JP2002514643A - A benzofuran derivative, a pharmaceutical composition containing the same and a method for producing the active ingredient thereof. - Google Patents

Abstract

(57) Abstract: The present invention provides a compound represented by the formula (I) New benzofuran derivatives, processes for preparing these compounds and pharmaceutical compositions containing their active substances.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a novel benzofuran derivative, a pharmaceutical composition containing the same as an active ingredient, and a method for producing the active ingredient. The new compounds affect the circulatory system and the heart and have further effects on the central nervous system.

The present invention relates to a compound of formula I (Wherein, R ¹ and R ² are independently hydrogen atom or C _{1 ~ 4} alkyl, X is oxygen atom or sulfur atom, Y is a hydrogen atom or a hydroxy, Z is a hydrogen atom halo atom, C _{1 ~ 4} alkyl group, C _{1 ~ 4} alkoxy group, an amino group, a nitro group, a cyano group, a trifluoromethyl group, wherein -COOR ^3, -NHCOR ^3, or with -SO ₂ NR ³ R ⁴ There, in which case, R ³ is a hydrogen atom or a C _{1 ~ 4} alkyl group, R ⁴ is a C _{1 ~ 4} alkyl group, or R ³ and R ^4, will together with the adjacent nitrogen atom, 5 Forming a 10-membered, saturated or unsaturated heterocyclic group, which has, as further heteroatoms, one or more nitrogen atoms and / or one or more oxygen atoms and / or one or more sulfur atoms; Get

A represents a formula CH, COH, C-CN, C-COOR ³ or COR ⁴ , wherein R ³ and R ⁴ are as described above; B is a methylene group; Alternatively, A together with B forms a group of the formula -C = C-,

[0004] Ar is a hydrogen atom, C_{1 ~ Four}Alkyl group, phenyl (C_{1 ~ Four}Alkyl) group, bife
Nyl group, naphthyl group (however, C_{1 ~ Four}Alkoxy group or C_{Two ~ Four}By alkenyl group
May be optionally substituted), partially saturated, condensed with a phenyl group,
A 5- or 6-membered heterocyclic group containing an elemental atom, wherein _{1 ~ Four}  Optionally substituted with alkyl groups); 5- or 6-membered, saturated or unsaturated.
Saturated and, as heteroatoms, nitrogen and / or oxygen and / or sulfur
A heterocyclic group containing: or a substituent; R^Five, R⁶And R⁷Phenyl substituted with
Where R is^Five, R⁶And R⁷Are, independently of one another, a hydrogen atom, a halo atom,
Oromethyl group, C_{1 ~ Four}Alkyl group, methylenedioxy group, phenoxy group (however,
Indeed, C_{1 ~ Four}R) optionally substituted by alkoxy or halo atoms, C)_{Two ~ Four}  Alkenyl group, C_{Two ~ Four}An alkenyloxy group, optionally di (C_{1 ~ Four}An alkyl group or a 5- or 6-membered, saturated heterocyclic group (provided that one or more nitrogen atoms and oxygen atoms
And the heterocyclic group optionally has C_{1 ~ Four}Optionally substituted with an alkyl group)
Or

A is a group of formula N— (CH ₂ ) _n —Ar ′, and Ar ′ is a diphenylmethyl group, a pyridyl group, a pyrimidinyl group, a naphthyl group (
Here, optionally C _{1 ~ 4} alkyl may be substituted with a group or a C _{2 ~ 4} alkenyl group); partially saturated, fused with a phenyl group, containing 1-2 oxygen atoms, 5- or 6-membered Hajime Tamaki (said heterocyclic group may optionally be substituted with 1 to 3 alkyl groups of C _{1 ~ 4);} or substituted by a substituent R ^5, R ⁶ and R ⁷ A phenyl group (R ⁵ , R ⁶ and R ⁷ are as defined above; n is 0 or 1) and novel benzofuran derivatives and their pharmaceutically acceptable acid addition salts.

[0006]

According to the literature, certain furancarboxylic amides have anti-inhibitory properties (Ya
kugaku Zasshi, 97 (5), 540 (1977); CA, 87, 152125d (1997) is, benzofuran derivatives having amino furan ring, amidino, thio carboxamides Mi Gino or dialkylaminoalkyl group, H ₂ receptor antagonists And therefore has no anti-ulcer effect
(Published PCT application number WO86 02550; CA, 105 , 226586u (1986)).

[0007] Tetrahydronaphthoxy derivatives having hypoglycemic activity are described in DE-OS No. 22 35 597
Known to. The chemical structure of the known compound is similar to that of the piperazinylalkylbenzofuran derivative of formula Ia.

[0008] It is an object of the present invention to produce novel benzofuran derivatives which affect the circulatory system and cardiac function, but which are also representative of those having an effect on the central nervous system,

It has been found that the above objects are achieved by the novel benzofuran derivatives of the formula I.

In the description and the claims, in the definition of substituent, the halo atom is primarily fluoro, chloro, bromo or iodo, preferably fluoro, chloro. Or bromo.

C_{1 ~ Four}Alkyl groups are methyl, ethyl, n-prolyl, isopropyl, n-butyl.
 Butyl, secondary butyl, tertiary butyl or isobutyl. Preferably, C_{1 ~ Four}  An alkyl group is a methyl group.

[0012] C _{2 ~ 4} alkenyl group are vinyl, Aruriru, Ri Metaruriru or crotyl der, preferably a Aruriru or Metaruriru group.

[0013] C _{1 ~ 4} alkoxy group, the first, methoxy, ethoxy, n- propoxy, iso-propoxy or butoxy, preferably a methoxy or isopropoxy.

[0014] C _{2 ~ 4} alkenyloxy group is suitably a Aruriruokishi or Metaruriruo alkoxy group.

[0015] di C _{1 ~ 4} alkoxy group substituted with (C _{1 ~ 4} alkyl) amino group is first place, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy or 4-dimethylamino-butoxy group And preferably a 2-dimethylaminobutoxy group.

A partially saturated, 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms is dihydrobenzofuran, benzodioxotan, It is a dihydrobenzplan or benzodioxane group.

The 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 is preferably The hetero atom is a nitrogen atom or an oxygen atom or a heterocyclic group consisting of a transfer or nitrogen atom and an oxygen atom, and the hetero ring does not contain a double bond or contains one or more double bonds. Such a heterocyclic group is, for example, a pyrrolyl, pyrrolidinyl, piperazinyl, pyridyl, morpholinyl, furyl or thienyl group. The above heterocyclic group is suitably a thienyl group.

The 5- or 6-membered heterocyclic group containing one or two nitrogen atoms or a nitrogen atom and an oxygen atom is preferably pyrrolidinyl, piperidinyl, piperazinyl,
Or a morpholino group, the nitrogen atom is one that is bound to a carbon atom of C _{1 ~ 4} alkoxy group.

The 5- to 10-membered saturated or unsaturated heterocyclic group is, for example, pyrrolidinyl, pyrrolyl, piperidinyl, pyridyl, furyl, tetrahydrofuryl, morpholinyl,
Groups such as piperazinyl, imidazolidinyl, pyrimidinyl, pyrazolyl, pyrazolidinyl, thienyl, hexamethyleneimin-1-yl, heptamethyleneimine-1-yl and the like.

Pharmaceutically suitable acid addition salts are acid addition salts combined with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid or organic acids such as acetic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, etc. It is.

The present invention includes the possible isomers of the compounds of formula I and mixtures thereof.

[0022] Preferred subgroups of benzofuran derivatives of the present invention, the formula I (where in the formula I, R ¹ is hydrogen atom or C _{1 ~ 4} alkyl group, R ² is a hydrogen atom X is an oxygen atom, Y is a hydrogen atom or hydroxy, Z is a hydrogen atom, a halo atom or a nitro group,

A is a formula CH, COH or C—CN, B is a methylene group, or A forms a group with B, ie, a formula —C 基 C—, Ar is a hydrogen atom, benzyl Phenyl substituted with a group, substituents R ⁵ , R ⁶ and R ⁷
Group, a biphenyl group, a naphthyl group (provided that optionally substituted with C _{1 ~ 4} alkoxy group), or a thienyl group, wherein, R ^5, R ⁶ and R ⁷ independently of one another, a hydrogen atom , halo atoms, trifluoromethyl group, C _{1 ~ 4} alkyl group, C _{1 ~ 4} alkoxy group, C _{2 ~ 4} alkenyloxy group, a phenoxy group or compound and pharmaceutically suitable acid methylene di-oxy group) Consists of addition salts.

Within the above subgroup, suitable benzofuran derivatives of the present invention include compounds of formula I wherein R ¹ is a methyl group, R ² is a hydrogen atom, and X is an oxygen atom Y is hydroxy; Z is a hydrogen atom; A represents a formula CH, COH or C-CN; B is a methylene group; Ar is a phenyl group optionally substituted with a halo atom, a trifluoromethyl group, a methyl group or a methoxy group; or a methoxynaphthyl group, or a pharmaceutically suitable acid thereof. Consists of addition salts.

Particularly preferred benzofuran derivatives of the formula I) are: 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4- (3-trifluoro-methylphenyl) -1,2,3,6 -Tetrahydropyridine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4- (3-trifluoro-methylphenyl) Piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4- (4-trifluoro-phenyl) piperidine, 1 -/ 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4-phenyl- Peridine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (3-chloro-phenyl) piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4- (3-methoxy-phenyl) piperidine, 1- / 3- ( 2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (4-methoxy-phenyl) piperidine, 1 / 3- (2,2- Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4- (3-trifluoromethyl-phenyl) piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4- (4-methyl-phenyl) piperidine, 1- / 3- ( 2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-cyano-4-phenyl-piperidine, 1 / 3- (2,2-dimethyl-2,3 -Dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (4-chloro-phenyl) piperidine, 1 / 3- (2,2-dimethyl-2,3-dihydro-benzofuran -7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (6-methoxy-naphthyl-2-yl) piperidine, and acid addition of these compounds .

Further, a preferred subgroup of the benzofuran derivatives of the present invention includes compounds of formula Ia(However, R¹Is C_{1 ~ Four}Alkyl, R^TwoIs a hydrogen atom, X is an oxygen atom, Y is hydroxy, Z is a hydrogen atom, Ar 'is a diphenylmethyl group, a pyridyl group, partially saturated, and a phenyl group
A 5- or 6-membered heterocyclic group fused and containing two oxygen atoms;
Substituent R^Five, R⁶And R⁷A phenyl group substituted by^Five, R⁶ 
 And R⁷Is independently of each other a hydrogen atom, a halo atom, a trifluoromethyl group,_{1 ~ Four} Alkyl group, C_{1 ~ Four}An alkoxy group or a methylenedioxy group, n is 0 or 1), and a piperazinylalkylbenzofuran derivative;
Consists of pharmaceutically suitable acid addition salts.

Within the subgroup of Formula Ia, suitable piperazinylalkylbenzofuran derivatives of the present invention are those of Formula Ia, wherein R ¹ is a methyl group, R ² is a hydrogen atom, and X is Y is hydroxy, Z is a hydrogen atom, Ar ′ is a diphenylmethyl group, a pyridyl group, a benzo-1,3-dioxolanyl group or one or two halo atoms, 1 or 2 methyl groups, methylenedioxy groups, phenyl groups optionally substituted with a trifluoromethyl group or a methoxy group, and n is 0 or 1.) Acid addition salts.

Particularly preferred benzofuran derivatives of the formula Ia) include: 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-benzofura) -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-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, And acid addition salts of these compounds.

The compound of the present invention is produced as follows. a) Formula II Wherein R ¹ , R ² , X, Y and Z are as defined in relation to formula I, and Hal
Is a halo atom) Wherein A, B and Ar are as defined in relation to Formula I, or

B) Formula III(However, R¹, R^Two, X and Z are as defined in relation to formula I)
Is substituted with a compound of formula IV, wherein A, B and Ar are as defined in relation to formula I.
By reacting with a secondary amine, a compound of formula I wherein Y is a hydroxy group and R ¹ , R^Two, X, Z, A, B and Ar are as defined in relation to formula I)
Producing zofuran derivatives, or

C) Equation V Wherein R ¹ , X and Z are as defined in relation to Formula I,
XI Wherein R ² , Y, A, B and Ar are as defined in relation to formula I,
l is a halogen atom).

D) A compound of formula V (as defined above) is converted to a compound of formula XII (Wherein R ² , A, B and Ar are as defined above)
Wherein R ¹ , R ² , X, Z, A, B and Ar are of the formula I
As defined in relation to), or

E) Formula I (where A is a formula COH group, B is a methylene group, and R ¹ , R ² , X, Y, Z and Ar are as defined above) Benzofuran derivative of
By dehydration, A forms together with B a group of formula -C = C-, wherein R ¹ , R ² , X, Y, Z and Ar are related to formula I Benzofuran derivatives), or

F) Formula XV Wherein R ¹ , R ² , X, Y and Z are as defined in relation to Formula I, with a ketone of Formula XVI: Hal-Mg-Ar, where Ar is as defined above; Hal is a halo atom, and is reacted with an arylmagnesium halide of formula I wherein A is a group of the formula COH and R ¹ , R ² , X, Y, Z and Ar are as defined in formula I Benzofuran derivatives), or

G) converting a ketone of formula XV (R ¹ , R ² , X, Y and Z is as defined above) to a compound of formula XV
VII: Li-Ar (where Ar is as described above) with a lithium compound and the adduct formed is decomposed with water to give a compound of formula I (where R ¹ , R ² , X ,
Y, Z and Ar are as defined in relation to formula I), or

H) Formula I (A forms together with B a group of the formula —C ＝ C—, R ¹ , R ² , X, Y, Z
And Ar is as defined in relation to formula I, by hydrogenating a compound of formula I wherein A is a group of formula CH, B is a methylene group, R ¹ , R ² , X, Y, Z and Ar are as defined in relation to formula I), or

I) d) of formula III wherein R ¹ , R ² , X and Z are as defined in relation to formula I
The poxide is reacted with a secondary amine of formula IV where A is a group of formula CHOH, and B and Ar are as described above under dehydration reaction conditions, and the formed formula I (A together with B forms the formula -C = C-, R ¹ , R ² , X, Y, Z
And Ar is as described above) in the prepared reaction mixture.

Then, if desired, the obtained base of the formula I is reacted with an inorganic or organic acid to form a pharmaceutically suitable acid addition salt or to be liberated from the acid addition salt with a base. According to formula I (where A is a group of formula CH, B is a methylene group and R ¹ , R ² , X, Y, Z and Ar are as defined in relation to formula I)
Wherein the benzofuran derivative of formula I (R ¹ , R ² , Z, X, Y, A, B and Ar is the definition related to formula I according to claim 1, wherein Is produced).

In the process (a) according to the invention, the reaction of the halide of the formula II with the secondary amine of the formula IV is suitably effected in a substantial excess of the secondary amine of the formula IV. However,
This reaction can also be performed in an inert solvent, in the presence of a suitable base, and in a two-phase system.

In this reaction, the solvent is, for example, an alcohol, preferably methanol, ethanol or isopropanol, diisopropyl ether, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide, a halogenated solvent, preferably dichloromethane. , 1,2-dichloroethane or chlorobenzene can be used.

In this reaction, the base is an alkali metal hydroxide or an alkali metal hydroxide, preferably an inorganic substance such as sodium or potassium hydroxide, or preferably a trialkylamine or tetraalkylammonium hydroxide. An inorganic base such as a substance can be used. The base is calculated from 0.8-1.
It is used in 1 molar equivalent, preferably 0.9 to 1.0 molar equivalent.

The product of the formula I is separated from the reaction mixture in a manner known per se. Thus, if the product can be crystallized from the solvent used in the reaction mixture or precipitated with another solvent that is miscible with the organic solvent, the product is filtered, recrystallized or purified by chromatography.

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

In some cases, it is convenient to subject the evaporation residue to separation between water and a water-immiscible organic solvent, so that the mixed alkalis are separated into phases and the organic layer is evaporated. It is convenient to purify the residual base by recrystallization.

In step (b) of the present invention, an epoxide of formula III and a secondary amine of formula IV
Is carried out in an insufficient solvent in excess of a secondary amine.

The solvent for the reaction is, for example, methanol, ethanol, isopropanol,
Butanol, diisopropyl ether, acetonitrile, acetone, methyl ethylene ketone, dimethylformamide, water or a mixture of water, preferably ethanol, isopropanol, more preferably a 10% by weight aqueous solution thereof.

Each mole of the epoxide of formula III is from 0.8 to 2.0 moles, preferably 0.85
React with ~ 1.2 moles of a secondary amine of formula IV. If a secondary amine of the formula IV is used as the base, the base is added in the reaction mixture itself by adding a molar equivalent of an inorganic or organic base, calculated on the amount of the secondary amine salt. , Can be released.

As the inorganic base, first, an alkali metal or alkaline earth metal hydroxide,
Preferably, a 5 to 40% by weight, preferably 10 to 25% by weight solution of an aqueous solution of sodium or potassium hydroxide is used.

As the organic base, a trialkalamine or a tetraalkylammonium hydroxide, particularly, triethylamine is preferably used.

Generally, 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 in process (a) above.

In the production step (c) of the present invention, the reaction between the compound of the formula V and the halo compound of the formula XI is carried out in an inert solvent in the presence of an inorganic or organic base and a phase conversion catalyst. be able to.

The inorganic base is firstly a hydroxide or carbonate of an alkali metal or alkaline earth metal, preferably sodium or potassium hydroxide or potassium carbonate. Organic bases include trialkylamine or tetraalkylammonium hydroxide, preferably triethylamine. The base is used in 1 to 2 molar equivalents, preferably 1.2 molar equivalents, calculated relative to the compound of formula V.

The halo compound of formula XI is calculated as 1 to 3 molar equivalents relative to the compound of formula V,
Preferably, 1.8 to 2 molar equivalents are used.

The solvent for the reaction is, for example, methanol, ethanol, propanol, butanol, acetone, methyl ethylene ketone, dimethyl ketone, acetonitrile,
Dimethylformamide and water, preferably ethanol, acetone or methyl methyl ketone.

The phase change catalyst includes tetraalkylammonium hydroxide or halide,
Preferably, trimethylbenzylammonium hydroxide, triethylenebenzylammonium hydroxide, trimethylbenzylammonium chloride,
There is tetrabutylammonium bromide or tetrabutylammonium hydrosulfite.

The reaction is carried out at a temperature in the range from 40 to 100 ° C., preferably from 60 to 80 ° C.

The products are separated by methods known per se. After completion of the reaction, the reaction mixture
For example, evaporation to dryness under reduced pressure, the residue is subjected to a partition between water and water and an immiscible organic solvent, the separated organic phase is dried and evaporated to dryness under reduced pressure, while the residue Is purified by recrystallization from a suitable solvent or by vacuum fractionation.

In the production step (d) of the present invention, the compound of the formula V is reacted with the epoxide of the formula XII in an inert solvent.

The solvent is, for example, methanol, ethanol, isopropanol, butanol,
Diisopropyl ether, acetonitrile, acetone, methyl ethylene ketone,
Dimethylformamide, water or a mixture thereof, preferably ethanol,
Isopropanol or a 10% by weight water mixture thereof.

The compound of formula V is calculated from 0.8 to 2.0, calculated on the epoxide of formula XII.
Molar equivalents, preferably 0.85 to 1.2 molar equivalents, are used.

In general, the reactions are carried out at or near the boiling point used.

The product is separated from the reaction mixture according to claim 1 in connection with the above-mentioned production step (c).

In the production step (e) of the present invention, the dehydration reaction of the compound of the formula I (where A is a group of the formula COH and B is a methylene group) is preferably carried out by a strong acid, The reaction is carried out with hydrochloric acid in an inert solvent, preferably in alcohol, in ethanol, under heating, preferably at the boiling point. A concentration of 5 to 40%, preferably 15 to
It is convenient to use the starting compound in a 25% solution. The product is separated from the solution after cooling, then filtered and, in the reverse case, a solution that does not dissolve the product but is miscible with the solvent used in the reaction. And the precipitated crystals are filtered.

In the production steps (c) and (d) of the present invention, the ketone of the formula XV is preferably combined with the allyl magnesium halide of the formula XVI or the allyl lithium compound of the formula XVII in an unrelated nonpolar organic solvent. Is carried out in ether, tetrahydrofuran or dioxane at a temperature between −10 ° C. and the boiling point of the solvent, preferably at a temperature between 10 and 30 ° C. The product is obtained from the reaction mixture-after decomposing the double salt formed with the acid in the reaction and evaporating the solvent-by simple recrystallization or salt formation. If the product or its salt does not crystallize, the acid-decomposed reaction mixture is made alkaline, the product is dissolved in a water-immiscible organic solvent and the organic phase is dried. , Evaporated and the base obtained is purified by crystallization or chromatography.

In the production steps (h) and (i) of the present invention, the compound of the formula I (where A together with B forms a group of the formula —C 一 緒 C—) is formed on a carbon support. Conveniently by catalytic hydrogenation using a noble metal catalyst, preferably palladium on carbon, particularly preferably 10% palladium on carbon catalyst, in an alcohol, preferably in methanol,
Be reduced. Alternatively, the evaporation residue can be converted to a salt.

If the product or a salt thereof does not crystallize, the reaction mixture is subjected to a partition between water and an organic solvent immiscible with water, the organic phase is dried and evaporated, and the residual base is removed. And purified by crystallization or chromatography.

The reduction reaction can also be performed in the reaction mixture from which the starting compound has been prepared.

The halides of the formula II are novel compounds and the invention therefore also covers these compounds. Wherein Y, R ² and Hal are as defined above, and a dihaloalkane
It can be produced by reacting.

The halide of formula II can be used to convert a compound of formula V to a compound of formula VI Wherein Y, R ² and Hal are as defined above, and a dihaloalkane
It is produced by reacting.

Alternatively, the halide of formula II can be prepared by converting a compound of formula V to a compound of formula VII (Where Y, R ² and Hal are as defined above)
Reacting with the derivative and then reacting with formula VIII (Where Y, R ² and Hal are as defined above)
It is produced by converting a hydroxy group of a rukyl derivative into a halo atom.

The compound of formula V is reacted with a dihaloalkane of formula VI in an inert solution with an inorganic or organic base in the presence of a phase-change catalyst.

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

The dihaloalkanes of the formula VI are used in 1 to 3 molar equivalents, preferably 1.8 to 2 molar equivalents, calculated for the compound of the formula V.

During the reaction, the solvent is, for example, methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide, water, preferably ethanol, acetone or methyl ethyl ketone.

The phase transfer (conversion) catalyst is a tetraalkylammonium hydroxide or halide, preferably trimethylbenzylammonium hydroxide, triethylbenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide, or tetrabutyl. Ammonium hydrosulfite can be used.

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

[0078] The product is separated from the reaction mixture by known methods. For example, after the end of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residue is subjected to a partition between water and a water-immiscible organic solvent, the organic phase is separated off, dried and dried under reduced pressure. And evaporated, and the residue is purified by recrystallization from a suitable solvent or by vacuum distillation.

The reaction of a compound of formula V with a haloalkanol derivative of formula VII is carried out in a similar manner as described in connection with the reaction of a compound of formula V with dihaloalkanes of formula VI.

The formed hydroxyalkyl derivative of formula VIII is a thionyl chloride,
Using phosphorous oxychloride, phosphorous pentachloride, thionyl bromide, phosphorous oxybromide, phosphorous pentabromide, phosphorous pentaiodide, phosphorous tribromide, preferably using thionyl chloride, the formula II Converted to the desired hydride.

The halogenating agent is used per mole of starting hydroxyalkyl derivative of formula VIII
, 1 to 4 molar excess, preferably 1.2 to 2.2 molar excess.

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

After evaporation of the solvent, the product is separated by a method similar to that described in relation to the reaction of the compound of formula V and of the dihaloalkanes of formula VI.

Those of the epoxide of the formula III are described in the literature: Japanese Patent Publication J60258-1
74-A; CA, 104 , 207136K (1986) /. This is from the compound of formula V:
Produced by reaction with epichlorohydrin in an alkaline medium. Instead, they react a compound of formula V with a halide of formula IX, and (Where R ² and Hal are as defined above), and can be prepared by oxidizing the formed allyl derivative of formula X. (However, R ¹ , R ² , X and Z are as defined above)

The compound of formula V is used in 1 to 3 molar equivalents, epichlorohydrin and a hydroxide of an alkali metal or alkaline earth metal, preferably in 1 to 3 molar equivalents. React with sodium or potassium.

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

The epoxide of the formula III formed during the reaction can be separated off in a manner known per se. For example, after the end of the reaction, the reaction mixture is evaporated to dryness under reduced pressure and the residue is
It is subjected to a partition between water and a water-immiscible organic solvent, and the separated organic phase is dried and evaporated to dryness under reduced pressure. Generally, the residue is sufficiently pure for the next reaction. If necessary, the product can be purified by chromatography or crystallization.

^One of the allyl derivatives of the formula X (where X is an oxygen element, R ¹ is a methyl group, R ² is a hydrogen atom and Z is a hydrogen atom) is described in Aust. J. Chem., 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 the reaction, the alkaline medium is an alkali metal or alkaline earth metal hydroxide or carbonate, preferably sodium or potassium hydroxide,
Alternatively, it is achieved by potassium carbonate. The listed bases are used in 12 molar equivalents.

In the reaction, the solvent is, for example, methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, diethyl ketone, acetonitrile,
Dimethylformamide, water or a mixture thereof, preferably ethanol, acetone or methyl ethyl ketone.

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

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

The products are separated by known methods. For example, after the end of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residue is partitioned between water and an organic solvent immiscible with water, the separated organic phase is dried and dried under reduced pressure. And evaporated to dryness, and the residue is purified by recrystallization from a suitable solvent or by vacuum distillation.

The allyl derivative of formula X is oxidized with an organic oxidizing agent to the corresponding epoxide of formula III, preferably m-chloroperbenzoic acid, peracetic acid, perphthalic acid, 2,3-
Dichloro-5,5-dicyano-1,4-benzoquinone (DDQ), preferably m
-Oxidation with chloroperbenzoic acid at a temperature of 0 to 40C, preferably at a temperature of 20 to 30C.

In the reaction, dichloromethane, 1,2-dichloroethane, chloroform, 1,1,2-trichloroethylene, chlorobenzene, preferably dichloromethane or 1,2-dichloroethane is used as a solvent.

The products are separated in a self-based manner. For example, after the reaction is complete,
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 evaporated to dryness under reduced pressure. The residue is purified by recrystallization or chromatography from a suitable solvent.

Some of the halo compounds of formula XI) are known (Peltz, K., Protiva, M., Coll.
Chem. Commun., 32 (8), 2840 (1967), US-P No. 4,110,536; Chem. Abstr., 90 , P121596r). They comprise the corresponding secondary amines of the formula IV and the corresponding dihalides of the formula VI
It is produced by reacting with a loalkane. Other halo compounds of formula XI are also readily prepared by the above procedure.

Certain epoxides of the formula XII are known. They are prepared from the corresponding compound of formula IV reacted with epichlorohydrin in an alkaline medium
(CH-P No. 474,511; Chem. Abstr., 72 , 55506m (1970)). Certain compounds of formula XII are
Reacting a corresponding secondary amine of formula IV with a corresponding halide of formula IX;
Converting the double bond of the forming compound of formula XIV, Wherein R ² , A, B and Ar are as described above. Conversion to an epoxide group under the conditions described in connection with the oxidation of the compound of formula X.
Other epoxides of Formula XII can be readily prepared by the above-described processing methods.

The ketones of the formula XV are novel compounds and the invention therefore also covers these compounds. They use a halide of formula II or an epoxide of formula III
, By reacting with piperidone of formula XIII.

The reaction conditions are the same as those used in the processing methods a) and b) of the present invention.

The ketone of the formula XV ′ is described in the literature: JP No. 14,632 ('67): Chem. Abstr., 68 , 114618s (
1968).

The reaction of an aryllithium derivative of formula XVII with a ketone of formula XV is also described in the literature: El
pern, B., Wetteran, W., Carabates, Ph., Grunbach, L., J. Am. Chem. Soc., 8 , 4916 (195
It can be performed by the method known from 8).

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

The secondary amines of the formula IV are generally commercially available or can be easily prepared by known methods.

The biological activity of the compounds of the present invention was studied by the following tests. 1. Measurement of cardioprotective effect in ischemic rat heart (Langendorff) preparation

Cardioprotective compounds protect against damage during ischemia and / or reperfusion. Of the many methods used for measuring the cardioprotective effect, one of the most known and commonly used methods is the isolated and perfused rat heart subjected to whole body ischemia / Longman, SD and Hamilton, TC, Medical Research Review, 12 / More
Things. During systemic ischemia, cardiomyopathy spasticity results from elevated calcium levels in cardiomyopathy. Elapsed time from the start of whole body ischemia to the end of spasticity (that is, Time to co
tracture = TTC) is prolonged by some cardioprotective compounds, thus
The efficacy of a compound can be tested by measuring TTC.

Male Sprague-Dawley rats weighing 300-350 g were given 2500 IU (international units) of heparin, i. p. And 10 minutes later the animals are treated with sodium pentabarbital / 5-ethyl-5- (1-methylbutyl) -2,4,6
(1H, 3H, 5H) -pyrimidinetrione sodium salt / 60 mg / k
Anesthetize with a dose of g. The heart is quickly dissected and the aorta is connected to a cannula fixed to a Langendorff apparatus. The heart is under constant pressure (8000P
In a), the modified carbogenized Krebs-Henseleit solution
The solution was perfused. The composition of the solution was (mM): NaCl 118, KCl 4.7, MgSO ₄ 1.6, CaCl ₂ 2.5, NaHCO ₃ 24.88, KH ₂ PO ₄ 1.18, EDT
A 0.5, group 11. The partial CO ₂ pressure and the pH of the solution are within physiological limits (pCO ₂ 4000-4650 Pa, pH = 7.3-
7.45)

A hole was drilled in the wall of the left atrium, and a water-filled plastic balloon attached to a metal cannula was inserted into the left ventricle. During the equilibration period, the end-diastolic pressure of the left ventricle was fixed at a value between 600 and 1333 Pa by changing the volume of fluid in the balloon, but is not corrected thereafter.

After a 20 minute equilibration phase, the heart was perfused with vehicle (0.04% dimethyl sulfoxide) for 10 minutes in the case of the control group and in the case of the treated group: The test substance was perfused with a solution at a concentration of 10 ⁻⁶ or 10 ⁻⁵ M. At the end of the 10-minute period, the activity of the test compound was determined without further experimentation, and the left ventricular systolic pressure was 20% lower than the control value measured prior to treatment.
% Or more.

[0110] Systemic ischemia is initiated by completely closing the perfusion and carbogenizing for 25 minutes. The time from the onset of ischemia to the formation of cardiomyopathy spasticity, ie, a 666 Pa rise in left ventricular end diastolic pressure (TTC), was measured.

Three parallel experiments were performed on the test compound at each concentration, and
Parameters of three additional vehicle (0.04% dimethyl sulfoside) treated hearts were measured for the test substance.

The individual TTC values were averaged and the effect of the test substance is expressed as a percentage change compared to the vehicle treated group. Compared to the control group,
Compounds that extend TTC are cardioprotective. As a control substance, remacalin, ie, (3S) -trans-3,4-dihydro-3-hydroxy-2,
Use 2-dimethyl-4- (2-oxo-1-pyrrolidinyl) -2H-1-benzpyran-6-carbonitrile. The results obtained are shown in Table I.

[0113]

[Table 1]

At the concentration of 10 ⁻⁶ M, some of the benzofuran derivatives tested produced a significantly higher TTC-prolonging effect than the control substance remacalin.

The compounds of the present invention are isolated and perfused during ischemia in the rat heart.
Caused a considerable prolongation of TTC. This fact is proof of the cardioprotective effect.

The compound of Example 9 is significantly better than the effect of remacalin, especially when measured at a concentration of 10 ⁻⁶ M. Thus, the cardioprotective effects of the compounds of the present invention can be used in treating humans. The above-mentioned cardioprotective effects increase the likelihood of preventing the adverse effects of severe coronary arrhythmias common in ischemic atrial disease by providing prolonged administration of the active substance. In this disease, which is considered to be a condition with a cardiomyopathy infarction, treatments used to change angina patients, in particular, because the treatment used can reduce the rate of irreversible cardiomyopathy damage that occurs in subsequent cardiomyopathy infarcts, Seems suitable.

The further use of this compound has a therapeutic effect on cardioprotection before surgery, for example, in the case of pseudo-blocked coronary circulation (dilation of coronary arteries by balloon) or in the case of surgical cardiac arrest. . Faster and more thorough coordination of cardiac function can be obtained with a cardioprotective procedure of the heart prepared for implantation. In this case, the compound of the invention is added to the nutrient solution of the heart.

[0118] 2. Measurement of effects on serotonin neuronal transition 5-HT _1A receptor binding assay

The 5-HT _1A receptor binding assay was performed according to the method of Peroutka / Peroutka, SJ, J. Ne.
urochem., 47 , 529 (1986). Binding was measured on a diaphragm fragment manufactured from rat frontal cortex using 8-hydroxy-N, N-dipropyl-2-aminotetralin as a specific ligand, labeled with tritium. The final culture volume was 250 microliter. Assay samples were incubated at 25 ° C. for 30 minutes.

The reaction was stopped by adding 9 ml of an ice-cooled solution of tris (hydroxymethyl) aminomethane having a pH of 7.7 and immediately filtering under reduced pressure. Filtration was performed using Whatman GFIB glass fiber filter paper soaked with a 0.05% solution of polyethyleneimine for 2 hours before use. The radioactivity retained on the filter was measured with a liquid scintillation counter.

The results obtained are outlined in Table II. As a reference compound, buspirone, ie, 8- {4- [4- (2-pyrimidinyl) -1-piperidinyl] butyl} -8.
-Azospiro / 4,5 / decane-7,9-dione was used.

[0122]

[Table 2]

From the data in Table II, it can be seen that the compounds of the invention have considerable affinity for the serotonin 5-HT _1A receptor. Most of the compounds tested were superior to buspirone used as a control compound.

Enhanced Plasma Test on Rats The test was performed according to the modified method of Pelow et al./J. Neurosci. Methods, 14 , 149 (1985).
It was conducted. The raised pluses are of the same size (5
(0 × 50 cm), consisting of two open arms and two 40 cm closed arms. Arms of the same type are located opposite each other. The junction of the four arms forms a central square area (15 × 15 cm). The device is 50 cm high,
Made of wooden material illuminated by dim light from above. Male Sprague-Dawley rats weighing 220-260 g were used in the experiments.

Rats were treated with the test or control compound 60 minutes prior to the test. Animals are placed on the central square area and the test is performed for 5 minutes. Four different parameters were measured: time spent in the open arm time spent in the closed arm number going into the open arm number going into the closed arm

Compounds are considered to be efficacious as they show a significant increase in either elapsed time in open arms (seconds) or in numbers entering open arms when compared to control animals. . The minimum effective dose (MED) was determined based on the elapsed time in the open arm for each compound tested. The results obtained are shown in Table III.
Buspirone is used as a control (reference) substance.

[0127]

[Table 3]

From Table III, it can be seen that the compound of Example 25 is superior to buspirone in the above test by one order of magnitude, characterized by anxiolytic effects. It should be noted that buspirone, which binds strongly to the 5-HT _1A receptor, is widely used in therapeutic practice.

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

Many therapeutic and pre-treatment studies suggest that the 5-HT _1A receptor has a role in different pathophysiological processes. In this study, buspirone, used as a control and acting via the 5-HT _1A receptor, inhibited the aggressive behavior of the rhesus monkey / Tomkins, EC, Clemento, AJ, Taylor, DP, Perlach, J. et al. , Re
s. Commun, Physiol. Psychiat. Behav., 5 , 337 (1980) /
Showed an anti-anxiety effect / Goldberg, HL and Finnerty, RJ, Am., J. Psychiatg
ry, 136 , 1184 (1979) /. In this experiment, some compounds of the present invention are superior to the anti-anxiety activity of buspirone.

5-HT_1AThe ligand is also a test model using experimental animals,
5-HT_1AReceptors also play a role in depression treatment patterns
Assume to Stand / Porsolt, R.D., Roux, S. and Wetstein, J.G., Pharmacol. Res., 31 , 169 (1995). A further therapeutic potential is 5-HT_1AFor drugs that work on receptors
Even consist of the treatment of nutritional deficiencies. 8-hydroxy-N, N-dipropyl-2-a
Administration of minotetralin to rats improves memory and learning abilities / Carli,
M. and Samanin, R., Br. J. Pharmacol.,105, 720 (1992) /. In addition to the above treatment patterns
Well, 5-HT_1AIn the case of active substances acting via receptors, various nutritional diseases
Can be used. This hypothesis states that under certain conditions, 5-HT_1AThrough the receptor
Acting, 8-hydroxy-N, N-diphenyl-2-aminotetralin
Based on the fact that, while increasing food intake, under other conditions, reduce food intake
Dourish, C.T., Hutson, P.H. and Curson, G., Brain Res. Bull.,15, 377
(1985) /. Accordingly, the compounds of the present invention may be used to treat anxiety, depression, cognitive deficits or nutritional disorders.
Effective in several treatment patterns associated with diseases of the central nervous system, such as those with disease
Can be.

The above hypothesis is also confirmed by the following test.

[0133] 3. Measurement of anti-anxiety effect based on Vogel's collision test

The anti-anxiety effect was measured by Vogel et al./Vogel, JR, Beer, B., Clody, DE, Psychopharmacol
ogia (Berl.), 21 , 1 (1971) /. Weighing 180-200g
Male Wistar rats were left thirst for 48 hours and prior to testing,
Starved for 24 hours. The substance to be tested and the carrier were each administered to the experimental animals one and a half hours before the experiment. In the test room, the rats are allowed to drink from a beverage tube that extends into the test room. The device generates a 0.7 mA electric shock via the drinking tube every 20 licks. During the test, which lasted for 5 minutes, the number of these electric shocks the animals performed to satisfy their thirst was recorded. The effect of the compound is
It was displayed as an increase in the number of allowable electric shocks. The minimum effect dose (MED) was determined for each compound.

Meprobamate / 2-methyl-2-propyltrimethylene carbamate /
Used as a control. The results obtained are shown in Table IV.

[0136]

[Table 4]

From Table IV it is clear that the benzofuran derivatives tested were superior to the effect of meprobamate as a control in the vogel impact test by a factor of two or more. Briefly, the above tests consistently show that the compounds of the present invention have valuable effects on the heart. At the same time, due to the mechanism of action, the compounds of the invention
It is suitable for treating diseases of the central nervous system, such as depression, anxiety, cerebral ischemia, schizophrenia and the like.

Accordingly, the novel benzofuran derivatives of the present invention can be used as an active ingredient in a pharmaceutical composition.

The pharmaceutical compositions of the present invention contain a therapeutically active amount of Formula I, or a pharmaceutically suitable 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 are suitable for topical devices, and may be solid or liquid.

Solid pharmaceutical compositions suitable for oral administration include powders, capsules, tablets, coated tablets, microcapsules and the like as carriers, and binders such as gelatin, sorbitol, poly (vinyl-pyrrolidone) and the like. Fillers such as lactose, starch, calcium phosphate, etc .; auxiliary for tableting, such as magnesium stearate, talc, poly (ethylene glycol), silica, etc .; having a wetting agent, such as sodium lauryl sulfite. Can be.

Pharmaceutical compositions suitable for oral administration can be solutions, suspensions, or emulsions and, as carriers, suspending agents such as gelatin, carboxymethyl cellulose, and the like.
Sorbitan has emulsifiers such as oleate, water, oil, solvents such as glycerol, propylene glycol, ethanol, etc., and preservatives such as methyl p-hydroxybenzoic acid.

Pharmaceutical compositions suitable for oral administration generally comprise a sterile solution of the active ingredient.

The above dosage forms and other dosage forms are known and include, for example, Remington's Pharmac.
See eutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990).

The pharmaceutical compositions of the present invention generally contain from 0.1 to 95.0% by weight of a compound of formula I or a pharmaceutically suitable acid addition salt thereof. The dosage for adult patients is from 0.1 to 1000 mg of the compound of formula I or a pharmaceutically suitable acid addition salt thereof per day. The above dosages can be administered in one or more portions. The actual dosage will depend on many factors, and will be decided by the physician.

The pharmaceutical compositions of the present invention comprise mixing a compound of Formula 1 or a pharmaceutically suitable acid addition salt thereof with one or more carriers, and combining the resulting mixture with known pharmaceutical methods by known methods. It is manufactured by converting into a chemical composition. Useful methods are described in the literature: for example, R
See emington's Pharmaceutical Science.

[0147] Suitable subgroup of pharmaceutical compositions of the present invention, as active ingredient, a benzofuran derivative of the formula I (where, R ¹ is hydrogen atom or C _{1 ~ 4} alkyl group, R ² is X is an oxygen atom; Y is a hydrogen atom or hydroxy; Z is a hydrogen atom, a halo atom or a nitro group; and A is a group represented by the formula CH, COH or C-CN. B is a methylene group, or

A forms together with B a group of the formula -C = C-, wherein Ar is phenyl, substituted by hydrogen, benzyl, substituents R ⁵ , R ⁶ and R ⁷
Group, a biphenyl group, a naphthyl group (provided that optionally substituted with C _{1 ~ 4} alkoxy group), or a thienyl group, wherein, R ^5, R ⁶ and R ⁷ independently of one another, a hydrogen atom , halo atoms, trifluoromethyl group, C _{1 ~ 4} alkyl group, C _{1 ~ 4} alkoxy group, C _{2 ~ 4} alkenyloxy group, a phenoxy group or a methylenedioxy group), or acceptable acid their pharmaceutically Addition salt

Suitably, within the above subgroup, the pharmaceutical composition of the present invention is a benzofuran derivative of the formula I wherein R ¹ is a methyl group, R ² is a hydrogen atom, X is an oxygen atom, Y is hydroxy, Z is a hydrogen atom, A represents a formula CH, COH or C-CN, B is a methylene group, or A is , B together form a group -C = C-, wherein Ar is a phenyl group optionally substituted with a halo atom, a trifluoromethyl group, a methyl group or a methoxy group; or a methoxynaphthyl group) or Has a pharmaceutically acceptable acid addition salt.

Further, a preferred sub-group of the pharmaceutical compositions of the present invention is that of the formula:
A piperazinylalkylbenzofuran derivative of Ia (provided that R¹Is C_{1 ~ Four}Alkyl, R^TwoIs a hydrogen atom, X is an oxygen atom, Y is hydroxy, Z is a hydrogen atom, Ar 'is a diphenylmethyl group, a pyridyl group, partially saturated, and a phenyl group
A 5- or 6-membered heterocyclic group fused and containing two oxygen atoms;
Substituent R^Five, R⁶And R⁷A phenyl group substituted by^Five, R⁶ And R⁷Is independently of each other a hydrogen atom, a halo atom, a trifluoromethyl group,_{1 ~ Four} Alkyl group, C_{1 ~ Four}An alkoxy group or a methylenedioxy group, and n is 0 or 1) or a pharmaceutically acceptable acid addition salt thereof.
Things.

Suitably, within the above subgroups, preferred subgroups of the pharmaceutical compositions of the present invention are, as active ingredients, piperazinylalkylbenzofuran derivatives of formula Ia wherein R ¹ is methyl R ² is a hydrogen atom, X is an oxygen atom, Y is hydroxy, Z is a hydrogen atom, Ar ′ is a diphenylmethyl group, a pyridyl group, a benzo-1 , 3-dioxolanyl group, 1 or 2 halo atoms, 1 or 2 methyl groups, methylenedioxy group, phenyl group optionally substituted with trifluoromethyl group or methoxy group, and n is , 0 or 1) or their pharmaceutically acceptable acid addition salts.

A particularly preferred pharmaceutical composition of the present invention has the following benzofuran derivative or a pharmaceutically suitable acid addition salt thereof as an active ingredient. 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4- (3-trifluoro-methylphenyl) -1,2,3,6 -Tetrahydropyridine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4- (3-trifluoro-methylphenyl) Piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4- (4-trifluoro-phenyl) piperidine, 1 -/ 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4-phenyl- Peridine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (3-chloro-phenyl) piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4- (3-methoxy-phenyl) piperidine, 1- / 3- ( 2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (4-methoxy-phenyl) piperidine, 1 / 3- (2,2- Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4- (3-trifluoromethyl-phenyl) piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4- (4-methyl-phenyl) piperidine, 1- / 3- ( 2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-cyano-4-phenyl-piperidine, 1 / 3- (2,2-dimethyl-2,3 -Dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (4-chloro-phenyl) 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-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-dihydride - benzofuran-7-yloxy) -2-hydroxypropyl / -4- (benzo-1,3-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, 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

Furthermore, the present invention relates to a method of treating a therapeutically effective and non-toxic amount of a benzofuran derivative of the formula I or a pharmaceutically acceptable acid addition salt thereof, in particular for atrial or central nervous system diseases. A method of treating a disease by administering to a patient suffering from the disease.

The present invention is further embodied by the following examples. Preparation of halides of formula II

1) 7- (3-Bromopropyloxy) -2,2-dimethyl-2,3-dihydrobenzofuran 32.8 g (0.2 mol) of 2,2-dimethyl-2 in 600 ml of acetone.
80.8 g (0.4 mol) in a solution of 2,3-dihydrobenzofuran-7-ol
Of 1,3-dibromopropane and 83.0 g (0.6 mol) of anhydrous potassium carbonate are added, and the reaction mixture is added with stirring for 24 hours. After cooling, the inorganic salts are filtered off and the filtrate is evaporated to dryness under reduced pressure. The residual product is recrystallized from methanol, filtered and dried at room temperature. In this way, 34.7 g (61%) of the title compound are obtained. Melting point: 54
~ 56 ° C.

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

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

In this way, 20.4 g (99%) of the title compound are obtained. After recrystallization from methanol, melting point: 49-50 ° C.

B) 7-acetoxy-5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran 16.0 g (0.1 mol) of bromine in 40 ml of glacial acetic acid are added in 150 ml of chloroform. To a solution of 20.6 g (0.1 mol) of 7-acetoxy-2,2-dimethyl-2,3-dihydrobenzofuran while stirring and cooling to a temperature of 15-20 ° C. for 30 minutes. . The resulting solution is stirred for 15 minutes and then evaporated to dryness under reduced pressure. The residual honey product is triturated with 150 ml of ice-water, the precipitated crystals are filtered and then washed with ice-water until neutral. The crystals thus obtained are suspended at 0 ° C. in 80 ml of methanol, filtered again and dried under reduced pressure.

In this way, 22.0 g (77%) of the title compound are obtained. Melting point: 76
° C.

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

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

D) 5-bromo-2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran 19.9 g (0.082 mol) in 60 ml of 10% aqueous sodium hydroxide solution
To a solution of 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 13.65 g (0.147 mol) of epichlorohydrin was added and the reaction mixture was heated to 45-50 ° C. And stir 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 in each case 20 ml of water, and anhydrous sodium sulfate is extracted. Dry over salt, filter and evaporate to dryness under reduced pressure.

In this way, 23.5 g (98%) of the title compound are obtained as a honey which is used directly for the preparation of the compounds of the formula (I). On standing for a long time, the product crystallizes, melting point: 46-48 ° C.

3) 2,5.0-dimethyl-5-nitro-7-oxiranylmethoxy-2,3-dihydrobenzofuran 15.0 g (0.09 mol) in 100 ml of a 10% aqueous sodium hydroxide solution.
To a solution of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in
0.0 g (0.216 mol) of epichlorohydrin is added and the reaction mixture is stirred at 48-50 ° C. for 2.5 hours. After cooling, the separated oil was added to 10
Dissolve in 0 ml of dichloromethane, extract the aqueous phase with 50 ml of dichloromethane, extract the combined organic phases twice with 20 ml of water each time, dry over anhydrous sodium sulphate, filter and Evaporate to dryness under reduced pressure. The title compound is
Obtained as a thick honey-like substance and polished with 60 ml of n-hexane to give white crystals. The precipitated crystals are filtered and dried under reduced pressure.

In this way, 19.5 g (97%) of the title compound are obtained. Melting point: 51
~ 52 ° C.

4) 2,2-Dimethyl-5-nitro-7-oxiranylmethoxy-2,3-dihydrobenzofuran 0.35 g of 82% m-chloroperbenzoic acid in 0.24 g of 5 ml of dichloromethane ( (0.001 mol) of 2,2-dimethyl-7- (2-propenyloxy) -2,3-dihydrobenzofuran and the reaction mixture is stirred for 10 hours. To the reaction mixture, 5 ml of a 10% aqueous sodium hydroxide solution are added, the phases are separated, the organic phase is dried over anhydrous sodium sulphate, filtered and the solvent is eliminated in vacuo. . The residual oily product is purified by column chromatography (the column is packed with silica gel and eluted with 24 volumes of dichloromethane and 1 volume of acetone).

Thus, 0.068 g (31%) of the title compound is obtained. Melting point: 4
9-51 ° 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 was added 6 ml (0.08
6 mol) of anhydrous acetic acid with stirring and cooling to 15-20 ° C. for 30 minutes,
Added. To the resulting stirred and cooled solution, 4 ml (5.53 g,
0.06 mol) of concentrated nitric acid (density: 1.42; 62%) is added dropwise over a period of 30-40 minutes, taking care that the temperature of the mixture is within 25-28 ° C. To the reaction mixture stirred for a further 10 minutes, 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 Then, the solvent is removed under reduced pressure. The crystalline product obtained is suspended in 40 ml of methanol at a temperature of 0 ° C., filtered and dried under reduced pressure.

In this way, 14.8 g (74%) of the title compound are obtained. Melting point: 14
2-143 ° C.

B) 2,3-Dimethyl-5-nitro-2,3-dihydrobenzofuran-7-ol 13.3 g (0.053 mol) of 7-acetoxy-2,2-dimethyl-5-nitro-2 , 3-Dihydrobenzofuran in 42.5 ml of methanol and 42.
In a mixture of 5 ml of a 10% aqueous sodium hydroxide solution at 20-25 ° C., 30
Stir for minutes. The purple solution obtained is acidified to pH 1 with concentrated hydrochloric acid, the methanol is distilled off under reduced pressure and the residue is extracted with 50 ml of dichloromethane. The phases are separated and the aqueous phase is extracted twice with in each case 25 ml of dichloromethane. The combined organic phases were extracted twice with in each case 20 ml of water to remove the acid and furthermore
Dry over anhydrous sodium sulfate, filter and evaporate to dryness under reduced pressure. The residue is triturated with n-hexane, the crystalline material obtained is filtered and then dried under reduced pressure.

In this way, 10.8 g (97.8%) of the title compound are obtained. Melting point:
96-97 ° C.

C) 2,2-Dimethyl-5-nitro-7-oxiranylmethoxy-2,3-dihydrobenzofuran 14.5 g (0.156 mol) of epichlorohydrin in 62 ml of 10% aqueous sodium hydroxide solution Of 2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-7-ol is added and the reaction mixture is heated at 48-52 ° C.
Stir for 2.5 hours. After cooling, the oily isolate is dissolved in 60 ml of dichloromethane, the aqueous phase is extracted twice with in each case 60 ml of dichloromethane and the combined organic phases are extracted twice with in each case 20 ml of water. Extract, dry over anhydrous sodium sulfate, filter, and evaporate to dryness under reduced pressure. The residue is polished with n-hexane and then dried under reduced pressure.

In this way, 13.3 g (96.7%) of the title compound are obtained. Melting point:
108 ° C (after recrystallization from methanol)

6) 2,2-Dimethyl-7- (2-allyloxy) -2,3-dihydrobenzofuran 8.20 g (0.05 mol) of 2,2-dimethyl- in 100 ml of acetone
To the 2,3-dihydrobenzofuran-7-ol solution, 12.1 g (0.12 mol) of metaaryl bromide and 20.75 g (0.15 mol) of anhydrous potassium carbonate were added, and the reaction mixture was stirred. Bring to a boil for 12 hours. After cooling, the inorganic salts are filtered off and the filtrate is evaporated under reduced pressure to remove the solvent. The residual oily product is purified by vacuum distillation.

In this way, 9.20 g (90%) of the title compound are obtained. Melting point: 77
° C / 53.3Pa.

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

In this way, 8.90 g (87%) of the title compound are obtained. Melting point: 77
° C / 53.3Pa.

Preparation of Compounds of Formula X 8) 2,2-Dimethyl-7- (2-methyl-2-propenyloxy) -2,3-
Dihydrobenzofuran

24.6 g (0.15 mol) of 2,2-dimethyl- in 350 ml of acetone
27.1 g (0.3 mol) in 2,3-dihydrobenzofuran-7-ol solution
Of metaaryl chloride and 62.25 g (0.45 mol) of anhydrous potassium carbonate are added and the reaction mixture is boiled for 22 hours with stirring. After cooling, the inorganic salts are filtered off and the filtrate is evaporated under reduced pressure to remove the solvent. The residual oily product is purified by vacuum distillation.

In this way, 25.0 g (76.5%) of the title compound are obtained. Melting point:
80-83 ° C / 27-40 Pa.

Preparation of Benzofuran Derivatives of Formula (I)

[0185]

Example 1 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl / 4- (4-methoxyphenyl) -1,2,3,6 Tetorahidoropi lysine Hydrochloride 4.0 g (0.14 mol) of 7- (3-bromo) in 60 ml of dichloromethane.
Propoxy) -2,2-dimethyl-2,3-dihydrobenzofuran solution
. 28 g (0.012 mol) of 4- (4-methoxyphenyl) -1,2,3,6
Add tetrahydropyridine hydrochloride and 12 ml of 10% aqueous sodium hydroxide solution. The reaction mixture is stirred at room temperature for 12 hours, then the two phases are separated. The organic phase is extracted twice with in each case 50 ml of water, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure and the solvent is eliminated. The residue is dissolved in 30 ml of ethanol containing 5% hydrogen chloride and evaporated to dryness under reduced pressure on a water bath. The residual product is triturated with 40 ml of ethyl acetate and the precipitated crystalline product is filtered.

In this way, 3.75 g (72.8%) of the title compound are obtained. Melting point:
165 ° C.

[0187]

Example 2 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl / -4- (4-methoxyphenyl) -1,2,3,6-tetrahydro pyridine 2.15 g (0.005 mol) of 1- / 3- (2,2-dimethyl-2,3-dihydride
Robenzofuran-7-yloxy) propyl / -4- (4-methoxyphenyl)
Stir -1,2,3,6-tetrahydropyridine hydrochloride, 20 ml of dichloromethane and 3 ml of 10% aqueous sodium hydroxide solution for 10 minutes. Next, the two phases are separated. The organic phase is extracted twice, each time with 5 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The evaporation residue is recrystallized from a small amount of ethanol.

In this way, 1.54 g (78.5%) of the title compound are obtained. Melting point:
96-97 ° C.

[0189]

Example 3 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl / 4- (4-methoxyphenyl) -1,2,3,6 Tetorahidoropi lysine Hydrochloride 3.0 g (0.0105 mol) of 7- (3-
To a solution of (bromopropoxy) -2,2-dimethyl-2,3-dihydrobenzofuran, 2.07 g (0.01 mol) of 4-hydroxy-4- (4-methoxyphenyl) piperidine and 5 ml of 10% hydroxylated solution. An aqueous sodium solution is added. The reaction mixture is stirred at room temperature for 14 hours. The phases are then separated and the organic phase is extracted twice, each time 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) is dissolved at 40 ° C. in 30 ml of ethanol containing 5% hydrogen chloride and the resulting solution is evaporated under reduced pressure at the above temperature. The residue is triturated with 30 ml of ethyl acetate, filtered and dried under reduced pressure.

In this way, 2.79 g (85%) of the title compound are obtained. Melting point: 16
5 ° C.

[0191]

Example 4 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl / 4- (4-methoxyphenyl) -1,2,3,6 Tetorahidoropi lysine 0.83 g (0.002 mol) of the hydrochloride salt of 1- / 3- (2,2-dimethyl-2,3-dihydrogen
Robenzofuran-7-yloxy) propyl / 4- (4-methoxyphenyl)-
The 1,2,3,6-tetrahydropyridine is stirred in 10 ml ethanol containing 5% hydrogen chloride at 40 ° C. for 5 minutes, then the solution is polished with 30 ml ethyl acetate, Filter and dry under reduced pressure.

Thus, 0.35 g (43%) of the title compound is obtained. Melting point: 11
6-117 ° C.

[0193] 1

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

In this way, 3.86 g (82.5%) of the title compound are obtained. Melting point:
186-187 ° C.

[0195]

Example 6 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl / 4-hydroxy-4- (3-trifluoromethylphenyl) -1,2,3 3.00 g (0.0105 mol) of 7- (3-, 3 -tetrahydropyridine hydrochloride in 50 ml of dichloromethane.
To a solution of (bromopropoxy) -2,2-dimethyl-2,3-dihydrobenzofuran, 2.63 g (0.01 mol) of 4- (3-trifluoromethylphenyl)-
1,2,3,6-Tetrahydropyridine hydrochloride and 10 ml of 10% aqueous sodium hydroxide solution are added. The reaction mixture is stirred at room temperature for 24 hours, then the phases are separated. The organic phase is extracted twice, each time with 10 ml of water each time, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure and the solvent is eliminated. Residue (4
. 68 g) are dissolved in 20 ml of ethanol containing 5% hydrogen chloride and evaporated to dryness on a water bath under reduced pressure. The crystalline residue is triturated with ethanol, filtered and dried under reduced pressure.

In this way, 3.86 g (82.5%) of the title compound are obtained. Melting point:
186-187 ° C.

[0197]

Example 7 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl / 4-hydroxy-4- (3-trifluoromethyl - phenyl) piperazino-lysine monohydrochloride 50ml 3.00 g (0.0105 mol) of 7- (3-
To a solution of (bromopropoxy) -2,2-dimethyl-2,3-dihydrobenzofuran, 2.45 g (0.01 mol) of 4-hydroxy-4- (3-trifluoromethylphenyl) piperidine and 5 ml of 10% An aqueous sodium hydroxide solution is added. The reaction mixture is stirred at room temperature for 24 hours, then the phases are separated. The organic phase is extracted twice, each time with 10 ml of water each time, dried over anhydrous sodium sulphate, filtered and
Evaporate under reduced pressure to remove the solvent. The residue (4.91 g) is dissolved in 20 ml of ethanol containing 5% hydrogen chloride and the solution is again evaporated under reduced pressure. The crystalline residue is triturated with ether, filtered and dried under reduced pressure.

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

[0199]

Example 8 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxy / 4- (3-trifluoromethylphenyl) -1,2,3,3 6-tetrahydropyridine hydrochloride 1.20 g (0.0055 mol) of 2,2-in 10 ml of isopropanol
In a dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran solution,
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 solution are added. The reaction mixture is boiled for 5 hours and evaporated under reduced pressure. The residue is partitioned between 15 ml of dichloromethane and 10 ml of water.
The organic phase is extracted twice, each time with 10 ml of water, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure and the solvent is eliminated.

The residue (2.42 g) is dissolved in 15 ml of ethanol containing 5% of hydrogen chloride and the resulting solution is distilled again under reduced pressure. The crystalline residue is polished in ethanol, filtered and dried under reduced pressure.

In this way, 2.02 g (83.5%) of the title compound are obtained. Melting point:
160-162 ° C (recrystallized from isopropanol).

[0202]

Example 9 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4- (3-trifluoromethylphenyl ) piperidine hydrochloride 3. To a solution of 4.40 g (0.02 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of isopropanol salt .
90 g (0.02 mol) of 4-hydroxy-4- (3-trifluoromethylphenyl) piperidine are added. The reaction mixture is boiled for 6 hours and then evaporated to dryness under reduced pressure. The oily residue is dissolved in 15 ml of methanol and to the cooled solution a mixture of 3 ml of concentrated hydrochloric acid and 3 ml of water is added at room temperature of 15-20 ° C. The precipitated crystals are filtered, washed with cold methanol and evaporated under reduced pressure.

[0203] In this way, 8.06 g (86%) of the title compound are obtained. Melting point: 15
6-158 ° C (recrystallized from isopropanol).

[0204]

Example 10 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / 4- (4-chlorophenyl) -1,2,3,6- Tetrahydropyridine hydrochloride In a solution of 2.80 g (0.013 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of isopropanol, 2
. 30 g (0.01 mol) of 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride and 2.2 ml of a 20% aqueous sodium hydroxide solution are added. The reaction mixture is boiled for 6 hours and then evaporated under reduced pressure. The residue is subjected to a partition between 20 ml of methanol and 10 ml of water and the organic phase is separated twice for each time.
Extract twice with 0 ml of water, dry over anhydrous sodium sulphate, evaporate under reduced pressure and remove the solvent.

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

In this way, 3.48 g (77.3%) of the title compound are obtained. Melting point:
164-166 ° C (recrystallized from isopropanol).

[0207]

Example 11 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / 4- (2-thienyl) -1,2,3,6- in dichloromethane tetrahydropyridine hydrochloride 20 ml, 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran solution of 2.80 g (0.013 mol), 2.
04 g (0.01 mol) of 4- (2-thienyl) -1,2,3,6-tetrahydropyridine hydrochloride and 2.2 ml of a 20% aqueous sodium hydroxide solution are added.
The reaction mixture is boiled for 6 hours and then evaporated under reduced pressure. Residue, 20m
After partitioning between 1 l of chloroform and 20 ml of water, the organic phase is extracted twice, each time with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. And remove the solvent. The residue contains 10% hydrogen chloride,
Dissolve in 15 ml of ethanol and evaporate the resulting solution to dryness under reduced pressure. The crystalline residue is triturated with ethanol, filtered and dried under reduced pressure.

In this way, 3.50 g (82%) of the title compound are obtained. Melting point: 18
0 ° C.

[0209]

Example 12 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / 4- (4-fluorophenyl) -1,2,3,6 Tetrahydropyridine hydrochloride In a solution of 2.80 g (0.013 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of dichloromethane.
13 g (0.01 mol) of 4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride and 2.2 ml of a 20% aqueous sodium hydroxide solution are added. The reaction mixture is boiled 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 separated
Each time, extract with 20 ml of water each time, dry over anhydrous sodium sulfate, filter, evaporate under reduced pressure and remove the solvent. The residue is dissolved in 15 ml of ethanol containing 10% hydrogen chloride and the resulting solution is again evaporated to dryness under reduced pressure. The crystalline residue is triturated with ethanol, filtered and dried under reduced pressure.

In this way, 3.2 g (73.8%) of the title compound are obtained. Melting point: 1
53-155 ° C.

[0211]

Example 13 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / 4-benzylpiperidine hydrochloride Dimethyl-7-oxiranyl-meth
Toxi) -2,3-dihydrobenzofuran solution, 2.62 g (0.015 mol) of 4-benzylpiperidine are added. The reaction mixture is boiled for 6 hours and then evaporated under reduced pressure. The residue is partitioned between 20 ml of chloroform and 20 ml of water, and the organic phase is extracted twice, each time with 20 ml of water each time,
Dry over anhydrous sodium sulfate, filter, evaporate under reduced pressure and remove the solvent. The residue is dissolved in 15 ml of ethanol containing 10% hydrogen chloride and the resulting solution is evaporated to dryness under reduced pressure. The crystalline residue is triturated with ethanol, filtered and dried under reduced pressure.

In this way, 2.67 g (62%) of the title compound are obtained. Melting point: 13
0-132 ° C.

[0213]

Example 14 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4- (4-chlorophenyl) -piperidine 30 ml of isopropanol 3.40 g (0.015 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran solution in
. 15 g (0.015 mol) of 4-hydroxy-4- (4-chlorophenyl) piperidine are added. The reaction mixture is boiled for 6 hours, cooled, the precipitated crystals are filtered, washed with isopropanol and dried under reduced pressure.

In this way, 5.40 g (83.4%) of the title compound are obtained. Melting point:
148-150 ° C (recrystallized from acetone).

[0215]

Example 15 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4- (4-chlorophenyl) pin Perijin hydrochloride 0 0.89 g (0.002 mol) of 1- / 3- (2,2-dimethyl-2,3-dihydro
Benzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-
Dissolve 4- (4-chlorophenyl) piperidine in 10 ml of methanol,
Then, to the resulting solution, 2 ml of methanol containing 5% hydrogen chloride is added while cooling with ice. The solution is evaporated to dryness under reduced pressure, the crystalline residue is triturated with ethanol, filtered and dried under reduced pressure.

In this way, 0.87 g (93%) of the title compound are obtained. Melting point: 17
2-174 ° C.

[0219]

Example 16 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy - (4-fluorophenyl) isopropanol peak Perijin 30ml To a solution of 3.4 g (0.015 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran.
53 g (0.013 mol) of 4-hydroxy-4- (4-fluorophenyl) piperidine are added and the reaction mixture is boiled for 4 hours. Isopropanol was distilled off under reduced pressure, and the residue was treated with 120 ml of petroleum ether (boiling point: 60 ° C
), Filter the precipitated crystals, wash with a mixture of 1 volume acetone and 4 volumes of petroleum ether and dry under reduced pressure.

In this way, 4.55 g (84%) of the title compound are obtained. Melting point: 14
7-148 ° C (after recrystallization from ethanol).

[0219]

Example 17 1- / 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-dihydro
Benzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-
4- (4-Fluorophenyl) piperidine is dissolved in 10 ml of methanol and the resulting solution is treated with 2 ml of methanol containing 5% hydrogen chloride.
Add while ice cooling. The solution is evaporated to dryness under reduced pressure, the crystalline residue is triturated with ethanol, filtered and dried under reduced pressure.

In this way 0.79 g (87.5%) of the title compound is obtained. Melting point:
173-175 ° C.

[0221]

Example 18 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4-phenyl) -1,2,3,6 Tetorahido Ropirijin 1.40 g (0.0063 mol) of 2,2- hydrochloride in 10 ml of isopropanol
In a solution of dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran,
0.98 g (0.005 mol) of 4- (4-phenyl) -1,2,3,6-tetrahydropiperidine hydrochloride and 1.1 ml of a 20% aqueous sodium hydroxide solution are added. The reaction mixture is boiled for 5 hours and then fractionally distilled under reduced pressure. The residue is 1
Partition between 0 ml of chloroform and 10 ml of water and separate the organic phase for 1
Extract twice with 0 ml of water, dry over anhydrous sodium sulfate, filter,
Then, the solvent is evaporated under reduced pressure to remove the solvent. The residue containing 5% hydrogen chloride,
Dissolve in 15 ml of ethanol and evaporate the resulting solution under reduced pressure. The crystalline residue is triturated with ethanol, filtered and dried under reduced pressure.

In this way, 1.93 g (92.8%) of the title compound are obtained. Melting point:
166-167 ° C.

[0223]

Example 19 1.30 g (0.0105 mol) of 1 / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / piperidine in 10 ml of isopropanol 2,2-
In a solution of dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran,
0.85 g (0.01 mol) of piperidine are added. The solution obtained is boiled for 3 hours, cooled and 20 ml of ethanol containing 5% hydrogen chloride are added.
Add while cooling to 15-20 ° C. The reaction mixture is evaporated to dryness under reduced pressure. The residue is recrystallized from a mixture of ethanol and ether, the separated crystals are filtered, washed with ether and dried under reduced pressure.

In this way, 2.60 g (76%) of the title compound are obtained. Melting point: 12
8-130 ° C.

[0225]

Example 20 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4-phenyl - ethanol piperidine salt salt 20ml 3.3 g (0.015 mol) of 2,2-dimethyl-
2.5 g (7-oxiranylmethoxy-2,3-dihydrobenzofuran solution)
0.014 mol) of 4-hydroxy-4-phenylpiperidine. The resulting solution is boiled for 3 hours, then cooled to 15 ° C., and containing 1% hydrogen chloride containing 1%.
0 ml of ethanol is added while cooling to 15-20 ° C. 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.

In this way, 3.62 g (60%) of the title compound are obtained. Melting point: 17
6-177 ° C.

[0227]

Example 21 1.4 g of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4-phenyl-piperidine (0. 003 mol) of 1- / 3- (2,2-dimethyl-2,3-dihydrobe
(Nzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4
Dissolve phenylpiperidine hydrochloride in 50 ml of warm water and add 5 ml of 10% aqueous sodium hydroxide solution to the resulting solution. The precipitated crystals are filtered, washed with water and then recrystallized from methanol.

In this way, 1.00 g (78%) of the title compound are obtained. Melting point: 12
7-129 ° C.

[0229]

Example 22 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4- (2-methoxyphenyl) - piperidine salt salt 30ml 3.40 g (0.0153 mol) of 2,2-in isopropanol
In a solution of dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran,
3.10 g (0.015 mol) of 4-hydroxy-4- (2-methoxy-phenyl) piperidine are added. The reaction mixture is boiled for 5 hours, cooled to 15.degree.
4 ml of ethanol containing 5% hydrogen chloride are added while cooling to 15-20 ° C. The solution obtained is evaporated to dryness under reduced pressure and the residue is recrystallized from a mixture of ethanol and ether. The precipitated crystals are filtered and dried under reduced pressure.

In this way, 4.73 g (68%) of the title compound are obtained. Melting point: 10
2-104 ° C.

[0231]

Example 23 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4- (6-methoxynaphth-2-yl) Piperi Jin hydrochloride In a solution of 2.42 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of salt in ethanol, 2.6 g was added.
(0.01 mol) of 4-hydroxy-4- (6-methoxynaphth-2-yl) piperidine is added. The resulting solution is boiled for 6 hours, cooled to 15 ° C.,
3 ml of ethanol containing hydrogen chloride are added. The reaction mixture is evaporated to dryness under reduced pressure and the residue is triturated with ether. The precipitated crystals are filtered, recrystallized from a mixture of ethyl acetate and ethanol, again and evaporated under reduced pressure.

In this way, 4.6 g (89.5%) of the title compound are obtained. Melting point: 1
25-127 ° C.

[0233]

Example 24 15 ml of 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 ethanol of
g (0.01 mol) of 4-hydroxy-4- (3-chlorophenyl) -piperidine are added. The solution obtained is boiled for 6 hours, cooled to 15 ° C. and 3 ml of ethanol containing 15% hydrogen chloride are added while cooling to 15 ° C. to 20 ° C. The reaction mixture is evaporated to dryness under reduced pressure and the residue is triturated with ether. The precipitated crystals are filtered, recrystallized from a mixture of ethyl acetate and ethanol and dried under reduced pressure.

In this way, 3.64 g (77.8%) of the title compound are obtained. Melting point:
138-140 ° C.

[0235]

Example 25 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (3-methoxyphenyl ) -piperidine hydrochloride 3.80 g (0.0173 mol) of 2,2-in 30 ml of salt in isopropanol
In a solution of dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran,
3.10 g (0.015 mol) of 4-hydroxy-4- (3-methoxyphenyl) -piperidine are added. The solution obtained is boiled for 4 hours and then evaporated to dryness under reduced pressure. The residue is dissolved in 40 ml of ethyl acetate, cooled to 15 ° C.
6 ml of ethanol containing 5% hydrogen chloride are added while cooling to 15-20 ° C. The reaction mixture is evaporated to dryness under reduced pressure and the residue is triturated with ether. The precipitated crystals are filtered, recrystallized from a mixture of acetone and ether, and
Dry under reduced pressure.

In this way, 5.90 g (84.8%) of the title compound are obtained. Melting point:
128-130 ° C.

[0237]

Example 26 20 ml of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (4-methoxyphenyl ) -piperidine 3.80 g (0.0173 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in ethanol in 3.1
0 g (0.015 mol) of 4-hydroxy-4- (3-methoxyphenyl) -piperidine are added. The solution obtained is boiled for 4 hours and 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.

In this way, 4.70 g (73.4%) of the title compound are obtained. Melting point:
144-146 ° C.

[0239]

Example 27 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (5-fluoro-2- menu butoxy Phenyl) piperidine hydrochloride was added to a solution of 3.80 g (0.0173 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol by 3.3.
7 g (0.015 mol) of 4-hydroxy-4- (5-fluoro-2-methoxyphenyl) -piperidine are added. The resulting solution is boiled for 6 hours, 15%
4 ml of ethanol containing hydrogen chloride are added while cooling to 15-20 ° C. The reaction mixture is evaporated to dryness under reduced pressure and the residue is triturated with 40 ml of ethyl acetate. The precipitated crystals are filtered and recrystallized from 40 ml of ethyl acetate.

In this way, 5.60 g (77.5%) of the title compound are obtained. Melting point:
156-158 ° C.

[0241]

Example 28 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (3-trifluoromethyl butylphenyl) piperidine To a solution of 3.96 g (0.018 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of the hydrochloride ethanol was 3.34.
g (0.015 mol) of 4- (3-trifluoromethylphenyl) piperidine hydrochloride and 2 ml of a 40% aqueous sodium hydroxide solution are added. The reaction mixture is boiled for 6 hours and evaporated to dryness under reduced pressure. The residue is partitioned between 30 ml of water and 50 ml of dichloromethane, the phases are separated and the organic phase is separated with 2 times 20 ml of water.
Wash once, dry over anhydrous sodium sulfate, filter and evaporate to dryness 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 separated crystals are filtered and evaporated to dryness under reduced pressure.

In this way, 5.15 g (77.1%) of the title compound are obtained. Melting point:
172-174 ° C.

[0243]

Example 29 20 ml of 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 ethanol was added 2.86.
g (0.015 mol) of 4-hydroxy-4- (4-methylphenyl) -piperidine are added. The resulting solution is boiled for 5 hours. After cooling, the solution was
Cool in an ice bath at 0 ° C., filter the precipitated crystals and evaporate to dryness under reduced pressure.

In this way, 5.17 g (83.8%) of the title compound are obtained. Melting point:
138-139 ° C.

[0245]

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-dihydrobe
(Nzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4
-/ 4-Hydroxy-4- (4-methylphenyl) piperidine is dissolved in 15 ml of methanol and to the ice-cooled solution is added 12 ml of methanol containing 5% hydrogen chloride. The solution was evaporated to dryness under reduced pressure and the crystalline residue was
Triturate with ether, filter and dry under reduced pressure.

In this way, 4.17 g (93%) of the title compound are obtained. Melting point: 16
4-166 ° C.

[0247]

Example 31 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4- (4-methoxyphenyl) -1,2,3, To a solution of 3.52 g (0.016 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 25 ml of 6-tetrahydropyridine in ethanol 3.37
g (0.015 mol) of 4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridine hydrochloride and 2 ml of a 40% aqueous sodium hydroxide solution are added. The reaction mixture is boiled for 6 hours, 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.

In this way, 6.1 g (92.8%) of the title compound are obtained. Melting point: 1
04-105 ° C (after recrystallization from petroleum ether having a boiling point of 120 ° C).

[0249]

Example 32 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4- (4-methoxyphenyl) -1,2,3,3 6-tetrahydropyridine hydrochloride (4.09 g, 0.01 mol) of 1- / 3- (2,2-dimethyl-2,3-dihydrobe
Nzofuran-7-yloxy) -2-hydroxypropyl / 4- (4-methoxy
Phenyl) -1,2,3,6-tetrahydropyridine is dissolved in 15 ml of methanol and to the ice-cooled solution is added 12 ml of methanol containing 5% hydrogen chloride. The solution is evaporated to dryness under reduced pressure, the crystalline residue is triturated with ether, filtered and dried under reduced pressure.

In this way, 4.05 g (91%) of the title compound are obtained. Melting point: 16
2-164 ° C.

[0251]

Example 33 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4- (4-methoxyphenyl) -1,2,3,3 6-tetrahydropyridine hydrochloride 1.10 g (0.0025 mol) of 1- / 3- (2,2-dimethyl-2,3-dihydrogen
Robenzofuran-7-yloxy) -2-hydroxypropyl / 4- (4-metho
(Xyphenyl) -1,2,3,6-tetrahydropyridine in 5 ml of 20%
Dissolve in ethanol containing hydrogen chloride and boil the solution for 10 minutes. After cooling, the precipitated crystals are filtered, washed with ether and dried under reduced pressure.

Thus, 0.98 g (93%) of the title compound is obtained. Melting point: 16
1-163 ° C.

[0253]

Example 34 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (3,5-dimethyl-4 - Methoxyphenyl) piperidine hydrochloride was added to a solution of 3.60 g (0.0165 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol by 3.4.
5 g (0.015 mol) of 4-hydroxy-4- (3,5-dimethyl-4-methoxyphenyl) -piperidine are added. The reaction mixture is reacted at 55-60 ° C. for 2 hours, then cooled to 0 ° C. and 5 ml of ethanol containing 10% hydrogen chloride are added with cooling. The reaction mixture is evaporated to dryness under reduced pressure and the residue is triturated with ether. The precipitated crystals are filtered and dried under reduced pressure.

In this way, 6.42 g (87%) of the title compound are obtained. Melting point: 92
~ 96 ° C.

[0255]

Example 35 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (3,5-dimethyl-4 - methoxyphenyl) piperidine hydrochloride 1.26g of (0.0057 mol) of 2,2-dimethyl-7-oxiranylmethoxy methoxide
To c-2,3-dihydrobenzofuran, 1.18 g (0.005 mol) of 4-hydroxy-4- (3,5-dimethyl-4-methoxyphenyl) -piperidine are added and the reaction mixture is added to 60%. Reaction for 1 hour. The melt is cooled, then dissolved in ether, and to the resulting solution is added 1 ml of ethanol containing 20% hydrogen chloride. The precipitated crystals are filtered, washed with ether and dried under reduced pressure.

In this way, 2.04 g (83%) of the title compound are obtained. Melting point: 94
~ 96 ° C.

[0257]

Example 36 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (3,4-Mechirenjio Kishifeniru) 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.
g (0.01 mol) of 4-hydroxy-4- (3,4-methylenedioxy-phenyl) piperidine hydrochloride and 4.2 ml of 10% aqueous sodium hydroxide solution are added. The reaction mixture is boiled for 5 hours and then evaporated to dryness under reduced pressure. Residue 2
The mixture is partitioned between 0 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is washed twice with in each case 20 ml of water, dried over anhydrous sodium sulphate, filtered and reduced in vacuo. Evaporate to dryness. The residue is recrystallized from a mixture of ethyl acetate and n-hexane, the precipitated crystals are filtered and dried under reduced pressure.

Thus, 3.01 g (73%) of the title compound are obtained. Melting point: 12
8-130 ° C.

[0259]

Example 37 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4- / 4- (2-methyl-2 4.8 g (0.022 mol) of 2,2 in 20 ml of diisopropyl ether in propenyloxyphenyl / piperidine
-Dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran solution
4.94 g (0.02 mol) of 4-hydroxy-4- / 4- (2-methyl-2
-Propenyloxy) phenylpiperidine is added. The reaction mixture is boiled for 6 hours, then cooled to 0 ° C., the precipitated crystals are filtered, washed with diisopropyl ether and dried under reduced pressure.

In this way, 7.95 g (85%) of the title compound are obtained. Melting point: 10
8-110 ° C.

[0261]

Example 38 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (4-biphenyl) 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.
g (0.01 mol) of 4-hydroxy-4- (4-biphenylyl) piperidine are added. The reaction mixture is stirred at 70 ° C. for 1 hour and then evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of ether and 1.5 ml of 2
Ethanol containing 0% hydrogen chloride is added with cooling. Filtering the precipitated crystals,
Wash with ether and dry under reduced pressure.

In this way, 4.45 g (87%) of the title compound are obtained. Melting point: 16
6-167 ° C.

[0263]

Example 39 1- / 3- (7-2,2-dimethyl-2,3-dihydrobenzofuran-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (4-aminophenoxy phenyl-) piperidine 16ml 2.64 g (0.012 mol) of a solution of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in ethanol at 2.70 g.
g (0.01 mol) of 4-hydroxy-4- (4-phenoxyphenyl) -piperidine are added. The reaction mixture is stirred at 70 ° C. for 1 hour and evaporated to dryness under reduced pressure. The residue is recrystallized from a small amount of methanol, filtered and dried under reduced pressure.

In this way, 4.47 g (91%) of the title compound are obtained. Melting point: 11
3-115 ° C.

[0265]

Example 40 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (4-chloro-3- trifluoro Methylphenyl) piperidine hydrochloride In 20 ml of ethanol, 3.90 g (0.0177 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran solution was added.
9 g (0.015 mol) of 4-hydroxy-4- (4-chloro-3-trifluoromethylphenyl) piperidine are added. The reaction mixture is 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 to the resulting solution is added 2.5 ml of ethanol containing 20% hydrogen chloride. The precipitated crystals are filtered and dried under reduced pressure.

In this way, 7.00 g (88%) of the title compound are obtained. Melting point: 14
6-148 ° C.

[0267]

Example 41 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4-cyano-4-phenylpiperidine hydrochloride in 15 ml of isopropanol In 0.20 g (0.005 mol) of sodium hydroxide solution, 1.21 g (0.0055 mol) of 2,2-dimethyl-7-oxo was added.
Silanylmethoxy-2,3-dihydrobenzofuran and 1.11 g (0.005
Mol) of 4-cyano-4-phenylpiperidine hydrochloride is added. The reaction mixture is boiled with stirring for 6 hours and evaporated to dryness under reduced pressure. Residue, 50
partition between 50 ml of water and 50 ml of dichloromethane, separate the phases, extract the organic phase twice with in each case 20 ml of water, dry over anhydrous sodium sulphate, filter and Evaporate to dryness under reduced pressure. The residue is dissolved in 50 ml of ether and to the resulting solution is added 1 ml of ethanol containing 20% hydrogen chloride. The precipitated crystals are filtered, washed with ether and dried under reduced pressure.

In this manner, 1.60 g (74%) of the title compound are obtained. Melting point: 20
4-206 ° C.

[0269]

Example 42 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4-cyano-4- (3-trifluoromethylphenyl Eniru) 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-oxo.
Silanylmethoxy-2,3-dihydrobenzofuran and 1.40 g (0.005
Mol) of 4-cyano-4- (3-trifluoromethylphenyl) piperidine hydrochloride. The reaction mixture is boiled with stirring for 6 hours and evaporated to dryness under reduced pressure. The residue is partitioned between 50 ml of water and 50 ml of dichloromethane,
The phases are separated, the organic phase is extracted twice with in each case 20 ml of water, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. Residue, 50m
and 20% hydrogen chloride containing 1%
Add ml ethanol. The precipitated crystals are filtered, washed with ether and dried under reduced pressure.

In this manner, 1.48 g (59.2%) of the title compound are obtained. Melting point:
213-216 ° C.

[0271]

Example 43 1- / 3- (5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7 - yloxy) 2-hydroxypropyl / -4-hydroxy-4- (4-meth Kishifeniru) 2.63 g (0.0088 mol) of 5-bromide in 10 ml of piperidine isopropanol.
To the solution of mo-2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 1.66 g (0.008 mol) of 4-hydroxy-4-methoxyphenyl) piperidine are added. The reaction mixture is boiled for 10 hours with stirring and then cooled to 0 ° C. The precipitated crystals are filtered, washed with cold isopropanol and dried under reduced pressure.

In this way, 2.67 g (66%) of the title compound are obtained. Melting point: 12
0-121 ° C (after recrystallization from isopropanol).

[0273]

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 3.30 g (0.011 mol) of 5-bromo-2,20 ml of ethanol.
2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran solution
To this is added 2.80 g (0.01 mol) of 4-hydroxy-4- (4-chloro-3-trifluoromethylphenyl) piperidine. The reaction mixture is 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 to the resulting solution 2.5 ml of ethanol containing 20% hydrogen chloride is added under cooling. The separated crystals are filtered and dried under reduced pressure.

In this way, 4.86 g (79%) of the title compound are obtained. Melting point: 10
8-110 ° C.

[0275]

Example 45 1- / 3- (2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-7 - yloxy) 2-hydroxypropyl / -4-hydroxy-4- (4-meth Kishifeniru) Dissolve 2.62 g (0.01 mol) of 2,2-dimethyl-5-nitro-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 8 ml of piperidine isopropanol
1.86 g (0.009 mol) of 4-hydroxy-4- (4-methoxyphenyl) piperidine are added to the liquid. The reaction mixture is boiled with stirring for 2 hours and then cooled to 2 ° C. The precipitated crystals are filtered, washed with cold isopropanol and dried under reduced pressure.

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

[0277]

Example 46 1- / 3- (2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-7 - yloxy) 2-hydroxypropyl / -4- (3-trifluoromethylphenyl Eniru) - 1,2,3,6-tetrahydropyridine hydrochloride 2.46 g (0.012 mol) of 2,2-dimethyl-5-nitro-7-oxiranylmethoxy-2,3-dihydro in 20 ml of isopropanol Benzofura
2.11 g (0.01 mol) of 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride and 2.2 ml of a 20% sodium hydroxide solution were added to the solution. I do. The reaction mixture is boiled for 5 hours with stirring and then evaporated to dryness under reduced pressure. The residue is partitioned between 30 ml of dichloromethane and 10 ml of water, the organic phase is extracted twice with in each case 20 ml of water, dried over anhydrous sodium sulphate, filtered and filtered under reduced pressure. And remove the solvent. The residue is dissolved in 50 ml of ethanol containing 5% hydrochloric acid and
The solution obtained is evaporated to dryness under reduced pressure. The crystalline residue is triturated with ether, filtered and dried under reduced pressure.

In this way, 3.89 g (73.7%) of the title compound are obtained. Melting point:
162-165 ° C.

[0279]

Example 47 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (6-methoxynaphth-2-yl) -1 , 3.34 g (0.0065 mol) of 1 / 3- (2,2-dimethyl-2,3-dihydrobenzofuran in 15 ml of 2,3,6-tetrahydropyridine hydrochloride in ethanol containing 20% hydrochloric acid -7-yloxy) -2-hydroxypropyl / 4- (6-methoxynaphth-2-yl)
The solution of piperidine hydrochloride is boiled 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.

In this way, 2.96 g (92%) of the title compound are obtained. Melting point: 18
6-188 ° C.

[0281]

Working Example 48 1- / 3- (5-Bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7 -yloxy) -2-hydroxypropyl / -4- (3-trifluoromethylphenyl )- 2.63 g (0.0088 mol) of 5-bromo-2 in 15 ml of 1,2,3,6-tetrahydropyridine hydrochloride
, 2-Dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran solution
To the solution are added 2.11 g (0.008 mol) of 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride and 3.2 ml of a 10% sodium hydroxide solution. . Bring the reaction mixture to a boil for 6 hours while stirring,
Next, it evaporates under reduced pressure. The residue is partitioned between 50 ml of dichloromethane and 50 ml of water. The organic phase is extracted twice with in each case 20 ml of water, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent. The residue is dissolved in 10 ml of ethanol containing 10% hydrochloric acid and the resulting solution is evaporated to dryness under reduced pressure. The crystalline residue is boiled with 50 ml of ethyl acetate, the crystals are filtered from the hot mixture and dried under reduced pressure.

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

[0283]

Example 49 1- / 3- (5-Nitro-2,2-dimethyl-2,3-dihydrobenzofuran-7 -yloxy) -2-hydroxypropyl / -4- (3-trifluoromethylphenyl )- 2.30 g (0.0077 mol) of 5-bromo-2 in 10 ml of 1,2,3,6-tetrahydropyridine hydrochloride
, 2-Dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran solution
1.72 g (0.007 mol) of 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine are added to the liquid and the reaction mixture is boiled for 6 hours while stirring. And then evaporated to dryness under reduced pressure. 10 ml of residue
The mixture is boiled in ethanol containing 20% hydrochloric acid for 30 minutes and the mixture is evaporated under reduced pressure. The crystalline is boiled with 30 ml of ethyl acetate, the crystals are filtered and dried under reduced pressure.

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

[0285]

Example 50 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4- (3-trifluoromethylphenyl) pin Perijin hydrochloride 20ml 1.78 g (0.004 mol) of 1 / 3- (2,
2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydro
Xypropyl / -4- (3-trifluoromethylphenyl) -1,2,3,6-
The tetrahydropyridine hydrochloride solution is hydrogenated at 20 ° C. and atmospheric pressure in the presence of 0.1 g of 10% palladium / carbon catalyst. As soon as the calculated amount of hydrogen (96 ml) has been absorbed, the catalyst is removed by filtration and the solution is evaporated under reduced pressure. The crystalline residue is triturated with 20 ml of ether, the crystals are filtered and dried under reduced pressure.

In this way, 1.75 g (98%) of the title compound are obtained. Melting point: 17
2-174 ° C (recrystallized from isopropanol).

[0287]

Example 51 1- / 3- (7-2,2-dimethyl-2,3-dihydrobenzofuran Iruoki) -2-hydroxypropyl / -4- (3-trifluoromethylphenyl) piperidine hydrochloride 2 0.31 g (0.0105 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran and 2.45 g (0.01 mol) of 4-hydroxy-4- (3-trifluoro A mixture of (methylphenyl) piperidine is melted at 80 ° C. for 1 hour and dissolved in 10 ml of ethanol containing 20% hydrochloric acid,
The mixture is then diluted with 10 ml of ethanol, cooled to 30 ° C. and 0.1 g
Of 10% palladium on carbon catalyst is added and the mixture is hydrogenated. As soon as the calculated amount of hydrogen (240 ml) has been absorbed, the catalyst is removed by filtration and the solution is evaporated under reduced pressure. The crystalline residue is triturated with 20 ml of ether, the crystals are filtered and dried under reduced pressure.

Thus, 4.05 g (91%) of the title compound are obtained. Melting point: 17
2-174 ° C.

[0289]

Example 52 1.32 / g of 10-ml of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4-hydroxypiperidine hydrochloride in tetrahydrofuran (0.006 mol) of 2,2-
In a solution of dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran,
0.55 g (0.0055 mol) of 4-hydroxypiperidine are added. The reaction mixture is boiled for 3 hours with stirring and then evaporated to dryness under reduced pressure. The residue is subjected to a partition between 5 ml of 2-propanol and 1.5 ml of 2-propanol containing 16% hydrochloric acid. The solution obtained 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 filtered and 2
-Recrystallize from propanol and dry under reduced pressure.

Thus, 1.22 g (57%) of the title compound are obtained. Melting point: 13
9-141 ° C.

[0291]

Example 53 1.32 g (0.006 mol) of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / 4-hydroxypiperidine hydrochloride A mixture of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 0.44 g (0.0045 mol) of 4-methylpiperidine and 8 ml of water are boiled for 9 hours. The oily phase of the mixture formed is dissolved in 20 ml of ether, washed with water, dried over anhydrous sodium sulphate, dried under reduced pressure and taken up in 3 ml of 2-propanol containing 16% hydrochloric acid. Dissolve and dry under reduced pressure. The residue is dissolved in ethyl acetate, precipitated with ether, the crystals are filtered, dissolved in hot 2-propanol, precipitated again with ether, the crystals are filtered and dried under reduced pressure.

Thus, 1.25 g (59%) of the title compound are obtained. Melting point: 14
6-148 ° C.

[0293]

Example 54 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-4-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (4-trifluoromethanesulfonyl butylphenyl) piperidine hydrochloride 3.28 g (0.02 mol) of the salt , 2,2-dimethyl-2,3-dihydrobenzofuran-4-ol, are dissolved in 25 ml of a 10% aqueous sodium hydroxide solution. To this solution was added 3.70 g (0.04 mol) of epichlorohydrin, then
The reaction mixture is stirred at 45-50 ° C for 3 hours. After cooling, the oily product which has been separated off is dissolved in 30 ml of dichloromethane, the phases are separated and the organic phase is separated in two portions each.
Wash twice with 0 ml of water, dry over anhydrous sodium sulfate, filter,
Then, it is evaporated to dryness under reduced pressure. Thick honey-like epoxide (3.78 g)
, 85.3%) in 40 ml of ethanol, and
3.80 g (0.0155 mol) of 4-hydroxy-4- (3-trifluoromethylphenyl) piperidine are added and the reaction mixture is boiled for 6 hours. After cooling, 15 ml of ethanol containing 5% hydrochloric acid was added to the resulting solution for 1 hour.
At room temperature below 5 ° C., add and evaporate the mixture 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. Melting point: 16
2-164 ° C.

[0295]

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 repeated using the epoxide obtained in the first reaction step (3.75 g,
85.2%) in 50 ml of ethanol. To this solution, 3.94 g (0.0153 mol) of 4-hydroxy-4- (6
-Methoxy-naphth-2-yl) piperidine is added and the reaction mixture is treated with 4 parts
Bring to a boil for an hour. After cooling, 13 ml of ethanol containing 5% hydrochloric acid are added to the solution, and the reaction mixture is evaporated to dryness under reduced pressure. The residual crystal product is
Recrystallize from a mixture of ethanol and ether.

In this way, 5.35 g (68%) of the title compound are obtained. Melting point: 11
8-120 ° C.

[0297]

Example 56 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-5-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (4-trifluoromethanesulfonyl butylphenyl) piperidine hydrochloride 3.28 g (0.02 mol) of the salt , 2,2-dimethyl-2,3-dihydrobenzofuran-4-ol, are dissolved in 30 ml of an aqueous solution containing 3 g of sodium hydroxide. To this solution is added 3.70 g (0.04 mol) of epichlorohydrin, then the reaction mixture is stirred at 48-50 ° C. for 3 hours. After cooling, the separated oily product is dissolved in 30 ml of dichloromethane, the phases are separated and the organic phase is washed twice with in each case 20 ml of water, dried over anhydrous sodium sulphate, Filter and evaporate to dryness under reduced pressure. Thick residue wax-like epoxide (3.
85 g, 87.3%) in 50 ml of ethanol and 3.80 g (0.0155 mol) of 4-hydroxy-4- (3-trifluoromethylphenyl) piperidine are added to the resulting solution. Is added and the reaction mixture is boiled for 5 hours. After cooling, 15 ml of ethanol containing 5% hydrochloric acid are added to the resulting solution at room temperature below 15 ° C. and the mixture is evaporated to dryness under reduced pressure. The crystallized residue is recrystallized from a mixture of ethanol and ether, filtered and washed with ether.

In this manner, 4.97 g (64%) of the title compound are obtained. Melting point: 17
2-173 ° C.

[0299]

Example 57 1.64 g of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-6-yloxy ) -2-hydroxypropyl / 4-hydroxy-4-phenyl-piperidine hydrochloride ( 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 is added 1.85 g (0.02 mol) of epichlorohydrin, then the reaction mixture is stirred at 48-50 ° C. for 2.5 hours. After cooling, the oily product separated off was dissolved in 25 ml of dichloromethane, the phases were separated and the organic phase was washed twice with 15 ml of water each time and dried over anhydrous sodium sulfate, Filter and evaporate to dryness under reduced pressure. 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-phenylpiperidine are added and the reaction mixture is boiled for 6 hours. After cooling, 10 ml of ethanol containing 5% hydrochloric acid are added to the resulting solution at room temperature below 15 ° C. and the mixture is evaporated to dryness under reduced pressure. The crystallite residue is recrystallized from a mixture of ethanol and ether, filtered and washed with ether.

In this way, 4.97 g (64%) of the title compound are obtained. Melting point: 18
4-186 ° C.

[0301]

Example 58 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / 4-4 -hydroxy-4- (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-oxo.
Silanylmethoxy-2,3-dihydrobenzofuran and 1.48 g (0.005
Mol) of 4-methoxy-4- (3-trifluoromethylphenyl) piperidine hydrochloride. The reaction mixture is boiled for 6 hours with stirring 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, the organic phase is washed twice with in each case 20 ml of water, dried over anhydrous sodium sulphate, filtered and Then, it is evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of ether and 1 ml of 20 ml
% Ethanol containing hydrochloric acid is added with cooling, the precipitated crystals are filtered, washed with ether and dried under reduced pressure.

In this way, 1.62 g (62.8%) of the title compound are obtained. Melting point:
192-195 ° C.

[0303]

Example 59 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (diphenylmethyl) piperazine in 30 ml of isopropanol. 20 g (0.01 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.52
A solution of g (0.01 mol) of 1- (diphenylmethyl) piperazine is boiled for 6 hours. The solution is evaporated to dryness under reduced pressure, the residue product is triturated with n-hexane and filtered. The crude product thus obtained (4.53 g) is recrystallized from 25 ml of ethanol, filtered and dried under reduced pressure.

In this way, 3.89 g (82%) of the title compound are obtained. Melting point: 12
9-130 ° C.

[0305]

Working Example 60 2.20 g (0.01 mol ) of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (diphenylmethyl) piperazine ) Of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran and 2.52 g (0.01 mol) of 1- (diphenylmethyl) piperazine are melted at 80 ° C. and Hold at temperature for 1 hour.
Upon solidification, the material obtained is recrystallized from 25 ml of ethanol, filtered and dried under reduced pressure.

In this way, 3.92 g (83%) of the title compound are obtained. Melting point: 12
9-130 ° C.

[0307]

Example 61 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-Iruoki) -2-hydroxypropyl / -4- (diphenylmethyl) piperazine 2.20 g (0.01 Mol) 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran and 2.52 g (0.01 mol) of 1- (diphenylmethyl) piperazine at 60 ° C. Temperature for 1 hour.
Upon solidification, the material obtained is recrystallized from 25 ml of ethanol, filtered and dried under reduced pressure.

In this way, 3.82 g (81%) of the title compound are obtained. Melting point: 12
9-130 ° C.

[0309]

Example 62 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (diphenylmethyl) piperazine in 20 ml of ethanol. To a solution of 31 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran was added 2.5
2 g (0.01 mol) of 1- (diphenylmethyl) piperazine are added and the reaction mixture is boiled for 4 hours. After cooling, the precipitated crystals are filtered and dried under reduced pressure.

[0310] In this way, 3.87 g (81%) of the title compound are obtained. Melting point: 12
9-130 ° C.

[0311]

Example 63 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (4-fluorophenyl) piperazine in 30 ml of ethanol, 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 is boiled for 5 hours. The solution is evaporated to dryness under reduced pressure and the residue product is chromatographed on a column packed with Kieselgel 60 using a mixture of 30 volumes of chloroform and 1 volume of ethanol as eluent. The fractions containing the product are evaporated and the residual product is triturated with n-hexane and filtered and dried under reduced pressure.

[0312] In this way, 7.30 g (91%) of the title compound are obtained. Melting point: 80
~ 82 ° C.

[0313]

Example 64 2.31 g (0.3 g ) of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (4-fluorophenyl) piperazine 011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran and 1.80 g (0.01 mol) of 1- (4-fluorophenyl) piperazine at 60 ° C. Melt and hold at final temperature for 1.5 hours. The resulting melt was used as eluent for 30 volumes of chloroform and 1 volume
Chromatograph on a column packed with Kieselgel 60 using a mixture consisting of a volume of ethanol. The fractions containing the product are evaporated and the residue is triturated with n-hexane, then filtered and dried under reduced pressure.

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

[0315]

Example 65 2.20 g of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (4-fluorophenyl) piperazine (0. 011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran and 1.80 g (0.01 mol) of 1- (4-fluorophenyl) piperazine at 70 ° C. Melt and hold at last temperature for 1 hour. To the obtained melt, 60 ml of n-hexane are added, the mixture is cooled, the precipitated crystals are filtered and dried under reduced pressure.

In this way, 3.26 g (81%) of the title compound are obtained. Melting point: 80
~ 82 ° C.

[0317]

Example 66 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (3-fluorophenyl) piperazine in 20 ml of isopropanol, 2.20 g (0.01 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.30
A solution of g (0.01 mol) of 1- (3-trifluoromethylphenyl) piperazine is boiled for 4 hours. The solution is evaporated to dryness under reduced pressure and the residue product is chromatographed on a column packed with Kieselgel 60 using a mixture of 30 volumes of chloroform and 1 volume of ethanol as eluent. The fractions containing the product are evaporated and the product obtained is triturated with n-hexane, filtered and dried under reduced pressure.

[0318] In this way, 3.76 g (84%) of the title compound are obtained. Melting point: 82
~ 84 ° C.

[0319]

Example 67 2.20 g of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (3-fluorophenyl) piperazine (0.20 g ) 01 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran and 2.30 g (0.01 mol) of 1- (3-trifluoromethylphenyl) piperazine. Melt at ° C and hold at final temperature for 1.5 hours. To the resulting hot melt, 60 ml of n-hexane are added, the mixture is cooled, the precipitated crystals are filtered and dried under reduced pressure.

[0320] In this way, 3.77 g (84%) of the title compound are obtained. Melting point: 82
~ 84 ° C.

[0321]

Example 68 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (4-methoxyphenyl) piperazine 40 ml of methyl tertiary butyl 3.80 g (0.017 mol) in ether
Of a solution of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.88 g (0.015 mol) of 1- (4-methoxyphenyl) piperazine were boiled for 8 hours. Then, cool. The precipitated crystals are filtered and dried under reduced pressure.

In this way, 5.21 g (84%) of the title compound are obtained. Melting point: 93
~ 94 ° C.

[0323]

Working Example 69 1.10 g of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (4-methoxyphenyl) piperazine (0. 005 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran and 0.96 g (0.005 mol) of 1- (4-methoxyphenyl) piperazine at 80 ° C. Melt and hold at last temperature for 1 hour. To the resulting hot melt, 10 ml of methyl tertiary butyl ether are added, the mixture is cooled, the precipitated crystals are filtered and dried under reduced pressure.

In this way, 1.88 g (91%) of the title compound are obtained. Melting point: 93
~ 94 ° C.

[0325]

Example 70 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (benzo-1,3-dioxolan-5- yl) 3.80 g (0.017 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 3.30 g of piperazine dihydrochloride in 30 ml of ethanol (
A solution of 0.015 mol) of 1- (benzo-1,3-dioxolan-5-yl) piperazine is boiled for 10 hours. The solution was evaporated to dryness under reduced pressure and the residue (8.0)
g) is dissolved in 30 ml of ethanol containing 4.0 g of hydrochloric acid. Crystals begin to separate from the homogeneous solution. The suspension is diluted with 60 ml of methyl tertiary butyl ether, filtered and the crystals are dried under reduced pressure.

In this way, 5.40 g (70%) of the title compound are obtained. Melting point: 21
6-218 ° C.

[0327]

Example 71 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (benzo-1,3-dioxolan-5- yl) 3.80 g (0.017 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 3.33 g of piperazine dihydrochloride in 30 ml of isopropanol.
A solution of 0 g (0.015 mol) of 1- (benzo-1,3-dioxolan-5-yl) piperazine is boiled for 6 hours. The solution was evaporated to dryness under reduced pressure and the residue was
Dissolve in 20 ml of ethanol containing 15% hydrochloric acid. Crystals begin to separate from the homogeneous solution. The suspension is diluted with 60 ml of methyl tertiary butyl ether, filtered and the crystals are dried under reduced pressure.

In this way, 5.43 g (71%) of the title compound are obtained. Melting point: 21
6-218 ° C.

[0329]

Example 72 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (benzo-1,3-dioxolan-5- yl) Piperazine dihydrochloride 2.31 g (0.011 mol) of 2 in 30 ml of diisopropyl ether
Of a solution of 1,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.20 g (0.01 mol) of 1- (benzo-1,3-dioxolan-5-yl) piperazine in 6 Boil for an hour and then add 7 ml of ethanol containing 20% hydrochloric acid. The precipitated crystals are cooled, filtered and the crystals are dried under reduced pressure.

In this way, 4.41 g (86%) of the title compound are obtained. Melting point: 21
6-218 ° C.

[0331]

Example 73 2.42 / g (0.0115 ) of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (4-chlorophenyl) piperazine Mol) 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 2.70 g (0.01 mol) 1- (4-chlorophenyl) piperazine dihydrochloride, 26 ml ethanol, 3 ml Water and 0.
A mixture of 9 g (0.0225 mol) of sodium hydroxide in water is boiled with stirring 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 in each case 30 ml of water, dried over anhydrous sodium sulphate, filtered and reduced in vacuo. Evaporate to dryness. The residue is recrystallized from 8 ml of methanol, the precipitated crystals are filtered and dried under reduced pressure.

In this way, 3.25 g (78%) of the title compound are obtained. Melting point: 96
~ 98 ° C.

[0333]

Example 74 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (4-chlorophenyl) piperazine To a solution of 0.70 g (0.01 mol) of 1- (4-chlorophenyl) piperazine dihydrochloride was added 3 ml of water and 0.9 g (0.0225).
Mol) of sodium hydroxide and the mixture is boiled for 10 hours. Next, 2.40 g (0.011 mol) of 2,2-dimethyl-7-O was added to the reaction mixture.
Xylanylmethoxy-2,3-dihydrobenzofuran is added with stirring and the mixture is boiled for a further 4 hours and then evaporated to dryness under reduced pressure. To the residue is added 50 ml of water, with which the slowly hardening material is decanted and the residue is polished with some water. The precipitated crystals are filtered, washed with water, recrystallized from methanol, filtered and dried under reduced pressure.

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

[0335]

Example 75 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4- (4-chlorophenyl) ethanol piperazine 2 salt salt 5ml Of 0.40 g (0.001 mol) of 1- / 3- (2,2
To a solution of -dimethyl-2,3-dihydrobenzofuran-7-yl) -2-hydroxypropyl / 4- (4-chlorophenyl) piperazine is added 1 ml of ethanol containing 20% hydrochloric acid and the mixture is evacuated. Evaporate to dryness below. Residue, 5
Boil for 5 minutes with 5 ml of ethyl acetate, filter the hot suspension and
The crystals are dried under reduced pressure.

In this way, 0.43 g (91%) of the title compound are obtained. Melting point: 16
8-170 ° C.

[0337]

Example 76 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4- (3-methoxyphenyl) piperazine salt 1.32g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 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 m
Boil 1 liter of water mixture 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 is dissolved in 3 ml of 2-propanol and, based on the resulting solution, 3 ml of 2% containing 16% hydrochloric acid.
-Propanol is added and the reaction mixture is kept at 0 ° C for 5 days. The precipitated crystals are filtered, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 1.48 g (60%) of the title compound are obtained. Melting point: 16
8-170 ° C.

[0339]

Example 77 1.32 g (0.006 mol) of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / 4-benzylpiperazine dihydrochloride ) Of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 0.97 g (0.0055 mol) of 1-benzyl-piperazine and 8 ml of 2-propanol are boiled for 4 hours Let 20
Cool to ° C. To the reaction mixture, 20 ml of petroleum ether are added, the mixture is kept at 0 ° C. for 5 days, the crystals formed are filtered and recrystallized from n-hexane. The precipitated crystals are dissolved in 15 ml of 2-propanol and
To the resulting solution is added 1.5 ml of 2-propanol containing 16% hydrochloric acid. After cooling, the precipitated crystalline salt is filtered and dried under reduced pressure.

Thus, 1.50 g (58%) of the title compound are obtained. Melting point: 18
8-191 ° C.

[0341]

Example 78 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4- (2,4-dichlorophenyl) piperazine down hydrochloride 1. 32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 1.15 g (0.005 mol) of 1- (2,3-mol
A mixture of dichlorophenyl) piperazine and 8 ml of 2-propanol is boiled for 5 hours and then cooled to 20 ° C. 2.4 ml of 2-
Propanol and 2.4 ml of 2-propanol containing 16% hydrochloric acid were added,
Then the reaction mixture is stirred at room temperature for 5 hours. The precipitated crystals are filtered, recrystallized from 2-propanol, filtered and then dried under reduced pressure.

Thus, 1.19 g (45%) of the title compound are obtained. Melting point: 16
9-171 ° C.

[0343]

Example 79 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4- (3-chlorophenyl) piperazine hydrochloride 2.64 g (0 .012 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 2.36 g (0.012 mol) of 1- (3-chlorophenyl) piperazine and 16 ml of 2-propanol The mixture is boiled for 3 hours. After cooling, 7 ml of 2-propanol containing 16% hydrochloric acid were added at 20 ° C.
Add in. The reaction mixture is kept at 0 ° C. for 2 days. The precipitated crystals are filtered and 2
-Recrystallize from propanol, filter again and dry under reduced pressure.

In this manner, 2.88 g (53%) of the title compound are obtained. Melting point: 18
7-190 ° C.

[0345]

Working Example 80 1.32 g of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (2-pyridyl) piperazine trihydrochloride ( 0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 0.78 g (0.0048 mol) of 1- (2-pyridyl) piperazine and 8 ml of petroleum ether Is boiled for 6 hours. After cooling to 20 ° C., in the separated phase, for the lower phase, 20 ml of 2-propanol and 4.5 ml of 2-propanol containing 16% hydrochloric acid are added and the reaction mixture is brought to 0%. Hold at ° C for 5 days. The separated crystals are filtered, recrystallized from 2-propanol, filtered and dried under reduced pressure.

In this way, 1.68 g (71%) of the title compound are obtained. Melting point: 13
3-136 ° C.

[0347]

Example 81 2.64 g of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (2 -methoxyphenyl ) piperazine dihydrochloride (0.012 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 2.36 g (0.011 mol) of 1- (2-methylphenyl) piperazine and 16 ml of 2 Boil the mixture of propanols for 5.5 hours. After cooling to 20 ° C., 10 ml of 2-propanol and 8 ml of 2-propanol containing 16% hydrogen chloride are added to the reaction mixture and the reaction mixture is kept at 0 ° C. for 2 days. The precipitated crystals are filtered using reduced pressure, washed with 2-propanol, recrystallized from 2-propanol, filtered and dried under reduced pressure.

Thus, 2.53 g (47%) of the title compound are obtained. Melting point: 12
8-130 ° C.

[0349]

Example 82 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4- (3,4-dimethylphenyl) piperazine down dihydrochloride 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 0.95 g (0.005 mol) of 1- (3,4-mol
A mixture of (dimethylphenyl) piperazine and 8 ml of ethanol is boiled for 6 hours. After cooling to 20 ° C., the reaction mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. To the residue, 5 ml of 2-propanol containing 16% hydrogen chloride are added, the reaction mixture is kept at 0 ° C. for 2 days, the precipitated crystals are filtered, recrystallized from 2-propanol and again Filter and dry under reduced pressure.

In this way, 1.50 g (62%) of the title compound are obtained. Melting point: 11
9-122 ° C.

[0351]

Example 83 1.32 g of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / -4- (2-pyrimidyl) piperazine dihydrochloride ( 0.006 mol) of a mixture of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 0.65 g (0.004 mol) of 2-pyrimidylpiperazine and 8 ml of tetrahydrofuran, Boil for 12 hours and cool to 20 ° C. To the oil formed, 20 ml of ether and 1.5 ml of 2-propanol containing 30% hydrogen chloride were added, the reaction mixture was kept at 0 ° C. and kept at 0 ° C. for 5 days, The precipitated crystals are filtered, dried under reduced pressure and recrystallized from 2-propanol.

Thus, 1.50 g (82%) of the title compound are obtained. Melting point: 12
8-130 ° C.

[0353]

Example 84 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4- (4-chloro-2-methylphenyl) pin Perazine hydrochloride 2.64 g (0.012 mol) of salt , 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 2.27 g (0.008 mol) of 1- (4-chloro-2- A mixture of (methylphenyl) piperazine hydrochloride, 0.64 g (0.016 mol) of sodium hydroxide and 8 ml of water was boiled for 3 hours and
Cool to ° C. The aqueous phase is removed by decantation from the organic phase,
Add 0 ml of ether and stir for 1 hour. Filtering the precipitated crystals,
Dry under reduced pressure and recrystallize from acetonitrile.

In this way, 2.07 g (60%) of the title compound are obtained. Melting point: 68
~ 70 ° C.

[0355]

Example 85 1.32 g (0.006 mol) of 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy ) -2-hydroxypropyl / 4-methylpiperazine dihydrochloride ) Of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 0.45 g (0.0045 mol) of 4-methylpiperazine and 8 ml of ethanol were boiled for 3 hours, And 20
Cool to ° C. To the mixture was added 4 ml of 2-propanol containing 30% hydrogen chloride, the reaction mixture was kept at -15 ° C. for 2 days, the precipitated crystals were filtered, dried under reduced pressure and hot 2-propanol And precipitated from the solution with diethyl ether.

In this manner, 1.15 g (65%) of the title compound are obtained. Melting point: 11
9-122 ° C.

[0357]

Example 86 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4- (trifluoromethyl benzyl) Pipera Jin dihydrochloride 1. 32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 1.43 g (0.0045 mol) of 4- (3-trifluoromethyl) benzylpiperazine 2 A mixture of the hydrochloride, 0.36 g (0.009 mol) of sodium hydroxide and 8 ml of water is boiled for 2.5 hours and cooled to 20 ° C., and the aqueous phase is decanted against the organic phase. Remove by tasting, add 2 ml of 2-propanol containing 30% hydrochloric acid, filter the precipitated crystals, dry under reduced pressure and recrystallize from 2-propanol.

Thus, 1.39 g (57%) of the title compound are obtained. Melting point: 20
9-211 ° C.

[0359]

Example 87 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4- (3,4-dichlorophenyl) piperazine down hydrochloride 1. 32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 1.04 g (0.0045 mol) of 1- (3,4
-Dichlorophenyl) piperazine and 8 ml of 2-propanol were added to 3
Boil for a time and cool to 20 ° C. To the reaction mixture is added a mixture of 10 ml of 2-propanol and 2 ml of 2-propanol containing 30% hydrogen chloride, the reaction mixture is stirred for 5 hours, the precipitated crystals are filtered and dried under reduced pressure. ,
Then, it is recrystallized from 2-propanol.

Thus, 1.63 g (62%) of the title compound are obtained. Melting point: 18
0-182 ° C.

[0361]

Example 88 1- / 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl / -4- (2,6-dimethylphenyl) piperazine down dihydrochloride 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 0.90 g (0.004 mol) of 1- (2,6-mol)
A mixture of (dimethylphenyl) piperazine hydrochloride, 0.32 g (0.008 mol) of sodium hydroxide and 8 ml of water is boiled for 2 hours and cooled to 20 ° C. The aqueous phase of the mixture formed is removed by decantation, relative to the organic phase, 2.5 ml of 2-propanol containing 30% hydrochloric acid are added and the reaction mixture is kept at -15 ° C. for 2 days Then, 10 ml of 2-propanol are added, the precipitated crystals are filtered, dried under reduced pressure and recrystallized from 2-propanol.

Thus, 1.00 g (41%) of the title compound are obtained. Melting point: 11
5-117 ° C.

[0363]

【Example 】

1- / 3- (7-2,2-dimethyl-2,3-dihydrobenzofuran-yloxy) -2-hydroxypropyl / -4- (2,6-dimethylphenyl) piperazine down dihydrochloride 0.5 g (0 .0016 mol) of 1-bromo-3- (2,2-dimethyl-2,
3-dihydrofuran-7-yloxy) -2-propanol, 0.45 g (0.
0016 mol) of 4-chloro-2-methylphenylpiperazine, 0.25 g (0
. (0063 mol) of sodium hydroxide and 6.5 ml of water are boiled for 3 hours and cooled to 20 ° C. The aqueous phase is removed by decantation, the residual oil is triturated with ether, the precipitated crystals are filtered, dried under reduced pressure and recrystallized from acetonitrile.

Thus, 0.25 g (40%) of the title compound is obtained. Melting point: 68
~ 70 ° C.

[Procedural Amendment] Submission of translation of Article 34 Amendment of the Patent Cooperation Treaty

[Submission date] July 25, 2000 (2000.7.25)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0007

[Correction method] Change

[Correction contents]

[0007] Tetrahydronaphthoxy derivatives having hypoglycemic activity are described in DE-OS No.
22 35 597. The chemical structure of the known compound is similar to that of the piperazinylalkylbenzofuran derivative of formula Ia. 1-Phenoxyalkylpiperidine derivatives useful for the treatment of cerebrovascular diseases are described in FR-A-2681319. 4-Substituted piperidinine derivatives are known from WO-A-9732216. Known compounds are antagonists of the NMDA receptor subtype and are also useful as neuroprotective agents in cardiovascular and CNS diseases.

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0363

[Correction method] Change

[Correction contents]

[0363]

Working Example 89 1- / 3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy
B ) -2-Hydroxypropyl / -4- (2,6-dimethylphenyl) piper
Di emissions dihydrochloride 1.32g of (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrofuran, 0.90 g of (0.004 mol) 1- (2, 6-
A mixture of (dimethylphenyl) piperazine hydrochloride, 0.32 g (0.008 mol) of sodium hydroxide and 8 ml of water is boiled for 2 hours and cooled to 20 ° C. The aqueous phase of the mixture formed is removed by decantation relative to the organic phase, 2.5 ml of 2-propanol containing 30% hydrochloric acid are added and the reaction mixture is kept at -50 ° C. for 2 days Then, 10 ml of 2-propanol are added, the precipitated crystals are filtered off, dried under reduced pressure and recrystallized from 2-propanol.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 9/00 A61P 9/00 9/10 9/10 25/00 25/00 25/18 25/18 25 / 22 25/22 25/24 25/24 C07D 405/14 C07D 405/14 409/14 409/14 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE , AL, AM, AT, AU, AZ, BA, BB, G, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, ID, IL, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Shuimig, Dura Hungary, Ha-1126 Budapest, Hollowshui Simon Uzza 25 (72) Inventor Ribo, Endre Hungary, Har-1062 Budapest, Bayeza Uzza 55 (72) Inventor Nazi, Zoltan, Thammas Hungary, Har-1028 Budapest, Sepesy Uzza 5 (72) Inventor Ondi, Levente Hungary, Har-5000 Solnock, Martinovics, Uzza 24 (72) Inventor Ivanichen, Medelli, Katarin Hungary, Ha-1147 Budapest, Istuvanfi Uzza 5 (72) Inventors Mikro シ ュ n, Kovack チ ュ, Aniko Hungary, Hár-1132 Budapest, Visegrady Uzza 64 (72) Inventors Názine, P ヂ no シ ュ, Ildi K h Hungary, H−1-1192 Budapest, Ahlmosh Uzza 65/3 ( 72) Inventor Kertes, Sabolchu, Hungary, Har-1067 Budapest, Chengerj Uzza 62 / B. (72) Inventor Senassi, Garbol Hungary, Har-1035 Budapest, Kerek Uzza 24 (72) Inventor Studmidut, Eve Hungary, Har-1021 Budapest, Seychel Uzza 51 / Bee (72) Inventor Pararagi, Katarin Hungary, Har-1054 Budapest, Hold Uzza 25 (72) Inventor Gachary, Istovan Hungary, Har-1021 Budapest G., Tarrogato Uzza 64 / B. (72) Inventors Perthuan, Istvan Hungary, Hah-1165 Budapest, Coronafilt Uzza 33 (72) Inventors Sabadosh, Tamahs Hungary, Hah-1173 Budapest, Borsaw Uzza 10 (72) ) Inventor Levi, Gordy Hungary, Har-2092 Budakesi, Fortale 3 (72) Inventor Eded, Andra ハ ン s Hungary, Har-1145 Budapest, Ujüvidek Uzza 58 F term (reference) 4C063 AA01 AA03 BB03 CC 76 CC92 DD10 DD34 DD76 EE01 4C086 AA01 AA03 AA04 BA06 GA04 GA12 MA04 NA14 ZA02 ZA36

Claims (17)

[Claims] 1. Formula (I)(However, R¹And R^TwoIs independently a hydrogen atom or C_{1 ~ Four}X is an oxygen atom or a sulfur atom, Y is a hydrogen atom or hydroxy, Z is a hydrogen atom, a halo atom, C_{1 ~ Four}Alkyl group, C_{1 ~ Four}Alkoxy group, amino group
, Nitro group, cyano group, trifluoromethyl group, formula -COOR^Three, -NHCOR^Three Or -SO_TwoNR^ThreeR^FourWhere R^ThreeIs a hydrogen atom or C_{1 ~ Four}In an alkyl group, R^FourIs C_{1 ~ Four}An alkyl group or R^ThreeAnd R^FourIs 5-10 membered saturated or unsaturated with the adjacent nitrogen atom
Which forms, as a further heteroatom, one or more nitrogen atoms
And / or one or more oxygen atoms and / or one or more sulfur atoms, wherein A is
, Formula CH, COH, C-CN, C-COOR^ThreeOr COR^FourWhere,
R^ThreeAnd R^FourIs as described above; B is a methylene group; or, A together with B forms a group of the formula -C = C-, Ar is a hydrogen atom, C_{1 ~ Four}Alkyl group, phenyl (C_{1 ~ Four}Alkyl) group, bife
Nyl group, naphthyl group (however, C_{1 ~ Four}Alkoxy group or C_{Two ~ Four}By alkenyl group
May be optionally substituted), partially saturated, condensed with a phenyl group,
A 5- or 6-membered heterocyclic group containing an elemental atom, wherein _{1 ~ Four}  Optionally substituted with alkyl groups); 5- or 6-membered, saturated or unsaturated.
Saturated and, as heteroatoms, nitrogen and / or oxygen and / or sulfur
A heterocyclic group containing: or a substituent; R^Five, R⁶And R⁷Phenyl substituted with
Where R is^Five, R⁶And R⁷Are, independently of one another, a hydrogen atom, a halo atom,
Oromethyl group, C_{1 ~ Four}Alkyl group, methylenedioxy group, phenoxy group (however,
Indeed, C_{1 ~ Four}R) optionally substituted by alkoxy or halo atoms, C)_{Two ~ Four}  Alkenyl group, C_{Two ~ Four}An alkenyloxy group, optionally di (C_{1 ~ Four}An alkyl group or a 5- or 6-membered, saturated heterocyclic group (provided that one or more nitrogen atoms and oxygen atoms
And the heterocyclic group optionally has C_{1 ~ Four}Optionally substituted with an alkyl group)
Alternatively, A is of the formula N- (CH_Two)_n-Ar 'group, wherein Ar' is a diphenylmethyl group, a pyridyl group, a pyrimidinyl group, a naphthyl group (
Where arbitrarily C_{1 ~ Four}Alkyl group or C_{Two ~ Four}A 5- or 6-membered heterocyclic group, partially saturated, condensed with a phenyl group and containing 1-2 oxygen atoms, wherein the heterocyclic group is optionally substituted with an alkenyl group); , 1-3 C_{1 ~ Four}No
Or a substituent R)^Five, R⁶And R⁷Replaced by
Enyl group (R^Five, R⁶And R⁷Is as described above); n is 0 or 1) and their pharmaceutically acceptable
Acid addition salts. Wherein formula (I) (where, in formula (I), R ¹ is a hydrogen atom or a C _{1 ~ 4} alkyl group, R ² is a hydrogen atom, X is an oxygen atom Y is a hydrogen atom or hydroxy; Z is a hydrogen atom, a halo atom or a nitro group; A is a group of formula CH, COH or C-CN; B is a methylene group or, a, together with B, to form a formula -C = C-group, Ar represents a hydrogen atom, a benzyl group, is substituted with a substituent R ^5, R ⁶ and R ^7, phenylene
Group, a biphenyl group, a naphthyl group (provided that optionally substituted with C _{1 ~ 4} alkoxy group), or a thienyl group, wherein, R ^5, R ⁶ and R ⁷ independently of one another, a hydrogen atom , halo atoms, trifluoromethyl group, benzofuran derivatives according to claim 1 of C _{1 ~ 4} alkyl group, C _{1 ~ 4} alkoxy group, C _{2 ~ 4} alkenyloxy group, a phenoxy group or a methylenedioxy group) And their pharmaceutically acceptable acid addition salts. 3. A compound of the formula (I) wherein R ¹ is a methyl group, R ² is a hydrogen atom, X is an oxygen atom, Y is hydroxy, Z is a hydrogen atom A represents a formula CH, COH or C-CN, B is a methylene group, or A forms together with B a formula -C = C- group, and Ar is a halo atom A phenyl group optionally substituted with a trifluoromethyl group, a methyl group or a methoxy group; or a methoxynaphthyl group). 4. The formula (Ia)(However, R¹Is C_{1 ~ Four}Alkyl, R^TwoIs a hydrogen atom, X is an oxygen atom, Y is hydroxy, Z is a hydrogen atom, Ar 'is a diphenylmethyl group, a pyridyl group, partially saturated, and a phenyl group
A 5- or 6-membered heterocyclic group fused and containing two oxygen atoms;
Substituent R^Five, R⁶And R⁷A phenyl group substituted by^Five, R⁶ 
 And R⁷Is independently of each other a hydrogen atom, a halo atom, a trifluoromethyl group,_{1 ~ Four} Alkyl group, C_{1 ~ Four}An alkoxy group or a methylenedioxy group, n is 0 or 1) and a piperazinylalkylbenzofuran derivative;
Pharmaceutically acceptable acid addition salts thereof. 5. A compound of the formula (Ia) wherein R ¹ is a methyl group, R ² is a hydrogen atom, X is an oxygen atom, Y is hydroxy, Z is a hydrogen atom Ar ′ is a diphenylmethyl group, a pyridyl group, a benzo-1,3-dioxolanyl group, or 1 or 2 halo atoms, 1 or 2 methyl groups, methylenedioxy group, and trifluoromethyl Or a phenyl group optionally substituted with a methoxy group, and n is 0 or 1.) and a pharmaceutically acceptable acid addition salt thereof. 6. 1- / 3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4- (3-trifluoro-methylphenyl) -1, 2,3,6-tetrahydropyridine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (3-tri (Fluoro-methylphenyl) piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (4-trifluoro- Phenyl) piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / 4-hydroxy-4 -Phenyl-piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (3-chloro-phenyl) piperidine 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (3-methoxy-phenyl) piperidine; 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (4-methoxy-phenyl) piperidine, 1 / 3- (2 , 2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4- (3-trifluoromethyl-phenyl) pipe Lysine, 1 / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (4-methyl-phenyl) piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / 4-cyano-4-phenyl-piperidine, 1 / 3- (2,2-dimethyl -2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (4-chloro-phenyl) piperidine, 1 / 3- (2,2-dimethyl-2,3 -Dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (6-methoxy-naphthyl-2-yl) piperidine, 1- / 3- ( , 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-yl Carboxymethyl) -2-hydroxypropyl / -4- (benzo-1,3-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, 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, And acid addition salts of these compounds. 7. A) Formula (II)(However, R¹, R^Two, X, Y and Z are as defined in relation to formula (I);
al is a halo atom)(Where A, B and Ar are as defined in relation to formula (I)), or b) reacting with a secondary amine of formula (III)(However, R¹, R^Two, X and Z are as defined in relation to formula (I))
By reacting the oxide with a secondary amine of formula (IV), wherein A, B and Ar are as defined in relation to formula (I), the formula (I) wherein Y is hydroxy In the base
R¹, R^Two, X, Z, A, B and Ar are as defined in relation to formula (I).
C) preparing a benzofuran derivative of formula (V)(However, R¹, X and Z are as defined in relation to formula (I))
, Formula (XI)(However, R^Two, Y, A, B and Ar are as defined in relation to formula (I);
Reacting a halo compound of formula (V) (as defined above) with a halo compound of formula (XII)(However, R¹, R^Two, X and Z are as defined in relation to formula (I))
By reacting with an oxide, the compound of formula (I) (where Y is a hydroxy group, ¹ , R^Two, X, Z, A, B and Ar are as defined in relation to formula (I))
Preparing a benzofuran derivative, or e) Formula (I) (where A is a COH group, B is a methylene group, R¹,
R^Two, X, Y, Z and Ar are as defined in relation to formula (I))
By dehydrating the furan derivative, the compound of formula (I) (where A is, together with B,
Forming a group of formula -C = C-,¹, R^Two, X, Y, Z and Ar are related to formula (I)
B) preparing a benzofuran derivative of the formula (XV)(However, R¹, R^Two, X, Y and Z are as defined in relation to formula (I))
The ketone may be an arylmag of the formula (XVI): Hal-Mg-Ar, where Ar is as described above and Hal is a halo atom.
By reacting with a nesium halide, the compound of the formula (I) (where A is a group of the formula COH)
Yes, R¹, R^Two, X, Y, Z and Ar are as defined in relation to formula (I)
G) to produce a benzofuran derivative of formula (XV)¹, R^Two, X, Y and Z are as defined above)
Reacting with a lithium compound of formula (XVII): Li-Ar, where Ar is as described above,
By decomposing the formed adduct with water, the formula (I) (where R¹, R^Two,
X, Y, Z and Ar are as defined in relation to formula (I))
H) forming a group of formula -C = C- together with B;¹, R^Two, X, Y
, Z and Ar are as defined in relation to formula (I)).
Thus, the formula (I) (where A is a group of the formula CH, and B is a methylene group)
R¹, R^Two, X, Y, Z and Ar are as defined in relation to formula (I))
To produce a benzofuran derivative of formula (III) or (R)¹, R^Two, X, and Z are as defined in relation to formula (I).
Epoxide of formula (IV), wherein A is a group of formula CHOH, B and A
r is as described above) with a secondary amine under dehydration reaction conditions.
And the formed formula (I) (A, together with B, forms the formula -C = C-¹ 
, R^Two, X, Y, Z and Ar are as defined above),
Hydrogenated in the reaction mixture; and, if desired, the resulting base of formula (I) is
Reacts with inorganic or organic acids to form pharmaceutically suitable acid addition salts thereof, or
Alternatively, the compound of formula (I) (where A is
, A group of formula CH, B is a methylene group,¹, R^Two, X, Y, Z and Ar are
, As defined in connection with formula (I)).
Benzofuran derivative of formula (I) (R¹, R^Two, Z, X, Y,
A, B and Ar are as defined in relation to formula (I) according to claim 1)
A process for producing a benzofuran derivative of the formula (I), characterized in that it is produced. 8. An active ingredient represented by the formula (I)(However, R¹And R^TwoIs independently a hydrogen atom or C_{1 ~ Four}X is an oxygen atom or a sulfur atom, Y is a hydrogen atom or hydroxy, Z is a hydrogen atom, a halo atom, C_{1 ~ Four}Alkyl group, C_{1 ~ Four}Alkoxy group, amino group
, Nitro group, cyano group, trifluoromethyl group, formula -COOR^Three, -NHCOR^Three Or -SO_TwoNR^ThreeR^FourWhere R^ThreeIs a hydrogen atom or C_{1 ~ Four}In an alkyl group, R^FourIs C_{1 ~ Four}An alkyl group or R^ThreeAnd R^FourRepresents a 5- to 10-membered, saturated or unsaturated,
Form a heterocyclic group, which is, as a further heteroatom, one or more nitrogen atoms
And / or may have one or more oxygen atoms and / or one or more sulfur atoms, wherein A has the formula CH, COH, C-CN, C-COOR^ThreeOr COR^FourMeans here
And R^ThreeAnd R^FourIs as described above; B is a methylene group; or, A together with B forms a group of the formula -C = C-, Ar is a hydrogen atom, C_{1 ~ Four}Alkyl group, phenyl (C_{1 ~ Four}Alkyl) group, bife
Nyl group, naphthyl group (however, C_{1 ~ Four}Alkoxy group or C_{Two ~ Four}By alkenyl group
May be optionally substituted), partially saturated, condensed with a phenyl group,
A 5- or 6-membered heterocyclic group containing an elemental atom, wherein _{1 ~ Four}  Optionally substituted with alkyl groups); 5- or 6-membered, saturated or unsaturated.
Saturated and, as heteroatoms, nitrogen and / or oxygen and / or sulfur
A heterocyclic group containing: or a substituent; R^Five, R⁶And R⁷Phenyl substituted with
Where R is^Five, R⁶And R⁷Are, independently of one another, a hydrogen atom, a halo atom,
Oromethyl group, C_{1 ~ Four}Alkyl group, methylenedioxy group, phenoxy group (however,
Indeed, C_{1 ~ Four}R) optionally substituted by alkoxy or halo atoms, C)_{Two ~ Four}  Alkenyl group, C_{Two ~ Four}An alkenyloxy group, optionally di (C_{1 ~ Four}An alkyl group or a 5- or 6-membered, saturated heterocyclic group (provided that one or more nitrogen atoms and oxygen atoms
And the heterocyclic group optionally has C_{1 ~ Four}Optionally substituted with an alkyl group)
Or A is of the formula N- (CH_Two)_n-Ar 'group, wherein Ar' is a diphenylmethyl group, a pyridyl group, a pyrimidinyl group, a naphthyl group (
Where arbitrarily C_{1 ~ Four}Alkyl group or C_{Two ~ Four}A 5- or 6-membered heterocyclic group, partially saturated, condensed with a phenyl group and containing 1-2 oxygen atoms, wherein the heterocyclic group is optionally substituted with an alkenyl group); , 1-3 C_{1 ~ Four}No
Or a substituent R)^Five, R⁶And R⁷File replaced by
Enyl group (R^Five, R⁶And R⁷N is 0 or 1) and pharmaceutically acceptable acid addition salts thereof, and one or more benzofuran derivatives.
Pharmaceutical composition characterized by containing usual carrier substances. 9. An active ingredient represented by the formula (I) wherein R ¹ is water
A atom or a C _{1 ~ 4} alkyl group, R ² is a hydrogen atom, X is an oxygen atom, Y is a hydrogen atom or a hydroxy, Z is a hydrogen atom, a halo atom or a nitro group in it, a is with B, to form a formula -C = C-group, Ar represents a hydrogen atom, a benzyl group, is substituted with a substituent R ^5, R ⁶ and R ^7, phenylene
Group, a biphenyl group, a naphthyl group (provided that optionally substituted with C _{1 ~ 4} alkoxy group), or a thienyl group, wherein, R ^5, R ⁶ and R ⁷ independently of one another, a hydrogen atom , halo atoms, trifluoromethyl group, C _{1 ~ 4} alkyl group, C _{1 ~ 4} alkoxy group, C _{2 ~ 4} alkenyloxy group, a pharmaceutically acceptable benzofuran derivatives and their phenoxy group or a methylenedioxy group) 9. The pharmaceutical composition according to claim 8, which comprises an acid addition salt. 10. An active ingredient represented by the formula (I) wherein R ¹ is a methyl group,
R ² is a hydrogen atom, X is an oxygen atom, Y is hydroxy, Z is a hydrogen atom, A represents a formula CH, COH or C-CN, and B represents A is a methylene group, or A is together with B a formula -C = C- group, and Ar is a phenyl group optionally substituted with a halo atom, a trifluoromethyl group, a methyl group or a methoxy group; The benzofuran derivative according to claim 1 or 2, and a pharmaceutically acceptable acid addition salt thereof, the pharmaceutical composition according to claim 8 or 9, which is a methoxynaphthyl group. 11. An active ingredient of the formula (Ia)(However, R¹Is C_{1 ~ Four}Alkyl, R^TwoIs a hydrogen atom, X is an oxygen atom, Y is hydroxy, Z is a hydrogen atom, Ar 'is a diphenylmethyl group, a pyridyl group, partially saturated, and a phenyl group
A 5- or 6-membered heterocyclic group fused and containing two oxygen atoms;
Substituent R^Five, R⁶And R⁷A phenyl group substituted by^Five, R⁶ 
And R⁷Is independently of each other a hydrogen atom, a halo atom, a trifluoromethyl group,_{1 ~ Four} Alkyl group, C_{1 ~ Four}An alkoxy group or a methylenedioxy group, n is 0 or 1) and a piperazinylalkylbenzofuran derivative;
9. The method according to claim 8, comprising a pharmaceutically acceptable acid addition salt thereof.
Pharmaceutical composition. 12. An active ingredient represented by the formula (Ia): wherein R ¹ is a methyl group, R ² is a hydrogen atom, X is an oxygen atom, Y is hydroxy, Z is Is a hydrogen atom, and Ar ′ is a diphenylmethyl group, a pyridyl group, a benzo-1,3-dioxolanyl group, or one or two halo atoms, one or two methyl groups, or a methylenedioxy group. , A phenyl group optionally substituted with a trifluoromethyl group or a methoxy group, and n is 0 or 1.) and a piperazinylalkylbenzofuran derivative according to claim 4, and a pharmaceutically acceptable acid thereof. Pharmaceutical composition according to claim 11, characterized in that it contains an addition salt. 13. An active ingredient comprising 1 / 3- (2,2-dimethyl-2,3-
Dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-
(3-trifluoro-methylphenyl) -1,2,3,6-tetrahydropyridine, 1 / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl //-4-hydroxy-4- (3-trifluoro-methylphenyl) piperidine, 1 / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl /- 4-hydroxy-4- (4-trifluoro-phenyl) piperidine, 1 / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy -4-phenyl-piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypro Pill / -4-hydroxy-4- (3-chloro-phenyl) piperidine, 1 / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4 -Hydroxy-4- (3-methoxy-phenyl) piperidine, 1 / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4 -(4-methoxy-phenyl) piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4- (3-trifluoromethyl- Phenyl) piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydr Roxy-4- (4-methyl-phenyl) piperidine, 1 / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-cyano-4- Phenyl-piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (4-chloro-phenyl) piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4-hydroxy-4- (6-methoxy-naphthyl-2-yl) piperidine, 1- / 3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl / -4- (diphenylmethyl) pipera Gin, 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-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, And one of the acid addition salts of these compounds.
A pharmaceutical composition according to claim 1. 14. The formula (I)(However, R¹And R^TwoIs independently a hydrogen atom or C_{1 ~ Four}X is an oxygen atom or a sulfur atom, Y is a hydrogen atom or hydroxy, Z is a hydrogen atom, a halo atom, C_{1 ~ Four}Alkyl group, C_{1 ~ Four}Alkoxy group, amino group
, Nitro group, cyano group, trifluoromethyl group, formula -COOR^Three, -NHCOR^Three Or -SO_TwoNR^ThreeR^FourWhere R^ThreeIs a hydrogen atom or C_{1 ~ Four}In an alkyl group, R^FourIs C_{1 ~ Four}An alkyl group or R^ThreeAnd R^FourRepresents a 5- to 10-membered, saturated or unsaturated,
Form a heterocyclic group, which is, as a further heteroatom, one or more nitrogen atoms
And / or may have one or more oxygen atoms and / or one or more sulfur atoms, wherein A has the formula CH, COH, C-CN, C-COOR^ThreeOr COR^FourMeans here
And R^ThreeAnd R^FourIs as described above; B is a methylene group; or, A together with B forms a group of the formula -C = C-, Ar is a hydrogen atom, C_{1 ~ Four}Alkyl group, phenyl (C_{1 ~ Four}Alkyl) group, bife
Nyl group, naphthyl group (however, C_{1 ~ Four}Alkoxy group or C_{Two ~ Four}By alkenyl group
May be optionally substituted), partially saturated, condensed with a phenyl group,
A 5- or 6-membered heterocyclic group containing an elemental atom, wherein _{1 ~ Four}  Optionally substituted with alkyl groups); 5- or 6-membered, saturated or unsaturated.
Saturated and, as heteroatoms, nitrogen and / or oxygen and / or sulfur
A heterocyclic group containing: or a substituent; R^Five, R⁶And R⁷Phenyl substituted with
Where R is^Five, R⁶And R⁷Are, independently of one another, a hydrogen atom, a halo atom,
Oromethyl group, C_{1 ~ Four}Alkyl group, methylenedioxy group, phenoxy group (however,
Indeed, C_{1 ~ Four}R) optionally substituted by alkoxy or halo atoms, C)_{Two ~ Four}  Alkenyl group, C_{Two ~ Four}An alkenyloxy group, optionally di (C_{1 ~ Four}An alkyl group or a 5- or 6-membered, saturated heterocyclic group (provided that one or more nitrogen atoms and oxygen atoms
And the heterocyclic group optionally has C_{1 ~ Four}Optionally substituted with an alkyl group)
Or A is of the formula N- (CH_Two)_n-Ar 'group, wherein Ar' is a diphenylmethyl group, a pyridyl group, a pyrimidinyl group, a naphthyl group (
Where arbitrarily C_{1 ~ Four}Alkyl group or C_{Two ~ Four}A 5- or 6-membered heterocyclic group, partially saturated, condensed with a phenyl group and containing 1-2 oxygen atoms, wherein the heterocyclic group is optionally substituted with an alkenyl group); , 1-3 C_{1 ~ Four}No
Or a substituent R)^Five, R⁶And R⁷File replaced by
Enyl group (R^Five, R⁶And R⁷Is as described above); n is 0 or 1) and their pharmaceutically acceptable
Non-toxic doses of acid addition salts to be administered, especially those with heart disease or
A method for treating a patient, comprising treating the patient after treatment. 15. The formula (I)(However, R¹And R^TwoIs independently a hydrogen atom or C_{1 ~ Four}X is an oxygen atom or a sulfur atom, Y is a hydrogen atom or hydroxy, Z is a hydrogen atom, a halo atom, C_{1 ~ Four}Alkyl group, C_{1 ~ Four}Alkoxy group, amino group
, Nitro group, cyano group, trifluoromethyl group, formula -COOR^Three, -NHCOR^Three Or -SO_TwoNR^ThreeR^FourWhere R^ThreeIs a hydrogen atom or C_{1 ~ Four}In an alkyl group, R^FourIs C_{1 ~ Four}An alkyl group or R^ThreeAnd R^FourRepresents a 5- to 10-membered, saturated or unsaturated,
Form a heterocyclic group, which is, as a further heteroatom, one or more nitrogen atoms
And / or may have one or more oxygen atoms and / or one or more sulfur atoms, wherein A has the formula CH, COH, C-CN, C-COOR^ThreeOr COR^FourMeans here
And R^ThreeAnd R^FourIs as described above; B is a methylene group; or, A together with B forms a group of the formula -C = C-, Ar is a hydrogen atom, C_{1 ~ Four}Alkyl group, phenyl (C_{1 ~ Four}Alkyl) group, bife
Nyl group, naphthyl group (however, C_{1 ~ Four}Alkoxy group or C_{Two ~ Four}By alkenyl group
May be optionally substituted), partially saturated, condensed with a phenyl group,
A 5- or 6-membered heterocyclic group containing an elemental atom, wherein _{1 ~ Four}  Optionally substituted with alkyl groups); 5- or 6-membered, saturated or unsaturated.
Saturated and, as heteroatoms, nitrogen and / or oxygen and / or sulfur
A heterocyclic group containing: or a substituent; R^Five, R⁶And R⁷Phenyl substituted with
Where R is^Five, R⁶And R⁷Are, independently of one another, a hydrogen atom, a halo atom,
Oromethyl group, C_{1 ~ Four}Alkyl group, methylenedioxy group, phenoxy group (however,
Indeed, C_{1 ~ Four}R) optionally substituted by alkoxy or halo atoms, C)_{Two ~ Four}  Alkenyl group, C_{Two ~ Four}An alkenyloxy group, optionally di (C_{1 ~ Four}An alkyl group or a 5- or 6-membered, saturated heterocyclic group (provided that one or more nitrogen atoms and oxygen atoms
And the heterocyclic group optionally has C_{1 ~ Four}Optionally substituted with an alkyl group)
Or A is of the formula N- (CH_Two)_n-Ar 'group, wherein Ar' is a diphenylmethyl group, a pyridyl group, a pyrimidinyl group, a naphthyl group (
Where arbitrarily C_{1 ~ Four}Alkyl group or C_{Two ~ Four}A 5- or 6-membered heterocyclic group, partially saturated, condensed with a phenyl group and containing 1-2 oxygen atoms, wherein the heterocyclic group is optionally substituted with an alkenyl group); , 1-3 C_{1 ~ Four}No
Or a substituent R)^Five, R⁶And R⁷File replaced by
Enyl group (R^Five, R⁶And R⁷Is as described above); n is 0 or 1) and their pharmaceutically acceptable
Use of one or more carrier substances commonly used in the manufacture of pharmaceuticals
By converting into a pharmaceutical composition.
Or a method of producing a pharmaceutical composition suitable for treating a central nervous system disease. 16. The formula (II) (Wherein, R ¹ and R ² are independently hydrogen atom or C _{1 ~ 4} alkyl, X is oxygen atom or sulfur atom, Y is a hydrogen atom or a hydroxy, Z is a hydrogen atom halo atom, C _{1 ~ 4} alkyl group, C _{1 ~ 4} alkoxy group, an amino group, a nitro group, a cyano group, a trifluoromethyl group, wherein -COOR ^3, -NHCOR ^3, or with -SO ₂ NR ³ R ⁴ There, in which case, R ³ is a hydrogen atom or a C _{1 ~ 4} alkyl group, R ⁴ is a C _{1 ~ 4} alkyl group, or R ³ and R ^4, will together with the adjacent nitrogen atom, 5 Forming a 10-membered, saturated or unsaturated heterocyclic group, which has, as further heteroatoms, one or more nitrogen atoms and / or one or more oxygen atoms and / or one or more sulfur atoms; Get, Ha
l is a halo atom). 17. The formula (XV) (Wherein, R ¹ and R ² are independently hydrogen atom or C _{1 ~ 4} alkyl, X is oxygen atom or sulfur atom, Y is a hydrogen atom or a hydroxy, Z is a hydrogen atom halo atom, C _{1 ~ 4} alkyl group, C _{1 ~ 4} alkoxy group, an amino group, a nitro group, a cyano group, a trifluoromethyl group, wherein -COOR ^3, -NHCOR ^3, or with -SO ₂ NR ³ R ⁴ There, in which case, R ³ is a hydrogen atom or a C _{1 ~ 4} alkyl group, R ⁴ is a C _{1 ~ 4} alkyl group, or R ³ and R ^4, will together with the adjacent nitrogen atom, 5 Forming a 10-membered, saturated or unsaturated heterocyclic group, which has, as further heteroatoms, one or more nitrogen atoms and / or one or more oxygen atoms and / or one or more sulfur atoms; Get, Ha
l is a ketone having a halo atom).