EP1077973A2 - Derives de benzofuranne, composition pharmaceutique renfermant ces derives et procede de preparation du principe actif - Google Patents

Derives de benzofuranne, composition pharmaceutique renfermant ces derives et procede de preparation du principe actif

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Publication number
EP1077973A2
EP1077973A2 EP99923772A EP99923772A EP1077973A2 EP 1077973 A2 EP1077973 A2 EP 1077973A2 EP 99923772 A EP99923772 A EP 99923772A EP 99923772 A EP99923772 A EP 99923772A EP 1077973 A2 EP1077973 A2 EP 1077973A2
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EP
European Patent Office
Prior art keywords
group
formula
atom
benzofuran
dimethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99923772A
Other languages
German (de)
English (en)
Inventor
Béla Agai
József Reiter
Gyula Simig
Endre Rivo
Zoltán Tamás NAGY
Levente Ondi
Katalin Ivanicsne Megyeri
Anikú MIKLOSNE KOVACS
Ildikú NAGYNE GYÖNÖS
Szabolcs Kertesz
Gábor SZENASI
Eva Schmidt
Katalin Pallagi
István GACSALYI
István GYERTYAN
Tamás Szabados
György; LEVAY
András Egyed
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
Original Assignee
Egyt Gyogyszervegyeszeti Gyar
Egis Pharmaceuticals PLC
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Filing date
Publication date
Priority claimed from HU9801085A external-priority patent/HUP9801085A3/hu
Priority claimed from HU9801086A external-priority patent/HUP9801086A3/hu
Application filed by Egyt Gyogyszervegyeszeti Gyar, Egis Pharmaceuticals PLC filed Critical Egyt Gyogyszervegyeszeti Gyar
Publication of EP1077973A2 publication Critical patent/EP1077973A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention refers to novel benzofuran derivatives, pharmaceutical compositions containing the same as the active ingredient, and a process for the preparation of the active ingredient.
  • novel compounds influence the circulatory system and the heart, furthermore have an effect on the central nervous system.
  • the invention refers to a novel benzofuran derivative of the formula
  • R 1 and R2 represent, independently, a hydrogen atom or a C, , alkyl group
  • X stands for an oxygen atom or a sulfur atom
  • Y means a hydrogen atom or a hydroxy group
  • Z represents a hydrogen atom, a halo atom, a C,_, alkyl group, a C-, , alkoxy group, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a group of the formula -COOR 3 , -NHCOR3 or 3 4 -SC NR R , wherein
  • R ⁇ stands for a hydrogen atom or a C-,_ 4 alkyl group
  • R is a C-, _ 4 alkyl group, or R 3 and R4 form, together with the adjacent nitrogen atom, a saturated or unsaturated heterocyclic group having 5 to 10 members and optionally comprising one or more nitrogen atom(s) and/or one or more oxygen atom(s) and/or one or more sulfur atom(s) as the further heteroatom( s ) ,
  • A means a group of the formula CH, COH, C-CN,
  • B represents a methylene group
  • Ar stands for a hydrogen atom, a C-, 4 alkyl group, a phenyl (C-, , alkyl) group, a biphenylyl group, a naphthyl group, wherein said latter species are optionally substituted by a C, 4 alkoxy group or a C2_ 4 alkenyl group; a partially saturated, 5- or 6-membered heterocyclic group condensed with a phenyl group and containing one or two oxygen atom(s), said heterocyclic group being optionally substituted by one to three C-.
  • R 5 , R6 and R7 mean, independently, a hydrogen atom, a halo atom, a trifluoro- methyl group, a C, _ . alkyl group, a methylenedioxy group, a phenoxy group optionally substituted by a C-, . alkoxy group or by a halo atom; a C favor . alkenyl group, a C ⁇ _ .
  • alkenyloxy group a C, _ . alkoxy group optionally substituted by a di(C, 4 alkyl) amino group or by a 5- or 6-membered, saturated hetero cyclic group containing one or two nitrogen atom(s) or a nitrogen atom and an oxygen atom, wherein said heterocyclic group is optionally substituted by a C, . alkyl group, or stands for a group of the formula
  • Ar ' represents a diphenylmethyl group, a pyridyl group, a pyrimidinyl group, a naphthyl group, wherein said latter group is optionally substituted by a C, _ 4 alkoxy group or a C_ . alkenyloxy group; a partially saturated, 5- or 6-membered heterocyclic group condensed with a phenyl group and containing one or two oxygen atom(s), said heterocyclic group being optionally substituted by one to three C-, .
  • n has a value of 0 or 1, and pharmaceutically suitable acid addition salts thereof.
  • furancarboxylic amides have antidepressant properties /Yakugaku Zasshi, 9J_ (5), 540 (1977); C.A., 87_, 152125d (1997)/, while benzofuran derivatives having amino, amidino, thiocarboxamidino or dialkylaminoalkyl substituents on the furan ring are H_ receptor antagonists, and, consequently, possess anantiulcer effect / Raced PCT application No. WO 86 02550; C.A., 105, 226586u (1986)/.
  • Tetrahydronaphthoxy derivatives having hypotensive activity are known from DE-OS No. 22 35 597.
  • the chemical structure of the known compounds resembles to that of the piperazinylalkylbenzofuran derivatives of the formula la.
  • the aim of the invention is to prepare novel benzofuran derivatives some representants of which influencing the circulatory system and the heart function, while other representants of which having an effect on the central nervous system.
  • a halo atom is, primarily, a fluoro, chloro, bromo or iodo atom, preferably a fluoro, chloro or bromo atom.
  • a C, 4 alkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. -butyl, tert. -butyl or isobutyl group.
  • a C ⁇ 4 alkyl group is a methyl group.
  • a C 2 _ 4 alkenyl group is a vinyl, allyl, methallyl or crotyl group, preferably an allyl or methallyl group.
  • a C,_ 4 alkoxy group is, primarily, a methoxy, ethoxy, n-propoxy, isopropoxy or butoxy group, preferably a methoxy or isopropoxy group.
  • a C 2 _ 4 alkenyloxy group is suitably an allyloxy or methallyloxy group.
  • a C-,_ 4 alkoxy group substituted by a di(C ⁇ alkyl) amino group is, in the first place, a 2-dimethylaminoethoxy , 3-dimethyl- aminopropoxy, 2-diethylaminoethoxy , 3-diethyl- aminopropoxy or 4-dimethylaminobutoxy group, preferably a 2-dimethylaminoethoxy group.
  • a partially saturated, 5- or 6-membered heterocyclic group condensed with a phenyl group and containing one or two oxygen atom(s) is a dihydrobenzofuran, benzodioxolan, dihydrobenzpyran or benzodioxan group.
  • a 5- or 6-membered, saturated or unsaturated heterocyclic group containing a nitrogen atom and/or an oxygen atom and/or a sulfur atom as the heteroatom is, preferably, a heterocyclic group wherein the heteroatom consists of a nitrogen atom or an oxygen atom or a sulfur atom or a nitrogen atom and an oxygen atom, and the heterocyclic ring contains no double bond or one or more double bond(s).
  • a heterocyclic group is, for example, a pyrrolyl, pyrrolidinyl, piperidinyl, pyridyl, morpholinyl, furyl or thienyl group.
  • the above heterocyclic group is suitably a thienyl group.
  • a 5- or 6-membered, saturated heterocyclic group containing one or two nitrogen atom(s) or a nitrogen atom and an oxygen atom is, preferably, a pyrrolidinyl, piperidinyl, piperazinyl or morpholino group, the nitrogen atom of which is linked to the carbon atom of the C ⁇ 4 alkoxy group.
  • a saturated or unsaturated heterocyclic group having 5 to 10 members is, for example, a pyrrolidinyl, pyrrolyl, piperidinyl, pyridyl, furyl, tetrahydrofuryl, morpholinyl, piperazinyl, imidazolidinyl , pyrimidinyl, pyrazolyl, pyrazolidinyl, thienyl, hexamethyleneimine-1-yl , heptamethylene- imine-1-yl etc. group.
  • a pharmaceutically suitable acid addition salt is an acid addition salt formed with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid etc. or with an organic acid such as acetic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid etc.
  • the invention includes any possible isomers of the compounds of the formula I and the mixtures thereof.
  • a preferred subgroup of the benzofuran derivatives of the invention consists of the compounds of the formula I wherein
  • R represents a hydrogen atom or a C ⁇ _ 4 alkyl group
  • R stands for a hydrogen atom
  • X means an oxygen atom
  • Y is a hydrogen atom or a hydroxy group
  • Z represents a hydrogen atom, a halo atom or a nitro group
  • A stands for a group of the formula CH, COH or C-CN
  • Ar represents a hydrogen atom, a benzyl group, a phenyl group substituted by substituents R , R and R , a biphenylyl group, a naphthyl group optionally substituted by a C ⁇ 4 alkoxy group; or a thienyl group, wherein R , R and R mean, independently, a hydrogen atom, a halo atom, a trifluoro- methyl group, a C-,_ 4 alkyl group, a C 1 _4 a l ko ⁇ y group, a C ⁇ _ 4 alkenyloxy group, a phenoxy group or a methylenedioxy group, and pharmaceutically suitable acid addition salts
  • the suitable benzofuran derivatives of the invention consist of compounds of the formula I wherein R represents a methyl group
  • X means an oxygen atom
  • Y is a hydroxy group
  • Z represents a hydrogen atom
  • A is a group of the formula CH, COH or C-CN,
  • Ar represents a phenyl group optionally substituted by a halo atom, a trifluoro- methyl group, a methyl group or a methoxy group; or a methoxynaphthyl group, and pharmaceutically suitable acid addition salts thereof.
  • a further preferred subgroup of the benzofuran derivatives of the invention consists of the piperazinylalkylbenzofuran derivatives of the formula
  • R represents a C-, _ . alkyl group
  • R 2 stands for a hydrogen atom
  • X means an oxygen atom
  • Y is a hydroxy group
  • Z represents a hydrogen atom
  • Ar ' represents a diphenylmethyl group, a pyridyl group, a partially saturated 5-membered heterocyclic group containing two oxygen atoms and being condensed with a phenyl group, or a phenyl group substituted by substituents R 5 , R6
  • R , R and R mean, independently, a hydrogen atom, a halo atom, a trifluoro- methyl group, a C,_. alkyl group, a
  • n has a value of 0 or 1, and pharmaceutically suitable acid addition salts thereof.
  • R represents a methyl group
  • X means an oxygen atom
  • Y is a hydroxy group
  • Z represents a hydrogen atom
  • Ar ' represents a diphenylmethyl group, a pyridyl group, a benzo-1 , 3-dioxolanyl group or a phenyl group optionally substituted by one or two halo atom(s), one or two methyl group(s), a methylenedioxy group, a trifluoromethyl group or a methoxy group, n has a value of 0 or 1, and pharmaceutically suitable acid addition salts thereof.
  • benzofuran derivatives of the formula la are as follows: 1-/3- ( 2, 2-dimethy1-2, 3-dihydro-benzof ran-7-yl- oxy ) -2-hydroxypropyl/-4- (diphenylmethyl ) - piperazine,
  • R 1 , R2 , X, Y and Z are as defined in connection with formula I, Hal represents a halo atom, is reacted with a secondary amine of the formula
  • A, B and Ar are as defined in connection with formula I, an epoxide of the formula
  • X, Y, Z and Ar are as defined in connection with formula I
  • a benzofuran derivative of the formula I wherein A stands for a group of the formula COH
  • B represents a methylene ggrroouupp,, RR 1 ,, RR2 ,, XX,, YY,, ZZ aarnd Ar are as stated above, is dehydrated; or f) for the preparation of a benzofuran derivative of the formula I, wherein A represents a group of the formula COH, B stands
  • Ar is other than a hydrogen atom, a ketone of the formula
  • Ar is other than a hydrogen atom, a ketone of the formula XV, wherein R 1 , R2 ,
  • X, Y, Z and Ar are as stated above, is hydrogenized in the reaction mixture in which it was prepared; and if desired, an obtained base of the formula I is reacted with an inorganic or organic acid to form a pharmaceutically suitable acid addition salt thereof, or liberated from the acid addition salt with a base.
  • reaction of the halide of the formula II with the secondary amine of the formula IV is suitably performed in an excess of the corresponding secondary amine of the formula IV.
  • reaction can be carried out also in an indifferent solvent in the presence of a suitable base, eventually in a two-phase system.
  • the solvent can be for example an alcohol, preferably methanol, ethanol or isopropanol, diisopropyl ether, dioxane, acetonitrile, dimethyl formamide, dimethyl sulfoxide, halogenated solvents, preferably dichloromethane, 1 , 2-dichloroethane or chlorobenzene.
  • the base can be an inorganic one such as an alkali metal hydroxide or an alkali earth metal hydroxide, preferably sodium or potassium hydroxide, or an organic base, preferably a trialkylamine or a tetraalkylammonium hydroxide.
  • An especially preferred base is triethylamine.
  • the base is used in a 0.8-1.1 molar equivalent, preferably 0.9-1.0 molar equivalent quantity, calculated to the compound of the formula II.
  • the formed product of the formula I is separated from the reaction mixture by a method known in itself. Thus, if the product crystallizes from the solvent employed in the reaction mixture or can be precipitated with another solvent that is miscible with the original solvent, then the product is filtered and purified by recrystallization or chromatography.
  • the solution is evaporated, and the residue is recrystallized from a suitable solvent.
  • reaction of the epoxide of the formula III with the secondary amine of the formula IV is carried out in an indifferent solvent or in an excess of the secondary amine.
  • the solvent for the reaction can be, for example, methanol, ethanol, isopropanol, butanol, diisopropyl ether, acetonitrile, acetone, methyl ethyl ketone, dimethyl formamide, water or mixtures thereof, preferably ethanol, isopropanol or 5-20 mass %, preferably 10 mass % solutions thereof in water.
  • each mole of the epoxide of the formula III is reacted with 0.8-2.0, preferably 0.85-1.2 moles of the secondary amine of the formula IV.
  • the secondary amine of the formula IV is added directly to the reaction mixture.
  • the base can be liberated in the reaction mixture in situ by adding a molar equivalent quantity of inorganic or organic base calculated to the amount of the salt of the secondary amine.
  • the inorganic base primarily a 5-40 mass %, preferably 10-25 mass % solution of an alkali metal or alkali earth metal hydroxide, preferably sodium or potassium hydroxide in water is used.
  • organic base preferably a trialkylamine or a tetraalkylammonium hydroxide, specifically triethylamine is employed.
  • reaction is performed at the boiling point of the solvent employed or at a lower temperature.
  • the product is separated from the reaction mixture as described under process a) above.
  • reaction of the compound of the formula V with the halo compound of the formula XI is carried out in an indifferent solvent in the presence of an inorganic or organic base and a phase transfer catalyst.
  • the inorganic base is primarily a hydroxide or carbonate of an alkali metal or alkali earth metal, preferably sodium or potassium hydroxide or potassium carbonate.
  • the organic base is a trialkylamine or a tetraalkylammonium hydroxide, preferably triethylamine.
  • the base is taken in 1-2, preferably 1.2 molar equivalent quantity, calculated to the compound of the formula V.
  • the halo compound of the formula XI is used in 1-3, preferably 1.8-2 molar equivalent quantity, calculated to the compound of the formula V.
  • the solvent for the reaction can be, for example, methanol, ethanol, propanol , butanol, acetone, methyl ethyl ketone, diethyl ketone, acetonitrile, dimethyl formamide, water, preferably ethanol, acetone or methyl ethyl ketone.
  • the phase transfer catalyst can be a tetraalkylammonium hydroxide or halide, preferably trimethylbenzylammonium hydroxide, triethylbenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium hydrosulfate.
  • the reaction is carried out at a temperature of 40 to 100 °C, preferably 60 to 80 °C.
  • the product is separated in a manner known in itself. After the end of the reaction, the reaction mixture is, for example, evaporated to dryness under reduced pressure, the residue is subjected to partition between water and an organic solvent that is immiscible with water, the separated organic phase is dried, evaporated to dryness under reduced pressure, and the residue is purified by recrystallization from a suitable solvent or by vacuum distillation.
  • the solvent can be, for example, methanol, ethanol, isopropanol, butanol, diisopropyl ether, acetonitrile, acetone, methyl ethyl ketone, dimethyl formamide, water or a mixture thereof, preferably ethanol, isopropanol or a 5-20 mass %, preferably 10 mass % mixture thereof in water.
  • the compound of the formula V is used in 0.8-2.0, preferably 0.85-1.2 molar equivalent quantity, calculated to the epoxide of the formula XII.
  • reaction is carried out at the boiling point of the solvent employed, or at a lower temperature.
  • the product can be separated from the reaction mixture as described in connection with process c) above.
  • the dehydration of the compound of the formula I, wherein A represents a group of the formula COH, B stands for a methylene group is carried out by means of a strong mineral acid, preferably hydrochloric acid, in an indifferent solvent, preferably an alcohol, especially preferably in ethanol under heating, preferably boiling. It is convenient to use the starting compound in a solution having a concentration of 5-40 %, preferably 15-25 %. If the product separates from the solution after cooling, then it is filtered; in the opposite case, a solution that does not dissolve the product, however, being miscible with the solvent used in the reaction, preferably ether is added to the reaction mixture, and the crystals precipitated are filtered.
  • a strong mineral acid preferably hydrochloric acid
  • an indifferent solvent preferably an alcohol, especially preferably in ethanol under heating, preferably boiling.
  • the ketone of the formula XV is reacted with the arylmagnesium halide of the formula XVI or the aryllithium compound of the formula XVII in an indifferent aprotic organic solvent, preferably ether, tetrahydrofuran or dioxane at a temperature between -10 °C and the boiling point of the solvent, preferably 10 to 30 °C.
  • an indifferent aprotic organic solvent preferably ether, tetrahydrofuran or dioxane
  • the product can be obtained from the reaction mixture - after decomposing the complex formed in the reaction with an acid and evaporating the solvent - by simple recrystallization or salt formation.
  • the reaction mixture decomposed with an acid is made alkaline, the product is dissolved in an organic solvent being immiscible with water, the organic phase is dried, evaporated, and the base obtained is purified by crystallization or chromatography.
  • a noble metal catalyst on a carbon carrier, preferably palladium on carbon, especially preferably 10 % palladium on carbon catalyst in an alcohol, preferably methanol.
  • the product is separated by evaporating the solvent and crystallizing the residue.
  • the evaporation residue can be converted to a salt.
  • the reaction mixture is subjected to partition between water and an organic solvent being immiscible with water, the organic phase is dried, evaporated, and the residual base is purified by crystallization or chromatography.
  • the reduction can be performed also in the reaction mixture in which the starting compound was prepared.
  • the halides of the formula II are novel compounds, thus, the invention includes these compounds, too.
  • the halides of the formula II can be prepared by reacting a compound of the formula V with a dihaloalkane of the formula
  • the halide of the formula II can be prepared by reacting a compound of the formula V with a haloalkanol derivative of the formula
  • the compound of the formula V is reacted with the dihaloalkane of the formula VI in an indifferent solvent in the presence of an inorganic or organic base and a phase transfer catalyst.
  • the inorganic base is, primarily, an alkali metal or alkali earth metal hydroxide or carbonate, preferably sodium or potassium hydroxide or potassium carbonate.
  • the organic base is a trialkylamine or a tetraalkylammonium hydroxide, preferably triethylamine.
  • the base is employed in 1 to 1.5 molar quantity, calculated to the compound of the formula V.
  • the dihaloalkane of the formula VI is taken in 1-3, preferably 1.8-2 molar equivalent quantity, calculated to the compound of the formula V.
  • the solvent can be, for example, methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, acetonitrile, dimethyl formamide, water, preferably ethanol, acetone or methyl ethyl ketone.
  • the phase transfer catalyst can be a tetraalkylammonium hydroxide or halide, preferably trimethylbenzylammonium hydroxide, triethylbenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium hydrosulfate.
  • the reaction can be carried out at a temperature of 40 to 100 C, preferably 60 to 80 °C.
  • the product is separated from the reaction mixture in a manner known in itself. For example, after the end of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residue is subjected to partition between water and an organic solvent being immiscible with water, the organic phase is separated, dried, evaporated to dryness under reduced pressure, and the residue is purified by recrystallization from a suitable solvent or by vacuum distillation.
  • reaction of the compound of the formula V with the haloalkanol derivative of the formula VII is carried out in an analogous manner as described in connection with the reaction of the compound of the formula V with the dihaloalkane of the formula VI.
  • the formed hydroxyalkyl derivatives of the formula VIII are converted to the desired halides of the formula II using a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, thionyl bromide, phosphorus oxybromide, phosphorus pentabromide, phosphorus pentaiodide, phosphorus tribromide, preferably thionyl chloride.
  • a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, thionyl bromide, phosphorus oxybromide, phosphorus pentabromide, phosphorus pentaiodide, phosphorus tribromide, preferably thionyl chloride.
  • the halogenating agent is used in an excess of 1-4 moles, preferably 1.2-2.2 moles for each mole of the starting hydroxyalkyl derivative of the formula VIII.
  • the reaction is carried out in an indifferent solvent, preferably halogenated alkanes, especially chloroform, dichloromethane or 1 , 2-dichloroethane, or an excess of the halogenating agent is used as the solvent.
  • an indifferent solvent preferably halogenated alkanes, especially chloroform, dichloromethane or 1 , 2-dichloroethane, or an excess of the halogenating agent is used as the solvent.
  • epoxides of the formula III are known from the literature /Japane Patent Application published under No. J6 0258-174-A; C.A., 104, 207136k (1986)/. They are prepared from the compounds of the formula V by reaction with epichlorohydrin in alkaline medium. As an alternative, they can be prepared by reacting the compound of the formula V with a halide of the formula
  • the compound of the formula V is reacted with 1-3 molar equivalent quantity of epichlorohydrin in the presence of an alkali metal or alkali earth metal hydroxide, preferably sodium or potassium hydroxide used in 1-3 molar equivalent quantity.
  • the reaction is carried out in methanol, ethanol, propanol, acetone, methyl ethyl ketone, acetonitrile, dimethyl formamide, water or a mixture thereof, preferably aqueous methanol or aqueous ethanol, conveniently at the boiling point of the solvent or at a lower temperature.
  • the epoxide of the formula III that forms in the reaction can be separated in a manner known in itself. For example, after the end of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residue is subjected to partition between water and an organic solvent being immiscible with water, the separated organic phase is dried, and evaporated to dryness under reduced pressure. In general, the residue is pure enough for the further reactions. If necessary, the product can be purified by chromatography or crystallization.
  • the alkaline medium is achieved by means of an alkali metal or alkali earth metal hydroxide or carbonate, preferably sodium or potassium hydroxide or potassium carbonate.
  • the bases listed are used in 12 molar equivalent quantity.
  • the solvent is, for example, methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, diethyl ketone, acetonitrile, dimethyl formamide, water or a mixture thereof, preferably ethanol, acetone or methyl ethyl ketone.
  • phase transfer catalyst a tetraalkylammonium hydroxide or halide, preferably trimethylbenzylammonium hydroxide, triethylbenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium hydrosulfate can be used.
  • the reaction is performed at a temperature of 40 to 100 °C, preferably 60 to 80 °C.
  • the product is separated in a manner known in itself. For example, after the end of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residue is subjected to partition between water and an organic solvent being immiscible with water, the organic phase separated is dried, evaporated to dryness under reduced pressure, and the residue is purified by recrystallization from a suitable solvent or by vacuum distillation.
  • the allyl derivative of the formula X is oxidized to the corresponding epoxide of the formula III with an organic oxidizing agent such as m-chloroperbenzoic acid, peracetic acid, perphthalic acid, 2 , 3-dichloro-5 , 5-dicyano-l , 4-benzoquinone (DDQ), preferably m-chloroperbenzoic acid at a temperature of 0 to 40 C, preferably 20 to 30 °C.
  • an organic oxidizing agent such as m-chloroperbenzoic acid, peracetic acid, perphthalic acid, 2 , 3-dichloro-5 , 5-dicyano-l , 4-benzoquinone (DDQ), preferably m-chloroperbenzoic acid at a temperature of 0 to 40 C, preferably 20 to 30 °C.
  • the solvent is dichloromethane , 1 , 2-dichloroethane , chloroform, 1, 1, 2-trichloroethylene, chloro- benzene, preferably dichloromethane or 1 , 2-dichloroethane.
  • the product is separated in a manner known in itself. For example, after the end of the reaction, water is added to the reaction mixture, the solution is made alkaline by the addition of sodium carbonate, the phases are separated, the organic phase is dried, then evaporated to dryness under reduced pressure. The residue is purified by recrystallization from a suitable solvent or by chromatography.
  • halo compounds of the formula XI are known /Peltz, K., Protiva, M., Coll. Czech. Chem. Commun., 32 (8), 2840 (1967), US-P No. 4,110,536; Chem. Abstr., 90, P 121596r)/. They are prepared by reacting a corresponding secondary amine of the formula IV with a corresponding dihaloalkane of the formula VI. The other halo compounds of the formula XI are also easily prepared according to the above processes.
  • epoxides of the formula XII are also known. They are prepared from a corresponding compound of the formula IV that is reacted with epichlorohydrin in alkaline medium /CH-P No. 474,511; Chem. Abstr., 72, 55506m (1970)/. Certain compounds of the formula XII can be also prepared by reacting a corresponding secondary amine of the formula IV with a corresponding halide of the formula IX, and converting the double bond of the formed compound of the formula
  • ketones of the formula XV are novel compounds, thus, the invention includes these compounds, too. They are prepared by reacting a halide of the formula II or an epoxide of the formula III with the piperidone of the formula
  • reaction conditions are identical with those employed in processes a) and b) of the invention.
  • the ketone of the formula XV is reacted with the arylmagnesium halide of the formula XVI as described in the literature /J-P No. 14,632 ('67); Chem. Abstr., 68., 114618s (1968)/.
  • reaction of the aryllithium derivatives of the formula XVII with the ketone of the formula XV can be also carried out in the manner known from the literature /Elpern, B., Wetteran, W., Carabates, Ph., Grunbach, L., J. Am. Chem. Soc, 80, 4916 (1958)/.
  • arylmagnesium halides of the formula XVI and the aryllithium derivatives of the formula XVII are commercially available.
  • the secondary amines of the formula IV are, in general, commercially available, or can be easily prepared by known methods.
  • Cardioprotective compounds protect the myocardium from any impairment during ischemia and/or reperfusion.
  • one of the best known and often employed test consists in the isolated perfused rat heart subjected to global ischemia /Longman, S.D. and Hamilton, T.C., Medicinal Research Reviews, 1_2/ .
  • myocardial contracture comes about due to a rise of the calcium concentration in the myocardium.
  • TTC time to contracture
  • the hearts were perfused for 10 minutes with the vehicle (0.04 % of dimethyl sulfoxide), in case of the control group, or with a solution of the test substance at 10 or
  • TTC left ventricular end diastolic pressure
  • the compounds of the invention caused a considerable prolongation of TTC in isolated perfused rat heart during ischemia. This fact is a proof of the cardioprotective effect.
  • the compound of Example 9 surpasses remarkably also the effect of lemakalim determined at a concentration of 10 M.
  • the cardioprotective effect of the compounds of the invention can be used for human therapy.
  • the above cardioprotective effect raises the possibility of preventing the unfavourable effects of serious coronary arrhythmia that frequently occur in ischemic heart disease by prolonged administration of active substances.
  • the treatment employed can reduce the rate of an irreversible myocardial damage caused by a later myocardial infarction.
  • a further use of the compounds can be a cardioprotective therapy before surgery, for example in case of temporarily blocked coronary circulation (coronary dilatation by balloon) or stopped heart due to surgery causes.
  • a faster and more complete regulation of heart function can be obtained by a cardioprotective treatment of the heart prepared for transplantation.
  • the compound of the invention is added to the nutritive solution of the heart . 2. Determination of the influence on serotonin neurotransmission 5-HT, a receptor binding assay
  • 5-HT, receptor assay was performed according to Peroutka ' s method /Peroutka, S.J., J. Neurochem., 47, 529 (1986)/. The binding was determined in membrane fragments prepared from rat frontal cortex using tritium-labelled
  • the test was carried out according to a modified method of Pelow et al . /J. Neurosci. Methods, 14_, 149 (1985)/.
  • the elevated plus-maze consists of two open and two 40 cm wall enclosed arms of the same size (50 x 15 cm) arranged in the shape of a cross. The arms of the same type are opposite to each other. The junction of the four arms forms a central square area (15 x 15 cm).
  • the apparatus is made of a wooden material elevated to a height of 50 cm and illuminated by a dim light from above. Male Sprague-Dawley rats weighing 220 to 260 g were used for the experiment .
  • the rats were treated with the test or reference compounds 60 minutes prior to the test. The animals were then placed onto a central square area and were subjected to the test for 5 minutes. The following 4 different parameters were determined:
  • Example 25 is superior by one order of magnitude to buspirone in the above test characterizing the anxiolytic effect. It is to be noted that buspirone binds strongly to the 5-HT j , , receptor is widely used in the clinical practice.
  • the compounds of the invention can be used in various diseases primarily due to disorders of the central nervous system.
  • 5-HT 5-HT
  • receptors play a role also in depression clinical patterns since it was shown that 5-HT, ligands had also an antidepressant potential in test models using animals /Porsolt, R.D., Roux, S. and Wettstein, J.G., Pharmacol. Res., 31 , 169 (1995)/.
  • a further therapeutical possibility consists in the therapy of cognitive defficiencies in case of drugs acting on the 5-HT, receptor.
  • the administration of 8-hydroxy-N,N-dipropyl-2-aminotetraline to rats improved the memory and learning performances /Carli, M. and Samanin, R., Br. J. Pharmacol., 105, 720 (1992)/.
  • the anxiolytic effect was examined by the method of Vogel et al. /Vogel, J.R., Beer, B., Clody, D.E., Psychopharmacologia (Berl.), 21, 1 (1971)/.
  • Male Wistar rats weighing 180 to 200 g were left to be thirsty for 48 hours and starved for 24 hours before the test.
  • the substances to be examined and the carriers, respectively, were administered to the animals half an hour before the examination.
  • the rats were allowed to drink from the drinking tube protruding into the chamber. Following every 20th lick, the apparatus emitted an electric shock of 0.7 mA through the drinking tube.
  • the minimum effective dose (MED) was determined for each compound.
  • the benzofurane derivative examined surpassed the effect of the meprobamate used as the reference in the Vogel 's conflict test by a factor of higher than 2. Summing up, the above tests indicate unanimously that the compounds of the invention have a valuable effect on the heart. Simultaneously, due to their mechanism of action, the compounds of the invention can be suitable for the treatment of diseases of the central nervous system such as depression, anxiety, cerebral ischemia, schizophrenia etc.
  • novel benzofuran derivatives of the invention can be used as active ingredients in pharmaceutical compositions.
  • compositions of the invention contain a therapeutically active amount of the compound of the formula I or a pharmaceutically suitable acid addition salt thereof and one or more conventional carrier ( s) .
  • compositions of the invention are suitable for peroral, parenteral or rectal administration or for local treatment, and can be solid or liquid.
  • the solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc., and can comprise binding agents such as gelatine, sorbitol, poly(vinyl- pyrrolidone) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, poly(ethyleneglycol) , silica etc.; wetting agents such as sodium laurylsulfate etc. as the carrier.
  • binding agents such as gelatine, sorbitol, poly(vinyl- pyrrolidone) etc.
  • filling agents such as lactose, glucose, starch, calcium phosphate etc.
  • auxiliary substances for tabletting such as magnesium stearate, talc, poly(ethyleneglycol) , silica etc.
  • wetting agents such as sodium laurylsulfate etc. as the carrier.
  • the liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e.g. suspending agents such as gelatine, carboxymethylcellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propyleneglycol , ethanol etc.; preservatives such as methyl p-hydroxybenzoate etc. as the carrier.
  • suspending agents such as gelatine, carboxymethylcellulose etc.
  • emulsifiers such as sorbitane monooleate etc.
  • solvents such as water, oils, glycerol, propyleneglycol , ethanol etc.
  • preservatives such as methyl p-hydroxybenzoate etc. as the carrier.
  • compositions suitable for parenteral administration consist of sterile solutions of the active ingredient, in general.
  • Dosage forms listed above as well as other dosage forms are known per se, see e.g. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990) .
  • the pharmaceutical compositions of the invention contain, in general, 0.1 to 95.0 per cent by mass of a compound of the formula I or a pharmaceutically suitable acid addition salt thereof.
  • a typical dose for adult patients amounts to 0.1 to 1000 mg of the compound of the formula I or a pharmaceutically suitable acid addition salt, daily.
  • the above dose can be administered in one or more portions. The actual dosage depends on many factors and is determined by the doctor.
  • the pharmaceutical compositions of the invention are prepared by admixing a compound of the formula I or a pharmaceutically suitable acid addition salt thereof to one or more carrier(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se. Useful methods are known from the literature, e.g. Remington's Pharmaceutical Sciences .
  • a preferred subgroup of the pharmaceutical compositions of the invention contains a benzofuran derivative of the formula I, wherein R represents a hydrogen atom or a C, _ . alkyl group,
  • X means an oxygen atom
  • Y is a hydrogen atom or a hydroxy group
  • Z represents a hydrogen atom, a halo atom or a nitro group
  • A stands for a group of the formula CH, COH or C-CN
  • Ar represents a hydrogen atom, a benzyl group, a phenyl group substituted by substituents R 5 , R6 and R7 , a biphenylyl group, a naphthyl group optionally substituted by a C, _ 4 alkoxy group; or a thienyl group, wherein
  • R , R and R mean, independently, a hydrogen atom, a halo atom, a trifluoromethyl group, a C, . a ⁇ kyi group, a C, 4 alkoxy group, a C 2 _ 4 alkenyloxy group, a phenoxy group or a methylenedioxy group, or a pharmaceutically suitable acid addition salt thereof as the active ingredient.
  • compositions of the invention comprise a benzofuran derivative of the formula I, wherein
  • R represents a methyl group
  • X means an oxygen atom
  • Y is a hydroxy group
  • Z represents a hydrogen atom
  • A is a group of the formula CH, COH or C-CN,
  • Ar represents a phenyl group optionally substituted by a halo atom, a trifluoro- methyl group, a methyl group or a methoxy group; or a methoxynaphthyl group, or a pharmaceutically suitable acid addition salt thereof as the active ingredient.
  • a further preferred subgroup of the pharmaceutical compositions of the invention contains a piperazinylalkylbenzofuran derivative of the formula la, wherein
  • R represents a C-, _ . alkyl group
  • R 2 stands for a hydrogen atom
  • X means an oxygen atom
  • Y is a hydroxy group
  • Z represents a hydrogen atom
  • Ar ' represents a diphenylmethyl group, a pyridyl group, a partially saturated 5-membered heterocyclic group containing two oxygen atoms and being condensed with a phenyl group, or a phenyl group substituted by substituents R , R and R , wherein R 5 , R6 and R7 mean, independently, a hydrogen atom, a halo atom, a trifluoro- methyl group, a C, . alkyl group, a
  • n has a value of 0 or 1, or a pharmaceutically suitable acid addition salt thereof as the active ingredient.
  • compositions of the invention contain a piperazinylalkylbenzofuran derivative of the formula la, wherein
  • R represents a methyl group
  • X means an oxygen atom
  • Y is a hydroxy group
  • Z represents a hydrogen atom
  • Ar ' represents a diphenylmethyl group, a pyridyl group, a benzo-1 , 3-dioxolanyl group or a phenyl group optionally substituted by one or two halo atom(s), one or two methyl group(s), a methylenedioxy group, a trifluoromethyl group or a methoxy group, n has a value of 0 or 1, or a pharmaceutically suitable acid addition salt thereof as the active ingredient.
  • compositions of the invention comprise one of the following benzofuran derivatives or a pharmaceutically suitable acid addition salt thereof as the active ingredient: 1-/3- ( 2 , 2-dimethyl-2 , 3-dihydro-benzofuran-7-yl- oxy ) -2-hydroxypropyl/-4-( 3-trifluoromethyl- phenyl ) -1 , 2 , 3 , 6-tetrahydropyridine , 1-/3- ( 2 , 2-dimethyl-2 , 3-dihydro-benzofuran-7-yl- oxy ) -2-hydroxypropyl/-4-hydroxy-4-( 3-trifluoro- methylpheny1 ) piperidine ,
  • the invention refers to a method for the treatment of diseases which comprises administering a therapeutically effective non-toxic amount of a benzofuran derivative of the formula I or a pharmaceutically suitable acid addition salt thereof to a patient suffering from especially a heart disease or a disease of the central nervous system.
  • a solution of 16.0 g (0.1 moles) of bromine in 40 ml of glacial acetic acid are added, drop by drop, to a salution of 20.6 g (0.1 moles) of 7-acetoxy-2 , 2-dimethyl- -2 , 3-dihydrobenzofuran in 150 ml of chloroform under stirring and cooling at a temperature of 15-20 °C in 30 minutes.
  • the solution obtained is stirred for 15 minutes, then evaporated to dryness under reduced pressure.
  • the residual honeylike product is rubbed with 150 ml of icewater, the crystals precipitated are filtered, then washed with ice-water until neutrality.
  • the thus-obtained crystals are suspended in 80 ml of methanol at 0 °C, filtered again, and dried under reduced pressure.
  • 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 3 times using 50 ml of dichloromethane each time.
  • the combined organic phases are washed twice using 20 ml of water each time to remove traces of the acid, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
  • the residue is rubbed with n-hexane to obtain a crystalline substance that is filtered, and dried under reduced pressure.
  • the combined organic phases are extracted twice with 20 ml of water each time to remove the acid, then dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue is rubbed with n-hexane to obtain a crystalline substance that is filtered and dried under reduced pressure.
  • Example 1 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran- -7-yloxy) propyl/-4-( 4-methoxyphenyl )-l,2, 3,6- -tetrahydropyridine hydrochloride
  • the residue is dissolved in 30 ml of ethanol containing 5 % of hydrogen chloride, and evaporated to dryness over a water bath under reduced pressure.
  • the residual product is rubbed with 40 ml of ethyl acetate, and the crystalline product precipitated is filtered.
  • Example 2 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran- -7-yloxy)propyl/-4- ( 4-methoxyphenyl ) -1 , 2 , 3 , 6- -tetrahydropyridine
  • Example 4 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran-7- -yloxy ) propyl/-4- ( 4-methoxyphenyl ) -1 , 2 , 3 , 6- -tetrahydropyridine hydrochloride
  • Example 6 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran-7- -yloxy ) propyl/-4- ( 3-trifluoromethylphenyl ) - -1,2,3, 6-tetrahydropyridine hydrochloride
  • the residue (4.91 g) is dissolved in 20 ml of ethanol containing 5 % of hydrogen chloride, and the solution is evaporated to dryness again under reduced pressure.
  • the crystalline residue is rubbed with ether, filtered, and dried under reduced pressure.
  • the residue is subjected to partition between 15 ml of dichloromethane and 10 ml of water, the organic layer is extracted twice with 10 ml of water, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent.
  • Example 10 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-( 4-chlorophenyl ) - -1,2,3, 6-tetrahydropyridine hydrochloride
  • reaction mixture is boiled for 6 hours, then evaporated under reduced pressure. The residue is subjected to partition between
  • Example 11 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran-7- -yloxy ) -2-hydroxypropyl/-4- ( 2-thienyl) -1,2,3,6- -tetrahydropyridine hydrochloride
  • the residue is subjected to partition between 20 ml of chloroform and 20 ml of water, the organic phase is extracted twice using 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent.
  • the residue is dissolved in 15 ml of ethanol containing 10 % of hydrogen chloride, and the solution obtained is evaporated to dryness again under reduced pressure.
  • the crystalline residue is rubbed with ether, filtered, and dried under reduced pressure.
  • Example 12 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran-7- -yloxy ) -2-hydroxypropyl/-4- ( 4-fluorophenyl ) - -1,2,3, 6-tetrahydropyridine hydrochloride
  • the residue is subjected to partition between 20 ml of chloroform and 20 ml of water, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent.
  • the residue is dissolved in 15 ml of ethanol containing 10 % of hydrogen chloride, and the solution obtained is evaporated to dryness again under reduced pressure.
  • the crystalline residue is rubbed with ether, filtered, and dried under reduced pressure.
  • Example 18 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran-7- -yloxy) -2-hydroxypropyl/-4-phenyl ) -1 , 2 , 3 , 6- -tetrahydropyridine hydrochloride
  • the residue is subjected to partition between 10 ml of chloroform and 10 ml of water, the organic phase is extracted twice using 10 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent.
  • the residue is dissolved in 15 ml of ethanol containing 5 % of hydrogen chloride, and the solution obtained is also evaporated under reduced pressure.
  • the crystalline residue is rubbed with ether, filtered, and dried under reduced pressure.
  • Example 20 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran-7- -yloxy ) -2-hydroxypropyl/-4-hydroxy-4-phenyl- piperidine hydrochloride
  • Example 23 1-/3- ( 2, 2-Dimethyl-2 , 3-dihydrobenzofuran-7- -yloxy ) -2-hydroxypropyl/-4- ( 6-methoxynaphth-2- -yl )piperidine hydrochloride
  • 2-dimethyl-7-oxiranylmethoxy-2 2-dimethyl-7-oxiranylmethoxy-2
  • 3-dihydrobenzofuran 2-dimethyl-7-oxiranylmethoxy-2
  • 3-dihydrobenzofuran in 20 ml of ethanol
  • 2.6 g (0.01 moles) of 4-hydroxy-4- ( 6-methoxynaphth- -2-yl ) piperidine are added.
  • the solution obtained is boiled for 6 hours, cooled to 15 C, and 3 ml of ethanol containing 15 % of hydrogen chloride are added.
  • the reaction mixture is evaporated to dryness under reduced pressure, and the residue is rubbed with ether.
  • the crystals precipitated are filtered, recrystallized from a mixture of ethyl acetate and ethanol, filtered again, and dried under reduced pressure.
  • the residue is subjected to partition between 30 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is extracted twice using 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
  • the residue is dissolved in 25 ml of ethanol containing 5 % of hydrogen chloride, and the solution is evaporated to dryness under reduced pressure.
  • the crystalline residue is rubbed with ether, the crystals separated are filtered, and dried under reduced pressure.
  • Example 31 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran-7- -yloxy ) -2-hydroxypropyl/-4- ( 4-methoxyphenyl ) - -1,2,3, 6-tetrahydropyridine
  • Example 33 1-/3- ( 2, 2-Dimethyl-2 , 3-dihydrobenzofuran-7-ylox y ) -2-hydroxypropyl/-4- ( 4-methoxyphenyl ) -1 , 2 , 3 , 6 -tetrahydropyridine hydrochloride
  • Example 35 1-/3- ( 2, 2-Dimethyl-2, 3-dihydrobenzofuran-7- -yloxy ) -2-hydroxypropyl/-4-hydroxy-4- (3,5- -dimethy1-4-methoxyphenyl )piperidine hydrochloride
  • 2-dimethyl- -7-oxiranylmethoxy-2 3-dihydrobenzofuran
  • 1.18 g (0.005 moles) of 4-hydroxy-4- ( 3 , 5- -dimethyl-4-methoxyphenyl ) piperidine are added, and the reaction mixture is reacted at 60
  • Example 36 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran-7- -yloxy ) -2-hydroxypropyl/-4-hydroxy-4- (3,4- -methylenedioxyphenyl ) piperidine
  • the residue is subjected to partition between 20 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
  • the residue is recrystallized from a mixture of ethyl acetate and n-hexane, the crystals precipitated are filtered, and dried under reduced pressure.
  • Example 37 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran-7- -yloxy) -2-hydroxypropyl/-4-hydroxy-4-/4- ( 2- -methyl-2-propenyloxy) phenyl/piperidine
  • the residue is subjected to partition between 50 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is extracted twice using 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
  • the residue is dissolved in 50 ml of ether, and, to the solution obtained, 1 ml of ethanol containing 20 % of hydrogen chloride are added under cooling. The crystals precipitated are filtered, washed with ether, then dried under reduced pressure.
  • the residue is subjected to partition between 50 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is extracted twice using 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
  • the residue is dissolved in 50 ml of ether, and, to the solution obtained, 1 ml of ethanol containing 20 % of hydrogen chloride is added. The crystals precipitated is filtered, washed with ether, and dried under reduced pressure.
  • the residue is subjected to partition between 30 ml of dichloromethane and 10 ml of water, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent.
  • the residue is dissolved in 50 ml of ethanol containing 5 % os hydrogen chloride, and the solution obtained is also evaporated to dryness under reduced pressure.
  • the crystalline residue is rubbed with ether, filtered, and dried under reduced pressure,
  • Example 48 1-/3- ( 5-Bromo-2 , 2-dimethyl-2 , 3-dihydrobenzo- furan-7-yloxy ) -2-hydroxypropyl/-4- ( 3-trifluoromethylphenyl ) -1 , 2 , 3 , 6-tetrahydropyridine hydrochloride
  • the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent.
  • the residue is dissolved in 10 ml of ethanol containing 10 % of hydrogen chloride, and the solution obtained is also 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.
  • Example 49 1-/3- ( 5-Bromo-2, 2-dimethy1-2 , 3-dihydrobenzo- furan-7-yloxy ) -2-hydroxypropyl/-4- ( 3-trifluoromethylphenyl ) -1 , 2 , 3 , 6-tetrahydropyridine hydrochloride
  • Example 52 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran-7- -yloxy ) -2-hydroxypropyl/-4-hydroxypiperidine hydrochloride
  • 2 , 2-dimethyl-7-oxiranylmethoxy-2 , 3-dihydro- benzofuran in 10 ml of tetrahydrofuran 0.55 g (0.0055 moles) of 4-hydroxypiperidine are added.
  • the reaction mixture is boiled for 3 hours under stirring, then evaporated to dryness under reduced pressure.
  • the residue is dissolved in a mixture of 5 ml of 2-propanol and 1.5 ml of 2-propanol containing 16 % of hydrogen chloride, the solution obtained is evaporated under reduced pressure, the residue is dissolved in 8 ml of 2-propanol, and allowed to stand at 0 °C for 5 days.
  • the crystals precipitated are filtered, recrystallized from 2-propanol, filtered, and dried under reduced pressure.
  • Example 54 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran-4- -yloxy ) -2-hydroxypropyl/-4-hydroxy-4- ( 4-tri- fluoromethylphenyl ) piperidine hydrochloride
  • Example 54 The procedure of Example 54 is followed with the difference that the epoxide obtained in the first reaction step (3.75 g, 85.2 %) is dissolved in 50 ml of ethanol. To the solution, 3.94 g (0.0153 moles) of 4-hydroxy- -4- ( 6-methoxy-naphth-2-yl ) piperidine are added, and the reaction mixture is boiled for 4 hours. After cooling, to the solution, 13 ml of ethanol containing 5 % of hydrogen chloride are added, and the reaction mixture is evaporated to dryness under reduced pressure. The residual crystalline product is recrystallized from a mixture of ethanol and ether.
  • the residual thick waxlike epoxide (3.85 g, 87.3 %) is dissolved in 50 ml of ethanol, to the solution, 3.80 g (0.0155 moles) of 4-hydroxy-4- ( trifluoromethylphenyl ) - piperidine are added, and the reaction mixture is boiled for 5 hours. After cooling, to the solution obtained, 15 ml of ethanol containing 5 % of hydrogen chloride are added at a temperature of less than 15 °C, and the mixture is evaporated to dryness under reduced pressure. The residue that crystallizes is recrystallized from a mixture of ethanol and ether, filtered, and washed with ether.
  • the residual thick honeylike epoxide (2.10 g, 95 %) is dissolved in 10 ml of ethanol, to the solution obtained, 1.52 g (0.0086 moles) of 4-hydroxy-4-phenyl- piperidine are added, and the reaction mixture is boiled for 6 hours. After cooling, to the solution obtained, 10 ml of ethanol containing 5 % of hydrogen chloride are added at a temperature of less than 15 C, and the mixture is evaporated to dryness under reduced pressure. The residue that crystallizes is recrystallized from a mixture of ethanol and ether, filtered, and washed with ether.
  • the residue is subjected to partition between 50 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
  • the residue is dissolved in 50 ml of ether, and, to the solution, 1 ml of ethanol containing 20 % of hydrogen chloride is added under cooling, the crystals precipitated are filtered, washed with ether, and dried under reduced pressure.
  • Example 60 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzof ran-7- -yloxy ) -2-hydroxypropyl /-4- (diphenylmethyl ) - piperazine
  • Example 64 1-/3- ( 2, 2-Dimethyl-2, 3-dihydrobenzofuran-7- -yloxy ) -2-hydroxypropyl/-4- ( 4-fluorophenyl ) - piperazine
  • a mixture of 2.31 g (0.011 moles) of 2 , 2-dimethyl-7-oxiranylmethoxy-2 , 3-dihydrobenzo- furan and 1.80 g (0.01 moles) of l-(4-fluoro- phenyl ) piperazine is melted at 60 C, and maintained at the above temperature for an hour.
  • the melt obtained is subjected to chromatography on a column filled with Kieselgel 60 using a mixture consisting og 30 volumes of chloroform and 1 volume of ethanol as the eluent.
  • the fractions containing the product are evaporated, and the residue is rubbed with n-hexane, then filtered, and dried under reduced pressure.
  • Example 65 1-/3- ( 2 ,2-Dimethyl-2, 3-dihydrobenzofuran-7- -yloxy ) -2-hydroxypropyl /-4- ( 4-fluorophenyl ) - piperazine
  • Example 70 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran-7- -yloxy ) -2-hydroxypropyl/-4-(benzo-1, 3- -dioxolane-5-yl )piperazine dihydrochloride
  • Example 72 1-/3- ( 2 , 2-Dimethyl-2 , 3-dihydrobenzofuran-7- -yloxy ) -2-hydroxypropyl /-4-( benzo-1, 3- -dioxolane-5-yl )piperazine dihydrochloride
  • the residue is subjected to partition between 80 ml of dichloromethane and 50 ml of water, the organic phase is extracted twice using 30 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
  • the residue is recrystallized from 8 ml of methanol, the crystals precipitated are filtered, and dried under reduced pressure.
  • the crystals formed are filtered, then recrystallized from n-hexane.
  • the crystals precipitated are dissolved in
  • Example 87 1-/3- ( 2, 2-Dimethyl-2, 3-dihydrobenzofuran-7- -yloxy ) -2-hydroxypropyl/-4- ( 3, 4-dichloro- phenyl ) piperazine hydrochloride
  • a mixture of 1.32 g (0.006 moles) of 2, 2-dimethyl-7-oxiranylmethoxy-2, 3-dihydro- benzofuran, 1.04 g (0.0045 moles) of l-(3,4- -dichlorophenyl ) piperazine and 8 ml of 2-propanol is boiled for 3 hours, then cooled to 20 °C.
  • the aqueous phase of the mixture formed is removed by decantation, to the organic phase, 2.5 ml of 2-propanol containing 30 % of hydrogen chloride are added, the reaction mixture is maintained at -15 °C for 2 days, then 10 ml of 2-propanol are added, the crystals precipitated are filtered, dried under reduced pressure, and recrystallized from 2-propanol.

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Abstract

L'invention concerne de nouveaux dérivés de benzofuranne de formule (I), leur procédé de préparation et les compositions pharmaceutiques renfermant ces principes actifs.
EP99923772A 1998-05-14 1999-05-13 Derives de benzofuranne, composition pharmaceutique renfermant ces derives et procede de preparation du principe actif Withdrawn EP1077973A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
HU1008698 1998-05-14
HU1008598 1998-05-14
HU9801085A HUP9801085A3 (en) 1998-05-14 1998-05-14 Piperazinyl-alkyl-benzofurane derivatives, pharmaceutical compositions containing them as active ingredient and process for producing the active ingredient
HU9801086A HUP9801086A3 (en) 1998-05-14 1998-05-14 Benzofurane derivatives, pharmaceutical compositions containing them as active ingredient process for producing the active ingredient and intermediates of them
PCT/HU1999/000038 WO1999058527A2 (fr) 1998-05-14 1999-05-13 Derives de benzofuranne, composition pharmaceutique renfermant ces derives et procede de preparation du principe actif

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EP1077973A2 true EP1077973A2 (fr) 2001-02-28

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EP (1) EP1077973A2 (fr)
JP (1) JP2002514643A (fr)
KR (1) KR20010043618A (fr)
AU (1) AU753706B2 (fr)
CA (1) CA2332275A1 (fr)
HR (1) HRP20000750A2 (fr)
PL (1) PL345309A1 (fr)
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WO (1) WO1999058527A2 (fr)

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Publication number Priority date Publication date Assignee Title
US6835733B2 (en) 1999-12-20 2004-12-28 Eli Lilly And Company Tropane linked benzofuran derivatives
AU2049601A (en) 1999-12-20 2001-07-03 Eli Lilly And Company Benzofuran derivatives
FR2845992B1 (fr) 2002-10-16 2005-02-04 Pf Medicament Derives de 3-(cyclopenten-1yl)-benzyl-ou3-(cyclopenten-1yl)- heteroarylmethyl-amines et leur utilisation a titre de medicaments pour le traitement de la schizophrenie
EP1853614A4 (fr) * 2005-02-17 2008-06-25 Bayer Cropscience Ag Procédé amélioré de synthèse de dihydrobenzofuranes substitués par des groupements (propényle disubstitué)phénylalkyle
HU230761B1 (hu) * 2007-05-30 2018-03-28 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Új, szelektív 5HT6-receptorgátló benzofurán-származékok és eljárás előállításukra
HU230729B1 (hu) * 2007-05-30 2017-12-28 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Új, szelektív 5HT7-receptorgátló benzofurán-származékok és eljárás előállításukra
GB201312499D0 (en) * 2013-07-12 2013-08-28 Isis Innovation Therapeutic compounds

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CH474511A (fr) * 1966-06-24 1969-06-30 F. Hoffmann-La Roche & Co. Aktiengesellschaft
DE2235597A1 (de) * 1972-07-20 1974-01-31 Boehringer Mannheim Gmbh 1-eckige klammer auf 3-(5,6,7,8tetrahydronaphth-1-yl-oxy) -propyl eckige klammer zu -piperazin-derivate und verfahren zu ihrer herstellung
FR2353291A1 (fr) * 1976-05-31 1977-12-30 Parcor Nouveaux derives du benzofuranne
US4110536A (en) * 1977-04-18 1978-08-29 Miles Laboratories, Inc. Derivatives of 5-(indol-3-yl)hydantoin
US4612309A (en) * 1984-10-23 1986-09-16 William H. Rorer, Inc. Antisecretory bicyclic benzo-oxy heterocyclic ethers and thioethers
US4966907A (en) * 1988-08-12 1990-10-30 Merck & Co., Inc. 6-substituted 5-hydroxy-2,3-dihydrobenzofurans as inhibitors of leukotriene biosynthesis
GB9005014D0 (en) * 1990-03-06 1990-05-02 Janssen Pharmaceutica Nv N.(4.piperidinyl)(dihydrobenzofuran or dihydro.2h.benzopyran)carboxamide derivatives
FR2681319B1 (fr) * 1991-09-12 1995-02-17 Synthelabo Derives de 1-(phenoxyalkyl)piperidine, leur preparation et leur application en therapeutique.
WO1996010027A1 (fr) * 1994-09-27 1996-04-04 Janssen Pharmaceutica N.V. Derives benzoates bicycliques de piperidinyle n-substitue
TW490465B (en) * 1994-11-24 2002-06-11 Janssen Pharmaceutica Nv Enterokinetic benzamide, the preparation process and the pharmaceutical compositions thereof
GB9507882D0 (en) * 1995-04-18 1995-05-31 Pharmacia Spa Substituted dihydrobenzofuran derivatives as 5-ht4 agonists
ZA9610745B (en) * 1995-12-22 1997-06-24 Warner Lambert Co 4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists
NZ330263A (en) * 1996-02-15 1999-06-29 Janssen Pharmaceutica Nv Esters of 3-hydroxy-piperidinemethanol derivatives to improve gastric emptying

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See references of WO9958527A2 *

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KR20010043618A (ko) 2001-05-25
HRP20000750A2 (en) 2001-06-30
AU4052999A (en) 1999-11-29
WO1999058527A2 (fr) 1999-11-18
AU753706B2 (en) 2002-10-24
SK17212000A3 (sk) 2001-05-10
WO1999058527A3 (fr) 2000-01-27
CA2332275A1 (fr) 1999-11-18
PL345309A1 (en) 2001-12-03
JP2002514643A (ja) 2002-05-21

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