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WO1999031056A1 - Derives d'ether alcoylique ou leurs sels, et antagonistes du calcium les contenant - Google Patents

Derives d'ether alcoylique ou leurs sels, et antagonistes du calcium les contenant Download PDF

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Publication number
WO1999031056A1
WO1999031056A1 PCT/JP1998/005610 JP9805610W WO9931056A1 WO 1999031056 A1 WO1999031056 A1 WO 1999031056A1 JP 9805610 W JP9805610 W JP 9805610W WO 9931056 A1 WO9931056 A1 WO 9931056A1
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Prior art keywords
group
substituted
ethyl
benzo
salt
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PCT/JP1998/005610
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English (en)
Japanese (ja)
Inventor
Satoshi Ono
Hirohiko Yamamoto
Tetsuo Yamafuji
Masaya Nakagawa
Akihito Saitoh
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Toyama Chemical Co., Ltd.
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Priority to AU15064/99A priority Critical patent/AU1506499A/en
Publication of WO1999031056A1 publication Critical patent/WO1999031056A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • Alkyl ether derivatives or salts thereof and calcium antagonists containing them Alkyl ether derivatives or salts thereof and calcium antagonists containing them
  • the present invention relates to an alkyl ether derivative having a calcium antagonistic action, a salt thereof, and a calcium antagonist containing the same.
  • An object of the present invention is to provide a drug which is effective as an agent for suppressing or preventing the progression of neurodegenerative diseases such as Alzheimer's type dementia and ischemic encephalopathy such as stroke by suppressing excessive influx of calcium into nerve cells and the like.
  • Another object of the present invention is to provide a medicament that is effective as a therapeutic agent for cardiovascular diseases such as hypertension and arrhythmia; mental diseases such as depression; epilepsy, convulsions, and pain.
  • R 1 is an aryl or heterocyclic group which may be substituted;
  • R 2 is a hydrogen atom or a hydroxyl group;
  • R 3 is a group represented by the following formula:
  • R 4 is a cyclic amino group which may be substituted
  • R 5 is an alkyl group which may be substituted; or together with R 4 , R 5 and a nitrogen atom which bonds to each other.
  • the alkyl ether derivative represented by or a salt thereof is an excellent calcium antagonist It has been found that the present invention has an advantage, and the present invention has been completed.
  • a halogen atom is a fluorine, chlorine, bromine or iodine atom;
  • an alkyl group is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl group
  • a lower alkyl group is a straight-chain or branched chain C 1-12 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.
  • An alkoxy group is a straight-chain or branched C 16 alkyl group; an alkoxy group is a straight-chain group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy.
  • Linear or branched C 1 -alkyloxy group lower Alkoxy groups are straight- or branched-chain C 1-6 alkyloxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and hexyloxy groups; alkenyl groups Means vinyl, probenyl, butenyl, pentenyl, hexenyl, heptenyl and octyl
  • a C 2-12 alkenyl group; a lower alkenyl group is a C 2-6 alkenyl group such as vinyl, propenyl, butenyl, pentenyl and hexenyl; an alkenyloxy group is a vinyloxy, propenyloxy, butenyloxy group , Penparuo carboxymethyl to, Kiseniruokishi, a C 2-12 Arukeniruokishi groups such Hepuentuokishi and Okuparuokishi groups; lower Arukeniruokishi group, Biniruokishi, profile Bae Niruokishi, Buarticuluokishi, C 2 such Pen Accordinguokishi and to Kiseniruokishi group - 6 alkenyloxy groups; cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups; alkylthio groups include methylthio,
  • a C1-12 alkylthio group such as tylthio, tert-butylthio, pentylthio, hexylthio, heptylthio and octylthio;
  • a lower alkylthio group is methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, C1-6alkoxy such as pentylthio and hexylthio
  • An aryl group as a phenyl, naphthyl, indanyl and indenyl group; an aryloxy group as a phenyloxy, naphthyloxy, indanyloxy and indenyloxy group; an aralkyl group as a benzyl, diphenylmethyl and phenylethyl group; Al lower alkyl group such as cinnam
  • Al lower alkylthio groups such as phenylmethylthio and naphthylmethylthio groups; al lower alkylthio groups such as phenylmethylthio and naphthylmethylthio groups; and lower alkylenedioxy groups such as methylenedioxy and ethylenedioxy groups.
  • the arylsulfonylamino group includes phenylsulfonylamino, P-toluenesulfonylamino, naphthylsulfonylamino and the like;
  • a cyclic amino group refers to one or more nitrogen atoms containing at least one nitrogen atom as a heteroatom which includes pyridinyl, piberidinyl, piperazinyl, homopiperazinyl, homopiberidinyl, morpholinyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolyl, quinuclidinyl, imidazolinyl and the like.
  • the aryl or heterocyclic group for R 1 is a halogen atom, amino group, lower alkyl group, aryl group, lower alkyl group, lower alkoxy group, lower alkoxy group, aryloxy group, carbamoyloxy group, lower alkylthio group.
  • Cyclic includes halogen atom, amino group, lower alkyl group, aryl group, ar lower alkyl group, ar lower alkenyl group, aroyl group, ar lower alkenoyl group, heterocyclic group, heterocyclic carbonyl group and heterocyclic group. It may be substituted with one or more groups selected from a sulfonyl group and the like.
  • cyclic amino group R 4, R 4 and R 5 force 'bonded to the nitrogen atom having a bond from a carbon atom in the ring in R 1, R 3 above
  • Substituents on the cyclic amino group formed by forming a halogen atom, a cyano group, an optionally protected hydroxyl group, an optionally protected carboxyl group, an optionally protected amino group, and a halogen atom It may be further substituted with one or more groups selected from a lower alkyl group, a lower alkoxy group, a lower acryl group, a cycloalkyl group, an aryl group and an ar lower alkyl group which may be substituted with an atom.
  • the carboxyl protecting group includes all groups that can be used as a normal carboxyl protecting group, for example, lower alkyl groups such as methyl, ethyl, propyl, isopropyl, 1,1-dimethylpropyl, butyl and te-butyl.
  • Aryl groups such as phenyl and naphthyl; lower alkyl groups such as benzyl, diphenylmethyl, trityl, P-nitrobenzyl, P-methoxybenzyl and bis (P-methoxyphenyl) methyl; acetylmethyl, benzoylmethyl, P Acyl-lower alkyl groups such as -nitrobenzoylmethyl, P-bromobenzoylmethyl and P-methanesulfonylbenzoylmethyl; oxygen-containing heterocyclic groups such as 2-tetradrodovilanyl and 2-tetrahydrofuranyl; 2, 2,2-trichloroethyl and other halogen
  • the hydroxyl-protecting group includes all groups that can be used as ordinary hydroxyl-protecting groups, such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, and 4-hydroxybenzyloxycarbonyl.
  • Oxygen- and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydrobilanyl and tetrahydrotiobilanyl; methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyhexoxymethyl, 2,2,2-trichloro Lower alkoxy- and lower-alkyl-lower alkyl groups such as ethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyl- and 1-methyl-l-methoxyl; lower alkyl groups such as methanesulfonyl and P-toluenesulfonyl And arylsulfonyl groups; and trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethyls
  • Examples of the protecting group for an amino group include all groups that can be used as a normal amino protecting group, and include, for example, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, and P-nitrobenzyloxycarbonyl.
  • 0-bromobenzyloxycarbonyl (mono-, g-, tri) chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, P-methoxybenzyloxycarbonyl, 3,4-Dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, Acyl groups such as royl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl and 8-quinolyloxycarbonyl; al-lower alkyl groups such as benzyl, diphenylmethyl and trityl; 2-ditrophene Arylthio
  • a nitrogen-containing heterocyclic alkylidene group Xylidine to black, the 2-ethoxycarbonyl cycloalkyl xylidine, 2- E Cycloalkylidene groups such as ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene and 3,3-dimethyl-15-oxycyclohexylidene; diaryl or diall-lower alkylphosphoryl groups such as diphenylphosphoryl and dibenzylphosphoryl; Oxygen-containing heterocyclic alkyl groups such as 5-methyl-2-oxo-1 2H-1,3-dioxol-4-ylmethyl; and substituted silyl groups such as trimethylsilyl.
  • Examples of the salt of the compound represented by the general formula [1] include a generally known salt in a basic group such as an amino group or an acidic group such as a hydroxyl or carboxyl group.
  • Salts in the basic group include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, malic acid, tartaric acid, aspartic acid, Salts with organic carboxylic acids such as trichloroacetic acid and trifluoroacetic acid; salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, P-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid;
  • Examples of the salts in the above include: salts with alkali metals such as sodium and potassium; salts with alkaline earth metals
  • salts include pharmacologically acceptable salt strengths.
  • Representative compounds of the compounds of the present invention include, for example, the compounds exemplified in Tables 1 to 10 below.
  • the alkyl ether derivative represented by the general formula [1] or a salt thereof can be produced by a method known per se or an appropriate combination thereof, for example, by a production method shown below.
  • R 1 CH- (CH 2 0- (CH2 C00H, m V no n-1 ⁇ R 5
  • RR 2, R 3, R 4, R 5, m and n have the same meaning as described above;
  • R 2 b is a hydrogen atom or a protected human Dorokishiru group;
  • X 1 and X 2 represents a leaving group.
  • Examples of the leaving group include a halogen atom, a lower alkylsulfonyloxy group and an arylsulfonyloxy group.
  • Examples of the salt of the compound of the general formula [1a] include the same salt power as described for the salt of the compound of the general formula [1].
  • the compound of the general formula [1] is produced by reacting the compound of the general formula [2] with the compound of the general formula [3] in the presence of a base and, if desired, removing the hydroxy protecting group. be able to.
  • Examples of the base include sodium hydride, sodium hydroxide, potassium hydroxide and potassium tert-butoxide.
  • the solvent used in this reaction may be any solvent that does not adversely affect the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran and dioxane; Aromatic hydrocarbons such as benzene, toluene, and xylene; sulfoxides such as dimethyl sulfoxide; amides such as N, N-dimethylformamide; and power such as water. You may mix and use.
  • halogenated hydrocarbons such as methylene chloride and chloroform
  • ethers such as tetrahydrofuran and dioxane
  • Aromatic hydrocarbons such as benzene, toluene, and xylene
  • sulfoxides such as dimethyl sulfoxide
  • amides such as N, N-dimethylformamide
  • power such as water. You may mix and use.
  • This reaction can be performed in the presence or absence of a catalyst.
  • the catalyst used typically a phase transfer catalyst force of quaternary Anmoniumu salts known force 5 'used, preferably, hydrogen sulfate tetra -? N-Petit Ruan monitor ⁇ beam and tetra -n- Buchiruanmoni Pum and the like.
  • the amounts of the compound represented by the general formula [3] and the base may be each at least equimolar to the compound represented by the general formula [2], and preferably 1 to 20 times. .
  • the amount of catalyst is 0.0 0.30 times mol. This reaction is usually carried out at a temperature of from 50 to 200, preferably from 0 to 150, for 10 minutes to 20 hours.
  • a compound of the general formula [6] can be produced by reacting a compound of the general formula [5] with a compound of the general formula [4] or a reactive derivative thereof.
  • This reaction can be carried out by a method known per se, for example, the method described in Experimental Chemistry, Vol. 22, edited by The Chemical Society of Japan, pp. 137-173 (Maruzen, 1992) or a method analogous thereto. ,.
  • Examples of the reactive derivative include an acid halide, an acid anhydride, an activated amide, and an activated ester.
  • reaction is preferably carried out in the presence of a condensing agent.
  • condensing agent examples include N, N-dialkylcarbodiimides such as N, N-dicyclohexylcarbodiimide; halogenating agents such as thionyl chloride; halogenated alkyl esters such as ethyl chloroformate; Activating amides such as carbonyldimidazole; and azidating agents such as diphenylphosphoric acid azide.
  • N, N-dialkylcarbodiimides such as N, N-dicyclohexylcarbodiimide
  • halogenating agents such as thionyl chloride
  • halogenated alkyl esters such as ethyl chloroformate
  • Activating amides such as carbonyldimidazole
  • azidating agents such as diphenylphosphoric acid azide.
  • the amount of the condensing agent to be used may be at least equimolar to the compound of the general formula [4], preferably 1 to 5 moles.
  • the solvent used in this reaction may be any solvent which does not adversely affect the reaction.
  • examples thereof include water; halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran and dioxane; Aromatic hydrocarbons such as benzene, toluene and xylene; Sulfoxides such as dimethyl sulfoxide; N ,: Amides such as N-dimethylformamide; Esters such as ethyl acetate; Acetone and methyl ethyl ketone And nitriles such as acetonitrile; and heteroaromatics such as pyridine. These solvents may be used in combination.
  • Bases include, for example, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] induec7-ene (DBU), pyridine, potassium tert-butoxy, sodium carbonate, potassium carbonate and hydrogenated hydrogen.
  • An organic base such as sodium or an inorganic base is exemplified.
  • the amount of the base to be used may be at least equimolar to the compound of the general formula [4], and is preferably 1 to 10 moles.
  • the amount of the compound of the general formula [5] to be used is 1 mol or more, preferably 1 to 20 times, the molar amount of the compound of the general formula [4].
  • This reaction is usually carried out at a temperature of 50 to 200 ° (preferably, ⁇ 30 to 100 ° C.) for 10 minutes to 20 hours.
  • the obtained compound of the general formula [6] may be used for the next reaction without isolation.
  • a compound of the general formula [la] can be produced by subjecting the compound of the general formula [6] to a usual reduction reaction.
  • This reduction reaction can be carried out by a method known per se, for example, the method described in Shin-Jikken Kagaku Koza, Vol. 15, [11], edited by The Chemical Society of Japan, pp. 29-244 (1977, Maruzen) or a method described therein. It may be implemented by a method similar to that.
  • the solvent used in this reaction may be any solvent that does not adversely affect the reaction.
  • examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran and dioxane, and benzene.
  • aromatic hydrocarbons such as toluene and xylene; and methanol, include such as an alcohol such as ethanol and iso-propanol, these solvents, Yo Le be a mixture thereof used, 0
  • Examples of the reducing agent include aluminum hydrides such as lithium aluminum hydride; and borohydrides such as diborane and sodium borohydride.
  • the amount of the reducing agent to be used may be 0.5 times mol or more, and preferably 1 to 10 times mol, of the compound of the general formula [6].
  • the amount of the Lewis acid used may be at least equimolar to the reducing agent, and is preferably 1 to 20 moles.
  • This reaction is carried out usually at a temperature of ⁇ 50 to 200, preferably 0 to 110, for 10 minutes to 20 hours.
  • a compound of the general formula [la] can be produced by reacting a compound of the general formula [5] with a compound of the general formula [7] in the presence or absence of a base.
  • the solvent used in this reaction may be any solvent which does not adversely affect the reaction.
  • examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform, and aromatic hydrocarbons such as benzene, toluene and xylene. Hydrogens; ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol; nitriles such as acetonitrile; amides such as N, N-dimethylformamide; and sulfoxides such as dimethylsulfoxide. These solvents may be used in combination.
  • Bases used as needed include, for example, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0.
  • Organic or inorganic bases such as potassium carbonate and sodium hydride are mentioned.
  • the amount of the base used is at least equimolar to the compound of the general formula [7], preferably! Up to 20-fold molar.
  • This reaction can also be performed in the presence of a catalyst.
  • Catalysts include, for example, powers such as lithium iodide and sodium iodide.
  • the catalyst may be used in an amount of 0.01 to 10 moles, preferably 0.1 to 1 mole, based on the compound of the general formula [7].
  • the compound of general formula [5] may be used in an amount of at least equimolar to the compound of general formula [7], and is preferably 1 to 20 moles.
  • This reaction is carried out usually at 0 to 200 ° C, preferably at 20 to 150, for 10 minutes to 20 hours.
  • the reaction reagent or base used in each of the above-mentioned production methods can be used as a solvent depending on their properties.
  • the compounds of the general formulas [2] to [7] can be used as salts, and the salts thereof include the same salts as the salts of the compound of the general formula [1]. .
  • isomers for example, optical isomers, geometric isomers and tautomers
  • all of these isomers must be used. Hydrates, solvates and all crystalline forms can be used.
  • the compound having a hydroxyl group, an amino group or a carboxyl group is prepared by preliminarily protecting these hydroxyl group, amino group or carboxyl group with an ordinary protecting group. After the reaction, these protective groups can be eliminated as necessary by a method known per se.
  • alkyl ether derivatives of the general formulas [1] and [la] or salts thereof can be subjected to, for example, an oxidation reaction, a reduction reaction, an alkylation reaction, a halogenation reaction, a sulfonylation reaction, a substitution reaction, a dehydration reaction and a hydrolysis reaction.
  • an oxidation reaction for example, an oxidation reaction, a reduction reaction, an alkylation reaction, a halogenation reaction, a sulfonylation reaction, a substitution reaction, a dehydration reaction and a hydrolysis reaction.
  • alkyl ether derivative of the general formula [1] or a salt thereof can be isolated and purified by a usual method such as extraction, crystallization, distillation and column chromatography.
  • the compound of the general formula [2] can be produced by a method known per se or a suitable combination thereof, for example, by the production method shown below.
  • R 1 and m have the same meanings as described above;
  • R 6 is a hydrogen atom, a hydroxyl group or a lower alkoxy group;
  • R 7 is a hydroxyl protecting group;
  • X 3 is X 1 and X and a similar leaving group;
  • p is an integer of 0 or 1 ⁇ 4;
  • q is an integer of 0 or 1-3, respectively.
  • a compound of the general formula [9] can be produced by subjecting the compound of the general formula [8] to a usual carbon chain extension reaction.
  • This reaction can be performed by a method known per se, for example, the method described in Experimental Chemistry, Vol. 22, edited by The Chemical Society of Japan, pp. 54-68 (Maruzen, 1992) or a method analogous thereto. ,.
  • examples of the carbon chain elongation reaction include a Wittig reaction and a Wittig-Horner reaction.
  • the compound of the general formula [2a] can be produced by subjecting the compound of the general formula [9] to a usual reduction reaction.
  • This reduction reaction can be performed by a method known per se, for example, New Experimental Chemistry, Vol. 15, [11], It may be carried out by the method described in the Chemical Society of Japan, pp. 29-244 (1977, Maruzen) or a method similar thereto.
  • the compound of the general formula [10a] can be produced by subjecting the compound of the general formula [9] to a usual catalytic hydrogenation reaction.
  • This hydrogenation reaction can be carried out by a method known per se, for example, the method described in Shin-Jikken Kagaku Koza, Vol. 15, [ ⁇ ], edited by The Chemical Society of Japan, pp. 333-448 (1977, Maruzen) or a method described therein. What is necessary is just to implement by the method similar to it.
  • the compound of the general formula [10a] can be produced by subjecting the compound of the general formula [8] to a usual carbon extension reaction.
  • This reaction can be carried out by a method known per se, for example, the method described in Experimental Chemistry Course, Vol. 21, edited by The Chemical Society of Japan, pages 124-133 (Maruzen, 1992) or a method analogous thereto. ,.
  • examples of the carbon chain elongation reaction include a force such as a Wittig reaction.
  • the compound of the general formula [12a] can be produced by subjecting the compound of the general formula [11a] to a usual cyanation reaction.
  • This reaction can be performed by a method known per se, for example, Experimental Chemistry, Vol. 22, edited by The Chemical Society of Japan, pp. 1-83 (Maruzen, 1992) and Experimental Chemistry, Vol. 21, edited by The Chemical Society of Japan, Vol. 72-97 (1
  • the compound of the general formula [2a] can be produced by subjecting the compound of the general formula [10a] to a usual reduction reaction.
  • This reduction reaction is carried out by a method known per se, for example, the method described in Shin-Jikken Kagaku Koza, Vol. 15, [11], edited by The Chemical Society of Japan, pp. 29-244 (1977, Maruzen) or a method similar thereto It can be done by a method.
  • a method for producing the compound of the general formula [2b] will be described.
  • a compound of the general formula [10b] can be produced by subjecting the compound of the general formula [8] to a usual addition reaction.
  • This reaction may be performed by a method known per se, for example, the method described in Experimental Chemistry Course, Vol. 22, edited by The Chemical Society of Japan, pp. 54-68 (1992, Maruzen) or a method analogous thereto.
  • the addition reaction includes, for example, an addition reaction of an enol ester, a Refomatsky reaction, and the like.
  • the compound of the general formula [12b] can be produced by subjecting the compound of the general formula [8] to a usual addition reaction.
  • This reaction is carried out by a method known per se, for example, the method described in Shin-Jikken Kagaku Koza, Vol. 14, [111], edited by The Chemical Society of Japan, pp. 1428-1484 (1977, Maruzen) or a method analogous thereto. You can do it.
  • Examples of the addition reaction include a cyanohydration reaction.
  • the compound of the general formula [12b] can be produced by subjecting the compound of the general formula [lib] to a usual cyanation reaction.
  • This reaction is carried out by a method known per se, for example, the method described in Shin-Jikken Kagaku Koza, Vol. 14, [m], edited by The Chemical Society of Japan, pp. 1428-1484 (1977, Maruzen) or a method analogous thereto. You can do it.
  • This reaction can be performed by a method known per se, for example, Experimental Chemistry, Vol. 22, edited by The Chemical Society of Japan, pp. 1-83 (1992, Maruzen) and Experimental Chemistry, Vol. 21, edited by The Chemical Society of Japan, Vol. 72-97 (1
  • the compound of the general formula [2b] can be produced by subjecting the compound of the general formula [10b] to a usual reduction reaction.
  • This reduction reaction is carried out by a method known per se, for example, the method described in Shin-Jikken Kagaku Koza, Vol. 15, [11], edited by The Chemical Society of Japan, pp. 29-244 (1977, Maruzen) or a method similar thereto It can be done by a method. Further, by repeating the reaction of ( ⁇ -1), ( ⁇ -3) and ( ⁇ ⁇ 4) from the compound of the general formula [10a] in which R ° is hydrogen as a raw material, Long compounds of general formula [2a] can be produced. Of the compounds of the general formula [10b], a compound in which R 6 is hydrogen is used as a raw material, and the reaction of (A-8), (A-10) and (A-11) is repeated to obtain a longer carbon chain. The compound of the general formula [2b] can be produced.
  • the compounds of the general formulas [4] and [7] can be produced by methods known per se or by appropriately combining them, for example, by the following production methods.
  • R 1, R 2, R 2 b, X 2, m and n are, have a same meaning as described above;
  • R 8 is a lower alkoxy group, an optionally substituted Amino or cyclic Amino X 4 , X 5 and X 6 each represent a halogen atom; r represents an integer of 1 to 5, respectively.
  • (B-1) A compound of the general formula [7] is produced by reacting a compound of the general formula [2] with a compound of the general formula [13] and, if desired, removing a hydroxy protecting group. be able to.
  • This reaction may be carried out in the same manner as in Production Method 1.
  • the solvent used in this reaction may be any solvent that does not adversely affect the reaction.
  • examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran and dioxane, and benzene.
  • Aromatic hydrocarbons such as benzene, toluene and xylene; Sulfoxides such as dimethyl sulfoxide Amides such as N, N-dimethylformamide; esters such as ethyl acetate; nitriles such as acetonitrile; and tertiary alcohols such as tert-butanol.
  • These solvents may be used as a mixture.
  • Bases used as needed include, for example, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] pandec-7-ene (DBU), pyridine, tert-butoxy.
  • Organic or inorganic bases such as potassium, sodium carbonate, potassium carbonate and sodium hydride;
  • the amounts of the compound of the general formula [14] and the base to be used are respectively equimolar or more, preferably 1 to 20 moles, per mol of the compound of the general formula [2].
  • This reaction may be carried out usually at a temperature of from 10 to 150, preferably from 0 to 50 ° C, for from 10 minutes to 20 hours.
  • the compound of the general formula [4] can be produced by subjecting the compound of the general formula [15] to a usual ester or amide hydrolysis reaction.
  • This reaction can be performed by a method known per se, for example, Protective Groups in Organic Synthesis, [Theodora W. Green (1981), John Wiley]. Lee's & Sons' Incorporated (John Wiley & Sons. In)] or a method similar thereto.
  • the compound of the general formula [16] can be produced by subjecting the compound of the general formula [4] or the compound of the general formula [15] to a usual reduction reaction.
  • This reduction reaction may be carried out by a method known per se, for example, the method described in Shin-Jikken Kagaku Koza, Vol. 15, pages 26-244 (1977, Maruzen) or a method analogous thereto.
  • (B-5) A compound of the general formula [7] is produced by reacting a compound of the general formula [16] with a halogenating agent or a sulfonylating agent in the presence or absence of a base. be able to.
  • the solvent used in this reaction may be any solvent that does not adversely affect the reaction.
  • examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran and dioxane, and benzene. , Toluene and Aromatic hydrocarbons such as ethylene oxide and xylene; sulfoxides such as dimethyl sulfoxide; amides such as N, N-dimethylformamide; esters such as ethyl acetate; and nitriles such as acetonitrile. These solvents may be used as a mixture.
  • Bases used as needed include, for example, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] pandec-7-ene (DBU), pyridine, tert-butoxy.
  • Organic or inorganic bases such as potassium, sodium carbonate, potassium carbonate and sodium hydride are mentioned.
  • halogenating agent examples include phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, and thionyl chloride.
  • sulfonylating agent examples include methanesulfonyl chloride and p.toluenesulfonyl chloride.
  • the amounts of the halogenating agent or sulfonylating agent and the base to be used may be at least equimolar to the compound of the general formula [16], and preferably 1 to 2 moles. This reaction is usually carried out at a temperature of 50 to 200 ° (preferably, 0 to 50 ° C.) for 10 minutes to 30 hours.
  • (B-6) The compound of the general formula [7a] can be produced by reacting the compound of the general formula [8] with the compound of the general formula [17].
  • the solvent used in this reaction may be any solvent that does not adversely affect the reaction, and examples thereof include ethers such as dimethyl ether, tetrahydrofuran and dioxane; and aromatic hydrocarbons such as benzene and toluene. These solvents may be used as a mixture.
  • the compound of the general formula [17] may be used in an amount of 0.8 to 100 moles, preferably 0.8 to 10 moles, per mole of the compound of the general formula [8].
  • This reaction is carried out usually at a temperature of from 78 to 100 ° C, preferably at a temperature of from -78 to 50 ° C, for 5 minutes to 24 hours.
  • the compound of the general formula [17] can be prepared by a method known per se, for example, Bulletin de la Sochete-Simiq de France (Bull.So Chim.Fr.), 1967 (5), 1533-1540 It can be manufactured by the method described on the page.
  • compounds having a hydroxyl group, amino group or carboxyl group are The hydroxy group, amino group or carboxyl group is protected with a usual protecting group, and after the reaction, if necessary, these protecting groups can be eliminated by a method known per se.
  • isomers for example, optical isomers, When geometric isomers and tautomers are present, all of these isomers can be used, and hydrates, solvates and all crystal forms can be used. it can.
  • the compound of the present invention includes excipients, binders, disintegrants, disintegration inhibitors, caking / anti-adhesion agents, lubricants, absorption / adsorption carriers, solvents, extenders, isotonic agents, solubilizing agents, and emulsifiers.
  • Suspending agents thickeners, coating agents, absorption accelerators, gelling, coagulation accelerators, light stabilizers, preservatives, moisture inhibitors, emulsification, suspension, dispersion stabilizers, anti-colorants, Oral tablets (tablets) containing various pharmaceutical additives such as oxygen, antioxidants, flavors, flavors, coloring agents, foaming agents, defoamers, soothing agents, antistatic agents, buffers, ⁇ regulators, etc.
  • Tabletsules powders, granules, granules, pills, suspensions, emulsions, solutions, syrups, etc.), injections, suppositories, external preparations (ointments, patches, etc.), aerosols, etc. Pharmaceutical preparations.
  • Oral solid preparations such as tablets, powders, and granules include, for example, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, anhydrous dibasic calcium phosphate, partially pregelatinized starch, cornstarch, and algi.
  • Excipients such as acid; simple syrup, budou sugar solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, sodium alginate, gum arabic , Hydroxypropyl methylcellulose, hydroxypropylcellulose, binders such as water and ethanol; dry starch, alginic acid, candied powder, starch, crosslinked polyvinylpyrrolidone, crosslinked Rubokishimechi Ruseruro one scan sodium, carboxymethylcellulose calcium and starch
  • Disintegrators such as sodium glycolate; disintegrators such as stearyl alcohol, stearic acid, lactic acid butter and hydrogenated oil; anti-caking agents such as aluminum silicate, calcium hydrogen phosphate, magnesium oxide, talc and citric anhydride -Anti-adhesion agent; Carnapa wax, light caustic anhydride, aluminum silicate, magnesium silicate, hard
  • the tablet can be a tablet coated with a usual coating, if necessary, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, a gastric-coated tablet, an enteric-coated tablet, and a water-soluble film-coated tablet.
  • Capsules are prepared by mixing with the various excipients exemplified above and filling in hard gelatin capsules, soft capsules and the like.
  • liquid formulation additives such as a solvent, a bulking agent, a tonicity agent, a solubilizing agent, an emulsifier, a suspending agent, and a thickener
  • a solvent such as a solvent, a bulking agent, a tonicity agent, a solubilizing agent, an emulsifier, a suspending agent, and a thickener
  • Suppositories may be prepared by adding an appropriate absorption enhancer to, for example, polyethylene glycol, cocoa butter, lanolin, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glyceride, and dietzol. Good.
  • an appropriate absorption enhancer for example, polyethylene glycol, cocoa butter, lanolin, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glyceride, and dietzol. Good.
  • Injectables include, for example, diluents such as water, ethyl alcohol, macrogol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid and sodium hydroxide; sodium citrate, sodium acetate and PH adjusters and buffers such as sodium phosphate; stabilizers such as sodium bisulfite, ethylenediaminetetraacetic acid, thioglycolic acid and thiolactic acid; isotonic agents such as sodium chloride, glucose, mannitol and glycerin Sodium carboxymethylcellulose, propylene glycol, sodium benzoate, benzyl benzoate, urethane, Dissolving aids such as ethanolamine and glycerin; soothing agents such as calcium gluconate, chlorobutanol, glucose and benzyl alcohol; and pharmaceutical additives for liquid formulation such as local anesthetics, prepared according to standard methods do it.
  • Ointments in paste, cream and gel form include, for example, white petrolatum, polyethylene, phenol, Bases such as raffin, glycerin, cellulose derivatives, polyethylene glycol, silicon and bentonite; preservatives such as methyl paraoxybenzoate, ethyl ethyl parabenzoate and propyl paraoxybenzoate; stabilizers; pharmaceutical additives such as wetting agents What is necessary is just to mix and formulate using a conventional method.
  • the above-mentioned ointment, cream, gel, base or the like may be applied to a usual support in a usual manner.
  • a woven or non-woven fabric made of cotton, staple and chemical fiber; a film or foam sheet 5 ′ made of soft vinyl chloride, polyethylene and polyurethane can be used.
  • the administration method of the above-mentioned preparation is appropriately determined depending on the power of the preparation, the form of the preparation, the age of the patient, gender and other conditions, and the degree of the symptoms of the patient.
  • the dosage of the active ingredient of the present invention formulation, regimen, patient's age, sex, forms of the disease, the force is appropriately selected depending on the other conditions?, The daily 0.1 ⁇ 500mg against adult 1
  • the administration may be divided into several doses.
  • Decapitate male Wistar rat and remove cerebral cortex The following operations were performed under ice cooling. Homogenize with a Teflon-glass homogenizer using a 0.32 M sucrose solution (5 mM HEPES pH 7.4, containing 0.1 mM EDTA) for 16 strokes. The homogenate is centrifuged at lOOOX g for 20 minutes, and the resulting supernatant is centrifuged at 12000 ⁇ g for 20 minutes. Settle to 0.3 ml per gram brain weight with 0.32 M sucrose solution containing 8.5% Percoll (Pharmacia). Resuspend. Overlay 10% Percoll and 16% Percoll and place the resuspension on it.
  • Fura2-AM that has not been taken up at room temperature is washed and removed with a NaCl buffer, and the precipitate is resuspended in a NaCl buffer to a protein amount of 200 ⁇ g / ml to prepare a synaptosome sample. It was added warmed NaCl buffer test compound 2ml to 30 to a final concentration of 10- 5 M, incubated for 5 minutes. CaCl 2 (final concentration ImM) and synaptosome standard 100 ⁇
  • All the mixing ratios in the eluent are volume ratios, and the carrier in column chromatography is silica gel 60, No.7733 (Merck) and BW silica gel, BW-127ZH (Fuji Silysia Chemical) Was used.
  • the aqueous layer is further extracted with 30 ml of ethyl acetate, combined with the previously separated organic layer, washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate.
  • Example 3 In the same manner as in (2) and (3), the compounds in Table D are obtained.
  • aqueous layer is extracted with 50 ml of ethyl acetate, and the extract is combined with the previously separated organic layer, washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate.
  • [b] Thiophene-5-ylethoxy) -1-piperidino-ethanone (No. 5-l) 8.50 g is obtained.
  • No.5-5 l-piperidino-2-[(3,4,5, -trimethoxyphenethyl) oxyto 1-ethanone IR (KBr) cm ': 2937, 1643,1462, 1239,1 128
  • No.5-10 2- [2- (l, 3-Benzodoxyl-5-yl) ethoxy] -1-piperidino-trethanone
  • No.5-ll 2- [2- (Naphthyl) ethoxy] -1-piperidinobutethanone
  • No.5-13 2- (2-Benzo [b] thiophen-7-ylethoxy) -1-piperidino-1-ethanone
  • No.5-14 2- [2- (2,3-dihydro-1, 4-benzodioxin-6-yl) ethoxy] -piperidino-ethanone
  • No.5-15 2- (2-Benzo [b] thiophene-4-ylethoxy) -1-piperidino-letanone
  • No.5-16 2- (2-Benzo [b] thiophene-6-ylethoxy) -repiperidino -1-Ethanone
  • No.5-17 2- [2- (2-methyl-1,3-benzothiazol-5-yl) ethoxy] -piperidino-ethanone
  • the aqueous layer is extracted with 25 ml of ethyl acetate, and the extract is combined with the previously separated organic layer, washed successively with water and a saturated saline solution, and dried over anhydrous magnesium sulfate.
  • aqueous layer is extracted with 30 ml of ethyl acetate, combined with the previously separated organic layer, washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate.
  • Example 5 In the same manner as in (5) and (6), compounds in Tables E1 to E9 are obtained.
  • Example 5 0.81 g of 2- (4-benzhydrylpiperazino) ethyl (2-benzo [b] furan-5-ylethyl) ether obtained in the same manner as in (5) was dissolved in 30 ml of ethyl acetate. Then, add 0.20 g of fumaric acid to this solution and stir at room temperature for 2 hours. The precipitated crystals are collected by filtration and recrystallized from isopropanol to give 2- (4-benzhydrylpiperazino) ethyl (2-benzo [b] furan-5-ylethyl) ether fumarate (No.93) 0.51 g Get.
  • Example 5 0.51 g of 1- [2- (2-benzo [b] thiophen-5-ylethoxy) ethyl 3- (3-methoxyphenyl) pyrrolidine obtained in the same manner as in (5) was added to 10 ml of ethyl acetate. And add oxalic acid to this solution, and stir at room temperature for 2 hours. The precipitated crystals were collected by filtration to give 1- [2- (2-benzo [b] thiophen-5-ylethoxy) ethyl] -3- (3-methoxyphenyl) pyrrolidinine oxalate (No. 96) 0.40 g Get.
  • the aqueous layer is extracted with 5 ml of ethyl acetate, combined with the previously separated organic layer, washed with saturated saline and dried over anhydrous magnesium sulfate.
  • the oily 2- [2- (6-fluorobenzo [b] thiophen-5-yl) ethoxytre [4- (4-methoxybenzyl) piperazino 1-ethanone (No. 9 -l) I get 1.43g.
  • No.9-2 1- (4-benzhydrylpiperazino) -2- [2- (tonaphthyl) ethoxy] -1-ethanone
  • No.9-3 2- (2-benzo [b] thiophene-7-ylethoxy M- [4- (4-methoxybenzyl) piperazino] _letanone
  • No.9-6 2- (2-benzo [b] thiophen-6-ylethoxy) -1- (4- (4-methoxybenzyl) pyrazino] -1-ethanone
  • No.9-7 1- [4- (4-Methoxybenzyl) piperazino] -2- [2- (2-methyl-1,3-benzothiazol-5-yl) ethoxy] -1-ethanone
  • No.9-12 1- [4- (4-Methoxybenzyl) piperazino] -2- [2- (2-phenyl-1,3-thiazolyl-4-yl) ethoxy] -leetanone
  • No.9-13 [4- (4-Methoxybenzyl) piperazino] -2-[(3,4,5-trimethoxyphenyl) oxy] -1-ethanone
  • Example 9 In the same manner as in (2) and (3), compounds in Table F1 and Table F2 are obtained.
  • No.112 1- (4-Methoxybenzyl) -4- ⁇ 2-[(3,4,5-trimethoxyphenethyl) oxy] ethyl ⁇ piperazine dihydrochloride
  • No.1 13 1- [2- (2-benzo [b] thiophen-2-ylethoxy) ethyl] -4- (4-methoxybenzyl) piperazine dihydrochloride
  • aqueous layer is further extracted with 5 ml of ethyl acetate, combined with the previously separated organic layer, washed with a saturated saline solution, and dried over anhydrous magnesium sulfate.
  • No.1 16 1- [2- (2-Benzo [b] thiophene-7-ylethoxy) ethyl] -4- (3-methoxybenzyl) pidazine dihydrochloride
  • No.1 17 6- (2- ⁇ 2- [4- (4-methoxybenzyl) piperazino] ethoxy ⁇ ethyl) quinoline.dihydrochloride
  • No.120 1- (4-Methoxybenzyl) -4- (2- ⁇ [4- (3-pyridyl) phenethyl] oxy ⁇ ethyl) pidazine.trihydrochloride
  • aqueous layer is extracted with 40 ml of toluene, combined with the previously separated organic layer, washed successively with water and saturated saline, and then dried over anhydrous potassium carbonate.
  • 37.87 g of 4- [2- (benzo [b] thiophen-5-ylethoxy) ethyl] -1-piperazinecarboxylic acid tert-butyl ester (No. l23) is obtained.
  • No.125 4- [2- (Benzo [b] thiophene-5-ylethoxy) ethyl] -1-piperidinecarboxylate tert-butyl ester
  • aqueous layer is extracted with 5 ml of ethyl acetate.
  • the extract is combined with the previously separated organic layer, washed with saturated saline, and dried over anhydrous potassium carbonate. If the solvent is distilled off under reduced pressure, ⁇ 4- [2- (2-benzo [b] thiophen-5-ylethoxy) ethyl] piperazino ⁇ (3-methoxyphenyl) methanone (No.129) 0.71 get g.

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Abstract

L'invention concerne des dérivés d'éther alcoylique de la formule générale (1) ou des sels desdits dérivés qui sont d'excellents antagonistes du calcium. Dans ladite formule R1 est aryle éventuellement substitué ou un composé hétérocyclique; R2 est hydrogène ou hydroxy; R3 est un composé de la formule (a) (dans laquelle R4 est un amino cyclique éventuellement substitué et R5 est alkyle éventuellement substitué, ou R4 et R5 peuvent ensemble former avec l'atome d'azote auquel ils sont liés un amino cyclique éventuellement substitué) ou un noyau saturé à six chaînons à base d'azote présentant une liaison avec un atome de carbone dans le noyau; m est un entier compris entre 1 et 5; et n est un entier compris entre 2 et 6.
PCT/JP1998/005610 1997-12-12 1998-12-11 Derives d'ether alcoylique ou leurs sels, et antagonistes du calcium les contenant WO1999031056A1 (fr)

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