Title of Invention	8-AZABICYCLO[3.2.1.] OCTANE-3-METHANAMINE DERIVATIVES COMPOUNDS
Abstract	Compounds of general formula (I) in which U represents a group of general formula (A) or in which formulae V represents a hydrogen or halogen atom, a (C1-C3)alkyl group or one or two (C1-C3) alkoxy groups, W and X each represent, respectively, either two oxygen atoms, or an oxygen atom and a CH2 group, or a CH2 group and an oxygen atom, or an oxygen atom and a CO group, n represents the number 0 or 1, R represents either a propyl group when U represents a group of general formula (A), or a hydrogen atom or a (C1-C3)alkyl group when U represents a group of general formula (B) , Y represents one or more atoms or groups chosen from the following: hydrogen, halogen, (C1-C3)alkyl and (C1-C3) alkoxy, Z represents two hydrogen atoms or an oxygen atom.

Title of Invention

8-AZABICYCLO[3.2.1.] OCTANE-3-METHANAMINE DERIVATIVES COMPOUNDS

Abstract

Compounds of general formula (I) in which U represents a group of general formula (A) or in which formulae V represents a hydrogen or halogen atom, a (C1-C3)alkyl group or one or two (C1-C3) alkoxy groups, W and X each represent, respectively, either two oxygen atoms, or an oxygen atom and a CH2 group, or a CH2 group and an oxygen atom, or an oxygen atom and a CO group, n represents the number 0 or 1, R represents either a propyl group when U represents a group of general formula (A), or a hydrogen atom or a (C1-C3)alkyl group when U represents a group of general formula (B) , Y represents one or more atoms or groups chosen from the following: hydrogen, halogen, (C1-C3)alkyl and (C1-C3) alkoxy, Z represents two hydrogen atoms or an oxygen atom.

Full Text	The present invention relates to compounds of general formula (I) in which U represents A) either a 2,3-dihydro-lH-inden-2-yl group of general formula (A) B) or a heterocyclic group of general formula (B) in which V represents a hydrogen or halogen atom, a (C1-C3)alkyl group or one or two (C1-C3) alkoxy groups, W and X each represent, respectively, either two oxygen atoms, or an oxygen atom and a CH2 group, or a CH2 group and an oxygen atom, or an oxygen atom and a CO group, n represents the number 0 or 1, R represents either a propyl group when U represents a 2,3-dihydro-lH-inden-2-yl group of general formula (A), or a hydrogen atom or a (C1-C3)alkyl group when U represents a heterocyclic group of general formula (B), Y represents one or more atoms or groups chosen from the following: hydrogen, halogen, (C1-C3)alkyl and (C1-C3)alkoxy, Z represents two hydrogen atoms or an oxygen atom. The compounds of the invention can exist in two forms of geometrical isomers, namely the a, or endo, isomeric form in which the CH2 group in the 3 position of the tropane ring-system (azabicyclooctane) is in an axial position, and the b, or exo, isomeric form in which the said CH2 group is in an equatorial position, in the so-called "chair" conformation of the piperidine unit of the tropane ring-system. The compounds of the invention can also exist in the form of bases or of addition salts with acids. When U represents a 2,3-dihydro-lH-inden-2-yl group of general formula (A), the compounds of the invention correspond to the general formula (IA) They can be prepared according to a process illustrated by Scheme 1A which follows. Ethyl 6- (phenylmethyl) -8-az.abicyclo [3 . 2 .1] - octane-3-carboxylate of formula (IIA) is reacted with a dimethylaluminium amide, prepared beforehand from trimethylaluminium and a 2,3-dihydro-1H-indene-2-amine derivative of general formula (IIIA), in which V is as defined above, in an inert solvent, for example toluene, at a temperature of from 0 to 100°C; a compound of general formula (IVA) is obtained, which is reduced by the action of a mixed alkali metal hydride such as lithium aluminium hydride, in an ether solvent, for example tetrahydrofuran, at a temperature of from 0 to 60°C, to give a compound of general formula (VA). This compound is subjected to an acylation using propanoyl chloride, in a chlorinated solvent, for example dichloromethane, in the presence of a base such as triethylamine, at a temperature of from o to 40°C, to give an amide of general formula (VIA} , which is reduced by the action of a mixed alkali metal hydride such as lithium aluminium hydride, in an ether solvent, for example tetrahydrofuran, at a temperature of from 0 to 60°C, to give a compound of general formula (Ia) which corresponds to the general formula (IA) when Y represents a hydrogen atom and Z represents two hydrogen atoms. To prepare another compound of general formula (IA), debenzylation is then carried out, for example by catalytic hydrogenation, to give the amine of general formula (VIIA), and finally this amine is reacted either with an acid chloride of general formula (VIIIA) in which Y is as defined above, Z represents an oxygen atom and T represents a chlorine atom, in a chlorinated solvent, for example dichloromethane, in the presence of a base such as triethylamine, at a temperature of from 20 to 40oC, or with a halogenated derivative of general formula (VIIIA) in which Y is as defined above, Z represents two hydrogen atoms and T represents a halogen atom, in an aprotic solvent, for example N, N-dimethylformamide , in the presence of a base such as potassium carbonate, at a temperature of from 20 to 100°C. The 2,3-dihydro-1H-indene-2-amine of general formula (IIIA) in which X represents hydrogen is commercially available; the substituted derivatives of 2,3-dihydro-1H-indene-2-amine of general formula (IIIA) can be prepared by methods analogous to those described in Can. J. Chem. (1974) 52 381-389. The ethyl 8-(phenylmethyl)-8- azabicyclo[3.2.1]octane-3-carboxylate of formula (IIA) can be prepared by a method analogous to that described in J. Med. Chem. (1994) 37 2831. When U represents a heterocyclic group of general formula (B), the compounds of the invention correspond to the general formula (IB) They can be prepared according to processes illustrated by Schemes 1B to 3B which follow . According to Schemes IBa, IBb and IBc, the compounds of general formula (IB1, in vhich W and x each represent an oxygen atom and n represents the number 1, are prepared by reacting ethyl 8- (phenylmethyl) - B-azabicyclo [3.2.1] -octane-3- carboxylate of formula (IIA) with a dimethylaluminium amide, prepared beforehand from trmethylaluminium and a 2,3-dihydro-1,4-benodioxane-2-methanamine derivative of general formula (IIB), in which V is as defined above, in an inert solvent such as toluene, at a temperature of from o to 100°c, to give a compound of general formula (IVB) , which is reduced by the action of a mixed alkali metal hydride, for example lithium aluminium hydride, in an ether solvent such as tetrahydrofuran, at a temperature of from 0 to 60oC. A compound of general formula (IBa) which corresponds to the general formula (IB) where R and Y each represent a hydrogen atom and Z represents two hydrogen atoms is obtained. If a final compound is desired, in the general formula of which R represents a hydrogen atom or an alkyl group, the compound of general formula (IBa) is then treated by one of the processes illustrated by Schemes IBb or IBc. Scheme IBb begins by protecting the secondary amine function of the compound of general formula (IBa) by the action of bis(1,1-dimethylethyl) dicarbonate, in a chlorinated solvent such as dichloromethane, to give a compound of general formula (VB), in which Boc represents a 1,1-dimethylethoxycarbonyl group. This compound is debenzylated by catalytic hydrogenation and the compound thus obtained, of general formula (VIB), is then reacted with an acid. chloride of general formula (VIIB) in which Y is as defined above and Hal represents a chlorine atom, in a chlorinated solvent, for example dichloromethane, in the presence of a base such as triethylamine, at a temperature of from 20 to 40oC. A compound of general formula (VIIIB) is obtained, the secondary amine function of which is deprotected using trifluoroacetic acid to give a compound of general formula (IBb). Finally, and if so desired, this compound is reduced by the action of a mixed alkali metal hydride, for example lithium aluminium hydride, in an ether solvent such as tetrahydrofuran., to give a compound of general formula (IBa). In Scheme IBc, a compound of general formula. (IBa) is subjected to an acylation using an acetic- forming mixed anhydride or a C1-C3 acid chloride, in a chlorinated solvent such as dichloromethane. at a temperature of from 0 to 40°C, to give a compound of general formula (IXB) , in which R' represents a hydrogen atom or a methyl or ethyl group, and this acylated compound is then reduced using a mixed alkali- metal hydride, for example lithium aluminium hydride, in an ether solvent such as tetrahydrocuran. to give a compound of general formula (IBd), in which R" represents a (C1-C3) alkyl group. This compound is then, treated as indicated with regard to the compound of general formula (VB), with the exception, of course, of the amine deprotection step. In Scheme 2B, the compounds of general formula (IB), in which X represents an oxygen atom, W represents an oxygen atom or a CH2 group, R represents a hydrogen atom and n represents the number 1, are prepared by reacting a compound of general formula (XIB) , in whicn V is as defined above and C represents a leaving group such as a halogen atom or a methanesulphonyloxy or 4-methylbenzenesulphonyloxy group, with an 8-azabicyclo[3.2.1] octane-3-amine of general formula (XIIB), in which Y, 2 and R are as defined above, in a solvent such as acetonitrile, in the presence of a base such as potassium carbonate. In Scheme 3B, the compounds of general formula (IB), in which X represents a CO group, w represents an oxygen atom, R represents a hydrogen atom and n represents the number 1, are prepared by reacting a compound, of general formula (XIIIB) in which V is as defined above, with paraformaldehyde and an a-azabicyclo[3.2.1] octane-3-amine of general formula (XIIB), in which Y, Z and R are as defined above, in a solvent such as 2-propanol, in the presence of a catalytic amount of hydrochloric acid. The starting compounds to be used in the processes illustrated by Schemes IB to 3B are commercially available or can be prepared according to methods identical or analogous to those described in the literature, in particular in patent applications EP-0,193,400 and EP-0,013,139 and in J. Med. Chem. (1983), 26 823, J. Med. Chem. (1989) 12 1402, and J. Med. Chem. (1994) 37 2831. The examples which follow illustrate the preparation of a number of compounds of the invention. The elemental dicroanalyses and the IR and NMR spectra confirm the structures of the compounds obtained. The numbers indicated in parentheses in the example titles correspond to those in the 1st column of Tables A and B given later. In the compound names, the hyphen " -" forms part of the name, and the underscore line "_" serves merely to indicate the line break; it should be removed if a line break does not occur at that point and should not be replaced either with a normal hyphen or with a space. Example 1A (Compound No. 4A). exo-N-(2,3-Dihydro-1H-inden-2-yl}-8-(phenylmethyl) -N- propyl-6-azabicyclo [3.2.1]octane-3-methanamine (E) -2- butenedioate (5:2). 1A.1. exo-N- (2,3-Dihydro-lH-inden-2-yl) -B- (phenylmethyl)-8-azabicyclo [3.2.1]octane-3- carboxamide. 20 ml of toluene are introduced into a 250 ml three-necked round-bottomed flask under an argon atmosphere, 1.48 g (2 0.4 mmol) of a 2 M solution of trimethylaluminium in heptane are added slowly, the mixture is cooled to 0°C with a bath of ice, water and salt, 3-64 g (27.4 mmol) of 2,3-dihydro-1H-inden-2- amine are added dropwise, the mixture is heated at 50oC for a few minutes, 3.6 g (13.2 mmol) of ethyl 8- {phenylmethyl) -a-azabicyclo [3.2.1] occane-1 - carboxylate are then added at this temperature and the mixture is refluxed for 4 h. It is cooled to 0oC and hydrolysed by adding 24 ml of water, the resulting mixture is filtered through infusorial earth, the filtrate is driee over sodium sulphate and filtered and the solvents are evaporated off under reduced pressure. The evaporation residue is purified by chromatography on a column of silica gel, elveing wich a 97/3 to 93/7 mixture of dicblorometbane and methanol. 4.56 9 of solid are obtained. Malting point: 129°C. 1A.2. exo-N- (2, 3-Dihydro-lH-inden-2-yl) -8- (phenylmethyl) -8-azabicyclo[3.2.l]octane-3- methanamine (E) -2-butenedioate (2:1) 0.56 g (14.7 mmol) of lithium aluminium hydride suspended in 3 0 ml of tetrahydrofuran is introduced into a 250 ml three-necked round-bottomed flask under an argon atmosphere, the mixture is cooled to 0°C, 2.65 g (7.35 mmol) of exo-N- (2,3-dihydro-1H- inden-2-yl)-8-(phenylmethyl)-8-azabicyclo[3.2.l] octane- 3-carboxamide dissolved in 50 ml of tetrahydrofuran are added and the mixture is reflusted for 12 h. The mixture is cooled to 0°C, the excess hydride is hydrolysed with aqueous 1 N sodium hydroxide, the insoluble material is removed by filtration, the filtrate is dried over sodium sulphate and this solution is filtered and concentrated under reduced pressure. 2.55 g of oily product are obtained, the salt of which is prepared by addition of 1.7 g (14.7 mmol) of fumaric acid dissolved in 200 ml of ethanol to a solution of 2.55 g of the base in 50 ml of ethanol, the solvent is evaporated off under reduced pressure and the residue is recrystallized from a 4/1 mixture of methanol and ethanol. 2.9 g of fumarate are obtained. Melting point: 216.5-219°C. 1A.3 . exo-N- (2, 3-Dihydro-1H-inden-2-yl) -N- 11B- (phenylmethyl)-8-azabicyclo[3.2.1]oct-3-yl- methyl]propanamide hydrochloride 0.95 g {2.74 mmol) of exo-N- (2,3-dihydro-1H- inden-2-yl)-8-(phenylmethyl)-8-azabicyclo[3.2.l]octane- 3-methanamine dissolved in 15 ml of dichloromethane is introduced into a 250 ml three-necked round-bottomed flask under an argon atmosphere, 0.31 g (3.02 mmol) of triethylamine is added, finally followed by dropwise addition of 0.27 g (2.88 mmol) of propanoyl chloride dissolved in S ml of dichloromethane, and the mixture is left stirring at room temperature for 5 h. The mixture is washed with three times 50 ml of water, the organic phase is dried over sodium sulphate, filcered and concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 96/2 to 92/8 mixture of dichloromethane and methanol. 0.9 g of base is obtained. The hydrochloride is prepared by addition of 25 ml of a 0.1 N solution of hydrochloric acid in 2-propanol to a solution of 0.9 g 22.4 mmol) of base in 10 ml of ethyl acetate. The solvents are evaporated off under reduced pressure and the residue is recrystallized from a 9/1 mixture of ethyl acetate and 2-propanol. 0.55 g of which solid is obtained. Melting point: 208-2l0°C. 1A.4. exo-N-(2,3-Dihydro-1H-inden-2-yl>-8- (phenylmethyl)-N-propyl-8- azabicyclo [3.2.1] octane - 3 -methanamine (E) -2 - butenedioate (5:2). 0.34 g (8.94 mmol) of lithium aluminium hydride suspended in 20 ml of tetrahydrofuran is introduced into a 250 ml three-necked round-bottomed flask under an argon atmosphere, the mixture is cooled to 0oC, 1.8 g (4.47 mmol) of exo-N-(2,3-dihydro-1H- inden-2-yl) -N- [[8- (phenylmethyl) -8- azabicyclo[3.2.1]oct-3-yl]methyl]propanamide dissolved in 40 ml of tetrahydrofuran are added and the mixture is refluxed for 6 h. The mixture is cooled to 0°C, the excess hydride is hydrolysed with aqueous 1 N sodium hydroxide, the insoluble material is removed by filtration, the filtrate is dried over sodium sulphate and the solution is filtered and concentrated under reduced pressure. 1.6 g of oily product are obtained. The difumarate is prepared by addition of 0.96 g (8.24 mmol) of fumaric acid dissolved in 250 ml of ethanol to a solution of 1-6 g (4-12 mmol) of base in 100 ml of ethanol. The solvent is evaporated off under reduced pressure and the solid residue is recrystallized from a 35/5 mixture of ethanol and methanol. fumarate (5:2) are obtained. Melting point: 190-192°C Example 2A (Compound No. 5A) exo-8- [(4-Chlorophenyl)methyl]-N- (2,3-dihydro-1H-inden- 2-yl) -N-propyl-8-azabicyclo[3.2.1}octane-3-methanamine (E) - 2-butenedioate (2:1) 2A,1. exo-N- (2, 3-dihydro-lH-inden-2-yl] -N-prc-pyl -8- azabicyclo[3.2.1]octane-3-methanamine. A suspension of 1.75 g (4.5 mmol) of exo-N- (2,3-dihydro-lH-inden-2-yl)-8-(phenylmethyl)-N-propyl- 8-azabicyclo[3.2.1]octane-3-methanamine in 40 ml of ethanol is prepared, 0.5 g of 10% palladium on charcoal is added and hydrogenation is carried out in Parr apparatus, at a pressure of about 0.32 Mpa, at 45oC. After cooling to room temperature, the catalyst is separated out by filtration, the filtrate is concentrated under reduced pressure, and the oily residue is taken up in aqueous ammonia solution and extracted with diethyl ether. The organic phase is- washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure, 1.1 g of oily yellow residue are obtained, which product is used without further purification in the following step. 2A.2. exo-8-[(4-Chlorophenyl)methyl]-N-(2,3- dihydro-1H-inden-Z-yl) -N-propyl-B- azabicyclo[3.2.1]octane-3-methanamine (E)-2- butenedioate (2:1) . 2.94 g (9.9 mmol) of exo-N-(2,3-dihydro-lH- inden-2-yl)-N-propyl-8-azabicyclo[3.2.1]octane-3- methanamine dissolved in 45 ml of N,N- dimethylformamide, 2.2 g (10.7 mmol) or 1-bromomethyl- 4-chlorobenzene, 2.7 g (19.6 mmol) of potassium carbonate and 0.1 g of sodium iodide are introduced into a 100 ml three-necked round-bottomed flask under an argon atmosphere and the mixture is then heated at 60°C for 3 h. The mixture is allowed to cool and is poured onto 150 ml of ice-cold water and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and filtered, the filtrate is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 100/0 to 30/10 mixture of dichloromethane and methanol. 4.0 g of base are obtained, the fumarate of which is prepared by addition of 2.1 9 (18,8 mmol) of fumaric acid dissolved in 50 ml of ethanol to 4.0 g (9.4 mmol) of base dissolved in 100 ml of ethanol, the solvent is evaporated off under reduced pressure and the residue is recrystallized from ethanol. 2.62 g of white solid are obtained. Melting point: 198-199°C. Example 3A (Compound No. 3A) exo-8- (3-Chlorobenzoyl) -N- (2, 3-dihydro-lH-inden-2-yl) - M-propyl-8-azabicyclo(1.2.1] octane-3-methanamine hydrochloride 0.75 g (2.51 mmol) of exo-N- (2,3-dihydro-1H- inden-2-yl) -N-propyl-8 -azabicyclo [3,2. 1]octane-3- methanamine dissolved in 18 ml of dichloromethane is introduced into a 50 ml three-necked round-bottomed flask under an argon atmosphere, 0.51 g 15.03 mmol) of triethylamine is added, followed by slow addition of 0.88 g (5.02 mmol) of 3 -chlorobenzoyl chloride, and the mixture is stirred at room temperature for 24 h. The mixture is poured onto 100 ml of water and extracted with ethyl acetate, the organic phase is separated out, washed with water, dried over sodium sulphate and filtered, the filtrate is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 99/l to 98/2 mixture of dichloromethane and methanol. 0.2 g of base is obtained, the hydrochloride of which is prepared by addition of 5 ml of a 0.l n solution of hydrochloric acid in 2-propanol to a solution of the 0.2 g (0.42 mmol) of base in 10 ml of ethyl acetate, the solvents are evaporated off under reduced pressure and the residue is recrystallized from a 95/5 mixture of ethyl acetate and 2-propanol. 0.12 g of white solid is obtained Melting point: 213-2l5oC. Example 4A (Compound No. 14A). exo-N- (4,7-Dimethoxy-2,3-dihydro-lH-inden-2-yl) -8- (phenylmethyl)-N-propyl-8-azabicyclo[3.2.1]octane-3 - methanamine (E) -2-butenedioate (2:l). 4A.1. exo-N- (4,7-dimethoxy-2,3-dihydro-lH-inden-2- yl) -8- (phenylmethyl) -8- azabicyclo[3.2.1]octane-3-carboxamide Using the procedure described in Example 1A.1, starting with 4-64 g (24 mmol) of 4,7-dimethoxy- 2,3-dihydro-lH-indene-2-amine and 3-3 g (13.9 mmol) of ethyl 8-(phenylmethyl)-8-azabicyclo [3-2.1] octane-3- carboxylate, 4.1 g of solid are obtained, which product is used without further purification in the following step. 4A. 2. exo -N- (4 , 7 - Dimethoxy- 2 , 3 -dihydro- 1H- inden - 2 - yl)-8-(phenylmethyl)-8- azabicyclo [3.2.1] obtane-3 -methanamine. Using the procedure described in Example 1A.2, starting with 4.85 g (11.5 mmol) of exo-N-(4,7- dimethoxy-2,3-dihydro-lH-inden-2-yl) -8- (phenylmethyl) - 8-azabicyclo[3-2.l]octane-3-carboxamide and 0.88 g (23 mmol) of lithium aluminium hydride. 4.6 g of oily produce are obtained, which product is used without further purification in the following step. 4A.3. exo-N-(4,7-Dimethoxy-2,3-dihydro-lH-indent- yl) -N- [[8- (phenylmethyl) -8- Using the procedure described in Example 1A.3, starting with 4.6 g (11.3 mmol) of exo-N-(4,7- dimethoxy-2,3-dihydro-lH-inden-2-yl)-8-(phenylmethyl) - 8-azabicyclo (3.2.1] octane-3-methanamine, 1.3 g (12.8 mmol) of triethylamine and 1.13 g (12.2 mmol) of propanoyl chloride, and after purification by ehromatography on a column of silica gel, eluting with a 98/2 to 92/8 mixture of dichloromethane and methanol, 4.7 g of oily product are obtained, which product is used without further purification in the following step. 4A.4. exo-N- (4, 7-Dimethoxy-2, 3-dihydro-lH-inden-2- yl) -8- (phenylmethyl) -N-propyl-8- azabicyclo[3.2.1} octane-3-methanamine (E) -2- butenedioate (2:1). Using the procedure described in Example 1A.4, starting with 4-7 g (10.1 mmol) of exo-N- (4,7- dimethoxy-2,3-dihydro-lH-inden-2-yl) -N- ((8- (phenylmethyl) -8-azabicyclo [3.2.1] oct-3- yl] methyl] propanamide and 0.78 g (20.6 mmol) of lithium aluminium hydride, and after purification by chromatography on a column of silica qel, elating with a 96/4 to 88/12 mixture of dichloromethane and methanol, 4.5 g of compound are obtained in the form of a yellow oil. 1.0 g (2.23 mmol) of this product is dissolved in l00 ml of ethanol a solution of 0.52 g (4.46 mmol) of fumaric acid in 100 ml of ethanol is added, che solvent is evaporated off under reduced pressure and the solid residue is recrystallized from ethanol. 0.68 g of fumarate (2:1) is obtained. Melting point: 167-189°C, Example 5A (Compound No. 13A) exo-N-(4,7-Dimethoxy-2,3-dihydro-lH-inden-2-yll -8-(3- ethoxybenzoyl) -N-propyl-8-azabicyclo [3.2.l] octane-3- methanamine hydrochloride. 5A.1. exo-N-(4,7-Dimethoxy-2,3-dihydro-lH-inden-2- yl)-N-propyl-8-azabicyclo[3.2.1] octane-3- methanamine. Using the procedure described in Example 2A.1, starting with 4.95 g (11 mmol) of exo-N-(4,7,- dimethoxy-2,3-dihydro-lH-inden-2-yl) -8- (phenylmethyl) - N-propyl-8-azabicyclo (3.2.1]octane-3-methanamine and 1.2 g of 10% palladium on charcoal, 3.4 g of oily compound are obtained, which product is used without further purification in the following step 5A.2. exo-N-(4,7-Dimethoxy-2,3-dihydro-lH-inden-2- yl) -8- (3-ethoxybenzoyl)-N-propyl-8- azabicyclo[3.2.1]octane-3-methanamine hydrochloride. Using the procedure descried in Example 3A, starting with 1.1 g (3.07 mmol) of exo-N-(4,7 dimethoxY-2,3-dihydro-1H-inden-2-yl)-N-propyl)-8- azabicyclo[3.2.l]octane-3-methanamine, 0.62 g (6,14 mmol) of triethylamine and 1.13 (6.12 mmol) of 3-ethoxybenzoyl chloride, and after purification by chromatography on a column of silica gel, eluting with a 99/1 to 96/4 mixture of dichloromethane and methanol, 1.43 g of compound are obtained in the form of an oil. The hydrochloride is prepared by addition of 30 ml of a 0. 1N solution of hydrochloric acid in 2- propanol to a solution of 1.43 g (2.82 mmol) of base in 30 ml of ethanol, the solvents are evaporated off under reduced pressure and the solid residue is recrystallized from a 9/1 mixture of ethyl acetate and ethanol. 0.56 g of white solid is obtained. Melting point: 161-163°C. Example 6A (Compound No. 12A), exo-8- (3, 4-Dimethoxybenzoyl) -N- (4 , 7-dimethoxy 2 , 3- dihydro-1H-inden-2-yl)-N-propyl-8- azabicyclo[3.2.1]octane-3-methanamine hydrochloride. Using the procedure described in Example 3A, starting with 1.25 g (3.49 mmol) of exo-N-(4,7- dimethoxy-2,3-dihvdro-1H-inden-2-yl)-N-propy1-8- azabicyclo[3.2.l]octane-3-methanamine, 0.71 g (6.98 mmol of criethylamine and 1.4 g (6.96 mmol) of 3,4-dimethoxybenzoyl chloride, and after purification by chromatography on a column of silica gel, eluting with a 99/l to 96.5/3.5 mixture of dichloromethane and methanol, 1.5 g of compound are obtained in the form of a yellow oil. The hydrochloride is prepared by addition of 20 ml of a 0.1 N solution of hydrochloric acid in 2- propanol to a solution of 1.5 g (2.87 mmol) of base in 30 ml of ethanol, the solvents are evaporated off under reduced pressure and the solid residue is recrystallized from a 9/1 mixture of ethyl acetate and ethanol. 1.12 g of white solid are obtained. Melting point: 134-136°C. Example 1B (Compound No. 1B). exo-N- [(2,3-Dihydro-l,4-benzodioxan-2-yl)methyl]-8- (phenylmethyl)-8-azabicyclo[3.2.1]octane-3-methanamine (E)-2-butenedioate (2:1). 1B.1. exo-N-[(2,3-dihydro-l,4-benzodioxan-2- yl)methyl]-8-(phenylmethyl)-8- azabicyclo[3.2.1]octane-3-carboxamide. 20 ml of a 2M solution of trimethylaluminium in toluene are introduced into a 500 ml three-necked round-bottomed flask under a nitrogen atmosphere, the mixture is cooled to 0°C, 7.75 g (39.7 mmol) of 2,3- dihydro-1,4-dioxane-2-methanamine dissolved in 150 ml of toluene are added dropwise, the mixture is heated to 50°C, 6.9 g (2S.1 mmol) of ethyl 8-(phenylmethyl)-8- azabicyclo [3 . 2 . 1] octane-3-carboxylate dissolved in 35 ml of toluene are then added at this temperature and the mixture is refluxed for 8 h. The mixture is cooled to 0°C and hydrolysed by adding 50 ml of water, it is filtered over infusorial earth, the filtrate is dried over sodium sulphate, the solution is filtered and the solvents are evaporated off under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with 95/5 mixture of dichloromethane and methanol. 8.4 g of compound are obtained in the form of an oil. 1B.2. exo-N- [(2,3-Dihydro-l,4-benzodioxan-2- yl)methyl]-8-(phenylmethyl)-8- azabicyclo[3.2.1]octane-3-methanamine (E)-2- butenedioate (2:1). 5 g (131 mmol} of lithium aluminium hydride suspended in 50 ml of tetrahydrofuran are introduced into all three-necked round-bottomed flask under a nitrogen atmosphere, the mixture is cooled to 0°c, 8.4 g (21.4 mmol) of exo-N- ((2, 3-dihydro-l, 4- benzodioxan-2-yl)methyl]-8-(phenylmethyl)-8- azabicyclo[3.2.1]octane-3-carboxamid« dissolved in 420 ml of tetrahydrofuran are added and the mixture is refluxed for 15 h. The mixture is cooled to 0oC. the excess hydride is hydrolysed with aqueous 1 N sodium hydroxide, the insoluble material is removed by filtration and the filtrate is dried over sodium sulphate and concentrated under reduced pressure. 7.3 g of base are obtained in oily form. 2.9 g (7.66 mmol) of this product are taken, 1.8 9 (15.5 mmol) of fumaric acid dissolved in ethanol are added, the solvent is evapprated off and the residue is recrystallized from 2-propanol and then from ethanol. 1.3 g of white solid are obtained. Melting point: 105-107oc. Example 2B (Compound No. 15B). exo-N-[(2,3-Dihydro-l,4-benzodioxan-2-yl)methyl]-8-(4- methoxybenzoyl) -8-azabicyclo[3.2.1]octane-3-methanamine hvdrochloride (1:1). 2B.l. 1,1-Dimethylethyl exo- [(2, 3-dihydro-1,4- henzodioxan-2-yl)methyl] [(8- (phenylmethyl) -8- azabicyclo (3.2.l) oct-3-yllmethyll csrbamate 7.3 g (193 mmol) of exo-N- [{2,3-dihydro-1,4- benzodioxan-2-yl)methyl)-8-(phenylmethyl)-8- azabicyclo[3.2 .1} octane-3-methanamine dissolved in 18 ml of dichloromethane are are introduced into a three- necked round-bottomed flask under a nicrogen atmosphere, 4.6 g (21 mmol) of bis(1,1-dimethylethyl) dicarbonate dissolved in 18 ml of dichloromethane are added dropwise and the mixture is stirred at room temperature for 24 h. The solvent is evaporated off under reduced pressure the residue is dissolved in 100 ml of diethyl ether, the solution is washed with water, dried over sodium sulphate and filtered, and the filtrate is concentrated under reduced prresure. 8.8 g of crude product are obtained, which product is purified by chromaeography on a column of silica gel, eluting with a 92.5/7.5 maxture of dichloromethane and methanol. 7.7 g of compound are obtained in the form of an oil. 2B.2. 1,1-Dimethylethyl exo-[(2,3-dihydro-l,4- benzodioxan-2-yl)methyl](8-azabicyclo- [3.2.1] oct-3-ylmethyl)carbamate. A solution of 7.4 g (15.45 mmol) of 1,1- dimethylethyl exo-[(2,3-dihydro-l,4-benzodioxan-2- yl)methyl][[S-(phenylmethyl)-8-azabicyclo[3.2.1]oct-3- yl]methyl]carbamate in 240 ml of ethanol is prepared, 3.5 g of 10% palladium on charcoal are added and a hydrogenation is carried out in Parr apparatus at 35oC at a pressure of 0.30 MPa. After cooling to room temperature, the catalyst is separated out by filtration and the filtrate is concentrated under reduced pressure. 5.23 g of oily residue are obtained, which product is used without further purification in the following step. 2B.3. 1,1-Dimethylethyl exo-[(2,3-dihydro-1,4- benzodioxan-2-yl)methyl] ((8-(4- methoxybenzoyl)-8-azabicyclo[3.2.1]oct-3- yl] methyl] carbamate 2 g (5.15 mmol of 1.1-dimethylethyl exo- [(2,3-dihydro-l-4-benzodioxan 2-yl)methyl] (8- azabicyclo [3.Z.1] oct-3-ylmethyl) carbamate, 52 m1 of N,N-dimethylformamide and 0.71 g (5.15 mmol) of potassium carbonate are introduced into a 250 ml three necked round-bottomed flask under a nitrogen atmosphere, the mixture is heated to 50°C, l g (5.66 mmol) of 4-methoxybenzoyl chloride is added and the mixture is stirred at 50°C for 10 h. The solvent is evaporated off under reduced pressure, 50 ml of water and 300 ml of ethyl acetate are added to the residue, the organic phase is separated out, washed with water, dried over sodium sulphate and filtered, the filtrate is concentrated under reduced pressure and the residue is ourified by chromatography on a column of silica gel, eluting with a 92/8 mixture of dichloromethane and methanol. 2.5 g of compound are obtained, which product is used without further purification in the following step. 2B.4. exo-N- [(2,3-Dihydro-1,4-benzodioxan-2- yl)methyl]-8-(4-methoxybenzoyl)-8- azabicyclo[3-2.1]octane-3-methanamine hydrochloride (1:1). 2.5 g (48 mmol) of 1,1-dimethylethy1 exo- [(2,3-dihydro-l,4-benzodioxau-2-yl)methyl] [(8-(4- methoxybenzoyl)-8-azabicyclo[3-2.1]oct-3- yl] methyl] carbamate, 25 ml of dichloromethane and 25 ml of trifluoroacetic acid are introduced into a 100 ml round-bottomed flask and the mixture is refluxed for a h. The mixture is cooled, 30 ml of aqueous 10 N sodium hydroxide solution are added dropwise, the aqueous phase is separated out and extracted with dichloromethane, the organic phase is washed with water, dried over sodium sulphate and filtered, the filtrate is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 96/4 mixture of dichloromethane and methanol. 0.85 g of base is obtained, which is converted into the hydrochloride by addition of diethyl ather saturated with gaseous hydroqen chloride. 0.45 g of white solid is obtained. Melting point: 93-110°C. Example 3B (Compound No. 12B) exo-N- [(2,3-Dihydro-l,4-benzodioxan-2-yl)methyll-8- (3- fluorobenzoyl)-8-azabicyclo[3.2.1]octane-3-methanamine hydrochloride (1:1). 3B.1. 1,1-Dimethylethyl exo-[(2,3-dihydro-l,4- benzodioxan-2-yl)methyl; [ [8 - (3 - fluorobenzoyl)-8-azabicyclo [3.2.1)oct-3- yl]methyl]carbamate. Using the procedure described in Example 2B.3, starting with 3.5 g (9 mmol) of 1,1-dimethylethyl exo-[(2,3-dihydro-l,4-benzodioxan-2-yl)methyll (8- azabicyclo[3.2.l]oct-3-ylmethyl)carbamate and 1.57 g (99 mmol) of 3-fluorobenzoyl chloride, in the presence of a catalytic amount of potassium iodide, 2.7 g of oily product are obtained, which product is used without further purification in the following step. 3B.2. exo-N- [ (2,3-Dihydro-l,4-benzodioxan-2- yl)methyl]-8-(3-fluorobenzoyl)-8- azabicyclo[3.2.1]octane-3-methanamine hydrochloride (1:1). Using the procedure described in Example 2B.4, starting with 2.7 g (5.28 mmol) of 1,1- dimethylethyl axo- [(2, 3-dihydro-l,4-benzodioxan-2- yl)methyl][[8-(3-fluorobenzoyl)-8-azabicyclo[3.2.1]oct- 3-yl]methyl]carbamate, and after purification by chromatography on a column of silica gel, eluting with a 96.5/3.5 mixture of dichloromethane and methanol, 1.6 g of compound are obtained in the form of base. The hydrochloride is prepared by treating 0.5 g of base with a 0.1 K solution of hydrochloric acid in 2-propanol, the solvent is evaporated off and the residue is recrystallized from ethyl acetate. 0.4 g of white solid is finally isolated. Melting point: 206-209°C. Example 4B (Compound No. 4B). exo-N-[(2,3-Dihydro-l,4-benzodioxan-2-yl)methyl]-8-{3- fluorophenyl) -8-azabicyclo [3.2.1] octane-3-roethanamine (E)- 2-butenedioate (1:1). 0.25 g (6.6 mmol) of lithium aluminium hydride, 10 ml of tetrahydrofuran and 1 g (2.4 mmol) of exo-N- [(2,3-dihydro-l,4-benzodioxan-2-yl)methyl] -8- (3- fluorobenzoyl)-8-azabicyclo[3.2.1]octane-3-methanamxne dissolved in 60 ml of tetrahydrofuran are introduced into a 250 ml three-necked round-bottomed flask under a nitrogen atmosphere and the mixture is stirred at the reflux temperature for 2 h and then at room temperature for 24 h. The mixture is cooled to 0°C, the excess hydride is hydrolysed with aqueous 1 N sodium hydroxide, the insoluble material is removed by filtration, the filtrate is dried over sodium sulphate, this solution is filtered, the filtrate is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 93/7 mixture of dichloromethane and methanol. 0.6 g of base is obtained, which is dissolved in 5 ml of ethanol, 0.35 g (3 mmol) of fumaric acid is added and the product is left to crystallize by cooling. 0.2 g of fumarate is obtained. Melting point: 132-134°C. Example 5B (Compound No. 8B). exo-N- [(2,3-Dihydro-1,4-benzodioxan-2-yl)methyl] -8- (phenylmethyl)-N-propyl-8-azabicyclo[3.2.1]octane-3- methanamine (E)-2-butenedioate (2:1}- 5B.1. exo-N- [(2,3-Dihydro-l,4-benzodioxan-2- yl)methyl] -N- [[8-(phenylmethyl)-8- azabicyclo[3.2.1]oct-3-yl]methyl]propanamide. 3 g (7.9 mmol) of exo-N-[(2,3-dihydro-1,4- benzodioxan-2-yl)methyl] -8-(phenylmethyl)-8- azabicyclo[3.2.1]octane-3-methanamine, 100 ml of dichloromethane and 0.75 g (8,7 mmol) of propanoyl chloride dissolved in 10 ml of dichloromethane are introduced into a 250 ml three-necked round-bottomed flask and the mixture is stirred at room temperature for 20 h. The mixture is washed with three times 50 ml of water, the organic phase is dried over sodium sulphate and filtered, the filtrate is concentrated under reduced pressure and the residue is purified by chromatography on silica gel, eluting with a 94/6 mixture of dichloromethane and methanol. 1.6 q of compound are obtained, which product is used without further purification in the following step: 5B.2. exo-N- [(2,3-Dihydro-l,4-benzodioxan-2- yl)methyl]-8-(phenylmethyl)-N-propyl-8- azabicyclo[3.2.1]octane-3-methanamine (E)-2- butenedioate (2:1). 0.3 g (7.4 mmol) of lithium aluminium hydride and 15 ml of tetrahydrofuran are introduced into a 100 ml three-necked round-bottomed flask under a nitrogen atmosphere, the mixture is cooled to 0°C, 1.6 g (3.7 mmol) of exo-N-[(2,3-dihydro-1,4- benzodioxan-2-yl)methyl]-N- [[8-(phenylmethyl)-8- azabicyclo[3.2.1]oct-3-yl]methyl]propanamide dissolved in 32 ml of tetrahydrofuran are added and the mixture is refluxed for 7 h. The mixture is cooled to 0°C, the excess hydride is hydrolysed with aqueous 1 N sodium hydroxide, the insoluble material is removed by filtration, the filtrate is dried over sodium sulphate, this solution is filtered and the filtrate is concentrated under reduced pressure. The fumarate is prepared from 1.45 g (3.44 mmol) of base dissolved in 5 ml of ethanol and 0.8 g (6.9 mmol) of fumaric acid dissolved in 10 ml of ethanol. The precipitate is collected by filtration and is recrystallized from ethanol. 1.1 g of white solid are obtained. Melting point: 190-191°C. Example 6B (Compound No. 21B). exo-N- t(2, 3-Dihydro-l, 4-benzodioxan-2-yl)methyl]-8-(4- methylbenzoyl)-N-propyl-8-azabicyclo[3.2.1]octane-3- methanamine hydrochloride (1:1). 6B.1. exo-N- [(2, 3-Dihydro-l, 4-benzodioxan-2- yl)methyl]-N-propyl-8- azabicyclo[3.2.1]octane-3-methanamine. 3.45 g (8.2 mmol) of exp-N- [(2,3-dihydro-1,4- benzodioxan-2-yl)methyl]-8-(phenylmethyl)-N-propyl-B- azabicyclo[3.2.1]octane-3-methanamine, 70 ml of methanol, 3.4 g of 10% palladium on charcoal and 3.4 g of ammonium formate are introduced into a 250 ml round- bottomed flask under a nitrogen atmosphere and the mixture is refluxed for 2 h. The mixture is left to cool, the catalyst is removed by filtration, the solvent is evaporated off under reduced pressure, the residue is dissolved in dichloromethane, the solution washed with water, dried over sodium sulphate and is filtered and the filtrate is concentrated under reduced pressure. 1.8 g of compound are obtained, which product is used without further purification in the following step. 6B.2. exo-N-[(2,3-Dihydro-l,4-benzodioxan-2- yl)methyl]-8-(4-methylbenzoyl)-N-propyl-8- azabicyclo[3.2.1]octane-3-methanamine hydrochloride (1:1). 1 g (3 mmol) of exo-N-[2,3-dihydro-l,4- benzodioxan-2-yl)methyl] -N-propyl-8- azabicyclo[3.2.l]octane-3-methanamine, 10 ml of tetrahydrofuran, 10 ml of ethyl acetate and 0.31 g (3 mmol) of triethylamine are introduced into a 100 ml three-necked round-bottomed flask under a nitrogen atmosphere. The mixture is cooled to 0°C, 0.51 g (3.3 mmol) of 4-methylbenzoyl chloride dissolved in 1 ml of ethyl acetate is added dropwise and the mixture is stirred at room temperature for 5 h. The triethylamine hydrochloride is removed by filtration, the filtrate is concentrated under reduced pressure, the residue is dissolved in dichloromethane the solution is washed with water, dried over sodium sulphate and filtered and the filtrate is concentrated under reduced pressure. 1.4 g of base are obtained, the hydrochloride of which is prepared by addition of 30 ml of diethyl ether saturated with gaseous hydrogen chloride. After recrystallization, 0.65 g of white solid is obtained. Melting point: 95-112°C. Example 7B (Compound No. 22B). 8-Benzoyl-N- [(3,4-dihydro-2H-l-benzopyran-2-yl)methyl]- 8-azabicyclo[3.2.1]octane-3-methanamine hydrochloride. A suspension of 0.6 g (1.9 mmol) of (3,4- dihydro-2H-1-benzopyran-2-yl)methyl 4-methylbenzenesulphonate, 1 g (4.1 mmol) of 8-benzoyl- 8-azabicyclo[3.2.1]octane-3-methanamine and 0.26 g (1.9 mmol) of potassium carbonate in 11 ml of acetonitrile is prepared and is refluxed for 18 h. A small amount of potassium iodide and an additional 0.15 g of potassium carbonate are added and the mixture is refluxed for a further 8 h. The insoluble material is removed by filtration, the filtrate is concentrated under reduced pressure, the residue is taken up in dichloromethane, the solution is washed with water dried over sodium sulphate and filtered, the filtrate is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elutirvg with an 80/20 and then 70/30 mixture of ethyl acetate and methanol. The hydrochloride is prepared using a 0.1 N solution of hydrochloric acid in 2-propanol. 0.4 g of solid is obtained. Melting point: 148.5-151.5°C. Example 8B (Compound No. 24B). 8-Benzoyl-N- [ (4-oxo-2, 3-dihydro-4H-l-benzopyran-3- yl)methyl] -8-azabicyclo[3.2.1]octane-3-methanamine hydrochloride. 1.71 g (6.1 mmol) of 8-benzoyl-8- azabicyclo[3.2.1]octane-3-methanamine hydrochloride, 0.2 g (6.3 mmol) of paraformaldehyde and a few drops of concentrated hydrochloric acid in 10 ml of 2-propanol are introduced into a three-necked round-bottomed flask, the mixture is refluxed for 5 min, 0.78 g (5.3 mmol) of 2,3-dihydro-4H-l-benzopyran-4-one dissolved in 10 ml of 2-propanol is added and refluxing is continued for 18 h. The mixture is cooled and the hydrochloride is collected directly by filtration. 1.26 g of solid are obtained. Melting point: 187-189°C. Example__9B (Compound No. 29B) . (S)-exo-8-Benzoyl-N-[8-methoxy-2, 3-dihydro-1,4- benzodioxan-2-yl) methyl]-8-azabicyclo [3.2.1] octane - 3- methanamine hydrochloride (l:1). 9B.1, (S)- 8-methoxy-1,4-benzodioxane-2-methanol. The preparation of this expound is described in Tet. Letters (1992) 33 6283-6286. 9B.2. (8-Methoxy-2,3-dihydro-l,4-benzodioxan-2- yl)methyl (R)-4-methylbenzenesulphonate. 410 mg (2.1 mmol) of (S) -e -methoxy-1,4- pyridine, 398 mg (2.1 mmol) of 4-methylbenzenesulphonyl chloride are added and the mixture is stirred at room temperature for 20 h. The mixture is poured onto 30 ml of ice-cold water and extracted with twice 15 ml of ethyl acetate, the organic phase is washed with aqueous 1 N hydrochloric acid solution, then with aqueous sodium hydrogen carbonate solution and then with, water and is dried over sodium sulphate. This solution is filtered, the solvent is evaporated off under reduced pressure, the residue is taken up in pentane and the gummy solid is collected, washed with pentane and dried under reduced pressure. 405 mg of compound are isolated, which product is used without further purification in the following step. 9B.3 , (S)-exo-8-Benzoyl-N- [8-methaxy-2,3-dihydro- 1,4-benzodioxan-2-yl)methyl) -8- azabicyclo(3.2.1]octane-3-methanamine hydrochloride (1:1). A suspension of 380 mg (1,08 mmol) of {8-methoxy-2,3-dihydro-1,4-benzodioxan-2-yl)methyl (R)-4-methylbenzenesulphonate, 530 mg (2.16 mmol) of a-benzoyl-8-azabicyclo[3.2.1]octane-3-methanamine and 180 mg (1.3 mmol) of potassium carbonate in 50 ml of acetonitrile is prepared under an inert atmosphere and the mixture is refluxed for 57 h. The solvent is evaporated off under reduced pressure, the residue is taken up in dichloromethane and water, the organic phase is separated out, washed with water to neutral pH and filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 98/2 and then 95/5 mixture of dichloromethane and methanol. The hydrochloride is prepared using a 0.1 N solution of hydrochloric acid in 2-propanol. 135 mg of solid are finally isolated. Melting point: 210-211°C [a]20D = -53o (c=0.1. MeOH). Example 10B (Compound No. 31B). (S)-exo-8-Benzoyl-N- (7-chloro-2,3-dihydro-l,4- benzodioxan-2-yl)methyl]-8-azabicyclo[3.2.l]octane-3- methanamine hydrochloride (1:1). 10B.1. (7-Chloro-2,3-dihydro-l,4-benzodioxan-2- yl)methyl (R)-4-methylbenzenesulphonate. The preparation of this compound is described in patent application WO 97/03071,, pages 42-43. 10B.2. (S) -exo-5-Benzoyl-N-[7-chloro-2,3-dihydro- l,4-benzodioxan-2-yl)methyl]-8- azabicyclo(3.2.1]octane- 3-methanamine hydrochloride (1:1). A suspension of 1.1 g (3.1 mmol) of (7-chloro-2, 3-dihydro-l,4-benzodioxan-2-yl)methyl (R) - 4-methylbenzenesulphonate, 1.5 g (6-2 mmol) of 8-benzoyl-8-azabicyclo[3.2.l}octane-3-methanamine and 515 mg (3.7 mmol) of potassium carbonate in 20 ml of acetonitrile is prepared and is refluxed for 48 h. The solvent is evaporated off under reduced pressure, the residue is taken up in dichloromethane and water, the organic phase is separated out, washed to neutral pH, dried over sodium sulphate and filtered, the filtrate is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 98/2 and then 95/5 mixture of dichloromethane and ethanol. The hydrochloride is prepared using a 0.1 N solution of hydrochloric acid in 2-propanol. 230 mg of solid are finally isolated. Melting point: 164.5-167°C [a]20D = -56° (c=0.1, MeOH). Tables A and B below illustrate the chemical structures and physical properties of a number of compounds of the invention. The geometrical isoform of the a2abicyclooctane ring-system is indicated in the "Isom" column. In the "Salt" column, "HC1" denotes a hydrochloride and "fum" denotes an (e) -2-butenedioate, or fumarate; the acid:base molar ratios are indicated. The numbering of the atoms in the heterocycle containing W and X is given as a guide, essentially to locate the substituent V; it does not necessarily conform to the nomenclature rules, in particular when X represents a CH2 or CD group. The geometrical isoform of the azabicyclooctane ring-system is indicated in the "Isom" column. The terms {R) and (S) relate to the atom in the 2-position of the 2, 3-dihydro-l,4-dioxane ring. In the "Salt" column, "-" denotes a compound in base form, "HC1" denotes a hydrochlorido and "fum" denotes an (E)-2-butenedioate, or fumarate; the acid:base molar ratios are indicated. In the "m.p. (°C}" cDluran, "(d)" indicates a melting point with decomposition: The optical rotations of compounds 29 to 32 are given for (c=0.1, MeOH). The compounds of the invention underwent a series of pharmacological tests which revealed their value as therapeutically active substances. Study of the affinity for D-type doeaminerais recptors in rat etriatum. The compounds displace the binding of a specific labelled ligand, spiperone (referred to hereinbelow as " [3H] spiperone" and described by Briley and Langer., Ear. J. Pharmacal (1978) 50, 283), on the Dz receptors present in rat striatum. The animals used are 150 to 250 g male Sprague Dawley rats. After decapitation, the brain is removed and the striatum is excised. The tissue is ground using a Polytron™ grinder in 50 volumes of 50 mM Tris-HCl buffer containing sodium chloride (120 mM), potassium chloride (5 mM) and the pH of which is adjusted to 7.4 (i.e. 100 mg of fresh tissue per 5 ml) . The homogenized tissues are washed twice at 4°C, centrifuging them each time for 10 min at 40,000 x g and resuspending the pellet in fresh cooled buffer. Lastly, the final pellet is suspended in the same volume of buffer and ascorbic acid (0.1% final concentration) and pargyline (10 mM final concentration) are added. The mixture is then incubated at 37°C for 10 min. The binding of [3H] spiperone (New England Nuclear, specific activity 20-40 mCi/mmol) is determined by incubating 100 ml of the membrane suspension with the radioligand (0.25 nM) in a final volume of 1 ml, for 20 minutes at 37°C, in the presence or absence of the test compound. The non-specific binding is determined in the presence of haloperidol at the concentration of 10 mM. After incubation, the membranes are recovered by filtration on Whatman GF/B™ filters, which are washed with two volumes of 5 ml of ice-cold buffer. The filters are extracted in the scintillation liquid and the radioactivity is measured by liquid scintigraphy with an efficacy of 50 to 60%. For each test compound, the results are expressed by the IC60, that is to say by the concentration which inhibits the binding of [3H]spiperone by 50%, calculated by a graphical or mathematical method. For the compounds of the invention, the IC50 values are between 0.05 and 2 mM. Study of the affinity for the D, doparnineraic receptors in bovine noyau caude The compounds underwent an in vitro study regarding their affinity for the D3 dopaminergic receptors obtained from a membrane preparation of bovine noyau caude, essentially as described by Schoemaker H. in Eur. J. Pharmacol. (1993), 242, R1-R2. On the day of the experiment, the bovine noyaux caudes (Collect Organe, Paris, France), stored at -80oC, are thawed and homogenized at 4oC in 10 volumes of buffer (10 mM Tris, 1 mM EDTA, pH 7.5 at 25oC) using a PolytroonTM (position 5, 30 s) . The homogenate is centrifuged at 2500 g for 1 min (Sorvall™ centrifuge fitted with an SS34 rator). The supernatant is recovered and centrifuged at 35,000 g for 15 min, the pellet is washed by resuspension in 10 volumes of buffer, homogenization and centrifugation, and the final pellet is suspended in 10 volumes of buffer and preincubated at 37oC for 10 min. The homogenate is centrifuged at 35,000 g for 15 min and the pellet is resuspended in the incubation buffer (50 mM HepES, 1 mM EDTA, 50 mM B-hydroxy- quinoline, 0.005% ascorbic acid, pH 7.5 at 25oC) in a proportion of 100 mh of initial tissue per ml. The membrane suspension (150 ml) is incubated at 23oC for 60 min in tubes, in the presence of 0.8 nM [3H]7-OH-DPAT (specific activity 120-160 Ci/mmol, Amersham™) in a final volume of 1 ml of incubation buffer containing 0.2 mM zolpidem hydrochloride and 1 mg of bovine serum albumin, in the presence or absence of test compound. The incubation is stopped by filtration on a Brandel Harvester M-48™, using Whatman GF/CTM filters pretreated with bovine serum albumin (0.1%) for 30 min. After predilution with 4 ml of buffer (50 mM Tris, 120 mM NaCl, 5 mM KC1, pH 7.4 at 25°C) of each reaction medium, the tubes are rinsed twice with 4 ml of this buffer. The filters are cut up and then dried in an oven at 120 °C for 10 min and the radioactivity retained on the filters is determined by liquid scintillation. spectrometry. The non-specific binding is determined in the presence of 1 mM of dopamine. For feach concentration of test compound, the percentage of inhibition of specific binding of the [3H] 7-OH-DFAT is calculated, after which the IC50, the concentration which inhibits the binding by 50% is determined. The IC50 values of the compounds of the invention are of the order of 0.01 mM to 2 mM Study of the affinity for 5-HT1A-type serotonsnerqic receptors The compounds displace the binding of a specific labelled ligand, [3H]-8-hydroxy-2-di-n- propylamino tetraline (referred to hereinbelow as " [3H] - 8-OH-DPAT" and described by Gozlan et al., Nature (1983), 305, 140), on the 5-HT1A receptors present in rat hippocampus. The animals used are 160 to 200 g male Sprague-Dawley rats. After decapitation, the brain is removed and the hippocampus is excised.. The tissue is ground in an Ultra-Turrax Polytron™ machine for 30 s at the half-maximal speed in 10 volumes of 50 mM Tris buffer of pH adjusted to 7.4 with hydrochloric acid (i.e. 100 mg of fresh tissue per ml). The homogenized tissues are washed twice at 4°C, centrifuging them each time for 10 min at 48,000 x g and resuspending the pellet in fresh cooled buffer. Lastly, the final pellet is suspended in the buffer to give a concentration of 50 mg of starting tissue per ml of buffer at 50 mM. The mixture is then incubated at 37°C for 10 min. The binding with [3H] 8-OH-DPAT (1 nM) xs determined by incubation of 50 ml of membrane suspension in a final volume of 250 ml of buffer containing 10 mM of pargyline and 3 mM of paroxetine. After incubation for 15 min at 37°C, the membranes are recovered by filtration on Whatman GF/B™ filters, which are washed three times with 5 ml aliquots of ice-cold buffer. The filters are extracted in the scintillation liquid and the radioactivity is measured by liquid scintigraphy. The specific binding of the [3H]8-OH-DPAT is defined as the amount of radioactivity retained on the filters and which may be inhibited by co-incubation with 10 mM 5-hydroxytryptamine. At a concentration of 1 nM of [3H]8-OH-DPAT, the specific binding represents 90% of the total radioactivity collected on the filter. For each concentration of test compound, the percentage of inhibition of the binding with [3H] 8-OH- DPAT is determined, and then the IC50 concentration, the concentration which inhibits the binding by 50%. For the compounds of the invention, the IC5O values are between 0.1 and 500 nM. Study of the affinity for the 5-HT2-type serotonineraic receptors The compounds of the invention also underwent an in vitro study of displacement of the binding of spiperone on the serotoninergic (5-HT2) receptors of rat cerebral cortex. For this test, the rat brains are removed, the cortex is dissected therefrom and is homogenized at 0°C in 10 volumes of a mixture containing, per litre, 50 millimol of Tris/HCl buffer at pH = 7.4, 120 millimol of sodium chloride and 5 millimol of potassium chloride. The homogeneous mixture is centrifuged at 4 0,000 x 9 for 10 min, after whxch the pellet is recovered and is washed by suspending it in the same buffer mixture, it is homogenized: again and is centrifuged, this treatment of the pellet being carried out twice. Lastly, the final pellet is diluted in the same buffer mixture, in a proportion of 100 mg of wet tissue per 1 ml of buffer. The tissue is then preincubated for 10 min at 37oC in the presence of 10 micromol/l of pargyline, followed by incubation for 20 min at 37°C in the presence of [3H] spiperone (specific activity: 15 to 36 Ci per millimole) at a concentration of 0.3 nanomol/1 and of the test compound. The membranes are then collected by filtration on Whatman GF/B™ filters which are washed twice with 5 ml of cold buffer. The radioactivity retained on the filter is measured by liquid scintigraphy. In order to evaluate the activity of the compounds, the curve of the percentage inhibition of the specific binding of [3H]spiperone is established as a function of the concentration of displacing drug. The IC50 concentration, the concentration which inhibits the specific binding by 50%, is determined graphically. The specific binding is defined as being the binding displaced by 100 micromol/1 of 5-HT. The IC50 concentrations of the compounds of the invention are between 0.02 and 5 mM. The results of the tests show that the compounds of the invention have strong affinity for D2-type and D3-type dopaminergic receptors and for 5-HT1A-type and 5-HT1-type serotoninergic receptrs. These results suggest that the compounds can be used for the treatment of complaints and pathologies associated with dopaminergic and serotoninergic transmission dysfunction, in particular of the D2 and D3 dopaminergic receptors and 5-HT1A and 5-HT2 serotoninergic receptors. Thus, they can be used for the treatment or psychoses, in particular schizophrenia (deficient form and productive form) and acute or chronic extrapyramidal symptoms induced by neuroleptic agents, for the treatment of various forms of anxietv. panic attacks, phobias, compulsive obsessional disorders, for the treatment of various forms of depression, including psychotic depression, for the treatment of disorders due to alcohol abuse or withdrawal, sexual behaviour disorders, eating disorders and for the treatment of miqraine. To this end, they may be in any farm appropriate for administering them orally or parenterally, combined with any suitable excipient, and may be dosed to allow a daily dosage of from 1 to 1000 mg. WE CLAIM: 1. 8-azabicyclo[ 3.2.1.] octane-3-methanamine derivative compounds, in the form of a pure geometrical isomer or a mixture of such isomers, corresponding to the general formula (I) in which U represents A) either a 2, 3-dihydro-lH-inden-2-yl group of general formula (A) B) or a heterocyclic group of general formula (B) in which V represents a hydrogen or halogen atom, a (C1-C3)alkyl group or one or two (C1-C3) alkoxy groups, W and X each represent, respectively, either two oxygen atoms, or an oxygen atom and a CH2 group, or a CH2 group and an oxygen atom, or an oxygen atom and a CO group, n represents the number 0 or 1, R represents either a propyl group when U represents a 2,3-dihydro-lH-inden-2-yl group of general formula (A), or a hydrogen atom or a (C1-C3)alkyl group when U represents a heterocyclic group of general formula (B), Y represents one or more atoms or groups chosen from the following: hydrogen, halogen, (C1-C3)alkyl and (C1-C3) alkoxy, and Z represents two hydrogen atoms or an oxygen atom. 2. Compound as claimed in claim 1, wherein it corresponds to the general formula (IA) in which V, Y and Z are as defined in Claim 1. 3. Compound as claimed in claim 1, wherein it corresponds to the general formula (IB) in which V, W, X, Y and Z are as defined in Claim 1. 4. Medicament, comprising a compound as claimed in one of claims 1 to 3. 5. Pharmaceutical composition, comprising a compound as claimed in one of claims 1 to 3, combined with an excipient. 6. Pharmaceutical compound, substantially as herein described, particularly with reference to the foregoing examples. 7. Pharmaceutical composition, substantially as herein described, particularly with reference to the foregoing examples. Compounds of general formula (I) in which U represents a group of general formula (A) or in which formulae V represents a hydrogen or halogen atom, a (C1-C3)alkyl group or one or two (C1-C3) alkoxy groups, W and X each represent, respectively, either two oxygen atoms, or an oxygen atom and a CH2 group, or a CH2 group and an oxygen atom, or an oxygen atom and a CO group, n represents the number 0 or 1, R represents either a propyl group when U represents a group of general formula (A), or a hydrogen atom or a (C1-C3)alkyl group when U represents a group of general formula (B) , Y represents one or more atoms or groups chosen from the following: hydrogen, halogen, (C1-C3)alkyl and (C1-C3) alkoxy, Z represents two hydrogen atoms or an oxygen atom.

Full Text

The present invention relates to compounds of
general formula (I)
in which
U represents
A) either a 2,3-dihydro-lH-inden-2-yl group of general
formula (A)
B) or a heterocyclic group of general formula (B)
in which
V represents a hydrogen or halogen atom, a (C1-C3)alkyl
group or one or two (C1-C3) alkoxy groups,
W and X each represent, respectively, either two oxygen
atoms, or an oxygen atom and a CH2 group, or a CH2 group
and an oxygen atom, or an oxygen atom and a CO group,
n represents the number 0 or 1,
R represents either a propyl group when U represents a
2,3-dihydro-lH-inden-2-yl group of general formula (A),
or a hydrogen atom or a (C1-C3)alkyl group when U
represents a heterocyclic group of general formula (B),
Y represents one or more atoms or groups chosen from
the following: hydrogen, halogen, (C1-C3)alkyl and
(C1-C3)alkoxy,
Z represents two hydrogen atoms or an oxygen atom.
The compounds of the invention can exist in
two forms of geometrical isomers, namely the a, or
endo, isomeric form in which the CH2 group in the 3
position of the tropane ring-system (azabicyclooctane)
is in an axial position, and the b, or exo, isomeric
form in which the said CH2 group is in an equatorial
position, in the so-called "chair" conformation of the
piperidine unit of the tropane ring-system.
The compounds of the invention can also exist
in the form of bases or of addition salts with acids.
When U represents a 2,3-dihydro-lH-inden-2-yl
group of general formula (A), the compounds of the
invention correspond to the general formula (IA)
They can be prepared according to a process
illustrated by Scheme 1A which follows.
Ethyl 6- (phenylmethyl) -8-az.abicyclo [3 . 2 .1] -
octane-3-carboxylate of formula (IIA) is reacted with a
dimethylaluminium amide, prepared beforehand from
trimethylaluminium and a 2,3-dihydro-1H-indene-2-amine
derivative of general formula (IIIA), in which V is as
defined above, in an inert solvent, for example
toluene, at a temperature of from 0 to 100°C; a
compound of general formula (IVA) is obtained, which is
reduced by the action of a mixed alkali metal hydride
such as lithium aluminium hydride, in an ether solvent,
for example tetrahydrofuran, at a temperature of from 0
to 60°C, to give a compound of general formula (VA).
This compound is subjected to an acylation using
propanoyl chloride, in a chlorinated solvent, for
example dichloromethane, in the presence of a base such
as triethylamine, at a temperature of from o to 40°C,
to give an amide of general formula (VIA} , which is
reduced by the action of a mixed alkali metal hydride
such as lithium aluminium hydride, in an ether solvent,
for example tetrahydrofuran, at a temperature of from 0
to 60°C, to give a compound of general formula (Ia)
which corresponds to the general formula (IA) when Y
represents a hydrogen atom and Z represents two
hydrogen atoms. To prepare another compound of general
formula (IA), debenzylation is then carried out, for
example by catalytic hydrogenation, to give the amine
of general formula (VIIA), and finally this amine is
reacted either with an acid chloride of general formula
(VIIIA) in which Y is as defined above, Z represents an
oxygen atom and T represents a chlorine atom, in a
chlorinated solvent, for example dichloromethane, in
the presence of a base such as triethylamine, at a
temperature of from 20 to 40oC, or with a halogenated
derivative of general formula (VIIIA) in which Y is as
defined above, Z represents two hydrogen atoms and T
represents a halogen atom, in an aprotic solvent, for
example N, N-dimethylformamide , in the presence of a
base such as potassium carbonate, at a temperature of
from 20 to 100°C.
The 2,3-dihydro-1H-indene-2-amine of general
formula (IIIA) in which X represents hydrogen is
commercially available; the substituted derivatives of
2,3-dihydro-1H-indene-2-amine of general formula (IIIA)
can be prepared by methods analogous to those described
in Can. J. Chem. (1974) 52 381-389.
The ethyl 8-(phenylmethyl)-8-
azabicyclo[3.2.1]octane-3-carboxylate of formula (IIA)
can be prepared by a method analogous to that described
in J. Med. Chem. (1994) 37 2831.
When U represents a heterocyclic group of
general formula (B), the compounds of the invention
correspond to the general formula (IB)
They can be prepared according to processes
illustrated by Schemes 1B to 3B which follow .
According to Schemes IBa, IBb and IBc, the
compounds of general formula (IB1, in vhich W and x
each represent an oxygen atom and n represents the
number 1, are prepared by reacting ethyl
8- (phenylmethyl) - B-azabicyclo [3.2.1] -octane-3-
carboxylate of formula (IIA) with a dimethylaluminium
amide, prepared beforehand from trmethylaluminium and
a 2,3-dihydro-1,4-benodioxane-2-methanamine derivative
of general formula (IIB), in which V is as defined
above, in an inert solvent such as toluene, at a
temperature of from o to 100°c, to give a compound of
general formula (IVB) , which is reduced by the action
of a mixed alkali metal hydride, for example lithium
aluminium hydride, in an ether solvent such as
tetrahydrofuran, at a temperature of from 0 to 60oC.
A compound of general formula (IBa) which
corresponds to the general formula (IB) where R and Y
each represent a hydrogen atom and Z represents two
hydrogen atoms is obtained.
If a final compound is desired, in the
general formula of which R represents a hydrogen atom
or an alkyl group, the compound of general formula
(IBa) is then treated by one of the processes
illustrated by Schemes IBb or IBc.
Scheme IBb begins by protecting the secondary
amine function of the compound of general formula (IBa)
by the action of bis(1,1-dimethylethyl) dicarbonate, in
a chlorinated solvent such as dichloromethane, to give
a compound of general formula (VB), in which Boc
represents a 1,1-dimethylethoxycarbonyl group. This
compound is debenzylated by catalytic hydrogenation and
the compound thus obtained, of general formula (VIB),
is then reacted with an acid. chloride of general
formula (VIIB) in which Y is as defined above and Hal
represents a chlorine atom, in a chlorinated solvent,
for example dichloromethane, in the presence of a base
such as triethylamine, at a temperature of from 20 to
40oC. A compound of general formula (VIIIB) is
obtained, the secondary amine function of which is
deprotected using trifluoroacetic acid to give a
compound of general
formula (IBb).
Finally, and if so desired, this compound is
reduced by the action of a mixed alkali metal hydride,
for example lithium aluminium hydride, in an ether
solvent such as tetrahydrofuran., to give a compound of
general formula (IBa).
In Scheme IBc, a compound of general formula.
(IBa) is subjected to an acylation using an acetic-
forming mixed anhydride or a C1-C3 acid chloride, in a
chlorinated solvent such as dichloromethane. at a
temperature of from 0 to 40°C, to give a compound of
general formula (IXB) , in which R' represents a
hydrogen atom or a methyl or ethyl group, and this
acylated compound is then reduced using a mixed alkali-
metal hydride, for example lithium aluminium hydride,
in an ether solvent such as tetrahydrocuran. to give a
compound of general formula (IBd), in which R"
represents a (C1-C3) alkyl group.
This compound is then, treated as indicated
with regard to the compound of general formula (VB),
with the exception, of course, of the amine
deprotection step.
In Scheme 2B, the compounds of general
formula (IB), in which X represents an oxygen atom, W
represents an oxygen atom or a CH2 group, R represents a
hydrogen atom and n represents the number 1, are
prepared by reacting a compound of general formula
(XIB) , in whicn V is as defined above and C represents
a leaving group such as a halogen atom or a
methanesulphonyloxy or 4-methylbenzenesulphonyloxy
group, with an 8-azabicyclo[3.2.1] octane-3-amine of
general formula (XIIB), in which Y, 2 and R are as
defined above, in a solvent such as acetonitrile, in
the presence of a base such as potassium carbonate.
In Scheme 3B, the compounds of general
formula (IB), in which X represents a CO group, w
represents an oxygen atom, R represents a hydrogen atom
and n represents the number 1, are prepared by reacting
a compound, of general formula (XIIIB) in which V is as
defined above, with paraformaldehyde and an
a-azabicyclo[3.2.1] octane-3-amine of general formula
(XIIB), in which Y, Z and R are as defined above, in a
solvent such as 2-propanol, in the presence of a
catalytic amount of hydrochloric acid.
The starting compounds to be used in the
processes illustrated by Schemes IB to 3B are
commercially available or can be prepared according to
methods identical or analogous to those described in
the literature, in particular in patent applications
EP-0,193,400 and EP-0,013,139 and in J. Med. Chem.
(1983), 26 823, J. Med. Chem. (1989) 12 1402, and J.
Med. Chem. (1994) 37 2831.
The examples which follow illustrate the
preparation of a number of compounds of the invention.
The elemental dicroanalyses and the IR and NMR spectra
confirm the structures of the compounds obtained.
The numbers indicated in parentheses in the
example titles correspond to those in the 1st column of
Tables A and B given later.
In the compound names, the hyphen " -" forms
part of the name, and the underscore line "_" serves
merely to indicate the line break; it should be removed
if a line break does not occur at that point and should
not be replaced either with a normal hyphen or with a
space.
Example 1A (Compound No. 4A).
exo-N-(2,3-Dihydro-1H-inden-2-yl}-8-(phenylmethyl) -N-
propyl-6-azabicyclo [3.2.1]octane-3-methanamine (E) -2-
butenedioate (5:2).
1A.1. exo-N- (2,3-Dihydro-lH-inden-2-yl) -B-
(phenylmethyl)-8-azabicyclo [3.2.1]octane-3-
carboxamide.
20 ml of toluene are introduced into a 250 ml
three-necked round-bottomed flask under an argon
atmosphere, 1.48 g (2 0.4 mmol) of a 2 M solution of
trimethylaluminium in heptane are added slowly, the
mixture is cooled to 0°C with a bath of ice, water and
salt, 3-64 g (27.4 mmol) of 2,3-dihydro-1H-inden-2-
amine are added dropwise, the mixture is heated at 50oC
for a few minutes, 3.6 g (13.2 mmol) of ethyl
8- {phenylmethyl) -a-azabicyclo [3.2.1] occane-1 -
carboxylate are then added at this temperature and the
mixture is refluxed for 4 h.
It is cooled to 0oC and hydrolysed by adding
24 ml of water, the resulting mixture is filtered
through infusorial earth, the filtrate is driee over
sodium sulphate and filtered and the solvents are
evaporated off under reduced pressure.
The evaporation residue is purified by
chromatography on a column of silica gel, elveing wich
a 97/3 to 93/7 mixture of dicblorometbane and methanol.
4.56 9 of solid are obtained.
Malting point: 129°C.
1A.2. exo-N- (2, 3-Dihydro-lH-inden-2-yl) -8-
(phenylmethyl) -8-azabicyclo[3.2.l]octane-3-
methanamine (E) -2-butenedioate (2:1)
0.56 g (14.7 mmol) of lithium aluminium
hydride suspended in 3 0 ml of tetrahydrofuran is
introduced into a 250 ml three-necked round-bottomed
flask under an argon atmosphere, the mixture is cooled
to 0°C, 2.65 g (7.35 mmol) of exo-N- (2,3-dihydro-1H-
inden-2-yl)-8-(phenylmethyl)-8-azabicyclo[3.2.l] octane-
3-carboxamide dissolved in 50 ml of tetrahydrofuran are
added and the mixture is reflusted for 12 h.
The mixture is cooled to 0°C, the excess
hydride is hydrolysed with aqueous 1 N sodium
hydroxide, the insoluble material is removed by
filtration, the filtrate is dried over sodium sulphate
and this solution is filtered and concentrated under
reduced pressure.
2.55 g of oily product are obtained, the salt
of which is prepared by addition of 1.7 g (14.7 mmol)
of fumaric acid dissolved in 200 ml of ethanol to a
solution of 2.55 g of the base in 50 ml of ethanol, the
solvent is evaporated off under reduced pressure and
the residue is recrystallized from a 4/1 mixture of
methanol and ethanol.
2.9 g of fumarate are obtained.
Melting point: 216.5-219°C.
1A.3 . exo-N- (2, 3-Dihydro-1H-inden-2-yl) -N- 11B-
(phenylmethyl)-8-azabicyclo[3.2.1]oct-3-yl-
methyl]propanamide hydrochloride
0.95 g {2.74 mmol) of exo-N- (2,3-dihydro-1H-
inden-2-yl)-8-(phenylmethyl)-8-azabicyclo[3.2.l]octane-
3-methanamine dissolved in 15 ml of dichloromethane is
introduced into a 250 ml three-necked round-bottomed
flask under an argon atmosphere, 0.31 g (3.02 mmol) of
triethylamine is added, finally followed by dropwise
addition of 0.27 g (2.88 mmol) of propanoyl chloride
dissolved in S ml of dichloromethane, and the mixture
is left stirring at room temperature for 5 h.
The mixture is washed with three times 50 ml
of water, the organic phase is dried over sodium
sulphate, filcered and concentrated under reduced
pressure and the residue is purified by chromatography
on a column of silica gel, eluting with a 96/2 to 92/8
mixture of dichloromethane and methanol.
0.9 g of base is obtained.
The hydrochloride is prepared by addition of
25 ml of a 0.1 N solution of hydrochloric acid in
2-propanol to a solution of 0.9 g 22.4 mmol) of base
in 10 ml of ethyl acetate. The solvents are evaporated
off under reduced pressure and the residue is
recrystallized from a 9/1 mixture of ethyl acetate and
2-propanol.
0.55 g of which solid is obtained.
Melting point: 208-2l0°C.
1A.4. exo-N-(2,3-Dihydro-1H-inden-2-yl>-8-
(phenylmethyl)-N-propyl-8-
azabicyclo [3.2.1] octane - 3 -methanamine (E) -2 -
butenedioate (5:2).
0.34 g (8.94 mmol) of lithium aluminium
hydride suspended in 20 ml of tetrahydrofuran is
introduced into a 250 ml three-necked round-bottomed
flask under an argon atmosphere, the mixture is cooled
to 0oC, 1.8 g (4.47 mmol) of exo-N-(2,3-dihydro-1H-
inden-2-yl) -N- [[8- (phenylmethyl) -8-
azabicyclo[3.2.1]oct-3-yl]methyl]propanamide dissolved
in 40 ml of tetrahydrofuran are added and the mixture
is refluxed for 6 h.
The mixture is cooled to 0°C, the excess
hydride is hydrolysed with aqueous 1 N sodium
hydroxide, the insoluble material is removed by
filtration, the filtrate is dried over sodium sulphate
and the solution is filtered and concentrated under
reduced pressure.
1.6 g of oily product are obtained.
The difumarate is prepared by addition of
0.96 g (8.24 mmol) of fumaric acid dissolved in 250 ml
of ethanol to a solution of 1-6 g (4-12 mmol) of base
in 100 ml of ethanol. The solvent is evaporated off under reduced pressure and the solid residue is
recrystallized from a 35/5 mixture of ethanol and
methanol.
fumarate (5:2) are obtained.
Melting point: 190-192°C
Example 2A (Compound No. 5A)
exo-8- [(4-Chlorophenyl)methyl]-N- (2,3-dihydro-1H-inden-
2-yl) -N-propyl-8-azabicyclo[3.2.1}octane-3-methanamine
(E) - 2-butenedioate (2:1)
2A,1. exo-N- (2, 3-dihydro-lH-inden-2-yl] -N-prc-pyl -8-
azabicyclo[3.2.1]octane-3-methanamine.
A suspension of 1.75 g (4.5 mmol) of exo-N-
(2,3-dihydro-lH-inden-2-yl)-8-(phenylmethyl)-N-propyl-
8-azabicyclo[3.2.1]octane-3-methanamine in 40 ml of
ethanol is prepared, 0.5 g of 10% palladium on charcoal
is added and hydrogenation is carried out in Parr
apparatus, at a pressure of about 0.32 Mpa, at 45oC.
After cooling to room temperature, the
catalyst is separated out by filtration, the filtrate
is concentrated under reduced pressure, and the oily
residue is taken up in aqueous ammonia solution and
extracted with diethyl ether. The organic phase is-
washed with water, dried over sodium sulphate, filtered
and concentrated under reduced pressure,
1.1 g of oily yellow residue are obtained,
which product is used without further purification in
the following step.
2A.2. exo-8-[(4-Chlorophenyl)methyl]-N-(2,3-
dihydro-1H-inden-Z-yl) -N-propyl-B-
azabicyclo[3.2.1]octane-3-methanamine (E)-2-
butenedioate (2:1) .
2.94 g (9.9 mmol) of exo-N-(2,3-dihydro-lH-
inden-2-yl)-N-propyl-8-azabicyclo[3.2.1]octane-3-
methanamine dissolved in 45 ml of N,N-
dimethylformamide, 2.2 g (10.7 mmol) or 1-bromomethyl-
4-chlorobenzene, 2.7 g (19.6 mmol) of potassium
carbonate and 0.1 g of sodium iodide are introduced
into a 100 ml three-necked round-bottomed flask under
an argon atmosphere and the mixture is then heated at
60°C for 3 h. The mixture is allowed to cool and is
poured onto 150 ml of ice-cold water and extracted with
ethyl acetate. The organic phase is washed with water,
dried over sodium sulphate and filtered, the filtrate
is concentrated under reduced pressure and the residue
is purified by chromatography on a column of silica
gel, eluting with a 100/0 to 30/10 mixture of
dichloromethane and methanol.
4.0 g of base are obtained, the fumarate of
which is prepared by addition of 2.1 9 (18,8 mmol) of
fumaric acid dissolved in 50 ml of ethanol to 4.0 g
(9.4 mmol) of base dissolved in 100 ml of ethanol, the
solvent is evaporated off under reduced pressure and
the residue is recrystallized from ethanol.
2.62 g of white solid are obtained.
Melting point: 198-199°C.
Example 3A (Compound No. 3A)
exo-8- (3-Chlorobenzoyl) -N- (2, 3-dihydro-lH-inden-2-yl) -
M-propyl-8-azabicyclo(1.2.1] octane-3-methanamine
hydrochloride
0.75 g (2.51 mmol) of exo-N- (2,3-dihydro-1H-
inden-2-yl) -N-propyl-8 -azabicyclo [3,2. 1]octane-3-
methanamine dissolved in 18 ml of dichloromethane is
introduced into a 50 ml three-necked round-bottomed
flask under an argon atmosphere, 0.51 g 15.03 mmol) of
triethylamine is added, followed by slow addition of
0.88 g (5.02 mmol) of 3 -chlorobenzoyl chloride, and the
mixture is stirred at room temperature for 24 h. The
mixture is poured onto 100 ml of water and extracted
with ethyl acetate, the organic phase is separated out,
washed with water, dried over sodium sulphate and
filtered, the filtrate is concentrated under reduced
pressure and the residue is purified by chromatography
on a column of silica gel, eluting with a 99/l to 98/2
mixture of dichloromethane and methanol.
0.2 g of base is obtained, the hydrochloride
of which is prepared by addition of 5 ml of a 0.l n
solution of hydrochloric acid in 2-propanol to a
solution of the 0.2 g (0.42 mmol) of base in 10 ml of
ethyl acetate, the solvents are evaporated off under
reduced pressure and the residue is recrystallized from
a 95/5 mixture of ethyl acetate and 2-propanol.
0.12 g of white solid is obtained
Melting point: 213-2l5oC.
Example 4A (Compound No. 14A).
exo-N- (4,7-Dimethoxy-2,3-dihydro-lH-inden-2-yl) -8-
(phenylmethyl)-N-propyl-8-azabicyclo[3.2.1]octane-3 -
methanamine (E) -2-butenedioate (2:l).
4A.1. exo-N- (4,7-dimethoxy-2,3-dihydro-lH-inden-2-
yl) -8- (phenylmethyl) -8-
azabicyclo[3.2.1]octane-3-carboxamide
Using the procedure described in Example
1A.1, starting with 4-64 g (24 mmol) of 4,7-dimethoxy-
2,3-dihydro-lH-indene-2-amine and 3-3 g (13.9 mmol) of
ethyl 8-(phenylmethyl)-8-azabicyclo [3-2.1] octane-3-
carboxylate, 4.1 g of solid are obtained, which product
is used without further purification in the following
step.
4A. 2. exo -N- (4 , 7 - Dimethoxy- 2 , 3 -dihydro- 1H- inden - 2 -
yl)-8-(phenylmethyl)-8-
azabicyclo [3.2.1] obtane-3 -methanamine.
Using the procedure described in Example
1A.2, starting with 4.85 g (11.5 mmol) of exo-N-(4,7-
dimethoxy-2,3-dihydro-lH-inden-2-yl) -8- (phenylmethyl) -
8-azabicyclo[3-2.l]octane-3-carboxamide and 0.88 g
(23 mmol) of lithium aluminium hydride. 4.6 g of oily
produce are obtained, which product is used without
further purification in the following step.
4A.3. exo-N-(4,7-Dimethoxy-2,3-dihydro-lH-indent-
yl) -N- [[8- (phenylmethyl) -8-
Using the procedure described in Example
1A.3, starting with 4.6 g (11.3 mmol) of exo-N-(4,7-
dimethoxy-2,3-dihydro-lH-inden-2-yl)-8-(phenylmethyl) -
8-azabicyclo (3.2.1] octane-3-methanamine, 1.3 g
(12.8 mmol) of triethylamine and 1.13 g (12.2 mmol) of
propanoyl chloride, and after purification by
ehromatography on a column of silica gel, eluting with
a 98/2 to 92/8 mixture of dichloromethane and methanol,
4.7 g of oily product are obtained, which product is
used without further purification in the following
step.
4A.4. exo-N- (4, 7-Dimethoxy-2, 3-dihydro-lH-inden-2-
yl) -8- (phenylmethyl) -N-propyl-8-
azabicyclo[3.2.1} octane-3-methanamine (E) -2-
butenedioate (2:1).
Using the procedure described in Example
1A.4, starting with 4-7 g (10.1 mmol) of exo-N- (4,7-
dimethoxy-2,3-dihydro-lH-inden-2-yl) -N- ((8-
(phenylmethyl) -8-azabicyclo [3.2.1] oct-3-
yl] methyl] propanamide and 0.78 g (20.6 mmol) of lithium
aluminium hydride, and after purification by
chromatography on a column of silica qel, elating with
a 96/4 to 88/12 mixture of dichloromethane and
methanol, 4.5 g of compound are obtained in the form of
a yellow oil.
1.0 g (2.23 mmol) of this product is
dissolved in l00 ml of ethanol a solution of 0.52 g
(4.46 mmol) of fumaric acid in 100 ml of ethanol is
added, che solvent is evaporated off under reduced
pressure and the solid residue is recrystallized from
ethanol.
0.68 g of fumarate (2:1) is obtained.
Melting point: 167-189°C,
Example 5A (Compound No. 13A)
exo-N-(4,7-Dimethoxy-2,3-dihydro-lH-inden-2-yll -8-(3-
ethoxybenzoyl) -N-propyl-8-azabicyclo [3.2.l] octane-3-
methanamine hydrochloride.
5A.1. exo-N-(4,7-Dimethoxy-2,3-dihydro-lH-inden-2-
yl)-N-propyl-8-azabicyclo[3.2.1] octane-3-
methanamine.
Using the procedure described in Example
2A.1, starting with 4.95 g (11 mmol) of exo-N-(4,7,-
dimethoxy-2,3-dihydro-lH-inden-2-yl) -8- (phenylmethyl) -
N-propyl-8-azabicyclo (3.2.1]octane-3-methanamine and
1.2 g of 10% palladium on charcoal, 3.4 g of oily
compound are obtained, which product is used without
further purification in the following step
5A.2. exo-N-(4,7-Dimethoxy-2,3-dihydro-lH-inden-2-
yl) -8- (3-ethoxybenzoyl)-N-propyl-8-
azabicyclo[3.2.1]octane-3-methanamine
hydrochloride.
Using the procedure descried in Example 3A,
starting with 1.1 g (3.07 mmol) of exo-N-(4,7
dimethoxY-2,3-dihydro-1H-inden-2-yl)-N-propyl)-8-
azabicyclo[3.2.l]octane-3-methanamine, 0.62 g
(6,14 mmol) of triethylamine and 1.13 (6.12 mmol) of
3-ethoxybenzoyl chloride, and after purification by
chromatography on a column of silica gel, eluting with
a 99/1 to 96/4 mixture of dichloromethane and methanol,
1.43 g of compound are obtained in the form of an oil.
The hydrochloride is prepared by addition of
30 ml of a 0. 1N solution of hydrochloric acid in 2-
propanol to a solution of 1.43 g (2.82 mmol) of base in
30 ml of ethanol, the solvents are evaporated off under
reduced pressure and the solid residue is
recrystallized from a 9/1 mixture of ethyl acetate and
ethanol.
0.56 g of white solid is obtained.
Melting point: 161-163°C.
Example 6A (Compound No. 12A),
exo-8- (3, 4-Dimethoxybenzoyl) -N- (4 , 7-dimethoxy 2 , 3-
dihydro-1H-inden-2-yl)-N-propyl-8-
azabicyclo[3.2.1]octane-3-methanamine hydrochloride.
Using the procedure described in Example 3A,
starting with 1.25 g (3.49 mmol) of exo-N-(4,7-
dimethoxy-2,3-dihvdro-1H-inden-2-yl)-N-propy1-8-
azabicyclo[3.2.l]octane-3-methanamine, 0.71 g
(6.98 mmol of criethylamine and 1.4 g (6.96 mmol) of
3,4-dimethoxybenzoyl chloride, and after purification
by chromatography on a column of silica gel, eluting
with a 99/l to 96.5/3.5 mixture of dichloromethane and
methanol, 1.5 g of compound are obtained in the form of
a yellow oil.
The hydrochloride is prepared by addition of
20 ml of a 0.1 N solution of hydrochloric acid in 2-
propanol to a solution of 1.5 g (2.87 mmol) of base in
30 ml of ethanol, the solvents are evaporated off under
reduced pressure and the solid residue is
recrystallized from a 9/1 mixture of ethyl acetate and
ethanol.
1.12 g of white solid are obtained.
Melting point: 134-136°C.
Example 1B (Compound No. 1B).
exo-N- [(2,3-Dihydro-l,4-benzodioxan-2-yl)methyl]-8-
(phenylmethyl)-8-azabicyclo[3.2.1]octane-3-methanamine
(E)-2-butenedioate (2:1).
1B.1. exo-N-[(2,3-dihydro-l,4-benzodioxan-2-
yl)methyl]-8-(phenylmethyl)-8-
azabicyclo[3.2.1]octane-3-carboxamide.
20 ml of a 2M solution of trimethylaluminium
in toluene are introduced into a 500 ml three-necked
round-bottomed flask under a nitrogen atmosphere, the
mixture is cooled to 0°C, 7.75 g (39.7 mmol) of 2,3-
dihydro-1,4-dioxane-2-methanamine dissolved in 150 ml
of toluene are added dropwise, the mixture is heated to
50°C, 6.9 g (2S.1 mmol) of ethyl 8-(phenylmethyl)-8-
azabicyclo [3 . 2 . 1] octane-3-carboxylate dissolved in
35 ml of toluene are then added at this temperature and
the mixture is refluxed for 8 h.
The mixture is cooled to 0°C and hydrolysed
by adding 50 ml of water, it is filtered over
infusorial earth, the filtrate is dried over sodium
sulphate, the solution is filtered and the solvents are
evaporated off under reduced pressure.
The residue is purified by chromatography on
a column of silica gel, eluting with 95/5 mixture of
dichloromethane and methanol.
8.4 g of compound are obtained in the form of
an oil.
1B.2. exo-N- [(2,3-Dihydro-l,4-benzodioxan-2-
yl)methyl]-8-(phenylmethyl)-8-
azabicyclo[3.2.1]octane-3-methanamine (E)-2-
butenedioate (2:1).
5 g (131 mmol} of lithium aluminium hydride
suspended in 50 ml of tetrahydrofuran are introduced
into all three-necked round-bottomed flask under a
nitrogen atmosphere, the mixture is cooled to 0°c,
8.4 g (21.4 mmol) of exo-N- ((2, 3-dihydro-l, 4-
benzodioxan-2-yl)methyl]-8-(phenylmethyl)-8-
azabicyclo[3.2.1]octane-3-carboxamid« dissolved in
420 ml of tetrahydrofuran are added and the mixture is
refluxed for 15 h.
The mixture is cooled to 0oC. the excess
hydride is hydrolysed with aqueous 1 N sodium
hydroxide, the insoluble material is removed by
filtration and the filtrate is dried over sodium
sulphate and concentrated under reduced pressure.
7.3 g of base are obtained in oily form.
2.9 g (7.66 mmol) of this product are taken,
1.8 9 (15.5 mmol) of fumaric acid dissolved in ethanol
are added, the solvent is evapprated off and the
residue is recrystallized from 2-propanol and then from
ethanol.
1.3 g of white solid are obtained.
Melting point: 105-107oc.
Example 2B (Compound No. 15B).
exo-N-[(2,3-Dihydro-l,4-benzodioxan-2-yl)methyl]-8-(4-
methoxybenzoyl) -8-azabicyclo[3.2.1]octane-3-methanamine
hvdrochloride (1:1).
2B.l. 1,1-Dimethylethyl exo- [(2, 3-dihydro-1,4-
henzodioxan-2-yl)methyl] [(8- (phenylmethyl) -8-
azabicyclo (3.2.l) oct-3-yllmethyll csrbamate
7.3 g (193 mmol) of exo-N- [{2,3-dihydro-1,4-
benzodioxan-2-yl)methyl)-8-(phenylmethyl)-8-
azabicyclo[3.2 .1} octane-3-methanamine dissolved in
18 ml of dichloromethane are are introduced into a three-
necked round-bottomed flask under a nicrogen
atmosphere, 4.6 g (21 mmol) of bis(1,1-dimethylethyl)
dicarbonate dissolved in 18 ml of dichloromethane are
added dropwise and the mixture is stirred at room
temperature for 24 h.
The solvent is evaporated off under reduced
pressure the residue is dissolved in 100 ml of diethyl
ether, the solution is washed with water, dried over
sodium sulphate and filtered, and the filtrate is
concentrated under reduced prresure.
8.8 g of crude product are obtained, which
product is purified by chromaeography on a column of
silica gel, eluting with a 92.5/7.5 maxture of
dichloromethane and methanol.
7.7 g of compound are obtained in the form of
an oil.
2B.2. 1,1-Dimethylethyl exo-[(2,3-dihydro-l,4-
benzodioxan-2-yl)methyl](8-azabicyclo-
[3.2.1] oct-3-ylmethyl)carbamate.
A solution of 7.4 g (15.45 mmol) of 1,1-
dimethylethyl exo-[(2,3-dihydro-l,4-benzodioxan-2-
yl)methyl][[S-(phenylmethyl)-8-azabicyclo[3.2.1]oct-3-
yl]methyl]carbamate in 240 ml of ethanol is prepared,
3.5 g of 10% palladium on charcoal are added and a
hydrogenation is carried out in Parr apparatus at 35oC
at a pressure of 0.30 MPa.
After cooling to room temperature, the
catalyst is separated out by filtration and the
filtrate is concentrated under reduced pressure.
5.23 g of oily residue are obtained, which
product is used without further purification in the
following step.
2B.3. 1,1-Dimethylethyl exo-[(2,3-dihydro-1,4-
benzodioxan-2-yl)methyl] ((8-(4-
methoxybenzoyl)-8-azabicyclo[3.2.1]oct-3-
yl] methyl] carbamate
2 g (5.15 mmol of 1.1-dimethylethyl exo-
[(2,3-dihydro-l-4-benzodioxan 2-yl)methyl] (8-
azabicyclo [3.Z.1] oct-3-ylmethyl) carbamate, 52 m1 of
N,N-dimethylformamide and 0.71 g (5.15 mmol) of
potassium carbonate are introduced into a 250 ml three
necked round-bottomed flask under a nitrogen
atmosphere, the mixture is heated to 50°C, l g
(5.66 mmol) of 4-methoxybenzoyl chloride is added and
the mixture is stirred at 50°C for 10 h.
The solvent is evaporated off under reduced
pressure, 50 ml of water and 300 ml of ethyl acetate
are added to the residue, the organic phase is
separated out, washed with water, dried over sodium
sulphate and filtered, the filtrate is concentrated
under reduced pressure and the residue is ourified by
chromatography on a column of silica gel, eluting with
a 92/8 mixture of dichloromethane and methanol.
2.5 g of compound are obtained, which product
is used without further purification in the following
step.
2B.4. exo-N- [(2,3-Dihydro-1,4-benzodioxan-2-
yl)methyl]-8-(4-methoxybenzoyl)-8-
azabicyclo[3-2.1]octane-3-methanamine
hydrochloride (1:1).
2.5 g (48 mmol) of 1,1-dimethylethy1 exo-
[(2,3-dihydro-l,4-benzodioxau-2-yl)methyl] [(8-(4-
methoxybenzoyl)-8-azabicyclo[3-2.1]oct-3-
yl] methyl] carbamate, 25 ml of dichloromethane and 25 ml
of trifluoroacetic acid are introduced into a 100 ml
round-bottomed flask and the mixture is refluxed for
a h.
The mixture is cooled, 30 ml of aqueous 10 N
sodium hydroxide solution are added dropwise, the
aqueous phase is separated out and extracted with
dichloromethane, the organic phase is washed with
water, dried over sodium sulphate and filtered, the
filtrate is concentrated under reduced pressure and the
residue is purified by chromatography on a column of
silica gel, eluting with a 96/4 mixture of
dichloromethane and methanol.
0.85 g of base is obtained, which is
converted into the hydrochloride by addition of diethyl
ather saturated with gaseous hydroqen chloride.
0.45 g of white solid is obtained.
Melting point: 93-110°C.
Example 3B (Compound No. 12B)
exo-N- [(2,3-Dihydro-l,4-benzodioxan-2-yl)methyll-8- (3-
fluorobenzoyl)-8-azabicyclo[3.2.1]octane-3-methanamine
hydrochloride (1:1).
3B.1. 1,1-Dimethylethyl exo-[(2,3-dihydro-l,4-
benzodioxan-2-yl)methyl; [ [8 - (3 -
fluorobenzoyl)-8-azabicyclo [3.2.1)oct-3-
yl]methyl]carbamate.
Using the procedure described in Example
2B.3, starting with 3.5 g (9 mmol) of 1,1-dimethylethyl
exo-[(2,3-dihydro-l,4-benzodioxan-2-yl)methyll (8-
azabicyclo[3.2.l]oct-3-ylmethyl)carbamate and 1.57 g
(99 mmol) of 3-fluorobenzoyl chloride, in the presence
of a catalytic amount of potassium iodide, 2.7 g of
oily product are obtained, which product is used
without further purification in the following step.
3B.2. exo-N- [ (2,3-Dihydro-l,4-benzodioxan-2-
yl)methyl]-8-(3-fluorobenzoyl)-8-
azabicyclo[3.2.1]octane-3-methanamine
hydrochloride (1:1).
Using the procedure described in Example
2B.4, starting with 2.7 g (5.28 mmol) of 1,1-
dimethylethyl axo- [(2, 3-dihydro-l,4-benzodioxan-2-
yl)methyl][[8-(3-fluorobenzoyl)-8-azabicyclo[3.2.1]oct-
3-yl]methyl]carbamate, and after purification by
chromatography on a column of silica gel, eluting with
a 96.5/3.5 mixture of dichloromethane and methanol,
1.6 g of compound are obtained in the form of base.
The hydrochloride is prepared by treating
0.5 g of base with a 0.1 K solution of hydrochloric
acid in 2-propanol, the solvent is evaporated off and
the residue is recrystallized from ethyl acetate.
0.4 g of white solid is finally isolated.
Melting point: 206-209°C.
Example 4B (Compound No. 4B).
exo-N-[(2,3-Dihydro-l,4-benzodioxan-2-yl)methyl]-8-{3-
fluorophenyl) -8-azabicyclo [3.2.1] octane-3-roethanamine
(E)- 2-butenedioate (1:1).
0.25 g (6.6 mmol) of lithium aluminium
hydride, 10 ml of tetrahydrofuran and 1 g (2.4 mmol) of
exo-N- [(2,3-dihydro-l,4-benzodioxan-2-yl)methyl] -8- (3-
fluorobenzoyl)-8-azabicyclo[3.2.1]octane-3-methanamxne
dissolved in 60 ml of tetrahydrofuran are introduced
into a 250 ml three-necked round-bottomed flask under a
nitrogen atmosphere and the mixture is stirred at the
reflux temperature for 2 h and then at room temperature
for 24 h.
The mixture is cooled to 0°C, the excess
hydride is hydrolysed with aqueous 1 N sodium
hydroxide, the insoluble material is removed by
filtration, the filtrate is dried over sodium sulphate,
this solution is filtered, the filtrate is concentrated
under reduced pressure and the residue is purified by
chromatography on a column of silica gel, eluting with
a 93/7 mixture of dichloromethane and methanol.
0.6 g of base is obtained, which is dissolved
in 5 ml of ethanol, 0.35 g (3 mmol) of fumaric acid is
added and the product is left to crystallize by
cooling.
0.2 g of fumarate is obtained.
Melting point: 132-134°C.
Example 5B (Compound No. 8B).
exo-N- [(2,3-Dihydro-1,4-benzodioxan-2-yl)methyl] -8-
(phenylmethyl)-N-propyl-8-azabicyclo[3.2.1]octane-3-
methanamine (E)-2-butenedioate (2:1}-
5B.1. exo-N- [(2,3-Dihydro-l,4-benzodioxan-2-
yl)methyl] -N- [[8-(phenylmethyl)-8-
azabicyclo[3.2.1]oct-3-yl]methyl]propanamide.
3 g (7.9 mmol) of exo-N-[(2,3-dihydro-1,4-
benzodioxan-2-yl)methyl] -8-(phenylmethyl)-8-
azabicyclo[3.2.1]octane-3-methanamine, 100 ml of
dichloromethane and 0.75 g (8,7 mmol) of propanoyl
chloride dissolved in 10 ml of dichloromethane are
introduced into a 250 ml three-necked round-bottomed
flask and the mixture is stirred at room temperature
for 20 h.
The mixture is washed with three times 50 ml
of water, the organic phase is dried over sodium
sulphate and filtered, the filtrate is concentrated
under reduced pressure and the residue is purified by
chromatography on silica gel, eluting with a 94/6
mixture of dichloromethane and methanol. 1.6 q of
compound are obtained, which product is used without
further purification in the following step:
5B.2. exo-N- [(2,3-Dihydro-l,4-benzodioxan-2-
yl)methyl]-8-(phenylmethyl)-N-propyl-8-
azabicyclo[3.2.1]octane-3-methanamine (E)-2-
butenedioate (2:1).
0.3 g (7.4 mmol) of lithium aluminium hydride
and 15 ml of tetrahydrofuran are introduced into a
100 ml three-necked round-bottomed flask under a
nitrogen atmosphere, the mixture is cooled to 0°C,
1.6 g (3.7 mmol) of exo-N-[(2,3-dihydro-1,4-
benzodioxan-2-yl)methyl]-N- [[8-(phenylmethyl)-8-
azabicyclo[3.2.1]oct-3-yl]methyl]propanamide dissolved
in 32 ml of tetrahydrofuran are added and the mixture
is refluxed for 7 h.
The mixture is cooled to 0°C, the excess
hydride is hydrolysed with aqueous 1 N sodium
hydroxide, the insoluble material is removed by
filtration, the filtrate is dried over sodium sulphate,
this solution is filtered and the filtrate is
concentrated under reduced pressure. The fumarate is
prepared from 1.45 g (3.44 mmol) of base dissolved in
5 ml of ethanol and 0.8 g (6.9 mmol) of fumaric acid
dissolved in 10 ml of ethanol. The precipitate is
collected by filtration and is recrystallized from
ethanol.
1.1 g of white solid are obtained.
Melting point: 190-191°C.
Example 6B (Compound No. 21B).
exo-N- t(2, 3-Dihydro-l, 4-benzodioxan-2-yl)methyl]-8-(4-
methylbenzoyl)-N-propyl-8-azabicyclo[3.2.1]octane-3-
methanamine hydrochloride (1:1).
6B.1. exo-N- [(2, 3-Dihydro-l, 4-benzodioxan-2-
yl)methyl]-N-propyl-8-
azabicyclo[3.2.1]octane-3-methanamine.
3.45 g (8.2 mmol) of exp-N- [(2,3-dihydro-1,4-
benzodioxan-2-yl)methyl]-8-(phenylmethyl)-N-propyl-B-
azabicyclo[3.2.1]octane-3-methanamine, 70 ml of
methanol, 3.4 g of 10% palladium on charcoal and 3.4 g
of ammonium formate are introduced into a 250 ml round-
bottomed flask under a nitrogen atmosphere and the
mixture is refluxed for 2 h. The mixture is left to
cool, the catalyst is removed by filtration, the
solvent is evaporated off under reduced pressure, the
residue is dissolved in dichloromethane, the solution
washed with water, dried over sodium sulphate and
is
filtered and the filtrate is concentrated under reduced
pressure. 1.8 g of compound are obtained, which product
is used without further purification in the following
step.
6B.2. exo-N-[(2,3-Dihydro-l,4-benzodioxan-2-
yl)methyl]-8-(4-methylbenzoyl)-N-propyl-8-
azabicyclo[3.2.1]octane-3-methanamine
hydrochloride (1:1).
1 g (3 mmol) of exo-N-[2,3-dihydro-l,4-
benzodioxan-2-yl)methyl] -N-propyl-8-
azabicyclo[3.2.l]octane-3-methanamine, 10 ml of
tetrahydrofuran, 10 ml of ethyl acetate and 0.31 g
(3 mmol) of triethylamine are introduced into a 100 ml
three-necked round-bottomed flask under a nitrogen
atmosphere. The mixture is cooled to 0°C, 0.51 g
(3.3 mmol) of 4-methylbenzoyl chloride dissolved in
1 ml of ethyl acetate is added dropwise and the mixture
is stirred at room temperature for 5 h.
The triethylamine hydrochloride is removed by
filtration, the filtrate is concentrated under reduced
pressure, the residue is dissolved in dichloromethane
the solution is washed with water, dried over sodium
sulphate and filtered and the filtrate is concentrated
under reduced pressure.
1.4 g of base are obtained, the hydrochloride
of which is prepared by addition of 30 ml of diethyl
ether saturated with gaseous hydrogen chloride.
After recrystallization, 0.65 g of white
solid is obtained.
Melting point: 95-112°C.
Example 7B (Compound No. 22B).
8-Benzoyl-N- [(3,4-dihydro-2H-l-benzopyran-2-yl)methyl]-
8-azabicyclo[3.2.1]octane-3-methanamine hydrochloride.
A suspension of 0.6 g (1.9 mmol) of (3,4-
dihydro-2H-1-benzopyran-2-yl)methyl
4-methylbenzenesulphonate, 1 g (4.1 mmol) of 8-benzoyl-
8-azabicyclo[3.2.1]octane-3-methanamine and 0.26 g
(1.9 mmol) of potassium carbonate in 11 ml of
acetonitrile is prepared and is refluxed for 18 h.
A small amount of potassium iodide and an
additional 0.15 g of potassium carbonate are added and
the mixture is refluxed for a further 8 h.
The insoluble material is removed by
filtration, the filtrate is concentrated under reduced
pressure, the residue is taken up in dichloromethane,
the solution is washed with water dried over sodium
sulphate and filtered, the filtrate is concentrated
under reduced pressure and the residue is purified by
chromatography on a column of silica gel, elutirvg with
an 80/20 and then 70/30 mixture of ethyl acetate and
methanol.
The hydrochloride is prepared using a 0.1 N
solution of hydrochloric acid in 2-propanol.
0.4 g of solid is obtained.
Melting point: 148.5-151.5°C.
Example 8B (Compound No. 24B).
8-Benzoyl-N- [ (4-oxo-2, 3-dihydro-4H-l-benzopyran-3-
yl)methyl] -8-azabicyclo[3.2.1]octane-3-methanamine
hydrochloride.
1.71 g (6.1 mmol) of 8-benzoyl-8-
azabicyclo[3.2.1]octane-3-methanamine hydrochloride,
0.2 g (6.3 mmol) of paraformaldehyde and a few drops of
concentrated hydrochloric acid in 10 ml of 2-propanol
are introduced into a three-necked round-bottomed
flask, the mixture is refluxed for 5 min, 0.78 g
(5.3 mmol) of 2,3-dihydro-4H-l-benzopyran-4-one
dissolved in 10 ml of 2-propanol is added and refluxing
is continued for 18 h.
The mixture is cooled and the hydrochloride
is collected directly by filtration.
1.26 g of solid are obtained.
Melting point: 187-189°C.
Example__9B (Compound No. 29B) .
(S)-exo-8-Benzoyl-N-[8-methoxy-2, 3-dihydro-1,4-
benzodioxan-2-yl) methyl]-8-azabicyclo [3.2.1] octane - 3-
methanamine hydrochloride (l:1).
9B.1, (S)- 8-methoxy-1,4-benzodioxane-2-methanol.
The preparation of this expound is described
in Tet. Letters (1992) 33 6283-6286.
9B.2. (8-Methoxy-2,3-dihydro-l,4-benzodioxan-2-
yl)methyl (R)-4-methylbenzenesulphonate.
410 mg (2.1 mmol) of (S) -e -methoxy-1,4-
pyridine, 398 mg (2.1 mmol) of 4-methylbenzenesulphonyl
chloride are added and the mixture is stirred at room
temperature for 20 h. The mixture is poured onto 30 ml
of ice-cold water and extracted with twice 15 ml of
ethyl acetate, the organic phase is washed with aqueous
1 N hydrochloric acid solution, then with aqueous
sodium hydrogen carbonate solution and then with, water
and is dried over sodium sulphate. This solution is
filtered, the solvent is evaporated off under reduced
pressure, the residue is taken up in pentane and the
gummy solid is collected, washed with pentane and dried
under reduced pressure.
405 mg of compound are isolated, which
product is used without further purification in the
following step.
9B.3 , (S)-exo-8-Benzoyl-N- [8-methaxy-2,3-dihydro-
1,4-benzodioxan-2-yl)methyl) -8-
azabicyclo(3.2.1]octane-3-methanamine
hydrochloride (1:1).
A suspension of 380 mg (1,08 mmol) of
{8-methoxy-2,3-dihydro-1,4-benzodioxan-2-yl)methyl
(R)-4-methylbenzenesulphonate, 530 mg (2.16 mmol) of
a-benzoyl-8-azabicyclo[3.2.1]octane-3-methanamine and
180 mg (1.3 mmol) of potassium carbonate in 50 ml of
acetonitrile is prepared under an inert atmosphere and
the mixture is refluxed for 57 h.
The solvent is evaporated off under reduced
pressure, the residue is taken up in dichloromethane
and water, the organic phase is separated out, washed
with water to neutral pH and filtered, the solvent is
evaporated off under reduced pressure and the residue
is purified by chromatography on a column of silica
gel, eluting with a 98/2 and then 95/5 mixture of
dichloromethane and methanol.
The hydrochloride is prepared using a 0.1 N
solution of hydrochloric acid in 2-propanol.
135 mg of solid are finally isolated.
Melting point: 210-211°C [a]20D = -53o (c=0.1. MeOH).
Example 10B (Compound No. 31B).
(S)-exo-8-Benzoyl-N- (7-chloro-2,3-dihydro-l,4-
benzodioxan-2-yl)methyl]-8-azabicyclo[3.2.l]octane-3-
methanamine hydrochloride (1:1).
10B.1. (7-Chloro-2,3-dihydro-l,4-benzodioxan-2-
yl)methyl (R)-4-methylbenzenesulphonate.
The preparation of this compound is described
in patent application WO 97/03071,, pages 42-43.
10B.2. (S) -exo-5-Benzoyl-N-[7-chloro-2,3-dihydro-
l,4-benzodioxan-2-yl)methyl]-8-
azabicyclo(3.2.1]octane- 3-methanamine
hydrochloride (1:1).
A suspension of 1.1 g (3.1 mmol) of
(7-chloro-2, 3-dihydro-l,4-benzodioxan-2-yl)methyl (R) -
4-methylbenzenesulphonate, 1.5 g (6-2 mmol) of
8-benzoyl-8-azabicyclo[3.2.l}octane-3-methanamine and
515 mg (3.7 mmol) of potassium carbonate in 20 ml of
acetonitrile is prepared and is refluxed for 48 h.
The solvent is evaporated off under reduced
pressure, the residue is taken up in dichloromethane
and water, the organic phase is separated out, washed
to neutral pH, dried over sodium sulphate and filtered,
the filtrate is evaporated under reduced pressure and
the residue is purified by chromatography on a column
of silica gel, eluting with a 98/2 and then 95/5
mixture of dichloromethane and ethanol.
The hydrochloride is prepared using a 0.1 N
solution of hydrochloric acid in 2-propanol.
230 mg of solid are finally isolated.
Melting point: 164.5-167°C [a]20D = -56° (c=0.1, MeOH).
Tables A and B below illustrate the chemical
structures and physical properties of a number of
compounds of the invention.
The geometrical isoform of the
a2abicyclooctane ring-system is indicated in the "Isom"
column.
In the "Salt" column, "HC1" denotes a
hydrochloride and "fum" denotes an (e) -2-butenedioate,
or fumarate; the acid:base molar ratios are indicated.
The numbering of the atoms in the heterocycle
containing W and X is given as a guide, essentially to
locate the substituent V; it does not necessarily
conform to the nomenclature rules, in particular when X
represents a CH2 or CD group.
The geometrical isoform of the
azabicyclooctane ring-system is indicated in the "Isom"
column. The terms {R) and (S) relate to the atom in the
2-position of the 2, 3-dihydro-l,4-dioxane ring.
In the "Salt" column, "-" denotes a compound
in base form, "HC1" denotes a hydrochlorido and "fum"
denotes an (E)-2-butenedioate, or fumarate; the
acid:base molar ratios are indicated.
In the "m.p. (°C}" cDluran, "(d)" indicates a
melting point with decomposition: The optical rotations
of compounds 29 to 32 are given for (c=0.1, MeOH).
The compounds of the invention underwent a
series of pharmacological tests which revealed their
value as therapeutically active substances.
Study of the affinity for D-type doeaminerais recptors
in rat etriatum.
The compounds displace the binding of a
specific labelled ligand, spiperone (referred to
hereinbelow as " [3H] spiperone" and described by Briley
and Langer., Ear. J. Pharmacal (1978) 50, 283), on
the Dz receptors present in rat striatum.
The animals used are 150 to 250 g male
Sprague Dawley rats. After decapitation, the brain is
removed and the striatum is excised. The tissue is
ground using a Polytron™ grinder in 50 volumes of 50 mM
Tris-HCl buffer containing sodium chloride (120 mM),
potassium chloride (5 mM) and the pH of which is
adjusted to 7.4 (i.e. 100 mg of fresh tissue per 5 ml) .
The homogenized tissues are washed twice at 4°C,
centrifuging them each time for 10 min at 40,000 x g
and resuspending the pellet in fresh cooled buffer.
Lastly, the final pellet is suspended in the same
volume of buffer and ascorbic acid (0.1% final
concentration) and pargyline (10 mM final
concentration) are added. The mixture is then incubated
at 37°C for 10 min.
The binding of [3H] spiperone (New England
Nuclear, specific activity 20-40 mCi/mmol) is
determined by incubating 100 ml of the membrane
suspension with the radioligand (0.25 nM) in a final
volume of 1 ml, for 20 minutes at 37°C, in the presence
or absence of the test compound. The non-specific
binding is determined in the presence of haloperidol at
the concentration of 10 mM. After incubation, the
membranes are recovered by filtration on Whatman GF/B™
filters, which are washed with two volumes of 5 ml of
ice-cold buffer. The filters are extracted in the
scintillation liquid and the radioactivity is measured
by liquid scintigraphy with an efficacy of 50 to 60%.
For each test compound, the results are expressed by
the IC60, that is to say by the concentration which
inhibits the binding of [3H]spiperone by 50%, calculated
by a graphical or mathematical method.
For the compounds of the invention, the IC50
values are between 0.05 and 2 mM.
Study of the affinity for the D, doparnineraic receptors
in bovine noyau caude
The compounds underwent an in vitro study
regarding their affinity for the D3 dopaminergic
receptors obtained from a membrane preparation of
bovine noyau caude, essentially as described by
Schoemaker H. in Eur. J. Pharmacol. (1993), 242, R1-R2.
On the day of the experiment, the bovine
noyaux caudes (Collect Organe, Paris, France), stored
at -80oC, are thawed and homogenized at 4oC in 10
volumes of buffer (10 mM Tris, 1 mM EDTA, pH 7.5 at
25oC) using a PolytroonTM (position 5, 30 s) . The
homogenate is centrifuged at 2500 g for 1 min (Sorvall™
centrifuge fitted with an SS34 rator). The supernatant
is recovered and centrifuged at 35,000 g for 15 min,
the pellet is washed by resuspension in 10 volumes of
buffer, homogenization and centrifugation, and the
final pellet is suspended in 10 volumes of buffer and
preincubated at 37oC for 10 min.
The homogenate is centrifuged at 35,000 g for
15 min and the pellet is resuspended in the incubation
buffer (50 mM HepES, 1 mM EDTA, 50 mM B-hydroxy-
quinoline, 0.005% ascorbic acid, pH 7.5 at 25oC) in a
proportion of 100 mh of initial tissue per ml.
The membrane suspension (150 ml) is incubated
at 23oC for 60 min in tubes, in the presence of 0.8 nM
[3H]7-OH-DPAT (specific activity 120-160 Ci/mmol,
Amersham™) in a final volume of 1 ml of incubation
buffer containing 0.2 mM zolpidem hydrochloride and
1 mg of bovine serum albumin, in the presence or
absence of test compound. The incubation is stopped by
filtration on a Brandel Harvester M-48™, using Whatman
GF/CTM filters pretreated with bovine serum albumin
(0.1%) for 30 min. After predilution with 4 ml of
buffer (50 mM Tris, 120 mM NaCl, 5 mM KC1, pH 7.4 at
25°C) of each reaction medium, the tubes are rinsed
twice with 4 ml of this buffer.
The filters are cut up and then dried in an
oven at 120 °C for 10 min and the radioactivity retained
on the filters is determined by liquid scintillation.
spectrometry. The non-specific binding is determined in
the presence of 1 mM of dopamine.
For feach concentration of test compound, the
percentage of inhibition of specific binding of the
[3H] 7-OH-DFAT is calculated, after which the IC50, the
concentration which inhibits the binding by 50% is
determined.
The IC50 values of the compounds of the
invention are of the order of 0.01 mM to 2 mM
Study of the affinity for 5-HT1A-type serotonsnerqic
receptors
The compounds displace the binding of a
specific labelled ligand, [3H]-8-hydroxy-2-di-n-
propylamino tetraline (referred to hereinbelow as " [3H] -
8-OH-DPAT" and described by Gozlan et al., Nature
(1983), 305, 140), on the 5-HT1A receptors present in
rat hippocampus.
The animals used are 160 to 200 g male
Sprague-Dawley rats. After decapitation, the brain is
removed and the hippocampus is excised.. The tissue is
ground in an Ultra-Turrax Polytron™ machine for 30 s at
the half-maximal speed in 10 volumes of 50 mM Tris
buffer of pH adjusted to 7.4 with hydrochloric acid
(i.e. 100 mg of fresh tissue per ml). The homogenized
tissues are washed twice at 4°C, centrifuging them each
time for 10 min at 48,000 x g and resuspending the
pellet in fresh cooled buffer. Lastly, the final pellet
is suspended in the buffer to give a concentration of
50 mg of starting tissue per ml of buffer at 50 mM. The
mixture is then incubated at 37°C for 10 min.
The binding with [3H] 8-OH-DPAT (1 nM) xs
determined by incubation of 50 ml of membrane
suspension in a final volume of 250 ml of buffer
containing 10 mM of pargyline and 3 mM of paroxetine.
After incubation for 15 min at 37°C, the membranes are
recovered by filtration on Whatman GF/B™ filters, which
are washed three times with 5 ml aliquots of ice-cold
buffer. The filters are extracted in the scintillation
liquid and the radioactivity is measured by liquid
scintigraphy. The specific binding of the [3H]8-OH-DPAT
is defined as the amount of radioactivity retained on
the filters and which may be inhibited by co-incubation
with 10 mM 5-hydroxytryptamine. At a concentration of
1 nM of [3H]8-OH-DPAT, the specific binding represents
90% of the total radioactivity collected on the filter.
For each concentration of test compound, the
percentage of inhibition of the binding with [3H] 8-OH-
DPAT is determined, and then the IC50 concentration, the
concentration which inhibits the binding by 50%.
For the compounds of the invention, the IC5O
values are between 0.1 and 500 nM.
Study of the affinity for the 5-HT2-type serotonineraic
receptors
The compounds of the invention also underwent
an in vitro study of displacement of the binding of
spiperone on the serotoninergic (5-HT2) receptors of rat
cerebral cortex.
For this test, the rat brains are removed,
the cortex is dissected therefrom and is homogenized at
0°C in 10 volumes of a mixture containing, per litre,
50 millimol of Tris/HCl buffer at pH = 7.4,
120 millimol of sodium chloride and 5 millimol of
potassium chloride. The homogeneous mixture is
centrifuged at 4 0,000 x 9 for 10 min, after whxch the
pellet is recovered and is washed by suspending it in
the same buffer mixture, it is homogenized: again and is
centrifuged, this treatment of the pellet being carried
out twice. Lastly, the final pellet is diluted in the
same buffer mixture, in a proportion of 100 mg of wet
tissue per 1 ml of buffer.
The tissue is then preincubated for 10 min at
37oC in the presence of 10 micromol/l of pargyline,
followed by incubation for 20 min at 37°C in the
presence of [3H] spiperone (specific activity: 15 to 36
Ci per millimole) at a concentration of 0.3 nanomol/1
and of the test compound.
The membranes are then collected by
filtration on Whatman GF/B™ filters which are washed
twice with 5 ml of cold buffer. The radioactivity
retained on the filter is measured by liquid
scintigraphy.
In order to evaluate the activity of the
compounds, the curve of the percentage inhibition of
the specific binding of [3H]spiperone is established as
a function of the concentration of displacing drug. The
IC50 concentration, the concentration which inhibits the
specific binding by 50%, is determined graphically.
The specific binding is defined as being the
binding displaced by 100 micromol/1 of 5-HT.
The IC50 concentrations of the compounds of
the invention are between 0.02 and 5 mM.
The results of the tests show that the
compounds of the invention have strong affinity for
D2-type and D3-type dopaminergic receptors and for
5-HT1A-type and 5-HT1-type serotoninergic receptrs.
These results suggest that the compounds can be used
for the treatment of complaints and pathologies
associated with dopaminergic and serotoninergic
transmission dysfunction, in particular of the D2 and D3
dopaminergic receptors and 5-HT1A and 5-HT2
serotoninergic receptors.
Thus, they can be used for the treatment or
psychoses, in particular schizophrenia (deficient form
and productive form) and acute or chronic
extrapyramidal symptoms induced by neuroleptic agents,
for the treatment of various forms of anxietv. panic
attacks, phobias, compulsive obsessional disorders, for
the treatment of various forms of depression, including
psychotic depression, for the treatment of disorders
due to alcohol abuse or withdrawal, sexual behaviour
disorders, eating disorders and for the treatment of
miqraine.
To this end, they may be in any farm
appropriate for administering them orally or
parenterally, combined with any suitable excipient, and
may be dosed to allow a daily dosage of from 1 to
1000 mg.
WE CLAIM:
1. 8-azabicyclo[ 3.2.1.] octane-3-methanamine
derivative compounds, in the form of a pure geometrical
isomer or a mixture of such isomers, corresponding to
the general formula (I)
in which
U represents
A) either a 2, 3-dihydro-lH-inden-2-yl group of general
formula (A)
B) or a heterocyclic group of general formula (B)
in which
V represents a hydrogen or halogen atom, a (C1-C3)alkyl
group or one or two (C1-C3) alkoxy groups,
W and X each represent, respectively, either two oxygen
atoms, or an oxygen atom and a CH2 group, or a CH2 group
and an oxygen atom, or an oxygen atom and a CO group,
n represents the number 0 or 1,
R represents either a propyl group when U represents a
2,3-dihydro-lH-inden-2-yl group of general formula (A),
or a hydrogen atom or a (C1-C3)alkyl group when U
represents a heterocyclic group of general formula (B),
Y represents one or more atoms or groups chosen from
the following: hydrogen, halogen, (C1-C3)alkyl and
(C1-C3) alkoxy, and
Z represents two hydrogen atoms or an oxygen atom.
2. Compound as claimed in claim 1, wherein
it corresponds to the general formula (IA)
in which V, Y and Z are as defined in Claim 1.
3. Compound as claimed in claim 1, wherein
it corresponds to the general formula (IB)
in which V, W, X, Y and Z are as defined in Claim 1.
4. Medicament, comprising a compound as
claimed in one of claims 1 to 3.
5. Pharmaceutical composition, comprising a
compound as claimed in one of claims 1 to 3, combined
with an excipient.
6. Pharmaceutical compound, substantially as
herein described, particularly with reference to the
foregoing examples.
7. Pharmaceutical composition, substantially
as herein described, particularly with reference to the
foregoing examples.
Compounds of general formula (I)
in which U represents a group of general formula (A) or
in which formulae V represents a hydrogen or halogen
atom, a (C1-C3)alkyl group or one or two (C1-C3) alkoxy
groups, W and X each represent, respectively, either
two oxygen atoms, or an oxygen atom and a CH2 group, or
a CH2 group and an oxygen atom, or an oxygen atom and a
CO group, n represents the number 0 or 1, R represents
either a propyl group when U represents a group of
general formula (A), or a hydrogen atom or a
(C1-C3)alkyl group when U represents a group of general
formula (B) , Y represents one or more atoms or groups
chosen from the following: hydrogen, halogen,
(C1-C3)alkyl and (C1-C3) alkoxy, Z represents two hydrogen
atoms or an oxygen atom.

Documents:

1782-CAL-1998-FORM 13-1.1.pdf

1782-CAL-1998-FORM 13.pdf

1782-cal-1998-granted-abstract.pdf

1782-cal-1998-granted-assignment.pdf

1782-cal-1998-granted-claims.pdf

1782-cal-1998-granted-correspondence.pdf

1782-cal-1998-granted-description (complete).pdf

1782-cal-1998-granted-examination report.pdf

1782-cal-1998-granted-form 1.pdf

1782-cal-1998-granted-form 13.pdf

1782-cal-1998-granted-form 18.pdf

1782-cal-1998-granted-form 2.pdf

1782-cal-1998-granted-form 3.pdf

1782-cal-1998-granted-form 6.pdf

1782-cal-1998-granted-gpa.pdf

1782-cal-1998-granted-priority document.pdf

1782-cal-1998-granted-reply to examination report.pdf

1782-cal-1998-granted-specification.pdf

1782-cal-1998-granted-translated copy of priority document.pdf

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Patent Number

223849

Indian Patent Application Number

1782/CAL/1998

PG Journal Number

39/2008

Publication Date

26-Sep-2008

Grant Date

23-Sep-2008

Date of Filing

08-Oct-1998

Name of Patentee

SANOFI-SYNTHELABO

Applicant Address

22, AVENUE GALILEE, 92350, LE PLESSIS-ROBINSON

Inventors:

#	Inventor's Name	Inventor's Address
1	BENOIT MARABOUT	21, RUE MARIE CURIE, 91380, CHILLY MAZARIN
2	MIREILLE SEVRIN	73, RUE RAYMOND LOSSERAND, 75014, PARIS
3	PASCAL GEORGE	19, RUE DES QUATRE VENTS, 78730, SAINT ARNOULT EN YVELINES
4	JEAN PIERRE MERLY	11, AVENUE JULES GUESDE, 92330, SCEAUX
5	DANIELE DE PERETTI	42, AVENUE DE VERDUN, 92160, ANTONY
6	JOCELYNE ROY	6, RUE DE I'HOTEL DE VILLE, 91130, RIS ORANGIS
7	DAVID MACHNIK	42, RUE DAREAU, 75014, PARIS

PCT International Classification Number

A61K 31/46

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	9712580	1997-10-09	France
2	9712583	1997-10-09	France