SK17212000A3 - Benzofuran derivatives, pharmaceutical composition containing the same, and a process for the preparation of the active ingredient - Google Patents

Abstract

The invention refers to novel benzofuran derivatives of formula (I), a process for preparing these compounds and to pharmaceutical compositions containing these active substances.

Description

The present invention relates to novel benzofuran derivatives, to pharmaceutical compositions containing them and to a process for the preparation of an active ingredient. Said novel compounds affect the circulatory system and heart activity, and further affect the central nervous system.

SUMMARY OF THE INVENTION

More particularly, the invention relates to a novel benzofuran derivative of the formula I

where

2

R and R are independently hydrogen or C 1-4 alkyl,

X represents an oxygen atom or a sulfur atom,

Y represents a hydrogen atom or a hydroxy group,

Z represents a hydrogen atom, a halogen atom, or a C1-6 alkyl group; ₄ alkyl, C _1-4 alkoxy, amino, nitro, cyano, trifluoromethyl, -COOR ³ , -NHCOR ³ , and SO ₂ NR ³ R ⁴ , wherein

R ³ represents a hydrogen atom or a C _1-4 alkyl group,

R ⁴ represents a C _1-4 alkyl group, or

R ³ and R ⁴ together with the associated nitrogen atom form a saturated or unsaturated heterocyclic group containing 5 to 10 members and optionally containing as further heteroatom (s) one or more nitrogen atoms and / or one or more oxygen atoms, and / or one or more or more sulfur atoms.

A is CH, COH, C-CN, C-COOR ³ or COR ⁴ wherein R ³ and R ⁴ are as defined above,

B represents a methylene group, or

A forms together with the group B a group of the formula -C = C-,

Ar is hydrogen; C _1-4 alkyl, phenyl (C _1-4 alkyl), biphenylyl, naphthyl, wherein the latter groups may be optionally substituted with a C 1-4 alkyl group. C ₄ alkoxy, or _{second 4} alkenyl; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C _1-4 alkyl groups; A 5- or 6-membered saturated or unsaturated heterocyclic group containing a nitrogen atom and / or an oxygen atom and / or a sulfur atom as a heteroatom; or phenyl substituted ^{with a} substituent comprising at R, R ⁶ and R ^7, wherein

R ⁵ , R ⁶ and R ⁷ independently represent hydrogen, halogen, trifluoromethyl, C 1-6 alkyl; ₄ alkyl, methylenedioxy, phenoxy optionally substituted by Ci. _{4 is} alkoxy or halogen; C ₂ . ₄ alkenyl, _{second 4} alkenyloxy; ₄ alkoxy optionally substituted by a di (C _1-4 alkyl) amino group or a 5 or 6-membered saturated heterocyclic group containing one or two nitrogen atoms, or a nitrogen atom and an oxygen atom, said heterocyclic group being optionally substituted by C 1-6 alkyl; _{4 with an} alkyl group, or ··· ··

A is a group of formula N _(CH2) "- Ar, wherein

Ar 1 represents a group selected from the group consisting of diphenylmethyl, pyridyl, pyrimidinyl, naphthyl, the latter group being optionally substituted by C 1-6 alkyl; ₄ alkoxy or C _2-4 alkenyloxy; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C _1-4 alkyl groups; or phenyl substituted with substituents comprising at R ^5, R ⁶ and R ^7, wherein R ^p, R ⁶ and R ⁷ are as defined above, n is 0 or 1, and pharmaceutically acceptable acid addition salts thereof.

BACKGROUND OF THE INVENTION

Literature data suggest that certain furancarboxamides have antidepressant effects (Yakugaku Zasshi, 97 (5), 540 (1977); CA, 87, 152125d (1997)), while benzofuran derivatives containing furan ring substituents on the furan ring group amino, amidino, thiocarboxamidino, or dialkylaminoalkyl are H ₂ receptor antagonists and therefore have anti-ulcer effects (PCT Publication No. WO 86 02550; CA, 105, 226586u (1986)).

DE-OS No. 22 35 597 discloses tetrahydronaphtoxy derivatives having hypotensive effects. The chemical structure of these known compounds is similar to that of the piperazinylalkylbenzofuran derivatives of formula Ia.

It is an object of the present invention to provide novel benzofuran derivatives, some of which affect the circulatory system, while others have central nervous system effects.

It has been found that the novel benzofuran derivatives of the formula I are able to achieve the above object.

• · · • · • « • • • • · · · • • • · • ··· • • • • • • · • • • • • • • · · · • · · · · • · • ·

In the description of the invention, in the claims and in the definitions of substituents, a halogen atom means in particular a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom.

A C 1-4 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl. Preferably Ci. ₄ alkyl means methyl.

A C _2-4 alkenyl group preferably represents a vinyl, allyl, metalyl or crotyl group, preferably an allyl or methallyl group.

C _1-4 alkoxy is in particular methoxy, ethoxy, n-propoxy, isopropoxy or butoxy, preferably is methoxy or isopropoxy.

C _2-4 alkenyloxy group is suitably allyloxy group or a methallyloxy group.

Ci. _{The 4} alkoxy group substituted by a di (C _1-4 alkyl) ammonium group is primarily a group selected from 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy or 4-dimethylaminobutoxy, preferably 2-dimethylaminoethoxy.

A partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms means a dihydrobenzofuran, benzodioxolane, dihydrobenzpyran or benzodioxane group.

A 5- or 6-membered saturated or unsaturated heterocyclic group containing a nitrogen atom and / or an oxygen atom and / or a sulfur atom as a heteroatom, preferably a heterocyclic group containing a nitrogen atom or an oxygen atom or a sulfur atom, or a nitrogen atom and an atom and wherein the heterocyclic group contains no double bonds, or contains one or more double bonds. The heterocyclic group is, for example, pyrrolyl, pyrrolidinyl, piperidinyl, pyridyl, morpholinyl, furyl or thienyl. It is preferably a thienyl group.

• ·· • · • ··· • · · • · ·· • · · e • · · · • · · • · · · • · · ·· ·· ··

A 5- or 6-membered saturated heterocyclic group containing one or two nitrogen atoms, or a nitrogen atom and an oxygen atom preferably represents a group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl or morpholino, the nitrogen atom being linked by the carbon atom of the C 1-4 alkoxy group.

A saturated or unsaturated 5 to 10 membered heterocyclic group is, for example, a group selected from the group consisting of, for example, pyrrolidinyl, pyrrolyl, piperidinyl, pyridyl, furyl, tetrahydrofuryl, morpholinyl, piperazinyl, imidazolidinyl, pyrimidinyl, pyrazolyl, pyrazolidinyl, thienyl, hexamethylenimine-1-yl, 1-yl, etc.

A pharmaceutically acceptable acid addition salt means, for example, an addition salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., or with an organic acid such as acetic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, etc. .

The invention includes all isomers of the compounds of formula I that are possible and mixtures thereof.

A preferred subgroup of benzofuran derivatives of the invention includes compounds of formula I wherein:

R ¹ represents a hydrogen atom or a C 1-4 alkyl group,

R ² is H,

X is an oxygen atom,

Y represents a hydrogen atom or a hydroxy group,

Z is hydrogen, halogen or nitro,

A is CH, COH or C-CN,

B represents a methylene group, or

A forms with the group B a group of the formula -C = C-, ········

Ar is hydrogen, benzyl, phenyl substituted with R ⁵ , R ⁶ and R ⁷ , biphenylyl, naphthyl optionally substituted with C 1-4 alkoxy; or thienyl, wherein R ⁵ , R ⁶ and R ⁷ independently represent hydrogen, halogen, trifluoromethyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyloxy, phenoxy, and methylenedioxy, and pharmaceutically acceptable acid addition salts thereof.

Within the above subgroup, preferred benzofuran derivatives of the invention include those compounds of formula I wherein:

R ¹ represents a methyl group,

R ² is H,

X is an oxygen atom,

Y is hydroxy,

Z represents a hydrogen atom,

A is CH, COH or C-CN,

B represents a methylene group, or

A forms with B a group of the formula -C = C-,

Ar represents a phenyl group optionally substituted by a group selected from halogen, trifluoromethyl, methyl or methoxy; or a methoxynaphthyl group, and pharmaceutically acceptable acid addition salts thereof.

Particularly preferred benzofuran derivatives of formula I are the following compounds:

- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4 (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 9-9 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-) 7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-trifluoromethylphenyl) -piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)] -2-hydroxypropyl] -4-hydroxy-4- (4-fluorophenyl) -piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] - 4-hydroxy-4-phenylpiperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-chlorophenyl) piperidine, 1 - [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-methoxyphenyl) piperidine, 1- [3- (2 2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methoxyphenyl) piperidine, 1- [3- (2,2-dimethyl-2,3) dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) ) -2- hydroxypropyl] -4-hydroxy-4- (4-methylphenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-cyano-4- phenylpiperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-chlorophenyl) piperidine, or 1- [3 - (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (6-methoxy-naphth-2-yl) -piperidine, and pharmaceutically acceptable addition thereof salts with acids.

A further preferred subgroup of benzofuran derivatives of the invention includes piperazinylalkylbenzofuran derivatives of formula la

where

R ¹ represents a C 1-4 alkyl group,

R ² is H,

X is an oxygen atom,

Y is hydroxy,

Z represents a hydrogen atom,

Ar 1 represents a diphenylmethyl group, a pyridyl group, a partially saturated 5-membered heterocyclic group containing two oxygen atoms which is condensed with a phenyl group, or a phenyl group substituted with a group selected from R ⁵ , R ⁶ , R ⁷ wherein R ⁵ , R 7 ⁶ , R ⁷ independently represent hydrogen, halogen, trifluoromethyl, C _1-4 alkyl, C 1-6 alkyl; ₄ alkoxy, or methylenedioxy, n is 0 or 1 and pharmaceutically acceptable acid addition salts thereof.

Within the subgroup of compounds of Formula Ia, suitable piperazinylalkylbenzofuran derivatives of the invention include compounds of Formula Ia wherein:

• · · • · • ··· • · · • · · · • · · ·· · • · ·· • · · • · · · ·· ··· ·· ··

R ¹ represents a methyl group,

R ² is H,

X is an oxygen atom,

Y is hydroxy,

Z represents a hydrogen atom,

Ar 1 represents diphenylmethyl, pyridyl, benzo-1,3-dioxolanyl or phenyl optionally substituted by one or two halogen atoms, one or two methyl groups, methylenedioxy, trifluoromethyl or methoxy, n is 0 or 1, and pharmaceutically acceptable salts thereof salts with an acid.

Particularly preferred benzofuran derivatives of formula Ia include the following compounds:

1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4 (diphenylmethyl) piperazine, 1- [3- (2,2-dimethyl- 2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-fluorophenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-) yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-trifluoromethylphenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2- hydroxypropyl] -4- (4-methoxyphenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (benzole, 3-dioxolane) 5-yl) piperazine,

• ·· • · • ··· • · • · • · • · · · • · · • · ·· ·· • · • · · ·· ·

1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-chlorophenyl) piperazine, 1- [3- (2,2-dimethyl) -2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-benzylpiperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) - 2-hydroxypropyl] -4- (2,4-dichlorophenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-chlorophenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (2-pyridyl) piperazine,

- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) piperazine, or 1- [3- (2,2-dimethyl) -2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-methoxyphenyl) piperazine, and pharmaceutically acceptable acid addition salts thereof.

The compounds of the invention are prepared as follows;

(a) a halide of formula II

wherein R ¹ , R ² , X, Y and Z are as defined for Formula I, Hal is a halogen atom, is reacted with a secondary amine of formula

Ar

IV

Wherein A, B and Ar have the meaning given for formula I; or

b) the preparation of a benzofuran derivative of the formula I wherein Y is hydroxy, R ^1, R ^2, X, Z, A, B and Ar are as defined for formula I, reacting an epoxide of the formula III

Wherein R ¹ , R ² , Z and X are as defined above, with a secondary amine of formula IV, wherein A, B and Ar are as defined above; or

c) a compound of formula V

wherein R ¹ , X and Z are as defined for Formula I, are reacted with a halogen compound of Formula XI,

XI wherein R ² , Y, A, B and Ar are as defined for formula I and Hal is a halogen atom;

d) in the preparation of a benzofuran derivative of the formula I wherein R ¹ , R ² , X, Z, A, B and Ar are as defined for formula I, a compound of the formula V is left, wherein R ¹ , X and Z are as defined above above, to react with an epoxide of formula XII

• ·· • · • ··· • · • · • · • ·· · · · • • · ·· • · · ·· ·· • · · · · ·· ··

^ ^B 'A' ^{and L}

XII wherein R ² , A, B and Ar are as defined above; or

e) a benzofuran derivative of the formula I wherein A forms a group B = -C = C- with B and R ¹ , R ² , X, Y, Z and Ar are as defined for formula I is prepared by dehydrating the benzofuran derivative I, wherein a is COH, B is methylene, and R ^1, R ^2, X, Y, Z and Ar are as defined above; or

f) in the preparation of a benzofuran derivative of the formula I wherein A is COH, B is methylene, R ¹ , R ² , X, Y, Z and Ar are as defined for formula I, provided that Ar is other than an atom hydrogen, the ketone of formula XV

wherein R ¹ , R ² , X, Y and Z are as defined above, reacted with an arylmagnesium halide of formula XVI

Hal-Mg-Ar (XVI) wherein Ar is as defined above, Hal represents a halogen atom and wherein the formed adduct is decomposed with water; or t · 0 · · · · · · · · · · · · · · · ·

g) a benzofuran derivative of the formula I, wherein A is COH, B is methylene, R ^1, R ^2, X, Y, Z and Ar are as defined for Formula I, provided that Ar is other than hydrogen, the prepared by reacting a ketone of formula XV, wherein R ¹ , R ² , X, Y and Z are as defined above, with an aryl lithium compound of formula XVII,

Li-Ar (XVII) wherein Ar is as defined above and wherein the resulting adduct is decomposed with water; or

h) a benzofuran derivative of the Formula I wherein A is CH, B is a methylene group, R ¹ , R ² , X, Y, Z and Ar are as defined for Formula I are prepared by hydrogenation of a compound of Formula I wherein A forms with B of the formula -C = C-, R ^1, R ^2, X, Y, Z and Ar are as defined above; or

(i) a benzofuran derivative of the Formula I wherein A is CH, B is a methylene group, R ¹ , R ² , X, Y, Z and Ar are as defined for Formula I is prepared by reacting an epoxide of Formula III wherein R ¹ , R ^2, Z and X are as defined above, with a secondary amine of formula IV, wherein a is CHOH, B and Ar are as stated above, under dehydrating conditions and the formation of a compound of formula I, wherein a forms with B a group of the formula -C = C-, and R ¹ , R ² , X, Y, Z and Ar are as defined above, and the compound thus prepared is hydrogenated in the reaction mixture in which it was prepared; and, if desired, the base of formula (I) obtained is reacted with an inorganic or organic acid to form a pharmaceutically acceptable acid addition salt of the compound, or it can be liberated from the acid addition salt of the compound with a base.

In process (a) of the invention, the reaction of the halide of formula II with the secondary amine of formula IV is conveniently carried out in excess of the corresponding secondary amine of formula IV. But this reaction can also be carried out in indife14 · · · · · ife ife ife ife ife ife ife ife ife ife ife ife ife ife ife ife In the presence of a suitable base, optionally in a two-phase system.

As the solvent, for example, an alcohol, preferably methanol, ethanol or isopropanol, diisopropyl ether, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, halogenated solvents, preferably dichloromethane, 1,2-dichloroethane or chlorobenzene can be used in this reaction.

As the base in this reaction, an inorganic base such as an alkali metal or alkaline earth metal hydroxide, preferably sodium hydroxide or potassium hydroxide, or an organic base, preferably trialkylamine or tetraalkylammonium hydroxide, can be used. A particularly preferred base is triethylamine. The base is used in an amount of 0.8-1.1 molar equivalents, preferably in an amount of 0.9-1.0 molar equivalents, calculated per compound of formula II.

The resulting product of formula I is separated from the reaction mixture by any method known in the art. If the product crystallizes from the solvent used in the reaction mixture, or it can be precipitated with another solvent that is miscible with the solvent initially used, the product can then be filtered off and purified by recrystallization or chromatography.

If the product does not crystallize from the reaction mixture, the solution can be evaporated and the residue recrystallized from a suitable solvent.

In some cases, it is desirable to treat the evaporation residue by partitioning between water and a water-immiscible organic solvent, then basifying the mixture, separating the phase, evaporating the organic phase and purifying the base as a residue by recrystallization.

In process (b) according to the invention, the reaction of the epoxide of formula III with a secondary amine of formula IV is carried out in an indifferent solvent or in an excess of the secondary amine.

As the solvent for the above reaction, for example, methanol, ethanol, isopropanol, butanol, diisopropyl ether, acetonitrile, acetone, methylethyl may be used. Tone, dimethylformamide, water or a mixture with water, preferably ethanol, isopropanol or 5-20% (w / w) thereof, preferably 10% (w / w) solutions in water.

One mole of the epoxide of formula III is reacted with 0.8-2.0, preferably 0.85-1.2 moles of the secondary amine of formula IV. When used as a base, the secondary amine of formula IV is added directly to the reaction mixture. When a secondary amine salt of formula IV is used, the base can be liberated in situ in the reaction mixture by the addition of an equivalent molar amount of inorganic or organic base calculated on the amount of secondary amine salt.

Generally, a 5-40% (w / w), preferably 10-25% (w / w) alkali metal hydroxide or alkaline earth metal hydroxide solution is used as the inorganic base, preferably sodium hydroxide or potassium hydroxide in water.

The organic base used is preferably trialkylamine or tetraalkylammonium hydroxide, preferably triethylamine.

Usually the reaction is carried out at the boiling point of the solvent used or at a lower temperature.

The product is separated from the reaction mixture as described for process (a) above.

In process (c) of the invention, the reaction of a compound of formula V with a halogen of a compound of formula XI is carried out in an indifferent solvent in the presence of an inorganic or organic base and a phase transfer catalyst.

The inorganic base used is generally an alkali metal or alkaline earth metal hydroxide or carbonate, preferably sodium or potassium hydroxide or potassium carbonate. The organic base used is trialkylamine or tetraalkylammonium hydroxide, preferably triethylamine.

The base is used in an amount of 1-2 moles, preferably in an amount of 1.2 moles, based on the compound of formula V.

• ··

The halogen compound of the formula XI is used in an amount of 1-3, preferably in an amount of 1.8 - 2 moles relative to the compound of the formula V.

As the solvent for the above reaction, for example, methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, diethyl ketone, acetonitrile, dimethylformamide, water, preferably ethanol, acetone or methyl ethyl ketone can be used.

As a phase transfer catalyst, tetraalkylammonium hydroxide or a halide, preferably trimethylbenzylammonium hydroxide, triethylbenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium hydrogen sulphate can be used.

The reaction is carried out at a temperature of 40 to 100 ° C, preferably at 60 to 80 ° C.

The separation of the product is carried out in some known manner. For example, after completion of the reaction, the reaction mixture is evaporated under reduced pressure, the residue is partitioned between water and a water-immiscible organic solvent, the organic phase is separated and dried, evaporated to dryness and the residue purified by recrystallization from a suitable solvent or vacuum distillation .

Using method (d) of the invention, the compound of formula V is reacted with an epoxide of formula XII in an indifferent solvent.

As the solvent, for example, methanol, ethanol, isopropanol, butanol, diisopropyl ether, acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, water or a mixture of water, preferably ethanol, isopropanol or a mixture thereof at a concentration of 5-20% (w / w), preferably 10% ( %) in water.

The compound of formula V is used in this reaction in an amount of 0.8-2.0, preferably in an amount of 0.85-1.2 moles relative to the epoxide of formula XII.

Usually, the reaction is carried out at or below the boiling point of the solvent used.

The product can be isolated from the reaction mixture as described above for process (c).

• ·· ·· ··· ·· ·

Using method (e) of the invention, a compound of formula I wherein A is COH, B is methylene is dehydrated with a strong mineral acid, preferably hydrochloric acid, in an indifferent solvent, preferably alcohol, particularly preferably ethanol, with heating preferably at boiling point. The starting compound is suitably used in the form of a solution having a concentration of 5-40%, preferably 15-25%. If, after cooling, the product falls out of solution, it is filtered off; otherwise, a solution is used in which the product does not dissolve but is miscible with the solvent used in the reaction, preferably ether is added to the reaction mixture, and the precipitated crystalline product is filtered off.

Using methods (f) and (g) of the invention, a ketone of formula XV is reacted with an arylmagnesium halide of formula XVI or an aryl lithium compound of formula XVII in an indifferent aprotic organic solvent, preferably ether, tetrahydrofuran or dioxane, at a temperature ranging from -10 ° C to the boiling point of the solvent, preferably at 10 to 30 ° C. The product is then recovered by simple crystallization or salt formation after decomposition of the acid reaction complex and evaporation of the solvent. If the product or salt does not crystallize, the acid-quenched reaction mixture is basified, the product is dissolved in a water-immiscible organic solvent, the organic phase is dried and the base obtained is purified by crystallization or chromatography.

In methods (h) and (i) of the invention, a compound of formula I wherein A forms with B a group of formula -C = C- is suitably reduced by catalytic hydrogenation using a noble metal catalyst on a carbon support, preferably palladium on carbon, preferably 10% palladium on carbon, in alcohol, preferably methanol. The catalyst is then removed by filtration and the product isolated by evaporation of the solvent and crystallization of the residue. Alternatively, the evaporation residue can be converted into a salt.

If the product or salt does not crystallize, the reaction mixture is partitioned between water and a water-immiscible organic solvent, the organic phase is dried, evaporated, the base containing residue is purified by crystallization or chromatography.

·························································

Said reduction can also be carried out in the reaction mixture in which the starting component has been prepared.

Halides of formula II are novel compounds and are also encompassed by the invention.

Halides of formula II can be prepared by reacting a compound of formula V with a dihaloalkane of formula VI

Hat

Y

vi wherein Y, R ² and Hal are as defined above.

Alternatively, the halide of formula II is prepared by reacting a compound of formula V with a haloalkanol derivative of formula VII

Y

R ¹ wherein Y, R ² and Hal are as defined above, wherein the hydroxy group of the resulting hydroxyalkyl derivative of general formula (VIII)

R 'in m

• ·· • · • ··· • e • · • · • • · • • · • • • · • • · · • · • • • • · · · · · · · · · · •

wherein R ¹ , R ² , X, Y and Z are as defined above, is transferred to a halogen atom.

The reaction of a compound of formula V with a dihaloalkane of formula VI is carried out in an indifferent solvent in the presence of an inorganic or organic base and a phase transfer catalyst.

The inorganic base used is, in particular, an alkali metal or alkaline earth metal hydroxide or a carbonate, preferably sodium hydroxide or potassium hydroxide. The organic base used is trialkylamine or tetraalkylammonium hydroxide, preferably triethylamine. The base is used in an amount of 1 to 1.5 moles relative to the compound of formula V.

The dihaloalkane of formula VI is used in an amount of 1-3, preferably in an amount of 1.8-2 moles relative to the compound of formula V.

The solvent used in the reaction may be, for example, methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide, water, preferably ethanol, acetone or methyl ethyl ketone.

The phase transfer catalyst in said reaction may be tetraalkylammonium hydroxide or halide, preferably trimethylbenzylammonium hydroxide, triethylbenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium hydrogen sulphate.

The reaction is carried out at a temperature of 40 to 100 ° C, preferably 60 to 80 ° C.

The product is isolated from the mixture by any of the known methods. For example, after completion of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residue is partitioned between water and a water immiscible organic solvent, the organic phase is separated, dried, evaporated to dryness under reduced pressure, and the residue purified by recrystallization from a suitable solvent or vacuum distillation.

The reaction of a compound of formula V with a haloalkanol derivative of formula VII is carried out in an analogous manner to that described for the reaction of a compound of formula V with a dihaloalkane of formula VI.

• ·· ·· · • · • · · • · • · • • · • ··· • t • • • • · · • · • • • ·· · · · · · · · · · · •

The prepared hydroxyalkyl derivatives of formula VIII are converted to the desired halides of formula II by halogenating agents such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, thionyl bromide, phosphorus oxybromide, phosphorus tribromide, phosphorus iodide, phosphorus tribromide, preferably thionyl chloride.

The halogenating agent is used in an excess of 1-4 moles, preferably 1.2-2.2 moles per mole of the starting hydroxyalkyl derivative of formula VIII.

The reaction is carried out in an indifferent solvent, preferably halogenated alkanes, preferably chloroform, dichloromethane or 1,2-dichloroethane, or an excess of halogenating agent is used as solvent.

The product is isolated after evaporation of the solvent in the same manner as described for the reaction of a compound of formula V with a dihaloalkane of formula VI.

Certain epoxides of formula III are described in the literature [Japanese Patent Application Publication No. US Pat. J6 0258-174-A; C.A., 104, 207136k (1986)]. They are prepared from compounds of formula V by reaction with epichlorohydrin in an alkaline medium. Alternatively, they can be prepared by reacting a compound of formula V with a halide of formula IX

IX wherein R ² and Hal are as defined above, and by oxidizing the prepared allyl derivative of formula X

• ·· • · • ··· · · • · • · • · · • ·· · • · · • · · · · · · · · ·· ··

wherein R ¹ , R ² , X and Z are as defined above.

In said reaction, the compound of formula V is reacted with 1-3 molar equivalents of epichlorohydrin in the presence of an alkali metal or alkaline earth metal hydroxide, preferably sodium or potassium hydroxide used in 1-3 molar equivalent amounts.

The reaction is carried out in methanol, ethanol, propanol, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide, water or a mixture of water, preferably in aqueous methanol or aqueous ethanol, suitably at the boiling point of the solvent or at a lower temperature.

The epoxide of formula (III) formed in the above reaction may be separated by any of the methods known in the art. After completion of the reaction, for example, the reaction mixture is evaporated to dryness under reduced pressure, the residue is partitioned between water and a water-immiscible organic solvent, the organic phase is separated, dried and evaporated under reduced pressure. Usually, the residue is of sufficient purity to be used in further reactions. If necessary, the product can be purified by chromatography or crystallization.

One of the allylic derivatives of formula X, wherein X is O, R ¹ is methyl, R ² is H and Z is H is described in the literature [Aust., 36 (6), 1263 (1983) ]. It is prepared from a compound of formula V, which is reacted with a halide of formula IX in an alkaline medium in the presence of a phase transfer catalyst.

• ·· ·· · · · • · • · · · · • • · • ··· • · • • • • • · · ··· ·· • · ·· • · · · • · · • •

In said reaction, the alkaline environment is achieved with an alkali or alkaline earth metal hydroxide or carbonate, preferably sodium or potassium hydroxide or potassium carbonate. These bases are used in an amount of 12 molar equivalents.

The solvent used in the reaction is, for example, methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, diethyl ketone, acetonitrile, dimethylformamide, water or mixtures with water, preferably ethanol, acetone or methyl ethyl ketone.

The phase transfer catalyst in said reaction may be tetraalkylammonium hydroxide or halide, preferably trimethylbenzylammonium hydroxide, triethylbenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium hydrogen sulphate.

The reaction is carried out at a temperature of 40 to 100 ° C, preferably 60 to 80 ° C.

The product is isolated from the mixture by any of the known methods. For example, after completion of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residue is partitioned between water and a water immiscible organic solvent, the organic phase is separated, dried, evaporated to dryness under reduced pressure, and the residue purified by recrystallization from a suitable solvent or vacuum distillation.

The allyl derivative of formula X is oxidized to the corresponding epoxide of formula III with an organic oxidizing agent such as m-chloroperbenzoic acid, peracetic acid, peroxyphthalic acid, 2,3-dichloro-5,5-dicyano-1,4-benzoquinone (DDQ), preferably used m-chloroperbenzoic acid at 0 to 40 ° C, preferably at 20 to 30 ° C.

Dichloromethane, 1,2-dichloroethane, chloroform, 1,1,2-trichlorethylene, chlorobenzene, preferably dichloromethane or 1,2-dichloroethane are used as solvents in the reaction.

The separation of the product is carried out by any of the known methods. For example, after completion of the reaction, water is added to the reaction mixture, the solution is made alkaline by addition of sodium carbonate, the phases are separated, the organic phase is dried and then

Φ ·· • · 0 000 00 • · 0 · 0 · · 0 00 • · 0 0 • · 0 · · · • 0 · · · · · · ·

is evaporated under reduced pressure. The residue is purified by recrystallization from a suitable solvent or by chromatography.

Certain halogen compounds of formula XI are known [Peltz K., Protiva M., Coli.Czech.Chem.Commun., 32 (8), 2840 (1967), US-P. 4,110,536; Chem.Abstr., 90. P121596 (R)]. They are prepared by reacting an appropriate secondary amine of formula IV with an appropriate dihaloalkane of formula VI. Other halogen compounds of formula XI can also be readily prepared by the above methods.

Also, some epoxides of formula XII are known. They are prepared by reacting the corresponding compound of formula IV with epichlorohydrin in an alkaline medium [CH-P no. 474.511; Chem. Astr., 72, 55506m (1970)]. Certain compounds of formula XII may also be prepared by reacting the corresponding secondary amine of formula IV with the corresponding halide of formula IX, and converting the double bond of the resulting compound of formula XIV

XIV wherein R ² , A, B and Ar are as defined above, to an epoxy group under the conditions described above for the oxidation of compounds of formula X. Other epoxides of formula XII can also be readily prepared by the above methods.

The ketones of formula XV are novel compounds and are also included in the present invention. They are prepared by reacting a halide of formula II or an epoxide of formula III with a piperidone of formula XIII

• ·· • · • ··· ·· · • · ·· • · · · · • · • · • · ·· ·· ·· ··· · · · ·

XIII

The reaction conditions are identical to those described for processes (a) and (b) of the invention.

The reaction of the ketone of formula XV with an arylmagnesium halide of formula XVI is carried out as described in [J-P no. 14,632 ('67); Chem. Abstr., 68, 114618 (1968)].

The reaction of aryl lithium derivatives of formula XVII with a ketone of formula XV can also be carried out according to methods known in the literature [Elpern B., Wetteran W., Carabates Ph., Grunbach L., J. Am. Chem. Soc., 80, 4916 (1958)] .

Said arylmagnesium halides of formula XVI and aryllithium derivatives of formula XVII are commercially available.

Secondary amines of formula IV are usually commercially available or can be readily prepared by known methods.

The biological activity of the compounds of the invention was evaluated by the following tests.

1. Determination of cardioprotective effect on ischemized rat heart (Langendorff)

Cardioprotective compounds protect the myocardium from damage caused by ischemia or reperfusion. Of the multiple methods used to determine cardioprotective effect, the best known and frequently used assays are isolated perfused heart tests subjected to general ischemia [Longman S.D. and Hamilton T.C., Medicinal Research Reviews, 12). During general ischemia,

• ·· • · • ··· • · • · · • • • • • • • • · · • • • • ·· ·· · · · · ·

·· Myocardial contraction probably due to an increase in myocardial calcium concentration. The time from onset of total ischemia to contraction (i.e., time to contraction = TTC) is prolonged by the application of various cardioprotective compounds, and thus the efficacy of the test compounds can be assessed by determining TTC.

Male Sprague-Dawley rats weighing 300-350 g are injected ip with 2,500 IU (0.5 ml) of heparin, and after 10 minutes the animals are anesthetized with sodium pentobarbital [5-ethyl-5- (1-methylbutyl) sodium - 2,4,6 (1H, 3H, 5H) -pyrimidine trione] at an ip dose of 60 mg / kg. Then, the heart is quickly removed and the aorta attached to the cannula associated with the Langendorff device. The heart is perfused at a constant pressure (8,000 Pa) with a modified carbogenized Krebs-Henseleite solution. The composition of this solution is as follows (in mM): NaCl 118, KCl 4.7, MgSO ₄ 1.6, CaCl ₂ 2.5, NaHCO ₃ 24.88, KH ₂ PO ₄ 1.18, EDTA 0.5, glucose 11. The CO ₂ partial pressure and the pH of the solution are maintained within physiological values (pCO ₂ 4000-450 Pa, pH = 7.3 7.45).

A hole is cut into the wall of the left atrium and a plastic balloon filled with water connected to a metal cannula is inserted into the left ventricle. The internal diastolic pressure in the left ventricle is adjusted to 666 - 1333 Pa during equilibrium by varying the volume of fluid in the balloon, but then this amount does not change.

After equilibration for 20 minutes, hearts are perfused in the control group for 10 minutes with vehicle (0.04% dimethylsulfoxide) and in the test group with the test compound at 10 ' ⁶ M or 10' ⁵ M. For a 1 minute interval, the left ventricular systolic pressure is reduced by more than 20% compared to the control value obtained before perfusion.

Total ischemia is initiated by complete interruption of perfusate flow and carbogenisation for 25 minutes. The time of TTC from the onset of ischemia to the formation of myocardial contraction, i. increase in internal diastolic pressure in the left ventricle by 666 Pa.

• ·· • · • ··· · · • · · • · · • · • · • • • • ·· ·· · · · · · · ·

Three concurrent assays for each concentration were performed with the test compounds, and 3 additional concurrent assays were performed on vehicle-treated hearts (0.04% dimethylsulfoxide) at the same time.

Mean TTC values are calculated and the effect of test compounds is expressed as a percentage change in the vehicle treated group. Compounds with a prolonged TTC to the control group are cardioprotective. Lemacalim was used as a reference compound in the evaluation of the compounds of the invention, i. (3S) -trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4- (2-oxo-l-pyrrolidinyl) -2 H lbenzpyrán-6-carbonitrile. The results are shown in Table I.

Table I

Prolongation effect on TTC determined on Langendorff-isolated rat heart

compound (example number) TTC change (%) 10 ' ⁵ M 10 ' ⁶ M lemakalim 55 20 9 90 8 90 43 20 65 18 24 47 16 78 5 26 43 25 59 2 41 53 32 63 111 -3 66 66 5 68 43 0 73 49 19 76 80 25

···························

Several benzofuran derivatives tested showed a remarkably higher TTC prolongation at 10 ⁶ than the reference compound lemacalim at a concentration of 10 ⁶ .

The compounds of the invention induced significant prolongation of TTC on isolated perfused rat heart during ischemia. This confirms their cardioprotective effect. The compound of Example 9 also has the effect of remarkably overcome lemakalínu the determination of the concentration of 10 ^-6 M. The cardioprotective activity of compounds of this invention can be used in human therapy. The aforementioned cardioprotective effect increases the possibilities of preventing unwanted severe coronary arrhythmias, which often occur in coronary artery disease by prolonged administration of the active ingredients. In particular, in patients with unstable angina, said treatment appears appropriate because the disease is considered to be prior to myocardial infarction, and said treatment may reduce the rate of irreversible myocardial damage caused by later myocardial infarction. The compounds of the invention may find further application in cardioprotective therapy prior to surgery, for example in the case of temporarily blocked coronary circulation (in coronary balloon dilation) or in cardiac arrest during surgery. Cardioprotective treatment of the heart ready for transplantation can also achieve faster or more complete regulation of cardiac function. In this case, the compound of the invention is added to a nutritional solution for heart storage.

2. Determination of the effect on serotonin neurotransmission

Determination of 5-HT _1A receptor binding

Determination of 5-HT _1A receptor binding by Peroutka method [Peroutka

S. J., J. Neurochem., 47, 529 (1986)]. Binding assays are performed on membrane fragments prepared from rat frontal cortex using tritium labeled 8-hydroxy-N, N-dipropyl-2-aminotetralin as a specific ligand. Non-specific binding is determined in the presence of 10 μΜ 5-HT (5-hydroxytryptamine). The final volume for incubation is 250 microliters. The test samples were incubated at 25 ° C for 30 minutes. The reaction was quenched by the addition of 9 mL ice-cold28

• ·· • · • ··· • · • · • · • · · · • · • • · · · • · · • · · · • · · · ·· ··

of a solution of tris (hydroxymethyl) aminomethane hydrochloride at pH 7.7 followed by filtration under reduced pressure. Filtration is performed through Whatman GFIB glass fiber filter paper, which is pre-soaked 2-3 hours before use with a 0.05% polyethyleneimine solution. Radioactivity is measured by scintillation counting in a liquid scintillator.

The results obtained are summarized in Table II. buspirone was used as reference compound, i. 8- {4- [4- (2-Pyrimidinyl) -1-piperazinyl] butyl} -8-azaspiro [4,5] decane-7,9-dione.

Table II

Effect of compounds of the invention on the 5-HT _1A receptor

compound (example #) inhibition of receptor binding Ki in nmol / L 9 20 20 6 24 12 30 5 14 10 16 3 26 3 23 12 25 0.7 28 9 buspirone 19

The data in Table II shows that the compounds of the invention have significant affinity for serotonin 5-HT _1A receptors.

Most of the compounds evaluated had better effects than buspirone used as reference compound.

• ·· • · • ··· • * • · • · • · · • ·· · • t « ·· ·· • · · · · ·· ··

Increased plus-maze test in rats

The test is carried out in a modified manner according to Pelow et al. [J. Neurosci. Methods, 14, 149 (1985)]. The raised plus-maze consists of two open and two 40 cm wall-closed arms of the same size (50 x 15 cm) arranged in a cross shape. The arms of the same type are placed opposite each other. Thus, a central square area (15 x 15 cm) is formed at the intersection of the four arms. The whole device is made of wood up to a height of 50 cm and is illuminated from above by dim light. Male Sprague-Dawley rats weighing 220-260 g were used in the experiment.

minutes before the start of the test, rats are treated with test or reference compounds. The animals are then placed in the central area of the maze and evaluated for 5 minutes. The following 4 different parameters are determined:

- time spent in open arms;

- time spent in closed shoulders;

- number of entrances to open arms;

- number of entrances to closed arms;

A compound is considered to be effective if significant increases are found compared to control animals (in%) either at the time spent in the open arms (s) or in the number of entries into the open arms. Minimum effective doses (MED) are determined for each compound based on the time spent in the open arms. The results are shown in Table III. Buspirone was used as reference compound.

• · ··· ··

Table III

compound (example #) MED (mg / kg) after. 16 1 23 3 24 3 25 0.3 buspirone 3

It can be seen from Table III that the compound of Example 25 is one order of magnitude better than buspirone in the above test characterizing the anxiolytic effect. It should be noted that buspirone shows intense binding to the 5-HT _1A receptor and has widespread use in clinical practice.

Based on the results obtained in studies related to the effect on serotonin neurotransmission, the compounds of the invention can be used for the treatment of various diseases, in particular diseases of the central nervous system.

Many clinical and preclinical studies suggest that 5-HT _1A receptors are involved in various pathological processes. Buspirone, used in studies of compounds of the invention as a reference compound and acting through 5-HT _1A receptors, inhibits the aggressive behavior of rhesus monkeys [Tomkins

E.C., Clemento A.J., Taylor D.P., Perlach J., Res.Commun.Physiol.Psychiat. Behav., 5, 337 (1980)] and has shown anxiolytic effect in clinical trials [Goldberg H.L. and Finnerty R.J., Am.J.Psychiatry, 136, 1184 (1979)]. In evaluating the compounds of the invention, several compounds of the invention overcome the anxiolytic activity of buspirone.

5-HT _1A receptors are believed to have been implicated in the clinical manifestations of depression because animal tests have demonstrated the antidepressant potential of 5-HT _1A ligands [Porsolt RD, Roux S., and Wettstein JG, Pharmacol.Res., 31, 169 (1995)]. Another therapeutic option for drugs acting at the 5-HT _1A receptor involves therapy for cognitive impairment. Following the administration of 8-hydroxy-N, N-dipropyl-2-aminotetraline to rats, it improves their memory and learning ability by providing rats with 8-hydroxy-N, N-dipropyl-2-aminotetralin. / Carli, M. and Samanin, R., Br. J. Pharmacol., 105, 720 (1992)]. In addition to the clinical manifestations listed above, 5-HT 1A receptor compounds can be used for various diseases associated with eating disorders. This hypothesis is based on the finding that 8-hydroxy-N, N-dipropyl-2-amino-tetralin acting on the 5-HT _1A receptor promotes food intake under certain conditions, while reducing food intake under other conditions [Dourish CT, Hutson PH and Curzon G., Psychopharmacology, 86, 197 (1985)]; [Dourish CT, Hutson P, H and Curzon G., Brain Res.Bull., 15, 377 (1985)]. Thus, the compounds of the invention may be effective in several clinical manifestations associated with a central nervous system disease manifesting symptoms including anxiety, depression, cognitive deficiency, or eating disorders.

The above test also confirms the above hypothesis.

3. Determination of anxiolytic effect in Vogel conflict test

The anxiolytic effect is evaluated according to the method of Vogel et al. [Vogel J.R., Beer B., Clody D.E., Psychopharmacologia (Berl.), 21.1 (1971)]. Male Wistar rats weighing 180-200 g are left free of liquids and 24 hours prior to the experiment without food. Compounds to be evaluated and their carriers themselves are administered to the animals half an hour prior to evaluation. In the test chamber, the rats may be attached from a fluid supply tube drawn into the chamber. After each 20 licks of the tube, the device emits an electrical shock pulse of 0.7 mA through the supply tube. During the test, which lasts 5 minutes, the number of electrical shocks that the animals have received to water is registered. The effect of test compounds is expressed by increasing the tolerated number of electric shocks as a percentage The minimum effective dose (MED) is determined for each test compound.

• · ···

Meprobamate (2-methyl-2-propyltrimethylenecarbamate) was used as a reference compound in the evaluation of the compounds of the invention, and the results are summarized in Table IV.

Table IV

Anxiolytic effect

compound MED (example #) in mg / kg i.p. 68 20 meprobamate 50

It can be seen from Table IV that the benzofuran derivative evaluated overcomes the effect of meprobamate used in the Vogel conflict test as a reference compound by a factor greater than 2.

A summary of the results of the above tests undoubtedly shows the beneficial effect of the compounds of the invention on the heart. At the same time, due to their mechanism of action, the compounds of the invention may be useful in the treatment of central nervous system diseases such as depression, anxiety, cerebral ischemia, schizophrenia, etc.

The novel benzofuran derivatives of the invention can be used as active ingredients in compositions for pharmaceutical preparations.

The pharmaceutical compositions of the invention comprise a therapeutically active amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof and one or more conventional carriers.

The pharmaceutical compositions of the invention are suitable for oral, parenteral or rectal administration or for topical treatment, and may be solid or liquid.

Solid pharmaceutical compositions suitable for oral administration may be in the form of powders, capsules, tablets, film-coated tablets, microcapsules, etc., and may contain binders such as gelatin, sorbitol, polyvinylpyrrolidone, etc .; fillers such as lactose, glucose, starch, calcium phosphate, etc .; tabletting aids such as magnesium stearate, talc, poly (ethylene glycol), silica, etc .; wetting agents such as sodium laurosulfate etc. as a carrier.

· · • · · · · · • · • · • • · • • · • · · • · • · • · · · · · · ·· ·

Liquid pharmaceutical compositions suitable for oral administration may be in the form of solutions, suspensions or emulsions and may contain, for example, suspending agents such as gelatin, carboxymethylcellulose, etc .; emulsifiers such as sorbitan monooleate, etc .; solvents such as water, oils, glycerol, propylene glycol, ethanol, etc .; preservatives such as methyl p-hydroxybenzoate, etc. as a carrier.

Pharmaceutical compositions suitable for parenteral administration are generally sterile solutions of the active ingredient.

The dosage forms listed above as well as other dosage forms are generally known in the art, see, for example, Remington's Pharamceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA.

The pharmaceutical compositions of the invention generally contain 0.1 to 95.0 percent by weight of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof. A typical dose for an adult patient is from 0.1 to 1000 mg of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof per day. The above dosage may be administered in one or more sub-doses. The actual dose is dependent on many factors and will be determined by your doctor.

The pharmaceutical compositions of the invention are prepared by admixing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof with one or more carrier (s) and reacting the resulting mixture in the form of a pharmaceutical composition in a manner generally known in the art. Suitable methods are described in the literature, see for example Remington's Pharmaceutical Sciences.

* · ··· · · · · ··· ··· ···

A preferred subgroup of pharmaceutical compositions of the invention comprises a benzofuran derivative of the Formula I wherein

R ¹ represents a hydrogen atom or a C 1-4 alkyl group,

R ² is H,

X is an oxygen atom,

Y represents a hydrogen atom or a hydroxy group,

Z is hydrogen, halogen or nitro,

A is CH, COH or C-CN,

B represents a methylene group, or

A forms with the group B a group of the formula -C = C-,

Ar is hydrogen, benzyl, phenyl substituted with R ⁵ , R ⁶ and R ⁷ , biphenylyl, naphthyl optionally substituted with C 1-4 alkoxy; or thienyl, wherein R ⁵ , R ⁶ and R ⁷ are independently hydrogen, halogen, trifluoromethyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyloxy, phenoxy, and methylenedioxy, or a pharmaceutically acceptable addition salt thereof; acid as the active ingredient.

Within the aforementioned subgroup, the pharmaceutical compositions of the invention preferably comprise a benzofuran derivative of the general formula I wherein

R ¹ represents a methyl group,

R ² is H,

X is an oxygen atom,

Y represents a hydroxy group, and represents a hydroxy group.

Z represents a hydrogen atom,

A is CH, COH or C-CN,

B represents a methylene group, or

A forms with B a group of the formula -C = C-,

Ar represents a phenyl group optionally substituted by a group selected from halogen, trifluoromethyl, methyl or methoxy; or a methoxynaphthyl group, or a pharmaceutically acceptable acid addition salt thereof, as the active ingredient.

in

Another preferred subgroup of pharmaceutical compositions of the invention comprises a piperazinylalkylbenzofuran derivative of Formula Ia wherein:

R ¹ is C 1-6. _An alkyl group,

R ² is H,

X is an oxygen atom,

Y is hydroxy,

Z represents a hydrogen atom,

Ar 1 represents a diphenylmethyl group, a pyridyl group, a partially saturated 5-membered heterocyclic group containing two oxygen atoms which is fused with a phenyl group, or a phenyl group substituted with a group selected from R ⁵ , R ⁶ , R ⁷ , wherein

R ⁵ , R ⁶ , R ⁷ independently represent hydrogen, halogen, trifluoromethyl, C 1-4 alkyl, C 1-4 alkoxy, and methylenedioxy, n represents 0 or 1 and a pharmaceutically acceptable acid addition salt thereof as the active ingredient.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Within the above subgroup, the compositions of the invention comprise a piperazinylalkylbenzofuran derivative of the general formula Ia wherein:

R ¹ represents a methyl group,

R ² is H,

X is an oxygen atom,

Y is hydroxy,

Z represents a hydrogen atom,

Ar 1 represents diphenylmethyl, pyridyl, benzo-1,3-dioxolanyl or phenyl optionally substituted by one or two halogen atoms, one or two methyl groups, methylenedioxy, trifluoromethyl or methoxy, n is 0 or 1, and a pharmaceutically acceptable addition thereof acid salt.

Particularly preferred pharmaceutical compositions of the invention comprise one of the following benzofuran derivatives or pharmaceutically acceptable acid addition salts thereof as the active ingredient:

1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4 (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, 1 - [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-trifluoromethylphenyl) -piperidine, 1- [3- (2 2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-fluorophenyl) -piperidine, 1- [3- (2,2-dimethyl-2) (3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4-phenylpiperidine; 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4-yl - (3-chlorophenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-methoxyphenyl) piperidine 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methoxyphenyl) piperidine, 1- [3- ( 2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro) -b enzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methylphenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-cyano-4-phenylpiperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- ( 4-Chlorophenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (6-methoxy-naphth-2) 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4 (diphenylmethyl) piperazine, 1- [3- (2-yl) -piperidine] , 2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (4-fluorophenyl) piperazine,

- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-trifluoromethylphenyl) piperazine, 1- [3- (2, 3-trifluoromethylphenyl)] 2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (4-methoxyphenyl) piperazine,

• ·· • · · · • · • ··· • · · • · • · • · · · • · · • · • · • · · · · · · · · • · ·

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (benzol, 3-dioxolan-5-yl) piperazine, 1- [ 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-chlorophenyl) piperazine, 1- [3- (2,2-dimethyl-2, 2-hydroxypropyl) piperazine]; 3-Dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-benzylpiperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-chlorophenyl) piperazine] -4- (2,4-dichlorophenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (2-pyridyl) piperazine, 1- [3- (2,2-dimethyl) -2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) piperazine, or 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7)]. yl-oxy) -2-hydroxypropyl] -4- (3-methoxyphenyl) piperazine.

The invention further encompasses a method of treating diseases comprising administering to a patient suffering from cardiac or central nervous system diseases, a therapeutically effective, non-toxic amount of a benzofuran derivative of formula I or a pharmaceutically acceptable acid addition salt thereof.

The invention is further illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Preparation of Halides of Formula II

1) 7- (3-bromopropyloxy) -2,2-dimethyl-2,3-dihydrobenzofuran

To a solution of 32.8 g (0.2 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 600 ml of acetone is added 80.8 g (0.4 mol) of 1,3-dibromopropane and 1.0 g (0.6 mol) of anhydrous potassium carbonate, and the reaction mixture is heated to boiling under stirring for 24 hours. After cooling, the inorganic salts are filtered off and the filtrate is evaporated to dryness under reduced pressure. The residue was recrystallized from methanol, filtered and then dried at room temperature.

34.7 g (61%) of the title compound are obtained, m.p .: 54-56 ° C.

Preparation of epoxides of formula III

2) 5-bromo-2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran

(a) 7-acetoxy-2,2-dimethyl-2,3-dihydro-benzofuran

To a solution of 16.4 g (0.1 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 40 ml of glacial acetic acid was added 12.2 g (0.12 mol) of acetic anhydride and the reaction mixture was The mixture is heated at boiling point for 30 minutes and then evaporated to dryness under reduced pressure. The oily residue is triturated with 60 ml of ice-water and the white crystalline product is filtered off, washed with ice-water and dried under reduced pressure.

Thus, 20.4 g (99%) of the title compound are obtained. After recrystallization from methanol, mp .: 49-50 ° C.

b) 7-acetoxy-5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran

To a solution of 20.6 g (0.1 moles) of 7-acetoxy-2,2-dimethyl-2,3-dihydrobenzofuran in 150 ml of chloroform was added dropwise, with stirring and cooling to 15-20 ° C, over 30 minutes. 1.0 g (0.1 mol) of bromine in 40 ml of glacial acetic acid. The resulting solution was stirred for 15 minutes and then evaporated to dryness under reduced pressure. The honey-like residue is triturated with 150 ml of ice-water, the precipitated crystals are filtered off and then washed neutral with ice-water. The crystals thus obtained are suspended in 80 ml of methanol at 0 ° C, filtered again and dried under reduced pressure.

Thus, 22.0 g (77%) of the title compound are obtained, m.p .: 76 ° C.

c) 5-bromo-2,2-dimethyl-2,3-dihydro-benzofuran-7-ol

24.2 g (0.085 mol) of 7-acetoxy-5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran are stirred for 3 hours at 20-25 ° C in a mixture of 70 ml of methanol and 68 ml of 10% aqueous sodium hydroxide. . The reaction mixture is then acidified to pH 2 with concentrated hydrochloric acid, the methanol is distilled off under reduced pressure, and the residue is extracted three times with 50 ml of dichloromethane each time. The combined organic phases are washed twice with 20 ml of water each time to remove acid residues, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue is triturated with hexane and the crystalline substance is filtered off and dried under reduced pressure.

Thus, 19.9 g (96.4%) of the title compound are obtained, m.p .: 70 ° C.

d) 5-bromo-2,2-dimethyl-7-oxiranyl-methoxy-2,3-dihydrobenzofuran

To a solution of 19.9 g (0.082 mol) of 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 60 ml of 10% aqueous sodium hydroxide is added 13.65 g (0.147 mol) of epichlorohydrin and the reaction the mixture was stirred at 45-50 ° C for 3 hours. After cooling, the separated oil is dissolved in 100 ml of dichloromethane, the aqueous phase is extracted with 30 ml of dichloromethane, the combined organic phases are extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure.

• • • •

Thus, 23.5 g (98%) of the title compound are obtained in the form of a honey-like product which is used directly for the preparation of the compounds of formula I. After standing for a long time, the product crystallizes and has mp .: 46-48 ° C.

3) 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran

To a solution of 15.0 g (0.09 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 100 ml of 10% aqueous sodium hydroxide is added 20.0 g (0.216 mol) of epichlorohydrin and the reaction mixture Stir for 2.5 hours at 48-50 ° C. After cooling, the separated oil is dissolved in 100 ml of dichloromethane, the aqueous phase is extracted with 50 ml of dichloromethane, the combined organic phases are extracted twice with 20 ml of water each, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The title compound is obtained in the form of a thick honey-like product which is triturated with 60 ml of hexane to give white crystals. The precipitated crystals are filtered off and dried under reduced pressure.

Thus, 19.5 g (97%) of the title compound are obtained. Mp: 51-52 ° C.

4) 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran

To a solution of 0.204 g (0.001 mol) of 2,2-dimethyl-7- (2-propenyloxy) -2,3-dihydrobenzofuran in 5 ml of dichloromethane is added 0.35 g of 82% m-chloroperbenzoic acid and the reaction mixture is stirred for 10 hours . 5 ml of 10% aqueous sodium hydrogen carbonate solution are added to the reaction mixture, the phases are separated, the organic phase is dried over anhydrous sodium sulphate, filtered and the solvent is removed under reduced pressure. The oily residue was purified by column chromatography (silica gel column, eluting with 24 volumes of dichloromethane and 1 volume of acetone).

Thus, 0.068 g (31%) of the title compound are obtained. Mp 49-51 ° C.

··· · · · ···

5) 2,2-dimethyl-5-nitro-7-oxiranylmethoxy-2,3-dihydrobenzofuran

(a) 7-acetoxy-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran

To a solution of 16.5 g (0.08 mol) of 7-acetoxy-2,2-dimethyl-2,3-dihydrobenzofuran in 60 ml of chloroform, with stirring and cooling to 15 to 20 ° C, was added 6 ml (0) over 30 minutes. (06 mol) of acetic anhydride. To the stirred and cooled solution obtained, 4 ml (5.53 g, 0.06 mol) of concentrated nitric acid (density: 1.42; 65%) are added dropwise over 30 to 40 minutes, paying attention to the temperature the mixture should be in the range of 25 to 28 ° C. The reaction mixture is stirred for a further 10 minutes, then 100 ml of ice water are added, the phases are separated, the organic phase is washed with ice water until neutral, dried over anhydrous sodium sulphate, filtered and the solvent is removed under reduced pressure. The crystalline product obtained is suspended in 40 ml of methanol at 0 ° C, filtered off and dried under reduced pressure.

Thus, 14.8 g (74%) of the title compound are obtained. Mp: 142-143 ° C.

b) 2,2-dimethyl-5-nitro-2,3-dihydro-benzofuran-7-ol

13.3 g (0.053 mol) of 7-acetoxy-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran are stirred in a mixture of 40 ml of methanol and 42.5 ml of 10% aqueous sodium hydroxide at 20-25 ° C 30 minutes. The resulting purple solution was acidified to pH 1 with concentrated hydrochloric acid, the methanol was distilled off under reduced pressure, and the residue was extracted with 50 ml of dichloromethane. The phases are separated, the aqueous phase is extracted twice with 25 ml of dichloromethane each time. The combined organic phases are extracted twice with 20 ml of water each time to remove the acid, then dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was triturated with hexane to give a crystalline product which was filtered off and dried under reduced pressure.

Thus, 10.8 g (97.8%) of the title compound are obtained. Mp: 96-97 ° C.

• ·· • · • ··· • · · • · · · • · · • · • · • · • · • · · · ·· ··· · · • ·

b) 2,2-dimethyl-5-nitro-7-oxiranylmethoxy-2,3-dihydrobenzofuran

To a solution of 10.8 g (0.052 mol) of 2,2-dimethyl-5-nitro-2,3-dihydrobenzenfuran-7-ol in 62 ml of 10% aqueous sodium hydroxide is added 14.5 g (0.156 mol) of epichlorohydrin, and the reaction mixture was stirred at 48-52 ° C for 2.5 hours. After cooling, the separated oil is dissolved in 60 ml of dichloromethane, the aqueous phase is extracted twice with 60 ml portions of dichloromethane each time, the combined organic phases are extracted twice with 20 ml portions of water each, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. . The residue was triturated with hexane, then filtered off and dried under reduced pressure.

Thus, 13.3 g (96.7%) of the title compound are obtained. Mp: 108 ° C (after recrystallization from methanol).

6) 2,2-dimethyl-7- (2-allyloxy) -2,2-dihydrobenzofuran

To a solution of 8.20 g (0.05 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 100 ml of acetone is added 12.1 g (0.12 mol) of allyl bromide and 20.75 g ( Anhydrous potassium carbonate (0.15 mol) was added and the reaction mixture was heated at reflux for 12 hours with stirring. After cooling, the inorganic salts are filtered off and the filtrate is concentrated by evaporation of the solvent. The residue, as an oily product, is purified by vacuum distillation.

Thus, 9.20 g (90%) of the title compound are obtained. M.P .: 77 ° C / 53.3 Pa

7) 2,2-dimethyl-7- (2-allyloxy) -2,3-dihydrobenzofuran

To a solution of 8.20 g (0.05 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 100 ml of acetone was added 7.63 g (0.10 mol) of allyl chloride and 20.7 g ( Anhydrous potassium carbonate (0.15 mol) was added and the reaction mixture was heated to boiling under stirring for 12 hours. After cooling, the inorganic salts are filtered off, and the filtrate is evaporated under reduced pressure to remove the solvent. The product as an oily residue is purified by vacuum distillation.

Thus, 8.90 g (87%) of the title compound are obtained. M.P .: 77 ° C / 53.3 Pa.

Preparation of Compounds of Formula X

8) 2,2-Dimethyl-7- (2-methyl-2-propenyloxy) -2,3-dihydrobenzenfuran

To a solution of 24.6 g (0.15 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 350 ml of acetone is added 27.1 g (0.3 mol) of metalyl chloride and 62.25 g ( Anhydrous potassium carbonate (0.45 mol) was added and the reaction mixture was heated to boiling under stirring for 22 hours. After cooling, the inorganic salts are filtered off, and the filtrate is evaporated under reduced pressure to remove the solvent. The product as an oily residue is purified by vacuum distillation.

Thus, 25.0 g (76.5%) of the title compound are obtained. M.P .: 80-83 ° C / 27-40 Pa.

Preparation of Benzofuran Derivatives of Formula I

Example 1 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl] -4- (4-methoxyphenyl) 1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 4.0 g (0.14 mol) of 7- (3-bromopropyloxy) -2,2-dimethyl-2,3-dihydroxybenzofuran in 60 ml of dichloromethane is added 2.28 g (0.012 mol) of 4- (4-methoxyphenyl) - 1,2,3,6-tetrahydropyridine hydrochloride and 12 ml of 10% aqueous sodium hydroxide solution. The reaction mixture is stirred for 12 hours at room temperature and then the two phases are separated. The organic phase is extracted twice with 50 ml of water each time, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residue is dissolved in 30 ml of ethanol.

Containing 5% hydrogen chloride and evaporated in a water bath under reduced pressure. The residue is triturated with 40 ml of ethyl acetate and the precipitated crystalline product is filtered off.

Thus, 3.75 g (72.8%) of the title compound are obtained. Mp: 165 ° C.

Example 2 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl] -4- (4-methoxyphenyl) 1,2,3,6-tetrahydropyridine

A mixture of 2.15 g (0.005 mol) of 1- [3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl] -4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridine hydrochloride 20 ml of dichloromethane and 3 ml of 10% aqueous sodium hydroxide are stirred for 10 minutes. The phases are separated, the organic phase is extracted twice with 5 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. The evaporation residue is recrystallized from a small amount of ethanol.

Thus, 1.54 g (78.5%) of the title base are obtained. Mp: 96-97 ° C.

Example 3 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl] -4- (4-methoxyphenyl) 1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 3.0 g (0.0105 mol) of 7- (3-bromopropyloxy) -2,2-dimethyl-2,3-dihydrobenzofuran in 50 ml of dichloromethane is added 2.07 g (0.01 mol) of 4-hydroxy-4- ( 4-methoxyphenyl) piperidine and 5 ml of 10% aqueous sodium hydroxide, and the reaction mixture is stirred at room temperature for 14 hours. Then the phases are separated, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent. The residue (4.15 g) was dissolved at 40 ° C in 30 ml of ethanol containing 5% hydrogen chloride and then held at the above temperature for 5 minutes, and then held at this temperature for 5 minutes. · Evaporate under reduced pressure. The residue was triturated with 30 ml of ethyl acetate, filtered and dried under reduced pressure.

Thus, 2.79 g (85%) of the title compound are obtained. Mp: 165 ° C.

Example 4 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl] -4- (4-methoxyphenyl) 1,2,3,6-tetrahydropyridine hydrochloride

0.82 g (0.002 mol) of 1- [3- (2,2-dimethyl-2,3-dihydrobenzofuran-7yloxy) propyl-4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridine is stirred in 10 ml of ethanol containing 5% hydrogen chloride for 5 minutes at 40 ° C, and then the solution is evaporated under reduced pressure. The residue is then triturated with 30 ml of ethyl acetate, filtered and dried under reduced pressure.

Thus, 0.75 g (87%) of the title compound are obtained. Mp: 165 ° C.

Example 5 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl] -4-hydroxy-4- (4-methoxyphenyl) piperidine

To a solution of 7- (3-bromopropyloxy) -2,2-dimethyl-2,3-dihydrobenzofuran (0.57 g, 0.002 mol) in dichloromethane (10 ml) was added 4-hydroxy-4- (4-methoxyphenyl) (0.41 g, 0.002 mol). piperidine and 1 ml of 10% aqueous sodium hydroxide. The reaction mixture is then stirred at room temperature for 14 hours and then the phases are separated. The organic phase is then extracted twice with 5 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent. The residue is recrystallized from 3 ml of ethanol.

Thus, 0.35 g (43%) of the title compound are obtained. Mp: 116-117 ° C.

• ·· • · · • ··· · · • · • e • · · • · · • · • · 9 9 9 9 ··· ·· · · · · · 99 99 9

Example 6 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 7- (3-bromopropyloxy) -2,2-dimethyl-2,3-dihydrobenzofuran (3.0 g, 0.0105 mol) in dichloromethane (50 mL) was added 4- (3-trifluoromethylphenyl) (2.63 g, 0.01 mol). 1,2,3,6-tetrahydropyridine hydrochloride and 10 ml of 10% aqueous sodium hydroxide. The reaction mixture is stirred at room temperature for 24 hours and the phases are separated. The organic phase is extracted twice with 10 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent. The residue (4.68 g) was dissolved in 20 ml of ethanol containing 5% hydrogen chloride and evaporated to dryness again under reduced pressure. The crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 3.86 g (82.5%) of the title compound are obtained. Mp: 186-187 ° C.

Example 7 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl] -4-hydroxy-4- (3-trifluoromethylphenyl) piperidine Hydrochloride

To a solution of 3.0 g (0.0105 mol) of 7- (3-bromopropyloxy) -2,2-dimethyl-2,3-dihydrobenzofuran in 50 ml of dichloromethane is added 2.45 g (0.01 mol) of 4-hydroxy-4- ( 3-trifluoromethylphenyl) piperidine and 5 mL of 10% aqueous sodium hydroxide. The reaction mixture is stirred at room temperature for 24 hours and the phases are separated. The organic phase is extracted twice with 10 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent. The residue (4.91 g) was dissolved in 20 ml of ethanol containing 5% hydrogen chloride and evaporated to dryness again under reduced pressure. The crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 3.30 g (67.9%) of the title compound are obtained. Mp: 154-155 ° C.

Example 8 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 1.20 g (0.0055 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 10 ml of isopropanol is added 1.30 g (0.005 mol) of 4- (3-trifluoromethylphenyl) -1,2,3 6-tetrahydropyridine hydrochloride and 1.1 ml of 20% aqueous sodium hydroxide. The reaction mixture is then heated at reflux for 5 hours and then evaporated under reduced pressure. The residue was partitioned between 15 mL of dichloromethane and 10 mL of water, then the organic was extracted twice with 10 mL of water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent.

The residue (2.42 g) was dissolved in 15 ml of ethanol containing 5% hydrogen chloride and the solution was evaporated again under reduced pressure. The crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 2.02 g (83.5%) of the title compound are obtained. Mp: 160-162 ° C (after recrystallization from isopropanol).

Example 9 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-trifluoromethylphenyl) piperidine Hydrochloride

To a solution of 4.40 g (0.02 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of isopropanol is added 4.90 g (0.02 mol) of 4-hydroxy-4- (3-trifluoromethylphenyl) piperidine. The reaction mixture is heated at reflux for 6 hours and then evaporated under reduced pressure. The oily residue was dissolved in 15 ml of methanol and 3 ml of concentrated hydrochloric acid and 3 ml of water were added to the solution cooled to 15-20 ° C. The precipitated crystals are filtered off, washed with cold methanol and dried under reduced pressure.

• ·· • · • ··· · · • · • · • · · • · · • · • · • · ·· ·· · · · · · • · · ·

Thus, 8.06 g (86%) of the title compound are obtained. Mp: 156-158 ° C (after recrystallization from isopropanol).

Example 10 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 2.80 g (0.013 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of isopropanol is added 2.30 g (0.01 mol) of 4- (4-chlorophenyl) -1,2,3 6-tetrahydropyridine hydrochloride and 2.2 ml of 20% aqueous sodium hydroxide. The reaction mixture is then heated at boiling for 6 hours and then evaporated under reduced pressure. The residue is partitioned between 20 ml of chloroform and 20 ml of water, the organic phase is extracted twice with 20 ml of water each, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent.

The residue (4.3 g) was dissolved in 15 ml of ethanol containing 10% hydrogen chloride and the solution was evaporated to dryness again under reduced pressure. The crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 3.48 g (77.3%) of the title compound are obtained. Mp: 164-166 ° C (after recrystallization from isopropanol).

Example 11 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (2-thienyl) -1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 2.80 g (0.013 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of isopropanol is added 2.04 g (0.01 mol) of 4- (2-thienyl) -1,2,3 6-tetrahydropyridine hydrochloride and 2.2 ml of 20% aqueous sodium hydroxide. The reaction mixture is then heated at the boiling point for 6 hours, and then the reaction mixture is heated at reflux temperature for 6 hours. Evaporate under reduced pressure. The residue is partitioned between 20 ml of chloroform and 20 ml of water, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent.

The residue is dissolved in 15 ml of ethanol containing 10% hydrogen chloride and the solution is evaporated to dryness again under reduced pressure. The crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 3.50 g (82%) of the title compound are obtained. mp .; Mp 180 ° C.

Example 12 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 2.80 g (0.013 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of isopropanol was added 2.13 g (0.01 mol) of 4- (4-fluorophenyl) -1,2,3 6-tetrahydropyridine hydrochloride and 2.2 ml of 20% aqueous sodium hydroxide. The reaction mixture is then heated at reflux for 6 hours and then evaporated under reduced pressure. The residue is partitioned between 20 ml of chloroform and 20 ml of water, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent.

The residue is dissolved in 15 ml of ethanol containing 10% hydrogen chloride and the solution is evaporated to dryness again under reduced pressure. The crystalline residue is triturated with ether, filtered and dried under reduced pressure.

Thus, 3.2 g (73.8%) of the title compound are obtained. Mp: 153-155 ° C.

• ·· • · • III • I • · • · • · · • · · • · • I · · II ·· · · · · · • I · ·

Example 13 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-benzylpiperidine hydrochloride

To a solution of 2,2-dimethyl-7-oxiranyl-methoxy-2,3-dihydrobenzofuran in 30 ml of isopropanol was added 2.62 g (0.015 mol) of 4-benzylpiperidine. The reaction mixture is then heated at boiling for 6 hours and then evaporated under reduced pressure. The residue is partitioned between 20 ml of chloroform and 20 ml of water, the organic phase is extracted twice with 20 ml of water each, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residue is dissolved in 15 ml of ethanol containing 10% hydrogen chloride and the solution is evaporated to dryness again under reduced pressure. The crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 2.67 g (62%) of the title compound are obtained. Mp: 130-132 ° C.

Example 14 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-chlorophenyl) piperidine

To a solution of 3.40 g (0.015 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-benzofuran in 30 ml of isopropanol was added 3.15 g (0.015 mol) of 4-hydroxy-4- (4-chlorophenyl) piperidine. The reaction mixture is heated at reflux for 6 hours, then cooled, the precipitated crystals are filtered off, washed with isopropanol and dried under reduced pressure.

Thus, 5.40 g (83.4%) of the title compound are obtained. Mp: 148-150 ° C (crystallized from acetone).

* · · · · »» »» »» ·

Example 15 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-chlorophenyl) piperidine Hydrochloride

Dissolve 0.86 g (0.002 mol) of 1- (3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl) -4-hydroxy-4- (4-chlorophenyl) piperidine 2 ml of methanol containing 5% hydrogen chloride are added in 10 ml of methanol and the solution obtained is then evaporated to dryness under reduced pressure, the crystalline residue is triturated with ether, filtered and dried under reduced pressure.

Thus, 0.87 (93%) of the title compound are obtained. Mp: 172-174 ° C.

Example 16 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-fluorophenyl) piperidine

To a solution of 3.4 g (0.015 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of isopropanol was added 2.53 g (0.013 mol) of 4-hydroxy-4- (4-fluorophenyl) piperidine and the reaction mixture. is heated at boiling point for 4 hours. The isopropanol is then distilled off under reduced pressure, the residue is triturated with 120 ml of petroleum ether (b.p .: 60 ° C), the precipitated crystals are filtered off, washed with a mixture of acetone and petroleum ether (1 vol + 4 vol) and dried under reduced pressure.

Thus, 4.55 g (84%) of the title compound are obtained. Mp: 147-148 ° C (after recrystallization from ethanol).

Example 17

- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-fluorophenyl) piperidine hydrochloride · ··· ··· ··· ··· ·····················································

0.83 g (0.002 mol) of 1- (3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl) -4-hydroxy-4- (4-fluorophenyl) piperidine are dissolved in 10 2 ml of methanol containing 5% hydrogen chloride were added under ice-cooling, and the solution was evaporated to dryness under reduced pressure, the crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 0.79 g (87.5%) of the title compound are obtained. Mp: 173-175 ° C.

Example 18 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 1.40 g (0.0063 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 10 ml of isopropanol is added 0.98 g (0.005 mol) of 4- (4-phenyl) -1,2,3 6-tetrahydropyridine hydrochloride and 1.1 ml of 20% aqueous sodium hydroxide. The reaction mixture is then heated at reflux for 5 hours and then evaporated under reduced pressure. The residue was partitioned between 10 ml of chloroform and 10 ml of water, the organic phase was extracted twice with 10 ml of water each, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residue was dissolved in 15 ml of ethanol containing 5% hydrogen chloride and the solution was evaporated again under reduced pressure. The crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 1.93 g (92.8%) of the title compound are obtained. Mp: 166-167 ° C.

Example 19

- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] piperidine

To a solution of 2.30 g (0.0105 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 10 ml of isopropanol was added 0.85 g (0.01 mol) of piperidine.

• • · • • · • • • t • · · • · · · • · · ·· · • · ·· • · · • · · • · ·· ··· ·· · · ·

The solution is heated at boiling for 3 hours, then cooled and 20 ml of isopropanol containing 5% hydrogen chloride are added under cooling to 15-25 ° C. Then, the reaction mixture is evaporated to dryness under reduced pressure, the residue is recrystallized from a mixture of ethanol and ether, the crystals are filtered off, washed with ether and dried under reduced pressure.

Thus, 2.60 g (76%) of the title compound are obtained. Mp: 128-130 ° C.

Example 20 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4-phenylpiperidine Hydrochloride

To a solution of 3.3 g (0.015 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol was added 2.5 g (0.014 mol) of 4-hydroxy-4-phenylpiperidine. The solution obtained is heated at boiling for 3 hours, then cooled to 15 ° C and, while cooling to 15-20 ° C, 10 ml of ethanol containing 10% hydrogen chloride are added. Then, the reaction mixture is evaporated to dryness under reduced pressure, the residue is triturated with ether, the precipitated crystals are filtered off and dried under reduced pressure.

Thus, 3.62 g (60%) of the title compound are obtained. Mp: 176-177 ° C.

Example 21 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4-phenylpiperidine

1.4 g (0.003 mol) of 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxy-propyl] -4-hydroxy-4-phenyl-piperidine hydrochloride were dissolved in 50 ml. ml of hot water and 5 ml of 10% aqueous sodium hydroxide are added. The precipitated crystals are filtered off, washed with water and then recrystallized from methanol.

99 · 9 · 9 · 9 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Thus, 1.00 g (78%) of the title base are obtained. Mp: 127-129 ° C.

Example 22 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) piperidine Hydrochloride

To a solution of 3.40 g (0.0153 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of isopropanol was added 3.10 g (0.015 mol) of 4-hydroxy-4- (2-methoxyphenyl) piperidine. The solution obtained is heated at boiling for 5 hours, then cooled to 15 ° C and 4 ml of ethanol containing 15% hydrogen chloride are added under cooling to 15-25 ° C. The solution obtained is then evaporated to dryness under reduced pressure and the residue is recrystallized from a mixture of ethanol and ether. The precipitated crystals are filtered off and dried under reduced pressure.

Thus, 4.73 g (68%) of the title compound are obtained. Mp: 102-104 ° C.

Example 23 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (6-methoxynaphth-2-yl) piperidine Hydrochloride

To a solution of 2.42 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol is added 2.6 g (0.01 mol) of 4-hydroxy-4- (6-methoxynaphth-2- yl) piperidine. The resulting solution was heated at reflux for 6 hours, then cooled to 15 ° C and 3 ml of ethanol containing 15% hydrogen chloride were added. The reaction mixture was then evaporated to dryness under reduced pressure and the residue was triturated with ether. The precipitated crystals are filtered off, recrystallized from a mixture of ethyl acetate and ethanol, filtered again and dried under reduced pressure.

Thus, 4.6 g (89.5%) of the title compound are obtained. Mp: 125-127 ° C.

• ·

Example 24 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-chlorophenyl) piperidine Hydrochloride

To a solution of 2.64 g (0.012 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 15 ml of ethanol was added 2.12 g (0.01 mol) of 4-hydroxy-4- (3-chlorophenyl) piperidine. The resulting solution is heated at reflux for 6 hours, then cooled to 15 ° C and 3 ml of ethanol containing 15% hydrogen chloride are added under cooling to 15-25 ° C. The reaction mixture was then evaporated to dryness under reduced pressure and the residue was triturated with ether. The precipitated crystals are filtered off, recrystallized from a mixture of ethyl acetate and ethanol, filtered again and dried under reduced pressure.

Thus, 3.64 g (77.8%) of the title compound are obtained. Mp: 138-140 ° C.

Example 25 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-methoxyphenyl) piperidine Hydrochloride

To a solution of 3.80 g (0.0173 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of isopropanol was added 3.10 g (0.015 mol) of 4-hydroxy-4- (3-methoxyphenyl) piperidine. The solution obtained is heated at reflux for 4 hours and then evaporated to dryness under reduced pressure. The residue was dissolved in 40 mL of ethyl acetate, then cooled to 15 ° C and 6 mL of ethanol containing 15% hydrogen chloride was added under cooling to 15-20 ° C. The reaction mixture was then evaporated to dryness under reduced pressure and the residue was triturated with ether. The precipitated crystals are filtered off, recrystallized from a mixture of acetone and ether and dried under reduced pressure.

Thus, 5.90 g (84.8%) of the title compound are obtained. Mp: 128-130 ° C.

·············································

Example 26 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methoxyphenyl) piperidine

To a solution of 3.80 g (0.0173 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol was added 3.10 g (0.015 mol) of 4-hydroxy-4- (4-methoxyphenyl) piperidine. The resulting solution was heated for 4 hours and then evaporated to dryness under reduced pressure. The residue is triturated with 40 ml of ethyl acetate, the precipitated crystals are filtered off and dried under reduced pressure.

Thus, 4.70 g (73.4%) of the title compound are obtained. Mp: 144-146 ° C.

Example 27 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (5-fluoro-2-methoxyphenyl) piperidine Hydrochloride

To a solution of 3.80 g (0.0173 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol is added 3.37 g (0.015 mol) of 4-hydroxy-4- (5-fluoro-2-). methoxyphenyl) piperidine. The resulting solution was heated at reflux for 6 hours and then, with cooling to 15-20 ° C, 4 ml of ethanol containing 15% hydrogen chloride were added. The reaction mixture was then evaporated to dryness under reduced pressure and the residue was triturated with ether. The precipitated crystals are filtered off, recrystallized from 40 ml of ethyl acetate.

Thus, 5.60 g (77.5%) of the title compound are obtained. Mp: 156-158 ° C.

Example 28 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-trifluoromethylphenyl) piperidine Hydrochloride

• · · • · • BBB BB B B • B B BB • BB B B B B B B ·· ·· BB BBB BB BB

To a solution of 3.96 g (0.018 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of ethanol was added 3.34 g (0.015 mol) of 4- (3-trifluoromethylphenyl) piperidine hydrochloride and 2 ml of 40% aq. sodium hydroxide. The reaction mixture is then heated at reflux for 6 hours and then evaporated to dryness under reduced pressure. The residue is partitioned between 30 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is extracted twice with 20 ml of water each, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue is dissolved in 25 ml of ethanol containing 5% hydrogen chloride and the solution is evaporated to dryness under reduced pressure. The crystalline residue is triturated with ether, the crystals are filtered off and dried under reduced pressure.

Thus, 5.15 g (77.1%) of the title compound are obtained. Mp: 172-174 ° C.

Example 29 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methylphenyl) piperidine

To a solution of 3.4 g (0.0153 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol was added 2.86 g (0.015 mol) of 4-hydroxy-4- (4-methylphenyl) piperidine. The solution obtained is heated at reflux for 5 hours. After cooling, the solution was further cooled to 5 ° C in an ice bath and then the precipitated crystals were filtered off and dried under reduced pressure.

Thus, 5.17 g (83.8%) of the title compound are obtained. Mp .: 138-139 “C.

Example 30 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methylphenyl) piperidine Hydrochloride

4.11 g (0.01 mol) of 1- (3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl) -4-hydroxy-4- (4-methylphenyl) of piperidine was dissolved in 15 ml of meta

9 ml of methanol and 12 ml of methanol containing 5% hydrogen chloride are added to the obtained solution, which is cooled with ice. This solution is evaporated to dryness under reduced pressure, the crystalline residue is triturated with ether, filtered and dried under reduced pressure.

Thus, 4.17 g (93%) of the title compound are obtained. Mp: 164-166 ° C.

Example 31 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridine

To a solution of 3.52 g (0.016 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 25 ml of ethanol was added 3.37 (0.015 mol) of 4- (4-methoxyphenyl) -1,2,3,6- tetrahydropyridine hydrochloride and 2 ml of 40% aqueous sodium hydroxide. The reaction mixture is then heated to boiling for 6 hours and then evaporated to dryness under reduced pressure, the residue is diluted with 50 ml of water, the precipitated crystals are filtered off and dried under reduced pressure.

Thus, 6.1 g (92.8%) of the title compound are obtained. Mp: 104-105 ° C (after recrystallization from petroleum ether, b.p. 120 ° C).

Example 32 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridine hydrochloride

4.09 g (0.01 mol) of 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-methoxyphenyl) -1,2, The 3,6-tetrahydropyridine is dissolved in 15 ml of methanol and 12 ml of methanol containing 5% hydrogen chloride are added to the obtained solution, which is cooled with ice. This solution is evaporated to dryness under reduced pressure, the crystalline residue is triturated with ether, filtered and dried under reduced pressure.

• · · • · • ··· • · • · • · • · · • • · • · • · • · • · ·· · · • ·· · · · ·

Thus, 4.05 g (91%) of the title compound are obtained. mp .; Mp 162-164 ° C.

Example 3 3 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridine hydrochloride

1.10 g (0.0025 mol) of 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-methoxyphenyl) -1,2, The 3,6-tetrahydropyridine is dissolved in 5 ml of ethanol containing 20% hydrogen chloride and the solution is heated at reflux for 10 minutes. After cooling, the solution is diluted with 50 ml of ether, the precipitated crystals are filtered off, washed with ether and dried under reduced pressure.

Thus, 0.98 g (93%) of the title compound are obtained. mp .; Mp 161-163 ° C.

Example 34 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3,5-dimethyl-4-methoxyphenyl) piperidine Hydrochloride

To a solution of 3.60 g (0.0165 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol is added 3.45 g (0.015 mol) of 4-hydroxy-4 (3,5-dimethyl). 4-methoxyphenyl) piperidine. The reaction mixture is allowed to react for 2 hours at 55 to 60 ° C, then cooled to 0 ° C and 5 ml of ethanol containing 10% hydrogen chloride are added under cooling. The reaction mixture was then evaporated to dryness under reduced pressure and the residue was triturated with ether. The precipitated crystals are filtered off, dried under reduced pressure.

Thus, 6.42 g (87%) of the title compound are obtained. Mp: 92-96 ° C.

Example 35 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3,5-dimethyl-4-methoxyphenyl) piperidine Hydrochloride

To 1.26 g (0.0057 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran is added 1.18 g (0.015 mol) of 4-hydroxy-4- (3,5-dimethyl-4-methoxyphenyl) piperidine and the reaction mixture was allowed to react for 1 hour at 60 ° C. The mixture was cooled, dissolved in ether and 1 ml of ethanol containing 20% hydrogen chloride was added. The precipitated crystals are filtered off, washed with ether and dried under reduced pressure.

Thus, 2.04 g (83%) of the title compound are obtained. Mp: 94-96 ° C.

Example 36 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3,4-methylenedioxyphenyl) piperidine

To a solution of 2.42 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol was added 2.57 g (0.01 mol) of 4-hydroxy-4- (3,4-methylenedioxyphenyl). of piperidine hydrochloride and 4.2 ml of 10% aqueous sodium hydroxide. The reaction mixture is then heated at reflux for 5 hours and then evaporated to dryness under reduced pressure. The residue is partitioned between 20 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is extracted twice with 20 ml of water each, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue is recrystallized from ethyl acetate / hexane, the precipitated crystals are filtered off and dried under reduced pressure.

Thus, 3.01 g (73%) of the title compound are obtained. Mp: 128-130 ° C.

··· ·· ·· ···

Example 37 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- [4- (2-methyl-2-propenyloxy) phenyl] piperidine

To a solution of 4.8 g (0.022 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of diisopropyl ether is added 4.94 g (0.02 mol) of 4-hydroxy-4- [4- (2-methyl). 2-propenyloxy) phenyl] piperidine. The reaction mixture is heated at reflux for 6 hours, then cooled to 0 ° C and the precipitated crystals are filtered off, washed with diisopropyl ether and dried under reduced pressure.

Thus, 7.95 g (85%) of the title compound are obtained. Mp: 108-110 ° C.

Example 3 8 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-biphenylyl) piperidine hydrochloride

To a solution of 2.64 g (0.012 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 16 ml of ethanol was added 2.53 g (0.01 mol) of 4-hydroxy-4- (4-biphenylyl) piperidine. The reaction mixture was stirred at 70 ° C for 1 hour and then evaporated to dryness under reduced pressure. The residue was dissolved in 50 ml of ether and 1.5 ml of ethanol containing 20% hydrogen chloride were added thereto while cooling. The precipitated crystals are filtered off, washed with ether and dried under reduced pressure.

Thus, 4.45 g (87%) of the title compound are obtained. Mp: 166-167 ° C.

Example 39 1'P- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-phenoxyphenyl) piperidine

• * · • · • ··· · · • · • · • • · • ·· · • · ·· • · · • · · · · · · · · ·· ··

To a solution of 2.64 g (0.012 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 16 ml of ethanol was added 2.70 g (0.01 mol) of 4-hydroxy-4- (4-phenoxyphenyl) piperidine. The reaction mixture was stirred at 70 ° C for 1 hour and then evaporated to dryness under reduced pressure. The residue was recrystallized from a small amount of methanol, filtered off and dried under reduced pressure.

Thus, 4.47 g (91%) of the title compound are obtained. Mp: 113-115 ° C.

Example 40

- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-chloro-3-trifluoromethylphenyl) piperidine hydrochloride

To a solution of 3.90 g (0.0177 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol is added 4.19 g (0.015 mol) of 4-hydroxy-4- (4-chloro-3-). phenyl) piperidine. The reaction mixture was stirred at 60 ° C for 2 hours and then evaporated to dryness under reduced pressure. The residue is dissolved in 60 ml of ether and 2.5 ml of ethanol containing 20% hydrogen chloride are added. The precipitated crystals are filtered off, washed with ether and dried under reduced pressure.

Thus, 7.00 g (88%) of the title compound are obtained. Mp: 146-148 ° C.

Example 41 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-cyano-4-phenylpiperidine Hydrochloride

To a solution of 0.20 g (0.005 mol) sodium hydroxide in 15 ml isopropanol was added 1.21 g (0.0055 mol) 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.11 g (0.005 mol). mol) of 4-cyano-4-phenylpiperidine hydrochloride. The reaction mixture is then heated to boiling under stirring for 6 hours and then evaporated to dryness under reduced pressure. The residue is then partitioned between 50 ml of water and 50 ml of dichloromethane 64, the phases are separated, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. The residue was dissolved in 50 ml of ether and 1 ml of ethanol containing 20% hydrogen chloride was added to the obtained solution under cooling. The precipitated crystals are filtered off, washed with ether, and dried under reduced pressure.

Thus, 1.60 g (74%) of the title compound are obtained. Mp: 204-206 ° C.

Example 42 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-cyano-4- (3-trifluoromethylphenyl) piperidine Hydrochloride

To a solution of 0.20 g (0.005 mol) of sodium hydroxide in 15 ml of isopropanol was added 1.21 g (0.0055 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.40 g (0.005 mol). mol) 4-cyano-4- (3-trifluoromethylphenyl) piperidine hydrochloride. The reaction mixture is then heated to boiling under stirring for 6 hours and then evaporated to dryness under reduced pressure. The residue is then partitioned between 50 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of ether and 1 ml of ethanol containing 20% hydrogen chloride is added. The precipitated crystals are filtered off, washed with ether, and dried under reduced pressure.

Thus, 1.48 g (59.2%) of the title compound are obtained. Mp: 213-216 ° C.

Example 43 1- [3- (5-Bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methoxyphenyl) piperidine

To a solution of 2.63 g (0.0088 mol) of 5-bromo-2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 10 ml of isopropanol is added 1.66 g (0.008 mol) of 465.

• ·· • · • ··· · · 9 9 9 9 9 99 9 · · • · · • · ·· ·· 99 · · · ·· ·

hydroxy-4- (4-methoxyphenyl) piperidine. The reaction mixture is heated to boiling under stirring for 10 hours and then cooled to 0 ° C. The precipitated crystals are filtered off, washed with cold isopropanol and dried under reduced pressure.

Thus, 2.67 g (66%) of the title compound are obtained. Mp: 120-121 ° C (after recrystallization from isopropanol).

Example 44 1- [3- (5-Bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-chloro-3-trifluoromethylphenyl) piperidine Hydrochloride

To a solution of 3.30 g (0.011 mol) of 5-bromo-2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol is added 2.80 g (0.01 mol) of 4-hydroxy-4- ( 4-chloro-3-trifluoromethylphenyl) piperidine. The reaction mixture was stirred at 60 ° C for 2 hours, then evaporated to dryness under reduced pressure. The residue was then dissolved in 60 ml of ether, and 2.5 ml of ethanol containing 20% hydrogen chloride were added thereto while cooling. The crystals are filtered off, washed with ether and dried under reduced pressure.

Thus, 4.86 g (79%) of the title compound are obtained. Mp: 108-110 ° C.

Example 45 1- [3- (2,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methoxyphenyl) piperidine

To a solution of 2.62 g (0.01 mol) of 2,2-dimethyl-5-nitro-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 8 ml of isopropanol was added 1.86 g (0.009 mol) of 4-hydroxy-4- (4- methoxyphenyl) piperidine. The reaction mixture is heated under stirring for 2 hours at boiling point and then cooled to 2 ° C. The precipitated crystals are filtered off, washed with cold isopropanol and dried under reduced pressure.

«« ··· • · · · · ···

Thus, 3.48 g (81.8%) of the title compound are obtained. Mp: 136-138 ° C.

Example 46 1- [3- (2,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 2.46 g (0.012 mol) of 2,2-dimethyl-5-nitro-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of isopropanol was added 2.11 g (0.01 mol) of 4- (3-trifluoromethylphenyl) -1. 2,3,6-tetrahydropyridine hydrochloride and 2.2 ml of 20% aqueous sodium hydroxide. The reaction mixture is then heated with stirring at reflux for 5 hours and then evaporated under reduced pressure. The residue is partitioned between 30 ml of dichloromethane and 10 ml of water, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent. The residue is dissolved in 50 ml of ethanol containing 5% hydrogen chloride and the solution is evaporated to dryness under reduced pressure. The crystalline residue is triturated with ether, the crystals are filtered off and dried under reduced pressure.

Thus, 3.89 g (73.7%) of the title compound are obtained. Mp: 162-165 ° C.

Example 47 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (6-methoxynaphth-2-yl) -1,2,3,6- tetrahydropyridine hydrochloride

A solution of 1- [3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (6-methoxynaphth-2-yl) piperidine hydrochloride in 15 ml of ethanol containing 20% hydrogen chloride The mixture is heated at the boiling point for 20 minutes and then evaporated to dryness under reduced pressure. The crystalline residue is triturated with 30 ml of ether, filtered and dried under reduced pressure.

Thus, 2.96 g (92%) of the title compound are obtained. Mp 186-188 ° C.

9 99 ·· · • 99 9 • · · · • · • ··· • · • 9 · • · · · • · • 9 9 9 • · · • · • l · • · · · · · · · · · · · •

Example 48

- [3- (5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) -l, 2,3,6-tetrahydropyridine hydrochloride

To a solution of 2.63 g (0.0088 mol) of 5-bromo-2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 15 ml of ethanol was added 2.11 g (0.008 mol) of 4- (3-trifluoromethylphenyl) -1. 2,3,6-tetrahydropyridine hydrochloride and 3.2 ml of 10% aqueous sodium hydroxide. The reaction mixture is then heated with stirring at boiling point for 6 hours and then evaporated under reduced pressure. The residue was partitioned between dichloromethane (50 ml) and water (50 ml). The organic phase is extracted twice with 20 ml of water each, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent. The residue was dissolved in 10 ml of ethanol containing 10% hydrogen chloride and the solution was evaporated to dryness under reduced pressure. The crystalline residue is heated to boiling with 50 ml of ethyl acetate, the crystals are filtered off from the hot mixture and dried under reduced pressure.

Thus, 3.78 g (89.8%) of the title compound are obtained. Mp: 112-114 ° C.

Example 49 1- [3- (5-Bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 2.30 g (0.0077 mol) of 5-bromo-2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 15 ml of ethanol was added 1.72 g (0.007 mol) of 4- (3-trifluoromethylphenyl) -1. 2,3,6-tetrahydropyridine and the reaction mixture are heated under stirring at reflux for 6 hours and then evaporated under reduced pressure. The residue is heated at boiling point in 10 ml of ethanol containing 20% hydrogen chloride for 30 minutes and the mixture is again evaporated under reduced pressure. The crystalline residue is heated for 5 minutes with 30 ml of ethyl acetate at boiling point, then the crystals are filtered off and dried under reduced pressure.

Thus, 3.42 g (92.8%) of the title compound are obtained. Mp: 112 - 114 ° C ·· ···

Example 50 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) piperidine Hydrochloride

A solution of 1.78 g (0.004 mol) of 1- (3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-oxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) -1,2,3,6 -tetrahydropyridine hydrochloride in 20 ml of methanol is hydrogenated in the presence of 0.1 g of 10% palladium / carbon catalyst at atmospheric pressure. The crystalline residue is triturated with 20 ml of ether, the crystals are filtered off and dried under reduced pressure.

Thus, 1.75 g (98%) of the title compound are obtained. Mp: 172-174 ° C.

Example 51 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy (3-trifluoromethylphenyl) piperidine Hydrochloride

A mixture of 2.31 g (0.0105 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.45 g (0.01 mol) of 4-hydroxy-4- (3-trifluoromethylphenyl) piperidine is melted for 1 hour at 80 ° C and then dissolved in 10 ml of ethanol containing 20% hydrogen chloride and the resulting mixture is heated at boiling for 45 minutes. The solution is then diluted with 10 ml of ethanol, cooled to 30 ° C and hydrogenated in the presence of 0.1 g of 10% palladium / carbon catalyst. Once the calculated amount of hydrogen (240 ml) was taken up, the catalyst was filtered off and the solution was evaporated under reduced pressure. The crystalline residue is triturated with ether, the crystals are filtered off and dried under reduced pressure.

Thus, 4.05 g (91%) of the title compound are obtained. Mp: 172-174 ° C.

• ·· ·· ··· ··

Example 52 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxypiperidine hydrochloride

To a solution of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 10 ml of terahydrofuran is added 0.55 g (0.0055 mol) of 4-hydroxypiperidine. The reaction mixture is heated under stirring at boiling point for 3 hours and then evaporated under reduced pressure. The residue is dissolved in a mixture of 5 ml of 2-propanol and 1.5 ml of 2-propanol containing 16% hydrogen chloride and the solution is evaporated under reduced pressure, the residue is dissolved in 8 ml of 2-propanol and left at 0 ° C for 5 days. The precipitated crystals are then filtered off, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 1.22 g (57%) of the title compound are obtained. Mp: 139-141 ° C.

Example 53

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-methylpiperidine hydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.44 g (0.0045 mol) of 4-methylpiperidine and 8 ml of water was heated at boiling for 9 hours. The oily phase formed in the mixture is dissolved in 20 ml of ether, washed with water, dried over anhydrous sodium sulphate, evaporated under reduced pressure and the residue is dissolved in 3 ml of 2-propanol containing saline hydrogen chloride and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, precipitated with ether, then the precipitated crystals were filtered off, dissolved in hot

2-propanol, reprecipitated with ether, filtered and dried under reduced pressure.

Thus, 1.25 g (59%) of the title compound are obtained. Mp: 146-148 ° C.

·····································

Example 54 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-4-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-trifluoromethylphenyl) piperidine Hydrochloride

3.28 g (0.02 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-4-ol are dissolved in 25 ml of 10% aqueous sodium hydroxide. To this solution was added 3.70 g (0.04 mol) of epichlorohydrin and the reaction mixture was stirred at 45-50 ° C for 3 hours. The oily product is separated by cooling, dissolved in 30 ml of dichloromethane, the phases are separated, the organic phase is washed twice with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. The residue, a thick honey-like epoxide (3.78 g, 85.3%) was dissolved in 40 ml of ethanol, and 3.80 g (0.0155 mol) of 4-hydroxy-4- (3-trifluoromethylphenyl) piperidine was added, and the reaction mixture is heated at reflux for 6 hours. After cooling, 15 ml of ethanol containing 5% hydrogen chloride were added to the obtained solution at a temperature below 15 ° C and the mixture was evaporated to dryness under reduced pressure. The crystalline residue is recrystallized from a mixture of ethanol and ether, filtered and washed with ether.

Thus, 5.60 g (72%) of the title compound are obtained. Mp: 162-164 ° C.

Example 55 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-4-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (6-methoxynaphth-2-yl) piperidine Hydrochloride

The procedure of Example 54 was followed except that the epoxide prepared in the first step (3.75 g, 85.2%) was dissolved in 50 mL of ethanol. To this solution was added 3.94 g (0.0153 mol) of 4-hydroxy-4- (6-methoxy-naphth-2-yl) piperidine and the reaction mixture was heated at reflux for 4 hours. After cooling, 13 ml of ethanol containing 5% hydrogen chloride were added to the solution, and the reaction mixture was evaporated to dryness under reduced pressure. The remaining crystalline product is recrystallized from a mixture of ethanol and ether.

·· ···

Thus, 5.35 g (68%) of the title compound are obtained. Mp: 118-120 ° C.

Example 56 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-5-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-trifluoromethylphenyl) piperidine Hydrochloride

3.28 g (0.02 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-5-ol are dissolved in 30 ml of an aqueous solution containing 3 g of sodium hydroxide. To this solution was added 3.70 g (0.04 mol) of epichlorohydrin and the reaction mixture was stirred at 48-50 ° for 3 hours. The oily product is separated by cooling, dissolved in 30 ml of dichloromethane, the phases are separated, the organic phase is washed twice with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. The residue, a thick waxy epoxide (3.85 g, 87.3%) was dissolved in 50 mL of ethanol, and 3.80 g (0.0155 mol) of 4-hydroxy-4- (3-trifluoromethylphenyl) piperidine was added, and the reaction mixture is heated at reflux for 5 hours. After cooling, 15 ml of ethanol containing 5% hydrogen chloride were added to the obtained solution at a temperature below 15 ° C and the mixture was evaporated to dryness under reduced pressure. The crystalline residue is recrystallized from a mixture of ethanol and ether, filtered and washed with ether.

Thus, 4.97 g (64%) of the title compound are obtained. Mp: 172-173 ° C.

Example 57 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-6-yloxy) -2-hydroxypropyl] -4-hydroxy-4-phenylpiperidine Hydrochloride

1.64 g (0.01 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-6-ol are dissolved in 15 ml of 10% aqueous sodium hydroxide solution. To this solution was added 1.85 g (0.02 mol) of epichlorohydrin, and the reaction mixture was stirred at 48-50 ° C for 2.5 hours. The oily product is separated by cooling and dissolved in 25 ml of dichloromethane

• • · • · · • · · · 9 · • · • · • · • 9 9 9 9 9 9 9 • · · • · • · • · · 99 9

The phases are separated, the organic phase is washed twice with 15 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. The residue, thick honey-like epoxide (2.10 g, 95%) was dissolved in 10 mL of ethanol, and 1.52 g (0.0086 mol) of 4-hydroxy-4-phenyl) piperidine was added thereto, and the reaction was heated for 6 hours. at boiling point. After cooling, 10 ml of ethanol containing 5% hydrogen chloride were added to the obtained solution at a temperature below 15 ° C and the mixture was evaporated to dryness under reduced pressure. The crystalline residue is recrystallized from a mixture of ethanol and ether, filtered and washed with ether.

Thus, 4.97 g (64%) of the title compound are obtained. Mp: 184-186 ° C.

Example 58 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-methoxy-4- (3-trifluoromethylphenyl) piperidine Hydrochloride

To a solution of 0.20 g (0.005 mol) of sodium hydroxide in 15 ml of isopropanol was added 1.21 g (0.0055 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.48 g (0.005 mol). mol) 4-methoxy-4- (3-trifluoromethylphenyl) piperidine hydrochloride. The reaction mixture is then heated under stirring at reflux for 6 hours and then evaporated to dryness under reduced pressure. The residue is partitioned between 50 ml of water and 50 ml of dichloromethane, the phases are separated, and the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was dissolved in 50 ml of ether and 1 ml of ethanol containing 20% hydrogen chloride was added to the solution while cooling, the precipitated crystals were filtered off, washed with ether and dried under reduced pressure.

Thus, 1.62 g (62.8%) of the title compound are obtained. Mp: 192-195 ° C.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ·· ·

Example 59 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-diphenylmethylpiperazine

A solution of 2.20 g (0.01 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.52 g (0.01 mol) of 1- (diphenylmethyl) piperazine in 30 ml of isopropanol is heated at boiling point. 6 hours. The solution was then evaporated to dryness under reduced pressure, the residue was triturated with hexane and filtered. The crude product thus obtained (4.53 g) is then recrystallized from 25 ml of ethanol, filtered off and dried under reduced pressure.

Thus, 3.89 g (82%) of the title compound are obtained. Mp: 129-130 ° C.

Example 60 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-diphenylmethylpiperazine

A mixture of 2.20 g (0.01 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.52 g (0.01 mol) of 1- (diphenylmethyl) piperazine is melted at 80 ° C and maintained at this temperature for one hour. The solid which solidified is then recrystallized from 25 ml of ethanol, filtered off and dried under reduced pressure.

Thus, 3.92 g (83%) of the title compound are obtained. Mp: 129-130 ° C.

Example 61 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-diphenylmethylpiperazine

A mixture of 2.20 g (0.01 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.52 g (0.01 mol) of 1- (diphenylmethyl) piperazine is melted at < tb >

B ·· B Μ · · · · B · · · · ·

BB BBB BB ° C and held at this temperature for one hour. The solid which solidified is then recrystallized from 25 ml of ethanol, filtered off and dried under reduced pressure.

Thus, 3.82 g (81%) of the title compound are obtained. Mp: 129-130 ° C.

Example 62 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-diphenylmethylpiperazine

To a solution of 2.31 g (0.011 mol) of 2,2-dimethyl-7-oxiranyl-methoxy-2,3-dihydrobenzofuran in 20 ml of ethanol was added 2.52 g (0.01 mol) of 1- (diphenylmethyl) piperazine and the reaction mixture. is heated at boiling point for 4 hours. After cooling, the precipitated crystals are filtered off and dried under reduced pressure.

Thus, 3.87 g (81%) of the title compound are obtained. Mp: 129-130 ° C.

Example 63 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-fluorophenyl) piperazine

A solution of 4.40 g (0.02 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 3.60 g (0.02 mol) of 1- (4-fluorophenyl) piperazine in 30 ml of ethanol is heated at boiling 5 hours. The solution was then evaporated to dryness under reduced pressure, and the residue was chromatographed on a Kieselgel 60 column using a mixture of chloroform and ethanol (30 vol. + 1 vol.) As eluent. The product-containing fraction was evaporated, the residue was triturated with hexane, filtered off and dried under reduced pressure.

Thus, 7.30 g (91%) of the title compound are obtained. Mp: 80-82 ° C.

• ·· • · • ··· • · · • · ·· • · · • · · · · · · · · • e · • · · · ·· ··· ·· ··

Example 64 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-fluorophenyl) piperazine

A mixture of 2.31 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.80 g (0.01 mol) of 1- (4-fluorophenyl) -piperazine is melted at 60 ° C and maintained at this temperature for one hour. The melt obtained is then chromatographed on a Kieselgel 60 column using a mixture of chloroform and ethanol (30 vol. + 1 vol.) As eluent. The product-containing fraction was evaporated, the residue was triturated with hexane, filtered off and dried under reduced pressure.

Thus, 3.72 g (93%) of the title compound are obtained. Mp: 80-82 ° C.

Example 65 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-fluorophenyl) piperazine

A mixture of 2.20 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.80 g (0.01 mol) of 1- (4-fluorophenyl) -piperazine is melted at 70 ° C and maintained at this temperature for one hour. 60 ml of hexane are added to the obtained melt, the mixture is cooled, the precipitated crystals are filtered off and dried under reduced pressure.

Thus, 3.26 g (81%) of the title compound are obtained. Mp: 80-82 ° C.

Example 66 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-fluorophenyl) piperazine ··································

A solution of 2.20 g (0.01 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.30 g (0.01 mol) of 1- (3-trifluoromethyl-phenyl) piperazine in 20 ml isopropanol is heated at boiling point for 4 hours. The solution was then evaporated to dryness under reduced pressure, and the residue was chromatographed on a Kieselgel 60 column using a mixture of chloroform and ethanol (30 vol. + 1 vol.) As eluent. The product-containing fraction was evaporated, the residue was triturated with hexane, filtered off and dried under reduced pressure.

Thus, 3.76 g (84%) of the title compound are obtained. Mp: 82-84 ° C.

Example 67 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-fluorophenyl) piperazine

A mixture of 2.20 g (0.01 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.30 g (0.01 mol) of 1- (3-trifluoromethylphenyl) piperazine is melted at 70 ° C and held at this temperature for 1.5 hours. 60 ml of hexane are added to the obtained melt, the mixture is cooled, the precipitated crystals are filtered off and dried under reduced pressure.

Thus, 3.77 g (84%) of the title compound are obtained. Mp: 82-84 ° C.

Example 68 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-methoxyphenyl) piperazine

A solution of 3.80 g (0.017 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.88 g (0.015 mol) of 1- (4-methoxyphenyl) piperazine in 40 ml of methyl tert-butyl ether is heated. at boiling point for 8 hours and then cooled to 0 ° C. The precipitated crystals are then filtered off and dried under reduced pressure.

Thus, 5.21 g (84%) of the title compound are obtained. Mp: 93-94 ° C.

Example 69 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-methoxyphenyl) piperazine

A mixture of 1.10 g (0.005 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 0.96 g (0.005 mol) of 1- (4-methoxyphenyl) piperazine is melted at 80 ° C and maintained at this temperature for one hour. 10 ml of methyl tert-butyl ether are added to the hot melt, the mixture is cooled, the precipitated crystals are filtered off and dried under reduced pressure.

Thus, 1.88 g (91%) of the title compound are obtained. Mp: 93-94 ° C.

Example 70 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (benzo-1,3-dioxolan-5-yl) piperazine Dihydrochloride

A solution of 3.80 g (0.017 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 3.30 g (0.015 mol) of 1- (benzo-1,3-dioxolan-5-yl) piperazine in 30 ml of ethanol is heated at boiling point for 10 hours. The solution was then evaporated to dryness under reduced pressure and the residue (8.0 g) was dissolved in 30 ml of ethanol containing 4.0 g of hydrogen chloride. Crystals are then started to precipitate from the homogeneous solution. The suspension is then diluted with 60 ml of methyl tert-butyl ether and the crystals are dried under reduced pressure.

Thus, 5.40 g (70%) of the title compound are obtained. Mp: 216-218 ° C.

··················································

Example 71 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (benzol, 3-dioxolan-5-yl) piperazine Dihydrochloride

A solution of 3.80 g (0.017 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 3.30 g (0.015 mol) of 1- (benzo-1,3-dioxolan-5-yl) piperazine in 30 ml isopropanol is heated at boiling point for 6 hours. The solution is then evaporated to dryness under reduced pressure and the residue is dissolved in 20 ml of ethanol containing 15% hydrogen chloride. Crystals are then started to precipitate from the homogeneous solution. The suspension is then diluted with 60 ml of methyl tert-butyl ether and the crystals are dried under reduced pressure.

Thus, 5.43 g (71%) of the title compound are obtained. Mp: 216-218 ° C.

Example 72 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (benzol, 3-dioxolan-5-yl) piperazine Dihydrochloride

A solution of 2.31 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.20 g (0.01 mol) of 1- (benzo-1,3-dioxolan-5-yl) piperazine in 30 ml of diisopropyl ether are heated at boiling for 6 hours and then 7 ml of ethanol containing 20% hydrogen chloride are added. The precipitated crystals are cooled, filtered off and dried under reduced pressure.

Thus, 4.41 g (86%) of the title compound are obtained. Mp: 216-218 ° C.

Example 73 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-chlorophenyl) piperazine

• ·· • · • ··· · · • · • · • · · • · · • · • · • · · • · • • · ·· ·· · · · · · · ·

A mixture of 2.42 g (0.0115 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 2.70 g (0.01 mol) of 1- (4-chlorophenyl) piperazinedihydrochloride, 26 ml of ethanol, 3 ml water and 0.9 g (0.0225 mol) of sodium hydroxide are heated under stirring at reflux for 6 hours and then evaporated to dryness under reduced pressure. The residue is partitioned between 80 ml of dichloromethane and 50 ml of water, the organic phase is extracted twice with 30 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue is recrystallized from 8 ml of methanol, the precipitated crystals are filtered off and dried under reduced pressure.

Thus, 3.25 g (78%) of the title compound are obtained. Mp: 96-98 ° C.

Example 74 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-chlorophenyl) piperazine

To a solution of 2.70 g (0.01 moles) of 1- (4-chlorophenyl) piperazine dihydrochloride in 26 ml of ethanol was added 3 ml of water and 0.9 g (0.0225 moles) of sodium hydroxide and heated at room temperature for 10 minutes. reflux. Then, 2.40 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran is added to the reaction mixture with stirring and the mixture is heated at boiling for a further 4 hours, then evaporated to dryness under reduced pressure. 50 ml of water are added to the residue, which is decanted from the substance which slowly precipitates, and the residue is triturated with another portion of water. The precipitated crystals are filtered off, washed with water, recrystallized from methanol, filtered off and dried under reduced pressure.

Thus, 3.17 g (80%) of the title compound are obtained. Mp: 96-98 ° C.

····················································

Example 75 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-chlorophenyl) piperazine Dihydrochloride

To a solution of 0.40 g (0.001 mol) of 1- [3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-chlorophenyl) piperazine in 5 ml of ethanol is added 1 ml of ethanol containing 20% hydrogen chloride and the mixture is evaporated to dryness under reduced pressure. The residue is heated for 5 minutes with 5 ml of ethyl acetate at boiling point, the hot suspension is filtered off and the crystals are dried under reduced pressure.

Thus, 0.43 g (91%) of the title compound are obtained. Mp: 168-170 ° C.

Example 76 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-methoxyphenyl) piperazine Dihydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 1.46 g (0.0055 mol) of 1- (3-methoxyphenyl) piperazine dihydrochloride, 0.44 g (0.011) mol) of sodium hydroxide, 5 ml of ethanol, 3 ml of dimethylformamide and 10 ml of water are heated at reflux for 3 hours. The reaction mixture is cooled to 20 ° C, the phases are separated, the lower (organic) phase is dissolved in 20 ml of ether, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue was dissolved in 3 ml of 2-propanol and 3 ml of 2-propanol containing 16% hydrogen chloride was added to the obtained solution and the reaction mixture was kept at 0 ° C for 5 days. The precipitated crystals are filtered off, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 1.48 g (60%) of the title compound are obtained. Mp: 168-170 ° C.

• ·· • · • ··· · · • · 9 9 • · · • • · · · ··· • · · • · · · 99 · · · ·· 99

Example 77

- [3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4benzylpiperazín dihydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.97 g (0.0055 mol) of 1-benzylperazine and 8 ml of 2-propanol is heated for 4 hours and then the reaction the mixture was cooled to 20 ° C. 20 ml of petroleum ether are then added to the reaction mixture, the mixture is kept at 0 ° C for 5 days, the crystals formed are filtered off and then recrystallized from hexane. The precipitated crystals are dissolved in 15 ml of 2-propanol and 1.5 ml are added

2-propanol containing 16% hydrogen chloride. After cooling, the precipitated crystalline salt is filtered off and dried under reduced pressure.

Thus, 1.50 g (58%) of the title compound are obtained. Mp: 188-191 ° C.

Example 78

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (2,4-dichlorophenyl) piperazine Hydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 1.15 g (0.005 mol) of 1- (2,4-dichlorophenyl) piperazine and 8 ml

2-propanol was heated at reflux for 5 hours and then cooled to 20 ° C. To the reaction mixture was then added 3.6 mL of 2-propanol, 2.4 mL of 2-propanol containing 16% hydrogen chloride, and the mixture was stirred at room temperature for 5 hours. The precipitated crystals are filtered off, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 1.19 g (45%) of the title compound are obtained. Mp: 169-171 ° C.

• ··

Example 79 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-chlorophenyl) piperazine Hydrochloride

A mixture of 2.64 g (0.012 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 2.36 g (0.012 mol) of 1- (3-chlorophenyl) piperazine and 16 ml of 2-propanol is heated at room temperature for 3 hours. boiling point. After cooling, 7 ml of 2-propanol containing 16% hydrogen chloride were added to the obtained solution at 20 ° C. After the reaction mixture was left at 0 ° C for 2 days, the precipitated crystals were filtered off, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 2.88 g (53%) of the title compound are obtained. Mp: 187-190 ° C.

Example 80 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (2-pyridyl) piperazine trihydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.78 g (0.0048 mol) of 1- (2-pyridyl) -piperazine and 8 ml of petroleum ether is heated for 6 hours at boiling point. After cooling to 20 ° C, the phases are separated and 20 ml of 2-propanol and 4.5 ml of 2-propanol containing 16% hydrogen chloride are added to the lower phase and the reaction mixture is left at 0 ° C for 5 days. The precipitated crystals are filtered off, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 1.68 g (71%) of the title compound are obtained. Mp: 133-136 ° C.

Example 81 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) piperazine Dihydrochloride

A mixture of 2.64 g (0.012 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 2.36 g (0.011 mol) of 1- (2-methoxyphenyl) piperazine and 16 ml of 2-propanol is heated for 5 hours. 5 hours at boiling point. After cooling to 20 ° C, 10 ml of 2-propanol and 8 ml of 2-propanol containing 16% hydrogen chloride were added to the reaction mixture, and the reaction mixture was left at 0 ° C for 2 days. The precipitated crystals are filtered off under reduced pressure, washed with 2-propanol, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 2.53 g (47%) of the title compound are obtained. Mp: 128-130 ° C.

Example 82 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3,4-dimethylphenyl) piperazine Dihydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.95 g (0.005 mol) of 1- (3,4-dimethylphenyl) piperazine and 8 ml of ethanol is heated for 6 hours. hours at boiling point. After cooling to 20 ° C, the reaction mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. 5 ml of 2-propanol containing 16% hydrogen chloride are added to the residue, the reaction mixture is left at 0 ° C for 2 days, the precipitated crystals are filtered off, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 1.50 g (62%) of the title compound are obtained. Mp: 119-122 ° C.

v v························

Example 83 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (2-pyrimidyl) piperazine Dihydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.65 g (0.004 mol) of 2-pyrimidylpiperazine and 8 ml of tetrahydrofuran is heated at reflux for 12 hours and then cooled to reflux. Deň: 18 ° C. 20 ml of ether and 1.5 ml of 2-propanol containing 30% hydrogen chloride were added to the oil which formed, the reaction mixture was left at 0 ° C for 5 days, the precipitated crystals were filtered off, dried under reduced pressure and recrystallized from ethyl acetate. 2-propanol.

Thus, 1.50 g (82%) of the title compound are obtained. Mp: 128-130 ° C.

Example 84

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-chloro-2-methylphenyl) piperazine Hydrochloride

A mixture of 2.64 g (0.012 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 2.27 g (0.008 mol) of 1- (4-chloro-2-methylphenyl) piperazine hydrochloride, 0.64 (0.016) mol) of sodium hydroxide and 16 ml of water are heated to boiling for 3 hours and then cooled to 20 ° C. The aqueous phase is removed by decantation and 30 ml of ether are added to the organic phase and the reaction mixture is stirred for 1 hour. The precipitated crystals are filtered off, dried under reduced pressure and recrystallized from acetonitrile.

Thus, 2.07 g (60%) of the title compound are obtained. Mp: 68-70 ° C.

EXAMPLE 85 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-methylpiperazine dihydrochloride ·· ·· ··· ·· ·

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.45 g (0.0045 mol) of 4-methylpiperazine and 8 ml of ethanol is heated at room temperature for 3 hours. and then cooled to 20 ° C. Then 4 ml of 2-propanol containing 30% hydrogen chloride are added to the mixture and the reaction mixture is left at -15 ° C for 2 days, the precipitated crystals are filtered off, dried under reduced pressure, dissolved in hot 2-propanol and precipitated from solution. diethyl ether.

Thus, 1.15 g (65%) of the title compound are obtained. Mp: 119-122 ° C.

Example 86 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4 (trifluoromethylbenzyl) piperazine Dihydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 1.43 g (0.0045 mol) of 4- (3-trifluoromethyl) benzylpiperazine dihydrochloride, 0.36 (0.009 mol) mol) of sodium hydroxide and 8 ml of water are heated at boiling temperature for 2.5 hours and then cooled to 20 [deg.] C., the aqueous phase is removed by decantation and 2 ml of propan-2-ol containing 30% hydrogen chloride are added to the organic phase. , dried under reduced pressure and recrystallized from 2-propanol.

Thus, 1.39 g (57%) of the title compound are obtained. Mp: 209-211 ° C.

Example 87

- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3,4-dichlorophenyl) piperazine Hydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 1.04 g (0.0045 mol) of 1- (3,4-dichlorophenyl) piperazine and 8 ml of 2- of propanol is heated at boiling for 3 hours and then cooled to 20 ° C. A mixture of 10 ml of 2-propanol is then added to the mixture, 2 ml of 2-propanol containing 30% of chlorine is added to the mixture. The reaction mixture was stirred for 5 hours, the precipitated crystals were filtered off, dried under reduced pressure and recrystallized from 2-propanol.

Thus, 1.63 g (62%) of the title compound are obtained. Mp: 180-182 ° C.

Example 88

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (2,6-dimethylphenyl) piperazine Dihydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.90 g (0.004 mol) of 1- (2,6-dimethylphenyl) piperazine hydrochloride, 0.32 (0.008 mol) mol) of sodium hydroxide and 8 ml of water are heated at boiling for 2 hours and then cooled to 20 ° C. The aqueous phase formed in the mixture was removed by decantation and 2.5 ml of 2-propanol containing 30% hydrogen chloride were added to the organic phase, the reaction mixture was left at -15 ° C for 2 days, then 10 ml was added.

The 2-propanol and the precipitated crystals are filtered off, dried under reduced pressure and recrystallized from 2-propanol.

Thus, 1.00 g (41%) of the title compound are obtained. Mp: 115-117 ° C.

Example 89

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-chloro-2-methylphenyl) piperazine

A mixture of 0.5 g (0.0016 mol) of 1-bromo-3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-propanol, 0.45 g (0.0016 mol) of 4-chloro The 2-methylphenylpiperazine, 0.25 g (0.0063 mol) of sodium hydroxide and 6.5 ml of water are heated at reflux for 3 hours and then cooled to 20 ° C. The aqueous phase is removed by decantation and the residual oil is stirred with ether, the precipitated crystals are filtered off, dried under reduced pressure and recrystallized from acetonitrile.

• BB • B • ··· • · • · • · • • · B B B · B B BB B B · BB BB • · BBB BB BB

Thus, 0.25 g (40%) of the title compound are obtained. Mp: 68-70 ° C.

• ·

Claims (17)

PATENT CLAIMS A benzofuran derivative of the general formula I wherein R ¹ and R ² each independently are hydrogen or C ₄ alkyl group, X represents an oxygen atom or a sulfur atom, Y represents a hydrogen atom or a hydroxy group, Z is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, amino, nitro, cyano, trifluoromethyl, -COOR ³ , NHCOR ³ , and -SO ₂ NR ³ R ⁴ , wherein: R ³ represents a hydrogen atom or a C 1-4 alkyl group, R ⁴ represents a C 1-4 alkyl group, or R ³ and R ⁴ together with the adjacent nitrogen atom form a saturated or unsaturated heterocyclic group containing 5 to 10 members and optionally containing as further heteroatom (s) one or more nitrogen atoms and / or one or more oxygen atoms, and / or one or more or more sulfur atoms, ee · e · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ··· ·· A is CH, COH, C-CN, C-COOR ³ or COR ⁴ wherein R ³ and R ⁴ are as defined above, B represents a methylene group, or A forms together with the group B a group of the formula -C = C-, Ar represents a hydrogen atom, C 1-4 alkyl, phenyl (C _1-4 alkyl), biphenylyl, naphthyl, wherein the last mentioned groups may be optionally substituted by a C _1-4 alkoxy or a C _2-4 alkenyl group; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C 1-6 alkyl groups; ₄ alkyl groups; A 5- or 6-membered saturated or unsaturated heterocyclic group containing a nitrogen atom and / or an oxygen atom and / or a sulfur atom as a heteroatom; or a phenyl group substituted with substituents including R ⁵ , R ⁶ and R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ independently represent hydrogen, halogen, trifluoromethyl, C 1-6 alkyl; _An alkyl, methylenedioxy, phenoxy group optionally substituted by C 1-6 alkyl; _A alkoxy group or a halogen atom; C 2 ₄ alkenyl, C 2 ₄ alkenyloxy, C. _{A 4} alkoxy group optionally substituted with a di (C _1-4 alkyl) amino group or a 5- or 6-membered saturated heterocyclic group containing one or two nitrogen atoms, or a nitrogen atom and an oxygen atom, said heterocyclic group being optionally substituted with a C _1-4 alkyl group or A is a group of formula N _(CH2) "- Ar, wherein Ar 1 represents diphenylmethyl, pyridyl, pyrimidinyl, naphthyl, the latter being optionally substituted with C 1-6 alkyl. _{A 4} alkoxy group or a C _2-4 alkenyloxy group; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C 1-6 alkyl groups; ₄ alkyl groups; or phenyl substituted ^{with a} substituent comprising at R, R ⁶ and R ^7, wherein R ^5, R ⁶ and R ⁷ are as defined above, n is 0 or 1; acid and its pharmaceutically acceptable acid addition salts thereof. The benzofuran derivative according to claim 1, wherein in formula I R ¹ represents a hydrogen atom or a C 1-4 alkyl group, R ² is H, X is an oxygen atom, Y represents a hydrogen atom or a hydroxy group, Z is hydrogen, halogen or nitro, A is CH, COH or C-CN, B represents a methylene group, or A forms with the group B a group of the formula -C = C-, Ar is hydrogen, benzyl, phenyl substituted with R ⁵ , R ⁶ and R ⁷ , biphenylyl, naphthyl optionally substituted with C 1-6 alkyl; ₄ alkoxy; or thienyl, wherein R ^5, R ⁶ and R ⁷ are independently from the group consisting of hydrogen, halogen, trifluoromethyl, C ₄ alkyl, C. ₄ alkoxy, C _2-4 alkenyloxy, phenoxy, or methylenedioxy, acid and its pharmaceutically acceptable acid addition salts thereof. ·· • ·· ·· · • ··· • · • in ··· ·· The benzofuran derivative according to claim 1 or 2, wherein in the general formula I R ¹ represents a methyl group, R ² is H, X is an oxygen atom, Y is hydroxy, Z represents a hydrogen atom, A is CH, COH or C-CN, B represents a methylene group, or A forms with B a group of the formula -C = C-, Ar represents a phenyl group optionally substituted by a group selected from halogen, trifluoromethyl, methyl or methoxy; or a methoxynaphthyl group, and pharmaceutically acceptable acid addition salts thereof. A piperazinylalkylbenzofuran derivative according to claim 1 of formula la, X ·· • · ··· Where R ¹ represents a C 1-4 alkyl group, R ² is H, X is an oxygen atom, Y represents a hydroxy group, Z represents a hydrogen atom, Ar 1 represents a diphenylmethyl group, a pyridyl group, a partially saturated five membered heterocyclic group containing two oxygen atoms which is fused to a phenyl group, or a phenyl group substituted with R ⁵ , R ⁶ , R ⁷ , wherein R ⁵ , R ⁶ , R ⁷ independently represent hydrogen, halogen, trifluoromethyl, C 1-6 alkyl; N is 0 or 1; and pharmaceutically acceptable acid addition salts thereof. A piperazinylalkylbenzofuran derivative according to claim 4, wherein in formula Ia R ¹ represents a methyl group, R represents a hydrogen atom, X is an oxygen atom, Y represents a hydroxy group, Z represents a hydrogen atom, Ar 1 represents diphenylmethyl, pyridyl, benzo-1,3-dioxolanyl or phenyl optionally substituted by one or two halogen atoms, one or two methyl groups, methylenedioxy, trifluoromethyl or methoxy, n is 0 or 1, and its pharmaceutically acceptable acid addition salts. 6. 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4 (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-trifluoromethylphenyl) -piperidine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-fluorophenyl) -piperidine, 1- [3- (2,2-dimethyl) -2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4-phenylpiperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl) -oxy) -2-hydroxypropyl] -4-hydroxy-4- (3-chlorophenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl 4-hydroxy-4- (3-methoxyphenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- ( 4-methoxyphenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) piperidine, • ·· • · • ··· · · • · • · · · • · • · · • · • · · · · · · · · ·· · 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methylphenyl) piperidine, 1- [3- (2 , 2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-cyano-4-phenylpiperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran) 7-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4- (4-chlorophenyl) piperidine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (6-methoxy-naphth-2-yl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (diphenylmethyl) piperazine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-fluorophenyl) piperazine, 1- [3- (2,2- dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-trifluoromethylphenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro) -benzofuran-7-yloxy) -2-hydroxypropyl] -4 (4-methoxyphenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) - 2-hydroxypropyl] -4 (benzo-1,3-dioxolan-5-yl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2- hydroxypropyl] -4 (4-chlorophenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-benzylpiperazine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (2,4-dichlorophenyl) piperazine, 1- [3- (2,2-dimethyl-2) 3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-chlorophenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl) -oxy) -2-hydroxypropyl] -4 (2-pyridyl) piperazine, [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- ( 2-methoxyphenyl) piperazine; or 1- [3- (2,2-di methyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-methoxyphenyl) piperazine, and pharmaceutically acceptable acid addition salts thereof. A process for the preparation of a benzofuran derivative of the formula I, wherein R ¹ , R ² , Z, X, Y, A, B, and Ar are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, characterized in that a) a halide of formula II wherein R ¹ , R ² , X, Y and Z are as defined for formula I, and Hal is a halogen atom, is reacted with a secondary amine of formula IV IV • ·· • · • ··· · · • · • · • · · Φ ·· · • · ·· • · · ·· ·· • · · · · ·· ·· wherein A, B and Ar are as defined for Formula I; or b) to prepare a benzofuran derivative of the formula I wherein Y is a hydroxy group, R ¹ , R ² , X, Z, A, B and Ar are as defined for formula I, an epoxide of the formula III is reacted III wherein R ¹ , R ² , Z of formula IV, wherein A, B and X are as defined above, with a secondary amine and Ar are as defined above; or c) reacting a compound of formula V wherein R ¹ , X and Z are as defined for a halogen of a compound of formula XI, formula I, is reacted Wherein R ² , Y, A, B and Ar are as defined for formula I and Hal is a halogen atom; d) for the preparation of a benzofuran derivative of the formula I, wherein R ^1, R ^2, X, Z, A, B and Ar are as defined for Formula I, reacting a compound of formula V wherein R ^1, X and Z are as above, to react with an epoxide of formula XII XII wherein R ² , A, B and Ar are as defined above; or e) a benzofuran derivative of the formula I wherein A forms a group B = -C = C- with B and R ¹ , R ² , X, Y, Z and Ar are as defined for formula I are prepared by dehydrating the benzofuran derivative of the formula I, wherein A is COH, B is methylene and R ¹ , R ² , X, Y, Z and Ar are as defined above; or f) for the preparation of a benzofuran derivative of the formula I, wherein A is COH, B is methylene, R ^1, R ^2, X, Y, Z and Ar are as defined for Formula I, provided that Ar is other a hydrogen atom, ketone of formula XV O x N XV · kde kde kde R R R R R R R R R R R R R R R R R R where R ¹ , R ^2, X, Y and Z are as defined above, is reacted with an aryl magnesium XVI Hal-Mg-Ar (XVI) wherein Ar is as defined above, Hal represents a halogen atom and wherein the formed adduct is decomposed with water; or g) a benzofuran derivative of the formula I, wherein A is COH, B is methylene, R ^1, R ^2, X, Y, Z and Ar are as defined for Formula I, provided that Ar is other than hydrogen are prepared by reacting a ketone of formula XV, wherein R ¹ , R ² , X, Y and Z are as defined above, with an aryl lithium compound of formula XVII, Li-Ar (XVII) wherein Ar is as defined above and wherein the resulting adduct is decomposed with water; or h) a benzofuran derivative of the formula I wherein A is CH, B is a methylene group, R ¹ , R ² , X, Y, Z and Ar are as defined for formula I are prepared by hydrogenating a compound of the formula I wherein A forms with B is -C =C-, and R ¹ , R ² , X, Y, Z are as defined above; or (i) a benzofuran derivative of the Formula I wherein A is CH, B is a methylene group, R ¹ , R ² , X, Y, Z and Ar are as defined for Formula I is prepared by reacting an epoxide of Formula III wherein R ¹ , R ^2, Z and X are as defined above, with a secondary amine of formula IV, wherein a is CHOH, B and Ar are as stated above, under dehydrating conditions and the formation of a compound of formula I, wherein a forms with B a group of the formula -C = C-, and R ¹ , R ² , X, Y, Z and Ar are as defined above, and the compound thus prepared is hydrogenated in the reaction mixture in which it was prepared; and if desired, the base of formula I obtained is reacted with an inorganic or organic acid to form a pharmaceutically acceptable acid addition salt of the compound, or it can be liberated from the acid addition salt of the compound with a base. A pharmaceutical composition comprising a benzofuran derivative of the formula I wherein R ¹ and R ² each independently represent a hydrogen atom or a C to C 4 alkyl radical, X represents an oxygen atom or a sulfur atom, Y represents a hydrogen atom or a hydroxy group, Z is hydrogen, halogen, C 1-4 alkyl, C _1-4 alkoxy, amino, nitro, cyano, trifluoromethyl, -COOR ³ , NHCOR ³ , and -SO ₂ NR ³ R ⁴ , wherein: R ³ represents a hydrogen atom or a C 1-6 alkyl group, R ⁴ represents a C 1-4 alkyl group, or R ³ and R ⁴ together with the associated nitrogen atom form a saturated or unsaturated heterocyclic group containing 5 to 10 members and optionally containing as further heteroatom (s) one or more nitrogen atoms and / or one or more oxygen atoms and / or one or more sulfur atoms, ··· · ··· · ··· 100 • · ··· ·· ··· ·· · A is CH, COH, C-CN, C-COOR ³ or COR ⁴ wherein R ³ and R ⁴ are as defined above, B represents a methylene group, or A forms together with the group B a group of the formula -C = C-, Ar is hydrogen; C _1-4 alkyl, phenyl (C _1-4 alkyl), biphenylyl, naphthyl, wherein the latter groups may be optionally substituted with a C 1-4 alkyl group. C ₄ alkoxy, or _{second 4} alkenyl; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C 1-6 alkyl groups; ₄ alkyl groups; A 5- or 6-membered saturated or unsaturated heterocyclic group containing a nitrogen atom and / or an oxygen atom and / or a sulfur atom as a heteroatom; or a phenyl group substituted with substituents including R ⁵ , R ⁶ and R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ independently represent hydrogen, halogen, trifluoromethyl, C 1-6 alkyl; C _1-4 alkyl, methylenedioxy, phenoxy optionally substituted by C _1-4 alkoxy or halogen; C ₂ . ₄ alkenyl, _{second 4} alkenyloxy, C _1-4 alkoxy optionally substituted by a di (C _1-4 alkyl) amino group or a 5- or 6-membered saturated heterocyclic group containing one or two nitrogen atoms, or a nitrogen atom and an oxygen atom, said heterocyclic group being optionally substituted Ci. ₄ alkyl, or A is a group of formula N _{(CH2) n-Ar} ', wherein Ar 1 represents a group selected from the group consisting of diphenylmethyl, pyridyl, pyrimidinyl, naphthyl, the latter group being optionally substituted by C 1-6 alkyl; ₄ alkoxy or C _{2nd 4} alkenyloxy; a partially saturated 5- or 6-membered heterocyclic group fused ·· ·· With a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C 1-4 alkyl groups; or a phenyl group substituted with substituents comprising R ³ , R ⁶ and R ⁷ , wherein R ³ , R ⁶ and R ⁷ are as defined above, n is 0 or 1, or a pharmaceutically acceptable acid addition salt thereof, as an active ingredient and one or more commonly used carriers. Pharmaceutical composition according to claim 8, characterized in that it comprises a benzofuran derivative of the general formula I, wherein R ¹ represents a hydrogen atom or C 1-6 alkyl; _An alkyl group, R ² is H, X is an oxygen atom, Y represents a hydrogen atom or a hydroxy group, Z is hydrogen, halogen or nitro, A is CH, COH or C-CN, B represents a methylene group, or A forms with the group B a group of the formula -C = C-, Ar is hydrogen, benzyl, phenyl substituted with R ³ , R ⁶ and R ⁷ , biphenylyl, naphthyl optionally substituted with C _1-4 alkoxy; or thienyl, wherein R ³ , R ⁶ and R ⁷ independently represent hydrogen, halogen, trifluoromethyl, C 1-6 alkyl or C 1-6 alkyl; ₄ alkyl, C ₄ alkoxy, C ₂ -4alkenyloxy, phenoxy and methylenedioxy, ·· ·· · · · · · · • · · · · · · · · · · · · Or a pharmaceutically acceptable acid addition salt thereof as the active ingredient. Pharmaceutical composition according to claim 8 or 9, characterized in that it comprises a benzofuran derivative of the general formula I, wherein: R ¹ represents a methyl group, R ² is H, X is an oxygen atom, Y is hydroxy, Z represents a hydrogen atom, A is CH, COH or C-CN, B represents a methylene group, or A forms with B a group of the formula -C = C-, Ar represents a phenyl group optionally substituted by a group selected from halogen, trifluoromethyl, methyl or methoxy; or a methoxynaphthyl group, or a pharmaceutically acceptable acid addition salt thereof, as the active ingredient. Pharmaceutical composition according to claim 8, characterized in that it contains a piperazinylalkylbenzofuran derivative of the general formula Ia. ·· ·· ·· ··· ·· · where R ¹ represents a C 1-4 alkyl group, R ² is H, X is an oxygen atom, Y represents a hydroxy group, Z represents a hydrogen atom, Ar 1 represents a diphenylmethyl group, a pyridyl group, a partially saturated 5-membered heterocyclic group containing two oxygen atoms which is fused with a phenyl group, or a phenyl group substituted with a group selected from R ⁵ , R ⁶ , R ⁷ , wherein R ⁵ , R ⁶ , R ⁷ independently represent hydrogen, halogen, trifluoromethyl, C 1-4 alkyl, C 1-6 alkyl; ₄ alkoxy, or methylenedioxy * s, n is 0 or 1, or a pharmaceutically acceptable acid addition salt thereof as the active ingredient. 104 ··· ·· · Pharmaceutical composition according to claim 11, characterized in that it comprises a piperazinylalkylbenzofuran derivative of the general formula Ia, wherein: R. ¹ represents a methyl group, R ² is H, X is an oxygen atom, Y is hydroxy, Z represents a hydrogen atom, Ar 1 represents diphenylmethyl, pyridyl, benzo-1,3-dioxolanyl or phenyl optionally substituted by one or two halogen atoms, one or two methyl groups, methylenedioxy, trifluoromethyl or methoxy, n is 0 or 1, or a pharmaceutically acceptable addition thereof an acid salt as an active ingredient. A pharmaceutical composition according to claim 8 comprising one of the following compounds; 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4 (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, 1 - [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4- (3-trifluoromethylphenyl) piperidine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-fluorophenyl) -piperidine · 99 9 9 99 9 9 9 9 9 105 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4-phenylpiperidine, 1- [3- (2,2-dimethyl) -2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-chlorophenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro- benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-methoxyphenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methoxyphenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] - 4- (3-Trifluoromethylphenyl) piperidine; 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methylphenyl) piperidine 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-cyano-4-phenylpiperidine, 1- [3- (2,2-dimethyl) -2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-chlorophenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro- benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4- (6-methoxy-naphth-2-yl) piperidine 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl-4- (diphenylmethyl) piperazine, 1- [3- (2,2-dimethyl-2) 3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-fluorophenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl) oxy) -2-hydroxypropyl] -4-hydroxy-4- (3-trifluoromethylphenyl) piperazine, 106 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy)] -2-hydroxypropyl] -4 (4-methoxyphenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4 (benzo- 1,3-dioxolan-5-yl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4 (4-chlorophenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-benzylpiperazine, 1- [3- (2,2-dimethyl-2, 2-hydroxypropyl) piperazine, 3-Dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (2,4-dichlorophenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-) yloxy) -2-hydroxypropyl] -4 (3-chlorophenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] - 4- (2-pyridyl) piperazine; 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) piperazine; or 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4 (3-methoxyphenyl) piperazine, or a pharmaceutically acceptable acid addition salt thereof, as the active components. 14. A method of treating a patient, in particular a patient suffering from a heart disease or a central nervous system disorder, wherein the patient is treated with a non-toxic dose of a benzofuran derivative of formula I 107 • ·· • · • ··· · · • · · • • · • • • • • • • • • · · • • • • • • · · · · · · · · · · where R ¹ and R ² each independently represent a hydrogen atom or a C to C 4 alkyl radical, X represents an oxygen atom or a sulfur atom, Y represents a hydrogen atom or a hydroxy group, Z is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, amino, nitro, cyano, trifluoromethyl, -COOR, NHCOR ³ , and -SO ₂ NR ³ R ⁴ , wherein: R ³ represents a hydrogen atom or C 1-6 alkyl; _An alkyl group, R ⁴ represents a C 1-4 alkyl group, or R ³ and R ⁴ together with the associated nitrogen atom form a saturated or unsaturated heterocyclic group containing 5 to 10 members and optionally containing as further heteroatom (s) one or more nitrogen atoms and / or one or more oxygen atoms, and / or one or more or more sulfur atoms, A is CH, COH, C-CN, C-COOR ³ or COR ⁴ wherein R ³ and R ⁴ are as defined above, B represents a methylene group, or A forms together with the group B a group of the formula -C = C-, 108 • · ··· Ar is hydrogen, C _1-4 alkyl, phenyl (C _1-4 alkyl), biphenylyl, naphthyl, wherein the latter may optionally be substituted with C 1-6 alkyl. C ₄ alkoxy, or _{second 4} alkenyl; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C 1-6 alkyl groups; ₄ alkyl groups; A 5- or 6-membered saturated or unsaturated heterocyclic group containing a nitrogen atom and / or an oxygen atom and / or a sulfur atom as a heteroatom; or phenyl substituted ^{with a} substituent comprising at R, R ⁶ and R ^7, wherein R ⁵ , R ⁶ and R ⁷ independently represent hydrogen, halogen, trifluoromethyl, C 1-6 alkyl; ₄ alkyl, methylenedioxy, phenoxy optionally substituted by Ci. _{4 is} alkoxy or halogen; C ₂ . ₄ alkenyl, _{second 4} alkenyloxy, Ci. ₄ alkoxy optionally substituted by a di (C _1-4 alkyl) amino group or a 5- or 6-membered saturated heterocyclic group containing one or two nitrogen atoms, or a nitrogen atom and an oxygen atom, said heterocyclic group being optionally substituted by a C _1-4 alkyl group, or A is a group of formula N _{(CH2) n-Ar} ', wherein Ar 1 represents a group selected from the group consisting of diphenylmethyl, pyridyl, pyrimidinyl, naphthyl, the latter group being optionally substituted by C 1-6 alkyl; ₄ alkoxy or C _{2nd 4} alkenyloxy; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C 1-6 alkyl groups; ₄ alkyl groups; or a phenyl group substituted with substituents including R ⁵ , R ⁶ and R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are as defined above, n is 0 or 1, 109 • ·· • · • ··· · · • · • · • • · • ·· · • · · • · · · · · · · · ·· ·· or a pharmaceutically acceptable acid addition salt thereof. 15. A process for the preparation of a pharmaceutical composition which has a cardioprotective effect, or is suitable for the treatment of a central nervous system disease, characterized in that the benzofuran derivative of the general formula I wherein: R ¹ and R ² independently represent hydrogen or C 1-6 alkyl; _An alkyl group, X represents an oxygen atom or a sulfur atom, Y represents a hydrogen atom or a hydroxy group, Z represents a hydrogen atom, a halogen atom, or a C1-6 alkyl group; C _1-4 alkyl; ₄ alkoxy, amino, nitro, cyano, trifluoromethyl, -COOR ³ , -NHCOR ³ , and SO ₂ NR ³ R ⁴ , wherein R ³ represents a hydrogen atom or C 1-6 alkyl; _An alkyl group, R ⁴ is C 1-6. ₄ alkyl, or R ³ and R ⁴ together with the associated nitrogen atom form a saturated or unsaturated heterocyclic group containing 5 to 10 members and optionally containing as further heteroatom (s) one or more nitrogen atoms and / or one or more oxygen atoms, and / or one or more or more sulfur atoms, A is CH, COH, C-CN, C-COOR ³ or COR ⁴ 110 • ·· ·· · · · ·· · • • • · • • · • ··· • • • • • • • · · • • • • • ··· ·· · · · · · ·· · wherein R ³ and R ⁴ are as defined above, B represents a methylene group, or A forms together with the group B a group of the formula -C = C-, Ar is hydrogen; ₄ alkyl, phenyl (Ci. ₄ alkyl), biphenyl, naphthyl, wherein the group as the latter may be optionally substituted by the group consisting of C |. ₄ alkoxy or C _2-4 alkenyl; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C 1-6 alkyls; ₄ alkyl groups; A 5- or 6-membered saturated or unsaturated heterocyclic group containing a nitrogen atom and / or an oxygen atom and / or a sulfur atom as a heteroatom; or a phenyl group substituted with substituents including R ⁵ , R ⁶ and R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ independently represent hydrogen, halogen, trifluoromethyl, C 1-6 alkyl; ₄ alkyl, methylenedioxy, phenoxy optionally substituted by Ci. _{4 is} alkoxy or halogen; C _2-4 alkenyl, C _2-4 alkenyloxy, C. ₄ alkoxy optionally substituted by a di (C _1-4 alkyl) amino group or a 5 or 6-membered saturated heterocyclic group containing one or two nitrogen atoms, or a nitrogen atom and an oxygen atom, said heterocyclic group being optionally substituted by C 1-6 alkyl; ₄ alkyl, or A is a group of formula N _{(CH2) n-Ar} ', wherein Ar 'is selected from the group consisting of diphenylmethyl, pyridyl, pyrimidinyl, naphthyl, the latter being optionally substituted by C _1-4 alkoxy or C _2-4 alkenyloxy; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C 1-6 alkyl groups; ₄ alkyl groups; or phenyl 111 • ·· • · • ··· · · • · • · • • · • ·· · • · ·· • · · • · ·· · · · · · ·· ·· a group substituted with substituents comprising R ⁵ , R ⁶ and R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are as defined above, n is 0 or 1, or a pharmaceutically acceptable acid addition salt thereof, is formulated into a pharmaceutical composition, using one or more pharmaceutical carriers commonly used in the pharmaceutical art. A halide of formula II wherein I 7 R and R independently represent a hydrogen atom or a C 1-4 alkyl group, X represents an oxygen atom or a sulfur atom, Y represents a hydrogen atom or a hydroxy group, Z represents a group selected from the group consisting of hydrogen atom, halogen atom, C 1-6 alkyl group; ₄ alkyl, C _1-4 alkoxy, amino, nitro, cyano, trifluoromethyl, -COOR ³ , -NHCOR ³ , and SO ₂ NR ³ R ⁴ , wherein R ³ represents a hydrogen atom or a C 1-4 alkyl group, R ⁴ is C 1-6. ₄ alkyl, or R ³ and R ⁴ together with the associated nitrogen atom form a saturated or unsaturated heterocyclic group containing 5 to 10 members and optionally containing 112 • ·· • · • ··· • 9 9 · • · 9 99 • • · • · • · • · • · · • · • • · ·· ·· 99 • · · · · · · one or more nitrogen atoms, and / or one or more oxygen atoms, and / or one or more sulfur atoms. Hal represents a halogen atom. A ketone of formula XV wherein R ¹ and R ² independently represent hydrogen or C 1-6 alkyl; _An alkyl group, X represents an oxygen atom or a sulfur atom, Y represents a hydrogen atom or a hydroxy group, Z is from the group of hydrogen, halo, C ₄ alkyl, C. ₄ alkoxy, amino, nitro, cyano, trifluoromethyl, -COOR ³ , -NHCOR ³ , and SO ₂ NR ³ R ⁴ , wherein R ³ represents a hydrogen atom or C 1-6 alkyl; _An alkyl group, R ⁴ represents a C _1-4 alkyl group, or R ³ and R ⁴ together with the associated nitrogen atom form a saturated or unsaturated heterocyclic group containing 5 to 10 members and optionally containing one or more nitrogen atoms and / or one or more oxygen atoms and / or one or more sulfur atoms.