Title of Invention	"TETRAHYDROISOQUINOLINE SULFONAMIDE DERIVATIVES, THE PREPARATION THEREOF, AND THE USE OF THE SAME IN THERAPEUTICS"
Abstract	The invention relates to a compound of formula (1) wherein n can represent a value between 1 and 6: -(C)n- represents a C1-6 alkylidene group, optionally substituted by between 1 and 4 substituents; R1 represents a hydrogen atom, or a C1-6 alkyl group; R2 represents a hydrogen atom, a C1-6 alkyl or C3-6 cycloalkyl group optionally substituted by between 1 and 4 substituents; and B represents NR3R4, R3 and R4 independently representing a C1-6 alkyl group or a hydrogen atom, or together representing a C1-6 alkylidene group, a C2-8 alkenylidene group, a C1-3 alkylidene-O-C1-3 alkylidene group, or a C1-3 alkylidcne-N(R5)-C1-3 alkylidene group wherein R5 represents a hydrogen atom, or a C1-3 alkyl or C1-6 alkylcarbonyl group, said C1-3 alkyl and C1-6 alkylcarbonyl groups being substitutable, or an aminocycle which is linked by a carbon to the group -NRl-(C)n-, such as aziridine, azetidine, pyrrolidine, piperidine or morpholine, the groups R3, R4, the aminocycle, and the nitrogen atom being optionally substituted. The invention can be applied to therapeutics.

Title of Invention

"TETRAHYDROISOQUINOLINE SULFONAMIDE DERIVATIVES, THE PREPARATION THEREOF, AND THE USE OF THE SAME IN THERAPEUTICS"

Abstract

The invention relates to a compound of formula (1) wherein n can represent a value between 1 and 6: -(C)n- represents a C1-6 alkylidene group, optionally substituted by between 1 and 4 substituents; R1 represents a hydrogen atom, or a C1-6 alkyl group; R2 represents a hydrogen atom, a C1-6 alkyl or C3-6 cycloalkyl group optionally substituted by between 1 and 4 substituents; and B represents NR3R4, R3 and R4 independently representing a C1-6 alkyl group or a hydrogen atom, or together representing a C1-6 alkylidene group, a C2-8 alkenylidene group, a C1-3 alkylidene-O-C1-3 alkylidene group, or a C1-3 alkylidcne-N(R5)-C1-3 alkylidene group wherein R5 represents a hydrogen atom, or a C1-3 alkyl or C1-6 alkylcarbonyl group, said C1-3 alkyl and C1-6 alkylcarbonyl groups being substitutable, or an aminocycle which is linked by a carbon to the group -NRl-(C)n-, such as aziridine, azetidine, pyrrolidine, piperidine or morpholine, the groups R3, R4, the aminocycle, and the nitrogen atom being optionally substituted. The invention can be applied to therapeutics.

Full Text	The present invention relates to sulfonamide derivatives, to the preparation thereof and to the therapeutic use thereof, in particular in the treatment of disorders that are improved by modulation of the histamine H3 receptor, such as obesity, diabetes and central nervous system diseases such as vigilance and sleep disorders. Consequently, a first subject of the present invention is the compounds corresponding to formula I in which: n can represent a value between 1 and 6; -(C)n- represents a -C1-6 alkylidene group optionally substituted with 1 to 4 substituents chosen from a halogen atom, and a hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino or C1-3 alkoxy group; R1 represents • a hydrogen atom, • a C1-6 alkyl group; R2 represents • a hydrogen atom, • a C1-6 alkyl or C3-6 cycloalkyl group optionally substituted with 1 to 4 substituents chosen from a halogen atom, a hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-2 perhaloalkyl, C1-3 haloalkyl, C1-3 alkoxy or C3-6 cycloalkyl group, a monocyclic heteroaryl such as a thienyl, furyl or pyrrolyl, or an aryl, such as a phenyl or a naphthyl; the aryl being optionally substituted with 1 to 4 substituents chosen from a halogen atom, a hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl, C1-2 perhaloalkyl, C1-3 haloalkyl or C1-3 alkoxy group or a C1-3 alkylidenedioxy group; B represents • NR3R4, - R3 and R4 represent, independently of one another, a C1-6 alkyl group, or a hydrogen atom; or - R3 and R4 together represent a C1-6 alkylidene group, a C2-8 alkenylidene group, a C1-3 alkyIidene-O-C1-3 alkylidene group, or a C1-3 alkylidene-N(R5)-C1-3 alkylidene group where R5 represents a hydrogen atom, or a C1-3 alkyl or C1-6 alkylcarbonyl group, it being possible for these C1-3 alkyl and C1-6 alkylcarbonyl groups to be substituted with a halogen atom, or a hydroxyl, C1-3 alkoxy, nitro, cyano or amino group; or • an aminocycle, linked via a carbon to the group -NR1-(C)n-, such as aziridine, azetidine, pyrrolidine, piperidine or morpholine; the groups R3 and R4 and also the aminocycle being optionally substituted with 1 to 4 substituents chosen from a phenyl, a benzyl, a halogen atom, and a hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl or C1-3 alkoxy group; and the nitrogen atom optionally substituted with a C1-3 alkyl. In the context of the present invention, the term: - "Cx-z" is intended to mean a carbon-based chain that may contain from x to z carbon atoms; for example, C1-3 indicates a carbon-based chain that may contain from 1 to 3 carbon atoms; - "alkyl" is intended to mean a linear or branched, saturated aliphatic group; for example, a C1-4 alkyl group represents a linear or branched, saturated carbon- based chain containing from 1 to 6 carbon atoms, more particularly a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc. radical; the term "Cx-y alkylidene" denoting a divalent, linear or branched Cx-y alkyl group; the term "C2-8 alkenylidene" denoting a divalent, linear or branched, unsaturated Cx-y alkyl group; - "Cx-y alkoxy" is intended to mean an alkyloxy group comprising a linear or branched, saturated aliphatic chain, containing x to y carbon atoms; - "halogen atom" is intended to mean a fluorine, a chlorine, a bromine or an iodine; - "C1-3 monoalkylamino" is intended to mean an amino monosubstituted with a C1-3 alkyl group; - "C2-6 dialkylamino" is intended to mean an amino disubstituted with two C1-3 alkyl groups; - "C1-2 perhaloalkyl" is intended to mean a C1-2 alkyl group in which all the hydrogen atoms are substituted with halogen atoms; - "C1-3 haloalkyl" is intended to mean a C1-3 alkyl group in which at least one hydrogen atom is substituted with a halogen atom. The compounds of formula I can contain one or more asymmetrical carbon atoms. They can therefore exist in the form of enantiomers or of diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, are part of the invention. The compounds of general formula I can be in the form of free bases or of addition salts with acids, which are also part of the invention. According to the present invention, these salts comprise those with pharmaceutically acceptable acids, but also those with inorganic or organic acids that allow a suitable separation or crystallization of the compounds of formula I. These salts can be prepared, according to methods known to those skilled in the art, for example, by reaction of the compound of formula I in the form of a base with the acid in an appropriate solvent, such as an alcoholic solution or an organic solvent, and then separation of the media that contains it by evaporation of the solvent or by filtration. The compounds of formula I can also exist in the form of hydrates or of solvates, i.e. in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the invention. Furthermore, in the context of the present invention, the term "protective group Pg" is intended to mean a group that makes it possible, firstly, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, secondly, to regenerate the intact reactive function at the end of synthesis. Examples of protective groups and also the methods of protection and deprotection are given in "Protective groups in Organic Synthesis 3rd Ed.", Greene and Wuts (John Wiley & Sons, Inc., New York, 1999). A subject of the present invention is also the compounds chosen from the following subgroups, in which: n is equal to 2, 3 or 4; and/or R1 represents a hydrogen atom or a C1-2 alkyl group; and/or R2 represents a hydrogen atom, or a C1-4 alkyl or C5-6 cycloalkyl group optionally substituted with 1 to 4 substituents chosen from a phenyl, and a C3-6 cycloalkyl, C1-2 perhaloalkyl, C1-3 haloalkyl or C1-3 alkoxy group; the phenyl being optionally substituted with 1 to 4 substituents chosen from a halogen atom, a hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl, C1-2 perhaloalkyl, C1-3 haloalkyl or C1-3 alkoxy group or a C1-3 alkylidenedioxy group; and/or B represents • NR3R4, - R3 and R4 represent, independently of one another, a C1-4 alkyl group; or - when R3 and R4 together represent a C1-6 alkylidene group, a C2-8 alkenylidene group, a C1-3 alkylidene-O- C1-3 alkylidene group or a C1-3 alkylidene-N(R5)-C1-3 alkylidene group, B represents a group: or • an aminocycle linked via a carbon to the group -NR1-(C)n, such as aziridine, azetidine, pyrrolidine, piperidine or morpholine; the groups R3, R4 and R5 and also the aminocycle being optionally substituted; and, more specifically, the subgroup where at the same time n, R1, R2 and B are as defined above. More particularly, when B represents NR3R4 and R3 and R4 together form a C1-6 alkylidene group, a C2-8 alkenylidene group, a C1-3 alkylidene-O-C1-3 alkylidene group or a C1-3 alkylidene-N(R5)-C1-3 alkylidene group, or when B represents an aminocycle, then B is chosen from the following groups: Another subject of the present invention concerns the following compounds: 1. N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; 2. (+/-)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; 3. N-[3-(diethylamino)propyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; 4. N-[3-(diethylamino)propyl]-N-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; 5. 2-benzyl-N-[3-(diethyIamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; 6. 2-(cyclopropylmethyl)-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; 7. 2-(cyclohexylmethyl)-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; 8. (+/-)-N-[3-(2-methylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; 9. N-[3-(3,6-dihydropyridin-1 (2H)-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; 10. N-[3-(diethylamino)propyl]-2-isopropyl-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; 11. N-[3-(diethylamino)propyl]-2-(2-thienylmethyl)-1,2)3,4-tetrahydroisoquinoline-7- sulfonamide; 12. N-[3-(diethylamino)propyl]-2-(3-thienylmethyI)-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; 13. N-[3-(2,5-dihydro-1H-pyrrol-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; 14. 2-cyclohexyl-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoIine-7- sulfonamide; 15. (+/-)-2-(cycIohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide; 16. N-[3-(2,5-dihydro-1H-pyrrol-1 -yI)propyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline- 7-sulfonamide; 17. N-[3-(4-benzylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; 18. N-(3-pyrrolidin-1 -ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; 19. N-(3-morpholin-4-ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; 20. N-[3-(dimethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; 21.2-(cyclohexylmethyl)-N-(3-pyrrolidin-1-ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; 22. (+/-)-2-(cyclopropylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyI]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide; 23. (+/-)-2-benzyl-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1)2,3,4-tetrahydroisoquinoline- 7-sulfonamide; 24. (+/-)-2-(4-isopropylbenzyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide; 25. (+/-)-2-(1,3-benzodioxol-5-ylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide; 26. (+)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; 27. (-)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; 28. (+)-2-(cyclohexylmethyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide; 29. (-)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide; 30. (+/-)-2-(4-bromobenzyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide 31. (+/-)-2-(2,5-dimethoxybenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoIine-7-sulfonamide 32. (+/-)-2-(2-methylbutyl)-N-[2-(1 -methylpyrroIidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide 33. (+/-)-2-(3-methoxybenzyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide and 34. (+/-)-2-(3,5-dimethyl-benzyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide. A second subject of the present invention is processes for preparing the compounds of formula I according to the invention. Thus, the compounds of formula I can be prepared according to the process represented in Scheme 1. According to the process of Scheme 1, the compounds of formula i, in which R2 is other than a hydrogen atom, are prepared by amminative reduction, by reacting a secondary amine of formula I, in which R2 represents H, with an aldehyde or a ketone of formula III, where R6 and R7, after reaction, together form R2 as defined in formula I. The compounds of formula I where R2 represents a hydrogen atom can be obtained by deprotection of the compounds of formula II, according to conventional methods known to those skilled in the art. For example, the compounds of formula II, when Pg is a trifluoroacetyl group, can be deprotected in the presence of a base such as, for example, sodium carbonate, potassium carbonate, ammonia or barium hydroxide in a protic solvent, such as water or methanol or a mixture of these solvents, at a temperature between 0 and 100°C. Alternatively, the deprotection of the compounds of formula II, when Pg is a trifluoroacetyl group, can be carried out in the presence of an acid such as, for example, hydrochloric acid in a protic or aprotic solvent, such as water, methanol, ethanol or ethyl acetate or a mixture of these solvents, at a temperature between 0 and 100°C. Illustrations of the process are given in the examples. The starting compounds of formula II can be prepared according to Scheme 2 or can be synthesized by conventional methods known to those skilled in the art. According to this scheme, the compounds of formula II, in which n, R1 and B are as defined in formula I, can be prepared by reaction of an amine of formula V, in which R1 and B are as defined in formula I, with a sulfonyl chloride of formula IV, in which Pg represents an appropriate protective group such as, for example, a trifluoroacetamide, so as to form a derivative of sulfonamide type of formula II, according to conventional methods known to those skilled in the art, for example, the reaction can be carried out in a protic or aprotic solvent, such as tetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethyIformamide or acetonitrile or a mixture of these solvents, at a temperature of between 0 and 100°C, in the presence of a base such as, for example, potassium carbonate, sodium carbonate, diisopropylethylamine or triethylamine. Alternatively, the compounds of formula II can be prepared by a Mitsunobu type reaction, according to Scheme 3. According to this alternative, a sulfonamide of formula VII, in which R1 is as defined in formula I, is reacted with an amino alcohol of formula VIII, in which n and B are as defined above. The reaction can be carried out conventionally in the presence of Mitsunobu reagents, such as an azo derivative, for example diethylazodicarboxylate, diisopropylazodicarboxylate, di-tert-butylazodicarboxylate, 1,1'- (azodicarbonyl)dipiperidine or N,N,N',N -tetramethylazodicarboxamide, and a phosphine, for example triphenylphosphine or tributylphosphine. The reaction can be carried out in an aprotic solvent, such as tetrahydrofuran or dioxane or a mixture of these solvents, at a temperature between 0 and 100°C, to give the compound of formula II. The sulfonamide of formula VII in which R1 is as defined in formula I can be prepared by reaction of an amine of formula VI, in which R1 is as defined in formula I, with a sulfonyl chloride of formula IV, in which Pg represents an appropriate protective group such as, for example, a trifluoroacetamide, according to conventional methods known to those skilled in the art, for example, the reaction can be carried out in a protic or aprotic solvent, such as tetrahydrofuran, dichloromethane, ethyl acetate, la N,N-dimethylformamide or acetonitrile or a mixture of these solvents, at a temperature between 0 and 100°C, in the presence of a base such as, for example, potassium carbonate, sodium carbonate, diisopropylethylamine or triethylamine. The starting compounds IV and the amines of formulae V and VIII are directly commercially available, can be synthesized by conventional methods known to those skilled in the art, or are known in the literature. For example, the diamines of formula V, in which n is equal to 3, can be prepared according to Scheme 4. According to this process, the compounds of formula V, in which n is equal to 3, R1 represents a hydrogen atom and B represents an amine group, can be prepared by means of an addition reaction of an amine of formula X, in which R3 and R4 are as defined above, with the acrylonitrile of formula IX, so as to form a derivative of aminonitrile type of formula XI, according to conventional methods known to those skilled in the art, followed by reduction of the nitrile. The reduction can be carried out according to methods known to those skilled in the art, for example in the presence of diisobutylaluminum hydride at a temperature between -70°C and 40°C in an aprotic solvent such as dichloromethane or toluene or a mixture of these solvents; the reduction can also be carried out in the presence of a reducing agent, such as hydrogen, in the presence of a catalyst such as platinum, palladium or Raney nickel, in a solvent such as methanol or ethyl acetate, so as to give the compound of formula V, in which n is equal to 3, R1 represents a hydrogen atom and B represents an amine group. The compounds of formula V, in which R1 represents a C1-6alkyl group, can be prepared by alkylation of the compound of formula V obtained above, according to conventional methods known to those skilled in the art. A subject of the present invention is also the compounds of formula II, when Pg represents a protective group or a hydrogen atom, as intermediates for the preparation of the compound of formula I. The following examples illustrate the processes and techniques suitable for the preparation of this invention, without, however, limiting the scope of the claim. Example 1-N-[2-(1-Methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide hydrochloride 1.1 - (+/-)-N-[2-(1 -Methylpyrrolidin-2-yl)ethyl]-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide hydrochloride A solution of 5.00 g (0.015 mol) of 2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro- isoquinoline-7-sulfonyl chloride and 2.00 g (0.015 mol) of (+/-)-2-(1-methyl-pyrrolidin- 2-yl)-ethylamine, in 50 ml of dichloromethane, is stirred overnight at ambient temperature. The solution is concentrated to dryness. The solid formed is purified by silica gel column chromatography, with a dichloromethane/methanol (97:3) mixture used as eluant, to give 4.30 g of the desired product in the form of a white solid. Yield: 62% Mp = amorphous 1.2- C+/-N-[2-(1 -Methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide hydrochloride A solution of 4.30 g (0.0094 mol) of 2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinoline-7-sulfonamido-[2-(1-methylpyrrolidin-2-yl)ethyl] hydrochloride in 50 ml of methanol saturated with hydrogen chloride is heated for twelve hours at 60°C. The mixture is cooled and the solid that has formed is filtered off, washed with methanol and dried. 2.00 g of the desired product are obtained as a white solid. Yield: (65%) Mp = 209-212°C 1H-NMR (DMSO-d6) δ(ppm): 7.9 (1H, t), 7.7 (2H, d), 7.5 (1H, d), 4.3 (2H, s), 3.6 (5H, m), 3.1 (3H, m), 2.9 (2H, m), 2.7 (3H, m), 2.1 (1H, m), 1.9 (3H, m), 1.6 (2H, m), 2.7 (3H, s); 2.9 (2H, t). 1.3- (+) or (-)-N-[2-(1-Methylpyrrolidin-2-yl]ethyll-1,2,3,4-tetrahydroisoquinoline- 7-sulfonamide hydrochloride The compound obtained above in 1.2 is separated by chiral-phase preparative chromatography, to give its enantiomers. Specifically, the separation of 15.00 g of (+/-)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hydrochloride is carried out with a PROCHROM LC50 preparative HPLC system, with a CHIRALPACK AD stationary phase and a mobile phase formed from isohexane/ethanol/methanol (80%:10%:10%)+0.2% of diethylamine, to give 5.39 g of the dextrorotatory product, in the form of a white powder, with a chiral-phase enantiomeric purity of 99.67%, and 4.89 g of the levorotatory product, in the form of a white solid, with a chiral-phase enantiomeric purity of 99.48%. The two products are converted into their corresponding hydrochloride by a treatment with isopropanol saturated with hydrogen chloride. Dextrorotatory enantiomer: Mp = 114-117°C; [α]* = +16 (c=0.5, methanol) Levorotatory enantiomer: Mp = 115-117°C; [α]" = -16 (c=0.5, methanol) Example 2-(+/-)-2-(Cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2"yl)ethyl]- 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide oxalate (1:2) 0.32 g (0.0003 mol) of palladium-on-charcoal at 10% is added to a solution of 2.02 g (0.0063 mol) of (+/-)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamido-[2-(1 -methyl- pyrrolidin-2-yl)ethyl] and 0.70 g (0.0063 mol) of cyclohexanecarboxaldehyde in 100 ml of methanol. The solution is hydrogenated for 24 hours in a Paar hydrogenator at a pressure of 45 Psi. The catalyst is removed by filtration and the filtered solution is evaporated to dryness. The crude oil obtained (2.90 g) is purified by silica gel column chromatography, with a dichloromethane/methanol (95:5) mixture used as eluant. The desired product (1.62 g; 62%) is obtained in the form of an oil. The above oil is dissolved in 20 ml of ethanol, and then 0.77 g (0.0086 mol) of oxalic acid dissolved in 15 ml of ethanol is added. The precipitate is filtered off and washed with cold ethanol. 2.01 g of the desired product are obtained in the form of a white solid. Yield: 86% Mp = 142-147°C 1H-NMR (DMSO-d6) δ(ppm): 7.5 (2H, m), 7.29 (1H, m), 3.84 (2H, s), 3.35 (2H, m), 3.1 (1H, m), 2.9 (1H, m), 2.8 (2H, s), 2.7 (1H, m), 2.6 (3H, s), 2.5 (2H, m), 2.1-1.4 (13H, m), 1.15 (4H, m), 0.8 (2H, m). Example 3- (+)-2-(Cyclohexylmethyl)-N-[2-(1-methylpyrrolldin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide oxalate (1:1.5) According to a process similar to Example 2, with 1.00 g (0.0031 mol) of (+)-N-[2-(1- methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and 0.35 g (0.0031 mol) of cyclohexanecarboxaldehyde in 50 ml of methanol as starting product, 0.46 g of base is obtained, which base is converted into the corresponding sesquioxalate hydrate, as a white solid. Yield: 20% Mp = 134-140°C [α]20D = +12 (c=0.5, methanol) Example 4-(-)-2-(Cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide oxalate (1:2) According to a process similar to Example 2, with 1.00 g (0.0031 mol) of (-)-N-[2-(1- methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and 0.35 g (0.0031 mol) of cyclohexanecarboxaldehyde in 50 ml of methanol as starting product, 0.90 g of base is obtained, which base is converted into the corresponding dioxalate hydrate, as a white solid. Yield: 27% Mp=133-138°C [α]" = -8 (c=0.5, methanol) Example 5- 2-Benzyl-N-[3-(diethylamino)propyl]- 1,2,3,4-tetrahydroisoquinoline- 7-sulfonamide oxalate (1:2) 5.1 - N-[2-(3-Diethylaminopropyl)-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide hydrochloride A solution of 1.00 g (0.0031 mol) of 2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinoline-7-sulfonyl chloride and 0.61 g (0.0047 mol) of N,N-diethyl- N- aminopropylamine in 25 ml of dichloromethane is stirred overnight at ambient temperature. The solution is concentrated to dryness and the oil formed is purified by silica gel column chromatography, with a dichloromethane/methanol (97:3) mixture used as eluant. 1.27 g are obtained. Yield: 97% Mp = Oil 5.2-N-[3-(Diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hydrochloride A solution of 5.39 g (0.013 mol) of N-[2-(3-diethylaminopropyl)-2-(2,2,2- trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hydrochloride, dissolved in 60 ml of methanol saturated with hydrogen chloride, is heated for twelve hours at 60°C. The mixture is cooled and the solid that has formed is filtered off, washed with methanol and dried. The residue is dissolved in an aqueous solution of sodium hydroxide. The aqueous phase is extracted several times with ethyl ether. The organic phases are combined and dried over anhydrous magnesium sulfate. The oil obtained (2.80 g) is used without additional purification. Yield: 67% Mp = Oil 5.3-2-Benzyl-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide oxalate (1:2) 1.5 ml of acetic acid are added to a suspension of 0.45 g (0.0014 mol) of N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and 0.149 g (0.0014 mol) of benzaldehyde in 12 ml of tetrahydrofuran. The suspension is stirred for 1 hour at ambient temperature and then 0.14 g (0.0021 mol) of sodium cyanoborohydride was added. The mixture was stirred overnight. The mixture is concentrated to dryness and the residue is treated with water and washed with ethyl ether. The aqueous phase is basified to pH = 10 and is extracted several times with ethyl ether. The organic phases are combined and dried over anhydrous magnesium sulfate. The oil obtained is purified by silica gel column chromatography, with a dichloromethane/methanol (95:5) mixture used as eluant. The desired product (0.13 g; 22%) is obtained in the form of an oil. The above oil is dissolved in 5 ml of ethanol, and then 0.06 g (0.0007 mol) of oxalic acid, dissolved in 5 ml of ethanol, is added. The precipitate is filtered off and washed with cold ethanol. 0.12 g of the desired product is obtained as a white solid. Yield: 63% Mp = 91-103°C 1H-NMR (DMSO-d6) δ(ppm): 7.5-7.1 (8H, m), 3.52 (2H, d), 2.9-2.5 (14H, m), 1.5 (2H, m), 0.9 (6H, t). Example 6 N-[3-(Diethylamino)propyl]-N-methyl-1,2,3,4-tetrahydroisoquinoline- 7-sulfonamide hydrochloride 6.1 - N-[2-(3-Diethylaminopropyl)-N-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinoline-7 -sulfonamide 0.09 g (0.0022 mol) of a dispersion of sodium hydride (60%) in a mineral oil is added to a solution of 0.91 g (0.0021 mol) of N-[2-(3-diethylaminopropyl)-2-(2,2,2- trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (obtained according to the method described in stage 5.1- of Example 5) in 17 ml of dimethylformamide, cooled to 0°C. The mixture is stirred for one hour and 0.60 g (0.0042 mol) of methyl iodide is added. The mixture is stirred overnight at ambient temperature, and the solution is concentrated to dryness. The residue is treated with water. The aqueous phase is extracted several times with ethyl acetate. The organic phases are combined and dried over anhydrous magnesium sulfate. The oil obtained after filtration and evaporation of the solvent is purified by silica gel column chromatography, with a dichloromethane/methanol (95:5) mixture used as eluant, to give 0.31 g of the desired product in the form of an oil. Yield: 34% Mp = Oil 6.2-N-[2-(3-Diethylaminopropyl)-N-methyl-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide To a solution of 0.20 g (0.00046 mol) of N-[2-(3-diethylaminopropyl)-N-methyl-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide dissolved in 10 ml of methanol saturated with hydrogen chloride is heated for twelve hours at 60°C. The solution is concentrated to dryness and the residue is treated with water. The aqueous phase is extracted several times with ethyl ether. The organic phases are combined and dried over anhydrous magnesium sulfate, and the solution is concentrated to dryness, to give 0.02 g of the desired product in the form of an oil. Yield: 12% Mp = Oil 1H-NMR (DMSO) δ (ppm): 9.67 (1H, s, NH), 7.7 (1H, s), 7.68 (1H, d), 7.5 (1H, d), 4.4 (2H, s), 3.5-2.9 (12H, m), 2.7 (3H, s), 1.9 (2H, m), 1.15 (6H, t). Example 7. 2-Cyclohexyl-N-[3-(diethylamino)propyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide ethanodioate (1:1) 5 ml of acetic acid are added to a suspension of 1.70 g (0.0050 mol) of N-[3- (diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-suffonamide (obtained according to the method described in stage 3.2- of Example 3) and 0.98 g (0.0014 mol) of cyclohexanone in 50 ml of tetrahydrofuran. The mixture is stirred for 3 hours at ambient temperature and 0.47 g (0.0075 mol) of sodium cyanoborohydride is added. The mixture is stirred overnight. The mixture is concentrated to dryness. The residue is treated with water and washed with ethyl ether. The aqueous phase is basified to pH = 10 and is extracted several times with ethyl ether. The organic . phases are combined and dried over anhydrous magnesium sulfate. The oil obtained is purified by silica gel column chromatography, with a dichloromethane/methanol (95:5) mixture used as eluant. The desired product (0.22 g; 11%) is obtained in the form of an oil. The above oil is dissolved in 5 ml of ethanol, and then a solution of 0,11 g (0.0012 mol) of oxalic acid, dissolved in 5 ml of ethanol, is added. The precipitate is filtered off and washed with cold ethanol. 0.32 g of the desired product is obtained as a white solid. Yield: 97% Mp = 76-83°C. 1H-NMR (DMSO-d6) δ(ppm): 7.6 (2H, m), 7.4 (1H, m), 4.2 (2H, s), 3.3 (H, m), 3.0 ( H, m), 2.7 (H, m), 2.4 (H, m), 2.0 (H, m), 1.7 (H, m), 1.4 (H, m), 1.1 (H, m). Example 8- 1-Aminopropylpyrroline 8.1- 1-(2-Cyanoethyl)pyrroline 0.95 ml (0.0014 mol) of acrylonitrile is added, at 0°C, to a solution of 1.00 g (0.0014 mol) of pyrroline in methanol. The mixture is stirred overnight at ambient temperature and is concentrated to dryness, to give 1.65 g of the desired product in the form of an oil. Yield: 93 % Mp = Oil 8.2- 1-(3-Aminopropyl)pyrroline 0.024 g of 1M diisobutylaluminum hydride in toluene is added to a solution of 1.00 g (0.0089 mol) of 1-(2-cyanoethyl)pyrroline in 20 ml of dichloromethane. The mixture is stirred overnight at ambient temperature. The solution is treated with sodium sulfate decahydrate. The mixture is stirred for half an hour. The inorganic phases are filtered and the filtrate is concentrated to dryness, so as to obtain 1.00 g of a colorless oil. Yield: 97% Mp = Oil 1H-NMR (CD3CI) δ (ppm): 5.75 (2H, s), 3.47 (4H, s), 2.75 (2H, t), 2.56 (2H, t), 1.69 (2H, q). The table below illustrates the chemical structures and the physical properties of some compounds according to the invention. The elemental microanalyses and the NMR, IR or mass spectra confirm the structures of the compounds obtained. In the table, for the compounds of formula I, "Mp." corresponds to the melting point. The compounds of the invention of formula I were subjected to pharmacological assays which showed their advantage as active substances in therapeutics. More particularly, the compounds of the invention are histamine H3-receptor antagonists. H3 receptors are known to those skilled in the art and their advantage in therapeutics has been described in the literature ("Histamine H3 receptor antagonists" Exp. Opinion Ther. Patents (2000) ;U) (7) -.1045-1055). Thus, the compounds of the invention of formula I were subjected to an in vitro affinity assay on the native histamine H3 receptor in an adult rat brain membrane preparation, by specific binding of [3H]-N-a-methylhistamine to this receptor, according to the methods described by A. Korte et al., in Biochem. Biophys. Res. Commun. 168, 979-986(1990) and by R.E. West Jr. et al., in Mol. Pharmacol. 38, 61O-613(1990). The Kj values for the compounds of the invention with respect to H3 receptors are between 0.1 nM and 5.0 \|j.M, and, more particularly, (+/-)-2-(cyclohexylmethyl)-N-[2- (1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (compound 15; Table 1) has a Ki of 0.3 nM. The compounds of the invention of formula I were also subjected to a cAMP formation assay, on the human histamine H3 receptor transfected into CHO cells, by inhibition of the agonism caused by the specific binding of R-a-methylhistamine to this receptor, according to the methods described by T.W. Lovenberg et al., in J. Pharmacol. Exp. Ther. 293, 771-778(2000). The IC50 values for the compounds of the invention with respect to H3 receptors are between 0.1 nM and 5.0 µM. By way of example, compound 15, included in Table 1, has an IC50 EIA kit (Amersham) to measure cAMP formation, on the human histamine H3 receptor transfected into CHO cells, by inhibition of the agonism caused by the specific binding of R-a-methylhistamine to this receptor. The compounds according to the invention have an activity that is selective for the histamine H3 receptor. Effectively, the compounds have a Ki of greater than 7.0 µM in the in vitro affinity assay on the native histamine H1 receptor in an adult rat brain membrane preparation by specific binding of [3H]-pirilamine to this receptor, according to the method described by Y.Q. Liu et al., in J. Pharmacol. Exp. Ther. 268,959(1994). Furthermore, the compounds of the invention of formula I were subjected to in vivo tests showing their ability to reduce food intake in rats fasting for 24 h. The experiments were carried out on Wistar rats. The rats were placed individually in transparent plastic cages 48x26, 5x21.5 cm. These cages were placed in a room insulated against any noise, at a temperature of 20 to 22°C, with a light cycle from 7 o'clock in the morning to 7 o'clock in the evening, the rats having free access to water and to the food. Before the experiment was carried out, the rats were made to fast for 24 h, with access, however, to water ad libitum. On the day of the experiment, the carrier or the compound according to the present invention was administered i.p. or p.o., 15 or 30 minutes before a known amount of food (30 g) was made available. Each hour, for 6 hours, the amount of food ingested by the rat was measured. It was shown that the AD50 values (mg/kg i.p. or p.o.) for the compounds of the invention with respect to food intake may be less than 10. For example, (+/-)-2-(4- isopropylbenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide (compound 24; Table 1) δecreases food intake by 54% during the first hour after the i.p. administration of 10 mg/kg of the product. The results of the tests show that the compounds of the invention make it possible to reduce food intake in animals. Thus, they make it possible to control weight gain, to treat obesity or to aid weight loss, in animals, but also in humans. Thus, according to another of its aspects, a subject of the invention is medicaments which comprise a compound of formula I or an addition salt of the latter with a pharmaceutically acceptable acid or else a hydrate or a solvate of the compound of formula I. These medicaments find their use in therapeutics, in particular in the treatment of pathologies in which a histamine H3-receptor antagonist provides a therapeutic benefit. In particular, such pathologies are obesity and diabetes. In addition, these compounds may be used in the treatment of central nervous system diseases such as vigilance and sleep disorders, narcolepsy, Alzheimer's disease and other dementias, Parkinson's disease, attention disorders in hyperkinetic children, memory and learning disorders, epilepsy, schizophrenia, moderate cognitive disorders, depression and anxiety. The states of depression and anxiety include, for example, anxieties of anticipatory type (before a surgical procedure, before a dental treatment, etc), anxiety caused by alcohol or drug dependency or withdrawal, mania, seasonal affective disorders, migraines and nausea. They can also be used in the treatment of sexual dysfunction, dizziness and travel sickness. The use of the compounds according to the invention for the preparation of a medicament for use in treating the pathologies mentioned above is an integral part of the invention. According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active ingredient, at least one compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or a solvate of said compound, and also at least one or more pharmaceutically acceptable excipients. Said excipients are chosen according to the pharmaceutical form and the method of administration desired, from the usual excipients that are known to those skilled in the art. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula I above, or possible salt, solvate or hydrate thereof, can be administered in unit administration form, as a mixture with conventional pharmaceutical excipients, to animals or to human beings for the prophylaxis or the treatment of the disorders or of the diseases above. The appropriate unit administration forms comprise oral administration forms, such as tablets, soft or hard gelatin capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal or intranasal administration forms, forms for administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms, and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions. In order to obtain the desired prophylactic or therapeutic effect, the dose of active ingredient can range between 0.1 µg and 50 mg per kg of bodyweight and per day. Each unit dose can contain from 0.1 to 1000 mg, preferably from 1 to 500 mg, of active ingredient in combination with a pharmaceutical excipient. This unit dose can be administered 1 to 5 times a day so as to administer a daily dose of from 0.5 to 5000 mg, preferably from 1 to 2500 mg. There may be specific cases were higher or lower dosages are appropriate. Such dosages also belong to the invention. According to the usual practice, the dosage appropriate for each patient is determined by the physician according to the method of administration and the weight and response of said patient. By way of example, a unit administration form of a compound according to the invention: Compound according to the invention 50.0 mg Mannitol 223.75 mg Sodium croscaramellose 6.0 mg Cornstarch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg According to another of its aspects, the present invention also relates to a method of treating the pathologies indicated above, which comprises the administration, to a patient, of an effective dose of a compound according to the invention or a pharmaceutically acceptable salt or hydrate or solvate thereof. WE CLAIM : 1. A compound of formula I: in which: n can represent a value between 1 and 6; -(C)n- represents a C1-6 alkylidene group optionally substituted with 1 to 4 substituents chosen from a halogen atom, and a hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino or C1-3 alkoxy group; R1 represents • a hydrogen atom, • a C1-6 alkyl group; R2 represents • a hydrogen atom, • a C1-6 alkyl or C3-6 cycloalkyl group optionally substituted with 1 to 4 substituents chosen from a halogen atom, a hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-2 perhaloalkyl, C1-3 haloalkyl, C1-3 alkoxy or C3-6 cycloalkyl group, a monocyclic heteroaryl such as a thienyl, furyl or pyrrolyl, or an aryl, such as a phenyl or a naphthyl; the aryl being optionally substituted with 1 to 4 substituents chosen from a halogen atom, a hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl, C1-2 perhaloalkyl, C1-3 haloalkyl or C1-3 alkoxy group or a C1-3 alkylidenedioxy group; B represents • NR3R4, - R3 and R4 represent, independently of one another, a C1-6 alkyl group, or a hydrogen atom; or - R3 and R4 together represent a C1-6 alkylidene group, a C2-8 alkenylidene group, a C1-3 alkylidene-O-C1-3 alkylidene group, or a C1-3 alkylidene-N(R5)-C1-3 alkylidene group where R5 represents a hydrogen atom, or a C1-3 alkyl or C1-6 alkylcarbonyl group, it being possible for these C1-3 alkyl and C1-6 alkylcarbonyl groups to be substituted with a halogen atom, or a hydroxyl, C1-3 alkoxy, nitro, cyano or amino group; or • an aminocycle, linked via a carbon to the group -NR1-(C)n-, chosen from aziridine, azetidine, pyrrolidine, piperidine and morpholine; the groups R3 and R4 and also the aminocycle being optionally substituted with 1 to 4 substituents chosen from a phenyl, a benzyl, a halogen atom, and a hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl or C1-3 alkoxy group; and the nitrogen atom optionally substituted with a C1-3 alkyl, in the form of a base or of an addition salt with an acid, and also in the form of a hydrate or of a solvate, with the exclusion of the compound in which R1 and R2 represent hydrogen atoms, B represents a dimethylamino group and -(C)n- represents an ethylidene group. 2. A compound as claimed in claim 1 wherein : n is equal to 2, .3 or 4; and R1 represents a hydrogen atom or a C1-2 alkyl group; and R2 represents a hydrogen atom, or a C1-4 alkyl or C5-6 cycloalkyl group optionally substituted with 1 to 4 substituents chosen from a phenyl, and a C3-6 cycloalkyl, C1-2 perhaloalkyl, C1-3 haloalkyl or C1-3 alkoxy group; the phenyl being optionally substituted with 1 to 4 substituents chosen from a halogen atom, a hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl, C1-2 perhaloalkyl, C1-3 haloalkyl or C1-3 alkoxy group or a C1-3 alkylidenedioxy group; and - B represents • NR3R4, - R3 and R4 represent, independently of one another, a C1-4 alkyl group; or - when R3 and R4 together represent a C1-6 alkylidene group, a C2-8 alkenylidene group, a C1-3 alkylidene-O- C1-3 alkylidene group or a C1-3 alkylidene-N(R5)-C1-3 alkylidene group , B represents a group: • or an aminocycle linked via a carbon to the group -NR1-(C)n, chosen from aziridine, azetidine, pyrrolidine, piperidine and morpholine; the groups R3, R4 and R5 and also the aminocycle being optionally substituted; in the form of a base or of an addition salt with an acid, and also in the form of a hydrate or of a solvate. 3. A compound as claimed in claim 2, wherein when B represents NR3R4 and R3 and R4 together form a C1-6 alkylidene group, a C2-8 alkenylidene group, a C1-3 alkylidene-O-C1-3 alkylidene group or a C1-3 alkylidene-N(R5)-C1-3 alkylidene group, or when B represents an aminocycle, then B is chosen from the following groups: 4. A compound as claimed in claim 1,2 or 3, wherein it consists of: • N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; • (+/-)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; • N-[3-(diethylamino)propyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; • N-[3-(diethylamino)propyl]-N-methyl-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; • 2-benzy[-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; • 2-(cyclopropylmethyl)-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline- 7-sulfonamide; • 2-(cyclohexylmethyl)-N-[3-(diethylamino)propy[]-1,2,3,4-tetrahydroisoquinoline- 7-sulfonamide; • (+/-)-N-[3-(2-methylpiperidin-1-yl)propy[]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; • N-[3-(3,6-dihydropyridin-1 (2H)-yl)propyl]-1,2,3,4-tetrahydroisoquinoiine-7- sulfonamide; • N-[3-(diethylamino)propyl]-2-isopropyl-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; • N-[3-(diethylamino)propyl]-2-(2-thienylmethyl)-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; • N-[3-(diethylamino)propyI]-2-(3-thienyImethyI)-1,2,3,4-tetrahydroisoquino[ine-7- sulfonamide; • N-[3-(2,5-dihydro-1H-pyrrol-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; • 2-cyclohexyl-N-[3-(diethyIamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; (+/-)-2-(cyclohexylmethyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethy[]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide; • N-[3-(2,5-dihydro-1H-pyrrol-1-yl)propyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline- 7-sulfonamide; • N-[3-(4-benzylpiperazin-1 -yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonaraide; • N-(3-pyrrolidin-1 -ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; • N-(3-morpholin-4-ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; • N-[3-(dimethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; • 2-(cyclohexylmethyl)-N-(3-pyrroIidin-1 -ylpropyl)-1,2,3,4-tetrahydroisoquinoIine- 7-suIfonamide; • (+/-)-2-(cyclopropyImethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide; • (+/-)-2-benzyl-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline- 7-sulfonamide; • (+/-)-2-(4-isopropylbenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide; • (+/-)-2-(1,3-benzodioxof-5-ylmethyI)-N-[2-(1 -methyIpyrroIidin-2-yI)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide; • (+)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7- sulfonamide; • (-)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoiine-7- sulfonamide; • (+)-2-(cyclohexylmethyI)-N-[2-.(1-methylpyrrolidin-2-yl)ethy[]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide; and • (-)-2-(cyclohexylmethyI)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-suIfonamide, in the form of a base or of an addition salt with an acid, and also in the form of a hydrate or a solvate. • (+/-)-2-(4-bromobenzyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide • (+/-)-2-(2,5-dimethoxybenzyI)-/V-[2-(1-methylpyrrolidin-2-yI)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide (+/-)-2-(2-methylbutyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide (+/-)-2-(3-methoxybenzyl)-)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-sulfonamide (+/-)-2-(3,5-dimethylbenzyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4- tetrahydroisoquinoline-7-suIfonamide. 5. A compound of formula II: in which Pg represents a hydrogen atom or a protective group, and -(C)n- and R1 are as defined in claim 1, and B represents: • NR3R4, where R3 and R4 are as defined in claim 1; • or an aminocycle linked via a carbon to the group -NR1 -(C)n-, chosen from aziridine, azetidine, pyrrolidine, piperidine and morpholine; the groups R3 and R4 and also the aminocycle being optionally substituted as defined in claim 1. 6. A pharmaceutical composition containing a compound of formula I, as claimed in any one of claims 1 to 4, or the salt, solvate or hydrate thereof, and at least one pharmaceutical excipient. (54) Title: TETRALLYDROISOQUINOLINE SULFONAMIDE DERIVETIVES, THE PREPARATION THEREOF, AND THE USE OF THE SAME IN THERAPEUTICS (57) Abstract: The invention relates to a compound of formula (1) wherein n can represent a value between 1 and 6: -(C)n- represents a C1-6 alkylidene group, optionally substituted by between 1 and 4 substituents; R1 represents a hydrogen atom, or a C1-6 alkyl group; R2 represents a hydrogen atom, a C1-6 alkyl or C3-6 cycloalkyl group optionally substituted by between 1 and 4 substituents; and B represents NR3R4, R3 and R4 independently representing a C1-6 alkyl group or a hydrogen atom, or together representing a C1-6 alkylidene group, a C2-8 alkenylidene group, a C1-3 alkylidene-O-C1-3 alkylidene group, or a C1-3 alkylidcne-N(R5)-C1-3 alkylidene group wherein R5 represents a hydrogen atom, or a C1-3 alkyl or C1-6 alkylcarbonyl group, said C1-3 alkyl and C1-6 alkylcarbonyl groups being substitutable, or an aminocycle which is linked by a carbon to the group -NRl-(C)n-, such as aziridine, azetidine, pyrrolidine, piperidine or morpholine, the groups R3, R4, the aminocycle, and the nitrogen atom being optionally substituted. The invention can be applied to therapeutics.

Full Text

The present invention relates to sulfonamide derivatives, to the preparation thereof
and to the therapeutic use thereof, in particular in the treatment of disorders that are
improved by modulation of the histamine H3 receptor, such as obesity, diabetes and
central nervous system diseases such as vigilance and sleep disorders.
Consequently, a first subject of the present invention is the compounds
corresponding to formula I

in which:
n can represent a value between 1 and 6;
-(C)n- represents a -C1-6 alkylidene group optionally substituted with 1 to 4
substituents chosen from a halogen atom, and a hydroxyl, nitro, cyano, amino, C1-3
monoalkylamino, C2-6 dialkylamino or C1-3 alkoxy group;
R1 represents
• a hydrogen atom,
• a C1-6 alkyl group;
R2 represents
• a hydrogen atom,
• a C1-6 alkyl or C3-6 cycloalkyl group optionally substituted with 1 to 4
substituents chosen from a halogen atom, a hydroxyl, nitro, cyano, amino, C1-3
monoalkylamino, C2-6 dialkylamino, C1-2 perhaloalkyl, C1-3 haloalkyl, C1-3
alkoxy or C3-6 cycloalkyl group, a monocyclic heteroaryl such as a thienyl, furyl
or pyrrolyl, or an aryl, such as a phenyl or a naphthyl; the aryl being optionally
substituted with 1 to 4 substituents chosen from a halogen atom, a hydroxyl,
nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl, C1-2
perhaloalkyl, C1-3 haloalkyl or C1-3 alkoxy group or a C1-3 alkylidenedioxy

group;
B represents • NR3R4,
- R3 and R4 represent, independently of one another, a
C1-6 alkyl group, or a hydrogen atom; or
- R3 and R4 together represent a C1-6 alkylidene group,
a C2-8 alkenylidene group, a C1-3 alkyIidene-O-C1-3
alkylidene group, or a C1-3 alkylidene-N(R5)-C1-3
alkylidene group where R5 represents a hydrogen
atom, or a C1-3 alkyl or C1-6 alkylcarbonyl group, it being
possible for these C1-3 alkyl and C1-6 alkylcarbonyl
groups to be substituted with a halogen atom, or a
hydroxyl, C1-3 alkoxy, nitro, cyano or amino group; or
• an aminocycle, linked via a carbon to the group
-NR1-(C)n-, such as aziridine, azetidine, pyrrolidine,
piperidine or morpholine;
the groups R3 and R4 and also the aminocycle being optionally substituted with 1 to
4 substituents chosen from a phenyl, a benzyl, a halogen atom, and a hydroxyl, nitro,
cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl or C1-3 alkoxy group;
and the nitrogen atom optionally substituted with a C1-3 alkyl.
In the context of the present invention, the term:
- "Cx-z" is intended to mean a carbon-based chain that may contain from x to z
carbon atoms; for example, C1-3 indicates a carbon-based chain that may contain
from 1 to 3 carbon atoms;
- "alkyl" is intended to mean a linear or branched, saturated aliphatic group; for
example, a C1-4 alkyl group represents a linear or branched, saturated carbon-
based chain containing from 1 to 6 carbon atoms, more particularly a methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc. radical; the term "Cx-y
alkylidene" denoting a divalent, linear or branched Cx-y alkyl group; the term "C2-8
alkenylidene" denoting a divalent, linear or branched, unsaturated Cx-y alkyl
group;
- "Cx-y alkoxy" is intended to mean an alkyloxy group comprising a linear or
branched, saturated aliphatic chain, containing x to y carbon atoms;
- "halogen atom" is intended to mean a fluorine, a chlorine, a bromine or an iodine;
- "C1-3 monoalkylamino" is intended to mean an amino monosubstituted with a C1-3
alkyl group;
- "C2-6 dialkylamino" is intended to mean an amino disubstituted with two C1-3 alkyl
groups;

- "C1-2 perhaloalkyl" is intended to mean a C1-2 alkyl group in which all the hydrogen
atoms are substituted with halogen atoms;
- "C1-3 haloalkyl" is intended to mean a C1-3 alkyl group in which at least one
hydrogen atom is substituted with a halogen atom.
The compounds of formula I can contain one or more asymmetrical carbon atoms.
They can therefore exist in the form of enantiomers or of diastereoisomers. These
enantiomers and diastereoisomers, and also mixtures thereof, including racemic
mixtures, are part of the invention.
The compounds of general formula I can be in the form of free bases or of addition
salts with acids, which are also part of the invention. According to the present
invention, these salts comprise those with pharmaceutically acceptable acids, but
also those with inorganic or organic acids that allow a suitable separation or
crystallization of the compounds of formula I. These salts can be prepared, according
to methods known to those skilled in the art, for example, by reaction of the
compound of formula I in the form of a base with the acid in an appropriate solvent,
such as an alcoholic solution or an organic solvent, and then separation of the media
that contains it by evaporation of the solvent or by filtration.
The compounds of formula I can also exist in the form of hydrates or of solvates, i.e.
in the form of associations or combinations with one or more water molecules or with
a solvent. Such hydrates and solvates are also part of the invention.
Furthermore, in the context of the present invention, the term "protective group Pg" is
intended to mean a group that makes it possible, firstly, to protect a reactive function
such as a hydroxyl or an amine during a synthesis and, secondly, to regenerate the
intact reactive function at the end of synthesis. Examples of protective groups and
also the methods of protection and deprotection are given in "Protective groups in
Organic Synthesis 3rd Ed.", Greene and Wuts (John Wiley & Sons, Inc., New York,
1999).
A subject of the present invention is also the compounds chosen from the following
subgroups, in which:
n is equal to 2, 3 or 4; and/or
R1 represents a hydrogen atom or a C1-2 alkyl group; and/or
R2 represents a hydrogen atom, or a C1-4 alkyl or C5-6 cycloalkyl group optionally
substituted with 1 to 4 substituents chosen from a phenyl, and a C3-6 cycloalkyl,
C1-2 perhaloalkyl, C1-3 haloalkyl or C1-3 alkoxy group; the phenyl being optionally

substituted with 1 to 4 substituents chosen from a halogen atom, a hydroxyl,
nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl, C1-2
perhaloalkyl, C1-3 haloalkyl or C1-3 alkoxy group or a C1-3 alkylidenedioxy group;
and/or
B represents • NR3R4,
- R3 and R4 represent, independently of one another, a
C1-4 alkyl group; or
- when R3 and R4 together represent a C1-6 alkylidene
group, a C2-8 alkenylidene group, a C1-3 alkylidene-O-
C1-3 alkylidene group or a C1-3 alkylidene-N(R5)-C1-3
alkylidene group, B represents a group:

or
• an aminocycle linked via a carbon to the group -NR1-(C)n,
such as aziridine, azetidine, pyrrolidine, piperidine or
morpholine;
the groups R3, R4 and R5 and also the aminocycle being optionally substituted; and,
more specifically, the subgroup where at the same time n, R1, R2 and B are as
defined above.
More particularly, when B represents NR3R4 and R3 and R4 together form a C1-6
alkylidene group, a C2-8 alkenylidene group, a C1-3 alkylidene-O-C1-3 alkylidene group
or a C1-3 alkylidene-N(R5)-C1-3 alkylidene group, or when B represents an
aminocycle, then B is chosen from the following groups:

Another subject of the present invention concerns the following compounds:
1. N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
2. (+/-)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
3. N-[3-(diethylamino)propyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
4. N-[3-(diethylamino)propyl]-N-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
5. 2-benzyl-N-[3-(diethyIamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
6. 2-(cyclopropylmethyl)-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
7. 2-(cyclohexylmethyl)-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
8. (+/-)-N-[3-(2-methylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
9. N-[3-(3,6-dihydropyridin-1 (2H)-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;

10. N-[3-(diethylamino)propyl]-2-isopropyl-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
11. N-[3-(diethylamino)propyl]-2-(2-thienylmethyl)-1,2)3,4-tetrahydroisoquinoline-7-
sulfonamide;
12. N-[3-(diethylamino)propyl]-2-(3-thienylmethyI)-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
13. N-[3-(2,5-dihydro-1H-pyrrol-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
14. 2-cyclohexyl-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoIine-7-
sulfonamide;
15. (+/-)-2-(cycIohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide;
16. N-[3-(2,5-dihydro-1H-pyrrol-1 -yI)propyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline-
7-sulfonamide;
17. N-[3-(4-benzylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
18. N-(3-pyrrolidin-1 -ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
19. N-(3-morpholin-4-ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
20. N-[3-(dimethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
21.2-(cyclohexylmethyl)-N-(3-pyrrolidin-1-ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
22. (+/-)-2-(cyclopropylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyI]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide;

23. (+/-)-2-benzyl-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1)2,3,4-tetrahydroisoquinoline-
7-sulfonamide;
24. (+/-)-2-(4-isopropylbenzyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide;
25. (+/-)-2-(1,3-benzodioxol-5-ylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide;
26. (+)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
27. (-)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
28. (+)-2-(cyclohexylmethyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide;
29. (-)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide;
30. (+/-)-2-(4-bromobenzyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide
31. (+/-)-2-(2,5-dimethoxybenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoIine-7-sulfonamide
32. (+/-)-2-(2-methylbutyl)-N-[2-(1 -methylpyrroIidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide
33. (+/-)-2-(3-methoxybenzyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide
and
34. (+/-)-2-(3,5-dimethyl-benzyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide.
A second subject of the present invention is processes for preparing the compounds
of formula I according to the invention.
Thus, the compounds of formula I can be prepared according to the process
represented in Scheme 1.

According to the process of Scheme 1, the compounds of formula i, in which R2 is
other than a hydrogen atom, are prepared by amminative reduction, by reacting a
secondary amine of formula I, in which R2 represents H, with an aldehyde or a
ketone of formula III, where R6 and R7, after reaction, together form R2 as defined in
formula I. The compounds of formula I where R2 represents a hydrogen atom can be
obtained by deprotection of the compounds of formula II, according to conventional
methods known to those skilled in the art. For example, the compounds of formula II,
when Pg is a trifluoroacetyl group, can be deprotected in the presence of a base
such as, for example, sodium carbonate, potassium carbonate, ammonia or barium
hydroxide in a protic solvent, such as water or methanol or a mixture of these
solvents, at a temperature between 0 and 100°C. Alternatively, the deprotection of
the compounds of formula II, when Pg is a trifluoroacetyl group, can be carried out in
the presence of an acid such as, for example, hydrochloric acid in a protic or aprotic
solvent, such as water, methanol, ethanol or ethyl acetate or a mixture of these
solvents, at a temperature between 0 and 100°C. Illustrations of the process are
given in the examples.
The starting compounds of formula II can be prepared according to Scheme 2 or can
be synthesized by conventional methods known to those skilled in the art.

According to this scheme, the compounds of formula II, in which n, R1 and B are as
defined in formula I, can be prepared by reaction of an amine of formula V, in which
R1 and B are as defined in formula I, with a sulfonyl chloride of formula IV, in which
Pg represents an appropriate protective group such as, for example, a
trifluoroacetamide, so as to form a derivative of sulfonamide type of formula II,
according to conventional methods known to those skilled in the art, for example, the
reaction can be carried out in a protic or aprotic solvent, such as tetrahydrofuran,
dichloromethane, ethyl acetate, N,N-dimethyIformamide or acetonitrile or a mixture of
these solvents, at a temperature of between 0 and 100°C, in the presence of a base

such as, for example, potassium carbonate, sodium carbonate, diisopropylethylamine
or triethylamine.
Alternatively, the compounds of formula II can be prepared by a Mitsunobu type
reaction, according to Scheme 3.

According to this alternative, a sulfonamide of formula VII, in which R1 is as defined
in formula I, is reacted with an amino alcohol of formula VIII, in which n and B are as
defined above. The reaction can be carried out conventionally in the presence of
Mitsunobu reagents, such as an azo derivative, for example diethylazodicarboxylate,
diisopropylazodicarboxylate, di-tert-butylazodicarboxylate, 1,1'-
(azodicarbonyl)dipiperidine or N,N,N',N -tetramethylazodicarboxamide, and a
phosphine, for example triphenylphosphine or tributylphosphine. The reaction can be
carried out in an aprotic solvent, such as tetrahydrofuran or dioxane or a mixture of
these solvents, at a temperature between 0 and 100°C, to give the compound of
formula II. The sulfonamide of formula VII in which R1 is as defined in formula I can
be prepared by reaction of an amine of formula VI, in which R1 is as defined in
formula I, with a sulfonyl chloride of formula IV, in which Pg represents an
appropriate protective group such as, for example, a trifluoroacetamide, according to
conventional methods known to those skilled in the art, for example, the reaction can
be carried out in a protic or aprotic solvent, such as tetrahydrofuran,
dichloromethane, ethyl acetate, la N,N-dimethylformamide or acetonitrile or a mixture
of these solvents, at a temperature between 0 and 100°C, in the presence of a base
such as, for example, potassium carbonate, sodium carbonate, diisopropylethylamine
or triethylamine.

The starting compounds IV and the amines of formulae V and VIII are directly
commercially available, can be synthesized by conventional methods known to those
skilled in the art, or are known in the literature.
For example, the diamines of formula V, in which n is equal to 3, can be prepared
according to Scheme 4.

According to this process, the compounds of formula V, in which n is equal to 3, R1
represents a hydrogen atom and B represents an amine group, can be prepared by
means of an addition reaction of an amine of formula X, in which R3 and R4 are as
defined above, with the acrylonitrile of formula IX, so as to form a derivative of
aminonitrile type of formula XI, according to conventional methods known to those
skilled in the art, followed by reduction of the nitrile. The reduction can be carried out
according to methods known to those skilled in the art, for example in the presence of
diisobutylaluminum hydride at a temperature between -70°C and 40°C in an aprotic
solvent such as dichloromethane or toluene or a mixture of these solvents; the
reduction can also be carried out in the presence of a reducing agent, such as
hydrogen, in the presence of a catalyst such as platinum, palladium or Raney nickel,
in a solvent such as methanol or ethyl acetate, so as to give the compound of formula
V, in which n is equal to 3, R1 represents a hydrogen atom and B represents an
amine group. The compounds of formula V, in which R1 represents a C1-6alkyl group,
can be prepared by alkylation of the compound of formula V obtained above,
according to conventional methods known to those skilled in the art.
A subject of the present invention is also the compounds of formula II, when Pg
represents a protective group or a hydrogen atom, as intermediates for the
preparation of the compound of formula I.
The following examples illustrate the processes and techniques suitable for the
preparation of this invention, without, however, limiting the scope of the claim.
Example 1-N-[2-(1-Methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide hydrochloride

1.1 - (+/-)-N-[2-(1 -Methylpyrrolidin-2-yl)ethyl]-2-(2,2,2-trifluoroacetyl)-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide hydrochloride
A solution of 5.00 g (0.015 mol) of 2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-
isoquinoline-7-sulfonyl chloride and 2.00 g (0.015 mol) of (+/-)-2-(1-methyl-pyrrolidin-
2-yl)-ethylamine, in 50 ml of dichloromethane, is stirred overnight at ambient
temperature. The solution is concentrated to dryness. The solid formed is purified by
silica gel column chromatography, with a dichloromethane/methanol (97:3) mixture
used as eluant, to give 4.30 g of the desired product in the form of a white solid.
Yield: 62%
Mp = amorphous
1.2- C+/-N-[2-(1 -Methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide hydrochloride
A solution of 4.30 g (0.0094 mol) of 2-(2,2,2-trifluoroacetyl)-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamido-[2-(1-methylpyrrolidin-2-yl)ethyl] hydrochloride
in 50 ml of methanol saturated with hydrogen chloride is heated for twelve hours at
60°C. The mixture is cooled and the solid that has formed is filtered off, washed with
methanol and dried. 2.00 g of the desired product are obtained as a white solid.
Yield: (65%)
Mp = 209-212°C
1H-NMR (DMSO-d6) δ(ppm): 7.9 (1H, t), 7.7 (2H, d), 7.5 (1H, d), 4.3 (2H, s), 3.6 (5H,
m), 3.1 (3H, m), 2.9 (2H, m), 2.7 (3H, m), 2.1 (1H, m), 1.9 (3H, m), 1.6 (2H, m), 2.7
(3H, s); 2.9 (2H, t).
1.3- (+) or (-)-N-[2-(1-Methylpyrrolidin-2-yl]ethyll-1,2,3,4-tetrahydroisoquinoline-
7-sulfonamide hydrochloride
The compound obtained above in 1.2 is separated by chiral-phase preparative
chromatography, to give its enantiomers. Specifically, the separation of 15.00 g of

(+/-)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide
hydrochloride is carried out with a PROCHROM LC50 preparative HPLC system, with
a CHIRALPACK AD stationary phase and a mobile phase formed from
isohexane/ethanol/methanol (80%:10%:10%)+0.2% of diethylamine, to give 5.39 g of
the dextrorotatory product, in the form of a white powder, with a chiral-phase
enantiomeric purity of 99.67%, and 4.89 g of the levorotatory product, in the form of a
white solid, with a chiral-phase enantiomeric purity of 99.48%. The two products are
converted into their corresponding hydrochloride by a treatment with isopropanol
saturated with hydrogen chloride.
Dextrorotatory enantiomer: Mp = 114-117°C; [α]* = +16 (c=0.5, methanol)
Levorotatory enantiomer: Mp = 115-117°C; [α]" = -16 (c=0.5, methanol)
Example 2-(+/-)-2-(Cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2"yl)ethyl]-
1,2,3,4-tetrahydroisoquinoline-7-sulfonamide oxalate (1:2)

0.32 g (0.0003 mol) of palladium-on-charcoal at 10% is added to a solution of 2.02 g
(0.0063 mol) of (+/-)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamido-[2-(1 -methyl-
pyrrolidin-2-yl)ethyl] and 0.70 g (0.0063 mol) of cyclohexanecarboxaldehyde in
100 ml of methanol. The solution is hydrogenated for 24 hours in a Paar
hydrogenator at a pressure of 45 Psi. The catalyst is removed by filtration and the
filtered solution is evaporated to dryness. The crude oil obtained (2.90 g) is purified
by silica gel column chromatography, with a dichloromethane/methanol (95:5)
mixture used as eluant. The desired product (1.62 g; 62%) is obtained in the form of
an oil.
The above oil is dissolved in 20 ml of ethanol, and then 0.77 g (0.0086 mol) of oxalic
acid dissolved in 15 ml of ethanol is added. The precipitate is filtered off and washed
with cold ethanol. 2.01 g of the desired product are obtained in the form of a white
solid.
Yield: 86%
Mp = 142-147°C
1H-NMR (DMSO-d6) δ(ppm): 7.5 (2H, m), 7.29 (1H, m), 3.84 (2H, s), 3.35 (2H, m),
3.1 (1H, m), 2.9 (1H, m), 2.8 (2H, s), 2.7 (1H, m), 2.6 (3H, s), 2.5 (2H, m), 2.1-1.4

(13H, m), 1.15 (4H, m), 0.8 (2H, m).
Example 3- (+)-2-(Cyclohexylmethyl)-N-[2-(1-methylpyrrolldin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide oxalate (1:1.5)
According to a process similar to Example 2, with 1.00 g (0.0031 mol) of (+)-N-[2-(1-
methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and 0.35 g
(0.0031 mol) of cyclohexanecarboxaldehyde in 50 ml of methanol as starting product,
0.46 g of base is obtained, which base is converted into the corresponding
sesquioxalate hydrate, as a white solid.
Yield: 20%
Mp = 134-140°C
[α]20D = +12 (c=0.5, methanol)
Example 4-(-)-2-(Cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide oxalate (1:2)
According to a process similar to Example 2, with 1.00 g (0.0031 mol) of (-)-N-[2-(1-
methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and 0.35 g
(0.0031 mol) of cyclohexanecarboxaldehyde in 50 ml of methanol as starting product,
0.90 g of base is obtained, which base is converted into the corresponding dioxalate
hydrate, as a white solid.
Yield: 27%
Mp=133-138°C
[α]" = -8 (c=0.5, methanol)
Example 5- 2-Benzyl-N-[3-(diethylamino)propyl]- 1,2,3,4-tetrahydroisoquinoline-
7-sulfonamide oxalate (1:2)

5.1 - N-[2-(3-Diethylaminopropyl)-2-(2,2,2-trifluoroacetyl)-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide hydrochloride
A solution of 1.00 g (0.0031 mol) of 2-(2,2,2-trifluoroacetyl)-1,2,3,4-
tetrahydroisoquinoline-7-sulfonyl chloride and 0.61 g (0.0047 mol) of N,N-diethyl- N-

aminopropylamine in 25 ml of dichloromethane is stirred overnight at ambient
temperature. The solution is concentrated to dryness and the oil formed is purified by
silica gel column chromatography, with a dichloromethane/methanol (97:3) mixture
used as eluant. 1.27 g are obtained.
Yield: 97%
Mp = Oil
5.2-N-[3-(Diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide
hydrochloride
A solution of 5.39 g (0.013 mol) of N-[2-(3-diethylaminopropyl)-2-(2,2,2-
trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hydrochloride, dissolved
in 60 ml of methanol saturated with hydrogen chloride, is heated for twelve hours at
60°C. The mixture is cooled and the solid that has formed is filtered off, washed with
methanol and dried. The residue is dissolved in an aqueous solution of sodium
hydroxide. The aqueous phase is extracted several times with ethyl ether. The
organic phases are combined and dried over anhydrous magnesium sulfate. The oil
obtained (2.80 g) is used without additional purification.
Yield: 67%
Mp = Oil
5.3-2-Benzyl-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide oxalate (1:2)
1.5 ml of acetic acid are added to a suspension of 0.45 g (0.0014 mol) of
N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and 0.149 g
(0.0014 mol) of benzaldehyde in 12 ml of tetrahydrofuran. The suspension is stirred
for 1 hour at ambient temperature and then 0.14 g (0.0021 mol) of sodium
cyanoborohydride was added. The mixture was stirred overnight. The mixture is
concentrated to dryness and the residue is treated with water and washed with ethyl
ether. The aqueous phase is basified to pH = 10 and is extracted several times with
ethyl ether. The organic phases are combined and dried over anhydrous magnesium
sulfate. The oil obtained is purified by silica gel column chromatography, with a
dichloromethane/methanol (95:5) mixture used as eluant. The desired product
(0.13 g; 22%) is obtained in the form of an oil.
The above oil is dissolved in 5 ml of ethanol, and then 0.06 g (0.0007 mol) of oxalic
acid, dissolved in 5 ml of ethanol, is added. The precipitate is filtered off and washed

with cold ethanol. 0.12 g of the desired product is obtained as a white solid.
Yield: 63%
Mp = 91-103°C
1H-NMR (DMSO-d6) δ(ppm): 7.5-7.1 (8H, m), 3.52 (2H, d), 2.9-2.5 (14H, m), 1.5 (2H,
m), 0.9 (6H, t).
Example 6 N-[3-(Diethylamino)propyl]-N-methyl-1,2,3,4-tetrahydroisoquinoline-
7-sulfonamide hydrochloride

6.1 - N-[2-(3-Diethylaminopropyl)-N-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-
tetrahydroisoquinoline-7 -sulfonamide
0.09 g (0.0022 mol) of a dispersion of sodium hydride (60%) in a mineral oil is added
to a solution of 0.91 g (0.0021 mol) of N-[2-(3-diethylaminopropyl)-2-(2,2,2-
trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (obtained according to
the method described in stage 5.1- of Example 5) in 17 ml of dimethylformamide,
cooled to 0°C. The mixture is stirred for one hour and 0.60 g (0.0042 mol) of methyl
iodide is added. The mixture is stirred overnight at ambient temperature, and the
solution is concentrated to dryness. The residue is treated with water. The aqueous
phase is extracted several times with ethyl acetate. The organic phases are
combined and dried over anhydrous magnesium sulfate. The oil obtained after
filtration and evaporation of the solvent is purified by silica gel column
chromatography, with a dichloromethane/methanol (95:5) mixture used as eluant, to
give 0.31 g of the desired product in the form of an oil.
Yield: 34%
Mp = Oil
6.2-N-[2-(3-Diethylaminopropyl)-N-methyl-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide
To a solution of 0.20 g (0.00046 mol) of N-[2-(3-diethylaminopropyl)-N-methyl-2-
(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide dissolved in 10 ml
of methanol saturated with hydrogen chloride is heated for twelve hours at 60°C. The
solution is concentrated to dryness and the residue is treated with water. The
aqueous phase is extracted several times with ethyl ether. The organic phases are
combined and dried over anhydrous magnesium sulfate, and the solution is
concentrated to dryness, to give 0.02 g of the desired product in the form of an oil.
Yield: 12%
Mp = Oil
1H-NMR (DMSO) δ (ppm): 9.67 (1H, s, NH), 7.7 (1H, s), 7.68 (1H, d), 7.5 (1H, d), 4.4
(2H, s), 3.5-2.9 (12H, m), 2.7 (3H, s), 1.9 (2H, m), 1.15 (6H, t).

Example 7. 2-Cyclohexyl-N-[3-(diethylamino)propyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide ethanodioate (1:1)

5 ml of acetic acid are added to a suspension of 1.70 g (0.0050 mol) of N-[3-
(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-suffonamide (obtained
according to the method described in stage 3.2- of Example 3) and 0.98 g
(0.0014 mol) of cyclohexanone in 50 ml of tetrahydrofuran. The mixture is stirred for 3
hours at ambient temperature and 0.47 g (0.0075 mol) of sodium cyanoborohydride
is added. The mixture is stirred overnight. The mixture is concentrated to dryness.
The residue is treated with water and washed with ethyl ether. The aqueous phase is
basified to pH = 10 and is extracted several times with ethyl ether. The organic
. phases are combined and dried over anhydrous magnesium sulfate. The oil obtained
is purified by silica gel column chromatography, with a dichloromethane/methanol
(95:5) mixture used as eluant. The desired product (0.22 g; 11%) is obtained in the
form of an oil.
The above oil is dissolved in 5 ml of ethanol, and then a solution of 0,11 g
(0.0012 mol) of oxalic acid, dissolved in 5 ml of ethanol, is added. The precipitate is
filtered off and washed with cold ethanol. 0.32 g of the desired product is obtained as
a white solid.
Yield: 97%
Mp = 76-83°C.
1H-NMR (DMSO-d6) δ(ppm): 7.6 (2H, m), 7.4 (1H, m), 4.2 (2H, s), 3.3 (H, m), 3.0 (
H, m), 2.7 (H, m), 2.4 (H, m), 2.0 (H, m), 1.7 (H, m), 1.4 (H, m), 1.1 (H, m).

Example 8- 1-Aminopropylpyrroline

8.1- 1-(2-Cyanoethyl)pyrroline
0.95 ml (0.0014 mol) of acrylonitrile is added, at 0°C, to a solution of 1.00 g
(0.0014 mol) of pyrroline in methanol. The mixture is stirred overnight at ambient
temperature and is concentrated to dryness, to give 1.65 g of the desired product in
the form of an oil.
Yield: 93 %
Mp = Oil
8.2- 1-(3-Aminopropyl)pyrroline
0.024 g of 1M diisobutylaluminum hydride in toluene is added to a solution of 1.00 g
(0.0089 mol) of 1-(2-cyanoethyl)pyrroline in 20 ml of dichloromethane. The mixture is
stirred overnight at ambient temperature. The solution is treated with sodium sulfate
decahydrate. The mixture is stirred for half an hour. The inorganic phases are filtered
and the filtrate is concentrated to dryness, so as to obtain 1.00 g of a colorless oil.
Yield: 97%
Mp = Oil
1H-NMR (CD3CI) δ (ppm): 5.75 (2H, s), 3.47 (4H, s), 2.75 (2H, t), 2.56 (2H, t), 1.69
(2H, q).
The table below illustrates the chemical structures and the physical properties of
some compounds according to the invention. The elemental microanalyses and the
NMR, IR or mass spectra confirm the structures of the compounds obtained.
In the table, for the compounds of formula I, "Mp." corresponds to the melting point.

The compounds of the invention of formula I were subjected to pharmacological
assays which showed their advantage as active substances in therapeutics.

More particularly, the compounds of the invention are histamine H3-receptor
antagonists. H3 receptors are known to those skilled in the art and their advantage in
therapeutics has been described in the literature ("Histamine H3 receptor
antagonists" Exp. Opinion Ther. Patents (2000) ;U) (7) -.1045-1055).
Thus, the compounds of the invention of formula I were subjected to an in vitro
affinity assay on the native histamine H3 receptor in an adult rat brain membrane
preparation, by specific binding of [3H]-N-a-methylhistamine to this receptor,
according to the methods described by A. Korte et al., in Biochem. Biophys. Res.
Commun. 168, 979-986(1990) and by R.E. West Jr. et al., in Mol. Pharmacol. 38,
61O-613(1990).
The Kj values for the compounds of the invention with respect to H3 receptors are
between 0.1 nM and 5.0 |j.M, and, more particularly, (+/-)-2-(cyclohexylmethyl)-N-[2-
(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide
(compound 15; Table 1) has a Ki of 0.3 nM.
The compounds of the invention of formula I were also subjected to a cAMP
formation assay, on the human histamine H3 receptor transfected into CHO cells, by
inhibition of the agonism caused by the specific binding of R-a-methylhistamine to
this receptor, according to the methods described by T.W. Lovenberg et al., in
J. Pharmacol. Exp. Ther. 293, 771-778(2000).
The IC50 values for the compounds of the invention with respect to H3 receptors are
between 0.1 nM and 5.0 µM.
By way of example, compound 15, included in Table 1, has an IC50 EIA kit (Amersham) to measure cAMP formation, on the human histamine H3
receptor transfected into CHO cells, by inhibition of the agonism caused by the
specific binding of R-a-methylhistamine to this receptor.
The compounds according to the invention have an activity that is selective for the
histamine H3 receptor. Effectively, the compounds have a Ki of greater than 7.0 µM in
the in vitro affinity assay on the native histamine H1 receptor in an adult rat brain
membrane preparation by specific binding of [3H]-pirilamine to this receptor,
according to the method described by Y.Q. Liu et al., in J. Pharmacol. Exp. Ther.
268,959(1994).

Furthermore, the compounds of the invention of formula I were subjected to in vivo
tests showing their ability to reduce food intake in rats fasting for 24 h.
The experiments were carried out on Wistar rats. The rats were placed individually in
transparent plastic cages 48x26, 5x21.5 cm. These cages were placed in a room
insulated against any noise, at a temperature of 20 to 22°C, with a light cycle from 7
o'clock in the morning to 7 o'clock in the evening, the rats having free access to water
and to the food.
Before the experiment was carried out, the rats were made to fast for 24 h, with
access, however, to water ad libitum. On the day of the experiment, the carrier or the
compound according to the present invention was administered i.p. or p.o., 15 or 30
minutes before a known amount of food (30 g) was made available.
Each hour, for 6 hours, the amount of food ingested by the rat was measured.
It was shown that the AD50 values (mg/kg i.p. or p.o.) for the compounds of the
invention with respect to food intake may be less than 10. For example, (+/-)-2-(4-
isopropylbenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide (compound 24; Table 1) δecreases food intake by 54% during the first
hour after the i.p. administration of 10 mg/kg of the product.
The results of the tests show that the compounds of the invention make it possible to
reduce food intake in animals. Thus, they make it possible to control weight gain, to
treat obesity or to aid weight loss, in animals, but also in humans.
Thus, according to another of its aspects, a subject of the invention is medicaments
which comprise a compound of formula I or an addition salt of the latter with a
pharmaceutically acceptable acid or else a hydrate or a solvate of the compound of
formula I.
These medicaments find their use in therapeutics, in particular in the treatment of
pathologies in which a histamine H3-receptor antagonist provides a therapeutic
benefit. In particular, such pathologies are obesity and diabetes. In addition, these
compounds may be used in the treatment of central nervous system diseases such
as vigilance and sleep disorders, narcolepsy, Alzheimer's disease and other
dementias, Parkinson's disease, attention disorders in hyperkinetic children, memory
and learning disorders, epilepsy, schizophrenia, moderate cognitive disorders,
depression and anxiety. The states of depression and anxiety include, for example,
anxieties of anticipatory type (before a surgical procedure, before a dental treatment,

etc), anxiety caused by alcohol or drug dependency or withdrawal, mania, seasonal
affective disorders, migraines and nausea. They can also be used in the treatment of
sexual dysfunction, dizziness and travel sickness.
The use of the compounds according to the invention for the preparation of a
medicament for use in treating the pathologies mentioned above is an integral part of
the invention.
According to another of its aspects, the present invention relates to pharmaceutical
compositions comprising, as active ingredient, at least one compound according to
the invention. These pharmaceutical compositions contain an effective dose of at
least one compound according to the invention, or a pharmaceutically acceptable
salt, a hydrate or a solvate of said compound, and also at least one or more
pharmaceutically acceptable excipients. Said excipients are chosen according to the
pharmaceutical form and the method of administration desired, from the usual
excipients that are known to those skilled in the art.
In the pharmaceutical compositions of the present invention for oral, sublingual,
subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal,
transdermal or rectal administration, the active ingredient of formula I above, or
possible salt, solvate or hydrate thereof, can be administered in unit administration
form, as a mixture with conventional pharmaceutical excipients, to animals or to
human beings for the prophylaxis or the treatment of the disorders or of the diseases
above.
The appropriate unit administration forms comprise oral administration forms, such as
tablets, soft or hard gelatin capsules, powders, granules and oral solutions or
suspensions, sublingual, buccal, intratracheal or intranasal administration forms,
forms for administration by inhalation, topical, transdermal, subcutaneous,
intramuscular or intravenous administration forms, rectal administration forms, and
implants. For topical application, the compounds according to the invention can be
used in creams, gels, ointments or lotions.
In order to obtain the desired prophylactic or therapeutic effect, the dose of active
ingredient can range between 0.1 µg and 50 mg per kg of bodyweight and per day.
Each unit dose can contain from 0.1 to 1000 mg, preferably from 1 to 500 mg, of
active ingredient in combination with a pharmaceutical excipient. This unit dose can
be administered 1 to 5 times a day so as to administer a daily dose of from 0.5 to
5000 mg, preferably from 1 to 2500 mg.

There may be specific cases were higher or lower dosages are appropriate. Such
dosages also belong to the invention. According to the usual practice, the dosage
appropriate for each patient is determined by the physician according to the method
of administration and the weight and response of said patient.
By way of example, a unit administration form of a compound according to the
invention:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Sodium croscaramellose 6.0 mg
Cornstarch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
According to another of its aspects, the present invention also relates to a method of
treating the pathologies indicated above, which comprises the administration, to a
patient, of an effective dose of a compound according to the invention or a
pharmaceutically acceptable salt or hydrate or solvate thereof.

WE CLAIM :
1. A compound of formula I:

in which:
n can represent a value between 1 and 6;
-(C)n- represents a C1-6 alkylidene group optionally substituted with 1 to 4
substituents chosen from a halogen atom, and a hydroxyl, nitro, cyano, amino, C1-3
monoalkylamino, C2-6 dialkylamino or C1-3 alkoxy group;
R1 represents
• a hydrogen atom,
• a C1-6 alkyl group;
R2 represents
• a hydrogen atom,
• a C1-6 alkyl or C3-6 cycloalkyl group optionally substituted with 1 to 4
substituents chosen from a halogen atom, a hydroxyl, nitro, cyano, amino, C1-3
monoalkylamino, C2-6 dialkylamino, C1-2 perhaloalkyl, C1-3 haloalkyl, C1-3
alkoxy or C3-6 cycloalkyl group, a monocyclic heteroaryl such as a thienyl, furyl
or pyrrolyl, or an aryl, such as a phenyl or a naphthyl; the aryl being optionally
substituted with 1 to 4 substituents chosen from a halogen atom, a hydroxyl,
nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl, C1-2
perhaloalkyl, C1-3 haloalkyl or C1-3 alkoxy group or a C1-3 alkylidenedioxy
group;
B represents • NR3R4,
- R3 and R4 represent, independently of one another, a
C1-6 alkyl group, or a hydrogen atom; or
- R3 and R4 together represent a C1-6 alkylidene group,
a C2-8 alkenylidene group, a C1-3 alkylidene-O-C1-3
alkylidene group, or a C1-3 alkylidene-N(R5)-C1-3
alkylidene group where R5 represents a hydrogen
atom, or a C1-3 alkyl or C1-6 alkylcarbonyl group, it being
possible for these C1-3 alkyl and C1-6 alkylcarbonyl
groups to be substituted with a halogen atom, or a
hydroxyl, C1-3 alkoxy, nitro, cyano or amino group; or
• an aminocycle, linked via a carbon to the group

-NR1-(C)n-, chosen from aziridine, azetidine, pyrrolidine,
piperidine and morpholine;
the groups R3 and R4 and also the aminocycle being optionally substituted with 1
to 4 substituents chosen from a phenyl, a benzyl, a halogen atom, and a
hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl
or C1-3 alkoxy group; and the nitrogen atom optionally substituted with a C1-3 alkyl,
in the form of a base or of an addition salt with an acid, and also in the form of a
hydrate or of a solvate,
with the exclusion of the compound in which R1 and R2 represent hydrogen
atoms, B represents a dimethylamino group and -(C)n- represents an ethylidene
group.
2. A compound as claimed in claim 1 wherein :
n is equal to 2, .3 or 4; and
R1 represents a hydrogen atom or a C1-2 alkyl group; and
R2 represents a hydrogen atom, or a C1-4 alkyl or C5-6 cycloalkyl group optionally
substituted with 1 to 4 substituents chosen from a phenyl, and a C3-6 cycloalkyl,
C1-2 perhaloalkyl, C1-3 haloalkyl or C1-3 alkoxy group; the phenyl being optionally
substituted with 1 to 4 substituents chosen from a halogen atom, a hydroxyl,
nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl, C1-2
perhaloalkyl, C1-3 haloalkyl or C1-3 alkoxy group or a C1-3 alkylidenedioxy group;
and
- B represents • NR3R4,
- R3 and R4 represent, independently of one another, a
C1-4 alkyl group; or
- when R3 and R4 together represent a C1-6 alkylidene
group, a C2-8 alkenylidene group, a C1-3 alkylidene-O-
C1-3 alkylidene group or a C1-3 alkylidene-N(R5)-C1-3
alkylidene group , B represents a group:

• or an aminocycle linked via a carbon to the group
-NR1-(C)n, chosen from aziridine, azetidine, pyrrolidine,
piperidine and morpholine;
the groups R3, R4 and R5 and also the aminocycle being

optionally substituted;
in the form of a base or of an addition salt with an acid, and also in the form of
a hydrate or of a solvate.
3. A compound as claimed in claim 2, wherein when B represents
NR3R4 and R3 and R4 together form a C1-6 alkylidene group, a C2-8 alkenylidene
group, a C1-3 alkylidene-O-C1-3 alkylidene group or a C1-3 alkylidene-N(R5)-C1-3
alkylidene group, or when B represents an aminocycle, then B is chosen from the
following groups:

4. A compound as claimed in claim 1,2 or 3, wherein it consists of:
• N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
• (+/-)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
• N-[3-(diethylamino)propyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
• N-[3-(diethylamino)propyl]-N-methyl-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
• 2-benzy[-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
• 2-(cyclopropylmethyl)-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-
7-sulfonamide;
• 2-(cyclohexylmethyl)-N-[3-(diethylamino)propy[]-1,2,3,4-tetrahydroisoquinoline-
7-sulfonamide;
• (+/-)-N-[3-(2-methylpiperidin-1-yl)propy[]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
• N-[3-(3,6-dihydropyridin-1 (2H)-yl)propyl]-1,2,3,4-tetrahydroisoquinoiine-7-
sulfonamide;
• N-[3-(diethylamino)propyl]-2-isopropyl-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
• N-[3-(diethylamino)propyl]-2-(2-thienylmethyl)-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
• N-[3-(diethylamino)propyI]-2-(3-thienyImethyI)-1,2,3,4-tetrahydroisoquino[ine-7-
sulfonamide;

• N-[3-(2,5-dihydro-1H-pyrrol-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
• 2-cyclohexyl-N-[3-(diethyIamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
(+/-)-2-(cyclohexylmethyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethy[]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide;
• N-[3-(2,5-dihydro-1H-pyrrol-1-yl)propyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline-
7-sulfonamide;
• N-[3-(4-benzylpiperazin-1 -yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonaraide;
• N-(3-pyrrolidin-1 -ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
• N-(3-morpholin-4-ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
• N-[3-(dimethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;
• 2-(cyclohexylmethyl)-N-(3-pyrroIidin-1 -ylpropyl)-1,2,3,4-tetrahydroisoquinoIine-
7-suIfonamide;
• (+/-)-2-(cyclopropyImethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide;
• (+/-)-2-benzyl-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-
7-sulfonamide;
• (+/-)-2-(4-isopropylbenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide;
• (+/-)-2-(1,3-benzodioxof-5-ylmethyI)-N-[2-(1 -methyIpyrroIidin-2-yI)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide;
• (+)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-
sulfonamide;
• (-)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoiine-7-
sulfonamide;
• (+)-2-(cyclohexylmethyI)-N-[2-.(1-methylpyrrolidin-2-yl)ethy[]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide; and
• (-)-2-(cyclohexylmethyI)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-suIfonamide, in the form of a base or of an addition salt
with an acid, and also in the form of a hydrate or a solvate.
• (+/-)-2-(4-bromobenzyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide
• (+/-)-2-(2,5-dimethoxybenzyI)-/V-[2-(1-methylpyrrolidin-2-yI)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide
(+/-)-2-(2-methylbutyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide

(+/-)-2-(3-methoxybenzyl)-)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-sulfonamide
(+/-)-2-(3,5-dimethylbenzyl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-1,2,3,4-
tetrahydroisoquinoline-7-suIfonamide.
5. A compound of formula II:

in which Pg represents a hydrogen atom or a protective group, and -(C)n- and R1
are as defined in claim 1, and B represents:
• NR3R4, where R3 and R4 are as defined in claim 1;
• or an aminocycle linked via a carbon to the group -NR1 -(C)n-, chosen
from aziridine, azetidine, pyrrolidine, piperidine and morpholine;
the groups R3 and R4 and also the aminocycle being optionally substituted as
defined in claim 1.
6. A pharmaceutical composition containing a compound of formula I, as claimed in
any one of claims 1 to 4, or the salt, solvate or hydrate thereof, and at least one
pharmaceutical excipient.

(54) Title: TETRALLYDROISOQUINOLINE SULFONAMIDE DERIVETIVES, THE PREPARATION THEREOF, AND THE
USE OF THE SAME IN THERAPEUTICS
(57) Abstract: The invention relates to a compound of formula (1) wherein n can represent a value between 1 and 6: -(C)n- represents
a C1-6 alkylidene group, optionally substituted by between 1 and 4 substituents; R1 represents a hydrogen atom, or a C1-6 alkyl group;
R2 represents a hydrogen atom, a C1-6 alkyl or C3-6 cycloalkyl group optionally substituted by between 1 and 4 substituents; and
B represents NR3R4, R3 and R4 independently representing a C1-6 alkyl group or a hydrogen atom, or together representing a C1-6
alkylidene group, a C2-8 alkenylidene group, a C1-3 alkylidene-O-C1-3 alkylidene group, or a C1-3 alkylidcne-N(R5)-C1-3 alkylidene
group wherein R5 represents a hydrogen atom, or a C1-3 alkyl or C1-6 alkylcarbonyl group, said C1-3 alkyl and C1-6 alkylcarbonyl
groups being substitutable, or an aminocycle which is linked by a carbon to the group -NRl-(C)n-, such as aziridine, azetidine,
pyrrolidine, piperidine or morpholine, the groups R3, R4, the aminocycle, and the nitrogen atom being optionally substituted. The
invention can be applied to therapeutics.

Documents:

03287-kolnp-2006 abstract.pdf

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03287-kolnp-2006 claims.pdf

03287-kolnp-2006 correspondence others.pdf

03287-kolnp-2006 description (complete).pdf

03287-kolnp-2006 form-1.pdf

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03287-kolnp-2006 priority document.pdf

03287-kolnp-2006-assignment-1.1.pdf

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3287-KOLNP-2006-ABSTRACT 1.1.pdf

3287-KOLNP-2006-AMANDED CLAIMS.pdf

3287-KOLNP-2006-ASSIGNMENT.pdf

3287-KOLNP-2006-CORRESPONDENCE 1.2.pdf

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3287-kolnp-2006-form 18.pdf

3287-KOLNP-2006-FORM 2.pdf

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Patent Number

253619

Indian Patent Application Number

3287/KOLNP/2006

PG Journal Number

32/2012

Publication Date

10-Aug-2012

Grant Date

07-Aug-2012

Date of Filing

09-Nov-2006

Name of Patentee

SANOFI-AVENTIS

Applicant Address

174, AVENUE DE FRANCE FR-75013 PARIS FRANCE

Inventors:

#	Inventor's Name	Inventor's Address
1	DIAZ MARTIN JUAN ANTONIO	C/COLOMBIA 30-5 IZDA 28016 MADRID ESPAGNE SPAIN
2	JIMENEZ BARGUENO MARIA DOLORES	C/PASEO DE LA CHOPERA N 102 28100 ALCOBENDAS (MADRID) ESPAGNE SPAIN

PCT International Classification Number

C07D 217/02

PCT International Application Number

PCT/FR2005/001279

PCT International Filing date

2005-05-24

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	04/05,607	2004-05-25	France