy) methyl]-1-piperidinecarboxylate 1.0 g (2.69 mmol) of 2-(ethyloxy)-2-oxoethyl 4-[(1-naphthalenyloxy)methyl]-1-piperidinecarboxylate, prepared in Step 7.3., is dissolved in 12 ml of a 7N solution of ammonia (84 mmol) in methanol. The solution is left to react at ambient temperature for 3 days. It is evaporated to dryness and the residue is purified by chromatography on silica gel, eluting with a 90/10 then 80/20, 70/30 and 50/50 mixture of dichloromethane and ethyl acetate and then with a 95/5 mixture of ethyl acetate and methanol. The eluate is subsequently recrystallized from ethyl acetate, to give 0.77 of product. Melting point (°C): 135-136 LC-MS: M+H = 343 XH NMR (DMSO) 5(ppm): 8.15 (dd, 1H), 7.80 (dd, 1H), 7.50-7..30 (m, 4H) , 7.30 (m, 1H) , 7.15 (m, 1H) , 6.95 (d, 1H), 4.35 (s, 2H), 4.15-4.00 (m+d, 4H), 4.90 (m, 2H) , 2.10 (m, 1H), 1.90 (d, 2H), 1.45-1.25 (m, 2H) Example 8 (compound 148) 2-amino-2-oxoethyl 4-[(7-quinolinyloxy)methyl]- 1-piperidinecarboxylate 8.1. 2-(methyloxy)-2-oxoethyl 4-(hydroxymethyl)-1-piperidinecarboxylate The procedure described in Example 2.1. is repeated, using 6.84 g (59.4 mmol) of 4-(hydroxy- methyl )piperidine, in place of ethanolamine, to give 7.85 g of product in colourless oil form. 8.2. 2-amino-2-oxoethyl 4-[(7-quinolinyl- oxy) methyl] -1-piperidinecarboxylate 0.2 6 g (1.03 mmol) of 1,1'-(azodicarbonyl)- dipiperidine (ADDP) is added to a solution of 0.16 g (0.69 mmol) of 2-(methyloxy)-2-oxoethyl 4- (hydroxymethyl)-1-piperidinecarboxylate, prepared in Step 8.1., 0.26 ml (1.03 mmol) of tri-n-butylphosphine and 0.13 g (0.90 mmol) of 7-hydroxyquinoline in 2.5 ml of benzene, which is cooled by means of an ice bath. The mixture is stirred at 0°C for 15 minutes and then at ambient temperature for 16 hours. It is filtered over celite and rinsed with diethyl ether. The filtrates are evaporated to dryness and purified by chromatography on silica gel, eluting with a 70/3 0 mixture of ethyl acetate in n-hexane. The product obtained is dissolved in 3 ml (21 mmol) of a 7M solution of ammonia in methanol. The solution is stirred for 3 hours and then evaporated to dryness. The product is purified by chromatography on silica gel, eluting with a 90/10 mixture of ethyl acetate in ethanol, and recrystallized from ethyl acetate, to give 0.115 g of product in white solid form. Melting point (°C): 137-139 LC-MS: M+H = 344 XH NMR (CDC13) 8(ppm): 7.80 (dd, 1H) , 8.05 (dd, 1H) , 7.70 (d, 1H), 7.40 (d, 1H), 7.30-7,15 (m, 2H), 6.05 (m, 1H), 5.65 (m, 1H), 4.60 (s, 2H), 4.25 (m, 2H), 4.00 (d, 2H), 2.90 (m, 2H), 2.10 (m, 1H), 1.95 (d, 2H), 1.50-1.30 (m, 2H) Example 9 (compound 168) 2-(methylamino)-2-oxoethyl 4-{2-[(4-bromophenyl)- oxy]ethyl}-l-piperidinecarboxylate 9.1. 1,1-dimethylethyl 4-{2-[(4-bromophenyl)- oxy]ethyl}-1-piperidinecarboxylate The procedure described in Example 4.1. is repeated. Starting from 1.93 g (8.4 mmol) of 1,1-dimethylethyl 4-(2-hydroxyethyl)-1-piperidine- carboxylate and 5.88 g (33.6 mmol) of 1-bromo- 4-fluorobenzene gives 4.1 g of crude product in oil form. 9.2. 4-{2-[(4- bromophenyl)oxy]ethyl}piperidine The procedure described in Example 4.2. is repeated. Starting from 1,1-dimethylethyl 4-{2-[(4- bromophenyl)oxy]ethyl}-1-piperidinecarboxylate, prepared in Step 9.1., gives 1.79 g of product in powder form. Melting point (°C) : 100-102 9.3. 2-(ethyloxy)-2-oxoethyl 4-{2-[(4- bromophenyl)oxy]ethyl}-1-piperidinecarboxylate The procedure described in Example 4.3. is repeated. Starting from 1.76 g (6.19 mmol) of 4-{2-[(4 bromophenyl)oxy]ethyl} prepared in Step 9.2., and 1.39 g (6.19 mmol) of ethyl {[(phenyloxy)carbonyl]oxy}- acetate, prepared in accordance with Example 1.1., gives 1.4 g of product in oil form. 9.4. 2-(methylamino)-2-oxoethyl 4-{2-[(4- bromophenyl)oxy]ethyl}-1-piperidinecarboxylate The procedure described in Example 4.4. is repeated. Starting from 1.3 g (3.14 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{2- [ (4- bromophenyl)oxy]ethyl}-l-piperidinecarboxylate, prepared in Step 9.3., gives 0.95 g of product in powder form. Melting point (°C): 101-103 LC-MS: M+H =4 00 XE NMR (CDC13) 8(ppm): 7.55 (d, 2H) , 7.00 (d, 2H) , 6.25 (broads, NH), 4.90-4.70 (m, 2H), 4.50-4.25 (m, 2H), 4.20 (t, 2H), 3.20-2.90 (m, 2H), 3.10 (d, 3H), 2.05-1.90 (m, 5H), 1.55-1.30 (m, 2H) Example 10 (compound 186) 2- (methylamino)-2-oxoethyl 4-{2-[(4'-chloro-4- biphenyl)oxy]ethyl}-1-piperidinecarboxylate The procedure described in Example 4.5 is repeated. Starting from 0.1 g (0.25 mmol) of 2-(methylamino)-2-oxoethyl 4-{2-[(4-bromophenyl)- oxy]ethyl}-1-piperidinecarboxylate, prepared in accordance with Example 9, and 0.117 g (0.75 mmol) of 4-chlorophenylboronic acid gives 0.087 g of product in powder form. Melting point (°C): 104-106 LC-MS: M+H = 431 XH NMR (CDC13) S(ppm): 7.70-7.50 (m, 6H) , 7.10 (d, 2H) , 6.20 (broad s, NH) , 4.85-4.60 (m, 2H), 4.45-4.15 (m, 2H), 4.20 (t, 2H), 3.15-2.95 (m, 2H), 3.05 (d, 3H) , 2.10-1.85 (m, 5H), 1.50-1.25 (m, 2H) Example 11 (compound 183) 2-amino-2-oxoethyl 4-[2-(7-isoquinolinyloxy)ethyl]-1- piperidinecarbamate 11.1. 2-(methyloxy)-2-oxoethyl 4-(2- hydroxyethyl)-1-piperidinecarboxylate The procedure described in Example 2.1. is repeated, using7.6 g (59.4 mmol) of 4-(2-hydroxy- ethyDpiperidine, in place of ethanolamine, to give 7.1 g of product in colourless oil form. 11.2. 2-amino-2-oxoethyl 4-[2-(7- isoquinolinyloxy)ethyl]-1-piperidinecarbamate The procedure described in Example 8.2. is repeated, starting from 0.46 g (1.84 mmol) of ADDP, 0.3 0 g (1.24 mmol) of 2-(methyloxy)-2-oxoethyl 4-(2- hydroxyethyl)-1-piperidinecarboxylate, prepared in Step 11.1., 0.46 ml of tri-n-butylphosphine and 0.26 g (1.84 mmol) of 7-hydroxyisoquinoline in 4 ml of benzene. The product is purified by chromatography on silica gel, eluting with ethyl acetate and -then with a 95/5 mixture of ethyl acetate and ethanol, to give 0.25 g of product in white solid form. Melting point (°C): 179-181 LC-MS: M+H = 358 XH NMR (CDC13) 8(ppm): 9.15 (s, 1H) , 8.45 (d, 1H) , 7.60 (d, 1H), 7.35 (dd, 1H), 7.20 (d, 1H), 6.05 (m, 1H), 5.75 (m, 1H), 4.60 (s, 2H), 4.20 (t, 4H), 2.90 (m, 2H), 1.90-1.70 (m, 5H), 1.40-1.20 (m, 2H) Example 12 (compound 83) 2-amino-2-oxoethyl 3-[(1-naphthalenyloxy)methyl]-1- pyrrolidinecarboxylate 12.1. 1,1-dimethylethyl 3-[(1-naphthalenyl- oxy )methyl]-1-pyrrolidinecarboxylate A solution of 1.0 g (4.9 mmol) of 1,1- dimethylethyl 3-(hydroxymethyl)-1- pyrrolidinecarboxylate (described in WO 0066557), 0.95 g (6.4 mmol) of 1-naphthalenol and 1.4 g (6.9 mmol) of tri-n-butylphosphine in 40 ml of toluene and 2 0 ml of tetrahydrofuran, cooled under nitrogen by- means of an ice bath, is admixed dropwise with a solution of 1.74 g (6.9 mmol) of ADDP. The reaction mixture is allowed to return to ambient temperature and stirring is continued for 24 hours. The mixture is filtered and the precipitate is rinsed with toluene. It is evaporated to dryness. The residue is taken up in dichloromethane and washed with a 1M aqueous sodium hydroxide solution. It is dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a silica gel column, eluting with dichloromethane and then with a 98/2 mixture of dichloromethane and methanol, to give 0.80 g of product in colourless oil form 12.2. 3- [ (1-naphthalenyloxy)methyl] - pyrrolidine A solution of 0.42 g (1.28 mmol) of 1,1-dimethylethyl 3-[(1-naphthalenyloxy)methyl]- 1-pyrrolidinecarboxylate, prepared in Step 12.1., in 10 ml of 1,4-dioxane and 6 ml of a 2N solution of aqueous hydrochloric acid is stirred for 6 hours. It is evaporated to dryness and then coevaporation is carried out twice with toluene. The solid residue is washed with diethyl ether. The solid is taken up in dichloromethane and concentrated ammonia solution is added until a basic pH is obtained. The system is filtered on a Whatman PTFE cartridge and the organic phase is concentrated, to give 0.21 g of oily product, which is used as it is in the following step. 12.3. 2-(ethyloxy)-2-oxoethyl 3-[(l- naphthalenyloxy)methyl]-1-pyrrolidinecarboxylate A solution of 0.20 g (0.88 mmol) of 3-[(l- naphthalenyloxy)methyl]pyrrolidine, prepared in Step 12.2., and 0.35 g (1.5 mmol) of ethyl [ (phenyloxycarbonyl)oxy]acetate, prepared in accordance with Example 1.1, in 6 ml of toluene is heated at 60°C overnight. It is evaporated to dryness and the residue is taken up in a mixture of water, dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The organic phase is decanted, dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a silica gel column, eluting with dichloromethane and then with a 99/1 mixture of dichloromethane and methanol. This gives 0.24 g of product in oil form, which is used as it is in the following step. 12.4. 2-amino-2-oxoethyl 3-[(1-napthalenyl- oxy)methyl]-1-pyrrolidinecarboxylate 0.24 g (0.67 mmol) of 2-(ethyloxy)-2-oxoethyl 3- [ (1-naphthenyloxy)methyl]-1-pyrrolidinecarboxylate, prepared in Step 12.3., is dissolved in 15 ml of a 7N solution of ammonia (105 mmol) in methanol. The solution is stirred in a stoppered tube at ambient temperature for 3 days. It is evaporated to dryness and the residue is purified by chromatography on a silica gel column, eluting with a 97/3 then 94/6 mixture of dichloromethane and methanol. The solid obtained is triturated in diethyl ether and filtered, to give 0.15 g of product. Melting point (°C): 161-163 LC-MS: M+H = 329 XH NMR (DMSO) 5(ppm) : 8.15 (m, 1H) , 7.75 (m, 1H) , 7.50-7.30 (m, 4H), 7.10-6.90 (s, 2H), 6.80 (m, 1H), 4.40 (s, 2H), 4.20-4.05 (m, 2H), 3.90-3.30 (m, 4H) , 2.90-2.70 (m, 1H), 2.30-2.10 (m, 1H), 2.05-1.85 (m, 1H) . The table which follows the chemical structures and the physical properties of some compounds according to the invention. The compounds of the invention were subjected to pharmacological tests permitting determination of their inhibitory effect on the enzyme PAAH (Fatty Acid Amide Hydrolase). The inhibitory activity was demonstrated in a radioenzymatic assay based on measuring the product of hydrolysis (ethanolamine [1-3H] ) of anandamide [ethanolamine 1-3H] by FAAH {Life Sciences (1995), 56, 1999-2005 and Journal of Pharmacology and Experimental Therapeutics (1997), 283, 729-734). Accordingly, mouse brains (minus the cerebellum) are removed and stored at -80°C. Membrane homogenates are prepared at the time of use by homogenizing the tissues in a Polytron in a 10 mM Tris-HCl buffer (pH 8.0) containing 150 mM NaCl and 1 mM EDTA. The enzyme reaction is subsequently conducted in 70 /zl of buffer containing bovine serum albumin without fatty acids (1 mg/ml). In succession, the test compounds, at various concentrations, anandamide [ethanolamine 1-3H] (specific activity: 15-2 0 Ci/mmol) diluted to 10 /xM with cold anandamide, and the membrane preparation (400 /xg of frozen tissue per assay) are added. After 15 minutes at 25°C the enzyme reaction is terminated by adding 140 /zl of chloroform/methanol (2:1). The mixture is stirred for 10 minutes and then centrifuged for 15 minutes at 350 0 g. An aliquot (3 0 til) of the aqueous phase containing the ethanolamine [1-3H] is counted by liquid scintillation. Under these conditions, the most active compounds of the invention exhibit IC50 values (concentration inhibiting by 50% the control enzyme activity of FAAH) of between 0.001 and 1 /zM. For example, compound 58 of the table exhibits an IC50 of 0.47 /M. It is therefore apparent that the compounds according to the invention have an inhibitory effect on the FAAH enzyme. The in vivo activity of the compounds of the invention was evaluated in an analgesia test. Accordingly, intraperitoneal (i.p.) administration of PBQ (phenylbenzoquinone, 2 mg/kg in a 0.9% sodium chloride solution containing 5% of ethanol) to male OF1 mice weighing 25 to 3 0 g causes abdominal stretches, on average 3 0 twists or contractions during the period from 5 to 15 minutes after injection. The test compounds are administered orally in suspension in Tween 80 at 0.5%, 60 minutes or 120 minutes before the administration of PBQ. Under these conditions the most potent compounds of the invention reduce by 35 to 70% the number of stretches induced by PBQ, within a dose range of between 1 and 3 0 mg/kg. For example, compound 58 of the table reduces by 51% the number of stretches induced by PBQ, at a dose of 1 mg/kg at 2 hours. The enzyme FAAH {Chemistry and Physics of Lipids, (2000), 108, 107-121) catalyses the hydrolysis of endogenous derivatives of amides and of esters of various fatty acids such as N-arachidonylethanolamine (anandamide), N-palmitoylethanolamine, N-oleoyl- ethanolamine, oleamide or 2-arachidonoylglycerol. These derivatives exert various pharmacological activities by interacting, inter alia, with cannabinoid and vanilloid receptors. The compounds of the invention block this degradation pathway and increase the tissue level of these endogenous substances. They can be used in this respect in the prevention and treatment of pathologies in which endogenous cannabinoids and/or any other substrates metabolized by the FAAH enzyme are involved. Mention may be made, for example, of the following diseases and conditions: pain, especially acute or chronic pain of the neurogenic type: migraine, neuropathic pain, including forms associated with the herpes virus and with diabetes; acute or chronic pain associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's diease, irritable bowel syndrome; acute or chronic peripheral pain; dizziness, vomiting, nausea, especially those subsequent to chemotherapy; eating disorders, especially anorexia and cachexia of various kinds; neurological and psychiatric pathologies: shaking, dyskinesia, dystonia, spasticity, obsessive-compulsive behaviours, Tourette's syndrome, all forms of depression and anxiety of any kind and cause, mood disorders, psychoses; acute and chronic neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, lesions associated with cerebral ischemia and with cranial and medullary trauma; epilepsy; sleep disorders, including sleep apnoea; cardiovascular diseases, especially hypertension, cardiac arrhythmias, arteriosclerosis, heart attack, cardiac ischemias; renal ischemia; cancers: benign skin tumours, papillomas and brain tumours, prostate tumours, brain tumours (glioblastomas, medulloepitheliomas, medulloblastomas, neuroblastomas, tumours of embryonic origin, astrocytomas, astroblastomas, ependyomas, oligodendrogliomas, plexus tumour, neuroepitheliomas, epiphyseal tumour, ependymoblastomas, malignant meningiomas, sarcomatoses, malignant melanomas, schwannomas); disorders of the immune system, especially autoimmune diseases: psoriasis, lupus erythematosis, diseases of the connective tissue or collagen diseases, Sjogrer's syndrome, ankylosing spondylarthritis, undifferentiated spondylarthritis, Behcet's disease, haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloses, transplant rejection, diseases affecting the plasmocytic line; allergic diseases: immediate or delayed hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis; parasitic, viral or bacterial infectious diseases: AIDS, meningitis; inflammatory diseases, especially diseases of the joints: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome; osteoporosis; ocular conditions: ocular hypertension, glaucoma; pulmonary conditions: diseases of the respiratory tracts, bronchospasms, coughing, asthma, chronic bronchitis, chronic obstruction of the respiratory tracts, emphysema; gastrointestinal diseases: irritable bowel syndrome, intestinal inflammatory disorders, ulcers, diarrhoea; urinary incontinence and bladder inflammation. The use of compounds of formula (I) in base, salt, hydrate or pharmaceutically acceptable solvate form for preparing a medicinal product intended for treating the abovementioned pathologies forms an integral part of the invention. The invention likewise provides medicinal products which comprise a compound of formula (I), or a salt or else a hydrate or a pharmaceutically acceptable solvate of the compound of formula (I). These medicinal products are employed in therapy, particularly in the treatment of the abovementioned pathologies. In accordance with another of its aspects the present invention provides pharmaceutical compositions comprising as active principle at least one compound of formula (I). These pharmaceutical compositions include an effective dose of a compound according to the invention, or a salt or a hydrate or pharmaceutically acceptable solvate of the said compound, and optionally one or more pharmaceutically acceptable excipients. Said excipients are selected, according to the pharmaceutical form and the desired mode of administration, from the customary excipients, which are known to the person skilled in the art. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intrathecal, intranasal, transdermal, pulmonary, ocular or rectal administration the active principle of formula (I) above, or its salt, solvate or hydrate where appropriate, may be administered in single-dose administration form, in a mixture with conventional pharmaceutical excipients, to animals and to humans for the prophylaxis or treatment of the above disorders or diseases. The unit-dose administration forms which are appropriate include oral forms such as tablets, soft or hard gelatin capsules, powders, granules, chewing gums and oral solutions or suspensions, forms for sublingual, buccal, intratracheal, intraocular and intranasal administration and for administration by inhalation, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal or vaginal administration. For topical application the compounds according to the invention may be used in creams, ointments or lotions. By way of example a single-dose administration form of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscaramellose sodium 6.0 mg Maize starch 15.0 mg Hydroxypropyl-methylcellulose 2.25 mg Magnesium stearate 3.0 mg The said single-dose forms contain a dose permitting daily administration of from 0.01 to 20 mg of active principle per kg of bodyweight, depending on the pharmaceutical form. There may be particular cases in which higher or lower dosages are appropriate; such dosages also belong to the invention. In accordance with common practice the dosage appropriate to each patient is determined by the doctor according to the method of administration, the weight and the response of the said patient. According to another of its aspects the invention also provides a method of treating the pathologies indicated above, which comprises administering an effective dose of a compound according to the invention, one of its pharmaceutically acceptable salts, or a solvate or a hydrate of the said compound. We Claim: 1. Compound conforming to the formula (I) in which m represents 0, 1, 2 or 3; n represents 0, 1, 2 or 3; X represents an oxygen or sulphur atom or an SO or SO2 group; R1 and R2 represent independently of one another a hydrogen atom or a C1-3 alkyl group, or R1 and R2 together form a group -(CH2)P-, where p represents an integer ranging from 1 to 5 such that n + p is an integer ranging from 2 to 5; R3 represents a hydrogen or fluorine atom or a hydroxyl or methyl group; R4 represents a group of general formula CHR5CONHR6 in which R5 represents a hydrogen atom or a C1-6 alkyl group and R6 represents a hydrogen atom or a C1-6 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl-C1-6 alkylene group; Y represents a group Y1 selected from in particular a phenyl, pyridinyl, pyrimidinyl, thiazolyl, naphthyl, quinolinyl, isoquinolinyl and benzoxazolyl; the group Y1 being optionally substituted by one or more substituents Y2, which are identical to or different from one another, or by a group Y3; Y2 represents a halogen atom, a cyano, C1-8 alkyl, C1-8 alkoxy, C1-8 fluoroalkyl, C1-8 fluoroalkoxy, phenyloxy or phenyl-C1-C8 alkylene group; Y3 represents a phenyl group; it being possible for Y3 to be substituted by one or more groups Y2 which are identical to or different from one another; in the form of a base, addition salt with an acid, hydrate or solvate. 2. Compound of formula (I) as claimed in Claim 1, wherein Y represents a group Y1 selected from in particular a phenyl or a naphthyl; the group Y1 being optionally substituted by one or more substituents Y2, which are identical to or different from one another, or by a group Y3; Y2 represents a halogen atom, a cyano, C1-8 alkyl, C1-8 alkoxy, C1-8 fluoroalkyl, C1-8 fluoroalkoxy, phenyloxy or phenyl-C1-C8 alkylene group; Y3 represents a phenyl group; it being possible for Y3 to be substituted by one or more groups Y2 which are identical to or different from one another; in the form of a base, addition salt with an acid, hydrate or solvate. 3. Compound of formula (I) as claimed in any one of Claims 1 and 2, wherein m represents 0, 1, 2 or 3; n represents 0, 1, 2 or 3; R1 and R2 represent independently of one another a hydrogen atom or a C1-3 alkyl group, or R1 and R2 together form a group -(CH2)P-, where p represents an integer ranging from 1 to 5 such that n + p is an integer ranging from 2 to 5; with the proviso that, when R1 and R2 represent independently of one another a hydrogen atom or a C1-3 alkyl group, m + n > 1; in the form of a base, addition salt with an acid, hydrate or solvate. 4. Compound of formula (I) as claimed in any one of Claims 1 to 3, wherein m represents 0, 1, 2 or 3; and/or n represents 0, 1, 2 or 3; and/or R1 and R2 together form a group -(CH2)P-, where p represents an integer ranging from 1 to 4 such that n + p is equal to 4; in the form of a base, addition salt with an acid, hydrate or solvate. 5. Compound of formula (I) as claimed in any one of Claims 1 to 4, wherein X represents an oxygen atom; in the form of a base, addition salt with an acid, hydrate or solvate. 6. Compound of formula (I) as claimed in any one of Claims 1 to 5, wherein R3 represents a hydrogen atom; in the form of a base, addition salt with an acid, hydrate or solvate. 7. Compound of formula (I) as claimed in any one of Claims 1 to 6, selected from the following compounds: 2-(methylamino)-2-oxoethyl {2-[(4-chlorophenyl)oxy]ethyl} carbamate; 2-amino-2-oxoethyl (2-[(4-cyanophenyl)oxy]ethyl) carbamate; 2-amino-2-oxoethyl [4-(1-naphthalenyloxy]butyl] carbamate; 2-(methylamino)-2-oxoethyl 4-[(4'-fluoro-4-biphenyl) oxy]-1-piperidinecarboxylate; 2-(methylamino)-2-oxoethyl 4-{[(4-bromophenyl)oxy] methyl}-1-piperidinecarboxylate; 2-(methylamino)-2-oxoethyl 4-{[(4'-(trifluoromethyl)- 4-biphenyl)oxy]methyl}-1-piperidinecarboxylate; 2-amino-2-oxoethyl 4-[(1-naphthalenyloxy)methyl]-1- piperidinecarboxylate; 2-amino-2-oxoethyl 4-[(7-quinolinyloxy)methyl]-1- piperidinecarboxylate; 2-(methylamino)-2-oxoethyl 4-{2-[(4- bromophenyl)oxy]ethyl}-1-piperidinecarboxylate; 2-(methylamino)-2-oxoethyl 4-{2-[(4'-chloro-4- biphenyl)oxy]ethyl}-1-piperidinecarboxylate; 2-amino-2-oxoethyl 4-[2-(7-isoquinolinyloxy)ethyl]-1- piperidinecarbamate; 2-amino-2-oxoethyl 3-[(1-naphthalenyloxy)methyl]-1- pyrrolidinecarboxylate. 8. Process for preparing a compound of formula (I) as claimed in any one of Claims 1 to 7, comprising the step consisting in converting a compound of the formula (IV) in which Y, X, Rl, R2, R3, R5, n and m are as defined according to any one of Claims 1 to 7 and R represents a methyl or ethyl group, by aminolysis by means of an amine of formula R6NH2 where R6 is as defined in formula (I) according to Claim 1. 9. Pharmaceutical composition comprising at least one compound of formula (I) as claimed in any one of Claims 1 to 7, in base, salt, hydrate or solvate form that is pharmaceutically acceptable, and, optionally, one or more pharmaceutically acceptable excipients. 10. The composition as claimed in claim 9, wherein said composition is useful in the prevention or the treatment of a pathology in which endogenous cannabinoids and/or any other substrates metabolized by the enzyme FAAH are involved. 11. The composition as claimed in any one of claims 9 and 10, wherein said composition is useful in the prevention or the treatment of acute or chronic pain, dizziness, vomiting, nausea, eating disorders, neurological and psychiatric pathologies, acute or chronic neurodegenerative diseases, epilepsy, sleep disorders, cardiovascular diseases, renal ischemia, cancers, disorders of the immune system, allergic diseases, parasitic, viral or bacterial infectious diseases, inflammatory diseases, osteoporosis, ocular conditions, pulmonary conditions, gastrointestinal diseases or urinary incontinence. The invention discloses a compound conforming to the formula (I) wherein X, Y, R1, R2, R3. R4, m, n and p are as defined in the specification. The invention is also for a process for preparation of said compound and pharmaceutical composition comprising it.

Full Text

The invention relates to aryloxyalkyl-
carbamate derivatives, to their preparation and to
their application in therapy.
The compounds of the invention conform to the
general formula (I):

in which
m represents 0, 1, 2 or 3;
n represents 0, 1, 2 or 3;
X represents an oxygen or sulphur atom or an
SO or SO2 group; —
R1 and R2 represent independently of one
another a hydrogen atom or a C1-3 alkyl group, or R1 and
R2 together form a group -(CH2)P-, where p represents an
integer ranging from 1 to 5 such that n + p is an
integer ranging from 2 to 5;
R3 represents a hydrogen or fluorine atom or a
hydroxyl or methyl group;
R4 represents a group of general formula

CHR5CONHR6 in which
R5 represents a hydrogen atom or a C1-6 alkyl
group and
R6 represents a hydrogen atom or a C1-6 alkyl,
C3-7 cycloalkyl or C3-7 cycloalkyl-C1-6 alkylene group;
Y represents
a group Y1 selected from in particular a phenyl,
pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,
triazinyl, thiazolyl, naphthyl, guinolinyl,
isoquinolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, cinnolinyl, benzofuranyl,
dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl,
indolyl, isoindolyl, indolinyl, benzimidazolyl,
benzoxazolyl, benzisoxazolyl, benzothiazolyl,
benzisothiazolyl, benzotriazolyl, benzoxadiazolyl and
benzothiadiazolyl; the group Y1 being optionally
substituted by one or more substituents Y2, which are
identical to or different from one another, or by a
group Y3 ;
Y2 represents a halogen atom or a cyano,
nitro, C1-8 alkyl, C1-8 alkoxy, C1-8 thioalkyl, C1-8

fluoroalkyl, C1-8 fluoroalkoxy, C1-8 fluorothioalkyl, C3-7
cycloalkyl, C3-7 cycloalkyloxy, C3-7 cycloalkyl-C1-8
alkylene, C3-7 cycloalkyl-C1-8 alkyloxy, hydroxyl, NR7R8,
NHCOR7, NHSO2R7, COR7, CO2R7, CONR7R8, SO2R7, SO2NR7R8, -O-
(C1-3 alkylene)-O-, phenyloxy, phenylthio, phenyl-C1-C8
alkylene, phenyl-Ci-C8 alkyloxy or phenyl-Ci-C8 alkylthio

group;
Y3 represents a group selected from in
particular a phenyl, pyridinyl, pyrimidinyl, pyrazinyl
or pyridazinyl;
it being possible for the group or groups Y3 to be
substituted by one or more groups Y2 which are identical
to or different from one another;
R7 and R8 represent independently of one
another a hydrogen atom or a Ci-6 alkyl group, or with
the nitrogen atom carrying them form an azetidine,
pyrrolidine, piperidine, morpholine, thiomorpholine,
azepine or piperazine ring optionally substituted by a
C1-3 alkyl or benzyl group.
Among the compounds of general formula (I) a
first group of compounds is that for which:
Y represents
a group Yi selected from in particular a phenyl,
pyridinyl, pyrimidinyl, thiazolyl, naphthyl,
quinolinyl, isoquinolinyl and benzoxazolyl; the group Yi
being optionally substituted by one or more
substituents, more particularly by one or two
substituents, Y2, which are identical to or different
from one another, or by a group Y3;
Y2 represents a halogen atom, more
particularly a chlorine, a fluorine or a bromine, a
cyano, Ci.8 alkyl, more particularly a methyl,
isopropyl, butyl, tert-butyl or tetramethylbutyl, Ci_8

alkoxy, more particularly a methoxy, ethoxy or propoxy,
Ci-8 fluoroalkyl, more particularly a trifluoromethyl,
Ci-8 fluoroalkoxy, more particularly a trifluoromethoxy,
phenyloxy or phenyl-Ci-C8 alkylene group, more
particularly a phenyl(1,1-dimethylmethylene);
Y3 represents a phenyl group; it being
possible for Y3 to be substituted by one or more groups,
more particularly by one or two groups, Y2 which are
identical to or different from one another.
Among the compounds of the first group as
defined above a second group of compounds is that for
which: ^
Y represents
a group Yx selected from in particular a phenyl or a
naphthyl; the group Y3. being optionally substituted by
one or more substituents, more particularly by one or
two substituents, Y2, which are identical to or
different from one another, or by a group Y3;
Y2 represents a halogen atom, more
particularly a chlorine, a fluorine or a bromine, a
cyano, Ci_8 alkyl, more particularly a methyl,
isopropyl, butyl, tert-butyl or tetramethylbutyl, Ci.8
alkoxy, more particularly a methoxy, ethoxy or propoxy,
Ci-8 fluoroalkyl, more particularly a trifluoromethyl,
Ca-s fluoroalkoxy, more particularly a trifluoromethoxy,
phenyloxy or phenyl-Ci-C8 alkylene group, more
particularly a phenyl(1,1-dimethylmethylene);

Y3 represents a phenyl group; it being
possible for Y3 to be substituted by one or more groups,
more particularly by one or two groups, Y2 which are
identical to or different from one another.
Among the compounds of general formula (I) a
third group of compounds is that for which:
m represents 0, 1, 2 or 3; and/or
n represents 0, 1,-2 or 3; and/or
Ri and R2 represent independently of one
another a hydrogen atom or a Ci_3 alkyl group, or Ri and
R2 together form a group -(CH2)P-, where p represents an
integer ranging from 1 to 5 such that n + p is an
integer ranging from 2 to 5;
with the proviso that, when Ri and R2 represent
independently of one another a hydrogen atom or a Ci_3
alkyl group, m + n > 1.
Among the compounds of the third group as
defined above, a fourth group of compounds is that for
which:
m represents 0, 1, 2 or 3; and/or
n represents 0, 1, 2 or 3; and/or
Ri and R2 together form a group -(CH2)P-, where
p represents an integer ranging from 1 to 4 such that
n + p is equal to 4.—
Among the compounds of general formula (I), a
fifth group of compounds is that for which X represents
an oxygen atom.

Among the compounds of general formula (I), a
sixth group of compounds is that for which R3 represents
a hydrogen atom.
A seventh group is formed of the compounds
for which simultaneously Rlf R2, R3, R4, R5, R6, R7, Rs/
X, Y, Yi, Y2/ Y3/ n and m are as defined in the
subgroups of compounds above.
The compounds of general formula (I) may
include one or more asymmetric carbons. They may exist
in the form of enantiomers or diastereoisomers. These
enantiomers and diastereoisomers, and also mixtures
thereof, including the racemic mixtures, form part of
the invention.
The compounds of formula (I) may exist in the
form of bases or of addition salts with acids. Such-———-- -
addition salts form part of the invention.
These salts are advantageously prepared with
pharmaceutically acceptable acids, although the salts
of other acids which are of use, for example, for
purifying or isolating compounds of formula (I)
likewise form part of the invention. The compounds of
general formula (I) may be in the form of hydrates or
solvates, namely in the form of associations or
combinations with one or more molecules of water or
with a solvent. Such hydrates and solvates likewise
form part of the invention.
In the context of the invention the terms are

understood as follows:
Ct-z/ where t and z may take the values from 1
to 8, is a carbon chain which may have from t to z
carbon atoms; for example, Ci_3 is a carbon chain which
may have from 1 to 3 carbon atoms;
alkyl is a saturated, linear or branched
aliphatic group; for example, a C3.-3 alkyl group
represents a linear or branched carbon chain of 1 to 3
carbon atoms, more particularly a methyl, ethyl, propyl
or 1-methylethyl;
alkylene is a saturated, linear or branched
divalent alkyl group; for example, a C1-3 alkylene group
represents a linear or branched, divalent carbon chain
of 1 to 3 carbon atoms, more particularly a methylene,
ethylene, 1-methylethylene, propylene or 1,1-dimethyl-
methylene;
cycloalkyl is a cyclic alkyl group; for
example, a C3.5 cycloalkyl group represents a cyclic
carbon group of 3 to 5 carbon atoms, more particularly
a cyclopropyl, cyclobutyl or cyclopentyl;
alkenylene is a divalent unsaturated
aliphatic group containing 2 carbons, more particularly
an ethylene;
alkoxy is an -O-alkyl group having a
saturated, linear or branched aliphatic chain;
thioalkyl is an -S-alkyl group having a
saturated linear or branched aliphatic chain;

fluoroalkyl is an alkyl group in which one or
more hydrogen atoms have been substituted by a fluorine
atom;
fluoroalkoxy is an alkoxy group in which one
or more hydrogen atoms have been substituted by a
fluorine atom;
fluorothioalkyl is a thioalkyl group in which
one or more hydrogen atoms have been substituted by a
fluorine atom; and
a halogen atom is a fluorine, a chlorine, a
bromine or an iodine.
The compounds of the invention may be
prepared according to different methods, which are
illustrated by the schemes which follow.
Thus one method of preparation (Scheme 1)
consists in reacting an amine of general formula (II),
in which Y, X, Ri, R2, R3, m and n are as defined in the
general formula (I.) , with a carbonate of general
formula (III), in which Z represents a hydrogen atom or
a nitro group, R5 is as defined in the general formula
(I) and R represents a methyl or ethyl group, in a
solvent such as toluene or dichloroethane, at a
temperature of between 0 and 80°C . The resultant
carbamate esters of general formula (IV) are
subsequently converted into compounds of general
formula (I) by aminolysis, by means of an amine of
general formula R6NH2 where R6 is as defined in the

general formula (I). The aminolysis reaction may be
carried out in a solvent such as methanol or ethanol,
or a mixture of solvents such as methanol and
tetrahydrofuran.

Another method (Scheme 2) of obtaining the
compounds of general formula (I) in which R2 represents
more particularly a hydrogen atom consists in reacting
a derivative of general formula (Ila) in which W
represents a hydroxyl, mesylate or tosylate group or a
chlorine, bromine or iodine atom, and in which Y, X, Ri,
R3, m and n are as defined in the general formula (I),
with an oxazolidine dione of general structure (V), in
which R5 is as defined in the general formula (I), to
give the oxazolidine dione derivative of general
structure (VI). In the case where W represents a
hydroxyl group the reaction may be conducted according

to the conditions of Mitsunobu (Synthesis, 1981, 1-28) ;
for example, by the action of diethyl or diisopropyl
azodicarboxylate in the presence of triphenylphosphine.
In the case where W represents a chlorine, bromine or
iodine atom or a mesylate or tosylate group the
reaction may be conducted in the presence of a base
such as 1,1,3,3-tetramethylguanidine, sodium hydride or
sodium tert-butoxide in a solvent such as
tetrahydrofuran, acetonitrile or dimethylformamide at a
temperature of between 0°C and the reflux temperature
of the solvent. The resultant oxazolidine dione
derivative of general formula (VI) is subsequently
converted into a compound of general formula (I) by
aminolysis, by means of an amine of general formula
R6NH2 where R6 is as defined in the general formula (I) .

Another variant (Scheme 3), for obtaining the

compounds of general formula (I) in which X represents
more particularly an oxygen atom, consists in reacting
an alcohol derivative of general formula (Vila), (Vllb)
or (VIIc) with a phenol derivative of general structure
YOH, in which the Y is as defined in the general
formula (I), for example in accordance with the
Mitsunobu reaction conditions (Synthesis, 1981, 1-28)
or modified conditions (Tetrahedron Letters 1993, 34,
1639-1642), the carbamate ester (IVa) and oxazolidine
dione (Via) derivatives being subsequently converted
into compounds of general formula (I) by aminolysis
reaction by means of an amine of general structure R6NH2
where R6 is as defined in the general formula (I).
In the general formulae (Vila), (Vllb) and
(VIIc) , the groups Ri, R2, R3, R5, R6, m, n and R are as
defined above.
Scheme 3

Another variant (Scheme 4) for obtaining the
compounds of general formula (I) in which Y represents
more particularly a group Yx-Y3 of aryl-aryl, aryl-
heteroaryl, heteroaryl-aryl or heteroaryl-heteroaryl
type, consists in reacting an aryl halide derivative of
general structure (VIII), in which U is a bromine or
iodine atom and Yi, X, Ri, R2/ R3, R5, R6, n and m are as
defined in the general formula (I), with an arylboronic
or heteroarylboronic acid derivative of formula
Y3B(OH)2, where Y3 is as defined in the general formula
(I), in accordance with the Suzuki reation conditions
(Chem. Rev. 1995, 9_5, 2457-2483) or with an aryl- or
heteroaryl-tri-alkylstannane derivative of formula
Y3Sn(R')3/ where Y3 is as defined in the general formula
(I) and R' is a Ci_4 alkyl, in accordance with the ^—
Stille reaction conditions (Angew. Chem. Int. Ed. 1986,
25, 504-524).

The compounds of general formulae (II) ,
(Ha) , (III), (V), (Vila), (Vllb) , (VIIc) and (VIII)
and the phenol derivatives of general structure YOH,
when the method by which they are prepared is not
described, are available commercially or are described
in the literature, or else may be prepared according to
methods which are described therein or which are known
to the person skilled in the art.
The amines of general formula R6NH2 are
available commercially.
The examples which follow illustrate the
preparation of some compounds of the invention. These
examples are not limitative, and merely illustrate the
invention. The microanalyses, the IR and NMR spectra
and/or the LC-MS (Liquid Chromatography coupled to Mass
Spectroscopy) confirm the structures and purities of
the compounds obtained.
m.p. (°C) represents the melting point in
degrees Celsius.
The numbers indicated in parentheses in the
titles of the examples correspond to those from the 1st

column of the table thereafter.
The IUPAC (International Union of Pure and
Applied Chemistry) nomenclature has been used for
naming the compounds in the following examples. For
example, for the biphenyl group, the following
numbering has been respected:

Example 1 (Compound 1)
2-(methylamino)-2-oxoethyl {2-[(4-chlorophenyl)-
oxy]ethyl}carbamate

1.1 ethyl [(phenyloxycarbonyl)oxy]acetate
A solution of 25 g (240 mmol) of ethyl
glycolate and of 55 ml (315 mmol) of
diisopropylethylamine in 500 ml of toluene is admixed
slowly at ambient temperature with 32 ml (256 mmol) of
phenyl chloroformate. Stirring is continued at ambient
temperature for 2 hours. The salt formed is separated
off and the filtrate is concentrated under reduced

pressure. This gives 53.7 g of oily product, used as it
is in the following step.
1.2. ethyl {[({2-[(4-chlorophenyl)oxy]ethyl}-
amino)carbonyl]oxy}acetate
A solution of 0.6 g (3.5 mmol) of [(4-chloro-
phenyl) oxy] ethylamine (Chim. Ther. 1973, £, 259-270)
and 1.3 g (5.8 mmol) of ethyl [(phenyloxy-
carbonyl)oxy]acetate, prepared in Step 1.1., in 3 0 ml
of toluene is heated at 60°C overnight. It is
evaporated to dryness and the product is purified by
chromatography on silica gel, eluting with a 30/70
mixture of ethyl acetate and cyclohexane. This gives
0.7 g of oily product, containing -10% of cyclized
oxazolidine dione product, used as it is in the
following step.
1.3. 2-(methylamino)-2-oxoethyl {2-[(4-
chlorophenyl)oxy]ethyl}carbamate
3.5 ml (7 mmol) of a 2M solution of'
methylamine in tetrahydrofuran are added to a solution
of 0.7 g (2.3 mmol) of ethyl {[({2-[(4-chlorophenyl)-
oxy]ethyl}amino)carbonyl]oxy}acetate, prepared in
Step 1.2., in 5 ml of methanol. The mixture is left to
react at ambient temperature overnight. It is
evaporated to dryness and the residual solid is washed
v_„
with hexane and then with diisopropyl ether, to give
0.59 g of product in powder form.
Melting point (°C): 147-149

LC-MS: M+H = 287
XH NMR (DMSO) 5(ppm): 7.75 (m, 1H), 7.40 (m, 1H), 7.25
(d, 2H) , 6.95 (d, 2H), 4.35 (s, 2H), 3.95 (t, 2H), 3.35
(m, 2H), 2.60 (d, 3H).
Example 2 (compound 11)
2 - amino-2 -oxoethyl (2-[(4-cyanophenyl)oxy]ethyl)-
carbamate
2.1 3-(2-hydroxyethyl)-1,3-oxazolidine-
2,4-dione

A solution of 3 ml (39.6 mmol) of methyl
glycolate in 25 ml of tetrahydrofuran is added dropwise
over 2 hours to a solution of 49 ml (95 mmol) of
phosgene, 1.9M in toluene, which is diluted in 50 ml of
tetrahydrofuran and cooled using an ice bath. The
mixture is subsequently stirred at ambient temperature
for 16 hours and evaporated to dryness. Coevaporation
is carried out 4 times with 3 0 ml of dichloromethane.
The residue is taken up with 4 0 ml of acetonitrile and
added dropwise over 1 hour to a solution of 3.4 ml
(59.4 mmol) of ethanolamine and 30 ml (178 mmol) of
diisopropylethylamine in a 50/10 mixture of
acetonitrile and dichloromethane, cooled using an ice
bath. The mixture is subsequently stirred at ambient
temperature for 16 hours. It is filtered over celite
and evaporated to dryness and the product is purified

by chromatography on silica gel, eluting with a 70/3 0
then 80/20 mixture of ethyl acetate and n-hexane, to
give 4.9 g of product in white solid form.
2.2. 2-amino-2-oxoethyl (2-[(4-cyanopheny1)-
oxy]ethyl)carbamate
0.61 ml (1.35 mmol) of a 2.2M solution of
diethyl azodicarboxylate in toluene is added dropwise
to a solution of 0.13 g (0.88 mmol) of 3-(2-
hydroxyethyl)-1,3-oxazolidine-2,4-dione, prepared in
Step 2.1., 0.35 g (1.35 mmol) of triphenylphosphine and
0.10 g (0.89 mmol) of 4-hydroxybenzonitrile in 2 ml of
benzene, cooled using an ice bath. The reaction mixture
is subsequently stirred at ambient temperature for
16 hours. It is evaporated to dryness and the product
is purified by chromatography on silica gel, eluting
with a 99/1 then 98/2 mixture of dichloromethane and
ethyl acetate. The product is taken up in 1.5 ml of a
7M solution of ammonia (10.5 mmol) in methanol. This
solution is stirred for one hour. The precipitate is
filtered off and washed with ethyl acetate, to give
0.035 g of white solid. '
Melting point (°C): 204-206
LC-MS: M+H = 264
XH NMR (DMSO) 8(ppm): 7.55 (d, 2H), 7.05 (m, 1H), 6.90-
6.80 (m+d, 4H), 4.35 (s, 2H), 4.05 (t, 2H), 3.45 (m,
2H)
Example 3 (compound 58)

2-amino-2-oxoethyl [4-(1-naphthalenyloxy]butyl]-
carbamate

3.1. 3-[4-(1-naphthalenyloxy]butyl]-1,3-
oxazolidine-2,4-dione
A solution of 3.1 g (11.1 mmol) of l-[(4-
bromobutyl)oxy]naphthalene (Eur. J. Med. Chem. 1997,
32, 175-179) and 1.35 g (13.3 mmol) of 1,3-oxazolidine-
2,4-dione (J. Med. Chem. 1991, 34, 1542-1543) in 30 ml
of tetrahydrofuran is admixed dropwise with a solution
of 2.55 g (22.2 mmol) of 1,1,3,3-tetramethylguanidine
in 15 ml of tetrahydrofuran. The mixture is heated at
reflux for 8 hours. 0.28 g (2.7 mmol) of
1,3-oxazolidine-2,4-dione and 0.32 g (2.7 mmol) of
1,1,3,3-tetramethylguanidine are added and the mixture
is heated at reflux for 4 more hours. The reaction
mixture is cooled using an ice bath, and 100 ml of
ethyl acetate and then 50 ml of 1M aqueous hydrochloric
acid are added. The system is decanted and the aqueous
phase is extracted with 2 x 80 ml of ethyl acetate. The
organic phases are subsequently washed with 80 ml of
water and then with 80 ml of saturated aqueous sodium
chloride solution. They are dried over sodium sulphate
and then evaporated to dryness. The product is purified
by chromatography on silica gel, eluting with an 80/20

mixture of cyclohexane and ethyl acetate, to give 2.0 g
of product, which is used as it is in the following
step.
3.2. 2-amino-2-oxoethyl [4-(1-naphthalenyl-
oxy)butyl]carbamate
1.50 g (5.0 mmol) of 3-[4-(1-naphthalenyl-
oxy) butyl] -1, 3-oxazolidine-2 , 4-dione, prepared in
Step 3.1., are dissolved in a mixture of 10 ml of
tetrahydrofuran and 2 8 ml of a 7N solution of ammonia
(200 mmol) in methanol. The solution is left to react
overnight at ambient temperature and then evaporated to
dryness. The product is purified by chromatography on
silica gel, eluting with a 97/3 mixture of
dichloromethane and methanol. It is recrystallized from
ethyl acetate and then washed with diethyl ether, to
give 0.73 g of product in white solid form.
Melting point (°C): 80-82
LC-MS: M+H =317
XH NMR (CDC13) (J(ppm) : 8.25 (dd, 1H) , 7.80 (dd, 1H) ,
7.55-7.30 (m, 4H), 6.80 (d, 1H), 6.00 (m, 1H), 5.65 (m,
1H), 5.05 (m, 1H), 4.65 (s, 2H), 4.20 (t, 2H), 3.35 (m,
2H), 2.00 (m, 2H), 1.90 (m, 2H)
Example 4 (compound 85)
2-(methylamino)-2-oxoethyl 4-[(4'-fluoro-4-biphenyl)-
oxy]-1-piperidinecarboxylate

4.1. 1,1-dimethylethyl 4-[(4-bromophenyl)-
oxy]-1-piperidinecarboxylate
A solution of 2.01 g (10 mmol) of
1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate in
20 ml of dimethylformamide is admixed with 7 g
(40 mmol) of l-bromo-4-fluorobenzene and 2.5 g
(50 mmol) of sodium hydride at 50% in mineral oil. The
mixture is stirred at 100°C for 3 hours and then
evaporated to dryness. The residue is taken up in 50 ml
of ice-water and extracted with dichloromethane. The
organic extracts are evaporated to dryness, to give
3.5 g of an oily product, which is used as it is in the
following step.
4.2. 4-[(4-bromophenyl)oxy]piperidine
A solution of 3.5 g (9.83 mmol) of 1,1-
dimethylethyl 4-[(4-bromophenyl)oxy]-1-piperidine-
carboxylate, prepared in Step 4.1., in 2 0 ml of
dichloromethane is admixed with 10 ml of
trifluoroacetic acid and the solution is stirred at
ambient temperature for 1 hour. It is evaporated to
dryness and then the residue is taken up in 3 0 ml of
toluene, which is evaporated again to dryness. The
residue is subsequently washed with pentane and then
taken up in a mixture of 60 ml of dichloromethane and
20 ml of 4N aqueous ammonia solution. It is stirred

vigorously for 15 minutes and then the organic phase is
decanted, dried over sodium sulphate and evaporated to
dryness, to give 2.7 g of product in oil form, which is
used as it is in the following step.
4.2. 2- (ethyloxy) -2-oxoethyl 4- [ (4-bromo- _^-' "
phenyl)oxy]-1-piperidinecarboxylate
2.7 g (7.58 mmol) of 4-[ (4-bromophenyl) - ^s^'
oxy]piperidine, prepared in Step 4.2., and 1.70 g
(7.6 mmol) of ethyl {[(phenyloxy)carbonyl]oxy}acetate,
prepared in accordance with Example 1.1, are mixed in
40 ml of toluene and the solution is heated at 50°C for
20 hours. After cooling, it is evaporated to dryness
and the product is purified by chromatography on silica
gel, eluting with a 40/60 mixture of ethyl acetate and
cyclohexane. The eluate is subsequently triturated in
diisopropyl ether, to give 2.9 g of product in powder
form. —....-
Melting point (°C): 87-88
4.3. 2-(methylamino)-2-oxoethyl
4-[(4-bromophenyl)oxy]-1-piperidinecarboxylate
2.9 g (7.5 mmol) of 2-(ethyloxy)-2-oxoethyl
4-[(4-bromophenyl)oxy]-1-piperidinecarboxylate,
prepared in Step 4.3., in solution in 10 ml of a 33%
ethanolic solution of methylamine are stirred at
ambient temperature for 20 hours. Following
evaporation, the product is purified by chromatography
on silica gel, eluting with ethyl acetate, to give
^ .

0.8 g of product in gum form, which is used as it is in
the following step.
4.5. 2-(methylamino)-2-oxoethyl ^^
4- [ (4'-fluoro-4-biphenyl)oxy]-1-piperidinecarboxylate
0.1 g (0.27 mmol) of 2-(methylamino)-
2-oxoethyl 4-[(4-bromophenyl)oxy]-1-piperidine- .^"
carboxylate, prepared in Step 4.4., 0.01 g of
tetrakis(triphenylphosphine)palladium(0) and 0.057 g
(0.4 mmol) of 4-fluorophenylboronic acid are placed in
a glass tube with stopper. 4 ml of toluene, 2 ml of a
2N aqueous solution of sodium carbonate and 0.5 ml of
ethanol are added. The mixture is heated at 8 0°C with
stirring for 2 hours. After it has cooled, 1 ml of
water and 2 ml of toluene are added. The organic phase
is withdrawn and the product is purified by
chromatography on silica gel, eluting with a 95/5
mixture of dichloromethane and methanol. The product is
redissolved in 1 ml of ethanol and then reprecipitated
by adding 2 ml of water, to give 0.031 g of product in
powder form.
Melting point (°C) : 117-119 v— "'
LC-MS: M+H 3 87
XH NMR (CDC13) 5(ppm): 7.70 (dd, 2H) , 7.65 (d, 2H) , 7.30
(dd, 2H) , 7.20 (d, 2H) , 6.25 (broad s, 1H) , 4.80 (s +
m, 3H) , 4.00-3.70 (m, 4H) , 3.05 (d, 3H), 2.25-2.00 (m,
4H)
Example 5 (compound 12 0)

2-(methylamino)-2-oxoethyl 4-{[(4-bromophenyl)oxy] -
methyl}-l-piperidinecarboxylate

5.1. 1,1-dimethylethyl 4-{[(4-bromophenyl)-
oxy]methyl}-1-piperidinecarboxylate
The procedure described in Example 4.1. is
repeated. Starting from 2.5 g (11.6 mmol) of
1,1-dimethylethyl 4-(hydroxymethyl)-1-piperidine-
carboxylate and 8.13 g (4 6.4 mmol) of 1-bromo-
4-fluorobenzene gives 5.75 g of crude product in oil
form.
5.2. 4-{ [ (4-bromophenyl)oxy]methyl}piperidine
The procedure described in Example 4.2 is
repeated. Starting from 5.75 g of 1,1-dimethylethyl
4-{ [ (4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate,
prepared in Step 5.1, gives 3 g of product in oil form.
5.3. 2-(ethyloxy)-2-oxoethyl 4-{[(4-
bromophenyl)oxy]methyl}-1-piperidinecarboxylate
The procedure described in Example 4.3. is
repeated. Starting from 1.6 g (5.9 mmol) of 4-{[(4-
bromophenyl)oxy]methyl}piperidine, prepared in Step
5.2., and from 1.32 g (5.9 mmol) of ethyl
{t(phenyloxy)carbonyl]oxy}acetate, prepared in
accordance with Example 1.1., gives the product in oil
form.

5.4. 2-(methylamino)-2-oxoethyl 4-{[(4-
bromophenyl)oxy]methyl}-1-piperidinecarboxylate
The procedure described in Example 4.4. is
repeated. Starting from 2-(ethyloxy)-2-oxoethyl 4-{[(4-
bromophenyl)oxy]methyl}-1-piperidinecarboxylate,
prepared in Step 5.3, gives 1.1 g of product in powder
form.
Melting point (°C): 163-165
LC-MS: M+H = 386
XH NMR (CDC13) 8(ppm): 7.35 (d, 2H) , 6.75 (d, 2H) , 6.05
(broad s, 1H), 4.70-4.50 (m, 2H), 4.30-4.10 (m, 2H) ,
3.80 (d, 2H), 3.00-2.75 (m, 2H), 2.85 (d, 3H),
2.10-1.80 (m, 3H), 1.45-1.20 (m, 2H)
Example 6 (compound 154)
2-(methylamino)-2-oxoethyl 4-{[(4'-(trifluoromethyl)-
4-biphenyl)oxy]methyl}-1-piperidinecarboxylate

The procedure described in Example 4.5. is repeated.
Starting from 0.1 g (0,26 mmol) of 2-(methylamino)-2-
oxoethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidine-
carboxylate, prepared in accordance with Example 5, and
from 0.074 g (0.389 mmol) of 4-trifluoromethylphenyl-
boronic acid gives 0.049 g of product in powder form.
Melting point (°C): 197-199

LC-MS: M+H =451
XH NMR (DMSO) 8(ppm) : 7.85-7.65 (m, 7H) , 7.05 (d, 2H) ,
4.35 (s, 2H) , 4.05 (broad d, 2H), 3.90 (d, 2H), 2.85
(m, 2H), 2.60 (d, 3H), 2.00 (m, 1H), 1.80 (broad d,
2H), 1.35-1.10 (m, 2H).
Example 7 (compound 137)
2-amino-2-oxoethyl 4-[(l-naphthalenyloxy)methyl]-
1-piperidinecarboxylate

7.1. 1,1-dimethylethyl 4-[(1-naphthalenyl-
oxy)methyl]-1-piperidinecarboxylate
A solution of 5.0 g (23.2 mmol) of 1,1-
dimethylethyl 4-(hydroxymethyl)-1-piperidine-
carboxylate, 4.3 g (2 9.8 mmol) of 1-naphthalenol and
7.82 g (29.8 mmol) of triphenylphosphine in 12 0 ml of
tetrahydrofuran, cooled under nitrogen by means of an
ice bath, is admixed dropwise with a solution of 6.03 g
(29.8 mmol) of diisopropyl azodicarboxylate. The
reaction mixture is allowed to return to ambient
temperature and stirring is continued overnight. 2 ml
of methanol are added and then the mixture is
evaporated to dryness. The residue is taken up in
2 00 ml of dichloromethane and washed in succession with

a 10% aqueous potassium hydrogen sulphate solution,
water and a 1M aqueous solution of sodium hydroxide.
The system is dried over sodium sulphate and evaporated
to dryness. The product is purified by chromatography
on silica gel, eluting with an 80/20 then 70/30 and
50/50 mixture of cyclohexane and dichloromethane, to
give 7.96 g of product in oil form, which solidifies.
Melting point (°C): 97-100
7.2. 4- [ (1-naphthalenyloxy)methyl]piperidine
A solution of 7.96 g (29.1 mmol) of
1,1-dimethylethyl 4-[(1-naphthalenyloxy)methyl]-
1-piperidinecarboxylate, prepared in Step 7.1., in
120 ml of methanol and 2 8 ml of 35% aqueous
hydrochloric acid is heated at 60°C for 6 hours. It is
cooled to ambient temperature and evaporated to
dryness, and then coevaporation is carried out twice
with ethanol. The solid residue is washed with diethyl
ether and then dried under vacuum in the presence of
phosphorus pentoxide, to give 3.1 g of white solid.
The solid is taken up in 80 ml of water and a
3 0% aqueous sodium hydroxide solution is added until a
basic pH is obtained, after which the system is
extracted twice with 150 ml of diethyl ether. The
extracts are dried over sodium sulphate and
concentrated to dryness, to give 2.75 g of oily
product, which is used as it is in the following step.
7.3. 2-(ethyloxy)-2-oxoethyl 4-[(l-

naphthalenyloxy)methyl]-1-piperidinecarboxylate
A solution of 2.75 g (11.4 mmol) of 4-[ (1-
naphthalenyloxy)methyl]piperidine, prepared in Step
7.2., and 2.56 g (11.4 mmol) of ethyl [(phenyloxy-
carbonyl)oxy]acetate, prepared in accordance with
Example 1.1, in 80 ml of toluene is heated at 50°C
overnight. It is evaporated to dryness and the residue
is taken up in a mixture of water, dichloromethane and
saturated aqueous sodium hydrogen carbonate solution.
The organic phase is decanted, dried over sodium
sulphate and evaporated to dryness. The product is
purified by chromatography on silica gel, eluting with
a 50/50 mixture of cyclohexane and dichloromethane and
then with dichloromethane and with a 95/5 mixture of
dichloromethane and ethyl acetate. This gives 2.05 g of
product in oil form, which is used as it is in the
following step.
7.4. 2-amino-2-oxoethyl 4-[(1-naphthalenyl-
oxy) methyl]-1-piperidinecarboxylate
1.0 g (2.69 mmol) of 2-(ethyloxy)-2-oxoethyl
4-[(1-naphthalenyloxy)methyl]-1-piperidinecarboxylate,
prepared in Step 7.3., is dissolved in 12 ml of a 7N
solution of ammonia (84 mmol) in methanol. The solution
is left to react at ambient temperature for 3 days. It
is evaporated to dryness and the residue is purified by
chromatography on silica gel, eluting with a 90/10 then
80/20, 70/30 and 50/50 mixture of dichloromethane and

ethyl acetate and then with a 95/5 mixture of ethyl
acetate and methanol. The eluate is subsequently
recrystallized from ethyl acetate, to give 0.77 of
product.
Melting point (°C): 135-136
LC-MS: M+H = 343
XH NMR (DMSO) 5(ppm): 8.15 (dd, 1H), 7.80 (dd, 1H),
7.50-7..30 (m, 4H) , 7.30 (m, 1H) , 7.15 (m, 1H) , 6.95 (d,
1H), 4.35 (s, 2H), 4.15-4.00 (m+d, 4H), 4.90 (m, 2H) ,
2.10 (m, 1H), 1.90 (d, 2H), 1.45-1.25 (m, 2H)
Example 8 (compound 148)
2-amino-2-oxoethyl 4-[(7-quinolinyloxy)methyl]-
1-piperidinecarboxylate

8.1. 2-(methyloxy)-2-oxoethyl
4-(hydroxymethyl)-1-piperidinecarboxylate
The procedure described in Example 2.1. is
repeated, using 6.84 g (59.4 mmol) of 4-(hydroxy-
methyl )piperidine, in place of ethanolamine, to give
7.85 g of product in colourless oil form.
8.2. 2-amino-2-oxoethyl 4-[(7-quinolinyl-
oxy) methyl] -1-piperidinecarboxylate
0.2 6 g (1.03 mmol) of 1,1'-(azodicarbonyl)-
dipiperidine (ADDP) is added to a solution of 0.16 g

(0.69 mmol) of 2-(methyloxy)-2-oxoethyl 4-
(hydroxymethyl)-1-piperidinecarboxylate, prepared in
Step 8.1., 0.26 ml (1.03 mmol) of tri-n-butylphosphine
and 0.13 g (0.90 mmol) of 7-hydroxyquinoline in 2.5 ml
of benzene, which is cooled by means of an ice bath.
The mixture is stirred at 0°C for 15 minutes and then
at ambient temperature for 16 hours. It is filtered
over celite and rinsed with diethyl ether. The
filtrates are evaporated to dryness and purified by
chromatography on silica gel, eluting with a 70/3 0
mixture of ethyl acetate in n-hexane. The product
obtained is dissolved in 3 ml (21 mmol) of a 7M
solution of ammonia in methanol. The solution is
stirred for 3 hours and then evaporated to dryness. The
product is purified by chromatography on silica gel,
eluting with a 90/10 mixture of ethyl acetate in
ethanol, and recrystallized from ethyl acetate, to give
0.115 g of product in white solid form.
Melting point (°C): 137-139
LC-MS: M+H = 344
XH NMR (CDC13) 8(ppm): 7.80 (dd, 1H) , 8.05 (dd, 1H) ,
7.70 (d, 1H), 7.40 (d, 1H), 7.30-7,15 (m, 2H), 6.05 (m,
1H), 5.65 (m, 1H), 4.60 (s, 2H), 4.25 (m, 2H), 4.00 (d,
2H), 2.90 (m, 2H), 2.10 (m, 1H), 1.95 (d, 2H),
1.50-1.30 (m, 2H)
Example 9 (compound 168)

2-(methylamino)-2-oxoethyl 4-{2-[(4-bromophenyl)-
oxy]ethyl}-l-piperidinecarboxylate

9.1. 1,1-dimethylethyl 4-{2-[(4-bromophenyl)-
oxy]ethyl}-1-piperidinecarboxylate
The procedure described in Example 4.1. is
repeated. Starting from 1.93 g (8.4 mmol) of
1,1-dimethylethyl 4-(2-hydroxyethyl)-1-piperidine-
carboxylate and 5.88 g (33.6 mmol) of 1-bromo-
4-fluorobenzene gives 4.1 g of crude product in oil
form.
9.2. 4-{2-[(4-
bromophenyl)oxy]ethyl}piperidine
The procedure described in Example 4.2. is
repeated. Starting from 1,1-dimethylethyl 4-{2-[(4-
bromophenyl)oxy]ethyl}-1-piperidinecarboxylate,
prepared in Step 9.1., gives 1.79 g of product in
powder form.
Melting point (°C) : 100-102
9.3. 2-(ethyloxy)-2-oxoethyl 4-{2-[(4-
bromophenyl)oxy]ethyl}-1-piperidinecarboxylate
The procedure described in Example 4.3. is
repeated. Starting from 1.76 g (6.19 mmol) of 4-{2-[(4
bromophenyl)oxy]ethyl} prepared in Step 9.2., and
1.39 g (6.19 mmol) of ethyl {[(phenyloxy)carbonyl]oxy}-

acetate, prepared in accordance with Example 1.1.,
gives 1.4 g of product in oil form.
9.4. 2-(methylamino)-2-oxoethyl 4-{2-[(4-
bromophenyl)oxy]ethyl}-1-piperidinecarboxylate
The procedure described in Example 4.4. is
repeated. Starting from 1.3 g (3.14 mmol) of
2-(ethyloxy)-2-oxoethyl 4-{2- [ (4-
bromophenyl)oxy]ethyl}-l-piperidinecarboxylate,
prepared in Step 9.3., gives 0.95 g of product in
powder form.
Melting point (°C): 101-103
LC-MS: M+H =4 00
XE NMR (CDC13) 8(ppm): 7.55 (d, 2H) , 7.00 (d, 2H) , 6.25
(broads, NH), 4.90-4.70 (m, 2H), 4.50-4.25 (m, 2H),
4.20 (t, 2H), 3.20-2.90 (m, 2H), 3.10 (d, 3H),
2.05-1.90 (m, 5H), 1.55-1.30 (m, 2H)
Example 10 (compound 186)
2- (methylamino)-2-oxoethyl 4-{2-[(4'-chloro-4-
biphenyl)oxy]ethyl}-1-piperidinecarboxylate

The procedure described in Example 4.5 is
repeated. Starting from 0.1 g (0.25 mmol) of
2-(methylamino)-2-oxoethyl 4-{2-[(4-bromophenyl)-

oxy]ethyl}-1-piperidinecarboxylate, prepared in
accordance with Example 9, and 0.117 g (0.75 mmol) of
4-chlorophenylboronic acid gives 0.087 g of product in
powder form.
Melting point (°C): 104-106
LC-MS: M+H = 431
XH NMR (CDC13) S(ppm): 7.70-7.50 (m, 6H) , 7.10 (d, 2H) ,
6.20 (broad s, NH) , 4.85-4.60 (m, 2H), 4.45-4.15 (m,
2H), 4.20 (t, 2H), 3.15-2.95 (m, 2H), 3.05 (d, 3H) ,
2.10-1.85 (m, 5H), 1.50-1.25 (m, 2H)
Example 11 (compound 183)
2-amino-2-oxoethyl 4-[2-(7-isoquinolinyloxy)ethyl]-1-
piperidinecarbamate

11.1. 2-(methyloxy)-2-oxoethyl 4-(2-
hydroxyethyl)-1-piperidinecarboxylate
The procedure described in Example 2.1. is
repeated, using7.6 g (59.4 mmol) of 4-(2-hydroxy-
ethyDpiperidine, in place of ethanolamine, to give
7.1 g of product in colourless oil form.
11.2. 2-amino-2-oxoethyl 4-[2-(7-
isoquinolinyloxy)ethyl]-1-piperidinecarbamate
The procedure described in Example 8.2. is
repeated, starting from 0.46 g (1.84 mmol) of ADDP,
0.3 0 g (1.24 mmol) of 2-(methyloxy)-2-oxoethyl 4-(2-
hydroxyethyl)-1-piperidinecarboxylate, prepared in

Step 11.1., 0.46 ml of tri-n-butylphosphine and 0.26 g
(1.84 mmol) of 7-hydroxyisoquinoline in 4 ml of
benzene. The product is purified by chromatography on
silica gel, eluting with ethyl acetate and -then with a
95/5 mixture of ethyl acetate and ethanol, to give
0.25 g of product in white solid form.
Melting point (°C): 179-181
LC-MS: M+H = 358
XH NMR (CDC13) 8(ppm): 9.15 (s, 1H) , 8.45 (d, 1H) , 7.60
(d, 1H), 7.35 (dd, 1H), 7.20 (d, 1H), 6.05 (m, 1H),
5.75 (m, 1H), 4.60 (s, 2H), 4.20 (t, 4H), 2.90 (m, 2H),
1.90-1.70 (m, 5H), 1.40-1.20 (m, 2H)
Example 12 (compound 83)
2-amino-2-oxoethyl 3-[(1-naphthalenyloxy)methyl]-1-
pyrrolidinecarboxylate

12.1. 1,1-dimethylethyl 3-[(1-naphthalenyl-
oxy )methyl]-1-pyrrolidinecarboxylate
A solution of 1.0 g (4.9 mmol) of 1,1-
dimethylethyl 3-(hydroxymethyl)-1-
pyrrolidinecarboxylate (described in WO 0066557),
0.95 g (6.4 mmol) of 1-naphthalenol and 1.4 g
(6.9 mmol) of tri-n-butylphosphine in 40 ml of toluene

and 2 0 ml of tetrahydrofuran, cooled under nitrogen by-
means of an ice bath, is admixed dropwise with a
solution of 1.74 g (6.9 mmol) of ADDP. The reaction
mixture is allowed to return to ambient temperature and
stirring is continued for 24 hours. The mixture is
filtered and the precipitate is rinsed with toluene. It
is evaporated to dryness. The residue is taken up in
dichloromethane and washed with a 1M aqueous sodium
hydroxide solution. It is dried over sodium sulphate
and evaporated to dryness. The residue is purified by
chromatography on a silica gel column, eluting with
dichloromethane and then with a 98/2 mixture of
dichloromethane and methanol, to give 0.80 g of product
in colourless oil form
12.2. 3- [ (1-naphthalenyloxy)methyl] -
pyrrolidine
A solution of 0.42 g (1.28 mmol) of
1,1-dimethylethyl 3-[(1-naphthalenyloxy)methyl]-
1-pyrrolidinecarboxylate, prepared in Step 12.1., in
10 ml of 1,4-dioxane and 6 ml of a 2N solution of
aqueous hydrochloric acid is stirred for 6 hours. It is
evaporated to dryness and then coevaporation is carried
out twice with toluene. The solid residue is washed
with diethyl ether. The solid is taken up in
dichloromethane and concentrated ammonia solution is
added until a basic pH is obtained. The system is
filtered on a Whatman PTFE cartridge and the organic

phase is concentrated, to give 0.21 g of oily product,
which is used as it is in the following step.
12.3. 2-(ethyloxy)-2-oxoethyl 3-[(l-
naphthalenyloxy)methyl]-1-pyrrolidinecarboxylate
A solution of 0.20 g (0.88 mmol) of 3-[(l-
naphthalenyloxy)methyl]pyrrolidine, prepared in
Step 12.2., and 0.35 g (1.5 mmol) of ethyl
[ (phenyloxycarbonyl)oxy]acetate, prepared in accordance
with Example 1.1, in 6 ml of toluene is heated at 60°C
overnight. It is evaporated to dryness and the residue
is taken up in a mixture of water, dichloromethane and
saturated aqueous sodium hydrogen carbonate solution.
The organic phase is decanted, dried over sodium
sulphate and evaporated to dryness. The residue is
purified by chromatography on a silica gel column,
eluting with dichloromethane and then with a 99/1
mixture of dichloromethane and methanol. This gives
0.24 g of product in oil form, which is used as it is
in the following step.
12.4. 2-amino-2-oxoethyl 3-[(1-napthalenyl-
oxy)methyl]-1-pyrrolidinecarboxylate
0.24 g (0.67 mmol) of 2-(ethyloxy)-2-oxoethyl
3- [ (1-naphthenyloxy)methyl]-1-pyrrolidinecarboxylate,
prepared in Step 12.3., is dissolved in 15 ml of a 7N
solution of ammonia (105 mmol) in methanol. The
solution is stirred in a stoppered tube at ambient
temperature for 3 days. It is evaporated to dryness and

the residue is purified by chromatography on a silica
gel column, eluting with a 97/3 then 94/6 mixture of
dichloromethane and methanol. The solid obtained is
triturated in diethyl ether and filtered, to give
0.15 g of product.
Melting point (°C): 161-163
LC-MS: M+H = 329
XH NMR (DMSO) 5(ppm) : 8.15 (m, 1H) , 7.75 (m, 1H) ,
7.50-7.30 (m, 4H), 7.10-6.90 (s, 2H), 6.80 (m, 1H),
4.40 (s, 2H), 4.20-4.05 (m, 2H), 3.90-3.30 (m, 4H) ,
2.90-2.70 (m, 1H), 2.30-2.10 (m, 1H), 2.05-1.85
(m, 1H) .
The table which follows the chemical
structures and the physical properties of some
compounds according to the invention.

The compounds of the invention were subjected
to pharmacological tests permitting determination of
their inhibitory effect on the enzyme PAAH (Fatty Acid
Amide Hydrolase).
The inhibitory activity was demonstrated in a
radioenzymatic assay based on measuring the product of
hydrolysis (ethanolamine [1-3H] ) of anandamide
[ethanolamine 1-3H] by FAAH {Life Sciences (1995), 56,
1999-2005 and Journal of Pharmacology and Experimental
Therapeutics (1997), 283, 729-734). Accordingly, mouse
brains (minus the cerebellum) are removed and stored at
-80°C. Membrane homogenates are prepared at the time of
use by homogenizing the tissues in a Polytron in a
10 mM Tris-HCl buffer (pH 8.0) containing 150 mM NaCl
and 1 mM EDTA. The enzyme reaction is subsequently
conducted in 70 /zl of buffer containing bovine serum
albumin without fatty acids (1 mg/ml). In succession,
the test compounds, at various concentrations,
anandamide [ethanolamine 1-3H] (specific activity: 15-2 0
Ci/mmol) diluted to 10 /xM with cold anandamide, and the
membrane preparation (400 /xg of frozen tissue per
assay) are added. After 15 minutes at 25°C the enzyme
reaction is terminated by adding 140 /zl of

chloroform/methanol (2:1). The mixture is stirred for
10 minutes and then centrifuged for 15 minutes at
350 0 g. An aliquot (3 0 til) of the aqueous phase
containing the ethanolamine [1-3H] is counted by liquid
scintillation.
Under these conditions, the most active
compounds of the invention exhibit IC50 values
(concentration inhibiting by 50% the control enzyme
activity of FAAH) of between 0.001 and 1 /zM. For
example, compound 58 of the table exhibits an IC50 of
0.47 /M.
It is therefore apparent that the compounds
according to the invention have an inhibitory effect on
the FAAH enzyme.
The in vivo activity of the compounds of the
invention was evaluated in an analgesia test.
Accordingly, intraperitoneal (i.p.)
administration of PBQ (phenylbenzoquinone, 2 mg/kg in a
0.9% sodium chloride solution containing 5% of ethanol)
to male OF1 mice weighing 25 to 3 0 g causes abdominal
stretches, on average 3 0 twists or contractions during
the period from 5 to 15 minutes after injection. The
test compounds are administered orally in suspension in
Tween 80 at 0.5%, 60 minutes or 120 minutes before the
administration of PBQ. Under these conditions the most
potent compounds of the invention reduce by 35 to 70%
the number of stretches induced by PBQ, within a dose

range of between 1 and 3 0 mg/kg. For example, compound
58 of the table reduces by 51% the number of stretches
induced by PBQ, at a dose of 1 mg/kg at 2 hours.
The enzyme FAAH {Chemistry and Physics of
Lipids, (2000), 108, 107-121) catalyses the hydrolysis
of endogenous derivatives of amides and of esters of
various fatty acids such as N-arachidonylethanolamine
(anandamide), N-palmitoylethanolamine, N-oleoyl-
ethanolamine, oleamide or 2-arachidonoylglycerol. These
derivatives exert various pharmacological activities by
interacting, inter alia, with cannabinoid and vanilloid
receptors.
The compounds of the invention block this
degradation pathway and increase the tissue level of
these endogenous substances. They can be used in this
respect in the prevention and treatment of pathologies
in which endogenous cannabinoids and/or any other
substrates metabolized by the FAAH enzyme are involved.
Mention may be made, for example, of the
following diseases and conditions: pain, especially
acute or chronic pain of the neurogenic type: migraine,
neuropathic pain, including forms associated with the
herpes virus and with diabetes; acute or chronic pain
associated with inflammatory diseases: arthritis,
rheumatoid arthritis, osteoarthritis, spondylitis,
gout, vasculitis, Crohn's diease, irritable bowel
syndrome;

acute or chronic peripheral pain;
dizziness, vomiting, nausea, especially those
subsequent to chemotherapy;
eating disorders, especially anorexia and cachexia of
various kinds;
neurological and psychiatric pathologies: shaking,
dyskinesia, dystonia, spasticity, obsessive-compulsive
behaviours, Tourette's syndrome, all forms of
depression and anxiety of any kind and cause, mood
disorders, psychoses; acute and chronic
neurodegenerative diseases: Parkinson's disease,
Alzheimer's disease, senile dementia, Huntington's
chorea, lesions associated with cerebral ischemia and
with cranial and medullary trauma;
epilepsy;
sleep disorders, including sleep apnoea;
cardiovascular diseases, especially hypertension,
cardiac arrhythmias, arteriosclerosis, heart attack,
cardiac ischemias;
renal ischemia;
cancers: benign skin tumours, papillomas and brain
tumours, prostate tumours, brain tumours
(glioblastomas, medulloepitheliomas, medulloblastomas,
neuroblastomas, tumours of embryonic origin,
astrocytomas, astroblastomas, ependyomas,
oligodendrogliomas, plexus tumour, neuroepitheliomas,
epiphyseal tumour, ependymoblastomas, malignant

meningiomas, sarcomatoses, malignant melanomas,
schwannomas);
disorders of the immune system, especially autoimmune
diseases: psoriasis, lupus erythematosis, diseases of
the connective tissue or collagen diseases, Sjogrer's
syndrome, ankylosing spondylarthritis, undifferentiated
spondylarthritis, Behcet's disease, haemolytic
autoimmune anaemias, multiple sclerosis, amyotrophic
lateral sclerosis, amyloses, transplant rejection,
diseases affecting the plasmocytic line;
allergic diseases: immediate or delayed
hypersensitivity, allergic rhinitis or conjunctivitis,
contact dermatitis;
parasitic, viral or bacterial infectious diseases:
AIDS, meningitis; inflammatory diseases, especially
diseases of the joints: arthritis, rheumatoid
arthritis, osteoarthritis, spondylitis, gout,
vasculitis, Crohn's disease, irritable bowel syndrome;
osteoporosis; ocular conditions: ocular hypertension,
glaucoma;
pulmonary conditions: diseases of the respiratory
tracts, bronchospasms, coughing, asthma, chronic
bronchitis, chronic obstruction of the respiratory
tracts, emphysema;
gastrointestinal diseases: irritable bowel syndrome,
intestinal inflammatory disorders, ulcers, diarrhoea;
urinary incontinence and bladder inflammation.

The use of compounds of formula (I) in base,
salt, hydrate or pharmaceutically acceptable solvate
form for preparing a medicinal product intended for
treating the abovementioned pathologies forms an
integral part of the invention.
The invention likewise provides medicinal
products which comprise a compound of formula (I), or a
salt or else a hydrate or a pharmaceutically acceptable
solvate of the compound of formula (I). These medicinal
products are employed in therapy, particularly in the
treatment of the abovementioned pathologies.
In accordance with another of its aspects the
present invention provides pharmaceutical compositions
comprising as active principle at least one compound of
formula (I). These pharmaceutical compositions include
an effective dose of a compound according to the
invention, or a salt or a hydrate or pharmaceutically
acceptable solvate of the said compound, and optionally
one or more pharmaceutically acceptable excipients.
Said excipients are selected, according to
the pharmaceutical form and the desired mode of
administration, from the customary excipients, which
are known to the person skilled in the art.
In the pharmaceutical compositions of the
present invention for oral, sublingual, subcutaneous,
intramuscular, intravenous, topical, local,
intrathecal, intranasal, transdermal, pulmonary, ocular

or rectal administration the active principle of
formula (I) above, or its salt, solvate or hydrate
where appropriate, may be administered in single-dose
administration form, in a mixture with conventional
pharmaceutical excipients, to animals and to humans for
the prophylaxis or treatment of the above disorders or
diseases.
The unit-dose administration forms which are
appropriate include oral forms such as tablets, soft or
hard gelatin capsules, powders, granules, chewing gums
and oral solutions or suspensions, forms for
sublingual, buccal, intratracheal, intraocular and
intranasal administration and for administration by
inhalation, forms for subcutaneous, intramuscular or
intravenous administration and forms for rectal or
vaginal administration. For topical application the
compounds according to the invention may be used in
creams, ointments or lotions.
By way of example a single-dose
administration form of a compound according to the
invention in tablet form may comprise the following
components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Croscaramellose sodium 6.0 mg
Maize starch 15.0 mg
Hydroxypropyl-methylcellulose 2.25 mg

Magnesium stearate 3.0 mg
The said single-dose forms contain a dose
permitting daily administration of from 0.01 to 20 mg
of active principle per kg of bodyweight, depending on
the pharmaceutical form.
There may be particular cases in which higher
or lower dosages are appropriate; such dosages also
belong to the invention. In accordance with common
practice the dosage appropriate to each patient is
determined by the doctor according to the method of
administration, the weight and the response of the said
patient.
According to another of its aspects the
invention also provides a method of treating the
pathologies indicated above, which comprises
administering an effective dose of a compound according
to the invention, one of its pharmaceutically
acceptable salts, or a solvate or a hydrate of the said
compound.

We Claim:
1. Compound conforming to the formula (I)

in which
m represents 0, 1, 2 or 3;
n represents 0, 1, 2 or 3;
X represents an oxygen or sulphur atom or an
SO or SO2 group;
R1 and R2 represent independently of one
another a hydrogen atom or a C1-3 alkyl group, or R1 and
R2 together form a group -(CH2)P-, where p represents an
integer ranging from 1 to 5 such that n + p is an
integer ranging from 2 to 5;
R3 represents a hydrogen or fluorine atom or a
hydroxyl or methyl group;
R4 represents a group of general formula
CHR5CONHR6 in which
R5 represents a hydrogen atom or a C1-6 alkyl
group and
R6 represents a hydrogen atom or a C1-6 alkyl,
C3-7 cycloalkyl or C3-7 cycloalkyl-C1-6 alkylene group;
Y represents
a group Y1 selected from in particular a phenyl,
pyridinyl, pyrimidinyl, thiazolyl, naphthyl,

quinolinyl, isoquinolinyl and benzoxazolyl; the group Y1
being optionally substituted by one or more
substituents Y2, which are identical to or different
from one another, or by a group Y3;
Y2 represents a halogen atom, a cyano, C1-8
alkyl, C1-8 alkoxy, C1-8 fluoroalkyl, C1-8 fluoroalkoxy,
phenyloxy or phenyl-C1-C8 alkylene group;
Y3 represents a phenyl group; it being
possible for Y3 to be substituted by one or more groups
Y2 which are identical to or different from one another;
in the form of a base, addition salt with an acid,
hydrate or solvate.
2. Compound of formula (I) as claimed in Claim 1,
wherein
Y represents
a group Y1 selected from in particular a phenyl or a
naphthyl; the group Y1 being optionally substituted by
one or more substituents Y2, which are identical to or
different from one another, or by a group Y3;
Y2 represents a halogen atom, a cyano, C1-8
alkyl, C1-8 alkoxy, C1-8 fluoroalkyl, C1-8 fluoroalkoxy,
phenyloxy or phenyl-C1-C8 alkylene group;
Y3 represents a phenyl group; it being
possible for Y3 to be substituted by one or more groups
Y2 which are identical to or different from one another;

in the form of a base, addition salt with an acid,
hydrate or solvate.
3. Compound of formula (I) as claimed in any one of
Claims 1 and 2, wherein
m represents 0, 1, 2 or 3;
n represents 0, 1, 2 or 3;
R1 and R2 represent independently of one
another a hydrogen atom or a C1-3 alkyl group, or R1 and
R2 together form a group -(CH2)P-, where p represents an
integer ranging from 1 to 5 such that n + p is an
integer ranging from 2 to 5;
with the proviso that, when R1 and R2 represent
independently of one another a hydrogen atom or a C1-3
alkyl group, m + n > 1;
in the form of a base, addition salt with an acid,
hydrate or solvate.
4. Compound of formula (I) as claimed in any one of
Claims 1 to 3, wherein
m represents 0, 1, 2 or 3; and/or
n represents 0, 1, 2 or 3; and/or
R1 and R2 together form a group -(CH2)P-, where
p represents an integer ranging from 1 to 4 such that
n + p is equal to 4;
in the form of a base, addition salt with an acid,
hydrate or solvate.

5. Compound of formula (I) as claimed in any one of
Claims 1 to 4, wherein X represents an oxygen atom;
in the form of a base, addition salt with an acid,
hydrate or solvate.
6. Compound of formula (I) as claimed in any one of
Claims 1 to 5, wherein R3 represents a hydrogen atom;
in the form of a base, addition salt with an acid,
hydrate or solvate.
7. Compound of formula (I) as claimed in any one of
Claims 1 to 6, selected from the following compounds:
2-(methylamino)-2-oxoethyl {2-[(4-chlorophenyl)oxy]ethyl}
carbamate;
2-amino-2-oxoethyl (2-[(4-cyanophenyl)oxy]ethyl)
carbamate;
2-amino-2-oxoethyl [4-(1-naphthalenyloxy]butyl]
carbamate;
2-(methylamino)-2-oxoethyl 4-[(4'-fluoro-4-biphenyl)
oxy]-1-piperidinecarboxylate;
2-(methylamino)-2-oxoethyl 4-{[(4-bromophenyl)oxy]
methyl}-1-piperidinecarboxylate;
2-(methylamino)-2-oxoethyl 4-{[(4'-(trifluoromethyl)-
4-biphenyl)oxy]methyl}-1-piperidinecarboxylate;
2-amino-2-oxoethyl 4-[(1-naphthalenyloxy)methyl]-1-
piperidinecarboxylate;
2-amino-2-oxoethyl 4-[(7-quinolinyloxy)methyl]-1-
piperidinecarboxylate;
2-(methylamino)-2-oxoethyl 4-{2-[(4-
bromophenyl)oxy]ethyl}-1-piperidinecarboxylate;
2-(methylamino)-2-oxoethyl 4-{2-[(4'-chloro-4-
biphenyl)oxy]ethyl}-1-piperidinecarboxylate;
2-amino-2-oxoethyl 4-[2-(7-isoquinolinyloxy)ethyl]-1-

piperidinecarbamate;
2-amino-2-oxoethyl 3-[(1-naphthalenyloxy)methyl]-1-
pyrrolidinecarboxylate.
8. Process for preparing a compound of formula (I) as
claimed in any one of Claims 1 to 7, comprising the
step consisting in converting a compound of the formula
(IV)

in which Y, X, Rl, R2, R3, R5, n and m are as defined
according to any one of Claims 1 to 7 and R represents
a methyl or ethyl group,
by aminolysis by means of an amine of formula R6NH2
where R6 is as defined in formula (I) according to
Claim 1.
9. Pharmaceutical composition comprising at least one
compound of formula (I) as claimed in any one of Claims
1 to 7, in base, salt, hydrate or solvate form that is
pharmaceutically acceptable, and, optionally, one or
more pharmaceutically acceptable excipients.
10. The composition as claimed in claim 9, wherein
said composition is useful in the prevention or the
treatment of a pathology in which endogenous
cannabinoids and/or any other substrates metabolized by

the enzyme FAAH are involved.
11. The composition as claimed in any one of claims 9
and 10, wherein said composition is useful in the
prevention or the treatment of acute or chronic pain,
dizziness, vomiting, nausea, eating disorders,
neurological and psychiatric pathologies, acute or
chronic neurodegenerative diseases, epilepsy, sleep
disorders, cardiovascular diseases, renal ischemia,
cancers, disorders of the immune system, allergic
diseases, parasitic, viral or bacterial infectious
diseases, inflammatory diseases, osteoporosis, ocular
conditions, pulmonary conditions, gastrointestinal
diseases or urinary incontinence.

The invention discloses a compound conforming to the
formula (I)

wherein X, Y, R1, R2, R3. R4, m, n and p are as defined
in the specification.
The invention is also for a process for preparation of
said compound and pharmaceutical composition comprising
it.

Documents:

01944-kolnp-2006 abstract.pdf

01944-kolnp-2006-abstract-1.1.pdf

01944-kolnp-2006-assignment.pdf

01944-kolnp-2006-claims-1.1.pdf

01944-kolnp-2006-claims.pdf

01944-kolnp-2006-correspondence others-1.1.pdf

01944-kolnp-2006-correspondence others.pdf

01944-kolnp-2006-correspondence-1.2.pdf

01944-kolnp-2006-description complete.pdf

01944-kolnp-2006-form-18.pdf

01944-kolnp-2006-form1.pdf

01944-kolnp-2006-form3.pdf

01944-kolnp-2006-form5.pdf

01944-kolnp-2006-international publication.pdf

01944-kolnp-2006-international search authrity report.pdf

01944-kolnp-2006-priority document.pdf

1944-KOLNP-2006-ABSTRACT 1.1.pdf

1944-KOLNP-2006-AMANDED PAGES OF SPECIFICATION.pdf

1944-KOLNP-2006-CLAIMS.pdf

1944-kolnp-2006-correspondence.pdf

1944-kolnp-2006-description (complete) 1.1.pdf

1944-KOLNP-2006-ENGLISH TRANSLATION OF PCT.pdf

1944-KOLNP-2006-EXAMINATION REPORT REPLY RECIEVED.pdf

1944-kolnp-2006-examination report.pdf

1944-KOLNP-2006-FORM 1 1.1.pdf

1944-kolnp-2006-form 13.1.pdf

1944-KOLNP-2006-FORM 13.pdf

1944-kolnp-2006-form 18.pdf

1944-KOLNP-2006-FORM 2.pdf

1944-KOLNP-2006-FORM 3 1.1.pdf

1944-kolnp-2006-form 3.pdf

1944-kolnp-2006-form 5.pdf

1944-kolnp-2006-gpa.pdf

1944-kolnp-2006-granted-abstract.pdf

1944-kolnp-2006-granted-claims.pdf

1944-kolnp-2006-granted-description (complete).pdf

1944-kolnp-2006-granted-form 1.pdf

1944-kolnp-2006-granted-form 2.pdf

1944-kolnp-2006-granted-specification.pdf

1944-KOLNP-2006-OTHERS.pdf

1944-kolnp-2006-others1.1.pdf

1944-KOLNP-2006-PETITION UNDER RULE 137.pdf

1944-kolnp-2006-reply to examination report.pdf

1944-kolnp-2006-translated copy of priority document.pdf

abstract-01944-kolnp-2006.jpg

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Patent Number

249627

Indian Patent Application Number

1944/KOLNP/2006

PG Journal Number

44/2011

Publication Date

04-Nov-2011

Grant Date

31-Oct-2011

Date of Filing

11-Jul-2006

Name of Patentee

SANOFI-AVENTIS

Applicant Address

174, AVENUE DE FRANCE, F-75013, PARIS

Inventors:

#	Inventor's Name	Inventor's Address
1	FROISSANT JACQUES	LA MULOTIERE, CEDEX 981, F-41160 BREVAINVILLE
2	ABOUABDELLAB AHMED	2, RUE DES EGLANTIERS, F-94320 THIAIS
3	HOORNAERT CHRISTIAN	49, AVENUE ARISTIDE BRIAND, F-92160, ANTONY
4	ALMARIO GARCIA ANTONIO	26, AVENUE ROGER SALENGRO, F-92290, CHATENAY MALABRY

PCT International Classification Number

C07D 207/08

PCT International Application Number

PCT/FR2005/000028

PCT International Filing date

2005-01-07

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0400389	2004-01-16	France