GB2176785A

GB2176785A - Annellated benzamide derivatives

Info

Publication number: GB2176785A
Application number: GB08614176A
Authority: GB
Inventors: Gosta Lennart Florvall; Lars George Johansson; Yatendra Kumar; Tomas De Paulis; Sven Ove Ogren
Original assignee: Astra Lakemedel AB
Current assignee: Astra Lakemedel AB
Priority date: 1985-06-19
Filing date: 1986-06-11
Publication date: 1987-01-07
Also published as: SE8503055D0; GB8614176D0

Abstract

Novel neuropharmacologically active compounds of the formula <IMAGE> wherein R<1> is a hydrogen atom or a lower alkyl group, Z is oxygen or CHR<1>, R<2> is a hydrogen atom, a halogen atom, an alkyl group or a trifluoro alkyl group or an alkylthio group, A<1> is a hydrogen atom or OR<4>, wherein R<4> is a hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group or a mono- or dialkyl-carbamoyl group. R<3> is a hydrogen atom, an alkyl group, a cykloalkyl group, an alkenyl or an alkynyl group, a phenyl group or a substituted phenyl group. n is an integer 1, 2 or a physiologically acceptable salt or optical isomer thereof, the corresponding free acid inter mediates, and methods for their preparation, pharmaceutical preparations containing the compounds and methods for their therapeutical use.

Description

SPECIFICATION Annellated benzamide derivatives Field of the Invention The present invention relates to novel, pharmacologically active derivatives of piperonylcarboxamides, intermediates and processes for their preparation, pharmaceutical compositions containing the piperonylcarboxamido derivatives and the methods of their pharmacological use.

The object of the invention is to provide a substituted benzamide neuroleptic useful for the blockade of dopamine receptors in brain. Such substances will be useful in the treatment of emesis, anxiety states, psychosomatic diseases and psychotic states, such as schizophrenia, and depression, alcoholic related deseases, confusional states and sleep disturbances in the elderly.

Prior Art Through US patent 3342826 the compound of the formula

is known. This compound is claimed to be an inhibitor of the conditioned avoidance behaviour in the rat.

Through US patent 4232037 the compound of the formula

is known. This compound is claimed to be an antagonist of the apomorphine syndrome in the rat.

Through UK patent application 2088364 the compound of the formula

is known. This compound is claimed to be an inhibitor of the apomorphine syndrome in the mouse, and to possess anti-emetic effect in the dog.

Through European patent application EP 60235 the compound of the formula

is known. This compound is claimed to be an inhibitor of the apomorphine syndrome in the rat.

Through French patent application 2 534 255 the compound of the formula

is known. This compound is claimed to antagonize the apomorphine syndrome.

Disclosure of the Invention The present invention describes new compounds useful for treating mental disturbances such as psychotic states and schizophrenia. These agents are potent in their ability to block the dopamine ligand spiperone.

It has been shown that certain benzamide neuroleptics such as raclopride are relatively short acting DA blockers in the rat due to a considerable elimination. This new class of ringannelated benzamide derivatives are potent DA blockers which are affected differently by metabolic enzymes, thus offering advantages in the form of prolonged duration.

The compounds of the invention are characterized by the general formula

wherein R' is a hydrogen atom or a lower alkyl group, Z is oxygen or CHR1, R2 is a hydrogen atom, a halogen atom, an alkyl group or a trifluoro alkyl group, or an alkylthio group, A' is a hydrogen atom or OR4, wherein R4 is a hydrogen atom, an alkyl group, an acyl group, an alkoxy carbonyl group or a mono- or dialkylcarbamoyl group, R3 is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a phenyl group or a substituted phenyl group, n is an integer 1, 2 or a physiologically acceptable salt or optical isomer thereof.

The invention thus provides compounds, and physiologically acceptable salts thereof, which are useful in therapeutic treatment of emesis, anxiety states, psychosomatic diseases such as gastric and duodenal ulcer, and psychotic states such as schizophrenia and depression, alcoholic related diseases, confusional states and sleep disturbances in the elderly.

Halogens atoms in formula I comprises chlorine, bromine, fluorine and iodine atoms.

Alkyl groups in formula I are straight or branched alkyl groups with 1 to 4 carbon atoms, i.e.

methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl and t-butyl Alkylthio groups in the formula I are groups -S-alkyl, wherein the alkyl moiety is defined as alkyl above.

Trifluoroalkyl group in formula I is a group F3C-(CH2)-wherein n is 0, 1 or 2.

Alkenyl groups in formula I are straight or branched hydrocarbon chains with 2 or 3 carbon atoms and a double bond, such as vinyl, allyl or isopropenyl.

Alkynyl groups in formula I are hydrocarbon chains with 2 to 3 carbon atoms with a triple bond, that is -C-=CH, -CH2-C=-CH and -C-=CCH3.

Cycloalkyl groups in formula I are unsubstituted 3-6 membered cyclomethylene groups -CH(CH,),=2-5.

Alkoxycarbonyl groups in formula I are alkyl -O-CO wherein the alkyl moiety is a straight or branched hydrocarbon chain with 1-20 C, preferably 1-15 carbon atoms.

Monoalkylcarbamoyl groups in formula I are groups alkyl -NH-CO- wherein the alkyl moiety is a straight or branched hydrocarbon chain with 1-20 C, preferably 1-15 carbon atoms.

Dialkylcarbamoyl groups in formula I are groups

wherein the alkyl1 and alkyl2 can be the same or different and each is a straight or branched hydrocarbon chain with 1-20 C, preferably 1-15 carbon atoms.

Acyl groups in formula I are alkyl-CO- where the alkyl moiety is a straight or branched hydrocarbon chain with 1 to 20 carbon atoms, preferably 1-15 carbon atoms.

Substituted phenyl in the formula I is a phenyl group substituted by one or more of fluoro, chloro, bromo, trifluoromethyl, ethyl, methoxy or ethoxy in the ortho, meta or para positions, or substituted by methylenedioxy.

Phenyl substituted with methylenedioxy in formula I is the group

or

A preferred group of compounds of the invention is obtained when in formula I R1 is a hydrogen atom, Z is oxygen or CH2, R2 is a halogen atom or an alkyl group, A' is a hydrogen atom, a hydroxy or an alkoxy group, R3 is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyi group, a phenyl group or a substituted phenyl group, n is 1 or 2.

A second preferred group of compounds of the invention is obtained when in the formula I R' is a hydrogen atom or CH3, Z is CH2, R2 is a halogen atom or an alkyl group, A1 is a hydrogen atom, a hydroxy or an alkoxy group, R3 is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a phenyl group or a substituted phenyl group, n is 1 or 2.

A third preferred group compounds of the invention is obtained when in the formula I R' is a hydrogen atom, Z is oxygen or CH2, R2 is a chloro or a bromo atom, or a methyl, ethyl or propyl group, Al is a hydrogen atom, a hydroxy or methoxy group, R3 is a methyl, ethyl or vinyl group, n is 1 or 2.

A further preferred group compounds of the invention is obtained when in the formula 1 R' is a hydrogen atom, Z is oxygen or CH2, R2 is a bromo or chloro atom or an ethyl group, A' is a hydrogen atom or a hydroxy group, R3 is a methyl group and n is 1 or 2.

Compounds particularly preferred are

The new compounds of this invention may be used therapeutically as the racemic mixtures of (+)- and (-)-forms, which are obtained by synthesis. They may also be resolved into the corresponding enantiomers which, likewise, may be used in therapy. The (+)- and (-)-forms may also be obtained by the reaction of the corresponding enantiomeric 2-(aminomethyl)pyrrolidine with the benzoic acid moiety. Preferably R3=lower alkyl or alkenyl the configuration being S (sinister), R3=phenyl or substituted phenyl the configuration being R (rectus).

Pharmaceutical preparations In clinical practice the compounds of the present invention will normally be administered orally, rectally or by injection in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, e.g.

the hydrobromide, hydrochloride, phosphate, sulphate, sulphonate, sulphamate, citrate, lactate, maleate, tartrate, acetate and the like in association with a pharmaceutically acceptable carrier.

Accordingly, terms relating to the novel compounds of this invention whether generically or specifically are intended to include both the free amine base and the acid addition salts of the free base, unless the contect in which such terms are used, e.g. in the specific examples would be inconsistent with the broad concept.

The carrier may be a solid, semisolid or liquid diluent or capsule. These pharmaceutical preparations constitute a further aspect of this invention. Usually the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by weight for preparations intended for injection and between 2 and 50% by weight for preparations suitable for oral administration.

To produce pharmaceutical preparations containing a compound of the invention in the form of dosage units for oral application, the selected compound may be mixed with a solid pulverulent carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, or gelatine, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol waxes, and the like, and then compressed to form tablets.

If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like.

Alternatively, the tablet can be coated with a lacquer dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compound.

For the preparation of soft gelatine capsules (pearl-shaped closed capsules) consisting of gelatine and for example, glycerol or similar closed capsules, the active substance may be admixed with a vegetable oil. Hard gelatine capsules may contain granulates of the active substance in combination with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine.

Dosage units for rectal application can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.

Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.2 to about 20% by weight of the active substance herein described, the balance being sugar and a mixture of ethanol, water, glycerol, and propyleneglycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent.

Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5 to 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.

Compounds of the formula I wherein A' is a substituent -O-CO-R may advantageously be used in pharmaceutical preparations intended for intramuscular administration in order to obtain a sustained release effect, that is a depot effect.

Suitable daily doses for oral administration of the compounds of this invention are 1-50 mg, preferably 5-20 mg.

Methods of preparation The compounds of the invention may be obtained by one of the following methods.

A. The compounds of the formula

wherein R' is a hydrogen atom or a lower alkyl group, Z is oxygen or CHR', R2 is a hydrogen atom, a halogen atom, an alkyl group or a trifluoroalkyl group or an alkylthio group, A' is a hydrogen atom or OR4, wherein R4 is a hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group or a mono- or dialkylcarbamoyl group, R3 is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a phenyl group or a substituted phenyl group.

n is an integer 1, 2 can be obtained by reaction of a compound of the formula

wherein Ra, R2, A1, Z and n have the above given definitions and -CO-Z' is a reactive group capable of reacting with an amino group under formation of an amide moiety, with a compound of the formula

wherein R3 has the above given definition, or a reactive derivative thereof.

The reaction is carried out in a suitable solvent, such as diethyl ether, THF, dichloromethane, acetone, methylethyl ketone, chloroform or toluene between O"C and the boiling point of the reaction mixture. The resulting amine can be isolated as a salt recovered e.g. by filtration.

Alternatively, the amine obtained can be converted to the free base using conventional techniques, such as the addition of aqueous ammonia or a sodium hydroxide solution, and extraction with an organic solvent.

Z' in the acylating group -CO-Z1 may be a halogen group, such as chlorine or bromine, a mixed anhydride with inorganic acids or their esters (e.g. phenylphosphate), a thio group, an organic residue or a hydroxy group in combination with a coupling agent or reactive amine derivative.

The organic residue comprises groups which can form reactive acid derivatives. These can be aliphatic carboxylic acid esters, e.g. methyl and ethyl esters or comparable reactive esters, e.g.

cyanomethyl or methoxymethyl ester, N-hydroxyimido ester or substituted or unsubstituted aromatic esters; acyl azides; acyl nitrile; symmetrical anhydrides; mixed anhydrides; azolides, e.g.

triazolide, tetrazolide or imidazolide.

According to the invention the following compounds can be used as reactive derivatives of the cyclic amine above: Reaction products of the amine with phosphorus chloride, phosphorus oxychloride, dialkyl, diaryl or o-phenylenechlorophosphites or alkyl or aryldichlorophosphites, or an isothiocyanate or isocyanate of the amine. The mentioned reactive derivatives can be reacted with the acid in situ or after previous isolation.

It is also possible to react the free acid and the free amine in the presence of a condensating agent, e.g. silicon tetrachloride, diphosphorouspentoxide, a phosphine or hexamethylphosphorous triamide plus a carbon tetrahalide, diphenyl phosphite, N-ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroqui- noline, titanium tetrachloride or carbodiimides such as dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole and diethyldiazodicarboxylate.

B. The compounds of the formula I with the definition as in A can be obtained by Nsubstitution of a compound of the formula

wherein Rl, R2, Al, Z and n have the above given definition, with a compound of the formula R3-CH2-X wherein R3 has the above given definition and X is a leaving group such as chlorine, bromine, sulphate, phosphate, benzenesulphonate or toluenesulphonate.

The reaction can preferably be effected by treating the reactants at 20"C to reflux in a suitable solvent, e.g. acetone, alcohols, dimethylformamide (DMF), dimethylsulphoxide (DMSO) in the presence of a base, for example NaOH or K2CO3.

Alternatively, the secondary amine can be N-substituted by reductive alkylation with an aldehyde of the formula R3-CHO wherein R3 has the above definition, in the presence of a reducing agent such as sodium cyanoborohydride, Raney nickel, boranes, hydrogen/Pt, hydrogen/Pd or a metal/acid system having a metal like zinc.

Alternatively, the secondary amine can be N-substituted by acylation with a reagent such as R3COCI, (R3-CO)2O or R3-COOCH3 to give

wherein Rl, R2, R3, Al, Z and n have the above given definitions, which is subsequently reduced with a reducing agent such as LiAIH4 and alkoxy complexes thereof; NaBH4 in pyridine or with addition of transition metal salts, or AICI2 or Bf3 or POCI3 or carboxylic acids such as CH3COOH and CF3COOH; B2H6. The reduction is preferably carried out in ether solvents such as diethylether, dimethoxyethane, diglyme, THF or dioxane at temperatures from 0 C to reflux.

C. The compounds of the formula I with the definition as in A with the exception that R2 is bromine or chlorine can be obtained by reaction of a compound of the formula

wherein R', R3, Al, Z and n have the above given definitions, E is hydrogen or Si(CH3) with a chlorinating or brominating reagent.

Chlorination is effected by treating the starting compound with chlorine with or without Lewis acid catalysis or with sulphurylchloride or with HOCI or with N-chloroamides in the presence of acid catalyst in suitable solvent, e.g. chloroform, nitrobenzene.

Bromination is carried out with Br2 with or without Lewis acid catalysis or bromination in acetic acid in the presence of a base e.g. sodium acetate or by using bromine-dioxane complex.

Other reagents can be used among them HOBr and N-bromoamides especially N-bromosuccinimide with acid catalysis.

D. The compounds pf the formula I with the definition as in A with the exception that A' is not a hydrogen atom or a hydroxy group can be obtained by reaction of a compound of the formula

with a compound of the formula R4-B wherein R4 has the above given definition and B is a suitable leaving group such as halogen in a suitable solvent preferably in the presence of a base such as a tertiary amine or alkali metal carbonate.

Alternatively, the reaction can be done with an isocyanate R4-N=C=O in the case of R4 being monoalkylcarbamoyl.

Intermediates The compound of the formula

wherein R' is a hydrogen atom or an alkyl group, Z is oxygen, or CHR', R2 is a hydrogen atom, a halogen atom, an alkyl group or a trifluoroalkyl group, A' is a hydrogen atom or OR4, wherein R4 is a hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group or a mono- or dialkylcarbamoyl group, n is an integer 1, 2 are valuable intermediates for the preparation of the compounds of this invention by the process A.

These compounds can be prepared according to the following reaction scheme

wherein E is Cl, I, F, Me, Et, Pr, Bu, CF3-alkyl or S-alkyl.

The preferred intermediates have R2=ethyl.

Working examples I Preparation of end-compounds Example 1: - )-N-( 1 -ethyl-2-pyrrolidinyl)methyl-5-bromo-2,3-dihydro-6-methoxybenzofuranyl-7-carboxamide (1). Method A.

5-bromo-2,3-dihydro-6-methoxybenzofuranyl-7-carboxylic acid (0.54 9, 0.002 mol) was treated with thionyl chloride (0.71 g, 0.006 mol) in toluene (15 ml) at 650C for 1 h. The solvent was removed in vacuo and the residue was dissolved in 10 ml chloroform. A solution of S-(-)-Nethyl-2-aminomethylpyrrolidine (0.389, 0.003 mol) in 10 ml chloroform was added and stirred at 40"C for 30 min. Addition of 2M sodium hydroxide (5 ml), separation and evaporation of the organic layer gave 0.61 g of amide 1. The hydrochloride salt was prepared from hydrogen chloride-ether and was crystallized from acetone. Yield 0.55 9 (66%); m.p. 169-170 C.

Anal. (C17H24BrClN2O2): %C: Calcd 48.64, found 48.57; %H: Calcd. 5.76, found 5.73; %Br: Calcd 19.04, found 18.93; %CI: Calcd 8.45, found 8.39; %N: Calcd 6.67, found 6.65.

By an analogous method as described for compound 1 above, the following compounds were prepared: S-( -)-N[( 1 -ethyl-2-pyrrolidinyl)methyl]-2,3-dihydro-5-ethyl-6-methoxybenzofuranyl-7-carboxamide (2), oil; Yield: 74%. 13C NMR 164.9, 157.1, 155.5, 129.1, 126.3, 123.2, 113.2, 72.2, 62.5, 62.2, 53.5, 48.0, 41.2, 29.3, 28.4, 22.6, 22.4, 15.2, 13.8. 1H NMR 7.06 (s), 4.61 (t), 3.76 (s), 3.7 (m), 3.28 (dq), 3.15 (t), 2.87 (m), 2.58 (q), 2.30-1.6 (m), 1.19 (t) 1.13 (t).

S-(- )-N-[( 1 -ethyl-2-pyrrnlidinyl)methyl]-2,3-dihydrobenzofurnnyl-7carboxamide (5), oil; Yield: 72%. 1H NMR 8.0 (br,NH), 7.9 (d), 7.3 (d), 6.9 (t), 4.7 (t), 3.8-1.5 (m), 1.1 (t).

S-( -)-N-[( 1 -ethyl-2-pyrrolidinyl)methyl]-5-chlorn-2,3-dihydrnbenzofurnnyl-7-carboxamide (6). m.p.

192-1940C. Yield: 70%.

S-(-)-N-[(1 -ethyl-2-pyrrolidinyl)methyl]-5-bromo-2,3-dihydrobenzofuranyl-7-carboxamide (7). m p.

52-540C. Yield: 65%.

S-(- )-N-[(l -ethyl-2-pyrrolidinyl)methyl]-2,3-dihydro-5-ethylbenzofuranyl- -7-carboxamide (8). m. p.

157-159 C. Yield: 80%.

S-(-)-N-[( 1 -ethyl-2-pyrrolidinyl)methyl]-5-bromo-6-methoxy-2,3-methylenedioxybenzamide (9).

m.p. 114-115 C. Yield: 88%.

S-()-N-[(1 -ethyl-2-pyrrolidinyl)methyl]-5-ethyl-6-methoxy-2,3-methylenedioxybenzamide (10).

m.p. 145-146 C. Yield: 60% S-( -)-N-[( 1 -ethyl-2-pyrrolidinyl)methyl]-2,3-methylenedioxybenzamide (12). m.p. 88-900C. Yield: 91%.

S-( -)-N-[( 1 -ethyl-2-pyrrolidinyl)methyl]-5-bromo-2,3-ethylenedioxybenzamide (13), oil; Yield: 82%. 1H NMR 8.0 (br, NH), 7.8 (d, J=2.4 Hz), 7.1 (d, J=2.4 Hz), 4.3 (m, OCH2CH2O), 3.8-1.0 (m). 12C NMR 163.6, 144.3, 141.3, 126.4, 123.8, 122.9, 113.1, 66.6, 63.6, 62.1, 53.6, 47.9, 41.6, 28.5, 22.9, 14.2.

S-(- )-N-[( 1 -ethyl-2-pyrrnlidinyl)methyl]-5-brnmo-2,3-methylenedioxybenzamide (14). 13C NMR 162.0, 148.4, 144.5, 124.6, 116.8, 114.3, 113.3, 102.1, 61.9, 53.4, 48.0, 41.6, 28.3, 22.8, 14.0. 1H NMR 7.8 (d), 7.1 (d), 6.1 (s), 3.7-1.4 (m), 1.1 (t).

Example 2 S-(-)-N-[(1 -ethyl-2-pyrrolidinyl)methyl]-5-bromo-2,3-dihydro-6-hydroxybenzofuranyl-7-carboxam- ide (3). Method B.

To a solution of the hydrochloride of S-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-bromo-2,3-dihy- dro-6-methoxybenzofuranyl-7-carboxamide, compound 1, (0.30 9, 0.008 mol) in methylene chloride (15 ml) boron tribromide (0.15 g, 0.009 mol) in methylene chloride (10 ml) was added dropwise at ambient temperature. After 0.5 h 2M ammonia (20 ml) was added. The organic layer was separated, dried (Na2SO4) and the solvent was evaporated. The residue was crystallized from hexane. Yield: 0.15 g (58%); m.p. 58-600C.

Anal. (C,6H2,BrN203): %C: Calcd. 52.04, found 52.04; %H: Calcd. 5.73, found 5.70; %Br: Calcd. 21.64, found 21.85; %N:Calcd. 7.59, found 7.55; O/oO: Calcd. 13.00, found 12.87.

By an analogous method as described for compound 3 above the following compounds were prepared.

S-(-)-N-[(1 -ethyl-2-pyrrolidinyl)methyl]-2,3-dihydro-5-ethyl-6-hydroxybenzofuranyl-7-carboxamide (4). m.p. 175-177"C. Yield: 60%.

S-(-)-N-[(1 -ethyl-2-pyrrolidinyl)methyl]-5-bromo-6-hydroxy-2,3-methylenedioxybenzamide (11).

m.p. 74-76"C. Yield: 66%.

II Preparation of intermediates Example 3 5-bromo-2, 3-dihydrobenzofuranyl- 7-carooxylic acid 2,3-dihydrobenzofuran-7-carboxylic acid (0.55 g, 0.0034 mol) and sodium acetate (0.50 g, 0.0061 mol) were suspended in acetic acid (10 ml). Bromine (0.70 g, 0.0044 mol) in acetic acid (5 ml) was added dropwise. The reaction mixture was heated at 80"C for 3 h and poured in an icewater mixture. The solid was filtered and crystallized from ethylacetate. Yield 0.65 9 (80%); m.p. 232-40C. Anal. (CgH7BrO3): %C: Calcd. 44.45, found 44.44; %H: Calcd. 2.83, found 2.88; %Br: Calcd. 33.07, found 32.92; 960: Calcd. 19.52, found 19.75.

By using an analogous method as described above the following compounds were prepared: 5-bromo-6-methoxy-2 ,3-methylenedioxybenzoic acid 5-bromo-2,3-dihydro-6-methoxybenzofuran-7-carboxylic acid 5-bromo-2,3-ethylenedioxybenzoic acid 5.6-dibromo-2,3-ethylenedioxybenzoic acid.

Example 4 5-chloro-2,3-dEhydrobenzofuran-7-carboxylic acid 2,3-dihydrobenzofuran-7-carboxylic acid (1.64 9, 0.01 mol) was dissolved in chloroform (50 ml). Sulfuryl chloride (1.3 ml, 0.014 mol) was added and the reaction mixture was stirred at room temperature for 24 h. The solvent was removed and the residue was crystallized from ethyl acetate. Yield: 1.5 9 (79%), m.p. 21 1-2130C. Anal. (CgH7CI03). %C: Calcd. 54.41, found 54.29; %H: Calcd. 3.53, found 3.75; %CI: Calcd. 17.88, found 17.79.

Example 5 6-methoxy-2,3-methylenedioxybenzoic acid A mixture of sesamol (13.8 9, 0.1 mol), potassium carbonate (27.6 9, 0.2 mol) and dimethylsulfate (12.6 g, 0.1 mol) in acetone (250 ml) was refluxed for 8 h. After cooling the solid was filtered and the filtrate was concentrated to give an oil. The obtained oil was dissolved in tetrahydrofuran (200 ml) and butyl lithium (75 ml, 1.6 M solution in hexane) was added dropwise under nitrogen atmosphere at room temperature. After stirring for 1 h, the solution was poured on to crushed dry ice. When the temperature reached 20"C, the solution was acidified by 2M hydrochloric acid. The product was extracted with methylene chloride. The organic layer was dried (Na2SO4). The solvent was evaporated and the solid thus obtained was crystallized from chloroform.Yield 9.5 g (48%); m.p. 137-139"C. Anal. (C9H8OJ. %C: Calcd.

55.10, found 55.21; %H: Calcd. 4.08, found 4.07; %0 Calcd. 40.80, found 40.79.

Example 6 5-ethyl-2,3-dihydrobenzofuran- 7-carboxylic acid 5-bromo-2,3-dihydrobenzofuran-7-carboxylic acid (5 g, 0.02 mol) was suspended in toluene.

Thionyl chloride (4 ml) and a catalytic amount of dimethylformamide (0.5 ml) were added and the mixture was heated at 809C for 2 h. The solvent was removed. The acid chloride was dissolved in methylene chloride (50 ml) and added at 00C-50C to the solution of 2-amino-2methyl-1-propanol (3.74 g, 0.04 mol) in methylene chloride (20 ml). The reaction mixture was stirred for 2.5 h, washed with water and the organic layer was dried (Na2SO4). The solvent was removed. The solid thus obtained was crystallized from ethylacetate. Yield 5.8 g (95%), m.p.

172-174"C. The obtained alcohol (5.1 g, 0.016 mol) was cyclized by stirring with thionyl chloride (3.7 g, 0.05 mol) for 0.5 h. Excess of thionylchloride was removed under reduced pressure. The obtained product (4.4 g, 0.014 mol) was dissolved in tetrahydrofuran (50 ml).

Butyllithium (10 ml, 1.6M solution in hexane) was added at --78"C under nitrogen atmosphere.

The mixture was stirred for 1 h and then ethyl iodide (2.4 ml, 0.03 mol) was added dropwise maintaining the temperature below -70"C. The reaction mixture was stirred 15 min at - 700C and then allowed to heat slowly up to -20"C. The mixture was poured in 2M sodium hydroxide solution and extracted with ether. The ether layer was separated and the solvent was removed.

The residue was dissolved in 2M hydrochloric acid (100 ml) and refluxed for 5 h. The acid, separated as an oil, was extracted with ether. The organic layer was separated and dried (Na2SO4). The solvent was removed and the solid thus obtained was crystallized from ethyl acetate/diisopropyl ether. Yield 1.20 g (42%), m.p. 161-162"C. Anal. (C1,H1203) %C: Calcd.

68.75, found 68.80; %H: Calcd. 6.25, found 6.18; %0: Calcd. 25.00, found 25.10.

Example 7 2,3-dehydro-5-ethyl-6-methoxybenzofuran-7-carboxylic acid A mixture of 5-ethyl-6-hydroxy-3-benzofuranone (1.78 g, 0.01 mol), potassium carbonate (2.76 g, 0.02 mol) and dimethylsulfate (1.26 g, 0.01 mol) in acetone (25 ml) was refluxed for 6 h. After cooling the solid was filtered. The filtrate was concentrated. The residue was dissolved in ethanol (20 ml) and was hydrogenated over 10% palladium (0.2 g) on carbon at NTP. The catalyst was filtered and the filtrate was concentrated to give an oil. Lithiation and carboxylation of the obtained oil was performed described in the example 5.Yield 0.8 g (36%). lH NMR (CDCL3): 1.22 (t, 3H, C-CH3), 2.67 (q, 2H, Ar-CH2), 3.27 (t, 2H, Ar-CH2), 3.93 (S, 3H, O-CH3), 4.83 (t, 2H, O-CH2), 7.36 (s, 1H, Ar-H).

Example 8 5-ethyl-6-methoxy-2,3-methylenedioxybenzoic acid A mixture of 2-hydrqxy-4,5-methylenedioxyacetophenone (0.82 g, 0.005 mol) potassium carbonate (1.38 g, 0.01 mol) and dimethylsulfate (0.63 g, 0.005 mol) in acetone (20 ml) was refluxed overnight. After cooling the solid was filtered. The filterate was concentrated and dissolved in ether. After washing with water, the organic layer was dried and concentrated to give white solid which was crystallized from hexane. Yield 0.80 g (83%), m.p. 67-69"C. The obtained product was dissolved in ethanol (20 ml) and was hydrogenated over 10% Pd/C at normal temperature and pressure (NTP). After 8 h the catalyst was filtered and the solvent was concentrated to give an oil. Yield 0.6 g (81%).The obtained oil was dissolved in tetrahydrofuran (20 ml) and butyl lithium (2.5 ml, 1.6 M solution in hexane) was added dropwise under nitrogen atmosphere at room temperature. After stirring for 2 h, the solution was poured on to dry ice.

When the temperature reached 20"C, 2M HCI was added to reach pH 1 and the product was extracted with ether. The solvent was dried (Na2SO4) and concentrated to give 0.4 g of 5-ethyl6-methoxy-2,3-methylenedioxybenzoic acid as an oil.

1H NMR(CDCl3): 1.23 (t, 3H, C-CH3), 2.63 (q, 2H, Ar-CH2), 3.86 (s, 1H, O-CH3), 6.17 (s, 2H, O-CH2-O), 6.93 (s, 1H, Ar-H).

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

Formulation A. Soft gelatin capsules 500 g of active substance were mixed with 500 g of corn oil, whereupon the mixture was filled in soft gelatin capsules, each capsule containing 100 mg of the mixture (i.e. 50 mg of active substance).

Formulation B. Soft gelatin capsules 500 g of active substance were mixed with 750 g of pea nut oil, whereupon the mixture was filled in soft gelatin capsules, each capsule containing 125 mg of the mixture (i.e. 50 mg of active substance).

Formulation C. Tablets 50 kg of active substance were mixed with 20 kg of silicic acid of the trademark Aerosil. 45 kg of potato starch and 50 kg of lactose were mixed therewith and the mixture was moistened with a starch paste prepared from 5 kg of potato starch and distilled water, whereupon the mixture was granulated through a sieve. The granulate was dried and sieved, whereupon 2 kg of magnesium stearate was mixed into it. Finally the mixture was pressed into tablets each weighing 172 mg.

Formulation D. Effervescing tablets 100 g of active substance, 140 g of finely divided citric acid, 100 g of finely divided sodium hydrogen carbonate, 3.5 g of magnesium stearate and flavouring agents (q.s.) were mixed and the mixture was pressed into tablets each containing 100 mg of active substance.

Formulation E. Sustained release tablet 200 g of active substance were melted together with 50 g of stearic acid and 50 g of carnauba wax. The mixture thus obtained was cooled and ground to a particle size of at most 1 mm in diameter. The mixture thus obtained was mixed with 5 g of magnesium stearate and pressed into tablets each weighing 305 mg. Each tablet thus contains 200 mg of active substance.

Formulation F. Injection solution Active substance 3.000 mg Sodium pyrosulfite 0.500 mg Disodium edetate 0.100 mg Sodium chloride 8.500 mg Sterile water for injection ad 1.00 ml Formulation G. Hard gelatine capsules 10 g of active substance was mixed with 400 g of lactose and finally 2 g of magnesium stearate was added. The mixture was then filled in hard gelatine capsules, each capsule containing 206 mg of the mixture (i.e. 5 mg of active substance).

Formulation H. Tablets 50 g of active substance was mixed with 1500 g of lactose, 200 g of microcrystalline cellulose and 10 mg magnesium stearate. Tablets of 5 mg active substance with a core weight of 176 mg were finally comprotted.

Formulation I. Depot preparation S-(-)-N-[(1-ethyl-2-pyrrolidinyl)- methyl]-5-ethyl-6-hydroxybenzofuranyl-7-carboxamide 200 mg Peanut oil ad 1 ml Pharmacology A number of studies suggest that the antipsychotic action of neuroleptic drugs is in some way related to the decrease in catecholamine transmission in the brain caused by these drugs and more specifically due to central dopamine (DA) receptor blockade in cortical and subcortical brain regions. The clinical efficacy of antipsychotic drugs has been shown to correlate with their ability to displace tritiated spiperone from preparations of dopamine receptors (Seeman, Biochem.

Pharmacol. 26, 1741 (1977).

Method for in vitro receptor binding assay The method of Burt et al. (Proc. Nat. Acad. Sci. USA 72, 4655 (1975) was used. Male Spraque-Dawley rats weighing 150-200 g were decapitated, and their brains were rapidly removed. The striata were dissected, pooled and homogenized in 50 mM Tris-HCI buffer (pH 7.6). The membrane fraction was collected by centrifugation (48000 g for ten minutes), washed once with the buffer, and resuspended in 50 mM Tris-HCI (pH 7.6) containing 0.1% ascorbic acid, 10 mM pargyline, 120 mM NaCI, 5 mM KCI, 2 mM CaCI2 and 1 mM MgCI2. The suspension was preincubated at 37"C for 10 minutes and then kept on ice until use.

The assays have been carried out using a cell harvester equipment. The incubations were made in quadruplicate, each well containing membrane suspension (2.5 mg/0.5 ml), 3H-spiperone (0.4 nM) and the test compound in a final volume of 0.5 ml. After incubation for 10 minutes at 37"C, the contents of the wells were rapidly filtered and washed on Whatman GF/B filters using the Cell harvester. The specific binding was defined as the difference of ligand bound in the presence and in the absence of 1 uM (+)-butaclamol. The test results are expressed as It50.

The IC50 value given in nM, indicates the concentration of the test substance which reduces the amount of specifically bound spiperone by 50%.

Test results The test results are given in the following table.

Test compound In vitro Block of 3H-spi perone binding IC50 (nM) Prior art compounds:

(remoxipride, US patent 4 232 037)

t racloprtae EP 60235)

(ex 5 of US 3 342 826) Compounds of the present invention

Test compound In vitro Block of 3H-spi perone binding IC50 (nM)

Claims

1. A compound of the formula

wherein R' is a hydrogen atom or a lower alkyl group, Z is oxygen or CHR', R2 is a hydrogen atom, a halogen atom, an alkyl group or a trifluoro alkyl group or an alkylthio group, A' is a hydrogen atom or OR4 wherein R4 is a hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group or a mono- or dialkylcarbamoyl group, R3 is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, a phenyl group or a sybstituted phenyl group, n is an integer 1, 2 or a physiologically acceptable salt or optical isomer thereof.

2. A compound according to claim 1 with the formula I wherein R1 is a hydrogen atom, Z is oxygen or CH2, R2 is a halogen atom or an alkyl group, A' is a hydrogen atom, a hydroxy or an alkoxy group, R3 has the definition given in claim 1, n is 1 or 2 or a physiologically acceptable salt or optical isomer thereof.

3. A compound according to claim 1 with the formula I wherein R1 is a hydrogen atom or CH3, Z is CH2, R2 is a halogen atom or an alkyl group, A' is a hydrogen atom, a hydroxy or an alkoxy group, R3 has the definition given in claim 1, n is 1 or 2 or a physiologically acceptable salt or optical isomer thereof.

4. A compound according to claim 1 with the formula I wherein R' is a hydrogen atom, Z is oxygen or CH2, R2 is a chloro or a bromo atom or a methyl, ethyl, or propyl group, A' is a hydrogen atom, a hydroxy or methoxy group, R3 is a methyl, ethyl or vinyl group, n is 1 or 2, or a physiologically acceptable salt or optical isomer thereof.

5. A compound according to claim 1 with the formula I wherein R1 is a hydrogen atom, Z is oxygen or CH2, R2 is a bromo atom or an ethyl group, A' is a hydrogen atom or a hydroxy group, R3 is a methyl group and n is 1 or a physiologically acceptable salt or optical isomer thereof.

6. A compound according to claim 1 with the formula

7. A compound according to any of claims 1-6 in the form of an optical isomer thereof.

8. A compound according to any of claims 1-7 in the form of a physiologically acceptable salt thereof.

9. A process for the preparation of a compound of the formula

wherein R1 is a hydrogen atom or a lower alkyl group, Z is oxygen or CHR', R2 is a hydrogen atom, a halogen atom, an alkyl group or a trifluoro alkyl group or an alkylthio group, A' is a hydrogen atom or OR4 wherein R4 is a hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group or a mono- or dialkylcarbamoyl group, R3 is a hydrogen atom, an alkyl group, a cykloalkyl group, an alkenyl group, an alkynyl group, a phenyl group or a substituted phenyl group, n is an integer 1, 2 or a physiologically acceptable salt or optical isomer thereof, which process comprises a) reaction of a compound of the formula

wherein R', R2, A(, Z and n have the definitions as in the preamble of the claim and -CO-Z' is a reactive group capable of reacting with an amino group under formulation of an amide moiety, with a compound of the formula

wherein R3 has the definition as in the preamble of the claim or a reactive derivative thereof, to the formation of a compound of the formula I, or b) N-substitution of a compound of the formula

wherein R', R2, Al, Z and n have the definition as in the preamble of the claim, with a compound of the formula 1) R3-CH2-X 2) R3CHO in the presence of a reducing agent, or 3) R3COCL, (R2CO)20 or R3COOCH3 and subsequent reduction, wherein R3 has the definition as in the preamble claim and X is a leaving group, to formation of a compound of the formula I, or c) reaction of a compound of the formula

wherein R', R3, Al, Z and n have the definition as in the preamble of the claim and E is H or Si(CH3)3 with a brominating or chlorinating agent to the formation of a compound of the formula I with the definition as in the preamble of the claim with the exception that R2 is a bromine or a chlorine atom, or d) esterification of a compound of the formula

wherein R', R2, R3, Z and n have the definition as in the preamble of the claim with a compound of the formula R-CO-Z2 wherein R is a hydrogen atom or an alkyl group and Z2 is Cl or Br, to the formation of a compound of the formula I, wherein A' is a substituent -O-CO-R wherein R is as defined above, whereafter, if desired, the compound obtained by any of methods a)-d) is converted to a physiologically acceptable salt thereof and/or converted to a substantially pure stereoisomer thereof.

10. A process according to claim 9 characterized in that a compound according to any of claims 1-8 is prepared.

11. Compounds useful as intermediates for the preparation of therapeutically valuable piperonylcarboxamide derivatives, which intermediates are characterized by the formula

wherein R' is a hydrogen atom or a lower alkyl group, Z is oxygen or CHR', R2 is a hydrogen atom, a halogen atom, an alkyl group or a trifluoro alkyl group or an alkylthio group.

A' is a hydrogen atom or OR4, wherein R4 is a hydrogen atoms, an alkyl group, an acyl group, an alkoxycarbonyl group or a mono- or dialkylcarbamoyl group, n is 1 or 2.

12. A pharmaceutical preparation comprising as active ingredient a compound according to any of claims 1-8 or a physiologically acceptable salt or an optical isomer thereof.

13. A pharmaceutical preparation according to claim 12 in dosage unit form.

14. A pharmaceutical preparation according to claims 12-13 comprising the active ingredient in association with a pharmaceutically acceptable carrier.

15. The use of a compound according to any of claims 1-8 or a physiologically accetpable salt thereof for the preparation of a pharmaceutical preparation comprising as an active ingredient an amount of said compound.

16. A method for the treatment of diseases related to a dysfunction of the dopaminergic system in man, characterized by the administration to a host in need of such treatment of an effective amount of a compound according to any of claims 1-8 or a physiologically acceptable salt thereof.

17. A compound according to any of claims 1-8 for use as a drug for the treatment of diseases related to a dysfunction of the dopaminergic system.