MXPA98000963A - Derivatives of benzene sulfonamide, its preparation and its applications in terapeut - Google Patents

Abstract

The present invention relates to: The benzenesulfonamide compounds of the general formula (I), wherein R 1 is a hydrogen atom or halogen such as chlorine or fluorine or a C 1-4 alkyl or straight or branched C 1-4 alkoxy group, each R 2 , R3 and R4, which are the same or different, is a hydrogen atom or a straight, branched or cyclic C1-4 alkyl group and R5 is a hydrogen atom or a C1-2 alkyl group. C1-2 Fluoroalkyl or C1-2 perfluoroalkyl, in the form of enantiomers, diastereoisomers or mixtures thereof, including racemic mixtures, as well as the acid addition salts thereof, are provided for their therapeutic

Description

DERIVATIVES OF BENCENSULFONAMIDE. Sü PREPARATION AND ITS APPLICATIONS IN THERAPEUTICS The present invention relates to benzenesulfonamide derivatives, as their preparation and their applications in therapeutics. The compounds of the invention correspond to the general formula (I) wherein: R2 represents a hydrogen or halogen atom, such as chlorine or fluorine, or an alkyl group with 1 to 4 carbon atoms or straight or branched chain alkoxy with 1 to 4 carbon atoms, R2, R3 and R independently from each other, hydrogen atoms or alkyl groups with 1 to 4 carbon atoms, straight chain, branched or cyclic, and R 5 represents a hydrogen atom, an alkyl group with 1 to 2 carbon atoms, fluoroalkyl with 1 or 2 carbon atoms, or perfluoroalkyl with 1 or 2 carbon atoms.

The term C 1 -C 4 -alkyl comprises linear, branched-chain or cyclized radicals, having up to 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl , preferably alkyl with 1 or 2 carbon atoms, such as methyl and ethyl. The term "fluoroalkyl with 1 to 2 carbon atoms" comprises straight-chain radicals with 1 to 2 carbon atoms, as defined above, in which at least one of the hydrogen atoms is replaced by a fluorine, it being understood that all hydrogen atoms are not replaced by fluorine atoms. The term "perfluoroalkyl with 1 or 2 carbon atoms" comprises straight-chain radicals with 1 or 2 carbon atoms as defined above, in which all hydrogen atoms are replaced by a fluorine. The term C 1 -C 4 -alkoxy comprises straight or branched chain radicals, up to 4 carbon atoms, linked by an oxygen atom, comprising methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and veltobutoxy, preferably alkoxy with 1 to 2 carbon atoms, methoxy and ethoxy. The compounds of the general formula (I) have one or more asymmetric carbon atoms. Therefore, they can exist in the form of enantiomers or diastereomers. These enantiomers, diastereoisomers, as well as their mixtures including the racemic mixtures, form pof the invention. The compounds of the general formula (I) can be presented in the form of pharmaceutically acceptable acid addition salts, which also form pof the invention. According to the present invention, the preferred salts are the salts of methanesulfonates, oxalates and fumarates. The compounds of the general formula (I) in which R 5 represents an alkyl group with 1 to 2 carbon atoms, fluoroalkyl with 1 to 2 carbon atoms, or perfluoroalkyl with 1 to 2 carbon atoms, exist in the form of isomers without or trans. These forms as well as their mixtures form pof the invention. Preferred compounds are those for which R 5 represents a hydrogen atom, a methyl or ethyl, preferably a hydrogen or a methyl, in the form of enantiomers or diastereomers, or mixtures of these different forms, including mixtures racemates, as well as their addition salts to pharmaceutically acceptable acids. Other preferred compounds are those for which it represents a hydrogen atom, a fluorine, a chlorine, or an alkoxy group with 1 to 4 carbon atoms, preferably methoxy or ethoxy, in the form of enantiomers or diastereoisomers, or mixtures thereof. these different forms, including racemic mixtures, as well as their addition salts to pharmaceutically acceptable acids. Other compounds of choice are those for which R 2 and R 3 independently represent a hydrogen atom, a methyl, an ethyl, or an isopropyl, preferably a hydrogen, in the form of enantiomers or diastereoisomers, or a mixture of these different forms, including racemic mixtures, as well as their pharmaceutically acceptable acid addition salts. Mention may be made, among these, of the compounds for which: R x represents a hydrogen atom, such as a fluorine, a chlorine or an alkoxy group with 1 to 4 carbon atoms, preferably methoxy or ethoxy, R 2 and R 3 independently represent one another, a hydrogen atom, a methyl, an ethyl, or an isopropyl, preferably a hydrogen, R represents a hydrogen atom or an alkyl group with 1 to 4 straight carbon atoms, branched or cyclic and R5 represents a hydrogen atom, a methyl or an ethyl, preferably a hydrogen atom or a methyl, in the form of enantiomers or diastereoisomers, or of mixtures of these different forms, including racemic mixtures, as well as their addition salts to pharmaceutically acceptable acids, and very particularly mention may be made of a- (aminomethyl) -2-methoxy-5-sulfonamidobenzenemethanol and its salts, (+) -a- (aminomethyl) -2-methoxy-5-sulfonamidobenzene-methanol and its salts, (-) -a- (aminomethyl) -2-methoxy-5-sulfonamidobenzenemethanol and its salts, a- (aminomethyl) -2-chloro-5-sulfonamidobenzenemethanol and its salts, Y - (aminomethyl) -2-fluoro-5-sulfonamidobenzenemethanol and its salts. The compounds of the general formula (I) in which R? represents an alkoxy group and R2 and R3 represent carbon atoms can be prepared according to the procedure represented in Annex 1, which consists of treating a benzaldehyde derivative of the formula (V) in which Rx is defined as above, by the ethyl orthoformate, in the presence of ammonium chloride, and then sulfuric chlorohydrin, treating the 5-chlorosulfonylbenzaldehyde derivative of the formula (IV) with an amine of the formula RNH2 in which R4 is defined as or in the formula (I), then reacting the 5-sulfonamidobenzaldehyde derivative of the formula (III) with the trimethylsilyl cyanide (TMSCN), in the presence of iodide and finally reducing the compound of the formula (II) thus obtained, by the borohydride of lithium, in the presence of tri-ethylsilyl chloride (TMSC1). The compounds of the general formula (I) can also be prepared, according to the process represented in Annex 2, from a sulfonamidoacetophenone derivative of the formula (XII). For the case where R? defined as in the general formula (I), with the exception of the alkyl value, this process consists in treating the 5-sulfonamidophenylketone derivative of the formula (XII) by bromine, and then reacting the compound of the formula (XI), either with the lithium chloride to obtain the compound of the formula (X) which is then reduced by borane to give the compound of the formula (IX), then treated with the sodium nitride to give the compound of the formula (VIII ), already. either with sodium nitride and then with sodium borohydride to obtain the compound of formula (VIII), or with sodium borohydride in the presence of potassium carbonate to obtain the compound of formula (VII), to finally treat the compound of the formula (VIII) with hydrogen in the presence of a catalyst such as palladium on carbon, and in the case where R? it is not a chlorine atom, either by triphenylphosphine and then by ammonia in the case where R1 is a chlorine atom, to obtain the compound of the general formula (I) in which R2 and R3 are hydrogen atoms, or treating the compound of the formula (VI) either with an amine of the formula R (R3) NH in which R2 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms and R3 is an alkyl group with 1 to 4 carbon atoms, to obtain the compound of the general formula (I) in which R2 and R3 are defined as above, either with an amine of the formula R2 (Bn) NH in which R2 is an alkyl group with 1 to 4 carbon atoms and Bn is a benzyl group, to obtain a compound of the formula (VI), which is then reduced with hydrogen in the presence of a catalyst, such as palladium on carbon, to give the compound of the formula general (I) in which R2 is an alkyl group. In the case where R1 is an alkyl group, this process consists in treating the compound of the formula (XII) with the benzyltrimethylammonium dichloroiodate to obtain the compound of the formula (X) in which R? is an alkyl group, which is then treated as indicated above, to obtain the compound of the general formula (I) in which R2 and R3 are hydrogen atoms and R1 is an alkyl group, by the compounds of the corresponding formulations (IX) and (VIII). The compounds of the formula (XII) in which R? , R4 and R5 defined as in the general formula (I) can be prepared by reaction of a phenylketone derivative of the formula (XIV) wherein R is defined as in the general formula (I) with sulfuric chlorohydrin to give a chlorosulfonylphenyl ketone derivative of the formula (XIII) 1* which is then treated with an amine of the formula R 4 NH 2, in which R is defined as in the general formula (I). The compounds of the formula (XII) in which R4 represents a hydrogen atom can also be prepared by reaction of a compound of the formula (XVII) wherein A is identical to R1 as defined in general formula (I) or represents a hydroxyl group, with nitric acid, to obtain a nitrophenyl ketone derivative of the formula (XVI) (XVI) which is reduced as a derivative of aminophenyl ketone with hydrogen in the presence of palladium on carbon or with tin chloride, optionally after treatment with an alkyl iodide, for the case where A represents a hydroxyl group, to obtain the derivative of 2-alkylphenyl ketone, to finally treat the compound of the formula (XV) with sodium nitrite, cuprous chloride and sulfur dioxide. The enantiomers of the compounds of the general formula (I) are prepared from the enantiomers of the compounds of the formula (VIII) which are obtained at the same time, either by enantio-eelective ententee, which comprises the treatment of the composition of the formula (XI) with the eodium nitride and the reaction of the compound of the formula (XVIII) thus obtained and (XVIII) with the (+) or (-) - B-chlorodiisopinocanphenylborane (DIP-C1) to obtain respectively the energetic (+) and (-) of the compound of the formula (VIII), or by enzymatic resolution of the compound (IX) ) which comprises the treatment of the compound of the racemic formula (IX) with acetic acid, selective enzymatic hydrolysis, with lipase SP 523 (lipase obtained by the DNA technique recombined from Aspergillus orysae), the compound of the formula (XIX) as well as formed leading to the (+) enantiomer of the compound of the formula (IX) and the (-) enantiomer of the compound of the formula (XIX) not hydrolyzed, the separation by chromatography of the (+) enantiomer of the compound of the formula (IX) and of the enantiomer (-) of the compound of the formula (XIX) and the hydroylness of the (-) enantiomer of the compound of the formula (XIX) to obtain the (-) enantiomer of the compound of the formula (IX) and finally the reaction of the enantiomers (+) and (-) of the compound of the formula (IX) with the sodium nitride, or by chemical resolution, which comprises the reaction of the compound of the formula (VIII) with N-carbobenzyloxy-L-alanine (N) -CBZ-alanine), the separation by chromatography and then the hydrolysis of the enantiomeric loe of the compound of the formula (XX) The salts of the compounds of the general formula (I) are obtained by reaction of the compounds of the general formula (I) in base form with the pharmaceutically acceptable acids. The starting products are known in the literature or are available directly on the market. The following examples illustrate the procedures and techniques suitable for the preparation of this invention, but without limiting the scope of the claim. The elemental microanalyses and the NMR and IR spectra confirm the structures of the obtained compounds. Example 1; O- (aminomethyl) -2-methoxy-5-sulfonamidobenzenemethanol methanesulfonate 1.1. 2-methoxy-5-sulfonamidobenzaldehyde This compound is obtained according to the process described in French Patent FR 73 35277, by passing a stream of ammonia in a solution of 2-methoxy-5-chlorosulfonylbenzaldehyde in chloroform. According to the same procedure, treating the 2-methoxy-5-chloro-eulphonylbenzaldehyde with 10 equivalents of amine of the formula R 4 NH 2, for 3 hours at room temperature, the following compounds were obtained: 2-methoxy-5-methylsulfonamidobenzaldehyde. Melting point: 118 ° C. - 2-methoxy-5-cyclopropylsulfonamidobenzaldehyde. Melting point: 162 ° C. 2-methoxy-5-isopropylsulfonamidobenzaldehyde. Melting point: 125 ° C. - 2-methoxy-5-t-butylsulfonamidobenzaldehyde. Melting point: 99 ° C. 1. 2. a-aminomethyl-2-methoxy-5-sulfonamidobenzenemethanol In a 100 ml round flask, introduce 10.4 g (48.3 millimole) of 2-methoxy-5-eulphonamidobenzaldehyde and 18.4 ml (96.6 millimole) of trimethylsilyl cyanide, then 0.5 g (1.56 mmol) of zinc iodide are added and the mixture is stirred at room tempere for 10 minutes. Then 20 ml of anhydrous tetrahydrofuran are added and the solution is transferred to an ampoule of bromine. On the other hand, in a 500 ml round flask, 100 ml of anhydrous tetrahydrofuran and 2.6 g (119 mmoles) of lithium borohydride are introduced. The solution is stirred, and then 30 ml (236 mmol) of trimethylylyl chloride are added dropwise and the mixture is stirred at room tempere for 10 minutes. The trimethylcyanohydrin solution prepared above is then added dropwise. The mixture is stirred for 16 hours and then 20 ml of ethanol are added dropwise and the solution is concentd. Afterwards, 120 ml of a 20% solution of potassium hydroxide are added dropwise and the solution is concentd. The residue is purified by chromatography on a column with a 90/9/1 mixture of dichloromethane, methanol and ammonia and then recrystallized from ethanol and dried with a vacuum desiccator over phosphoric anhydride. 0.30 g of product are obtained. Melting point: 217 at 220 ° C. 1. 3. α-Aminomethyl-2-methoxy-5-sulfonamidobenzenemethanol methanesulfonate. To the product obtained in step 1.2, one equivalent of methanesulfonic acid in 2M solution in methanol is added. After recrystallization from methanol and diethyl ether and drying in the desiccator under vacuum over phosphoric anhydride, 0.370 g of product are obtained. Melting point: 210 to 212 ° C Example 2: (-) - Ot- .aminOmethyl) -2-metOXi-5-sulfonamidobenzenemethanol methanesulfonate 2.1. 2-methoxy-5-chlorosulfonylacetophenone In a 1-liter round container, 951 g (8.16 mol) of sulfuric chlorohydrin. It is cooled to approximately -5 ° C, and then 81.5 g are added dropwise. (0.544 mol) of 2-methoxy-acetophenone without exceeding 0 ° C. The mixture is then stirred at room tempere for 16 hours and then slowly emptied onto stacked ice while stirring. It is filtered, the product is washed with ice water and then dried in the desiccator under vacuum over phosphoric anhydride. 87.5 g of product are obtained. Melting point: 85-86 ° C. 2.2. 2-methoxy-5-sulfonamidoacetophenone In a 1 liter round container, introduce 86 g (0.344 mol) of 2-methoxy-5-chlorosulfonylacetophenone and 690 ml of chloroform. The mixture is stirred until dissolved and then cooled to 0 ° C with an ice bath and a stream of ammonia is passed in the solution for 1 hour. The mixture is then allowed to return to room tempere, then the solvent is evapod and then 250 ml of 1M hydrochloric acid are added. The suspension obtained is stirred for 3 hours, then it is filtered, the product is washed with ice water and dried in the desiccator under vacuum over phosphoric anhydride. 72.8 g of product are obtained. Melting point: 161-162 ° C. According to the same procedure, 2-methyl-5-sulfonamidoacetophenone was obtained. Melting point: 215 ° C. 2.3. a-bromo-2-methoxy-5-sulfonamidoacetophenone 60.36 g (0.262 mol) of 2-methoxy-5-sulfonamidoacetophenone and 530 ml of acetic acid are introduced into a three-neck flask with a liter capacity. The mixture is stirred and heated to 50 ° C. Then, 41.95 g (0.262 mol) of bromine are added dropwise, the mixture is stirred for 16 hours and allowed to return to room tempere and filtered. The precipitate is washed with a minimum of ethanol and dried in the desiccator under vacuum over phosphoric anhydride. 49. g of product are obtained. Melting point: 154 to 156 ° C. 2.4. a-azido-2-methoxy-5-sulfonamidoacetophenone In a three neck flask with a capacity of 100 ml, 7 g (0.023 mole) of a-bromo-2-methoxy-5-sulfonamidoacetophenone, 2.6 ml (0.045 mole) of acetic acid and 23 ml of ethanol are introduced. The suspension is heated at 50 ° C by stirring and then adding, dropwise, a solution of 2.94 g (0.045 moles) of sodium nitride in 8 ml of water. The suspension is stirred at 50 ° C for 45 minutes, and then allowed to return to room temperature. It is filtered, the precipitate is washed with a minimum of cold ethanol, and then dried in the desiccator under vacuum over phosphoric anhydride. 5.46 g of product are obtained. Melting point: 155 to 160 ° C. (with decomposition). 2.5. (-) -a-Azidomethyl-2-methoxy-5-sulfonamidobenzene-methanol 16.2 g (0.060 mole) of a-azido-2-methoxy-5-sulfonamidoacetophenone are introduced into a three-necked flask with a capacity of 500 ml. ml of anhydrous tetrahydrofuran. The solution is cooled to -25 ° C, and a solution of 38.5 g (0.12 mol) of (-) - DIP-Cl in 30 ml of anhydrous tetrahydrofuran is added, under a flow rate of 1.5 ml per minute. After 90 minutes the solution is allowed to return to room temperature and 10 ml of methanol are added. The reaction mixture is then concentrated and the residue is purified by column chromatography with a mixture of 40/60 petroleum ether and ethyl acetate. After recrystallization from isopropanol and drying in the desiccator under vacuum over phosphoric anhydride, 11.55 g of product are obtained (ee = 99.9%). Melting point: 122 to 125 ° C. -a_20D = ~ 1 7-7 ° (or = 1; di-ethyl sulfoxide). 2.6. (-) - a-aminomethyl-2-methoxy-5-sulfonamidobenzenemethanol In a 1 liter reactor, 11 g (0.040 mol) of (-) - c.-azidomethyl-2-methoxy-5-sulfonamidobenzenemethanol, 500 ml are introduced of ethanol and 2.2 g of 10% palladium on carbon. The reactor is closed, purged with nitrogen and the mixture is stirred under 400 kPa of hydrogen, at room temperature, for 3 hours. The reaction mixture is then filtered on whatman paper, the catalyst recovered in 200 ml of methanol is suspended and the mixture is heated to boiling for 30 minutes. It is then filtered on whatman paper, the filtrates are combined and the material is concentrated and the residue is dried in the desiccator under vacuum over anhydrous phosphoric. 9.4 g of (-) -a-aminomethyl-2-methoxy-5-sulfonamidobenzenemethanol are obtained. Recrystallization of the product from 388 ml of methanol gives 5.46 g of product. On the other hand, by concentrating the mother liquor and recrystallizing the residue in 400 ml of ethanol, 1.93 g of product are obtained, ie a total of 7.39 g of product. Melting point: 217 at 220 ° C. [α] 20 D = - 85.2 ° (methanol). 2.7. (-) -a-Aminomethyl-2-methoxy-5-sulfonamidobenzenemethanol methanesulfonate The product obtained in the previous step, is added one equivalent of methanesulfonic acid in 2M solution in methanol. After recrystallization from methanol and diethyl ether and drying the product in the desiccator under vacuum over foephoric anhydride, the (-) -a-aminomethyl-2-methoxy-5-sulfonamidobenzenemethanesulfonate is obtained. Melting point: 232-233 ° C. [a] 20D = - 41.0 ° (c = 0.796, water).

Example 3; Metansulfonate of (+)? of (+) -a-aminomethyl-2-methoxy-5-sulfonamidobenzenemethanol 3.1. a-chloro-2-methoxy-5-sulfonamidoacetophenone 4.36 g (14.1 millimoles) of a-bromo-2-methoxy-5-sulfonamidoacetophenone, 200 ml of anhydrous acetone and 50 g of water are introduced into a round container with a capacity of 500 ml. Lithium chloride. The mixture is heated under reflux for 16 hours, then the solution is concentrated, 200 ml of water are added and 80 ml of ethyl acetate are extracted 3 times each time. The organic phases are combined, the material is dried over magnesium sulfate and concentrated. 3.56 g of product are obtained. Melting point: 162 QC. 3.2. a-chloromethyl-2-methoxy-5-sulfonamidobenzenemethanol In a round flask with a capacity of 100 ml, introduce 10 ml of anhydrous tetrahydrofuran and 4 ml of a 1M solution of borane in tetrahydrofuran. A solution of 1.0 g (3.8 mmol) of a-chloro-2-methoxy-5-sulfonamido-acetophenone in 10 ml of tetrahydrofuran is added dropwise. The mixture is stirred for 10 hours at room temperature and then 10 ml of methanol are added. The solution is concentrated, 40 ml of water are added and it is extracted 3 times each time with 60 ml of ethyl acetate. The organic phases are combined, the material is taken up over magnesium sulfate and concentrated. 1.0 g of product are obtained. Melting point: 112 ° C. 3.3. Acetate (+) -a-chloromethyl-2-methoxy-5-sulfonamidobenzyl In a 250 ml round container, introduce 2. 64 g (9.9 mmol) of -chloromethyl-2-methoxy-5-sulfonamidobenzenemethanol and 100 ml of dichloromethane. Then, with stirring, 10 ml of dimethylformamide, then 852 μl of acetic acid, 2.56 g of dicyclohexylcarbodiimide and 121 mg of dimethylaminopyridine are added. The mixture is allowed to react for 1 hour at room temperature, then it is filtered, rinsed with 50 ml of a 5% sodium hydrogencarbonate solution and then with 50 ml of water. The rinse water is extracted 2 times, each time with 20 ml of acetic acid and then the organic phases are combined, the material is dried and concentrated. Chromatography of the residue on a silica column with a mixture of 25/75 ethyl acetate and cyclohexane gives 1.9 grams of product. Melting point: 131 ° C. 3. 4. (+) - and (-) -a-chloromethyl-2-methoxy-5-sulfonamidobenzenemethanol In a three-necked flask with a capacity of 500 ml, 2.86 g (9.3 mmol) of (±) - - acetate is introduced. chloromethyl-2-methoxy-5-sulfonamido benzyl and 110 ml of t-butyl methyl ether. It is stirred for 15 minutes, and then 170 ml of phosphate buffer is added and stirred vigorously until an emulsion is obtained. Then 0.57 g (20%) of SP 523 lipase is added and the reaction is followed at room temperature by "pHstat" (addition of 1M sodium hydroxyl) and by HPLC on qiral column and the conversion rate of the ester and the enantiomeric excesses of ester and alcohol. After 45 hours of reacting with the enantheromeric excesses of the ester and alcohol being greater than 95%, the reaction medium is diluted with 800 ml of ethyl acetate, the organic phase is separated and the aqueous phase is extracted again. times each time with 500 ml of ethyl acetate. The organic faees are combined, the material is dried, the residue is concentrated and the residue is purified with 2 flash chromatographs, successively on a silica column with a mixture of 30/70 ethyl acetate and cyclohexane. 1.32 g of (-) - a-chloromethyl-2-methoxy-5-sulfonoamidobenzyl acetate (ee = 99%) and 1.05 g of (+) -a-chloromethyl-2-methoxy-5-sulfonoamidobenzenemethanol are obtained. The (+) enantiomer is purified by dissolving in 10 ml of ethyl acetate and recrystallizing by addition of hexane (ee: 98%). Melting point: 117-118 ° C. [a] 20D = + 40 ° (c = 0.305; methanol). 61 μl of acetyl chloride is added to 100 ml of methanol and the mixture is stirred for 15 minutes. Then 1.32 g of (-) - a-chloromethyl-2-methoxy-5-sulfonamidebenzyl acetate is added and the mixture is refluxed for 1 hour (97% conversion rate indicated by HPLC). The mixture is then evaporated and then the residue is introduced into 100 ml of ethyl acetate and neutralized in medium with 5 ml of 2% ethyl hydrogencarbonate. The carbonate phase is extracted twice each time with 5 ml of ethyl acetate and then the organic phases are combinedThe material is dried and concentrated to 30 ml and cyclohexane is added. After one night at room temperature, the crystallized product is filtered. 1 g of (-) - chloromethyl-2-methoxy-5-sulfonoamidobenzenemethanol is obtained. Melting point: 114-115 ° C. [a] 20D = -41.4 ° (c = 0.295; methanol). 3. 5. (+) -a-Azidomethyl-2-methoxy-5-sulphonoamidobenzenemethanol 1.58 g (5.9 mmol) of (+) - chloromethyl-2-methoxy-5-sulfonamidebenzenemethanol are introduced into a round flask with a capacity of 250 ml. 20 ml of dimethylformamide and 1.54 g of sodium nitride. The reaction mixture is heated at 110 ° C for 16 hours, and then 200 ml of water are added and extracted 3 times each time with 80 ml of ethyl acetate. The organic phases are then combined, the material is dried over magnesium sulfate and concentrated. 1.2 g of product are obtained. Melting point: 122 ° C. [α] 20 D = + 144 ° (c = 1; dimethylsulfoxide). According to the same procedure from (-) - chloromethyl-2-methoxy-5-eulphonamidobenzenemethanol, ee obtained (-) - azide-methyl-2-methoxy-5-eulphonamidobenzenemethanol. Melting point: 122 ° C. [a320D = -147.7 ° (c = 1; dimethylsulfoxide). 3. 6. (+) -at-Aminomethyl-2-methoxy-5-sulfonoamidobenzenemethanol From (+) - Azidomethyl-2-methoxy-5-sulfonoamidobenzenemethanol treated under the conditions described in step 6 of Example 2, (+) - a-aminomethyl-2-methoxy-5-sulfonoamidobenzenemethanol was obtained. fusion: 217-220 ° C. [α] 20 D = + 40 ° (c = 1; di-ethylsulfoxide). According to the same procedure from (-) - azide-methyl-2-methoxy-5-sulfonamidobenzenemethanol, (-) - a-aminometi1-2-methoxy-5-sulfonamidobenzenemethanol was obtained. Melting point: 217-220 ° C. [< *] 20D = -44 ° (c = 1; dimethylsulfoxide). 3. 7. (+) - α-Aminomethyl-2-methoxy-5-sulfonamidobenzenemethanesulfonate. From (+) - c.-aminomethyl-2-methoxy-5-sulfonamidobenzenemethanol treated with one equivalent of methanesulfonic acid in solution in 2M solution in methanol, recrystallization from methanol and diethyl ether and drying in the desiccator under vacuum over phosphoric anhydride (e) methanesulfonothane was obtained from (+) - -aminomet il-2-methoxy-5-eulphonamidobenzenemethanol. Melting point: 234 ° C. [a] 20D = + 41 ° (c = 0.9945, water). According to the same procedure from (-) - α-aminomethyl-2-methoxy-5-sulfonamidobenzenemethanol, the methanesulfonate of (-) - c_-aminomet i 1-2-methoxy-5-sulphonamidobenzenemethanol was obtained.

Melting point: 235 ° C. [a] 20D = -37.3 ° (c = 0.969; 80/20 methanol / water) Example 4; (+) And (-) - O.-aminomethyl-2-methoxy-5-sulfonamidebenzenemethanesulfonate 4.1. (+.) -a-Azidomethyl-2-methoxy-5-sulfonamidobenzenemethanol. In a round flask with a capacity of 500 ml, 5 g (18.5 mmol) of azido-2-methoxy-5-sulfonamidoacetophenone and 150 ml of methanol are introduced. The solution is cooled to 0 ° C, then 0.963 g (16.6 millimoles) of sodium borohydride are added. The solution is stirred for 10 minutes and then allowed to return to room temperature and 15 ml of a 5% hydrochloric acid solution are added. The mixture is then concentrated to the reaction mixture, then the residue is purified by column chromatography with a 40/60 mixture of petroleum ether and ethyl acetate and dried in the desiccator under vacuum over phosphoric anhydride. 3.85 g of product are obtained. Fusion Point: 123 ° C. 4. 2. (+) - and (-) -a - Az idome ti 1 - 2 -me t ox i -5-sulfonamidobenzenemethanol / N-carbobenzyloxy-L-alanine ester In a round flask with a capacity of 250 ml, 4.66 are introduced. g (20.9 millimole) of N-carbobenzyloxy-L-alanine, 25 ml of dichloromethane and 3.58 g (17.4 millimole) of 1,3-dicyclohexylcarbodiimide. The mixture is stirred for 20 minutes at room temperature, and then 3.8 g (13.9 mmol) of a-azidomethyl-2-methoxy-5-sulfonamidobenzenemethanol and 0.17 g (0.14 mmol) of dimethyl-aminopyridine are added. The reaction mixture is stirred for two hours, and then concentrated under vacuum and the residue is purified by several silica column chromatographies with a 99/1 mixture of dichloromethane and acetone. 1.58 g of (+) - azide-methyl-2-methoxy-5-sulfonamidobenzenemethanol, N-carbobezyloxy-L-alanine ester and 2.92 g of (-) - a-azidomethyl-2-methoxy-5-sulfonamidobenzenemethanol, N- are obtained. carbobenciloi-L-alanine ester. Melting point: 170 ° C (with decomposition). 4. 3. (+) - ot-Azidomethyl-2-methoxy-5-sulfonamidobenzenemethanol In a round flask with a capacity of 100 ml, 0.91 g (1.9 mmol) of (+) -a-azidomethyl-2-methoxy are introduced. sulfonamidobenzenemethanol, N-carbobenzyloxy-L-alanine ester, 20 ml of ethanol and 3 ml of a 1M solution of potassium hydroxide in a mixture of 1/1 ethanol and water. The reaction mixture is stirred for 25 minutes at room temperature and then concentrated under vacuum and the residue is purified by chromatography on a column with a 95/5 mixture of dichloromethane and methanol. 0.41 g of product is obtained. Melting point: 122 ° C. According to the same procedure, from (-) - a-azidomet i 1-2-methoxy-5-sulphonamidobenzenemethanol, N-carbobenzyloxy-L-alanine ester, (-) - azidomethyl-2-methoxy- was obtained 5-sulfonamidobenzenemethanol. Melting point: 122 ° C. 4.4. (+) - -Aminomethyl-2-methoxy-5-sulfonamidobenzenemethanol methanesulfonate From hydrogenated (+) - azide-methyl-2-methoxy-5-sulfonamidobenzenemethanol under the conditions described in step 6 of example 2, and then treated with an equivalent of methanesulfonic acid, ee obtained the methanesulfonate of () -a-aminomet i 1 -2-methoxy-5-sulfonamidobenzenemethanol. Melting point: 235 ° C. [a] 20 D = + 35 ° (c = 1; methanol / water 80/20). According to the same procedure from (-) - a-azidomethyl-2-methoxy-5-eulphonamidobenzenemethanol, methanesulfonate was obtained from (-) -a-aminomet i 1 -2-methoxy-5-sulfonamidobenzenemethanol Melting point : 233 ° C. [α] 20 D = -41.8 ° (c = 1; methanol / water 80/20).

Example 5: α-Diethylaminomethyl-2-methoxy-5-sulfonamidobenzenemethanol methanesulfonate. 5.1. Oxide of 2-methoxy-5-sulfonamidoestyrene In a round flask with a capacity of 100 ml, 2 g (6.5 mmol) of a-bromo-2-methoxy-5-sulfonamidoacetophenone, 20 ml of anhydrous ethanol and 1.0 g are introduced ( 7.0 mmol) of potassium carbonate. Then add 0.41 g (10.8 millimole) of sodium borohydride, stir the mixture at room temperature for 20 minutes, and then add 5 ml of a 0.1M solution of sodium hydroxide and stir for 30 minutes. The solution is concentrated, 30 ml of water are added and it is extracted 3 times, each time with 30 ml of ethyl acetate. The organic phases are combined, the material is dried over magnesium sulphate and concentrated. 1.41 g of product are obtained. Melting point: 118 ° C. . 2. α-Diethylaminomethyl-2-methoxy-5-sulfonamidobenzenemethanesulfonate In a round flask with a capacity of 100 ml, 1.41 g (6.1 mmol) of 2-methoxy-5-eulphonamidoethene oxide, 10 ml of anhydrous ethanol are introduced. and 17.8 g (244 millimoles) of diethylamine. The mixture is heated to reflux under stirring for 16 h and then the solution is concentrated. The residue is purified by column chromatography with a 90/9/1 mixture of dichloromethane, methanol and ammonia and then the material is dried in the desiccator under vacuum over phosphoric anhydride. 1.42 g of product are obtained in the form of an oil which is treated with an equivalent of methanesulfonic acid in 2M solution in methanol. After recrystallization of the methanol and diethyl ether and drying in the desiccator under vacuum over phosphoric anhydride, 0.875 g of α-diethylaminomethyl-2-methoxy-5-sulfonamidobenzenemethanesulfonate is obtained. Melting point: 90-92 ° C.

Example 6; Α-Methylaminomethyl-2-methoxy-5-sulfonamidobenzenemethanol methanesulfonate. 6.1. a-Benzylmethylaminomethyl-2-methoxy-5-sulfonamidobenzene anol The ido-styrene-2-methoxy-5-sulfone oxide obtained in step 1 of example 4, treated with benzylmethylamine, under the conditions described in step 2 of example 4, produces a-benzylaminomethyl-2-methoxy-5-sulfonamidobenzenemethanol in the form of an oil. 6. 2. α-Methylaminomethyl-2-methoxy-5-sulfonamidobenzenemethanesulfonate By hydrogenation of 1.90 g (5.4 mmol) of a-benzylmethylaminomethyl-2-methoxy-5-sulfonamidobenzene methanol under the conditions described in step 6 of Example 2, obtains a-methyl-1-aminomethyl-1-2-methoxy-5-sulfonamidobenzene-methanol. After recrystallization from ethyl acetate and methanol, the product obtained is treated with an equivalent of methanesulfonic acid in 2M solution in methanol and the salt is recrystallized from methanol, dichloromethane and diethyl ether. 0.396 g of methanesulfonate of c-methylaminomethyl-2-methoxy-5-sulfonamidobenzenemethanol are thus obtained. Melting point: 194-196 ° C.

Example 7: α-aminomethyl-2-fluoro-5-sulfonamidobenzenemethanol methanesulfonate. 7.1. 2-Pluoro-5-nitroacetophenone In a three-necked flask with a capacity of 100 ml containing 60 ml of concentrated sulfuric acid, cooled to -5 ° C, 25 ml (180 mmol) 2-fluoroacetophenone are introduced dropwise. A mixture of 14 ml of nitric acid (d = 1.42) and 20 ml of concentrated sulfuric acid is added dropwise, without exceeding 0 ° C. The mixture is stirred at -5 ° C for 30 minutes and then * the material is emptied onto stacked ice. It is then extracted 3 times, each time with 60 ml of ethyl acetate and then the organic phases are combined, the material is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography with a 70/30 mixture of hexane and ethyl acetate and then dried in the desiccator under vacuum over phosphoric anhydride. 26 g of product are obtained. Melting point: 72 ° C. According to the same procedure, the following compounds were obtained: - 2-chloro-5-nitroacetophenone Melting point: 65 ° C. - 2-hydroxy-5-nitroacetophenone Melting point: 98 ° C, which is converted, by phase transfer catalysis reaction with isopropyl iodide, to 2-isopropoxy-5-nitro-acetophenone, Melting point: 78 ° C. 7. 2. 5-Amino-2-fluoroacetophenone 25.4 g (152 mmol) of 2-fluoro-5-nitroacetophenone, 343 g (1.52 mol) of tin chloride dihydrate are introduced into a three-necked flask with a one liter capacity. 250 ml of ethyl acetate. The reaction mixture is heated at 70 ° C for 30 minutes and then emptied onto one liter of stacked ice, a 30% sodium hydroxide solution is added and it is extracted 3 times each time with 350 ml of ethyl acetate. The organic phases are combined, the material is dried over magnesium sulfate and concentrated. 11.26 g of product are obtained in the form of an oil. According to the same procedure, the following compounds were obtained: - 5-amino-2-chloroacetophenone, in the form of oil; - 5-amino-2-isopropoxyacetophenone, in the form of oil. 7.3. 2-Fluoro-5-sulfonamideacetophenone In a 250 ml three-necked flask, 15.3 g (100 millimms) of 5-amino-2-fluoroacetophenone and 50 ml of acetic acid are introduced, then 50 ml of hydrochloric acid are added. concentrated. The reaction mixture is cooled to 0 ° C and then added dropwise as a solution of 10.3 g (150 mmol) of sodium nitrite instead of 25 ml of water and left at 0 ° C for 30 minutes. Then a suspension, cooled at 15 ° C, of 5 g (29 mmol) of cuprous chloride dihydrate and 30 g (470 mmol) of sulfur dioxide in 75 ml of acetic acid is added. The mixture is kept at 0 ° C for 48 hours, then 20 ml of water are added, it is extracted 3 times each time with 120 ml of dichloromethane and then the organic phases are combined, the material is dried over magnesium sulfate and concentrated . The residue is dissolved in 100 ml of tetrahydrofuran, then a 28% ammonia solution is added dropwise at 0 ° C. The reaction mixture is stirred for 16 h at room temperature and then concentrated. The residue is purified by column chromatography with a 60/40 mixture of hexane and ethyl acetate and the material is dried in the desiccator under vacuum over phosphoric anhydride. 11.23 g of product are obtained. Melting point: 112 ° C. According to the same procedure, the following compounds were obtained: 2-chloro-5-sulfonamidoacetophenone. Melting point: 106 °. 2-isopropoxy-5-sulfonamidoacetophenone. Melting point: 85 °. - 3-sulfonamidoacetophenone. Melting point: 144 °. 7. 4. a-Bromo-2-fluoro-5-sulfonamidoacetophenone From 2-fluoro-5-sulfonamidoacetophenone treated under the conditions described in step 3 of example 2, a-bromo-2-fluoro-5-sulfonamidoacetophenone was obtained. . Melting point: 122 °. According to the same procedure, the following compounds were obtained: α-bromo-2-chloro * o-5-sulfonamidoacetophenone. Melting point: 126 °. -bromo-3-isopropoxy-5-eulphonamidoacetophenone. Melting point: 105 °. a-bromo-3-sulfonamidoacetophenone Melting point: 130 °.7. 5. Chloro-2-fluoro-5-sulfonamidoacetophenone From a-bromo-2-fluoro-5-sulfonamidoacetophenone treated under the conditions described in step 1 of Example 3, a-chloro-2-fluoro-3- was obtained. sulfonamidoacetophenone. Melting point: 114 °. According to the same procedure, the following compounds were obtained: a-chloro-2-chloro-5-sulfonamidoacetophenone. Melting point: 124 °. - a-chloro-2-isopropoxy-5-sulfonamidoacetophenone. Melting point: 98 °. a-chloro-3-sulfonamidoacetophenone. Melting point: 128 °. 7. 6. a-Chloromethyl-2-fluoro-5-sulfonamidobenzenemethanol From a-chloro-2-fluoro-5-sulfonamidoacetophenone treated under the conditions of step 2 of Example 3, a-chloromethyl-2-fluoro-5 was obtained. -sulfonamidobenzenemethanol. Melting point: 11 * 2 °. According to the same procedure, the following compounds were obtained: a-chloromethyl-2-chloro-5-sulfonamidobenzenemethanol. Melting point: 115 °. a-chloromethyl-2-isopropoxy-5-sulfonamidobenzenemethanol. Melting point: 93 °. a-chloromethyl-3-sulfonamidobenzenemethanol. Melting point: 122 °. 7. 7. ot-Azidomethyl-3-fluoro-5-sulfonamidobenzenemethanol From c 1 or orne thi-2-f -or- 5 -sulfonamidobenzenemethanol, treated under the conditions described in step 4 of example 3, a- azidomethyl-2-fluoro-5-sulfonamidobenzenemethanol. Melting point: 86 °. According to the same procedure, the following compounds were obtained: α-azidomethyl-2-chloro-5-sulfonamidobenzenemethanol. Melting point: 122 °. a-azidomethyl-2-isopropoxy-5-sulfonamidobenzenemethanol. Melting point: 95 °. - a-azidomethyl-3-sulfonamidobenzenemethanol. Melting point: 118 °. 7. 8. A-aminomethyl-2-fluoro-5-sulfonamidobenzenemethanol methanesulfonate. From the α-azidomethyl-2-f luoro-5-sulfonamidobenzenemethanol treated under the conditions of step 6 of Example 2, the methanesulfonate of a-aminomethyl-2-fluoro-5-sulfonamidobenzenemethanol was obtained. Melting point: 164 °.

Example 8; Α-Aminomethyl-2-methyl-5-sulfonamidobenzenemethanol methanesulfonate. 8.1. ac-Chloro-2-methyl-5-sulfonamidoacetophenone In a round flask with a capacity of 500 ml, 26.4 g (76.0 mmol) of benzyltrimethylammonium dichloroiodate are introduced (prepared according to the method described in Synthesis 7, (1988), 545), 8.25 g (43.4 mmol) of 2-methyl-5-sulfonamidoacetophenone, 90 ml of methanol and 220 ml of 1,2-dichloroethane. Heat to reflux for 16 hours, then concentrate in reaction medium and add 200 ml of a saturated solution of sodium bicarbonate. They are extracted 3 times, each time with 120 ml of ethyl acetate, then the organic phases are combined, the material is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography with a 60/40 mixture of hexane and ethyl acetate and dried in the desiccator under vacuum over phosphoric anhydride. 1.7 g of product are obtained. Melting point: 114 °. 8. 2. a-Chloromethyl-2-methyl-5-sulfonamidobenzenemethanol From a-chloro-2-methyl-5-sulfonamidoacetophenone treated under the conditions of step 2 of Example 3, a-chloromethyl-2-methyl-5 was obtained. -sulfonamidobenzenemethanol. Melting point: 126 °. 8. 3. a-Azidomethyl-2-methyl-5-sulfonamidobenzenemethanol From ac omet i 1 - 2 -met i 1 - 5-sulfonamidobenzenemethanol treated under the conditions described in step 4 in example 3, the azidomethyl-2-methyl-5-sulfonamidobenzenemethanol. Melting point: 98 °. 8. 4. Methansulfonate-3-methyl-methyl-2-methyl-5-sulfonamidobenzenemethanol From-azome 1-2-met i 1 -5-sulphonamidobenzenemethanol treated under the conditions described in step 6 of Example 2, methanesulfonate was obtained from a-aminomethyl-2-methyl-5-sulfonamidobenzenemethanol. Melting point: 185 °.

Example 9 a-aminomethyl-2-chloro-5-sulfonamidobenzenemethanesulfonate In a round flask with a capacity of 250 ml, 1.35 g * (4.9 mmol) of a-azidomethyl-2-chloro-5-sulfonamidobenzenemethanol, 90 ml of pyridine are introduced. anhydrous and 9.67 g (29.0 mmol) of triphenylphosphine on support. The mixture is stirred at room temperature for 9 hours, and then 100 ml of 28% ammonia is added, the suspension is stirred for 16 hours and filtered. The filtrate is concentrated and the residue is recrystallized from methanol. 0.523 g of a-aminomethyl-2-chloro-5-sulfonamidobenzenemethanol are obtained. 1 equivalent of methanesulfonic acid in 2M solution in methanol is added.

After recrystallizing the methanol and diethyl ether and drying in the desiccator under vacuum over phosphoric anhydride, 0.439 g of a-aminomethyl-2-chloro-5-sulfonamidobenzenemethanesulfonate methanesulfonate are obtained. Melting point: 206 to 208 ° C. EXAMPLE 10 Sin and anti (2'-methoxy-5'-aminosulfonyl-phenyl-2-amino-propan-1-ol 10.1. 2-methoxy-5-chlorosulfonyl-propiophenone From 2-methoxy-propiophenone treated under the conditions of In step 1 of Example 2, 2-methoxy-5-chlorosulfonyl-propiophenone was obtained: melting point: 86 to 89 ° C. 10.2 2-methoxy-5-sulfonamidopropiophenone From 2-methoxy-5-chlorosulfonylpropiophenone treated in the conditions of step 2 of example 2, 2-methoxy-5-sulfonamidopropiophenone was obtained Melting point: 16 * 2-165 ° C. 10.3.2-bromo-2'-methoxy-5'-sulfonamidopropiophenone From 2-methoxy-5-sulfonamidopropiophenone treated under the conditions of step 3 of example 2, 2-bromo-2 / -methoxy-5'-sulphonamidopropiophenone was obtained Melting point: 108-110 ° C. azido-2'-methoxy-5'-sulfonamidopropiophenone From a-bromo-2-methoxy-5-sulfonamido propiophenone treated under the conditions of step 4 of Example 2, 2-azido-2-methoxy-S was obtained '-sulfonamidopropiophenone. of fusion: 113-114 ° C. 10.5. (2-methoxy-5'-aminosulfonyl) -phenyl-2-azidopropan-1-ol Starting from 2-azido-2'-methoxy-5'-eulphonamido propiophenone treated under the conditions of step 1 of example 2, obtained (2'-methoxy-5'-aminosulfonyl) -phenyl-2-azidopropan-1-ol. Melting point: 109-110 ° C. 10.6. Sin and Anti (2 '-methoxy-5' -aminosulfonyl) -phenyl-2-aminopropan-1-ol From (2 '-methoxy-5' -aminosulfonyl) -phenyl-2-azidopropan-1-ol treated in the conditions of step 6 of example 2, a mixture of sin and anti (2'-methoxy-5'-aminoeulphonyl) -phenyl-2-aminopropan-1-ol was obtained, which are separated by successive chromatography on a silica column with an elution solvent dichloromethane: methanol: ammonia 95: 5: 0.5 to provide the diaetereoieómeroe sin and anti. After recrystallization from isopropanol and drying in a vacuum desiccator under vacuum over phosphoric anhydride, sin (2'-methoxy-5 '-a -osulfonyl) -phenyl-2-aminopropan-1-ol is obtained. Melting point: 176-177 ° C. and the anti (2 '-methoxy-5'-ammonosulfonyl) -phenyl-2-aminopropan-1-ol. Melting point: 233-237 ° C.

Example 11: (-) - Sin- (2-methoxy-5-sulfonamido) -phenyl-2-aminopropan-1-ol 11.1. (-) - Sin- (2'-methoxy-5'-sulfonamido) -phenyl-2-azidopropan-1-ol From 2-azido-2'-methoxy-5'-sulphonamidopropiophenone treated under the conditions of Step 5 of Example 2, a mixture of 2 recrystallizations in isopropanol was obtained (-) - syn- (2'-methoxy-5'-sulfonamido) -phenyl-2-aminopropan-1-ol. Melting point: 143-145 ° C [a] 20D = ~ 125 ° (methanol). 11. 2. (-) - Sin- (2'-methoxy-5'-sulfonamido) -phenyl-2-aminopropan-1-o1 From (-) -Sin- (2'-methoxy-5'-sulfonamido) - phenyl-2-azidopropan-1-ol treated in the conditions of step 6 of Example 2, was obtained after two recrystallizations in isopropanol (-) - syn- (2'-methoxy-5'-sulfonamidophenyl-2-aminopropane -1-ol Melting point: 190-191 ° C [c.] 20D _ _ 34.10 (methanol) The compounds of the invention have been combined in the following table with their characteristics.

Table MeS03H Represents metansulfonate OMe Represents methoxy O-iPr Represents isopropoxy i-Pr Represents isopropyl Represents cyclopropyl The compounds of the invention were subjected to biological tests designed to demonstrate their agonist activity of a1-adrenergic receptors.

They were subjected in particular to binding tests to the ala, al, and ct? R sub-receptors performed respectively on the tissue of the rat ealival gland, on the rat liver tissue and on the tranexfected CHO cells. The affinity for each type of sub-receptor, expressed by IC50 (50% inhibitory concentration of the linkage to the [3i] prazosin), was determined and the values relative to the affinity for the wing receptor were calculated with respect to the affinity for the receptors. alb and c.lc receivers, expressed by the relations of IC50, [alb / ala] [ald and ala]. For the compounds of the invention, these ratios vary respectively from 9.3 to 21.6 and from 7.8 to 20.9, which indicates an important selectivity for the wing receptor. The in vitro activity of the compounds of the invention was studied in the urethral and arterial smooth muscles. These tests were performed on New Zealand female rabbits weighing 3 to 3.5 kg. The animals were sacrificed by vertebral dislocation and then tissue rings were removed from the mesenteric arteries and the urethra. These tissue rings were immersed in a modified Krebs solution, oxygenated with a 95% mixture of 02 and 5% C02. Each tissue sample was subjected to a tension of 1 g and then phenylephrine was introduced at cumulative doses and the dose / reepheeta curve was established. After rinsing the samples, the compound under study was introduced at cumulative doses and the dosie / reepuesta curve was established. The effect - adrenergic of each compound was evaluated by the calculation of pD2 (negative logarithm of the concentration of antagonist in the presence of which the effect of a dose of the agonist is divided by two) as well as by the maximum effect that represents the percentage of the maximum contraction obtained with phenylephrine (% Emax). For the * compounds of the invention, the urethral and arterial pD2 vary respectively between 4.18 and 4.93 (pD2 phenylephrine = 5.2-5.5) and between 3.73 and 4.55 (pD2 phenylephrine = 5.2-5.5) and the percentages of Ema? urethral and arterial vary respectively between 58.4 and 76 and between 76 and 94.6. The in vivo activity of the compounds of the invention in blood and urethral pressure was studied in the rabbit. These tests were performed on New Zealand female rabbits weighing 3 to 4 kg. After an anesthetic with pentobarbital, catheters were introduced into the abdominal orta, through the femoral artery, into a jugular vein and into the urethra (1 cm below the bladder neck). The compounds under study were administered 5 to 15 days after the operation, either intravenously or orally. The compounds were administered intravenously in 5 minutes, in a single dose, or in a cumulative manner, at 15 minute intervals between doses, at a dose of 3 to 100 g / kg. Blood pressure (BP) and urethral precession (PU) were measured continuously for each dose. For the compounds of the invention, the increase in the PA values is of the order of 5 mm Hg at the dose of 10 g / kg and 15 mm of Hg at the dose of 100 μg / kg; the PU increase is approximately 14 cm H20 at the dose of 10 μg / kg and 54 cm H20 at the dose of 100 μg / kg. At the different doses tested, the compounds of the invention have a strong uroselectivad since they increase in a considerable way the urethral pressure without sensitively modifying the arterial pressure. Orally, the compounds were administered by priming in a single dose of 300 and 1000 μg / kg, under a volume of 1 ml / kg. The PA and PU were measured 5, 10, 30, 45 and 60 minutes after the fattening. For the compounds of the invention, the variations in the PA are respectively of the order of 0.2 and 0.9 mm Hg at the doses of 300 and 1000 μg / kg, after 30 minutes and of approximately 5.3 and 1.1 mm of Hg. at the end of 60 minutes and the variations in the PUs are respectively of the order of 1.6 and 7.8 cm of H20 at the doses of 300 and 1000 μg / kg, after 30 minutes and of approximately 3.7 and 8.3 cmH20 after 60 minutes . Orally, the compounds of the invention have a total uroselectivity since the ural preemption ee increases in a sensitive manner without modifying the arterial pressure. The set of results obtained shows that the compounds of the invention have a strong urethral action and a weak arterial action. They are agonists of the a-L-adrenergic receptors, selective of the wing receptors. Therefore they can be used in the treatment of urinary incontinence. For this purpose they can be presented in all kinds of forms suitable for enteral or parenteral administration, in association with pharmaceutical excipients, for example, in the form of tablets, coated tablets, wrapped tablets, capsules, ingestible or injectable solutions, eupositories, dosed to allow a daily dose of 0.001 to 1000 mg of active substance.

Appendix 1 R, - akoxy (IV) R 4NH2 (ID (III) L3H. TMSO (I) (R. = alcoxy) Annex 2 Baiat-ijH ta? Hj. N / C ou "<. H- .. Pd / C 1 P (Ph), NH4OH

Claims (15)

1. CLAIMS; 1. Benzenesulfonamide compounds of the general formula (I) wherein: RL represents a hydrogen or halogen atom, such as chlorine or fluorine, or an alkyl group with 1 to 4 carbon atoms or straight or branched chain alkoxy with 1 to 4 carbon atoms, R2, R3 and R4 independently represent hydrogen atoms or alkyl groups with 1 to 4 carbon atoms, straight chain, branched or cyclic, and R5 represents a hydrogen atom, an alkyl group with 1 to 2 carbon atoms, fluoroalkyl with 1 to 2 carbon atoms, or perfluoroalkyl with 1 or 2 carbon atoms, in the form of enantiomers or diastereoisomers, or mixtures of these different forms, with the addition of racemic eece, as well as pharmaceutically acceptable addition salts acceptable
2. 2. The compounds according to claim 1, characterized in that R 5 represents a hydrogen atom, methyl or ethyl.
3. 3. The compounds according to claim 1, characterized in that R2 represents a hydrogen atom, fluorine, chlorine or an alkoxy group with 1 to 4 carbon atoms.
4. 4. The compounds according to claim 1, characterized in that R2 and R3 independently represent a hydrogen atom, methyl, ethyl or isopropyl.
5. 5. The compounds according to claim 1, characterized in that R? represents a hydrogen atom, fluorine, chlorine, or an alkoxy group with 1 to 4 carbon atoms, R2 and R3 independently of each other, a hydrogen atom, methyl, ethyl, or isopropyl, R4 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms straight chain, branched or cyclic and R5 represents a hydrogen, methyl or ethyl atom.
6. 6. The compounds according to claim 1, characterized in that R represents a hydrogen, fluorine, chlorine, methoxy or ethoxy atom, R2 and R3 represents a hydrogen atom, R4 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms. carbon, straight chain, branched or cyclic and R 5 represents a hydrogen or methyl atom.
7. 7. The α- (aminomethyl) -2-methoxy-5-sulfonamidobenzenemethanol, its pharmaceutically acceptable salts and its enantiomers.
8. 8. The (+) - - (am ino et i 1) -2-methoxy-5-sulphonamidobenzenemethanol and its pharmaceutically acceptable salts.
9. 9. (-) -a- (aminomethyl) -2-methoxy-5-eulphonamidobenzenemethanol and its pharmaceutically acceptable salts.
10. 10. The α- (aminomethyl) -2-chloro-5-sulfonamidobenzenemethanol, its pharmaceutically salts and its enantiomers.
11. 11. The - (aminomethyl) -2-f luoro-5-sulfonamidobenzenemethanol, pharmaceutically acceptable salts thereof and their enantiomers.
12. 12. Medicament characterized in that it contains a compound of the general formula (I) according to claim 1.
13. 13. Pharmaceutical composition characterized in that it contains a compound of the general formula (I) according to claim 1, in association with any suitable excipient.
14. 14. Process for the preparation of the compounds of the general formula (I) in which: R? represents an alkoxy group with 1 to 4 carbon atoms, straight or branched chain, and R2 and R3 represent hydrogen atoms, R4 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, straight chain, cyclic branched and R5 represents a hydrogen atom, in the form of enantiomers or diastereomers, or mixtures of these different forms including the racemic mixtures as well as their pharmaceutically acceptable acid addition salts, comprising: (a) the reaction of a compound of the formula (III) in the cuai R? and R4 are as defined above, with a trimethylsilyl cyanide, in the presence of zinc iodide to give the derivative of the formula (II) wherein R 2 and R 4 are as defined above, (b) reduction of the resulting derivative (II) with lithium borohydride, in the presence of tri ethylethyloyl chloride to give the starting compound of the general formula (I), (c) ) the eventual transformation of this compound (I) resulting in its enantiomers, diastereomers, or pharmaceutically acceptable salts thereof.
15. 15. The process for the preparation of the compounds of the general formula (I) wherein: R represents a hydrogen or halogen atom such as chlorine or fluorine, or an alkyl group with 1 to 4 carbon atoms, or straight or branched chain alkoxy with 1 to 4 carbon atoms, R2 'R3 R4 independently represent hydrogen atoms or alkyl groups with 1 to 4 carbon atoms, straight chain, branched or cyclic, and R5 represents a hydrogen atom, an alkyl group with 1 to 2 carbon atoms, fluoroalkyl with 1 or 2 carbon atoms, or perfluoroalkyl with 1 or 2 carbon atoms, in the form of enantiomeric or diaeteroisomers or mixtures of these different forms, including racemic mixtures, as well as their Exit from addition to pharmaceutically acceptable acids, comprising: (a) either the eventual reaction of a derivative of the formula (VIII) in the form of an enantiomer or a diaeteroisomer, or a mixture of eetae different forms, including racemic mixtures, in which R and R5 are as defined above with hydrogen in the presence of a catalyst such as palladium on carbon in which R ? is defined as above with the exception of chlorine, or with triphenyl foefine, and then with ammonia in which R1 is a chlorine atom, to prepare the compounds of the general formula (I), in which Rl7 R4 and R5 are as defined above, and R2 and R3 are hydrogen atoms, (b) or the eventual reaction of a derivative of the formula (VII) wherein R 1 t R 4 and R 5 are as defined above, with an amine of the formula R 2 (R 3) NH in the lime R 2 represents a hydrogen atom only an alkyl group with 1 to 4 carbon atoms and R 3 represents an alkyl group with a to 4 carbon atoms, to obtain the compound of the general formula (I) in which R2 and R3 are as defined above, either with an amine of the formula R2 (Bn) NH in which R2 is a alkyl group and benzyl Bn, to obtain a derivative of the formula (VI), which is then reduced with hydrogen in the presence of a catalyst, such as palladium on carbon, to give the compound of the general formula (I), in which R2 is an alkyl group with 1 to 4 carbon atoms, (c) the eventual transformation of this compound (I) resulting, in its enantiomers, diastereoisomers or pharmaceutically acceptable sue ealee.