HK1013651A - N-[(1,4-diazabicyclo [2.2.2] oct-2-yl) methyl] benzamide derivatives, their preparation and their application in therapeutics - Google Patents

Description

The present invention relates to N-[1,4-diazabicyclo[2.2.2]oct-2-yl) methyl]benzamide derivatives, their preparation and their therapeutic application.

The compounds of the invention satisfy the general formula (I) in which R1 represents a methoxy or cyclopropylmethoxy group,R2 represents a hydrogen, chlorine or bromine atom, or else R1 and R2 form together, and in this order, a group with the formula -O-CH2-O-, -O-CH2-O-, -O-CH2-O- or -O-CH2-O-, R3 represents a hydrogen atom or an amino group, andR4 represents a hydrogen, chlorine or bromine atom.

They may exist as free bases or as salts of addition to acids, or they may contain an asymmetric carbon atom in the diazoctane cycle and may therefore exist as pure enantiomers or as mixtures of enantiomers.

The most interesting compounds are, in general, those of general formula (I) in which R3 represents an amino group and R4 represents a chlorine atom.

The most commonly used compounds include (+)-8-amino-7-chloro-N-[1,4-diazabicyclo[2,2.2]oct-2-yl) methyl]-2,3-dihydro-1,4-benzodioxin-5-carboxamide, (-)-8-amino-7-chloro-N-[1,4-diazabicyclo[2,2.2]oct-2-yl) methyl]-2,3-dihydro-1,4-benzodioxin-5-carboxamide, (+)-4-amino-5-chloro-2-cyclopropylmetoxy) -N-[1,4-diazabicyclo[2,2.2]oct-2-cyclo-benzodioxin-4-carboxamide, (-)-8-amino-5-chloro-benzodioxin-2-metoxy-N-box-1,[2,2-diazodioxin-1,2-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl

According to the invention, compounds of general formula (I) can be prepared by a process illustrated by the following diagram.

A protected aminomethylloxirane of formula (II) in which Pht represents a phthalimide group (or 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) is reacted with a protected piperazine of formula (III) in which Bn represents a benzyl group at 80 to 120 °C in the absence of solvent or in an aprotic solvent, e.g. toluene or dioxane. The alcohol of formula (IV) is obtained by reacting with methanesulfonyl chloride in the presence of triethylamine in an aprotic solvent, e.g. dichloromethane, at a temperature of - 5 to + 20 °C. The resulting compound of formula (V) is then heated to 110 °C for 2 to 8 hours.in an aprotic solvent, e.g. toluene, to obtain quaternary ammonium of formula (VI). The latter is debenzyled by catalytic hydrogenation in the presence of palladium carbon to obtain the compound of formula (VII) and then deprotected by hydrazine hydrate in an alcoholic solvent, e.g. ethanol, at reflux temperature for 1 to 3 h. Formulation amine (VIII) is obtained, from which an addition salt, e.g. trichlorohydrate, is prepared. Finally, the compound is reacted with an acid of general formula (IX), in which R1, R2, R3 and R4 are as defined above, in the presence of dicyclohexylcarbodiimide,in an aprotic solvent, e.g. pyridine, at room temperature.

The starting compound of formula (II) can be obtained from 4-methylbenzenesulfonate of oxyranylmethyl and the potassium salt of 1H-isoindole-1,3(2H) -dione, commercially available in toluene and in the presence of a phase transfer agent such as hexadecyltributylphosphonium bromide.

Another method of preparing the compound of formula (II) from either enantiomer of 2,2-dimethyl-1,3-dioxolan-4-methanol, both commercially available, is illustrated in detail in the following example 4: It consists of reacting one of the enantiomers of 2,2-dimethyl-1,3-dioxolan-4-methanol with methanol sulphonyl chloride to obtain the corresponding methanesulfonate of (2-2-dimethyl-1,3-dioxolan-4-methanol) and then treating the latter with potassium phthalate in the presence of a phase transfer agent such as hexazoylphosphonyl bromide, to obtain the corresponding 2-methyl-1,3-hydroxybromide, and finally reacting with this latter to obtain the corresponding 2-methyl-1,3-hydroxybromide, to obtain the latter, and finally treating the latter with 2-methyl-1,3-methanol, to obtain the corresponding 2-methyl-1,3-hydroxybromide, to obtain the corresponding 2-methyl-1,3-methyl-1,3-benzoyl-1,3-dioxybromide, to obtain the latter, and finally treating the latter with 2-methyl-1,3-methanol, to obtain the corresponding 2-methyl-1,3-hydroxybromide, to obtain the latter, and finally treating with 2-methyl-1,3-methanol, to obtain the corresponding 2-methyl-1,3-methyl-1,3-benzoyl-1,3-hydroxybromide, to obtain the latter, to obtain the corresponding 2-methyl-12-hydroxybromide, to obtain the latter, and the latter, to obtain the corresponding 2-methyl-12-methyl-1-3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1-3-methyl-1,3-methyl-1-3-methyl-1,3-methyl-1,3-methyl-1,3-methyl-1, to obtain the latter, and the latter, to obtain the latter, the latter, the latter, the latter, the latter, the latter, the latter, the latter, the latter, the latter, the latter, the latter, the latter, the, the, the, the, the,

Benzylpiperazine formula (III) is commercially available.

Some acids of general formula (IX) are commercially available; others can be prepared by methods such as those described in J. Med. Chem. (1993), 36, 4121-4123 and in patent applications EP-0234872, WO-9305038 and ES-2019042, or by saponification of corresponding esters such as those described in patents DE-3001328 and DE-36433103.

The following examples illustrate in detail the preparation of some compounds according to the invention. The numbers of compounds in brackets in the titles correspond to those given in the table below.

Example 1 (composite No 1)

The active substance is a hydrochloride of (±) -4-amino-5-chloro-N-[1,4-diazabicyclo-[2.2.2]oct-2-yl) methyl]-2-methoxybenzamide.

The following substances are to be classified in the same category as the active substance:

Heat 34.7 g (0.197 mole) of 1-phenylmethylpiperazine to 80 °C, add in small portions 40.0 g (0.197 mole) of 2-oxyranylmethyl-1H-isoindol-1,3-H) -dione, and heat the mixture to 100 °C for 5 min. You let it cool, you take it back with 50 ml of toluene, you add 350 ml of heptane, and you get an oil that crystallizes when you cool it. After filtration and drying of the crystals, 71.2 g of the compound is obtained. The melting point is 94 °C.

The chemical composition of the active substance is determined by the following equation:

A 59.8 g (0.158 mole) solution of 2-[2-hydroxy-3-[4-(phenylmethyl) piperazine-1-yl]propyl]-1H-isoindol-1,3(2H) -dione is cooled to 0 °C in 350 ml of dichloromethane, 19.1 g (0.189 mole) of triethylamine is added, then, drop by drop, 19.8 g (0.173 mole) of methanesulfonyl chloride. After 1 h, 400 ml of water is added, the organic phase is purified, the solvent is evaporated under reduced gel and the residue is chromatographically purified on a silica column by exhaling with a mixture of ethyl acetate and heptane 90/10. You get 62.3 grams of the compound, which you use as is in the next step.

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

A 61 g (0.133 mole) solution of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[4-(phenylmethyl) piperazine-1-yl]methyl]ethyl methanesulfonate is heated for 14 h at reflux temperature in 500 ml of toluene, the mixture is cooled, the solid is separated by filtration, rinsed with toluene and dried. You get 52.9 grams of the compound, which you use as is in the next step. The melting point is > 260 °C.

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

A solution of 52,6 g (0,115 mole) of methanesulfonate of (±)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl-1-(phenylmethyl)-4-aza-1-azoniabicyclo[2.2.2]octane is placed in a hydrogenator in 500 ml of methanol, 15 g of 10% palladium carbon is added and a catalytic hydrogenation is carried out at 50 °C at 0,1 MPa for 1 hour. You separate the catalyst by filtration, rinse it with methanol, and evaporate the filtrate at reduced pressure, and you get 21.1 grams of the compound. The melting point is 156 °C.

The active substance is a trichlorohydrate of (±)-1,4-diazabicyclo[2.2.2]octane-2-methanamine.

A mixture of 20.0 g (0.0737 mole) of 2-[1,4-diazabicyclo[2.2.2]oct-2-yl) methyl]-2H-isoindole-1,3(2H) -dione and 4.4 g (0.0884 mole) of hydrazine hydrate is heated in 200 ml of ethanol at the reflux for 2 h 30 min. The mixture is concentrated, the residue is taken up with 300 ml of chloroform, the insoluble is removed by filtration, the filtrate is evaporated at reduced pressure and the residue is purified on an alumina column by elution with a mixture of chloroform, methanol and ammonia 90/10/1 to obtain 9.3 g of yellow liquid distilled at reduced pressure to obtain 8.45 g of colourless liquid Boiling point: 70 °C at 100 Pa. The trichlorohydrate is prepared by dissolving 8.25 g (0.0584 mole) of this compound in 50 ml of ethanol at 10 °C, adding 50 ml of a 4N solution of hydrochloric acid to the ethanol, until pH = 1, cooling the solution to 0 °C and filtering the precipitated salt. The melting point is 280 °C.

The chemical composition of the active substance is determined by the following equation:

Add 1.25 g (0.005 mole) of 1,4-diazabicyclo[2.2.2]octane-2-methanamine trichlorhydrate to a 0.2 g (0.005 mole) solution of baking soda in 1.6 ml of water, add, drop by drop, a 1.11 g (0.0055 mole) solution of 4-amino-5-chloro-2-methoxybenzoic acid in 6.7 ml of pyridine, then, twice, and at intervals of 45 min, remove the insoluble by filtration, close the filter, add 1.86 g (0.009 mole) of dicyclohexylcarbodiimide, and keep stirring at room temperature for one night. Add 15 ml of water, stir for 45 minutes, filter the mixture and evaporate the filtrate at reduced pressure.The residue is taken with water, aqueous soda is added to pH = 10, the precipitate is collected by filtration and purified by chromatography on a silica gel column by elevating with a mixture of chloroform, methanol and ammonia 85/15/1,5. 1.28 g of product is obtained, which is purified by hot-crushing in 20 ml of ethanol. After filtration, evaporation and drying at 50 °C under reduced pressure, 1.2 g of the compound is obtained in the basic form. 1,0 g (0.00308 mole) of the suspension is added to 10 ml of ethanol,add 0.7 ml (0.008 mmole) of concentrated hydrochloric acid and then 2 ml of water, filter the resulting solution and dry concentrate. Re-concentrate the residue with ethanol and dry concentrate again. Repeat the process, then dry the product at reduced pressure. Finally, 0.93 g of dichlorohydrate is obtained. The melting point is 239 °C.

Example 2 (composite No 2)

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

(-) 2.1.-2- (oxyranylmethyl)-1H-isoindole-1,3 (oxyranyl)-2H-dione.

Heat a mixture of 40.75 g (0.22 mole) of potassium phthalimidide, 5.07 g (0.01 mole) of hexadecyltributylphosphonium bromide and 160 ml of toluene to 80 °C. Inject 45,6 g (0,2 mole) of (+) -4-methylbenzenesulfonate of oxyranylmethyl in solution into 80 ml of toluene in 30 min and maintain the heating temperature between 80 and 100 °C for 2 h. Filter the mixture, wash the filtrate four times with water, dry it, evaporate the solvent at reduced pressure, crystallize the residue in a mixture of ethyl acetate and diisopropyl ether 1/2 and purify by silica gel chromatography by eluting with a 50/50 mixture of ethyl acetate and heptane. You get 28 grams of product, you grind it in the diisopropyl ether, you get 24.9 grams of the compound. The melting point is 100 °C. [α] $\frac{\text{20}}{\text{D}}$ The following table shows the results of the analysis:

The active substance is a trichlorohydrate of (+)-1,4-diazabicyclo[2.2.2]octane-2-methanamine.

The procedure is as described in examples 1.2 to 1.5, but from the optically pure (-)-2- (oxyranylmethyl) - 1H-isoindole-1,3 (oxyranyl) - 2H-dione prepared in the previous step. The melting point is 240 °C (decomposition). [α] $\frac{\text{20}}{\text{D}}$ The temperature of the water is +20°C.

The chemical composition of the compound is determined by the addition of a mixture of hydrocarbons and hydrocarbons.

The procedure is as described in example 1.6, but from the trichlorohydrate of (+)-1,4-diazabicyclo[2.2.2]optically pure octane-2-methanamine prepared in the previous step. The melting point is 228°C (decomposition). [α] $\frac{\text{20}}{\text{D}}$ The temperature of the water is + 14.4° (c = 1 ; H2O).

Example 3 (composite No 3)

It is a dichlorohydrate of (-)-4-amino-5-chloro-N-[1,4-diazabicyclo[2.2.2]oct-2-yl) methyl]-2-methoxybenzamide.

The following substances are to be classified in the same heading as the active substance:

The procedure is as described in example 2.1 but from (-) -4-methylbenzene sulfonate of oxyranylmethyl. The melting point is 97 °C. [α] $\frac{\text{20}}{\text{D}}$ The temperature of the water is approximately +8,5° (c = 1; CH2Cl2).

The active substance is a trichlorohydrate of (-)-1,4-diazabicyclo[2.2.2]octane-2-methanamine.

Proceed as described in examples 1.2 to 1.5, but from the optically pure (+)-2- ((oxyranylmethyl) - 1H-isoindole-1,3 ((2H) -dione prepared in the previous step. The melting point is 240 °C (decomposition). [α] $\frac{\text{20}}{\text{D}}$ The temperature of the water is -22°C.

The chemical composition of the active substance is determined by the following equation:

The procedure is as described in example 1.6, but from the trichlorohydrate of (-)-1,4-diazabicyclo[2.2.2]optically pure octane-2-methanamine prepared in the previous step. The melting point is 215 °C (decomposition). [α] $\frac{\text{20}}{\text{D}}$ The temperature of the water is -12.7° (c = 1 ; H2O).

Example 4 (compound No.8)

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

4.1. methanesulphonate of (-) - 2,2-dimethyl-1,3-dioxolan-4-yl) methyl.

To a solution of 300 g (2,269 moles) of (-)-2,2-dimethyl-1,3-dioxolan-4-methanol in 2.05 l of dichloromethane, add 380 ml (2,723 moles) of triethylamine, cool the solution to -5°C and add, drop by drop and for 1h10, 193 ml (2,496 moles) of methanesulfonyl chloride. After 10 min of stirring, wash the solution four times with water, dry it and evaporate the solvent under reduced pressure. This results in 453 g of orange liquid product which is used as is in the next step.

The substance is to be classified in the additive as a substance of heading 2913 or 2913 and in the active substance as a substance of heading 2913 or 2913

Heat a mixture of 398.9 g (2,154 moles) of potassium salt of 1H-isoindole-1,3-dione and 109.3 g (0.215 moles) of hexadecyltributylphosphonium bromide in 3.25 l of toluene at 60 °C, then add 453 g (2,154 moles) of methanesulfonate of (-) -2,2-dimethyl-dioxolan-4-yl) methyl in 20 min, drop by drop, and heat the mixture at 80 °C for 4 hours. Add another 54.7 g (0.108 moles) of hexadecyltributylphosphonium bromide and continue heating at 80 to 100 °C for 5 hours. We cool the mixture to 60°C, wash it with water and then twice with a sodium chloride solution, dry the organic phase and evaporate the solvent under reduced pressure. This gives us 691.6 g of orange solids. The melting point is 81.9-82 °C. [α] $\frac{\text{20}}{\text{D}}$ The temperature of the water is +35,2° (c = 1 ; CH2Cl2).

The following substances are to be classified in the same heading as the active substance:

Heat a suspension of 261.3 g (2,154 moles) of (+) -[2,2-dimethyl-1,3-dioxolan-4-yl) methyl]-1H-isoindole-1,3-dione, 2,8 l of water and 5,6 ml of hydrochloric acid 12M at 60 °C for 2 h. The medium is neutralized with 11 ml of aqueous sodium hydroxide 10M and 800 ml of water is evaporated. We cool the residue to 12°C and we get 352.9 g of white solid. The melting point is 122,5 to 122,8 °C. [α] $\frac{\text{20}}{\text{D}}$ The temperature of the water is +48,4° (c = 1 ; CH3OH). [α] $\frac{\text{20}}{\text{365}}$ The temperature of the water is approximately 210,8° (c = 1; CH3OH).

The following substances are to be classified in the same category as the active substance:

A mixture of 22,1 g (0.1 mole) of (R) - ((+) - 2-(2,3-dihydroxypropyl) - 1H-isoindole-1,3 ((2H) - dione, 10,6 g (0.1 mole) of benzaldehyde, 100 ml of toluene and 0,1 g of paratoluenesulfonic acid is heated at the back-flow for 3 h. The mixture is cooled, washed with water and then with an aqueous solution of sodium hydrocarbonate, the organic phase is dried, the solvent is evaporated at reduced pressure and the residue is crystallized in 100 ml of a mixture of 20/80 diethyl ether and diisopropyl ether. You get 25.9 g of a 50/50 mixture of diasteroisomers. The melting point is 84 °C. [α] $\frac{\text{20}}{\text{D}}$ The temperature of the water is +62° (c = 1; CH2Cl2).

The following is added to the list of active substances:

In a solution of 19.4 g (0.0627 mole) of (+)-2-[(2-phenyl-1,3-dioxolan-4-yl) methyl]-1H-isoindole-1,3(2H) -dione in 100 ml of 1,2-dichloroethane, add in small portions 11.2 g (0.0627 mole) of N-bromosuccinimide and stir the mixture for 2 h. Filter the mixture, wash the filtrate with water containing sodium thiosulfate, dry the organic phase, evaporate the solvent at reduced pressure and crush the residue in diethyl ether. You get 28 grams of product. The melting point is 120 °C. [α] $\frac{\text{20}}{\text{D}}$ The temperature of the water is +57,5° (c = 1 ; CH2Cl2).

The following substances are to be classified in the same heading as the active substance:

Prepare a solution of sodium methylate from 1.17 g (0.051 mole) of sodium and 15 ml of methanol, add it to a solution of 19.7 g (0.0507 mole) of (+)-2-bromomomethyl-1-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) benzoate in 200 ml of toluene for 20 min at 30 °C and stir the mixture at room temperature overnight. The solution is washed with water, the solvent is evaporated at reduced pressure and the residue is crushed in a mixture of diisopropyl ether and heptane. We get 9.7 grams of product. The melting point is 101.4 to 101.5 °C. [α] $\frac{\text{20}}{\text{D}}$ The following table shows the results of the analysis: [α] $\frac{\text{20}}{\text{365}}$ The concentration of the product in the solution is calculated as follows:

4.7. dichlorohydrate of (+)-8-amino-7-chloro-N-[1,4-diazabicyclo[2.2.2]oct-2-yl) methyl]-2,3-dihydro-1,4-benzodioxin-5-carboxamide.

The procedure described in example 1 is to use (-)-2- (oxyranylmethyl) - 1H-isoindole-1,3 (oxyranyl) - 2H-dione, which is optically pure. The melting point is 231°C (decomposition). [α] $\frac{\text{20}}{\text{D}}$ The temperature of the water is + 17.8° (c = 1 ; H2O).

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

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

5.1. methanesulfonate of (+) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl.

The procedure is as described in example 4.1, but from (+) -2,2-dimethyl-1,3-dioxolan-4-methanol.

The substance is to be classified in the additive as a substance of heading 2913 or 2913 and in the additive as a substance of heading 2913 or 2913

The method is described in example 4.2 from methanesulfonate of (+) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl. The melting point is 81.2 to 81.3 °C. [α] $\frac{\text{20}}{\text{D}}$ The temperature of the water is approximately -34 °C.

The following substances are to be classified in the same heading as the active substance:

The procedure described in example 4.3 is to use (-)-2-[2,2-dimethyl-1,3-dioxolan-4-yl) methyl]-1H-isoindole-1,3(2H) -dione. The melting point is 122.8-122.9 °C. [α] $\frac{\text{20}}{\text{D}}$ The temperature of the water is -48,8° (c = 1; CH3OH).

The following substances are to be classified in the same heading as the active substance:

The method is described in example 4.4 from (-)-2- (2,3-dihydroxypropyl) - 1H-isoindole-1,3 (2,2-H) -dione. The melting point is 84 °C. [α] $\frac{\text{20}}{\text{D}}$ The temperature of the water is -59° (c = 1 ; CH2Cl2).

The following is added to the list of active substances:

The procedure described in example 4.5 is to use (-)-2-[(2-phenyl-1,3-dioxolan-4-yl)methyl]-1H-isoindole-1,3(2H) -dione. The melting point is 118.4-118.6 °C. [α] $\frac{\text{20}}{\text{D}}$ The following table shows the results of the analysis:

5.6. (+)-2- (oxyranylmethyl) - 1H-isoindole-1,3 (oxyranyl) - 2H-dione. Melting point is the following:

The test chemical is obtained from benzoate of (-)-2-bromomethyl-1- ((1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl as described in example 4.6. The melting point is 100.4-100.5°C. [α] $\frac{\text{20}}{\text{365}}$ The temperature of the solution is +45,5° (c = 1 ; CHCl3).

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

The procedure described in example 4.7 is to proceed from (+)-2- ((oxyranylmethyl) - 1H-isoindole-1,3 ((2H) -dione. The melting point is 220 °C (decomposition). [α] $\frac{\text{20}}{\text{D}}$ The temperature of the water is -16° (c = 1; H2O).

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

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

6.1. 6-chloro-1,3-benzodioxolane-4-carboxylic acid, whether or not chemically defined

Prepare a suspension of 5,0 g (30,1 mo) of 1,3-benzodioxolan-4-carboxylic acid in 50 ml of acetic acid, heat it to 70 °C, add, in 15 min, 1,0 g of N-chlorosuccinimide, continue heating for 30 min, add again 1,0 g of N-chlorosuccinimide, and, after another 15 min heating, add 2,0 g of N-chlorosuccinimide, for a total of 4,0 g (30,1 mo), and keep heating at 70 °C for 2 h. Let the mixture cool, pour it into 150 ml of water, collect the solid by filtration, wash it with water and vacuum dry. 1,72 g of solid is obtained and purified by chromatography on a silica gel column by eletion with a mixture of 95/5/0,5 dichloromethane, methanol and acetic acid. After recrystallization in a mixture of ethanol and water, 1.13 g of the compound is obtained. The melting point is 210 °C.

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

The reaction is performed with (-)-1,4-diazabicyclo[2.2.2]_octane-2-methanamine as described above and the dichlorohydrate of the resulting compound is prepared. The melting point is 212 °C. [α] $\frac{\text{20}}{\text{D}}$ The temperature of the water is -18° (c = 1 ; H2O).

Err1:Expecting ',' delimiter: line 1 column 185 (char 184) $\frac{\text{20}}{\text{D}}$ Err1:Expecting property name enclosed in double quotes: line 1 column 45 (char 44)

The compounds of the invention have been tested and shown to be of interest as substances with therapeutic activity.

Their affinity for 5-HT3 serotonergic receptors was demonstrated by the shift of binding of a specific, marked ligand, [3H]-(S) -Zacopride. The study is performed in vitro on 5-HT3 receptors in the rat cortex, essentially as described by Barnes N.M. et al., J. Pharm. Pharmacol. (1988) 40 548-551. Male Sprague-Dawley rats (OFA, Iffa Credo, Lyon, France) weighing 200 to 250 g are euthanized and the brain removed, the cortex dissected and homogenised using a PolytronTM crusher (position 7.20 s) in 20 volumes of Tris buffer (25 mM, pH = 7.4 at 22 °C),The homogenate is centrifuged at 45000 g for 10 min using a SorvallTM centrifuge with an SS34 rotor, the coil is resuspended in 10 Tris buffer volumes and incubated at 37°C for 10 min under stirring. The suspension is diluted to 20 volumes with a Tris pad, and centrifuged again under the same conditions, then the collet is resuspended in 5 volumes of Tris pad and broken into 5 ml aliquot fractions which are frozen at -80°C. On the day of the experiment, the preparation is thawed at +4°C and then diluted 1,2 times using the Tris-NaCl incubation buffer (Tris 25 mM,The test chemical is a mixture of two substances, NaCl 150 mM, pH = 7,4 at 22°C. The membrane suspension (100 μl, 1 mg proteins) is then incubated at 25°C for 25 min in the presence of 0.5 nM of [3H]-(S) -Zacopride (specific activity 75-85 Ci/mmole, Amersham, Little Chalfont, UK) in a final 500 μl volume of Tris-NaCl buffer with or without test compound. The incubation is stopped by filtration on Whatman GF/B filters previously treated with 0.1% polyethyleneimine. Each test tube is pre-diluted with 4 ml Tris-NaCl buffer and then rinsed three times with 4.5 ml Tris-NaCl buffer. The filters are pre-cut before drying in the oven (120°C,The radioactivity on the filters is determined by liquid scintigraphy, and the non-specific bond is determined in the presence of 10 μM of MDL 72222 (the ligand described in the above article). For each concentration of compound studied, the percentage of specific binding inhibition of [3H]-(S) -Zacopride is determined, followed by the CI50 concentration, a concentration of this compound that inhibits 50% of this specific binding. The CI50 of the compounds of the invention is between 0,009 and 1 μM.

The compounds of the invention have also been studied for their affinity for 5-HT4 receptors in the striatum of the guinea pig according to the method described by Grossman et al. in Br. J. Pharmacol. (1993) 109 618-624. The test subjects (Hartley, Charles River, France) are euthanized at 300 to 400 g, the brains removed, the striata excision performed, and the test subjects frozen at -80 °C. On the day of the experiment, the fabric is thawed at +4°C in 33 volumes of HEPES-NaOH buffer (50 mM, pH = 7.4 to 20°C), homogenised with a PolytronTM mill, the homogenate is centrifuged at 48000 g for 10 min, the coating is recovered,The final collet is resuspended in HEPES-NaOH buffer at a rate of 30 mg tissue per ml. Incubate 100 μl of this membrane suspension at 0 °C for 120 min in the presence of [3H]GR113808 (ligand described in the above article, specific activity 80-85 Ci/mmole) in a final volume of 1 ml of HEPES-NaOH buffer (50 mM, pH = 7,4), with or without test compound.1%, each tube is rinsed with 4 ml of buffer at 0°C, filtered again and the radioactivity in the filter is measured by liquid scintigraphy. Non-specific binding is determined in the presence of 30 μM serotonin. Specific binding accounts for 90% of the total radioactivity collected on the filter. For each concentration of the test compound, the percentage of specific binding inhibition of [3H]GR113808 and then CI50 shall be determined, the concentration of the test compound which inhibits 50% of the specific binding. The CI50 of the compounds of the invention is between 0,008 and 1 μM.

The compounds of the invention have also been studied for their agonist or antagonist effects on 5-HT4 receptors in the rat esophagus according to the method described by Baxter et al. in Naunyn Schmied. Arch. Pharmacol. (1991) 343 439. Male Sprague-Dawley rats weighing 300 to 450 g are used. A fragment of about 1.5 cm is rapidly removed from the terminal part of the esophagus, the muscle layer is removed, the inner muscular mucosa is opened longitudinally, and the animal is placed in a tank containing a Krebs-Henseleit solution at 32 °C, oxygenated by a carboxygen current (95% O2 and 5% CO2),and connect it to an isometric transducer at a basal voltage of 0.5 g. The tissue is contracted by adding 05 μM of carbachol, the contraction is allowed to stabilize (15 min), and the preparation is then exposed to serotonin (1 μM) to quantify maximum relaxation. The tissue is washed and after a period of 20 min, 0.5 μM of carbachol is added again, and the preparation is exposed to the test compound in increasing cumulative doses of 0.1 to 1 μM. Relaxation-inducing compounds are characterized as 5-HT4 agonists.- What? For non-relaxation inducing compounds, the preparation is exposed to serotonin in increasing cumulative concentrations of 0.1 nM to a maximum relaxation inducing concentration, and the serotonin relaxation curve in the presence of the test compound is then compared with a control curve in the absence of the test compound. Finally, the compounds of the invention were studied for their antagonistic effects on 5-HT3 receptors in the smooth muscle of the descending colon isolated from a guinea pig, using the method described by Grossman et al.In the case of the use of the drug in the production of the product, the maximum dose should be calculated as follows: Serotonin (0.1-100 μM), after blocking 5-HT1 and 5-HT2 receptors (Methysergide 0.1 μM) and desensitizing 5-HT4 receptors (5-methoxytryptamine 10 μM), causes a concentration-dependent contraction of the smooth muscle portion of the descending test tube colon by stimulation of 5-HT3 receptors. The antagonistic effect of a compound on 5-HT3 serotonergic receptors is quantified by measuring the shift of a control serotonin effect-concentration curve (successive, non-cumulative, increasing concentrations) at compound concentrations between 1 nM and 0,1 μM, with an incubation period of 30 min.

The results of biological tests performed on the compounds of the invention show that they are ligands of 5-HT3 and/or 5-HT4 serotonergic receptors and act as 5-HT4 and/or 5-HT3 agonists or antagonists.

The compounds may therefore be used for the treatment and prevention of disorders in which 5-HT3 and/or 5-HT4 receptors are involved, whether in the central nervous system, gastrointestinal system, cardiovascular system or urinary system.

At the central nervous system level, these disorders and disorders include neurological and psychiatric disorders such as cognitive disorders, psychosis, compulsive and obsessive behaviors, and states of depression and anxiety. Cognitive disorders include, for example, memory and attention deficits, dementia (senile dementias such as Alzheimer's disease or age-related dementias), vascular brain defects, Parkinson's disease. Psychosis includes, for example, paranoia, schizophrenia, moodiness and autism. Compulsive and obsessive disorders include eating disorders or anxiety disorders such as anxiety or depression, anxiety disorders such as depression, anxiety, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression

At the gastrointestinal system level, these disorders and disorders include vomiting induced by antitumor therapy, direct or indirect gastrointestinal disturbances of the esophagus, stomach or intestines, specific diseases such as dyspepsia, ulceration, gastro-oesophageal reflux, flatulence, irritable bowel syndrome, intestinal discharge disorders, diarrhoea, e.g. those induced by cholera or carcinoid syndrome.

In the cardiovascular system, these disorders and disorders include, in particular, pathologies directly or indirectly related to cardiac arrhythmias.

In the urinary system, these disorders and disorders include incontinence of all kinds, as well as their causes or consequences, for example infections, stones or kidney damage.

The compounds of the invention may be presented in any form of composition suitable for enteral or parenteral administration, such as tablets, drops, capsules, capsules, suspensions or solutions for oral or injectable use such as syrups or ampoules, etc., combined with suitable excipients, and dosed to allow a daily dose of 0.005 to 20 mg/kg.

Claims (12)

1. Compound, in the form of a pure enantiomer or a mixture of enantiomers, of a general formula (I) in which - What?

   R1 is a methoxy or cyclopropyl methoxy group,

   R2 is an atom of hydrogen, chlorine or bromine, or

   R1 and R2 together form, and in that order, a group of the formulas -O-CH2-O-, -O- (CH2) 2-, -O- (CH2) 2-O- or -O- (CH2) 3-O-,

   R3 represents a hydrogen atom or an amino group, and

   R4 is a hydrogen, chlorine or bromine atom in the free base state or as an acid addition salt.
2. Compound according to claim 1, characterised by R3 representing an amino group and R4 representing a chlorine atom.
3. Composed according to claim 1, in this case (+)-8-amino-7-chloro-N-[(1,4-diazabicyclo[2.2.2]oct-2-yl) methyl]-2,3-dihydro-1,4-benzodioxin-5-carboxamide, as a free base or as an acid addition salt.
4. Composed according to claim 1, in this case (-)-8-amino-7-chloro-N-[(1,4-diazabicyclo[2.2.2]oct-2-yl) methyl]-2,3-dihydro-1,4-benzodioxin-5-carboxamide, in the free base state or as an acid addition salt.
5. Composed according to claim 1, in this case (+) -4-amino-5-chloro -2-(cyclopropylmethoxy) -N-[(1,4-diazabicyclo[2.2.2]oct-2-yl) methyl]benzamide, in the free base state or as an acid addition salt.
6. Composed according to claim 1, in this case (-)-4-amino-5-chloro -2-(cyclopropylmethoxy) -N-[(1,4-diazabicyclo[2.2.2]oct-2-yl) methyl]benzamide, in the free base state or as an acid addition salt.
7. Composed according to claim 1, in this case (-)-8-amino-7-bromo-N-[(1,4-diazabicyclo[2.2.2]oct-2-yl) methyl]-2,3-dihydro-1,4-benzodioxin-5-carboxamide, in the free base state or as an acid addition salt.
8. Composed according to claim 1, in this case (-)-9-amino-8-chloro-N-[(1,4-diazabicyclo[2.2.2]oct-2-yl) methyl]-3,4-dihydro-2H-1,5-benzodioxepine-6-carboxamide, as a free base or as an acid addition salt.
9. Process for preparation of a compound according to claim 1, characterised by the reaction of a protected aminomethyloxyirane of formula (II) in which Pht represents a phthalimide group, with a protected piperazine of formula (III) where Bn is a benzyl group, to obtain the alcohol of formula (IV) is reacted with methanesulfonyl chloride in the presence of triethylamine and then the resulting compound of formula (V) is heated for the production of quaternary ammonium of formula (VI) then the latter is debenzyled by catalytic hydrogenation to obtain the compound with formula (VII) then the latter is de-protected by hydrazine hydrate to obtain the amine of formula (VIII) And finally we react this compound with an acid of general formula (IX) wherein R1, R2, R3 and R4 are as defined in claim 1.
10. Processed according to claim 9, characterised by the reaction of one of the enantiomers of 2,2-dimethyl-1,3-dioxolan-4-methanol with methanesulfonyl chloride to obtain the corresponding methanesulfonate of (2,2-dimethyl-1,3-dioxolan-4-ylindo) methyl, then treatment of the latter with potassium phthalate to obtain the corresponding [2,2-dimethyl-1,3-dioxolan-4-methanol]-1-1,2-H-dioxolan-1,3-dioxolan-4-methanol, then reaction of the latter with the corresponding benzoyl-hydroxybromide to obtain the corresponding 2-dioxybromide, and finally reaction of the latter with 2-dioxybromide to obtain the corresponding 2-dioxybromide, 2-dioxyl-methanol, 2-dioxybromide, 2-dioxybromide, 2-dioxyl-methanol, 2-dioxybromide, 2-dioxybromide, 2-dioxybromide, 2-dioxyl-methanol, 2-dioxybromide, 2-dioxybromide, 2-dioxyl-methanol, 2-dioxybromide, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-methanol, 2-dioxybromethyl-met
11. A medicinal product characterised by the fact that it consists of a compound as claimed 1.
12. Pharmaceutical composition characterised by the presence of a compound as claimed 1, combined with an excipient.