NO863924L - INTERMEDIATES FOR USE IN THE PREPARATION OF THERAPEUTICALLY EFFECTIVE BENZAMIDE DERIVATIVES. - Google Patents

Description

The present invention relates to new intermediates for use in the production of therapeutically effective benzamide derivatives.

Mentioned benzamide derivatives are suitable for use in the treatment of nausea and vomiting, psychosomatic diseases and psychiatric disorders.

Sulpiride (US patent 3,342,826) with the following formula

is an antipsychotic that has recently been marketed. Sulpiride causes weak extrapyramidal side effects in humans and weak catalepsy in experimental animals. US patent 4,232,037 describes antipsychotic compounds with the following formula where R 1 is an alkyl group with from 1 to 3 carbon atoms, R<9> and R 3 are the same or different and each is hydrogen, chlorine or bromine. Among these compounds, a compound with the following formula is described and which is given the designation FLA 731. The compounds according to US patent 4,232,037 have a less effective antipsychotic effect than compounds according to the present invention. The present invention relates to compounds with the formula

1 2

where R and R are the same or different and each may represent a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group or an alkyl group, R 3 is a lower alkyl group; an alkenyl group-; or a benzyl group optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, lower alkyl or lower alkoxy, A 1 and A<2> are the same or different and each may represent a hydrogen atom, a lower alkyl group, an alkyl group, an alkoxycarbonyl group or a dialkylcarbamyl group, provided that when A 1 and A<2> are the same lower alkyl group and R 3 is ethyl, then R 1 or R 2 or both are selected from the group consisting of cyano, lower alkyl and alkyl. The invention further provides physiologically acceptable salts or isomers of such compounds.

Said compounds have been found to have valuable properties

therapeutic properties.

The invention thus provides compounds and their physiologically acceptable salts which can be used in the therapeutic treatment of nausea and vomiting, of psychosomatic diseases such as stomach ulcers and duodenal ulcers, and for psychiatric disorders such as depressions, nervous disorders and more particularly psychosis, e.g. schizophrenia.

Halogen atoms in formula I include chlorine, bromine,

iodine and fluorine atoms.

Lower alkyl groups in formula I are straight or branched alkyl groups with from 1 to 5 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, pentyl, 2-methylbutyl and 2,2-dimethylpropyl.

Alkyl groups in formula I are the groups alkyl-CO-, where the alkyl group is as defined as the lower alkyl groups above.

The alkenyl groups in formula I are straight or branched hydrocarbon chains with from 1 to 5 carbon atoms and contain one, two or more double bonds, e.g. vinyl, allyl, isopropenyl, but-2-ethyl, buta-1,3-dienyl and pent-2-enyl.

Lower oxy groups in formula I are groups with the formula alkyl-O-, where the alkyl group is as defined as the lower alkyl groups above.

The alkoxycarbonyl groups in formula I are groups with the formula alkyl-0-CO-, where the alkyl group is as defined for lower alkyl groups above.

The dialkylcarbamyl groups in formula I are groups of the formula (alkyl)2-N-CO-, where the alkyl group is as defined as the lower alkyl groups above.

The first preferred subgroup of compounds according to the present invention is obtained when R 1 and R 2 in formula I are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group or an alkyl group, R 2 is a lower alkyl group; an alkenyl group or an optionally substituted benzyl group, and one of the groups A<1> and A 2 is a lower alkyl group while the other is a hydrogen atom.

Within the first-mentioned subgroup of compounds of formula I, those are preferred where R<1>is bromine or chlorine and R<2>is hydrogen or bromine, R<3>is ethyl and one of the groups A and A 2 is methyl or ethyl while the other is hydrogen.

Another preferred subgroup of compounds according to the present invention are those of formula I where R1 and R2 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group or an alkyl group, R<3> is a lower alkyl group; an alkenyl group or an optionally substituted benzyl group, and where one of the groups A<1> and A 2 is a lower alkyl group while the other is an alkyl group, an alkoxycarbonyl group or

a dialkylcarbamyl group.

Within this second subgroup of compounds of formula I, those are preferred where R<1>is bromine, R<2>is hydrogen, 3 1 2

■ .R is ethyl, A is methyl and A is acetyl, ethyloxycarbonyl or dimethylcarbamyl.

A third preferred subgroup of compounds according to the present invention is obtained when in formula I R 1 and R 2 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group or an alkyl group, A<1> and A 2 are the same or different and each represents a hydrogen atom, a lower alkyl group, an alkyl group, an alkoxycarbonyl group or a dialkylcarbamyl group, and R 3 is a lower alkyl group other than ethyl, or an alkenyl group or an optionally substituted benzyl group.

Within this third subgroup of compounds of formula I, those where R<1> is chlorine or bromine, R<2> are preferred

12 3

is hydrogen, A is methyl, A is methyl and R is methyl, n-propyl, allyl or benzyl.

The new compounds according to the invention can be used therapeutically as racemic mixtures of (+) and (-) forms, as they are obtained by synthesis. They can also be dissolved into their corresponding enantiomers which can be similarly used in therapy. Said (+) and (-) forms can also be obtained by reacting the corresponding enantiomeric 2-(aminomethyl)-1-alkyl/alkenylpyrrolidine with the benzoic acid group. The compounds according to the invention can be supplied in the form of free bases or their salts with non-toxic acids. As typical examples of these salts, mention may be made of hydrobromide, hydrochloride, phosphate, sulphate, sulphonate, citrate, lactate, maleate and tartrate.

In clinical practice, compounds according to the invention will normally be administered orally, rectally or by injection in the form of pharmaceutical preparations which include the active ingredient, either as a free base or as a pharmaceutically acceptable non-toxic acid addition salt, e.g. as a hydrochloride, hydrobromide, lactate, acetate, sulfate, sulfamate and the like, together with a pharmaceutically acceptable carrier or diluent. Terms which thus relate to the new compounds according to the present invention, whether this applies generally or more specifically, include both the free amine base and their acid addition salts, if nothing else is indicated in the specific examples.

The carrier may be solid, semi-solid or liquid, or it may be in the form of a capsule. These pharmaceutical preparations form part of the invention. Generally, the active ingredient will constitute from 0.1 to 99% by weight of the preparation, more

in particular between 0.5 and 20% by weight for preparations used for injection, and between 2 and 50% by weight for preparations suitable for oral administration.

To prepare pharmaceutical preparations containing a compound according to the present invention in the form of dosage units for oral use, the selected compound can be mixed with a solid powdered carrier, e.g. lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives or gelatin, as well as a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol wax and the like, and then pressed into tablets. If coated tablets are desired, the prepared cores can be coated with a concentrated sugar solution which can e.g. contain gum arabic, gelatin, talc, titanium dioxide and the like. Alternatively, the tablet can be coated with a varnish dissolved in a slightly volatile organic solvent or mixture of organic solvents. Dyes can be added to these coatings so that one can easily distinguish between tablets containing different active ingredients or different amounts of the active compound.

For the production of soft gelatin capsules (bead-shaped closed capsules) consisting of gelatin and e.g. glycerol or similar closed capsules, then the active compounds can be mixed with a vegetable oil. Hard gelatin capsules may contain granules of the active compound in combination with solid powdered carriers such as lactose, sucrose, sorbitol, mannitol, starch (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal use can be prepared

in the form of suppositories containing the active ingredient mixed with a neutral fat base or gelatin rectal capsules containing the active compound mixed with a vegetable oil or paraffin oil.

Liquid preparations for oral use can be in the form of syrups or suspensions, e.g. solutions containing from 0.2 to 20% by weight of the active ingredient, and where the remainder is sugar and a mixture of ethanol, water, glycerol or propylene glycol. Optionally, such liquid preparations may also contain colourants, flavourings, saccharin and carboxymethyl cellulose as a thickening agent.

Solutions for parenteral application by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active compound, preferably in a concentration from approx. 0.5 to approx. 10% by weight. These solutions may also contain stabilizers and/or buffers and can suitably be filled into ampoules of different sizes.

Suitable peroral daily doses of compounds according to the present invention are from 100 to 500 mg, preferably 200-300 mg.

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Compounds according to the present invention can be prepared using one of the following methods. A. Compounds with the following formula

where R 1 and R 2 are the same or different, and each represents a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group or an alkyl group, R"^ is a lower alkyl group; an alkenyl group; or a benzyl group optionally substituted with fluorine, chlorine, bromine , trifluoromethyl, lower alkyl or lower alkoxy, A<1> and A 2 are the same or different and each represents a hydrogen atom, a lower alkyl group, an alkyl group, an alkoxycarbonyl group or a dialkylcarbamyl group, provided that when A 1 and A<2> are the same lower alkyl group and R 3 is ethyl, then R 1 or R 2 or both are selected from the group consisting of cyano, lower alkyl and alkyl, can be prepared by reacting a compound with the formula where R 1, R 2 , A<1> and A<2> are as defined above, and -CO-Z is a reactive group capable of reacting with an amino group during the formation of an amide group, with a compound of formula

where R 3 has the same definition as stated above, or a reactive derivative of such a compound.

The reaction is carried out in a suitable solvent such as diethyl ether, acetone, methyl ethyl ketone, chloroform or toluene between 0°C and the boiling point of the reaction mixture. The resulting amine hydrochloride salt can be readily recovered, e.g. by filtration. Alternatively, the produced salt can be dissolved in water and converted to the free base in a commonly known manner, e.g. by adding a sodium hydroxide solution.

Z in the alkylation group -CO-Z can be a halogen atom, e.g. chlorine or bromine, a hydroxy group or an organic residue.

The organic residue includes groups that can form reactive acid derivatives, this can e.g. be carboxylic acid esters, e.g. methyl, ethyl, propyl, butyric acid, isobutyric acid, and pentyl esters or comparable reactive esters, e.g. cyanomethyl or methoxymethyl ester, N-hydroxyimido ester or substituted or unsubstituted aromatic esters; acid hydrazides, acid azides, symmetrical anhydrides, mixed anhydrides e.g. prepared with lower alkyl halogen formates; azolides, e.g. triazolide, tetraazolide or imidazolide, or acid isocyanates.

According to the present invention, the following compounds can be used as reactive derivatives of the amine with formula III: Reaction products of the amine with phosphorus chloride, phosphorus oxychloride, dialkyl, diaryl or o-phenylene chlorophosphites or alkyl or aryl dichlorophosphites or an isothiocyanate of the amine. The aforementioned reactive derivative can be reacted with acid in situ or after a previously carried out isolation.

It is also possible to react the free acid and the free amine in the presence of a condensing agent, e.g. silicon tetrachloride, diphosphorus pentoxide or carbodiimides such as dicyclohexylcarbodiimide, N,N<1->carbonyldiimidazole, N,N'-thionyldiimidazole and diethyldiazodicarboxylate.

B. Compounds with the following formula

12 3 1 2 where R , R , R , A and A are as indicated above, can be prepared by N-alkylating a compound with the formula

12 1 2

where R , R , A and A are as defined above, with a compound of the formula

R<3->X

where R 3 is as defined above, and X is chlorine, bromine, sulfate, phosphate, benzenesulfonate or toluenesulfonate.

The reaction can be carried out by treating the reactants at 50-100°C in a suitable solvent, e.g. acetone, alcohols, dimethylformamide (DMF), dimethylsulfoxide (DMSO) in the presence of a base, e.g. NaOH or K 2 CO 3 .

C. Compounds with the following formula

12 3 1 2 where R , R , R , A and A are as defined above, can be prepared by reacting a compound with the formula 12 1 2 where R , R , A and A are as defined above, and Hal is chlorine or bromine, with a compound of the formula

3

'where R is as defined above.

The reaction is carried out with the amine in excess, either without solvent or with a suitable solvent, such as lower alcohols, halogenated aliphatic hydrocarbons, DMF, DMSO at temperatures from 0°C to 100°C.

D. Compounds with the formula

12 3 12 where R , R , R , A and A are as defined above, can be prepared by reducing a compound with the formula

12 12' 31

where R , R , A and A are as defined above, and R means the same as R 3 , but that there is one less carbon atom.

Suitable reducing agents which act on the less sterically hindered amide group are a) LiAlH^ and alkoxy complexes thereof; b) NaBH^ with the addition of transition metal salts, or AlC 13 or BF^ or POC 13 or carboxylic acids such as CH 3 COOH and CF 3 COOH; c) ^ 2U6'

The reaction is carried out in alkyl ethers such as diethyl ether, dimethoxyethane, diglyme, THF, dioxane, at temperatures from 0°C to the boiling point of the reaction mixture.

E. Compounds with the formula

where R 1 , R 2 and R<3 > are as defined above, and A 1 " and/or A 2 " is a hydrogen atom and the other, when this is necessary, is a lower alkyl group, can be prepared by dealkylating with a protonic acid or a Lewis acid, a compound of the following formula 12 3 1 ' 2 ' where R , R and R are as defined above, and A and A are lower alkyl groups.

Suitable protonic acids are e.g. HBr and HI.

Suitable Lewis acids are BBr3, BC13, BF3, A1C13 and AlBr_.

Via selective dealkylation, one of the groups A and A (A and A is alkyl) in formula IV can be transferred to a hydrogen atom. In a selective dealkylation, an equivalent amount of the dealkylating agent must be used.

-ti 2 1 1 1 2'

Otherwise, both A and A (A and A are alkyl) in formula IV can be transferred in the same reaction step to hydrogen atoms. In such a method, an excess of the dealkylating agent is used.

The reaction is carried out between 0 and 20°C in a halogenated lower aliphatic hydrocarbon, such as methylene chloride or chloroform. In this case, it is preferred to use hydrogen halide acetic acid as solvent and the reaction is carried out at elevated temperatures.

F. Compounds with the following formula

3 12 1 where R , A and A are as defined above, and R and/or R 2 'is a halogen atom, a lower alkyl group, an alkyl group or a cyano group, while the other, when necessary, is a hydrogen atom, can be prepared by halogenating with a halogen or a halogen-dioxane complex, or reacting with an alkyl halide with a Lewis acid catalysis or reacting with an alkyl halide with a Lewis acid catalysis or reacting with a cyanogen halide with a Lewis acid catalyst respectively, a connection with the following formula

where R 3 , A 1 and A 2 are as defined above.

The introduction of a cyano group is carried out by adding . trichloroacetonitrile or cyanogen halide in the presence of a Lewis acid.

Chlorination is carried out by heating the starting compound with chlorine with or without a Lewis acid catalysis or with HOCl, N-chloramides in the presence of an acid catalyst, and this is carried out in a suitable solvent such as chloroform, nitrobenzene etc.

Bromination is carried out with Br2 with or without a Lewis acid catalyst, or bromination is carried out in acetic acid in the presence of a base such as sodium acetate or by using a bromine-dioxane complex. Other reagents that can be used are HOBr and N-bromamides, especially N-bromosuccinimide with acid catalysis.

Acylations, alkylations and introduction of a cyano group are carried out using the well-known Friedel-Craft methods.

G. Compounds with the following formula

3 12 1 " where R , A and A are as defined above, and R and/or R 2 " is halogen or cyano, while the other, when necessary, is a hydrogen atom, can be prepared by reacting in a first step with NaN02 and in a second step with copper halide or copper cyanide in a compound with the following formula 3 12 12 where R , A and A are as defined above, and D and D are the same or different and each represents a hydrogen atom or an amino group, and where at least one of the groups 1 2

D and D is an amino group.

Diazotization is carried out in water at 0°C with NaNO_ in near-1 " 2 1

be of a mineral acid. Compounds where R and R are Cl,

Br or CN is prepared by using Sandmeyer's reaction with CuBr, CuCl or CuCN. Compounds where R and/or R is fluorine can be prepared by heating the corresponding di-azonium tetrafluoroborate salt in a dry state (Schiemann reaction).

Introduction of a cyano group is carried out as described in method F.

H. Connections with the formula

1 2 3 1 " 2 " where R , R , R , A and A are as defined above, can be prepared by reacting a compound with the formula 12 3 • where R , R and R are as defined above, with a compound with the formula;

where A 1 'is a lower alkyl group and B is -(SO^).^.,, - (PO^) ^ ^ or halogen.

The reaction is carried out selectively in a suitable solvent such as acetone, DMF, at elevated temperatures with an equivalent alkylating agent in the presence of a base such as an alkali metal carbonate or hydroxide.

I. Compounds with the formula

where R 1 , R 2 and R 3 are as defined above, and A 1 1 " and/or 2 1 " A is an alkyl group, an alkoxycarbonyl group or a dialkylcarbamyl group, while the other, when necessary, is a lower alkyl group, can be prepared by reacting a compound with the formula 1 2 3 1 " 2" where R , R , R , A and A are as defined above, with a compound of the formula

where R is an alkyl, alkoxy or dialkylamino group, and

Z' is Cl or Br.

in ii2'"

Compounds where A and/or A is alkyl can be prepared by reaction with a suitable acid anhydride with a solvent or in a suitable solvent such as benzene or chloroform with acid catalysis or by using a tertiary amine as solvent and/or catalyst.

The alkoxycarbonyl group and the alkylcarbamyl group are introduced by a reaction with a corresponding halide in a suitable . solvent in the presence of a tertiary amine.

Between^r^d^kter^

Connections with the formula

1 2 where R and R are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group or an alkyl group, and A<1> and A<2> are the same or different and each represents a hydrogen atom, a lower alkyl group, an alkyl group, an alkoxycarbonyl group or a dialkylcarbamyl group, provided that when 12 1 2 both A and A are a lower alkyl group, then R and R are selected from the group consisting of cyano, lower alkyl and alkyl, and further provided that when R 1 /R 2 is H, Cl or 12 1

Br and A /A is H or CH~, then the substituent on R is different from the substituent on R 2 and the substituent on A 1 is different from the substituent on A 2 are valuable intermediates for the preparation of compounds according to the present invention by means of method A .

The intermediate benzo acids can be prepared by reacting a compound with the formula

in the following way:

12 a) when R and/or R is Cl or Br: by chlorinating or brominating, e.g. as described under method F above; b) when R 1 and/or R 2 is F: by fluorination, e.g. as described under method G above; c) when R 1 and/or R 2 is lower alkyl or alkyl: by reacting with an alkyl halide or an alkyl halide, e.g. as described under method F above; d) when R 1 and/or R 2 is cyano, by reacting with a cyanogen halide or trichloroacetonitrile with Lewis acid catalysis as described under method F above.

Any of the free acids can be converted into a compound of formula II by esterification, e.g. to an alkyl halide, an alkyl anhydride, a haloformic acid ester or a di-alkylcarbamyl halide.

Particularly preferred intermediates are those with the following formulas

Examples

Example_el_1_

N-ethyl-2-(3-bromo-2,6-dihydroxybenzamidomethyl)-pyrrolidine.

5.0 g (0.0118 mol) of N-ethyl-2-(3-bromo-2,6-dimethoxy-benzamidomethyl)pyrrolidine in 125 ml of methylene chloride was added dropwise to 7 ml (0.07 mol) of boron tribromide. The reaction mixture was left at room temperature for 9 days. It was then washed with 2M NH 4 and water, dried over sodium sulfate after which the solvent was evaporated. The residue was recrystallized from ethanol. Yield 0.3 g. Melting point 166-168°C.

Example_el_2

N-ethyl-2-(3-bromo-2-hydroxy-6-methoxybenzamidomethyl)-pyrrolidine.

5.0 g (0.0118 mol) N-ethyl-2-(3-bromo-2,6-dimethoxy-benzamidomethyl)pyrrolidine hydrochloride in 125 ml methylene chloride

1.3 ml (0.0135 mol) of boron tribromide was added. A white precipitate was obtained. The reaction mixture was left for 2 hours at room temperature with stirring. It was then washed with 2M ammonia and then with water after which the organic phase was dried over sodium sulphate. Evaporation gave 4.1 g of product which was recrystallized from ethanol. Yield 2.0 g (48%). Melting point 68.8-69.4°C.

Example_el_3

(-)-N-ethyl-2-(3-bromo-2-hydroxy-6-methoxybenzamidomethyl)-pyrrolidine hydrochloride. 10.0 g (0.025 ml) of (-)-N-ethyl-2-(3-bromo-2,6-dimethoxy-benzamidomethyl)pyrrolidine was dissolved in . 250 ml of methylene chloride and 2.6 ml of 0.027 mol boron tribromide were added. The mixture was left overnight at room temperature and was then washed with 2N ammonia, dried over sodium sulfate and evaporated after addition of hydrochloric acid and ether. The residue was dissolved in water and extracted with ether. The ether phase was made alkaline with ammonia and then extracted with chloroform. The chloroform phase was dried over sodium sulfate and evaporated. Hydrochloric acid and ether were added to the residue, the salt was filtered off, washed with ether and dried over ^ 2^ 5' Melting Point *• Sintering at 100°C. Yield 6.6 g. Hygroscopic ^7^° = -45'5° (base). Example_4 (-)-N-ethyl-2-(3-chloro-2-hydroxy-6-methoxybenzamidomethyl)-pyrrolidine hydrochloride. 9.1 g (0.025 mol) (-)-N-ethyl-2-(3-chloro-2,6-dimethoxy-benzamidomethyl)pyrrolidine was dissolved in 250 ml of methylene chloride. 2.6 ml (0.027 mol) boron tribromide was added, the mixture was left overnight at room temperature and then washed with 2 x 100 ml 2N ammonia and 100 ml water, dried over sodium sulfate and evaporated. The residue was dissolved in dilute hydrochloric acid and extracted with ether. The aqueous phase was made alkaline with ammonia and extracted with chloroform. The extract was dried over sodium sulfate and evaporated. The residue was dissolved in ether after which HCl and ether were added. The precipitate was filtered off and dried over P2°5*Melting point: Sintering at 100°C. Yield 7.4 g. /α7p° = -51.4° (2% ethanol; pH 10.3).

N- ethyl- 2-( 3- bromo- 6- ethoxy- 2- hydroxybenzamidomethyl) pyrrolidine.

5.0 g (0.0115 mol) of N-ethyl-2-(3-bromo-2,6-diethoxybenzamidomethyl)pyrrolidine hydrochloride was dissolved in 125 ml of methylene chloride. 1.25 ml (0.013 mole) of boron tribromide was added, and

the mixture set aside for 2 hours at room temperature. It was then washed with 2M ammonia and then with water. The organic phase was dried over sodium sulfate and evaporated. The oily base was crystallized after treatment with petroleum ether. The precipitate was filtered off and recrystallized from ethanol. Melting point 83-83.5°C. Yield 2.4 g (56%).

Example 6 (-)-N-ethyl-2-(3-bromo-6-ethoxy-2-hydroxybenzamidomethyl)-pyrrolidine.

10.0 g (0.023 mol) of (-)-N-ethyl-2-(3-bromo-2,6-diethoxy-benzamidomethyl)pyrrolidine was dissolved in 250 ml of methylene chloride, and 2.4 ml (0.025 mol) of boron tribromide was added. The mixture was left overnight at room temperature and then washed with 2N ammonia. The extract was dried with sodium sulfate and evaporated. The oily residue crystallized after a while. Petroleum ether was added to the product which was filtered off. Yield 7.0 g. Melting point 74-76°C. /a7p°

-66.7° (1% acetone).

Example 7 (-)-N-ethyl-2-(3,5-dibromo-2-hydroxy-6-methoxybenzamidomethyl)-pyrrolidine hydrochloride.

44.0 g (10.1 mol) (-)-2-(aminomethyl)-1-ethylpyrrolidine-(-)ditartrate was dissolved in 200 ml of 20% sodium hydroxide. The mixture was then extracted with 2 x 100 ml chloroform, and

the extract was dried with chloroform.

34.0 g (0.1 mol) of 3,5-dibromo-2,6-dimethoxybenzoic acid was added to 40 ml of thionyl chloride and 300 ml of toluene. The mixture was heated with stirring on a steam bath for 30 minutes. The toluene and excess thionyl chloride were evaporated. The residue was added to the above chloroform extract. The mixture was then heated for 10 minutes on a steam bath. The chloroform was then evaporated, and the residue dissolved in dilute hydrochloric acid and the mixture extracted with ether. The water phase was cooled and made

alkaline with NaOH, and the resulting precipitate was filtered off, dissolved in 500 ml of methanol, acidified with HCl ether and evaporated. A yield of 32.0 g (0.065 mol) of (-)-N-ethyl-2-(3,5-dibromo-2,6-dimethoxybenzamidomethyl)pyrrolidine hydrochloride was obtained. The 0.065 mol product was dissolved in 500 mL of CHCl 3 , and then 6.3 mL (0.065 mol) of boron tribromide was added. The mixture was left overnight at room temperature and then washed with 2N ammonia and then with water. The organic phase was dried with sodium sulfate and evaporated. The residue was dissolved in 400 ml of petroleum ether, and the undissolved residue was filtered off. The ether was evaporated, and the residue dissolved in ether and acidified with hydrochloric acid and ether. The precipitate was filtered off and dried over P2°5" yield 27.3 g. Melting point after sintering. /a7^° -8.6° (2% H 2 O) .

Example_el_8

N-ethyl-2-(2-acetoxy-3-bromo-6-methoxybenzamidomethyl)pyrrolidine.

A suspension of 2-6-dimethoxybenzoic acid (80 g, 0.44 mol) in 1.5 L of dry chloroform was added dropwise with stirring to a solution of 70.4 g of bromine in 100 ml of dry chloroform over 3 hours at 0° C. The solution was then allowed to slowly warm to room temperature over 20 hours. The solvent was evaporated in vacuo and the remaining crystalline mass was recrystallized from methanol to 3-bromo-2-hydroxy-6-methoxybenzoic acid. Yield 82 g (76%). Melting point 143-144°C.

24.6 g 0.1 mol 3-bromo-2-hydroxy-6-methoxybenzoic acid

was dissolved in 50 ml of acetic anhydride. A few drops of concentrated sulfuric acid were added and the mixture heated to 60°C over 20 hours. After cooling, approx. 100 mg sodium bicarbonate added and then ice water. The solvents were then evaporated under reduced pressure. The residue was crystallized from diisopropyl ether, and 34.5 g (85%) of the desired acetoxy acid was obtained. Melting point 146-147°C.

The aforementioned acetoxy acid (5.8 g, 20 mmol) was dissolved in 30 ml of thionyl chloride. The solution was stirred at room temperature for 20 hours, after which the solvent was evaporated and dry toluene was distilled from the residue twice. The resulting acid chloride weighing 6 g was used in the next step without further purification.

The above impure acid chloride was dissolved in 50 mL of dry toluene, and to the solution was added 1-ethyl-2-(aminomethyl)-pyrrolidine (2.6 g, 20 mmol) in 10 mL of dry toluene at room temperature. Stirring was continued overnight. The precipitate was filtered off and washed with dry toluene and then dried. The impure amine hydrochloride was then recrystallized from acetone to give the desired amine salt as white crystals.

Yield 7.2 g (83%). Melting point 156°C (decomposition).

Eczema<p>_<e>l_9

. N-ethyl-2-(3-bromo-6-hydroxy-2-methoxybenzamidomethyl)pyrrolidine.

A solution of N-ethyl-2-(2,6-dimethoxybenzamido-methyl)-pyrrolidine hydrochloride (23.0 g, 0.07 mol) in 300 ml of dry dichloromethane was added dropwise with stirring to a solution of 17.5 g , 0.07 mol of boron tribromide in 25 ml of dry dichloromethane at 0°C. After the addition, the solution was allowed to warm to room temperature overnight. Water was added and the pH adjusted to 7. The organic layer was washed with water and dried over magnesium sulfate. The solvent was evaporated in vacuo to give the title compound as a viscous oil weighing 20 g. The product was found to be sufficiently pure by TLC and GC analysis to be used in the next step without further purification.

Eng.

A solution of bromine (4.3 g, 27 mmol) in 10 ml of glacial acetic acid was added dropwise with stirring to a solution of the aforementioned impure amine (7.5 g, 27 mmol) in 100 ml of glacial acetic acid at room temperature. Stirring was continued for 15 hours. The solvent was evaporated in vacuo and 8.5 g of a viscous oil was obtained. This product was analyzed by GC (3% OV-17) and constituted 10% of the above 2-methoxy-3-bromo-6-hydroxy substituted isomer and 90% of the 2-hydroxy-3-bromo-6-methoxy substituted isomer. The desired phenol isomer was isolated using preparative thin layer chromatography (SiO 2 , CHCl 2 + EtOH + conc. NH 3 , 97 + 3 + 0.1). The solvent was evaporated in vacuo and the residue

•.oil crystallized on standing. Yield 0.75 g. Recrystallization from n-hexane gave the pure title compound, yield 0.6 g (6.5%). Melting point 62-63°C. Example_<el_>_0 (-)-N-n-propyl-2-(3-bromo-2,6-dimethoxybenzamidomethyl)-pyrrolidine. The title compound was prepared from 3-bromo-2,6-dimethoxybenzoic acid via the alkyl chloride and (-)-1-n-propyl-2-(aminomethyl)pyrrolidine in the same manner as described in example 8. Yield 79%. Melting point 103-10.4°C. Ia7^ ° = -85.4°C(c = 0.5; CHCl3).Exemgel__<M>(-)-N-ethyl-2-(3,5-dichloro-6-hydroxy-2-methoxybenzamidomethyl)- pyrrolidine.

The title compound was prepared from (-)-N-ethyl-2-(3,5-dichloro-2,6-dimethoxybenzamidomethyl)pyrrolidine by dealkylation in the same manner as stated in Example 2. Yield 37%. Melting point 48-49°C (i-octane). Z 7p 5 = -64°C (c = 1.26; CHCl 3 ). (-)-N-n-propyl-2-(3-bromo-2-hydroxy-6-methoxybenzamidomethyl)-pyrrolidine hydrochloride.

The title compound was prepared from (-)-N-n-propyl-2-(3-bromo-2,6-dimethoxybenzamidomethyl)pyrrolidine by dealkylation in the same manner as stated in Example 2. Yield 48%. Melting point (HCl) 140-141°C (acetone).

/_7q5= -78°C (c = 0.80, EtOH) base. (-)-N-benzyl-2-(3-bromo-2-hydroxy-6-methoxybenzamidomethyl)-pyrrolidine hydrochloride.

The title compound was prepared from (-)-N-benzyl-2-(3-bromo-2,6-dimethoxybenzamidomethyl)pyrrolidine by dealkylation in the same manner as described in Example 2. Yield 55%. Melting point (HCl) 207-209°C (EtOH).

Example_el__<4>. (-)-N-n-propyl-2-(3-bromo-6-hydroxy-2-methoxybenzamidomethyl)-pyrrolidine hydrochloride.

The title compound was prepared from (-)-N-n-propyl-2-(3-bromo-2,6-dimethoxybenzamidomethy1)pyrrolidine by dealkylation in the same manner as described in Example 2. Yield 55%. Melting point (HCl) 137-138°C (acetone).

__7<q>5 = -68°C (c = 0.12; MeOH).

Table I provides an overview of physical data for compounds prepared as indicated in the previous examples.

Compounds prepared as indicated in the preceding examples were examined by means of nuclear magnetic resonance spectra. These data were consistent with the stated structure.

Exe<_>£el__5

The following examples illustrate the preparation of pharmaceutical preparations according to the invention. The term "active ingredient" means a compound according to the present invention or a salt thereof, preferably the compound N-ethyl-2-(3-bromo-2-hydroxy-6-methoxy-benzamidomethyl)-pyrrolidine or the 3-bromo-6- the hydroxy-2-methoxy substituted isomer.

Preparation A. Soft gelatin capsule.

500 g of the active ingredient was mixed with 500 g of corn oil, after which the mixture was filled into soft gelatin capsules, each capsule containing 100 g of the mixture (i.e.

50 mg active ingredient).

Preparation B. Soft gelatin capsule.

500 g of active ingredient was mixed with 750 g of peanut oil, after which the mixture was filled into soft gelatin capsules, and each capsule contained 125 mg of the mixture (ie 50 mg of active ingredient).

Preparation C. Tablets.

50 kg of active ingredient was mixed with 20 kg of silicic acid of the brand name Aerosil. 45 kg of potato starch and 50 kg of lactose were mixed with the above mixture, and the whole was moistened with a paste prepared from 5 kg of potato starch and distilled water, after which the mixture was granulated through a sieve. The granules were then dried and sieved, after which 2 kg of magnesium stearate was added. Finally, the mixture was pressed into tablets each weighing 172 mg.

Preparation D. Effervescent tablets.

100 g of active ingredient, 140 g of finely divided citric acid, 100 g of finely divided sodium bicarbonate, 3.5 g of magnesium stearate and flavorings (k.s.) were mixed, and the mixture was pressed into tablets each containing 100 mg of active ingredient.

same

Preparation E. Delayed-release tablets.

200 g of active ingredient was fused with 50 g of stearic acid and 50 g of carnuba wax. The prepared mixture was cooled and ground to a particle size with a diameter of approx. 1 mm. The prepared mixture was then mixed with 5 g of magnesium stearate and pressed into tablets each weighing 305 mg. Each tablet thus contained 200 mg of active ingredient.

Preparation F. Injection solution.

Pharmacology.

A number of studies suggest that the antipsychotic action of neuroleptic compounds is somehow related to the reduction of catecholamine transmission that occurs in the brain due to these compounds, and more specifically to a central dopamine (DA) receptor blockade in the cerebral cortex itself or the subcortex of the brain. Most compounds with an antipsychotic effect affect multiple DA systems in the brain. There is much evidence that the antipsychotic effect can be associated with a blockade of the DA receptors in the subcortex or in the limbic structure of the cortex itself (J. Pharm. Pharmacol. 2_5 , 346 , 1 973; Lancet, Nov. 6_, 1027, 1976 ), while the well-known extrapyramidal side effects that are often experienced in connection with neuroleptic drugs are due to a blockade of the DA receptors in the nigroneostriatal DA system (Intern. J. Neurol. 6_, 27-45 , 1 967).

Many types of technique are currently available

to investigate DA receptor blockade in the brain in vivo. One method is based on the fact that the antipsychotic compounds have an ability to block the behavioral effects induced by the DA agonist apomorphine in rats. Several investigations indicate an excellent correlation between an in vivo DA receptor blockade as measured in the apomorphine test and the therapeutic effect of various antipsychotic compounds. Apomorphine causes in rats and other mammals a characteristic syndrome consisting of repetitive movements (stereotypy) and a hyperactivity which seems to be due to an activation of the postsynaptic DA receptors in the brain (J. Pharm. Pharmacol. _9 , 627 , 1967; J. Neurol. Transm. 4_0 , 97-1 1 3, 1 977). These repetitive movements (stereotypes) such as chewing, biting and licking appear to be essentially induced via the activation of DA receptors which are connected to the neostriatal DA system (J. Psykiat. Res., __, 1, 1974), while the increased hyperactivity essentially seems to be due to an activation of DA receptors in the mesolimbic structures (nucleus olfac-torium, nucleus accumbens), i.e. in the mesolimbic DA system (J. Pharm. Pharmacol. 2_5, 1003, 1 973).

A number of investigations have shown that neuroleptics of different structural types block apomorphine stereotypies in rats, and that this blockade is well correlated with a blockade of DA transmission as this can be measured using biochemical or neurophysiological techniques. The antiapomorphine technique is thus well correlated with changes in the combustion of the DA produced by the neuroleptic compounds (Eur. J. Pharmacol., 303, 1970), DA receptor binding studies (Life Science, 1_7'993-1002 , 1976 ) and most importantly with the antipsychotic effect (Nature, 263, 388-341 , 1976) .

____2<_>___<_>å<_>§r

Mock Sprague-Dawley rats weighing from 225 to 275 g were used in the study. The rats were observed in perspex cages (40 (length) x 25 (width) x 30 (height) cm) and their behavior was assessed 5, 20, 40 and 60 minutes after apomorphine. The compounds were injected 60 minutes before said apomorphine hydrochloride (1 mg/kg) which was injected subcutaneously in the neck. This dose and form of administration was found to produce very consistent reactions and very little variation with regard to reaction strength. Apomorphine given subcutaneously also produces a very constant hyperactivity.

Immediately after injection, the animals were placed in the cages, one animal in each cage. Assessment of the stereotypes was carried out by two separate procedures. In the first system, a modified version of the system introduced by Costall and Naylor (1973) was used. The strength of the stereotype was judged on a scale from 0-3 in the following way:

Judgment. Description of stereotypical behaviour

0 No change in behavior compared to saline controls

or animals that were under sedation

1 Discontinuous sniffing.

2 Continuous sniffing.

3 Continuous sniffing. Chewing, biting and licking.

In the second system, a number of animals were assessed that showed hyperactivity due to apomorphine. Each group consisted of 6-8 animals. Controls with saline solutions were always performed at the same time. ED^Qi the first rating system (0-3 scale)

was the dose that reduced the strength of the stereotypy by 50% over an observation period of 60 minutes. ED_g in the second system is the dose that reduces the number of animals showing hyperactivity by 50% over an observation period of 60 minutes. ED<-0 was calculated from the logarithmic curve that showed the relationship between dose and reaction using the least squares method from 4 to 6 dose levels with 6-8 animals per dose level.

Results

The results are shown in Table II. Compounds according to the invention were compared with the previously known antipsychotic compounds sulpiride (Life Science, 1_7, 1551-1556, 1975) and N-ethyl-2-(3-bromo-2,6-dimethoxybenzamidomethyl)-pyrrolidine (racemic and left- rotating) designated FLA 731 and FLA 731 (-), respectively. The stated results indicate that compounds according to the present invention are effective inhibitors of DA receptors in the brain. Because of their ability to antagonize both apomorphine stereotypy and hyperactivity, they probably block DA receptors in both striatal and limbic areas (see introduction). Compounds of the present invention are clearly more potent and stronger than previously known compounds FLA 731 and FLA 731 (-) (racemic and levorotatory compounds compared separately) in inhibiting apomorphine. Furthermore, the compounds are significantly more effective than the antipsychotic compound sulpiride. As there is a high significant correlation between blockade of apomorphine and clinical antipsychotic effects (Nature, 263, 338-341, 1976), it is highly probable that compounds according to the present invention will show strong antipsychotic effects in humans.

It appears that sulpiride has lost all activity. This is in contrast to the tested compounds according to the invention, which are very effective even after oral administration to rats.

<_____>_<___>2<_>§_<_>2<_>__i<__________>_<__>Y2EE<_________>-

The compounds which, according to the present invention, represent the best method for treating psychosis are the following compounds of formula I: The levorotatory enantiomers of N-ethyl-2-(5-chloro-2-hydroxy-6-methoxybenzamidomethyl)pyrrolidine, N- ethyl 2-(3,5-dibromo-2-hydroxy-6-methoxybenzamidomethyl)pyrrolidine, N-ethyl-2-(3,5-diethyl-2-hydroxy-6-methoxybenzamidomethyl)pyrrolidine, N-ethyl-2- (3-bromo-2-hydroxy-6-methoxybenzamidomethyl)pyrrolidine.

Claims (1)

Intermediates for use in the production of therapeutically effective benzamidomethylpyrrolidone derivatives, characterized by the formula: where R 1 and R 2 are the same or equivalent, and each is hydrogen, 1 2 halogen, cyano, alkyl or acyl; and A and A are the same or different and each is hydrogen, alkyl, acyl, alkoxy-1 2 carbonyl or dialkylcarbamyl, provided that when both A and A is alkyl, then R 1 and R 2 are cyano, alkyl or acyl, and further provided that when R 1 /R 2 is H, Cl or Br, and 12 1 A /A is H or CH_, then the substituent on The R group for different from the substituent on R 2 , and the substituent on A 1 are different from the substituent on A 2 , in that alkyl and alkoxy in the above context have 1-5 carbon atoms.