WO2008146063A1

WO2008146063A1 - New benzofuran derivatives as selective 5ht6 receptor inhibitors and process for their preparation

Info

Publication number: WO2008146063A1
Application number: PCT/HU2008/000060
Authority: WO
Inventors: Endre RIVÓ; Ibolya Prauda; József Reiter; József Barkóczy; István Gacsályi; Hajnalka Kompagne; Nóra SZIRAY; Katalin Pallagi; András Egyed; Endre HEGEDÜS; György Lévay; László Gábor HÁRSING
Original assignee: EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársagág
Priority date: 2007-05-30
Filing date: 2008-05-30
Publication date: 2008-12-04
Also published as: HUP0700378A2; HUP0700378A3; HU230761B1; HU0700378D0

Abstract

The present invention relates to new selective 5HT6 receptor binding benzofuran derivatives of general formula (I) wherein, Z represents a hydrogen atom, C1-4 acyl group, C1-6 alkyl sulfonyl group, phenyl sulfonyl group substituted with one or more halogen atom; or naphthyl sulfonyl group optionally substituted with a halogen atom, tetrahydro naphthyl sulfonyl group, (lS)(+)-10-camphor-sulfonyl group, (lR)(-)-10-camphor-sulfonyl group or benzofuranyl sulfonyl group, substituted with a halogen atom and C1 -4 alkyl group, Y represents C2-6 alkylene group, R1 and R2 represent, independently, a hydrogen atom, C1-4 alkyl group, benzyl group, or together with one or more halogen atoms, trifluoromethyl group, or C1-4 alkoxy group substituted 4-phenyl-piperazine-l-yl group; and/or their pharmaceutically suitable acid addition salts, to the process for producing said compounds, to pharmaceutical compositions containing said compounds and to their use in treatment and/or prevention of disorders of the central nervous system and cardiovascular system.

Description

NEW BENZOFURAN DERIVATIVES AS SELECTIVE 5HT₆ RECEPTOR INHIBITORS AND PROCESS FOR THEIR PREPARATION

The invention relates to new, selective 5HT₆ receptor inhibitors of general formula (I), pharmaceutical formulations containing the same as active ingredients and a process of the preparation thereof. The new compounds are effective in the treatment of 5HT₆ receptor relating disorders, and for the treatment and/or prevention of the disorders of the central nervous system and cardiovascular system.

More specifically, the invention relates to selective 5HT₆ receptor binding benzofuran derivatives of general formula (I),

(I) wherein,

Z represents a hydrogen atom, C₁^ acyl group, C_1-6 group alkyl sulfonyl group, phenyl sulfonyl group substituted with one or more halogen atom; or naphthyl sulfonyl group optionally substituted with a halogen atom, or tetrahydro naphthyl sulfonyl group, (lS)(+)-10-camphor-sulfonyl group, (lR)(-)-10-camphor-sulfonyl group, or benzofuranyl sulfonyl group, substituted with a halogen atom and C_1-4 alkyl group, Y represents C₂^ alkylene group,

R¹ and R² represent, independently, a hydrogen atom, C₁^ alkyl group, benzyl group, or together with one or more halogen atoms, trifluoromethyl group, or CM alkoxy group substituted 4-phenyl-piperazin-l-yl group; and/or their pharmaceutically suitable acid addition salts. According to the literature certain furan carboxylic amides have antidepressant properties [Yakugaku Zasshi 97 (5), 540 (1977); C.A., 87. 152125d (1997)], while benzofuran derivatives having amino, amidino, thiocarboxamidino or dialkylaminoalkyl substituents on the furan ring are H₂ receptor antagonists, and, consequently, possess an antiulcer effect [published PCT application No. 86 02550. C.A., 105, 226586 u (1986)].

Tetrahydro-naphthoxy derivatives having hypotensive activity are known from published German patent application No. 22 35 597. The chemical structure of the known compounds resembles to the benzofurane derivatives of general formula (I).

International Patent Application No. WO99/58527 describes novel benzofuran derivatives, pharmaceutical preparations containing the same and the process for the preparation thereof. The novel compounds have physiological effect on the cardiovascular system, on the heart and the nervous system through the 5HT₁A receptors.

Patent Application No. US 2004/0224994 of the United States relates to benzofuran derivatives, some of them having a similar structure to the subject of the present invention. The compounds are used as pesticides.

A huge number of 5-HT₆ receptors are located in the central nervous system, in the cortex, in the nucleus caudatus, in the nucleus accumbens and in the hippocampus (Ward et al., 1995). The receptor antagonists of 5-HT₆ receptors are responsible for the regulation of the neurotransmitter functions of the stimulating amino acids, dopamine and acethylkoline (Dawson and Nguyen, 2000). These neurotransmitters have an essential role in the regulation of the mood, and the maitenance of the memory and psychical activity.

It was found that the compounds of general formula (I) are selective inhibitors of the 5-HT₆ receptors. This unique receptor profile allows the application of the compounds of the present invention in the disorders, arising from disorders of the central nervous system and/or medical disorders such as the disorders of the heart, cardiovascular system or the kidneys. The aim of the present invention is to prepare novel benzofuran derivatives effective in the treatment of 5HT₆ receptor related disorders of the central nervous system and/or cardiovascular system.

The above aim can be reached by the new selective 5HT₆ receptor binding benzofuran derivatives of general formula (I),

(I) wherein,

Z represents a hydrogen atom, Ci_-4 acyl group, Ci_-6 alkyl sulfonyl group, phenyl sulfonyl group substituted with one or more halogen atom; or naphthyl sulfonyl group optionallly substituted with a halogen atom, or tetrahydro naphthyl sulfonyl group, (lS)(+)-10-camphor-sulfonyl group, (lR)(-)-10- camphor-sulfonyl group, or benzofuranyl sulfonyl group, substituted with a halogen atom and C_1-4 alkyl group, Y represents C_2-6 alkylene group,

R¹ and R represent, independently, a hydrogen atom, C_1-4 alkyl group, benzyl group, or together with one or more halogen atoms, trifluoromethyl group, or C_1-4 alkoxy group substituted 4-phenyl-piperazin-l-yl group; and/or their pharmaceutically suitable acid addition salts.

The definition of the substituents are detailed below.

In the description and claims a halogen atom is primarily fluoro, chloro, bromo or iodo atom, preferably chloro or bromo atom.

A C_M acyl group represents acetyl, propionyl, or butyryl, preferably acetyl group. A C^alkylsulfonyl group represents methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, .fee-butyl-, pentyl- or hexylsulfonyl-, preferably isopropylsulfonyl group.

A phenylsulfonyl group substituted with one or more halogen atoms represents o-, m-, or^-chloro-phenyl, 2,3-dichloro-phenyl-, 2,4-dichloro-phenyl, 2,5-dichloro-phenyl-, 2,6-dichloro-phenyl, 3,5-dichloro-phenyl-, preferably 2,5- dichloro-phenyl sulfonyl group.

A naphthyl-sulfonyl group optionally substituted with halogen atom represents 1-naphtyl, 2-naphthyl-, l-chloro-2-naphthyl-, 2-chloro-l-naphthyl-, 3-chloro-l-naphthyl-, 4-chloro-l-naphthyl-, 5-chloro-l-naphthyl- l-bromo-2- naphthyl-, 2-bromo-l-naphthyl-, 3-bromo-l-naphthyl-, 4-bromo-l-naphthyl-, 5- bromo-1 -naphthyl-sulfonyl-, preferably 1-naphthyl, 2-naphthyl, 4-chloro-l- naphthyl, 5-chloro-l -naphthyl-sulfonyl group.

A benzofuranyl-sulfonyl group, substituted with a halogen atom and C_1-4 alkyl group . represents 5-chloro-3-methyl-benzofuran-2-, 5-chloro-3-ethyl- benzofuran-2-, 5-chloro-3-propyl-benzofuran-2-, 5-chloro-3-isopropyl- benzofuran-2-, 5-chloro-3-butyl-benzofuran-2-sulfonyl, preferably 5-chloro-3- methyl-benzofuran-2 -sulfonyl group.

A C_1-6 alkylene group represents ethylene, propylene, butylene, pentylene, hexylene, ethylene-, propylene-, butylene, pentylene, or hexylene group, preferably ethylene or propylene group.

A CM alkyl-group represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, preferably methyl or ethyl group.

A 4-phenyl-piperazine-l-yl group substituted with one or more halogen atoms, trifluoromethyl group or C_1-4 alkoxy group represents 4-(2-chloro- phenyl)-piperazin-l-yl, 4-(3-chloro-phenyl)-piperazin-l-yl, 4-(4-chloro-phenyl)- piperazin- 1 -yl, 4-(2-bromo-phenyl)-piperazin- 1 -yl, 4-(3 -bromo-phenyl)- piperazin- 1 -yl, 4-(4-bromo-phenyl)-piperazin- 1 -yl, 4-(2-trifluoro-methyl- phenyl)-piperazin- 1 -yl, 4-(3-trifluoro-methyl-phenyl)-piperazin- 1 -yl, 4-(4- trifluoro-methyl-phenyl)-piperazin- 1 -yl, 4-(2-methoxy-5-trifluoro-methyl- phenyl)-piperazin- 1 -yl, 4-(2-ethoxy-5-trifluoro-methyl-phenyl)-piperazin- 1 -yl-, 4-(2-propoxy-5-trifluoro-methyl-phenyl)-piperazin- 1 -yl-, 4-(2-butoxy-5- trifluoro-methyl-phenyl)-piperazin- 1 -yl-, 4-(5 -methoxy-2-trifluoro-methy 1- phenyl)-piperazin-l-yl group, preferably 4-(3-chloro-phenyl;-piperaafiKi/3fl-n4fl (3-trifluoro-methyl-phenyl)-piperazin- 1 -yl-, or 4-(2-methoxy-5-trifluoro-methyl- phenyl)-piperazin-l-yl group.

A preferred subgroup of selective 5HT₆ receptor binding benzofuran derivatives of the invention consists of the benzofuran derivatives of general formula (I)

(I)

wherein,

Z represents a hydrogen atom, C_1-2 acyl group, C_1-3 group alkyl sulfonyl group, phenyl sulfonyl group substituted with one or more halogen atom; or naphthyl sulfonyl group optionally substituted with a halogen atom, or tetrahydro naphthyl sulfonyl group, (lS)(+)-10-camphor-sulfonyl group, (lR)(-)-10-camphor-sulfonyl group, or benzofuranyl sulfonyl group, substituted with a halogen atom and Ci_-2 alkyl group, Y represents C₂.₃ alkylene group,

R¹ and R² represent, independently, a hydrogen atom, C_1-2 alkyl group, benzyl group, or together with one or more halogen atoms, trifluoromethyl group, or Cj-₄ alkoxy group substituted 4-phenyl-piperazin-l-yl group; and/or their pharmaceutically suitable acid addition salts.

The especially preferred benzofuran derivatives of general formula (I) are the following:

5-Chloro-2-naphthalenesulfonyl-jV-{2,3-dihydro-2,2-dimethyl-7-[2-(dimethyl- amino)-ethoxy] -benzofuran-5 -yl } -amide,

4-Chloro-l-naphthalenesulfonyl-N-{7-[2-(dimethylamino)-ethoxy]-2,3-dihydro- 2,2-dimethyl-benzofuran-5-yl} -amide. Compounds of general formula (I) of the invention and tnetr pharmaceutically suitable acid addition salts can be prepared according by the preparation process, wherein the aromatic nitro group of compound of general formula (VII)

(VII) wherein Y, R¹ and R² represent as defined in claims 1 and 2, is reduced, and the obtained compound of general formula (VIII)

(VIII) wherein Y, R¹ and R² represent as defined in claims 1 and 2, is amidated with a compound of general formula (IX)

HaI - Z (IX)

wherein Hal represents a halogen atom, Z represent as defined in claims 1 and 2 or with an acid anhydride of general formula (X)

(X) wherein Z represents as defined in claims 1 and 2; or the aromatic nitro group of compound of general formula (IV)

(IV) wherein Y represents as defined in claims 1 and 2, is reduced, and the obtained compound of general formula (XIII)

(XIII) wherein Y represents as defined in claims 1 and 2, is reacted with a compound of general formula (IX)

HaI - Z (IX)

wherein Hal represents a halogen atom, Z represent as defined in claims 1 and 2, acid anhydride of general formula (X)

_/Z

O

^z

(X) wherein Z represents as defined in claims 1 and 2, and the obtained compound of general formula (XIV)

(XIV) wherein Z and Y represent as defined in claims 1 and 2, is reacted with a halogenating agent, and the obtained compound of general formula (XV)

(XV) wherein Hal represents a halogen atom, Z and Y represent as defined in claims 1 and 2, is reacted with an amine of general formula (VI)

HN

(VI) wherein, R¹ and R² represent as defined in claims 1 and 2; then the obtained compound of general formula (I) wherein Z, Y, R¹ and R² represent as defined in claims 1 and 2, if desired pharmaceutically suitable acid addition salts of compound of general formula (I) are obtained.

A further subject of our invention is a process for the preparation of compounds of general formula (VII) wherein a. the compound of formula (II)

is reacted with a compound of general formula (III),

HO - Y - Hal

(III) wherein Hal represents a halogen atom, Y represents as defined in claims 1 and 2, and the obtained compound of general formula (IV),

(IV) wherein Y represents as defined in claims 1 and 2, is halogenated and the obtained compound of general formula (V),

(V) wherein Hal represents a halogen atom, Y represents as defined in claims 1 and 2, is reacted with a compound of general formula (VI)

R¹

HN J

R2

(VI) wherein R¹ and R² represent as defined in claims 1 and 2, or b. the compound of formula (II)

is reacted with a compound of general formula (XI)

HaI₁-Y-HaI

(XI) wherein Hal and Hal¹ represent the same or a different halogen atom, and the obtained compound of general formula (V),

wherein Y represents as defined in claims 1 and 2 and Hal represents as αenneα above, is reacted with a compound of general formula (VI),

/ ^R1 HN

^NR²

(VI) wherein R¹ and R² represent as defined in claims 1 and 2; or c. the compound of formula (II)

(H) is reacted with a compound of general formula (XII)

(XII) wherein Hal, Y, R¹ and R² represent as defined above.

A further subject of our invention are new compounds of general formula (IV), (V), (VII), (VIII), (XIII), (XIV) and (XV). The invention also relates to all possible isomer, tautomer, or crystalline forms of the compounds.

The reaction of compound of formula (II) with a compound of general formula (III) is carried out in water, or in aqueous alcoholic media, preferably in water in the presence of a phase transfer catalyst, preferably a tetraalkyl ammonium halogen, more preferably triethylbenzylammonium chloride and a base, preferably alkali metal hydroxide, more preferably sodium hydroxide. The product can be obtained by a method known in itself, preferably the product is dissolved in a water-immiscible solvent, the phases are separated, the organic phase is washed with water, dried and evaporated. The conversion of ω-hydroxyalkoxy benzofuran derivatives υi gcuciai formula (IV) to a ω-haloalkoxy derivative of general formula (V), is carried out with a known halogenizing agent, preferably with a phosphor-trihalogenide, more preferably with phosphor-tribromide in the presence of an indifferent solution in relation of the present reaction, preferably with an aromatic or halogenated solvent, more preferably in toluene, or dichloromethane, between a temperature of 0 C⁰ and room temperature, preferably between 0 C⁰ and 10 C⁰, more preferably between 0 and 5 C⁰. The product can be obtained by a method known in itself, for example after evaporating the solutions with chromathography or the residue is dissolved in a water immiscible solvent, preferably with a halogenated solvent, more preferably in dichloromethane, and the solvent is washed with water, dried and evaporated. When required the evaporated residue is purified with chromathography.

The reaction of ω-haloalkoxy derivatives of general formula (V) with the amine derivatives of general formula (VI) is carried out in the presence of an indifferent solution in relation of the present reaction, in water or alcohol, in halogenated solvents, or in a mixture thereof. Especially preferably the media is water, a mixture of water and dichloromethane and methanol, or a mixture of water and isopropanol, when required the reaction is carried out in the presence of a phase transfer catalyst and a base. As phase transfer catalyst a tertiary ammonium salt, preferably a trimethylbenzylammonium chloride can be used. As a base an alkali metal hydroxide, preferably sodium hydroxide is used. The reaction is performed at a temperature between 10 C⁰ and 50 C⁰, preferably between 15 C⁰ and 30 C⁰, more preferably at room temperature. The obtained ω- monoaminoalkoxy, or ω-dialkylaminoalkoxy derivatives general formula (VII) can be separated by a method known in itself, usually, after removing the organic solvents, the product is dissolved in a water immiscible solvent, the solution is washed with water, dried, and evaporated until dry.

The reduction of ω-monoaminoalkoxy, or ω-dialkylamino-alkoxy derivatives of general formula (VII) to an aniline derivative of general formula (VIII) is carried out by hydrogenation or by a reduction with hydrazine hydrate, in the presence of an indifferent solution in relation of the present reaction, preferably in alcohol, more preferably in methanol, or in ethanol. The reaction is performed in the presence of palladium (5 - 10 %) or plauuum/ L.<UUUII υαuupi (5 - 10 %). The product is separated after filtering the catalyst, by evaporation until dry or by washing the crystalline product with ether.

The reaction of aniline derivatives of general formula (VIII) is performed with an acyl or sulfonyl-halogenide of general formula (IX), or an acid anhydride of general formula (X). Thus, compounds of general formula (I) are obtained. The reaction is carried out in the presence of an indifferent solution in relation of the present reaction, preferably in a halogenated solvent, more preferably in dichloromethane in the presence of pyridine, at a temperature between 0 and 40 C⁰, preferably at room temperature. The product is separated by adding to the reaction mixture water, or aqueous sodium hydrogencarbonate (10 %) and the phases are separated, the organic is washed with water, dried, then evaporated. The obtained crystals are washed with ether and when required can be purified with chromathography.

The reaction of 2,2-dimethyl-5-nitro-2,3-dihydro-benzofuran-7-ol, compound of formula (II) is carried out with an α,ω-dihalogen derivative of general formula (XI) in the presence of aqueous alkali metal hydroxide, preferably sodium hydroxide and in the presence of a tertiary ammonium halogenide, preferably triethylbenzylammonium chloride catalyst. The obtained ω-haloalkoxy derivative of general formula (V) can be separated after cooling the reaction mixture by an extraction with a water immiscible organic solvent, preferably with ether, and thereafter the organic solvent is washed, dried, then evaporated.

According to another preferable manner of the reaction of 2,2-dimethyl- 5-nitro-2,3-dihydro-benzofuran-7-ol of formula (II) with an α,ω-dihalogen derivative of general formula (XI) is carried out in dimethylformamide in the presence of anhydrous potassium carbonate at 110 C⁰. The ω-haloalkoxy derivative of general formula (V) is performed by the aqueous dilution of the reaction mixture, mixing the α,ω-dihalogen of general formula (XI) with a water immiscible solvent, washing, drying, then evaporating until dry.

The reaction of 2,2-dimethyl-5-nitro-2,3-dihydro-benzofuran-7-ol of formula (II) with an aminoalkyl halogenide of general formula (XII) is carried out in absolute alcohol, preferably in absolute ethanol, in the presence of sodium ethylate, under boiling the reaction mixture. The product can De ooiameα again by a method known in itself, accordingly after cooling the reaction mixture by filtering and calibrating the pH to pH = 6, then dividing between water and a water immiscible organic solvent, preferably between water and toluene. The ω- monoaminoalkoxy, or ω-dialkylaminoalkoxy derivative of general formula (VII) in the aqueous phase is isolated by calibrating the pH of the solution to 12, then extracting with a water immiscible organic solvent, preferably with dichloromethane, drying and evaporating.

According to another preferable method of the reaction of 2,2-dimethyl- 5-nitro-2,3-dihydro-benzofuran-7-ol of formula (II) with an aminoalkyl halogenide of general formula (XII) is carried out in the mixture of dimethylformamide and xylene with anhydrous potassium carbonate at 110 C⁰. The obtained ω-monoaminoalkoxy, or ω-dialkylaminoalkoxy derivative of general formula (VII) can be separated by cooling the reaction mixture, adding water to it, and adding to the product a water immiscible solvent, preferably dichloromethane, then washing the solvent with water, drying and evaporating.

According to another preferable manner of the reaction of 2,2-dimethyl- , 5-nitro-2,3-dihydro-benzofuran-7-ol of formula (II) with an aminoalkyl halogenide of general formula (XII) is carried out in dimethylformamide and pure dimethylformamide, in the presence of anhydrous potassium carbonate at 60 C⁰. The obtained ω-monoaminoalkoxy, or ω-dialkylaminoalkoxy derivative of general formula (VII) can be separated by cooling the reaction mixture, adding water to it, and adding to the product a water immiscible solvent, preferably dichloromethane, then washing the solvent with water, drying and evaporating.

According to another preferable manner of the reaction of 2,2-dimethyl- 5-nitro-2,3-dihydro-benzofuran-7-ol of formula (II) with an aminoalkyl halogenide of general formula (XII) is carried out in dimethylformamide in a two-phase-system under boiling, in the presence of an aqueous alkali metal hydroxide, preferably sodium hydroxide, a water immiscible organic solvent, preferably dichloromethane, and a catalyst, a tertiary organic ammonium halogenide, preferably triethyl-benzyl-ammonium chloride. The obtained ω- monoaminoalkoxy, or ω-dialkylaminoalkoxy derivative of general formula (VII) can be separated according to the above, by dividing the proαuci oeiween waicr and a water immiscible solvent, preferably dichloromethane, then washing the solvent with water, drying and evaporating.

The reduction of aromatic nitro group of the hydroxyalkoxy benzofuran derivatives of general formula (IV) is carried out by hydrogenation of a hydroxy-aniline derivative of general formula (XIII) in an alkanol, preferably in methanol, in the presence of a palladium/carbon (5-10 %) or platinum/carbon (5-10 %), preferably platinum/carbon catalyst. The obtained hydroxy-aniline derivative of general formula (XIII) can be separated after filtering the catalyst, is carried out by the evaporation of the reaction mixture.

The reaction of hydroxy-aniline derivative of general formula (XIII) and an acyl, or sulfonyl halogenide of general formula (DC), or an acid anhydride of general formula (X) can be obtained the hydroxyalkoxy acid amides of general formula (XIV) in the presence of an indifferent solution in relation of the present reaction, preferably a halogenated solvent, more preferably in dichloromethane, in the presence of pyridine at a temperature between 0 and 40 C⁰, preferably at room temperature. The product can be separated from the reaction mixture by dividing with water, or with aqueous sodium hydrogencarbonate (10 %) then separating the phases and washing the organic phase with an aqueous solvent, drying and evaporating the product. The obtained crystals are washed with ether and when required can be purified with chromathography.

The conversion of hydroxy-alkoxy acid amides of general formula (XIV) to halo-alkoxy acid amides of general formula (XV) is carried out with a know halogenating agent, preferably with a phosphor-trihalogenide, more preferably phosphor-tribromide in the presence of an indifferent solution in relation of the present reaction, preferably an aromatic, or halogenated solvent, more preferably in toluene, or in dichloromethane, at 0 C⁰ and room temperature, preferably at a temperature between 0 and 10 C⁰, more preferably between 0 and 5 C⁰.

The product can be obtained by a method known in itself, for example after evaporating the solvent purified by chromathography, or dissolving the residue in a water immiscible solvent, preferably in a halogenated solvent, more preferably in dichloromethane, and washing the solution with water and drying and evaporating the product. When required the evaporaxeα resiαue can oe purified with chromatography.

The reaction of halo-alkoxy acid amides of general formula (XV) with an amine of general formula (VI) is carried out in the presence of an indifferent solution in relation of the present reaction, preferably in a halogenated solvent, more preferably in dichloromethane, in the presence of a tertiary amine, preferably triethylamine at room temperature. The obtained compound of general formula (I) can be separated from the reaction mixture by evaporating the mixture, dividing the residue between water and a water immiscible solvent, preferably dichloromethane then separating the phases and washing the organic phase with water drying and evaporating the product. When required the product can be purified with chromathography.

A further subject of the invention is a pharmaceutical composition comprising as active ingredient one or more compounds of general formula (I) as defined in claims 1 to 3 and/or pharmaceutically suitable acid additional salts thereof and one or more pharmaceutically applicable diluent, excipient and/or inert carrier.

Pharmaceutical compositions of the present invention comprise a therapeutically effective dose of one or more compounds of general formula (I) and/or pharmaceutically suitable acid additional salts thereof and one or more pharmaceutically applicable diluent, excipient and/or inert carrier.

The pharmaceutical compositions containing compounds of general formula (I) and/or pharmaceutically suitable acid additional salts thereof are suitable for peroral, parenteral (including subcutaneous, intramuscular and intravenous mode of administration), buccal, sublingual, nasal or rectal administration or for local treatment, and can be solid or liquid.

The solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc., and optionally comprise binding agents such as gelatine, sorbitol, poly(vinyl-pyrrolidone) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, poly (ethyleneglycol), silica etc.; werang agents sucn as sodium laurylsulfate etc. as the carrier.

The liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and may comprise e.g. suspending agents such as gelatine, carboxymethylcellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propyleneglycol, ethanol etc.; preservatives such as methyl p-hydroxybenzoate etc. as the carrier.

Typical parenteral compositions consising of a solution or suspension of the compound of formula (I) and/or and/or pharmaceutically suitable acid additional salts thereof in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

Compositions of the present invention for nasal administration containing a compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof may conveniently be formulated as aerosols, drops, gels and powders.

Aerosol formulations of the present invention typically comprise a solution or fine suspension of the compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in a single or multidose quantities in sterile form is a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas, such as compressed air or an organic propellant, such as a fluorochlorohydrocarbon. The aerosol dosages form can also take the form af a pump-atomiser.

Compositions of the present invention containing a compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof are suitable for buccal or sublingual administration including tamets, lozenges ana pastilles, wherein the active ingredient is formulated with a carrier, such as sugar and acacia, tragacanth, or gelatine, glycerine etc.

Compositions of the present invention containing a compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.

Compositions of the present invention containing a compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof for transdermal administration include ointments, gels and patches.

Dosage forms listed above as well as other dosage forms are known per se, see e. g. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990).

The pharmaceutical compositions of the invention are prepared by admixing a selective 5HT₆ receptor binding benzofuran derivative of general formula (I) or a pharmaceutically suitable acid addition salt thereof to one or more carrier (s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se. Useful methods are known from the literature, e. g. Remington's Pharmaceutical Sciences.

The pharmaceutical compositions of the invention contain, in general, 0.1 to 95.0 per cent by mass of a benzofuran derivative of formula (I) or a pharmaceutically suitable acid addition salt thereof. The amount of the active ingredient mixed with the suitable carrier, wich is for one administration can be different depending on the treated recipient or the route of administration.

The typical dosege for adult patients is 0,1-20 mg of a compound of formula (I) and/or pharmaceutically suitable acid additional salts thereof, which can be administered once or portions. The actual dose depends on many factors for example: the age, sex, weight or general health condition of the patient etc. A further subject of the invention use of a pharmaceutical composmon comprising as active ingredient a therapeutically effective dose of one or more compounds of general formula (I) as defined in claims 1 to 3 and/or pharmaceutically suitable acid additional salts for the treatment and prevention of 5HT₆ receptor relating disorders of the central nervous system and/or cardiovascular disorders.

In addition the invention relates to the use of one or more compounds of general formula (I) as defined above and/or pharmaceutically suitable acid additional salts thereof, in the manufacture of a medicament for the prevention and/or treatment of 5HT₆ receptor relating disorders of the central nervous system and/or cardiovascular disorders.

Furthermore our invention relates to a method of treatment, administering for a patient suffering from 5HT₆ receptor relating disorders, especially disorders of the central nervous system and/or cardiovascular disorders a non-toxic dose of one or more compounds of general formula (I) as defined in claims 1 to 3 and/or pharmaceutically suitable acid additional salts thereof.

It has been found that the compounds of the invention, namely compounds of general formula (I) are selective 5-HT₆-receptor antagonists. This unique receptor profile makes possible the use of the compounds in the treatment of such diseases, which have in the background disorders of the central nervous system and/or some other internal disorders, such as problems of the heart-circulatory system, or diseases of the kidney.

Thus, it is expected that the compounds of the invention are well suited for the prevention and/or treatment of the following disorders of the mental and cardiovascular system such as depression, the different types of anxiety (such as Generalized Anxiety Disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia), schisofrenia, schisoaffective disorder, different mood disorders, psychosomatic disorders (for example hypertonia, stomach ulcer etc.), catastrophes of the brain, cell death oh a defined area of the central nervous system, mental disorders caused by the cell deaths of the brain (pi.: Alzheimer disease, stroke, dementias etc.), disorders of the circadian rhythm and sleep disorders. We emphasize that among the cardiovascular disorders, the compounds of the present invention in the treatment of hypertonia are effective.

The following experiments demonstrate the physiological effectiveness of the compounds of the present invention.

Receptor binding tests

Receptors are from different region of the brain of Wistar-rats with a body weight of 20-200 g. 5-HT₆ receptors are human cloned receptors. The protein content of the membrane preparations was defined according to the method of Lowry (1951). The following table contains the basic data of the receptor binding:

Compounds having less than 30 nM K₁ are demonstrated in Table I. Table I.

According to the above results it can be stated, that the compounds of general formula (I) have selective binding affinity to the central 5-HT₆ receptors, but do not show strong considerable affinity to the different central 5-HT subtype receptors.

The invention is further elucidated by means of the following Examples, without restricting the scope of the present invention to the examples.

Example 1 2,2-Dimethyl-5-nitro-7-(2-hydroxy-ethoxy)-2,3-dihydro-benzofuran

To 2,2-dimethyl-5-nitro-2,3-dihydro-benzofuran-7-ol (33.0 g, 0.16 mol) a solution of sodium hydroxide (8.96 g, 0.224 mol) with water (100 ml), triethyl- benzyl-ammonium chloride (0.68 g) and 2-bromo ethanol (34 ml, 60 g, 0.48 mol) are added, then the reaction mixture is boiled for 18 hours under stirring. After cooling the aqueous phase is decanted from the brown oil, it is dissolved in dichloromethane (400 ml), and the obtained solution is extracted with a solution of sodium hydroxide (112 g) and water (120 ml) and with water again (2 x 100 ml), dried over anhydrous sodium sulfate, evaporated until dry in vacuum. Thus, 37.5 g (92.5 %) of the yellow, crystalline product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (CDCl₃): δ, ppm 7.77 d (IH), 7.73 d (IH), 4.22 1 (2H), 4.02 1 (2H), 3.10 s (2H), 1.56 s (6H). Example 2 2,2-Dimethyl-5-nitro-7-(3-hydroxy-propoxy)-2,3-dihydro-benzofuran

To 2,2-dimethyl-5-nitro-2,3-dihydro-benzofuran-7-ol (16.72 g, 0.08 mol), a solution of sodium hydroxide (4.48 g, 0.112 mol) and water (48 ml), triethyl- benzyl ammonium chloride (0.35 g) and 3-bromo-propanol (21.7 ml, 33.4g, 0.24 mol) are added, then the reaction mixture under stirring is boiled for 16 hours. After cooling the aqueous phase is decanted from the brown oil, it is solved in dichloromethane (200 ml), the obtained solution is extracted with water (2 x 100 ml), and dried over anhydrous sodium sulfate, then evaporated until dry in vacuum. Thus, 21.0 g (98.3 %) of the yellow, crystalline product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (CDCl₃): δ, ppm 7.76 d (IH), 7.74 d (IH), 4.27 1 (2H), 3.87 t (2H), 3.10 s (2H), 2.10m (2H), 1.55 s (6H).

Example 3 2_f2-Dimethyl-5-nitro-7-(2-chloro-ethoxy)-2,3-dihydro-benzofuran

To 2,2-dimethyl-5-nitro-2,3-dihydro-benzofuran-7-ol (20.9 g, 0.1 mol) a solution of sodium hydroxide (5.56 g, 0.129 mol) and water (63 ml), triethyl- benzyl-ammonium chloride (0.4 g) and l-bromo-2-chloro-ethane (18.72 ml, 32.26 g, 0.225 mol) are added, then the reaction mixture is boiled under stirring for 5 hours. After cooling from the precipitated yellow, oily crystals the aqueous phase is decanted, to the residue ether is added, filtered, washed with water, then with ether. Thus, 20.52 g (75.5 %) of the crystalline product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (CDCl₃): δ, ppm 7.78 d (IH)), 7.73 d (IH), 4.38 1 (2H), 3.85 t (2H), 3.10 d (2H), 1.56 s (6H).

Example 4 2,2-Dimethyl-5-nitro-7-(3-chloro-propoxy)-2,3-dihydro-benzofuran

To 2,2-dimethyl-5-nitro-2,3-dihydro-benzofuran-7-ol (10.48 g, 0.05 mol) a solution of sodium hydroxide (2.8 g, 0.112 mol) and water (32 ml), triethyl- benzyl-ammonium chloride (0.2 g) and l-bromo-S-chlorυ-pxυpcuic ^ i.κ mi, 17.37g, 0.113 mol) are added. Then the reaction mixture is boiled under stirring for 4 hours. After cooling the precipitated yellow crystals are filtered, then washed with water and ether. Thus, 20.52 g (75.5 %) of the crystalline product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (CDCl₃): δ, ppm 7.76 d (IH), 7.72 d (IH), 4.26 t (2H), 3.76 t (2H), 3.10 s (2H), 2.30 qi (2H), 1.56 s (6H).

Example 5 2,2-Dimethyl-5-nitro-7-(3-bromo-propoxy)-2,3-dihydro-benzofuran

To the solution of dimethylformamide (200 ml) under stirring anhydrous potassium carbonate (27.6 g, 0.2 mol), ) 2,2-dimethyl-5-nitro-2,3-dihydro- benzofuran-7-ol (41.8 g, 0.2 mol) and 1,3-dibromo-propane (104.2 ml, 201.9 g, 1 mol) are added, then the reaction mixture is stirred on an oil bath at 110 C⁰ for 30 minutes. After cooling to the reaction mixture water (500 ml) is added, and extracted with dichloromethane (2 x 500 ml). The united phase of dichloromethane is extracted with potassium carbonate solvent (2 x 250 ml, 10 %), with water (300 ml), then dried over anhydrous sodium sulfate. The solution of dichloromethane is filtered, then evaporated until dry in vacuum. Thus, 53.3 g (80.6 %) of the crystalline title product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (CDCl₃): δ, ppm 7.77 d (IH), 7.74 d (IH), 4.25 t (2H), 3.62 t (2H), 3.10 s (2H), 2.38 qi (2H), 1.56 s (6H).

Example 6 2,2-Dimethyl-5-nitro-7-(2-dimethylamino-ethoxy)-2,3-dihydro-benzofuran

Sodium metal (2.94 g, 0.0735 mol) is dissolved in absolute ethanol (140 ml) under stirring, and the solution is cooled to room temperature, then 2- dimethylamino-ethylchloride hydrochloride (10.58 g, 0.0735 mol) is added to the a reaction mixture and it is stirred for 15 minutes at room temperature. Then 2,2-dimethyl-5-nitro-2,3-dihydro-ben2ofuran-7-ol (10.25 g, 0.049 mol) is added to the reaction mixture and it is boiled for 16 hours under siunug. ΛIICI uυυmig the reaction mixture is filtered, the pH of residue is calibrated to pH=6 with aqueous hydrochloric acid (1:1), then evaporated. The residue is diluted with water (100 ml), then is extracted with toluene (2x30 ml). The pH of the aqueous phase is calibrated to pH=12 with cc. ammonium hydroxide solution, the product is extracted with dichloromethane (2x60 ml), the united organic solvent is dried over anhydrous sodium sulfate, filtered and evaporated in vacuum until dry. Thus, 6.6 g (46.7 %) of the yellow-brown crystalline product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (CDCl₃): δ, ppm 7.75 d (IH), 7.72 d (IH), 4.20 1 (2H), 3.10 s (2H), 2.78 t (2H), 2.35 s (6H), 1.55 s (6H).

Example 7 2,2-Dimethyl-5-nitro-7-(3-dimethylamino-propoxy)-2,3-dihydro-benzofuran

To dimethylformamide (80 ml) at room temperature under stirring anhydrous potassium carbonate (13.8 g, 0.1 mol), 2,2-dimethyl-5-nitro-2,3-dihydro- benzofuran-7-ol (20.9 g, 0.1 mol), and a solution 3-dimethylamino-propyl- chloride and xylene (200 ml, 38 %) are added, then the reaction mixture is stirred on an oil bath at 110 C⁰ for 40 minutes. After cooling to the reaction mixture water (250 ml) is added and extracted with dichloromethane (3 x 400 ml). The united phase of dichloromethane is extracted with a potassium carbonate solution (2 x 200 ml, 10 %), with water (300 ml), then dried over anhydrous sodium sulfate. The solution of dichloromethane is filtered, then evaporated until dry in vacuum. Thus, 25.6 g (87.0 %) of the crystalline product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (CDCl₃): δ, ppm 7.74 d (2H), 4.171 (2H), 3.09 s (2H), 2.44 1 (2H), 2.25 s (2H), 2.01 qi (2H), 1.56 s (6H). Example 8 2,2-Dimethyl-5-nitro-7-(3-dimethylamino-propoxy)-2,3-dihydro-benzofuran

To a solution of sodium hydroxide (3.4 g, 0.085 mol) with water (30 ml) at room temperature dichloromethane (30 ml), triethylbenzyl ammonium chloride (0.3 g), 2,2-dimethyl-5-nitro-2,3-dihydro-benzofuran-7-ol (8.37 g, 0.04 mol), and 3-dimethylamino-propyl-chloride-hydrochloride (200 ml) are added, then the reaction mixture is boiled under stirring for 16 hours. After cooling dichloromethane (100 ml) is added to the reaction mixture, extracted with water (100 ml), then dried over anhydrous sodium sulfate. After filtering and evaporating in vacuum the solution of dichloromethane 5.15 g (43.7 %) of the crystalline product are obtained, which is identical with the product obtained according to the title product of example 7.

Example 9 2,2-Dimethyl-5-nitro-7-(3-dimethylamino-propoxy)-2,3-dihydro-benzofuran

To dimethylformamide (10 ml) 2,2-dimethyl-5-nitro-2,3-dihydro-benzofuran-7- ol (2.09 g, 0.01 mol), anhydrous potassium carbonate (1.38 g. 0.01 mol) and 3- dimethylamino-propyl-chloride hydrochloride (1.73 g, 0.011 mol) are added, then the reaction mixture is stirred on an oil bath at 60 C⁰ for 18 hours. The obtained reaction mixture is evaporated in vacuum until dry, to the residue water (20 ml) is added, then the solution is extracted with dichloromethane (3x30 ml). The united organic phases are dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. Thus, 2.62 g (89.1 %) of the title product are obtained, which is identical with the product obtained according to the title product of example 7.

Example 10 2,2-Dimethyl-5-nitro-7-(3-dimethylamino-propoxy)-2,3-dihydro-benzofuran

To a solution of 2,2-dimethyl-5-nitro-7-(3-bromo-propoxy)-2,3-dihydro-benzo- furan (7.30 g, 0.022 mol) with dichloromethane (100 ml) under stirring, at room temperature methanol (70 ml), aqueous dimethylamine soiuxion pυ πu, oυ yo; and 0.2 g trimethyl-benzyl ammonium chloride are added, then the reaction mixture is boiled under stirring for 14 hours. The obtained reaction mixture is evaporated until dry in vacuum, the residue is dissolved in dichloromethane (250 ml), is extracted with a solution of sodium hydroxide (120 ml, 10 %) and sodium chloride (50 g), then dried over anhydrous sodium sulfate. After filtering it is evaporated in vacuum. Thus, 5.21 g (80.4 %) of the title product are obtained, which is identical with the product obtained according to the title product of example 7.

Example 11

2,2-Dimethyl-5-nitro-7-{2-[4-(3-trifluor-methyl-phenyl)-piperazine-l-yl]- ethoxy}-2,3-dihydro-benzofuran

To a solution of sodium hydroxide (1.6 g, 0.040mol) and water (20 ml) l-(3- trifluoromethyl-phenyl)-piperazine-hydrochloride (5.33 g, 0.02 mol) and 2,2- dimethyl-5-nitro-7-(2-chloro-ethoxy)-2,3-dihydro-benzofuran (5.43 g, 0.02 mol) are added, then the reaction mixture is boiled under stirring for 16 hours. After cooling dichloromethane (50 ml) is added to the reaction mixture, the phases are separated, the solution of a dichloromethane is washed with water, dried over anhydrous sodium sulfate, filtered, then evaporated until dry in vacuum. The residual crystalline product is mixed with ether, filtered and washed thoroughly with ether. Thus, 6.14 g (66.1 %) of the title product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (CDCl₃): δ, ppm 7.77 s (IH), 7.73 s (IH), 7.26-7.38 m (IH), 7.04-7.11 m (3H), 4.28 1 (2H), 3.15-3.29 m (4H), 3.09 s (2H), 2.91 1 (2H), 2.73-2.78 m (4H), 1.56 s (6H).

Example 12

2,2-Dimethyl-5-ntiro-7-{2-[4-(2-methoxy-5-trifluoro-methyl-phenyl)- piperazine-l-yl]-ethoxy}-2,3-dihydro-benzofuran

To the solution of sodium hydroxide (0.93 g, 0.0223 mol) with water (10 ml) 1- (2-methoxy-5-trifluoromethyl-phenyl)-piperazine hydrochloride (3.7 g, 0.011 mol) and 2,2-dimethyl-5-nitro-7-(2-chloro-ethoxy)-2,3-dihydro-benzofuran (2.85 g, 0.0105 mol) are added, then the reaction mixture is boiled under stirring for 8.5 hours. After cooling, to the reaction mixture dichloromethane (30 ml) is added, the phases are separated, the solution of a dichloromethane is washed with water, dried over anhydrous sodium sulfate, filtered, then evaporated until dry in vacuum. The residual crystalline product is mixed with ether, filtered and washed thoroughly with ether. Thus, 3.97 g (76.3 %) of the title product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (DMSO- d₆): δ, ppm 7.81 d (IH), 7.79 d (IH), 7.29-7.33 m (IH), 7.08-7.13 m (2H), 4.25 t (2H), 3.87 s (3H), 3.22 m (4H), 3.13 s (2H), 3.03 m (2H), 2.76-2.81 m (4H), 1.49 s (6H).

Example 13

2,2-Dimethyl-5-nitro-7-{3-[4-(3-chloro-phenyl)-piperazin-l-yl)-propoxy]}-2,3- dihydro-benzofuran

To the solution of sodium hydroxide (0.8 g, 0.02 mol) and water (15 ml) 4-(3- chloro-phenyl)-piperazine (3.9 g, 0.02 mol) and 2,2-dimethyl-5-nitro-7-(3- chloro-propoxy)-2,3-dihydro-benzofuran (5.7 g, 0.02 mol) are added, then the reaction mixture is boiled under stirring for 16 hours. After cooling to the reaction mixture dichloromethane (100 ml) is added, the phases are separated, the solution is washed with dichloromethane and water, dried over anhydrous sodium sulfate, filtered, then evaporated until dry in vacuum.The residual crystalline product is mixed with ether, filtered and washed thoroughly with ether. Thus, 7.33 g (82.1 %) of the title product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (DMSOd₆): δ, ppm 7.79 d (IH), 7.69 d (IH), 7.20 1 (IH), 6.85-6.93 m (2H), 6.77 dd (IH), 4.16 t (2H), 3.14-3.19 m (4H), 2.51 m (6H), 1.93 qi (2H), 1.48 s (6H).

Example 14

2,2-Dimethyl-5-nitro-7-{3-[4-(2-methoxy-5-trifluro-methyl-phenyl)-piperazin- l-yl)-propoxy]}-2,3-dihydro-benzofuran To the solution of sodium hydroxide (1.76 g, 0.049 mol) and water (15 ml) 4-(2- methoxy-5-trifluoro-methyl-phenyl)-piperazine (6.25 g, 0.021 mol) and 2,2- dimethyl-5-nitro-7-(3-chloro-propoxy)-2,3-dihydro-benzofuran (5.71 g, 0.02 mol) are added, then the reaction mixture is boiled under stirring for 16 hours. After cooling to the reaction mixture dichloromethane (100 ml) is added, the phases are separated, the solution of a dichloromethane is washed with water, dried over anhydrous sodium sulfate, filtered, then evaporated until dry in vacuum. The residual crystalline product is mixed with ether, filtered, washed thoroughly with ether. Thus, 5.67 g (55.6 %) of the title product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (DMSO-d₆): δ, ppm 7.80 d (IH), 7.70 d (IH), 7.28-7.29 m (IH), 7.07-7.12 m (2H), 4.16 t (2H), 3.86 s (3H), 3.12 s (2H), 3.02 m (4H), 2.45-2.53 m (6H), 1.93 qi (2H), 1.48 s (6H).

Example 15 2,2-Dimethyl-S-amino-7-(3-hydroxy-propoxy)-2,3-dihydro-benzofuran

To the solution of 2,2-dimethyl-5-nitro-7-(3-hydroxy-propoxy)-2,3-dihydro- benzofuran (21.0 g, 0.0786 mol) and methanol (500 ml) platinum/carbon catalyst (2.5 g, 5 %) is added, then it is hydrogenated for 2.5 hours in a bomb pipe at room temperature (hydrogen admission: 16 atm). The catalyst is filtered, then methanolic solution is evaporated until dry in vacuum. Thus, 14.8 g (79.4 %) of the purple crystalline product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (CDCl₃): δ, ppm 6.19 d (2H), 4.15 t (2H), 3.83 t (2H), 3.00 bs (2H), 2.92 s (2H), 2.00 qi (2H), 1.46 s (6H).

Example 16 2,2-Dimethyl-5-amino-7-(2-dimethyl-amino-ethoxy)-2,3-dihydro-benzofuran

To the solution of 2,2-dimethyl-5-nitro-7-(2-dimethyl-amino-ethoxy)-2,3- dihydro-benzofuran (6.2 g, 0.022 mol) and ethanol (83 ml) palladium/carbon catalyst (1.5 g, 5 %) and hydrazine hydrate (3.1 ml, 0.062 mol, 100 %) are added then the reaction mixture is boiled under stirring for 2 hours. After cooling the catalyst is filtered, washed with ethanol, then the solution is evaporated until dry in vacuum. Thus, 5.4 g (98 %) of the white crystalline product are obtained, which is directly suitable for use in the next steps. ¹H- NMR (CDCl₃): δ, ppm 6.17 d (2H), 4.09 t (3H), 2.92 s (2H), 2.72 t (2H), 2.31 s (6H), 1.46 s (6H).

Example 17 2,2-Dimethyl-5-amino-7-(2-dimethyl-amino-ethoxy)-2,3-dihydro-benzofuran

To the solution of 2,2-dimethyl-5-nitro-7-(2-dimethyl-amino-ethoxy)-2,3- dihydro-benzofuran (8.0 g, 0.022 mol) and ethanol (650 ml) platinum/carbon (5.0 g, 5 %) catalyst is added, then it is hydrogenated for 2 hours in a bomb pipe at room temperature (hydrogen admission: 14 atm). The catalyst is filtered, washed with ethanol, then the solution is evaporated until dry in vacuum. The crystalline residue is suspended with ether, filtered, and washed with ether. Thus, 4.25 g (59.5 %) of the white crystalline product are obtained, which is identical with the product obtained according to the title product of example 16.

Example 18 2,2-Dimethyl-5-amino-7-(3-dimethyl-amino-propoxy)-2,3-dihydro-benzofuran

To the solution of 2,2-dimethyl-5-nitro-7-(3-dimethyl-amino-propoxy)-2,3- dihydro-benzofuran (25.5 g, 0.091 mol) and ethanol (400 ml) platinum/carbon catalyst (2.0 g, 5 %) is added, then it is hydrogenated for 2.5 hours in a bomb pipe at room temperature (hydrogen admission: 14 atm). The catalyst is filtered, then the methanolic solution evaporated until dry in vacuum. Thus, 24.0 g (89.6 %) of the brown crystalline product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (DMSO-de): δ, ppm 6.06 d (IH), 6.02 d (IH), 4.4 b (2H), 3.89 t (2H), 2.82 s (2H), 2.31 t (2H), 2.13 s (6H), 1.77 qi (2H), 1.34s (6H).

Example 19

2,2-Dimethyl-5-amino-7-[2-(N-methyl-N-benzyl)-ethoxy]-2,3-dihydro-benzo- furan To the solution of 2,2-dimethyl-5-nitro-7-(2-dimethyl-amino-ethoxy)-2,3- dihydro-benzofuran (8.0 g, 0.0224 mol) and ethanol (125 ml) cooled with icy water palladium/carbon catalyst (I g 5 %) is added, then at 0 C⁰ hydrazine hydrate (9.6 ml, 0.18 mol, 100 %) added dropwise too the solution. The reaction mixture is stirred for 5 hours, then after standing the solution for one night, next day the solution is stirred for 6 hours at room temperature, then it is left standing for another night in refrigerator. The catalyst is filtered, washed with ethanol, then the solution is evaporated until dry in vacuum. Thus, 7.1 g (96.8 %) yellow, oily product are obtained, which is directly suitable for use in the next steps. ¹H- NMR (DMSOd₆): δ, ppm 7.30 m (5H), 6.08 m (IH), 6.04 m (IH), 4.00 t (J = 6.3 Hz) (2H), 3.55 s (2H), 2.82 s (2H), 2.68 t (J = 6.3 Hz) (2H), 2.20 s (3H), 1.33 s (6H).

Example 20

2,2-Dimethyl-5-amino-7-[3-(N-methyl-N-benzyl)-propoxy]-2,3-dihydro- benzofuran

To the solution of 2,2-dimethyl-5-nitro-7-(3-dimethyl-amino-propoxy)-2,3- dihydro-benzofuran (35.0 g, 0.0945 mol) and ethanol (550 ml) cooled with icy water palladium/carbon catalyst (4 g, 5 %) is added, then at 0 C⁰ hydrazine hydrate (35 ml, 0.68 mol, 100 %) is added dropwise. The reaction mixture is stirred for 5 hours at 0 C⁰, then at room temperature for a further 18 hours. The catalyst is filtered, washed with ethanol, then the solution is evaporated until dry in vacuum. Thus, 31.4 g (97.6 %) yellow, oily product is obtained, which is directly suitable for use in the next steps. ¹H-NMR (CDCl₃): δ, ppm 7.29 bs (5H), 6.16 s (2H), 4.08 t (J = 7.0 Hz) (2H), 3.50 s (2H), 2.91 s (2H), 2.53 t (J = 7.0 Hz) (2H), 2.19 s (3H), 2.01 qui (J = 7.0 Hz) (2H)^', 1.46 s (6H).

Example 21

2,2-Dimethyl-5-amino-7-{2-(4-(3-trifluoromethyl-phenyl)-piperazin-l-yl]- ethoxy}-2,3-dihydro-benzofuran To the suspension of 2,2-dimethyl-5-nitro-7-{2-(4-(3-trifluoromethyl-phenyl)- piperazin-l-yl]-ethoxy}-2,3-dihydro-benzofuran (5.4 g, 0.0116 mol) and ethanol (60 ml) under stirring palladium/carbon catalyst (1.5 g, 5 %) and hydrazine hydrate (4.0 ml, 0.08 mol, 100 %) are added, then the reaction mixture is boiled for 2 hours. After cooling the catalyst is filtered, washed with ethanol, then the solution is evaporated until dry in vacuum. The obtained crystalline product is mixed with ether and filtered. Thus, 4.0 g (79.1 %) product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (DMSOd₆): δ, ppm 7.41 t (IH), 7.19 d (IH), 7.16 bs (IH), 7.05 d (IH), 6.11 d (IH), 6.06 d (IH), 4.48 bs (2H), 4.04 1 (2H), 3.23-3.32 m (4H), 2.83 s (2H), 2.60-2.73 m (6H), 1.35 s (6H).

Example 22

2,2-Dimethyl-5-amino-7-{2-(4-(2-methoxy-5-trifluoromethyl-phenyl)- piperazin-l-yl]-ethoxy}-2,3-dihydro-benzofuran

To the suspension of 2,2-dimethyl-5-nitro-7-{2-(4-(2-methoxy-5- trifiuoromethyl-phenyl)-piperazin-l-yl]-ethoxy}-2,3-dihydro-benzofuran (3.4 g, 0.00686 mol) and ethanol (50 ml) palladium/carbon catalyst (1.0 g, 5 %) and a solution of hydrazine hydrate (3.0 ml, 0.0588 mol, 100 %) are added under stirring, then the reaction mixture is boiled for 2 hours. After cooling the catalyst is filtered, washed with ethanol, then the solution is evaporated until dry in vacuum. The obtained oily product ether is added, and evaporated until dry again. Thus, 3.09 g (96.7 %) of the oily product are obtained,^' which is directly suitable for use in the next steps. ¹H-NMR (DMSOd₆): δ, ppm 7.28-7.33 m (IH), 7.08-7.12 m (2H), 6.09 d (IH), 6.04 d (IH), 4.03 t (2H), 3.86 s (3H), 3.34- 3.41m (4H), 2.83 s (2H), 2.63-2.73 m (6H), 1.35 s (6H).

Example 23

2,2-Dimethyl-5-amino-7-{3-(4-(3-chloro-phenyl)-piperazin-l-yl]-propoxy}-2,3- dihydro-benzofuran

To the suspension of 2,2-dimethyl-5-nitro-7-{3-(4-(3-chloro-phenyl)-piperazin- l-yl]-propoxy}-2,3-dihydro-benzofuran (7.0 g, 0.0156 mol) and ethanol (150 ml) platinum/carbon catalyst (1.5 g, 5 %) is added, then it is hydrogenated for 2.5 hours in a bomb pipe at room temperature (hydrogen admission: 7.5 atm). The catalyst is filtered, then the methanolic solution is evaporated until dry in vacuum. The residue is mixed with acetonitrile and filtered again. Thus, 5.87 g (89.9 %) of the crystalline product are obtained, melting point: 144-146°. The product is directly suitable for use in the next steps of the preparation process. ¹H-NMR (DMSOd₆): δ, ppm 7.20 1 (IH), 6.92 d (IH), 6.86-6.89 m (IH), 6.77 d (IH), 6.08 d (IH), 6.03 d (IH), 4.46 bs (2H), 3.93 t (2H), 3.14-3.16 m (4H), 2.82 s (2H), 2.42-2.51 m (6H), 1.85 qi (2H), 1.35 s (6H).

Example 24 l-Naphthalenesulfonyl-N-[7-(3-hydroxy-propoxy)-2,3-dihydro-2,2-dimethyl- benzofuran-5-ylJ-amide

To the solution of 2,2-dimethyl-5-amino-7-(3-hydroxy-propoxy)-2,3-dihydro- benzofuran (14.0 g, 0.059 mol) and dichloromethane (70 ml) pyridine (4.0 ml, 3.95 g, 0.05 mol) are added, the reaction mixture is cooled to 0 C°, then at this temperature naphthalene- 1-sulfonyl-chloride (10.6 g, 0.047 mol) is added to it. The stirring is continued for 3 hours at 0 C°, then the reaction mixture is left to warm itself at room temperature, and it is stirred for a further 2 days at this temperature. The obtained mixture is divided with water (100 ml), the phases are separated, the organic phase is extracted with water (100 ml), dried over anhydrous sodium sulfate, filtered, then evaporated until dry in vacuum. Thus, 20.46 g (81.1 %) oily product is obtained, which is purified on Kieselgel column with an eluent of cyclohexane - ethylacetate. The suitable fractions are evaporated and thus, 14.31 g (56.7 %) of the crystalline product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (DMSOd₆): δ, ppm 10.16 bs (IH), 8.70-8.72 m (IH), 8.05-8.20 m (3H), 7.58-7.74 m (3H), 6.40 d (J = 1.4 Hz) (IH), 6.38 d (J = 1.8 Hz) (IH), 4.5 bs (IH), 3.76 t (2H), 3.46 m (2H), 2.78 s (2H), 1.69 m (2H), 1.29 s (6H). Example 25

4-Chloro-l-naphthalenesulfonyl-N-[7-(3-hydroxy-propoxy)-2,3-dihydro-2,2- dimethyl-benzofuran-5-ylJ-amide

To the solution of 2,2-dimethyl-5-amino-7-(3-hydroxy-propoxy)-2,3-dihydro- benzofuran (13.0 g, 0.055 mol) and dichloromethane (70 ml) pyridine (4.6 ml, 4.56 g, 0.0577 mol) is added, the reaction mixture is cooled to 0 C⁰, then at this temperature 4-chloro-l-naphthalene-sulfonyl-chloride (10.6 g, 0.047 mol) is added to the solution. Stirring is continued at 0 C⁰ for 3 hours, then the reaction mixture is left warming and at room temperature is stirred for 2 days. The obtained mixture is divided with water (50 ml), the phases are separated, the organic phase is extracted with water (2x50 ml), dried over anhydrous sodium sulfate, filtered, then evaporated until dry in vacuum. Thus, 22.6 g (88.9 %) oily product are obtained, which is purified on Kieselgel column with an eluent of cyclohexane - ethylacetate. The suitable fractions are evaporated and thus, 12.3 g (48.5 %) of the crystalline product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (CDCl₃): δ, ppm 8.69-8.74 m (IH), 8.35-8.41 m (IH), 8.04 d (J = 8.1 Hz) (IH), 7.64-7.69 m (2H), 7.54 d (J = 8.0 Hz) (IH), 7.2 bs (IH), 6.37 d (J = 1.1 Hz) (IH), 6.27 d (J = 1.8 Hz) (IH), 3.87 t (J = 5.8 Hz) (2H), 3.72 t (2H), 2.80 s (2H), 2.3 bs (IH), 1.83 qi (J = 6.0 Hz) (2H), 1.39 s (6H).

Example 26

5-Chloro-3-methyl-benzofuran-2-sulfonyl-N-[7-(3-hydroxy-propoxy)-2,3- dihydro-2,2-dimethyl-benzofuran-S-yl]-amide

To the solution of 2,2-dimethyl-5-amino-7-(3-hydroxy-propoxy)-2,3-dihydro- benzofuran (9.15 g, 0.0386 mol) and dichloromethane (70 ml) pyridine (3.3 ml, 3.2 g, 0.0405 mol) is added, the reaction mixture is cooled to 0 C⁰, then at this temperature 3-chloro-5-methyl-benzofuran-2-sulfonyl-chloride (9.6 g, 0.036 mol) is added to the solution. Stirring is continued at 0 C⁰ for 3 hours, then the reaction mixture is left warming and at room temperature is stirred for 2 days. The obtained mixture is divided with water (50 ml), the organic phase is extracted with water (2x50 ml), dried over anhydrous sodium sulfate, filtered, then evaporated until dry in vacuum. Thus, 17.1 g (95.1 %) oily product are obtained, which is purified on Kieselgel column with an eluent of cyclohexane - ethylacetate. The suitable fractions are evaporated and thus, 9.65 g (53.6 %) of the pure crystalline product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (CDCl₃): δ, ppm 7.52 m (IH), 7.43 m (2H), 6.85 bs (IH), 6.57 d (IH), 6.46 d (IH), 3.95 t (2H), 3.74 m (2H), 2.90 s (2H), 2.25 s (3H), 1.90 qi (2H), 1.68 bs (IH), 1.44 s (6H).

Example 27

2-Naphthalenesulfonyl-N-[7-(2-hydroxy-ethoxy)-2,3-dihydro-2,2-dimethyl- benzofuran-5-yl]-amide

To the solution of 2,2-dimethyl-5-amino-7-(2-hydroxy-ethoxy)-2,3-dihydro- benzofuran (7.3 g, 0.0327 mol) and dichloromethane (35 ml) pyridine (3.2 ml, 3.16 g, 0.04 mol) is added, the reaction mixture is cooled to 0 C⁰, then at this temperature 2-naphthalene-sulfonyl-chloride (5.9 g, 0.026 mol) is added to the solution. Stirring is continued at 0 C⁰ for 5 hours, then the reaction mixture is left warming and at room temperature is stirred for 2 days. The obtained mixture is divided with water (30 ml), the phases are separated, the organic phase is extracted (30 ml) with water, dried over anhydrous sodium sulfate, filtered, then evaporated until dry in vacuum. Thus, 10.83 g (80.1 %) oily product are obtained, which is purified on Kieselgel column with an eluent of cyclohexane - ethylacetate. The suitable fractions are evaporated and thus, 6.9 g (51.0 %) of the crystalline product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (DMSOd₆): δ, ppm 9.91b (IH), 8.35 d (J = 1.3 Hz) (IH), 8.10 m (2H), 8.00 d (J = 8.0 Hz ) (IH), 7.76 m (2H), 7.64 m (2H), 6.53 d (2.1 Hz) (IH), 6.50 d (J = 1.0 Hz) (IH), 4.80 bs (IH), 3.77 t (J = 5.1 Hz) (2H), 3.59 bs (2H), 3.37 bs (2H), 2.84 s (2H), 1.31 s (6H).

Example 28

2-Naphthalenesulfonyl-N-[7-(3-bromo-propoxy)-2,3-dihydro-2,2-dimethyl- benzofuran-5-ylJ-amide The solution of 2-naphthalenesulfonyl-iV-[7-(3-hydroxy-propoxy)-2,3-dihydro- 2,2-dimethyl-benzofuran-5-yl]-amide (6.6 g, 0.0154 mol) and dichloromethane (38 ml) is cooled to 0 C⁰, then at this temperature a solution of phosphor- tribromide (0.55 ml, 1.59 g, 0.059 mol) and dichloromethane (20 ml) is added dropwise. Stirring is continued for 3 hours at 0-5 C⁰, then the solution is stirred for a further one day at room temperature. The obtained mixture is divided with water (40 ml), the phases are separated, the organic phase is extracted (2 x 40 ml) with water, dried over anhydrous sodium sulfate, filtered, then evaporated until dry in vacuum. To the residue ether is added, the precipitated crystals are filtered, and washed with ether. Thus, 3.23 g (42.8 %) title product is obtained, which is purified on Kieselgel column with an eluent of cyclohexane - ethylacetate. The suitable fractions are evaporated and thus, 1.62 g (21.4 %) of the pure crystalline product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (DMSOd₆): δ, ppm 9.91 bs (IH), 8.34 d (J = 1.1 Hz) (IH), 8.09 d (J = 8.4 Hz) (2H), 8.03 d ( J = 9.2 Hz) (IH), 7.75 dd (J = 7.8 and 1.8 Hz) (2H), 7.64 m (2H), 6.54 d ( J = 1.2 Hz) (IH), 6.49 d ( J = 2.2 Hz) (IH), 3.86 t (J = 6.5 Hz) (2H), 3.50 1 (J = 6.6 Hz) (2H), 2.85 s (2H), 2.05 qui (J = 6.3 Hz) (2H), 1.31 s (6H).

Example 29

5-Chloro-3-methyl-benzofuran-2-sulfonyl-N-[7-(3-bromo-propoxy)-2,3- dihydro-2,2-dimethyl-benzofuran-5-yl]-amide

The solution of 5-chloro-3-methyl-benzofuran-2-sulfonyl-iV-[7-(3-hydroxy- propoxy)-2,3-dihydro-2,2-dimethyl-benzofuran-5-yl]-amide (9.0 g, 0.0194 mol) and toluene (168 ml) is cooled to 0 C⁰, then at this temperature a solution of phosphor-tribromide (0.7 ml, 1.97 g, 0.073 mol) and toluene (30 ml) is added dropwise. Stirring is continued for 3 hours at at 0-5 C⁰, then to the reaction mixture dichloromethane (15 ml) is added and the solution is stirred for 2 days further at room temperature. The solvents are evaporated in vacuum, to the residue ether is added, then it is left to stand. The precipitated crystals are filtered, washed with ether. Thus, 9.8 g (95.5 %) title product is obtained, which is purified on Kieselgel column with an eluent of cyclohexane - ethylacetate. The suitable fractions are evaporated and thus, 5.11 g (49.8 %) of the pure crystalline product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (CDCl₃): δ, ppm 7.53 dd (J = 1.8 and 0.7 Hz) (IH), 7.42 m (2H), 6.74 (IH), 6.59 d (J = 1.8 Hz) (IH), 6.43 d (J = 1.8 Hz) (IH), 3.90 t (J = 6.0 Hz) (2H)₃ 3.47 1 (J = 5.4 Hz) (2H), 2.90 s (2H), 2.25 s (3H), 2.18 qui (J = 6.2 Hz), 1.45 s (6H).

Example 30

4-Chloro-l-naphthalenesulfonyl-N-[7-(2-bromo-ethoxy)-2,3-dihydro-2,2- dimethyl-benzofuran-5-yl]-amide

The suspension of 4-chloro-l-naphthalenesulfonyl-iV-[7-(2-hydroxy-ethoxy)- 2,3-dihydro-2,2-dimethyl-benzofuran-5-yl]-amide (8.8 g, 0.0197 mol) and dichloromethane (50 ml) is cooled to 0 C⁰, then at this temperature a solution of phosphor-tribromide (1.4 ml, 4.11 g, 0.0152 mol) and dichloromethane (25 ml) is added dropwise. Stirring is continued for 3 hours at 0-5 C⁰, the solution is stirred for a further one day at room temperature. The obtained mixture is divided with water (30 ml), the phases are separated, the organic phase is extracted with water (2 x 30 ml), dried over anhydrous sodium sulfate, filtered, then evaporated until dry in vacuum. To the residue ether is added, the precipitated crystals are filtered, and washed with ether. Thus, 6.0 g (59.6 %) of the title product are obtained, which is purified on Kieselgel column with an eluent of cyclohexane - ethylacetate. The suitable fractions are evaporated and thus, 3.6 g (35.8 %) of the pure crystalline product are obtained, which is directly suitable for use in the next steps. ¹H-NMR (DMSO-d₆): δ, ppm 10.29 bs (IH), 8.76 m (IH), 8.34 m (IH), 8.09 d (J = 9.2 Hz) (IH), 7.83 m (3H), 6.45 d (J = 2.2 Hz) (IH), 6.35 d (J = 2.1 Hz) (IH), 4.06 t (J = 5.6 Hz) (2H), 3.58 t (J = 5.5 Hz) (2H), 2.82 s (2H), 1.31 s (6H).

Example 31 l-Naphthalenesulfonyl-N-[7-(3-diethylamino-propoxy)-2,3-dihydro-2,2- dimethyl-benzofuran-5-yl]-amide To the solution of l-naphthalenesulfonyl-N-[7-(3-bromo-propoxy)-2,3-dihydro- 2,2-dimethyl-benzofuran-5-yl]-amide (3.4 g, 0.0069 mol) and dichloromethane (13 ml) under stirring triethylamine (1.9 ml, 1.39 g, 0.0138 mol) and diethylamine (1.4 ml, 1.0 g, 0.0138 mol) are added at room temperature, then stirring is continued for 2 days. The reaction mixture is evaporated until dry in vacuum, the residue is dissolved in dichloromethane (40 ml), is extracted with water (30 ml), dried over anhydrous sodium sulfate, filtered and evaporated until dry again. Thus, 3.24 g (96.7 %) oily product are obtained, which is purified on Kieselgel column with an eluent of cyclohexane - ethylacetate. The suitable fractions are evaporated and thus, 2,0 g (59,7 %) of the pure crystalline product are obtained, which is directly suitable for biological experiments. ¹H- NMR (DMSO-de): δ, ppm 8.69 m (IH). 8.18 d (IH), 8.10 m (IH), 8.05 m (IH), 7.70 m (IH), 7.65 m (IH), 7.57 t (IH), 6.40 d (IH), 6.31 d (IH), 3.68 t (2H), 2.78 s (2H), 2.38 m (6H), 1.59 qi (2H), 1.28 s (6H), 0.88 t (6H).

Example 32

4-Chloro-l-naphthalenesulfonyl-N-[7-(3-dimethylamino-propoxy)-2,3- dihydro-2,2-dimethyl-benzofuran-5-yl]-amide

To the solution of triethylamine (1.4 ml, 1.0 g, 0.0099 mol) and dimethylformamide (8 ml) under stirring at room temperature a solution of dimethylamine and alcohol (3 ml, 33 %) is added, 4-chloro-l- naphthalenesulfonyl-iV-[7-(3-bromo-propoxy)-2,3-dihydro-2,2-dimethyl-benzo- furan-5-yl]-amide (1.7 g, 0.0032 mol). Stirring is continued for a further 18 hours, then the reaction mixture evaporated until dry in vacuum. Thus, 1.5 g (94.7 %) oily product are obtained, which is purified on Kieselgel column with an eluent of cyclohexane - ethylacetate. The suitable fractions are evaporated and thus, 0.9 g (56.8 %) of the pure crystalline product are obtained, melting point:. 94-97 C⁰, which is directly suitable for biological experiments. ¹H-NMR (DMSO-d₆): δ, ppm 8.78 m (IH), 8.34 m (IH), 8.11 d (IH), 7.85 dm (3H), 6.45 d (IH), 6.40 d (IH), 3.81 t (2H), 3.00 m (2H), 2.81 s (2H), 2.68 s (6H), 1.96 qi (2H), 1.31 s (6H). Example 33

4-Chloro-l-naphthalenesulfonyl-N-{7-[3-(diethylamino)-propoxy]-2,3- dihydro-2,2-dimethyl-benzofuran-5-yl}-amide

To the solution of triethylamine (2.0 ml, 2.0 g, 0.02 mol) and dichloromethane (10 ml) under stirring at room temperature diethylamine (3 ml, 0.041 mol) is added, then under stirring and cooling with tap water 4-chloro-l- naphthalenesulfonyl-iV-[7-(3-bromo-propoxy)-2,3-dihydro-2,2-dimethyl-benzo- furan-5-yl]-amide (1.94 g, 0.0037 mol). Stirring is continued for a further 2 days, then the reaction mixture is evaporated until dry in vacuum. The residue is dissolved in dichloromethane (20 ml), is extracted with water (20 ml), dried over anhydrous sodium sulfate, filtered, then in vacuum evaporated until dry again. Thus, 1.60 g (83.7 %) oily product are obtained, which is purified on Kieselgel column with an eluent of cyclohexane - ethylacetate. The suitable fractions are evaporated and thus, 0.88 g (46.0 %) of the pure crystalline product are obtained, melting point 52-55 C⁰, which is directly suitable for biological experiments. ¹H-NMR (DMSOd₆): δ, ppm 8.78 m (IH), 8.33 m (IH), 8.07 m (1H)7,83 m (3H). 6,42 d (IH), 6.27 d (IH), 3.68 t (2H), 2.81 s (2H), 2.38 m (6H), 1.59 qi (2H), 1.30 s (6H), 0.88 t (6H).

Example 34

5-Chloro-3-methyl-benzqfuran-2-sulfonyl-N-[2,3-dihydro-2,2-dimethyl-7-(3- methylamino-propoxy)-benzofuran-5-yl]-amide

To the solution of triethylamine (1.3 ml, 0.95 g, 0.00946 mol) and dichloromethane (10 ml) under stirring at room temperature an alkoholic solution of methylamine (12 ml, 33 %) is added, then under stirring and cooling with tap water 5-chloro-3-methyl-benzofuran-2-sulfonyl-N-{2,3-dihydro-2,2- dimethyl-7-[3-bromo-propoxy]-benzofuran-5-yl} -amide (2.5 g. 0.00473 mol). Stirring is continued for 3 days, then the reaction mixture is evaporated until dry in vacuum, the residue is suspended with ether, then the precipitated crystals are filtered. Thus, 2.25 g (99.4 %) product are obtained, which is purified on Kieselgel column with an eluent of cyclohexane - ethylacetate. The suitable fractions are evaporated and thus, 1.07 g (47.2 %) of the pure crystalline product are obtained, melting point: 195-198 C⁰, which is directly suitable for biological experiments. ¹H-NMR (DMSOd₆): δ, ppm 7.78 d (IH), 7.64 d (IH), 7.45 dd (IH), 6.43 d (IH), 6.36 d (IH), 3.79 t (2H), 2.84 s (2H), 2.67 t (2H), 2.37 s (3H), 2.28 s, (2H), 1.78 qi (2H), 1.33 s (6H).

Example 35

2,2-Dimethyl-5-acetamino-7-{3-[4-(3-chloro-phenyl)-piperazine-l-yl)- propoxy]}-2,3-dihydro-benzofuran

To the solution of 2,2-dimethyl-5-amino-7-{3-[4-(3-chloro-phenyl)-piperazine- l-yl)-propoxy]}-2,3-dihydro-benzofuran (1.9 g, 0.0046 mol) and dichloromethane (25 ml) at room temperature pyridine (0.55 ml, 0.54 g, 0.0055 mol) and acetic anhydride (0.51 ml, 0.56 g, 0.0055 mol) are added, then it is stirred at room temperature for 56 hours. The reaction mixture is divided with a solution of sodium hydrogencarbonate (10 ml, 10 %), the phases are separated, the organic phase washed with water (20 ml), dried over anhydrous sodium sulfate, filtered, then evaporated until dry in vacuum. The residue is suspended with ether, filtered, washed with ether. Thus, 1.25 g (59.3 %) crystalline, title product are obtained, which has a melting point 129-131 C⁰, after recrystallization with acetonitrile. ¹H-NMR (DMSOd₆): δ, ppm 9.67 s (IH), 7.19 1 (IH), 7.05 s (IH), 6.92 s (IH), 6.87 d (IH), 6.77 d (IH), 3.98 t (2H), 3.35 s (2H), 3.15 m (4H), 2.95 s (2H), 2.49 m (6H), 1.99 s (3H), 1.88 m (2H), 1.39 s (6H).

Example 36

6-(l,2,3,4-Tetrahydronaphthalene)-sulfonyl-N-{7-[3-(N-benzyl-N-methyl)- amino-propoxy]-2,3-dihydro-2,2-dimethyl-benzofuran-5-yl}-amide

To the solution of sodium hydroxyde (0.6 g, 0.015 mol) and water (10 ml) under stirring at room temperature 2,2-dimethyl-5-amino-7-[3-(N-methyl-N-benzyl)- propoxy]-2,3-dihydro-benzofuran (5.1 g, 0.015 mol) and 1,2,3,4- _

39 tetrahydronaphthalene-6-sulfonyl chloride (3.46 g, 0.015 mol) are added, then the reaction mixture is boiled for 6 hours. After cooling the reaction mixture is extracted with dichloromethane (50 ml), the organic phase washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. The residual 5.87 g (73.1 %) oily product is purified on Kieselgel column with an eluent of cyclohexane - ethylacetate. The suitable fractions are evaporated and thus, 4.42 g (55.1 %) of the pure crystalline product are obtained, which is directly suitable for biological experiments. ¹H-NMR (DMSOd₆): δ, ppm 9.69 b (IH), 7.40 m (2H), 7.23 m (5H), 7.16 d (J = 7.8 Hz) (IH), 6.52 m (IH), 6.48 m (IH), 3.86 t (J = 6.5 Hz) (2H), 3.44 s (2H), 2.87 s (2H), 2.68 m (4H), 2.40 t (J= 6.9 Hz) (2H), 2.10 s (3H), 1.80 qui (J = 6.7 Hz) (2H), 1.67 m (4H), 1.32 s (6H).

Example 37

2-Propyl-sulfonyl-N-(2,3-dihydro-2,2-dimethyl-{7-[2-[4-(2-methoxy-5- trifluoromethyl-phenyl)-piperazino]-ethoxy}-benzofuran-5-yl)-amide

To the mixture of dichloromethane (22 ml) and pyridine (0.4 ml, 0.38 g, 0.0049 mol) at room temperature 2,2-dimethyl-5-amino-7-{2-(4-(2-methoxy-5- trifluoromethyl-phenyl)-piperazine- 1 -yl] -ethoxy } -2,3 -dihydro-benzofuran (1.9 g, 0.0041 mol) and 2-propanesulfonylchloride (0.5 ml, 0.64 g, 0.0045 mol) are added, then the reaction mixture is stirred at room temperature for 48 hours. The obtained reaction mixture is divided with a sodium hydrogencarbonate solution (30 ml, 10 %), the phases are separated, the organic phase is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. Thus, 1.83 g (78.1 %) oily product are obtained, which is purified on Kieselgel column with an eluent of cyclohexane - ethylacetate. The suitable fractions are evaporated and thus, 0.74 g (31.6 %) crystalline pure product, melting point: 64-66 C⁰, which is directly suitable for biological experiments. ¹H-NMR (DMSOd₆): δ, ppm 9.31 bs (IH), 7.30 d (J = 8.2 Hz) (IH), 7.10 d(J = 8.4 Hz) (IH), 7.06 d (J = 1.6 Hz) (IH), 6.71s (IH), 6.69 s (IH), 4.07 t (J = 5.9 Hz) (2H), 3.85 s (3H), 3.14 hep (J = 6.8 Hz) (IH), 3.01 m (4H), 2.96 s (2H), 2.72 1 (J = 5.8 Hz) (2H), 2.63 m (4H), 1.39 s (6H), 1.23 d (J = 6.8 Hz), (6H). Example 38

2,5-Dichloro-phenylsulfonyl-N-[2,3-dihydro-2,2-dimethyl-7-(2-dimethyl- amino-ethoxy)-benzofuran-S-yl]-amide

To the mixture of dichloromethane (13 ml) and 2,2-dimethyl-5-amino-7-(2- dimethyl-amino-ethoxy)-2,3-dihydro-benzofuran (2.5 g, 0.01 mol) under stirring at room temperature pyridine (0.8 ml, 0.79 g, 0.01 mol) is added, the reaction mixture is cooled to 0 C⁰ and at this temperature a solution of 2,5-dichloro- benzolsulfonylchloride (2.45 g, 0.01 mol) and dichloromethane (8 ml) is added dropwise. The reaction mixture is stirred at 0 C°-on for 5 hours, then it is left to warm itself and is stirred at this temperature for a further 20 hours. The obtained reaction mixture is evaporated until dry in vacuum, the residue is dissolved in dichloromethane (30 ml), the solution is extracted sodium hydroxide (10 ml, 5 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. The residue is 1.40 g (30.5 %) crystalline product after crystallization with acetonitrile. After recrystallization with acetonitrile 1.19 g (25.9 %) of the product are obtained. Melting point: 104-109 C⁰. The obtained product is directly suitable for biological experiments. ¹H- NMR (DMSOd₆): δ, ppm 7.89 s (IH), 7.70 m (2H), 6.55 s (IH), 6.51 s (IH), 3.91 1 (J = 5.9 Hz) (2H), 2.52 m (2H), 2.89 s (2H)₃ 2.18 (6H), 1.34 s (6H).

Example 39

2,5-Dichloro-phenylsulfonyl-N-{2,3-dihydro-2,2-dimethyl-7-{2-[4-(trifluoro- methyl-phenyl)-piperazino]-ethoxy}-benzofuran-5-yl)-amide

To the mixture of dichloromethane (10 ml) and 2,2-dimethyl-5-amino-7-{2-(4- (3-trifluoromethyl-phenyl)-piperazine-l-yl]-ethoxy}-2,3-dihydro-benzofuran (2.0 g, 0.0046 mol) under stirring at room temperature pyridine (1.9 ml, 1.4 g, 0.0177 mol) are added, the reaction mixture is cooled to 0 C⁰, and at this temperature a solution of 2,5-dichloro-benzolsulfonyl chloride (1.10 g, 0.0046 mol) and dichloromethane (10 ml) is added dropwise. The reaction mixture is stirred for 3 hours at 0 C⁰, it is left to warm itself and is stirred at this temperature for a further 2 hours. The obtained reaction mixture is left to stand for 2 days and evaporated until dry in vacuum, the residue is dissolved in dichloromethane (30 ml), the solution is extracted with sodium hydroxide (10 ml, 5 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. To the oily residue ether is added and a crystalline product is obtained, which is filtered and washed with ether. Thus, 1.05 g (35.4 %) of the crystalline product are obtained, which has a melting point 108-110 C⁰, after recrystallization with acetonitrile. The obtained product is directly suitable for biological experiments. ¹H-NMR (DMSOd₆): δ, ppm 10.3 bs (IH), 7.90 d (J = 1.5 Hz) (IH)₅. 7.69 m (2H), 7.41 t (J = 7.7 Hz) (IH), 7.21 d (J = 8.3 Hz) (IH), 7.16 s (IH), 7.06 d (J = 7.6 Hz) (IH), 6.55 dd (J = 7.4 and 2.0 Hz) (2H), 3.99 t (J = 6.8 Hz) (2H), 3.35 m (4H), 3.22 m (4H), 2.90 s (2H), 2.60 m (2H), 1.35 (6H).

Example 40

2,5-Dichloro-phenylsulfonyl-N-{2,3-dihydro-2,2-dimethyl-7-{2-[4-(2-methoxy- 5-trifluoromethyl-phenyl)-piperazino]-ethoxy}-benzofuran-5-yl)-amide dihydro-chloride

To the mixture of dichloromethane (3 ml) and 2,2-dimethyl-5-amino-7-{2-(4-(2- methoxy-5 -trifluoromethyl-phenyl)-piperazine- 1 -yl] -ethoxy } -2,3 -dihydrobenzo- furan (1.5 g, 0.0033 mol) under stirring at room temperature pyridine (0.8 ml, 0.78 g, 0.0177 mol) is added, the reaction mixture is cooled to 0 C⁰ and at this temperature a solution of 2,5-dichloro-benzenesulfonyl chloride (1.10 g, 0.0099 mol) and dichloromethane (2.5 ml) is added dropwise. The reaction mixture is stirred for 4 hours at 0 C⁰, then it is left to warm itself at room temperature and it is left to stand for 2 days. The obtained solution is evaporated until dry in vacuum, the residue is dissolved in dichloromethane (20 ml) the solution is extracted with sodium hydroxide (10 ml, 5 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. The oily residue is dissolved in dichloromethane (10 ml), hydrochloric acidic isopropanol (2.0 ml, 25 %) is added to the solution, then evaporated until dry again. To the residue ether is added and the obtained crystalline product is filtered and washed with ether. Thus, 1.6 g (64.8 %) of the crystalline product are obtained, which has a melting point 192-194 C⁰, after recrystallization with acetonitrile. The obtained product is directly suitable for biological experiments. ¹H-NMR (DMSO-d₆): δ, ppm 11.6 b (IH), 10.4 s (IH), 7.92 s (IH), 7.72 s (2H), 7.38 m (IH), 7.15 m (2H), 6.66 s (IH), 6.62 s (IH), 5.5 b (2H), 4.39 m (2H), 3.39 s (3H), 3.57 m (4H), 3.36 qua (J = 10 Hz) (2H), 3.21 t (J = 11.0 Hz) (2H), 2.93 s (2H), 1.37 s (6H).

Example 41

5-Chloro-2-naphthalenesulfonyl-N-{2,3-dihydro-2,2-dimethyl-7-[2-(dimethyl- amino)-ethoxy]-benzofuran-5-yl}-amide

To the mixture of dichloromethane (20 ml) and 2,2-dimethyl-5-arnino-7-[2- (dimethylarnino)-ethoxy}-2,3-dihydro-benzofuran (2.0 g, 0.0046 mol) under stirring at room temperature pyridine (0.48 ml, 0.47 g, 0.006 mol) and 5-chloro- 2-naphthalenesulfonyl chloride (1.56 g, 0.006 mol) are added, then the reaction mixture is stirred for 48 hours. The obtained solution is extracted with sodium hydroxyde (30 ml, 10 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. Az oily residue (2.5 g) is subjected to chromatography on a column filled with Kieselgel 60 using as an eluent a mixture of cyclohexane - ethylacetate in different ratios. The suitable fractions are united then evaporated until dry. Thus, 1.1 g (46.3 %) of the crystalline product are obtained, which has a melting point: 61-65 C⁰. The obtained product is directly suitable for biological experiments. ¹H-NMR (DMSO-de): δ, ppm 8.44 d (J = 1.5 Hz) (IH), 8.34 d (J = 9.0 Hz) (IH), 8.14 d (J = 8.3 Hz) (IH), 7.94 dd ( J = 9.0 and 1.9 Hz), 7.86 dd (J = 7.6 and 1.0 Hz) (IH), 6.56 d ( J = 1.0 Hz) (IH), 6.41 d (J = 1.7 Hz), 3.79 t (J = 6.0 Hz) (2H), 2.86 s (2H), 2.39 1 (J = 6.0 Hz) (2H), 2.06 s (6H), 1.32 s (6H).

Example 42

4-Chloro-l-naphthalenesulfonyl-N-{2,3-dihydro-2,2-dimethyl-7-{2-[4-(2- methoxy-5-trifluoromethyl-phenyl)-piperazine]-ethoxy}-benzofuran~5-yl)- amide-hydrochloride To the mixture of dichloromethane (30 ml) and 2,2-dimethyl-5-amino-7-{3-(4- (2-methoxy-5-trifluoromethyl-phenyl)-piperazine-l-yl]-propoxy}-2,3-dihydro- benzofuran (2.3 g, 0.005mol) under stirring at room temperature pyridine (0.48 ml, 0.47 g, 0.006 mol) and (1.56 g, 0.006 mol) 4-chloro-l-naphthalenesulfonyl chloride are added, then the reaction mixture is stirred at room temperature for 48 hours. The reaction mixture is divided with aqueous sodium hydrogen carbonate solution (30 ml, 10 %), the phases are separated, the organic phase washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated until dry in vacuum. To the oily residue ether is added and the obtained crystalline product is filtered and washed with ether. Thus, 1.9 g (55.0 %) crystalline product are obtained, which has a melting point of 249-253 C⁰, after recrystallization with methanol and adding to the hot solution hydrochloric acid (3 ml, 25 w/w%). The obtained product is directly suitable for biological experiments. ¹H-NMR (DMSOd₆): δ, ppm 11.0 bs (IH), 10.4 s (IH), 8.77 m (IH), 8.34 m (IH), 8.14 d (IH), 7.85 m (3H), 7.39 m (IH), 7.15 m (2H), 6.57 bs (IH), 6.44 d (J = 1.3 Hz) (IH), 4.28 m (2H), 3.88 s (2H), 3.55 m (4H), 3.34 m (4H), 3.1 m (2H), 2.83 s (2H), 2.51 s (3H), 1.33 s (6H).

Example 43

5-Chloro-2-naphthalenesulfonyl-N-{2,3-dihydro-2,2-dimethyl-7-[2-[4-(2- methoxy-5-trifluoromethyl-phenyl)-piperazino]-ethoxy-benzofuran-5-yl}- amide

To dichloromethane (15 ml) pyridine (0.48 ml, 0.47 g, 0.006 mol) is added under stirring at room temperature, then 2,2-dimethyl-5-amino-7-{2-(4-(2- methoxy-5-trifluoromethyl-phenyl)-piperazine-l-yl]-ethoxy}-2,3-dihydro- benzofuran (2.0 g, 0.0043 mol) and 5-chloro-2-naphthalenesulfonyl chloride (1.22 g, 0.0047 mol) are added, then the reaction mixture is stirred at room temperature for 40 hours. The reaction mixture is divided with aqueous sodium hydrogen carbonate solution (30 ml, 10 %), the phases are separated, the organic phase washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. To the oily residue ether is added and the obtained crystalline product is filtered and washed with ether. Thus, 1.0 g (33.7 %) crystalline pure product are obtained, melting point: 170-173 C⁰. The obtained product is directly suitable for biological experiments. ¹H-NMR (DMSOd₆): δ, ppm 9.98 bs (IH), 8.44 d (J = 1.4 Hz) (IH), 8.35 d (J = 9.0 Hz) (IH), 8.15 d (J = 8.3 Hz) (IH), 7.94 dd (J = 9.0 and 1.8 Hz) (IH), 7.85 dd (J = 7.5 and 1.0 Hz) (IH), 7.62 t (J = 8.0 Hz) (IH), 7.31 dd (J = 8.5 and 1.3 Hz) (IH), 7.11 d (J = 8.5 Hz) (2H), 7.6 d ( J = 1.9 Hz) (IH), 6.60 d ( J = 1.1 Hz) (IH), 6.40 d ( J = 1.8 Hz) (IH), 3.87 m (2H), 2.95 m (4H), 2.87 m (2H), 2.47 m (4H), 1.33 s (6H).

Example 44

(lS)-(+)-10-Camphorsulfonyl-N-[2,3-dihydro-2,2-dimethyl-7-(2-dimethyl- amino-ethoxy)-benzofuran-5-ylJ-amide

To the mixture of dichloromethane (13 ml) and 2,2-dimethyl-5-amino-7-[2- (dimethylamino)-ethoxy]-2,3-dihydro-benzofuran (2.5 g, 0.01 mol) pyridine (0.8 ml, 0.79 g, 0.01 mol) is added under stirring at room temperature, the reaction mixture is cooled to 0 C⁰, and at this temperature a solution of (lS)-(+)- 10-camphorsulfonylchloride (2.5 g, 0.01 mol) and dichloromethane (8 ml) is added to it dropwise. The reaction mixture is stirred at 0 C⁰ for 5 hours, then it is left to warm itself at room temperature and it is left to stand for 20 hours. The obtained solution is evaporated until dry in vacuum, the residue is dissolved in dichloromethane (30 ml), the solution is extracted with sodium hydroxide (10 ml, 5 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. The crystalline residue is suspended with ether, filtered, washed with ether. Thus, 2.08 g (44.8 %) of the product are obtained, which has a melting point of 133-134 C⁰ after recrystallization with acetonitrile. The obtained product is directly suitable for biological experiments. ¹H-NMR (DMSOd₆): δ, ppm 9.3 b (IH), 6.74 d (J = 1.9 Hz) (IH), 6.67 d (J = 1.7 Hz) (IH), 4.02 t (J = 6.0 Hz) (2H), 3.37 t (J = 5.0 Hz) (IH), 3.32 s (3H), 2.98 s (2H), 1.91 d (J = 4.9 Hz) (IH), 2.58 t (J = 6.0 Hz) (2H), 2.36 m (2H), 2.19 s (6H), 2.05 m (IH), 1.94 m (2H), 1.50 m (IH), 1.40 s (6H), 1.01 s (3H), 0.77 s (3H). Example 45

(lR)-(-)-10-Camphorsulfonyl-N-(2,3-dihydro-2,2-dimethyl-7-[2,2- (dimethylamino)-ethoxy/-benzofuran-5-yl)-amide

To the mixture of dichloromethane (8 ml) and 2,2-dimethyl-5-amino-7-[2- (dimethylamino)-ethoxy]-2,3-dihydro-benzofuran (1.4 g, 0.0056 mol) pyridine (0.45 ml, 0.44 g, 0.0056 mol) is added under stirring at room temperature. The reaction mixture is cooled to 0 C⁰, and at this temperature a solution of (lR)-(-)- 10-camphorsulfonyl chloride (1.4 g, 0.0056 mol) and dichloromethane (5 ml) is added dropwise. The reaction mixture is stirred at 0 C⁰ for 5 hours, then it is left to warm itself at room temperature and it is left to stand for 20 hours. The obtained solution is evaporated until dry in vacuum, the residue is dissolved in dichloromethane (20 ml), the solution is extracted with sodium hydroxide (10 ml, 5 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. The oily residue (1.32 g, 50.8 % ) is subjected to chromatography on a column filled with Kieselgel 60 using as eluent a mixture of cyclohexane - ethylacetate in different ratios. The residue is suspended with ether, then filtered. Thus, 0.52 g (20.0 %) of the crystalline product are obtained, which has a melting point: 131.5-133 C⁰. The obtained product is directly suitable for biological experiments. ¹H-NMR (DMSOd₆): δ, ppm 9.3 b (IH), 6.74 d (J = 1.7 Hz) (IH), 6.68 s (IH), 4.03 t (J = 6.0 Hz) (2H), 3.37 1 (J = 5.1 Hz) (IH), 3.32 s (IH), 2.98 s (2H), 2.91 d (J = 4.8 Hz) (IH), 2.58 t (J = 6.0 Hz) (2H), 2.36 m (2H), 2.20 s (6H), 2.05 m (IH), 1.94 m (2H), 1.50 m (IH), 1.40 s (6H), 1.01 s (3H), 0.77 s (3H).

Example 46

(lS)-(+)-10-Camphorsulfonyl-N-(2,3-dihydro-2,2-dimethyl-7-{2-[4-(3- trifluoromethyl-phenyl)-piperazino]-ethoxy}-benzofuran-5-yl)-amide

To the mixture of dichloromethane (10.5 ml) and 2,2-dimethyl-5-amino-7-{2- [4-(3-trifluoromethyl-phenyl)-piperazino]-ethoxy}-2,3-dihydro-benzofuran (2.0 g, 0.0046 mol) triethylamine (0.9 ml, 1.4 g, 0.043 mol) is added under stirring at room temperature. The reaction mixture is cooled to 0 C⁰, and at this temperature a solution of (lS)-(+)-10-camphorsulfonyl chloride (1.15 g, 0.0046 mol) and dichloromethane (4 ml) is added dropwise. The reaction mixture is stirred at 0 C⁰ for 5 hours, then it is left to warm itself at room temperature and left to stand for 16 hours. The obtained solution is evaporated until dry in vacuum, the residue is dissolved in dichloromethane (20 ml), the solution is extracted with sodium hydroxide (10 ml, 5 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. The oily residue (2.0 g, 66.9 % ) is subjected to chromatography on a column filled with Kieselgel 60 using as an eluent a mixture of cyclohexane - ethylacetate in different ratios. The residue is suspended with ether, then filtered. Thus, 0.8 g (26.8 %) of the crystalline product are obtained, melting point: 65-67 C⁰. The obtained product is directly suitable for biological experiments. ¹H-NMR (DMSO-Cl₆): δ, ppm 9.3 s (IH), 7.41 t (J = 8.0 Hz) (IH), 7.21 d (J = 8.5 Hz) (IH), 7.15 s (IH), 7.05 d (J = 7.4 Hz) (IH), 6.78 d (J = 1.8 Hz) (IH), 6.69 d ( J = 1.7 Hz) (IH), 4.12 t (J = 5.7 Hz) (IH), 3.34 s (6H), 3.24 m (3H), 2.98 s (2H), 2.92 d (J = 4.9 Hz) (IH), 2.73 t (J = 5.8 Hz) (2H), 2.63 m (3H), 2.36m (2H), 2.04 t (J = 4.3 Hz) (IH), 1.93 m (IH), 1.89 m (IH), 1.53 m (IH), 1.41 s (6H), 1.01 s (3H), 0.77 s (3H).

Example 47

(lS)-(+)-10-Camphorsulfonyl-N-(2,3-dihydro-2,2-dimethyl-7-{2-[4-(2- methoxy-5-triβuoromethyl-phenyl)-piperazino]-ethoxy}-benzofuran-5-yl)- amide

To the mixture of dichloromethane (8 ml) and 2,2-dimethyl-5-amino-7-{2-[4-(2- methoxy-5-trifluoromethyl-phenyl)-piperazino]-ethoxy}-2,3-dihydro-benzo- furan (1.5 g, 0.0033 mol) pyridine (0.8 ml, 0.78 g, 0.0099 mol) is added under stirring at room temperature. The reaction mixture is cooled to 0 C⁰, and at this temperature a solution of (lS)-(+)-10-camphorsulfonyl chloride (0.82 g, 0.0033 mol) and dichloromethane (2.5 ml) is added dropwise. The reaction mixture is stirred at 0 C⁰ for 5 hours, then it is left to warm itself at room temperature and left to stand for 18 hours. The obtained solution is evaporated until dry in vacuum, the residue is dissolved in dichloromethane (20 ml), the solution is extracted with sodium hydroxide (10 ml, 5 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. The oily residue (2.5 g) is subjected to chromatography on a column filled with Kieselgel 60 using as an eluent a mixture of cyclohexane - ethylacetate in different ratios. The suitable fractions are united then evaporated until dry. Thus, 0.35 g (15.6 %) of the crystalline product are obtained, which has a melting point: 75-78 C⁰. The obtained product is directly suitable for biological experiments. ¹H-NMR (DMSO-d₆): δ, ppm 9.35 s (IH), 7.30 d (J = 8.3 Hz) (IH), 7.08 dd (J = 8.7 and 1.4 Hz) (2H), 6.78 s (IH), 6.70 s (IH), 4.11 t (J = 5.7 Hz) (2H), 3.86 s (3H), 3.34 bs (6H), 2.99 m (4H), 2.74 m (2H), 2.64 m (3H), 2.33 m (2H), 2.04 m (IH), 1.94 bs (2H), 1.41 s (6H), 1.01 s (3H), 0.77 s (3H).

Example 48

(lR)-(-)-10-Camphorsulfonyl-N-{2,3-dihydro-2,2-dimethyl-7-{2-[4-(2- methoxy-5-trifluoromethyl-phenyl)-piperazino]-ethoxy}-benzofuran-5-yl)- amide

To the mixture of dichloromethane (20 ml) and 2,2-dimethyl-5-amino-7-{2-[4- (2-methoxy-5-trifluoromethyl-phenyl)-piperazino]-ethoxy}-2,3-dihydro- benzofuran (1.76 g, 0.0038 mol) pyridine (0.36 ml, 0.35 g, 0.00456 mol) is added under stirring at room temperature. The reaction mixture is cooled to 0 C⁰ and at this temperature a solution of (lS)-(+)-10-camphorsulfonyl chloride (1.04 g, 0.00418 mol) and dichloromethane (2.5 ml) is added dropwise. The reaction mixture is stirred at 0 C⁰ for 5 hours, then it is left to warm itself at room temperature and left to stand for 28 hours. The obtained solution is extracted with sodium hydroxide (30 ml, 10 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. The oily residue (2.29 g) is subjected to chromatography on a column filled with Kieselgel 60 using as an eluent a mixture of cyclohexane - ethylacetate in different ratios. The suitable fractions are united then evaporated until dry. The residue is suspended with ether, then filtered. Thus, 0.35 g (15.6 %) of the crystalline product are obtained, which has a melting point: 74-78 C⁰. The obtained product is directly suitable for biological experiments. ¹H-NMR (DMSO-d₆): δ, ppm 9.35 s (IH), 7.30 d (J = 8.4 Hz) (IH), 7.09 dd (J = 8.5 and 2.0 Hz) (2H), 6.78 d (J = 1.6 Hz) (IH), 6.69 d ( J = 1.2 Hz) (IH), 4.10 t (J = 5.9 Hz) (2H), 3.86 s (3H), 3.32 s (3H), 2.98 - 3.02 m (6H), 2.73 t (J = 5.6 Hz) (2H), 2.64 bs (3H), 2.50 s (IH), 2.30 - 2.38 m (2H), 2.04 t (J = 4.3 Hz) (IH), 1.89 - 1.95 m (2H), 1.50 m (IH), 1.41 s (6H), 1.01 s (3H), 0.77 s (3H).

Example 49

(lS)-(+)-10-Camphorsulfonyl-N-{2,3-dihydro-2,2-dimethyl-7~{3-[4-(2- methoxy-5-trifluoromethyl-phenyl)-piperazino]-propoxy}-benzofuran-5-yl)- amide

To the mixture of dichloromethane (20 ml) and 2,2-dimethyl-5-amino-7-{3-[4- (2-methoxy-5-trifluoromethyl-phenyl)-piperazine]-propoxy}-2,3-dihydro- benzofuran (2.8 g, 0.006 mol) pyridine (0.73 ml, 0.71 g, 0.0072 mol) is added. The reaction mixture is cooled to 0 C⁰, and at this temperature a solution of (lS)-(+)-10-camphorsulfonyl chloride (1.8 g, 0.0072 mol) and dichloromethane (2.5 ml) is added dropwise. The reaction mixture is stirred at 0 C⁰ for 5 hours, then it is left to warm itself at room temperature and it is left to stand for 48 hours. The obtained solution is extracted with sodium hydroxide (30 ml, 10 %), washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. The oily residue (2.68 g) is subjected to chromatography on a column filled with Kieselgel 60 using as an eluent a mixture of cyclohexane - ethylacetate in different ratios. The suitable fractions are united then evaporated until dry. The residue is suspended with ether, then filtered. Thus, 1.2 g (28.8 %) of the crystalline product are obtained, which has a melting point: 64-67 C⁰. The obtained product is directly suitable for biological experiments. ¹H-NMR (DMSOd₆): δ, ppm 9.34 s (IH), 7.30 d (J = 7.3 Hz) (IH), 7.07 dd (J = 8.6 and 2.0 Hz) (2H), 6.75 d (J = 1.9 Hz) (IH), 6.68 d (J = 1.8 Hz), 4.02 t (J = 6.5 Hz) (2H), 3.86 s (3H), 3.34 s (3H), 2.98 - 3.02 m (4H), 2.50 s (IH), 2.32 - 2.35 m (2H), 1.81 - 2.04 m (6H), 1.50 m (IH), 1.41 s (6H), 1.01 s (3H), 0.77 s (3H). Example 50

4-Chloro-l-naphthalenesulfonyl-N-{7-[2-(dimethylamino)-ethoxy]-2,3- dihydro-2,2-dimethyl-benzofuran-5-yl}-amide

To a mixture of dichloromethane (25 ml) and pyridine (0.48 ml, 0.47 g, 0.006 mol) at room temperature 2,2-dimethyl-5-amino-7-(2-dimethylamino-ethoxy)- 2,3-dihydro-benzofuran (1.25 g, 0.005 mol) and 4-chloro-l- naphthalenesulfonyl-chloride (1.56 g, 0.006 mol) are added. Then the reaction mixture is stirred at room temperature for 35 hours. The obtained reaction mixture is divided with sodium hydrocarbonate solution (30 ml, 10 %), the phases are separated, the organic phase is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated until dry in vacuum. Thus, 2.0 g (84.2 %) oily product are obtained, and crystallized with ethyl acetate. The precipitated crystals are filtered, then washed with ethyl acetate and ether. The obtained product is directly suitable for biological experiments. ¹H-NMR (DMSO-d₆): δ. ppm 8.78 m (IH)₅ 8.35 m (IH), 8.11 d (IH), 7.84 m (3H), 6.45 d (IH), 6.40 d (IH), 4.08 t (3H), 2.91 s (2H), 2.72 t (2H), 2.31 s (6H), 1.45 s (6H).

Claims

1. Selective 5HT₆ receptor binding benzofuran derivatives of general formula (I)

(I) wherein,

Z represents a hydrogen atom, C_1-4 acyl group, C_1-6 group alkyl sulfonyl group, phenyl sulfonyl group substituted with one or more halogen atoms; or naphthyl sulfonyl group optionally substituted with a halogen atom, or tetrahydro naphthyl sulfonyl group, (lS)(+)-10-camphor-sulfonyl group, (lR)(-)-10-camphor-sulfonyl group, or benzofuranyl sulfonyl group, substituted with a halogen atom and C_1-4 alkyl group, Y represents C_2-6 alkylene group,

R¹ and R² represent, independently, a hydrogen atom, C_1-4 alkyl group, benzyl group, or together with one or more halogen atoms, trifluoromethyl group, or CM alkoxy group substituted 4-phenyl-piperazine-l-yl group; and/or their pharmaceutically suitable acid addition salts.

2. Selective 5HT₆ receptor binding benzofuran derivatives of general formula (I)

(D

wherein,

Z represents a hydrogen atom, C_1-2 acyl group, C_1-3 group alkyl sulfonyl group, phenyl sulfonyl group substituted with one or more halogen atom; or naphthyl sulfonyl group optionallly substituted with a halogen atom, or tetrahydro naphthyl sulfonyl group, (lS)(+)-10-camphor-sulfonyl group, (lR)(-)-10-camphor-sulfonyl group, or benzofuranyl sulfonyl group, substituted with a halogen atom and C_1-2 alkyl group, Y represents C_2-3 alkylene group,

R¹ and R² represent, independently, a hydrogen atom, C_1-2 alkyl group, benzyl group, or together with one or more halogen atoms, trifluoromethyl group, or C_1-4 alkoxy group substituted 4-phenyl-piperazine-l-yl group; and/or their pharmaceutically suitable acid addition salts.

3. 5-Chloro-2-naphthalenesulfonyl-N-{2,3-dihydro-2,2-dimethyl-7- [2-(dimethylamino)-ethoxy] -benzofuran-5 -yl } -amide,

4-Chloro- 1 -naphthalenesulfonyl-N- {7- [2-(dimethylamino)- ethoxy]-2,3-dihydro-2,2-dimethyl-benzofuran-5-yl}-amide.

4. Process for the preparation of compounds of general formula (I) and their pharmaceutically suitable acid addition salts characterized that i. the aromatic nitro group of compound of general formula (VII)

HaI - Z (IX)

wherein Hal represents a halogen atom, Z is as defined in claims 1 and 2, or with an acid anhydride of general formula (X)

_/ Z

(X) wherein Z represents as defined in claims 1 and 2; or ii. the aromatic nitro group of compound of general formula (IV)

wherein Y represents as defined in claims 1 and 2, is reacted with a compound of general formula (IX)

HaI - Z (IX)

wherein Hal represents a halogen atom, Z represent as defined in claims 1 and 2, or with an acid anhydride of general formula (X)

(X) wherein Z represents as defined in claims 1 and 2, and the obtained compound of general formula (XFV)

(XV) wherein Hal represents a halogen atom, Z and Y are as defined in claims 1 and 2, is reacted with an amine of general formula (VI)

R¹

HN

\ R²

(VI) wherein the meaning of R¹ and R² is as defined in claims 1 and 2; from the obtained compound of general formula (I) wherein Z, Y, R¹ and R² represent as defined in claims 1 and 2, if desired pharmaceutically suitable acid addition salts of compound of general formula (I) are obtained.

5. Process for the preparation of compounds of general formula (VII) characterized in that a. the compoumd of formula (II)

is reacted with a compound of general formula (III),

HO - Y - Hal

(V) wherein Hal represents a halogen atom, Y represents as defined in claims 1 and 2, is reacted with a compound of general formula (VI) R¹

/

HN I

R²

is reacted with a compound of general formula (XI)

(V) wherein Y represents as defined in claims 1 and 2 and Hal represents as defined above, is reacted with a compound of general formula (VI),

HN XR²

is reacted with a compound of general formula (XII)

(XII) wherein Hal, Y, R¹ and R² represent as defined above.

6. Compounds of general formula (IV)

(IV) wherein Y represents C_2-6 alkylene group.

7. Compounds of general formula (V)

(V) wherein Y represents C_2-6 alkylene group, Hal represents halogen atom.

8. Compounds of general formula (VII)

wherein Y represents C_2-6 alkylene group, R¹ and R² represent, independently, a hydrogen atom, C_1-4 alkyl group, benzyl group, or together with one or more halogen atoms, trifluoromethyl group, or C_1-4 alkoxy group substituted 4- phenyl-piperazin-1-yl group.

9. Compounds of general formula (VIII),

(VIII) wherein Y represents C_2-6 alkylene group R¹ and R² represent, independently, a hydrogen atom, Cj_-4 alkyl group, benzyl group, or together with one or more halogen atoms, trifluoromethyl group, or C_M alkoxy group substituted 4- phenyl-piperazin-1-yl group.

10. Compounds of general formula (XIII)

(XIII) wherein Y represents C_2-6 alkylene group.

11. Compounds of general formula (XIV)

(XIV) wherein Z represents C_1-4 acyl group, C_1-6 group alkyl sulfonyl group, phenyl sulfonyl group substituted with one or more halogen atom; or naphthyl sulfonyl group optionally substituted with a halogen atom, or tetrahydro naphthyl sulfonyl group, (lS)(+)-10-camphor-sulfonyl group, (lR)(-)-10-camphor- sulfonyl group, or benzofuranyl sulfonyl group, substituted with a halogen atom and C_M alkyl group, Y represents C_2-6 alkylene group.

12. Compounds of general formula (XV)

(XV) wherein Z represents C_1-4 acyl group, C_1-6 group alkyl sulfonyl group, phenyl sulfonyl group substituted with one or more halogen atom; or naphthyl sulfonyl group optionally substituted with a halogen atom, or tetrahydro naphthyl sulfonyl group, (lS)(+)-10-camphor-sulfonyl group, (lR)(-)-10-camphor- sulfonyl group, or benzofuranyl sulfonyl group, substituted with a halogen atom and C_1-4 alkyl group, Y represents C_2-6 alkylene group and Hal represents halogen atom.

13. A pharmaceutical composition comprising as active ingredient a therapeutically effective dose of one or more compounds of general formula (I) as defined in claims 1 to 3 and/or pharmaceutically suitable acid additional salts thereof and one or more pharmaceutically applicable diluent, excipient and/or inert carrier.

14. Use of a pharmaceutical composition according to claim 13 for the treatment and prevention of 5HT₆ receptor relating disorders of the central nervous system and/or cardiovascular disorders.

15. Use of one or more compounds of general formula (I) as defined in claims 1 to 3 and/or pharmaceutically suitable acid additional salts thereof, in the manufacture of a medicament for the prevention and/or treatment of 5HT₆ receptor relating disorders of the central nervous system and/or cardiovascular disorders.

16. Method of treatment characterized in that administering for a patient suffering from 5HT₆ receptor relating disorders, especially disorders of the central nervous system and/or cardiovascular disorders a non-toxic dose of one or more compounds of general formula (I) as defined in claims 1 to 3 and/or pharmaceutically suitable acid additional salts thereof.