HK1029108B

HK1029108B - 8-azabicyclo 3.2.1) octane-3-methanamine derivatives as ligands of d2 and d3 dopamine and 5ht1a and 5ht2 serotonin receptors

Info

Publication number: HK1029108B
Application number: HK00107648.1A
Authority: HK
Inventors: Marabout Benoit; Sevrin Mireille; George Pascal; Merly Jean-Pierre; De Peretti Daniele; Roy Jocelyne; Machnik David
Original assignee: Sanofi-Aventis
Priority date: 1997-10-09
Filing date: 1998-10-07
Publication date: 2002-07-19

Description

The present invention relates to compounds of general formula (I) in which U is A) either a 2,3-dihydro-1H-indene-2-yl group with the general formula (A) B) is a heterocyclic group of general formula (B) in which V represents a hydrogen or a halogen atom, a (C1-C3) alkyl group or one or two (C1-C3) alcoxy groups,W and X each represent, respectively, either two oxygen atoms, or one oxygen atom and one CH2 group, or one CH2 group and one oxygen atom, or one oxygen atom and one CO group,n represents the number 0 or 1,R represents either a propyl group when U represents a 2,3-dihydro-1H-2-indeneyl 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 of the following atoms: hydrogen,C1-C1-C3-alkyloxy,C1-C1-alkyloxy, or choxy (Y) represents one of the following atoms: hydrogen,C1-C3-alkyloxy,C1-alkyloxy, or choxy (Z3) represents one of the following atoms:

Err1:Expecting ',' delimiter: line 1 column 386 (char 385)

The compounds of the invention may also exist as bases or salts of addition to acids.

When U is a 2,3-dihydro-1H-indene-2-yl group of general formula (A), the compounds of the invention satisfy the general formula (IA) - What?

They can be prepared by a process illustrated in Figure 1A below.

8- ((phenylmethyl) - 8-azabicyclo[3.2.1]octane-3-carboxylate of formula ethyl (IIA) is reacted with a dimethyl aluminium starch, previously prepared from trimethyl aluminium and a 2,3-dihydro-1H-indene-2-amine derivative of formula general (IIIA), in which V is as defined above, in an inert solvent, e.g. toluene, at 0 to 100 °C; a compound of formula general (IVA) is obtained by reduction by the action of a mixed alkaline hydride such as aluminium hydride and lithium in an etheric solvent, e.g. tetrahydrofuran, at a temperature of 0 °C, to obtain a propyl chloride of formula general (OVA), subjected to 60 °C.in a chlorinated solvent, e.g. dichloromethane, in the presence of a base such as triethylamine, at 0 to 40 °C, to obtain an amide of general formula (VIA), which is reduced by the action of a mixed alkaline hydride such as aluminium and lithium hydride, in an etheric solvent, e.g. tetrahydrofuran, at 0 to 60 °C, to obtain a compound of general formula (Ia), which corresponds to the general formula (IA) when Y represents one hydrogen atom and Z represents two hydrogen atoms. To prepare another compound of general formula (IA), a de-benzylation is then carried out,e.g. by catalytic hydrogenation to obtain the amine of general formula (VIIA), and finally react the latter either with a general formula acid chloride (VIIIA) in which Y is as defined above, Z is one oxygen atom and T is one chlorine atom in a chlorinated solvent, e.g. dichloromethane, in the presence of a base such as triethylamine, at 20 to 40 °C, or with a halogenated derivative of general formula (VIIIA) in which Y is as defined above, Z is two hydrogen atoms and T is one halogen atom in an aprotic solvent,For example, N,N-dimethylformamide, in the presence of a base such as potassium carbonate, at 20 to 100 °C.

2,3-dihydro-1H-indene-2-amine of general formula (IIIA) in which X represents hydrogen is commercially available; substituted derivatives of 2,3-dihydro-1H-indene-2-amine of general formula (IIIA) can be prepared by methods similar to those described in Can. J. Chem. (1974) 52 381-389.

8- ((phenylmethyl) - 8-azabicyclo[3.2.1]octane-3-carboxylate of ethyl formula (IIA) can be prepared by a method similar 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 satisfy the general formula (IB) - What?

They can be prepared by processes illustrated in the following diagrams 1B to 3B.

In accordance with schemes 1Ba, 1Bb and 1Bc, compounds of general formula (IB) in which W and X each represent one oxygen atom and n represents the number 1 are prepared by reacting 8- ((phenylephylmethyl) -8-azabicyclo[3.2.1]-octane-3-carboxylate of formula (IIA) with a dimethyl aluminium starch, previously prepared from lithium-ethyl aluminium and a derivative of 2,3-diethyl-1,4-benzodioxane-2-trimethylamine of general formula (IIB), in which V is as defined above, in an inert soil such as toluene, at a temperature of 0 to 100 °C, to obtain a compound of general formula (IVBrah), reducing the action of a solvent such as allyl trihydrate and allyl trihydrate in a medium, for example, aluminium, at 60 °C. A compound of general formula (IBa) is obtained which corresponds to the general formula (IB) where R and Y each represent one hydrogen atom and Z two hydrogen atoms.

Depending on whether 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 processed by one of the processes illustrated in Figures 1Bb or 1Bc.

In Scheme 1Bb, the secondary amine function of the general formula (IBa) is first protected by action of bis dicarbonate (1,1-dimethyl ethyl) in a chlorinated solvent such as dichloromethane to obtain a general formula (VB) compound, in which Boc represents a 1,1-dimethyl ethoxycarbonyl group. A compound of general formula (VIIIB) is obtained by deprotecting the secondary amine function with trifluoroacetic acid to obtain a compound of general formula (IBb). Finally, if desired, this compound is reduced by the action of a mixed alkaline hydride, e.g. aluminium and lithium hydride, in an etheric solvent such as tetrahydrofuran, to obtain a compound of general formula (IBa).

Err1:Expecting ',' delimiter: line 1 column 651 (char 650)

In Scheme 2B, compounds of general formula (IB) are prepared 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 by reacting a general formula (XIB) compound, in which V is as defined above and G represents a leaving group such as a halogen atom or a methanesulfonylxy or 4-methylbenzenesulfonylxy group, with an 8-bicyclo[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 acetyl, in the presence of a base such as potassium carbonate.

In Figure 3B, 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 8-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 propanol, in the presence of a catalytic amount of hydrochloric acid.

The starting compounds for use in the processes illustrated in Schemes 1B to 3B are commercially available or may be prepared by methods identical or analogous to those described in the literature, in particular in patent applications EP-0 193 400 and EP-0 013 138 and in J. Med. Chem. (1983) 26 823, J. Med. Chem. (1989) 32 1402, J. Med. Chem. (1994) 37 2831.

Err1:Expecting ',' delimiter: line 1 column 437 (char 436)

The following is the list of the components of the test chemical:

The chemical composition of the product is determined by the following equation:

1A.1. exo-N-(2,3-dihydro-1H-indene-2-yl)-8- ((phenylmethyl)-8-azabicyclo[3.2.1]octane-3-carboxamide.

In a 250 ml tricol balloon, under argon atmosphere, 20 ml of toluene is introduced, 1.48 g (20.4 mmoles) of trimethylaluminium is slowly added to 2 M solution in heptane, the mixture is cooled to 0 °C with a bath of ice, water and salt, 3.64 g (27.4 mmoles) of 2,3-dihydro-1H-indene-2-amine is added, drip, heated to 50 °C for a few minutes and then at this temperature, 3.6 g (13.2 mmoles) of 8-phenylmethyl) azabicyclo-azabicycle[3.2.1]octane-3-carboxylate of ethyl reflux is added, and the mixture is reheated for 4 hrs. We cool it to 0°C, hydrolyze it with 24 ml of water, filter it in infusion soil, dry the filtrate on sodium sulphate, filter it and evaporate the solvents at reduced pressure. The evaporation residue is purified by chromatography on a silica gel column by eleution with a mixture of dichloromethane and methanol 97/3 to 93/7. You get 4.56 grams of solid. The melting point is 129 °C.

The chemical composition of the product is determined by the chemical composition of the product.

In a 250 ml tricol balloon, in an argon atmosphere, 0,56 g (14.7 mmoles) of aluminium hydride and lithium suspension are introduced into 30 ml of tetrahydrofuran, the mixture is cooled to 0 °C, 2,65 g (7.35 mmoles) of exo-N-(2,3-dihydro-1H-indene-2-yl)-8-phenylmethyl)-8-azabicyclo[3.2.1]octane-3-carboxamide is added in solution in 50 ml of tetrahydrofuran and the mixture is heated at reflux for 12 h. The mixture is cooled to 0°C, the excess hydride is hydrolyzed with 1 N aqueous soda, the insoluble is removed by filtration, the filtrate is dried on sodium sulphate, filtered and concentrated under reduced pressure. The salt of 2.55 g of the oil product is prepared by adding 1.7 g (14.7 mmol) of fumaric acid in solution in 200 ml of ethanol to a 2.55 g solution of the base in 50 ml of ethanol, evaporate the solvent at reduced pressure and recrystallize the residue in a mixture of 4/1 methanol and ethanol. You get 2.9 grams of fumarate. The melting point is 216.5-219 °C.

1A.3. Hydrochloride of exo-N- (2,3-dihydro-1H-indene-2-yl) N-[[8- ((phenylmethyl) - 8-azabicyclo[3.2.1]oct-3-yl]methyl]propanamide.

In a 250 ml tricol balloon, in an argon atmosphere, 0.95 g (2.74 mmoles) of exo-N-(2,3-dihydro-1H-indene-2-yl)-8-(phenylmethyl)-8-azabicyclo[3.2.1]octane-3-methane in solution in 15 ml of dichloromethane is introduced, 0.31 g (3.02 mmoles) of triethylamine is added and finally, drop by drop, 0.27 g (2.88 mmoles) of propanoyl chloride in solution in 5 ml of dichloromethane is added and the mixture is stirred at room temperature for 5 h. Wash the mixture three times with 50 ml of water, dry the organic phase on sodium sulphate, filter it, concentrate it under reduced pressure and purify the residue by chromatography on a silica gel column by eluting with a mixture of 98/2 to 92/8 dichloromethane and methanol, to obtain 0.9 g of base. The hydrochloride is prepared by adding 25 ml of hydrochloric acid in 0.1 N solution in propan-2-ol to a solution of 0.9 g (22.4 mO) of base in 10 ml of ethyl acetate, evaporating the solvents at reduced pressure and recrystallizing the residue in a mixture of 9/1 of ethyl acetate and propan-2-ol. You get 0.65 grams of white solid. Melting point: 20 to 210 °C.

1A.4. (E) -But-2-enediate of exo-N- (2,3-dihydro-1H-indene-2-yl) -8- (phenylmethyl) -N-propyl-8-azabicyclo[3.2.1]; octane-3-methane (5:2).

In a 250 ml tricol balloon, in an argon atmosphere, 0.34 g (8.94 mmoles) of aluminium hydride and lithium suspension is introduced into 20 ml of tetrahydrofuran, the mixture is cooled to 0 °C, 1.8 g (4.47 mmoles) of exo-N- (2,3-dihydro-1H-indene-2-yl) -N-[[8-phenylmethyl) -8-azabicyclo[3.2.1] oct-3-yl-methyl]propanamide is added in solution in 40 ml of tetrahydrofuran and the mixture is heated at reflux for 6 h. It is cooled to 0°C, the excess hydride is hydrolyzed with 1 N aqueous soda, the insoluble is removed by filtration, the filtrate is dried on sodium sulphate, filtered and concentrated under reduced pressure. You get 1.6 grams of oily product. The difumarate is prepared by adding 0.96 g (8.24 mO) of fumaric acid in solution in 250 ml of ethanol to a solution of 1.6 g (4.12 mO) of base in 100 ml of ethanol, evaporating the solvent at reduced pressure and recrystallizing the solid residue in a 95/5 mixture of ethanol and methanol. After filtration and drying, 1.3 g of fumarate (5:2) is obtained. The melting point is 190-192 °C.

The following is the list of the components of the test chemical:

A suspension of 1.75 g (4.5 mmoles) of exo-N-(2,3-dihydro-1H-indene-2-yl)-8-(phenylmethyl) N-propyl-8-azabicyclo[3.2.1]octane-3-methaneamine is prepared in 40 ml of ethanol, 0.5 g of 10% palladium carbon is added and hydrogenation is carried out in a Parr apparatus at a pressure of about 0.32 MPa at 45 °C.

After returning to room temperature, the catalyst is separated by filtration, the filtrate is concentrated at reduced pressure, the oil residue is taken up with an ammonia solution and extracted with diethyl ether, the organic phase is washed with water, dried on sodium sulphate, filtered and concentrated at reduced pressure. 1.1 g of yellow oil residue is obtained and used as is in the next step.

In a 100 ml tricol balloon, under argon atmosphere, 2.94 g (9.8 mmoles) of exo-N-(2,3-dihydro-1H-indene-2-yl) -N-propyl-8-azabicyclo[3.2.1]octane-3-methanamine is introduced into solution in 45 ml of N,N-dimethylformamide, 2.2 g (10.7 mmoles) of 1-bromethyl-4-chlorobenzene, 2.7 g (19.6 mmoles) of potassium carbonate and 0.1 g of sodium iodide, then the mixture is heated to 60 °C for 3 h. It is cooled, poured over 150 ml of ice water and extracted with methanol acetate. The mixture is washed in water, dried with sodium sulphate and methanol sulphate, and purified with a 100/10 of dichloromethane chloride gel, reduced to 90/10 of the filter pressure, and filtered with a silicon dichloromethane gel. 4,0 g of base from which fumarate is prepared by adding 2,1 g (18,8 mO) of fumaric acid in solution in 50 ml of ethanol to 4,0 g (9,4 mO) of base in solution in 100 ml of ethanol, evaporate the solvent at reduced pressure, and recrystallize the residue in ethanol. You get 2.62 grams of white solid. The melting point is 198-199°C.

The following is the list of the components of the test equipment:

It is a hydrochloride of exo-8- (3-chlorobenzoyl) -N-(2,3-dihydro-1H-indene-2-yl) -N-propyl-8-azabicyclo[3.2.1]octane-3-methanamine.

In a 50 ml tricol balloon, in an argon atmosphere, 0.75 g (2.51 mmoles) of exo-N-(2,3-dihydro-1H-indene-2-yl) N-propyl-8-azabicyclo[3.2.1]octane-3-methane is introduced in solution in 18 ml of dichloromethane, 0.51 g (5.03 mmoles) of triethylamine is added, 0.88 g (5.02 mmoles) of 3-chlorobenzoyl chloride is added slowly, and the mixture is stirred at room temperature for 24 h. Pour the mixture over 100 ml of water, extract it with ethyl acetate, separate the organic phase, wash it with water, dry it on sodium sulphate, filter it, concentrate the filtrate at reduced pressure and purify the residue by chromatography on a silica gel column by elevating with a mixture of 99/1 to 98/2 dichloromethane and methanol. 0,2 g of base of which the hydrochloride is prepared by adding 5 ml of a 0.1 N solution of hydrochloric acid in propan-2-ol to a solution of 0,2 g (0.42 mmole) of base in 10 ml of dethylacetate, evaporate the solvents at reduced pressure and recrystallize the residue in a mixture of 95/5 ethyl acetate and propan-2-ol. You get 0.12 grams of white solid. The melting point is 213-215°C.

The following is the list of the products covered by the exemption:

(E) But-2-enediate of exo-N-(4,7-dimethoxy-2,3-dihydro-1H-indene-2-yl)-8- ((phenylmethyl) -N-propyl-8-azabicyclo[3.2.1]; octane-3-methanamine (2:1).

The following is added to the list of active substances:

Using the method described in Example 1A.1, 4,64 g (24 moles) of 4,7-dimethoxy-2,3-dihydro-1H-indene-2-amine and 3,8 g (13,9 moles) of 8- ((phenylmethyl) - 8-azabicyclo[3.2.1]octane-3-carboxylate ethyl are used to obtain 4,1 g of solid, which is used as is in the next step.

Using the method described in Example 1A.2, 4,85 g (11,5 moles) of exo-N- ((4,7-dimethoxy-2,3-dihydro-1H-indene-2-yl)-8- ((phenylmethyl) -8-azabicyclo[3.2.1]octane-3-carboxamide and 0,88 g (23 moles) of aluminium and lithium hydride are used to produce 4,6 g of oil product, which is used as is in the next step.

The active substance is a mixture of hydrocarbons obtained from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of the distillation of hydrocarbons from the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the

Using the method described in Example 1A.3, starting from 4,6 g (11,3 moles) of exo-N-(4,7-dimethoxy-2,3-dihydro-1H-indene-2-yl)-8- ((phenylmethyl) -8-azabicyclo, [3.2.1]octane-3-methane, 1,3 g (12,8 moles) of triethylamine and 1,13 g (12,2 moles) of propanoyl chloride, 4,7 g of hot product is obtained after chromatographic purification on silica gel column by eletion with a mixture of 98/2 to 92/8 of dichloromethane and methanol and used as such in the next step.

The following is a list of the active substances that may be used in the manufacture of the products:

Using the method described in Example 1A.4, starting from 4,7 g (10,1 moles) of exo-N-(4,7-dimethoxy-2,3-dihydro-1H-indene-2-yl) -N-8- (phenylmethyl)-8-azabicyclo[3.2.1]oct-3-yl]methyl]propanamide and 0,78 g (20,6 moles) of aluminium and lithium hydride, 4,5 g of the compound in the form of yellow oil is obtained after chromatographic purification on a silica gel column by eluting with a mixture of dichloromethane and methanol 96/4 to 88/12. Dissolve 1.0 g (2.23 mO) of it in 100 ml of ethanol, add a solution of 0.52 g (4.46 mO) of fumaric acid to 100 ml of ethanol, evaporate the solvent at reduced pressure, and recrystallize the solid residue in ethanol. This results in 0.68 g of fumarate (2:1). The melting point is 187-189 °C.

The following is the list of the products covered by the exemption:

It is a hydrochloride of exo-N- ((4,7-dimethoxy-2,3-dihydro-1H-indene-2-yl)-8- ((3-ethoxybenzoyl) -N-propyl-8-azabicyclo[3.2.1].

Using the method described in Example 2A.1, 4,95 g (11 mmoles) of exo-N- ((4,7-dimethoxy-2,3-dihydro-1H-indene-2-yl)-8- ((phenylmethyl) N-propyl-8-azabicyclo[3.2.1]octane-3-methaneamine and 1,2 g of 10% palladium carbon are used to obtain 3,4 g of the oily compound, which is used as is in the next step.

The chemical composition of the product is determined by the addition of a mixture of the following:

Using the method described in example 3A, starting from 1.1 g (3.07 mo) of exo-N-(4,7-dimethoxy-2,3-dihydro-1H-indene-2-yl) N-propyl-8-azabicyclo[3.2.1]octane-3-methane, 0,62 g (6,14 mo) of triethylamine and 1,13 g (6,12 mo) of 3-ethyoxybenzoyl chloride, 1,43 g of the oil-like compound is obtained after chromatographic purification on a silica gel column by eluting with a mixture of 99/1 to 96/4 dichloromethane and methanol. The hydrochloride is prepared by adding 30 ml of hydrochloric acid in 0.1 N solution in propane-2-ol to a solution of 1.43 g (2.82 mmoles) of base in 30 ml of ethanol, evaporate the solvents at reduced pressure, and recrystallize the solid residue in a mixture of 9/1 ethyl acetate and ethanol. You get 0.56 grams of white solid. The melting point is 161-163°C.

The following is the list of the products covered by the exemption:

Using the method described in example 3A, starting from 1,25 g (3,49 mo) of exo-N-(4,7-dimethoxy-2,3-dihydro-1H-indene-2-yl) N-propyl-8-azabicyclo[3.2.1]octane-3-methane, 0,71 g (6,98 mo) of triethylamine and 1,4 g (6,96 mo) of 3,4-dimethoxybenzoyl chloride, 1,5 g of the compound is obtained, after chromatographic purification on silica gel column by eluting with a mixture of 99/1 to 96,5/3,5 dichloromethane and methanol, in the form of a yellowish ring. The hydrochloride is prepared by adding 30 ml of hydrochloric acid in 0.1 N solution in propane-2-ol to a solution of 1.5 g (2.87 mmoles) of base in 30 ml of ethanol, evaporate the solvents at reduced pressure, and recrystallize the solid residue in a mixture of 9/1 ethyl acetate and ethanol. We get 1.12 grams of white solid. The melting point is 134-136°C.

The following is the list of the components of the test chemical:

1B.1. exo-N-[2,3-dihydro-1,4-benzodioxan-2-yl]methyl]-8-phenylmethyl)-8-azabicyclo[3.2.1]octane-3-carbox amide.

In a 500 ml tricol balloon, 20 ml of trimethyl aluminium in solution 2 M is introduced under nitrogen atmosphere into toluene, the mixture is cooled to 0°C, 7.75 g (39.7 mmoles) of 2,3-dihydro-1,4-dioxane-2-methaneamine in solution in 150 ml of toluene is added, the mixture is heated to 50°C and then, at this temperature, 6.9 g (25.1 mmoles) of 8-phenylmethyl) -8-azabiclo[3.2.1]o-cycctane-3-ethyl carboxylate in solution in 35 ml of toluene is added and the mixture is heated at the reflux for 8 h. We cool it to 0°C, hydrolyze it with 50 ml of water, filter it in infusion soil, dry the sodium sulfate filter, filter it, and evaporate the solvents at reduced pressure. The residue is purified by chromatography on a silica gel column by eluting with a 95/5 mixture of dichloromethane and methanol. You get 8.4 grams of the compound in oil form.

In a 1 litre tricol balloon, in a nitrogen atmosphere, 5 g (131 mmoles) of aluminium hydride and lithium suspension are introduced into 50 ml of tetrahydrofuran, the mixture is cooled to 0 °C, 8,4 g (21,4 mmoles) of exo-N-[(2,3-dihydro-1,4-benzodioxan-2-yl) methyl]-8-(phenylmethyl)-8-azabicyclo[3.2.1]octane-3-carboxamide is added in solution in 420 ml of tetrahydrofuran and the mixture is heated at reflux for 15 h. It is cooled to 0°C, the excess hydride is hydrolyzed with 1 N aqueous soda, the insoluble is removed by filtration, the filtrate is dried on sodium sulphate and concentrated at reduced pressure. You get 7.3 grams of base in oily form. Take 2.9 g (7.66 mmol), add 1.8 g (15.5 mmol) of fumaric acid in solution to ethanol, evaporate the solvent and recrystallize the residue in propan-2-ol and then ethanol. We get 1.3 grams of white solid. The melting point is 105-107°C.

The following is the list of the substances which are to be used in the preparation of the product:

It is a hydrochloride of exo-N-[2,3-dihydro-1,4-benzodioxan-2-yl-methyl]-8-(4-methoxybenzoyl)-8-azabicyclo[3.2.1]octane-3-methanamine (1:1).

2B.1. exo-[2,3-dihydro-1,4-benzodioxan-2-yl]methyl] 8-phenylmethyl-8-azabicyclo[3.2.1]oct-3-yl]methyl. carbamate of 1,1-dimethylethyl.

In a tricol balloon, in a nitrogen atmosphere, 7.3 g (193 mmoles) of exo-N-[2,3-dihydro-1,4-benzodioxan-2-yl]-methyl-8-phenylmethyl)-8-azabicyclo[3.2.1]octane-3-methane in solution in 18 ml of dichloromethane is introduced, 4.6 g (21 mmoles) of bis dicarbonate (1,1-dimethyl) in solution in solution in 18 ml of dichloromethane is added, drop by drop, and the mixture is stirred at room temperature for 24 h. Evaporate the solvent at reduced pressure, dissolve the residue in 100 ml diethyl ether, wash the solution with water, dry it on sodium sulphate, filter it and concentrate the filtrate at reduced pressure. The raw product is obtained by chromatographic purification on a silica gel column by electrolysis with a mixture of 92.5/7.5 dichloromethane and methanol. You get 7.7 grams of the compound in oil form.

2B.2. exo-[2,3-dihydro-1,4-benzodioxan-2-yl]methyl]8-azabicyclo[3.2.1]oct-3-yl-methyl) carbamate of 1,1-dimethyl.

A solution of 7.4 g (15.45 mmoles) of exo-[2,3-dihydro-1,4-benzodioxan-2-yl]methyl[8-phenylmethyl) -azabicyclo[3.2.1]oct-3-yl]methyl]carbamate of 1,1-dimethylethyl is prepared in 240 ml of ethanol, 3.5 g of 10% palladium carbon is added and hydrogenation is performed in a Parr apparatus at 35 °C at a pressure of 0.30 MPa. After cooling to room temperature, the catalyst is separated by filtration and the filtrate is concentrated at reduced pressure. This results in 5.23 g of oil residue which is used as is in the next step.

2B.3. exo-[2,3-dihydro-1,4-benzodioxan-2-yl]methyl]8-[4-methoxybenzoyl)-8-azabicyclo[3.2.1]oct-3-yl]methyl]carbamate of 1,1-dimethyl.

In a 250 ml tricol balloon, in a nitrogen atmosphere, 2 g (5.15 mmoles) of exo-[2,3-dihydro-1,4-benzodioxan-2-yl]methyl[2,3-azabicyclo[3,2.1]oct-3-yl. methyl) 1,1-dimethyl carbamate, 52 ml of N,N-dimethylformamide and 0,71 g (5.15 mmoles) of potassium carbonate are introduced, the mixture is heated to 50 °C, 1 g (5.66 mmoles) of 4-methoxybenzoyl chloride is added and the mixture is stirred at 50 °C for 10 h. Evaporate the solvent at reduced pressure, add 50 ml of water and 300 ml of ethyl acetate to the residue, separate the organic phase, wash it with water, dry it on sodium sulphate, filter it, concentrate the filtrate at reduced pressure and purify the residue by chromatography on a silica gel column by eluting with a mixture of 92/8 dichloromethane and methanol. You get 2.5 grams of the compound, and you use it as it is in the next step.

2B.4. Hydrochloride of exo-N-[2,3-dihydro-1,4-benzodioxan-2-yl]methyl]-8-[4-methoxybenzoyl)-8-azabicyclo. [3.2.1]Octane-3-methanamine (1:1).

In a 100 ml flask, 2.5 g (48 mmoles) of exo-[2,3-dihydro-1,4-benzodioxan-2-yl]methyl]8-[4-metho_xybenzoyl)-8-azabicyclo[3.2.1]oct-3-yl]methyl]carbamate of 1,1-dimethylethyl, 25 ml of dichloromethane and 25 ml of trifluoroacetic acid are introduced and the mixture is heated at the back for 8 h. Cool it, add 30 ml of 10 N aqueous solution of soda, separate the aqueous phase, extract it with dichloromethane, wash the organic phase with water, dry it on sodium sulphate, filter it, concentrate the filtrate at reduced pressure and purify the residue by chromatography on a silica gel column by eluting with a mixture of 96/4 dichloromethane and methanol. 0,85 g of base is obtained and converted into hydrochloride by addition of saturated diethyl ether with hydrochloric acid gas. You get 0.45 grams of white solid. Melting point: between 93 and 110 °C.

It is a hydrochloride of exo-N-[2,3-dihydro-1,4-benzodioxan-2-yl]methyl]-8-(3-fluorobenzoyl)-8-azabicyclo[3.2.1]octane-3-methanamine (1:1).

3B.1. exo-[2,3-dihydro-1,4-benzodioxan-2-yl]methyl]8-[3-fluorobenzoyl)-8-azabicyclo[3.2.1]oct-3-yl]methyl] carbamate of 1,1-dimethyl.

Using the method described in Example 2B.3, starting from 3,5 g (9 moles) of exo-[2,3-dihydro-1,4-benzodioxan-2-yl]methyl[2,3-azabicyclo[3,2-oct-3-yl-methyl]carbamate of 1,1-dimethylethyl and 1,57 g (99 moles) of 3-fluenzoorobyl chloride, in the presence of a catalytic amount of potassium iodide, 2,7 g of oil product is obtained, which is used in the next step.

3B.2. Hydrochloride of exo-N-[2,3-dihydro-1,4-benzodioxan-2-yl]methyl]-8-(3-fluorobenzoyl)-8-azabicyclo[3.2.1]octane-3-methane (1:1).

Using the method described in example 2B.4, 2,7 g (5.28 mmol) of exo-[2,3-dihydro-1,4-benzodioxan-2-yl]methyl]8-[3-fluorobenzoyl)-8-azabicyclo [3.2.1]oct-3-yl]methyl]-1,1-dimethyl carbamate is obtained, after chromatographic purification on a silica gel column by eluting with a mixture of 96,5/3,5 g of dichloromethane and 1,6 g of methanol, in the form of the basic compound. The hydrochloride is prepared by treating 0,5 g of base with a 0,1 N solution of hydrochloric acid in propan-2-ol, evaporating the solvent and recrystallizing the residue in ethyl acetate. Finally, we isolate 0.4 g of white solid. The melting point is 206-209 °C.

(E) But-2-enediate of exo-N- [2,3-dihydro-1,4-benzodioxan-2-yl) methyl]-8- (3-fluorophenyl) -8-azabicyclo[3.2.1]octane-3-methane (1:1).

In a 250 ml tricol balloon, in a nitrogen atmosphere, 0.25 g (6.6 mmoles) of aluminium and lithium hydride, 10 ml of tetrahydrofuran and 1 g (2.4 mmoles) of exo-N-[(2,3-dihydro-1,4-benzodioxan-2-yl) methyl]-8-(3-fluenzoyl)-8-azabicyclo[3.2.1]octane-3-methanamine are introduced in solution in 60 ml of tetrahydrofuran, and the mixture is stirred at reflux temperature for 2 h and then at room temperature for 24 h. It is cooled to 0°C, the excess hydride is hydrolysed with 1 N aqueous soda, the insoluble is removed by filtration, the filtrate is dried on sodium sulphate, it is filtered, the filtrate is concentrated at reduced pressure and the residue is purified by chromatography on a silica gel column by elevating with a mixture of 93/7 dichloromethane and methanol. Get 0.6 g of base, dissolve in 5 ml of ethanol, add 0.35 g (3 mO) of fumaric acid and let it crystallize by cooling. You get 0.2 grams of fumarate. The melting point is between 132 and 134 °C.

The chemical is classified as a non-metallic compound with a molecular weight of less than 0,01 g/cm3 and a molecular weight of less than 0,01 g/cm3.

In a 250 ml tricol balloon, 3 g (7.9 mmoles) of exo-N- [(2,3-dihydro-1,4-benzodioxan-2-yl) methyl]-8-(phenylmethyl)-8-azabicyclo[3.2.1]octane-3-methane, 100 ml of dichloromethane, 0.75 g (8.7 mmoles) of propanoyl chloride in solution in 10 ml of dichloromethane are introduced and the mixture is stirred at room temperature for 20 h. Wash the mixture with 50 ml of water three times, dry the organic phase on sodium sulphate, filter it, concentrate the filtrate at reduced pressure, and purify the residue by silica gel chromatography by eluting with a mixture of 94/6 dichloromethane and methanol. You get 1.6 grams of the compound, and you use it as it is in the next step.

In a 100 ml tricol balloon, in a nitrogen atmosphere, 0.3 g (7.4 mmoles) of aluminium and lithium hydride and 15 ml of tetrahydrofuran are introduced, the mixture is cooled to 0 °C, 1.6 g (3.7 mmoles) 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 is added in solution in 32 ml of tetrahydrofuran, and the mixture is heated at reflux for 7 h. The fumarate is cooled to 0 °C, the excess hydride is hydrolyzed with 1 N aqueous soda, the insoluble is removed by filtration, the filtrate is dried on sodium sulfate, filtered and the filtrate is concentrated at reduced pressure. The fumarate is prepared from 1.45 g (3.44 mO) of base in solution in 5 ml of ethanol and 0.8 g (6.9 mO) of fumaric acid in solution in 10 ml of ethanol. The precipitate is collected by filtration and recrystallized in ethanol. We get 1.1 grams of white solid. The melting point is 190-191°C.

It consists of a mixture of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

In a 250 ml balloon, under nitrogen atmosphere, 3.45 g (8.2 mmoles) of exo-N-[(2,3-dihydro-1,4-benzodioxan-2-yl) methyl]-8-(phenylmethyl) N-propyl-8-azabicyclo[3.2.1]octane-3-methane, 70 ml of methanol, 3.4 g of 10% palladium carbon and 3.4 g of ammonium formate are introduced into a 250 ml balloon and the mixture is heated at low reflux for 2 h. It is allowed to cool, the catalyst is removed by filtration, the solvent is evaporated under low pressure, the residue is dissolved in dichloromethane, the solution is washed with water, the sodium sulfate is dried, the filter is filtered and the solution is reduced under high pressure. You get 1.8 grams of the compound, and you use it as it is in the next step.

6B.2. Exo-N-[2,3-dihydro-1,4-benzodioxan-2-yl]methyl]-8- (4,4-methylbenzoyl) -N-propyl-8-azabi. cyclo[3.2.1]octane-3-methanamine (1:1) hydrochloride, which is a mixture of hydrocarbons obtained from the distillation of hydrocarbons from the distillation of hydrocarbons.

In a 100 ml tricol balloon, 1 g (3 mmoles) of exo-N-[2,3-dihydro-1,4-benzodioxan-2-yl) methyl]-N-propyl-8-azabicyclo[3.2.1] is introduced into a 100 ml tricol balloon under nitrogen atmosphere. Octane-3-methane, 10 ml of tetrahydrofuran, 10 ml of ethyl acetate and 0.31 g (3 mmoles) of triethyl acetate are added. You remove the triethylamine hydrochloride by filtration, concentrate the filtrate at reduced pressure, dissolve the residue in dichloromethane, wash the solution with water, dry it on sodium sulfate, filter it, and concentrate the filtrate at reduced pressure. 1.4 g of base is obtained from which the hydrochloride is prepared by adding 30 ml of saturated diethyl ether of hydrochloric acid gas. After recrystallization, 0.65 g of white solid is obtained. Melting point: 95 to 112 °C.

It is a hydrochloride of 8-benzoyl-N-[3,4-dihydro-2H-1-benzopyran-2-yl) methyl]-8-azabicyclo[3,2.1]octane-3-methanamine.

A suspension of 0.6 g (1.9 mo) of 4-methylbenzenesulfonate of (3,4-dihydro-2H-1-benzopyran-2-yl) methyl, 1 g (4.1 mo) of 8-benzoyl-8-azabicyclo[3.2.1]octane-3-methane and 0.26 g (1.9 mo) of potassium carbonate is prepared in 11 ml of acetonitrile and heated at the back for 18 h. Add a little potassium iodide and an extra 0.15 g of potassium carbonate and heat at low tide for another 8 hours. The insoluble is removed by filtration, the filtrate is concentrated at reduced pressure, the residue is taken up with dichloromethane, the solution is washed with water, dried on sodium sulphate, filtered, the filtrate is concentrated at reduced pressure and the residue is purified by chromatography on a silica gel column by eluting with a mixture of 80/20 and then 70/30 ethyl acetate and methanol. The hydrochloride is prepared by a 0.1 N solution of hydrochloric acid in propan-2-ol. We get 0.4 g of solid. The melting point is 148.5-151.5°C.

It is a hydrochloride of 8-benzoyl-N-[(4-oxo-2,3-dihydro-4H-1-benzopyran-3-yl) methyl]-8-azabicyclo[3.2.1]octane-3-methanamine.

In a tricol balloon, 1.71, g (6,1 mmoles) of 8-benzoyl-8-azabicyclo[3.2.1]octane-3-methane hydrochloride, 0.2, g (6,3 mmoles) of paraformaldehyde and a few drops of concentrated hydrochloric acid are introduced into 10 ml of propan-2-ol, the mixture is heated at the reflux for 5 min, 0,78 g (5,3 mmoles) of 2,3-dihydro-4H-1-benzopyran-4-one is added in solution in 10 ml of propan-2-ol and the reflux heating is resumed for 18 h. The mixture is cooled and the hydrochloride is collected directly by filtration. We get 1.26 grams of solid. The melting point is 187-189 °C.

It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C4.]

9B.1. (S)-8-methoxy-1,4-benzodioxane-2-methanol. The preparation of this compound is described in Tet. Letters (1992) 33 6283-6286. 9B.2. (R) -4-Methylbenzenesulfonate of (8-methoxy-2,3-dihydro-1,4-benzodioxan-2-yl) methyl.

Dissolve 410 mg (2,1 mmoles) of (S)-8-methoxy-1,4-benzodioxane-2-methanol in 5 ml of pyridine, add 398 mg (2,1 mmoles) of 4-methylbenzenesulfonyl chloride and stir the mixture at room temperature for 20 h. Pour it into 30 ml of ice water, extract it with 2 times 15 ml of ethyl acetate, wash the organic phase with 1 N aqueous solution of hydrochloric acid, then with an aqueous solution of sodium hydrocarbonate, then with water, and dry on sodium sulphate. Filter, evaporate the solvent under pressure, remove the solid with the residue, wash the gum, reduce the pentane to the dry solution and reduce the pressure. 405 mg of the compound is isolated and used as is in the next step.

9B.3. Hydrochloride of (S) -exo-8-benzoyl-N-[8-methoxy-2,3-dihydro-1,4-benzodioxan-2-yl) methyl]-8-azabicyclo[3.2.1]octane-3-methanamine (1:1).

Inert atmosphere, a suspension of 380 mg (1.08 mmole) of (R) -4-methylbenzenesulfonate of (8-methoxy-2,3-dihydro-1,4-benzodioxan-2-yl) methyl, 530 mg (2,16 mmole) of 8-benzoyl-8-azabicyclo[3.2.1]octane-3-methane and 180 mg (1,3 mmole) of potassium carbonate is prepared in 5 ml of acetonite and heated at the back for 57 h. The solvent is evaporated at low pressure, the residue is taken up with dichloromethane and water, the organic phase is separated, washed with water to a neutral pH, filtered, the solvent is evaporated at low pressure, and the residue is purified by chromatography on a silica gel column by elevating with a mixture of 98/2 and then 95/5 dichloromethane and methanol. The hydrochloride is prepared by a 0.1 N solution of hydrochloric acid in propan-2-ol. We finally isolate 135 mg of solid. The melting point is 210-211 °C [α]D20=-53° (c=0.1, MeOH).

10B.1. (R)-4-Methylbenzenesulfonate of (7-chloro-2,3-dihydro-1,4-benzodioxan-2-yl) methyl.

The preparation of this compound is described in patent application WO 97/03071, pages 42-43.

10B.2. Hydrochloride of (S) -exo-8-benzoyl-N-[7-chloro-2,3-dihydro-1,4-benzodioxan-2-yl) methyl]-8-azabicyclo[3.2.1]octane-3-methane (1:1)

A suspension of 1.1 g (3.1 mo) of (R) -4-methylbenzenesulfonate of (7-chloro-2,3-dihydro-1,4-benzodioxan-2-yl) methyl, 1.5 g (6.2 mo) of 8-benzoyl-8-azabicyclo[3.2.1]octane-3-methaneamine and 515 mg (3.7 mo) of potassium carbonate is prepared in 20 ml of aceto nitrile and heated at the back for 48 h. The solvent is evaporated at low pressure, the residue is taken up with dichloromethane and water, the organic phase is separated, washed to a neutral pH, dried on sodium sulphate, filtered, the filtrate is evaporated at low pressure, and the residue is purified by chromatography on a silica gel column by eluting with a mixture of 98/2 and then 95/5 dichloromethane and methanol. The hydrochloride is prepared by a 0.1 N solution of hydrochloric acid in propan-2-ol. We finally isolate 230 mg of solid. The melting point is 164.5-167 °C [α]D20=-56° (c=0.1, MeOH).

The following tables A and B illustrate the chemical structures and physical properties of some of the compounds of the invention.

Err1:Expecting ',' delimiter: line 1 column 59 (char 58)

Err1:Expecting ',' delimiter: line 1 column 329 (char 328)

The compounds of the invention have been subjected to a series of pharmacological tests which have shown their interest as substances with therapeutic activities.

Affinity study for dopamine receptors of type D2 in the striatum of rats.

Err1:Expecting ',' delimiter: line 1 column 144 (char 143)The homogenized fabrics are washed twice at 4°C, centrifuged each time for 10 min at 40000 × g and the coating is placed back in the cooling buffer, and the last coating is placed in the same volume of buffer and ascorbic acid (0.1% final concentration) and pargyline (10 μM final concentration) are added. The binding of [3H]spiperon (New England Nuclear, specific activity 20-40 mCi/mmol) is determined by incubating 100 μl of the membrane suspension with the radio-ligand (0,The non-specific bond is determined in the presence of haloperidol at a concentration of 10 μM. After incubation, the membranes are recovered by filtration on Whatman GF/BTM filters and washed with two 5 ml ice buffer. The filters are removed from the scintillation fluid and the radioactivity is measured by liquid scintigraphy with an efficiency of 50 to 60%. For each test compound, the results are expressed by CI50, i.e. the concentration that inhibits 50 per cent of the binding of [3H]spipérone,calculated by a graphical or mathematical method. For the compounds of the invention, CI50 is between 0,005 and 2 μM.

Affinity study for dopamine D3 receptors in the bovine caudate nucleus.

The compounds have been studied in vitro for their affinity for dopaminergic D3 receptors obtained from a membrane preparation of the bovine caudate nucleus, essentially as described by Schoemaker H. in Eur. J. Pharmacol. (1993) 242 R1-R2. On the day of the experiment, the bovine tail cores (Collect Organe, Paris, France), stored at -80°C, are thawed and homogenised at 4°C in 10 buffer volumes (Tris 10 mM, EDTA 1 mM, pH 7,5 to 25°C) by a PolytronTM (position 5, 30 s). The homogenate is centrifuged at 2500 g for 1 min (SorvallTM centrifuge with SS34 rotor).The final product is washed by resuspending it in 10 buffer volumes, homogenising and centrifuging, and the final product is suspended in 10 buffer volumes and pre-incubated at 37°C for 10 min. The homogenate is centrifuged at 35000 g for 15 min, the coil is resuspended in the incubation buffer (HEPES 50 mM, EDTA 1 mM, 8-hydroxyquinoline 50 μM, ascorbic acid 0,005%, pH 7,5 at 25°C), at a rate of 100 mh of initial tissue per ml. The membrane suspension (150 μl) is incubated at 23°C for 60 min in tubes in the presence of 0,8 nM [3H]7-OH-DPAT (specific activity 120-160 Ci/mmol,The incubation is stopped by filtration on Brandel Harvester M-48TM using Whatman GF/CTM filters pre-treated with bovine serum albumin (0.1% for 30 min. After pre-diluting with 4 ml of buffer (Tris 50 mM, NaCl 120 mM, KCl 5 mM, pH 7.4 at 25°C) from each reaction medium, the tubes are rinsed 2 times with 4 ml of this buffer. The filters are cut and then dried in a 120°C oven for 10 min and the radioactivity on the filters is determined by liquid scintillation spectrometry.Non-specific binding is determined in the presence of 1 μM of dopamine. For each concentration of the test compound, the percentage of specific binding inhibition of [3H]7-OH-DPAT is calculated and then the CI50 concentration, which inhibits 50% of binding, is determined. The CI50 of the compounds of the invention is in the range of 0,005 to 2 μM.

Affinity study for serotonergic receptors of the 5-HT1A type.

Err1:Expecting ',' delimiter: line 1 column 178 (char 177)The homogenised tissue is washed twice at 4°C, centrifuged each time for 10 min at 48000 × g and the suspended coat is placed back in the cooling buffer. Finally, the last suspended coat is placed in the buffer to reach a concentration of 50 mg of starting tissue per ml of buffer at 50 mM. It is then left to incubate at 37°C for 10 min. Binding to [3H]8-OH-DPAT (1 nM) is determined by incubating 50 μl of membrane suspension in a final 250 μl volume of buffer containing 10 μM pargyline and 3 μM paroxetine.After incubation for 15 minutes at 37°C, the membranes are recovered by filtration on Whatman GF/BTM filters which are washed three times with aliquot amounts of 5 ml of iced buffer. The filters are removed from the scintillation fluid and the radioactivity is measured by liquid scintigraphy. The specific bond of [3H]8-OH-DPAT is defined as the amount of radioactivity retained on the filters and which can be inhibited by co-incubation with 5-hydroxytryptamine at 10 μM. At a concentration of 1 nM of [3H]8-OH-DPAT the specific bond represents 90% of the total radioactivity recovered on the filter.- What? For each concentration of the compound studied, the percentage of inhibition of binding to [3H]8-OH-DPAT is determined, followed by the CI50 concentration, which inhibits 50% of binding. For the compounds of the invention, CI50 is between 0,5 and 500 nM.

Affinity study for serotonergic receptors of the 5-HT2 type

The compounds of the invention were further tested in vitro to displace the binding of spiperone to the serotonergic receptors (5-HT2) of the rat cerebral cortex. For this test, the rat brains are taken, the cortex is dissected and homogenised at 0°C in 10 volumes of a mixture containing 50 millimoles of Tris/HCl buffer per litre at pH = 7.4, 120 millimoles of sodium chloride and 5 millimoles of potassium chloride.The final blob is then diluted in the same buffer mixture at a rate of 100 mg of wet tissue per ml of buffer. The tissue is then incubated for 10 min at 37°C in the presence of 10 micromoles/l of pargyline and then incubated for 20 min at 37°C in the presence of [3H]spiperone (specific activity: 15 to 30 Ci per millimole) at a concentration of 0.3 nanomoles/l and the test compound. The membranes are then collected by filtration on Whatman GF/BTM filters, which are washed twice with 5 ml of cold tampon.The radioactivity retained by the filter is measured by liquid scintigraphy. To evaluate the activity of the compounds, the percentage inhibition curve of specific binding of [3H]spiperone is established as a function of the concentration in the displacement drug and the CI50 concentration, which inhibits 50% of the specific binding, is graphically determined. Specific binding is defined as the 100 micromole/l displaced binding of 5-HT. The CI50 concentrations of the compounds of the invention are between 0,2 and 5 μM.

The results of the tests show that the compounds of the invention have a high affinity for dopaminergic receptors of type D2 and D3 and for serotonin receptors of type 5-HT1A and 5-HT2. These results suggest that the compounds may be used for the treatment of conditions and pathologies related to dysfunction of dopamine-energy and serotonergic transmissions, particularly dopamine D2 and D3 and serotonergic 5-HT1A and 5-HT2 receptors. Thus they can be used for the treatment of psychosis, in particular schizophrenia (deficiency and working condition) and acute or chronic extrapyramidal symptoms induced by neuroleptics, for the treatment of various forms of anxiety, panic attacks, phobias, obsessive compulsive disorders, for the treatment of various forms of depression, including psychotic depression, for the treatment of alcohol abuse or withdrawal disorders, sexual behaviour disorders, eating disorders, and for the treatment of migraine. For this purpose, they may be presented in all forms suitable for oral or parenteral administration, in combination with all appropriate excipients, and dosed to allow a daily dose of 1 to 1000 mg.

Claims

Compound, 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-1H-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-1H-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.
Compound according to Claim 1, characterized in that it corresponds to the general formula (IA) in which V, Y and Z are as defined in Claim 1.
Compound according to Claim 1, characterized in that it corresponds to the general formula (IB) in which V, W, X, Y and Z are as defined in Claim 1.
Compound according to Claim 3, characterized in that V represents a chlorine atom in position 7, W represents an oxygen atom, X represents an oxygen atom, Y represents a hydrogen atom, Z represents an oxygen atom, n represents the number 1, and R represents a hydrogen atom.
Medicament, characterized in that it consists of a compound according to one of Claims 1 to 3.
Pharmaceutical composition, characterized in that it contains a compound according to one of Claims 1 to 3, combined with an excipient.